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7f7aa842dadbc19f3d54d312c055f7fc5b359455	nice	Subfascial endoscopic perforator vein surgery	Subfascial endoscopic perforator vein surgery # Guidance Current evidence on the safety and efficacy of subfascial endoscopic perforator vein surgery (SEPS) does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research. Clinicians wishing to undertake SEPS should take the following action. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended. Audit and review clinical outcomes of all patients having SEPS. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence.# The procedure # Indications The procedure is used for patients with either healed or active ulcers (CEAP classifications 5 or 6), caused by chronic venous insufficiency, in whom incompetent calf perforating veins are thought to be an important contributing factor, particularly where conservative management (such as leg elevation, compression therapy and medication) has failed. Deep venous occlusion and/or infected ulcers are usually contraindications to SEPS. SEPS has also been used for patients with post-thrombotic valvular incompetence, but there is now evidence that this particular group of patients may have poorer outcomes following SEPS, compared with patients with primary valvular incompetence. SEPS is a minimally invasive alternative to open subfascial perforator vein surgery. # Outline of the procedure Preoperative evaluation is performed by duplex scanning of the superficial, deep and perforator venous systems to diagnose both valvular incompetence and obstruction. During the operation, the limb is exsanguinated and two endoscopic ports are placed in the subfascial space in the calf at sites remote from the area of venous ulceration. A space-maker balloon is introduced and inflated in this subfascial space to improve access. Carbon dioxide is then insufflated to facilitate dissection. The incompetent perforating veins are clipped and divided with endoscopic scissors or, alternatively, coagulated and divided with an ultrasonic coagulator (harmonic scalpel). # Efficacy One randomised controlled trial (RCT), two non-randomised comparative studies and two case series were reviewed. The studies showed great potential for bias: there were large losses to follow-up, considerable discrepancies in length of follow-up between SEPS and open procedure groups, and uncertainties about patient selection. The studies that compared SEPS with open procedures found ulcer-healing to be 85% (17/20 patients) to 90% (18/20 patients) in the SEPS groups and 100% (18/18 and 19/19 patients) in the open procedure groups. Ulcer recurrence rates in these studies were 12% (2/17 patients) to 28% (5/18 patients) in the SEPS groups and 22% (4/18 patients) to 68% (13/19 patients) in the open procedure groups. For more details, refer to the 'Sources of evidence' section. The Specialist Advisors considered the efficacy of this procedure to be unproven. They also noted that the indications for SEPS are not well established. # Safety The results of the RCT showed a considerably lower wound infection rate in the SEPS group of 0% (0/20 patients) compared with the open procedure group's rate of 53% (10/19 patients). This trial was closed early because the high rate of wound infection in the open procedure group made it unethical to continue. One of the non-randomised comparative studies also found the wound complication rate to be lower in the SEPS group (7%, 2/27 patients) when compared with the open procedure group (45%, 13/29 patients). For more details, refer to the 'Sources of evidence' section. Other reported complications of the SEPS procedure included nerve injury and deep vein thrombosis (DVT). The reported incidence of nerve injury ranged from 0% (0/20 patients) to 7% (2/30 patients); and incidence of DVT ranged from 0% (0/27 patients) to 14% (21/146 limbs). The study that reported 14% incidence of DVT originally had a total of 254 patients, of which data from only 130 patients (146 limbs) were analysed due to high loss to follow-up. In this study, DVTs occurred in 2 patients directly after surgery and in an additional 19 patients during the follow-up period. For more details, refer to the 'Sources of evidence' section. The Specialist Advisors noted safety concerns similar to those reported in the studies: wound infection, nerve injury, DVT and haematoma. # Other comments It was noted that the indications for this procedure are uncertain, and that careful patient selection is particularly important. Andrew DillonChief ExecutiveMay 2004 CEAP is a standardised classification system for rating the severity of venous disease where 'C' is for clinical signs, 'E' is for etiologic classification, 'A' is for anatomic distribution and 'P' is for pathophysiologic dysfunction.# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of subfascial endoscopic perforator vein surgery', November 2002. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication The guidance was considered for reassessment in January 2009 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of subfascial endoscopic perforator vein surgery (SEPS) does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research.\n\nClinicians wishing to undertake SEPS should take the following action.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having SEPS.\n\nPublication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence.", 'The procedure': "# Indications\n\nThe procedure is used for patients with either healed or active ulcers (CEAP classifications 5 or 6), caused by chronic venous insufficiency, in whom incompetent calf perforating veins are thought to be an important contributing factor, particularly where conservative management (such as leg elevation, compression therapy and medication) has failed. Deep venous occlusion and/or infected ulcers are usually contraindications to SEPS.\n\nSEPS has also been used for patients with post-thrombotic valvular incompetence, but there is now evidence that this particular group of patients may have poorer outcomes following SEPS, compared with patients with primary valvular incompetence.\n\nSEPS is a minimally invasive alternative to open subfascial perforator vein surgery.\n\n# Outline of the procedure\n\nPreoperative evaluation is performed by duplex scanning of the superficial, deep and perforator venous systems to diagnose both valvular incompetence and obstruction. During the operation, the limb is exsanguinated and two endoscopic ports are placed in the subfascial space in the calf at sites remote from the area of venous ulceration. A space-maker balloon is introduced and inflated in this subfascial space to improve access. Carbon dioxide is then insufflated to facilitate dissection. The incompetent perforating veins are clipped and divided with endoscopic scissors or, alternatively, coagulated and divided with an ultrasonic coagulator (harmonic scalpel).\n\n# Efficacy\n\nOne randomised controlled trial (RCT), two non-randomised comparative studies and two case series were reviewed. The studies showed great potential for bias: there were large losses to follow-up, considerable discrepancies in length of follow-up between SEPS and open procedure groups, and uncertainties about patient selection. The studies that compared SEPS with open procedures found ulcer-healing to be 85% (17/20 patients) to 90% (18/20 patients) in the SEPS groups and 100% (18/18 and 19/19 patients) in the open procedure groups. Ulcer recurrence rates in these studies were 12% (2/17 patients) to 28% (5/18 patients) in the SEPS groups and 22% (4/18 patients) to 68% (13/19 patients) in the open procedure groups. For more details, refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors considered the efficacy of this procedure to be unproven. They also noted that the indications for SEPS are not well established.\n\n# Safety\n\nThe results of the RCT showed a considerably lower wound infection rate in the SEPS group of 0% (0/20 patients) compared with the open procedure group's rate of 53% (10/19 patients). This trial was closed early because the high rate of wound infection in the open procedure group made it unethical to continue. One of the non-randomised comparative studies also found the wound complication rate to be lower in the SEPS group (7%, 2/27 patients) when compared with the open procedure group (45%, 13/29 patients). For more details, refer to the 'Sources of evidence' section.\n\nOther reported complications of the SEPS procedure included nerve injury and deep vein thrombosis (DVT). The reported incidence of nerve injury ranged from 0% (0/20 patients) to 7% (2/30 patients); and incidence of DVT ranged from 0% (0/27 patients) to 14% (21/146 limbs). The study that reported 14% incidence of DVT originally had a total of 254 patients, of which data from only 130 patients (146 limbs) were analysed due to high loss to follow-up. In this study, DVTs occurred in 2 patients directly after surgery and in an additional 19 patients during the follow-up period. For more details, refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors noted safety concerns similar to those reported in the studies: wound infection, nerve injury, DVT and haematoma.\n\n# Other comments\n\nIt was noted that the indications for this procedure are uncertain, and that careful patient selection is particularly important.\n\nAndrew DillonChief ExecutiveMay 2004\n\n CEAP is a standardised classification system for rating the severity of venous disease where 'C' is for clinical signs, 'E' is for etiologic classification, 'A' is for anatomic distribution and 'P' is for pathophysiologic dysfunction.", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of subfascial endoscopic perforator vein surgery', November 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': 'The guidance was considered for reassessment in January 2009 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us.\n\nJanuary 2012: minor maintenance.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg59
cd9ebde05d2be56f079e7de44b00466eca41a8ac	nice	Thrombin injections for pseudoaneurysms	Thrombin injections for pseudoaneurysms # Guidance Current evidence on the safety and efficacy of thrombin injections for pseudoaneurysms appears adequate to support the use of this procedure, provided that the normal arrangements are in place for consent, audit and clinical governance.# The procedure # Indications A pseudoaneurysm (also called a false aneurysm) is a collection of blood and blood clot that has formed outside a blood vessel, usually after an injury. The collection is connected by a channel to the blood vessel, so blood flows through it. A pseudoaneurysm may rupture and bleed. Pseudoaneurysms differ from true aneurysms in that blood within a true aneurysm is contained by the weakened wall of the blood vessel. The most common cause of a pseudoaneurysm is femoral artery puncture during cardiac catheterisation. A pseudoaneurysm may also occur after other procedures that involve puncture of an artery, including removal of an arterial blood pressure line or an intra-aortic balloon pump, or after accidental trauma. Many pseudoaneurysms resolve spontaneously by thrombosis and need no treatment. If treatment is required, treatment options include compression under ultrasound control, embolisation of the pseudoaneurysm with a variety of materials, or surgical repair. # Outline of the procedure In this procedure, thrombin (a blood-clotting agent) is injected under ultrasound guidance into the pseudoaneurysm. This causes thrombosis of the pseudoaneurysm cavity, which seals the arterial puncture site. The resulting clot is gradually reabsorbed. # Efficacy Three historically controlled studies and one retrospective cohort study were identified comparing thrombin injection with compression. All four studies reported greater success in treating pseudoaneurysms with thrombin injection. In these studies, success rates ranged between 93% (27/29 patients) and 100% (24/24 patients) using thrombin injection, and between 63% (25/40 patients) and 95% (102/107 patients) using compression. For more details, refer to the 'Sources of evidence' section. The Specialist Advisors did not note any concerns regarding the efficacy of this procedure. # Safety In the studies identified, the main complications reported were: intra-arterial thrombin injection necessitating thrombectomy for artery occlusion (2%, 3/131 patients); pseudoaneurysm rupture after thrombosis (1%, 1/131 patients); groin abscess (1%, 1/114 patients); leg ischaemia (1%, 1/114 patients); blue toe (1%, 1/114 patients); and buttock pain (1%, 1/114 patients). For more details, refer to the 'Sources of evidence' section. The Specialist Advisors listed the main potential adverse events of this procedure as thrombosis of the damaged artery and treatment of a clinically infected pseudoaneurysm (because infection can cause late recanalisation and rupture). Andrew DillonChief ExecutiveMay 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of thrombin injections for pseudoaneurysms', December 2002. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of thrombin injections for pseudoaneurysms appears adequate to support the use of this procedure, provided that the normal arrangements are in place for consent, audit and clinical governance.', 'The procedure': "# Indications\n\nA pseudoaneurysm (also called a false aneurysm) is a collection of blood and blood clot that has formed outside a blood vessel, usually after an injury. The collection is connected by a channel to the blood vessel, so blood flows through it. A pseudoaneurysm may rupture and bleed. Pseudoaneurysms differ from true aneurysms in that blood within a true aneurysm is contained by the weakened wall of the blood vessel. The most common cause of a pseudoaneurysm is femoral artery puncture during cardiac catheterisation. A pseudoaneurysm may also occur after other procedures that involve puncture of an artery, including removal of an arterial blood pressure line or an intra-aortic balloon pump, or after accidental trauma.\n\nMany pseudoaneurysms resolve spontaneously by thrombosis and need no treatment. If treatment is required, treatment options include compression under ultrasound control, embolisation of the pseudoaneurysm with a variety of materials, or surgical repair.\n\n# Outline of the procedure\n\nIn this procedure, thrombin (a blood-clotting agent) is injected under ultrasound guidance into the pseudoaneurysm. This causes thrombosis of the pseudoaneurysm cavity, which seals the arterial puncture site. The resulting clot is gradually reabsorbed.\n\n# Efficacy\n\nThree historically controlled studies and one retrospective cohort study were identified comparing thrombin injection with compression. All four studies reported greater success in treating pseudoaneurysms with thrombin injection. In these studies, success rates ranged between 93% (27/29 patients) and 100% (24/24 patients) using thrombin injection, and between 63% (25/40 patients) and 95% (102/107 patients) using compression. For more details, refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors did not note any concerns regarding the efficacy of this procedure.\n\n# Safety\n\nIn the studies identified, the main complications reported were: intra-arterial thrombin injection necessitating thrombectomy for artery occlusion (2%, 3/131 patients); pseudoaneurysm rupture after thrombosis (1%, 1/131 patients); groin abscess (1%, 1/114 patients); leg ischaemia (1%, 1/114 patients); blue toe (1%, 1/114 patients); and buttock pain (1%, 1/114 patients). For more details, refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors listed the main potential adverse events of this procedure as thrombosis of the damaged artery and treatment of a clinically infected pseudoaneurysm (because infection can cause late recanalisation and rupture).\n\nAndrew DillonChief ExecutiveMay 2004", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of thrombin injections for pseudoaneurysms', December 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg60
d1f9e43022fedbf01fbef51d189db0b2ff23fedf	nice	Complete cytoreduction for pseudomyxoma peritonei (Sugarbaker technique)	Complete cytoreduction for pseudomyxoma peritonei (Sugarbaker technique) # Guidance Current evidence on the safety and efficacy of complete cytoreduction for pseudomyxoma peritonei does not appear adequate for this procedure to be used in the NHS outside centres funded by the National Specialist Commissioning Advisory Group (NSCAG). Clinicians wishing to undertake complete cytoreduction for pseudomyxoma peritonei should take the following action. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended. Audit and review clinical outcomes of all patients having complete cytoreduction for pseudomyxoma peritonei. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence. These recommendations apply only to the use of this technique to treat pseudomyxoma peritonei. The Institute will consider complete cytoreduction for peritoneal carcinomatosis separately.# The procedure # Indications Pseudomyxoma peritonei is a rare, borderline malignant, slowly progressing tumour. It arises from the appendix or bowel and spreads throughout the peritoneal cavity, producing a large amount of mucus. Most patients will develop symptoms due to the bulk of the tumour. Most patients will eventually die of this condition, but they often survive for several years. Standard treatment for pseudomyxoma peritonei is surgical debulking, in which the surgeon attempts to remove as much tumour as possible. Chemotherapy is also used. Recurrence is common, and therefore repeated debulking operations may be needed. Patients with pseudomyxoma peritonei may be treated by 'watchful waiting', using surgery only when unacceptable symptoms or life-threatening complications, such as intestinal obstruction, arise. # Outline of the procedure The Sugarbaker technique combines complete surgical tumour removal (complete cytoreduction) with intraoperative heated chemotherapy, and is followed by postoperative intraperitoneal chemotherapy. The operation takes around 10 hours and includes: removal of the right hemicolon, spleen, gallbladder, greater omentum and lesser omentum stripping of the peritoneum from the pelvis and diaphragm stripping of the tumour from the surface of the liver removal of the uterus and ovaries in women removal of the rectum in some cases. # Efficacy No controlled studies were found. The studies were of poor quality. One study of 385 patients showed 5-year survival to be 86% for those with less malignant pathology (adenomucinosis) and 50% for those with more malignant pathology (mucinous adenocarcinoma). However, not all patients in this study were followed up for 5 years, and it is not clear how survival was calculated. Another study showed overall 5-year survival to be around 74% in 98 out of 321 patients who underwent repeat cytoreductive surgery. For more details, refer to the Sources of evidence section. The Specialist Advisors commented that there is international controversy about the effectiveness of this procedure, given the slow natural history of pseudomyxoma peritonei. One Advisor noted that uncertainty about efficacy emanates from the difficulty in accurately diagnosing pseudomyxoma peritonei preoperatively. # Safety In a study of 46 patients the main complications included: prolonged gastric paresis (almost all patients); neutropenia (49%); re-operation for postoperative complications (24%); stomach or bowel perforation (22%); enteric fistula (13%); and peripheral pressure neuropathy (11%). Most studies, however, were of poor quality with regard to safety outcomes. For more details, refer to the Sources of evidence section. The Specialist Advisors listed the potential complications as: death; major blood loss; respiratory infection; peritonitis; bowel perforation; obstruction; adhesions; wound dehiscence; and wound infection. One Advisor commented that such prolonged surgery increased the risk of morbidity and mortality. # Other comments It was noted that the procedure has a considerable risk of serious side effects, and that efficacy is not clearly established. The procedure needs to be evaluated in comparison with less radical surgery. Andrew Dillon Chief ExecutiveApril 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of complete cytoreduction (Sugarbaker technique) in patients with pseudomyxoma peritonei', October 2002. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication As part of NICE's work programme, the current guidance was considered for review but did not meet the review criteria as set out in the IP process guide. This guidance therefore remains current. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of complete cytoreduction for pseudomyxoma peritonei does not appear adequate for this procedure to be used in the NHS outside centres funded by the National Specialist Commissioning Advisory Group (NSCAG).\n\nClinicians wishing to undertake complete cytoreduction for pseudomyxoma peritonei should take the following action.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having complete cytoreduction for pseudomyxoma peritonei.\n\nPublication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence.\n\nThese recommendations apply only to the use of this technique to treat pseudomyxoma peritonei. The Institute will consider complete cytoreduction for peritoneal carcinomatosis separately.", 'The procedure': "# Indications\n\nPseudomyxoma peritonei is a rare, borderline malignant, slowly progressing tumour. It arises from the appendix or bowel and spreads throughout the peritoneal cavity, producing a large amount of mucus. Most patients will develop symptoms due to the bulk of the tumour. Most patients will eventually die of this condition, but they often survive for several years.\n\nStandard treatment for pseudomyxoma peritonei is surgical debulking, in which the surgeon attempts to remove as much tumour as possible. Chemotherapy is also used. Recurrence is common, and therefore repeated debulking operations may be needed.\n\nPatients with pseudomyxoma peritonei may be treated by 'watchful waiting', using surgery only when unacceptable symptoms or life-threatening complications, such as intestinal obstruction, arise.\n\n# Outline of the procedure\n\nThe Sugarbaker technique combines complete surgical tumour removal (complete cytoreduction) with intraoperative heated chemotherapy, and is followed by postoperative intraperitoneal chemotherapy. The operation takes around 10 hours and includes:\n\nremoval of the right hemicolon, spleen, gallbladder, greater omentum and lesser omentum\n\nstripping of the peritoneum from the pelvis and diaphragm\n\nstripping of the tumour from the surface of the liver\n\nremoval of the uterus and ovaries in women\n\nremoval of the rectum in some cases.\n\n# Efficacy\n\nNo controlled studies were found. The studies were of poor quality. One study of 385 patients showed 5-year survival to be 86% for those with less malignant pathology (adenomucinosis) and 50% for those with more malignant pathology (mucinous adenocarcinoma). However, not all patients in this study were followed up for 5 years, and it is not clear how survival was calculated. Another study showed overall 5-year survival to be around 74% in 98 out of 321 patients who underwent repeat cytoreductive surgery. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors commented that there is international controversy about the effectiveness of this procedure, given the slow natural history of pseudomyxoma peritonei. One Advisor noted that uncertainty about efficacy emanates from the difficulty in accurately diagnosing pseudomyxoma peritonei preoperatively.\n\n# Safety\n\nIn a study of 46 patients the main complications included: prolonged gastric paresis (almost all patients); neutropenia (49%); re-operation for postoperative complications (24%); stomach or bowel perforation (22%); enteric fistula (13%); and peripheral pressure neuropathy (11%). Most studies, however, were of poor quality with regard to safety outcomes. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors listed the potential complications as: death; major blood loss; respiratory infection; peritonitis; bowel perforation; obstruction; adhesions; wound dehiscence; and wound infection. One Advisor commented that such prolonged surgery increased the risk of morbidity and mortality.\n\n# Other comments\n\nIt was noted that the procedure has a considerable risk of serious side effects, and that efficacy is not clearly established.\n\nThe procedure needs to be evaluated in comparison with less radical surgery.\n\nAndrew Dillon Chief ExecutiveApril 2004", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of complete cytoreduction (Sugarbaker technique) in patients with pseudomyxoma peritonei', October 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': "As part of NICE's work programme, the current guidance was considered for review but did not meet the review criteria as set out in the IP process guide. This guidance therefore remains current.\n\nJanuary 2012: minor maintenance.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg56
0c3205803a8ea4cbb67c6cdc2a0012e3e74daa70	nice	Endoscopic injection of bulking agents for gastro-oesophageal reflux disease	Endoscopic injection of bulking agents for gastro-oesophageal reflux disease # Guidance Current evidence on the safety and efficacy of endoscopic injection of bulking agents for gastro-oesophageal reflux disease does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research. Clinicians wishing to undertake endoscopic injection of bulking agents for gastro-oesophageal reflux disease should take the following action. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended. Audit and review clinical outcomes of all patients having endoscopic injection of bulking agents for gastro-oesophageal reflux disease. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence.# The procedure # Indications Gastro-oesophageal reflux disease (GORD) is a common condition that can have a significant impact on the quality of life of an individual. It is caused by failure of the sphincter mechanism at the lower end of the oesophagus. Symptoms of GORD can be broadly grouped into those directly related to reflux episodes, such as heartburn, regurgitation and waterbrash; and those symptoms caused by complications of reflux disease, including dysphagia and respiratory symptoms. Lifestyle modifications and drug therapy are the standard treatment for patients with mild symptomatic GORD. Drug therapy includes antacids/alginates and acid-lowering agents, such as H-2 antagonists and proton pump inhibitors (PPIs). Patients with volume reflux or symptoms that do not respond to medical treatment may be treated with anti-reflux surgery. Injection therapy may be considered as an alternative to surgery. # Outline of the procedure The patient is sedated and given an injection of antibiotics. A needle catheter is then introduced through an endoscope and passed down the oesophagus into the gastro-oesophageal junction, so narrowing the lumen. This catheter is filled with a bio-compatible polymer and solvent and is used to inject or implant the polymer into the gastro-oesophageal junction. The injection is made along the muscle layer or deep submucosal layer of the cardia. Multiple injections (often four) are performed in a circumferential manner around the oesophagus under fluoroscopic and endoscopic control. # Efficacy Evidence of efficacy was based primarily on one uncontrolled study of 85 patients with GORD receiving chronic PPI therapy. This study reported that, at 12 months, 67% (57/85) of patients were no longer taking PPIs and that a further 9% (8/85) of patients had reduced PPI usage by 50% or more. Both heartburn and regurgitation symptom scores had improved at 12 months. Small reductions in acid reflux, as assessed by measuring oesophageal pH, were seen but no improvement in endoscopic grades was observed. Efficacy of treatment was related to the residual implant volume, and repeat treatments may be required to enhance this volume. For more details, refer to the Sources of evidence section. The Specialist Advisors considered that this was a procedure at an early stage of development and that its efficacy was unknown. # Safety Transient mild-to-moderate chest pain was the most commonly reported adverse event occurring after injection; the incidence in the studies ranged from 53% (8/15) to 92% (78/85). Other complications included dysphagia, fever and nausea. For more details, refer to the Sources of evidence section. The Specialist Advisors had no major safety concerns. # Other comments These recommendations were based on evidence presented to the Interventional Procedures Advisory Committee on the use of a bio-compatible polymer as a bulking agent. The Institute may review the procedure if further data become available. Andrew DillonChief ExecutiveApril 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of endoscopic injection of bulking agents for gastro-oesophageal reflux disease', August 2003. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication As part of NICE's work programme, the current guidance was considered for review but did not meet the review criteria as set out in the IP process guide. This guidance therefore remains current. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of endoscopic injection of bulking agents for gastro-oesophageal reflux disease does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research.\n\nClinicians wishing to undertake endoscopic injection of bulking agents for gastro-oesophageal reflux disease should take the following action.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having endoscopic injection of bulking agents for gastro-oesophageal reflux disease.\n\nPublication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence.", 'The procedure': '# Indications\n\nGastro-oesophageal reflux disease (GORD) is a common condition that can have a significant impact on the quality of life of an individual. It is caused by failure of the sphincter mechanism at the lower end of the oesophagus. Symptoms of GORD can be broadly grouped into those directly related to reflux episodes, such as heartburn, regurgitation and waterbrash; and those symptoms caused by complications of reflux disease, including dysphagia and respiratory symptoms.\n\nLifestyle modifications and drug therapy are the standard treatment for patients with mild symptomatic GORD. Drug therapy includes antacids/alginates and acid-lowering agents, such as H-2 antagonists and proton pump inhibitors (PPIs). Patients with volume reflux or symptoms that do not respond to medical treatment may be treated with anti-reflux surgery. Injection therapy may be considered as an alternative to surgery.\n\n# Outline of the procedure\n\nThe patient is sedated and given an injection of antibiotics. A needle catheter is then introduced through an endoscope and passed down the oesophagus into the gastro-oesophageal junction, so narrowing the lumen. This catheter is filled with a bio-compatible polymer and solvent and is used to inject or implant the polymer into the gastro-oesophageal junction. The injection is made along the muscle layer or deep submucosal layer of the cardia. Multiple injections (often four) are performed in a circumferential manner around the oesophagus under fluoroscopic and endoscopic control.\n\n# Efficacy\n\nEvidence of efficacy was based primarily on one uncontrolled study of 85 patients with GORD receiving chronic PPI therapy. This study reported that, at 12 months, 67% (57/85) of patients were no longer taking PPIs and that a further 9% (8/85) of patients had reduced PPI usage by 50% or more. Both heartburn and regurgitation symptom scores had improved at 12 months. Small reductions in acid reflux, as assessed by measuring oesophageal pH, were seen but no improvement in endoscopic grades was observed. Efficacy of treatment was related to the residual implant volume, and repeat treatments may be required to enhance this volume. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors considered that this was a procedure at an early stage of development and that its efficacy was unknown.\n\n# Safety\n\nTransient mild-to-moderate chest pain was the most commonly reported adverse event occurring after injection; the incidence in the studies ranged from 53% (8/15) to 92% (78/85). Other complications included dysphagia, fever and nausea. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors had no major safety concerns.\n\n# Other comments\n\nThese recommendations were based on evidence presented to the Interventional Procedures Advisory Committee on the use of a bio-compatible polymer as a bulking agent. The Institute may review the procedure if further data become available.\n\nAndrew DillonChief ExecutiveApril 2004', 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of endoscopic injection of bulking agents for gastro-oesophageal reflux disease', August 2003.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': "As part of NICE's work programme, the current guidance was considered for review but did not meet the review criteria as set out in the IP process guide. This guidance therefore remains current.\n\nJanuary 2012: minor maintenance.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg55
26b8a3e4bbc69cbcd200e82ffc7303bc18429f58	nice	Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia	Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia Evidence-based recommendations on zolpidem and zopiclone for treating insomnia in adults. # Guidance When, after due consideration of the use of non-pharmacological measures, hypnotic drug therapy is considered appropriate for the management of severe insomnia interfering with normal daily life, it is recommended that hypnotics should be prescribed for short periods of time only, in strict accordance with their licensed indications. It is recommended that, because of the lack of compelling evidence to distinguish between zolpidem, zopiclone or the shorter-acting benzodiazepine hypnotics, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be prescribed. It is recommended that switching from one of these hypnotics to another should only occur if a patient experiences adverse effects considered to be directly related to a specific agent. These are the only circumstances in which the drugs with the higher acquisition costs are recommended. Patients who have not responded to one of these hypnotic drugs should not be prescribed any of the others.# Clinical need and practice Insomnia is a disturbance of normal sleep patterns commonly characterised by difficulty in initiating sleep (sleep onset latency) and/or difficulty maintaining sleep (sleep maintenance). However, insomnia is highly subjective and although most healthy adults typically sleep between 7 and 9 hours per night, patterns vary greatly between people, and in any given person there are variations from night to night. Insomnia can have a number of different causes: primary insomnia can be differentiated from insomnia associated with factors such as personal circumstances, physical or psychiatric co-morbidities, concomitant drug treatments or substance abuse (drugs, nicotine, alcohol or caffeine). A 1996 World Health Organization survey indicated that 52% of people reporting a sleep problem had a well-defined mental health disorder and 54% reported a physical disorder. The published estimates of the prevalence of insomnia vary from 10–38%. This variation can be attributed to the epidemiology surveys utilising different definitions, classification systems and diagnostic criteria. A recent systematic review of the epidemiological literature suggested that, while 30–48% of people reported the presence of insomnia symptoms and 8–18% reported dissatisfaction with sleep quality or quantity, only 6% met the criteria for a diagnosis of insomnia. Although one in twenty people are believed to present to healthcare professionals with insomnia-related symptoms, it is thought that many people with insomnia do not seek medical help. The prevalence of insomnia has been reported to be higher in women and to increase with age. The age-related increase is believed to be multifactorial in origin and has been associated with changes in the time spent in different stages of sleep, increasing co-morbidities, and lifestyle related factors. Sleep disturbance and the resulting daytime fatigue cause distress and impairment of daytime functioning, both social and occupational, which have been associated with reduced quality of life. People with insomnia have been shown to have higher rates of mental health problems, drug and alcohol abuse, cardiac morbidity and healthcare utilisation, and to be at increased risk of accidents and overall mortality. However, it is difficult to differentiate the effects of insomnia from the effects of any associated factors, for example, co-morbidities. The electrophysiological parameters of sleep can be objectively assessed using polysomnography (PSG), which monitors sleep architecture by using electrodes applied to the scalp. However, insomnia is very subjective and there is great variation in sleep parameters both between individuals and in individuals on different nights. Therefore, although objective data on sleep parameters (for example, time taken to get to sleep, duration of sleep and number of awakenings) can be collected, such data are difficult to interpret and do not fully capture the impact of the condition. More subjective evaluations can be made using generic and disease-specific quality of life instruments and self-report measures such as sleep diaries and sleep quality indices. The choice of management strategy for insomnia is dependent upon both the duration and nature of the presenting symptoms. Appropriate management of existing co-morbidities may relieve the symptoms. The provision of advice on appropriate routines to encourage good sleep is fundamental to the overall management strategy, for example, avoiding stimulants and maintaining regular sleeping hours with a suitable environment for sleep. Other non-pharmacological interventions (for example, cognitive behavioural therapies) have also been shown to be effective in the management of persistent insomnia. However, although GPs and pharmacists can deliver appropriate advice and education, access to many non-pharmacological therapies is restricted through a combination of a lack of trained providers, cost and a poor understanding of available options. A drug used to induce sleep is described as a 'hypnotic'. Although hypnotics can provide relief from the symptoms of insomnia, they do not treat any underlying cause. A number of hypnotic agents are licensed for the treatment of insomnia, including the benzodiazepines and zaleplon, zolpidem and zopiclone (Z-drugs). It is difficult to ascertain how many prescriptions for hypnotics are written annually because benzodiazepines, which are commonly prescribed for insomnia, are also prescribed for other conditions. Up to 40% of people with insomnia self-medicate with hypnotics that are available without prescription from pharmacies (for example, sedative antihistamines). Benzodiazepines are a group of structurally related compounds that enhance the effects of gamma (γ)- aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system. The British National Formulary (BNF) 46th edition lists six benzodiazepines (nitrazepam, flunitrazepam, flurazepam, loprazolam, lormetazepam and temazepam) in Section 4.1.1 on hypnotics. These agents are all available in generic form except for flunitrazepam and flurazepam, which are 'blacklisted' and cannot be prescribed within the NHS. A further two benzodiazepines, diazepam and lorazepam, are licensed for both insomnia and anxiety and are listed in the anxiolytic section of the BNF (Section 4.1.2). The effects of specific benzodiazepines are dependent upon the dose administered and the pharmacokinetic profile. Although there is variation between the estimates of elimination half-life, the BNF refers to loprazolam, lorazepam, lormetazepam and temazepam as having a shorter duration of action. Benzodiazepines with a longer elimination half-life (for example, diazepam and nitrazepam) tend to have prolonged effects and, if used as hypnotics, have a greater tendency to have next-day residual effects. This may affect mental function and cause psychomotor impairment, which can interfere with activities such as driving and working with machinery. One of the key concerns about the use of benzodiazepines is that many people develop tolerance to their effects, gain little therapeutic benefit from chronic consumption, become dependent on them (both physically and psychologically), and suffer a withdrawal syndrome when they stop taking them. The withdrawal syndrome may be prolonged and may develop at any time up to 3 weeks after cessation of a long-acting benzodiazepine, or a few hours after cessation of a short-acting one. The syndrome includes anxiety, depression, nausea and perceptual changes. 'Rebound insomnia' also occurs and is characterised by a worsening of the original insomnia symptoms. There are also problems of abuse with benzodiazepines as they enhance and often prolong the 'high' obtained from other drugs and alleviate their withdrawal effects. It has been estimated that 10–30% of chronic benzodiazepines users are physically dependent on them and 50% of all users suffer withdrawal symptoms. Factors potentially associated with an increased risk of developing dependency include short duration of action, long-term use, high dose, high potency, alcoholism and other drug dependency, personality disorders and use without medical supervision. The BNF notes that lorazepam is associated with a greater risk of withdrawal symptoms. The concerns over dependence led the Committee on Safety of Medicines to recommend that the use of benzodiazepines for the treatment of insomnia should be restricted to severe insomnia and that treatment should be at the lowest dose possible and not be continued beyond 4 weeks.# The technologies Zaleplon, zolpidem and zopiclone (the Z-drugs) are nonbenzodiazepine hypnotics. Although the Z-drugs differ structurally from the benzodiazepines, they are also agonists of the GABA receptor complex and therefore enhance GABA-mediated neuronal inhibition. The Z-drugs were developed with the aim of overcoming some of the disadvantages of benzodiazepines – for example, next day sedation, dependence and withdrawal. Zaleplon is a pyrazolopyrimidine with an elimination half-life of 1 hour. It is licensed for "the treatment of patients with insomnia who have difficulty falling asleep". It is indicated only when the disorder is severe, disabling or subjecting the patient to extreme distress. The Summary of Product Characteristics (SPC) specifies that treatment should be as short as possible with a maximum duration of 2 weeks. Zolpidem is an imidazopyridine and has an elimination half-life of 2.5 hours. It is licensed for "the short-term treatment of insomnia in situations where the insomnia is debilitating or is causing severe distress for the patient". The SPC states that the duration of treatment should usually vary from a few days to 2 weeks with a maximum of 4 weeks, including tapering off where appropriate. Zopiclone is a cyclopyrrolone and has an elimination half-life of 3.5–6.5 hours. It is licensed for "the short-term treatment of insomnia (including difficulties in falling asleep, nocturnal awakening and early awakening, transient, situational or chronic insomnia, and insomnia secondary to psychiatric disturbances) in situations where the insomnia is debilitating or is causing severe distress for the patient". The SPC states that long-term continuous use is not recommended, that a course of treatment should employ the lowest effective dose, and a single period of treatment should not exceed 4 weeks including any tapering off. The SPC also states that the duration of treatment should be 2–5 days for transient insomnia and 2–3 weeks for short-term insomnia. In common with the benzodiazepines, the sedative effects of the Z-drugs may persist into the next day. The SPCs for all three Z-drugs carry warnings about their potential to cause tolerance, dependence and withdrawal symptoms. For full details of side effects and contraindications, see the SPCs. The current acquisition costs for an adult dose are zaleplon (10 mg) £0.29, zolpidem (10mg) £0.16 and zopiclone (7.5 mg) £0.16 (excluding VAT; BNF 46th edition). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (Appendix A) considered evidence from a number of sources (see Appendix B). The remit given to NICE by the Department of Health/Welsh Assembly Government was to advise on the clinical and cost effectiveness of zaleplon, zolpidem and zopiclone relative to benzodiazepines. The appraised evidence was therefore restricted to that informing comparison of the Z-drugs with benzodiazepines that are approved for the treatment of insomnia and may be prescribed within the NHS (diazepam, nitrazepam, loprazolam, lorazepam, lormetazepam and temazepam). # Clinical effectiveness The Assessment Report reviewed data from 24 randomised controlled trials (RCTs) that compared the Z-drugs with either a benzodiazepine or with another Z-drug in patients with insomnia. In total, 11 different comparisons were made between benzodiazepines (temazepam, lormetazepam or nitrazepam) and zolpidem (4 RCTs) or zopiclone (13 RCTs). No RCTs were identified that compared zaleplon with a benzodiazepine. Six RCTs were reviewed that compared zaleplon with zolpidem and one that compared zolpidem with zopiclone. The duration of the studies ranged from 1 night to 6 weeks. Ten studies included a follow-up period, which ranged from 3 to 11 days. The number of patients included in the trials ranged from 10 to 615. The most common comparator used in the RCTs was nitrazepam, which has a prolonged duration of action and may give rise to residual effects on the following day. None of the trials compared the Z-drugs against 10 mg temazepam or 1 mg loprazolam. One of the ten studies used objective PSG recordings; the remaining nine collected data from post-sleep questionnaires and sleep diaries. Five RCTs restricted their inclusion criteria to people of 60 years of age or older. Although it is recommended that the doses of both the Z-drugs and the benzodiazepine hypnotics should be reduced in older people, only three of the five RCTs used recommended doses for this age group. People over the age of 60 were amongst the population enrolled in a further 12 of the included RCTs. In these studies, standard dose hypnotics (benzodiazepines and Z-drugs) were used with no reported dose reductions for the people over the age of 60. The Assessment Group reported that it was difficult to compare the results of individual studies because of methodological problems and variations in the outcome measures used. In addition, direct statistical comparisons between the hypnotics included in individual RCTs were not always made, and often insufficient data were reported to permit further analysis. There was also evidence of multiple testing of outcomes, with selective reporting of significant findings. Although in the individual RCTs there were some statistically significant differences between the Z-drugs and the benzodiazepines for some of the efficacy outcome measures, the differences were not consistent across the trials. In addition, in most cases the absolute difference was small and the clinical significance of the differences was difficult to ascertain. The Assessment Group concluded that there was no consistent pattern of superiority of one drug over another. Six RCTs compared zaleplon with zolpidem. One RCT found that 10 mg zaleplon per night resulted in statistically significant shorter sleep onset latency than 5 mg zolpidem (median time 31 minutes versus 42 minutes). Pooled data from three RCTs indicated the sleep was of less quality (odds ratio 0.66; 95% confidence interval : 0.51 to 0.87) and the median sleep time was statistically significantly less with 5 mg zaleplon per night compared with 5 mg zopiclone (291 minutes versus 309 minutes). Compared with 7.5 mg zopiclone, 10 mg zolpidem per night was associated with shorter sleep onset latency (OR 1.72; 95% CI: 1.04 to 2.84) in the 2-week trial identified. In the cross-over study, there were no statistically significant differences between 10 mg zaleplon and 10 mg zolpidem in the patients' global impression of treatment (38% versus 62%). There was little consistency in the reporting of adverse events, which prevented comparison of individual event rates or meta-analysis. There were no statistically significant differences in the rates of treatment-emergent adverse events associated with any of the comparisons of Z-drugs versus benzodiazepines. There were no consistent differences between the Z-drugs and the benzodiazepines in the incidence of next-day residual effects. In the RCT comparisons between the Z-drugs and benzodiazepines in people with insomnia, no data were identified on the frequencies of symptoms associated with withdrawal or dependency. In their submissions, the manufacturers also referenced a number of other studies that examined the rates of tolerance and dependency associated with the Z-drugs. The studies were not considered to be methodologically robust and there were no direct comparisons between the Z-drugs and the benzodiazepines used in the NHS. The Assessment Group also searched for studies of other designs that specifically evaluated rates of dependence and withdrawal symptoms following treatment with the Z-drugs. Six studies were identified, four of which evaluated patients after extended treatment periods. Two placebo-controlled studies examined relative rates of withdrawal symptoms after patients receiving zolpidem were switched to placebo after 3 or 4 weeks of treatment. In one study, no patient in either group reported more than one symptom after 4 weeks treatment with 10 mg zolpidem or placebo and in the second study, three older patients who had received zolpidem at doses of 10–20 mg experienced adverse events. In addition, information on cases of dependence reported to the Committee on Safety of Medicines was sought and 16 case reports were identified in the literature relating to zolpidem (11) and zopiclone (5). There are problems with the interpretation of such reports, as rates of reporting are dependent on the publicity and awareness of certain adverse reactions and the pattern of use of the drugs. In addition to the RCTs conducted in people with insomnia, a further 9 RCTs, which were conducted in healthy volunteers in whom insomnia had been induced, were submitted by the manufacturers. Most of these 9 studies had very small sample sizes (less than 30 people) or were of very short duration (for example 1–3 nights). The largest study was conducted in 630 people and compared 10 mg zolpidem with 15 mg temazepam, 0.25 mg triazolam or placebo. Data were collected from multiple outcome measures. There were no statistically significant differences between zolpidem and temazepam in objective measures of sleep latency and sleep efficiency. The zolpidem group had statistically significantly fewer awakenings than the temazepam group. For the subjective measures, the group receiving zolpidem reported greater ease in falling asleep, more sleep time and less wake time than those receiving temazepam. There were no statistically significant differences in subjects' ratings of their ability to concentrate or morning sleepiness. A manufacturer submitted evidence from two RCTs that compared continuous zolpidem use (10 mg per night) with intermittent use. Data for each night were not reported but the submission reported that there were no statistically significant differences in the sleep efficacy outcomes, other than the investigators' assessment of sleep onset latency, which was statistically significantly greater in the continuous zolpidem group. No similar studies were located for zaleplon, zopiclone or any benzodiazepine. In summary, the Assessment Group did not find any RCTs that appropriately compared the Z-drugs with shorter-acting benzodiazepines, used at appropriate doses. In the RCTs that were reviewed by the Committee, which had been conducted in both healthy volunteers and people with insomnia, there were no consistent differences between the drugs. However, this lack of consistency was attributed in part to the poor quality of reporting. # Cost effectiveness None of the submissions contained an economic evaluation that compared the costs and effects of the short-term use of Z-drugs with benzodiazepines. In addition, the Assessment Group was unable to identify any evaluations in the health economics literature. No comparative data on the health-related quality of life associated with Z-drugs and benzodiazepines using generic health status measures were identified, and there was no evidence to link the clinical endpoints from the trials with quality of life. The manufacturer of zaleplon submitted two models based upon the key assumption that zaleplon does not cause 'mental impairment' the day after administration. The first model consisted of a cost–consequence algorithm comparing the costs and additional road traffic accidents (RTAs) associated with the residual effects of zopiclone and zaleplon. This model was based on a study mapping residual effects of zopiclone and zaleplon to RTAs using data from three other studies. The first stage of the mapping procedure was to estimate the impact of the residual effects of the Z-drugs on driving performance. This was taken from a doubleblind study of 28 healthy volunteers given zaleplon, zopiclone or placebo in the evening. The volunteers were woken in the middle of the night and given either placebo (those who had earlier taken active medication) or zaleplon, zopiclone or placebo (those who had earlier taken placebo). Participants undertook a series of tests, including a driving performance test, the following morning. The results found that driving performance was statistically significantly worse in the zopiclone group, and performance after zaleplon was similar to that for placebo. These results were linked to data from a similar study designed to measure the driving performance associated with differing levels of blood alcohol content. The relationship between blood alcohol content and the residual effects of the Z-drugs was then estimated. The relationship between relative risk of RTAs and blood alcohol content was estimated using data from a case–control study. The results of the model suggest that the expected excess accident costs, combined with drug purchase costs, over a 2-week period were US$71 per person for 10 mg zaleplon and US$92 per person for 10 mg zopiclone. In support of the economic model, the manufacturer of zaleplon also cited a UK-based study which examined a sample of drivers involved in RTAs and compared the odds of having an accident whilst exposed or not exposed to specified drugs. The study found that zopiclone and anxiolytic benzodiazepines, but not hypnotic benzodiazepines, were associated with increased risk of RTAs. The manufacturer also cited a Canadian study estimating the relationship between hypnotic drugs and RTAs in older people. The study found that benzodiazepines with a long half-life were associated with an increased risk of RTAs, but that those with a short-half life were not. Concern was expressed regarding this study at the time of publication, particularly with regard to the failure to adequately control for confounding effects and the lack of distinction between benzodiazepines used as hypnotics and those used as anxiolytics. The manufacturer of zaleplon also submitted a model designed to estimate the costs associated with hip fractures caused by falls as a result of the residual effects of zolpidem, nitrazepam, temazepam and zaleplon. The model assumed treatment on a basis of 2 weeks on therapy followed by 2 weeks off therapy over a one-year period and did not take into account benefits relating to treatment. This model was based on a published retrospective study, which examined the use of sedative hypnotics using Medicare data in a sample of older patients. Each case, defined as a patient who underwent surgical care for hip fracture, was matched by four age–gender matched controls from the Medicare database. Confounding factors are likely to bias results in studies of this type, particularly as insomnia may be a result of co-morbid conditions, which in turn could increase the risk of falls. Attempts to reduce confounding were made by adjusting crude odds ratios by a number of factors, including a measure of co-morbid illness severity. The study found that zolpidem use and benzodiazepine use were associated with a statistically significant increase in the risk of hip fracture. The model used the adjusted odds ratios from this study to represent the increased risk of hip fracture. The manufacturer assumed no additional risk of hip fracture was associated with zaleplon (that is, adjusted OR 1.0), although this drug had not been evaluated in the published study. The results of the model suggest that per year zolpidem, nitrazepam and temazepam therapy were more expensive than zaleplon when treating a cohort of 10,000 patients by £821,000, £129,000 and £111,000, respectively. The Assessment Group reanalysed the hip fractures model after correcting some errors and adding illustrative qualityadjusted life year (QALY) values, but retaining the key assumption that zaleplon was not associated with increased risk of hip fractures. The Assessment Group concluded from the results of the amended model that at current acquisition costs, after taking into account the uncertainty surrounding all of the model inputs, the drugs included in the analysis appeared similarly cost effective compared with no treatment. A manufacturer of zolpidem submitted a discussion of a model to estimate the costs of long-term zolpidem treatment compared with temazepam treatment. The model used estimates of dependence based on national prescribing data and concluded that despite having higher costs per dependent and non-dependent patient, zolpidem was shown to cost less on average because of its lower likelihood of high-cost dependency. However, the manufacturer stated that, "in the absence of robust data on the incidence of dependence, the author had to rely on a weak surrogate indicator of dependence in the form of continuous use". In summary, the manufacturers suggest that the additional acquisition costs of Z-drugs would be offset by reduced consumption of other healthcare resources or lead to an improvement in health outcomes as a result of decreased dependence or reduced residual effects. # Consideration of the evidence The Committee reviewed the evidence available on the clinical and cost effectiveness of zaleplon, zolpidem and zopiclone, having considered evidence on the nature of the condition and the value placed by users on the benefits of zaleplon, zolpidem and zopiclone from people with insomnia, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources. The Committee heard testimony that insomnia is generally not well managed and that there is a lack of availability of training for healthcare providers in this field. It was advised that, despite national recommendations and restrictions specified in the SPCs, hypnotic agents are commonly used for minor degrees of insomnia and also prescribed for long periods. Use of these agents for extended periods is associated with increased likelihood of dependence. The Committee heard evidence that some non-pharmacological strategies, including simple techniques such as the provision of advice on appropriate routines to encourage good sleep, (for example, avoiding stimulants and maintaining regular sleeping hours with a suitable environment for sleep) had been shown to be effective in the management of insomnia. The Committee considered that it was likely that such strategies could replace some of the current prescribing of hypnotics. However, nonpharmacological therapies did not fall within the remit of this appraisal and therefore their clinical and cost effectiveness had not been determined. The Committee appreciated that there were differences in the pharmacokinetics of the individual hypnotics (both Z-drugs and benzodiazepines) which may have some benefits in specific clinical situations. For example, a hypnotic that is rapidly absorbed and rapidly cleared will inevitably result in shorter sleep onset latency, but it may not extend the total sleep duration as its effects will rapidly wear off. The Committee was not however persuaded that these differences resulted in any overall benefit for the majority of patients in terms of perceived quality of sleep, daytime functioning or quality of life. The Committee was also aware that when comparing the Z-drugs with nitrazepam and diazepam, consideration needed to be given to the fact that it was inevitable that the longer half-life of these benzodiazepines would be associated with an increased likelihood of persistence of the sedative effects into the next day. The Committee considered that the RCTs available, in both people with insomnia and healthy volunteers, did not reflect current NHS practice: none of the Z-drugs had been compared with appropriate hypnotic doses of temazepam and the most common comparator used in the RCTs was nitrazepam, which has a prolonged duration of action and may give rise to residual effects on the following day. The Committee also appreciated that the effects of both the Z-drugs and the benzodiazepines were dose-related and that inappropriate comparisons, particularly in older people, would confound the results of the RCTs. The Committee was made aware by the patient organisation that warnings regarding potential dependence associated with extended use of hypnotics are often not passed to patients. The Committee was particularly concerned that patients may be preferentially prescribed Z-drugs or transferred from benzodiazepines to the Z-drugs because of a perception that they are less likely to induce dependency than the benzodiazepines. In addition, the Committee considered that the substitution of the Z-drugs for patients who were being withdrawn from benzodiazepines was inappropriate and not supported by available evidence of reduced potential for dependency. The Committee recognised that the benzodiazepines are abused and was informed by both the experts and the patient representatives that, although there was limited epidemiological evidence, abuse of the Z-drugs was increasing. Having considered the results of the RCTs and healthy volunteer studies, together with the testimony from the professional and patient experts, the Committee concluded that currently there was no compelling evidence of a clinically useful difference between the Z-drugs and shorter-acting benzodiazepine hypnotics from the point of view of their effectiveness, adverse effects, or potential for dependence or abuse. There was no evidence to suggest that if a patient did not respond to one of these hypnotic drugs, they were likely to respond to another and this was supported by testimony from the clinical and patient experts. The Committee therefore concluded that 'switching' between these hypnotics was not an appropriate management strategy. The Committee considered the economic models submitted by one of the manufacturers. The Committee fully discussed the basis of the manufacturer's models and recognised that they were based on the premise that the use of individual Z-drugs in preference to other Z-drugs or benzodiazepines would prevent road traffic accidents or hip fractures caused by falls. The Committee did not accept these models as it considered that the evidence used in them was not robust and the additional assumptions underpinning the models were not appropriate. In addition, the Committee considered that there was no reliable evidence to support the claim that the higher acquisition costs of the Z-drugs would be offset by the reductions in the use of other health service resources. In summary, given the lack of compelling evidence on any clinically useful differences between the Z-drugs and the shorter-acting benzodiazepine hypnotics, the Committee concluded that, unless a patient experiences adverse effects considered to be directly related to a specific hypnotic, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be used in preference to more expensive alternatives.# Recommendations for further research Although RCTs to assess the relative clinical effectiveness and cost effectiveness of the Z-drugs and the shorter-acting benzodiazepines could potentially clarify some of the uncertainty, it is unlikely that they would be a cost-effective use of NHS resources. Efforts should therefore be concentrated on determining the clinical and cost effectiveness of pharmacological treatments relative to non-pharmacological interventions, including their relative roles in the long-term management of insomnia. Previous trials have concentrated on the use of sleep-specific measures of outcomes, which have not been directly related to improvements in daytime functioning and quality of life. Further research should therefore include the impact of hypnotics and any resultant improvement in sleep quality, on daytime functioning and health-related quality of life. There is limited evidence on the risk of dependency associated with the Z-drugs and benzodiazepines. In particular, the risk of dependence should be examined with respect to intermittent use of hypnotics, and the relationship between risk of dependence and length of treatment. The patient groups informed the Committee that there was a lack of support for patients and inadequate information about the management of insomnia and the risks associated with the use of hypnotics. Research should therefore be conducted to establish the most suitable method of conveying good quality information to people with insomnia# Implications for the NHS It is likely that this guidance will result in the preferential prescription of hypnotics with lower acquisition costs and possibly lead to a reduction in the prescribing of hypnotics, both overall and more specifically for long-term use. It is therefore expected that there will be some savings in terms of costs directly associated with the prescription of hypnotics. In 2002, a total of 3.9 million prescriptions were written for Z-drugs with a net ingredient cost of £15.9 million. However, the overall effect and the timescale of this effect on NHS resources will depend on any reduction in overall hypnotic prescribing, the proportion of prescriptions relating to the short-term management, the proportion of patients prescribed more expensive hypnotics as a result of adverse effects directly related to the cheaper alternatives and the uptake of any non-pharmacological alternatives.# Related guidance There is no specific related NICE guidance for the management of insomnia.# Appendix C. Detail on criteria for audit of the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia # Possible objectives for an audit An audit could be carried out on the appropriateness of use of zaleplon, zolpidem and zopiclone. # Possible patients to be included in the audit An audit could be carried out on all patients treated for insomnia for a suitable time period for audit, for example, 3–6 months. Alternatively, an audit could be carried out over a suitable time period, for example, 3–6 months, on all patients for whom hypnotic drug therapy is prescribed. # Measures that could be used as a basis for audit The measures that could be used in an audit of zaleplon, zolpidem and zopiclone for the management of insomnia are as follows. Criterion Standard Exception Definition of terms . Non-pharmacological measures are considered before then prescription of drug therapy for insomnia. % of patients being treated for insomnia. None For audit purposes, clinicians will need to agree locally on how non-pharmacological measures are defined and how consideration of their use is documented. . When hypnotic drug therapy is used, the drug used is prescribed for a short period of time only, in strict accordance with the licensed indications % of patients for whom hypnotic drug therapy is prescribed None Drug therapy for insomnia can include zaleplon, zolpidem, zopiclone or the shorter-acting benzodiazepine hypnotics (loprazolam, lormetazepam and temazepam). For audit purposes, clinicians will need to agree locally on how to define the duration of a prescription. The maximum duration of a prescription for zaleplon is 2 weeks and for zolpidem and zopiclone is 4 weeks. Also for audit purposes, clinicians will need to agree locally on how to define and measure the consistency of prescriptions with licensed indications for each drug. . When hypnotic drug therapy is prescribed, the drug with the lowest purchase cost is chosen % of patients for whom hypnotic drug therapy is prescribed A. The patient experiences adverse effects considered to be directly related to the firstline choice The lowest purchase cost takes into account the daily required dose and the product price per dose. For audit purposes, clinicians will need to agree locally on the source of cost information and on how adverse effects of a specific drug are documented. . A patient is switched from one hypnotic drug to another % of patients for whom hypnotic drug therapy is prescribed A. The patient experiences adverse effects considered to be directly related to a specific agent Clinicians will need to agree locally on how adverse effects of a specific drug are documented for audit purposes. An audit on all patients for whom hypnotic drug therapy is prescribed could be carried out using the measures above. # Calculation of compliance Compliance (%) with each measure described in the table above is calculated as follows. Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed x 100 Number of patients to whom the measure applies Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.	{'Guidance': 'When, after due consideration of the use of non-pharmacological measures, hypnotic drug therapy is considered appropriate for the management of severe insomnia interfering with normal daily life, it is recommended that hypnotics should be prescribed for short periods of time only, in strict accordance with their licensed indications.\n\nIt is recommended that, because of the lack of compelling evidence to distinguish between zolpidem, zopiclone or the shorter-acting benzodiazepine hypnotics, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be prescribed.\n\nIt is recommended that switching from one of these hypnotics to another should only occur if a patient experiences adverse effects considered to be directly related to a specific agent. These are the only circumstances in which the drugs with the higher acquisition costs are recommended.\n\nPatients who have not responded to one of these hypnotic drugs should not be prescribed any of the others.', 'Clinical need and practice': "Insomnia is a disturbance of normal sleep patterns commonly characterised by difficulty in initiating sleep (sleep onset latency) and/or difficulty maintaining sleep (sleep maintenance). However, insomnia is highly subjective and although most healthy adults typically sleep between 7 and 9 hours per night, patterns vary greatly between people, and in any given person there are variations from night to night.\n\nInsomnia can have a number of different causes: primary insomnia can be differentiated from insomnia associated with factors such as personal circumstances, physical or psychiatric co-morbidities, concomitant drug treatments or substance abuse (drugs, nicotine, alcohol or caffeine). A 1996 World Health Organization survey indicated that 52% of people reporting a sleep problem had a well-defined mental health disorder and 54% reported a physical disorder.\n\nThe published estimates of the prevalence of insomnia vary from 10–38%. This variation can be attributed to the epidemiology surveys utilising different definitions, classification systems and diagnostic criteria. A recent systematic review of the epidemiological literature suggested that, while 30–48% of people reported the presence of insomnia symptoms and 8–18% reported dissatisfaction with sleep quality or quantity, only 6% met the criteria for a diagnosis of insomnia. Although one in twenty people are believed to present to healthcare professionals with insomnia-related symptoms, it is thought that many people with insomnia do not seek medical help.\n\nThe prevalence of insomnia has been reported to be higher in women and to increase with age. The age-related increase is believed to be multifactorial in origin and has been associated with changes in the time spent in different stages of sleep, increasing co-morbidities, and lifestyle related factors.\n\nSleep disturbance and the resulting daytime fatigue cause distress and impairment of daytime functioning, both social and occupational, which have been associated with reduced quality of life. People with insomnia have been shown to have higher rates of mental health problems, drug and alcohol abuse, cardiac morbidity and healthcare utilisation, and to be at increased risk of accidents and overall mortality. However, it is difficult to differentiate the effects of insomnia from the effects of any associated factors, for example, co-morbidities.\n\nThe electrophysiological parameters of sleep can be objectively assessed using polysomnography (PSG), which monitors sleep architecture by using electrodes applied to the scalp. However, insomnia is very subjective and there is great variation in sleep parameters both between individuals and in individuals on different nights. Therefore, although objective data on sleep parameters (for example, time taken to get to sleep, duration of sleep and number of awakenings) can be collected, such data are difficult to interpret and do not fully capture the impact of the condition. More subjective evaluations can be made using generic and disease-specific quality of life instruments and self-report measures such as sleep diaries and sleep quality indices.\n\nThe choice of management strategy for insomnia is dependent upon both the duration and nature of the presenting symptoms. Appropriate management of existing co-morbidities may relieve the symptoms. The provision of advice on appropriate routines to encourage good sleep is fundamental to the overall management strategy, for example, avoiding stimulants and maintaining regular sleeping hours with a suitable environment for sleep. Other non-pharmacological interventions (for example, cognitive behavioural therapies) have also been shown to be effective in the management of persistent insomnia. However, although GPs and pharmacists can deliver appropriate advice and education, access to many non-pharmacological therapies is restricted through a combination of a lack of trained providers, cost and a poor understanding of available options.\n\nA drug used to induce sleep is described as a 'hypnotic'. Although hypnotics can provide relief from the symptoms of insomnia, they do not treat any underlying cause. A number of hypnotic agents are licensed for the treatment of insomnia, including the benzodiazepines and zaleplon, zolpidem and zopiclone (Z-drugs).\n\nIt is difficult to ascertain how many prescriptions for hypnotics are written annually because benzodiazepines, which are commonly prescribed for insomnia, are also prescribed for other conditions. Up to 40% of people with insomnia self-medicate with hypnotics that are available without prescription from pharmacies (for example, sedative antihistamines).\n\nBenzodiazepines are a group of structurally related compounds that enhance the effects of gamma (γ)- aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system. The British National Formulary (BNF) 46th edition lists six benzodiazepines (nitrazepam, flunitrazepam, flurazepam, loprazolam, lormetazepam and temazepam) in Section 4.1.1 on hypnotics. These agents are all available in generic form except for flunitrazepam and flurazepam, which are 'blacklisted' and cannot be prescribed within the NHS. A further two benzodiazepines, diazepam and lorazepam, are licensed for both insomnia and anxiety and are listed in the anxiolytic section of the BNF (Section 4.1.2).\n\nThe effects of specific benzodiazepines are dependent upon the dose administered and the pharmacokinetic profile. Although there is variation between the estimates of elimination half-life, the BNF refers to loprazolam, lorazepam, lormetazepam and temazepam as having a shorter duration of action. Benzodiazepines with a longer elimination half-life (for example, diazepam and nitrazepam) tend to have prolonged effects and, if used as hypnotics, have a greater tendency to have next-day residual effects. This may affect mental function and cause psychomotor impairment, which can interfere with activities such as driving and working with machinery.\n\nOne of the key concerns about the use of benzodiazepines is that many people develop tolerance to their effects, gain little therapeutic benefit from chronic consumption, become dependent on them (both physically and psychologically), and suffer a withdrawal syndrome when they stop taking them. The withdrawal syndrome may be prolonged and may develop at any time up to 3 weeks after cessation of a long-acting benzodiazepine, or a few hours after cessation of a short-acting one. The syndrome includes anxiety, depression, nausea and perceptual changes. 'Rebound insomnia' also occurs and is characterised by a worsening of the original insomnia symptoms. There are also problems of abuse with benzodiazepines as they enhance and often prolong the 'high' obtained from other drugs and alleviate their withdrawal effects.\n\nIt has been estimated that 10–30% of chronic benzodiazepines users are physically dependent on them and 50% of all users suffer withdrawal symptoms. Factors potentially associated with an increased risk of developing dependency include short duration of action, long-term use, high dose, high potency, alcoholism and other drug dependency, personality disorders and use without medical supervision. The BNF notes that lorazepam is associated with a greater risk of withdrawal symptoms. The concerns over dependence led the Committee on Safety of Medicines to recommend that the use of benzodiazepines for the treatment of insomnia should be restricted to severe insomnia and that treatment should be at the lowest dose possible and not be continued beyond 4 weeks.", 'The technologies ': 'Zaleplon, zolpidem and zopiclone (the Z-drugs) are nonbenzodiazepine hypnotics. Although the Z-drugs differ structurally from the benzodiazepines, they are also agonists of the GABA receptor complex and therefore enhance GABA-mediated neuronal inhibition. The Z-drugs were developed with the aim of overcoming some of the disadvantages of benzodiazepines – for example, next day sedation, dependence and withdrawal.\n\nZaleplon is a pyrazolopyrimidine with an elimination half-life of 1 hour. It is licensed for "the treatment of patients with insomnia who have difficulty falling asleep". It is indicated only when the disorder is severe, disabling or subjecting the patient to extreme distress. The Summary of Product Characteristics (SPC) specifies that treatment should be as short as possible with a maximum duration of 2 weeks.\n\nZolpidem is an imidazopyridine and has an elimination half-life of 2.5 hours. It is licensed for "the short-term treatment of insomnia in situations where the insomnia is debilitating or is causing severe distress for the patient". The SPC states that the duration of treatment should usually vary from a few days to 2 weeks with a maximum of 4 weeks, including tapering off where appropriate.\n\nZopiclone is a cyclopyrrolone and has an elimination half-life of 3.5–6.5 hours. It is licensed for "the short-term treatment of insomnia (including difficulties in falling asleep, nocturnal awakening and early awakening, transient, situational or chronic insomnia, and insomnia secondary to psychiatric disturbances) in situations where the insomnia is debilitating or is causing severe distress for the patient". The SPC states that long-term continuous use is not recommended, that a course of treatment should employ the lowest effective dose, and a single period of treatment should not exceed 4 weeks including any tapering off. The SPC also states that the duration of treatment should be 2–5 days for transient insomnia and 2–3 weeks for short-term insomnia.\n\nIn common with the benzodiazepines, the sedative effects of the Z-drugs may persist into the next day. The SPCs for all three Z-drugs carry warnings about their potential to cause tolerance, dependence and withdrawal symptoms. For full details of side effects and contraindications, see the SPCs.\n\nThe current acquisition costs for an adult dose are zaleplon (10 mg) £0.29, zolpidem (10mg) £0.16 and zopiclone (7.5 mg) £0.16 (excluding VAT; BNF 46th edition). Costs may vary in different settings because of negotiated procurement discounts.', 'Evidence and interpretation': 'The Appraisal Committee (Appendix A) considered evidence from a number of sources (see Appendix B). The remit given to NICE by the Department of Health/Welsh Assembly Government was to advise on the clinical and cost effectiveness of zaleplon, zolpidem and zopiclone relative to benzodiazepines. The appraised evidence was therefore restricted to that informing comparison of the Z-drugs with benzodiazepines that are approved for the treatment of insomnia and may be prescribed within the NHS (diazepam, nitrazepam, loprazolam, lorazepam, lormetazepam and temazepam).\n\n# Clinical effectiveness\n\nThe Assessment Report reviewed data from 24 randomised controlled trials (RCTs) that compared the Z-drugs with either a benzodiazepine or with another Z-drug in patients with insomnia. In total, 11 different comparisons were made between benzodiazepines (temazepam, lormetazepam or nitrazepam) and zolpidem (4 RCTs) or zopiclone (13 RCTs). No RCTs were identified that compared zaleplon with a benzodiazepine. Six RCTs were reviewed that compared zaleplon with zolpidem and one that compared zolpidem with zopiclone.\n\nThe duration of the studies ranged from 1 night to 6 weeks. Ten studies included a follow-up period, which ranged from 3 to 11 days. The number of patients included in the trials ranged from 10 to 615. The most common comparator used in the RCTs was nitrazepam, which has a prolonged duration of action and may give rise to residual effects on the following day. None of the trials compared the Z-drugs against 10 mg temazepam or 1 mg loprazolam. One of the ten studies used objective PSG recordings; the remaining nine collected data from post-sleep questionnaires and sleep diaries.\n\nFive RCTs restricted their inclusion criteria to people of 60 years of age or older. Although it is recommended that the doses of both the Z-drugs and the benzodiazepine hypnotics should be reduced in older people, only three of the five RCTs used recommended doses for this age group. People over the age of 60 were amongst the population enrolled in a further 12 of the included RCTs. In these studies, standard dose hypnotics (benzodiazepines and Z-drugs) were used with no reported dose reductions for the people over the age of 60.\n\nThe Assessment Group reported that it was difficult to compare the results of individual studies because of methodological problems and variations in the outcome measures used. In addition, direct statistical comparisons between the hypnotics included in individual RCTs were not always made, and often insufficient data were reported to permit further analysis. There was also evidence of multiple testing of outcomes, with selective reporting of significant findings.\n\nAlthough in the individual RCTs there were some statistically significant differences between the Z-drugs and the benzodiazepines for some of the efficacy outcome measures, the differences were not consistent across the trials. In addition, in most cases the absolute difference was small and the clinical significance of the differences was difficult to ascertain. The Assessment Group concluded that there was no consistent pattern of superiority of one drug over another.\n\nSix RCTs compared zaleplon with zolpidem. One RCT found that 10 mg zaleplon per night resulted in statistically significant shorter sleep onset latency than 5 mg zolpidem (median time 31 minutes versus 42 minutes). Pooled data from three RCTs indicated the sleep was of less quality (odds ratio [OR] 0.66; 95% confidence interval [CI]: 0.51 to 0.87) and the median sleep time was statistically significantly less with 5 mg zaleplon per night compared with 5 mg zopiclone (291 minutes versus 309 minutes). Compared with 7.5 mg zopiclone, 10 mg zolpidem per night was associated with shorter sleep onset latency (OR 1.72; 95% CI: 1.04 to 2.84) in the 2-week trial identified. In the cross-over study, there were no statistically significant differences between 10 mg zaleplon and 10 mg zolpidem in the patients\' global impression of treatment (38% versus 62%).\n\nThere was little consistency in the reporting of adverse events, which prevented comparison of individual event rates or meta-analysis. There were no statistically significant differences in the rates of treatment-emergent adverse events associated with any of the comparisons of Z-drugs versus benzodiazepines. There were no consistent differences between the Z-drugs and the benzodiazepines in the incidence of next-day residual effects.\n\nIn the RCT comparisons between the Z-drugs and benzodiazepines in people with insomnia, no data were identified on the frequencies of symptoms associated with withdrawal or dependency. In their submissions, the manufacturers also referenced a number of other studies that examined the rates of tolerance and dependency associated with the Z-drugs. The studies were not considered to be methodologically robust and there were no direct comparisons between the Z-drugs and the benzodiazepines used in the NHS.\n\nThe Assessment Group also searched for studies of other designs that specifically evaluated rates of dependence and withdrawal symptoms following treatment with the Z-drugs. Six studies were identified, four of which evaluated patients after extended treatment periods. Two placebo-controlled studies examined relative rates of withdrawal symptoms after patients receiving zolpidem were switched to placebo after 3 or 4 weeks of treatment. In one study, no patient in either group reported more than one symptom after 4 weeks treatment with 10 mg zolpidem or placebo and in the second study, three older patients who had received zolpidem at doses of 10–20 mg experienced adverse events. In addition, information on cases of dependence reported to the Committee on Safety of Medicines was sought and 16 case reports were identified in the literature relating to zolpidem (11) and zopiclone (5). There are problems with the interpretation of such reports, as rates of reporting are dependent on the publicity and awareness of certain adverse reactions and the pattern of use of the drugs.\n\nIn addition to the RCTs conducted in people with insomnia, a further 9 RCTs, which were conducted in healthy volunteers in whom insomnia had been induced, were submitted by the manufacturers. Most of these 9 studies had very small sample sizes (less than 30 people) or were of very short duration (for example 1–3 nights). The largest study was conducted in 630 people and compared 10 mg zolpidem with 15 mg temazepam, 0.25 mg triazolam or placebo. Data were collected from multiple outcome measures. There were no statistically significant differences between zolpidem and temazepam in objective measures of sleep latency and sleep efficiency. The zolpidem group had statistically significantly fewer awakenings than the temazepam group. For the subjective measures, the group receiving zolpidem reported greater ease in falling asleep, more sleep time and less wake time than those receiving temazepam. There were no statistically significant differences in subjects\' ratings of their ability to concentrate or morning sleepiness.\n\nA manufacturer submitted evidence from two RCTs that compared continuous zolpidem use (10 mg per night) with intermittent use. Data for each night were not reported but the submission reported that there were no statistically significant differences in the sleep efficacy outcomes, other than the investigators\' assessment of sleep onset latency, which was statistically significantly greater in the continuous zolpidem group. No similar studies were located for zaleplon, zopiclone or any benzodiazepine.\n\nIn summary, the Assessment Group did not find any RCTs that appropriately compared the Z-drugs with shorter-acting benzodiazepines, used at appropriate doses. In the RCTs that were reviewed by the Committee, which had been conducted in both healthy volunteers and people with insomnia, there were no consistent differences between the drugs. However, this lack of consistency was attributed in part to the poor quality of reporting.\n\n# Cost effectiveness\n\nNone of the submissions contained an economic evaluation that compared the costs and effects of the short-term use of Z-drugs with benzodiazepines. In addition, the Assessment Group was unable to identify any evaluations in the health economics literature. No comparative data on the health-related quality of life associated with Z-drugs and benzodiazepines using generic health status measures were identified, and there was no evidence to link the clinical endpoints from the trials with quality of life.\n\nThe manufacturer of zaleplon submitted two models based upon the key assumption that zaleplon does not cause \'mental impairment\' the day after administration.\n\nThe first model consisted of a cost–consequence algorithm comparing the costs and additional road traffic accidents (RTAs) associated with the residual effects of zopiclone and zaleplon. This model was based on a study mapping residual effects of zopiclone and zaleplon to RTAs using data from three other studies. The first stage of the mapping procedure was to estimate the impact of the residual effects of the Z-drugs on driving performance. This was taken from a doubleblind study of 28 healthy volunteers given zaleplon, zopiclone or placebo in the evening. The volunteers were woken in the middle of the night and given either placebo (those who had earlier taken active medication) or zaleplon, zopiclone or placebo (those who had earlier taken placebo). Participants undertook a series of tests, including a driving performance test, the following morning. The results found that driving performance was statistically significantly worse in the zopiclone group, and performance after zaleplon was similar to that for placebo. These results were linked to data from a similar study designed to measure the driving performance associated with differing levels of blood alcohol content. The relationship between blood alcohol content and the residual effects of the Z-drugs was then estimated. The relationship between relative risk of RTAs and blood alcohol content was estimated using data from a case–control study. The results of the model suggest that the expected excess accident costs, combined with drug purchase costs, over a 2-week period were US$71 per person for 10 mg zaleplon and US$92 per person for 10 mg zopiclone.\n\nIn support of the economic model, the manufacturer of zaleplon also cited a UK-based study which examined a sample of drivers involved in RTAs and compared the odds of having an accident whilst exposed or not exposed to specified drugs. The study found that zopiclone and anxiolytic benzodiazepines, but not hypnotic benzodiazepines, were associated with increased risk of RTAs. The manufacturer also cited a Canadian study estimating the relationship between hypnotic drugs and RTAs in older people. The study found that benzodiazepines with a long half-life were associated with an increased risk of RTAs, but that those with a short-half life were not. Concern was expressed regarding this study at the time of publication, particularly with regard to the failure to adequately control for confounding effects and the lack of distinction between benzodiazepines used as hypnotics and those used as anxiolytics.\n\nThe manufacturer of zaleplon also submitted a model designed to estimate the costs associated with hip fractures caused by falls as a result of the residual effects of zolpidem, nitrazepam, temazepam and zaleplon. The model assumed treatment on a basis of 2 weeks on therapy followed by 2 weeks off therapy over a one-year period and did not take into account benefits relating to treatment. This model was based on a published retrospective study, which examined the use of sedative hypnotics using Medicare data in a sample of older patients. Each case, defined as a patient who underwent surgical care for hip fracture, was matched by four age–gender matched controls from the Medicare database. Confounding factors are likely to bias results in studies of this type, particularly as insomnia may be a result of co-morbid conditions, which in turn could increase the risk of falls. Attempts to reduce confounding were made by adjusting crude odds ratios by a number of factors, including a measure of co-morbid illness severity. The study found that zolpidem use and benzodiazepine use were associated with a statistically significant increase in the risk of hip fracture. The model used the adjusted odds ratios from this study to represent the increased risk of hip fracture. The manufacturer assumed no additional risk of hip fracture was associated with zaleplon (that is, adjusted OR 1.0), although this drug had not been evaluated in the published study. The results of the model suggest that per year zolpidem, nitrazepam and temazepam therapy were more expensive than zaleplon when treating a cohort of 10,000 patients by £821,000, £129,000 and £111,000, respectively.\n\nThe Assessment Group reanalysed the hip fractures model after correcting some errors and adding illustrative qualityadjusted life year (QALY) values, but retaining the key assumption that zaleplon was not associated with increased risk of hip fractures. The Assessment Group concluded from the results of the amended model that at current acquisition costs, after taking into account the uncertainty surrounding all of the model inputs, the drugs included in the analysis appeared similarly cost effective compared with no treatment.\n\nA manufacturer of zolpidem submitted a discussion of a model to estimate the costs of long-term zolpidem treatment compared with temazepam treatment. The model used estimates of dependence based on national prescribing data and concluded that despite having higher costs per dependent and non-dependent patient, zolpidem was shown to cost less on average because of its lower likelihood of high-cost dependency. However, the manufacturer stated that, "in the absence of robust data on the incidence of dependence, the author had to rely on a weak surrogate indicator of dependence in the form of continuous use".\n\nIn summary, the manufacturers suggest that the additional acquisition costs of Z-drugs would be offset by reduced consumption of other healthcare resources or lead to an improvement in health outcomes as a result of decreased dependence or reduced residual effects.\n\n# Consideration of the evidence\n\nThe Committee reviewed the evidence available on the clinical and cost effectiveness of zaleplon, zolpidem and zopiclone, having considered evidence on the nature of the condition and the value placed by users on the benefits of zaleplon, zolpidem and zopiclone from people with insomnia, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee heard testimony that insomnia is generally not well managed and that there is a lack of availability of training for healthcare providers in this field. It was advised that, despite national recommendations and restrictions specified in the SPCs, hypnotic agents are commonly used for minor degrees of insomnia and also prescribed for long periods. Use of these agents for extended periods is associated with increased likelihood of dependence.\n\nThe Committee heard evidence that some non-pharmacological strategies, including simple techniques such as the provision of advice on appropriate routines to encourage good sleep, (for example, avoiding stimulants and maintaining regular sleeping hours with a suitable environment for sleep) had been shown to be effective in the management of insomnia. The Committee considered that it was likely that such strategies could replace some of the current prescribing of hypnotics. However, nonpharmacological therapies did not fall within the remit of this appraisal and therefore their clinical and cost effectiveness had not been determined.\n\nThe Committee appreciated that there were differences in the pharmacokinetics of the individual hypnotics (both Z-drugs and benzodiazepines) which may have some benefits in specific clinical situations. For example, a hypnotic that is rapidly absorbed and rapidly cleared will inevitably result in shorter sleep onset latency, but it may not extend the total sleep duration as its effects will rapidly wear off. The Committee was not however persuaded that these differences resulted in any overall benefit for the majority of patients in terms of perceived quality of sleep, daytime functioning or quality of life. The Committee was also aware that when comparing the Z-drugs with nitrazepam and diazepam, consideration needed to be given to the fact that it was inevitable that the longer half-life of these benzodiazepines would be associated with an increased likelihood of persistence of the sedative effects into the next day.\n\nThe Committee considered that the RCTs available, in both people with insomnia and healthy volunteers, did not reflect current NHS practice: none of the Z-drugs had been compared with appropriate hypnotic doses of temazepam and the most common comparator used in the RCTs was nitrazepam, which has a prolonged duration of action and may give rise to residual effects on the following day. The Committee also appreciated that the effects of both the Z-drugs and the benzodiazepines were dose-related and that inappropriate comparisons, particularly in older people, would confound the results of the RCTs.\n\nThe Committee was made aware by the patient organisation that warnings regarding potential dependence associated with extended use of hypnotics are often not passed to patients. The Committee was particularly concerned that patients may be preferentially prescribed Z-drugs or transferred from benzodiazepines to the Z-drugs because of a perception that they are less likely to induce dependency than the benzodiazepines. In addition, the Committee considered that the substitution of the Z-drugs for patients who were being withdrawn from benzodiazepines was inappropriate and not supported by available evidence of reduced potential for dependency.\n\nThe Committee recognised that the benzodiazepines are abused and was informed by both the experts and the patient representatives that, although there was limited epidemiological evidence, abuse of the Z-drugs was increasing.\n\nHaving considered the results of the RCTs and healthy volunteer studies, together with the testimony from the professional and patient experts, the Committee concluded that currently there was no compelling evidence of a clinically useful difference between the Z-drugs and shorter-acting benzodiazepine hypnotics from the point of view of their effectiveness, adverse effects, or potential for dependence or abuse. There was no evidence to suggest that if a patient did not respond to one of these hypnotic drugs, they were likely to respond to another and this was supported by testimony from the clinical and patient experts. The Committee therefore concluded that \'switching\' between these hypnotics was not an appropriate management strategy.\n\nThe Committee considered the economic models submitted by one of the manufacturers. The Committee fully discussed the basis of the manufacturer\'s models and recognised that they were based on the premise that the use of individual Z-drugs in preference to other Z-drugs or benzodiazepines would prevent road traffic accidents or hip fractures caused by falls. The Committee did not accept these models as it considered that the evidence used in them was not robust and the additional assumptions underpinning the models were not appropriate. In addition, the Committee considered that there was no reliable evidence to support the claim that the higher acquisition costs of the Z-drugs would be offset by the reductions in the use of other health service resources.\n\nIn summary, given the lack of compelling evidence on any clinically useful differences between the Z-drugs and the shorter-acting benzodiazepine hypnotics, the Committee concluded that, unless a patient experiences adverse effects considered to be directly related to a specific hypnotic, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be used in preference to more expensive alternatives.', 'Recommendations for further research': 'Although RCTs to assess the relative clinical effectiveness and cost effectiveness of the Z-drugs and the shorter-acting benzodiazepines could potentially clarify some of the uncertainty, it is unlikely that they would be a cost-effective use of NHS resources. Efforts should therefore be concentrated on determining the clinical and cost effectiveness of pharmacological treatments relative to non-pharmacological interventions, including their relative roles in the long-term management of insomnia.\n\nPrevious trials have concentrated on the use of sleep-specific measures of outcomes, which have not been directly related to improvements in daytime functioning and quality of life. Further research should therefore include the impact of hypnotics and any resultant improvement in sleep quality, on daytime functioning and health-related quality of life.\n\nThere is limited evidence on the risk of dependency associated with the Z-drugs and benzodiazepines. In particular, the risk of dependence should be examined with respect to intermittent use of hypnotics, and the relationship between risk of dependence and length of treatment.\n\nThe patient groups informed the Committee that there was a lack of support for patients and inadequate information about the management of insomnia and the risks associated with the use of hypnotics. Research should therefore be conducted to establish the most suitable method of conveying good quality information to people with insomnia', 'Implications for the NHS': 'It is likely that this guidance will result in the preferential prescription of hypnotics with lower acquisition costs and possibly lead to a reduction in the prescribing of hypnotics, both overall and more specifically for long-term use. It is therefore expected that there will be some savings in terms of costs directly associated with the prescription of hypnotics. In 2002, a total of 3.9 million prescriptions were written for Z-drugs with a net ingredient cost of £15.9 million. However, the overall effect and the timescale of this effect on NHS resources will depend on any reduction in overall hypnotic prescribing, the proportion of prescriptions relating to the short-term management, the proportion of patients prescribed more expensive hypnotics as a result of adverse effects directly related to the cheaper alternatives and the uptake of any non-pharmacological alternatives.', 'Related guidance': 'There is no specific related NICE guidance for the management of insomnia.', 'Appendix C. Detail on criteria for audit of the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia': '# Possible objectives for an audit\n\nAn audit could be carried out on the appropriateness of use of zaleplon, zolpidem and zopiclone.\n\n# Possible patients to be included in the audit\n\nAn audit could be carried out on all patients treated for insomnia for a suitable time period for audit, for example, 3–6 months. Alternatively, an audit could be carried out over a suitable time period, for example, 3–6 months, on all patients for whom hypnotic drug therapy is prescribed.\n\n# Measures that could be used as a basis for audit\n\nThe measures that could be used in an audit of zaleplon, zolpidem and zopiclone for the management of insomnia are as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. Non-pharmacological measures are considered before then prescription of drug therapy for insomnia.\n\n% of patients being treated for insomnia.\n\nNone\n\nFor audit purposes, clinicians will need to agree locally on how non-pharmacological measures are defined and how consideration of their use is documented.\n\n. When hypnotic drug therapy is used, the drug used is prescribed for a short period of time only, in strict accordance with the licensed indications\n\n% of patients for whom hypnotic drug therapy is prescribed\n\nNone\n\nDrug therapy for insomnia can include zaleplon, zolpidem, zopiclone or the shorter-acting benzodiazepine hypnotics (loprazolam, lormetazepam and temazepam).\n\nFor audit purposes, clinicians will need to agree locally on how to define the duration of a prescription. The maximum duration of a prescription for zaleplon is 2 weeks and for zolpidem and zopiclone is 4 weeks.\n\nAlso for audit purposes, clinicians will need to agree locally on how to define and measure the consistency of prescriptions with licensed indications for each drug.\n\n. When hypnotic drug therapy is prescribed, the drug with the lowest purchase cost is chosen\n\n% of patients for whom hypnotic drug therapy is prescribed\n\nA. The patient experiences adverse effects considered to be directly related to the firstline choice\n\nThe lowest purchase cost takes into account the daily required dose and the product price per dose.\n\nFor audit purposes, clinicians will need to agree locally on the source of cost information and on how adverse effects of a specific drug are documented.\n\n. A patient is switched from one hypnotic drug to another\n\n% of patients for whom hypnotic drug therapy is prescribed\n\nA. The patient experiences adverse effects considered to be directly related to a specific agent\n\n\n\nClinicians will need to agree locally on how adverse effects of a specific drug are documented for audit purposes.\n\nAn audit on all patients for whom hypnotic drug therapy is prescribed could be carried out using the measures above.\n\n# Calculation of compliance\n\nCompliance (%) with each measure described in the table above is calculated as follows.\n\nNumber of patients whose care is consistent with the criterion plus number of patients who meet any exception listed\n\nx 100\n\nNumber of patients to whom the measure applies\n\nClinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.'}	https://www.nice.org.uk/guidance/ta77	Evidence-based recommendations on zolpidem and zopiclone for treating insomnia in adults.
541991f44d61981fff04bcc94b31e08f50f78145	nice	Fluid-filled thermal balloon and microwave endometrial ablation techniques for heavy menstrual bleeding	Fluid-filled thermal balloon and microwave endometrial ablation techniques for heavy menstrual bleeding Evidence-based recommendations on fluid-filled thermal balloon and microwave endometrial ablation techniques for heavy menstrual bleeding in adults. # Guidance Fluid-filled thermal balloon endometrial ablation and microwave endometrial ablation are recommended as treatment options for women with heavy menstrual bleeding in cases where it has been decided (by the woman and the clinician responsible for her treatment) that surgical intervention is appropriate for the management of the condition. For heavy menstrual bleeding, the choice of surgical treatment should be made jointly by the woman and the clinician responsible for treatment. The decision should be made after an informed discussion taking into account the desired outcome of the treatment (such as reduced menstrual bleeding or complete cessation of menstrual bleeding ), the relative benefits of all other treatment options and the adverse events associated with them, as well as the clinical condition, anatomical suitability and preferences of the woman.# Clinical need and practice Heavy menstrual bleeding (HMB, also known as menorrhagia) is a significant cause of morbidity in premenopausal women in England and Wales. HMB is objectively defined as menstrual blood loss of more than 80 ml/cycle, or menstrual bleeding lasting longer than 7 days, over several consecutive cycles. However, in practice, the diagnosis is based on the woman's subjective assessment of blood loss. HMB is a common disorder. It is estimated that 1 in 20 women in the UK aged 30–49 years consults her GP each year with HMB – approximately 1.5 million women in England and Wales. Referrals for menstrual disorders account for about 20% of all referrals to specialist gynaecology services, placing a significant burden on secondary healthcare services. Many women who are referred to secondary care for HMB will eventually undergo hysterectomy. More than 47,000 hysterectomies were carried out in the NHS in England in 2000–01. It is estimated that HMB was the presenting complaint in about half of these cases. Furthermore, about half of all women who have a hysterectomy for HMB are believed to have a normal uterus removed. HMB has adverse implications for quality of life. Women with HMB may have difficulties with daily activities such as work, social activities, hobbies and holidays. Many women report anxiety, depression, embarrassment and problems in their sex lives because of HMB. Anaemia is also common amongst women with HMB, and this may further impair quality of life. Diagnosis of HMB is complex and is usually based on subjective evaluation of blood loss by the affected individuals. The blood loss can be estimated using pictorial blood-loss assessment charts (PBACs); this method takes into account the number of items of sanitary wear used and the degree of staining of each item. A PBAC score greater than 100 would normally indicate HMB. Although the 'gold standard' method of measuring blood loss is the alkaline haematin technique, which requires women to collect their used sanitary wear, this technique is rarely used outside research settings. The cause of HMB is not known in the majority of cases, in which no pelvic or organic pathology is identified. However, HMB may have structural organic causes such as fibroids, adenomyosis, polyps, infections, pre-cancerous conditions or haematological disorders. Treatment of HMB aims to reduce menstrual loss and hence to improve the quality of life of the individuals. First-line treatment is drug therapy. The most commonly used drugs are tranexamic acid (an antifibrinolytic drug), mefenamic acid (a non-steroidal anti-inflammatory drug) and combined oral contraceptives. The Royal College of Obstetricians and Gynaecologists' (RCOG) guidelines recommend that drug treatment should be given for at least three cycles before considering another treatment option. Another alternative sometimes used before surgical intervention is a levonorgestrel-releasing intrauterine system. Surgical treatment is usually offered to patients who do not respond to drug treatment. Hysterectomy (removing the uterus as a whole or in part) is the only treatment for HMB that guarantees amenorrhoea (complete cessation of menstrual periods), but it is associated with peri- and postoperative complications, including incontinence and other urinary problems, fatigue, infection, pelvic pain and sexual problems. Overall, 1 in 30 women suffers a major adverse event during or soon after the operation. Additionally, the procedure has a mortality rate of 0.4–1.1 per 1000 operations. Hysterectomy is costly and has significant resource implications because it requires general anaesthesia, long operating theatre times and a hospital stay of up to 7 days after the operation. Full recovery may take 1–3 months. First-generation endometrial ablation (EA) techniques were introduced almost 20 years ago as alternatives to hysterectomy. These techniques aim to reduce the menstrual bleeding by destroying (ablating) the entire thickness of the innermost layer of the uterus (the endometrium) and some of the underlying muscular layer (the myometrium) using electrical, thermal or laser energy. EA techniques do not guarantee amenorrhoea, but are less invasive and require fewer resources than hysterectomy. Preoperative medical therapy is given to suppress endometrial growth, because ablation is more likely to be successful if the endometrium is thin. All organic and structural causes of HMB should be excluded before considering EA, by any means, as a treatment option. EA techniques are not suitable for women who wish to maintain fertility. The most widely used first-generation EA techniques are transcervical resection of endometrium (TCRE), using a loop diathermy electrode, and roller-ball ablation (RB), using an electrode with a movable ball or cylinder. All first-generation EA techniques require direct visualisation of the endometrium using a hysteroscope. The success rates of these techniques depend heavily on the skills and experience of the operator. Possible perioperative adverse effects with the firstgeneration EA techniques include electrosurgical burns, uterine perforation, haemorrhage, infection, and fluid overload (which may cause congestive cardiac failure, hypertension, haemolysis, coma and death). The incidences of complications following first-generation EA ablation techniques were reported by the MISTLETOE study (of more than 10,000 women) in England and Wales, and the Scottish Audit of Hysteroscopic Surgery (of around 1000 women). The rate of emergency hysterectomy was 6.6 per 1000 procedures in the MISTLETOE study and 2.0 per 1000 procedures in the Scottish Audit, and blunt uterine perforation was reported in 14.7 per 1000 procedures and 11.2 per 1000 procedures respectively. Combining the two audits, mortality from the first-generation EA methods was shown to be 0.26 per 1000 procedures.# The technologies Second-generation EA techniques have been introduced with the aim of providing simpler, quicker and more effective treatment options for HMB compared with first-generation EA techniques and hysterectomy. These techniques are less operator-dependent than the first-generation techniques, but they rely heavily on the devices themselves to ensure safety and efficacy. Second-generation EA techniques include fluid-filled thermal balloon EA (TBEA), radiofrequency (thermoregulated) balloon EA, hydrothermal EA, 3D bipolar radiofrequency EA, microwave EA (MEA), diode laser hyperthermy, cryoablation and photodynamic therapy. The most frequently used second-generation EA techniques in UK clinical practice, and the focus of this appraisal, are fluidfilled TBEA and MEA. These techniques do not require direct visualisation of the uterine cavity, and can be carried out under either local or general anaesthesia. TBEA destroys the inner layers of the uterus by transferring heat from heated liquid within a balloon inserted into the uterine cavity. The two devices available in the UK, Cavaterm and Thermachoice, both involve an electronic controller, a single-use latex or silicone balloon catheter housing a heating element and two thermocouples, and an umbilical cable. TBEA cannot be used on women with large or irregular uterine cavities because the balloon must be in direct contact with the uterine wall to cause ablation. Cavaterm is contraindicated for women whose uterine cavity is more than 10 cm long (from the internal os to the fundus), and Thermachoice for women whose uterine cavity is more than 12 cm long, and for those who have a latex allergy. TBEA is also contraindicated if classical caesarean section (vertical midline incision in the upper segment of the uterus) has been performed, or if other uterine surgery has left a scar where the uterine wall is less than 8 mm thick. The use of endometrial thinning agents before TBEA is not recommended. The MEA technique uses microwaves (at a fixed frequency of 9.2 GHz) to destroy the uterine glandular lining, using a hand-held applicator (microwave probe) that is inserted into the uterine cavity. The Microsulis MEA system consists of a system console that houses a control module with an embedded computer, a microwave generator, and a power supply. Additional components are a hand-held applicator, a pneumatic footswitch, coaxial and data cables, a printer (optional), a power cord and a portable trolley. The MEA applicator must be cleaned and sterilised before each use. MEA can be used in women whose uterine cavity is irregular in shape as a result of mild to moderate fibroids, polyps or congenital abnormalities. MEA is contraindicated if classical caesarean section (vertical midline incision in the upper segment of the uterus) has been performed, or if other uterine surgery has left a scar where the uterine wall is less than 8 mm thick. The use of endometrial thinning agents before MEA is recommended. Although equipment failures for MEA and TBEA were reported in early usage, the devices have been improved and these failures are now much less common. Adverse events with second-generation EA techniques include uterine infection, perforation, visceral burn, bleeding, haematometra, laceration, intra-abdominal injury and cyclical pain. Women who do not respond to initial EA may require further ablations or, eventually, hysterectomy. The outcome of EA is dependent on selecting the most appropriate technique for the individual patients' needs. The Cavaterm and Thermachoice control unit/generators cost £3990 and £6000 respectively, and the disposable balloon catheters cost £280 and £350. The Microsulis MEA system costs around £40,000 (with an additional £5000 per annum for the maintenance contract). However, most centres in the UK have a 'placement arrangement' with manufacturers, under which centres pay a fixed fee per treatment (about £280 per treatment with no capital cost for MEA).# Evidence and interpretation The Appraisal Committee considered evidence from a number of sources (see Appendix B). # Clinical effectiveness A total of 13 publications relating to seven trials were identified by literature searches. One of the trials compared MEA with TCRE/RB, and six compared TBEA with TCRE, with RB, or with both. Two of these trials had a non-randomised, controlled design, and the rest were randomised controlled trials (RCTs). In addition, one manufacturer provided the translation of a small trial, published in German, that compared TBEA with RB, and another unpublished RCT comparing TBEA with TCRE – this was submitted in confidence. Another manufacturer provided details of a study comparing MEA with RB that it conducted as part of its submission to the US Food and Drug Administration (FDA). In summary, 10 trials (two MEA and eight TBEA trials) were included in this review. ## Microwave endometrial ablation (MEA) One trial reported that at 12 months, 87% of women who had undergone MEA and 83% of women who had undergone RB had normal bleeding levels, defined as a PBAC score of less than 75. The difference could have arisen by chance (p = 0.359). Another trial that compared MEA with TCRE/RB reported a median bleeding score of 3 in both groups at 12 months, which fell at 24 months to 1 for the MEA group and 0 for the TCRE group. This bleeding score is the sum of the daily scores reported by the women, who were asked to grade the heaviness of their period on a fivepoint scale for each day of their period. The differences could have arisen by chance. Only one trial, which compared MEA with TCRE/RB, reported bleeding patterns in terms of the length and severity of bleeding. Based on intention-to-treat (ITT) populations, at 12 months 6% of the MEA group and 5% of the TCRE/RB group had more than 3 days of heavy bleeding (2% MEA, 5% TCRE/RB at 24 months), and 11% of women in the MEA group required at least double their usual sanitary protection compared with 12% in the TCRE/RB group (7% MEA, 13% TCRE/RB at 24 months). The differences between the groups could have arisen by chance. Amenorrhoea was reported as a clinical outcome in two MEA trials. In one trial, amenorrhoea at 12 months was reported for a median of 40% of women undergoing MEA, compared with 40% undergoing RB. At 36 months follow-up, the median amenorrhoea rates were 47% and 41% respectively (p = 0.19). The other trial reported similar median values for amenorrhoea in ITT populations at 12 months (55% in MEA versus 46% in RB, p = 0.106). Two MEA trials reported patient satisfaction. In one trial, 69% of both MEA and TCRE/RB groups were totally or generally satisfied at 12 months, and 74% of those undergoing MEA and 64% of those undergoing TCRE/RB were totally or generally satisfied at 24 months. The study was underpowered to detect whether this observed clinically important difference of 10% could have arisen by chance. Another trial, which compared MEA with RB, reported that 98% of women undergoing MEA were very satisfied or satisfied at 12 months compared with 99% of those undergoing RB. One trial used the SF-36 questionnaire to examine the impact of MEA and TCRE on quality of life. Following treatment, six of the eight items improved significantly compared with baseline in the MEA group, and seven items improved significantly in the TCRE group. Although the duration of procedures was defined inconsistently in the trials, MEA procedures took less time than TCRE and/or RB. In one trial, the mean operating time was 11.4 minutes for MEA and 15.0 minutes for TCRE/RB (p < 0.001). The other trial reported 'anaesthesia times' of 39.3 minutes for MEA and 47.1 minutes for RB, and 'treatment times' of 3.5 minutes for MEA and 20.3 minutes for RB. These differences were all statistically significant at the p < 0.01 level. One trial reported that 8% of women in the MEA group had undergone further ablation or hysterectomy at 12 months (6% hysterectomy, 1% TCRE and 1% other ablation), and 8% of women in the TCRE plus RB group had undergone hysterectomy, but none of this group had undergone further ablation. The difference could have arisen by chance. Another trial reported that 1 out of 209 women in the MEA group and 1 out of 106 women in the RB group had undergone hysterectomy after 12 months, and none required further ablation. ## Thermal balloon endometrial ablation (TBEA) Four TBEA trials reported changes in PBAC score. One trial, which compared TBEA with RB, reported that at 12 months, 73% of the TBEA and 70% of the RB group had normal bleeding levels, defined as a PBAC score of less than 100. Another trial reported that 71% of the TBEA and 79% of the RB group had normal bleeding levels at 12 months, defined by a more stringent criterion (that is, a PBAC score of less than 76). This second study reported mean PBAC scores of 41.1 in the TBEA group and 40.2 in the RB group (mean score reductions of 343.2 and 345.5, respectively). Another trial did not report actual PBAC scores, but stated that these were significantly better for the TBEA group than for the RB group at 24 months (p = 0.01), although not at 6 or 12 months. This trial measured treatment success as a post-operative PBAC score of less than 185, and 78% of women in the TBEA group and 76% of women in the TCRE group achieved this at 24 months. Results from the fourth trial were submitted to the Institute in confidence. At 24 months, between 5% and 8% of patients who had undergone TBEA, and between 9% and 15% of those who had undergone TCRE or RB, were still experiencing HMB. At 60 months, these figures were 2% for the TBEA group and 1% for the TCRE or RB group. No trial reported statistically significant differences between the groups for recurrent HMB. Amenorrhoea was reported as a clinical outcome in five TBEA trials. Amenorrhoea at 12 months was reported in between 10% and 40% of women for TBEA, and between 17% and 30% for TCRE/RB. The differences were statistically significant in only one trial (14% for TBEA versus 22% for RB, p < 0.05). At 36 months, 13% of women undergoing TBEA and 21% of women undergoing RB had amenorrhoea, and at 60 months 10% of women undergoing TBEA and 14% of those undergoing RB had amenorrhoea. These results are for ITT populations. Six TBEA trials reported patient satisfaction. Of these, five reported non-significant differences in patient satisfaction between TBEA and TCRE and/or RB groups. The proportion of women who were satisfied or very satisfied with the treatment ranged between 79% and 100% in TBEA groups, and between 54% and 100% in TCRE and/or RB groups at 12 months. The trial with the longest follow-up reported that 42% of women in the TBEA group and 44% of women in the RB group were satisfied at 60 months (ITT populations). Only one trial reported statistically significant differences between the TBEA and the TCRE and/or RB groups. In this trial, 43% of women undergoing TBEA evaluated the treatment outcome as 'excellent' at 12 months compared with 24% of women undergoing TCRE and RB. These figures were 35% and 4% respectively at 24 months. Five trials consistently reported shorter procedure times for TBEA compared with TCRE and/or RB. Of these, two studies reported the percentages of operations that took less than 30 minutes. For TBEA these percentages were 65% and 100%, and for TCRE and RB they were 24% and 53% respectively. These differences were significant in both studies (p < 0.05). The mean operating times were between 11.5 and 24 minutes in the TBEA groups compared with between 37 and 45 minutes in the TCRE and/or RB groups. The differences were statistically significant in all trials. Six trials reported the proportion of women who required further intervention. At 12 months, between 1% and 10% of women in the TBEA group required further interventions compared with between 2% and 16% in the TCRE and/or RB groups. In one trial, 5% of women undergoing TBEA and 10% of women undergoing TCRE plus RB had had an additional procedure, and these percentages rose to 6% and 15% respectively at 24 months. This difference in the repeat surgery rate was statistically significant (p < 0.01). In the trial with the longest follow-up period, repeat procedures had been done for 15 of the 76 women (19.7%) in the TBEA group (13 hysterectomies and two repeat ablations), compared with 9 of 71 women (12.7%) in the RB group (seven hysterectomies, two repeat ablations, and one dilatation and curettage) at 60 months. # Cost effectiveness Only one published study was identified. Three economic analyses were made available to the Institute as part of manufacturers' submissions, and the Assessment Group developed its own model. The published study compared the costs of vaginal hysterectomy, TBEA and RB in 147 women in France. The total costs for each treatment group were calculated 24–36 months after the surgery, taking into account the subsequent resource use only (for example, re-interventions). The total costs were estimated to be around £3670 for vaginal hysterectomy, £870 for TBEA and £910 for RB (€5321, €1263 and €1320 respectively, converted to pounds sterling at 2003 rates). The Microsulis model suggested that MEA is less costly and more effective than other EA techniques, and therefore is a dominant strategy. However, hysterectomy was more effective but more costly than MEA, at an incremental cost-effectiveness ratio (ICER) of around £4600 per quality-adjusted life-year (QALY). The Cavaterm model estimated that TBEA is cost saving when compared with hysterectomy or other EA techniques. Cost per treatment success was £767 for Cavaterm, £828 for Thermachoice, £865 for TCRE or RB, and £2050 for hysterectomy, based on RCT data only. The Thermachoice model, which used the cost estimates from the published French study (see Section 4.2.2), estimated that the ICERs for hysterectomy and TCRE compared with TBEA were £1197 (€1736) and £950 (€1378) respectively per additional woman with amenorrhoea, £13,648 (€19,789) and £11,552 (€16,751) per additional woman with eumenorrhoea or less, and £9748 (€14,135) and £18,379 (€26,650) per additional satisfied patient. The Assessment Group's model was a Markov model, which examined the progress of six hypothetical cohorts of women with HMB treated separately by TBEA, MEA, TCRE, TCRE and RB, RB, or hysterectomy. The model took the perspective of the NHS and calculated incremental cost utility between different treatment options over 10 years. This model concluded that the second-generation techniques (MEA and TBEA) are more cost effective than the first-generation techniques (TCRE and/or RB). Although base-case analysis showed that TBEA dominated MEA (in other words TBEA was less costly and more effective than MEA), the overall differences in costs and utilities were negligible, and moreover the results were sensitive to small changes in utility values. Both TBEA and MEA were dominated by hysterectomy; however the model did not take into account either patient preference or suitability. The ICER of hysterectomy versus second-generation EA techniques was around £2000 per QALY in the base-case analysis. # Consideration of the evidence The Committee reviewed the data available on the clinical and cost effectiveness of TBEA and MEA, having considered evidence on the nature of the condition and the value placed on the benefits of these treatments from women with HMB, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources. Based on the available evidence on the effectiveness of TBEA and MEA, the Committee concluded that TBEA and MEA are likely to be as effective as first-generation EA techniques in terms of reducing abnormal menstrual bleeding patterns in women with HMB. However, the Committee considered that there was not sufficient evidence to differentiate between TBEA and MEA in terms of their overall effectiveness when all potential outcomes were considered jointly. The Committee took into account the potentially less invasive nature of the second-generation techniques and the possibility that they could be performed under local anaesthesia as outpatient procedures. The Committee was also mindful of the potential advantages of delivering these treatments (TBEA and MEA) under local anaesthesia and in an outpatient setting. However they heard from consultees that the application of EA techniques other than under general anaesthesia was by no means universal in the NHS. Having reviewed the economic models submitted to the Institute, the Committee concluded that TBEA and MEA are cost-effective treatment alternatives for HMB. However, the Committee concluded that in the absence of reliable effectiveness data (particularly from head-to-head trials), it was not possible to draw conclusions on the relative clinical and cost effectiveness of TBEA and MEA. Additionally, the Committee was persuaded that the relative merits of these techniques varied greatly for individual patients, and was highly dependent on the specific outcome that was appropriate for any particular patient. The Committee therefore considered that the issue of choice for the individual rendered differences in overall effectiveness between the techniques less relevant. It concluded that these techniques may separately be appropriate for specific subgroups of women, and the choice between them should be made by the woman and the clinician responsible for her treatment, following informed discussion. Having consulted with experts, the Committee concluded that the continued availability of first-generation EA techniques is important because for some women with HMB these techniques may remain the most appropriate options. The NHS should consider locally how it will ensure that both second-generation techniques are available, in order to facilitate appropriate choices for individual patients. The Committee accepted that hysterectomy is the only option that can guarantee amenorrhoea, but considered that it should not be offered to patients by default, even when the desired outcome is the complete cessation of menstruation. The potential risks and benefits of all available options should be clearly explained to the individual. The patient and the clinician responsible for treatment should make the decision jointly.# Recommendations for further research Further good-quality studies are needed in the following areas. To investigate the comparative clinical and cost effectiveness of TBEA and MEA, preferably in head-to-head RCTs. To investigate the clinical and cost effectiveness of second-generation EA techniques compared with levonorgestrel-releasing intrauterine systems.# Implications for the NHS The impact of second-generation EA techniques on the NHS budget will depend on the number of women eligible for each technique and the uptake rates, which will be greatly influenced by the preferences of patients and clinicians. It is estimated that around 26,000 hysterectomies are performed in the UK each year for HMB and a further 16,000 EAs are carried out, of which about 2000 are performed using second-generation techniques. The Assessment Group estimated that if all hysterectomies were replaced by EA, the annual cost saving would be of the order of £29 million, assuming half of the procedures were replaced by firstgeneration techniques, and the remaining half were split between TBEA and MEA. Under a hypothetical scenario of all hysterectomies being replaced by second-generation EA techniques, the cost saving would be more than £32 million per annum. However, these figures represent ceilings of the potential cost savings, and it is highly unlikely that all hysterectomies for HMB will be replaced by EA, because hysterectomy will remain the most appropriate option for some women. Also, it is unlikely that such savings would be realised in financial terms for two reasons: the estimates represent amounts of resources that would remain within the system (but might nevertheless be redeployed); and the estimates are based on average costs (for example, of days in hospital avoided), some of which are fixed and therefore would not be saved, but could be available for other purposes.# Related guidance The Institute has issued the following related guidance. National Institute for Clinical Excellence (2003) Balloon thermal endometrial ablation.NICE Interventional Procedures Guidance No. 6. National Institute for Clinical Excellence (2003) Microwave endometrial ablation.NICE Interventional Procedures Guidance No. 7. National Institute for Clinical Excellence (2004) Free fluid thermal endometrial ablation.NICE Interventional Procedures Guidance No. 51.# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. The guidance on this technology will be reviewed in April 2007. Andrew DillonChief ExecutiveApril 2004# Appendix C. Detail on criteria for audit of the use of fluid-filled thermal balloon and microwave endometrial ablation techniques for heavy menstrual bleeding # Possible objectives for an audit An audit on the treatment of women with heavy menstrual bleeding (HMB) could be carried out to ensure the following, when surgery is considered appropriate for the management of the condition Thermal balloon endometrial ablation (TBEA) and microwave endometrial ablation (MEA) are being offered as treatment options. Women with HMB are involved in the choice of treatment. # Possible patients to be included in the audit An audit on the treatment of women with HMB could be carried out on women referred for surgical Measures that could be used as a basis for an audit # Measures that could be used as a basis for audit The measures that could be used in an audit of TBEA and MEA are as follows. Criterion Standard Exception Definition of terms . The woman is offered TBEA and MEA as treatment options % of the women in the audit. A. The woman has contraindications for TBEA and MEA as follows: For TBEA: (1) the woman's uterine cavity is large or irregularly shaped or (2) the woman has a latex allergy (for Thermachoice) or (3) the woman has had uterine surgery that has left a scar where the uterine wall is less than 8 mm thick or (4) the woman has had a classical caesarean section. For MEA: (1) the woman has had uterine surgery that has left a scar where the uterine wall is less than 8 mm thick or (2) the woman has had a classical caesarean section Clinicians will need to agree locally on how the offer of the option of TBEA and MEA is documented for audit purposes. A large uterine cavity is > 10 cm from the internal os to the fundus for Cavaterm and > 12 cm in length for Thermachoice. 'Classical caesarean section' means that the procedure was done with a vertical midline incision in the upper segment of the uterus. . The woman and the clinician responsible for treatment decide jointly on the choice of treatment for HMB after an informed discussion of a. the woman's desired outcome of the treatment and b. the relative benefits of all the treatment options and the adverse events associated with them and c. the clinical condition, anatomical suitability and preferences of the woman. % of the women in the audit None terms Clinicians will need to agree locally on all other treatment options and the adverse events associated with them and on how an informed discussion is documented for audit purposes. The clinician responsible for treatment is ordinarily the specialist gynaecologist. For 2a, desired outcomes could be normal reduced bleeding or complete cessation of menstrual bleeding. A locally based audit on HMB also could include measures related to previous drug treatments for HMB and to appropriateness of the use of hysterectomy. # Calculation of compliance Compliance (%) with each measure described in the table above is calculated as follows. Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed x 100 Number of patients to whom the measure applies Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.# Changes after publication March 2014: implementation section updated to clarify that fluid-filled thermal balloon and microwave endometrial ablation techniques are recommended as options for treating heavy menstrual bleeding. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Fluid-filled thermal balloon endometrial ablation and microwave endometrial ablation are recommended as treatment options for women with heavy menstrual bleeding in cases where it has been decided (by the woman and the clinician responsible for her treatment) that surgical intervention is appropriate for the management of the condition.\n\nFor heavy menstrual bleeding, the choice of surgical treatment should be made jointly by the woman and the clinician responsible for treatment. The decision should be made after an informed discussion taking into account the desired outcome of the treatment (such as reduced menstrual bleeding or complete cessation of menstrual bleeding [amenorrhoea]), the relative benefits of all other treatment options and the adverse events associated with them, as well as the clinical condition, anatomical suitability and preferences of the woman.', 'Clinical need and practice': "Heavy menstrual bleeding (HMB, also known as menorrhagia) is a significant cause of morbidity in premenopausal women in England and Wales. HMB is objectively defined as menstrual blood loss of more than 80 ml/cycle, or menstrual bleeding lasting longer than 7 days, over several consecutive cycles. However, in practice, the diagnosis is based on the woman's subjective assessment of blood loss.\n\nHMB is a common disorder. It is estimated that 1 in 20 women in the UK aged 30–49 years consults her GP each year with HMB – approximately 1.5 million women in England and Wales. Referrals for menstrual disorders account for about 20% of all referrals to specialist gynaecology services, placing a significant burden on secondary healthcare services.\n\nMany women who are referred to secondary care for HMB will eventually undergo hysterectomy. More than 47,000 hysterectomies were carried out in the NHS in England in 2000–01. It is estimated that HMB was the presenting complaint in about half of these cases. Furthermore, about half of all women who have a hysterectomy for HMB are believed to have a normal uterus removed.\n\nHMB has adverse implications for quality of life. Women with HMB may have difficulties with daily activities such as work, social activities, hobbies and holidays. Many women report anxiety, depression, embarrassment and problems in their sex lives because of HMB. Anaemia is also common amongst women with HMB, and this may further impair quality of life.\n\nDiagnosis of HMB is complex and is usually based on subjective evaluation of blood loss by the affected individuals. The blood loss can be estimated using pictorial blood-loss assessment charts (PBACs); this method takes into account the number of items of sanitary wear used and the degree of staining of each item. A PBAC score greater than 100 would normally indicate HMB. Although the 'gold standard' method of measuring blood loss is the alkaline haematin technique, which requires women to collect their used sanitary wear, this technique is rarely used outside research settings.\n\nThe cause of HMB is not known in the majority of cases, in which no pelvic or organic pathology is identified. However, HMB may have structural organic causes such as fibroids, adenomyosis, polyps, infections, pre-cancerous conditions or haematological disorders.\n\nTreatment of HMB aims to reduce menstrual loss and hence to improve the quality of life of the individuals. First-line treatment is drug therapy. The most commonly used drugs are tranexamic acid (an antifibrinolytic drug), mefenamic acid (a non-steroidal anti-inflammatory drug) and combined oral contraceptives. The Royal College of Obstetricians and Gynaecologists' (RCOG) guidelines recommend that drug treatment should be given for at least three cycles before considering another treatment option. Another alternative sometimes used before surgical intervention is a levonorgestrel-releasing intrauterine system.\n\nSurgical treatment is usually offered to patients who do not respond to drug treatment. Hysterectomy (removing the uterus as a whole or in part) is the only treatment for HMB that guarantees amenorrhoea (complete cessation of menstrual periods), but it is associated with peri- and postoperative complications, including incontinence and other urinary problems, fatigue, infection, pelvic pain and sexual problems. Overall, 1 in 30 women suffers a major adverse event during or soon after the operation. Additionally, the procedure has a mortality rate of 0.4–1.1 per 1000 operations. Hysterectomy is costly and has significant resource implications because it requires general anaesthesia, long operating theatre times and a hospital stay of up to 7 days after the operation. Full recovery may take 1–3 months.\n\nFirst-generation endometrial ablation (EA) techniques were introduced almost 20 years ago as alternatives to hysterectomy. These techniques aim to reduce the menstrual bleeding by destroying (ablating) the entire thickness of the innermost layer of the uterus (the endometrium) and some of the underlying muscular layer (the myometrium) using electrical, thermal or laser energy. EA techniques do not guarantee amenorrhoea, but are less invasive and require fewer resources than hysterectomy. Preoperative medical therapy is given to suppress endometrial growth, because ablation is more likely to be successful if the endometrium is thin. All organic and structural causes of HMB should be excluded before considering EA, by any means, as a treatment option. EA techniques are not suitable for women who wish to maintain fertility.\n\nThe most widely used first-generation EA techniques are transcervical resection of endometrium (TCRE), using a loop diathermy electrode, and roller-ball ablation (RB), using an electrode with a movable ball or cylinder. All first-generation EA techniques require direct visualisation of the endometrium using a hysteroscope. The success rates of these techniques depend heavily on the skills and experience of the operator.\n\nPossible perioperative adverse effects with the firstgeneration EA techniques include electrosurgical burns, uterine perforation, haemorrhage, infection, and fluid overload (which may cause congestive cardiac failure, hypertension, haemolysis, coma and death). The incidences of complications following first-generation EA ablation techniques were reported by the MISTLETOE study (of more than 10,000 women) in England and Wales, and the Scottish Audit of Hysteroscopic Surgery (of around 1000 women). The rate of emergency hysterectomy was 6.6 per 1000 procedures in the MISTLETOE study and 2.0 per 1000 procedures in the Scottish Audit, and blunt uterine perforation was reported in 14.7 per 1000 procedures and 11.2 per 1000 procedures respectively. Combining the two audits, mortality from the first-generation EA methods was shown to be 0.26 per 1000 procedures.", 'The technologies': "Second-generation EA techniques have been introduced with the aim of providing simpler, quicker and more effective treatment options for HMB compared with first-generation EA techniques and hysterectomy. These techniques are less operator-dependent than the first-generation techniques, but they rely heavily on the devices themselves to ensure safety and efficacy. Second-generation EA techniques include fluid-filled thermal balloon EA (TBEA), radiofrequency (thermoregulated) balloon EA, hydrothermal EA, 3D bipolar radiofrequency EA, microwave EA (MEA), diode laser hyperthermy, cryoablation and photodynamic therapy. The most frequently used second-generation EA techniques in UK clinical practice, and the focus of this appraisal, are fluidfilled TBEA and MEA. These techniques do not require direct visualisation of the uterine cavity, and can be carried out under either local or general anaesthesia.\n\nTBEA destroys the inner layers of the uterus by transferring heat from heated liquid within a balloon inserted into the uterine cavity. The two devices available in the UK, Cavaterm and Thermachoice, both involve an electronic controller, a single-use latex or silicone balloon catheter housing a heating element and two thermocouples, and an umbilical cable. TBEA cannot be used on women with large or irregular uterine cavities because the balloon must be in direct contact with the uterine wall to cause ablation. Cavaterm is contraindicated for women whose uterine cavity is more than 10 cm long (from the internal os to the fundus), and Thermachoice for women whose uterine cavity is more than 12 cm long, and for those who have a latex allergy. TBEA is also contraindicated if classical caesarean section (vertical midline incision in the upper segment of the uterus) has been performed, or if other uterine surgery has left a scar where the uterine wall is less than 8 mm thick. The use of endometrial thinning agents before TBEA is not recommended.\n\nThe MEA technique uses microwaves (at a fixed frequency of 9.2 GHz) to destroy the uterine glandular lining, using a hand-held applicator (microwave probe) that is inserted into the uterine cavity. The Microsulis MEA system consists of a system console that houses a control module with an embedded computer, a microwave generator, and a power supply. Additional components are a hand-held applicator, a pneumatic footswitch, coaxial and data cables, a printer (optional), a power cord and a portable trolley.\n\nThe MEA applicator must be cleaned and sterilised before each use. MEA can be used in women whose uterine cavity is irregular in shape as a result of mild to moderate fibroids, polyps or congenital abnormalities. MEA is contraindicated if classical caesarean section (vertical midline incision in the upper segment of the uterus) has been performed, or if other uterine surgery has left a scar where the uterine wall is less than 8 mm thick. The use of endometrial thinning agents before MEA is recommended.\n\nAlthough equipment failures for MEA and TBEA were reported in early usage, the devices have been improved and these failures are now much less common. Adverse events with second-generation EA techniques include uterine infection, perforation, visceral burn, bleeding, haematometra, laceration, intra-abdominal injury and cyclical pain. Women who do not respond to initial EA may require further ablations or, eventually, hysterectomy.\n\nThe outcome of EA is dependent on selecting the most appropriate technique for the individual patients' needs.\n\nThe Cavaterm and Thermachoice control unit/generators cost £3990 and £6000 respectively, and the disposable balloon catheters cost £280 and £350. The Microsulis MEA system costs around £40,000 (with an additional £5000 per annum for the maintenance contract). However, most centres in the UK have a 'placement arrangement' with manufacturers, under which centres pay a fixed fee per treatment (about £280 per treatment with no capital cost for MEA).", 'Evidence and interpretation': "The Appraisal Committee considered evidence from a number of sources (see Appendix B).\n\n# Clinical effectiveness\n\nA total of 13 publications relating to seven trials were identified by literature searches. One of the trials compared MEA with TCRE/RB, and six compared TBEA with TCRE, with RB, or with both. Two of these trials had a non-randomised, controlled design, and the rest were randomised controlled trials (RCTs). In addition, one manufacturer provided the translation of a small trial, published in German, that compared TBEA with RB, and another unpublished RCT comparing TBEA with TCRE – this was submitted in confidence. Another manufacturer provided details of a study comparing MEA with RB that it conducted as part of its submission to the US Food and Drug Administration (FDA). In summary, 10 trials (two MEA and eight TBEA trials) were included in this review.\n\n## Microwave endometrial ablation (MEA)\n\nOne trial reported that at 12 months, 87% of women who had undergone MEA and 83% of women who had undergone RB had normal bleeding levels, defined as a PBAC score of less than 75. The difference could have arisen by chance (p = 0.359). Another trial that compared MEA with TCRE/RB reported a median bleeding score of 3 in both groups at 12 months, which fell at 24 months to 1 for the MEA group and 0 for the TCRE group. This bleeding score is the sum of the daily scores reported by the women, who were asked to grade the heaviness of their period on a fivepoint scale for each day of their period. The differences could have arisen by chance.\n\nOnly one trial, which compared MEA with TCRE/RB, reported bleeding patterns in terms of the length and severity of bleeding. Based on intention-to-treat (ITT) populations, at 12 months 6% of the MEA group and 5% of the TCRE/RB group had more than 3 days of heavy bleeding (2% MEA, 5% TCRE/RB at 24 months), and 11% of women in the MEA group required at least double their usual sanitary protection compared with 12% in the TCRE/RB group (7% MEA, 13% TCRE/RB at 24 months). The differences between the groups could have arisen by chance.\n\nAmenorrhoea was reported as a clinical outcome in two MEA trials. In one trial, amenorrhoea at 12 months was reported for a median of 40% of women undergoing MEA, compared with 40% undergoing RB. At 36 months follow-up, the median amenorrhoea rates were 47% and 41% respectively (p = 0.19). The other trial reported similar median values for amenorrhoea in ITT populations at 12 months (55% in MEA versus 46% in RB, p = 0.106).\n\nTwo MEA trials reported patient satisfaction. In one trial, 69% of both MEA and TCRE/RB groups were totally or generally satisfied at 12 months, and 74% of those undergoing MEA and 64% of those undergoing TCRE/RB were totally or generally satisfied at 24 months. The study was underpowered to detect whether this observed clinically important difference of 10% could have arisen by chance. Another trial, which compared MEA with RB, reported that 98% of women undergoing MEA were very satisfied or satisfied at 12 months compared with 99% of those undergoing RB.\n\nOne trial used the SF-36 questionnaire to examine the impact of MEA and TCRE on quality of life. Following treatment, six of the eight items improved significantly compared with baseline in the MEA group, and seven items improved significantly in the TCRE group.\n\nAlthough the duration of procedures was defined inconsistently in the trials, MEA procedures took less time than TCRE and/or RB. In one trial, the mean operating time was 11.4 minutes for MEA and 15.0 minutes for TCRE/RB (p < 0.001). The other trial reported 'anaesthesia times' of 39.3 minutes for MEA and 47.1 minutes for RB, and 'treatment times' of 3.5 minutes for MEA and 20.3 minutes for RB. These differences were all statistically significant at the p < 0.01 level.\n\nOne trial reported that 8% of women in the MEA group had undergone further ablation or hysterectomy at 12 months (6% hysterectomy, 1% TCRE and 1% other ablation), and 8% of women in the TCRE plus RB group had undergone hysterectomy, but none of this group had undergone further ablation. The difference could have arisen by chance. Another trial reported that 1 out of 209 women in the MEA group and 1 out of 106 women in the RB group had undergone hysterectomy after 12 months, and none required further ablation.\n\n## Thermal balloon endometrial ablation (TBEA)\n\nFour TBEA trials reported changes in PBAC score. One trial, which compared TBEA with RB, reported that at 12 months, 73% of the TBEA and 70% of the RB group had normal bleeding levels, defined as a PBAC score of less than 100. Another trial reported that 71% of the TBEA and 79% of the RB group had normal bleeding levels at 12 months, defined by a more stringent criterion (that is, a PBAC score of less than 76). This second study reported mean PBAC scores of 41.1 in the TBEA group and 40.2 in the RB group (mean score reductions of 343.2 and 345.5, respectively). Another trial did not report actual PBAC scores, but stated that these were significantly better for the TBEA group than for the RB group at 24 months (p = 0.01), although not at 6 or 12 months. This trial measured treatment success as a post-operative PBAC score of less than 185, and 78% of women in the TBEA group and 76% of women in the TCRE group achieved this at 24 months. Results from the fourth trial were submitted to the Institute in confidence.\n\nAt 24 months, between 5% and 8% of patients who had undergone TBEA, and between 9% and 15% of those who had undergone TCRE or RB, were still experiencing HMB. At 60 months, these figures were 2% for the TBEA group and 1% for the TCRE or RB group. No trial reported statistically significant differences between the groups for recurrent HMB.\n\nAmenorrhoea was reported as a clinical outcome in five TBEA trials. Amenorrhoea at 12 months was reported in between 10% and 40% of women for TBEA, and between 17% and 30% for TCRE/RB. The differences were statistically significant in only one trial (14% for TBEA versus 22% for RB, p < 0.05). At 36 months, 13% of women undergoing TBEA and 21% of women undergoing RB had amenorrhoea, and at 60 months 10% of women undergoing TBEA and 14% of those undergoing RB had amenorrhoea. These results are for ITT populations.\n\nSix TBEA trials reported patient satisfaction. Of these, five reported non-significant differences in patient satisfaction between TBEA and TCRE and/or RB groups. The proportion of women who were satisfied or very satisfied with the treatment ranged between 79% and 100% in TBEA groups, and between 54% and 100% in TCRE and/or RB groups at 12 months. The trial with the longest follow-up reported that 42% of women in the TBEA group and 44% of women in the RB group were satisfied at 60 months (ITT populations). Only one trial reported statistically significant differences between the TBEA and the TCRE and/or RB groups. In this trial, 43% of women undergoing TBEA evaluated the treatment outcome as 'excellent' at 12 months compared with 24% of women undergoing TCRE and RB. These figures were 35% and 4% respectively at 24 months.\n\nFive trials consistently reported shorter procedure times for TBEA compared with TCRE and/or RB. Of these, two studies reported the percentages of operations that took less than 30 minutes. For TBEA these percentages were 65% and 100%, and for TCRE and RB they were 24% and 53% respectively. These differences were significant in both studies (p < 0.05). The mean operating times were between 11.5 and 24 minutes in the TBEA groups compared with between 37 and 45 minutes in the TCRE and/or RB groups. The differences were statistically significant in all trials.\n\nSix trials reported the proportion of women who required further intervention. At 12 months, between 1% and 10% of women in the TBEA group required further interventions compared with between 2% and 16% in the TCRE and/or RB groups. In one trial, 5% of women undergoing TBEA and 10% of women undergoing TCRE plus RB had had an additional procedure, and these percentages rose to 6% and 15% respectively at 24 months. This difference in the repeat surgery rate was statistically significant (p < 0.01). In the trial with the longest follow-up period, repeat procedures had been done for 15 of the 76 women (19.7%) in the TBEA group (13 hysterectomies and two repeat ablations), compared with 9 of 71 women (12.7%) in the RB group (seven hysterectomies, two repeat ablations, and one dilatation and curettage) at 60 months.\n\n# Cost effectiveness\n\nOnly one published study was identified. Three economic analyses were made available to the Institute as part of manufacturers' submissions, and the Assessment Group developed its own model.\n\nThe published study compared the costs of vaginal hysterectomy, TBEA and RB in 147 women in France. The total costs for each treatment group were calculated 24–36 months after the surgery, taking into account the subsequent resource use only (for example, re-interventions). The total costs were estimated to be around £3670 for vaginal hysterectomy, £870 for TBEA and £910 for RB (€5321, €1263 and €1320 respectively, converted to pounds sterling at 2003 rates).\n\nThe Microsulis model suggested that MEA is less costly and more effective than other EA techniques, and therefore is a dominant strategy. However, hysterectomy was more effective but more costly than MEA, at an incremental cost-effectiveness ratio (ICER) of around £4600 per quality-adjusted life-year (QALY).\n\nThe Cavaterm model estimated that TBEA is cost saving when compared with hysterectomy or other EA techniques. Cost per treatment success was £767 for Cavaterm, £828 for Thermachoice, £865 for TCRE or RB, and £2050 for hysterectomy, based on RCT data only.\n\nThe Thermachoice model, which used the cost estimates from the published French study (see Section 4.2.2), estimated that the ICERs for hysterectomy and TCRE compared with TBEA were £1197 (€1736) and £950 (€1378) respectively per additional woman with amenorrhoea, £13,648 (€19,789) and £11,552 (€16,751) per additional woman with eumenorrhoea or less, and £9748 (€14,135) and £18,379 (€26,650) per additional satisfied patient.\n\nThe Assessment Group's model was a Markov model, which examined the progress of six hypothetical cohorts of women with HMB treated separately by TBEA, MEA, TCRE, TCRE and RB, RB, or hysterectomy. The model took the perspective of the NHS and calculated incremental cost utility between different treatment options over 10 years. This model concluded that the second-generation techniques (MEA and TBEA) are more cost effective than the first-generation techniques (TCRE and/or RB). Although base-case analysis showed that TBEA dominated MEA (in other words TBEA was less costly and more effective than MEA), the overall differences in costs and utilities were negligible, and moreover the results were sensitive to small changes in utility values. Both TBEA and MEA were dominated by hysterectomy; however the model did not take into account either patient preference or suitability. The ICER of hysterectomy versus second-generation EA techniques was around £2000 per QALY in the base-case analysis.\n\n# Consideration of the evidence\n\nThe Committee reviewed the data available on the clinical and cost effectiveness of TBEA and MEA, having considered evidence on the nature of the condition and the value placed on the benefits of these treatments from women with HMB, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.\n\nBased on the available evidence on the effectiveness of TBEA and MEA, the Committee concluded that TBEA and MEA are likely to be as effective as first-generation EA techniques in terms of reducing abnormal menstrual bleeding patterns in women with HMB. However, the Committee considered that there was not sufficient evidence to differentiate between TBEA and MEA in terms of their overall effectiveness when all potential outcomes were considered jointly.\n\nThe Committee took into account the potentially less invasive nature of the second-generation techniques and the possibility that they could be performed under local anaesthesia as outpatient procedures. The Committee was also mindful of the potential advantages of delivering these treatments (TBEA and MEA) under local anaesthesia and in an outpatient setting. However they heard from consultees that the application of EA techniques other than under general anaesthesia was by no means universal in the NHS.\n\nHaving reviewed the economic models submitted to the Institute, the Committee concluded that TBEA and MEA are cost-effective treatment alternatives for HMB. However, the Committee concluded that in the absence of reliable effectiveness data (particularly from head-to-head trials), it was not possible to draw conclusions on the relative clinical and cost effectiveness of TBEA and MEA. Additionally, the Committee was persuaded that the relative merits of these techniques varied greatly for individual patients, and was highly dependent on the specific outcome that was appropriate for any particular patient. The Committee therefore considered that the issue of choice for the individual rendered differences in overall effectiveness between the techniques less relevant. It concluded that these techniques may separately be appropriate for specific subgroups of women, and the choice between them should be made by the woman and the clinician responsible for her treatment, following informed discussion.\n\nHaving consulted with experts, the Committee concluded that the continued availability of first-generation EA techniques is important because for some women with HMB these techniques may remain the most appropriate options. The NHS should consider locally how it will ensure that both second-generation techniques are available, in order to facilitate appropriate choices for individual patients.\n\nThe Committee accepted that hysterectomy is the only option that can guarantee amenorrhoea, but considered that it should not be offered to patients by default, even when the desired outcome is the complete cessation of menstruation. The potential risks and benefits of all available options should be clearly explained to the individual. The patient and the clinician responsible for treatment should make the decision jointly.", 'Recommendations for further research': 'Further good-quality studies are needed in the following areas.\n\nTo investigate the comparative clinical and cost effectiveness of TBEA and MEA, preferably in head-to-head RCTs.\n\nTo investigate the clinical and cost effectiveness of second-generation EA techniques compared with levonorgestrel-releasing intrauterine systems.', 'Implications for the NHS': 'The impact of second-generation EA techniques on the NHS budget will depend on the number of women eligible for each technique and the uptake rates, which will be greatly influenced by the preferences of patients and clinicians.\n\nIt is estimated that around 26,000 hysterectomies are performed in the UK each year for HMB and a further 16,000 EAs are carried out, of which about 2000 are performed using second-generation techniques. The Assessment Group estimated that if all hysterectomies were replaced by EA, the annual cost saving would be of the order of £29 million, assuming half of the procedures were replaced by firstgeneration techniques, and the remaining half were split between TBEA and MEA. Under a hypothetical scenario of all hysterectomies being replaced by second-generation EA techniques, the cost saving would be more than £32 million per annum. However, these figures represent ceilings of the potential cost savings, and it is highly unlikely that all hysterectomies for HMB will be replaced by EA, because hysterectomy will remain the most appropriate option for some women. Also, it is unlikely that such savings would be realised in financial terms for two reasons: the estimates represent amounts of resources that would remain within the system (but might nevertheless be redeployed); and the estimates are based on average costs (for example, of days in hospital avoided), some of which are fixed and therefore would not be saved, but could be available for other purposes.', 'Related guidance': 'The Institute has issued the following related guidance.\n\nNational Institute for Clinical Excellence (2003) Balloon thermal endometrial ablation.NICE Interventional Procedures Guidance No. 6.\n\nNational Institute for Clinical Excellence (2003) Microwave endometrial ablation.NICE Interventional Procedures Guidance No. 7.\n\nNational Institute for Clinical Excellence (2004) Free fluid thermal endometrial ablation.NICE Interventional Procedures Guidance No. 51.', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review.\n\nThe guidance on this technology will be reviewed in April 2007.\n\nAndrew DillonChief ExecutiveApril 2004', 'Appendix C. Detail on criteria for audit of the use of fluid-filled thermal balloon and microwave endometrial ablation techniques for heavy menstrual bleeding': "# Possible objectives for an audit\n\nAn audit on the treatment of women with heavy menstrual bleeding (HMB) could be carried out to ensure the following, when surgery is considered appropriate for the management of the condition\n\nThermal balloon endometrial ablation (TBEA) and microwave endometrial ablation (MEA) are being offered as treatment options.\n\nWomen with HMB are involved in the choice of treatment.\n\n# Possible patients to be included in the audit\n\nAn audit on the treatment of women with HMB could be carried out on women referred for surgical Measures that could be used as a basis for an audit\n\n# Measures that could be used as a basis for audit\n\nThe measures that could be used in an audit of TBEA and MEA are as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. The woman is offered TBEA and MEA as treatment options\n\n% of the women in the audit.\n\nA. The woman has contraindications for TBEA and MEA as follows:\n\nFor TBEA:\n\n(1) the woman's uterine cavity is large or irregularly shaped or\n\n(2) the woman has a latex allergy (for Thermachoice) or\n\n(3) the woman has had uterine surgery that has left a scar where the uterine wall is less than 8 mm thick or (4) the woman has had a classical caesarean section.\n\nFor MEA:\n\n(1) the woman has had uterine surgery that has left a scar where the uterine wall is less than 8 mm thick or (2) the woman has had a classical caesarean section\n\nClinicians will need to agree locally on how the offer of the option of TBEA and MEA is documented for audit purposes.\n\nA large uterine cavity is > 10 cm from the internal os to the fundus for Cavaterm and > 12 cm in length for Thermachoice.\n\n'Classical caesarean section' means that the procedure was done with a vertical midline incision in the upper segment of the uterus.\n\n. The woman and the clinician responsible for treatment decide jointly on the choice of treatment for HMB after an informed discussion of\n\na. the woman's desired outcome of the treatment and\n\nb. the relative benefits of all the treatment options and the adverse events associated with them and\n\nc. the clinical condition, anatomical suitability and preferences of the woman.\n\n% of the women in the audit\n\nNone\n\nterms\n\nClinicians will need to agree locally on all other treatment options and the adverse events associated with them and on how an informed discussion is documented for audit purposes.\n\nThe clinician responsible for treatment is ordinarily the specialist gynaecologist.\n\nFor 2a, desired outcomes could be normal reduced bleeding or complete cessation of menstrual bleeding.\n\nA locally based audit on HMB also could include measures related to previous drug treatments for HMB and to appropriateness of the use of hysterectomy.\n\n# Calculation of compliance\n\nCompliance (%) with each measure described in the table above is calculated as follows.\n\nNumber of patients whose care is consistent with the criterion plus number of patients who meet any exception listed\n\n\n\nx 100\n\nNumber of patients to whom the measure applies\n\nClinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.", 'Changes after publication': 'March 2014: implementation section updated to clarify that fluid-filled thermal balloon and microwave endometrial ablation techniques are recommended as options for treating heavy menstrual bleeding. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta78	Evidence-based recommendations on fluid-filled thermal balloon and microwave endometrial ablation techniques for heavy menstrual bleeding in adults.
453f9223563e08b8f2047978d71ff70c953f4837	nice	Computed tomography-guided thermocoagulation of osteoid osteoma	Computed tomography-guided thermocoagulation of osteoid osteoma # Guidance Current evidence on the safety and efficacy of computed tomography (CT)-guided thermocoagulation of osteoid osteoma appears adequate to support its use, provided that the normal arrangements are in place for consent, audit and clinical governance.# The procedure # Indications Osteoid osteomas are benign, bone-forming tumours that occur most frequently in the legs, especially in the femur and tibia. Almost all patients have pain as a result of the tumour. Other symptoms include growth disturbances, bony deformity, scoliosis and, if located within a joint, swelling, synovitis, restricted movement and contracture. This condition may regress spontaneously, but the resolution of symptoms is unpredictable and may take months or years. Standard treatment initially focuses on pain management using non-steroidal anti-inflammatory drugs. Patients who continue to have pain or who experience other tumour-related complications are offered surgical excision. Surgery requires a hospital stay of several days and the patient cannot undertake weight-bearing activity for a substantial period of time. Aggressive resection carries the risk of postoperative fracture, infection and haematoma. In recent years several minimally invasive techniques using imaging, such as percutaneous resection and radiofrequency ablation, have been introduced in patients with osteoid osteoma in order to achieve removal or destruction of the tumour without the subsequent morbidity of standard surgical treatment. # Outline of the procedure In this procedure, the lesion is located using computed tomography (CT). Under general anaesthetic, an entry hole is created through the bone using a fine drill. A radiofrequency electrode probe is introduced into the centre of the osteoma and heated. The electrode is then removed and a CT scan is done later to assess the outcome of the procedure # Efficacy Resolution of pain was the main outcome reported in the studies. In a case series of 97 consecutive patients with a mean follow up of 41 months, 76% (74/97) of patients reported a good response after one treatment session and 92% (89/97) reported a good response after one or two sessions. In the smaller studies, resolution of symptoms was reported by 82–95% of patients at final follow up. For more details, refer to the Sources of evidence section. The Specialist Advisors considered that this was an established procedure with no concerns or uncertainties about its efficacy. One Advisor stated that the procedure was better than open surgery as there is less risk of recurrence. # Safety Few complications were observed in the studies. Five out of 239 patients (2%) experienced complications, including three who experienced superficial burns. For more details, refer to the Sources of evidence section. The Specialist Advisors noted transient pain as the most common complication of the procedure. Infection was also listed, but described as a rare adverse event. It was noted that if the tumour is in a difficult area, adjacent structures may be at risk from inappropriate positioning of the electrode, but Advisors commented that the procedure is still safer than surgery in similar situations. # Other comments Particular care is required in selecting and treating patients with osteoid osteoma in the spine because of the proximity of nerve roots and the potential risk of neurological complications. Andrew DillonChief ExecutiveMarch 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of CT-guided thermocoagulation of osteoid osteoma', May 2003. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of computed tomography (CT)-guided thermocoagulation of osteoid osteoma appears adequate to support its use, provided that the normal arrangements are in place for consent, audit and clinical governance.', 'The procedure': '# Indications\n\nOsteoid osteomas are benign, bone-forming tumours that occur most frequently in the legs, especially in the femur and tibia.\n\nAlmost all patients have pain as a result of the tumour. Other symptoms include growth disturbances, bony deformity, scoliosis and, if located within a joint, swelling, synovitis, restricted movement and contracture. This condition may regress spontaneously, but the resolution of symptoms is unpredictable and may take months or years.\n\nStandard treatment initially focuses on pain management using non-steroidal anti-inflammatory drugs. Patients who continue to have pain or who experience other tumour-related complications are offered surgical excision. Surgery requires a hospital stay of several days and the patient cannot undertake weight-bearing activity for a substantial period of time. Aggressive resection carries the risk of postoperative fracture, infection and haematoma.\n\nIn recent years several minimally invasive techniques using imaging, such as percutaneous resection and radiofrequency ablation, have been introduced in patients with osteoid osteoma in order to achieve removal or destruction of the tumour without the subsequent morbidity of standard surgical treatment.\n\n# Outline of the procedure\n\nIn this procedure, the lesion is located using computed tomography (CT). Under general anaesthetic, an entry hole is created through the bone using a fine drill. A radiofrequency electrode probe is introduced into the centre of the osteoma and heated. The electrode is then removed and a CT scan is done later to assess the outcome of the procedure\n\n# Efficacy\n\nResolution of pain was the main outcome reported in the studies. In a case series of 97 consecutive patients with a mean follow up of 41 months, 76% (74/97) of patients reported a good response after one treatment session and 92% (89/97) reported a good response after one or two sessions. In the smaller studies, resolution of symptoms was reported by 82–95% of patients at final follow up. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors considered that this was an established procedure with no concerns or uncertainties about its efficacy. One Advisor stated that the procedure was better than open surgery as there is less risk of recurrence.\n\n# Safety\n\nFew complications were observed in the studies. Five out of 239 patients (2%) experienced complications, including three who experienced superficial burns. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors noted transient pain as the most common complication of the procedure. Infection was also listed, but described as a rare adverse event. It was noted that if the tumour is in a difficult area, adjacent structures may be at risk from inappropriate positioning of the electrode, but Advisors commented that the procedure is still safer than surgery in similar situations.\n\n# Other comments\n\nParticular care is required in selecting and treating patients with osteoid osteoma in the spine because of the proximity of nerve roots and the potential risk of neurological complications.\n\nAndrew DillonChief ExecutiveMarch 2004', 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of CT-guided thermocoagulation of osteoid osteoma', May 2003.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg53
4cf495e1264c4aa680f5ecdca6b2fb9a4b8be29d	nice	Photodynamic endometrial ablation	Photodynamic endometrial ablation # Guidance Current evidence on the safety and efficacy of photodynamic endometrial ablation does not appear adequate to support the use of this procedure outside formal research. It is suitable for use only within good quality research studies approved by a research ethics committee and with explicit patient consent. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute is not undertaking further investigation at present.# The procedure # Indications Photodynamic endometrial ablation is used to treat heavy menstrual periods, also known as menorrhagia. Menorrhagia is a very common problem. Hysterectomy has been the standard treatment for women with menorrhagia who have not responded to medical therapy. Minimally invasive procedures used to destroy the lining of the uterus (the endometrium) are alternatives to hysterectomy. They include using lasers, radiofrequency waves, electrocautery, microwaves, heated saline or a heated balloon. Photodynamic endometrial ablation is one of these minimally invasive procedures. # Outline of the procedure Photodynamic endometrial ablation involves injecting a photosensitive chemical into the uterine cavity through a hysterosalpingography catheter. A probe inserted through the cervix uses a laser to activate the photosensitive chemical, which destroys the endometrium. It can often be carried out under local anaesthetic on a day-case basis. # Efficacy The evidence relating to this procedure was extremely limited and was based on one very small case series that included two women with menorrhagia and one woman with prolonged postmenopausal bleeding. For more details, refer to the Sources of evidence section. The Specialist Advisors considered photodynamic endometrial ablation to be an experimental procedure not yet ready for routine clinical use. # Safety The evidence considered by the Advisory Committee was limited – the single study offered no assessment of pain or discomfort during the operation. For more details, refer to the Sources of evidence section. The Specialist Advisors noted that the photosensitive chemical used in the procedure may cause skin photosensitivity. They commented that the evidence available was too limited to allow accurate assessment of the safety of the procedure.# Further information The Institute has issued guidance on microwave endometrial ablation, balloon thermal endometrial ablation, and free fluid thermal endometrial ablation. Fluid-filled thermal balloon and microwave endometrial ablation techniques for heavy menstrual bleeding have been appraised as part of the Institute's technology appraisal work programme. Guidance is being prepared The Institute is in the process of developing a clinical guideline on hysterectomy and alternative surgical treatments for menorrhagia and other conditions. The expected date of issue of this guideline is September 2005 . Andrew DillonChief ExecutiveMarch 2004 # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of photodynamic endometrial ablation', November 2002. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication The guidance was considered for reassessment in January 2011 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of photodynamic endometrial ablation does not appear adequate to support the use of this procedure outside formal research. It is suitable for use only within good quality research studies approved by a research ethics committee and with explicit patient consent. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute is not undertaking further investigation at present.', 'The procedure': '# Indications\n\nPhotodynamic endometrial ablation is used to treat heavy menstrual periods, also known as menorrhagia.\n\nMenorrhagia is a very common problem. Hysterectomy has been the standard treatment for women with menorrhagia who have not responded to medical therapy. Minimally invasive procedures used to destroy the lining of the uterus (the endometrium) are alternatives to hysterectomy. They include using lasers, radiofrequency waves, electrocautery, microwaves, heated saline or a heated balloon. Photodynamic endometrial ablation is one of these minimally invasive procedures.\n\n# Outline of the procedure\n\nPhotodynamic endometrial ablation involves injecting a photosensitive chemical into the uterine cavity through a hysterosalpingography catheter. A probe inserted through the cervix uses a laser to activate the photosensitive chemical, which destroys the endometrium. It can often be carried out under local anaesthetic on a day-case basis.\n\n# Efficacy\n\nThe evidence relating to this procedure was extremely limited and was based on one very small case series that included two women with menorrhagia and one woman with prolonged postmenopausal bleeding. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors considered photodynamic endometrial ablation to be an experimental procedure not yet ready for routine clinical use.\n\n# Safety\n\nThe evidence considered by the Advisory Committee was limited – the single study offered no assessment of pain or discomfort during the operation. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors noted that the photosensitive chemical used in the procedure may cause skin photosensitivity. They commented that the evidence available was too limited to allow accurate assessment of the safety of the procedure.', 'Further information': "The Institute has issued guidance on microwave endometrial ablation, balloon thermal endometrial ablation, and free fluid thermal endometrial ablation.\n\nFluid-filled thermal balloon and microwave endometrial ablation techniques for heavy menstrual bleeding have been appraised as part of the Institute's technology appraisal work programme. Guidance is being prepared [Now published as 'Fluid-filled thermal balloon and microwave endometrial ablation techniques for heavy menstrual bleeding']\n\nThe Institute is in the process of developing a clinical guideline on hysterectomy and alternative surgical treatments for menorrhagia and other conditions. The expected date of issue of this guideline is September 2005 [Now published as 'Heavy menstrual bleeding: investigation and treatment'].\n\nAndrew DillonChief ExecutiveMarch 2004\n\n# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of photodynamic endometrial ablation', November 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': 'The guidance was considered for reassessment in January 2011 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us.\n\nJanuary 2012: minor maintenance.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg47
1317e8dc411ad68c272ab8ae8411dff0b3f6e62c	nice	Radiotherapy for age-related macular degeneration	Radiotherapy for age-related macular degeneration # Guidance Current evidence shows radiotherapy for age-related macular degeneration to have little efficacy. There are also concerns about its safety. It is suitable for use only within good quality research studies approved by a research ethics committee, specifying the dose of radiation used and with explicit patient consent. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute is not undertaking further investigation at present.# The procedure # Indications Age-related macular degeneration (AMD) is characterised by damage to the central part of the retina (the macula) resulting in progressive loss of central vision. Peripheral vision is not affected so individuals retain some useful vision. The prevalence of macular degeneration increases with age. Ninety percent of people with age-related macular degeneration have dry (atrophic) macular degeneration, characterised by thinning of the macular retina. The other 10% have wet (exudative or neovascular) macular degeneration, characterised by the growth of abnormal new blood vessels in the choroid layer underneath the retina. These new vessels can leak fluid and cause scarring, which can threaten vision. The vessels can be classified using fluoroscein angiography into 'classic' if they can be seen clearly and 'occult' if they cannot. Wet macular degeneration usually occurs in people who already have dry macular degeneration. Of these two conditions, wet macular degeneration progresses more quickly and vision loss is more severe. Laser therapy is used to coagulate new vessels in wet macular degeneration. However, the procedure itself may permanently impair vision, especially if the vessels are very close to the fovea. Recurrence is common. Standard laser therapy appears to work only in people with classic neovascular macular degeneration. Other new treatments for macular degeneration include surgery to remove new vessels, macular translocation, photodynamic therapy and new drugs that suppress new vessel formation (antiangiogenic drugs). # Outline of the procedure This procedure involves the use of radiotherapy to destroy the new vessels formed in patients with wet neovascular AMD. The beam of radiotherapy is angled to avoid damage to the optic nerve and structures in the other eye. # Efficacy Three randomised controlled trials (RCTs) reported radiotherapy as having no significant benefit on visual acuity when compared with sham treatment or observation. Two RCTs found that radiotherapy reduced loss of visual acuity when compared with very low dose (effectively sham) radiation or observation only. However, the dose of radiation used varied among the studies, ranging from 2 Gy to 20 Gy. For more details, refer to the Sources of evidence section. The Specialist Advisors considered trials to have shown little or no benefit from using radiotherapy, and that any effect was likely to be modest. One Specialist Advisor also noted that all patients in the UK being treated with this procedure were enrolled in clinical trials. # Safety In the RCTs identified, the main complication reported was cataract which ranged from 2% (1/51 eyes) to 67% (28/42 eyes). Other potentially serious complications reported were: vitreous haemorrhage (1/42 eyes) and retinal detachment (1/42 eyes). For more details, refer to the Sources of evidence section. One Specialist Advisor considered the main safety concerns of this procedure to be radiation retinopathy, dry eyes and cataract. # Other comments Current evidence does not show the procedure to be efficacious. The efficacy of this procedure may be related to the dose of radiation administered, but there is insufficient evidence to support this hypothesis.# Further information The Institute has issued guidance on the use of photodynamic therapy for age-related macular degeneration and macular translocation for age-related macular degeneration (replaced by NICE interventional procedure guidance 339, 'Limited macular translocation for wet age-related macular degeneration', and interventional procedure guidance 340, 'Macular translocation with 360° retinotomy for wet age related macular degeneration') Andrew DillonChief ExecutiveMarch 2004 # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of radiotherapy for macular degeneration', December 2002. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication The guidance was considered for reassessment in January 2011 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence shows radiotherapy for age-related macular degeneration to have little efficacy. There are also concerns about its safety. It is suitable for use only within good quality research studies approved by a research ethics committee, specifying the dose of radiation used and with explicit patient consent. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute is not undertaking further investigation at present.', 'The procedure': "# Indications\n\nAge-related macular degeneration (AMD) is characterised by damage to the central part of the retina (the macula) resulting in progressive loss of central vision. Peripheral vision is not affected so individuals retain some useful vision. The prevalence of macular degeneration increases with age.\n\nNinety percent of people with age-related macular degeneration have dry (atrophic) macular degeneration, characterised by thinning of the macular retina. The other 10% have wet (exudative or neovascular) macular degeneration, characterised by the growth of abnormal new blood vessels in the choroid layer underneath the retina. These new vessels can leak fluid and cause scarring, which can threaten vision. The vessels can be classified using fluoroscein angiography into 'classic' if they can be seen clearly and 'occult' if they cannot. Wet macular degeneration usually occurs in people who already have dry macular degeneration. Of these two conditions, wet macular degeneration progresses more quickly and vision loss is more severe.\n\nLaser therapy is used to coagulate new vessels in wet macular degeneration. However, the procedure itself may permanently impair vision, especially if the vessels are very close to the fovea. Recurrence is common. Standard laser therapy appears to work only in people with classic neovascular macular degeneration.\n\nOther new treatments for macular degeneration include surgery to remove new vessels, macular translocation, photodynamic therapy and new drugs that suppress new vessel formation (antiangiogenic drugs).\n\n# Outline of the procedure\n\nThis procedure involves the use of radiotherapy to destroy the new vessels formed in patients with wet neovascular AMD. The beam of radiotherapy is angled to avoid damage to the optic nerve and structures in the other eye.\n\n# Efficacy\n\nThree randomised controlled trials (RCTs) reported radiotherapy as having no significant benefit on visual acuity when compared with sham treatment or observation. Two RCTs found that radiotherapy reduced loss of visual acuity when compared with very low dose (effectively sham) radiation or observation only. However, the dose of radiation used varied among the studies, ranging from 2 Gy to 20 Gy. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors considered trials to have shown little or no benefit from using radiotherapy, and that any effect was likely to be modest. One Specialist Advisor also noted that all patients in the UK being treated with this procedure were enrolled in clinical trials.\n\n# Safety\n\nIn the RCTs identified, the main complication reported was cataract which ranged from 2% (1/51 eyes) to 67% (28/42 eyes). Other potentially serious complications reported were: vitreous haemorrhage (1/42 eyes) and retinal detachment (1/42 eyes). For more details, refer to the Sources of evidence section.\n\nOne Specialist Advisor considered the main safety concerns of this procedure to be radiation retinopathy, dry eyes and cataract.\n\n# Other comments\n\nCurrent evidence does not show the procedure to be efficacious.\n\nThe efficacy of this procedure may be related to the dose of radiation administered, but there is insufficient evidence to support this hypothesis.", 'Further information': "The Institute has issued guidance on the use of photodynamic therapy for age-related macular degeneration and macular translocation for age-related macular degeneration (replaced by NICE interventional procedure guidance 339, 'Limited macular translocation for wet age-related macular degeneration', and interventional procedure guidance 340, 'Macular translocation with 360° retinotomy for wet age related macular degeneration')\n\nAndrew DillonChief ExecutiveMarch 2004\n\n# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of radiotherapy for macular degeneration', December 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': 'The guidance was considered for reassessment in January 2011 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us.\n\nJanuary 2012: minor maintenance.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg49
df086a858141e1670b2d4d06f429780c890e62b9	nice	Laparoscopic pyeloplasty	Laparoscopic pyeloplasty # Guidance Current evidence on the safety and efficacy of laparoscopic pyeloplasty appears adequate to support the use of this procedure, provided that the normal arrangements are in place for consent, audit and clinical governance. Clinicians undertaking this procedure should have adequate training before performing the technique. The British Association of Urological Surgeons has agreed to produce standards for training.# The procedure # Indications Pelviureteric junction (PUJ) obstruction occurs when the connection between the renal pelvis and the ureter is narrow or tight. When this occurs, urine passing from the kidney to the ureter can not drain easily and accumulates, causing enlargement of the renal pelvis (hydronephrosis). The standard intervention for PUJ obstruction is open pyeloplasty. There are several different ways to approach the kidney to perform this operation. These include a flank incision, a subcostal incision, a transabdominal approach, or an incision in the back. # Outline of the procedure The purpose of the procedure is to refashion the narrowed portion of the PUJ and attach it to the ureter in a way that allows easy drainage of urine through the ureter. This procedure has the same goal as open pyeloplasty but uses the laparoscopic approach. Laparoscopy involves making three or four small incisions through which the operation is carried out. A stent may be inserted after the operation, which is later removed. # Efficacy No randomised studies were identified. One of the non-randomised, comparative studies looking at laparoscopic pyeloplasty versus open pyeloplasty found that 41 out of 42 patients (98%) who had the laparoscopic procedure had no obstruction at follow-up, compared with 33 out of 35 patients (94%) who had the open procedure. Of the 42 patients treated laparoscopically, 26 (62%) were pain-free and 12 (29%) had a significant reduction in flank pain postoperatively. Of the 35 patients who had the open procedure, 21 (60%) were pain-free and 11 (31%) had a significant reduction in flank pain postoperatively. For more details, refer to the Sources of evidence section. The Specialist Advisors expressed no concerns about the efficacy of this procedure. One Advisor, however, commented on the lack of randomised comparisons of open versus laparoscopic procedures, and a scarcity of long-term follow-up data. # Safety Few complications were reported in the studies identified. In some comparative studies obstruction after stent removal, stent migration and pyelonephritis were reported as occasional complications, however these complications were reported at similar levels in patients having open surgery. For more details, refer to the Sources of evidence section. One Specialist Advisor considered the risks of this procedure to be similar to those expected with conventional open surgery: infection, failure to correct obstruction and bleeding. This Advisor also noted that the usual safety issues associated with laparoscopic surgery applied, as well as the effects of a prolonged procedure, and the need to convert to open surgery. # Other comments It was noted that the procedure can be lengthy. Andrew DillonChief ExecutiveMarch 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of laparoscopic pyeloplasty', November 2002. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of laparoscopic pyeloplasty appears adequate to support the use of this procedure, provided that the normal arrangements are in place for consent, audit and clinical governance.\n\nClinicians undertaking this procedure should have adequate training before performing the technique. The British Association of Urological Surgeons has agreed to produce standards for training.', 'The procedure': '# Indications\n\nPelviureteric junction (PUJ) obstruction occurs when the connection between the renal pelvis and the ureter is narrow or tight. When this occurs, urine passing from the kidney to the ureter can not drain easily and accumulates, causing enlargement of the renal pelvis (hydronephrosis).\n\nThe standard intervention for PUJ obstruction is open pyeloplasty. There are several different ways to approach the kidney to perform this operation. These include a flank incision, a subcostal incision, a transabdominal approach, or an incision in the back.\n\n# Outline of the procedure\n\nThe purpose of the procedure is to refashion the narrowed portion of the PUJ and attach it to the ureter in a way that allows easy drainage of urine through the ureter. This procedure has the same goal as open pyeloplasty but uses the laparoscopic approach. Laparoscopy involves making three or four small incisions through which the operation is carried out. A stent may be inserted after the operation, which is later removed.\n\n# Efficacy\n\nNo randomised studies were identified. One of the non-randomised, comparative studies looking at laparoscopic pyeloplasty versus open pyeloplasty found that 41 out of 42 patients (98%) who had the laparoscopic procedure had no obstruction at follow-up, compared with 33 out of 35 patients (94%) who had the open procedure. Of the 42 patients treated laparoscopically, 26 (62%) were pain-free and 12 (29%) had a significant reduction in flank pain postoperatively. Of the 35 patients who had the open procedure, 21 (60%) were pain-free and 11 (31%) had a significant reduction in flank pain postoperatively. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors expressed no concerns about the efficacy of this procedure. One Advisor, however, commented on the lack of randomised comparisons of open versus laparoscopic procedures, and a scarcity of long-term follow-up data.\n\n# Safety\n\nFew complications were reported in the studies identified. In some comparative studies obstruction after stent removal, stent migration and pyelonephritis were reported as occasional complications, however these complications were reported at similar levels in patients having open surgery. For more details, refer to the Sources of evidence section.\n\nOne Specialist Advisor considered the risks of this procedure to be similar to those expected with conventional open surgery: infection, failure to correct obstruction and bleeding. This Advisor also noted that the usual safety issues associated with laparoscopic surgery applied, as well as the effects of a prolonged procedure, and the need to convert to open surgery.\n\n# Other comments\n\nIt was noted that the procedure can be lengthy.\n\nAndrew DillonChief ExecutiveMarch 2004', 'Further information ': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of laparoscopic pyeloplasty', November 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg46
f2c74b5dc04e700cba25890c56508392fab8025b	nice	Vagus nerve stimulation for refractory epilepsy in children	Vagus nerve stimulation for refractory epilepsy in children # Guidance Current evidence on the safety and efficacy of vagus nerve stimulation for refractory epilepsy in children appears adequate to support the use of this procedure, provided that the normal arrangements are in place for consent, audit and clinical governance. The procedure should only be undertaken by specialist paediatric epilepsy teams. Almost all the current evidence on the efficacy of the procedure relates to reducing seizure frequency only. However the effect on quality of life remains uncertain. Future audit and research should include quality of life measures. Patients, carers and children should be informed about the unpredictability of benefit. Use of the Institute's information for the public is recommended.# The procedure # Indications Vagus nerve stimulation is indicated for use as an adjunctive therapy in reducing the frequency of seizures in patients who are refractory to anti-epileptic medication. This includes patients whose epileptic disorder is dominated by partial seizures (with or without secondary generalisation) or generalised seizures. # Outline of the procedure A battery-powered pulse-generating device is implanted under the skin of the upper left chest. A wire is tunnelled under the skin and connected to the left vagus nerve in the neck. The stimulation parameters (pulse width and frequency, current intensity, and on/off cycles) are programmed into the pulse generator via a programming wand. Patients or carers can give additional stimulation or temporarily inhibit stimulation. The battery lasts 8–10 years and can be replaced under local anaesthesia. A typical treatment regimen might comprise intermittent stimulation for 30 seconds every 5 minutes throughout the day and night. # Efficacy In one study of 50 children aged 12 years and younger, 23 (46%) experienced a greater than 50% reduction in seizure frequency. In a study of 28 children aged 12 years and younger, a mean reduction of 62% in seizure frequency was reported at 1 year. There was some evidence to suggest that quality of life improved following the procedure. Comparisons are difficult to make between the studies because of variations in the patient populations, the methods of outcome assessment and the reporting of outcomes. For more details, refer to the Sources of evidence section. The Specialist Advisors also noted that the procedure seemed to have some benefits in terms of mood and quality of life. # Safety The most commonly reported complications were hoarseness, sore throat and cough. In a case series of 125 children, 73 children (58%) experienced voice alteration and 48 children (38%) experienced coughing during stimulation. More serious adverse events included infection (requiring device removal) in 3% (3/100) to 6% (1/16) of patients, and breathing irregularities in 19% (3/16) of patients. For more details, refer to the Sources of evidence section. The Specialist Advisors believed that this is a safe procedure with no major complications.# Further information The Institute is in the process of developing a clinical guideline on epilepsy. The expected date of issue is June 2004 . Andrew DillonChief ExecutiveMarch 2004 # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of vagus nerve stimulation for refractory epilepsy in children', October 2002. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It has been incorporated into the NICE pathway on epilepsy, along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of vagus nerve stimulation for refractory epilepsy in children appears adequate to support the use of this procedure, provided that the normal arrangements are in place for consent, audit and clinical governance.\n\nThe procedure should only be undertaken by specialist paediatric epilepsy teams.\n\nAlmost all the current evidence on the efficacy of the procedure relates to reducing seizure frequency only. However the effect on quality of life remains uncertain. Future audit and research should include quality of life measures. Patients, carers and children should be informed about the unpredictability of benefit. Use of the Institute's information for the public is recommended.", 'The procedure': '# Indications\n\nVagus nerve stimulation is indicated for use as an adjunctive therapy in reducing the frequency of seizures in patients who are refractory to anti-epileptic medication. This includes patients whose epileptic disorder is dominated by partial seizures (with or without secondary generalisation) or generalised seizures.\n\n# Outline of the procedure\n\nA battery-powered pulse-generating device is implanted under the skin of the upper left chest. A wire is tunnelled under the skin and connected to the left vagus nerve in the neck. The stimulation parameters (pulse width and frequency, current intensity, and on/off cycles) are programmed into the pulse generator via a programming wand. Patients or carers can give additional stimulation or temporarily inhibit stimulation. The battery lasts 8–10 years and can be replaced under local anaesthesia. A typical treatment regimen might comprise intermittent stimulation for 30 seconds every 5 minutes throughout the day and night.\n\n# Efficacy\n\nIn one study of 50 children aged 12 years and younger, 23 (46%) experienced a greater than 50% reduction in seizure frequency. In a study of 28 children aged 12 years and younger, a mean reduction of 62% in seizure frequency was reported at 1 year. There was some evidence to suggest that quality of life improved following the procedure. Comparisons are difficult to make between the studies because of variations in the patient populations, the methods of outcome assessment and the reporting of outcomes. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors also noted that the procedure seemed to have some benefits in terms of mood and quality of life.\n\n# Safety\n\nThe most commonly reported complications were hoarseness, sore throat and cough. In a case series of 125 children, 73 children (58%) experienced voice alteration and 48 children (38%) experienced coughing during stimulation. More serious adverse events included infection (requiring device removal) in 3% (3/100) to 6% (1/16) of patients, and breathing irregularities in 19% (3/16) of patients. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors believed that this is a safe procedure with no major complications.', 'Further information': "The Institute is in the process of developing a clinical guideline on epilepsy. The expected date of issue is June 2004 [Now published as 'The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care'].\n\nAndrew DillonChief ExecutiveMarch 2004\n\n# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of vagus nerve stimulation for refractory epilepsy in children', October 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt has been incorporated into the NICE pathway on epilepsy, along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg50
858bf12339345e2ab04904175454450ebb798cd5	nice	Endovenous laser treatment of the long saphenous vein	Endovenous laser treatment of the long saphenous vein # Guidance Current evidence on the safety and efficacy of endovenous laser treatment of the long saphenous vein appears adequate to support the use of this procedure provided that the normal arrangements are in place for consent, audit and clinical governance. Current evidence on the efficacy of this procedure is limited to case series with up to 3 years follow-up. Clinicians are encouraged to collect longer-term follow-up data.# The procedure # Indications Varicose veins are a sign of underlying venous insufficiency and affect 20–30% of adults. Long saphenous vein insufficiency is the most common form of venous insufficiency in people presenting with symptoms. People with venous insufficiency may have symptoms of fatigue, heaviness, aching, throbbing, itching and cramps in the legs. Chronic venous insufficiency can lead to skin discolouration, inflammatory dermatitis, cutaneous infarction and ulceration in some patients. Endovenous laser treatment is a minimally invasive alternative to surgical stripping of the long saphenous vein, which is an important part of the most common operation for varicose veins. # Outline of the procedure Under ultrasound guidance and local anaesthesia, a catheter is placed into the long saphenous vein. A laser fibre is passed through it and positioned below the saphenofemoral junction. An anaesthetic agent is then injected, and the fibre is slowly withdrawn while energy from a diode laser (810 nm or 940 nm wavelength) is applied in short pulses. This is repeated along the entire length of the vein until the long saphenous vein is closed from the saphenofemoral junction to the point of access. # Efficacy The evidence for efficacy was based on five case series. In these studies, the mean follow up ranged from 1 to 17 months. Saphenous vein closure rates were between 90% and 100%. One study reported a closure rate of 93.4% in patients followed up for 2 years (113/121 veins), and in 40 patients who were followed up for 3 years, no new recurrences were reported. For more details, refer to the Sources of evidence section. Opinion varied among the Specialist Advisors as to the efficacy of the procedure. One Advisor stated that short-term results were favourable but that long-term results were still unknown. A second Advisor commented that durability of the procedure had been established, at least in the medium term, while a third Advisor felt that efficacy had not yet been established. # Safety The most common complications reported in the studies were pain and bruising. In a case series report of 423 patients, 90% (381) of patients reported feeling tightness along the limb and 24% (102) of patients experienced bruising; this resolved within 1 month after treatment. Phlebitis was also reported in between 5% (21/423) and 12% (10/85) of patients. For more details, refer to the Sources of evidence section. The Specialist Advisors listed the potential complications as sensory loss, skin burns and perforation of deep veins. One Advisor stated that endovenous laser treatment had fewer complications than standard surgical treatment, whereas another Advisor believed that the complication rate was unknown. # Other comments It was noted that although the procedure may be effective in occluding the vein, few studies have reported on patient-orientated outcomes, such as improvement in symptoms.# Further information A randomised controlled trial is currently under way. Andrew DillonChief ExecutiveMarch 2004 # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of endovenous laser treatment of the long saphenous vein', April 2003. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of endovenous laser treatment of the long saphenous vein appears adequate to support the use of this procedure provided that the normal arrangements are in place for consent, audit and clinical governance. Current evidence on the efficacy of this procedure is limited to case series with up to 3 years follow-up. Clinicians are encouraged to collect longer-term follow-up data.', 'The procedure': '# Indications\n\nVaricose veins are a sign of underlying venous insufficiency and affect 20–30% of adults. Long saphenous vein insufficiency is the most common form of venous insufficiency in people presenting with symptoms.\n\nPeople with venous insufficiency may have symptoms of fatigue, heaviness, aching, throbbing, itching and cramps in the legs. Chronic venous insufficiency can lead to skin discolouration, inflammatory dermatitis, cutaneous infarction and ulceration in some patients.\n\nEndovenous laser treatment is a minimally invasive alternative to surgical stripping of the long saphenous vein, which is an important part of the most common operation for varicose veins.\n\n# Outline of the procedure\n\nUnder ultrasound guidance and local anaesthesia, a catheter is placed into the long saphenous vein. A laser fibre is passed through it and positioned below the saphenofemoral junction. An anaesthetic agent is then injected, and the fibre is slowly withdrawn while energy from a diode laser (810 nm or 940 nm wavelength) is applied in short pulses. This is repeated along the entire length of the vein until the long saphenous vein is closed from the saphenofemoral junction to the point of access.\n\n# Efficacy\n\nThe evidence for efficacy was based on five case series. In these studies, the mean follow up ranged from 1 to 17 months. Saphenous vein closure rates were between 90% and 100%. One study reported a closure rate of 93.4% in patients followed up for 2 years (113/121 veins), and in 40 patients who were followed up for 3 years, no new recurrences were reported. For more details, refer to the Sources of evidence section.\n\nOpinion varied among the Specialist Advisors as to the efficacy of the procedure. One Advisor stated that short-term results were favourable but that long-term results were still unknown. A second Advisor commented that durability of the procedure had been established, at least in the medium term, while a third Advisor felt that efficacy had not yet been established.\n\n# Safety\n\nThe most common complications reported in the studies were pain and bruising. In a case series report of 423 patients, 90% (381) of patients reported feeling tightness along the limb and 24% (102) of patients experienced bruising; this resolved within 1 month after treatment. Phlebitis was also reported in between 5% (21/423) and 12% (10/85) of patients. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors listed the potential complications as sensory loss, skin burns and perforation of deep veins. One Advisor stated that endovenous laser treatment had fewer complications than standard surgical treatment, whereas another Advisor believed that the complication rate was unknown.\n\n# Other comments\n\nIt was noted that although the procedure may be effective in occluding the vein, few studies have reported on patient-orientated outcomes, such as improvement in symptoms.', 'Further information': "A randomised controlled trial is currently under way.\n\nAndrew DillonChief ExecutiveMarch 2004\n\n# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of endovenous laser treatment of the long saphenous vein', April 2003.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg52
2bad24c8f0296e6159c53a89bb5ec69d87b710e2	nice	Cyanoacrylate instillation for occlusion of parotid sinuses	Cyanoacrylate instillation for occlusion of parotid sinuses # Guidance Current evidence on the safety and efficacy of cyanoacrylate instillation for occlusion of parotid sinuses does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research. Clinicians wishing to undertake cyanoacrylate instillation for occlusion of parotid sinuses should take the following action. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended. Audit and review clinical outcomes of all patients having cyanoacrylate instillation for occlusion of parotid sinuses. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence.# The procedure # Indications Superficial parotid gland surgery may be complicated in about 10–15% of patients by the development of an abnormal tract (sinus) between the remnants of the parotid gland and the outer surface of the cheek. The sinus may have unwanted cosmetic effects, and may cause chronic leakage of saliva with excoriation of the cheek. Management of parotid sinuses includes watchful waiting, bandaging, radiotherapy, local denervation of the gland or excision of the deep lobe of the gland. # Outline of the procedure A solution of lipiodol and cyanoacrylate is injected via the sinus into the parotid gland, sealing the sinus. If the procedure is unsuccessful and symptoms recur, the procedure can be repeated. # Efficacy The evidence was limited to one case report. Although this demonstrated the feasibility of the technique, the report was uncontrolled and did not provide any further information about efficacy and safety. For more details, refer to the 'Sources of evidence' section. No specialist advice was provided for this procedure. The Advisors who were approached were unaware of the technique. # Safety See Section 2.3.1. No specialist advice was provided for this procedure. The Advisors who were approached were unaware of the technique. # Other comments The procedure appears to have been carried out once, on one patient, by one clinician. Anyone considering its use may wish to contact that clinician, Mr AJ Marcus of the Edgware Hospital. Andrew DillonChief ExecutiveFebruary 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedures overview for cyanoacrylate instillation for occlusion of parotid sinuses', October 2002. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication As part of NICE's work programme, the current guidance was considered for review in May 2009 but did not meet the review criteria as set out in the IP process guide. The following guidance therefore remains current. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of cyanoacrylate instillation for occlusion of parotid sinuses does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research.\n\nClinicians wishing to undertake cyanoacrylate instillation for occlusion of parotid sinuses should take the following action.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having cyanoacrylate instillation for occlusion of parotid sinuses. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence.", 'The procedure': "# Indications\n\nSuperficial parotid gland surgery may be complicated in about 10–15% of patients by the development of an abnormal tract (sinus) between the remnants of the parotid gland and the outer surface of the cheek. The sinus may have unwanted cosmetic effects, and may cause chronic leakage of saliva with excoriation of the cheek.\n\nManagement of parotid sinuses includes watchful waiting, bandaging, radiotherapy, local denervation of the gland or excision of the deep lobe of the gland.\n\n# Outline of the procedure\n\nA solution of lipiodol and cyanoacrylate is injected via the sinus into the parotid gland, sealing the sinus. If the procedure is unsuccessful and symptoms recur, the procedure can be repeated.\n\n# Efficacy\n\nThe evidence was limited to one case report. Although this demonstrated the feasibility of the technique, the report was uncontrolled and did not provide any further information about efficacy and safety. For more details, refer to the 'Sources of evidence' section.\n\nNo specialist advice was provided for this procedure. The Advisors who were approached were unaware of the technique.\n\n# Safety\n\nSee Section 2.3.1.\n\nNo specialist advice was provided for this procedure. The Advisors who were approached were unaware of the technique.\n\n# Other comments\n\nThe procedure appears to have been carried out once, on one patient, by one clinician. Anyone considering its use may wish to contact that clinician, Mr AJ Marcus of the Edgware Hospital.\n\nAndrew DillonChief ExecutiveFebruary 2004", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedures overview for cyanoacrylate instillation for occlusion of parotid sinuses', October 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': "As part of NICE's work programme, the current guidance was considered for review in May 2009 but did not meet the review criteria as set out in the IP process guide. The following guidance therefore remains current.\n\nJanuary 2012: minor maintenance.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg42
00167361ee465798b9cf0a3276449973cfe41dcd	nice	Needle fasciotomy for Dupuytren's contracture	Needle fasciotomy for Dupuytren's contracture # Guidance Current evidence on the safety and efficacy of needle fasciotomy for Dupuytren's contracture appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.# The procedure # Indications Dupuytren's contracture is a benign, slowly progressive condition of unknown origin. The disease is characterised by a thickening of the connective tissue in the palm of the hand, leading to difficulties in extending the fingers. Most individuals with Dupuytren's contracture are affected in both hands. The most commonly involved digit is the ring finger, followed by the little finger and then the middle finger. Treatment seeks to restore hand function and prevent progression, because the underlying disease will remain. Both surgical and non-surgical options exist. Data are lacking on the effectiveness of most non-surgical treatments for Dupuytren's contracture, such as vitamin E cream and ultrasonic therapy. # Outline of the procedure Needle fasciotomy is an outpatient procedure in which one or more fibrous bands (contractures) are divided using a blade or the bevel of a needle. The procedure can be performed in either the palm or the fingers. # Efficacy On the basis of the evidence, the main benefit offered by this procedure is a short-term reduction in the degree of contracture. Recurrence rate is approximately 50% at 3–5 years and seems to depend on the severity of the disease. Some data also suggest that individuals with less severe disease and/or with metacarpophalangeal joint contracture benefited most from this procedure. For more details, refer to the Sources of evidence section. One Specialist Advisor commented that although the procedure was not as efficacious in the long term as open surgery, patients experienced less morbidity and had faster recovery. # Safety Common complications reported in the studies included splitting of the skin, localised pain and nerve injuries. For more details, refer to the Sources of evidence section. The Specialist Advisors listed nerve injury, tendon injury and infection as the main complications of the procedure, with one Advisor citing a complication rate of 1% or less. # Other comments The importance of patient selection was noted and the procedure was considered particularly suitable for older patients who are unsuitable for more major surgery. It was also noted that Dupuytren's contracture tends to recur after all types of treatment, but that needle fasciotomy can be repeated. Andrew DillonChief ExecutiveFebruary 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedures overview for needle fasciotomy for Dupuytren's contracture', April 2003. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of needle fasciotomy for Dupuytren's contracture appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.", 'The procedure': "# Indications\n\nDupuytren's contracture is a benign, slowly progressive condition of unknown origin. The disease is characterised by a thickening of the connective tissue in the palm of the hand, leading to difficulties in extending the fingers.\n\nMost individuals with Dupuytren's contracture are affected in both hands. The most commonly involved digit is the ring finger, followed by the little finger and then the middle finger.\n\nTreatment seeks to restore hand function and prevent progression, because the underlying disease will remain. Both surgical and non-surgical options exist. Data are lacking on the effectiveness of most non-surgical treatments for Dupuytren's contracture, such as vitamin E cream and ultrasonic therapy.\n\n# Outline of the procedure\n\nNeedle fasciotomy is an outpatient procedure in which one or more fibrous bands (contractures) are divided using a blade or the bevel of a needle. The procedure can be performed in either the palm or the fingers.\n\n# Efficacy\n\nOn the basis of the evidence, the main benefit offered by this procedure is a short-term reduction in the degree of contracture. Recurrence rate is approximately 50% at 3–5 years and seems to depend on the severity of the disease. Some data also suggest that individuals with less severe disease and/or with metacarpophalangeal joint contracture benefited most from this procedure. For more details, refer to the Sources of evidence section.\n\nOne Specialist Advisor commented that although the procedure was not as efficacious in the long term as open surgery, patients experienced less morbidity and had faster recovery.\n\n# Safety\n\nCommon complications reported in the studies included splitting of the skin, localised pain and nerve injuries. For more details, refer to the Sources of evidence section.\n\nThe Specialist Advisors listed nerve injury, tendon injury and infection as the main complications of the procedure, with one Advisor citing a complication rate of 1% or less.\n\n# Other comments\n\nThe importance of patient selection was noted and the procedure was considered particularly suitable for older patients who are unsuitable for more major surgery.\n\nIt was also noted that Dupuytren's contracture tends to recur after all types of treatment, but that needle fasciotomy can be repeated.\n\nAndrew DillonChief ExecutiveFebruary 2004", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedures overview for needle fasciotomy for Dupuytren's contracture', April 2003.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg43
2058128928a7b32422b517c3327ac0bf2fffcf55	nice	Non-surgical reduction of the myocardial septum	Non-surgical reduction of the myocardial septum # Guidance Current evidence on the safety and efficacy of non-surgical reduction of the myocardial septum appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance. The procedure should only be performed in specialist units by clinicians who have had adequate training in the technique. The British Cardiovascular Intervention Society has agreed to produce standards for training.# The procedure # Indications Non-surgical reduction of the myocardial septum is used to treat outflow tract obstruction in patients with hypertrophic obstructive cardiomyopathy (HOCM). Patients with HOCM have abnormally thickened heart muscle, which narrows the outflow tract from the left ventricle, often causing chest pain, breathlessness, palpitations and fainting spells. There is an increased risk of sudden death from heart attacks or abnormal heart rhythms. Most patients with HOCM are treated with medication. More invasive treatments may be considered in patients who still get symptoms despite drug treatment. The standard surgical treatment is ventricular septal myotomy-myectomy, using an open surgical technique that requires cardiopulmonary bypass. # Outline of the procedure Non-surgical reduction of the myocardial septum does not require open chest surgery or cardiopulmonary bypass. It involves inserting a catheter into the femoral artery and passing it up into the heart under X-ray control. Alcohol is injected into an artery that supplies blood to the septum. This destroys a part of the muscle in the septum, which then becomes thinner. # Efficacy The studies showed that non-surgical reduction of the myocardial septum is efficacious in the short term. In three non-randomised studies, the mean reduction in gradient across the left ventricular outflow tract (LVOT) ranged from 22 mmHg to 42 mmHg, and compared favourably to the mean reduction in LVOT gradient for open surgery. The studies also reported reduced numbers of patients suffering from severe breathlessness and fainting spells after treatment. There is, however, a lack of long-term follow-up. For more details, refer to the 'Sources of evidence' section. The Specialist Advisors considered the procedure to be an established alternative to surgical relief of outflow tract obstruction in patients with HOCM. # Safety In the studies, the most commonly reported complication was the need for patients to have a pacemaker implanted permanently because of complete heart block following the procedure. In one non-randomised study of 41 patients, 9 patients (22%) required a permanent pacemaker. The same study reported one procedure-related death. For more details, refer to the 'Sources of evidence' section. The Specialist Advisors cited a 10% risk of complete heart block, requiring patients to have a permanent pacemaker implanted after having the procedure. The Advisors considered the procedure to be safe when performed by experienced operators in specialist units with an established interest in HOCM. # Other comments Skilled use of ultrasound is required to identify the blood supply to the hypertrophic myocardium, and thus control the infarct size. Appropriate patient selection is essential. Andrew DillonChief ExecutiveFebruary 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of non-surgical reduction of myocardial septum', November 2002. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of non-surgical reduction of the myocardial septum appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.\n\nThe procedure should only be performed in specialist units by clinicians who have had adequate training in the technique. The British Cardiovascular Intervention Society has agreed to produce standards for training.', 'The procedure': "# Indications\n\nNon-surgical reduction of the myocardial septum is used to treat outflow tract obstruction in patients with hypertrophic obstructive cardiomyopathy (HOCM). Patients with HOCM have abnormally thickened heart muscle, which narrows the outflow tract from the left ventricle, often causing chest pain, breathlessness, palpitations and fainting spells. There is an increased risk of sudden death from heart attacks or abnormal heart rhythms.\n\nMost patients with HOCM are treated with medication. More invasive treatments may be considered in patients who still get symptoms despite drug treatment. The standard surgical treatment is ventricular septal myotomy-myectomy, using an open surgical technique that requires cardiopulmonary bypass.\n\n# Outline of the procedure\n\nNon-surgical reduction of the myocardial septum does not require open chest surgery or cardiopulmonary bypass. It involves inserting a catheter into the femoral artery and passing it up into the heart under X-ray control. Alcohol is injected into an artery that supplies blood to the septum. This destroys a part of the muscle in the septum, which then becomes thinner.\n\n# Efficacy\n\nThe studies showed that non-surgical reduction of the myocardial septum is efficacious in the short term. In three non-randomised studies, the mean reduction in gradient across the left ventricular outflow tract (LVOT) ranged from 22 mmHg to 42 mmHg, and compared favourably to the mean reduction in LVOT gradient for open surgery. The studies also reported reduced numbers of patients suffering from severe breathlessness and fainting spells after treatment. There is, however, a lack of long-term follow-up. For more details, refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors considered the procedure to be an established alternative to surgical relief of outflow tract obstruction in patients with HOCM.\n\n# Safety\n\nIn the studies, the most commonly reported complication was the need for patients to have a pacemaker implanted permanently because of complete heart block following the procedure. In one non-randomised study of 41 patients, 9 patients (22%) required a permanent pacemaker. The same study reported one procedure-related death. For more details, refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors cited a 10% risk of complete heart block, requiring patients to have a permanent pacemaker implanted after having the procedure. The Advisors considered the procedure to be safe when performed by experienced operators in specialist units with an established interest in HOCM.\n\n# Other comments\n\nSkilled use of ultrasound is required to identify the blood supply to the hypertrophic myocardium, and thus control the infarct size.\n\nAppropriate patient selection is essential.\n\nAndrew DillonChief ExecutiveFebruary 2004", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of non-surgical reduction of myocardial septum', November 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg40
ac919d19c443971cda0d35f52280ceff85a857bf	nice	Partial left ventriculectomy (the Batista procedure)	Partial left ventriculectomy (the Batista procedure) # Guidance Current evidence on the safety and efficacy of partial left ventriculectomy (PLV) does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research. Clinicians wishing to undertake PLV should take the following action. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended. Audit and review clinical outcomes of all patients having PLV. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence. This is a radical treatment for very ill patients that should only be considered in centres where alternative treatments for severe heart failure are available.# The procedure # Indications PLV is used to treat patients with irreversible (end-stage) heart failure secondary to dilated disease, or Chagas' disease. It has also been used in some patients with ischaemic heart disease. Surgical alternatives to PLV may include coronary artery bypass grafting (CABG), cardiac transplant and left ventricular assist devices (LVAD). Ventricular volume reduction procedures include mitral valve repair (mitralannuloplasty), endoventricular circular patch plasty and left ventricular aneurysmectomy. Medical therapy includes diuretics, vasodilator therapy, beta blockers and digoxin. # Outline of the procedure Partial left ventriculectomy seeks to restore left ventricular function by reducing cardiac volume (and left ventricular wall tension) through the resection of the posterolateral wall of the left ventricle. It is often accompanied by valvuloplasty (or mitral annuloplasty) to prevent postoperative mitral regurgitation. Variations of the technique for PLV include lateral PLV, extended PLV and anterior PLV. The procedure is usually performed with the aid of cardiopulmonary bypass. In lateral PLV, an incision is made at the apex of the left ventricle and extended towards the base. A wedge-shaped portion of the left ventricle is resected, leaving the papillary muscles intact where possible. Extended PLV additionally excises the papillary muscles and the mitral valve. In anterior PLV, the area between the left anterior descending artery and the attachment of the left anterolateral papillary muscle is resected and closed as in lateral PLV. # Efficacy Studies reported 30-day survival rates of between 50% and 99%. In one non-randomised study, there was no difference in survival rates between patients undergoing this procedure and patients undergoing heart transplant at 1 year. In a case series of 62 patients, survival was 80% and 60%, and event-free survival was 49% and 26%, at 1 and 3 years, respectively, after surgery. The survival rate at 1 year was achieved with the frequent use of ventricular assist devices and transplantation as salvage therapy. For more information, refer to the 'Sources of evidence' section. All the Specialist Advisors thought that efficacy, especially long-term efficacy, was uncertain. One Advisor commented that it is difficult to establish which patients would benefit from the procedure and that there is often no improvement in myocardial function. # Safety As noted in Section 2.3.1, 30-day mortality ranged from 1% to 50%. However, it is unclear from the studies whether these deaths were the result of the procedure or were attributable to the underlying condition. Reported complications included congestive heart failure, bleeding, arrhythmias, renal failure, respiratory failure and infection. For more information, refer to the 'Sources of evidence' section. The Specialist Advisors were concerned about the high (30-day) mortality rate associated with this procedure. One Advisor listed late complications as arrhythmias, mitral regurgitation, and progressive dilation of the left ventricle. The same Advisor considered the main disadvantage of the procedure to be the need for resection of viable myocardium. # Other comments The evidence for this procedure is difficult to interpret because of: inconsistencies in patient selection the variable nature of the surgery performed inadequate information about duration and quality of life after the operation. Andrew DillonChief ExecutiveFebruary 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee described in the following document. 'Interventional procedures overview for partial left ventriculectomy', October 2002. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication As part of NICE's work programme, the current guidance was considered for review but did not meet the review criteria as set out in the IP process guide. The guidance here therefore remains current. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of partial left ventriculectomy (PLV) does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research.\n\nClinicians wishing to undertake PLV should take the following action.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having PLV. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence.\n\nThis is a radical treatment for very ill patients that should only be considered in centres where alternative treatments for severe heart failure are available.", 'The procedure': "# Indications\n\nPLV is used to treat patients with irreversible (end-stage) heart failure secondary to dilated disease, or Chagas' disease. It has also been used in some patients with ischaemic heart disease.\n\nSurgical alternatives to PLV may include coronary artery bypass grafting (CABG), cardiac transplant and left ventricular assist devices (LVAD). Ventricular volume reduction procedures include mitral valve repair (mitralannuloplasty), endoventricular circular patch plasty and left ventricular aneurysmectomy. Medical therapy includes diuretics, vasodilator therapy, beta blockers and digoxin.\n\n# Outline of the procedure\n\nPartial left ventriculectomy seeks to restore left ventricular function by reducing cardiac volume (and left ventricular wall tension) through the resection of the posterolateral wall of the left ventricle. It is often accompanied by valvuloplasty (or mitral annuloplasty) to prevent postoperative mitral regurgitation. Variations of the technique for PLV include lateral PLV, extended PLV and anterior PLV. The procedure is usually performed with the aid of cardiopulmonary bypass.\n\nIn lateral PLV, an incision is made at the apex of the left ventricle and extended towards the base. A wedge-shaped portion of the left ventricle is resected, leaving the papillary muscles intact where possible. Extended PLV additionally excises the papillary muscles and the mitral valve. In anterior PLV, the area between the left anterior descending artery and the attachment of the left anterolateral papillary muscle is resected and closed as in lateral PLV.\n\n# Efficacy\n\nStudies reported 30-day survival rates of between 50% and 99%. In one non-randomised study, there was no difference in survival rates between patients undergoing this procedure and patients undergoing heart transplant at 1 year. In a case series of 62 patients, survival was 80% and 60%, and event-free survival was 49% and 26%, at 1 and 3 years, respectively, after surgery. The survival rate at 1 year was achieved with the frequent use of ventricular assist devices and transplantation as salvage therapy. For more information, refer to the 'Sources of evidence' section.\n\nAll the Specialist Advisors thought that efficacy, especially long-term efficacy, was uncertain. One Advisor commented that it is difficult to establish which patients would benefit from the procedure and that there is often no improvement in myocardial function.\n\n# Safety\n\nAs noted in Section 2.3.1, 30-day mortality ranged from 1% to 50%. However, it is unclear from the studies whether these deaths were the result of the procedure or were attributable to the underlying condition. Reported complications included congestive heart failure, bleeding, arrhythmias, renal failure, respiratory failure and infection. For more information, refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors were concerned about the high (30-day) mortality rate associated with this procedure. One Advisor listed late complications as arrhythmias, mitral regurgitation, and progressive dilation of the left ventricle. The same Advisor considered the main disadvantage of the procedure to be the need for resection of viable myocardium.\n\n# Other comments\n\nThe evidence for this procedure is difficult to interpret because of:\n\ninconsistencies in patient selection\n\nthe variable nature of the surgery performed\n\ninadequate information about duration and quality of life after the operation.\n\nAndrew DillonChief ExecutiveFebruary 2004", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee described in the following document.\n\n'Interventional procedures overview for partial left ventriculectomy', October 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': "As part of NICE's work programme, the current guidance was considered for review but did not meet the review criteria as set out in the IP process guide. The guidance here therefore remains current.\n\nJanuary 2012: minor maintenance.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg41
7ecde7059dd5b96bc4d875d5f6d160ab09b7e22b	nice	Pre-hospital initiation of fluid replacement therapy in trauma	Pre-hospital initiation of fluid replacement therapy in trauma # Guidance This guidance covers the management of adults, children and infants with physical injuries as a result of trauma, in whom there is evidence of obvious or probable blood loss. It does not cover the management of isolated closed head injury. For the purpose of this guidance, it is assumed that basic life support and ongoing assessment of the trauma victim are taking place as appropriate. The requirement for cannulation is considered only within the context of pre-hospital intravenous fluid (IV fluid) administration. It is recommended that in the pre-hospital management of adults and older children, IV fluid should not be administered if a radial pulse can be felt (or, for penetrating torso injuries, if a central pulse can be felt). In the absence of a radial pulse (or a central pulse for penetrating torso injuries) in adults and older children, it is recommended that IV fluid should be administered in boluses of no more than 250 ml. The patient should then be reassessed, and the process repeated until a radial pulse (or central pulse for penetrating torso injuries) is palpable. The administration of IV fluid should not delay transportation to hospital, but when given in accordance with 1.2 above, consideration should be given to administration en route to hospital. It is recommended that when IV fluid is indicated in the pre-hospital setting, crystalloid solutions should be the routine choice. There is inadequate evidence on which the Institute can base recommendations on when pre-hospital use of IV fluid in young children and infants following trauma is appropriate, or on the volumes of fluid to use. However, there is a broad consensus that transfer to hospital should not be delayed by attempts to administer IV fluid. It is recommended that only healthcare professionals who have been appropriately trained in advanced life-support techniques and pre-hospital care should administer IV fluid therapy to trauma patients in the pre-hospital setting. Training programmes for healthcare professionals should incorporate the above recommendations.# Clinical need and practice The term 'trauma' is used to describe injuries caused by external force through accidents, violence or acts of self-harm. Injuries are broadly categorised by the mechanism of injury. In penetrating injuries, the skin is breached by a sharp object such as a knife or glass, causing external and potential internal bleeding, and in blunt injuries, the skin is normally unbroken and the force of the injury damages the skin or internal organs. Blunt and penetrating injuries may cause severe bleeding and subsequent reduction in blood volume (hypovolaemia), which can lead to hypovolaemic shock (circulatory failure as a result of inadequate blood volume). If uncorrected, hypovolaemia will initially lead to inadequate perfusion and oxygenation of tissues and will subsequently cause permanent damage to vital organs and multiple organ failure, which is one of the major causes of death in trauma patients. Data from the Office for National Statistics on the causes of death in England and Wales in 2000 state that 15,462 deaths were caused by injury. The Royal College of Surgeons suggests that about 14,500 fatalities arose from 545,000 trauma admissions in the UK in 1988. Department of Transport Statistics for motor vehicle crashes in England and Wales in 1998 reported that there were about 320,000 injuries involving road vehicles and around 3400 deaths. Blunt injuries account for most of the trauma in the UK – there are about 10 times as many blunt as penetrating injuries. Ambulance services across the UK differ in their composition and may comprise emergency medical technicians (EMTs) trained in basic life support (BLS), paramedics (emergency medical specialists) trained in advanced life support (ALS), or a combination of EMTs and paramedics. BLS involves establishing a clear airway, starting expired-air resuscitation in the absence of breathing, and starting external chest compression in the absence of a carotid pulse. ALS includes immediate procedures such as defibrillation, the administration of oxygen and cardioactive drugs, monitoring of the electrocardiogram, endotracheal intubation and setting up of an intravenous infusion in a large peripheral or central vein. The British Association for Immediate Care (BASICS) also provides a service of voluntary doctors who are qualified in emergency medicine and equipped to attend accident scenes. Cannulation and administration of IV fluid can be undertaken by doctors or paramedics trained in ALS and may be initiated at the accident scene, in the ambulance en route to hospital, or in the accident and emergency department. Ambulance crews are usually the first healthcare professionals to attend an accident scene, where they assess the general physiological state of the patient to determine which pre-hospital interventions are needed. The evaluation includes an assessment of the degree of blood loss and whether bleeding is controlled or uncontrolled. This involves identifying possible sites of bleeding (which may be external or internal) and assessing whether there is a radial or central pulse. Other indicators of haemorrhage in adults are tachycardia, peripheral vasoconstriction and reduced blood pressure (if more than 750 ml of blood is lost). The severity of hypovolaemic shock in adults is classified according to the volume of blood lost, from class I when it is less than 750 ml, to class IV when it is more than 2000 ml.# The technology Fluid replacement therapy (intravenous infusion of fluid) attempts to reverse the effects of hypovolaemia by increasing circulatory blood volume and blood pressure back towards normal, in order to maintain the perfusion of vital organs and to reduce the risk of death from multiple organ failure. IV fluids used in the treatment of trauma patients are regulated as medicines, and are broadly classified as crystalloids, colloids, or combination fluids consisting of hypertonic saline with either starch or dextran. Paramedics may legally administer crystalloid and colloid solutions, including succinylated modified fluid gelatine, compound sodium lactate intravenous infusion, and sodium bicarbonate and sodium chloride infusions. Crystalloids are solutions of small ionic or non-ionic particles in water (salt or small sugars such as glucose), which pass through cell membranes into different body fluid compartments but over time become eliminated from the intravascular compartment. Fluid replacement with crystalloid solutions requires three to four times the volume of fluid to produce a given expansion in the intravascular compartment. Colloid solutions contain large molecules (molecular weight > 10kDa) of albumin, gelatins, polysaccharides or starch, which are unable to cross cell membranes, and remain in the intravascular fluid compartment for much longer. Smaller infusion volumes are required for fluid replacement with colloid fluids than with crystalloids. According to manufacturers' list prices, the cost of crystalloid solutions is about £1–£1.80 per 500 ml unit, compared with about £4–£16.50 per 500 ml unit for colloid solutions, excluding VAT. The list price of HyperHAES (a combination fluid comprising hypertonic saline solution and starch) is £28 per 250 ml unit, which is higher than for other colloids. HyperHAES is intended for single-dose administration and may be followed by standard volume-replacement therapy. Costs may vary in different settings because of negotiated procurement discounts. There are two approaches to the timing of IV fluid replacement in trauma. One approach is to start IV fluid replacement in the pre-hospital setting; this may be done by paramedics or doctors trained in ALS, either at the accident scene or in the ambulance en route to hospital. Administration of IV fluid before arrival at hospital may reduce the risk of tissue and organ damage in patients with severe hypovolaemia and may improve survival. However, potential benefits from stabilising the patient before transportation should be balanced against risks associated with increased delays in reaching hospital and with the possibility that restoring the blood volume and increasing the blood pressure back towards normal may exacerbate haemorrhage. Initiation of fluid replacement en route to hospital confers any potential benefits of early fluid replacement while minimising time delays at the accident scene. The other approach is to delay IV fluid replacement until patients arrive at hospital, where they receive definitive treatment for their injuries. Fluid may be administered before, or in conjunction with, the surgical management of haemorrhage. Delaying fluid replacement minimises time delay at the accident scene. Delaying fluid replacement is also believed to reduce the risk of re-bleeding caused by the mechanical disruption of blood clots and the dilution of clotting factors, which can occur, particularly when large volumes of IV fluid are administered. The setting for the initiation of fluid replacement is the main focus of this appraisal; other issues, such as delayed hospital arrival and the efficacy of different fluid types, are subsidiary considerations. A professional Consensus Statement on pre-hospital administration of fluid in trauma patients has been developed by the Faculty of Pre-hospital Care and the Royal College of Surgeons of Edinburgh, with representation from the Faculty of Accident and Emergency Medicine, the United Kingdom Military Defence Forces, the Ambulance Service Association, BASICS, the London Helicopter Emergency Medical Service and researchers with an interest in pre-hospital care. There are also clinical guidelines, developed by the Joint Royal Colleges Ambulance Liaison Committee (JRCALC). Both of these documents recommend a cautious policy on IV fluid resuscitation. In the absence of data on the audit and monitoring of the JRCALC guidelines for IV fluid replacement in trauma, it is difficult to establish current adherence to them.# Evidence and interpretation The Appraisal Committee (Appendix A) considered evidence from a number of sources (see Appendix B). # Clinical effectiveness ## Pre-hospital or hospital IV fluid replacement The Assessment Report identified randomised controlled trials (RCTs) and systematic reviews of RCTs that compared pre-hospital IV fluid replacement with withheld (no pre-hospital) fluid. Observational studies cited in the evidence base of the Consensus Statement and JRCALC guidelines were also critically appraised. Seven studies were identified: two RCTs comparing immediate pre-hospital IV fluid replacement with delayed replacement; two RCTs comparing the use of different volumes of fluid for IV fluid replacement; two systematic reviews of RCTs of IV fluid replacement in humans and animals; and one observational study. One US trial randomised (according to day of the week) 598 trauma patients with penetrating injuries either to receive IV fluid before surgery (en route to hospital or in a trauma centre), or to have fluid withheld until surgical intervention at hospital. This was the most methodologically sound of all of the studies, with appropriate randomisation and protocol compliance, although the study population was not representative of the majority of trauma patients in the UK, who have blunt injuries. Delayed IV fluid replacement was associated with a significant improvement in mortality until discharge (70% survival compared with 62%, p = 0.04). In a UK crossover RCT of 1309 trauma patients with mainly blunt injuries, paramedics were randomised either to withhold IV fluid until arrival at hospital (delayed fluid group) or to give pre-hospital fluids to those who would normally receive them (immediate fluid group), and the paramedics were 'crossed over' to the other protocol half way through the trial. The trial reported no statistically significant differences in mortality between groups (adjusted odds ratio, 0.93; 95% confidence interval, 0.58 to 1.49). However, poor adherence to the protocol meant that only about 10% more patients in the immediate fluid group received pre-hospital fluid than in the delayed fluid group. Two US studies compared the effect of IV fluid volume administered after hospital arrival on patient mortality. The studies did not appear to take into account fluid administered before arrival. One RCT randomised 36 hypovolaemic patients to the rapid infusion system or to a conventional infusion system. The rapid infusion system administered IV fluid via one catheter, which resulted in a higher rate of fluid infusion in the first hour than conventional infusion but a lower total volume administered over 24 hours. There were no significant differences in mortality between groups (5/16 deaths with rapid infusion and 4/20 deaths with conventional infusion), but there was a trend towards fewer complications among survivors of the rapid infusion group. In the other RCT of 110 patients with uncontrolled haemorrhage, IV fluid was administered to achieve a target systolic blood pressure of 70 mmHg in the intervention group and more than 100 mmHg in the control group. Again, there were no differences in mortality between groups. However, interpretation of both studies was hindered by methodological limitations, including the absence of details of randomisation, concealment, compliance and differences in surgical interventions between groups. One systematic review of RCTs comparing immediate and delayed IV fluid replacement included the four RCTs considered above and an additional two RCTs that did not meet the inclusion criteria for this appraisal because their focus was on blood transfusion. Another systematic review of animal models of IV fluid replacement in uncontrolled haemorrhage reported an improvement in mortality associated with early replacement, but this was not statistically significant (risk ratio, 0.88; 95% confidence interval, 0.73 to 1.07). Early IV fluid replacement appeared to improve survival in severe haemorrhage but to increase the risk of death with less severe haemorrhage. It is not clear, however, whether the findings are relevant to humans. A Canadian retrospective cohort study compared the effect of administering or withholding pre-hospital IV fluid in 360 patients with matched pre-hospital injury (PHI) scores. Pre-hospital administration of IV fluid was associated with a significant increase in mortality (adjusted odds ratio, 2.33; 95% confidence interval, 1.02 to 5.28). Despite the matching of the PHI scores of the two groups, there remained important differences in terms of age, injury severity score, mechanism and anatomical location of the injury, all of which are predictors of trauma-related mortality. In summary, there was insufficient evidence to draw definitive conclusions about the effectiveness of pre-hospital or delayed IV fluid administration in trauma. Although the most methodologically sound RCT provided some evidence that in certain circumstances pre-hospital IV fluid resuscitation may be harmful, it is not clear how different subgroups would be affected. ## Advanced life support (ALS) versus basic life support (BLS) Studies that compared the effectiveness of ALS (where additional interventions including the administration of pre-hospital IV fluid may be performed) with BLS (where no pre-hospital IV fluid is administered) were considered as indirect information on the effectiveness of pre-hospital and withheld IV fluid respectively. Six studies were identified: two systematic reviews, and the four observational studies that formed the evidence base of the Consensus Statement and JRCALC guidelines. One of the systematic reviews contained just one RCT, in which 2045 trauma patients in three areas of England (covering urban, suburban and rural areas) were randomised to treatment by paramedics or EMTs. Although the study was designed as an RCT, the results were analysed as a cohort study because poor protocol compliance meant only 16 patients were successfully randomised. When data from all areas were aggregated, the study showed that attendance by paramedics was associated with a non-significant increase in mortality (adjusted odds ratio, 1.74; 95% confidence interval, 0.89 to 3.41) but there was substantial regional variation (odds ratio 3.1 in area 1 and 0.78 in area 3). The other systematic review included 13 observational studies and two reports of one RCT. Of these studies, in terms of mortality, 3/15 favoured ALS and 12/15 supported BLS (overall unadjusted odds ratio 2.92, favouring BLS). Limiting the analysis to well-designed studies produced a crude odds ratio of 1.89 (favouring BLS to a lesser extent) but as confidence intervals were not stated it is not clear whether differences in mortality were statistically significant. Four observational studies were cited in the Consensus Statement and JRCALC guidelines: two reported higher mortality in patients attended by paramedics, one favoured LS and the other found that pre-hospital time did not affect survival. The results of these studies are included in the systematic reviews above. All the studies were critically appraised and were considered to have serious methodological flaws that increased the likelihood of bias, or to have controlled inadequately for confounding factors. In summary, studies comparing ALS with BLS care of trauma patients provide insufficient evidence to demonstrate the benefit or harm of paramedic interventions. There was a trend towards poorer outcomes with ALS but it is not possible to determine whether this is due to the delay associated with ALS, or to the additional procedures themselves, or because patients who have additional procedures may be more severely injured and have a poorer prognosis. ## Intravenous infusion with different fluid types As a subsidiary issue, systematic reviews of the effectiveness of IV infusion with different fluid types in a variety of settings were assessed. Ten systematic reviews of RCTs were identified that compared different IV fluid types: four reviews were general comparisons of crystalloid and colloid solutions; the other reviews compared more specific IV fluid types (for example, isotonic crystalloid versus colloid; albumin-based colloid versus non-albumin solutions; comparisons of different classes of colloid; and hypertonic crystalloid versus isotonic crystalloid). The four systematic reviews that were general comparisons of IV fluid types showed a potential trend towards crystalloids being more effective than colloids, although making general comparisons may have obscured the effect of individual crystalloid or colloid solutions. The Assessment Report concluded that there was insufficient evidence of benefit of a particular IV fluid because of clinical heterogeneity between studies (such as case-mix, additional interventions received, resuscitation protocols, amounts of IV fluid administered, and different types of colloids and crystalloids administered) and the fact that different types of patients were combined in the meta-analyses. # Cost effectiveness The Assessment Report identified two Health Technology Assessment reports of the cost effectiveness of pre-hospital IV fluid replacement from an NHS perspective. The first study, published in 1998, assessed the cost and effectiveness of treatment of trauma patients by paramedics, compared with treatment by EMTs. The additional cost of paramedic treatment (costs associated with trauma-related ALS training, salary and additional pre-hospital interventions) was presented per paramedic crew and per call out. The average unit cost of the ALS crew at £2.44 per minute was similar to the cost of a BLS crew at £2.43 per minute. There was an increase of £3 in the call out cost of an ALS crew (average of £81.08 per ALS call out) compared with a BLS crew call out (average of £78.02), because ALS crews spent more time at the scene. The total costs (pre-hospital and hospital costs combined) were also estimated. There was a non-significant increase of £22 in the average total costs for patients attended by a paramedic-crewed ambulance (£2231 per patient, compared with £2209 per patient attended by EMTs alone). Between 20% and 30% of the cost of paramedic training and salary was attributed to trauma. However, reductions in the level of trauma-related training had little effect on the overall cost of training. The second study was conducted alongside an RCT (discussed in Section 4.1.3) in which paramedics were randomised to different resuscitation protocols (pre-hospital IV fluid versus no pre-hospital fluid) to evaluate the cost effectiveness of pre-hospital IV fluid therapy. Although there was no difference in the median ambulance call-out time of 55 minutes, there was a 2-minute increase in the mean call-out time associated with pre-hospital IV fluid replacement. Costs were presented as initial costs (ambulance costs, consumables, and accident and emergency costs) and total costs (which also included inpatient costs). The cost of pre-hospital IV fluid replacement was higher (but not significantly higher) than that of delayed fluid replacement, by £3 in the initial phase of treatment (£419 compared with £416) and by £28 overall (£2706 compared with £2678). The Assessment Report did not include an economic model because it was considered that there was insufficient evidence on the effectiveness of IV fluid replacement therapy to inform such a model, and because the additional costs associated with pre-hospital IV fluid therapy, such as consumables and paramedic training, were thought to be minor – particularly because paramedics would be required to stock IV fluid and to undergo training in cannulation and IV fluid administration for the treatment of non-trauma patient groups. Adherence to a conservative pre-hospital IV fluid policy could, however, increase ambulance efficiency to a small extent by improving response times. # Consideration of the evidence The Committee reviewed the evidence, including the views of experts, on the clinical and cost effectiveness of IV fluid administered in a pre-hospital setting. In its considerations, the Committee was mindful of the need to take account of the effective use of NHS resources. The Committee considered that there was some evidence of benefit associated with delaying the initiation of IV fluid until hospital arrival. The Committee considered the extent to which evidence from the most methodologically sound RCT, which demonstrated a benefit in delaying IV fluid resuscitation in penetrating injuries, could be generalised to blunt injuries. The Committee heard, however, that the trial was based on the administration of larger quantities of IV fluid than would now be considered appropriate, and that it was, therefore, difficult to generalise the results to current clinical practice. In the absence of high-quality evidence on effectiveness, the Committee considered that guidance should take into account professional consensus, although the Institute did not formally evaluate the Consensus Statement and JRCALC guidelines. The Committee heard from experts that it would not be clinically appropriate to withdraw the use of IV fluid in a pre-hospital setting. The experts emphasised that there was a small proportion of severely hypovolaemic trauma patients at high risk of immediate death who might benefit from pre-hospital initiation of IV fluid therapy; they explained that the aim of IV fluid in these circumstances is to prevent further circulatory collapse without attempting to restore circulating volume fully back to normal or to achieve normal physiology. The Committee considered how these patients with severe hypovolaemic shock should best be identified and treated. The Committee heard that there are a number of physiological indicators of haemorrhagic shock such as pallor, tachycardia and capillary refill time, although the most readily available physiological measure was considered to be the absence of a palpable radial pulse. The Committee understood that presence or absence of a radial pulse has been used as an approximate guide to whether the systolic blood pressure is above or below 80–90 mmHg but that this is not fully validated. The Committee concluded, therefore, that IV fluid should be administered in the pre-hospital setting only if a radial pulse (or a central pulse, in penetrating injuries of the torso) is not palpable. The Committee was persuaded that in the presence of severe hypovolaemia, which is considered to be immediately life threatening, clinical judgement as to the best course of action would be required. The experts further advised the Committee that consideration should be given to how well the haemorrhage is controlled. Haemorrhages can be described as controlled (for example, by external pressure applied to a wound), self-limiting (for example, bleeding from a closed femoral fracture), potentially uncontrolled (when the bleeding has stopped but might start again if the blood pressure increased, and the injury is at a site where applying pressure would not stop the bleeding), or uncontrolled. The Committee heard that the risks associated with administration of IV fluid are different for controlled and uncontrolled haemorrhage, and it may be difficult to distinguish between these types of haemorrhage in the pre-hospital setting. Patients with severe uncontrolled bleeding with circulatory collapse are at risk of immediate cardiac arrest and death from extreme hypovolaemia/exsanguination. But the experts also highlighted that in patients with uncontrolled or potentially uncontrolled bleeding, vigorous fluid therapy may exacerbate bleeding by diluting blood clotting factors, reducing the concentration of circulating blood platelets, and by dislodging early clots forming at the site of haemorrhage. In patients with controlled or self-limiting bleeding, the infusion of IV fluid may help to restore tissue perfusion without exacerbating bleeding. Taking these factors into account, the Committee considered that a pragmatic approach would be to withhold IV fluid if the signs of shock are not marked. If the signs of shock are more severe (as illustrated by an absent radial pulse) administering IV fluid may prevent extreme hypovolaemia with its risk of producing organ damage and cardiac arrest. The experts advised that giving small volumes in this situation (and repeating, if necessary) may keep the patient alive without unduly exacerbating the bleeding, even if the bleeding is uncontrolled or potentially uncontrolled. The Committee concluded that IV fluid should be administered according to the above criteria in boluses of no more than 250 ml and should normally be started en route to hospital to avoid delays at the scene. This agrees with the recommendations in the Consensus Statement; the revised JRCALC guidelines (due in 2004) are also expected to include this recommendation. The Committee also concluded that administration of the first bolus should be followed by reassessment and administration of further boluses until a radial pulse (or a central pulse in penetrating injuries of the torso) becomes palpable. The Committee was advised that good patient-handling techniques in pre-hospital care were essential to minimise the risk of continued haemorrhage before the administration of IV fluid. The treatment of trauma in patients with isolated closed head injury was not considered in detail by the Committee because it fell outside the remit of this appraisal. However, the Committee heard from experts that consideration should be given to trauma patients with multiple injuries in whom both haemorrhagic shock and head injury might coexist. Altered consciousness in trauma may be indicative of severe haemorrhagic shock or of head injury, and it may be difficult to distinguish between the two in the pre-hospital setting. There was concern that if IV fluid was withheld from trauma patients with multiple injuries including head injury, this might have a deleterious effect on the outcome of the head injury because of low perfusion of the brain. The Committee considered cautious administration of IV fluid (with 250 ml boluses titrated against the presence of a radial pulse, with reassessment) was appropriate for trauma patients with uncontrolled bleeding and concomitant head injury in the same way as other hypovolaemic trauma patients. Experts advised that the guidance should take into account factors – such as the patient being trapped – that might delay arrival at hospital. The Committee concluded that there was inadequate evidence on which to base recommendations on the use of IV fluid in these circumstances. It was appreciated, however, that in these circumstances, other emergency procedures would be initiated that fall outside the remit of this guidance. On the balance of the evidence on the relative effectiveness of crystalloid and colloid solutions administered in the pre-hospital setting, the Committee was persuaded that the merits of different IV fluid types should be based on cost and risk of adverse events. Crystalloid solutions are not associated with the hypersensitivity reactions seen in some patients when colloids are infused, and they are less expensive than colloid solutions. The Committee therefore considered intravenous infusion with crystalloid solutions to be the preferred option. On balance of the evidence on the relative effectiveness of different crystalloids, the Committee considered normal saline, which has the lowest cost, to be the favoured option. Consideration was given to the use of pre-hospital IV fluid in young children and infants. The Committee heard from the experts that children, particularly those younger than 8 years, should be considered as a separate group because their physiology is different and different methods are needed to assess hypovolaemic shock. The experts advised that it would not be appropriate to use the absence of a radial pulse or an increased heart rate, in isolation, as criteria to determine whether pre-hospital IV fluid should be administered. The Committee discussed in detail both the available evidence and the experts' views on the appropriate use of IV fluid in the pre-hospital setting for young children and infants. In the absence of adequate evidence and any professional consensus, the Committee considered that they were unable to make specific recommendations for this group. However, they concluded that transfer to hospital should not be delayed in order that IV fluid can be administered. The Committee considered the issue of training for those administering pre-hospital IV fluid therapy, and concluded that only healthcare professionals with appropriate training in ALS techniques and pre-hospital care should administer IV fluid therapy to trauma patients in the pre-hospital setting. The Committee noted that the information available on cost effectiveness was poor. The Committee considered the costs associated with the IV fluid used for pre-hospital administration to be minimal. It also considered that costs associated with paramedic training would be unchanged regardless of whether IV fluid is administered for trauma in a pre-hospital setting, because all paramedics should have undergone the necessary training as part of routine preparation for pre-hospital care. The Committee concluded that, although the costs associated with pre-hospital IV fluid administration were minimal, there was an opportunity cost to be considered in terms of potential improvements in response times, throughput, and overall efficiency as a result of longer call-out times when IV fluid therapy was administered.# Recommendations for further research It is strongly recommended that studies be undertaken to evaluate the appropriateness of pre-hospital IV fluid therapy, including consideration of specific patient groups, for example, young children and infants, and patients with blunt versus penetrating injuries. Assessment of different protocols for pre-hospital care is essential in order to improve understanding of the risks and benefits of the use of IV fluids in this setting. Validation studies are needed to assess the suitability of the absence of a radial pulse as an indicative marker of hypovolaemia. It is recommended that studies be undertaken to compare the efficacy of blood volume resuscitation to different blood pressures.# Implications for the NHS Estimates of the numbers of trauma patients given pre-hospital IV fluid range from 8.6 to 65 patients per 100,000 population per year. The population of England and Wales is about 57 million, so pre-hospital IV fluid is likely to be administered to between 5000 and 37000 trauma patients annually. The cost of IV fluid replacement therapy in the pre-hospital phase is primarily determined by the unit cost of the IV fluid and the cost of the ambulance crew. A small cost increase for ALS was observed in the economic studies, predominantly because more time was spent at the scene. There is also likely to be substantial regional variation in costs, according to unit costs of services across ambulance trusts. Given the absence of reliable information on the current use and cost of pre-hospital IV fluids in people with trauma, it is difficult to quantify the likely cost of implementing the recommendations in Section 1. Limiting the use of pre-hospital IV fluid in the treatment of trauma patients would be unlikely to yield monetary savings within the ambulance service, but it could save time at the accident scene. This might release resources within the ambulance service – contributing to improved response times – and lead to small improvements in overall efficiency.# Related guidance There is no related guidance for this technology.# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. The guidance on this technology will be reviewed in January 2007. Andrew DillonChief ExecutiveOctober 2003# Appendix C. Detail on criteria for audit of the use of pre-hospital initiation of fluid replacement therapy in trauma # Possible objectives for an audit An audit on pre-hospital initiation of fluid replacement therapy in people experiencing trauma could be carried out to ensure the following. Fluid replacement is used appropriately. Training programmes for people providing pre-hospital care for people experiencing trauma are consistent with the guidance. # Possible patients to be included in the audit An audit on the first objective above could be carried out on the prehospital management of adults and older children who have physical injuries as a result of trauma (excluding those with an isolated head injury), over a reasonable time period for audit, for example 3 months. The audit could exclude individuals who are trapped or, alternatively, individuals who are trapped could be added as an exception to relevant audit criteria. An audit on the second objective above could be carried out on training programmes currently being attended by ambulance staff or by other healthcare professionals who provide pre-hospital care to people experiencing trauma. # Measures that could be used as a basis for audit The measures that could be used in an audit of the use of pre-hospital initiation of fluid replacement therapy in trauma are as follows. Criterion Standard Exception Definition of terms . IV fluid is not administered if a radial pulse (or for a penetrating torso injury, a central pulse) can be felt % of adults and older children for whom a radial or central pulse can be felt None . The woman and the clinician responsible for treatment decide jointly on the choice of treatment for HMB after an informed discussion of a. the woman's desired outcome of the treatment and b. the relative benefits of all the treatment options and the adverse events associated with them and c. the clinical condition, anatomical suitability and preferences of the woman. % of adults and older children who are given IV fluid in a pre-hospital setting None Paramedics and other healthcare professionals trained in advanced life support (ALS) will need to agree locally on when solutions other than crystalloids are to be used (any exceptions to criterion 2b) . IV fluid is initiated en route to hospital % of adults and older children who are given IV fluid in a pre-hospital setting If it is not considered appropriate to move the patient. Paramedics and other healthcare professionals trained in ALS will need to agree locally the circumstances in which it is not considered appropriate to move the patient (with documentation for audit purposes) . The individual who is given IV fluid is: a. reassessed following administration of each bolus of fluid and b. given boluses only until a radialpulse (or for an individual with a penetrating torso injury, a central pulse) is felt % of adults and older children who are given IV fluid in a pre-hospital setting None Paramedics and other healthcare professionals trained in ALS will need to agree locally on what constitutes reassessment, and how reassessment is documented, for audit purposes . IV fluid is administered only by a healthcare professional who has been appropriately trained in advanced life support and pre-hospital care % of adults and older children who are given IV fluid in a pre-hospital setting None Ambulance trusts will need to agree locally on what constitutes appropriate training, for audit purposes The measure that could be used in an audit of the training programmes for people providing pre-hospital care for individuals experiencing trauma is as follows. Criterion Standard Exception Definition of terms . The training programme for healthcare professionals is consistent with measures 1–4 above % of training programmes attended by staff employed by an ambulance or hospital trust None Trusts will need to agree to include basic training as well as continuous professional development sessions, for audit purposes. # Calculation of compliance Compliance (%) with the measures for audit of pre-hospital initiation of fluid replacement therapy described above is calculated as follows. Number of adults and older children whose care is consistent with the criterion plus number of adults and older children who meet any exception listed x 100 Number of adults and older children for which the measure applies Compliance (%) with the measure for audit of training programmes described in above is calculated as follows. Number of training programmes whose content is consistent with the guidance x 100 Number of training programmes to which the measure applies Ambulance and other relevant staff should review the findings of measurement, and use their judgement to review cases in which fluids have been administered. For example, if a radial pulse is barely palpable in an individual with severe tachycardia, pallor, reduced capillary return and clouded consciousness, the team may decide that it would be appropriate to administer a small aliquot of fluid and review carefully. The team should identify if practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.# Changes after publication March 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'This guidance covers the management of adults, children and infants with physical injuries as a result of trauma, in whom there is evidence of obvious or probable blood loss. It does not cover the management of isolated closed head injury. For the purpose of this guidance, it is assumed that basic life support and ongoing assessment of the trauma victim are taking place as appropriate. The requirement for cannulation is considered only within the context of pre-hospital intravenous fluid (IV fluid) administration.\n\nIt is recommended that in the pre-hospital management of adults and older children, IV fluid should not be administered if a radial pulse can be felt (or, for penetrating torso injuries, if a central pulse can be felt).\n\nIn the absence of a radial pulse (or a central pulse for penetrating torso injuries) in adults and older children, it is recommended that IV fluid should be administered in boluses of no more than 250 ml. The patient should then be reassessed, and the process repeated until a radial pulse (or central pulse for penetrating torso injuries) is palpable.\n\nThe administration of IV fluid should not delay transportation to hospital, but when given in accordance with 1.2 above, consideration should be given to administration en route to hospital.\n\nIt is recommended that when IV fluid is indicated in the pre-hospital setting, crystalloid solutions should be the routine choice.\n\nThere is inadequate evidence on which the Institute can base recommendations on when pre-hospital use of IV fluid in young children and infants following trauma is appropriate, or on the volumes of fluid to use. However, there is a broad consensus that transfer to hospital should not be delayed by attempts to administer IV fluid.\n\nIt is recommended that only healthcare professionals who have been appropriately trained in advanced life-support techniques and pre-hospital care should administer IV fluid therapy to trauma patients in the pre-hospital setting.\n\nTraining programmes for healthcare professionals should incorporate the above recommendations.', 'Clinical need and practice': "The term 'trauma' is used to describe injuries caused by external force through accidents, violence or acts of self-harm. Injuries are broadly categorised by the mechanism of injury. In penetrating injuries, the skin is breached by a sharp object such as a knife or glass, causing external and potential internal bleeding, and in blunt injuries, the skin is normally unbroken and the force of the injury damages the skin or internal organs.\n\nBlunt and penetrating injuries may cause severe bleeding and subsequent reduction in blood volume (hypovolaemia), which can lead to hypovolaemic shock (circulatory failure as a result of inadequate blood volume). If uncorrected, hypovolaemia will initially lead to inadequate perfusion and oxygenation of tissues and will subsequently cause permanent damage to vital organs and multiple organ failure, which is one of the major causes of death in trauma patients.\n\nData from the Office for National Statistics on the causes of death in England and Wales in 2000 state that 15,462 deaths were caused by injury. The Royal College of Surgeons suggests that about 14,500 fatalities arose from 545,000 trauma admissions in the UK in 1988. Department of Transport Statistics for motor vehicle crashes in England and Wales in 1998 reported that there were about 320,000 injuries involving road vehicles and around 3400 deaths. Blunt injuries account for most of the trauma in the UK – there are about 10 times as many blunt as penetrating injuries.\n\nAmbulance services across the UK differ in their composition and may comprise emergency medical technicians (EMTs) trained in basic life support (BLS), paramedics (emergency medical specialists) trained in advanced life support (ALS), or a combination of EMTs and paramedics. BLS involves establishing a clear airway, starting expired-air resuscitation in the absence of breathing, and starting external chest compression in the absence of a carotid pulse. ALS includes immediate procedures such as defibrillation, the administration of oxygen and cardioactive drugs, monitoring of the electrocardiogram, endotracheal intubation and setting up of an intravenous infusion in a large peripheral or central vein. The British Association for Immediate Care (BASICS) also provides a service of voluntary doctors who are qualified in emergency medicine and equipped to attend accident scenes. Cannulation and administration of IV fluid can be undertaken by doctors or paramedics trained in ALS and may be initiated at the accident scene, in the ambulance en route to hospital, or in the accident and emergency department.\n\nAmbulance crews are usually the first healthcare professionals to attend an accident scene, where they assess the general physiological state of the patient to determine which pre-hospital interventions are needed. The evaluation includes an assessment of the degree of blood loss and whether bleeding is controlled or uncontrolled. This involves identifying possible sites of bleeding (which may be external or internal) and assessing whether there is a radial or central pulse. Other indicators of haemorrhage in adults are tachycardia, peripheral vasoconstriction and reduced blood pressure (if more than 750 ml of blood is lost). The severity of hypovolaemic shock in adults is classified according to the volume of blood lost, from class I when it is less than 750 ml, to class IV when it is more than 2000 ml.", 'The technology': "Fluid replacement therapy (intravenous infusion of fluid) attempts to reverse the effects of hypovolaemia by increasing circulatory blood volume and blood pressure back towards normal, in order to maintain the perfusion of vital organs and to reduce the risk of death from multiple organ failure.\n\nIV fluids used in the treatment of trauma patients are regulated as medicines, and are broadly classified as crystalloids, colloids, or combination fluids consisting of hypertonic saline with either starch or dextran. Paramedics may legally administer crystalloid and colloid solutions, including succinylated modified fluid gelatine, compound sodium lactate intravenous infusion, and sodium bicarbonate and sodium chloride infusions. Crystalloids are solutions of small ionic or non-ionic particles in water (salt or small sugars such as glucose), which pass through cell membranes into different body fluid compartments but over time become eliminated from the intravascular compartment. Fluid replacement with crystalloid solutions requires three to four times the volume of fluid to produce a given expansion in the intravascular compartment. Colloid solutions contain large molecules (molecular weight > 10kDa) of albumin, gelatins, polysaccharides or starch, which are unable to cross cell membranes, and remain in the intravascular fluid compartment for much longer. Smaller infusion volumes are required for fluid replacement with colloid fluids than with crystalloids.\n\nAccording to manufacturers' list prices, the cost of crystalloid solutions is about £1–£1.80 per 500 ml unit, compared with about £4–£16.50 per 500 ml unit for colloid solutions, excluding VAT. The list price of HyperHAES (a combination fluid comprising hypertonic saline solution and starch) is £28 per 250 ml unit, which is higher than for other colloids. HyperHAES is intended for single-dose administration and may be followed by standard volume-replacement therapy. Costs may vary in different settings because of negotiated procurement discounts.\n\nThere are two approaches to the timing of IV fluid replacement in trauma. One approach is to start IV fluid replacement in the pre-hospital setting; this may be done by paramedics or doctors trained in ALS, either at the accident scene or in the ambulance en route to hospital. Administration of IV fluid before arrival at hospital may reduce the risk of tissue and organ damage in patients with severe hypovolaemia and may improve survival. However, potential benefits from stabilising the patient before transportation should be balanced against risks associated with increased delays in reaching hospital and with the possibility that restoring the blood volume and increasing the blood pressure back towards normal may exacerbate haemorrhage. Initiation of fluid replacement en route to hospital confers any potential benefits of early fluid replacement while minimising time delays at the accident scene.\n\nThe other approach is to delay IV fluid replacement until patients arrive at hospital, where they receive definitive treatment for their injuries. Fluid may be administered before, or in conjunction with, the surgical management of haemorrhage. Delaying fluid replacement minimises time delay at the accident scene. Delaying fluid replacement is also believed to reduce the risk of re-bleeding caused by the mechanical disruption of blood clots and the dilution of clotting factors, which can occur, particularly when large volumes of IV fluid are administered.\n\nThe setting for the initiation of fluid replacement is the main focus of this appraisal; other issues, such as delayed hospital arrival and the efficacy of different fluid types, are subsidiary considerations.\n\nA professional Consensus Statement on pre-hospital administration of fluid in trauma patients has been developed by the Faculty of Pre-hospital Care and the Royal College of Surgeons of Edinburgh, with representation from the Faculty of Accident and Emergency Medicine, the United Kingdom Military Defence Forces, the Ambulance Service Association, BASICS, the London Helicopter Emergency Medical Service and researchers with an interest in pre-hospital care. There are also clinical guidelines, developed by the Joint Royal Colleges Ambulance Liaison Committee (JRCALC). Both of these documents recommend a cautious policy on IV fluid resuscitation.\n\nIn the absence of data on the audit and monitoring of the JRCALC guidelines for IV fluid replacement in trauma, it is difficult to establish current adherence to them.", 'Evidence and interpretation': "The Appraisal Committee (Appendix A) considered evidence from a number of sources (see Appendix B).\n\n# Clinical effectiveness\n\n## Pre-hospital or hospital IV fluid replacement\n\nThe Assessment Report identified randomised controlled trials (RCTs) and systematic reviews of RCTs that compared pre-hospital IV fluid replacement with withheld (no pre-hospital) fluid. Observational studies cited in the evidence base of the Consensus Statement and JRCALC guidelines were also critically appraised. Seven studies were identified: two RCTs comparing immediate pre-hospital IV fluid replacement with delayed replacement; two RCTs comparing the use of different volumes of fluid for IV fluid replacement; two systematic reviews of RCTs of IV fluid replacement in humans and animals; and one observational study.\n\nOne US trial randomised (according to day of the week) 598 trauma patients with penetrating injuries either to receive IV fluid before surgery (en route to hospital or in a trauma centre), or to have fluid withheld until surgical intervention at hospital. This was the most methodologically sound of all of the studies, with appropriate randomisation and protocol compliance, although the study population was not representative of the majority of trauma patients in the UK, who have blunt injuries. Delayed IV fluid replacement was associated with a significant improvement in mortality until discharge (70% survival compared with 62%, p = 0.04).\n\nIn a UK crossover RCT of 1309 trauma patients with mainly blunt injuries, paramedics were randomised either to withhold IV fluid until arrival at hospital (delayed fluid group) or to give pre-hospital fluids to those who would normally receive them (immediate fluid group), and the paramedics were 'crossed over' to the other protocol half way through the trial. The trial reported no statistically significant differences in mortality between groups (adjusted odds ratio, 0.93; 95% confidence interval, 0.58 to 1.49). However, poor adherence to the protocol meant that only about 10% more patients in the immediate fluid group received pre-hospital fluid than in the delayed fluid group.\n\nTwo US studies compared the effect of IV fluid volume administered after hospital arrival on patient mortality. The studies did not appear to take into account fluid administered before arrival. One RCT randomised 36 hypovolaemic patients to the rapid infusion system or to a conventional infusion system. The rapid infusion system administered IV fluid via one catheter, which resulted in a higher rate of fluid infusion in the first hour than conventional infusion but a lower total volume administered over 24 hours. There were no significant differences in mortality between groups (5/16 deaths with rapid infusion and 4/20 deaths with conventional infusion), but there was a trend towards fewer complications among survivors of the rapid infusion group. In the other RCT of 110 patients with uncontrolled haemorrhage, IV fluid was administered to achieve a target systolic blood pressure of 70 mmHg in the intervention group and more than 100 mmHg in the control group. Again, there were no differences in mortality between groups. However, interpretation of both studies was hindered by methodological limitations, including the absence of details of randomisation, concealment, compliance and differences in surgical interventions between groups.\n\nOne systematic review of RCTs comparing immediate and delayed IV fluid replacement included the four RCTs considered above and an additional two RCTs that did not meet the inclusion criteria for this appraisal because their focus was on blood transfusion.\n\nAnother systematic review of animal models of IV fluid replacement in uncontrolled haemorrhage reported an improvement in mortality associated with early replacement, but this was not statistically significant (risk ratio, 0.88; 95% confidence interval, 0.73 to 1.07). Early IV fluid replacement appeared to improve survival in severe haemorrhage but to increase the risk of death with less severe haemorrhage. It is not clear, however, whether the findings are relevant to humans.\n\nA Canadian retrospective cohort study compared the effect of administering or withholding pre-hospital IV fluid in 360 patients with matched pre-hospital injury (PHI) scores. Pre-hospital administration of IV fluid was associated with a significant increase in mortality (adjusted odds ratio, 2.33; 95% confidence interval, 1.02 to 5.28). Despite the matching of the PHI scores of the two groups, there remained important differences in terms of age, injury severity score, mechanism and anatomical location of the injury, all of which are predictors of trauma-related mortality.\n\nIn summary, there was insufficient evidence to draw definitive conclusions about the effectiveness of pre-hospital or delayed IV fluid administration in trauma. Although the most methodologically sound RCT provided some evidence that in certain circumstances pre-hospital IV fluid resuscitation may be harmful, it is not clear how different subgroups would be affected.\n\n## Advanced life support (ALS) versus basic life support (BLS)\n\nStudies that compared the effectiveness of ALS (where additional interventions including the administration of pre-hospital IV fluid may be performed) with BLS (where no pre-hospital IV fluid is administered) were considered as indirect information on the effectiveness of pre-hospital and withheld IV fluid respectively. Six studies were identified: two systematic reviews, and the four observational studies that formed the evidence base of the Consensus Statement and JRCALC guidelines.\n\nOne of the systematic reviews contained just one RCT, in which 2045 trauma patients in three areas of England (covering urban, suburban and rural areas) were randomised to treatment by paramedics or EMTs. Although the study was designed as an RCT, the results were analysed as a cohort study because poor protocol compliance meant only 16 patients were successfully randomised. When data from all areas were aggregated, the study showed that attendance by paramedics was associated with a non-significant increase in mortality (adjusted odds ratio, 1.74; 95% confidence interval, 0.89 to 3.41) but there was substantial regional variation (odds ratio 3.1 in area 1 and 0.78 in area 3).\n\nThe other systematic review included 13 observational studies and two reports of one RCT. Of these studies, in terms of mortality, 3/15 favoured ALS and 12/15 supported BLS (overall unadjusted odds ratio 2.92, favouring BLS). Limiting the analysis to well-designed studies produced a crude odds ratio of 1.89 (favouring BLS to a lesser extent) but as confidence intervals were not stated it is not clear whether differences in mortality were statistically significant.\n\nFour observational studies were cited in the Consensus Statement and JRCALC guidelines: two reported higher mortality in patients attended by paramedics, one favoured LS and the other found that pre-hospital time did not affect survival. The results of these studies are included in the systematic reviews above. All the studies were critically appraised and were considered to have serious methodological flaws that increased the likelihood of bias, or to have controlled inadequately for confounding factors.\n\nIn summary, studies comparing ALS with BLS care of trauma patients provide insufficient evidence to demonstrate the benefit or harm of paramedic interventions. There was a trend towards poorer outcomes with ALS but it is not possible to determine whether this is due to the delay associated with ALS, or to the additional procedures themselves, or because patients who have additional procedures may be more severely injured and have a poorer prognosis.\n\n## Intravenous infusion with different fluid types\n\nAs a subsidiary issue, systematic reviews of the effectiveness of IV infusion with different fluid types in a variety of settings were assessed.\n\nTen systematic reviews of RCTs were identified that compared different IV fluid types: four reviews were general comparisons of crystalloid and colloid solutions; the other reviews compared more specific IV fluid types (for example, isotonic crystalloid versus colloid; albumin-based colloid versus non-albumin solutions; comparisons of different classes of colloid; and hypertonic crystalloid [with or without dextran] versus isotonic crystalloid). The four systematic reviews that were general comparisons of IV fluid types showed a potential trend towards crystalloids being more effective than colloids, although making general comparisons may have obscured the effect of individual crystalloid or colloid solutions. The Assessment Report concluded that there was insufficient evidence of benefit of a particular IV fluid because of clinical heterogeneity between studies (such as case-mix, additional interventions received, resuscitation protocols, amounts of IV fluid administered, and different types of colloids and crystalloids administered) and the fact that different types of patients were combined in the meta-analyses.\n\n# Cost effectiveness\n\nThe Assessment Report identified two Health Technology Assessment reports of the cost effectiveness of pre-hospital IV fluid replacement from an NHS perspective.\n\nThe first study, published in 1998, assessed the cost and effectiveness of treatment of trauma patients by paramedics, compared with treatment by EMTs.\n\nThe additional cost of paramedic treatment (costs associated with trauma-related ALS training, salary and additional pre-hospital interventions) was presented per paramedic crew and per call out. The average unit cost of the ALS crew at £2.44 per minute was similar to the cost of a BLS crew at £2.43 per minute. There was an increase of £3 in the call out cost of an ALS crew (average of £81.08 per ALS call out) compared with a BLS crew call out (average of £78.02), because ALS crews spent more time at the scene. The total costs (pre-hospital and hospital costs combined) were also estimated. There was a non-significant increase of £22 in the average total costs for patients attended by a paramedic-crewed ambulance (£2231 per patient, compared with £2209 per patient attended by EMTs alone). Between 20% and 30% of the cost of paramedic training and salary was attributed to trauma. However, reductions in the level of trauma-related training had little effect on the overall cost of training.\n\nThe second study was conducted alongside an RCT (discussed in Section 4.1.3) in which paramedics were randomised to different resuscitation protocols (pre-hospital IV fluid versus no pre-hospital fluid) to evaluate the cost effectiveness of pre-hospital IV fluid therapy.\n\nAlthough there was no difference in the median ambulance call-out time of 55 minutes, there was a 2-minute increase in the mean call-out time associated with pre-hospital IV fluid replacement. Costs were presented as initial costs (ambulance costs, consumables, and accident and emergency costs) and total costs (which also included inpatient costs). The cost of pre-hospital IV fluid replacement was higher (but not significantly higher) than that of delayed fluid replacement, by £3 in the initial phase of treatment (£419 compared with £416) and by £28 overall (£2706 compared with £2678).\n\nThe Assessment Report did not include an economic model because it was considered that there was insufficient evidence on the effectiveness of IV fluid replacement therapy to inform such a model, and because the additional costs associated with pre-hospital IV fluid therapy, such as consumables and paramedic training, were thought to be minor – particularly because paramedics would be required to stock IV fluid and to undergo training in cannulation and IV fluid administration for the treatment of non-trauma patient groups. Adherence to a conservative pre-hospital IV fluid policy could, however, increase ambulance efficiency to a small extent by improving response times.\n\n# Consideration of the evidence\n\nThe Committee reviewed the evidence, including the views of experts, on the clinical and cost effectiveness of IV fluid administered in a pre-hospital setting. In its considerations, the Committee was mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee considered that there was some evidence of benefit associated with delaying the initiation of IV fluid until hospital arrival.\n\nThe Committee considered the extent to which evidence from the most methodologically sound RCT, which demonstrated a benefit in delaying IV fluid resuscitation in penetrating injuries, could be generalised to blunt injuries. The Committee heard, however, that the trial was based on the administration of larger quantities of IV fluid than would now be considered appropriate, and that it was, therefore, difficult to generalise the results to current clinical practice. In the absence of high-quality evidence on effectiveness, the Committee considered that guidance should take into account professional consensus, although the Institute did not formally evaluate the Consensus Statement and JRCALC guidelines.\n\nThe Committee heard from experts that it would not be clinically appropriate to withdraw the use of IV fluid in a pre-hospital setting. The experts emphasised that there was a small proportion of severely hypovolaemic trauma patients at high risk of immediate death who might benefit from pre-hospital initiation of IV fluid therapy; they explained that the aim of IV fluid in these circumstances is to prevent further circulatory collapse without attempting to restore circulating volume fully back to normal or to achieve normal physiology.\n\nThe Committee considered how these patients with severe hypovolaemic shock should best be identified and treated. The Committee heard that there are a number of physiological indicators of haemorrhagic shock such as pallor, tachycardia and capillary refill time, although the most readily available physiological measure was considered to be the absence of a palpable radial pulse. The Committee understood that presence or absence of a radial pulse has been used as an approximate guide to whether the systolic blood pressure is above or below 80–90 mmHg but that this is not fully validated. The Committee concluded, therefore, that IV fluid should be administered in the pre-hospital setting only if a radial pulse (or a central pulse, in penetrating injuries of the torso) is not palpable. The Committee was persuaded that in the presence of severe hypovolaemia, which is considered to be immediately life threatening, clinical judgement as to the best course of action would be required.\n\nThe experts further advised the Committee that consideration should be given to how well the haemorrhage is controlled. Haemorrhages can be described as controlled (for example, by external pressure applied to a wound), self-limiting (for example, bleeding from a closed femoral fracture), potentially uncontrolled (when the bleeding has stopped but might start again if the blood pressure increased, and the injury is at a site where applying pressure would not stop the bleeding), or uncontrolled. The Committee heard that the risks associated with administration of IV fluid are different for controlled and uncontrolled haemorrhage, and it may be difficult to distinguish between these types of haemorrhage in the pre-hospital setting. Patients with severe uncontrolled bleeding with circulatory collapse are at risk of immediate cardiac arrest and death from extreme hypovolaemia/exsanguination. But the experts also highlighted that in patients with uncontrolled or potentially uncontrolled bleeding, vigorous fluid therapy may exacerbate bleeding by diluting blood clotting factors, reducing the concentration of circulating blood platelets, and by dislodging early clots forming at the site of haemorrhage. In patients with controlled or self-limiting bleeding, the infusion of IV fluid may help to restore tissue perfusion without exacerbating bleeding.\n\nTaking these factors into account, the Committee considered that a pragmatic approach would be to withhold IV fluid if the signs of shock are not marked. If the signs of shock are more severe (as illustrated by an absent radial pulse) administering IV fluid may prevent extreme hypovolaemia with its risk of producing organ damage and cardiac arrest. The experts advised that giving small volumes in this situation (and repeating, if necessary) may keep the patient alive without unduly exacerbating the bleeding, even if the bleeding is uncontrolled or potentially uncontrolled. The Committee concluded that IV fluid should be administered according to the above criteria in boluses of no more than 250 ml and should normally be started en route to hospital to avoid delays at the scene. This agrees with the recommendations in the Consensus Statement; the revised JRCALC guidelines (due in 2004) are also expected to include this recommendation. The Committee also concluded that administration of the first bolus should be followed by reassessment and administration of further boluses until a radial pulse (or a central pulse in penetrating injuries of the torso) becomes palpable. The Committee was advised that good patient-handling techniques in pre-hospital care were essential to minimise the risk of continued haemorrhage before the administration of IV fluid.\n\nThe treatment of trauma in patients with isolated closed head injury was not considered in detail by the Committee because it fell outside the remit of this appraisal. However, the Committee heard from experts that consideration should be given to trauma patients with multiple injuries in whom both haemorrhagic shock and head injury might coexist. Altered consciousness in trauma may be indicative of severe haemorrhagic shock or of head injury, and it may be difficult to distinguish between the two in the pre-hospital setting. There was concern that if IV fluid was withheld from trauma patients with multiple injuries including head injury, this might have a deleterious effect on the outcome of the head injury because of low perfusion of the brain. The Committee considered cautious administration of IV fluid (with 250 ml boluses titrated against the presence of a radial pulse, with reassessment) was appropriate for trauma patients with uncontrolled bleeding and concomitant head injury in the same way as other hypovolaemic trauma patients.\n\nExperts advised that the guidance should take into account factors – such as the patient being trapped – that might delay arrival at hospital. The Committee concluded that there was inadequate evidence on which to base recommendations on the use of IV fluid in these circumstances. It was appreciated, however, that in these circumstances, other emergency procedures would be initiated that fall outside the remit of this guidance.\n\nOn the balance of the evidence on the relative effectiveness of crystalloid and colloid solutions administered in the pre-hospital setting, the Committee was persuaded that the merits of different IV fluid types should be based on cost and risk of adverse events. Crystalloid solutions are not associated with the hypersensitivity reactions seen in some patients when colloids are infused, and they are less expensive than colloid solutions. The Committee therefore considered intravenous infusion with crystalloid solutions to be the preferred option. On balance of the evidence on the relative effectiveness of different crystalloids, the Committee considered normal saline, which has the lowest cost, to be the favoured option.\n\nConsideration was given to the use of pre-hospital IV fluid in young children and infants. The Committee heard from the experts that children, particularly those younger than 8 years, should be considered as a separate group because their physiology is different and different methods are needed to assess hypovolaemic shock. The experts advised that it would not be appropriate to use the absence of a radial pulse or an increased heart rate, in isolation, as criteria to determine whether pre-hospital IV fluid should be administered. The Committee discussed in detail both the available evidence and the experts' views on the appropriate use of IV fluid in the pre-hospital setting for young children and infants. In the absence of adequate evidence and any professional consensus, the Committee considered that they were unable to make specific recommendations for this group. However, they concluded that transfer to hospital should not be delayed in order that IV fluid can be administered.\n\nThe Committee considered the issue of training for those administering pre-hospital IV fluid therapy, and concluded that only healthcare professionals with appropriate training in ALS techniques and pre-hospital care should administer IV fluid therapy to trauma patients in the pre-hospital setting.\n\nThe Committee noted that the information available on cost effectiveness was poor. The Committee considered the costs associated with the IV fluid used for pre-hospital administration to be minimal. It also considered that costs associated with paramedic training would be unchanged regardless of whether IV fluid is administered for trauma in a pre-hospital setting, because all paramedics should have undergone the necessary training as part of routine preparation for pre-hospital care. The Committee concluded that, although the costs associated with pre-hospital IV fluid administration were minimal, there was an opportunity cost to be considered in terms of potential improvements in response times, throughput, and overall efficiency as a result of longer call-out times when IV fluid therapy was administered.", 'Recommendations for further research': 'It is strongly recommended that studies be undertaken to evaluate the appropriateness of pre-hospital IV fluid therapy, including consideration of specific patient groups, for example, young children and infants, and patients with blunt versus penetrating injuries. Assessment of different protocols for pre-hospital care is essential in order to improve understanding of the risks and benefits of the use of IV fluids in this setting.\n\nValidation studies are needed to assess the suitability of the absence of a radial pulse as an indicative marker of hypovolaemia.\n\nIt is recommended that studies be undertaken to compare the efficacy of blood volume resuscitation to different blood pressures.', 'Implications for the NHS': 'Estimates of the numbers of trauma patients given pre-hospital IV fluid range from 8.6 to 65 patients per 100,000 population per year. The population of England and Wales is about 57 million, so pre-hospital IV fluid is likely to be administered to between 5000 and 37000 trauma patients annually.\n\nThe cost of IV fluid replacement therapy in the pre-hospital phase is primarily determined by the unit cost of the IV fluid and the cost of the ambulance crew. A small cost increase for ALS was observed in the economic studies, predominantly because more time was spent at the scene. There is also likely to be substantial regional variation in costs, according to unit costs of services across ambulance trusts.\n\nGiven the absence of reliable information on the current use and cost of pre-hospital IV fluids in people with trauma, it is difficult to quantify the likely cost of implementing the recommendations in Section 1. Limiting the use of pre-hospital IV fluid in the treatment of trauma patients would be unlikely to yield monetary savings within the ambulance service, but it could save time at the accident scene. This might release resources within the ambulance service – contributing to improved response times – and lead to small improvements in overall efficiency.', 'Related guidance': 'There is no related guidance for this technology.', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review.\n\nThe guidance on this technology will be reviewed in January 2007.\n\nAndrew DillonChief ExecutiveOctober 2003', 'Appendix C. Detail on criteria for audit of the use of pre-hospital initiation of fluid replacement therapy in trauma': "# Possible objectives for an audit\n\nAn audit on pre-hospital initiation of fluid replacement therapy in people experiencing trauma could be carried out to ensure the following.\n\nFluid replacement is used appropriately.\n\nTraining programmes for people providing pre-hospital care for people experiencing trauma are consistent with the guidance.\n\n# Possible patients to be included in the audit\n\nAn audit on the first objective above could be carried out on the prehospital management of adults and older children who have physical injuries as a result of trauma (excluding those with an isolated head injury), over a reasonable time period for audit, for example 3 months. The audit could exclude individuals who are trapped or, alternatively, individuals who are trapped could be added as an exception to relevant audit criteria. An audit on the second objective above could be carried out on training programmes currently being attended by ambulance staff or by other healthcare professionals who provide pre-hospital care to people experiencing trauma.\n\n# Measures that could be used as a basis for audit\n\nThe measures that could be used in an audit of the use of pre-hospital initiation of fluid replacement therapy in trauma are as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. IV fluid is not administered if a radial pulse (or for a penetrating torso injury, a central pulse) can be felt\n\n% of adults and older children for whom a radial or central pulse can be felt\n\nNone\n\n\n\n. The woman and the clinician responsible for treatment decide jointly on the choice of treatment for HMB after an informed discussion of\n\na. the woman's desired outcome of the treatment and\n\nb. the relative benefits of all the treatment options and the adverse events associated with them and\n\nc. the clinical condition, anatomical suitability and preferences of the woman.\n\n% of adults and older children who are given IV fluid in a pre-hospital setting\n\nNone\n\nParamedics and other healthcare professionals trained in advanced life support (ALS) will need to agree locally on when solutions other than crystalloids are to be used (any exceptions to criterion 2b)\n\n. IV fluid is initiated en route to hospital\n\n% of adults and older children who are given IV fluid in a pre-hospital setting\n\nIf it is not considered appropriate to move the patient.\n\nParamedics and other healthcare professionals trained in ALS will need to agree locally the circumstances in which it is not considered appropriate to move the patient (with documentation for audit purposes)\n\n. The individual who is given IV fluid is:\n\na. reassessed following administration of each bolus of fluid and\n\nb. given boluses only until a radialpulse (or for an individual with a penetrating torso injury, a central pulse) is felt\n\n% of adults and older children who are given IV fluid in a pre-hospital setting\n\nNone\n\nParamedics and other healthcare professionals trained in ALS will need to agree locally on what constitutes reassessment, and how reassessment is documented, for audit purposes\n\n. IV fluid is administered only by a healthcare professional who has been appropriately trained in advanced life support and pre-hospital care\n\n% of adults and older children who are given IV fluid in a pre-hospital setting\n\nNone\n\nAmbulance trusts will need to agree locally on what constitutes appropriate training, for audit purposes\n\nThe measure that could be used in an audit of the training programmes for people providing pre-hospital care for individuals experiencing trauma is as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. The training programme for healthcare professionals is consistent with measures 1–4 above\n\n% of training programmes attended by staff employed by an ambulance or hospital trust\n\nNone\n\nTrusts will need to agree to include basic training as well as continuous professional development sessions, for audit purposes.\n\n# Calculation of compliance\n\nCompliance (%) with the measures for audit of pre-hospital initiation of fluid replacement therapy described above is calculated as follows.\n\nNumber of adults and older children whose care is consistent with the criterion plus number of adults and older children who meet any exception listed\n\nx 100\n\nNumber of adults and older children for which the measure applies\n\nCompliance (%) with the measure for audit of training programmes described in above is calculated as follows.\n\nNumber of training programmes whose content is consistent with the guidance\n\nx 100\n\nNumber of training programmes to which the measure applies\n\nAmbulance and other relevant staff should review the findings of measurement, and use their judgement to review cases in which fluids have been administered. For example, if a radial pulse is barely palpable in an individual with severe tachycardia, pallor, reduced capillary return and clouded consciousness, the team may decide that it would be appropriate to administer a small aliquot of fluid and review carefully. The team should identify if practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.", 'Changes after publication': 'March 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta74
9797d05b9405d5fc118e0785e1db936009d55c19	nice	Transilluminated powered phlebectomy for varicose veins	Transilluminated powered phlebectomy for varicose veins # Guidance Current evidence on the safety and efficacy of transilluminated powered phlebectomy for varicose veins includes small numbers of patients and is of limited quality. It does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake transilluminated powered phlebectomy for varicose veins should inform the clinical governance leads in their Trusts. They should ensure that patients offered it understand the uncertainty about the procedure's safety and efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.# The procedure # Indications Transilluminated powered phlebectomy is used to treat varicose veins, which affect 25–33% of women and 10–15% of men. Varicose veins are a sign of underlying venous insufficiency. People with venous insufficiency may have symptoms of fatigue, heaviness, aching, burning, throbbing, itching and cramps in the legs. Chronic venous insufficiency can lead to skin discolouration, inflammatory dermatitis, recurrent or chronic cellulitis, cutaneous infarction and ulceration. Transilluminated powered phlebectomy is intended as an alternative to hook phlebectomy for symptomatic varicose veins in the leg, and is usually done as an adjunct to surgery for long or short saphenous vein incompetence. # Outline of the procedure Under anaesthetic, an endoscopic transilluminator is inserted underneath the skin to illuminate the vein clusters to be resected; tumescent anaesthesia is then instilled under pressure via the cannulated illuminated device. A suction device with guarded blades (resector device) is then introduced via another incision at the other end of the varicose vein, and the varicosities are cut and removed by suction. Once removal of the veins is complete, tumescent anaesthesia is again introduced via a cannulated illuminator device to minimise bruising, pain and haematoma formation. The resector device can also be inserted through the first incision, minimising the number of incisions made during the procedure. # Efficacy The main efficacy outcomes identified in the studies were reduced pain and greater cosmetic satisfaction compared to hook phlebectomy. Comparative data suggested that transilluminated powered phlebectomy resulted in similar or less pain, at six weeks, and greater cosmetic satisfaction. The evidence reported in the non-comparative studies supported these findings. The available studies reported short-term results only. The evidence indicated that fewer incisions were required for transilluminated powered phlebectomy than with hook phlebectomy (mean 6 versus 17 incisions in one study). There was also some evidence to suggest that the number of incisions reduced with surgeon experience. For more details, refer to the 'Sources of evidence' section. One Specialist Advisor commented that the cosmetic advantages of the procedure can be negligible because of damage to the subcutaneous fat. It was noted by one Advisor that this procedure might be particularly suitable for the treatment of multiple and recurrent varicosities, which can be difficult to treat by hook phlebectomy. # Safety The comparative data indicated that transilluminated powered phlebectomy had fewer complications than hook phlebectomy. Common complications reported in the studies included haematomas, bruising and paraesthesia. One case of deep vein thrombosis, in a study of 114 patients (0.9%), was also reported as a complication of the procedure. For more details, refer to the 'Sources of evidence' section. The Specialist Advisors listed the main potential complications as haematoma, pain and bruising. Neuropraxia, causing sensory disturbance, was also listed by one Advisor as a potential complication, although it was considered that the incidence of this would be low. # Other comments Although the evidence suggested the procedure is effective, the evidence was too limited to be conclusive. A particular weakness is that there are no data on the number of veins treated during the procedure in each patient. The Institute noted the lack of long-term follow-up data and the Specialist Advisors' anxiety about potential complications. Andrew DillonChief ExecutiveJanuary 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedures overview of transilluminated powered phlebectomy for varicose veins', April 2003. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication The guidance was considered for reassessment in October 2009 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of transilluminated powered phlebectomy for varicose veins includes small numbers of patients and is of limited quality. It does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake transilluminated powered phlebectomy for varicose veins should inform the clinical governance leads in their Trusts. They should ensure that patients offered it understand the uncertainty about the procedure's safety and efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.", 'The procedure': "# Indications\n\nTransilluminated powered phlebectomy is used to treat varicose veins, which affect 25–33% of women and 10–15% of men. Varicose veins are a sign of underlying venous insufficiency.\n\nPeople with venous insufficiency may have symptoms of fatigue, heaviness, aching, burning, throbbing, itching and cramps in the legs. Chronic venous insufficiency can lead to skin discolouration, inflammatory dermatitis, recurrent or chronic cellulitis, cutaneous infarction and ulceration.\n\nTransilluminated powered phlebectomy is intended as an alternative to hook phlebectomy for symptomatic varicose veins in the leg, and is usually done as an adjunct to surgery for long or short saphenous vein incompetence.\n\n# Outline of the procedure\n\nUnder anaesthetic, an endoscopic transilluminator is inserted underneath the skin to illuminate the vein clusters to be resected; tumescent anaesthesia is then instilled under pressure via the cannulated illuminated device. A suction device with guarded blades (resector device) is then introduced via another incision at the other end of the varicose vein, and the varicosities are cut and removed by suction. Once removal of the veins is complete, tumescent anaesthesia is again introduced via a cannulated illuminator device to minimise bruising, pain and haematoma formation.\n\nThe resector device can also be inserted through the first incision, minimising the number of incisions made during the procedure.\n\n# Efficacy\n\nThe main efficacy outcomes identified in the studies were reduced pain and greater cosmetic satisfaction compared to hook phlebectomy. Comparative data suggested that transilluminated powered phlebectomy resulted in similar or less pain, at six weeks, and greater cosmetic satisfaction. The evidence reported in the non-comparative studies supported these findings. The available studies reported short-term results only.\n\nThe evidence indicated that fewer incisions were required for transilluminated powered phlebectomy than with hook phlebectomy (mean 6 versus 17 incisions in one study). There was also some evidence to suggest that the number of incisions reduced with surgeon experience. For more details, refer to the 'Sources of evidence' section.\n\nOne Specialist Advisor commented that the cosmetic advantages of the procedure can be negligible because of damage to the subcutaneous fat. It was noted by one Advisor that this procedure might be particularly suitable for the treatment of multiple and recurrent varicosities, which can be difficult to treat by hook phlebectomy.\n\n# Safety\n\nThe comparative data indicated that transilluminated powered phlebectomy had fewer complications than hook phlebectomy. Common complications reported in the studies included haematomas, bruising and paraesthesia.\n\nOne case of deep vein thrombosis, in a study of 114 patients (0.9%), was also reported as a complication of the procedure. For more details, refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors listed the main potential complications as haematoma, pain and bruising. Neuropraxia, causing sensory disturbance, was also listed by one Advisor as a potential complication, although it was considered that the incidence of this would be low.\n\n# Other comments\n\nAlthough the evidence suggested the procedure is effective, the evidence was too limited to be conclusive. A particular weakness is that there are no data on the number of veins treated during the procedure in each patient.\n\nThe Institute noted the lack of long-term follow-up data and the Specialist Advisors' anxiety about potential complications.\n\nAndrew DillonChief ExecutiveJanuary 2004", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedures overview of transilluminated powered phlebectomy for varicose veins', April 2003.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': 'The guidance was considered for reassessment in October 2009 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us.\n\nJanuary 2012: minor maintenance.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg37
ace8fc2da5855678addd8806937d2aca883ebb61	nice	Extracorporeal membrane oxygenation (ECMO) in postneonatal children	Extracorporeal membrane oxygenation (ECMO) in postneonatal children # Guidance Current evidence on the safety and efficacy of extracorporeal membrane oxygenation in postneonatal children appears adequate to support the use of this procedure, provided that the normal arrangements are in place for consent, audit and clinical governance. All children undergoing this treatment, including those treated after cardiopulmonary bypass, should be entered onto the international registry of the Extracorporeal Life Support Organization (ELSO), based at the University of Michigan, USA.# The procedure # Indications Extracorporeal membrane oxygenation (ECMO) is used to treat respiratory or cardiac failure that is unresponsive to all other measures, but is considered to have a reversible cause. ECMO may be used following heart surgery in postneonatal children to ease the transition from cardiopulmonary bypass. Postneonatal children are at least one month old. Most children treated with ECMO are very ill and at risk of death. The causes of respiratory and cardiac failure in children include: pneumonia; septic shock; congenital heart disease; cardiomyopathy; severe burns; and pulmonary haemorrhage. Standard treatment is maximal intensive care support without ECMO. # Outline of the procedure ECMO is a temporary life support technique. It involves connecting the patient's internal circulation to an external blood pump and artificial lung. A catheter placed in the right side of the heart carries blood to a pump, then to a membrane oxygenator (artificial lung), where gas exchange of oxygen and carbon dioxide takes place. The blood then passes through tubing back into either the venous or arterial circulation. Patients are given an anticoagulant to prevent blood clotting in the external system. # Efficacy Most of the evidence reviewed comprised case series from the ELSO database, and these ranged in size from 67 to 763 patients. Survival rates ranged from 40% (27/67 patients) to 71% (91/128 patients). The largest case series of 763 patients reported a 57% survival rate. For more details, refer to the 'Sources of evidence' section. The Specialist Advisors considered that the efficacy of ECMO in providing cardiorespiratory support in postneonatal children is proven. They considered that survival in this group of patients is reasonably well known from the worldwide ELSO database. # Safety From the studies, the most common complications included bleeding (with an incidence between 40% and 58% ) and renal failure (the largest case series reported this at 45% ). Other, less frequent complications included seizures and haemolysis. For more details, refer to the 'Sources of evidence' section. The Specialist Advisors considered that the incidence of complications associated with ECMO was low. They listed infection, bleeding, neurological damage and technical problems with the ECMO circuit as potential complications. However, they considered that the procedure was sufficiently well-established in the centres in which it was used and was delivered by trained specialists in a manner designed to minimise risks. # Other comments The Health Technology Assessment Programme's CESAR trial (Conventional Ventilation or Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure) will provide additional evidence about the use of the procedure in adults. Andrew DillonChief ExecutiveJanuary 2004# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of extracorporeal membrane oxygenation for postneonatal children', December 2002. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of extracorporeal membrane oxygenation in postneonatal children appears adequate to support the use of this procedure, provided that the normal arrangements are in place for consent, audit and clinical governance.\n\nAll children undergoing this treatment, including those treated after cardiopulmonary bypass, should be entered onto the international registry of the Extracorporeal Life Support Organization (ELSO), based at the University of Michigan, USA.', 'The procedure': "# Indications\n\nExtracorporeal membrane oxygenation (ECMO) is used to treat respiratory or cardiac failure that is unresponsive to all other measures, but is considered to have a reversible cause. ECMO may be used following heart surgery in postneonatal children to ease the transition from cardiopulmonary bypass. Postneonatal children are at least one month old.\n\nMost children treated with ECMO are very ill and at risk of death. The causes of respiratory and cardiac failure in children include: pneumonia; septic shock; congenital heart disease; cardiomyopathy; severe burns; and pulmonary haemorrhage.\n\nStandard treatment is maximal intensive care support without ECMO.\n\n# Outline of the procedure\n\nECMO is a temporary life support technique. It involves connecting the patient's internal circulation to an external blood pump and artificial lung. A catheter placed in the right side of the heart carries blood to a pump, then to a membrane oxygenator (artificial lung), where gas exchange of oxygen and carbon dioxide takes place. The blood then passes through tubing back into either the venous or arterial circulation. Patients are given an anticoagulant to prevent blood clotting in the external system.\n\n# Efficacy\n\nMost of the evidence reviewed comprised case series from the ELSO database, and these ranged in size from 67 to 763 patients. Survival rates ranged from 40% (27/67 patients) to 71% (91/128 patients). The largest case series of 763 patients reported a 57% survival rate. For more details, refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors considered that the efficacy of ECMO in providing cardiorespiratory support in postneonatal children is proven. They considered that survival in this group of patients is reasonably well known from the worldwide ELSO database.\n\n# Safety\n\nFrom the studies, the most common complications included bleeding (with an incidence between 40% [27/67] and 58% [137/237]) and renal failure (the largest case series reported this at 45% [343/763]). Other, less frequent complications included seizures and haemolysis. For more details, refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors considered that the incidence of complications associated with ECMO was low. They listed infection, bleeding, neurological damage and technical problems with the ECMO circuit as potential complications. However, they considered that the procedure was sufficiently well-established in the centres in which it was used and was delivered by trained specialists in a manner designed to minimise risks.\n\n# Other comments\n\nThe Health Technology Assessment Programme's CESAR trial (Conventional Ventilation or Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure) will provide additional evidence about the use of the procedure in adults.\n\nAndrew DillonChief ExecutiveJanuary 2004", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of extracorporeal membrane oxygenation for postneonatal children', December 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg38
e210d953cf0726f6560cfaf6218ca3236435f517	nice	Laparo-endogastric surgery	Laparo-endogastric surgery # Guidance Current evidence on the safety and efficacy of laparo-endogastric surgery does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake laparo-endogastric surgery should inform the clinical governance leads in their Trusts. They should ensure that patients offered it understand the uncertainty about the procedure's safety and efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present. The procedure should only be performed by specialists in laparoscopic surgery who have observed at least one patient undergoing the procedure.# The procedure # Indications Laparo-endogastric surgery is also known as laparoscopic endoluminal surgery, endo-organ gastric surgery and laparoendoscopic gastric surgery. It is used to treat lesions located in the fundus of the stomach, the gastroesophageal junction, and near the pylorus. These include gastric polyps, gastric wall tumours (lymphomas, leiomyomas, leiomyosarcomas, carcinoids), gastric cancer, Dieulafoy's lesion (arterial malformation) and intractable gastroduodenal ulcers. Lesions on the greater and lesser curvatures are relatively inaccessible. Large or advanced gastric cancers are rarely suitable for laparo-endogastric surgery. Traditional approaches to gastric surgery are resection operations through a laparotomy incision or laparoscopy. # Outline of the procedure Laparo-endogastric surgery is a minimally invasive approach to surgery for gastric wall lesions, and attempts to avoid resection of the full thickness of the stomach wall. With the patient under general anaesthetic, the surgeon passes an endoscope through the oesophagus into the stomach. A laparoscope is inserted through a small incision in the upper abdominal wall, passed into the stomach, and surgery is performed from inside the stomach. # Efficacy Evidence was from small, uncontrolled case series. The efficacy of the procedure compared with conventional open laparotomy or laparoscopic partial gastrectomy remains uncertain. For more details refer to the sources of evidence section. Specialist Advisors considered laparo-endogastric surgery to be a very new procedure carried out in very few specialist units worldwide. The technique is not widely disseminated, and there are few opportunities for training. One Specialist Advisor questioned the procedure's efficiency in excising small malignant lesions completely. # Safety Few complications were reported in the studies. As the case series are so small, it is not possible to reliably estimate the frequency of complications. For more details refer to the sources of evidence section. Specialist Advisors noted that possible complications include leaking at the site of repair to the stomach following surgery and subsequent infection or bleeding, but these were uncommon. # Other comments The Interventional Procedures Advisory Committee noted that the inadequate visualisation of tumours might lead to staging errors, and identified tumour spillage as a potential risk. The Advisory Committee also noted that the technique is likely to have limited application in the foreseeable future. Andrew DillonChief ExecutiveDecember 2003# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of laparo-endogastric surgery', November 2002. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication As part of NICE's work programme, the current guidance was considered for review but did not meet the review criteria as set out in the IP process guide. This guidance therefore remains current. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of laparo-endogastric surgery does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake laparo-endogastric surgery should inform the clinical governance leads in their Trusts. They should ensure that patients offered it understand the uncertainty about the procedure's safety and efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.\n\nThe procedure should only be performed by specialists in laparoscopic surgery who have observed at least one patient undergoing the procedure.", 'The procedure': "# Indications\n\nLaparo-endogastric surgery is also known as laparoscopic endoluminal surgery, endo-organ gastric surgery and laparoendoscopic gastric surgery. It is used to treat lesions located in the fundus of the stomach, the gastroesophageal junction, and near the pylorus. These include gastric polyps, gastric wall tumours (lymphomas, leiomyomas, leiomyosarcomas, carcinoids), gastric cancer, Dieulafoy's lesion (arterial malformation) and intractable gastroduodenal ulcers. Lesions on the greater and lesser curvatures are relatively inaccessible.\n\nLarge or advanced gastric cancers are rarely suitable for laparo-endogastric surgery.\n\nTraditional approaches to gastric surgery are resection operations through a laparotomy incision or laparoscopy.\n\n# Outline of the procedure\n\nLaparo-endogastric surgery is a minimally invasive approach to surgery for gastric wall lesions, and attempts to avoid resection of the full thickness of the stomach wall. With the patient under general anaesthetic, the surgeon passes an endoscope through the oesophagus into the stomach. A laparoscope is inserted through a small incision in the upper abdominal wall, passed into the stomach, and surgery is performed from inside the stomach.\n\n# Efficacy\n\nEvidence was from small, uncontrolled case series. The efficacy of the procedure compared with conventional open laparotomy or laparoscopic partial gastrectomy remains uncertain. For more details refer to the sources of evidence section.\n\nSpecialist Advisors considered laparo-endogastric surgery to be a very new procedure carried out in very few specialist units worldwide. The technique is not widely disseminated, and there are few opportunities for training. One Specialist Advisor questioned the procedure's efficiency in excising small malignant lesions completely.\n\n# Safety\n\nFew complications were reported in the studies. As the case series are so small, it is not possible to reliably estimate the frequency of complications. For more details refer to the sources of evidence section.\n\nSpecialist Advisors noted that possible complications include leaking at the site of repair to the stomach following surgery and subsequent infection or bleeding, but these were uncommon.\n\n# Other comments\n\nThe Interventional Procedures Advisory Committee noted that the inadequate visualisation of tumours might lead to staging errors, and identified tumour spillage as a potential risk.\n\nThe Advisory Committee also noted that the technique is likely to have limited application in the foreseeable future.\n\nAndrew DillonChief ExecutiveDecember 2003", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of laparo-endogastric surgery', November 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': "As part of NICE's work programme, the current guidance was considered for review but did not meet the review criteria as set out in the IP process guide. This guidance therefore remains current.\n\nJanuary 2012: minor maintenance.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg25
b379de262cdc3cf817a26cfcd16cba1bd218fb9e	nice	Magnetic resonance (MR) image-guided percutaneous laser ablation of uterine fibroids	Magnetic resonance (MR) image-guided percutaneous laser ablation of uterine fibroids # Guidance Evidence on safety and efficacy outcomes of MR image-guided percutaneous laser ablation of uterine fibroids is insufficient to support its use without special arrangements for consent and for audit or research. Clinicians wishing to undertake MR image-guided percutaneous laser ablation should inform the clinical governance leads in their Trusts. They should ensure that women offered the procedure understand the uncertainty about its safety and efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.# The procedure # Indications MR image-guided percutaneous laser ablation is used to treat uterine fibroids, also known as uterine leiomyomas or uterine myomas. Fibroids are benign tumours of the uterine muscle. They are very common and are often asymptomatic. They may cause abnormal bleeding, pelvic pressure and pain, and reproductive problems. Hysterectomy is the standard treatment for women with fibroids whose symptoms have not resolved with medical treatment. However, in the past decade, there has been increased interest in minimally invasive surgical techniques. # Outline of the procedure Under MR-image guidance needles are inserted, through an area of skin that has been locally anaesthetised, into the centre of the targeted uterine fibroid. Bare laser fibres are inserted down the centre of each of the needles into the targeted fibroid. Laser energy is then used to destroy the fibroid. A thermal mapping sequence is used to depict the extent of the heated tissue in the target area as the procedure is carried out. A catheter is placed in the bladder before the start of the procedure and women receive intravenous sedation and analgesia throughout. # Efficacy The evidence for efficacy was based on four reports published by one UK study group. Some women were included in more than one report. Limited evidence suggested that the procedure resulted in a short-term (3-month) reduction in fibroid volume of around 30%. For more details refer to the sources of evidence section. The main comment from the Specialist Advisors related to the relatively new nature of the procedure. One Advisor commented on patient selection, stating that the procedure might only be appropriate for fibroids of a certain size, and that it might not be of benefit for women with larger or multiple fibroids. # Safety Adverse events were reported in a minority of patients. Potential complications included urinary tract infections, skin burns and vaginal bleeding. These events were relatively minor and of a transitory nature. For more details refer to the sources of evidence section. The Specialist Advisors listed the potential adverse effects as infection, burns, uterine damage and bowel or bladder damage. # Other comments This is a very specialised procedure and currently only one centre in the UK undertakes it. As such, the evidence available was limited.# Further information The Institute has issued safety and efficacy guidance on uterine artery embolisation and laparoscopic laser myomectomy, and will issue interventional procedures guidance on laparoscopic total hysterectomy in 2004 . The Institute is also in the process of developing a clinical guideline on hysterectomy and alternative surgical treatments for menorrhagia and other conditions. The expected date of issue of this guideline is September 2005 . Andrew DillonChief ExecutiveDecember 2003 # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of magnetic resonance image-guided percutaneous laser ablation for uterine fibroids', April 2003. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication As part of NICE's work programme, the current guidance was considered for review in May 2009 but did not meet the review criteria as set out in the IP process guide. This guidance therefore remains current. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Evidence on safety and efficacy outcomes of MR image-guided percutaneous laser ablation of uterine fibroids is insufficient to support its use without special arrangements for consent and for audit or research. Clinicians wishing to undertake MR image-guided percutaneous laser ablation should inform the clinical governance leads in their Trusts. They should ensure that women offered the procedure understand the uncertainty about its safety and efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.", 'The procedure': '# Indications\n\nMR image-guided percutaneous laser ablation is used to treat uterine fibroids, also known as uterine leiomyomas or uterine myomas. Fibroids are benign tumours of the uterine muscle. They are very common and are often asymptomatic. They may cause abnormal bleeding, pelvic pressure and pain, and reproductive problems.\n\nHysterectomy is the standard treatment for women with fibroids whose symptoms have not resolved with medical treatment. However, in the past decade, there has been increased interest in minimally invasive surgical techniques.\n\n# Outline of the procedure\n\nUnder MR-image guidance needles are inserted, through an area of skin that has been locally anaesthetised, into the centre of the targeted uterine fibroid. Bare laser fibres are inserted down the centre of each of the needles into the targeted fibroid. Laser energy is then used to destroy the fibroid.\n\nA thermal mapping sequence is used to depict the extent of the heated tissue in the target area as the procedure is carried out.\n\nA catheter is placed in the bladder before the start of the procedure and women receive intravenous sedation and analgesia throughout.\n\n# Efficacy\n\nThe evidence for efficacy was based on four reports published by one UK study group. Some women were included in more than one report. Limited evidence suggested that the procedure resulted in a short-term (3-month) reduction in fibroid volume of around 30%. For more details refer to the sources of evidence section.\n\nThe main comment from the Specialist Advisors related to the relatively new nature of the procedure. One Advisor commented on patient selection, stating that the procedure might only be appropriate for fibroids of a certain size, and that it might not be of benefit for women with larger or multiple fibroids.\n\n# Safety\n\nAdverse events were reported in a minority of patients. Potential complications included urinary tract infections, skin burns and vaginal bleeding. These events were relatively minor and of a transitory nature. For more details refer to the sources of evidence section.\n\nThe Specialist Advisors listed the potential adverse effects as infection, burns, uterine damage and bowel or bladder damage.\n\n# Other comments\n\nThis is a very specialised procedure and currently only one centre in the UK undertakes it. As such, the evidence available was limited.', 'Further information': "The Institute has issued safety and efficacy guidance on uterine artery embolisation and laparoscopic laser myomectomy, and will issue interventional procedures guidance on laparoscopic total hysterectomy in 2004 [Now published as 'Laparoscopic hysterectomy (including laparoscopic total hysterectomy and laparoscopically assisted vaginal hysterectomy) for endometrial cancer'].\n\nThe Institute is also in the process of developing a clinical guideline on hysterectomy and alternative surgical treatments for menorrhagia and other conditions. The expected date of issue of this guideline is September 2005 [Now published as 'Heavy menstrual bleeding: investigation and treatment'].\n\nAndrew DillonChief ExecutiveDecember 2003\n\n# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of magnetic resonance image-guided percutaneous laser ablation for uterine fibroids', April 2003.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': "As part of NICE's work programme, the current guidance was considered for review in May 2009 but did not meet the review criteria as set out in the IP process guide. This guidance therefore remains current.\n\nJanuary 2012: minor maintenance.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg30
ecc0ad0b89dc7e1245baf9a0f6fe0efda8913f6f	nice	Endoscopic laser foraminoplasty	Endoscopic laser foraminoplasty # Guidance Current evidence of the safety and efficacy of endoscopic laser foraminoplasty does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake endoscopic laser foraminoplasty should inform the clinical governance leads in their Trusts. They should ensure that patients offered the procedure understand the uncertainty about its safety and efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Further research into safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.# The procedure # Indications Endoscopic laser foraminoplasty is used mainly to treat chronic back and leg pain from a variety of causes. Annually, 2–5% of people suffer acute back pain, and 0.5% of these have pain and neurological conditions requiring surgery. # Outline of the procedure This endoscope-assisted laser technique is used to widen the lumbar exit foramina for nerves from the lumbar spine. A laser is inserted to ablate portions of the intervertebral disc that have protruded and caused narrowing of the foramina. # Efficacy The research on efficacy undertaken to date is based on case series only and has all been led by a single clinician. In general, pain was decreased after the procedure. For more details, refer to the sources of evidence section. The Specialist Advisors believed the efficacy of this procedure to be unproven. # Safety The research on safety undertaken to date has all been led by a single clinician. The rates of reported complications were low, with discitis and neurological deficit being the most common (both with incidence lower than 1%). For more details, refer to the sources of evidence section. The Specialist Advisors noted a number of potential complications including nerve injury and infection.# Further information NICE has also issued guidance on laser lumbar discectomy (replaced by NICE interventional procedure 357; 'Percutaneous intradiscal laser ablation in the lumbar spine'). Guidance on prosthetic intervertebral disc replacement, percutaneous intradiscal electrothermocoagulation and percutaneous radiofrequency thermocoagulation are currently in progress and will be published in 2004 after public consultation . Andrew DillonChief ExecutiveDecember 2003 # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of endoscopic laser foraminoplasty', October 2002. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication The guidance was considered for reassessment in October 2009 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence of the safety and efficacy of endoscopic laser foraminoplasty does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake endoscopic laser foraminoplasty should inform the clinical governance leads in their Trusts. They should ensure that patients offered the procedure understand the uncertainty about its safety and efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Further research into safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.", 'The procedure': '# Indications\n\nEndoscopic laser foraminoplasty is used mainly to treat chronic back and leg pain from a variety of causes. Annually, 2–5% of people suffer acute back pain, and 0.5% of these have pain and neurological conditions requiring surgery.\n\n# Outline of the procedure\n\nThis endoscope-assisted laser technique is used to widen the lumbar exit foramina for nerves from the lumbar spine. A laser is inserted to ablate portions of the intervertebral disc that have protruded and caused narrowing of the foramina.\n\n# Efficacy\n\nThe research on efficacy undertaken to date is based on case series only and has all been led by a single clinician. In general, pain was decreased after the procedure. For more details, refer to the sources of evidence section.\n\nThe Specialist Advisors believed the efficacy of this procedure to be unproven.\n\n# Safety\n\nThe research on safety undertaken to date has all been led by a single clinician. The rates of reported complications were low, with discitis and neurological deficit being the most common (both with incidence lower than 1%). For more details, refer to the sources of evidence section.\n\nThe Specialist Advisors noted a number of potential complications including nerve injury and infection.', 'Further information': "NICE has also issued guidance on laser lumbar discectomy (replaced by NICE interventional procedure 357; 'Percutaneous intradiscal laser ablation in the lumbar spine'). Guidance on prosthetic intervertebral disc replacement, percutaneous intradiscal electrothermocoagulation and percutaneous radiofrequency thermocoagulation are currently in progress and will be published in 2004 after public consultation [Now published as 'Prosthetic intervertebral disc replacement in the lumbar spine', 'Percutaneous intradiscal electrothermal therapy for low back pain' and 'Percutaneous intradiscal radiofrequency thermocoagulation for lower back pain', respectively].\n\nAndrew DillonChief ExecutiveDecember 2003\n\n# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of endoscopic laser foraminoplasty', October 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': 'The guidance was considered for reassessment in October 2009 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us.\n\nJanuary 2012: minor maintenance.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg31
70202907a2118938091092973cdb78c7e2527917	nice	Circular stapled haemorrhoidectomy	Circular stapled haemorrhoidectomy # Guidance Current evidence on the safety and efficacy of circular stapled haemorrhoidectomy appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance. Clinicians wishing to learn circular stapled haemorrhoidectomy should be trained, mentored and monitored, as described in the Association of Coloproctology's consensus document on the procedure (see the Association's website).# The procedure # Indications Circular stapled haemorrhoidectomy is used to treat internal haemorrhoids, which develop when cushions of vascular tissue in the anus undergo pathological change. Haemorrhoids may prolapse and cause bleeding, faecal soiling, itching and occasionally pain. # Outline of the procedure In circular stapled rectal haemorrhoidectomy, a stapler is used to excise an annulus of rectal mucosa above the haemorrhoids. This reduces the size of internal haemorrhoids by interrupting their blood supply, and reducing the available rectal mucosa with the potential to prolapse. By contrast, conventional surgical haemorrhoidectomy involves excision of haemorrhoidal tissue, anoderm and perianal skin. # Efficacy The studies suggested that patients had less pain and returned to normal activity more quickly after stapled haemorrhoidectomy than after conventional haemorrhoidectomy. In one randomised controlled trial with 84 patients, th average time of return to work was 6 days after the circular stapled technique, compared with 15 days after conventional surgery. For more details refer to the 'Sources of evidence' section. The Specialist Advisors stated that circular stapled haemorrhoidectomy was relatively new, but that an increasing number of surgeons were using this approach. The Advisors considered stapled haemorrhoidectomy to be as effective as the surgical alternative. They noted that there were limited long-term data, and that the durability of the procedure was therefore unclear. # Safety The studies suggested a lower overall postoperative complication rate with circular stapled haemorrhoidectomy than with conventional haemorrhoidectomy. A systematic review published in 2001 indicated a significant reduction in the risk of bleeding during the first 2 weeks after the procedure. For more details refer to the 'Sources of evidence' section. The Association of Coloproctology's consensus document stated that adverse events were related to the possibility of a full thickness excision to the rectal wall, with the potential for injury to the internal anal sphincter. In addition, stretching of the anal sphincter by the stapler head may, in theory, cause injury. The Specialist Advisors suggested that most of the safety concerns were theoretical and that many of them were not supported by the trials that have been published. # Other comments It was noted that long-term data were lacking and that the Association of Coloproctology of Great Britain and Ireland is undertaking an audit on this procedure. Surgeons doing this procedure are strongly encouraged to include patients in this audit. Andrew DillonChief ExecutiveDecember 2003# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of circular stapled haemorrhoidectomy', November 2002. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of circular stapled haemorrhoidectomy appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.\n\nClinicians wishing to learn circular stapled haemorrhoidectomy should be trained, mentored and monitored, as described in the Association of Coloproctology's consensus document on the procedure (see the Association's website).", 'The procedure': "# Indications\n\nCircular stapled haemorrhoidectomy is used to treat internal haemorrhoids, which develop when cushions of vascular tissue in the anus undergo pathological change. Haemorrhoids may prolapse and cause bleeding, faecal soiling, itching and occasionally pain.\n\n# Outline of the procedure\n\nIn circular stapled rectal haemorrhoidectomy, a stapler is used to excise an annulus of rectal mucosa above the haemorrhoids. This reduces the size of internal haemorrhoids by interrupting their blood supply, and reducing the available rectal mucosa with the potential to prolapse. By contrast, conventional surgical haemorrhoidectomy involves excision of haemorrhoidal tissue, anoderm and perianal skin.\n\n# Efficacy\n\nThe studies suggested that patients had less pain and returned to normal activity more quickly after stapled haemorrhoidectomy than after conventional haemorrhoidectomy. In one randomised controlled trial with 84 patients, th average time of return to work was 6 days after the circular stapled technique, compared with 15 days after conventional surgery. For more details refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors stated that circular stapled haemorrhoidectomy was relatively new, but that an increasing number of surgeons were using this approach. The Advisors considered stapled haemorrhoidectomy to be as effective as the surgical alternative. They noted that there were limited long-term data, and that the durability of the procedure was therefore unclear.\n\n# Safety\n\nThe studies suggested a lower overall postoperative complication rate with circular stapled haemorrhoidectomy than with conventional haemorrhoidectomy. A systematic review published in 2001 indicated a significant reduction in the risk of bleeding during the first 2 weeks after the procedure. For more details refer to the 'Sources of evidence' section.\n\nThe Association of Coloproctology's consensus document stated that adverse events were related to the possibility of a full thickness excision to the rectal wall, with the potential for injury to the internal anal sphincter. In addition, stretching of the anal sphincter by the stapler head may, in theory, cause injury.\n\nThe Specialist Advisors suggested that most of the safety concerns were theoretical and that many of them were not supported by the trials that have been published.\n\n# Other comments\n\nIt was noted that long-term data were lacking and that the Association of Coloproctology of Great Britain and Ireland is undertaking an audit on this procedure. Surgeons doing this procedure are strongly encouraged to include patients in this audit.\n\nAndrew DillonChief ExecutiveDecember 2003", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of circular stapled haemorrhoidectomy', November 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg34
1939fb75d42f70f7fbc76e438487cc76a11c7c0a	nice	Extracorporeal shockwave therapy for Peyronie's disease	Extracorporeal shockwave therapy for Peyronie's disease # Guidance Current evidence on the safety of extracorporeal shockwave therapy (ESWT) for Peyronie's disease appears adequate. However, the evidence on the efficacy does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake ESWT for Peyronie's disease should inform the clinical governance leads in their Trusts. They should ensure that patients offered the procedure understand the uncertainty about its efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure appropriate arrangements are in place for audit or research. Publication of efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.# The procedure # Indications Peyronie's disease is a localised connective tissue disorder of unknown cause. It is characterised by the formation of inelastic fibrous plaques within the erectile tissue of the penis. The hardened plaque reduces flexibility, causing pain and causing the penis to bend or arc during erection. For many patients, Peyronie's disease results in sexual problems because there is difficulty in attaining and/or maintaining erections. Treatment options for Peyronie's disease include pharmacological interventions, radiation and surgery. They are designed to alleviate the symptoms rather than to cure the disease. A number of surgical techniques have been developed for patients with more severe symptoms and for patients who have been refractory to conservative treatment. # Outline of the procedure The procedure involves the use of shockwave lithotripsy technology. Extracorporeal shockwaves are high-pressure, low-frequency sound waves, generated by a device outside the body and applied to the affected tissue in a site-specific manner. In Peyronie's disease, the penile plaque is the target of the shockwaves, and it is generally localised using an ultrasound scanner. The procedure can be performed with or without sedation. # Efficacy From comparative studies, the main benefits of ESWT were the alleviation of pain and reduction of angulation of the penis. In one comparative study, 50% of patients (10/20) receiving ESWT experienced a decrease in curvature of at least 30%. Case series evidence also suggested some improvement of sexual performance. For more details refer to the sources of evidence section. The Specialist Advisors commented on the difficulty of evaluating efficacy, given the lack of controlled data and agreement regarding relevant endpoints. The Advisors also noted that placebo response, inter-patient variability, and the natural history of the disease were potential problems when evaluating the evidence. # Safety In the studies identified, relatively few complications were reported. Complications were mostly of a transient nature and included urethral bleeding, bruising, skin discoloration due to petechiae, and haematoma. The relationship between the energy level used in the treatment and the reported complications is unclear. For more details refer to the sources of evidence section. The Specialist Advisors did not note any particular safety concerns about this procedure. Superficial bruising and moderate local pain were noted as potential adverse events. # Other comments Good comparative data would be useful in establishing the efficacy of this procedure. Andrew DillonChief ExecutiveDecember 2003# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of extracorporeal shockwave therapy for Peyronie's disease', March 2002. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Changes since publication As part of NICE's work programme, the current guidance was considered for review but did not meet the review criteria as set out in the IP process guide. This guidance therefore remains current. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety of extracorporeal shockwave therapy (ESWT) for Peyronie's disease appears adequate. However, the evidence on the efficacy does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake ESWT for Peyronie's disease should inform the clinical governance leads in their Trusts. They should ensure that patients offered the procedure understand the uncertainty about its efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure appropriate arrangements are in place for audit or research. Publication of efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.", 'The procedure': "# Indications\n\nPeyronie's disease is a localised connective tissue disorder of unknown cause. It is characterised by the formation of inelastic fibrous plaques within the erectile tissue of the penis. The hardened plaque reduces flexibility, causing pain and causing the penis to bend or arc during erection.\n\nFor many patients, Peyronie's disease results in sexual problems because there is difficulty in attaining and/or maintaining erections.\n\nTreatment options for Peyronie's disease include pharmacological interventions, radiation and surgery. They are designed to alleviate the symptoms rather than to cure the disease. A number of surgical techniques have been developed for patients with more severe symptoms and for patients who have been refractory to conservative treatment.\n\n# Outline of the procedure\n\nThe procedure involves the use of shockwave lithotripsy technology. Extracorporeal shockwaves are high-pressure, low-frequency sound waves, generated by a device outside the body and applied to the affected tissue in a site-specific manner. In Peyronie's disease, the penile plaque is the target of the shockwaves, and it is generally localised using an ultrasound scanner. The procedure can be performed with or without sedation.\n\n# Efficacy\n\nFrom comparative studies, the main benefits of ESWT were the alleviation of pain and reduction of angulation of the penis. In one comparative study, 50% of patients (10/20) receiving ESWT experienced a decrease in curvature of at least 30%. Case series evidence also suggested some improvement of sexual performance. For more details refer to the sources of evidence section.\n\nThe Specialist Advisors commented on the difficulty of evaluating efficacy, given the lack of controlled data and agreement regarding relevant endpoints. The Advisors also noted that placebo response, inter-patient variability, and the natural history of the disease were potential problems when evaluating the evidence.\n\n# Safety\n\nIn the studies identified, relatively few complications were reported. Complications were mostly of a transient nature and included urethral bleeding, bruising, skin discoloration due to petechiae, and haematoma. The relationship between the energy level used in the treatment and the reported complications is unclear. For more details refer to the sources of evidence section.\n\nThe Specialist Advisors did not note any particular safety concerns about this procedure. Superficial bruising and moderate local pain were noted as potential adverse events.\n\n# Other comments\n\nGood comparative data would be useful in establishing the efficacy of this procedure.\n\nAndrew DillonChief ExecutiveDecember 2003", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of extracorporeal shockwave therapy for Peyronie's disease', March 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Changes since publication': "As part of NICE's work programme, the current guidance was considered for review but did not meet the review criteria as set out in the IP process guide. This guidance therefore remains current.\n\nJanuary 2012: minor maintenance.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg29
8f8ba0e5a69a867b869c54d1fc4ec68edc433810	nice	Endoscopic transsphenoidal pituitary adenoma resection	Endoscopic transsphenoidal pituitary adenoma resection # Guidance Current evidence on the safety and efficacy of endoscopic transsphenoidal pituitary adenoma resection appears adequate to support the use of the procedure, provided that the normal arrangements are in place for consent, audit and clinical governance. The procedure should be carried out by clinicians with special experience in endoscopic pituitary surgery, and within a multidisciplinary centre.# The procedure # Indications Endoscopic transsphenoidal pituitary adenoma resection is used to treat pituitary adenomas. Pituitary adenomas are benign slow-growing tumours that arise within the pituitary gland. The symptoms of pituitary adenoma depend on the location, type and size of tumour and any hormone that it may secrete. The treatment options for pituitary adenoma include surgery, pharmacological therapy, and radiotherapy. # Outline of the procedure Under general anaesthetic, an endoscope is inserted into the nose and is directed towards the base of the tumour at the skull base. Surgical instruments are then inserted and the tumour is removed. # Efficacy The evidence indicated that endoscopic transsphenoidal pituitary adenoma resection results in surgical outcomes, such as adequacy of removal and normalisation of hormone levels, comparable with those achieved using conventional surgery. The operating time for endoscopic transsphenoidal resection was shorter compared with conventional surgery. For more details refer to the 'Sources of evidence' section. The majority of the Specialist Advisors considered the procedure to be a variation of an existing procedure, and the likely efficacy of resection to be unchanged. # Safety The evidence indicated that major morbidity (cerebrospinal fluid leak, meningitis, stroke, intracranial haemorrhage, or visual loss) occurred in between 1.4% (3/215) and 15% (3/20) of patients. Less serious complications (sinusitis and nasal septal perforations) occurred in less than 7% of patients. The complication rate associated with endoscopic transsphenoidal pituitary adenoma resection was lower than the rates associated with conventional surgery. The most serious reported complication of the procedure was meningitis. This occurred in two patients in the two largest case series, which included 310 patients. For more details refer to the 'Sources of evidence' section. The Specialist Advisors did not report any particular safety concerns, though bleeding, optic nerve damage, cerebrospinal fluid leakage, and carotid artery injury were noted as potential complications of endoscopic transsphenoidal pituitary adenoma resection. # Other comments It was noted that there was a lack of long-term follow-up data on this procedure. Andrew DillonChief ExecutiveDecember 2003# Further information # Information for patients NICE has produced information describing its guidance on this procedure for patients, carers and those with a wider interest in healthcare. It explains the nature of the procedure and the decision made, and has been written with patient consent in mind. # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of transsphenoidal pituitary adenoma resection', April 2003.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of endoscopic transsphenoidal pituitary adenoma resection appears adequate to support the use of the procedure, provided that the normal arrangements are in place for consent, audit and clinical governance.\n\nThe procedure should be carried out by clinicians with special experience in endoscopic pituitary surgery, and within a multidisciplinary centre.', 'The procedure': "# Indications\n\nEndoscopic transsphenoidal pituitary adenoma resection is used to treat pituitary adenomas. Pituitary adenomas are benign slow-growing tumours that arise within the pituitary gland.\n\nThe symptoms of pituitary adenoma depend on the location, type and size of tumour and any hormone that it may secrete.\n\nThe treatment options for pituitary adenoma include surgery, pharmacological therapy, and radiotherapy.\n\n# Outline of the procedure\n\nUnder general anaesthetic, an endoscope is inserted into the nose and is directed towards the base of the tumour at the skull base. Surgical instruments are then inserted and the tumour is removed.\n\n# Efficacy\n\nThe evidence indicated that endoscopic transsphenoidal pituitary adenoma resection results in surgical outcomes, such as adequacy of removal and normalisation of hormone levels, comparable with those achieved using conventional surgery.\n\nThe operating time for endoscopic transsphenoidal resection was shorter compared with conventional surgery. For more details refer to the 'Sources of evidence' section.\n\nThe majority of the Specialist Advisors considered the procedure to be a variation of an existing procedure, and the likely efficacy of resection to be unchanged.\n\n# Safety\n\nThe evidence indicated that major morbidity (cerebrospinal fluid leak, meningitis, stroke, intracranial haemorrhage, or visual loss) occurred in between 1.4% (3/215) and 15% (3/20) of patients. Less serious complications (sinusitis and nasal septal perforations) occurred in less than 7% of patients. The complication rate associated with endoscopic transsphenoidal pituitary adenoma resection was lower than the rates associated with conventional surgery.\n\nThe most serious reported complication of the procedure was meningitis. This occurred in two patients in the two largest case series, which included 310 patients. For more details refer to the 'Sources of evidence' section.\n\nThe Specialist Advisors did not report any particular safety concerns, though bleeding, optic nerve damage, cerebrospinal fluid leakage, and carotid artery injury were noted as potential complications of endoscopic transsphenoidal pituitary adenoma resection.\n\n# Other comments\n\nIt was noted that there was a lack of long-term follow-up data on this procedure.\n\nAndrew DillonChief ExecutiveDecember 2003", 'Further information': "# Information for patients\n\nNICE has produced information describing its guidance on this procedure for patients, carers and those with a wider interest in healthcare. It explains the nature of the procedure and the decision made, and has been written with patient consent in mind.\n\n# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of transsphenoidal pituitary adenoma resection', April 2003.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg32
ec6e01fa5c9c48a1803d08b8b6b14180d1193199	nice	Endoscopic stapling of pharyngeal pouch	Endoscopic stapling of pharyngeal pouch # Guidance Current evidence on the safety and efficacy of endoscopic stapling of pharyngeal pouch appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.# The procedure # Indications Pharyngeal pouch, which is also known as Zenker's diverticulum, occurs when a piece of the pharyngeal lining herniates through the muscles of the pharyngeal wall. It occurs mainly in older people, with an estimated overall incidence of about 1 per 100,000 people per year. Pharyngeal pouch may cause difficulty in swallowing or a cough, and sometimes causes respiratory problems because of aspiration of the pouch contents into the lungs. The standard treatment for pharyngeal pouch is open surgery to the neck. Endoscopic techniques are less invasive than open surgery. The standard endoscopic technique, known as Dohlman's procedure, uses diathermy or lasers to divide the wall between the pouch and the oesophagus. Endoscopic stapling of pharyngeal pouch is an alternative to the standard endoscopic technique. # Outline of the procedure Endoscopic stapling of pharyngeal pouch involves stapling the bar of tissue that divides the pouch from the oesophagus. A specially designed endoscope is used to gain access to the bar and the openings of both the pouch and the oesophagus. The procedure is performed under general anaesthetic. # Efficacy The evidence suggested that endoscopic stapling allows a more rapid recovery, and requires a shorter stay in hospital (1–2 days) than open surgery. Patients returned to normal swallowing promptly. For more details refer to the sources of evidence section. The Specialist Advisors considered endoscopic stapling to be an established procedure, now widely practiced in specialist centres by specifically trained otorhinolaryngologists. They considered it effective in terms of reducing operating time and the duration of hospital stay. The Specialist Advisors noted that the problem can recur but that the procedure can be repeated if this happens. # Safety Few complications were reported in the studies reviewed. Mild bleeding, perforation of the pharynx and a need for nasogastric feeding were reported, but these were uncommon. For more details refer to the sources of evidence section. The Specialist Advisors concurred that perforation and leakage from the pharynx were no more common with endoscopic stapling than with alternative procedures. # Other comments Training and post-operative care are of great importance. The 1996/97 'Annual Report of the National Confidential Enquiry into Peri-operative Deaths' recommended that sub-specialisation within otorhinolaryngology departments should occur for this procedure. Andrew Dillon Chief Executive November 2003# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of endoscopic stapling of pharyngeal pouch', November 2002. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of endoscopic stapling of pharyngeal pouch appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.', 'The procedure': "# Indications\n\nPharyngeal pouch, which is also known as Zenker's diverticulum, occurs when a piece of the pharyngeal lining herniates through the muscles of the pharyngeal wall. It occurs mainly in older people, with an estimated overall incidence of about 1 per 100,000 people per year.\n\nPharyngeal pouch may cause difficulty in swallowing or a cough, and sometimes causes respiratory problems because of aspiration of the pouch contents into the lungs.\n\nThe standard treatment for pharyngeal pouch is open surgery to the neck. Endoscopic techniques are less invasive than open surgery. The standard endoscopic technique, known as Dohlman's procedure, uses diathermy or lasers to divide the wall between the pouch and the oesophagus. Endoscopic stapling of pharyngeal pouch is an alternative to the standard endoscopic technique.\n\n# Outline of the procedure\n\nEndoscopic stapling of pharyngeal pouch involves stapling the bar of tissue that divides the pouch from the oesophagus. A specially designed endoscope is used to gain access to the bar and the openings of both the pouch and the oesophagus. The procedure is performed under general anaesthetic.\n\n# Efficacy\n\nThe evidence suggested that endoscopic stapling allows a more rapid recovery, and requires a shorter stay in hospital (1–2 days) than open surgery. Patients returned to normal swallowing promptly. For more details refer to the sources of evidence section.\n\nThe Specialist Advisors considered endoscopic stapling to be an established procedure, now widely practiced in specialist centres by specifically trained otorhinolaryngologists. They considered it effective in terms of reducing operating time and the duration of hospital stay.\n\nThe Specialist Advisors noted that the problem can recur but that the procedure can be repeated if this happens.\n\n# Safety\n\nFew complications were reported in the studies reviewed. Mild bleeding, perforation of the pharynx and a need for nasogastric feeding were reported, but these were uncommon. For more details refer to the sources of evidence section.\n\nThe Specialist Advisors concurred that perforation and leakage from the pharynx were no more common with endoscopic stapling than with alternative procedures.\n\n# Other comments\n\nTraining and post-operative care are of great importance. The 1996/97 'Annual Report of the National Confidential Enquiry into Peri-operative Deaths' recommended that sub-specialisation within otorhinolaryngology departments should occur for this procedure.\n\nAndrew Dillon Chief Executive November 2003", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of endoscopic stapling of pharyngeal pouch', November 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg22
f6b28728ebf3721b897635971926b31ff159507f	nice	Laparoscopic laser myomectomy	Laparoscopic laser myomectomy # Guidance Current evidence on the safety and efficacy of laparoscopic laser myomectomy does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake laparoscopic laser myomectomy should inform the clinical governance leads in their Trusts. They should ensure that patients offered it understand the uncertainty about the procedure's safety and efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present. Clinicians undertaking this procedure should undergo training as recommended by the Royal College of Obstetricians and Gynaecologists Working Party on Training in Endoscopic Surgery.# The procedure # Indications Laparoscopic laser myomectomy is used to treat uterine fibroids, also known as uterine leiomyomas or uterine myomas. Fibroids are benign tumours of the uterine muscle. They are very common and are often asymptomatic. They may cause abnormal bleeding, pelvic pressure and pain, and reproductive problems. Hysterectomy is the standard treatment for women with fibroids whose symptoms have not resolved with medical treatment. # Outline of the procedure Laparoscopic laser myomectomy destroys fibroids using a laparoscope passed through a small incision in the abdomen and then through the wall of the uterus. The fibroids are destroyed with a laser. For more details refer to the sources of evidence section. # Efficacy The evidence reviewed was of poor quality and did not clearly report efficacy outcomes, particularly outcomes relating to symptomatic relief. For more details refer to the sources of evidence section. The Specialist Advisors noted that the indications for this treatment were unclear, which made it difficult to assess its efficacy. One Advisor noted that the procedure was suitable only for removing relatively small fibroids, which tend to be asymptomatic, and therefore questioned the clinical value of the procedure. # Safety The evidence reviewed was too limited to establish the safety of this procedure. For more details refer to the sources of evidence section. The Specialist Advisors reported that there are risks associated with the use of both laparoscopic and laser surgery, including bowel and urinary tract damage, and rupture of the uterine scar during subsequent labour. # Other comments Fibroids that are symptomatic are generally of a size and location that would make treatment by laparoscopic laser myomectomy difficult. Andrew DillonChief ExecutiveNovember 2003# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of laparoscopic laser myomectomy', February 2003. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on laparoscopic laser myomectomy Further recommendations have been made as part of the clinical guideline on heavy menstrual bleeding published in January 2007. Clinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. The IP guidance on Laparoscopic laser myomectomy disease remains current, and should be read in conjunction with the clinical guideline.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of laparoscopic laser myomectomy does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake laparoscopic laser myomectomy should inform the clinical governance leads in their Trusts. They should ensure that patients offered it understand the uncertainty about the procedure's safety and efficacy and should provide them with clear written information. Use of the Institute's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.\n\nClinicians undertaking this procedure should undergo training as recommended by the Royal College of Obstetricians and Gynaecologists Working Party on Training in Endoscopic Surgery.", 'The procedure': '# Indications\n\nLaparoscopic laser myomectomy is used to treat uterine fibroids, also known as uterine leiomyomas or uterine myomas. Fibroids are benign tumours of the uterine muscle. They are very common and are often asymptomatic. They may cause abnormal bleeding, pelvic pressure and pain, and reproductive problems.\n\nHysterectomy is the standard treatment for women with fibroids whose symptoms have not resolved with medical treatment.\n\n# Outline of the procedure\n\nLaparoscopic laser myomectomy destroys fibroids using a laparoscope passed through a small incision in the abdomen and then through the wall of the uterus. The fibroids are destroyed with a laser. For more details refer to the sources of evidence section.\n\n# Efficacy\n\nThe evidence reviewed was of poor quality and did not clearly report efficacy outcomes, particularly outcomes relating to symptomatic relief. For more details refer to the sources of evidence section.\n\nThe Specialist Advisors noted that the indications for this treatment were unclear, which made it difficult to assess its efficacy. One Advisor noted that the procedure was suitable only for removing relatively small fibroids, which tend to be asymptomatic, and therefore questioned the clinical value of the procedure.\n\n# Safety\n\nThe evidence reviewed was too limited to establish the safety of this procedure. For more details refer to the sources of evidence section.\n\nThe Specialist Advisors reported that there are risks associated with the use of both laparoscopic and laser surgery, including bowel and urinary tract damage, and rupture of the uterine scar during subsequent labour.\n\n# Other comments\n\nFibroids that are symptomatic are generally of a size and location that would make treatment by laparoscopic laser myomectomy difficult.\n\nAndrew DillonChief ExecutiveNovember 2003', 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of laparoscopic laser myomectomy', February 2003.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Other NICE recommendations on laparoscopic laser myomectomy ': 'Further recommendations have been made as part of the clinical guideline on heavy menstrual bleeding published in January 2007. Clinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. The IP guidance on Laparoscopic laser myomectomy disease remains current, and should be read in conjunction with the clinical guideline.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg23
994e286afc1ba964a8854149b36b3c97b2006c51	nice	Holmium laser prostatectomy	Holmium laser prostatectomy # Guidance Current evidence on the safety and efficacy of holmium laser prostatectomy appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance. Clinicians undertaking this procedure require specialist training. The British Association of Urological Surgeons has agreed to produce training standards.# The procedure # Indications Benign prostatic obstruction (BPO) is due to a non-malignant enlargement of the prostate. It is a common cause of bladder outlet obstruction and lower urinary tract symptoms in men over 40 years of age. Holmium laser prostatectomy is used to treat BPO. The procedure is used both for resection and enucleation of prostatic tissue. BPO can be managed medically or surgically. The standard surgical treatment of BPO is transurethral resection of the prostate (TURP). However, relatively high morbidity associated with TURP has led to the development of a range of minimally invasive techniques, some of which use thermal energy. One such minimally invasive technique is the use of a holmium:yttrium–aluminium–garnet (YAG) laser. # Outline of the procedure Holmium laser resection of the prostate uses the holmium laser and is performed with a modified continuous flow resectoscope that has a circular fibre guide in the tip of the scope. An end-firing laser fibre is used as a precise cutting instrument to resect large pieces of prostate. The laser is then used to cut the resected tissue into smaller pieces before their removal. A further evolution of the procedure is holmium laser enucleation of the prostate, in which the intact prostatic lobes are removed with the holmium laser and then passed into the bladder where they are cut into smaller pieces before removal. # Efficacy The studies reviewed showed that holmium laser prostatectomy is at least as effective as TURP at improving bladder neck obstruction, symptom scores and quality of life. Duration of catheterisation and hospital stay were reported to be shorter than for TURP. However, the studies were characterised by short follow-up periods and small sample sizes. For more details refer to 'Sources of evidence'. The Specialist Advisors considered holmium laser prostatectomy to be established practice and preferable in many cases to TURP, requiring a shorter stay in hospital. Some Specialist Advisors were concerned about the completeness of evacuation of debris from the bladder after the procedure. # Safety The studies revealed no significant differences in safety between holmium laser prostatectomy and TURP. Blood loss was reported to be lower with holmium laser prostatectomy than with TURP. For more details refer to 'Sources of evidence'. Specialist Advisors had few concerns about the safety of holmium laser prostatectomy, although one expressed concern about damage to the bladder. The Specialist Advisors also noted that there was less blood loss with this procedure than with TURP.# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the interventional procedure overview of holmium laser prostatectomy. # Information for patients NICE has produced information for patients and carers on this procedure. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on holmium laser prostatectomy Further recommendations have been made as part of the clinical guideline on lower urinary tract symptoms published in May 2010, as follows: If offering surgery for managing voiding lower urinary tract symptoms (LUTS) presumed secondary to benign prostatic enlargement (BPE), offer monopolar or bipolar transurethral resection of the prostate (TURP), monopolar transurethral vaporisation of the prostate (TUVP) or holmium laser enucleation of the prostate (HoLEP). Perform HoLEP at a centre specialising in the technique, or with mentorship arrangements in place. Clinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. More information about this guideline is available in NICE's guideline on lower urinary tract symptoms in men on the NICE website. The IP guidance on holmium laser prostatectomy remains current, and should be read in conjunction with the clinical guideline.	{'Guidance': 'Current evidence on the safety and efficacy of holmium laser prostatectomy appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.\n\nClinicians undertaking this procedure require specialist training. The British Association of Urological Surgeons has agreed to produce training standards.', 'The procedure': "# Indications\n\nBenign prostatic obstruction (BPO) is due to a non-malignant enlargement of the prostate. It is a common cause of bladder outlet obstruction and lower urinary tract symptoms in men over 40 years of age. Holmium laser prostatectomy is used to treat BPO. The procedure is used both for resection and enucleation of prostatic tissue.\n\nBPO can be managed medically or surgically. The standard surgical treatment of BPO is transurethral resection of the prostate (TURP). However, relatively high morbidity associated with TURP has led to the development of a range of minimally invasive techniques, some of which use thermal energy. One such minimally invasive technique is the use of a holmium:yttrium–aluminium–garnet (YAG) laser.\n\n# Outline of the procedure\n\nHolmium laser resection of the prostate uses the holmium laser and is performed with a modified continuous flow resectoscope that has a circular fibre guide in the tip of the scope. An end-firing laser fibre is used as a precise cutting instrument to resect large pieces of prostate. The laser is then used to cut the resected tissue into smaller pieces before their removal.\n\nA further evolution of the procedure is holmium laser enucleation of the prostate, in which the intact prostatic lobes are removed with the holmium laser and then passed into the bladder where they are cut into smaller pieces before removal.\n\n# Efficacy\n\nThe studies reviewed showed that holmium laser prostatectomy is at least as effective as TURP at improving bladder neck obstruction, symptom scores and quality of life. Duration of catheterisation and hospital stay were reported to be shorter than for TURP. However, the studies were characterised by short follow-up periods and small sample sizes. For more details refer to 'Sources of evidence'.\n\nThe Specialist Advisors considered holmium laser prostatectomy to be established practice and preferable in many cases to TURP, requiring a shorter stay in hospital. Some Specialist Advisors were concerned about the completeness of evacuation of debris from the bladder after the procedure.\n\n# Safety\n\nThe studies revealed no significant differences in safety between holmium laser prostatectomy and TURP. Blood loss was reported to be lower with holmium laser prostatectomy than with TURP. For more details refer to 'Sources of evidence'.\n\nSpecialist Advisors had few concerns about the safety of holmium laser prostatectomy, although one expressed concern about damage to the bladder. The Specialist Advisors also noted that there was less blood loss with this procedure than with TURP.", 'Further information': '# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the interventional procedure overview of holmium laser prostatectomy.\n\n# Information for patients\n\nNICE has produced information for patients and carers on this procedure. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'Other NICE recommendations on holmium laser prostatectomy': "Further recommendations have been made as part of the clinical guideline on lower urinary tract symptoms published in May 2010, as follows:\n\nIf offering surgery for managing voiding lower urinary tract symptoms (LUTS) presumed secondary to benign prostatic enlargement (BPE), offer monopolar or bipolar transurethral resection of the prostate (TURP), monopolar transurethral vaporisation of the prostate (TUVP) or holmium laser enucleation of the prostate (HoLEP). Perform HoLEP at a centre specialising in the technique, or with mentorship arrangements in place.\n\nClinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. More information about this guideline is available in NICE's guideline on lower urinary tract symptoms in men on the NICE website.\n\nThe IP guidance on holmium laser prostatectomy remains current, and should be read in conjunction with the clinical guideline."}	https://www.nice.org.uk/guidance/ipg17
b1bae1712664c69cda1aaa8e90d443d7ba507f13	nice	Deep brain stimulation for Parkinson's disease	Deep brain stimulation for Parkinson's disease # Guidance Current evidence on the safety and efficacy of deep brain stimulation for Parkinson's disease appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance. The clinical and cost effectiveness of deep brain stimulation for Parkinson's disease is being evaluated by the PD Surg trial, which is expected to complete randomisation in 2005/6. The results of this trial are likely to provide evidence on the most appropriate use of the procedure and clinicians are encouraged to consider randomising patients in the trial. It is recommended that patient selection should be made with the involvement of a multidisciplinary team, and that patients should be offered the procedure only when their disease has become refractory to best medical treatment.# The procedure # Indications Parkinson's disease is a chronic disease of the brain characterised by gradually worsening tremor, muscle rigidity and difficulties with starting and stopping movements. The condition is usually treated with drugs. Surgery may be considered in people who have responded poorly to drugs, who have severe side effects from medication or who have severe fluctuations in response to drugs (on–off syndrome). Parkinson's disease is common, affecting about 0.5% of people aged 65 to 74 years and 1–2% of people aged 75 years and older. Experts believe that 1–10% of people with Parkinson's disease might be suitable for brain surgery. Surgery for Parkinson's disease is carried out on structures within the brain that are responsible for the modification of movements, such as the thalamus, the globus pallidus and the subthalamic nucleus. Each of these structures consists of two parts: one on the left hand side of the brain and one on the right. Surgery may be carried out on one or both sides. Surgical treatment aims to correct the imbalance created by diminished function of the substantia nigra, the underlying abnormality in Parkinson's disease. Surgery alters, through either destruction or electrical stimulation, the function of brain nuclei – such as the thalamus, globus pallidus or subthalamus – that interact functionally with the substantia nigra. Deep brain stimulation is one form of surgery for Parkinson's disease. # Outline of the procedure This procedure involves inserting very fine needles into the brain through small holes made in the skull to determine the exact position of the nucleus to be stimulated, which may be different in each patient. This part of the procedure is usually carried out under local anaesthetic. Once the nucleus is identified, a permanent electrode is placed into it. Under general anaesthetic, this electrode is then connected to a pulse generator, which is implanted subcutaneously on the anterior chest wall. # Efficacy The evidence suggested that deep brain stimulation results in improved motor skills, function and movement in patients with Parkinson's disease. For more details refer to 'Sources of evidence'. The Specialist Advisors considered the procedure to be established practice within specialised units. They did not question short-term efficacy, but commented that long-term efficacy was unknown. One Specialist Advisor commented that careful selection of patients was crucial to maximise the chances of success of the procedure. # Safety The complications associated with deep brain stimulation include risk of stroke, confusion, speech disorders and visual problems. In the two largest studies, involving 102 and 111 patients, the incidence of stroke was approximately 3%. For more details refer to 'Sources of evidence'. The Specialist Advisors noted that all procedures involving deep brain stimulation carried similar risks. They considered the procedure to be safe if performed by a multidisciplinary team in a neuroscience unit. The team should include a neurologist and a neurosurgeon, and the unit should have facilities for psychological assessment and, ideally, neurophysiology. # Other comments The Interventional Procedures Advisory Committee noted that current evidence relates to relatively young patients. Andrew DillonChief ExecutiveNovember 2003# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of deep brain stimulation in Parkinson's disease', April 2003. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on deep brain stimulation Further recommendations have been made as part of the clinical guideline on Parkinson's disease published in June 2006. Clinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. The IP guidance on deep brain stimulation for Parkinson's disease remains current, and should be read in conjunction with the clinical guideline.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of deep brain stimulation for Parkinson's disease appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.\n\nThe clinical and cost effectiveness of deep brain stimulation for Parkinson's disease is being evaluated by the PD Surg trial, which is expected to complete randomisation in 2005/6. The results of this trial are likely to provide evidence on the most appropriate use of the procedure and clinicians are encouraged to consider randomising patients in the trial.\n\nIt is recommended that patient selection should be made with the involvement of a multidisciplinary team, and that patients should be offered the procedure only when their disease has become refractory to best medical treatment.", 'The procedure': "# Indications\n\nParkinson's disease is a chronic disease of the brain characterised by gradually worsening tremor, muscle rigidity and difficulties with starting and stopping movements. The condition is usually treated with drugs. Surgery may be considered in people who have responded poorly to drugs, who have severe side effects from medication or who have severe fluctuations in response to drugs (on–off syndrome).\n\nParkinson's disease is common, affecting about 0.5% of people aged 65 to 74 years and 1–2% of people aged 75 years and older. Experts believe that 1–10% of people with Parkinson's disease might be suitable for brain surgery.\n\nSurgery for Parkinson's disease is carried out on structures within the brain that are responsible for the modification of movements, such as the thalamus, the globus pallidus and the subthalamic nucleus. Each of these structures consists of two parts: one on the left hand side of the brain and one on the right. Surgery may be carried out on one or both sides.\n\nSurgical treatment aims to correct the imbalance created by diminished function of the substantia nigra, the underlying abnormality in Parkinson's disease. Surgery alters, through either destruction or electrical stimulation, the function of brain nuclei – such as the thalamus, globus pallidus or subthalamus – that interact functionally with the substantia nigra. Deep brain stimulation is one form of surgery for Parkinson's disease.\n\n# Outline of the procedure\n\nThis procedure involves inserting very fine needles into the brain through small holes made in the skull to determine the exact position of the nucleus to be stimulated, which may be different in each patient. This part of the procedure is usually carried out under local anaesthetic. Once the nucleus is identified, a permanent electrode is placed into it. Under general anaesthetic, this electrode is then connected to a pulse generator, which is implanted subcutaneously on the anterior chest wall.\n\n# Efficacy\n\nThe evidence suggested that deep brain stimulation results in improved motor skills, function and movement in patients with Parkinson's disease. For more details refer to 'Sources of evidence'.\n\nThe Specialist Advisors considered the procedure to be established practice within specialised units. They did not question short-term efficacy, but commented that long-term efficacy was unknown. One Specialist Advisor commented that careful selection of patients was crucial to maximise the chances of success of the procedure.\n\n# Safety\n\nThe complications associated with deep brain stimulation include risk of stroke, confusion, speech disorders and visual problems. In the two largest studies, involving 102 and 111 patients, the incidence of stroke was approximately 3%. For more details refer to 'Sources of evidence'.\n\nThe Specialist Advisors noted that all procedures involving deep brain stimulation carried similar risks. They considered the procedure to be safe if performed by a multidisciplinary team in a neuroscience unit. The team should include a neurologist and a neurosurgeon, and the unit should have facilities for psychological assessment and, ideally, neurophysiology.\n\n# Other comments\n\nThe Interventional Procedures Advisory Committee noted that current evidence relates to relatively young patients.\n\nAndrew DillonChief ExecutiveNovember 2003", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of deep brain stimulation in Parkinson's disease', April 2003.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Other NICE recommendations on deep brain stimulation': "Further recommendations have been made as part of the clinical guideline on Parkinson's disease published in June 2006.\n\nClinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. The IP guidance on deep brain stimulation for Parkinson's disease remains current, and should be read in conjunction with the clinical guideline.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg19
6255cf1bb9d1a93380d63995f2c1459aef70cf01	nice	Bone-anchored cystourethropexy	Bone-anchored cystourethropexy Evidence-based recommendations on bone-anchored cystourethropexy for treating stress urinary incontinence in women. Bone-anchored cystourethropexy is a minimally invasive bladder neck needle suspension procedure. # Guidance Current evidence of the safety and efficacy of bone-anchored cystourethropexy does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake bone-anchored cystourethropexy should inform the clinical governance leads in their Trusts. They should ensure that patients offered it understand the uncertainty about the procedure's safety and efficacy and should provide them with clear written information. In particular patients should be informed that the long-term efficacy of the procedure appears to be poor. Use of NICE's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.# The procedure # Indications Bone-anchored cystourethropexy is used to treat stress incontinence in women. Stress incontinence refers to urine leakage that occurs when the pressure within the abdomen is raised during, for example, lifting, coughing or laughing. It is often a result of damage to the pelvic muscles during childbirth, which leads to the bladder 'dropping', so that the normal muscular mechanism that prevents the flow of urine into the urethra is disturbed. Stress urinary incontinence is a common problem. Most women with stress incontinence are treated without surgery. Surgical options in women with stress incontinence include colposuspension and sling procedures. During 2000/01, about 10,000 operations on the outlet of the female bladder were carried out in England. These were largely performed through open abdominal operations or transvaginally. # Outline of the procedure Bone-anchored cystourethropexy is a minimally invasive bladder-neck needle-suspension procedure. Bone anchors are screwed into the pubic bone through the vagina or by a small abdominal incision. Sutures are passed into the vaginal wall on either side of the bladder neck and pulled upwards to elevate the vaginal wall and the bladder neck. These sutures are then tied to the bone anchors. # Efficacy In three studies of the In-tac® cystourethropexy bone-anchoring system, 1-year continence rates were between 80% (24/30) and 82% (50/61). In a more recent case series of 28 women with a mean follow-up of 67.7 months, only six (21.4%) women remained continent at final follow-up. Four studies of the Vesica® cystourethropexy bone-anchoring system have followed up women for at least 1 year, with one study reporting on 5-year outcomes. This study reported that 95% (39/41) of women were continent at 6 months but only 15% (6/41) remained continent at 5 years. For more details refer to 'Sources of evidence'. The Specialist Advisors considered that the long-term data for this procedure were poor. # Safety The studies reported a number of complications including bone and urinary tract infection, urinary retention and dyspareunia. However, the incidence of these complications was low. The procedure may be undertaken percutaneously or transvaginally and these approaches may be associated with different complication rates. For more details refer to 'Sources of evidence'. The Specialist Advisors reported that osteomyelitis is a potentially important complication. # Other comments Evidence was presented to the Interventional Procedures Advisory Committee on the use of two devices for this procedure (In-tac‚ and Vesica‚) as specified in the Safety and Efficacy Register of New Interventional Procedures (SERNIP). The Committee's decision was made on the basis of data from the use of these two devices.# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following documents. Interventional procedure overview of bone-anchored cystourethropexy (In-tac®) Interventional procedure overview of bone-anchored cystourethropexy (Vesica®) # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.	{'Guidance': "Current evidence of the safety and efficacy of bone-anchored cystourethropexy does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research. Clinicians wishing to undertake bone-anchored cystourethropexy should inform the clinical governance leads in their Trusts. They should ensure that patients offered it understand the uncertainty about the procedure's safety and efficacy and should provide them with clear written information. In particular patients should be informed that the long-term efficacy of the procedure appears to be poor. Use of NICE's information for the public is recommended. Clinicians should ensure that appropriate arrangements are in place for audit or research. Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. NICE is not undertaking further investigation at present.", 'The procedure': "# Indications\n\nBone-anchored cystourethropexy is used to treat stress incontinence in women. Stress incontinence refers to urine leakage that occurs when the pressure within the abdomen is raised during, for example, lifting, coughing or laughing. It is often a result of damage to the pelvic muscles during childbirth, which leads to the bladder 'dropping', so that the normal muscular mechanism that prevents the flow of urine into the urethra is disturbed.\n\nStress urinary incontinence is a common problem. Most women with stress incontinence are treated without surgery. Surgical options in women with stress incontinence include colposuspension and sling procedures. During 2000/01, about 10,000 operations on the outlet of the female bladder were carried out in England. These were largely performed through open abdominal operations or transvaginally.\n\n# Outline of the procedure\n\nBone-anchored cystourethropexy is a minimally invasive bladder-neck needle-suspension procedure. Bone anchors are screwed into the pubic bone through the vagina or by a small abdominal incision. Sutures are passed into the vaginal wall on either side of the bladder neck and pulled upwards to elevate the vaginal wall and the bladder neck. These sutures are then tied to the bone anchors.\n\n# Efficacy\n\nIn three studies of the In-tac® cystourethropexy bone-anchoring system, 1-year continence rates were between 80% (24/30) and 82% (50/61). In a more recent case series of 28 women with a mean follow-up of 67.7 months, only six (21.4%) women remained continent at final follow-up. Four studies of the Vesica® cystourethropexy bone-anchoring system have followed up women for at least 1 year, with one study reporting on 5-year outcomes. This study reported that 95% (39/41) of women were continent at 6 months but only 15% (6/41) remained continent at 5 years. For more details refer to 'Sources of evidence'.\n\nThe Specialist Advisors considered that the long-term data for this procedure were poor.\n\n# Safety\n\nThe studies reported a number of complications including bone and urinary tract infection, urinary retention and dyspareunia. However, the incidence of these complications was low. The procedure may be undertaken percutaneously or transvaginally and these approaches may be associated with different complication rates. For more details refer to 'Sources of evidence'.\n\nThe Specialist Advisors reported that osteomyelitis is a potentially important complication.\n\n# Other comments\n\nEvidence was presented to the Interventional Procedures Advisory Committee on the use of two devices for this procedure (In-tac‚ and Vesica‚) as specified in the Safety and Efficacy Register of New Interventional Procedures (SERNIP). The Committee's decision was made on the basis of data from the use of these two devices.", 'Further information': '# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following documents.\n\nInterventional procedure overview of bone-anchored cystourethropexy (In-tac®)\n\nInterventional procedure overview of bone-anchored cystourethropexy (Vesica®)\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.'}	https://www.nice.org.uk/guidance/ipg18	Evidence-based recommendations on bone-anchored cystourethropexy for treating stress urinary incontinence in women. Bone-anchored cystourethropexy is a minimally invasive bladder neck needle suspension procedure.
d84d8e9944ea71bccd3d221b92348e73d495cd02	nice	Guidance on the use of liquid-based cytology for cervical screening	Guidance on the use of liquid-based cytology for cervical screening Evidence-based recommendations on using liquid-based cytology for cervical screening in adults. # Guidance This guidance replaces 'Liquid-based cytology for cervical screening' (NICE Technology Appraisal Guidance No. 5) issued in June 2000. For details, see 'About this guidance'. It is recommended that liquid-based cytology (LBC) is used as the primary means of processing samples in the cervical screening programme in England and Wales. There is currently insufficient evidence to recommend one LBC product over another. The NHS Cervical Screening Programme and Cervical Screening Wales may wish to consider evaluating further the different products as the method is introduced.# Clinical need and practice The annual incidence of cervical cancer in the UK in 2003 was estimated to be 9.7 per 100,000 population, which corresponds to a mortality rate of 3.9 per 100,000 population (2001). Pre-cancerous cervical cells cause no symptoms and may only be detected by population screening methods. The NHS Cervical Screening Programme (NHSCSP) began national coordination of cervical screening in 1989. The nature of a screening programme is to screen a large subsection of the population (in this case women) to identify a subpopulation that is thought to be at sufficient higher risk of developing a disease such as cervical cancer to warrant further diagnostic investigation and treatment. Diagnostic tests used in screening programmes are not 100% sensitive (some false-negative tests are reported), and there is a possibility that pre-cancerous cells will not be detected in a small number of women. Screening programmes like the NHSCSP and Cervical Screening Wales, which screen women at regular intervals, reduce the likelihood of pre-cancerous cells and invasive cancer being missed on the basis of one false-negative result because they are picked up at subsequent cervical smear tests. The NHSCSP and Cervical Screening Wales use the Papanicolaou (Pap) smear test for cytological screening. Women aged 20–64 years are screened at 3–5-yearly intervals (depending on Strategic Health Authority policy) for the early detection and treatment of pre-cancerous cells, with the aim of reducing the incidence and associated mortality of cervical cancer. Approximately 3.9 million women are tested in England each year, equating to coverage of 71.2% for 3-yearly screening and 81.6% for 5-yearly screening in 2001–02. The Pap smear is usually carried out by a GP or nurse at a primary care or community clinic. Cervical cells are collected using a disposable spatula device, spread on a glass slide and fixed. The slide is then sent to a hospital laboratory where it is stained and examined by a cytologist. Smear tests are evaluated according to morphological features of the cervical cells, which indicate the degree of cellular abnormality (dyskaryosis). In the UK, smears are categorised using the British Society for Clinical Cytologists (BSCC) guidelines as negative, borderline, mild, moderate, severe, '?glandular neoplasia', '?invasive' or inadequate. In the USA, the Bethesda system is used to classify cervical smears as atypical squamous cells of undetermined significance, atypical glandular cells of undetermined significance, low-grade squamous intraepithelial lesions or high-grade squamous intraepithelial lesions. Approximately 90% of cervical cancers are squamous cell carcinomas; the potential precursors of these relate to the borderline, mild, moderate and severe dyskaryosis in the BSCC guidelines or the atypical squamous cells of uncertain significance, low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions in the Bethesda system. Approximately 15% of cervical cancers are adenocarcinomas and are frequently undetected by screening, although potential precursors are recognised (described as cervical glandular intraepithelial neoplasia or adenocarcinoma in situ) and may be detected on cytology as '?glandular neoplasia' in the BSCC classification ('atypical glandular cells of undetermined significance' or adenocarcinoma in situ in the Bethesda system). The BSCC and Bethesda classification systems are similar but not directly comparable. Patient management depends on the classification of the smear test. Women with negative tests are invited for re-screening at the standard 3–5-year interval, while those with borderline or mildly dyskaryotic smears are monitored at a reduced screening interval. Women with moderately or severely dyskaryotic smear tests, mildly dyskaryotic smears on a maximum of two tests, or persistent inadequate or borderline tests are referred for additional diagnostic testing, such as visual examination of the cervix with a binocular microscope (colposcopy), when a tissue biopsy may be taken for histological examination. The principal criteria used to assess the effectiveness of the LBC method compared with the Pap smear are the sensitivity and specificity of each method, and the rate of 'inadequate' specimens. Sensitivity is the extent to which a test identifies true-positive samples (sensitivity decreases as the number of false-negatives rises), and specificity is the extent to which the test excludes true-negatives (specificity decreases as the number of false-positives increases). Knowledge of the prevalence of pre-cancerous disease is required in order to assess the number of false-negatives, and so surrogates of sensitivity are used, such as detection rates for high-grade and low-grade cytological abnormalities. On average, approximately 8% (range of 5.9–11.0%) of Pap smear tests are inadequate; that is they cannot be interpreted because of problems with sample collection or preparation (such as insufficient cervical cells), or the presence of inflammatory cells, blood or mucus, which obscure the sample. Women with inadequate test results are required to attend a repeat test, which is inconvenient and may cause anxiety.# The technology LBC is a new method of cervical cell sample preparation. Samples are collected in the usual way, but using a brush-like device rather than a spatula. The head of the device is rinsed or broken off into a vial of preservative fluid so that most or all of the cervical cells are retained. Samples are transported to the laboratory where they are mixed to disperse the cells. Cellular debris, such as blood or mucus, is removed and a thin layer of cervical cells is deposited on a microscope slide, which is then stained. Potential advantages of the LBC method include an improved means of slide preparation, producing more homogeneous samples than the Pap smear (which may make slides easier to read), increased sensitivity and specificity, and improved efficiency of handling laboratory samples, resulting in increased laboratory productivity. Current methods that use LBC technology include: SurePath (formerly AutoCytePREP or CytoRich LBC)The SurePath method requires that the collection device be retained in the proprietary SurePath collection vial, which contains transport fluid, so that all cervical cells collected are sent to the laboratory. Vials are vortexed and centrifuged by laboratory personnel; all subsequent preparation of the sample and slide is automated using the Prepstain machine, which processes 48 samples at a time. CytoscreenCytoscreen is a manual method of sample preparation using a proprietary sample collection device (CYTOPREP) and transport fluid (CYTeasy). Samples are vortexed and a photometric reading taken to estimate the cellularity of the sample. An aliquot of the sample is centrifuged onto a glass slide that is then stained using normal laboratory procedures. Labonard Easy PrepLabonard Easy Prep is a manual method of sample preparation that uses a proprietary sample collection device (CYTOPREP brush) and fixative (CYTOscreen). An aliquot of sample fluid is placed in a separation chamber attached to a glass slide containing absorbent paper. Cervical cells sediment onto the slide in a thin layer and slides are stained using normal laboratory procedures. ThinPrepThinPrep provides a semi-automated (T2000) or fully automated (T3000) method of sample preparation. Cervical samples are rinsed with proprietary PreservCyt transport medium into a vial, which is then processed by the ThinPrep method using the T2000 or T3000 machine. The T2000 machine processes slides individually, while the T3000 machine is a fully automated device that can batch process up to 80 specimens per cycle. Subsequent staining and microscopic evaluation of the slides is conducted in a similar manner to a conventional smear test. NICE first issued guidance on the use of LBC for cervical screening in June 2000 (see Section 8).# Evidence and interpretation The Appraisal Committee (Appendix A) considered evidence from a number of sources (Appendix B). All evidence reviewed relates to the ThinPrep and SurePath methods of LBC. No information relating to the Labonard Easy Prep or Cytoscreen methods was submitted by the manufacturers or identified during the course of the appraisal. # Clinical effectiveness The Department of Health commissioned an independent evaluation of the English pilot study, which compared LBC with the Pap smear test at three sites (Norfolk and Norwich University Hospital; Southmead Hospital, North Bristol NHS Trust; and Royal Victoria Infirmary, Newcastle upon Tyne). Since the publication of the Assessment Report for the earlier appraisal (see Section 8), evidence has also become available from the following new studies: six studies comparing LBC and Pap smears with a reference method (histology/pathologist diagnosis); eight split-sample studies; six two-cohort studies; a Scottish implementation study; a New Zealand Health Technology Assessment of LBC; and a cross sectional study by Coste et al. A meta-analysis of 14 studies (comprising all new studies, and studies contained in the previous assessment where data were available) comparing the sensitivity of LBC and the Pap smear in the detection of abnormalities of low-grade squamous intraepithelial lesions or greater demonstrated that sensitivity may be up to 12% better with LBC compared with the Pap smear. When the results of the Coste study are included in the meta-analysis, the total sensitivity improvement for LBC is 4.9% for the ordinary population and 2.8% for the high-risk and ordinary populations combined. Split-sample studies and two-cohort studies supported increased sensitivity with LBC. A meta-analysis of six studies that reported specificity found no difference between the specificity of LBC and Pap smear. The English pilot study showed a statistically significant decrease in the number of inadequate samples, from 9.1% with Pap slides to an average of 1.6% with LBC (87% reduction, p < 0.0001). The majority of 34 studies reporting the rate of inadequate samples noted that the rate was reduced with LBC. The English pilot study reported a statistically significant reduction in the detection of glandular neoplasm, from an average of 0.08% with the Pap smear to 0.04% with LBC (RR 0.496, 95% CI 0.292 to 0.807). Follow-up data from the pilot sites demonstrated that although there was a reduction in the cytological detection of glandular neoplasm during the pilot period with LBC, the number of histologically confirmed cases of adenocarcinoma remained unchanged. Pilot study data on the performance of LBC in the post-pilot period demonstrated that the cytological detection of glandular neoplasm with the LBC test is similar to the pre-pilot rate using the Pap smear. # Cost effectiveness A literature review identified four new economic evaluations of LBC compared with the Pap smear in the US population. These are of limited application to the UK because of differences in US incidence rates and costs, and differences in the Bethesda (US) and BSCC (UK) classification systems for cervical smears. PathLore Limited provided a cost analysis of the SurePath test. Increased capital costs of £50,000 and consumables costs of £2.50 per test may be offset by savings from the reduction in the number of inadequate samples and a quicker diagnosis, to give a gross saving of £0.89 per LBC test compared with the Pap smear. This is consistent with the costs reported in the pilot studies. The Assessment Group updated the economic model in the previous Assessment Report with the data from the English pilot study and literature to estimate the incidence of, and mortality from, cervical cancer among women who had had cervical screening using LBC and Pap smear technologies. The model simulated a cohort of 100,000 15-year-old women enrolled in the cervical screening programme (screened between the ages of 21 and 64 years), who were followed throughout their lifetime using a state transition model. Key outcomes of the English pilot study used to update the economic model were the rate of inadequate specimens, and the cost per test (incorporating capital, consumables and the amount of staff time required for smear taking, slide preparation and smear diagnosis). For LBC, the economic evaluation was based on the costs of the T3000 device, which represented the average cost across the three methods. In the English pilot study, laboratory report forms indicated a 5-minute reduction in the time required for smear taking and consultation with LBC (average of 8 minutes and 35 seconds compared with 13 minutes and 20 seconds for the Pap smear). Staff questionnaires estimating the time required for smear taking suggested that the LBC method may be 1 minute quicker than the Pap smear. The extent of the increase in slide preparation time with LBC depended on the labour requirements of different LBC methods. Slide preparation with LBC took 4 minutes and 15 seconds (ThinPrep T2000), 38 seconds (ThinPrep T3000), or 1 minute and 52 seconds (SurePath system) compared with an average of 15 seconds for the conventional Pap smear. The average aggregate cost of LBC was £22.30 (£22.99 for T3000, £23.15 for T2000, and £20.76 for PrepStain) compared with £21.68 for the conventional Pap smear. Overall, there was an increase in the throughput of slides at the screening stage with LBC compared with the Pap smear. At primary screening, 9.04 slides were read per hour with LBC compared with 8.3 slides read per hour with the Pap smear. At rapid review, 44.1 slides were read per hour with LBC compared with 46.7 slides read per hour with Pap, and at slide checking, 12.4 slides were read per hour with LBC compared with 9.5 slides read per hour with the Pap smear. The English pilot study estimated that a one-off transition cost of £10.27 million (see Section 6 for more detail) would be required for the national implementation of LBC. The one-off transition cost of implementing LBC was incorporated into the economic model as a cost of £0.13 per smear test (discounted over a 20-year lifetime of LBC). If the transition cost were discounted over a 10-year lifetime of the LBC technology, this would equate to £0.34 per smear test. Assumptions of the base-case economic analysis were based on data from the English pilot study and included a laboratory processing capacity of 60,000 tests per annum, sensitivity improvements with LBC relative to Pap of 13.4% for the detection of CIN1 and CIN2 combined and 4% for the detection of CIN3, and a reduction in the rate of inadequate samples from 9% with the Pap smear to 1.4% with LBC. The results of the base-case economic analysis demonstrated the following. At each screening interval LBC dominated the Pap smear as it was less costly and more effective. -yearly screening with LBC was found to be a cost-effective alternative to 5-yearly Pap screening, with an incremental cost effectiveness ratio below £8000 per life-year gained. The cost effectiveness of LBC screening at different intervals was compared. The incremental cost-effectiveness ratio of moving from 5-yearly to 3-yearly screening with LBC was £9621 per life-year gained. Conventional screening with the Pap smear at 5-yearly intervals is extremely cost effective compared with no screening, at a cost of £372 per life-year gained. Sensitivity analysis for differences in the natural history of cervical cancer (cancer incidence, progression and regression), sensitivity of LBC and the Pap smear, the rate of inadequate samples and the marginal cost of LBC demonstrated that under most conditions, 5- and 3-yearly screening with LBC is a cost-effective alternative to 5-yearly screening with the Pap test. The assumptions of the base-case analysis were changed to a scenario where there was decreased processing capacity for LBC of 30,000 tests per annum, a 20% increase in capital costs and 50% increase in consumable costs, and a time saving of 1 minute per test at smear taking. The resulting increase of £6.50 in the marginal cost of LBC compared with the Pap smear did not greatly affect the cost effectiveness of screening using the LBC method. Another sensitivity analysis combined an increase in the unit cost of LBC to £25.88 per test that is, £4.21 more than the Pap test, with various improvements in sensitivity with LBC relative to Pap (2.8%, 4.9% and 12%). At 2.8% improved sensitivity relative to the Pap test, the cost per life-year gained of LBC compared with 5-yearly screening with the Pap test was £5500 and £38,250 for 5- and 3-yearly screening respectively. At 4.9% improved sensitivity the cost per life-year gained of LBC compared with 5-yearly screening with the Pap test was £3250 and £22,500 for 5- and 3-yearly screening respectively. At 12% improved sensitivity, the cost per life-year gained of LBC compared with 5-yearly screening with the Pap test was £1500 and £10,250 for 5- and 3-yearly screening respectively. No studies were identified that compared the difference in the quality of life between women who had LBC smears and those who had Pap smears, and thus a cost per quality-adjusted life year for different screening scenarios could not be reliably determined. The Assessment Group's model incorporated the assumption that the decrease in utility associated with living with invasive cancer, undergoing a colposcopy and receiving a borderline test would have an adverse effect on a woman's quality of life because of anxiety. When quality of life is taken into consideration, LBC still dominates conventional screening if the baseline 12% improvement in sensitivity is assumed. The report of the English pilot study also contained an economic evaluation, which was consistent with the results of the model generated by the Assessment Group. The increased capital, consumable and implementation costs of LBC may be offset by savings in the reduction of inadequate samples and time savings in sample collection and time to diagnosis. It was not possible to distinguish between specific LBC technologies on the basis of the available data. # Consideration of the evidence The Committee reviewed the data available on the clinical and cost effectiveness of LBC. It carefully considered results from the pilot site studies undertaken since the original guidance was issued, and the opinions of clinical experts, and took into account the likely effect LBC would have on women taking part in the NHSCSP and Cervical Screening Wales. It was also mindful of the need to take account of the effective use of NHS resources. The Committee considered evidence from cytopathologists and representatives of cervical screeners that LBC produced a more homogeneous cellular preparation that was free from exudates, and that this would be likely to decrease the number of smears classified as inadequate (that is, considered unreadable and in need of repeat smear). However, there were concerns that, with the LBC method, there are no formal criteria defining the adequacy of a slide preparation in terms of the cell numbers required. Because the LBC sample is a homogenate there is no way of verifying that a sufficient number of cervical cells have been harvested by the smear taker. The Committee considered this to be an important issue that must be addressed as part of the implementation of LBC. Poor sampling technique, resulting in the collection of too few cells, could mean that a sample might not adequately represent cells on the surface of the cervix. Consequently abnormalities may be missed, resulting in some false-negative results. However, the Committee concluded that this potential risk of false-negatives should be balanced against the likelihood of abnormalities being detected at a subsequent screen because of the regular screening frequency of the cervical screening programme, and the increased detection of high-grade lesions (severe dyskaryosis) with the LBC technique. Overall, the Committee was persuaded that LBC was likely to be an improvement over the currently used technique, and in particular that the reduction of inadequate smears would be an important benefit to women in the NHSCSP and Cervical Screening Wales because it would reduce the requirement for repeat smears. Experts expressed concerns that sensitivity improvements with LBC may not be as great as 12%, and the Committee was made aware of various confounding factors that may have contributed to the perceived increase in sensitivity of LBC, such as increased training and experience of the smear screeners and the type of sampling device used by the smear takers. However, experts and the Committee agreed that the overall sensitivity of LBC was at least as good as, and may be better than, the Pap smear. The Committee reviewed the recent paper by Coste et al. (2003) and expressed concerns regarding the robustness of the conclusions of the study, which were not in favour of LBC. In the light of the sensitivity analysis that included the results of the Coste study, the Committee concluded that LBC is likely to be a cost-effective alternative to the Pap smear test. In addition, the Committee understood that an important factor in the assessment of the increased sensitivity of LBC was its enhanced ability to detect high-grade lesions (severe dyskaryosis), which was confirmed by the results from the pilot study. The Committee considered the difference in the detection of glandular neoplasm in the English pilot study report, and the potential this may have for differences in the detection of adenocarcinoma between the LBC method and the Pap smear. The Committee reviewed in detail the results from the pilot sites on the rate of histologically proven adenocarcinoma and the evidence from the post-pilot results of detection of glandular abnormalities. They were satisfied on the basis of this evidence that LBC is at least as good at detecting these abnormalities as the Pap smear. The Committee reviewed the report from the UK English pilot study and noted a lack of consistency between the results of the pilot site using the SurePath device and two sites using the ThinPrep device. However, the Committee considered that, taking into account the advice from experts, the possible confounding factors of indirect comparisons, and the fact that the pilot studies were not designed to evaluate clinical effectiveness, there was currently insufficient evidence to suggest that one technique should be recommended over another. The Committee heard from experts that LBC was likely to result in increased productivity in cytology laboratories because of a rise in the number of slides that can be read per hour and a reduced workload as a result of a lower incidence of inadequate samples and a reduced number of repeat smears. Although the screening of LBC thin layers is quicker because of the ease of reading a 'cleaner' slide preparation and screening a smaller area of the slide, it was mentioned that screening LBC slides is more tiring for staff, who consequently may require more breaks. However, the experts involved with the pilot sites said that, overall, smear takers and readers favoured the LBC method above the Pap smear. The Committee considered that, taking into account a number of factors – including the potential for increased sensitivity, reduction of inadequate smears and probable improvements in laboratory efficiency – the LBC method was likely to be cost effective compared with the Pap smear, despite its higher associated cost. The Committee discussed whether the use of LBC would affect the cost effectiveness of population screening at different screening intervals. However, this was considered to be beyond the remit of this review and to be the responsibility of the NHSCSP and Cervical Screening Wales. The Committee was aware that a number of manufacturers have LBC-related products. Evidence received during the appraisal related only to the SurePath and ThinPrep devices – no evidence was provided by the other manufacturers.# Recommendations for further research It is recommended that high-quality studies be undertaken to ompare differences in performance between the ThinPrep and SurePath LBC methods. Validation is needed of the number of cells per LBC sample that will be required to establish the adequacy of smears. For further reviews of LBC, clinical data relating to the sensitivity, specificity and rate of inadequate smears should be provided for EasyPrep, Cytoscreen and any future devices. Evaluation of automated technologies for the analysis of cervical samples is needed.# Implications for the NHS Information in the pilot studies estimated a one-off cost of £10.1–10.3 million for the conversion from Pap smears to LBC in England, which equates to a cost of approximately £73,000 for a local laboratory processing 30,000 tests per annum. These figures only include the cost of training smear takers and laboratory staff, producing training material, sending off a backlog of samples, and structural changes to the laboratory and assume that all GPs and nurses will be trained in the use of LBC. Proportionately similar costs will be incurred in Wales. In both countries the precise costs will be a function of the number and size of laboratories undertaking LBC. The cost of acquiring the LBC slide preparation equipment itself has not been estimated because there are a number of possible solutions that could alter the nature and timing of the cost impact. These solutions should be investigated fully, as part of implementation planning taking into full consideration the cost of consumables and maintenance, as part of a whole life cost analysis demonstrating a value for money solution to the NHS. In England, the NHS Purchasing and Supply Agency will evaluate options for the purchase of capital equipment. Procurement in Wales will be managed on an all-Wales basis by the West Wales Procurement Consortium. If sample preparation using LBC is to be centralised in regional laboratories, consideration will need to be given to the logistics and costs associated with sample transport and communication of the central processing laboratories with the local reporting laboratories. The English pilot report estimated the running costs of Pap smears and LBC to be comparable, and with LBC time savings in the diagnosis of smears may contribute to increased laboratory productivity. In addition, increases in laboratory productivity may reduce the time that patients need to wait for the results of a smear test. The use of LBC in accordance with this guidance is likely to release resources within NHS organisations, although the nature and amounts involved will vary between local NHS communities. Existing smear takers and laboratory staff will need additional training in the LBC method before implementation of the recommendation in Section 1.1. Training of new smear takers and laboratory staff in the LBC method is likely to require similar resources to those for the training of staff in Pap smears. The rate at which LBC is taken up throughout the NHS in England and Wales will depend on a number of logistical factors, which should be determined by the NHSCSP and Cervical Screening Wales with the involvement of the NHS Purchasing and Supplies Agency and the West Wales Procurement Consortium. During this period, the standard cervical screening method will need to run in parallel.# Related guidance NICE issued the following guidance on the use of LBC for cervical screening in June 2000. National Institute for Clinical Excellence (2000) Guidance on the use of liquid-based cytology for cervical screening. NICE Technology Appraisal Guidance No. 5. London: National Institute for Clinical Excellence.# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. The guidance on this technology will be reviewed in August 2006. Andrew DillonChief ExecutiveOctober 2003# Changes after publication March 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance replaces 'Liquid-based cytology for cervical screening' (NICE Technology Appraisal Guidance No. 5) issued in June 2000. The Institute reviews each piece of guidance it issues. The review and re-appraisal of the use of liquid-based cytology for cervical screening has resulted in a change in the guidance. Specifically there has been: a recommendation of the use of liquid-based cytology as the primary means of processing samples in the cervical screening programme in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This guidance replaces 'Liquid-based cytology for cervical screening' (NICE Technology Appraisal Guidance No. 5) issued in June 2000.\n\nFor details, see 'About this guidance'.\n\nIt is recommended that liquid-based cytology (LBC) is used as the primary means of processing samples in the cervical screening programme in England and Wales.\n\nThere is currently insufficient evidence to recommend one LBC product over another. The NHS Cervical Screening Programme and Cervical Screening Wales may wish to consider evaluating further the different products as the method is introduced.", 'Clinical need and practice': "The annual incidence of cervical cancer in the UK in 2003 was estimated to be 9.7 per 100,000 population, which corresponds to a mortality rate of 3.9 per 100,000 population (2001). Pre-cancerous cervical cells cause no symptoms and may only be detected by population screening methods. The NHS Cervical Screening Programme (NHSCSP) began national coordination of cervical screening in 1989. The nature of a screening programme is to screen a large subsection of the population (in this case women) to identify a subpopulation that is thought to be at sufficient higher risk of developing a disease such as cervical cancer to warrant further diagnostic investigation and treatment. Diagnostic tests used in screening programmes are not 100% sensitive (some false-negative tests are reported), and there is a possibility that pre-cancerous cells will not be detected in a small number of women. Screening programmes like the NHSCSP and Cervical Screening Wales, which screen women at regular intervals, reduce the likelihood of pre-cancerous cells and invasive cancer being missed on the basis of one false-negative result because they are picked up at subsequent cervical smear tests.\n\nThe NHSCSP and Cervical Screening Wales use the Papanicolaou (Pap) smear test for cytological screening. Women aged 20–64 years are screened at 3–5-yearly intervals (depending on Strategic Health Authority policy) for the early detection and treatment of pre-cancerous cells, with the aim of reducing the incidence and associated mortality of cervical cancer. Approximately 3.9 million women are tested in England each year, equating to coverage of 71.2% for 3-yearly screening and 81.6% for 5-yearly screening in 2001–02.\n\nThe Pap smear is usually carried out by a GP or nurse at a primary care or community clinic. Cervical cells are collected using a disposable spatula device, spread on a glass slide and fixed. The slide is then sent to a hospital laboratory where it is stained and examined by a cytologist.\n\nSmear tests are evaluated according to morphological features of the cervical cells, which indicate the degree of cellular abnormality (dyskaryosis). In the UK, smears are categorised using the British Society for Clinical Cytologists (BSCC) guidelines as negative, borderline, mild, moderate, severe, '?glandular neoplasia', '?invasive' or inadequate. In the USA, the Bethesda system is used to classify cervical smears as atypical squamous cells of undetermined significance, atypical glandular cells of undetermined significance, low-grade squamous intraepithelial lesions or high-grade squamous intraepithelial lesions. Approximately 90% of cervical cancers are squamous cell carcinomas; the potential precursors of these relate to the borderline, mild, moderate and severe dyskaryosis in the BSCC guidelines or the atypical squamous cells of uncertain significance, low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions in the Bethesda system. Approximately 15% of cervical cancers are adenocarcinomas and are frequently undetected by screening, although potential precursors are recognised (described as cervical glandular intraepithelial neoplasia [CGIN] or adenocarcinoma in situ) and may be detected on cytology as '?glandular neoplasia' in the BSCC classification ('atypical glandular cells of undetermined significance' or adenocarcinoma in situ in the Bethesda system). The BSCC and Bethesda classification systems are similar but not directly comparable.\n\nPatient management depends on the classification of the smear test. Women with negative tests are invited for re-screening at the standard 3–5-year interval, while those with borderline or mildly dyskaryotic smears are monitored at a reduced screening interval. Women with moderately or severely dyskaryotic smear tests, mildly dyskaryotic smears on a maximum of two tests, or persistent inadequate or borderline tests are referred for additional diagnostic testing, such as visual examination of the cervix with a binocular microscope (colposcopy), when a tissue biopsy may be taken for histological examination.\n\nThe principal criteria used to assess the effectiveness of the LBC method compared with the Pap smear are the sensitivity and specificity of each method, and the rate of 'inadequate' specimens. Sensitivity is the extent to which a test identifies true-positive samples (sensitivity decreases as the number of false-negatives rises), and specificity is the extent to which the test excludes true-negatives (specificity decreases as the number of false-positives increases). Knowledge of the prevalence of pre-cancerous disease is required in order to assess the number of false-negatives, and so surrogates of sensitivity are used, such as detection rates for high-grade and low-grade cytological abnormalities.\n\nOn average, approximately 8% (range of 5.9–11.0%) of Pap smear tests are inadequate; that is they cannot be interpreted because of problems with sample collection or preparation (such as insufficient cervical cells), or the presence of inflammatory cells, blood or mucus, which obscure the sample. Women with inadequate test results are required to attend a repeat test, which is inconvenient and may cause anxiety.", 'The technology': 'LBC is a new method of cervical cell sample preparation. Samples are collected in the usual way, but using a brush-like device rather than a spatula. The head of the device is rinsed or broken off into a vial of preservative fluid so that most or all of the cervical cells are retained. Samples are transported to the laboratory where they are mixed to disperse the cells. Cellular debris, such as blood or mucus, is removed and a thin layer of cervical cells is deposited on a microscope slide, which is then stained.\n\nPotential advantages of the LBC method include an improved means of slide preparation, producing more homogeneous samples than the Pap smear (which may make slides easier to read), increased sensitivity and specificity, and improved efficiency of handling laboratory samples, resulting in increased laboratory productivity.\n\nCurrent methods that use LBC technology include:\n\nSurePath (formerly AutoCytePREP or CytoRich LBC)The SurePath method requires that the collection device be retained in the proprietary SurePath collection vial, which contains transport fluid, so that all cervical cells collected are sent to the laboratory. Vials are vortexed and centrifuged by laboratory personnel; all subsequent preparation of the sample and slide is automated using the Prepstain machine, which processes 48 samples at a time.\n\nCytoscreenCytoscreen is a manual method of sample preparation using a proprietary sample collection device (CYTOPREP) and transport fluid (CYTeasy). Samples are vortexed and a photometric reading taken to estimate the cellularity of the sample. An aliquot of the sample is centrifuged onto a glass slide that is then stained using normal laboratory procedures.\n\nLabonard Easy PrepLabonard Easy Prep is a manual method of sample preparation that uses a proprietary sample collection device (CYTOPREP brush) and fixative (CYTOscreen). An aliquot of sample fluid is placed in a separation chamber attached to a glass slide containing absorbent paper. Cervical cells sediment onto the slide in a thin layer and slides are stained using normal laboratory procedures.\n\nThinPrepThinPrep provides a semi-automated (T2000) or fully automated (T3000) method of sample preparation. Cervical samples are rinsed with proprietary PreservCyt transport medium into a vial, which is then processed by the ThinPrep method using the T2000 or T3000 machine. The T2000 machine processes slides individually, while the T3000 machine is a fully automated device that can batch process up to 80 specimens per cycle. Subsequent staining and microscopic evaluation of the slides is conducted in a similar manner to a conventional smear test.\n\nNICE first issued guidance on the use of LBC for cervical screening in June 2000 (see Section 8).', 'Evidence and interpretation': "The Appraisal Committee (Appendix A) considered evidence from a number of sources (Appendix B).\n\nAll evidence reviewed relates to the ThinPrep and SurePath methods of LBC. No information relating to the Labonard Easy Prep or Cytoscreen methods was submitted by the manufacturers or identified during the course of the appraisal.\n\n# Clinical effectiveness\n\nThe Department of Health commissioned an independent evaluation of the English pilot study, which compared LBC with the Pap smear test at three sites (Norfolk and Norwich University Hospital; Southmead Hospital, North Bristol NHS Trust; and Royal Victoria Infirmary, Newcastle upon Tyne). Since the publication of the Assessment Report for the earlier appraisal (see Section 8), evidence has also become available from the following new studies: six studies comparing LBC and Pap smears with a reference method (histology/pathologist diagnosis); eight split-sample studies; six two-cohort studies; a Scottish implementation study; a New Zealand Health Technology Assessment of LBC; and a cross sectional study by Coste et al.\n\nA meta-analysis of 14 studies (comprising all new studies, and studies contained in the previous assessment where data were available) comparing the sensitivity of LBC and the Pap smear in the detection of abnormalities of low-grade squamous intraepithelial lesions or greater demonstrated that sensitivity may be up to 12% better with LBC compared with the Pap smear. When the results of the Coste study are included in the meta-analysis, the total sensitivity improvement for LBC is 4.9% for the ordinary population and 2.8% for the high-risk and ordinary populations combined. Split-sample studies and two-cohort studies supported increased sensitivity with LBC.\n\nA meta-analysis of six studies that reported specificity found no difference between the specificity of LBC and Pap smear.\n\nThe English pilot study showed a statistically significant decrease in the number of inadequate samples, from 9.1% with Pap slides to an average of 1.6% with LBC (87% reduction, p < 0.0001). The majority of 34 studies reporting the rate of inadequate samples noted that the rate was reduced with LBC.\n\nThe English pilot study reported a statistically significant reduction in the detection of glandular neoplasm, from an average of 0.08% with the Pap smear to 0.04% with LBC (RR 0.496, 95% CI 0.292 to 0.807). Follow-up data from the pilot sites demonstrated that although there was a reduction in the cytological detection of glandular neoplasm during the pilot period with LBC, the number of histologically confirmed cases of adenocarcinoma remained unchanged. Pilot study data on the performance of LBC in the post-pilot period demonstrated that the cytological detection of glandular neoplasm with the LBC test is similar to the pre-pilot rate using the Pap smear.\n\n# Cost effectiveness\n\nA literature review identified four new economic evaluations of LBC compared with the Pap smear in the US population. These are of limited application to the UK because of differences in US incidence rates and costs, and differences in the Bethesda (US) and BSCC (UK) classification systems for cervical smears.\n\nPathLore Limited provided a cost analysis of the SurePath test. Increased capital costs of £50,000 and consumables costs of £2.50 per test may be offset by savings from the reduction in the number of inadequate samples and a quicker diagnosis, to give a gross saving of £0.89 per LBC test compared with the Pap smear. This is consistent with the costs reported in the pilot studies.\n\nThe Assessment Group updated the economic model in the previous Assessment Report with the data from the English pilot study and literature to estimate the incidence of, and mortality from, cervical cancer among women who had had cervical screening using LBC and Pap smear technologies. The model simulated a cohort of 100,000 15-year-old women enrolled in the cervical screening programme (screened between the ages of 21 and 64 years), who were followed throughout their lifetime using a state transition model. Key outcomes of the English pilot study used to update the economic model were the rate of inadequate specimens, and the cost per test (incorporating capital, consumables and the amount of staff time required for smear taking, slide preparation and smear diagnosis). For LBC, the economic evaluation was based on the costs of the T3000 device, which represented the average cost across the three methods.\n\nIn the English pilot study, laboratory report forms indicated a 5-minute reduction in the time required for smear taking and consultation with LBC (average of 8 minutes and 35 seconds compared with 13 minutes and 20 seconds for the Pap smear). Staff questionnaires estimating the time required for smear taking suggested that the LBC method may be 1 minute quicker than the Pap smear. The extent of the increase in slide preparation time with LBC depended on the labour requirements of different LBC methods. Slide preparation with LBC took 4 minutes and 15 seconds (ThinPrep T2000), 38 seconds (ThinPrep T3000), or 1 minute and 52 seconds (SurePath system) compared with an average of 15 seconds for the conventional Pap smear. The average aggregate cost of LBC was £22.30 (£22.99 for T3000, £23.15 for T2000, and £20.76 for PrepStain) compared with £21.68 for the conventional Pap smear. Overall, there was an increase in the throughput of slides at the screening stage with LBC compared with the Pap smear. At primary screening, 9.04 slides were read per hour with LBC compared with 8.3 slides read per hour with the Pap smear. At rapid review, 44.1 slides were read per hour with LBC compared with 46.7 slides read per hour with Pap, and at slide checking, 12.4 slides were read per hour with LBC compared with 9.5 slides read per hour with the Pap smear.\n\nThe English pilot study estimated that a one-off transition cost of £10.27 million (see Section 6 for more detail) would be required for the national implementation of LBC. The one-off transition cost of implementing LBC was incorporated into the economic model as a cost of £0.13 per smear test (discounted over a 20-year lifetime of LBC). If the transition cost were discounted over a 10-year lifetime of the LBC technology, this would equate to £0.34 per smear test.\n\nAssumptions of the base-case economic analysis were based on data from the English pilot study and included a laboratory processing capacity of 60,000 tests per annum, sensitivity improvements with LBC relative to Pap of 13.4% for the detection of CIN1 and CIN2 combined and 4% for the detection of CIN3, and a reduction in the rate of inadequate samples from 9% with the Pap smear to 1.4% with LBC. The results of the base-case economic analysis demonstrated the following.\n\nAt each screening interval LBC dominated the Pap smear as it was less costly and more effective.\n\n-yearly screening with LBC was found to be a cost-effective alternative to 5-yearly Pap screening, with an incremental cost effectiveness ratio below £8000 per life-year gained.\n\nThe cost effectiveness of LBC screening at different intervals was compared. The incremental cost-effectiveness ratio of moving from 5-yearly to 3-yearly screening with LBC was £9621 per life-year gained.\n\nConventional screening with the Pap smear at 5-yearly intervals is extremely cost effective compared with no screening, at a cost of £372 per life-year gained.\n\nSensitivity analysis for differences in the natural history of cervical cancer (cancer incidence, progression and regression), sensitivity of LBC and the Pap smear, the rate of inadequate samples and the marginal cost of LBC demonstrated that under most conditions, 5- and 3-yearly screening with LBC is a cost-effective alternative to 5-yearly screening with the Pap test.\n\nThe assumptions of the base-case analysis were changed to a scenario where there was decreased processing capacity for LBC of 30,000 tests per annum, a 20% increase in capital costs and 50% increase in consumable costs, and a time saving of 1 minute per test at smear taking. The resulting increase of £6.50 in the marginal cost of LBC compared with the Pap smear did not greatly affect the cost effectiveness of screening using the LBC method.\n\nAnother sensitivity analysis combined an increase in the unit cost of LBC to £25.88 per test that is, £4.21 more than the Pap test, with various improvements in sensitivity with LBC relative to Pap (2.8%, 4.9% and 12%). At 2.8% improved sensitivity relative to the Pap test, the cost per life-year gained of LBC compared with 5-yearly screening with the Pap test was £5500 and £38,250 for 5- and 3-yearly screening respectively. At 4.9% improved sensitivity the cost per life-year gained of LBC compared with 5-yearly screening with the Pap test was £3250 and £22,500 for 5- and 3-yearly screening respectively. At 12% improved sensitivity, the cost per life-year gained of LBC compared with 5-yearly screening with the Pap test was £1500 and £10,250 for 5- and 3-yearly screening respectively.\n\nNo studies were identified that compared the difference in the quality of life between women who had LBC smears and those who had Pap smears, and thus a cost per quality-adjusted life year for different screening scenarios could not be reliably determined. The Assessment Group's model incorporated the assumption that the decrease in utility associated with living with invasive cancer, undergoing a colposcopy and receiving a borderline test would have an adverse effect on a woman's quality of life because of anxiety. When quality of life is taken into consideration, LBC still dominates conventional screening if the baseline 12% improvement in sensitivity is assumed.\n\nThe report of the English pilot study also contained an economic evaluation, which was consistent with the results of the model generated by the Assessment Group.\n\nThe increased capital, consumable and implementation costs of LBC may be offset by savings in the reduction of inadequate samples and time savings in sample collection and time to diagnosis. It was not possible to distinguish between specific LBC technologies on the basis of the available data.\n\n# Consideration of the evidence\n\nThe Committee reviewed the data available on the clinical and cost effectiveness of LBC. It carefully considered results from the pilot site studies undertaken since the original guidance was issued, and the opinions of clinical experts, and took into account the likely effect LBC would have on women taking part in the NHSCSP and Cervical Screening Wales. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee considered evidence from cytopathologists and representatives of cervical screeners that LBC produced a more homogeneous cellular preparation that was free from exudates, and that this would be likely to decrease the number of smears classified as inadequate (that is, considered unreadable and in need of repeat smear). However, there were concerns that, with the LBC method, there are no formal criteria defining the adequacy of a slide preparation in terms of the cell numbers required. Because the LBC sample is a homogenate there is no way of verifying that a sufficient number of cervical cells have been harvested by the smear taker. The Committee considered this to be an important issue that must be addressed as part of the implementation of LBC. Poor sampling technique, resulting in the collection of too few cells, could mean that a sample might not adequately represent cells on the surface of the cervix. Consequently abnormalities may be missed, resulting in some false-negative results. However, the Committee concluded that this potential risk of false-negatives should be balanced against the likelihood of abnormalities being detected at a subsequent screen because of the regular screening frequency of the cervical screening programme, and the increased detection of high-grade lesions (severe dyskaryosis) with the LBC technique. Overall, the Committee was persuaded that LBC was likely to be an improvement over the currently used technique, and in particular that the reduction of inadequate smears would be an important benefit to women in the NHSCSP and Cervical Screening Wales because it would reduce the requirement for repeat smears.\n\nExperts expressed concerns that sensitivity improvements with LBC may not be as great as 12%, and the Committee was made aware of various confounding factors that may have contributed to the perceived increase in sensitivity of LBC, such as increased training and experience of the smear screeners and the type of sampling device used by the smear takers. However, experts and the Committee agreed that the overall sensitivity of LBC was at least as good as, and may be better than, the Pap smear.\n\nThe Committee reviewed the recent paper by Coste et al. (2003) and expressed concerns regarding the robustness of the conclusions of the study, which were not in favour of LBC. In the light of the sensitivity analysis that included the results of the Coste study, the Committee concluded that LBC is likely to be a cost-effective alternative to the Pap smear test. In addition, the Committee understood that an important factor in the assessment of the increased sensitivity of LBC was its enhanced ability to detect high-grade lesions (severe dyskaryosis), which was confirmed by the results from the pilot study.\n\nThe Committee considered the difference in the detection of glandular neoplasm in the English pilot study report, and the potential this may have for differences in the detection of adenocarcinoma between the LBC method and the Pap smear. The Committee reviewed in detail the results from the pilot sites on the rate of histologically proven adenocarcinoma and the evidence from the post-pilot results of detection of glandular abnormalities. They were satisfied on the basis of this evidence that LBC is at least as good at detecting these abnormalities as the Pap smear.\n\nThe Committee reviewed the report from the UK English pilot study and noted a lack of consistency between the results of the pilot site using the SurePath device and two sites using the ThinPrep device. However, the Committee considered that, taking into account the advice from experts, the possible confounding factors of indirect comparisons, and the fact that the pilot studies were not designed to evaluate clinical effectiveness, there was currently insufficient evidence to suggest that one technique should be recommended over another.\n\nThe Committee heard from experts that LBC was likely to result in increased productivity in cytology laboratories because of a rise in the number of slides that can be read per hour and a reduced workload as a result of a lower incidence of inadequate samples and a reduced number of repeat smears. Although the screening of LBC thin layers is quicker because of the ease of reading a 'cleaner' slide preparation and screening a smaller area of the slide, it was mentioned that screening LBC slides is more tiring for staff, who consequently may require more breaks. However, the experts involved with the pilot sites said that, overall, smear takers and readers favoured the LBC method above the Pap smear.\n\nThe Committee considered that, taking into account a number of factors – including the potential for increased sensitivity, reduction of inadequate smears and probable improvements in laboratory efficiency – the LBC method was likely to be cost effective compared with the Pap smear, despite its higher associated cost. The Committee discussed whether the use of LBC would affect the cost effectiveness of population screening at different screening intervals. However, this was considered to be beyond the remit of this review and to be the responsibility of the NHSCSP and Cervical Screening Wales.\n\nThe Committee was aware that a number of manufacturers have LBC-related products. Evidence received during the appraisal related only to the SurePath and ThinPrep devices – no evidence was provided by the other manufacturers.", 'Recommendations for further research': 'It is recommended that high-quality studies be undertaken to ompare differences in performance between the ThinPrep and SurePath LBC methods.\n\nValidation is needed of the number of cells per LBC sample that will be required to establish the adequacy of smears.\n\nFor further reviews of LBC, clinical data relating to the sensitivity, specificity and rate of inadequate smears should be provided for EasyPrep, Cytoscreen and any future devices.\n\nEvaluation of automated technologies for the analysis of cervical samples is needed.', 'Implications for the NHS': 'Information in the pilot studies estimated a one-off cost of £10.1–10.3 million for the conversion from Pap smears to LBC in England, which equates to a cost of approximately £73,000 for a local laboratory processing 30,000 tests per annum. These figures only include the cost of training smear takers and laboratory staff, producing training material, sending off a backlog of samples, and structural changes to the laboratory and assume that all GPs and nurses will be trained in the use of LBC. Proportionately similar costs will be incurred in Wales. In both countries the precise costs will be a function of the number and size of laboratories undertaking LBC. The cost of acquiring the LBC slide preparation equipment itself has not been estimated because there are a number of possible solutions that could alter the nature and timing of the cost impact. These solutions should be investigated fully, as part of implementation planning taking into full consideration the cost of consumables and maintenance, as part of a whole life cost analysis demonstrating a value for money solution to the NHS. In England, the NHS Purchasing and Supply Agency will evaluate options for the purchase of capital equipment. Procurement in Wales will be managed on an all-Wales basis by the West Wales Procurement Consortium. If sample preparation using LBC is to be centralised in regional laboratories, consideration will need to be given to the logistics and costs associated with sample transport and communication of the central processing laboratories with the local reporting laboratories.\n\nThe English pilot report estimated the running costs of Pap smears and LBC to be comparable, and with LBC time savings in the diagnosis of smears may contribute to increased laboratory productivity. In addition, increases in laboratory productivity may reduce the time that patients need to wait for the results of a smear test. The use of LBC in accordance with this guidance is likely to release resources within NHS organisations, although the nature and amounts involved will vary between local NHS communities.\n\nExisting smear takers and laboratory staff will need additional training in the LBC method before implementation of the recommendation in Section 1.1. Training of new smear takers and laboratory staff in the LBC method is likely to require similar resources to those for the training of staff in Pap smears.\n\nThe rate at which LBC is taken up throughout the NHS in England and Wales will depend on a number of logistical factors, which should be determined by the NHSCSP and Cervical Screening Wales with the involvement of the NHS Purchasing and Supplies Agency and the West Wales Procurement Consortium. During this period, the standard cervical screening method will need to run in parallel.', 'Related guidance': 'NICE issued the following guidance on the use of LBC for cervical screening in June 2000. National Institute for Clinical Excellence (2000) Guidance on the use of liquid-based cytology for cervical screening. NICE Technology Appraisal Guidance No. 5. London: National Institute for Clinical Excellence.', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review.\n\nThe guidance on this technology will be reviewed in August 2006.\n\nAndrew DillonChief ExecutiveOctober 2003', 'Changes after publication': 'March 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance replaces 'Liquid-based cytology for cervical screening' (NICE Technology Appraisal Guidance No. 5) issued in June 2000.\n\nThe Institute reviews each piece of guidance it issues.\n\nThe review and re-appraisal of the use of liquid-based cytology for cervical screening has resulted in a change in the guidance. Specifically there has been:\n\na recommendation of the use of liquid-based cytology as the primary means of processing samples in the cervical screening programme in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}	https://www.nice.org.uk/guidance/ta69	Evidence-based recommendations on using liquid-based cytology for cervical screening in adults.
5042be8290582f1f069a408021ea2327b5fa0456	nice	Transurethral electrovaporisation of the prostate	Transurethral electrovaporisation of the prostate # Guidance Current evidence on the safety and efficacy of transurethral electrovaporisation of the prostate appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.# The procedure # Indications Transurethral electrovaporisation of the prostate is used to treat benign prostatic obstruction (BPO). BPO is a non-malignant enlargement of the prostate and is a common cause of lower urinary tract symptoms (such as difficulty in passing urine) in men aged over 40 years. Transurethral electrovaporisation of the prostate is a minimally invasive alternative to the standard surgical treatment of BPO, transurethral resection of the prostate (TURP). # Outline of the procedure Transurethral electrovaporisation of the prostate, an electroablative technique, is performed using a specially designed modified rollerball electrode. The electrode is rolled over the prostatic tissue to create an area of vaporisation and an underlying coagulative necrosis. Vaporisation continues until an appropriate cavity is created. An in-dwelling urethral catheter is left in place at the end of the procedure. # Efficacy This procedure is a relatively well-established minimally invasive treatment for BPO. A number of randomised controlled trials of this procedure were available for review. Transurethral electrovaporisation of the prostate was shown to be as efficacious as TURP in the short term. The Specialist Advisors noted that the long-term durability of the procedure has yet to be established, and that efficacy is probably limited to smaller prostates. # Safety Complication rates of transurethral electrovaporisation of the prostate and TURP appeared to be similar, although some studies suggested that bleeding was less common with transurethral electrovaporisation of the prostate. One study reported that long-term irritative symptoms were more common with transurethral electrovaporisation of the prostate. The Specialist Advisors did not report any particular safety concerns, although one Advisor stated that postoperative bleeding and metabolic disorders were potential complications. Andrew DillonChief ExecutiveOctober 2003# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional Procedure Overview of Transurethral Electrovaporisation of the Prostate', October 2002. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on transurethral electrovaporisation of the prostate Further recommendations have been made as part of the clinical guideline on lower urinary tract symptoms published in May 2010, as follows: If offering surgery for managing voiding lower urinary tract symptoms (LUTS) presumed secondary to benign prostatic enlargement (BPE), offer monopolar or bipolar transurethral resection of the prostate (TURP), monopolar transurethral vaporisation of the prostate (TUVP) or holmium laser enucleation of the prostate (HoLEP). Clinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. More information is available. The IP guidance on transurethral electrovaporisation of the prostate remains current, and should be read in conjunction with the clinical guideline.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of transurethral electrovaporisation of the prostate appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.', 'The procedure': '# Indications\n\nTransurethral electrovaporisation of the prostate is used to treat benign prostatic obstruction (BPO). BPO is a non-malignant enlargement of the prostate and is a common cause of lower urinary tract symptoms (such as difficulty in passing urine) in men aged over 40 years. Transurethral electrovaporisation of the prostate is a minimally invasive alternative to the standard surgical treatment of BPO, transurethral resection of the prostate (TURP).\n\n# Outline of the procedure\n\nTransurethral electrovaporisation of the prostate, an electroablative technique, is performed using a specially designed modified rollerball electrode. The electrode is rolled over the prostatic tissue to create an area of vaporisation and an underlying coagulative necrosis. Vaporisation continues until an appropriate cavity is created. An in-dwelling urethral catheter is left in place at the end of the procedure.\n\n# Efficacy\n\nThis procedure is a relatively well-established minimally invasive treatment for BPO. A number of randomised controlled trials of this procedure were available for review. Transurethral electrovaporisation of the prostate was shown to be as efficacious as TURP in the short term.\n\nThe Specialist Advisors noted that the long-term durability of the procedure has yet to be established, and that efficacy is probably limited to smaller prostates.\n\n# Safety\n\nComplication rates of transurethral electrovaporisation of the prostate and TURP appeared to be similar, although some studies suggested that bleeding was less common with transurethral electrovaporisation of the prostate. One study reported that long-term irritative symptoms were more common with transurethral electrovaporisation of the prostate.\n\nThe Specialist Advisors did not report any particular safety concerns, although one Advisor stated that postoperative bleeding and metabolic disorders were potential complications.\n\nAndrew DillonChief ExecutiveOctober 2003', 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional Procedure Overview of Transurethral Electrovaporisation of the Prostate', October 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Other NICE recommendations on transurethral electrovaporisation of the prostate': 'Further recommendations have been made as part of the clinical guideline on lower urinary tract symptoms published in May 2010, as follows:\n\nIf offering surgery for managing voiding lower urinary tract symptoms (LUTS) presumed secondary to benign prostatic enlargement (BPE), offer monopolar or bipolar transurethral resection of the prostate (TURP), monopolar transurethral vaporisation of the prostate (TUVP) or holmium laser enucleation of the prostate (HoLEP).\n\nClinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. More information is available.\n\nThe IP guidance on transurethral electrovaporisation of the prostate remains current, and should be read in conjunction with the clinical guideline.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg14
3de9d6c9501501c2604fa0a6d2b24f73e90615ae	nice	Radiofrequency ablation of varicose veins	Radiofrequency ablation of varicose veins # Guidance Current evidence on the safety and efficacy of radiofrequency ablation of varicose veins appears adequate to support the use of this procedure as an alternative to saphenofemoral ligation and stripping, provided that the normal arrangements are in place for consent, audit and clinical governance.# The procedure # Indications Symptomatic venous insufficiency is common. Saphenous vein insufficiency is the most common form of venous insufficiency in those presenting with symptoms, which include pain, leg fatigue, oedema, skin changes and venous ulcers. # Outline of the procedure Radiofrequency ablation of varicose veins involves heating the wall of the vein using a bipolar generator and catheters with sheathable electrodes. The long saphenous vein is accessed above or below the knee, either percutaneously via an intravenous cannula/venepuncture sheath or via a small incision. The catheter is manually withdrawn at 2.5–3 cm/minute, and the vein wall temperature is maintained at 85°C. # Efficacy Evidence indicated that radiofrequency treatment resulted in immediate occlusion of 90–100% of long saphenous veins. In one study, patients who received radiofrequency ablation had less pain and required less analgesia compared with those who had standard surgery (stripping). In general, the evidence showed that fewer than 5% of patients continued to have symptoms, such as leg pain, leg fatigue, oedema and noticeable varicose veins, after the procedure. There were high patient satisfaction rates. For more details, refer to the Overview (see 'Sources of evidence'). The Specialist Advisors reported that the long-term results of this procedure were unknown, though in the short-term it seemed efficacious. # Safety One study showed similar postoperative complication rates of approximately 50% in the radiofrequency ablation and stripping arms, including minor complications. Other studies showed that skin burns occurred in 2–7% of patients who had radiofrequency ablation. Paraesthesiae occurred in 0–15% of patients, and were more common in patients whose treatment was below the knee. Clinical phlebitis occurred in 2–3% of patients, deep vein thrombosis occurred in 1% and pulmonary embolism was uncommon, occurring in fewer than 1%. For more details, refer to the Overview (see 'Sources of evidence'). The Specialist Advisors reported similar complications to those above. # Other comments The Committee noted that there were no long-term follow-up data; treated veins may undergo late re-canalisation. Andrew DillonChief ExecutiveSeptember 2003# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of radiofrequency ablation of varicose veins', October 2002. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of radiofrequency ablation of varicose veins appears adequate to support the use of this procedure as an alternative to saphenofemoral ligation and stripping, provided that the normal arrangements are in place for consent, audit and clinical governance.', 'The procedure': "# Indications\n\nSymptomatic venous insufficiency is common. Saphenous vein insufficiency is the most common form of venous insufficiency in those presenting with symptoms, which include pain, leg fatigue, oedema, skin changes and venous ulcers.\n\n# Outline of the procedure\n\nRadiofrequency ablation of varicose veins involves heating the wall of the vein using a bipolar generator and catheters with sheathable electrodes.\n\nThe long saphenous vein is accessed above or below the knee, either percutaneously via an intravenous cannula/venepuncture sheath or via a small incision. The catheter is manually withdrawn at 2.5–3 cm/minute, and the vein wall temperature is maintained at 85°C.\n\n# Efficacy\n\nEvidence indicated that radiofrequency treatment resulted in immediate occlusion of 90–100% of long saphenous veins. In one study, patients who received radiofrequency ablation had less pain and required less analgesia compared with those who had standard surgery (stripping).\n\nIn general, the evidence showed that fewer than 5% of patients continued to have symptoms, such as leg pain, leg fatigue, oedema and noticeable varicose veins, after the procedure. There were high patient satisfaction rates. For more details, refer to the Overview (see 'Sources of evidence').\n\nThe Specialist Advisors reported that the long-term results of this procedure were unknown, though in the short-term it seemed efficacious.\n\n# Safety\n\nOne study showed similar postoperative complication rates of approximately 50% in the radiofrequency ablation and stripping arms, including minor complications. Other studies showed that skin burns occurred in 2–7% of patients who had radiofrequency ablation. Paraesthesiae occurred in 0–15% of patients, and were more common in patients whose treatment was below the knee. Clinical phlebitis occurred in 2–3% of patients, deep vein thrombosis occurred in 1% and pulmonary embolism was uncommon, occurring in fewer than 1%. For more details, refer to the Overview (see 'Sources of evidence').\n\nThe Specialist Advisors reported similar complications to those above.\n\n# Other comments\n\nThe Committee noted that there were no long-term follow-up data; treated veins may undergo late re-canalisation.\n\nAndrew DillonChief ExecutiveSeptember 2003", 'Further information': "# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\n'Interventional procedure overview of radiofrequency ablation of varicose veins', October 2002.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg8
7e59c6fbb51d50258003b8e594976b0fb14accc3	nice	Percutaneous vertebroplasty	Percutaneous vertebroplasty # Guidance Current evidence on the safety and efficacy of percutaneous vertebroplasty appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance. The following are recommended. This procedure should only be undertaken when there are arrangements for good access to a spinal surgery service, and with prior discussion between a specialist multidisciplinary team that includes a radiologist and a spinal surgeon. Clinicians should receive training to reach an appropriate level of expertise before carrying out this procedure. In particular, they must follow the manufacturer's instructions for making the cement, to reduce the risk of embolisation. The procedure should be limited to patients whose pain is refractory to more conservative treatment.# The procedure # Indications Percutaneous vertebroplasty may be used to provide pain relief for people with severe painful osteoporosis with loss of height and/or compression fractures of the vertebral body, and also for people with symptomatic vertebral haemangioma and painful vertebral body tumours (metastases or myeloma). Vertebral compression fractures are a common cause of pain and disability. Osteopenia, associated with ageing or chronic steroid use, and metastatic disease are the most common causes of vertebral compression fractures. Nearly all people experience pain. Most people are treated conservatively with analgesics, bed rest and bracing, but a small percentage are left with persistent pain and limited mobility. # Outline of the procedure Percutaneous vertebroplasty is the injection of bone cement into the vertebral body to relieve pain, and to stabilise the fractured vertebrae. # Efficacy The evidence reviewed indicated some level of pain relief in 58–97% of patients, with an associated reduction in medication usage in 50–91% of patients. One study indicated that 93% of patients had improved mobility and that 100% of patients were satisfied with the procedure and would have it again. The opinions of the Specialist Advisors were divided about this procedure. Some believed that the procedure was proven to work, with numerous publications proving benefit. They believed that the procedure could have a major impact in the future as the incidence of osteoporotic spinal fractures increases in an ageing population. One Advisor suggested that it is effective in the majority of patients. Other Advisors suggested that the procedure is unnecessary, that the fractures will heal of their own accord, and that the procedure causes further fractures at a higher level of the spine. # Safety Reported complications of this procedure were uncommon. They included damage to neural or other structures by needle misplacement or migration of cement. One study observed cement leakage in up to 27% of patients. However, this event was often without sequelae and required further intervention in only 1% of patients in that study. The Specialist Advisors offered different estimates of risk but stated that the procedure carried a low risk in experienced hands. Some listed paraplegia as a risk (less than 5%), as well as the potential for nerve root damage and infection. # Other comments The Medicines and Healthcare products Regulatory Agency (MHRA) has recently issued a safety notice on the use of cement in percutaneous vertebroplasty (MDA/2007/088).# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. Interventional procedure overview of percutaneous vertebroplasty, December 2003. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on percutaneous vertebroplasty Further recommendations have been made as part of the clinical guideline on metastatic spinal cord compression published in November 2008, as follows: Vertebroplasty or kyphoplasty should be considered for patients who have vertebral metastases and no evidence of MSCC or spinal instability if they have either: mechanical pain resistant to analgesia, or vertebral body collapse. Vertebroplasty or kyphoplasty for spinal metastases should only be performed after agreement between appropriate specialists including an oncologist, interventional radiologist, and spinal surgeon, and in facilities where there is good access to spinal surgery. Clinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. For more information see the NICE guideline on metastatic spinal cord compression in adults. The IP guidance on percutaneous vertebroplasty remains current, and should be read in conjunction with the clinical guideline. The Medicines and Healthcare Products Regulatory Agency (MHRA) has issued safety notices relating to this procedure (Reference No. MDA/2003/021).	{'Guidance': "Current evidence on the safety and efficacy of percutaneous vertebroplasty appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.\n\nThe following are recommended.\n\nThis procedure should only be undertaken when there are arrangements for good access to a spinal surgery service, and with prior discussion between a specialist multidisciplinary team that includes a radiologist and a spinal surgeon.\n\nClinicians should receive training to reach an appropriate level of expertise before carrying out this procedure. In particular, they must follow the manufacturer's instructions for making the cement, to reduce the risk of embolisation.\n\nThe procedure should be limited to patients whose pain is refractory to more conservative treatment.", 'The procedure': '# Indications\n\nPercutaneous vertebroplasty may be used to provide pain relief for people with severe painful osteoporosis with loss of height and/or compression fractures of the vertebral body, and also for people with symptomatic vertebral haemangioma and painful vertebral body tumours (metastases or myeloma).\n\nVertebral compression fractures are a common cause of pain and disability. Osteopenia, associated with ageing or chronic steroid use, and metastatic disease are the most common causes of vertebral compression fractures. Nearly all people experience pain. Most people are treated conservatively with analgesics, bed rest and bracing, but a small percentage are left with persistent pain and limited mobility.\n\n# Outline of the procedure\n\nPercutaneous vertebroplasty is the injection of bone cement into the vertebral body to relieve pain, and to stabilise the fractured vertebrae.\n\n# Efficacy\n\nThe evidence reviewed indicated some level of pain relief in 58–97% of patients, with an associated reduction in medication usage in 50–91% of patients. One study indicated that 93% of patients had improved mobility and that 100% of patients were satisfied with the procedure and would have it again.\n\nThe opinions of the Specialist Advisors were divided about this procedure. Some believed that the procedure was proven to work, with numerous publications proving benefit. They believed that the procedure could have a major impact in the future as the incidence of osteoporotic spinal fractures increases in an ageing population. One Advisor suggested that it is effective in the majority of patients. Other Advisors suggested that the procedure is unnecessary, that the fractures will heal of their own accord, and that the procedure causes further fractures at a higher level of the spine.\n\n# Safety\n\nReported complications of this procedure were uncommon. They included damage to neural or other structures by needle misplacement or migration of cement. One study observed cement leakage in up to 27% of patients. However, this event was often without sequelae and required further intervention in only 1% of patients in that study.\n\nThe Specialist Advisors offered different estimates of risk but stated that the procedure carried a low risk in experienced hands. Some listed paraplegia as a risk (less than 5%), as well as the potential for nerve root damage and infection.\n\n# Other comments\n\nThe Medicines and Healthcare products Regulatory Agency (MHRA) has recently issued a safety notice on the use of cement in percutaneous vertebroplasty (MDA/2007/088).', 'Further information': '# Sources of evidence\n\nThe evidence considered by the Interventional Procedures Advisory Committee is described in the following document.\n\nInterventional procedure overview of percutaneous vertebroplasty, December 2003.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'Other NICE recommendations on percutaneous vertebroplasty': 'Further recommendations have been made as part of the clinical guideline on metastatic spinal cord compression published in November 2008, as follows:\n\nVertebroplasty or kyphoplasty should be considered for patients who have vertebral metastases and no evidence of MSCC or spinal instability if they have either:\n\nmechanical pain resistant to analgesia, or\n\nvertebral body collapse.\n\nVertebroplasty or kyphoplasty for spinal metastases should only be performed after agreement between appropriate specialists including an oncologist, interventional radiologist, and spinal surgeon, and in facilities where there is good access to spinal surgery.\n\nClinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. For more information see the NICE guideline on metastatic spinal cord compression in adults.\n\nThe IP guidance on percutaneous vertebroplasty remains current, and should be read in conjunction with the clinical guideline.\n\nThe Medicines and Healthcare Products Regulatory Agency (MHRA) has issued safety notices relating to this procedure (Reference No. MDA/2003/021).'}	https://www.nice.org.uk/guidance/ipg12
29f1cf7fe06c25ddbf26de77af47055640f734e6	nice	Human growth hormone (somatropin) in adults with growth hormone deficiency	Human growth hormone (somatropin) in adults with growth hormone deficiency Evidence-based recommendations on human growth hormone (somatropin; Genotropin, Humatrope, Norditropin, NutropinAq, Omnitrope, Saizen, Zomacton) for treating growth hormone deficiency in adults. # Guidance Recombinant human growth hormone (somatropin) treatment is recommended for the treatment of adults with growth hormone (GH) deficiency only if they fulfil all three of the following criteria. They have severe GH deficiency, defined as a peak GH response of less than 9 mU/litre (3 ng/ml) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test. They have a perceived impairment of quality of life (QoL), as demonstrated by a reported score of at least 11 in the disease-specific 'Quality of life assessment of growth hormone deficiency in adults' (QoL-AGHDA) questionnaire. They are already receiving treatment for any other pituitary hormone deficiencies as required. The QoL status of people who are given GH treatment should be re-assessed 9 months after the initiation of therapy (an initial 3-month period of GH dose titration, followed by a 6-month therapeutic trial period). GH treatment should be discontinued for those people who demonstrate a QoL improvement of less than 7 points in QoL-AGHDA score. Patients who develop GH deficiency in early adulthood, after linear growth is completed but before the age of 25 years, should be given GH treatment until adult peak bone mass has been achieved, provided they satisfy the biochemical criteria for severe GH deficiency (defined as a peak GH response of less than 9 mU/litre (3 ng/ml) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test). After adult peak bone mass has been achieved, the decision to continue GH treatment should be based on all the criteria in Section 1.1. Patients currently receiving GH treatment, for the management of adult onset GH deficiency, whether as routine therapy or as part of a clinical trial, could suffer loss of well being if their treatment were to be discontinued at a time they did not anticipate. Because of this, all NHS patients who are on therapy at the date of publication of this guidance should have the option to continue treatment until they and their consultant consider it is appropriate to stop. Children with GH deficiency should be treated as outlined in the Institute's guidance on the use of GH in children (NICE Technology Appraisal Guidance No. 42 ). At completion of linear growth (that is, growth rate < 2 cm/year), GH treatment should be stopped for 2–3 months, and then GH status should be re-assessed. GH treatment at adult doses should be re-started only in those satisfying the biochemical criteria for severe GH deficiency (defined as a peak GH response of less than 9 mU/litre (3 ng/ml) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test), and continued until adult peak bone mass has been achieved (normally around 25 years of age). After adult peak bone mass has been achieved, the decision to continue GH treatment should be based on all the criteria set out in Section 1.1. Initiation of GH treatment, dose titration and assessment of response during trial periods should be undertaken by a consultant endocrinologist with a special interest in the management of GH disorders. Thereafter, if maintenance treatment is to be prescribed in primary care, it is recommended that this should be under an agreed shared-care protocol.# Clinical need and practice Growth hormone is produced by the anterior pituitary gland. It has a role in the regulation of protein, lipid and carbohydrate metabolism, as well as in increasing growth in children. Its secretion is intermittent and occurs predominantly during deep sleep. Secretion reaches maximal levels during adolescence, and then declines with age by approximately 14% per decade. Adult GH deficiency may be of adult onset or childhood onset, and may occur as isolated GH deficiency or as part of multiple pituitary hormone deficiency. In adult onset, GH deficiency is commonly due to pituitary tumours or their treatment, and to cranial irradiation. Childhood-onset GH deficiency is often idiopathic, and may continue into adulthood. Also, iatrogenic GH deficiency may occur in childhood or adulthood in survivors of childhood malignancy, as a result of previous cranial irradiation and/or chemotherapy. The Society for Endocrinology estimates that the prevalence of adult-onset GH deficiency is approximately 1 in 10,000 of the adult UK population. If adults with childhood-onset GH deficiency are also considered, the prevalence may be as high approximately 12,600 adults with GH deficiency in England and Wales. GH deficiency in adults may be associated with the following adverse features to a variable degree in any individual: reduced quality of life (QoL) especially reduced energy levels; altered body composition (reduced lean mass and increased fat mass, especially in the trunk); osteopenia/osteoporosis (reduced bone mineral density); dry skin (reduced sweating); reduced muscle strength and exercise capacity; lipid abnormalities (especially elevated LDL cholesterol); insulin resistance; increased levels of fibrinogen and plasminogen activator inhibitor; reduced extracellular fluid volume; increased thickness of the intima media of blood vessels; and impaired cardiac function. Several tests are available for the diagnosis of GH deficiency. The ITT is regarded as the 'gold standard' test for adults. A general definition of severe GH deficiency in adults is a peak concentration of less than 9 mU/litre (3 ng/ml) in response to insulin-induced hypoglycaemia. When the ITT is contraindicated other tests – such as response to GH-releasing hormone, arginine or glucagon – can be used. The clinical management of GH deficiency in adults is centred on replacement therapy with biosynthetic human GH (somatropin). However, there has been local variation in practice within the UK. The Society for Endocrinology estimates that approximately 1750 adults with GH deficiency currently receive treatment in the UK.# The technology There are four preparations of GH available in the UK for the treatment of adults: Genotropin (Pharmacia), Humatrope (Lilly), Norditropin (Novo Nordisk) and Saizen (Serono). Each product is produced by recombinant DNA technology and has a sequence identical to that of human GH. GH is licensed for replacement therapy in adults with severe growth hormone deficiency. Patients with severe GH deficiency in adulthood are defined as patients with known hypothalamic pituitary abnormality and at least one known deficiency of another pituitary hormone excluding prolactin. These patients should undergo a single diagnostic test in order to diagnose the presence of GH deficiency. In patients with childhood onset isolated GH deficiency (no evidence of hypothalamic pituitary abnormality or cranial irradiation), two diagnostic tests should be recommended, except for those having low IGF-1 (a marker of GH response) concentrations (standard deviation score less than -2) who may be considered for one test. Treatment is self-administered by a daily subcutaneous injection. The initial dose is 0.2–0.3 mg (0.6–0.9 IU) daily (typically 0.27 mg daily). For the first 2–3 months dosage adjustments are made after monthly assessments of serum levels of IGF-1, and in response to the presence of adverse effects, until a maintenance dose is achieved. The currently used median maintenance dose is 0.4 mg (1.2 IU) daily. GH requirements may decrease with age. Side effects may include headache, arthralgia (joint pain), myalgia (muscle pain), fluid retention (peripheral oedema), mild hypertension, carpal tunnel syndrome, visual problems, nausea and vomiting, paraesthesia, antibody formation, and reactions at the injection site. Benign intracranial hypertension is a rare complication. GH treatment is contraindicated in people with any evidence of tumour activity, in critically ill patients (for example, after complications following open heart or abdominal surgery, multiple trauma, acute respiratory failure or similar conditions) and also in patients with known hypersensitivity to GH or to any of the excipients. GH treatment is also contraindicated during pregnancy and lactation. In patients with tumours, anti-tumour therapy must be completed before starting GH therapy. The cost of treatment depends on the dose, which is determined by the weight/size of the patient as well as the individual GH reserve. The cost of GH (excluding VAT; British National Formulary March 2003) is £23.18 per mg for Genotropin and Norditropin and £22.87 per mg for Humatrope and Saizen,. The average annual cost of GH treatment is around £3350 per patient. The cost of treatment reduces with age because the GH requirement decreases as people get older. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (Appendix A) considered evidence from a number of sources (Appendix B). The Institute commissioned two Assessment Reports: one was undertaken by the Wessex Institute for Health Research and Development and the other by the University of Sheffield School of Health and Related Research (ScHARR). The Wessex Assessment Report focused on evidence from double-blind, randomised, placebo-controlled trials to evaluate the efficacy of GH treatment in terms of QoL benefits, whereas the ScHARR Assessment Report included the additional evidence that was available from observational studies and some new data from two unpublished randomised controlled trials (RCTs). The Wessex Assessment Report also included a cost analysis of the GH treatment, and the ScHARR Assessment Report provided a detailed critique of the economic models submitted by the manufacturers. During the course of the appraisal some of the manufacturers submitted additional data from newly reported, unpublished trials and results from updated economic analyses. # Clinical effectiveness ## Quality-of-life evidence from randomised controlled trials The Assessment Reports identified 17 published RCTs evaluating the effects of GH on QoL in around 900 adult patients with GH deficiency. Twenty-three different QoL assessment scales were used, within a variety of trial designs. The duration of the studies was typically 6 months and the number of participants ranged from 6 to 173. Most studies included both adult- and childhood-onset GH deficiency. Ten studies evaluated health-related QoL using the Nottingham health profile (NHP), but not all reported the results. Additional unpublished data on QoL for one of the studies were made available to ScHARR. These data were supplied in confidence and have not been included in the pooled results presented below. However, including these data had only a small impact on the results of the meta-analyses and did not affect the conclusions of the ScHARR Assessment Report. The analysis of the individual dimensions of the NHP found some statistically significant changes in the GH-treated group compared with the control group. In one of the four published studies (the largest) that reported the social isolation dimension, the score was significantly improved in the GH-treated group compared with the placebo group. For this dimension, pooled analysis of all four studies found a small, statistically significant difference in favour of treatment (-0.3 points, 95% confidence interval, -0.4 to -0.1). The largest of the four studies that reported the emotional reactions dimension found a small but statistically significant difference in favour of treatment, but the difference was not statistically significant in the pooled analysis. Five studies reported the energy dimension. One of the smaller studies found a significant difference in favour of GH treatment, but the pooled analysis of all five did not. For the sleep and physical mobility dimensions, none of the four individual studies reporting these dimensions found a treatment effect of GH, and nor did the pooled analysis. For the pain dimension, one study found a significant difference in favour of placebo, but there was no significant difference in the pooled analysis of four studies. The NHP is not designed to produce an overall total score. However, two studies reported mean total scores. Both found improvements in favour of treatment, but these were not statistically significant in either of the individual studies or in the pooled analysis. Two RCTs used the QoL-assessment of growth hormone deficiency in adults (QoL-AGHDA) questionnaire – a self-completed questionnaire comprising 25 questions specifically designed to assess the consequences of GH deficiency and its treatment. A high QoL-AGHDA score indicates greater impairment of QoL. One study was conducted across three centres in Spain and included 69 patients. The other was conducted in the Netherlands and recruited 30 patients. Minimal data from these studies have been published in abstract form, but further results were made available in confidence to the ScHARR review group for evaluation. Data pooled from two trials reporting the Hamilton Depression Scale found in favour of GH treatment, but the results were not statistically significant. GH use was associated with an improvement of 2.4 points (95% confidence interval, -4.9 to 0.1). Meta-analysis of two trials reporting psychological well-being (using the Psychological General Well-being Schedule) found in favour of the GH-treated group, but the results were not statistically significant. In summary, based on the evidence from RCTs, in terms of QoL the effectiveness of GH treatment in adults with GH deficiency remains unproven. Many of the available studies were of poor quality. Also, because the patients involved had comparatively normal QoL values at baseline there was little scope for improvement. Furthermore, most of the RCTs used a dosage regimen determined by the patient's weight rather than one based on a titration technique, which is now common clinical practice. This raises difficulties with using this evidence to estimate the effectiveness of currently used GH regimens. ## Quality-of-life evidence from observational trials A 10-year study provided the longest period of observational follow-up of replacement therapy in GH deficiency. This study included patients who had previously participated in an RCT. Of the 24 patients in the original study, ten patients who had received GH continuously for 10 years were compared with 11 who had not. For the group receiving GH, QoL – as measured by the NHP – was improved over baseline in the domains of energy level and emotional reactions. Overall score was also improved. There was no change in the untreated group. However, the two groups may not be comparable because there are several reasons why patients may not continue treatment. Two shorter observational studies (12 months) reported improvements in overall NHP scores after GH treatment. Eight observational studies of GH therapy in GH deficiency reported QoL-AGHDA scores. Three of these reported results from the largest observational data set of GH-deficient patients, the KIMS database. KIMS is the Pharmacia international metabolic database and pharmacoepidemiological survey of adult GH-deficient patients receiving GH therapy. The three KIMS studies account for most of the published observational data on QoL. They each included between 300 and 665 participants. However, it is likely that data from many of the same patients were reported in all three publications. The extent to which this may have occurred was not clear. The number of participants lost to follow-up was also unclear. In these studies, the reported mean reduction in QoL-AGHDA score after GH treatment ranged from 2.8 to 4.8. The remaining five studies that used the QoL-AGHDA included between 10 and 65 patients, and reported reductions in mean QoL-AGHDA scores ranging from 3 to 7.2. A formal meta-analysis of the observational data was not performed. However, a crude estimate of average change in QoL-AGHDA was made. This suggested that, across the studies (weighted by number of patients), the average improvement from baseline in QoL-AGHDA after GH treatment was 3.7 points. In addition, limited data on specific subgroups (defined according to age and baseline QoL-AGHDA scores) were available from KIMS database. These data suggested that the mean improvement from baseline score in patients less than 65 years of age and with a baseline QoL-AGHDA score of 0-5 was 1.80 points at 1 year. The corresponding values for the groups with baseline QoL-AGHDA scores of 6-10, 11-15, and 15 and over were 5.55, 7.75, and 11.98 respectively, for people less than 65 years old. In clinical studies, improvements in QoL were observed within 3–6 months of initiating treatment. Limited data from observational studies suggested that the improvement was sustained in the long term (9–10 years) in patients who continued therapy. # Cost effectiveness One economic evaluation and three cost studies were identified. The only economic evaluation was reported in an outdated Wessex Development and Evaluation Committee (DEC) report (No. 47, 1995), which had subsequently been replaced by another Wessex DEC report (No. 75, 1997). The latter did not present an economic analysis. The utility element of the economic evaluation presented in the earlier DEC report was a set of scenarios not based on primary or secondary data sources and so could not be considered reliable or valid. The three cost studies identified were UK-based. One reported costs of diagnosis, GH treatment, and monitoring. The others reported drug costs. All studies reported the cost of the drug as the main factor determining treatment cost (around 90% of total cost). One study reported that annual treatment costs per patient could vary between £3472 and £6943 (1997 prices and GH dose from 0.125 to 0.25 IU/kg/week), and that costs were sensitive to assumptions about continuation rate and the price of GH. The other two studies reported annual drug costs of GH treatment in the range £3300 to £3453, using more up-to-date (median) drug doses. A cost analysis was presented in the Wessex Assessment Report and aimed to analyse the average annual and total lifetime costs of GH treatment for a patient starting treatment. There was no attempt to estimate the cost effectiveness (or the cost–utility) of GH treatment. The Assessment Group considered that it was not possible to estimate utility gain – which would ideally be expressed in terms of quality-adjusted life years (QALYs) – with the evidence available from RCTs, and so the analysis was limited to costs. It was estimated that GH treatment in GH-deficient adults costs £3424 annually at an average maintenance dose. The costs of life-long therapy are estimated to be between £42,000 (adult-onset GH deficiency) and £45,400 (childhood-onset GH deficiency) without the cost-savings from hospitalisations prevented, and between £40,500 (adult-onset GH deficiency) and £43,800 (childhood-onset GH deficiency) with the savings from hospitalisations prevented. These estimates assume that 20% of people discontinue GH treatment after 6 months. Drug therapy was found to be the single most important factor in determining cost; changes in the price of GH significantly altered treatment costs, so any price reductions could result in cost savings for the NHS. It was noted that the price at local level could significantly differ from the BNF list price, but there were no reliable data to inform the analysis. Three manufacturers submitted economic evaluations to the Institute; all three estimated the cost–utility of GH use in adults (that is, they expressed the benefits of treatment in terms of QALYs). One also expressed cost effectiveness in the form of cost per normalised life-year gained. Two economic models (Lilly and Novo Nordisk) adopted the methods used in the Wessex DEC report to generate utility estimates. The cost–utility ratios estimated by these models were between £4500 and £32,000 per additional QALY gained. These models did not use primary data but were based on estimates of the likely utility gains, for which there is little evidence. The models should therefore be treated with caution. One manufacturer's model estimated the cost effectiveness to be £15,648 per additional normalised life-year for adult-onset GH deficiency, and £16,522 per additional normalised life-year for childhood-onset GH deficiency. The data came from pre- and post-treatment scores of 124 UK patients using the questions on life satisfaction modules for hypopituitarism questionnaire (QLS-H) – a new QoL instrument for adults with GH deficiency, which covers nine domains. 'Normalisation' of QoL was defined as achieving a 'somewhat satisfied', 'satisfied' or 'very satisfied' score in all domains. Another manufacturer's model estimated the cost effectiveness of the use of GH replacement therapy in adults to be between £27,500 and £37,600 per additional QALY gained. This model used some inputs (especially those related to cardiovascular and fracture risks) derived from a simulation model, which was also provided. Utility estimates were derived from QoL data collected in the KIMS database. Because the QoL-AGHDA questionnaire is not designed to produce preference-based utilities, regression analysis was used to convert the available data into utility scores. Sub-group analyses for different age and QoL groups were also presented. It should be noted that the use of regression analysis to derive the utility scores is limited by the quality of the data from which they are estimated and the degree of overlap of the descriptive systems. The economic analysis presented by ScHARR demonstrated that the long-term effects on risk factors for fractures and cardiovascular events had very little impact on the cost effectiveness of GH treatment. The ScHARR report also included a series of sensitivity analyses to investigate the impact on the results of relaxing the manufacturers' assumptions, which were regarded as optimistic. The ScHARR estimate of the impact of GH treatment on QoL was based on the use of observational data using the QoL-AGHDA questionnaire. This was regarded as an optimistic scenario because observational data are very prone to overestimate the treatment effect, particularly for subjective outcomes for which the placebo effect may be especially problematic. A similar mapping exercise to that used in one of the manufacturer's analyses (see Section 4.2.8) was used to derive the utility scores. Additional QoL data made available to ScHARR by one of the manufacturers measured the benefits by using the QLS-H questionnaire, but there is currently no method to map these findings to utility scores. The ScHARR analysis, based on an overall utility gain of 0.04–0.12 depending on age and baseline QoL score, estimated the cost effectiveness of GH therapy to be between £25,300 (for people aged 65 years or older with a QoL-AGHDA score ≥16) and £124,950 (for people aged 18–30 years with a QoL-AGHDA score of 6–10). The overallcost effectiveness of GH therapy was estimated to be in the region of £45,000 per additional QALY. This figure is very sensitive to the estimate of effectiveness, and it should be regarded as the best-case scenario because it is based on observational data that are likely to overestimate the benefits of treatment. # Consideration of the evidence The Committee reviewed the data available on the clinical and cost effectiveness of GH treatment in adults with GH deficiency, having considered evidence on the nature of the condition and the value placed on the benefits of GH treatment from adults with GH deficiency, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources. The Committee considered in detail the significance of the effectiveness of GH treatment in GH-deficient adults in terms of its effects on QoL. In addition, the Committee considered the potential effect of GH deficiency on clinical parameters that might adversely affect cardiovascular risk profiles or the potential for bone fractures caused by reduced bone mineral density, both of which might adversely affect life expectancy. The possibility that GH deficiency might also contribute to a higher overall standardised mortality ratio (SMR), over and above that which can be attributed to the effects on cardiovascular risk and bone mineral density, was also taken into account. ## Effects of GH replacement on quality of life The Committee considered that improvement in QoL was an important, if not the only, determinant of the clinical and cost effectiveness of GH treatment. It therefore considered at length the assessment tools for QoL used in studies of GH therapy, and in particular the appropriateness and suitability of the NHP, QLS-H, EQ-5D and QoL-AGHDA scoring systems. In addition, the Committee reviewed the evidence on QoL effects from both the RCTs and the observational studies. The Committee was also aware of the high compliance rates among GH users (reported to be around 92%), as pointed out by both the patient representatives and experts. It was acknowledged that there were inconsistencies between the results of RCTs, observational studies, and the accounts of many individual patients about the effect of GH therapy on QoL. The Committee took into account the deficiencies in the evidence from RCTs. In particular, the Committee considered the possibility that a sub-group of patients – those with very poor QoL – were benefiting from treatment, but that the effect in these patients was obscured by the inclusion of a large proportion of patients with relatively good pre-treatment QoL and hence little scope for improvement. During the course of this appraisal, the Committee was presented with several analyses relating to improvement in QoL (in addition to the original submissions) that attempted to identify a subgroup of patients in whom GH therapy would be cost effective (that is, those who would gain an improvement in QoL much larger than the average improvements seen in RCTs and observational studies). The Committee reviewed data from an updated subgroup analysis based on a postal survey using the EQ-5D questionnaire of 197 people with GH deficiency. This reanalysis suggested that improvement in utility due to GH treatment might be up to 40% greater than that estimated by QoL-AGHDA. The Committee also reviewed additional data based on QLS-H assessments (from the Hypopituitary Control and Complication Study database). The results from this analysis also suggested that there was likely to be a subgroup of people with GH deficiency who would gain greater improvements in QoL on GH replacement. However, it was not possible to map the data from QLS-H scores into utilities, so this did not provide further direct information to inform the analysis of the cost effectiveness of this technology for selected subgroups. The Committee accepted that, although there was not sufficient information available to it to enable a detailed evaluation of the quality of the methods used to derive the new EQ-5D data, a greater degree of utility change using EQ-5D than using QoL-AGHDA would be anticipated because of the well-established differences in the properties of these two QoL tools. The Committee considered that these additional data suggested that a minimum improvement of at least 7 points in QoL-AGHDA score from baseline would be needed to achieve an acceptable level of cost effectiveness. ## Effects of GH replacement on mortality The Committee considered in detail the effect of GH replacement on overall mortality from various causes in people with GH deficiency. It considered the potential deleterious effects of GH deficiency on cardiovascular risk profiles and bone mineral density, as well as data on SMRs for people with GH deficiency compared with matched populations. The Committee noted that the association between increased mortality and GH deficiency was based on uncontrolled, observational data and on the assessment of cohorts from different periods. The Committee concluded that it was uncertain what impact GH treatment had on the longer-term clinical outcomes and mortality related to cardiovascular risk factors and changes in bone mineral density. However, the Committee believed that the best available evidence from observational studies f these risk factors on mortality had been included in the overall estimates of cost effectiveness that it had reviewed. The Committee considered that it was problematic to draw conclusions about the impact of isolated GH deficiency on overall SMRs (that is, mortality over and above that attributable to cardiovascular risk and bone mineral density changes), because the populations reported in different studies were heterogeneous, which made comparisons difficult. In addition, the SMR data were not adjusted for potential confounding factors, and causality could not be clearly explained. ## Summary of considerations for adult-onset GH deficiency The Committee was persuaded that there was a subgroup of people with GH deficiency whose QoL was significantly impaired, and for whom the benefits of GH replacement could be both clinically and cost effective. However, the effect of treatment on overall mortality was less certain and, on the basis of the present evidence, was likely to have been accounted for predominantly by taking into account effects on cardiovascular risk profiles. While accepting that other factors directly or indirectly affecting overall mortality may be present in GH-deficient people, the Committee believed that these would need to be explored in future research. The Committee reviewed the analyses of cost effectiveness of GH replacement in adult-onset GH deficiency, including the updated analysis submitted by one manufacturer, that assessed in detail the various factors that might influence the calculations of incremental cost-effectiveness ratios (ICERs), including QoL utility estimates based on different methodologies, the potential effects on overall mortality and the appropriateness of modelling benefits over different time periods. After reviewing the updated cost-effectiveness analyses, and the data from the KIMS database on the levels of improvement (in terms of QoL-AGHDA scores) for different patient groups, the Committee considered that the subgroup of people with GH deficiency for whom treatment may be cost effective would be those who had an improvement in QoL equivalent to an absolute change in their baseline QoL-AGHDA score of at least 7 points. The Committee considered that the ICER for this group of patients would be in the region of £25,000 to £45,000 per QALY. The Committee agreed, on the basis of testimony from the experts, that the QoL-AGHDA questionnaire was the best available evaluation tool for the assessment of both baseline QoL and the effect of treatment in people with GH deficiency. The Institute sought clarification on the availability of the QoL-AGHDA questionnaire for use by the clinical community from the developer, Pharmacia, who provided a written statement confirming that the questionnaire is freely accessible as a clinical tool across the UK. The Committee considered at length the issue of the baseline score of QoL-AGHDA that would identify the subset of people with severe GH deficiency for whom GH treatment would most clinically and cost effective. It took into account a variety of factors, including the information from the KIMS database and specifically the data that showed that an improvement of an average of 7 points in QoL-AGHDA was only documented in patients with a baseline QoL-AGHDA score of 11 or more. This, together with consideration of the effect of GH on QoL (see Sections 4.3.3 to 4.3.6) led the Committee to conclude that a trial of GH treatment could be recommended for people with GH deficiency who have a severe perceived impairment of QoL as demonstrated by a reported score of at least 11 in QoL-AGHDA. The Committee was persuaded by the evidence from expert endocrinologists that reassessment of the need for GH replacement should take place after a trial treatment period of 9 months (3 months for dose titration and 6 months for assessment of response). For GH treatment to continue after this trial period, it should be necessary to demonstrate a sustained improvement in QoL. In considering the minimum requirement for the degree of QoL improvement at the end of the trial period, the Committee took into account the data from the KIMS population, the cost-effectiveness considerations (see Section 4.3.11), and the views from the patient/carer organisations and the clinical experts. The Committee concluded that, on the balance of probabilities, an improvement during the trial with GH of 7 points or more in QoL-AGHDA score compared with the baseline measurement would be needed to justify the clinical and cost effectiveness of continuing GH treatment beyond the trial period. The Committee was aware that in the KIMS population the QoL improvement score of 7 in patients with a baseline QoL-AGHDA score of 11 or more was a mean value, which implies that there will be some people in this group who did not improve by 7 points and others who improved by more than 7 points. However, the Committee considered – on the basis of all the evidence it had reviewed, the uncertainties surrounding the precise definition of the subgroup that would most benefit from GH treatment, and the extent of any such benefit – that cost-effectiveness should be evident for individual patients. Thus in patients who demonstrate an improvement score lower than 7 points, the Committee concluded that cost effectiveness was not established, and the continued use of GH in these patients after the initial assessment period could not be justified. ## Transitional period The Committee considered the issues related to the treatment arrangements for those with childhood-onset GH deficiency from all causes, and the value of GH treatment after the completion of linear growth. It was agreed that people with childhood-onset GH deficiency should be re-tested after the attainment of final height to assess whether further GH replacement is necessary. The Committee was persuaded by evidence from experts that, for people with childhood-onset GH deficiency who had completed linear growth but still remained severely deficient in GH according to biochemical tests (defined as a peak GH response of less than 9 mU/litre (3 ng/ml) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test), treatment with GH should be continued until adult bone mass is achieved. The Committee accepted that there are likely to be significant disadvantages in later life for those who do not achieve peak adult bone mass, although this conclusion was not fully evidence-based. The Committee additionally accepted, on the basis of expert testimony, that the age at which peak adult bone mass is achieved can vary between 25 and 30 years depending on a number of factors, including the age of puberty. The Committee concluded, therefore, that there will be a proportion of people with childhood-onset GH deficiency for whom continuation of treatment until peak adult bone mass is achieved is desirable. Thereafter, GH treatment should be discontinued and only recommenced on the basis of the criteria laid down for adult-onset GH deficiency (see Section 1.1). The Committee was aware of clinical differences between children with idiopathic isolated GH deficiency (IIGHD) and those with multiple pituitary hormone deficiencies, including GH (MPHD). It was, however, not persuaded that there was sufficient evidence that they should be treated differently during the transition period. They concluded, therefore, that during the transition phase all childhood-onset GH deficiency should be managed as indicated in Section 1.5 of this guidance. The possibility that children with IIGHD or MPHD should be treated differentially within these criteria could be the subject of further research. The Committee considered the situation of people who develop GH deficiency in early adulthood after linear growth is completed, but before the age of 25 years. These people may require additional GH treatment in order to achieve full adult levels of bone mineral density. The Committee concluded that people in this period of 'transition' should be treated appropriately with GH, and then the criteria in Section 1.1 should apply for consideration of further GH therapy.# Recommendations for further research Further good-quality studies are needed in the following areas. To investigate whether titrated-dose GH therapy improves QoL more than placebo in GH-deficient adults, and to quantify the treatment effect more accurately. To ascertain the most sensitive way of measuring the QoL gain in GH-treated adults, particularly with regard to generating preference-based utilities. To investigate the relationship between SMR and GH deficiency for both adult-onset and childhood-onset GH deficiency, as well as for different subgroups. To investigate whether patients with MPHD and idiopathic isolated GH deficiency have different treatment requirements, in order to achieve cost effective use of GH treatment. To investigate whether different treatment criteria are warranted for childhood and adult onset GH deficiency, in order to optimise the benefits from GH treatment.# Implications for the NHS Although it is hard to estimate the number of eligible patients accurately, it is anticipated that only a small proportion of adults with GH deficiency will achieve sustained improvement of at least 7 points on the QoL-AGHDA scale at the end of the assessment period (that is, 9 months). If it is assumed that 30% of adult-onset and 10% of childhood-onset patients will fulfil the starting criteria, and of these 40% will fail to achieve an improvement of at least 7 points on the QoL-AGHDA scale, there will be around 1180 people in England and Wales who would be eligible for continuous GH treatment. This is less than the estimated number of patients currently receiving GH treatment, so implementing this guidance will not incur any additional costs to the NHS. However, in the absence of more accurate data on future uptake, it is not possible to indicate the scale of any potential savings.# Related guidance The Institute issued guidance in May 2002 on the use of GH treatment in children with growth failure. National Institute for Clinical Excellence (2000) Guidance on the use of human growth hormone (somatropin) in children with growth failure. NICE Technology Appraisal Guidance No. 42. London: National Institute for Clinical Excellence. # Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. It is proposed that the guidance on this technology is reviewed in June 2006. Andrew DillonChief ExecutiveAugust 2003# Appendix C. Detail on criteria for audit of the use of human growth hormone (somatropin) in adults with growth hormone deficiency # Possible objectives for an audit An audit on the appropriateness and effectiveness of the use of growth hormone (GH) treatment in adults with GH deficiency could be carried out to ensure the following. GH treatment is given to an adult with GH deficiency only if he or she meets defined criteria. An adult who is started on GH treatment is re-assessed and GH treatment is discontinued if there is an insufficient improvement in quality of life (QoL). Continued GH treatment is given only in appropriate circumstances to an individual who has been treated for GH deficiency as a child and who has completed linear growth. GH treatment is given to an adult who develops GH deficiency in early adulthood only in appropriate circumstances. Initial treatment of adults with GH deficiency is done only by a qualified specialist and maintenance GH treatment is continued in primary care only when there is an agreed shared-care protocol. # Possible patients to be included in the audit An audit could be carried out on all adults referred or seen for GH deficiency in a given time period, for example, 6 months or a year. Because the measures listed below refer to care provided after the start of GH treatment, it may be desirable to limit the audit to new patients or to agree on the specific time period of care that will apply to each of the measures. # Measures that could be used as a basis for audit The measures that could be used in an audit of GH treatment are as follows. Criterion Standard Exception Definition of terms . An adult given recombinant human growth hormone meets all three of a–c or d as follows: a. The individual has severe GH deficiency and b. The individual has a perceived impairment of quality of life (QoL) as demonstrated by a reported score of at least 11 in the QoL-AGHDA questionnaire and c. The individual is already receiving treatment for other pituitary hormone deficiencies as required or d. The individual is receiving GH treatment at the date of publication of this guidance and, following reassessment, it is considered appropriate to continue the therapy % of the adults who are on recombinant human growth hormone None 'Recombinant human growth hormone' means somatropin. 'Severe GH deficiency' means having a peak GH response of less than 9 mU/litre (less than 3 ng/ml) during an insulin tolerance test (ITT) or a cross-validated GH threshold in an equivalent test. For b, see the individual's self-reported score on the QoL-AGHDA questionnaire. For d, 're-assessment' means by the individual's consultant endocrinologist as part of routine follow-up. For d, 'appropriate to continue' assumes that the consultant considers the criteria stated in 1a–1c. Clinicians will have to agree locally on how consideration of the appropriateness of continuation of therapy, for patients on GH therapy at the date of publication of this guidance, is documented for audit purposes. . An adult who is started on GH treatment: a. Is re-assessed for QoL status 9 months after the initiation of therapy % of the adults started on GH treatment within the time period agreed for audit purposes None Clinicians will have to agree locally how far back in time care is to be reviewed for this criterion, and on where QoL status at 9 months after initiation of therapy will be documented for audit purposes (that is, where the QoL–AGHDA questionnaire scores are ordinarily recorded). b. Has GH treatment discontinued if the individual has a QoL improvement of less than 7 points in QoLAGHDA scor % of the adults started on GH treatment within the time period agreed for audit purposes who have insufficient QoL improvement None '9 months after the initiation of therapy' means after an initial 3-month period of GH dose titration followed by a 6-month therapeutic trial period. . The following are done for an individual who as a child was treated for GH deficiency and who has completed linear growth: a. GH treatment is stopped for 2–3 months and b. The GH status of the individual is re-assessed and For 3 a and b: 100% of the individuals who have been treated for GH deficiency as a child and who have completed linear growth For 3 a and b: None 'Completion of linear growth' means growth rate < 2cm/year. c. GH treatment at an adult dose is re-started only if the individual meets criterion 1a above and d. GH treatment at an adult dose is continued until adult peak bone mass is achieved and For 3 c and d: 100% of the individuals who have been treated for GH deficiency as a child, who have completed linear growth and who have GH treatment restarted For 3 c and d: None 'Re-assessed' means for GH status and QoL as defined in 1 above. e. When adult peak bone mass is achieved, GH treatment is continued only if the individual meets criteria 1a–c above For 3 e: 100% of the individuals who achieve adult peak bone mass and who have GH treatment continued For 3 e: None Adult peak bone mass is normally achieved by about 25 years of age. . The following are done for an individual who develops GH deficiency in early adulthood after linear growth is completed but before the age of 25: a. GH treatment is given until adult peak bone mass is achieved if the individual meets criterion 1a above and b. When adult peak bone mass is achieved, GH treatment is continued only if the individual meets criteria 1a–1c above % of the individuals who develop GH deficiency in early adulthood after linear growth is completed but before the age of 25 See 1 above for definition of GH deficiency and see 3 above for definition of adult bone mass. . The following are carried out by a qualified specialist: a. Initiation of GH treatment and b. Dose titration and c. Assessment of response during the trial period % of the individuals who are given GH therapy None A 'qualified specialist' is a consultant endocrinologist with a special interest in the management of GH disorders. Clinicians will have to agree locally how far back in time care is to be reviewed for this criterion. . If an individual's maintenance GH treatment is prescribed in primary care, there is an agreed shared-care protocol % of individuals seen for maintenance prescription in primary care None Clinicians will have to agree locally on what constitutes agreement on a shared-care protocol. # Calculation of compliance Compliance (%) with each measure described in the table above is calculated as follows. Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed x 100 Number of patients to whom the measure applies Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.# Changes after publication March 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "Recombinant human growth hormone (somatropin) treatment is recommended for the treatment of adults with growth hormone (GH) deficiency only if they fulfil all three of the following criteria.\n\nThey have severe GH deficiency, defined as a peak GH response of less than 9 mU/litre (3 ng/ml) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test.\n\nThey have a perceived impairment of quality of life (QoL), as demonstrated by a reported score of at least 11 in the disease-specific 'Quality of life assessment of growth hormone deficiency in adults' (QoL-AGHDA) questionnaire.\n\nThey are already receiving treatment for any other pituitary hormone deficiencies as required.\n\nThe QoL status of people who are given GH treatment should be re-assessed 9 months after the initiation of therapy (an initial 3-month period of GH dose titration, followed by a 6-month therapeutic trial period). GH treatment should be discontinued for those people who demonstrate a QoL improvement of less than 7 points in QoL-AGHDA score.\n\nPatients who develop GH deficiency in early adulthood, after linear growth is completed but before the age of 25 years, should be given GH treatment until adult peak bone mass has been achieved, provided they satisfy the biochemical criteria for severe GH deficiency (defined as a peak GH response of less than 9 mU/litre (3 ng/ml) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test). After adult peak bone mass has been achieved, the decision to continue GH treatment should be based on all the criteria in Section 1.1.\n\nPatients currently receiving GH treatment, for the management of adult onset GH deficiency, whether as routine therapy or as part of a clinical trial, could suffer loss of well being if their treatment were to be discontinued at a time they did not anticipate. Because of this, all NHS patients who are on therapy at the date of publication of this guidance should have the option to continue treatment until they and their consultant consider it is appropriate to stop.\n\nChildren with GH deficiency should be treated as outlined in the Institute's guidance on the use of GH in children (NICE Technology Appraisal Guidance No. 42 [Replaced by NICE Technology Appraisal Guidance 188]). At completion of linear growth (that is, growth rate < 2 cm/year), GH treatment should be stopped for 2–3 months, and then GH status should be re-assessed. GH treatment at adult doses should be re-started only in those satisfying the biochemical criteria for severe GH deficiency (defined as a peak GH response of less than 9 mU/litre (3 ng/ml) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test), and continued until adult peak bone mass has been achieved (normally around 25 years of age). After adult peak bone mass has been achieved, the decision to continue GH treatment should be based on all the criteria set out in Section 1.1.\n\nInitiation of GH treatment, dose titration and assessment of response during trial periods should be undertaken by a consultant endocrinologist with a special interest in the management of GH disorders. Thereafter, if maintenance treatment is to be prescribed in primary care, it is recommended that this should be under an agreed shared-care protocol.", 'Clinical need and practice': "Growth hormone is produced by the anterior pituitary gland. It has a role in the regulation of protein, lipid and carbohydrate metabolism, as well as in increasing growth in children. Its secretion is intermittent and occurs predominantly during deep sleep. Secretion reaches maximal levels during adolescence, and then declines with age by approximately 14% per decade.\n\nAdult GH deficiency may be of adult onset or childhood onset, and may occur as isolated GH deficiency or as part of multiple pituitary hormone deficiency. In adult onset, GH deficiency is commonly due to pituitary tumours or their treatment, and to cranial irradiation. Childhood-onset GH deficiency is often idiopathic, and may continue into adulthood. Also, iatrogenic GH deficiency may occur in childhood or adulthood in survivors of childhood malignancy, as a result of previous cranial irradiation and/or chemotherapy.\n\nThe Society for Endocrinology estimates that the prevalence of adult-onset GH deficiency is approximately 1 in 10,000 of the adult UK population. If adults with childhood-onset GH deficiency are also considered, the prevalence may be as high approximately 12,600 adults with GH deficiency in England and Wales.\n\nGH deficiency in adults may be associated with the following adverse features to a variable degree in any individual: reduced quality of life (QoL) especially reduced energy levels; altered body composition (reduced lean mass and increased fat mass, especially in the trunk); osteopenia/osteoporosis (reduced bone mineral density); dry skin (reduced sweating); reduced muscle strength and exercise capacity; lipid abnormalities (especially elevated LDL cholesterol); insulin resistance; increased levels of fibrinogen and plasminogen activator inhibitor; reduced extracellular fluid volume; increased thickness of the intima media of blood vessels; and impaired cardiac function.\n\nSeveral tests are available for the diagnosis of GH deficiency. The ITT is regarded as the 'gold standard' test for adults. A general definition of severe GH deficiency in adults is a peak concentration of less than 9 mU/litre (3 ng/ml) in response to insulin-induced hypoglycaemia. When the ITT is contraindicated other tests – such as response to GH-releasing hormone, arginine or glucagon – can be used.\n\nThe clinical management of GH deficiency in adults is centred on replacement therapy with biosynthetic human GH (somatropin). However, there has been local variation in practice within the UK. The Society for Endocrinology estimates that approximately 1750 adults with GH deficiency currently receive treatment in the UK.", 'The technology': 'There are four preparations of GH available in the UK for the treatment of adults: Genotropin (Pharmacia), Humatrope (Lilly), Norditropin (Novo Nordisk) and Saizen (Serono). Each product is produced by recombinant DNA technology and has a sequence identical to that of human GH.\n\nGH is licensed for replacement therapy in adults with severe growth hormone deficiency. Patients with severe GH deficiency in adulthood are defined as patients with known hypothalamic pituitary abnormality and at least one known deficiency of another pituitary hormone excluding prolactin. These patients should undergo a single diagnostic test in order to diagnose the presence of GH deficiency. In patients with childhood onset isolated GH deficiency (no evidence of hypothalamic pituitary abnormality or cranial irradiation), two diagnostic tests should be recommended, except for those having low IGF-1 (a marker of GH response) concentrations (standard deviation score less than -2) who may be considered for one test.\n\nTreatment is self-administered by a daily subcutaneous injection. The initial dose is 0.2–0.3 mg (0.6–0.9 IU) daily (typically 0.27 mg [0.8 IU] daily). For the first 2–3 months dosage adjustments are made after monthly assessments of serum levels of IGF-1, and in response to the presence of adverse effects, until a maintenance dose is achieved. The currently used median maintenance dose is 0.4 mg (1.2 IU) daily. GH requirements may decrease with age.\n\nSide effects may include headache, arthralgia (joint pain), myalgia (muscle pain), fluid retention (peripheral oedema), mild hypertension, carpal tunnel syndrome, visual problems, nausea and vomiting, paraesthesia, antibody formation, and reactions at the injection site. Benign intracranial hypertension is a rare complication.\n\nGH treatment is contraindicated in people with any evidence of tumour activity, in critically ill patients (for example, after complications following open heart or abdominal surgery, multiple trauma, acute respiratory failure or similar conditions) and also in patients with known hypersensitivity to GH or to any of the excipients. GH treatment is also contraindicated during pregnancy and lactation. In patients with tumours, anti-tumour therapy must be completed before starting GH therapy.\n\nThe cost of treatment depends on the dose, which is determined by the weight/size of the patient as well as the individual GH reserve. The cost of GH (excluding VAT; British National Formulary [BNF] March 2003) is £23.18 per mg for Genotropin and Norditropin and £22.87 per mg for Humatrope and Saizen,. The average annual cost of GH treatment is around £3350 per patient. The cost of treatment reduces with age because the GH requirement decreases as people get older. Costs may vary in different settings because of negotiated procurement discounts.', 'Evidence and interpretation': "The Appraisal Committee (Appendix A) considered evidence from a number of sources (Appendix B).\n\nThe Institute commissioned two Assessment Reports: one was undertaken by the Wessex Institute for Health Research and Development and the other by the University of Sheffield School of Health and Related Research (ScHARR). The Wessex Assessment Report focused on evidence from double-blind, randomised, placebo-controlled trials to evaluate the efficacy of GH treatment in terms of QoL benefits, whereas the ScHARR Assessment Report included the additional evidence that was available from observational studies and some new data from two unpublished randomised controlled trials (RCTs). The Wessex Assessment Report also included a cost analysis of the GH treatment, and the ScHARR Assessment Report provided a detailed critique of the economic models submitted by the manufacturers. During the course of the appraisal some of the manufacturers submitted additional data from newly reported, unpublished trials and results from updated economic analyses.\n\n# Clinical effectiveness\n\n## Quality-of-life evidence from randomised controlled trials\n\nThe Assessment Reports identified 17 published RCTs evaluating the effects of GH on QoL in around 900 adult patients with GH deficiency. Twenty-three different QoL assessment scales were used, within a variety of trial designs. The duration of the studies was typically 6 months and the number of participants ranged from 6 to 173. Most studies included both adult- and childhood-onset GH deficiency.\n\nTen studies evaluated health-related QoL using the Nottingham health profile (NHP), but not all reported the results. Additional unpublished data on QoL for one of the studies were made available to ScHARR. These data were supplied in confidence and have not been included in the pooled results presented below. However, including these data had only a small impact on the results of the meta-analyses and did not affect the conclusions of the ScHARR Assessment Report.\n\nThe analysis of the individual dimensions of the NHP found some statistically significant changes in the GH-treated group compared with the control group.\n\nIn one of the four published studies (the largest) that reported the social isolation dimension, the score was significantly improved in the GH-treated group compared with the placebo group. For this dimension, pooled analysis of all four studies found a small, statistically significant difference in favour of treatment (-0.3 points, 95% confidence interval, -0.4 to -0.1). The largest of the four studies that reported the emotional reactions dimension found a small but statistically significant difference in favour of treatment, but the difference was not statistically significant in the pooled analysis.\n\nFive studies reported the energy dimension. One of the smaller studies found a significant difference in favour of GH treatment, but the pooled analysis of all five did not. For the sleep and physical mobility dimensions, none of the four individual studies reporting these dimensions found a treatment effect of GH, and nor did the pooled analysis. For the pain dimension, one study found a significant difference in favour of placebo, but there was no significant difference in the pooled analysis of four studies.\n\nThe NHP is not designed to produce an overall total score. However, two studies reported mean total scores. Both found improvements in favour of treatment, but these were not statistically significant in either of the individual studies or in the pooled analysis.\n\nTwo RCTs used the QoL-assessment of growth hormone deficiency in adults (QoL-AGHDA) questionnaire – a self-completed questionnaire comprising 25 questions specifically designed to assess the consequences of GH deficiency and its treatment. A high QoL-AGHDA score indicates greater impairment of QoL. One study was conducted across three centres in Spain and included 69 patients. The other was conducted in the Netherlands and recruited 30 patients. Minimal data from these studies have been published in abstract form, but further results were made available in confidence to the ScHARR review group for evaluation.\n\nData pooled from two trials reporting the Hamilton Depression Scale found in favour of GH treatment, but the results were not statistically significant. GH use was associated with an improvement of 2.4 points (95% confidence interval, -4.9 to 0.1).\n\nMeta-analysis of two trials reporting psychological well-being (using the Psychological General Well-being Schedule) found in favour of the GH-treated group, but the results were not statistically significant.\n\nIn summary, based on the evidence from RCTs, in terms of QoL the effectiveness of GH treatment in adults with GH deficiency remains unproven. Many of the available studies were of poor quality. Also, because the patients involved had comparatively normal QoL values at baseline there was little scope for improvement. Furthermore, most of the RCTs used a dosage regimen determined by the patient's weight rather than one based on a titration technique, which is now common clinical practice. This raises difficulties with using this evidence to estimate the effectiveness of currently used GH regimens.\n\n## Quality-of-life evidence from observational trials\n\nA 10-year study provided the longest period of observational follow-up of replacement therapy in GH deficiency. This study included patients who had previously participated in an RCT. Of the 24 patients in the original study, ten patients who had received GH continuously for 10 years were compared with 11 who had not. For the group receiving GH, QoL – as measured by the NHP – was improved over baseline in the domains of energy level and emotional reactions. Overall score was also improved. There was no change in the untreated group. However, the two groups may not be comparable because there are several reasons why patients may not continue treatment. Two shorter observational studies (12 months) reported improvements in overall NHP scores after GH treatment.\n\nEight observational studies of GH therapy in GH deficiency reported QoL-AGHDA scores. Three of these reported results from the largest observational data set of GH-deficient patients, the KIMS database. KIMS is the Pharmacia international metabolic database and pharmacoepidemiological survey of adult GH-deficient patients receiving GH therapy. The three KIMS studies account for most of the published observational data on QoL. They each included between 300 and 665 participants. However, it is likely that data from many of the same patients were reported in all three publications. The extent to which this may have occurred was not clear. The number of participants lost to follow-up was also unclear. In these studies, the reported mean reduction in QoL-AGHDA score after GH treatment ranged from 2.8 to 4.8. The remaining five studies that used the QoL-AGHDA included between 10 and 65 patients, and reported reductions in mean QoL-AGHDA scores ranging from 3 to 7.2.\n\nA formal meta-analysis of the observational data was not performed. However, a crude estimate of average change in QoL-AGHDA was made. This suggested that, across the studies (weighted by number of patients), the average improvement from baseline in QoL-AGHDA after GH treatment was 3.7 points.\n\nIn addition, limited data on specific subgroups (defined according to age and baseline QoL-AGHDA scores) were available from KIMS database. These data suggested that the mean improvement from baseline score in patients less than 65 years of age and with a baseline QoL-AGHDA score of 0-5 was 1.80 points at 1 year. The corresponding values for the groups with baseline QoL-AGHDA scores of 6-10, 11-15, and 15 and over were 5.55, 7.75, and 11.98 respectively, for people less than 65 years old.\n\nIn clinical studies, improvements in QoL were observed within 3–6 months of initiating treatment. Limited data from observational studies suggested that the improvement was sustained in the long term (9–10 years) in patients who continued therapy.\n\n# Cost effectiveness\n\nOne economic evaluation and three cost studies were identified. The only economic evaluation was reported in an outdated Wessex Development and Evaluation Committee (DEC) report (No. 47, 1995), which had subsequently been replaced by another Wessex DEC report (No. 75, 1997). The latter did not present an economic analysis. The utility element of the economic evaluation presented in the earlier DEC report was a set of scenarios not based on primary or secondary data sources and so could not be considered reliable or valid.\n\nThe three cost studies identified were UK-based. One reported costs of diagnosis, GH treatment, and monitoring. The others reported drug costs. All studies reported the cost of the drug as the main factor determining treatment cost (around 90% of total cost). One study reported that annual treatment costs per patient could vary between £3472 and £6943 (1997 prices and GH dose from 0.125 to 0.25 IU/kg/week), and that costs were sensitive to assumptions about continuation rate and the price of GH. The other two studies reported annual drug costs of GH treatment in the range £3300 to £3453, using more up-to-date (median) drug doses.\n\nA cost analysis was presented in the Wessex Assessment Report and aimed to analyse the average annual and total lifetime costs of GH treatment for a patient starting treatment. There was no attempt to estimate the cost effectiveness (or the cost–utility) of GH treatment. The Assessment Group considered that it was not possible to estimate utility gain – which would ideally be expressed in terms of quality-adjusted life years (QALYs) – with the evidence available from RCTs, and so the analysis was limited to costs. It was estimated that GH treatment in GH-deficient adults costs £3424 annually at an average maintenance dose. The costs of life-long therapy are estimated to be between £42,000 (adult-onset GH deficiency) and £45,400 (childhood-onset GH deficiency) without the cost-savings from hospitalisations prevented, and between £40,500 (adult-onset GH deficiency) and £43,800 (childhood-onset GH deficiency) with the savings from hospitalisations prevented. These estimates assume that 20% of people discontinue GH treatment after 6 months.\n\nDrug therapy was found to be the single most important factor in determining cost; changes in the price of GH significantly altered treatment costs, so any price reductions could result in cost savings for the NHS. It was noted that the price at local level could significantly differ from the BNF list price, but there were no reliable data to inform the analysis.\n\nThree manufacturers submitted economic evaluations to the Institute; all three estimated the cost–utility of GH use in adults (that is, they expressed the benefits of treatment in terms of QALYs). One also expressed cost effectiveness in the form of cost per normalised life-year gained.\n\nTwo economic models (Lilly and Novo Nordisk) adopted the methods used in the Wessex DEC report to generate utility estimates. The cost–utility ratios estimated by these models were between £4500 and £32,000 per additional QALY gained. These models did not use primary data but were based on estimates of the likely utility gains, for which there is little evidence. The models should therefore be treated with caution.\n\nOne manufacturer's model estimated the cost effectiveness to be £15,648 per additional normalised life-year for adult-onset GH deficiency, and £16,522 per additional normalised life-year for childhood-onset GH deficiency. The data came from pre- and post-treatment scores of 124 UK patients using the questions on life satisfaction modules for hypopituitarism questionnaire (QLS-H) – a new QoL instrument for adults with GH deficiency, which covers nine domains. 'Normalisation' of QoL was defined as achieving a 'somewhat satisfied', 'satisfied' or 'very satisfied' score in all domains.\n\nAnother manufacturer's model estimated the cost effectiveness of the use of GH replacement therapy in adults to be between £27,500 and £37,600 per additional QALY gained. This model used some inputs (especially those related to cardiovascular and fracture risks) derived from a simulation model, which was also provided. Utility estimates were derived from QoL data collected in the KIMS database. Because the QoL-AGHDA questionnaire is not designed to produce preference-based utilities, regression analysis was used to convert the available data into utility scores. Sub-group analyses for different age and QoL groups were also presented. It should be noted that the use of regression analysis to derive the utility scores is limited by the quality of the data from which they are estimated and the degree of overlap of the descriptive systems.\n\nThe economic analysis presented by ScHARR demonstrated that the long-term effects on risk factors for fractures and cardiovascular events had very little impact on the cost effectiveness of GH treatment. The ScHARR report also included a series of sensitivity analyses to investigate the impact on the results of relaxing the manufacturers' assumptions, which were regarded as optimistic.\n\nThe ScHARR estimate of the impact of GH treatment on QoL was based on the use of observational data using the QoL-AGHDA questionnaire. This was regarded as an optimistic scenario because observational data are very prone to overestimate the treatment effect, particularly for subjective outcomes for which the placebo effect may be especially problematic. A similar mapping exercise to that used in one of the manufacturer's analyses (see Section 4.2.8) was used to derive the utility scores. Additional QoL data made available to ScHARR by one of the manufacturers measured the benefits by using the QLS-H questionnaire, but there is currently no method to map these findings to utility scores.\n\nThe ScHARR analysis, based on an overall utility gain of 0.04–0.12 depending on age and baseline QoL score, estimated the cost effectiveness of GH therapy to be between £25,300 (for people aged 65 years or older with a QoL-AGHDA score ≥\uf02016) and £124,950 (for people aged 18–30 years with a QoL-AGHDA score of 6–10). The overallcost effectiveness of GH therapy was estimated to be in the region of £45,000 per additional QALY. This figure is very sensitive to the estimate of effectiveness, and it should be regarded as the best-case scenario because it is based on observational data that are likely to overestimate the benefits of treatment.\n\n# Consideration of the evidence\n\nThe Committee reviewed the data available on the clinical and cost effectiveness of GH treatment in adults with GH deficiency, having considered evidence on the nature of the condition and the value placed on the benefits of GH treatment from adults with GH deficiency, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources.\n\nThe Committee considered in detail the significance of the effectiveness of GH treatment in GH-deficient adults in terms of its effects on QoL. In addition, the Committee considered the potential effect of GH deficiency on clinical parameters that might adversely affect cardiovascular risk profiles or the potential for bone fractures caused by reduced bone mineral density, both of which might adversely affect life expectancy. The possibility that GH deficiency might also contribute to a higher overall standardised mortality ratio (SMR), over and above that which can be attributed to the effects on cardiovascular risk and bone mineral density, was also taken into account.\n\n## Effects of GH replacement on quality of life\n\nThe Committee considered that improvement in QoL was an important, if not the only, determinant of the clinical and cost effectiveness of GH treatment. It therefore considered at length the assessment tools for QoL used in studies of GH therapy, and in particular the appropriateness and suitability of the NHP, QLS-H, EQ-5D and QoL-AGHDA scoring systems. In addition, the Committee reviewed the evidence on QoL effects from both the RCTs and the observational studies. The Committee was also aware of the high compliance rates among GH users (reported to be around 92%), as pointed out by both the patient representatives and experts.\n\nIt was acknowledged that there were inconsistencies between the results of RCTs, observational studies, and the accounts of many individual patients about the effect of GH therapy on QoL. The Committee took into account the deficiencies in the evidence from RCTs. In particular, the Committee considered the possibility that a sub-group of patients – those with very poor QoL – were benefiting from treatment, but that the effect in these patients was obscured by the inclusion of a large proportion of patients with relatively good pre-treatment QoL and hence little scope for improvement.\n\nDuring the course of this appraisal, the Committee was presented with several analyses relating to improvement in QoL (in addition to the original submissions) that attempted to identify a subgroup of patients in whom GH therapy would be cost effective (that is, those who would gain an improvement in QoL much larger than the average improvements seen in RCTs and observational studies). The Committee reviewed data from an updated subgroup analysis based on a postal survey using the EQ-5D questionnaire of 197 people with GH deficiency. This reanalysis suggested that improvement in utility due to GH treatment might be up to 40% greater than that estimated by QoL-AGHDA. The Committee also reviewed additional data based on QLS-H assessments (from the Hypopituitary Control and Complication Study database). The results from this analysis also suggested that there was likely to be a subgroup of people with GH deficiency who would gain greater improvements in QoL on GH replacement. However, it was not possible to map the data from QLS-H scores into utilities, so this did not provide further direct information to inform the analysis of the cost effectiveness of this technology for selected subgroups.\n\nThe Committee accepted that, although there was not sufficient information available to it to enable a detailed evaluation of the quality of the methods used to derive the new EQ-5D data, a greater degree of utility change using EQ-5D than using QoL-AGHDA would be anticipated because of the well-established differences in the properties of these two QoL tools. The Committee considered that these additional data suggested that a minimum improvement of at least 7 points in QoL-AGHDA score from baseline would be needed to achieve an acceptable level of cost effectiveness.\n\n## Effects of GH replacement on mortality\n\nThe Committee considered in detail the effect of GH replacement on overall mortality from various causes in people with GH deficiency. It considered the potential deleterious effects of GH deficiency on cardiovascular risk profiles and bone mineral density, as well as data on SMRs for people with GH deficiency compared with matched populations. The Committee noted that the association between increased mortality and GH deficiency was based on uncontrolled, observational data and on the assessment of cohorts from different periods.\n\nThe Committee concluded that it was uncertain what impact GH treatment had on the longer-term clinical outcomes and mortality related to cardiovascular risk factors and changes in bone mineral density. However, the Committee believed that the best available evidence from observational studies f these risk factors on mortality had been included in the overall estimates of cost effectiveness that it had reviewed. The Committee considered that it was problematic to draw conclusions about the impact of isolated GH deficiency on overall SMRs (that is, mortality over and above that attributable to cardiovascular risk and bone mineral density changes), because the populations reported in different studies were heterogeneous, which made comparisons difficult. In addition, the SMR data were not adjusted for potential confounding factors, and causality could not be clearly explained.\n\n## Summary of considerations for adult-onset GH deficiency\n\nThe Committee was persuaded that there was a subgroup of people with GH deficiency whose QoL was significantly impaired, and for whom the benefits of GH replacement could be both clinically and cost effective. However, the effect of treatment on overall mortality was less certain and, on the basis of the present evidence, was likely to have been accounted for predominantly by taking into account effects on cardiovascular risk profiles. While accepting that other factors directly or indirectly affecting overall mortality may be present in GH-deficient people, the Committee believed that these would need to be explored in future research.\n\nThe Committee reviewed the analyses of cost effectiveness of GH replacement in adult-onset GH deficiency, including the updated analysis submitted by one manufacturer, that assessed in detail the various factors that might influence the calculations of incremental cost-effectiveness ratios (ICERs), including QoL utility estimates based on different methodologies, the potential effects on overall mortality and the appropriateness of modelling benefits over different time periods.\n\nAfter reviewing the updated cost-effectiveness analyses, and the data from the KIMS database on the levels of improvement (in terms of QoL-AGHDA scores) for different patient groups, the Committee considered that the subgroup of people with GH deficiency for whom treatment may be cost effective would be those who had an improvement in QoL equivalent to an absolute change in their baseline QoL-AGHDA score of at least 7 points. The Committee considered that the ICER for this group of patients would be in the region of £25,000 to £45,000 per QALY.\n\nThe Committee agreed, on the basis of testimony from the experts, that the QoL-AGHDA questionnaire was the best available evaluation tool for the assessment of both baseline QoL and the effect of treatment in people with GH deficiency. The Institute sought clarification on the availability of the QoL-AGHDA questionnaire for use by the clinical community from the developer, Pharmacia, who provided a written statement confirming that the questionnaire is freely accessible as a clinical tool across the UK.\n\nThe Committee considered at length the issue of the baseline score of QoL-AGHDA that would identify the subset of people with severe GH deficiency for whom GH treatment would most clinically and cost effective. It took into account a variety of factors, including the information from the KIMS database and specifically the data that showed that an improvement of an average of 7 points in QoL-AGHDA was only documented in patients with a baseline QoL-AGHDA score of 11 or more. This, together with consideration of the effect of GH on QoL (see Sections 4.3.3 to 4.3.6) led the Committee to conclude that a trial of GH treatment could be recommended for people with GH deficiency who have a severe perceived impairment of QoL as demonstrated by a reported score of at least 11 in QoL-AGHDA.\n\nThe Committee was persuaded by the evidence from expert endocrinologists that reassessment of the need for GH replacement should take place after a trial treatment period of 9 months (3 months for dose titration and 6 months for assessment of response). For GH treatment to continue after this trial period, it should be necessary to demonstrate a sustained improvement in QoL.\n\nIn considering the minimum requirement for the degree of QoL improvement at the end of the trial period, the Committee took into account the data from the KIMS population, the cost-effectiveness considerations (see Section 4.3.11), and the views from the patient/carer organisations and the clinical experts. The Committee concluded that, on the balance of probabilities, an improvement during the trial with GH of 7 points or more in QoL-AGHDA score compared with the baseline measurement would be needed to justify the clinical and cost effectiveness of continuing GH treatment beyond the trial period.\n\nThe Committee was aware that in the KIMS population the QoL improvement score of 7 in patients with a baseline QoL-AGHDA score of 11 or more was a mean value, which implies that there will be some people in this group who did not improve by 7 points and others who improved by more than 7 points. However, the Committee considered – on the basis of all the evidence it had reviewed, the uncertainties surrounding the precise definition of the subgroup that would most benefit from GH treatment, and the extent of any such benefit – that cost-effectiveness should be evident for individual patients. Thus in patients who demonstrate an improvement score lower than 7 points, the Committee concluded that cost effectiveness was not established, and the continued use of GH in these patients after the initial assessment period could not be justified.\n\n## Transitional period\n\nThe Committee considered the issues related to the treatment arrangements for those with childhood-onset GH deficiency from all causes, and the value of GH treatment after the completion of linear growth. It was agreed that people with childhood-onset GH deficiency should be re-tested after the attainment of final height to assess whether further GH replacement is necessary.\n\nThe Committee was persuaded by evidence from experts that, for people with childhood-onset GH deficiency who had completed linear growth but still remained severely deficient in GH according to biochemical tests (defined as a peak GH response of less than 9 mU/litre (3 ng/ml) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test), treatment with GH should be continued until adult bone mass is achieved. The Committee accepted that there are likely to be significant disadvantages in later life for those who do not achieve peak adult bone mass, although this conclusion was not fully evidence-based. The Committee additionally accepted, on the basis of expert testimony, that the age at which peak adult bone mass is achieved can vary between 25 and 30 years depending on a number of factors, including the age of puberty.\n\nThe Committee concluded, therefore, that there will be a proportion of people with childhood-onset GH deficiency for whom continuation of treatment until peak adult bone mass is achieved is desirable. Thereafter, GH treatment should be discontinued and only recommenced on the basis of the criteria laid down for adult-onset GH deficiency (see Section 1.1).\n\nThe Committee was aware of clinical differences between children with idiopathic isolated GH deficiency (IIGHD) and those with multiple pituitary hormone deficiencies, including GH (MPHD). It was, however, not persuaded that there was sufficient evidence that they should be treated differently during the transition period. They concluded, therefore, that during the transition phase all childhood-onset GH deficiency should be managed as indicated in Section 1.5 of this guidance. The possibility that children with IIGHD or MPHD should be treated differentially within these criteria could be the subject of further research.\n\nThe Committee considered the situation of people who develop GH deficiency in early adulthood after linear growth is completed, but before the age of 25 years. These people may require additional GH treatment in order to achieve full adult levels of bone mineral density. The Committee concluded that people in this period of 'transition' should be treated appropriately with GH, and then the criteria in Section 1.1 should apply for consideration of further GH therapy.", 'Recommendations for further research': 'Further good-quality studies are needed in the following areas.\n\nTo investigate whether titrated-dose GH therapy improves QoL more than placebo in GH-deficient adults, and to quantify the treatment effect more accurately.\n\nTo ascertain the most sensitive way of measuring the QoL gain in GH-treated adults, particularly with regard to generating preference-based utilities.\n\nTo investigate the relationship between SMR and GH deficiency for both adult-onset and childhood-onset GH deficiency, as well as for different subgroups.\n\nTo investigate whether patients with MPHD and idiopathic isolated GH deficiency have different treatment requirements, in order to achieve cost effective use of GH treatment.\n\nTo investigate whether different treatment criteria are warranted for childhood and adult onset GH deficiency, in order to optimise the benefits from GH treatment.', 'Implications for the NHS': 'Although it is hard to estimate the number of eligible patients accurately, it is anticipated that only a small proportion of adults with GH deficiency will achieve sustained improvement of at least 7 points on the QoL-AGHDA scale at the end of the assessment period (that is, 9 months). If it is assumed that 30% of adult-onset and 10% of childhood-onset patients will fulfil the starting criteria, and of these 40% will fail to achieve an improvement of at least 7 points on the QoL-AGHDA scale, there will be around 1180 people in England and Wales who would be eligible for continuous GH treatment. This is less than the estimated number of patients currently receiving GH treatment, so implementing this guidance will not incur any additional costs to the NHS. However, in the absence of more accurate data on future uptake, it is not possible to indicate the scale of any potential savings.', 'Related guidance': 'The Institute issued guidance in May 2002 on the use of GH treatment in children with growth failure.\n\nNational Institute for Clinical Excellence (2000) Guidance on the use of human growth hormone (somatropin) in children with growth failure. NICE Technology Appraisal Guidance No. 42. London: National Institute for Clinical Excellence. [Replaced by NICE Technology Appraisal Guidance 188]', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review.\n\nIt is proposed that the guidance on this technology is reviewed in June 2006.\n\nAndrew DillonChief ExecutiveAugust 2003', 'Appendix C. Detail on criteria for audit of the use of human growth hormone (somatropin) in adults with growth hormone deficiency': "# Possible objectives for an audit\n\nAn audit on the appropriateness and effectiveness of the use of growth hormone (GH) treatment in adults with GH deficiency could be carried out to ensure the following.\n\nGH treatment is given to an adult with GH deficiency only if he or she meets defined criteria.\n\nAn adult who is started on GH treatment is re-assessed and GH treatment is discontinued if there is an insufficient improvement in quality of life (QoL).\n\nContinued GH treatment is given only in appropriate circumstances to an individual who has been treated for GH deficiency as a child and who has completed linear growth.\n\nGH treatment is given to an adult who develops GH deficiency in early adulthood only in appropriate circumstances.\n\nInitial treatment of adults with GH deficiency is done only by a qualified specialist and maintenance GH treatment is continued in primary care only when there is an agreed shared-care protocol.\n\n# Possible patients to be included in the audit\n\nAn audit could be carried out on all adults referred or seen for GH deficiency in a given time period, for example, 6 months or a year. Because the measures listed below refer to care provided after the start of GH treatment, it may be desirable to limit the audit to new patients or to agree on the specific time period of care that will apply to each of the measures.\n\n# Measures that could be used as a basis for audit\n\nThe measures that could be used in an audit of GH treatment are as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. An adult given recombinant human growth hormone meets all three of a–c or d as follows:\n\na. The individual has severe GH deficiency and\n\nb. The individual has a perceived impairment of quality of life (QoL) as demonstrated by a reported score of at least 11 in the QoL-AGHDA questionnaire and\n\nc. The individual is already receiving treatment for other pituitary hormone deficiencies as required or\n\nd. The individual is receiving GH treatment at the date of publication of this guidance and, following reassessment, it is considered appropriate to continue the therapy\n\n% of the adults who are on recombinant human growth hormone\n\nNone\n\n'Recombinant human growth hormone' means somatropin. 'Severe GH deficiency' means having a peak GH response of less than 9 mU/litre (less than 3 ng/ml) during an insulin tolerance test (ITT) or a cross-validated GH threshold in an equivalent test.\n\nFor b, see the individual's self-reported score on the QoL-AGHDA questionnaire.\n\nFor d, 're-assessment' means by the individual's consultant endocrinologist as part of routine follow-up.\n\nFor d, 'appropriate to continue' assumes that the consultant considers the criteria stated in 1a–1c.\n\nClinicians will have to agree locally on how consideration of the appropriateness of continuation of therapy, for patients on GH therapy at the date of publication of this guidance, is documented for audit purposes.\n\n. An adult who is started on GH treatment:\n\na. Is re-assessed for QoL status 9 months after the initiation of therapy\n\n% of the adults started on GH treatment within the time period agreed for audit purposes\n\nNone\n\nClinicians will have to agree locally how far back in time care is to be reviewed for this criterion, and on where QoL status at 9 months after initiation of therapy will be documented for audit purposes (that is, where the QoL–AGHDA questionnaire scores are ordinarily recorded).\n\nb. Has GH treatment discontinued if the individual has a QoL improvement of less than 7 points in QoLAGHDA scor\n\n% of the adults started on GH treatment within the time period agreed for audit purposes who have insufficient QoL improvement\n\nNone\n\n'9 months after the initiation of therapy' means after an initial 3-month period of GH dose titration followed by a 6-month therapeutic trial period.\n\n. The following are done for an individual who as a child was treated for GH deficiency and who has completed linear growth:\n\na. GH treatment is stopped for 2–3 months\n\nand\n\nb. The GH status of the individual is re-assessed\n\nand\n\nFor 3 a and b: 100% of the individuals who have been treated for GH deficiency as a child and who have completed linear growth\n\nFor 3 a and b: None\n\n\n\n'Completion of linear growth' means growth rate < 2cm/year.\n\n\n\nc. GH treatment at an adult dose is re-started only if the individual meets criterion 1a above\n\nand\n\nd. GH treatment at an adult dose is continued until adult peak bone mass is achieved\n\nand\n\nFor 3 c and d: 100% of the individuals who have been treated for GH deficiency as a child, who have completed linear growth and who have GH treatment restarted\n\nFor 3 c and d: None\n\n\n\n'Re-assessed' means for GH status and QoL as defined in 1 above.\n\n\n\ne. When adult peak bone mass is achieved, GH treatment is continued only if the individual meets criteria 1a–c above\n\nFor 3 e: 100% of the individuals who achieve adult peak bone mass and who have GH treatment continued\n\nFor 3 e: None\n\nAdult peak bone mass is normally achieved by about 25 years of age.\n\n. The following are done for an individual who develops GH deficiency in early adulthood after linear growth is completed but before the age of 25:\n\na. GH treatment is given until adult peak bone mass is achieved if the individual meets criterion 1a above\n\nand\n\nb. When adult peak bone mass is achieved, GH treatment is continued only if the individual meets criteria 1a–1c above\n\n% of the individuals who develop GH deficiency in early adulthood after linear growth is completed but before the age of 25\n\n\n\nSee 1 above for definition of GH deficiency and see 3 above for definition of adult bone mass.\n\n. The following are carried out by a qualified specialist:\n\na. Initiation of GH treatment\n\nand\n\nb. Dose titration\n\nand\n\nc. Assessment of response during the trial period\n\n% of the individuals who are given GH therapy\n\nNone\n\nA 'qualified specialist' is a consultant endocrinologist with a special interest in the management of GH disorders.\n\nClinicians will have to agree locally how far back in time care is to be reviewed for this criterion.\n\n. If an individual's maintenance GH treatment is prescribed in primary care, there is an agreed shared-care protocol\n\n% of individuals seen for maintenance prescription in primary care\n\nNone\n\nClinicians will have to agree locally on what constitutes agreement on a shared-care protocol.\n\n# Calculation of compliance\n\nCompliance (%) with each measure described in the table above is calculated as follows.\n\nNumber of patients whose care is consistent with the criterion plus number of patients who meet any exception listed\n\nx 100\n\nNumber of patients to whom the measure applies\n\nClinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.", 'Changes after publication': 'March 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta64	Evidence-based recommendations on human growth hormone (somatropin; Genotropin, Humatrope, Norditropin, NutropinAq, Omnitrope, Saizen, Zomacton) for treating growth hormone deficiency in adults.
dedfde633b2d5d78253eb393347588e48d58c742	nice	Radiofrequency ablation of hepatocellular carcinoma	Radiofrequency ablation of hepatocellular carcinoma # Recommendations Current evidence of the safety and efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma appears adequate to support use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance. It is recommended that: patient selection should be carried out by a multidisciplinary team that includes a hepatobiliary surgeon the procedure should be monitored by CT or ultrasound.# The procedure # Indications Hepatocellular carcinoma is one of two common malignant tumours affecting the liver. The majority of malignant liver tumours are unsuitable for surgical excision because of their number, distribution and/or the presence of residual disease elsewhere. Therefore, a number of alternative treatments have been developed, of which RFA is one. # Outline of the procedure RFA is a recently developed minimally invasive technique that destroys tissue by heating. Electrodes are inserted percutaneously into the tumour and current is applied to generate local heating and destroy tissue. # Efficacy There is evidence that RFA results in tumour destruction, which may be associated with higher survival rates. For more details refer to the overview (see 'Sources of evidence considered by the Committee'). # Safety Complications of RFA are not common, but include hepatic abscess and injury to bile ducts. The rate of complications appears lower than that with alternative treatments. Evidence suggests a mortality rate of 1% or less. For more details refer to the overview (see 'Sources of evidence considered by the Committee'). The specialist advisors suggested the complication rate to be 3–5%. # Other comments The Committee noted that there was less evidence available about the safety and efficacy of RFA in treatment of colorectal metastases. Guidance for this indication will be postponed pending the publication of a systematic review by the Australian Medical Services Advisory Committee.# Further information # Sources of evidence considered by the Committee The following source of evidence was considered by the Interventional Procedures Advisory Committee. 'Interventional procedure overview of radiofrequency ablation for the treatment of liver tumours' , October 2003. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication November 2011: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Recommendations': 'Current evidence of the safety and efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma appears adequate to support use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance.\n\nIt is recommended that:\n\npatient selection should be carried out by a multidisciplinary team that includes a hepatobiliary surgeon\n\nthe procedure should be monitored by CT or ultrasound.', 'The procedure': "# Indications\n\nHepatocellular carcinoma is one of two common malignant tumours affecting the liver. The majority of malignant liver tumours are unsuitable for surgical excision because of their number, distribution and/or the presence of residual disease elsewhere. Therefore, a number of alternative treatments have been developed, of which RFA is one.\n\n# Outline of the procedure\n\nRFA is a recently developed minimally invasive technique that destroys tissue by heating. Electrodes are inserted percutaneously into the tumour and current is applied to generate local heating and destroy tissue.\n\n# Efficacy\n\nThere is evidence that RFA results in tumour destruction, which may be associated with higher survival rates. For more details refer to the overview (see 'Sources of evidence considered by the Committee').\n\n# Safety\n\nComplications of RFA are not common, but include hepatic abscess and injury to bile ducts. The rate of complications appears lower than that with alternative treatments. Evidence suggests a mortality rate of 1% or less. For more details refer to the overview (see 'Sources of evidence considered by the Committee').\n\nThe specialist advisors suggested the complication rate to be 3–5%.\n\n# Other comments\n\nThe Committee noted that there was less evidence available about the safety and efficacy of RFA in treatment of colorectal metastases. Guidance for this indication will be postponed pending the publication of a systematic review by the Australian Medical Services Advisory Committee.", 'Further information': "# Sources of evidence considered by the Committee\n\nThe following source of evidence was considered by the Interventional Procedures Advisory Committee.\n\n'Interventional procedure overview of radiofrequency ablation for the treatment of liver tumours'\n , October 2003.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nNovember 2011: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg2
9fff1649aa2880b73fb0c8521d7feec2fe82d2c8	nice	Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer	Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer Evidence-based recommendations on capecitabine for treating metastatic colorectal cancer in adults. # Guidance Oral therapy with capecitabine is recommended as an option for the first-line treatment of metastatic colorectal cancer. The choice of regimen (intravenous fluorouracil/folinic acid or capecitabine) should be made jointly by the individual and the clinician(s) responsible for treatment. The decision should be made after an informed discussion between the clinician(s) and the patient; this discussion should take into account contraindications and the side-effect profile of the agents as well as the clinical condition and preferences of the individual. The use of capecitabine to treat metastatic colorectal cancer should be supervised by oncologists who specialise in colorectal cancer.# Clinical need and practice Colorectal cancer is one of the most common malignancies in the UK, with an annual incidence of about 47 cases per 100,000 individuals. In 1999, 31,000 new cases of colorectal cancer were reported in England and Wales, and in 1998 almost 15,000 deaths were reported. Colorectal cancer is rare in people under the age of 40 years. Approximately 41% of individuals with colorectal cancer are aged over 75 years, and 52% of deaths from colorectal cancer occur in this age group. Colorectal cancer is defined as advanced if, at presentation or recurrence, it is either metastatic or so locally invasive that surgical resection is unlikely to be carried out with curative intent. Approximately 30% of individuals diagnosed with colorectal cancer present with advanced disease. Approximately 50% of those individuals who do not have advanced disease at presentation will subsequently develop this condition. Individuals with advanced colorectal cancer may experience a wide range of physical and psychological symptoms resulting in decreased quality of life. The 5-year survival rate is, on average, less than 5%. The management of advanced colorectal cancer is mainly palliative, and involves a combination of specialist treatments (palliative surgery, chemotherapy and radiation), symptom control and psychosocial support. The aim is to improve both the duration and quality of the individual's remaining life, while also controlling symptoms. Early chemotherapy before onset of symptoms has been shown to prolong survival and improve overall quality of life. Individuals with advanced disease who are sufficiently fit (those with a World Health Organization performance status of 2 or better) are usually treated with systemic chemotherapy as first- or second-line therapy. In individuals with a WHO performance status of 3 or 4 the adverse effects of chemotherapy may often be judged to outweigh the potential benefits, although the decision depends on the individual's clinical circumstances. The standard chemotherapy regimen is typically a combination of 5-fluorouracil (5-FU) and folinic acid (calcium folinate, leucovorin). Thymidylate synthase (TS) – a key enzyme in pyrimidine biosynthesis – is inhibited by 5-FU, and folinic acid (FA) enhances TS inhibition by increasing the intracellular folate pool, thus stabilising the 5-FU–TS complex. However, an increasing number of alternative chemotherapeutic options are under evaluation. There are different 5-FU regimens, in which the drug is given either by intravenous infusion or bolus injection. There is considerable variability in current UK practice because of a lack of consensus over the optimum regimen. Although the rates obtained in individual trials have shown variation, there is some evidence to suggest that infusional regimens, for example the Lockich and de Gramont, may be more effective in terms of progression-free survival, tumour response, safety, toxicity and quality of life than bolus regimens, for example the Mayo. However, infusional regimens are more complex to administer and the use of central venous lines increases the rate of complications, such as infection and thrombosis. Approximately 60% of individuals experience a response or a period of stable disease following first-line 5-FU/FA therapy. There is evidence from five RCTs that early chemotherapy for advanced disease improves survival by 3–6 months compared with a policy of deferring chemotherapy until required for symptom relief. In the five studies, median survival was increased from a range of 5–9 months to a range of 7.5–14 months. However, the benefits of therapy must be considered against the side effects of treatment, the potential need for multiple hospital visits and, in many cases, the problems and anxieties of having a central venous line.# The technology # Capecitabine Capecitabine (Xeloda) is a fluoropyrimidine carbamate precursor of 5-FU. It is given orally and is converted via several enzymatic steps to give intratumoural release of 5-FU. The enzyme involved in the final conversion to 5-FU, thymidine phosphorylase, is found at higher levels in tumour tissues than in normal tissue, thereby reducing systemic exposure to 5-FU. Capecitabine is indicated for first-line monotherapy of metastatic colorectal cancer. The recommended dose of capecitabine is 1250 mg/m2 twice daily for 14 days, followed by a 7-day rest period before another cycle of treatment. The listed costs of 60 150-mg tablets and 120 500-mg tablets of capecitabine are £44 and £295 respectively (excluding VAT; British National Formulary 44, September 2002). Based on an assumed body surface area of 1.7 m2, the acquisition cost (excluding VAT) of treating an individual with capecitabine for 105 days (five cycles) is £1463. Costs may vary in different settings because of negotiated procurement discounts. # Tegafur with uracil Tegafur is a 5-FU prodrug, meaning that after administration it is metabolised into the pharmacologically active compound 5-FU. Tegafur is given in combination with uracil, which inhibits the degradation of 5-FU, resulting in sustained higher levels of 5-FU in tumour cells. FA is usually added to the tegafur and uracil (UFT) combination to act as a modulator. These drugs can be taken orally. UFT (Uftoral) is indicated for first-line treatment of metastatic colorectal cancer in combination with FA. Each capsule contains tegafur 100 mg plus uracil 224 mg. The recommended dose of UFT is tegafur 300 mg/m2 (with uracil 672 mg/m2) daily, combined with oral FA 90 mg/day, given in three divided doses (preferably every 8 hours) for 28 days. Subsequent courses are repeated at 7-day intervals, giving a treatment cycle of 35 days. The list cost of 21 UFT tablets is £67 (Monthly Index of Medical Specialties, February 2003). Based on an assumed body surface area of 1.7 m2, the acquisition cost (excluding VAT) of treating an individual with UFT for 105 days (three cycles) is £1358. FA obtained at a cost of £3.78 per 15-mg tablet incurs an additional cost of up to £1905. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee considered evidence from a number of sources (see Appendix A). # Clinical effectiveness ## Capecitabine Two phase III randomised controlled trials (RCTs), recruiting 602 and 605 individuals, and one pooled analysis of these study data were reviewed. Both RCTs compared capecitabine with a bolus (Mayo) 5-FU/FA regimen and were identical in design. Both studies included individuals with untreated, locally advanced or metastatic colorectal cancer, most of whom had undergone previous surgery. Although neither RCT was undertaken under blinded conditions because of the different routes of administration (oral or intravenous), both studies used an independent committee to review outcomes. The primary outcome measure in both trials was tumour response rate. Both studies were adequately powered to demonstrate equivalence in overall response rates. Differences in median overall survival were not statistically different at the 5% significance level in either RCT, with values of 12.5 and 13.3 months for capecitabine and 5-FU/FA respectively in one study, and 13.2 and 12.1 months respectively in the other study. The pooled study also did not report any statistically significant difference in overall survival. In both studies, the overall response rate was statistically significantly higher in the capecitabine groups than in the 5-FU/FA groups when outcomes were assessed by study investigators (p = 0.005 and p = 0.013). However, when the independent review committee assessed outcomes, these response rates were statistically significantly higher in only one of the studies (p = 0.0001). When the data from both studies were pooled, response rates statistically favoured capecitabine irrespective of who carried out the assessment (p < 0.0002 for the investigator assessment and p < 0.0001 for the independent review committee assessment). Neither study reported a statistically significant difference in mean duration of response between the capecitabine and 5-FU/FA groups, nor was a difference reported for the pooled data. Neither study, nor the pooled analysis, reported any statistically significant differences in time to disease progression, death or treatment failure between the capecitabine and 5-FU/FA groups. Neither of the studies reported any statistically significant difference in global quality of life as measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). With regard to treatment-related adverse events, the pooled analysis of the two trials indicated that individuals in the capecitabine groups reported less diarrhoea (48% vs 58%, p < 0.001), stomatitis (24% vs 62%, p < 0.001), nausea (38% vs 47%, p < 0.001) and alopecia (6% vs 21%, p < 0.001) of all grades than those in the 5-FU/FA groups. Patients in the capecitabine groups also had less grade III/IV neutropenia (2% vs 21%, no p-value available) and grade III stomatitis (2% vs 15%, p < 0.0001), and less frequent hospitalisation for adverse events (12% vs 18%, p = 0.002), but reported more hand–foot syndrome (54% vs 6.0%, no p-value available) and grade III hyperbilirubinaemia (18% vs 3%, p < 0.0001). In the pooled analysis, treatment mortality was 1% for each group. ## Tegafur with uracil (UFT) Two large, open, phase III RCTs (Studies 011 and 012) were reviewed. These trials recruited 816 and 380 individuals respectively. No independent review committee was used to compensate for the fact that the assessors were aware of treatment allocation. Study 011 compared UFT/FA with 5-FU/FA administered using the Mayo regimen, whereas Study 012 compared UFT/FA with 5-FU/FA administered using a modification of the Mayo regimen, where treatment was repeated every 35 days instead of the standard 28 days. This non-standard variation of the Mayo regimen is a less dose-intensive regimen and has not been tested for efficacy. In Study 011, individuals recruited in the USA received UFT plus FA 75 mg/day, while those in non-USA centres received UFT plus FA 90 mg/day. Study 011 used overall survival as the primary endpoint and was powered to demonstrate equivalence of the two treatments as non-inferiority of survival. Study 012 used time to disease progression as the primary endpoint, and was powered to detect a hazard ratio (HR) of 1.4 between the groups. A third study of crossover design was also identified, which assessed patient preference for UFT/FA compared with intravenous 5-FU/FA. In Study 011, median survival time was 12.4 months in the UFT/FA group and 13.4 months in the 5-FU/FA group. The HR for 5-FU/FA over UFT/FA was 0.96 (95% confidence interval : 0.83 to 1.13). In Study 012, median survival time was 12.2 months in the UFT/FA group and 10.3 months in the 5-FU/FA group. The HR for 5-FU/FA over UFT/FA in this study was 1.14 (95% CI: 0.92 to 1.42). A secondary analysis showed that individuals from the USA sites in Study 011, who received lower-dose FA, had worse overall survival than the total study population. In Study 011 the median time to disease progression was statistically significantly greater in the 5-FU/FA group than in the UFT/FA group (3.8 months vs 3.5 months, p = 0.01), although the actual difference was 10 days. No statistically significant difference in time to disease progression was reported in Study 012. In both studies there were no statistically significant differences between treatment arms with regard to overall tumour response rates. The rates in the UFT/FA and 5-FU/FA groups were 11.7% and 14.5% respectively in Study 011, and 10.5% and 9.0% respectively in Study 012. No statistically significant differences in duration of response were reported (actual values were not reported). In Study 011, compared with 5-FU/FA, UFT/FA was associated with statistically significantly less diarrhoea (67% vs 76%, p = 0.006), nausea/vomiting (67% vs 75%, p = 0.02), mucositis (24% vs 75%, p < 0.001), neutropenia (13% vs 77%, p < 0.001) and thrombocytopenia (21% vs 31%, p < 0.001) of all toxicity severity grades. UFT/FA was also associated with less grade III/IV mucositis (1% vs 20%, p < 0.001), neutropenia (1% vs 56%, p < 0.001), thrombocytopenia (0% vs 2%, p = 0.003) and anaemia (3% vs 7%, p = 0.03). Increased bilirubin, without other liver function abnormalities, was statistically significantly more common in individuals treated with UFT/FA than in those treated with 5-FU/FA (39% vs 22%, p < 0.001). In Study 012, UFT/FA treatment resulted in statistically significantly fewer episodes of stomatitis/mucositis (18% vs 55%, p < 0.001), neutropenia (11% vs 67%, p < 0.001), thrombocytopenia (18% vs 28%, p = 0.025) and anaemia (76% vs 89%, p = 0.002) of any grade than 5-FU/FA treatment. UFT/FA treatment resulted in statistically significantly less grade III/IV stomatitis/mucositis (2% vs 16%, p < 0.001) and neutropenia (3% vs 31%, p < 0.001). In all, 127 individuals were hospitalised during the study: 59 (31%) in the UFT/FA group and 68 (37%) in the 5-FU/FA group (p-values not reported). Health-related quality of life was measured in both studies using either the Functional Living Index-Cancer or EORTC QLQ-C30; no statistically significant differences in outcomes were reported between the treatment groups in either study. An unpublished preliminary report of a phase II randomised study in 202 individuals indicated that scores for functional and symptom scales were either improved or unchanged in the UFT/FA group but worse in the 5-FU/FA group. The only information available on preferences for treatment was a 37-patient crossover study in which individuals received either UFT (300 mg/m2/day) plus FA (90 mg/m2/day) for 28 days every 5 weeks, or intravenous FU (425 mg/m2/day) plus FA (20 mg/m2/day) for 5 days every 4 weeks. They were then crossed-over to the other treatment regimen for the second treatment cycle. Therapy preference questionnaires were completed before the first and after the second treatment cycle. Of the 31 individuals who completed the questionnaire, 84% preferred the UFT/FA regimen. The reasons for this preference included being able to take medication at home, experiencing less stomatitis and diarrhoea, and being able to use a tablet instead of having an injection. # Cost effectiveness ## Capecitabine Two economic evaluations of capecitabine compared with 5-FU/FA were identified, one conducted by the manufacturer and the other by the Assessment Group. Both evaluations assumed equivalent effectiveness, and thus only evaluated associated costs from an NHS perspective. Both models included costs associated with drug acquisition, chemotherapy administration (including inpatient stays) and adverse event management. The manufacturer estimated the costs of capecitabine and 5-FU/FA (using the Mayo bolus regimen) to be approximately £2700 and £5000, respectively. The Assessment Group estimated these costs to be £2100 and £3600, respectively. The Assessment Group also estimated the cost of 5-FU/FA to be £6300 when the de Gramont infusional regimen was used and £3500 when the modified de Gramont infusional method, which does not generally require inpatient administration, was used. In all instances, capecitabine was the least costly treatment option. ## Tegafur with uracil Both the manufacturer and the Assessment Group conducted economic analyses that compared UFT/FA with 5-FU/FA; both assessed costs from an NHS perspective and included categories of costs such as drug acquisition, chemotherapy administration (including inpatient stays), and adverse event management. A cost-minimisation study was also identified, although it was of limited use because it was from a non-UK perspective and did not specify the comparator regimen (for example Mayo or de Gramont). The manufacturer's cost-effectiveness analysis compared UFT/FA with 5-FU/FA based on a Mayo regimen. The analysis used adverse events as the health outcome of interest although the evaluation was conducted separately for the two RCTs, and the costs of UFT/FA and 5-FU/FA were found to be £3600 and £6100 respectively for Study 011, and £3200 and £4900 respectively for Study 012. The Assessment Group's cost-minimisation analysis showed a cost of approximately £3500 both for UFT/FA and for 5-FU/FA, administered using either the Mayo or modified de Gramont outpatient-based regimen. # Consideration of the evidence The Committee reviewed the evidence available on the clinical and cost effectiveness of capecitabine and UFT, having considered evidence on the nature of the condition and the value placed by users on the benefits of capecitabine and UFT/FA by people with colorectal cancer, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources. In the absence of patient preference data from adequately designed studies, the Committee took particular note of the opinions of both the professional and patient representatives regarding the advantages of oral compared with intravenous administration of chemotherapy, and of the potential problems of concordance with oral treatments. The patient representatives particularly emphasised that the vast majority of individuals expressed a strong preference for oral drugs provided that effectiveness was not compromised, because they reduce the disruptive impact of chemotherapy on individuals' lives and give them greater control over the management of their disease. The Committee was satisfied that the phase III RCT data demonstrated that both capecitabine and UFT/FA were likely to have clinical effectiveness similar to that of 5-FU/FA administered by the bolus Mayo regimen. The appropriateness of using the Mayo regimen as a comparator was questioned because of evidence that suggests that infusional regimens may be more effective and less toxic. Indirect comparison of the oral drugs with infusional regimens might therefore suggest that the oral drugs are less effective. However, this evidence has not been formally appraised, and both the professional experts and the Assessment Group questioned its robustness. The Committee did not therefore consider it sufficiently conclusive to be the basis of a recommendation against the use of the oral treatments. However, the Committee also firmly believed that an appropriately designed RCT was required to carry out a direct comparison of the effectiveness of the oral treatments versus the infusional regimens. In addition, the Committee considered there was insufficient evidence to enable a distinction to be made in terms of effectiveness between the two oral agents. There are also differences in the contraindications and side-effect profiles of the individual oral and intravenous regimens, and the Committee appreciated that the choice of the most appropriate treatment regimen might depend on the individual's circumstances. The Committee therefore concluded that intravenous regimens may be preferable under certain circumstances, and that capecitabine and UFT/FA should thus be available as options for treatment rather than as the preferred choice. The Committee considered that, given the lack of compelling evidence for a difference in effectiveness between the regimens, the correct approach to evaluation of cost effectiveness was cost minimisation. They took note of the variations in the estimates of the total costs obtained from the submitted models, and overall were convinced that the oral drugs were cost-effective compared with 5-FU/FA regimens, principally on the basis of the potential cost savings related to the method of administration. They were also aware that the reduced burden of preparation and administration on specialist staff might potentially allow reallocation of clinical resources.# Further research Further research is required to determine the place of capecitabine and tegafur with uracil in the treatment of metastatic colorectal cancer. In particular, RCTs are needed to assess the use of these oral treatments compared with infusional 5-FU/FA regimens. Such studies should include evaluations of quality of life, acceptability and cost effectiveness.# Implications for the NHS Given the available evidence, a conservative estimate of the cost savings that would be associated with all individuals receiving capecitabine instead of bolus 5-FU/FA is £10.5 million, including VAT. This is based on the assumption that 7000 people receive capecitabine (costing £2100 per person as estimated by the Assessment Group) instead of bolus Mayo 5-FU/FA (costing £3600 per person as estimated by the Assessment Group). The savings would be similar if it is assumed that capecitabine is used in preference to the modified de Gramont regimen (costing £3500 per person as estimated by the Assessment Group). However, this estimated cost saving is higher if the calculations are based on the assumption that people would otherwise receive the de Gramont infusional regimen 5-FU/FA (costing £6250 per person as estimated by the Assessment Group) or on the manufacturer's cost estimates. If it is assumed that 7000 people receive UFT/FA (costing £3400 per person as estimated by the Assessment Group) instead of 5-FU/FA administered using the Mayo or modified de Gramont outpatient-based regimen, there could be savings of up to £1.4 million. However, if 7000 people receive UFT/FA instead of the unmodified de Gramont infusion regimen, there could be a reduction in costs of nearly £20 million. However, it is unlikely that such savings would be realised in terms of 'cash' for two reasons: the estimates represent amounts of resources that would remain within the system (but might nevertheless be redeployed); and the estimates are based on average costs (for example, of days in hospital avoided), some of which are fixed costs and therefore will not be saved, but could be available for other purposes.# Related guidance The Institute has issued guidance on the use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. National Institute for Clinical Excellence (2002) Guidance on the use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. NICE Technology Appraisal Guidance No. 33. London: National Institute for Clinical Excellence. The Institute has issued guidance on the use of laparoscopic surgery for colorectal cancer. National Institute for Clinical Excellence (2000) Guidance on the use of laparoscopic surgery for colorectal cancer. NICE Technology Appraisal Guidance No. 17. London: National Institute for Clinical Excellence. # Appendix C. The use of capecitabine and tegafur with uracil for metastatic colorectal cancer A summary of this guidance for people with colorectal cancer and the public can be found on our website.# Appendix D. Detail on criteria for audit of the use of capecitabine and tegafur with uracil for metastatic colorectal cancer # Possible objectives for an audit An audit on the treatment of people with metastatic colorectal cancer could be carried out to ensure that capecitabine and tegafur with uracil are being used appropriately. # Possible people to be included in an audit An audit could be carried out on people with metastatic colorectal cancer referred over a suitable time period, for example 6 months or a year. # Measures that could be used as a basis for audit The measures that could be used in an audit of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer are as follows. Criterion Standard Exception Definition of terms . For the first-line treatment of metastatic colorectal cancer an individual is given the option of oral therapy with either capecitabine or tegafur with uracil (in combination with folinic acid) % of people diagnosed as having metastatic colorectal cancer None Clinicians will have to agree locally on how the offer of the option of oral therapy as an alternative to intravenous 5-FU/FA regimens is documented for audit purposes. . The individual and the clinician(s) responsible for treatment decide jointly on the choice of regimen after an informed discussion of the following: a. the relative clinical and cost-effectiveness of each treatment option and b. the side-effect profile of each treatment option and c. the preferences of the individual % of people diagnosed as having metastatic colorectal cancer None Clinicians will have to agree locally on how the joint decision will be documented for audit purposes. . An oncologist specialising in colorectal cancer supervises the use of capecitabine and tegafur with uracil % of the people receiving capecitabine or tegafur with uracil None Clinicians will have to agree locally on how supervision of the use of capecitabine and tegafur with uracil is defined and documented for audit purpose # Calculation of compliance Compliance (%) with each measure described in the table above is calculated as follows. Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed x 100 Number of patients to whom the measure applies Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.	{'Guidance': 'Oral therapy with capecitabine is recommended as an option for the first-line treatment of metastatic colorectal cancer.\n\nThe choice of regimen (intravenous fluorouracil/folinic acid [5-FU/FA] or capecitabine) should be made jointly by the individual and the clinician(s) responsible for treatment. The decision should be made after an informed discussion between the clinician(s) and the patient; this discussion should take into account contraindications and the side-effect profile of the agents as well as the clinical condition and preferences of the individual.\n\nThe use of capecitabine to treat metastatic colorectal cancer should be supervised by oncologists who specialise in colorectal cancer.', 'Clinical need and practice': "Colorectal cancer is one of the most common malignancies in the UK, with an annual incidence of about 47 cases per 100,000 individuals. In 1999, 31,000 new cases of colorectal cancer were reported in England and Wales, and in 1998 almost 15,000 deaths were reported.\n\nColorectal cancer is rare in people under the age of 40 years. Approximately 41% of individuals with colorectal cancer are aged over 75 years, and 52% of deaths from colorectal cancer occur in this age group.\n\nColorectal cancer is defined as advanced if, at presentation or recurrence, it is either metastatic or so locally invasive that surgical resection is unlikely to be carried out with curative intent. Approximately 30% of individuals diagnosed with colorectal cancer present with advanced disease. Approximately 50% of those individuals who do not have advanced disease at presentation will subsequently develop this condition. Individuals with advanced colorectal cancer may experience a wide range of physical and psychological symptoms resulting in decreased quality of life. The 5-year survival rate is, on average, less than 5%.\n\nThe management of advanced colorectal cancer is mainly palliative, and involves a combination of specialist treatments (palliative surgery, chemotherapy and radiation), symptom control and psychosocial support. The aim is to improve both the duration and quality of the individual's remaining life, while also controlling symptoms. Early chemotherapy before onset of symptoms has been shown to prolong survival and improve overall quality of life.\n\nIndividuals with advanced disease who are sufficiently fit (those with a World Health Organization [WHO] performance status of 2 or better) are usually treated with systemic chemotherapy as first- or second-line therapy. In individuals with a WHO performance status of 3 or 4 the adverse effects of chemotherapy may often be judged to outweigh the potential benefits, although the decision depends on the individual's clinical circumstances.\n\nThe standard chemotherapy regimen is typically a combination of 5-fluorouracil (5-FU) and folinic acid (calcium folinate, leucovorin). Thymidylate synthase (TS) – a key enzyme in pyrimidine biosynthesis – is inhibited by 5-FU, and folinic acid (FA) enhances TS inhibition by increasing the intracellular folate pool, thus stabilising the 5-FU–TS complex. However, an increasing number of alternative chemotherapeutic options are under evaluation.\n\nThere are different 5-FU regimens, in which the drug is given either by intravenous infusion or bolus injection. There is considerable variability in current UK practice because of a lack of consensus over the optimum regimen. Although the rates obtained in individual trials have shown variation, there is some evidence to suggest that infusional regimens, for example the Lockich and de Gramont, may be more effective in terms of progression-free survival, tumour response, safety, toxicity and quality of life than bolus regimens, for example the Mayo. However, infusional regimens are more complex to administer and the use of central venous lines increases the rate of complications, such as infection and thrombosis.\n\nApproximately 60% of individuals experience a response or a period of stable disease following first-line 5-FU/FA therapy. There is evidence from five RCTs that early chemotherapy for advanced disease improves survival by 3–6 months compared with a policy of deferring chemotherapy until required for symptom relief. In the five studies, median survival was increased from a range of 5–9 months to a range of 7.5–14 months. However, the benefits of therapy must be considered against the side effects of treatment, the potential need for multiple hospital visits and, in many cases, the problems and anxieties of having a central venous line.", 'The technology': '# Capecitabine\n\nCapecitabine (Xeloda) is a fluoropyrimidine carbamate precursor of 5-FU. It is given orally and is converted via several enzymatic steps to give intratumoural release of 5-FU. The enzyme involved in the final conversion to 5-FU, thymidine phosphorylase, is found at higher levels in tumour tissues than in normal tissue, thereby reducing systemic exposure to 5-FU.\n\nCapecitabine is indicated for first-line monotherapy of metastatic colorectal cancer. The recommended dose of capecitabine is 1250 mg/m2 twice daily for 14 days, followed by a 7-day rest period before another cycle of treatment.\n\nThe listed costs of 60 150-mg tablets and 120 500-mg tablets of capecitabine are £44 and £295 respectively (excluding VAT; British National Formulary 44, September 2002). Based on an assumed body surface area of 1.7 m2, the acquisition cost (excluding VAT) of treating an individual with capecitabine for 105 days (five cycles) is £1463. Costs may vary in different settings because of negotiated procurement discounts.\n\n# Tegafur with uracil\n\nTegafur is a 5-FU prodrug, meaning that after administration it is metabolised into the pharmacologically active compound 5-FU. Tegafur is given in combination with uracil, which inhibits the degradation of 5-FU, resulting in sustained higher levels of 5-FU in tumour cells. FA is usually added to the tegafur and uracil (UFT) combination to act as a modulator. These drugs can be taken orally.\n\nUFT (Uftoral) is indicated for first-line treatment of metastatic colorectal cancer in combination with FA. Each capsule contains tegafur 100 mg plus uracil 224 mg.\n\nThe recommended dose of UFT is tegafur 300 mg/m2 (with uracil 672 mg/m2) daily, combined with oral FA 90 mg/day, given in three divided doses (preferably every 8 hours) for 28 days. Subsequent courses are repeated at 7-day intervals, giving a treatment cycle of 35 days.\n\nThe list cost of 21 UFT tablets is £67 (Monthly Index of Medical Specialties, February 2003). Based on an assumed body surface area of 1.7 m2, the acquisition cost (excluding VAT) of treating an individual with UFT for 105 days (three cycles) is £1358. FA obtained at a cost of £3.78 per 15-mg tablet incurs an additional cost of up to £1905. Costs may vary in different settings because of negotiated procurement discounts.', 'Evidence and interpretation': "The Appraisal Committee considered evidence from a number of sources (see Appendix A).\n\n# Clinical effectiveness\n\n## Capecitabine\n\nTwo phase III randomised controlled trials (RCTs), recruiting 602 and 605 individuals, and one pooled analysis of these study data were reviewed. Both RCTs compared capecitabine with a bolus (Mayo) 5-FU/FA regimen and were identical in design. Both studies included individuals with untreated, locally advanced or metastatic colorectal cancer, most of whom had undergone previous surgery. Although neither RCT was undertaken under blinded conditions because of the different routes of administration (oral or intravenous), both studies used an independent committee to review outcomes. The primary outcome measure in both trials was tumour response rate. Both studies were adequately powered to demonstrate equivalence in overall response rates.\n\nDifferences in median overall survival were not statistically different at the 5% significance level in either RCT, with values of 12.5 and 13.3 months for capecitabine and 5-FU/FA respectively in one study, and 13.2 and 12.1 months respectively in the other study. The pooled study also did not report any statistically significant difference in overall survival.\n\nIn both studies, the overall response rate was statistically significantly higher in the capecitabine groups than in the 5-FU/FA groups when outcomes were assessed by study investigators (p = 0.005 and p = 0.013). However, when the independent review committee assessed outcomes, these response rates were statistically significantly higher in only one of the studies (p = 0.0001). When the data from both studies were pooled, response rates statistically favoured capecitabine irrespective of who carried out the assessment (p < 0.0002 for the investigator assessment and p < 0.0001 for the independent review committee assessment).\n\nNeither study reported a statistically significant difference in mean duration of response between the capecitabine and 5-FU/FA groups, nor was a difference reported for the pooled data. Neither study, nor the pooled analysis, reported any statistically significant differences in time to disease progression, death or treatment failure between the capecitabine and 5-FU/FA groups.\n\nNeither of the studies reported any statistically significant difference in global quality of life as measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).\n\nWith regard to treatment-related adverse events, the pooled analysis of the two trials indicated that individuals in the capecitabine groups reported less diarrhoea (48% vs 58%, p < 0.001), stomatitis (24% vs 62%, p < 0.001), nausea (38% vs 47%, p < 0.001) and alopecia (6% vs 21%, p < 0.001) of all grades than those in the 5-FU/FA groups. Patients in the capecitabine groups also had less grade III/IV neutropenia (2% vs 21%, no p-value available) and grade III stomatitis (2% vs 15%, p < 0.0001), and less frequent hospitalisation for adverse events (12% vs 18%, p = 0.002), but reported more hand–foot syndrome (54% vs 6.0%, no p-value available) and grade III hyperbilirubinaemia (18% vs 3%, p < 0.0001). In the pooled analysis, treatment mortality was 1% for each group.\n\n## Tegafur with uracil (UFT)\n\nTwo large, open, phase III RCTs (Studies 011 and 012) were reviewed. These trials recruited 816 and 380 individuals respectively. No independent review committee was used to compensate for the fact that the assessors were aware of treatment allocation. Study 011 compared UFT/FA with 5-FU/FA administered using the Mayo regimen, whereas Study 012 compared UFT/FA with 5-FU/FA administered using a modification of the Mayo regimen, where treatment was repeated every 35 days instead of the standard 28 days. This non-standard variation of the Mayo regimen is a less dose-intensive regimen and has not been tested for efficacy. In Study 011, individuals recruited in the USA received UFT plus FA 75 mg/day, while those in non-USA centres received UFT plus FA 90 mg/day. Study 011 used overall survival as the primary endpoint and was powered to demonstrate equivalence of the two treatments as non-inferiority of survival. Study 012 used time to disease progression as the primary endpoint, and was powered to detect a hazard ratio (HR) of 1.4 between the groups. A third study of crossover design was also identified, which assessed patient preference for UFT/FA compared with intravenous 5-FU/FA.\n\nIn Study 011, median survival time was 12.4 months in the UFT/FA group and 13.4 months in the 5-FU/FA group. The HR for 5-FU/FA over UFT/FA was 0.96 (95% confidence interval [CI]: 0.83 to 1.13). In Study 012, median survival time was 12.2 months in the UFT/FA group and 10.3 months in the 5-FU/FA group. The HR for 5-FU/FA over UFT/FA in this study was 1.14 (95% CI: 0.92 to 1.42). A secondary analysis showed that individuals from the USA sites in Study 011, who received lower-dose FA, had worse overall survival than the total study population.\n\nIn Study 011 the median time to disease progression was statistically significantly greater in the 5-FU/FA group than in the UFT/FA group (3.8 months vs 3.5 months, p = 0.01), although the actual difference was 10 days. No statistically significant difference in time to disease progression was reported in Study 012.\n\nIn both studies there were no statistically significant differences between treatment arms with regard to overall tumour response rates. The rates in the UFT/FA and 5-FU/FA groups were 11.7% and 14.5% respectively in Study 011, and 10.5% and 9.0% respectively in Study 012. No statistically significant differences in duration of response were reported (actual values were not reported).\n\nIn Study 011, compared with 5-FU/FA, UFT/FA was associated with statistically significantly less diarrhoea (67% vs 76%, p = 0.006), nausea/vomiting (67% vs 75%, p = 0.02), mucositis (24% vs 75%, p < 0.001), neutropenia (13% vs 77%, p < 0.001) and thrombocytopenia (21% vs 31%, p < 0.001) of all toxicity severity grades. UFT/FA was also associated with less grade III/IV mucositis (1% vs 20%, p < 0.001), neutropenia (1% vs 56%, p < 0.001), thrombocytopenia (0% vs 2%, p = 0.003) and anaemia (3% vs 7%, p = 0.03). Increased bilirubin, without other liver function abnormalities, was statistically significantly more common in individuals treated with UFT/FA than in those treated with 5-FU/FA (39% vs 22%, p < 0.001). In Study 012, UFT/FA treatment resulted in statistically significantly fewer episodes of stomatitis/mucositis (18% vs 55%, p < 0.001), neutropenia (11% vs 67%, p < 0.001), thrombocytopenia (18% vs 28%, p = 0.025) and anaemia (76% vs 89%, p = 0.002) of any grade than 5-FU/FA treatment. UFT/FA treatment resulted in statistically significantly less grade III/IV stomatitis/mucositis (2% vs 16%, p < 0.001) and neutropenia (3% vs 31%, p < 0.001). In all, 127 individuals were hospitalised during the study: 59 (31%) in the UFT/FA group and 68 (37%) in the 5-FU/FA group (p-values not reported).\n\nHealth-related quality of life was measured in both studies using either the Functional Living Index-Cancer or EORTC QLQ-C30; no statistically significant differences in outcomes were reported between the treatment groups in either study. An unpublished preliminary report of a phase II randomised study in 202 individuals indicated that scores for functional and symptom scales were either improved or unchanged in the UFT/FA group but worse in the 5-FU/FA group.\n\nThe only information available on preferences for treatment was a 37-patient crossover study in which individuals received either UFT (300 mg/m2/day) plus FA (90 mg/m2/day) for 28 days every 5 weeks, or intravenous FU (425 mg/m2/day) plus FA (20 mg/m2/day) for 5 days every 4 weeks. They were then crossed-over to the other treatment regimen for the second treatment cycle. Therapy preference questionnaires were completed before the first and after the second treatment cycle. Of the 31 individuals who completed the questionnaire, 84% preferred the UFT/FA regimen. The reasons for this preference included being able to take medication at home, experiencing less stomatitis and diarrhoea, and being able to use a tablet instead of having an injection.\n\n# Cost effectiveness\n\n## Capecitabine\n\nTwo economic evaluations of capecitabine compared with 5-FU/FA were identified, one conducted by the manufacturer and the other by the Assessment Group. Both evaluations assumed equivalent effectiveness, and thus only evaluated associated costs from an NHS perspective. Both models included costs associated with drug acquisition, chemotherapy administration (including inpatient stays) and adverse event management.\n\nThe manufacturer estimated the costs of capecitabine and 5-FU/FA (using the Mayo bolus regimen) to be approximately £2700 and £5000, respectively. The Assessment Group estimated these costs to be £2100 and £3600, respectively. The Assessment Group also estimated the cost of 5-FU/FA to be £6300 when the de Gramont infusional regimen was used and £3500 when the modified de Gramont infusional method, which does not generally require inpatient administration, was used. In all instances, capecitabine was the least costly treatment option.\n\n## Tegafur with uracil\n\nBoth the manufacturer and the Assessment Group conducted economic analyses that compared UFT/FA with 5-FU/FA; both assessed costs from an NHS perspective and included categories of costs such as drug acquisition, chemotherapy administration (including inpatient stays), and adverse event management. A cost-minimisation study was also identified, although it was of limited use because it was from a non-UK perspective and did not specify the comparator regimen (for example Mayo or de Gramont).\n\nThe manufacturer's cost-effectiveness analysis compared UFT/FA with 5-FU/FA based on a Mayo regimen. The analysis used adverse events as the health outcome of interest although the evaluation was conducted separately for the two RCTs, and the costs of UFT/FA and 5-FU/FA were found to be £3600 and £6100 respectively for Study 011, and £3200 and £4900 respectively for Study 012.\n\nThe Assessment Group's cost-minimisation analysis showed a cost of approximately £3500 both for UFT/FA and for 5-FU/FA, administered using either the Mayo or modified de Gramont outpatient-based regimen.\n\n# Consideration of the evidence\n\nThe Committee reviewed the evidence available on the clinical and cost effectiveness of capecitabine and UFT, having considered evidence on the nature of the condition and the value placed by users on the benefits of capecitabine and UFT/FA by people with colorectal cancer, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.\n\nIn the absence of patient preference data from adequately designed studies, the Committee took particular note of the opinions of both the professional and patient representatives regarding the advantages of oral compared with intravenous administration of chemotherapy, and of the potential problems of concordance with oral treatments. The patient representatives particularly emphasised that the vast majority of individuals expressed a strong preference for oral drugs provided that effectiveness was not compromised, because they reduce the disruptive impact of chemotherapy on individuals' lives and give them greater control over the management of their disease.\n\nThe Committee was satisfied that the phase III RCT data demonstrated that both capecitabine and UFT/FA were likely to have clinical effectiveness similar to that of 5-FU/FA administered by the bolus Mayo regimen. The appropriateness of using the Mayo regimen as a comparator was questioned because of evidence that suggests that infusional regimens may be more effective and less toxic. Indirect comparison of the oral drugs with infusional regimens might therefore suggest that the oral drugs are less effective. However, this evidence has not been formally appraised, and both the professional experts and the Assessment Group questioned its robustness. The Committee did not therefore consider it sufficiently conclusive to be the basis of a recommendation against the use of the oral treatments. However, the Committee also firmly believed that an appropriately designed RCT was required to carry out a direct comparison of the effectiveness of the oral treatments versus the infusional regimens. In addition, the Committee considered there was insufficient evidence to enable a distinction to be made in terms of effectiveness between the two oral agents.\n\nThere are also differences in the contraindications and side-effect profiles of the individual oral and intravenous regimens, and the Committee appreciated that the choice of the most appropriate treatment regimen might depend on the individual's circumstances. The Committee therefore concluded that intravenous regimens may be preferable under certain circumstances, and that capecitabine and UFT/FA should thus be available as options for treatment rather than as the preferred choice.\n\nThe Committee considered that, given the lack of compelling evidence for a difference in effectiveness between the regimens, the correct approach to evaluation of cost effectiveness was cost minimisation. They took note of the variations in the estimates of the total costs obtained from the submitted models, and overall were convinced that the oral drugs were cost-effective compared with 5-FU/FA regimens, principally on the basis of the potential cost savings related to the method of administration. They were also aware that the reduced burden of preparation and administration on specialist staff might potentially allow reallocation of clinical resources.", 'Further research': 'Further research is required to determine the place of capecitabine and tegafur with uracil in the treatment of metastatic colorectal cancer. In particular, RCTs are needed to assess the use of these oral treatments compared with infusional 5-FU/FA regimens. Such studies should include evaluations of quality of life, acceptability and cost effectiveness.', 'Implications for the NHS': "Given the available evidence, a conservative estimate of the cost savings that would be associated with all individuals receiving capecitabine instead of bolus 5-FU/FA is £10.5 million, including VAT. This is based on the assumption that 7000 people receive capecitabine (costing £2100 per person as estimated by the Assessment Group) instead of bolus Mayo 5-FU/FA (costing £3600 per person as estimated by the Assessment Group). The savings would be similar if it is assumed that capecitabine is used in preference to the modified de Gramont regimen (costing £3500 per person as estimated by the Assessment Group). However, this estimated cost saving is higher if the calculations are based on the assumption that people would otherwise receive the de Gramont infusional regimen 5-FU/FA (costing £6250 per person as estimated by the Assessment Group) or on the manufacturer's cost estimates.\n\nIf it is assumed that 7000 people receive UFT/FA (costing £3400 per person as estimated by the Assessment Group) instead of 5-FU/FA administered using the Mayo or modified de Gramont outpatient-based regimen, there could be savings of up to £1.4 million. However, if 7000 people receive UFT/FA instead of the unmodified de Gramont infusion regimen, there could be a reduction in costs of nearly £20 million.\n\nHowever, it is unlikely that such savings would be realised in terms of 'cash' for two reasons: the estimates represent amounts of resources that would remain within the system (but might nevertheless be redeployed); and the estimates are based on average costs (for example, of days in hospital avoided), some of which are fixed costs and therefore will not be saved, but could be available for other purposes.", 'Related guidance': 'The Institute has issued guidance on the use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.\n\nNational Institute for Clinical Excellence (2002) Guidance on the use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. NICE Technology Appraisal Guidance No. 33. London: National Institute for Clinical Excellence. [Replaced by NICE technology appraisal guidance 93]\n\nThe Institute has issued guidance on the use of laparoscopic surgery for colorectal cancer.\n\nNational Institute for Clinical Excellence (2000) Guidance on the use of laparoscopic surgery for colorectal cancer. NICE Technology Appraisal Guidance No. 17. London: National Institute for Clinical Excellence. [Replaced by NICE technology appraisal guidance 105]', 'Appendix C. The use of capecitabine and tegafur with uracil for metastatic colorectal cancer': 'A summary of this guidance for people with colorectal cancer and the public can be found on our website.', 'Appendix D. Detail on criteria for audit of the use of capecitabine and tegafur with uracil for metastatic colorectal cancer': '# Possible objectives for an audit\n\nAn audit on the treatment of people with metastatic colorectal cancer could be carried out to ensure that capecitabine and tegafur with uracil are being used appropriately.\n\n# Possible people to be included in an audit\n\nAn audit could be carried out on people with metastatic colorectal cancer referred over a suitable time period, for example 6 months or a year.\n\n# Measures that could be used as a basis for audit\n\nThe measures that could be used in an audit of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer are as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. For the first-line treatment of metastatic colorectal cancer an individual is given the option of oral therapy with either capecitabine or tegafur with uracil (in combination with folinic acid)\n\n% of people diagnosed as having metastatic colorectal cancer\n\nNone\n\nClinicians will have to agree locally on how the offer of the option of oral therapy as an alternative to intravenous 5-FU/FA regimens is documented for audit purposes.\n\n. The individual and the clinician(s) responsible for treatment decide jointly on the choice of regimen after an informed discussion of the following:\n\na. the relative clinical and cost-effectiveness of each treatment option and\n\nb. the side-effect profile of each treatment option and\n\nc. the preferences of the individual\n\n% of people diagnosed as having metastatic colorectal cancer\n\nNone\n\nClinicians will have to agree locally on how the joint decision will be documented for audit purposes.\n\n. An oncologist specialising in colorectal cancer supervises the use of capecitabine and tegafur with uracil\n\n% of the people receiving capecitabine or tegafur with uracil\n\nNone\n\nClinicians will have to agree locally on how supervision of the use of capecitabine and tegafur with uracil is defined and documented for audit purpose\n\n# Calculation of compliance\n\nCompliance (%) with each measure described in the table above is calculated as follows.\n\nNumber of patients whose care is consistent with the criterion plus number of patients who meet any exception listed\n\nx 100\n\nNumber of patients to whom the measure applies\n\nClinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.'}	https://www.nice.org.uk/guidance/ta61	Evidence-based recommendations on capecitabine for treating metastatic colorectal cancer in adults.
41db7a40751d999d688e19851796b237c8c1034d	nice	Guidance on the use of drugs for early thrombolysis in the treatment of acute myocardial infarction	Guidance on the use of drugs for early thrombolysis in the treatment of acute myocardial infarction Evidence-based recommendations on using thrombolytic drugs (alteplase [Actilyse], reteplase [Rapilysin], streptokinase [Streptase] and tenecteplase [Metalyse]) for treating acute myocardial infarction in adults. # Guidance This guidance provides recommendations on the selection of thrombolytic drugs in patients with acute myocardial infarction (AMI). Recommendations are made in relation to the use of the drugs in hospital and pre-hospital settings. The guidance does not compare hospital and pre-hospital models of delivering thrombolysis. It is recommended that, in hospital, the choice of thrombolytic drug (alteplase, reteplase, streptokinase or tenecteplase) should take account of: the likely balance of benefit and harm (for example, stroke) to which each of the thrombolytic agents would expose the individual patient current UK clinical practice, in which it is accepted that patients who have previously received streptokinase should not be treated with it again the hospital's arrangements for reducing delays in the administration of thrombolysis. Where pre-hospital delivery of thrombolytic drugs is considered a beneficial approach as part of an emergency-care pathway for AMI (for example, because of population geography or the accessibility of acute hospital facilities), the practicalities of administering thrombolytic drugs in pre-hospital settings mean that the bolus drugs (reteplase or tenecteplase) are recommended as the preferred option.# Clinical need and practice Acute myocardial infarction (AMI) is caused by blockage of a coronary artery by a thrombus or clot. This is usually the result of rupture of an atherosclerotic plaque within the artery. The heart muscle supplied by that artery is damaged or dies because of lack of oxygen (ischaemia). Patients with AMI may develop heart failure or potentially fatal cardiac arrhythmias as a result of damage to the heart muscle. These and other complications may occur early, within the first few hours of the event, or may develop over the subsequent months or years. Around 240,000 people experience AMI in England and Wales each year. Up to 50% of people who have an AMI die within 30 days of the event, and over half of these deaths occur before medical assistance arrives or the patient reaches hospital. Onset of AMI symptoms is usually rapid and the highest risk of death (usually as the result of an acute fatal arrhythmia) is within the first hour of experiencing symptoms – around one-third of all AMI deaths occur within the first hour. Thrombolytic drugs break down the thrombus so that the blood flow to the heart muscle can be restored to prevent further damage and assist healing. The sooner the blood flow can be restored, the better the chances of avoiding the death of the heart muscle. Along with clinical symptoms (typically but not exclusively chest pain), characteristic changes in the 12-lead electrocardiogram (ST segment elevation) provide the most immediate indication of the diagnosis of AMI for patients requiring thrombolysis for AMI. Intravenous thrombolytic therapy is an established standard treatment for AMI. It is estimated that around 50,000 patients currently receive thrombolysis in England and Wales each year. However, evidence suggests that thrombolysis continues to be under-used. Thrombolytic drugs are routinely given in hospital as soon as possible after a confirmed diagnosis of AMI. Additionally, their administration in pre-hospital settings, principally by ambulance paramedics, is becoming more common. Early primary percutaneous coronary intervention (PCI) may be an alternative to thrombolysis. Despite research evidence of the potential value of early PCI, currently few hospital trusts have the capacity to provide it. Treatment delivering thrombolytics in combination with glycoprotein IIb/IIIa inhibitors is also the subject of research studies. However, these interventions are beyond the scope of this appraisal.# The technology # Thrombolytic drugs In the UK, four thrombolytic agents are licensed and available to treat AMI. All act by promoting the activity of circulating plasminogen. There is a long history of use of one, streptokinase, whereas the other three, alteplase, reteplase and tenecteplase, are newer options. Streptokinase is derived from streptococcal bacteria. Streptokinase is given by intravenous (IV) infusion. Alteplase was introduced in the late 1980s. It is essentially the same as the naturally occurring activator of plasminogen in the human body, and is produced by recombinant DNA technology. It is given by IV infusion. Reteplase and tenecteplase have been introduced more recently (1997 and 2001, respectively). They are new modified forms of plasminogen activator and can be given by rapid IV bolus injection, rather than infusion. The timing of administration is a crucial factor determining the extent of benefit achieved by thrombolysis, and treatment should ideally be given as soon as possible (normally up to 12 hours) after the onset of AMI symptoms. Bleeding complications are the main risks associated with thrombolysis. The most important bleeding complication is haemorrhagic stroke, which occurs in 0.5–1.0% of patients and is associated with high mortality and long-term disability in survivors. Bleeding may occur at the injection site, in the gastrointestinal tract or elsewhere. Hypotension may also occur. The risks and benefits of giving thrombolysis need to be considered in individual patients and settings. The risk of haemorrhagic stroke following thrombolysis increases with age and blood pressure. Thrombolysis is contraindicated in individuals with bleeding disorders or a history of recent haemorrhage, trauma, surgery or acute cerebrovascular event. For full details of side effects and contraindications, see the Summary of Product Characteristics for the individual agents. Heparin (an anticoagulant) is given with all of the thrombolytic drugs except streptokinase. It is usually administered as an IV bolus injection before thrombolysis, followed by an IV infusion. When given with tenecteplase the heparin dose is weight adjusted. Aspirin (an antiplatelet agent) is also usually given with any thrombolytic drug, because it delivers a mortality benefit in its own right. Streptokinase (Streptase) is indicated up to 12 hours after onset of symptoms. It is administered as an IV infusion over 1 hour. It has been extensively studied and remains widely used. Streptokinase is associated with hypotension, infrequent allergic reactions and, rarely, anaphylaxis. Patients treated with streptokinase develop anti-streptococcal antibodies, which can inactivate the drug if subsequent treatment is needed. Consequently in current UK practice, patients are usually treated with streptokinase only once. It is estimated that around one-third of people with AMI have contraindications to streptokinase. A recent survey found that 82% of hospitals in England use streptokinase for eligible patients experiencing their first AMI; other data suggest that streptokinase represents between 53% and 65% of thrombolytic drug use. Streptokinase costs £80 to £90 per patient (excluding VAT) (British National Formulary 43, March 2002). Alteplase (Actilyse, recombinant human tissue plasminogen activator, rtPA) can be delivered in a standard or accelerated regimen. The accelerated regimen, which is much more commonly used, is indicated up to 6 hours after symptom onset and is delivered by an initial IV bolus injection, followed by two IV infusions, the first given over 30 minutes and the second over 60 minutes. The standard regimen is indicated between 6 and 12 hours after symptom onset and requires a bolus injection followed by five infusions over 3 hours. Like the other newer drugs, alteplase does not stimulate the production of antibodies, so it can be used repeatedly. It is estimated that alteplase represents between 23% and 32% of thrombolytic drug use in the UK. Alteplase costs £600 per patient (excluding VAT) (British National Formulary 43, March 2002). Reteplase (Rapilysin) is indicated up to 12 hours after symptom onset. It is given as two IV bolus injections 30 minutes apart. It is estimated that reteplase represents between 12% and 15% of thrombolytic drug use in the UK. Reteplase costs £716 per patient (excluding VAT) (British National Formulary 43, March 2002). Tenecteplase (Metalyse) is indicated up to 6 hours after symptom onset. It is administered as a single (weight-adjusted) IV bolus injection. It is estimated that tenecteplase currently accounts for around 1% of thrombolytic drug use in the UK, the manufacturer indicates that the proportion is increasing. Tenecteplase costs £700 to £770 per patient (excluding VAT) (British National Formulary 43, March 2002). # Delivering thrombolytic drugs The National Service Framework (NSF) for coronary heart disease (CHD) in England and Tackling CHD in Wales specify that eligible patients with AMI should be given thrombolysis within 60 minutes of calling for professional help ('call-to-needle' time) and should receive thrombolysis within 20 minutes of arriving at hospital ('door-to-needle' time). It is also suggested that it may be appropriate to provide pre-hospital thrombolysis where local 'call-to-hospital' times are likely to be over 30 minutes. The NHS Plan in England gave a commitment to train and equip ambulance paramedics to provide thrombolysis. Direct admission to a coronary care unit (CCU) is often not possible, and accident and emergency (A&E) departments are being encouraged to administer thrombolysis to reduce delays in door-to-needle times. The potential for specialist nursing input in the delivery of thrombolysis is being developed. Given the benefits of early administration of thrombolysis on reducing damage to heart muscle and consequently on long-term outcomes, pre-hospital administration of thrombolysis by ambulance paramedics is being gradually implemented in the NHS. Currently, pre-hospital thrombolysis is administered by fewer than five ambulance services and a small number of remote community hospitals in England and Wales. Ongoing changes in infrastructure and training will be required to implement the requirements of the NSF for CHD, Tackling CHD in Wales and the NHS Plan to allow more widespread delivery in pre-hospital settings. Currently, streptokinase is the only thrombolytic that paramedics are authorised to administer under the Prescription Only Medicines (Human Use) Order 1997. However, paramedics can administer other thrombolytic drugs under local Patient Group Directions, and guidelines on their use by paramedics have been developed by the Joint Royal Colleges Ambulance Liaison Committee (JRCALC). There are practical difficulties in giving controlled-rate infusions in pre-hospital settings, including drug preparation requirements, the practicalities of giving an infusion in an ambulance and, for streptokinase, concerns about higher rates of allergic reactions and hypotension, which are more difficult to manage away from hospital. Although they are not within the scope of this appraisal, a number of organisational models of service delivery are relevant when considering the feasibility of administering different thrombolytic agents and their effectiveness in particular settings. These involve organisational, practical and operator issues. In-hospital thrombolysis models include: assessment and treatment in A&E rapid assessment in A&E and transfer to CCU direct admission to CCU. Pre-hospital models include: community hospital administration (nurse or general practitioner) general practitioner administration (at the point of contact) telemetry-supported paramedic administration autonomous paramedic administration.# Evidence The Appraisal Committee reviewed the evidence from a number of sources (Appendix B). # Clinical effectiveness ## In-hospital thrombolysis Fourteen randomised controlled trials (RCTs) comparing thrombolytic drugs were included in the review. Overall the studies were considered to be of excellent quality. In total, the trials involved over 142,000 patients, and five of the trials included over 10,000 patients each. The trials had similar inclusion criteria in terms of age (usually <70 or <75 years), ECG changes, duration of symptoms, and presentation within 6 hours of symptom onset. Five of the trials included between 12% and 26% of patients aged over 70–75 years. Women were under-represented in all of the studies. Primary endpoints included 30-day mortality, 90-minute artery patency/flow rates and left ventricular function. Secondary endpoints included bleeding, stroke, congestive heart failure, reinfarction, allergy and anaphylaxis. The results of the trials were also pooled in a meta-analysis. No direct trial comparisons between tenecteplase and streptokinase or between tenecteplase and reteplase have been undertaken, and only cautious conclusions can be drawn from the indirect comparisons that can be deduced from other studies. Two placebo-controlled trials were instrumental in establishing the efficacy of streptokinase in reducing mortality. The GISSI trial (published in 1986) included 11,712 patients, and the ISIS-2 trial (published in 1988) included 17,187 patients. In the GISSI study, 21-day mortality was 10.7% in patients treated with streptokinase and 13% in those treated with placebo. This represents a statistically significant absolute reduction of 2.3% (risk ratio 0.81; 95% confidence ratio 0.72 to 0.9). In the ISIS-2 study, vascular mortality at 5 weeks was 9.2% in patients treated with streptokinase and 12% in those treated with placebo. This represents a statistically significant absolute reduction of 2.8%. These benefits were independent of those of early aspirin treatment. A meta-analysis of eight comparisons of standard alteplase with streptokinase found no significant difference between the two drugs in terms of mortality up to 35 days (odds ratio 1.0; 95% CI 0.94 to 1.06). A statistically significant difference in reinfarction rates in favour of alteplase was found (odds ratio 0.86; 95% CI 0.77 to 0.95). However, alteplase was associated with a statistically significant higher risk of stroke (odds ratio 1.37; 95% CI 1.16 to 1.62), due to a doubling in the risk of haemorrhagic stroke (odds ratio 2.13; 95% CI 1.04 to 4.36). However, streptokinase was associated with a statistically significant higher risk of major bleeds (other than stroke) than alteplase (odds ratio 0.81; 95% CI 0.68 to 0.97). The categorisation and reporting of major bleeding varied between the trials and so it is difficult to judge the clinical significance of these findings. The studies included in this meta-analysis used the standard alteplase administration regimen, whereas the GUSTO-I trial used the accelerated regimen and is the only trial to have demonstrated superiority between different thrombolytic agents. The GUSTO-I trial included over 40,000 patients. It found an odds ratio of 0.85 (95% CI 0.78 to 0.94) for 30-day mortality for accelerated alteplase compared with streptokinase, and an absolute reduction in mortality at 30 days of 1.0% (6.3% versus 7.3%; 95% CI 0.4% to 1.6%) in favour of accelerated alteplase. However, this benefit was balanced by a statistically significantly higher incidence of haemorrhagic stroke (odds ratio 1.42; 95% CI 1.05 to 1.91). Using a combined outcome measure of mortality and disabling stroke, the absolute advantage of accelerated alteplase over streptokinase was lower (0.9%; p = 0.006). Rates of bleeds (moderate or worse), allergic reaction, anaphylaxis, congestive heart failure, and sustained hypotension were statistically significantly lower in the group treated with accelerated alteplase. A further meta-analysis of nine comparisons of alteplase with streptokinase, including the findings of GUSTO-I (i.e. accelerated alteplase), found no significant difference between the two drugs in terms of mortality up to 35 days (odds ratio 0.94; 95% CI 0.85 to 1.04). Reteplase has also been compared with streptokinase in a study involving 5986 patients (the INJECT study). This study found an absolute difference of 0.5% (95% CI –1.98% to 0.96%) in 35-day mortality in favour of reteplase (not statistically significant). If it is accepted that a 1% difference in mortality is the limit of equivalence in thrombolytic therapy, this suggests that it is unlikely that reteplase is inferior to streptokinase. An alternative interpretation is that in terms of overall effects on mortality and disabling stroke reteplase may be inferior to streptokinase, as the trial also found a statistically significantly lower risk of haemorrhagic stroke (odds ratio 2.1; 95% CI 1.02 to 4.31) in the streptokinase group. However, the trial also found that the rates of heart failure (23.6% vs 26.3%, p<0.05) and allergic reactions (1.1% vs 1.8%, p<0.05) were statistically significantly lower in the reteplase group. Reteplase has also been compared with accelerated alteplase in one relatively small (n = 324) study that examined intermediate angiographic endpoints of coronary vessel patency (RAPID-2), and one larger study that examined patient-focused endpoints (GUSTO-III, n = 15,059). GUSTO-III was designed to test the clinical superiority of reteplase over accelerated alteplase, following the findings in RAPID-2 of better coronary artery patency with reteplase. However, GUSTO-III found no statistically significant difference between the two drugs, in terms of survival or adverse effects. The mortality rate at 30 days was 7.5% in the reteplase group and 7.2% in the accelerated alteplase group: an absolute risk reduction of 0.23% in favour of accelerated alteplase (95% CI –1.10% to 0.66%). Given the confidence limits, reteplase cannot be considered as equivalent to accelerated alteplase. ASSENT-2, an equivalence trial of over 16,000 patients compared tenecteplase and accelerated alteplase. The study found that 30-day mortality was almost the same in the tenecteplase group (6.2%) and the accelerated alteplase (6.2%) group. The absolute difference of 0.03% in favour of accelerated alteplase was not statistically significant (95% CI -0.55% to 0.61%). Given the confidence limits, tenecteplase and accelerated alteplase can be considered equivalent in terms of mortality. However, there was a small but statistically significant reduction in the incidence of bleeding with tenecteplase (26.4% compared with 28.9% in the accelerated alteplase group), resulting in fewer blood transfusions in the tenecteplase group (4.3% of patients compared with 5.5% in the accelerated alteplase group). Also, the rate of heart failure was statistically significantly lower in the tenecteplase group than in the accelerated alteplase group (6.1% vs 7.0%, p = 0.026). None of the trials discussed was designed to investigate clinical subgroups, such as by age or site of infarct (anterior, inferior). It was concluded that there was no convincing evidence of relative differences in the effectiveness of the available drugs in subgroups. The greater absolute benefit found in patients with anterior infarcts in GUSTO-I may simply be a reflection of the higher baseline risk in this group. The greater relative benefit in patients aged under 75 years was not reflected in their level of absolute risk reduction. None of the differences between the subgroups appeared to be statistically significant by interaction. In summary, given the evidence on clinical effectiveness, it can be concluded that, in the hospital setting, in terms of mortality: standard alteplase is as effective as streptokinase reteplase is at least as effective as streptokinase, and tenecteplase is as effective as accelerated alteplase. If accelerated alteplase is believed to be superior to streptokinase, then indirectly tenecteplase would also be considered to be superior to streptokinase. Conclusions regarding the equivalence of reteplase compared with accelerated alteplase depend on the interpretation of GUSTO-III. Furthermore, if reteplase is considered to be equivalent to accelerated alteplase, then this indirectly implies that reteplase is as effective as tenecteplase. Important differences in major adverse events between the thrombolytic agents are also apparent. The newer drugs are associated with a higher risk of haemorrhagic stroke compared with streptokinase, but there are no apparent differences in the frequency of haemorrhagic stroke between accelerated alteplase and reteplase (GUSTO-III), or between accelerated alteplase and tenecteplase (ASSENT-2). However, compared with streptokinase, the newer drugs may also be associated with a lower incidence of congestive heart failure. In addition, allergic reactions are more common with streptokinase than with the other drugs, and major bleeds (leading to transfusions) may also be more common with streptokinase, although the evidence on this is not consistent across the trials. There is also some evidence that tenecteplase may be associated with lower rates of major bleeds and heart failure than accelerated alteplase. ## Pre-hospital thrombolysis No RCTs were found comparing the different thrombolytic drugs in pre-hospital settings. However, nine RCTs and a systematic review investigating the feasibility, safety and efficacy of pre-hospital administration of thrombolysis compared with hospital administration were considered in the context of the appraisal. A number of other papers reporting non-randomised studies and audits of pre-hospital thrombolysis were also considered in relation to practical and implementation issues. The RCTs were small, except for one that included over 5000 patients (EMIP). They were undertaken in a mixture of urban and/or rural settings in Israel, continental Europe, Canada, the USA, Northern Ireland, and Scotland. A variety of thrombolytic drugs were studied – four studies used alteplase, four used streptokinase-type drugs, and one used urokinase (which is not available in the UK). Only the USA study (MITI) involved paramedics administering the thrombolytic (after remote consultation with a physician). In all but one of the other studies, a hospital physician attended the patient and administered the drug. In the rural Scottish trial (GREAT) a general practitioner undertook assessment and treatment. The RCTs found that, on average, pre-hospital thrombolysis was administered 58 minutes earlier than hospital thrombolysis; the differences ranged from 33 minutes in the MITI study to 130 minutes in the GREAT study. Individually, the trials failed to show statistically significant reductions in in-hospital mortality, although findings in all of the studies favoured pre-hospital administration. However, a meta-analysis of six of the trials found a statistically significant absolute reduction in mortality of 1.6% (95% CI 0.2% to 3%), and a relative risk reduction of 17% (95% CI 2% to 30%, p = 0.03) favouring pre-hospital administration of thrombolysis. This analysis is heavily influenced by the results of the GREAT study (in which thrombolysis was administered by general practitioners in rural Scotland) and therefore does not directly relate to the potential for paramedic based pre-hospital thrombolysis. A number of observational studies examining pre-hospital thrombolysis were considered, although these generally only provide further insight into feasibility and safety. They include studies of administration of anistreplase (a streptokinase-like drug that is no longer available in the UK) by paramedics or general practitioners in a Dutch city, reteplase administered by ambulance-based nurses in Sweden, reteplase administered by paramedics in the USA, anistreplase administered in a rural Italian emergency room, and two reports of a small number of cases of reteplase administered by paramedics with hospital telemetry support in England. # Cost effectiveness ## In-hospital thrombolysis The Assessment Group's literature review found eight published articles on the cost-effectiveness of thrombolytic agents that met the inclusion criteria for the review of cost effectiveness. All compared streptokinase and alteplase (standard and accelerated) in a hospital setting. Three of the articles reported different aspects of the same cost-effectiveness model. Most studies reported incremental costs per life-year gained, and three also reported incremental cost per quality-adjusted life year (QALY). Most of the studies were based on the effectiveness results of GUSTO-I, in which data on resource use were collected only for USA centres. Consequently the analyses undertaken in Canada, Ireland and France had to attempt to translate these to settings in other countries. In general, the studies had the following limitations: costs and benefits were not measured in the same populations; comparator treatments were often inadequately described; and the derivation of utility values was inadequately explained. None of the studies undertook costing at a patient level and, while in general similar cost categories were included, only some of the studies included the longer-term costs of stroke and heart failure. Some of the studies included consideration of adverse events, including stroke, reinfarction, major bleeds, anaphylaxis, and congestive heart failure. The analyses undertaken following GUSTO-I, which found a survival advantage for accelerated alteplase at 30 days, showed the drug to be cost effective compared with streptokinase within the context of the clinical trial in the US healthcare system. In all of the studies, sensitivity analyses found that assumptions regarding mortality differences and costs were important, and so any conclusions drawn are heavily dependent on the interpretation of the effectiveness findings of GUSTO-I. In particular, the economic analysis undertaken in the USA alongside GUSTO-I modelled lifetime costs and benefits, and reported an incremental cost per life-year gained of $32,678 and an incremental cost per QALY of $36,402 for accelerated alteplase compared with streptokinase. The subgroup analyses found that accelerated alteplase became more cost effective in patients with higher absolute mortality risk – for example, $13,410 per life-year gained in patients older than 75 years with anterior myocardial infarction. However, the analysis requires extremely cautious interpretation given a number of issues, including uncertainties over the interpretation of GUSTO-I (in general and in subgroups), application of US data on resource use, and the assumption that costs did not differ significantly between treatment groups. Overall, there is little relevant published evidence on the economics of thrombolytics in a UK setting, and none examining the currently available bolus drugs. However, two cost-effectiveness models were submitted by manufacturers. It is logical to assume that the earlier the administration the greater the reduction in damage to the heart. However, while precise assumptions about the survival/time-to-treatment curve affect the benefit results in any modelling, it is unlikely that any one drug has a large advantage over any other with regard to timing of administration. The two manufacturers' models are similar in structure and scope, although they differ in terms of method and level of detail. Roche's model examines costs up to 30 days, assumes all four drugs have equivalent efficacy, and has less detailed costing. In contrast the Boehringer Ingelheim model includes costing up to 10 years, includes long-term costing for individual complications (such as congestive heart failure and stroke), and incorporates differential survival and complication outcomes for the drugs and more detailed estimation of utilities. Both models incorporate a range of different assumptions regarding adverse events. The models also incorporate adjustment for the timing of administration, including time-savings in pre-hospital settings in which only bolus drugs are compared. The Roche model essentially represents a cost-minimisation analysis, and finds reteplase slightly less costly than accelerated alteplase or tenecteplase in hospital. The Boehringer Ingelheim model assumes better survival and a lower incidence of post-infarct congestive heart failure (streptokinase 15.4%, accelerated alteplase 13.5%, reteplase 13.5%, tenecteplase 11.8%) for tenecteplase. These assumptions, together with 10-year discounted costs, lead to a finding that tenecteplase dominates accelerated alteplase and reteplase in hospital (that is, it is of lower cost and greater effectiveness). The Assessment Group adjusted key parameters, tested sensitivities and presented revised results using the manufacturers' models. The sensitivity analysis examined the parameter values submitted by the manufacturers for the following: 30-day mortality, strokes, major bleeds, reinfarctions and congestive heart failure. The Assessment Group used the adjusted models to compare the three newer drugs with streptokinase. For each comparison, the additional benefit (using QALYs) of the newer thrombolytic was small, while the additional cost was substantial. The cost differences between the newer drugs are relatively small. The most reliable finding is that streptokinase is by far the cheapest drug and although it is a little less effective (in terms of discounted QALYs), it is the most cost effective. Using the adjusted manufacturers' models, the incremental costs per QALY reported for the three drugs compared with streptokinase were: accelerated alteplase, £7219 (adjusted Boehringer Ingelheim model) and £7878 (adjusted Roche model); reteplase, £7893 and £10,247; and tenecteplase, £8321 and £9509. However, these cost–utility rankings of the three drugs relative to streptokinase are sensitive to changes in assumptions in the models, and so are not conclusive. ## Pre-hospital thrombolysis No published articles examining the cost effectiveness of different thrombolytic drugs in pre-hospital settings were found. There is a published economic analysis of the GREAT study comparing cost effectiveness of pre-hospital and in-hospital thrombolysis (that is, the cost effectiveness of the different drugs), which found that pre-hospital delivery had an incremental cost per life saved of £3890. The sensitivity analysis found that the cost per life saved could increase to £88,000. It should also be borne in mind that the benefits found in the GREAT trial were larger than those found in other studies, the economic analysis was not undertaken alongside the trial, the interventions were not described in detail, and the model of rural Scottish general practitioner care is unlikely to be applicable throughout the NHS in England and Wales. In the pre-hospital setting, Roche's model assumes that reteplase and tenecteplase have equivalent efficacy and that reteplase is slightly cheaper. The Boehringer Ingelheim model finds that tenecteplase dominates reteplase in pre-hospital settings (that is, it has a lower cost and greater effectiveness). Building on the conclusions about in-hospital cost effectiveness, and since the general pre-hospital delivery costs for the two suitable bolus drugs (reteplase and tenecteplase) would be the same, the relative cost effectiveness of the drugs in pre-hospital settings is likely to be similar to that in hospital (assuming equal effectiveness of both drugs in each setting). On this basis it was concluded that it was not possible to distinguish between reteplase and tenecteplase on grounds of cost effectiveness in pre-hospital settings. # Consideration of the evidence ## In-hospital thrombolysis The Committee noted the debate over the applicability of the findings of GUSTO-I beyond the North American centres (where most of the benefit of alteplase over streptokinase was found). The Committee considered that the efficacy of accelerated alteplase should not be determined solely from the results of the GUSTO-I trial. Despite concerns over the interpretation of GUSTO-I, the Committee concluded that it was likely that the newer thrombolytic agents are more effective than streptokinase in terms of 30-day mortality. The Committee was aware of the documented higher rates of stroke associated with the newer agents and carefully considered the views of clinical experts on this issue. The Committee considered that differences in the benefit of one thromboloytic agent over another are less clear if the combination of mortality and stroke endpoints are taken into account, particularly for subgroups at higher risk of haemorrhagic stroke. Furthermore, when considering the combination of mortality and stroke endpoints, it could be argued that the differences in overall benefit are less clear, particularly for subgroups at higher risk of developing haemorrhagic stroke. In taking the view that the use of streptokinase is cost effective, the Committee concluded that, although the acquisition cost of each of the newer drugs is substantially higher than that of streptokinase, the available economic evidence demonstrates that the newer drugs have an acceptable incremental cost-effectiveness ratio when compared with streptokinase. Given that streptokinase is associated with a lower risk of stroke and is a cost-effective drug, the Committee also considered it appropriate that all of the available thrombolytic drugs should be considered as options for use in care pathways for AMI. Local organisational and clinical policy considerations, such as proximity of CCU facilities and A&E staffing, will also have an impact on decisions regarding the appropriate use of each of the drugs in hospital. Because the drugs will have different risk–benefit profiles for individual patients, the Committee concluded that the decision about which of the available drugs to use should be made after balancing the likelihood of the benefits and risks (for example, stroke) to which the different drugs would expose the individual. The Committee took into account the potential importance of the methods of administration of the different thrombolytics and their effect on door-to-needle times. However, the impact of this factor on reducing myocardial damage and important clinical outcomes was very dependent on the overall pain-to-needle time. Thus, a saving of a few minutes in the door-to-needle time was likely to have a much greater impact on these endpoints where the pain-to-needle time was 1 hour compared with the situation where the pain-to-needle time was 6 hours. ## Pre-hospital thrombolysis The Committee noted that while there is observational evidence to support pre-hospital thrombolysis, applying the results to the current NHS context is difficult, in that a minority used currently available bolus drugs, most are not paramedic based, and none was reliably generalisable to England and Wales. In the absence of comparative evidence on thrombolytics in pre-hospital settings, the Committee considered that the findings of trials comparing different thrombolytic drugs in hospital could still reasonably be applied to pre-hospital settings, with consideration of the additional relevant factors including safety and applicability examined in the pre-hospital studies outlined above. On the basis of advice from experts that only the bolus drugs were appropriate for pre-hospital administration given the practical difficulties explained in section 3.2.6, and given that no high-quality evidence was available to differentiate reteplase and tenecteplase in terms of clinical effectiveness or cost effectiveness in pre-hospital settings, the Committee considered that either reteplase or tenecteplase could be used in these settings, provided that the necessary infrastructure and training is provided to fully establish an appropriate model of pre-hospital thrombolytic administration. Given the risks associated with thrombolytic drugs and the fact that pre-hospital administration is an emerging practice in England and Wales, the Committee considered it important to ensure high-quality training and supervision of staff involved in the administration of thrombolysis. It was also considered important that clinicians and organisations delivering pre-hospital thrombolysis should develop clear clinical protocols for the use of thrombolytic drugs, such as those developed by the JRCALC, and adopt robust clinical governance arrangements to monitor the use of and outcomes associated with these drugs.# Proposed recommendations for further research In light of the on-going introduction of pre-hospital thrombolysis, it is recommended that opportunities for the evaluation of the administration of thrombolytic drugs in pre-hospital settings are explored.# Resource impact for the NHS Using estimates of the total number of people receiving thrombolysis and the mixture of thrombolytic drugs used, current annual spending on thrombolytic drugs in England and Wales is estimated to be between £13 million and £26 million (i.e. drug costs alone, excluding VAT). If, as is believed, the current need for thrombolysis is only partly met, and more clinically eligible patients were to receive thrombolytic drugs, cost estimates would be markedly higher. It is difficult to predict the local impact of the guidance on the hospital prescribing patterns of available thrombolytic drugs. Consequently only approximate estimates of the likely NHS resource impact of this guidance can be made, based on possible patterns of hospital prescribing of the alternative available drugs. Assuming that the current overall level of thrombolytic therapy remains unchanged, if streptokinase represented 20% of thrombolytic drugs prescribed, alteplase 10%, and reteplase and teneteplase each accounted for 35%, then the total annual spending on thrombolytic drugs in England and Wales would be between £27 million and £45 million. If these levels were assumed to be 35%, 20% and 22.5% respectively, then the total would be between £22 million and £36 million. In addition, substantial costs are associated with the introduction of pre-hospital thrombolysis. These include the costs of additional equipment, training, and potentially longer ambulance time spent treating patients with AMI. Also, any expansion of pre-hospital thrombolysis would result in a shift of drug costs from acute hospital trusts to other services such as ambulance trusts or primary care trusts and, potentially, result in an increase in total local spending on thrombolytic drugs where bolus drugs were not widely used in hospital. Such costs are difficult to estimate usefully on the basis of the information available to the Institute at the time of this appraisal.# Related guidance In April 2001, NICE issued an inherited clinical guideline on prophylaxis for patients who have experienced a myocardial infarction: National Institute for Clinical Excellence (2001), Prophylaxis for patients who have experienced a myocardial infarction. NICE Inherited Clinical Guideline A. London: National Institute for Clinical Excellence. # Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. For details on the review of this guidance, see the NICE website. Andrew DillonChief ExecutiveOctober 2002# Appendix C. Information for patients. Drugs for early thrombolysis in the treatment of acute myocardial infarction 'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.# Changes after publication March 2014: implementation section updated to clarify that thrombolytic drugs are recommended as an option for treating acute myocardial infarction. Additional minor maintenance update also carried out. March 2012: minor maintenance In January 2006, following consultation, the Institute decided to make this guidance 'static.' This means that the guidance remains in force and has no scheduled review date. See the review decision, under 'Background information', for further details.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This guidance provides recommendations on the selection of thrombolytic drugs in patients with acute myocardial infarction (AMI). Recommendations are made in relation to the use of the drugs in hospital and pre-hospital settings. The guidance does not compare hospital and pre-hospital models of delivering thrombolysis.\n\nIt is recommended that, in hospital, the choice of thrombolytic drug (alteplase, reteplase, streptokinase or tenecteplase) should take account of:\n\nthe likely balance of benefit and harm (for example, stroke) to which each of the thrombolytic agents would expose the individual patient\n\ncurrent UK clinical practice, in which it is accepted that patients who have previously received streptokinase should not be treated with it again\n\nthe hospital's arrangements for reducing delays in the administration of thrombolysis.\n\nWhere pre-hospital delivery of thrombolytic drugs is considered a beneficial approach as part of an emergency-care pathway for AMI (for example, because of population geography or the accessibility of acute hospital facilities), the practicalities of administering thrombolytic drugs in pre-hospital settings mean that the bolus drugs (reteplase or tenecteplase) are recommended as the preferred option.", 'Clinical need and practice': 'Acute myocardial infarction (AMI) is caused by blockage of a coronary artery by a thrombus or clot. This is usually the result of rupture of an atherosclerotic plaque within the artery. The heart muscle supplied by that artery is damaged or dies because of lack of oxygen (ischaemia). Patients with AMI may develop heart failure or potentially fatal cardiac arrhythmias as a result of damage to the heart muscle. These and other complications may occur early, within the first few hours of the event, or may develop over the subsequent months or years.\n\nAround 240,000 people experience AMI in England and Wales each year. Up to 50% of people who have an AMI die within 30 days of the event, and over half of these deaths occur before medical assistance arrives or the patient reaches hospital.\n\nOnset of AMI symptoms is usually rapid and the highest risk of death (usually as the result of an acute fatal arrhythmia) is within the first hour of experiencing symptoms – around one-third of all AMI deaths occur within the first hour.\n\nThrombolytic drugs break down the thrombus so that the blood flow to the heart muscle can be restored to prevent further damage and assist healing. The sooner the blood flow can be restored, the better the chances of avoiding the death of the heart muscle. Along with clinical symptoms (typically but not exclusively chest pain), characteristic changes in the 12-lead electrocardiogram (ST segment elevation) provide the most immediate indication of the diagnosis of AMI for patients requiring thrombolysis for AMI.\n\nIntravenous thrombolytic therapy is an established standard treatment for AMI. It is estimated that around 50,000 patients currently receive thrombolysis in England and Wales each year. However, evidence suggests that thrombolysis continues to be under-used.\n\nThrombolytic drugs are routinely given in hospital as soon as possible after a confirmed diagnosis of AMI. Additionally, their administration in pre-hospital settings, principally by ambulance paramedics, is becoming more common.\n\nEarly primary percutaneous coronary intervention (PCI) may be an alternative to thrombolysis. Despite research evidence of the potential value of early PCI, currently few hospital trusts have the capacity to provide it. Treatment delivering thrombolytics in combination with glycoprotein IIb/IIIa inhibitors is also the subject of research studies. However, these interventions are beyond the scope of this appraisal.', 'The technology': "# Thrombolytic drugs\n\nIn the UK, four thrombolytic agents are licensed and available to treat AMI. All act by promoting the activity of circulating plasminogen. There is a long history of use of one, streptokinase, whereas the other three, alteplase, reteplase and tenecteplase, are newer options. Streptokinase is derived from streptococcal bacteria. Streptokinase is given by intravenous (IV) infusion. Alteplase was introduced in the late 1980s. It is essentially the same as the naturally occurring activator of plasminogen in the human body, and is produced by recombinant DNA technology. It is given by IV infusion. Reteplase and tenecteplase have been introduced more recently (1997 and 2001, respectively). They are new modified forms of plasminogen activator and can be given by rapid IV bolus injection, rather than infusion.\n\nThe timing of administration is a crucial factor determining the extent of benefit achieved by thrombolysis, and treatment should ideally be given as soon as possible (normally up to 12 hours) after the onset of AMI symptoms.\n\nBleeding complications are the main risks associated with thrombolysis. The most important bleeding complication is haemorrhagic stroke, which occurs in 0.5–1.0% of patients and is associated with high mortality and long-term disability in survivors. Bleeding may occur at the injection site, in the gastrointestinal tract or elsewhere. Hypotension may also occur. The risks and benefits of giving thrombolysis need to be considered in individual patients and settings. The risk of haemorrhagic stroke following thrombolysis increases with age and blood pressure. Thrombolysis is contraindicated in individuals with bleeding disorders or a history of recent haemorrhage, trauma, surgery or acute cerebrovascular event. For full details of side effects and contraindications, see the Summary of Product Characteristics for the individual agents.\n\nHeparin (an anticoagulant) is given with all of the thrombolytic drugs except streptokinase. It is usually administered as an IV bolus injection before thrombolysis, followed by an IV infusion. When given with tenecteplase the heparin dose is weight adjusted. Aspirin (an antiplatelet agent) is also usually given with any thrombolytic drug, because it delivers a mortality benefit in its own right.\n\nStreptokinase (Streptase) is indicated up to 12 hours after onset of symptoms. It is administered as an IV infusion over 1 hour. It has been extensively studied and remains widely used. Streptokinase is associated with hypotension, infrequent allergic reactions and, rarely, anaphylaxis. Patients treated with streptokinase develop anti-streptococcal antibodies, which can inactivate the drug if subsequent treatment is needed. Consequently in current UK practice, patients are usually treated with streptokinase only once. It is estimated that around one-third of people with AMI have contraindications to streptokinase. A recent survey found that 82% of hospitals in England use streptokinase for eligible patients experiencing their first AMI; other data suggest that streptokinase represents between 53% and 65% of thrombolytic drug use. Streptokinase costs £80 to £90 per patient (excluding VAT) (British National Formulary 43, March 2002).\n\nAlteplase (Actilyse, recombinant human tissue plasminogen activator, rtPA) can be delivered in a standard or accelerated regimen. The accelerated regimen, which is much more commonly used, is indicated up to 6 hours after symptom onset and is delivered by an initial IV bolus injection, followed by two IV infusions, the first given over 30 minutes and the second over 60 minutes. The standard regimen is indicated between 6 and 12 hours after symptom onset and requires a bolus injection followed by five infusions over 3 hours. Like the other newer drugs, alteplase does not stimulate the production of antibodies, so it can be used repeatedly. It is estimated that alteplase represents between 23% and 32% of thrombolytic drug use in the UK. Alteplase costs £600 per patient (excluding VAT) (British National Formulary 43, March 2002).\n\nReteplase (Rapilysin) is indicated up to 12 hours after symptom onset. It is given as two IV bolus injections 30 minutes apart. It is estimated that reteplase represents between 12% and 15% of thrombolytic drug use in the UK. Reteplase costs £716 per patient (excluding VAT) (British National Formulary 43, March 2002).\n\nTenecteplase (Metalyse) is indicated up to 6 hours after symptom onset. It is administered as a single (weight-adjusted) IV bolus injection. It is estimated that tenecteplase currently accounts for around 1% of thrombolytic drug use in the UK, the manufacturer indicates that the proportion is increasing. Tenecteplase costs £700 to £770 per patient (excluding VAT) (British National Formulary 43, March 2002).\n\n# Delivering thrombolytic drugs\n\nThe National Service Framework (NSF) for coronary heart disease (CHD) in England and Tackling CHD in Wales specify that eligible patients with AMI should be given thrombolysis within 60 minutes of calling for professional help ('call-to-needle' time) and should receive thrombolysis within 20 minutes of arriving at hospital ('door-to-needle' time). It is also suggested that it may be appropriate to provide pre-hospital thrombolysis where local 'call-to-hospital' times are likely to be over 30 minutes. The NHS Plan in England gave a commitment to train and equip ambulance paramedics to provide thrombolysis.\n\nDirect admission to a coronary care unit (CCU) is often not possible, and accident and emergency (A&E) departments are being encouraged to administer thrombolysis to reduce delays in door-to-needle times. The potential for specialist nursing input in the delivery of thrombolysis is being developed.\n\nGiven the benefits of early administration of thrombolysis on reducing damage to heart muscle and consequently on long-term outcomes, pre-hospital administration of thrombolysis by ambulance paramedics is being gradually implemented in the NHS.\n\nCurrently, pre-hospital thrombolysis is administered by fewer than five ambulance services and a small number of remote community hospitals in England and Wales. Ongoing changes in infrastructure and training will be required to implement the requirements of the NSF for CHD, Tackling CHD in Wales and the NHS Plan to allow more widespread delivery in pre-hospital settings.\n\nCurrently, streptokinase is the only thrombolytic that paramedics are authorised to administer under the Prescription Only Medicines (Human Use) Order 1997. However, paramedics can administer other thrombolytic drugs under local Patient Group Directions, and guidelines on their use by paramedics have been developed by the Joint Royal Colleges Ambulance Liaison Committee (JRCALC).\n\nThere are practical difficulties in giving controlled-rate infusions in pre-hospital settings, including drug preparation requirements, the practicalities of giving an infusion in an ambulance and, for streptokinase, concerns about higher rates of allergic reactions and hypotension, which are more difficult to manage away from hospital.\n\nAlthough they are not within the scope of this appraisal, a number of organisational models of service delivery are relevant when considering the feasibility of administering different thrombolytic agents and their effectiveness in particular settings. These involve organisational, practical and operator issues. In-hospital thrombolysis models include:\n\nassessment and treatment in A&E\n\nrapid assessment in A&E and transfer to CCU\n\ndirect admission to CCU.\n\nPre-hospital models include:\n\ncommunity hospital administration (nurse or general practitioner)\n\ngeneral practitioner administration (at the point of contact)\n\ntelemetry-supported paramedic administration\n\nautonomous paramedic administration.", 'Evidence ': "The Appraisal Committee reviewed the evidence from a number of sources (Appendix B).\n\n# Clinical effectiveness\n\n## In-hospital thrombolysis\n\nFourteen randomised controlled trials (RCTs) comparing thrombolytic drugs were included in the review. Overall the studies were considered to be of excellent quality. In total, the trials involved over 142,000 patients, and five of the trials included over 10,000 patients each. The trials had similar inclusion criteria in terms of age (usually <70 or <75 years), ECG changes, duration of symptoms, and presentation within 6 hours of symptom onset. Five of the trials included between 12% and 26% of patients aged over 70–75 years. Women were under-represented in all of the studies. Primary endpoints included 30-day mortality, 90-minute artery patency/flow rates and left ventricular function. Secondary endpoints included bleeding, stroke, congestive heart failure, reinfarction, allergy and anaphylaxis. The results of the trials were also pooled in a meta-analysis.\n\nNo direct trial comparisons between tenecteplase and streptokinase or between tenecteplase and reteplase have been undertaken, and only cautious conclusions can be drawn from the indirect comparisons that can be deduced from other studies.\n\nTwo placebo-controlled trials were instrumental in establishing the efficacy of streptokinase in reducing mortality. The GISSI trial (published in 1986) included 11,712 patients, and the ISIS-2 trial (published in 1988) included 17,187 patients. In the GISSI study, 21-day mortality was 10.7% in patients treated with streptokinase and 13% in those treated with placebo. This represents a statistically significant absolute reduction of 2.3% (risk ratio 0.81; 95% confidence ratio [CI] 0.72 to 0.9). In the ISIS-2 study, vascular mortality at 5 weeks was 9.2% in patients treated with streptokinase and 12% in those treated with placebo. This represents a statistically significant absolute reduction of 2.8%. These benefits were independent of those of early aspirin treatment.\n\nA meta-analysis of eight comparisons of standard alteplase with streptokinase found no significant difference between the two drugs in terms of mortality up to 35 days (odds ratio 1.0; 95% CI 0.94 to 1.06). A statistically significant difference in reinfarction rates in favour of alteplase was found (odds ratio 0.86; 95% CI 0.77 to 0.95). However, alteplase was associated with a statistically significant higher risk of stroke (odds ratio 1.37; 95% CI 1.16 to 1.62), due to a doubling in the risk of haemorrhagic stroke (odds ratio 2.13; 95% CI 1.04 to 4.36). However, streptokinase was associated with a statistically significant higher risk of major bleeds (other than stroke) than alteplase (odds ratio 0.81; 95% CI 0.68 to 0.97). The categorisation and reporting of major bleeding varied between the trials and so it is difficult to judge the clinical significance of these findings.\n\nThe studies included in this meta-analysis used the standard alteplase administration regimen, whereas the GUSTO-I trial used the accelerated regimen and is the only trial to have demonstrated superiority between different thrombolytic agents. The GUSTO-I trial included over 40,000 patients. It found an odds ratio of 0.85 (95% CI 0.78 to 0.94) for 30-day mortality for accelerated alteplase compared with streptokinase, and an absolute reduction in mortality at 30 days of 1.0% (6.3% versus 7.3%; 95% CI 0.4% to 1.6%) in favour of accelerated alteplase. However, this benefit was balanced by a statistically significantly higher incidence of haemorrhagic stroke (odds ratio 1.42; 95% CI 1.05 to 1.91). Using a combined outcome measure of mortality and disabling stroke, the absolute advantage of accelerated alteplase over streptokinase was lower (0.9%; p = 0.006). Rates of bleeds (moderate or worse), allergic reaction, anaphylaxis, congestive heart failure, and sustained hypotension were statistically significantly lower in the group treated with accelerated alteplase. A further meta-analysis of nine comparisons of alteplase with streptokinase, including the findings of GUSTO-I (i.e. accelerated alteplase), found no significant difference between the two drugs in terms of mortality up to 35 days (odds ratio 0.94; 95% CI 0.85 to 1.04).\n\nReteplase has also been compared with streptokinase in a study involving 5986 patients (the INJECT study). This study found an absolute difference of 0.5% (95% CI –1.98% to 0.96%) in 35-day mortality in favour of reteplase (not statistically significant). If it is accepted that a 1% difference in mortality is the limit of equivalence in thrombolytic therapy, this suggests that it is unlikely that reteplase is inferior to streptokinase. An alternative interpretation is that in terms of overall effects on mortality and disabling stroke reteplase may be inferior to streptokinase, as the trial also found a statistically significantly lower risk of haemorrhagic stroke (odds ratio 2.1; 95% CI 1.02 to 4.31) in the streptokinase group. However, the trial also found that the rates of heart failure (23.6% vs 26.3%, p<0.05) and allergic reactions (1.1% vs 1.8%, p<0.05) were statistically significantly lower in the reteplase group.\n\nReteplase has also been compared with accelerated alteplase in one relatively small (n = 324) study that examined intermediate angiographic endpoints of coronary vessel patency (RAPID-2), and one larger study that examined patient-focused endpoints (GUSTO-III, n = 15,059). GUSTO-III was designed to test the clinical superiority of reteplase over accelerated alteplase, following the findings in RAPID-2 of better coronary artery patency with reteplase. However, GUSTO-III found no statistically significant difference between the two drugs, in terms of survival or adverse effects. The mortality rate at 30 days was 7.5% in the reteplase group and 7.2% in the accelerated alteplase group: an absolute risk reduction of 0.23% in favour of accelerated alteplase (95% CI –1.10% to 0.66%). Given the confidence limits, reteplase cannot be considered as equivalent to accelerated alteplase.\n\nASSENT-2, an equivalence trial of over 16,000 patients compared tenecteplase and accelerated alteplase. The study found that 30-day mortality was almost the same in the tenecteplase group (6.2%) and the accelerated alteplase (6.2%) group. The absolute difference of 0.03% in favour of accelerated alteplase was not statistically significant (95% CI -0.55% to 0.61%). Given the confidence limits, tenecteplase and accelerated alteplase can be considered equivalent in terms of mortality. However, there was a small but statistically significant reduction in the incidence of bleeding with tenecteplase (26.4% compared with 28.9% in the accelerated alteplase group), resulting in fewer blood transfusions in the tenecteplase group (4.3% of patients compared with 5.5% in the accelerated alteplase group). Also, the rate of heart failure was statistically significantly lower in the tenecteplase group than in the accelerated alteplase group (6.1% vs 7.0%, p = 0.026).\n\nNone of the trials discussed was designed to investigate clinical subgroups, such as by age or site of infarct (anterior, inferior). It was concluded that there was no convincing evidence of relative differences in the effectiveness of the available drugs in subgroups. The greater absolute benefit found in patients with anterior infarcts in GUSTO-I may simply be a reflection of the higher baseline risk in this group. The greater relative benefit in patients aged under 75 years was not reflected in their level of absolute risk reduction. None of the differences between the subgroups appeared to be statistically significant by interaction.\n\nIn summary, given the evidence on clinical effectiveness, it can be concluded that, in the hospital setting, in terms of mortality:\n\nstandard alteplase is as effective as streptokinase\n\nreteplase is at least as effective as streptokinase, and\n\ntenecteplase is as effective as accelerated alteplase.\n\nIf accelerated alteplase is believed to be superior to streptokinase, then indirectly tenecteplase would also be considered to be superior to streptokinase.\n\nConclusions regarding the equivalence of reteplase compared with accelerated alteplase depend on the interpretation of GUSTO-III.\n\nFurthermore, if reteplase is considered to be equivalent to accelerated alteplase, then this indirectly implies that reteplase is as effective as tenecteplase.\n\nImportant differences in major adverse events between the thrombolytic agents are also apparent. The newer drugs are associated with a higher risk of haemorrhagic stroke compared with streptokinase, but there are no apparent differences in the frequency of haemorrhagic stroke between accelerated alteplase and reteplase (GUSTO-III), or between accelerated alteplase and tenecteplase (ASSENT-2). However, compared with streptokinase, the newer drugs may also be associated with a lower incidence of congestive heart failure. In addition, allergic reactions are more common with streptokinase than with the other drugs, and major bleeds (leading to transfusions) may also be more common with streptokinase, although the evidence on this is not consistent across the trials. There is also some evidence that tenecteplase may be associated with lower rates of major bleeds and heart failure than accelerated alteplase.\n\n## Pre-hospital thrombolysis\n\nNo RCTs were found comparing the different thrombolytic drugs in pre-hospital settings.\n\nHowever, nine RCTs and a systematic review investigating the feasibility, safety and efficacy of pre-hospital administration of thrombolysis compared with hospital administration were considered in the context of the appraisal. A number of other papers reporting non-randomised studies and audits of pre-hospital thrombolysis were also considered in relation to practical and implementation issues.\n\nThe RCTs were small, except for one that included over 5000 patients (EMIP). They were undertaken in a mixture of urban and/or rural settings in Israel, continental Europe, Canada, the USA, Northern Ireland, and Scotland. A variety of thrombolytic drugs were studied – four studies used alteplase, four used streptokinase-type drugs, and one used urokinase (which is not available in the UK). Only the USA study (MITI) involved paramedics administering the thrombolytic (after remote consultation with a physician). In all but one of the other studies, a hospital physician attended the patient and administered the drug. In the rural Scottish trial (GREAT) a general practitioner undertook assessment and treatment.\n\nThe RCTs found that, on average, pre-hospital thrombolysis was administered 58 minutes earlier than hospital thrombolysis; the differences ranged from 33 minutes in the MITI study to 130 minutes in the GREAT study. Individually, the trials failed to show statistically significant reductions in in-hospital mortality, although findings in all of the studies favoured pre-hospital administration. However, a meta-analysis of six of the trials found a statistically significant absolute reduction in mortality of 1.6% (95% CI 0.2% to 3%), and a relative risk reduction of 17% (95% CI 2% to 30%, p = 0.03) favouring pre-hospital administration of thrombolysis. This analysis is heavily influenced by the results of the GREAT study (in which thrombolysis was administered by general practitioners in rural Scotland) and therefore does not directly relate to the potential for paramedic based pre-hospital thrombolysis.\n\nA number of observational studies examining pre-hospital thrombolysis were considered, although these generally only provide further insight into feasibility and safety. They include studies of administration of anistreplase (a streptokinase-like drug that is no longer available in the UK) by paramedics or general practitioners in a Dutch city, reteplase administered by ambulance-based nurses in Sweden, reteplase administered by paramedics in the USA, anistreplase administered in a rural Italian emergency room, and two reports of a small number of cases of reteplase administered by paramedics with hospital telemetry support in England.\n\n# Cost effectiveness\n\n## In-hospital thrombolysis\n\nThe Assessment Group's literature review found eight published articles on the cost-effectiveness of thrombolytic agents that met the inclusion criteria for the review of cost effectiveness. All compared streptokinase and alteplase (standard and accelerated) in a hospital setting. Three of the articles reported different aspects of the same cost-effectiveness model. Most studies reported incremental costs per life-year gained, and three also reported incremental cost per quality-adjusted life year (QALY). Most of the studies were based on the effectiveness results of GUSTO-I, in which data on resource use were collected only for USA centres. Consequently the analyses undertaken in Canada, Ireland and France had to attempt to translate these to settings in other countries.\n\nIn general, the studies had the following limitations: costs and benefits were not measured in the same populations; comparator treatments were often inadequately described; and the derivation of utility values was inadequately explained. None of the studies undertook costing at a patient level and, while in general similar cost categories were included, only some of the studies included the longer-term costs of stroke and heart failure. Some of the studies included consideration of adverse events, including stroke, reinfarction, major bleeds, anaphylaxis, and congestive heart failure.\n\nThe analyses undertaken following GUSTO-I, which found a survival advantage for accelerated alteplase at 30 days, showed the drug to be cost effective compared with streptokinase within the context of the clinical trial in the US healthcare system. In all of the studies, sensitivity analyses found that assumptions regarding mortality differences and costs were important, and so any conclusions drawn are heavily dependent on the interpretation of the effectiveness findings of GUSTO-I.\n\nIn particular, the economic analysis undertaken in the USA alongside GUSTO-I modelled lifetime costs and benefits, and reported an incremental cost per life-year gained of $32,678 and an incremental cost per QALY of $36,402 for accelerated alteplase compared with streptokinase. The subgroup analyses found that accelerated alteplase became more cost effective in patients with higher absolute mortality risk – for example, $13,410 per life-year gained in patients older than 75 years with anterior myocardial infarction. However, the analysis requires extremely cautious interpretation given a number of issues, including uncertainties over the interpretation of GUSTO-I (in general and in subgroups), application of US data on resource use, and the assumption that costs did not differ significantly between treatment groups.\n\nOverall, there is little relevant published evidence on the economics of thrombolytics in a UK setting, and none examining the currently available bolus drugs. However, two cost-effectiveness models were submitted by manufacturers.\n\nIt is logical to assume that the earlier the administration the greater the reduction in damage to the heart. However, while precise assumptions about the survival/time-to-treatment curve affect the benefit results in any modelling, it is unlikely that any one drug has a large advantage over any other with regard to timing of administration.\n\nThe two manufacturers' models are similar in structure and scope, although they differ in terms of method and level of detail. Roche's model examines costs up to 30 days, assumes all four drugs have equivalent efficacy, and has less detailed costing. In contrast the Boehringer Ingelheim model includes costing up to 10 years, includes long-term costing for individual complications (such as congestive heart failure and stroke), and incorporates differential survival and complication outcomes for the drugs and more detailed estimation of utilities. Both models incorporate a range of different assumptions regarding adverse events. The models also incorporate adjustment for the timing of administration, including time-savings in pre-hospital settings in which only bolus drugs are compared.\n\nThe Roche model essentially represents a cost-minimisation analysis, and finds reteplase slightly less costly than accelerated alteplase or tenecteplase in hospital. The Boehringer Ingelheim model assumes better survival and a lower incidence of post-infarct congestive heart failure (streptokinase 15.4%, accelerated alteplase 13.5%, reteplase 13.5%, tenecteplase 11.8%) for tenecteplase. These assumptions, together with 10-year discounted costs, lead to a finding that tenecteplase dominates accelerated alteplase and reteplase in hospital (that is, it is of lower cost and greater effectiveness).\n\nThe Assessment Group adjusted key parameters, tested sensitivities and presented revised results using the manufacturers' models. The sensitivity analysis examined the parameter values submitted by the manufacturers for the following: 30-day mortality, strokes, major bleeds, reinfarctions and congestive heart failure.\n\nThe Assessment Group used the adjusted models to compare the three newer drugs with streptokinase. For each comparison, the additional benefit (using QALYs) of the newer thrombolytic was small, while the additional cost was substantial. The cost differences between the newer drugs are relatively small. The most reliable finding is that streptokinase is by far the cheapest drug and although it is a little less effective (in terms of discounted QALYs), it is the most cost effective.\n\nUsing the adjusted manufacturers' models, the incremental costs per QALY reported for the three drugs compared with streptokinase were: accelerated alteplase, £7219 (adjusted Boehringer Ingelheim model) and £7878 (adjusted Roche model); reteplase, £7893 and £10,247; and tenecteplase, £8321 and £9509. However, these cost–utility rankings of the three drugs relative to streptokinase are sensitive to changes in assumptions in the models, and so are not conclusive.\n\n## Pre-hospital thrombolysis\n\nNo published articles examining the cost effectiveness of different thrombolytic drugs in pre-hospital settings were found.\n\nThere is a published economic analysis of the GREAT study comparing cost effectiveness of pre-hospital and in-hospital thrombolysis (that is, the cost effectiveness of the different drugs), which found that pre-hospital delivery had an incremental cost per life saved of £3890. The sensitivity analysis found that the cost per life saved could increase to £88,000. It should also be borne in mind that the benefits found in the GREAT trial were larger than those found in other studies, the economic analysis was not undertaken alongside the trial, the interventions were not described in detail, and the model of rural Scottish general practitioner care is unlikely to be applicable throughout the NHS in England and Wales.\n\nIn the pre-hospital setting, Roche's model assumes that reteplase and tenecteplase have equivalent efficacy and that reteplase is slightly cheaper. The Boehringer Ingelheim model finds that tenecteplase dominates reteplase in pre-hospital settings (that is, it has a lower cost and greater effectiveness).\n\nBuilding on the conclusions about in-hospital cost effectiveness, and since the general pre-hospital delivery costs for the two suitable bolus drugs (reteplase and tenecteplase) would be the same, the relative cost effectiveness of the drugs in pre-hospital settings is likely to be similar to that in hospital (assuming equal effectiveness of both drugs in each setting). On this basis it was concluded that it was not possible to distinguish between reteplase and tenecteplase on grounds of cost effectiveness in pre-hospital settings.\n\n# Consideration of the evidence\n\n## In-hospital thrombolysis\n\nThe Committee noted the debate over the applicability of the findings of GUSTO-I beyond the North American centres (where most of the benefit of alteplase over streptokinase was found). The Committee considered that the efficacy of accelerated alteplase should not be determined solely from the results of the GUSTO-I trial.\n\nDespite concerns over the interpretation of GUSTO-I, the Committee concluded that it was likely that the newer thrombolytic agents are more effective than streptokinase in terms of 30-day mortality.\n\nThe Committee was aware of the documented higher rates of stroke associated with the newer agents and carefully considered the views of clinical experts on this issue.\n\nThe Committee considered that differences in the benefit of one thromboloytic agent over another are less clear if the combination of mortality and stroke endpoints are taken into account, particularly for subgroups at higher risk of haemorrhagic stroke. Furthermore, when considering the combination of mortality and stroke endpoints, it could be argued that the differences in overall benefit are less clear, particularly for subgroups at higher risk of developing haemorrhagic stroke.\n\nIn taking the view that the use of streptokinase is cost effective, the Committee concluded that, although the acquisition cost of each of the newer drugs is substantially higher than that of streptokinase, the available economic evidence demonstrates that the newer drugs have an acceptable incremental cost-effectiveness ratio when compared with streptokinase.\n\nGiven that streptokinase is associated with a lower risk of stroke and is a cost-effective drug, the Committee also considered it appropriate that all of the available thrombolytic drugs should be considered as options for use in care pathways for AMI. Local organisational and clinical policy considerations, such as proximity of CCU facilities and A&E staffing, will also have an impact on decisions regarding the appropriate use of each of the drugs in hospital.\n\nBecause the drugs will have different risk–benefit profiles for individual patients, the Committee concluded that the decision about which of the available drugs to use should be made after balancing the likelihood of the benefits and risks (for example, stroke) to which the different drugs would expose the individual.\n\nThe Committee took into account the potential importance of the methods of administration of the different thrombolytics and their effect on door-to-needle times. However, the impact of this factor on reducing myocardial damage and important clinical outcomes was very dependent on the overall pain-to-needle time. Thus, a saving of a few minutes in the door-to-needle time was likely to have a much greater impact on these endpoints where the pain-to-needle time was 1 hour compared with the situation where the pain-to-needle time was 6 hours.\n\n## Pre-hospital thrombolysis\n\nThe Committee noted that while there is observational evidence to support pre-hospital thrombolysis, applying the results to the current NHS context is difficult, in that a minority used currently available bolus drugs, most are not paramedic based, and none was reliably generalisable to England and Wales.\n\nIn the absence of comparative evidence on thrombolytics in pre-hospital settings, the Committee considered that the findings of trials comparing different thrombolytic drugs in hospital could still reasonably be applied to pre-hospital settings, with consideration of the additional relevant factors including safety and applicability examined in the pre-hospital studies outlined above.\n\nOn the basis of advice from experts that only the bolus drugs were appropriate for pre-hospital administration given the practical difficulties explained in section 3.2.6, and given that no high-quality evidence was available to differentiate reteplase and tenecteplase in terms of clinical effectiveness or cost effectiveness in pre-hospital settings, the Committee considered that either reteplase or tenecteplase could be used in these settings, provided that the necessary infrastructure and training is provided to fully establish an appropriate model of pre-hospital thrombolytic administration.\n\nGiven the risks associated with thrombolytic drugs and the fact that pre-hospital administration is an emerging practice in England and Wales, the Committee considered it important to ensure high-quality training and supervision of staff involved in the administration of thrombolysis. It was also considered important that clinicians and organisations delivering pre-hospital thrombolysis should develop clear clinical protocols for the use of thrombolytic drugs, such as those developed by the JRCALC, and adopt robust clinical governance arrangements to monitor the use of and outcomes associated with these drugs.", 'Proposed recommendations for further research': 'In light of the on-going introduction of pre-hospital thrombolysis, it is recommended that opportunities for the evaluation of the administration of thrombolytic drugs in pre-hospital settings are explored.', 'Resource impact for the NHS': 'Using estimates of the total number of people receiving thrombolysis and the mixture of thrombolytic drugs used, current annual spending on thrombolytic drugs in England and Wales is estimated to be between £13 million and £26 million (i.e. drug costs alone, excluding VAT).\n\nIf, as is believed, the current need for thrombolysis is only partly met, and more clinically eligible patients were to receive thrombolytic drugs, cost estimates would be markedly higher.\n\nIt is difficult to predict the local impact of the guidance on the hospital prescribing patterns of available thrombolytic drugs. Consequently only approximate estimates of the likely NHS resource impact of this guidance can be made, based on possible patterns of hospital prescribing of the alternative available drugs.\n\nAssuming that the current overall level of thrombolytic therapy remains unchanged, if streptokinase represented 20% of thrombolytic drugs prescribed, alteplase 10%, and reteplase and teneteplase each accounted for 35%, then the total annual spending on thrombolytic drugs in England and Wales would be between £27 million and £45 million. If these levels were assumed to be 35%, 20% and 22.5% respectively, then the total would be between £22 million and £36 million.\n\nIn addition, substantial costs are associated with the introduction of pre-hospital thrombolysis. These include the costs of additional equipment, training, and potentially longer ambulance time spent treating patients with AMI. Also, any expansion of pre-hospital thrombolysis would result in a shift of drug costs from acute hospital trusts to other services such as ambulance trusts or primary care trusts and, potentially, result in an increase in total local spending on thrombolytic drugs where bolus drugs were not widely used in hospital. Such costs are difficult to estimate usefully on the basis of the information available to the Institute at the time of this appraisal.', 'Related guidance': 'In April 2001, NICE issued an inherited clinical guideline on prophylaxis for patients who have experienced a myocardial infarction:\n\nNational Institute for Clinical Excellence (2001), Prophylaxis for patients who have experienced a myocardial infarction. NICE Inherited Clinical Guideline A. London: National Institute for Clinical Excellence. [Replaced by NICE clinical guideline 48]', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. For details on the review of this guidance, see the NICE website.\n\nAndrew DillonChief ExecutiveOctober 2002', 'Appendix C. Information for patients. Drugs for early thrombolysis in the treatment of acute myocardial infarction': "'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.", 'Changes after publication': "March 2014: implementation section updated to clarify that thrombolytic drugs are recommended as an option for treating acute myocardial infarction. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance\n\nIn January 2006, following consultation, the Institute decided to make this guidance 'static.' This means that the guidance remains in force and has no scheduled review date. See the review decision, under 'Background information', for further details.", 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta52	Evidence-based recommendations on using thrombolytic drugs (alteplase [Actilyse], reteplase [Rapilysin], streptokinase [Streptase] and tenecteplase [Metalyse]) for treating acute myocardial infarction in adults.
f4ee955c1464d30f824968f7940f58d6f9dfc3ad	nice	Guidance on the use of ultrasound locating devices for placing central venous catheters	Guidance on the use of ultrasound locating devices for placing central venous catheters Evidence-based recommendations on using ultrasound locating devices for placing central venous catheters. # Guidance Two-dimensional (2-D) imaging ultrasound guidance is recommended as the preferred method for insertion of central venous catheters (CVCs) into the internal jugular vein (IJV) in adults and children in elective situations. The use of two-dimensional (2-D) imaging ultrasound guidance should be considered in most clinical circumstances where CVC insertion is necessary either electively or in an emergency situation. It is recommended that all those involved in placing CVCs using two-dimensional (2-D) imaging ultrasound guidance should undertake appropriate training to achieve competence. Audio-guided Doppler ultrasound guidance is not recommended for CVC insertion.# Clinical need and practice Central venous catheters (CVCs) are inserted for a number of reasons including haemodynamic monitoring, intravenous delivery of blood products and drugs (for example, chemotherapy and antibiotics), haemodialysis, total parenteralnutrition, cardiac pacemaker placement and management of perioperative fluids. Central venous catheterisation may be required for patients undergoing cancer treatment, dialysis, or coronary or other major surgery, and for those admitted to intensive therapy units (ITUs), high dependency units (HDUs) or accident and emergency departments. It has been estimated that about 200,000 CVCs are inserted annually in the NHS. Central venous access has traditionally been achieved by puncturing a central vein (venepuncture) and passing the needle along the anticipated line of the relevant vein by using surface anatomical landmarks and by knowing the expected anatomical relationship of the vein to its palpable companion artery. This is known as the 'landmark method'. Direct surgical access to a peripheral vein ('cut-down') is a less frequently used method for central venous access catheter insertion. CVCs are inserted in a wide range of clinical settings by a diverse group of clinicians including radiologists, anaesthetists, nephrologists, oncologists, surgeons, general physicians and paediatricians. In the USA and increasingly in the UK, nurse specialists are also undertaking CVC procedures. The range of settings in which CVCs are inserted includes operating theatres, emergency rooms, nephrology, oncology and other wards, radiology departments, ITUs and HDUs. Central venous access can be achieved using various puncture sites but the most common are the internal jugular vein (IJV), the subclavian vein (SV), the femoral vein (FV), and the upper limb veins (using peripherally inserted central catheters – PICCs). The choice of access route depends on multiple factors including the reason for CVC insertion, the anticipated duration of access, the intact venous sites available and the skills of the operator. Whilst experienced operators using the landmark method can achieve relatively high success rates with few complications, in the literature failure rates for initial CVC insertion have been reported to be as high as 35%. The most common complications associated with CVC placement are arterial puncture, arteriovenous fistula, pneumothorax, nerve injury and multiple unsuccessful attempts at catheterisation, which delay treatment. The risks and the consequences of complications vary substantially across different patient groups depending on the patient's anatomy (for example, morbid obesity, cachexia, short neck, or local scarring from surgery or radiation treatment), the circumstances in which CVC insertion is carried out (for example, for a patient receiving mechanical ventilation or during emergencies such as cardiac arrest) and co-morbidities (for example, bullous emphysema or coagulopathy). The National Confidential Enquiry into Perioperative Deaths recently reported that in a survey of over 3000 CVC procedures undertaken in the NHS, one fatality occurred as a result of a procedure-induced pneumothorax.# The technology Ultrasound technology has long been used in interventional radiology to guide percutaneous procedures at sites such as the kidneys, liver, arterial and venous circulation, pleural cavity, gallbladder and joints. Real-time ultrasound guidance of CVC insertion provides the operator with visualisation of the desired vein and the surrounding anatomical structures before and during the insertion. The advantages of ultrasound-guided central venous catheterisation include the identification of the precise position of the target vein and the detection of anatomical variants and of thrombosis within the vessel, together with the avoidance of inadvertent arterial puncture. Ultrasound guidance therefore has the potential to reduce the incidence of complications related to initial venous puncture, which is the first stage of CVC insertion. Two types of real-time ultrasound guidance are described: two-dimensional (2-D) imaging ultrasound guidance and audio-guided Doppler ultrasound guidance. Two-dimensional imaging ultrasound, which is the more commonly used method, provides a real-time grey-scale imaging of the anatomy. Audio-guided Doppler ultrasound generates an audible sound from flowing venous blood, which helps the operator localise the vein and differentiate it from its companion artery. The portable ultrasound machines can be used in operating theatres, accident and emergency departments, ITUs, HDUs and radiology suites, as well as at the bedside on the hospital ward. Operators need to be trained to use ultrasound-guided techniques. Training involves not only acquiring the necessary manual skills, but also having a basic understanding of ultrasound principles and being able to interpret ultrasound images.# Evidence and interpretation The Appraisal Committee reviewed the evidence from a number of sources (Appendix B). # Clinical effectiveness Twenty randomised clinical trials (RCTs) were identified. Of these, six evaluated audio-guided Doppler ultrasound against the landmark method, thirteen evaluated 2-D ultrasound guidance against the landmark method and one evaluated both audio-guided Doppler ultrasound and 2-D ultrasound guidance against the landmark method. There were no trials that compared the use of ultrasound locating devices (ULDs) against the surgical cut-down method. Insertion sites were the IJV (fifteen trials), SV (four trials) or FV (one trial). One trial did not specify the insertion point, and one investigated both the IJV and the SV as insertion sites. None addressed the placement of PICCs or ports, both of which can be considered types of CVCs. For most of the trials, the setting within the hospital where the cannulation took place was not reported clearly. In six of the trials the central venous catheterisation took place in an ITU or trauma unit, and in two trials catheterisations took place in emergency rooms. In the seven studies involving patients scheduled for cardiac surgery, the cannulation is most likely to have taken place on the way into theatre. In only three of the trials does it seem likely that CVCs were inserted on wards or in clinics. The CVC procedure was carried out by anaesthetists in seven studies and by other medical staff in four studies. One study involved 2-D ultrasound-guided catheterisation by junior radiologists. None of the studies involved nurses. The remaining nine studies did not make the specialty or profession of the operator clear. The range of experience of the operator, both with respect to medical career and use of the intervention, differed greatly from study to study. Six studies described the operators as having up to 5 years' postgraduate experience, eight described them as having more than 5 years' experience, and two described them as varying in experience. Four trials did not record the career experience of the operator. ## -D ultrasound imaging Pooled results from seven RCTs suggested that real-time 2-D ultrasound guidance was significantly better than the landmark method for all five outcome variables measured for insertions into the IJV in adults. Compared with the landmark method, 2-D ultrasound guidance was associated with reduced risks of failed catheter placements (86% reduction in relative risk, 95% confidence interval 67% to 94%, p < 0.001), catheter placement complications (57% reduction in relative risk, 95% CI 13% to 78%, p = 0.02), and failure on the first catheter placement attempt (41% reduction in relative risk, 95% CI 12% to 61%, p = 0.009), and fewer attempts to achieve successful catheterisation (on average, 1.5 fewer attempts, 95% CI 0.47 to 2.53, p = 0.004) The difference between the 2-D ultrasound method and the landmark method in the time taken to insert a catheter successfully was small and not statistically significant (2-D ultrasound-guided catheterisation was 20 seconds faster, 95% CI –83 to 124 seconds). However, there was significant heterogeneity for this endpoint (p < 0.01), which indicated that it might not be appropriate to pool these results. In the study which reported the longest time to achieve a successful catheterisation, the time taken to set up the ULD was also included in the outcome measurement. When the analysis was repeated, excluding this study, heterogeneity was no longer significant and the pooled result from the included trials showed that catheterisation was, on average, 69 seconds faster (95% CI 46 to 92 seconds) with the ULD than with the landmark method, which was a highly statistically significant difference (p < 0.001). It is acknowledged that the importance of this endpoint will vary between clinical situations. Three trials evaluated the effect of 2-D ultrasound guidance on the cannulation of the IJV in infants. In these trials, 2-D ultrasound guidance was significantly etter than the landmark method in terms of reductions in the risk of failed catheter placements (85% reduction in relative risk, 95% CI 36% to 97%, p = 0.01), the risk of catheter placement complications (73% reduction in relative risk, 95% CI 8% to 92%, p = 0.03), and the number of attempts required before catheterisation was successful (reduced by an average of 2, 95% CI 1.2 to 2.8, p = 0.001). Using 2-D ultrasound guidance, successful cannulation was achieved, on average, 349 seconds (95% CI –103 to 802 seconds) more quickly than with the landmark method, although this result was not statistically significant. Only one RCT was identified that analysed the effect of 2-D ultrasound guidance on SV catheterisation in adults. In the trial, in comparison with the landmark method, 2-D ultrasound guidance was associated with reduced risks of catheter placement failure (86% reduction in relative risk, 95% CI 43% to 96%, p = 0.006) and catheter placement complications (90% reduction in relative risk, 95% CI 29% to 99%, p = 0.02). However, in this trial, the operators were relatively inexperienced in both the landmark method and 2-D ultrasound guidance. The failure rate with the landmark method was 55%, which is higher than that reported in trials that involved more experienced operators (around 9–19%). No studies were found that investigated the effect of 2-D ultrasound guidance on SV catheterisation in infants. One study was identified that evaluated the effect of 2-D ultrasound guidance on femoral catheterisation in adults. In this trial, the operators took, on average, 2.7 (95% CI 0.1 to 5.3) fewer attempts to insert a catheter using 2-D ultrasound guidance than using the landmark method (p = 0.04). Compared with the landmark method, 2-D ultrasound guidance reduced the risk of failed catheter placement and the time to successful catheterisation, but the differences were not statistically significant. No studies in infants were found. No studies were found that investigated the effect of 2-D ultrasound guidance on FV catheterisation in infants. ## Audio-guided Doppler ultrasound Four RCTs were found that compared audio-guided Doppler ultrasound guidance with the landmark method for IJV catheterisation in adults. Pooled results from these RCTs suggest that audio-guided Doppler ultrasound guidance was significantly better than the landmark method in terms of risk of failed catheter placement (61% reduction in relative risk, 95% CI 8% to 83%, p = 0.03) and the risk of failure on the first catheter placement attempt (43% reduction in relative risk, 95% CI 12% to 63%, p = 0.01). With the audio-guided Doppler ultrasound method, the risk of catheter placement complications was reduced (57% reduction in relative risk, 95% CI –5% to 83%) and there were fewer attempts to achieve successful catheterisation (0.6 fewer attempts, 95% CI –0.6 to 1.8); however, the differences did not reach statistical significance (p = 0.06 and p = 0.40, respectively) so they could have arisen by chance. It took, on average, 35 seconds longer (95% CI –54 to 124 seconds) to successfully insert a catheter using Doppler ultrasound guidance than it did with the landmark method, although this difference was also not statistically significant. Only one trial was identified that studied the effect of audio-guided Doppler ultrasound in infants. The sample size of this study was small (n = 29) and so it lacked statistical power. It failed to show any differences with the landmark method. The pooled results from three RCTs (all involving adults) suggest that for SV catheterisation there was a significantly increased risk of failed catheter placement when the audio-guided Doppler ultrasound method was used compared with the landmark method (48% increased in relative risk, 95% CI 3% to 114%, p = 0.03) – in other words the landmark method was preferable to the audio-guided Doppler ultrasound guidance technique. In contrast, the pooled results from two of the trials, which reported the risk of catheter placement, showed a 43% fall (95% CI 89% to 188%) in relative risk in the audio-guided Doppler ultrasound group, although this result was not statistically significant. Only one study reported the effect of audio-guided Doppler ultrasound guidance on the risk of failure of the first catheter placement in adults. There was a slight increase (4%, 95% CI –24% to 43%) in the risk of catheter placement complications associated with the use of audio-guided Doppler ultrasound guidance compared with the landmark method, although this result was not statistically significant. Only one study recorded the effect of audio-guided Doppler ultrasound guidance on the number of attempts required to achieve successful catheterisation. This study found that an average of 0.4 (95% CI 0.2 to 0.6) fewer attempts were needed to achieve successful catheterisation with the audio-guided Doppler ultrasound guidance method compared with the landmark method, a highly statistically significant difference (p < 0.001). The same study was the only one to record the effect of Doppler ultrasound guidance on the time to achieve successful catheterisation. Catheterisation using the Doppler ultrasound guidance method was significantly (on average, 209 seconds, 95% CI 175 to 242) slower than catheterisation using the landmark method (p < 0.001). # Cost effectiveness No relevant economic evaluations were identified in the literature. Furthermore, none of the submissions made to the Institute included economic evaluations. The Assessment Group developed an economic analysis, based on the evidence from the systematic review of RCTs, to evaluate the cost effectiveness of 2-D ultrasound guidance compared with the landmark method. This model is a simple decision analytic model, and is based on a theoretical cohort of 1000 adult patients who required IJV cannulation before surgery and who had a low to moderate risk of complications. This model adopted a set of conservative assumptions. It was assumed that: the operators were experienced in using the landmark method; the time to achieve successful puncture was the same for both methods; complications were limited to arterial puncture; there was a 10-minute delay between the prior failure and the new attempt at another insertion site; there was a 100% success rate at the second insertion site; and each machine was used for 15 procedures per week. The results of the Assessment Group's model suggested that the ultrasound guidance not only avoided 90 arterial punctures for every 1000 patients treated, but also reduced costs by an average of almost £2 per patient. In other words the 2-D ultrasound guidance method was found to be both more effective and less costly than the landmark method. A threshold sensitivity analysis was undertaken to examine by how much key variables in the model needed to change to make the ultrasound guidance method cost-neutral instead of cost-saving. The modelled result was most sensitive to the utilisation of the ultrasound equipment. The cost-saving result was eradicated if the number of ultrasound procedures assumed per machine per week was less than around 11, or if the number of ultrasound procedures carried out by an individual trained practitioner was less than around 3 per month on average. Given that the model used relatively conservative estimates, the Assessment Group concluded that the results were probably generalisable to all anatomical catheter insertion sites, to infants, and to other sites within the hospital including the clinical wards. # Consideration of the evidence The Committee reviewed the evidence on both the clinical effectiveness and the cost effectiveness of ULDs for placing CVCs, having also considered the evidence from clinical experts. Furthermore, the Committee was mindful of the need to ensure that its advice took account of the efficient use of NHS resources. The Committee took note of the fact that the evidence on the effectiveness of CVC placement into IJVs in adult patients was more robust than that available for other insertion sites. For infants, evidence was available only from trials that evaluated central venous catheterisation of the IJV, and there was very limited evidence on the use of this technology in very small infants (i.e. those weighing less than 3 kg). In addition, the economic analysis presented to the Committee was based on an evaluation of the cost effectiveness of 2-D ultrasound-guided elective CVC placement into the IJV in the operating theatre prior to surgery. The Assessment Report provided justifications for extrapolating this analysis to other settings including ward-based management, other sites of CVC insertion and also to CVC placement in infants. Given the constraints outlined in 4.2.2, the Committee concluded that there was evidence of both the clinical and cost effectiveness of 2-D imaging ultrasound guidance as an adjunct for placing CVCs in the majority of clinical scenarios, but that the degree to which this technology would be most suitably applied would vary according to the clinical situation and the competence/previous experience of the operator. In addition, there could be potential benefits for patients arising from reduced discomfort from the procedure and reduced risk of complications compared with the landmark method, particularly for IJV insertions. The Committee found the evidence for the use of audio-guided Doppler ultrasound guidance less satisfactory, and therefore concluded that the 2-D imaging ultrasound guidance should be used in preference to audio-guided Doppler ultrasound guidance. While accepting that, from a patient's perspective, 2-D ultrasound imaging guidance in CVC insertion might be more appropriate and probably superior to the traditionally used landmark method in many circumstances, the Committee also considered the financial and service implications of purchasing the required equipment and of training sufficient numbers of competent practitioners. The Committee also considered that although 2-D ultrasound imaging guidance in CVC placement may eventually become the routine method for placing CVCs, the landmark method would remain important in some circumstances, such as emergency situations, when ultrasound equipment and/or expertise might not be immediately available. Consequently, the Committee thought it important that operators maintain their ability to use the landmark method and that the method continues to be taught alongside the 2-D-ultrasound-guided technique.# Recommendations for further research Good quality studies are needed: to investigate the possible economic and clinical implications to the NHS of nurse specialists or other healthcare practitioners carrying out routine insertion of CVCs to evaluate the use of ultrasound-guided central venous catheterisation in small infants (i.e. those weighing less than 3 kg).# Resource impact for the NHS The purchase cost of a portable 2-D ultrasound machine currently lies between £7000 and £15,000. The additional disposables necessary for the ultrasound-guided procedure cost less than £1 per procedure. Estimates made by the Assessment Group analysis indicate that the additional cost of using ultrasound equipment for the CVC placement procedure is likely to be less than £10 per procedure. It is likely that the NHS will need to invest in a significant number of additional 2-D ultrasound machines, although it is impossible to predict how many will be required, as local circumstances will vary considerably. Implementing the guidance will require local decisions regarding optimal number of machines, staff training and device service contracts. The Assessment Group analysis suggests that in the long term the implementation of ultrasonic locating devices will be costsaving. The majority of these savings are likely to be due to releasing resources such as staff, and operating theatre and ITU/HDU time and beds. A constraint upon the implementation of this technology will be the need to ensure that there are adequately trained competent operators to support the services. Many CVC placement procedures are performed on an emergency basis at the bedside in a diverse number of locations and therefore the necessary skills need to be spread across several related disciplines# Related guidance There is no related NICE guidance for this technology.# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. Information on the review of the guidance on this technology is available on the NICE website. Andrew DillonChief ExecutiveSeptember 2002# Appendix C. Patient information. Guidance on the use of ultrasound locating devices for placing central venous catheters 'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.# Appendix D. Detail on criteria for audit of the use of ultrasound locating devices for placing central venous catheters # Possible objectives for an audit An audit on the appropriate use of ultrasound locating devices could be carried out to ensure that: when a central venous catheter (CVC) is being inserted into the internal jugular vein (IJV) of an adult or a child in an elective situation, 2-dimensional (2-D) imaging ultrasound guidance is used healthcare practitioners involved in the placement of CVCs using 2-D imaging ultrasound guidance have appropriate training audio-guided Doppler ultrasound guidance is not used for CVC insertion. If healthcare practitioners have agreed locally on the clinical circumstances where 2-D imaging ultrasound guidance is to be used when a CVC insertion is necessary, the audit also could be carried out to ensure that the technique is used as agreed locally. # Possible patients to be included in the audit and time period for selection All patients who have a CVC inserted either in the IJV in an elective situation (or for any purpose on either an elective or emergency basis, if 2-D imaging ultrasound is more widely used) over a reasonable period of time for audit data collection, for example, for 1 to 3 months. A sample of patients stratified by clinical areas most likely to be involved, for example, critical care areas, theatres, and accident and emergency, could be used for the audit or the audit could be staged to include one clinical area at a time, working through all clinical areas. # Measures to be used as a basis for an audit Criterion Standard Exception Definition of Terms . 2-D imaging ultrasound guidance is used when a CVC is being inserted in the IJV in an elective situation % of patients with a CVC inserted in the IJV in an elective situation None Local clinical teams should agree on the types of elective situations to be included in the audit and should agree to any exceptions for the use of the technique such as an infant weighing less than 3 kg . The healthcare practitioner involved in the placement of the CVC is trained in the use of 2-D imaging ultrasound guidance % of patients having a CVC inserted None For audit purposes, it should be agreed at NHS Trust level how training to achieve competence in the technique is documented . Audio-guided Doppler ultrasound guidance is not used for CVC insertion % of patients having a CVC inserted None An additional measure that could be used when it has been agreed to use 2-D imaging ultrasound guidance for other clinical circumstances in which a patient has a CVC inserted is as follows. Criterion Standard Exception Definition of Terms . 2-D imaging ultrasound guidance is used when a CVC is being inserted % of patients having a CVC inserted for any purpose None Local healthcare practitioners may specify circumstances in which 2-D ultrasound guidance is to be used when a CVC is being inserted or may specify exceptions, for audit purposes # Calculation of compliance with the measure Compliance with each measure described in the table is calculated as follows: Number of patients whose care is consistent with the criterion plus the number of patients whose care is consistent with any locally agreed exception Number of patients to whom the measure applies X 100 Healthcare practitioners should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that desired improvement is being achieved.# Changes after publication March 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Two-dimensional (2-D) imaging ultrasound guidance is recommended as the preferred method for insertion of central venous catheters (CVCs) into the internal jugular vein (IJV) in adults and children in elective situations.\n\nThe use of two-dimensional (2-D) imaging ultrasound guidance should be considered in most clinical circumstances where CVC insertion is necessary either electively or in an emergency situation.\n\nIt is recommended that all those involved in placing CVCs using two-dimensional (2-D) imaging ultrasound guidance should undertake appropriate training to achieve competence.\n\nAudio-guided Doppler ultrasound guidance is not recommended for CVC insertion.', 'Clinical need and practice': "Central venous catheters (CVCs) are inserted for a number of reasons including haemodynamic monitoring, intravenous delivery of blood products and drugs (for example, chemotherapy and antibiotics), haemodialysis, total parenteralnutrition, cardiac pacemaker placement and management of perioperative fluids. Central venous catheterisation may be required for patients undergoing cancer treatment, dialysis, or coronary or other major surgery, and for those admitted to intensive therapy units (ITUs), high dependency units (HDUs) or accident and emergency departments. It has been estimated that about 200,000 CVCs are inserted annually in the NHS.\n\nCentral venous access has traditionally been achieved by puncturing a central vein (venepuncture) and passing the needle along the anticipated line of the relevant vein by using surface anatomical landmarks and by knowing the expected anatomical relationship of the vein to its palpable companion artery. This is known as the 'landmark method'. Direct surgical access to a peripheral vein ('cut-down') is a less frequently used method for central venous access catheter insertion.\n\nCVCs are inserted in a wide range of clinical settings by a diverse group of clinicians including radiologists, anaesthetists, nephrologists, oncologists, surgeons, general physicians and paediatricians. In the USA and increasingly in the UK, nurse specialists are also undertaking CVC procedures. The range of settings in which CVCs are inserted includes operating theatres, emergency rooms, nephrology, oncology and other wards, radiology departments, ITUs and HDUs.\n\nCentral venous access can be achieved using various puncture sites but the most common are the internal jugular vein (IJV), the subclavian vein (SV), the femoral vein (FV), and the upper limb veins (using peripherally inserted central catheters – PICCs). The choice of access route depends on multiple factors including the reason for CVC insertion, the anticipated duration of access, the intact venous sites available and the skills of the operator.\n\nWhilst experienced operators using the landmark method can achieve relatively high success rates with few complications, in the literature failure rates for initial CVC insertion have been reported to be as high as 35%.\n\nThe most common complications associated with CVC placement are arterial puncture, arteriovenous fistula, pneumothorax, nerve injury and multiple unsuccessful attempts at catheterisation, which delay treatment. The risks and the consequences of complications vary substantially across different patient groups depending on the patient's anatomy (for example, morbid obesity, cachexia, short neck, or local scarring from surgery or radiation treatment), the circumstances in which CVC insertion is carried out (for example, for a patient receiving mechanical ventilation or during emergencies such as cardiac arrest) and co-morbidities (for example, bullous emphysema or coagulopathy). The National Confidential Enquiry into Perioperative Deaths recently reported that in a survey of over 3000 CVC procedures undertaken in the NHS, one fatality occurred as a result of a procedure-induced pneumothorax.", 'The technology': 'Ultrasound technology has long been used in interventional radiology to guide percutaneous procedures at sites such as the kidneys, liver, arterial and venous circulation, pleural cavity, gallbladder and joints. Real-time ultrasound guidance of CVC insertion provides the operator with visualisation of the desired vein and the surrounding anatomical structures before and during the insertion. The advantages of ultrasound-guided central venous catheterisation include the identification of the precise position of the target vein and the detection of anatomical variants and of thrombosis within the vessel, together with the avoidance of inadvertent arterial puncture. Ultrasound guidance therefore has the potential to reduce the incidence of complications related to initial venous puncture, which is the first stage of CVC insertion.\n\nTwo types of real-time ultrasound guidance are described: two-dimensional (2-D) imaging ultrasound guidance and audio-guided Doppler ultrasound guidance. Two-dimensional imaging ultrasound, which is the more commonly used method, provides a real-time grey-scale imaging of the anatomy. Audio-guided Doppler ultrasound generates an audible sound from flowing venous blood, which helps the operator localise the vein and differentiate it from its companion artery. The portable ultrasound machines can be used in operating theatres, accident and emergency departments, ITUs, HDUs and radiology suites, as well as at the bedside on the hospital ward.\n\nOperators need to be trained to use ultrasound-guided techniques. Training involves not only acquiring the necessary manual skills, but also having a basic understanding of ultrasound principles and being able to interpret ultrasound images.', 'Evidence and interpretation': "The Appraisal Committee reviewed the evidence from a number of sources (Appendix B).\n\n# Clinical effectiveness\n\nTwenty randomised clinical trials (RCTs) were identified. Of these, six evaluated audio-guided Doppler ultrasound against the landmark method, thirteen evaluated 2-D ultrasound guidance against the landmark method and one evaluated both audio-guided Doppler ultrasound and 2-D ultrasound guidance against the landmark method. There were no trials that compared the use of ultrasound locating devices (ULDs) against the surgical cut-down method.\n\nInsertion sites were the IJV (fifteen trials), SV (four trials) or FV (one trial). One trial did not specify the insertion point, and one investigated both the IJV and the SV as insertion sites. None addressed the placement of PICCs or ports, both of which can be considered types of CVCs.\n\nFor most of the trials, the setting within the hospital where the cannulation took place was not reported clearly. In six of the trials the central venous catheterisation took place in an ITU or trauma unit, and in two trials catheterisations took place in emergency rooms. In the seven studies involving patients scheduled for cardiac surgery, the cannulation is most likely to have taken place on the way into theatre. In only three of the trials does it seem likely that CVCs were inserted on wards or in clinics.\n\nThe CVC procedure was carried out by anaesthetists in seven studies and by other medical staff in four studies. One study involved 2-D ultrasound-guided catheterisation by junior radiologists. None of the studies involved nurses. The remaining nine studies did not make the specialty or profession of the operator clear. The range of experience of the operator, both with respect to medical career and use of the intervention, differed greatly from study to study. Six studies described the operators as having up to 5 years' postgraduate experience, eight described them as having more than 5 years' experience, and two described them as varying in experience. Four trials did not record the career experience of the operator.\n\n## -D ultrasound imaging\n\nPooled results from seven RCTs suggested that real-time 2-D ultrasound guidance was significantly better than the landmark method for all five outcome variables measured for insertions into the IJV in adults. Compared with the landmark method, 2-D ultrasound guidance was associated with reduced risks of failed catheter placements (86% reduction in relative risk, 95% confidence interval [CI] 67% to 94%, p < 0.001), catheter placement complications (57% reduction in relative risk, 95% CI 13% to 78%, p = 0.02), and failure on the first catheter placement attempt (41% reduction in relative risk, 95% CI 12% to 61%, p = 0.009), and fewer attempts to achieve successful catheterisation (on average, 1.5 fewer attempts, 95% CI 0.47 to 2.53, p = 0.004)\n\nThe difference between the 2-D ultrasound method and the landmark method in the time taken to insert a catheter successfully was small and not statistically significant (2-D ultrasound-guided catheterisation was 20 seconds faster, 95% CI –83 to 124 seconds). However, there was significant heterogeneity for this endpoint (p < 0.01), which indicated that it might not be appropriate to pool these results. In the study which reported the longest time to achieve a successful catheterisation, the time taken to set up the ULD was also included in the outcome measurement. When the analysis was repeated, excluding this study, heterogeneity was no longer significant and the pooled result from the included trials showed that catheterisation was, on average, 69 seconds faster (95% CI 46 to 92 seconds) with the ULD than with the landmark method, which was a highly statistically significant difference (p < 0.001). It is acknowledged that the importance of this endpoint will vary between clinical situations.\n\nThree trials evaluated the effect of 2-D ultrasound guidance on the cannulation of the IJV in infants. In these trials, 2-D ultrasound guidance was significantly etter than the landmark method in terms of reductions in the risk of failed catheter placements (85% reduction in relative risk, 95% CI 36% to 97%, p = 0.01), the risk of catheter placement complications (73% reduction in relative risk, 95% CI 8% to 92%, p = 0.03), and the number of attempts required before catheterisation was successful (reduced by an average of 2, 95% CI 1.2 to 2.8, p = 0.001). Using 2-D ultrasound guidance, successful cannulation was achieved, on average, 349 seconds (95% CI –103 to 802 seconds) more quickly than with the landmark method, although this result was not statistically significant.\n\nOnly one RCT was identified that analysed the effect of 2-D ultrasound guidance on SV catheterisation in adults. In the trial, in comparison with the landmark method, 2-D ultrasound guidance was associated with reduced risks of catheter placement failure (86% reduction in relative risk, 95% CI 43% to 96%, p = 0.006) and catheter placement complications (90% reduction in relative risk, 95% CI 29% to 99%, p = 0.02). However, in this trial, the operators were relatively inexperienced in both the landmark method and 2-D ultrasound guidance. The failure rate with the landmark method was 55%, which is higher than that reported in trials that involved more experienced operators (around 9–19%).\n\nNo studies were found that investigated the effect of 2-D ultrasound guidance on SV catheterisation in infants.\n\nOne study was identified that evaluated the effect of 2-D ultrasound guidance on femoral catheterisation in adults. In this trial, the operators took, on average, 2.7 (95% CI 0.1 to 5.3) fewer attempts to insert a catheter using 2-D ultrasound guidance than using the landmark method (p = 0.04). Compared with the landmark method, 2-D ultrasound guidance reduced the risk of failed catheter placement and the time to successful catheterisation, but the differences were not statistically significant. No studies in infants were found.\n\nNo studies were found that investigated the effect of 2-D ultrasound guidance on FV catheterisation in infants.\n\n## Audio-guided Doppler ultrasound\n\nFour RCTs were found that compared audio-guided Doppler ultrasound guidance with the landmark method for IJV catheterisation in adults. Pooled results from these RCTs suggest that audio-guided Doppler ultrasound guidance was significantly better than the landmark method in terms of risk of failed catheter placement (61% reduction in relative risk, 95% CI 8% to 83%, p = 0.03) and the risk of failure on the first catheter placement attempt (43% reduction in relative risk, 95% CI 12% to 63%, p = 0.01). With the audio-guided Doppler ultrasound method, the risk of catheter placement complications was reduced (57% reduction in relative risk, 95% CI –5% to 83%) and there were fewer attempts to achieve successful catheterisation (0.6 fewer attempts, 95% CI –0.6 to 1.8); however, the differences did not reach statistical significance (p = 0.06 and p = 0.40, respectively) so they could have arisen by chance. It took, on average, 35 seconds longer (95% CI –54 to 124 seconds) to successfully insert a catheter using Doppler ultrasound guidance than it did with the landmark method, although this difference was also not statistically significant.\n\nOnly one trial was identified that studied the effect of audio-guided Doppler ultrasound in infants. The sample size of this study was small (n = 29) and so it lacked statistical power. It failed to show any differences with the landmark method.\n\nThe pooled results from three RCTs (all involving adults) suggest that for SV catheterisation there was a significantly increased risk of failed catheter placement when the audio-guided Doppler ultrasound method was used compared with the landmark method (48% increased in relative risk, 95% CI 3% to 114%, p = 0.03) – in other words the landmark method was preferable to the audio-guided Doppler ultrasound guidance technique. In contrast, the pooled results from two of the trials, which reported the risk of catheter placement, showed a 43% fall (95% CI 89% to 188%) in relative risk in the audio-guided Doppler ultrasound group, although this result was not statistically significant.\n\nOnly one study reported the effect of audio-guided Doppler ultrasound guidance on the risk of failure of the first catheter placement in adults. There was a slight increase (4%, 95% CI –24% to 43%) in the risk of catheter placement complications associated with the use of audio-guided Doppler ultrasound guidance compared with the landmark method, although this result was not statistically significant. Only one study recorded the effect of audio-guided Doppler ultrasound guidance on the number of attempts required to achieve successful catheterisation. This study found that an average of 0.4 (95% CI 0.2 to 0.6) fewer attempts were needed to achieve successful catheterisation with the audio-guided Doppler ultrasound guidance method compared with the landmark method, a highly statistically significant difference (p < 0.001). The same study was the only one to record the effect of Doppler ultrasound guidance on the time to achieve successful catheterisation. Catheterisation using the Doppler ultrasound guidance method was significantly (on average, 209 seconds, 95% CI 175 to 242) slower than catheterisation using the landmark method (p < 0.001).\n\n# Cost effectiveness\n\nNo relevant economic evaluations were identified in the literature. Furthermore, none of the submissions made to the Institute included economic evaluations.\n\nThe Assessment Group developed an economic analysis, based on the evidence from the systematic review of RCTs, to evaluate the cost effectiveness of 2-D ultrasound guidance compared with the landmark method. This model is a simple decision analytic model, and is based on a theoretical cohort of 1000 adult patients who required IJV cannulation before surgery and who had a low to moderate risk of complications.\n\nThis model adopted a set of conservative assumptions. It was assumed that: the operators were experienced in using the landmark method; the time to achieve successful puncture was the same for both methods; complications were limited to arterial puncture; there was a 10-minute delay between the prior failure and the new attempt at another insertion site; there was a 100% success rate at the second insertion site; and each machine was used for 15 procedures per week.\n\nThe results of the Assessment Group's model suggested that the ultrasound guidance not only avoided 90 arterial punctures for every 1000 patients treated, but also reduced costs by an average of almost £2 per patient. In other words the 2-D ultrasound guidance method was found to be both more effective and less costly than the landmark method.\n\nA threshold sensitivity analysis was undertaken to examine by how much key variables in the model needed to change to make the ultrasound guidance method cost-neutral instead of cost-saving. The modelled result was most sensitive to the utilisation of the ultrasound equipment. The cost-saving result was eradicated if the number of ultrasound procedures assumed per machine per week was less than around 11, or if the number of ultrasound procedures carried out by an individual trained practitioner was less than around 3 per month on average.\n\nGiven that the model used relatively conservative estimates, the Assessment Group concluded that the results were probably generalisable to all anatomical catheter insertion sites, to infants, and to other sites within the hospital including the clinical wards.\n\n# Consideration of the evidence\n\nThe Committee reviewed the evidence on both the clinical effectiveness and the cost effectiveness of ULDs for placing CVCs, having also considered the evidence from clinical experts. Furthermore, the Committee was mindful of the need to ensure that its advice took account of the efficient use of NHS resources.\n\nThe Committee took note of the fact that the evidence on the effectiveness of CVC placement into IJVs in adult patients was more robust than that available for other insertion sites. For infants, evidence was available only from trials that evaluated central venous catheterisation of the IJV, and there was very limited evidence on the use of this technology in very small infants (i.e. those weighing less than 3 kg). In addition, the economic analysis presented to the Committee was based on an evaluation of the cost effectiveness of 2-D ultrasound-guided elective CVC placement into the IJV in the operating theatre prior to surgery. The Assessment Report provided justifications for extrapolating this analysis to other settings including ward-based management, other sites of CVC insertion and also to CVC placement in infants.\n\nGiven the constraints outlined in 4.2.2, the Committee concluded that there was evidence of both the clinical and cost effectiveness of 2-D imaging ultrasound guidance as an adjunct for placing CVCs in the majority of clinical scenarios, but that the degree to which this technology would be most suitably applied would vary according to the clinical situation and the competence/previous experience of the operator. In addition, there could be potential benefits for patients arising from reduced discomfort from the procedure and reduced risk of complications compared with the landmark method, particularly for IJV insertions.\n\nThe Committee found the evidence for the use of audio-guided Doppler ultrasound guidance less satisfactory, and therefore concluded that the 2-D imaging ultrasound guidance should be used in preference to audio-guided Doppler ultrasound guidance.\n\nWhile accepting that, from a patient's perspective, 2-D ultrasound imaging guidance in CVC insertion might be more appropriate and probably superior to the traditionally used landmark method in many circumstances, the Committee also considered the financial and service implications of purchasing the required equipment and of training sufficient numbers of competent practitioners.\n\nThe Committee also considered that although 2-D ultrasound imaging guidance in CVC placement may eventually become the routine method for placing CVCs, the landmark method would remain important in some circumstances, such as emergency situations, when ultrasound equipment and/or expertise might not be immediately available. Consequently, the Committee thought it important that operators maintain their ability to use the landmark method and that the method continues to be taught alongside the 2-D-ultrasound-guided technique.", 'Recommendations for further research': 'Good quality studies are needed:\n\nto investigate the possible economic and clinical implications to the NHS of nurse specialists or other healthcare practitioners carrying out routine insertion of CVCs\n\nto evaluate the use of ultrasound-guided central venous catheterisation in small infants (i.e. those weighing less than 3 kg).', 'Resource impact for the NHS': 'The purchase cost of a portable 2-D ultrasound machine currently lies between £7000 and £15,000. The additional disposables necessary for the ultrasound-guided procedure cost less than £1 per procedure. Estimates made by the Assessment Group analysis indicate that the additional cost of using ultrasound equipment for the CVC placement procedure is likely to be less than £10 per procedure.\n\nIt is likely that the NHS will need to invest in a significant number of additional 2-D ultrasound machines, although it is impossible to predict how many will be required, as local circumstances will vary considerably. Implementing the guidance will require local decisions regarding optimal number of machines, staff training and device service contracts.\n\nThe Assessment Group analysis suggests that in the long term the implementation of ultrasonic locating devices will be costsaving. The majority of these savings are likely to be due to releasing resources such as staff, and operating theatre and ITU/HDU time and beds.\n\nA constraint upon the implementation of this technology will be the need to ensure that there are adequately trained competent operators to support the services. Many CVC placement procedures are performed on an emergency basis at the bedside in a diverse number of locations and therefore the necessary skills need to be spread across several related disciplines', 'Related guidance': 'There is no related NICE guidance for this technology.', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review.\n\nInformation on the review of the guidance on this technology is available on the NICE website.\n\nAndrew DillonChief ExecutiveSeptember 2002', 'Appendix C. Patient information. Guidance on the use of ultrasound locating devices for placing central venous catheters': "'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.", 'Appendix D. Detail on criteria for audit of the use of ultrasound locating devices for placing central venous catheters': '# Possible objectives for an audit\n\nAn audit on the appropriate use of ultrasound locating devices could be carried out to ensure that:\n\nwhen a central venous catheter (CVC) is being inserted into the internal jugular vein (IJV) of an adult or a child in an elective situation, 2-dimensional (2-D) imaging ultrasound guidance is used\n\nhealthcare practitioners involved in the placement of CVCs using 2-D imaging ultrasound guidance have appropriate training\n\naudio-guided Doppler ultrasound guidance is not used for CVC insertion.\n\nIf healthcare practitioners have agreed locally on the clinical circumstances where 2-D imaging ultrasound guidance is to be used when a CVC insertion is necessary, the audit also could be carried out to ensure that the technique is used as agreed locally.\n\n# Possible patients to be included in the audit and time period for selection\n\nAll patients who have a CVC inserted either in the IJV in an elective situation (or for any purpose on either an elective or emergency basis, if 2-D imaging ultrasound is more widely used) over a reasonable period of time for audit data collection, for example, for 1 to 3 months. A sample of patients stratified by clinical areas most likely to be involved, for example, critical care areas, theatres, and accident and emergency, could be used for the audit or the audit could be staged to include one clinical area at a time, working through all clinical areas.\n\n# Measures to be used as a basis for an audit\n\nCriterion\n\nStandard\n\nException\n\nDefinition of Terms\n\n. 2-D imaging ultrasound guidance is used when a CVC is being inserted in the IJV in an elective situation\n\n% of patients with a CVC inserted in the IJV in an elective situation\n\nNone\n\nLocal clinical teams should agree on the types of elective situations to be included in the audit and should agree to any exceptions for the use of the technique such as an infant weighing less than 3 kg\n\n. The healthcare practitioner involved in the placement of the CVC is trained in the use of 2-D imaging ultrasound guidance\n\n% of patients having a CVC inserted\n\nNone\n\nFor audit purposes, it should be agreed at NHS Trust level how training to achieve competence in the technique is documented\n\n. Audio-guided Doppler ultrasound guidance is not used for CVC insertion\n\n% of patients having a CVC inserted\n\nNone\n\n\n\nAn additional measure that could be used when it has been agreed to use 2-D imaging ultrasound guidance for other clinical circumstances in which a patient has a CVC inserted is as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of Terms\n\n. 2-D imaging ultrasound guidance is used when a CVC is being inserted\n\n% of patients having a CVC inserted for any purpose\n\nNone\n\nLocal healthcare practitioners may specify circumstances in which 2-D ultrasound guidance is to be used when a CVC is being inserted or may specify exceptions, for audit purposes\n\n# Calculation of compliance with the measure\n\nCompliance with each measure described in the table is calculated as follows:\n\nNumber of patients whose care is consistent with the criterion plus the number of patients whose care is consistent with any locally agreed exception\n\n/\n\nNumber of patients to whom the measure applies\n\nX 100\n\nHealthcare practitioners should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that desired improvement is being achieved.', 'Changes after publication': 'March 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta49	Evidence-based recommendations on using ultrasound locating devices for placing central venous catheters.
fdcb66d2b998779e83c0022171b025b41deb82d8	nice	Inhaler devices for routine treatment of chronic asthma in older children (aged 5–15 years)	Inhaler devices for routine treatment of chronic asthma in older children (aged 5–15 years) # Guidance It is recommended that in addition to therapeutic need (including chosen drug and dose), the following factors be taken into account when choosing inhaler devices for individual children with chronic asthma: the ability of the child to develop and maintain an effective technique with the specific device the suitability of a device for the child's and carer's lifestyles, considering factors such as portability and convenience the child's preference for and willingness to use a particular device. The general recommendations in 1.1 should be taken into account when considering the following specific guidance: A press-and-breathe pressurised metered dose inhaler (pMDI) and suitable spacer device is recommended as the first-line choice for the delivery of inhaled corticosteroids as part of regular planned daily therapy, with the aim of maximising benefits of preventive therapy in attaining good asthma control, and minimising potential systemic absorption. Where clinicians believe that an individual child's adherence to the press-and-breathe pMDI and spacer combination is likely to be so poor as to undermine effective asthma control, other alternative devices (taking account of the factors outlined in 1.1 and evidence of equivalence of clinical effectiveness) should be considered, bearing in mind the need to minimise the risks of systemic absorption of corticosteroids. In the case of other inhaled drugs, primarily bronchodilators, it is recommended that a wider range of devices be considered to take account of their more frequent spontaneous use, the greater need for portability, and the clear feedback that symptom response provides to the device user. In such circumstances the factors outlined in 1.1 are likely to be of greater importance in choosing a device. Where more than one device satisfies the considerations outlined above in a particular child, it is recommended that the device with the lowest overall cost (taking into account daily required dose and product price per dose) should be chosen. On selection of an inhaler device, it is important that consideration is given to other aspects of asthma care that influence the effective delivery of inhaled therapy, including: individual practical training in the use of the specific device monitoring of effective inhaler technique and adherence to therapy regular (i.e. no less than annual) review of inhaler needs, which may change over time with increasing age.# Clinical Need and Practice Asthma is a chronic inflammatory disease affecting the lower airways, which manifests as reversible airway obstruction and mucosal inflammation, resulting in airway narrowing (bronchoconstriction). Children with asthma experience recurrent symptoms of cough, wheeze and breathlessness, and acute exacerbations/attacks. Symptoms can be caused by a variety of triggers principally infection, allergy, airborne chemicals, passive smoking, and exercise. Acute episodes may be experienced by children with any level of chronic asthma. While symptoms vary in individual cases, acute episodes may have the following characteristics: mild episodes – cough, audible wheeze, normal speech between breaths, and peak expiratory flow rate and forced expiratory volume above 75% of predicted values; severe episodes – severe distress, cyanosis (bluish lips), reduced ability to speak (often limited to only a few words between breaths), and being chair or bed bound. Childhood asthma is common – studies suggest that the prevalence of diagnosed childhood asthma is between 10% and 23% in England. However, not all cases are diagnosed or treated, and it is estimated that in England and Wales 12% of boys and 10% of girls aged 5–15 years are treated for asthma. These treatment rates are higher than in any other age group and in the overall population (for which the treatment rate is 7%). A steady rise in the diagnosis of childhood asthma is reported in England and Wales, with increases from 7% to 13% in girls and from 10% to 17% in boys aged 5–14 years between 1990 and 1998. Childhood asthma is a rare cause of death. However, the burden of the disease is considerable, in terms of physical and psychological morbidity (i.e. anxiety and stigma), reduced quality of life for children and their carers, and impact on schooling and social activities. Childhood asthma also presents an economic burden on health care resources. The goals of asthma treatment are primarily the prevention of chronic symptoms, maintenance of near normal lung function and normal activity levels, and prevention of recurrent acute episodes (which may lead to hospitalisation), in order to maximise quality of life and satisfaction with the care being provided. It is likely that currently many asthma sufferers are achieving sub-optimal control of symptoms because of inadequate or inappropriate use of preventive therapy. A number of approaches to managing asthma are available, including non-pharmacological strategies (e.g. allergen and air pollutant avoidance), oral pharmacological therapy (e.g. corticosteroids, leukotriene receptor antagonists), and inhaled pharmacological therapy. Inhaled therapy aims to reverse and prevent airway inflammation and constriction, in order to control acute symptoms and maximise respiratory flow. Where available as a therapeutic option, inhaled, rather than oral, administration is generally preferred, in order to reduce the total dose of drug required to produce a treatment effect, reduce the potential for systemic effects, and allow the drug to act in the lung as quickly as possible. Two therapeutic approaches are used, often in combination. Bronchodilators (ß2-agonists, antimuscarinic bronchodilators) relieve symptoms of bronchoconstriction. Short-acting ß2-agonists deliver rapid relief, with a peak effect within 20 minutes. Long-acting ß2-agonists, which act for at least 12 hours, are used in conjunction with inhaled corticosteroids to treat children with more severe chronic asthma. Most children with chronic asthma are treated with inhaled bronchodilators. Anti-inflammatory agents (corticosteroids, cromoglicate and related compounds) act to prevent asthma symptoms. Three corticosteroid compounds are available: budesonide, beclometasone dipropionate, and fluticasone propionate. Sodium cromoglicate and nedocromil sodium are non-steroidal alternatives. Children with moderate or severe chronic asthma usually require inhaled anti-inflammatory treatment as well as bronchodilators. A guideline on the management of asthma in adults and children were issued by the British Thoracic Society (BTS) in 1997. These guidelines are the most commonly used in the UK, but are not explicitly evidence-based. They outline a five-step approach to managing asthma in adults and schoolchildren, usually starting with inhaled short-acting ß2-agonists, and introducing anti-inflammatory therapy, long-acting ß2-agonists and antimuscarinic bronchodilators if symptom control is not achieved. General guiding principles are set out regarding the appropriate selection of devices, though specific device recommendations are not made. The guideline is currently being updated in conjunction with the Scottish Intercollegiate Guidelines Network (SIGN). The vast majority of chronic asthma care takes place in a primary care setting, often involving practice nurses. The aim is to maximise self-management of the disease. If symptom control is not achieved, drugs, doses, device suitability, inhaler technique and adherence should be reviewed. Doses of inhaled steroids and other drugs should be regularly monitored and slowly stepped down to the minimum dose required to maintain good control of symptoms.# The technologies Three main types of inhaler device are available: 'press-and-breathe' pressurised metered dose inhalers (pMDIs), breath-actuated pressurised metered dose aerosol inhalers, and dry powder inhalers (DPIs). In addition, press-and-breathe pMDIs can be used in conjunction with spacer systems, and pMDIs use either chlorofluorocarbon (CFC) or CFC-free, hydrofluoroalkane (HFA) propellants. Over 70 individual inhaler products (including different drugs and doses), together with at least five further spacer device attachments, are licensed in the UK for use by children aged 5–15 years. Innovation is continuing and new devices are emerging into the market. The majority of research on asthma therapy concentrates on the effect of drugs rather than that of the delivery device. Consequently there is a shortage of independent and evidence-based information for clinicians and patients choosing devices. # Press-and-breathe pMDIs Around 60% of childhood asthma inhaler medication is delivered by press-and-breathe pMDIs. These comprise a small plastic construction carrying a metal aerosol canister, often containing 200 doses. Both branded and generic press-and-breathe pMDIs are available. The inhaler is prepared by shaking. Users should remove the mouthpiece cap, breathe out, then take a slow deep breath through the mouth, actuating the device (i.e. pressing the canister) as inhalation begins, and then hold their breath. Individuals may experience a number of problems with press-and-breathe pMDIs that can affect adherence to therapy and adequacy of delivery of drug to the lungs, and therefore effectiveness. It is estimated that at least 50% of press-and-breathe pMDI users have less than optimal technique. Problems include difficulty in co-ordinating device actuation and inhalation, oropharyngeal deposition of the drug, and, in the case of CFC devices, the 'cold freon effect', when the temperature of the propellant causes some individuals briefly to stop inhaling. # Spacer systems The use of various spacer systems, which attach directly to the inhaler device, is one approach to alleviating some of the problems associated with pMDI use. Two general types of spacer are available: Detachable chambers (small, medium or large volume): this type of spacer is attached to a press-and-breathe pMDI when required, and acts as a holding chamber for the aerosol and drug, allowing a number of breaths to be taken. Most spacers of this type incorporate a valve system, and inhalation techniques need to be taught. Five such spacers are currently available on NHS prescription. Small-volume extended mouthpiece spacers: these provide increased distance between the point of aerosol release and the oropharyngeal area. They are available for use with some press-and-breathe and breath-actuated pMDIs. Many spacers are designed in conjunction with specific press-and-breathe pMDIs. However, some are designed to allow attachment to a wider range of press-and-breathe pMDIs, and in these cases there may be some uncertainty about their performance with different inhalers compared with those spacers designed for use with an individual inhaler. Detachable plastic spacers are prone to developing an electrostatic charge, which causes adhesion of the drug to their surface, so reducing delivery. Careful washing and air-drying (i.e. leaving to dry) of spacers at appropriate intervals reduces this problem. A metal spacer, which aims to avoid problems with electrostatic charge, has also been developed. Other shortcomings associated with spacers are portability and inconvenience, and feelings of stigma, which children may experience with their use. # Breath-actuated pMDIs Breath-actuated pMDIs also deliver a pressurised aerosol metered dose of drug, but are automatically actuated when the user inhales through the mouthpiece. Automatic actuation removes the difficulty of actuation-inhalation co-ordination that is associated with press-and-breathe pMDIs. However, the sound of some devices and the different sensation of automatic actuation may hamper use in some children. Oropharyngeal deposition can be a problem in breath-actuated pMDIs. Two breath-actuated pMDIs are currently available. # Dry powder inhalers (DPIs) DPIs deliver the micronised drug, and generally a carrier powder, using the individual's own inspiratory flow. This is another approach to overcoming the problem of actuation–inhalation co-ordination associated with pMDIs. Many newer DPIs also incorporate approaches to counting doses used or the amount of drug remaining, which can be used to aid monitoring of adherence to treatment. Some children (generally younger ones) may not reliably generate inspiratory flows that are high enough for effective delivery. These problems may present difficulty during acute exacerbations, and a press-and-breathe pMDI and spacer may be required for back-up. There is greater variation in the design of DPIs than in other device types. A child may find one DPI device easier to use than another, or express a preference because of the appearance of a particular device. Seven DPIs are currently available for children. # Choosing suitable devices The benefit gained from inhaled therapy is a unique combination of the drug, device and the individual (i.e. physical, cognitive, psychological and lifestyle characteristics). Consequently the following factors require consideration when choosing a device. Inhaler technique – Poor technique, resulting either from poor training or from choosing a device poorly suited to the child, can significantly reduce the amount of drug delivered to the lungs and result in poor asthma control. Some children, especially the younger ones in the age range being considered, may have difficulty with actuation–inhalation co-ordination with a press-and-breathe pMDI, while others may have inconsistent inspiratory flow, which causes problems in using a DPI, or find the automatic actuation of some breath-actuated devices off-putting. Adherence to treatment – Even where good technique is possible, children may not use their devices appropriately. Device use may be influenced by a range of factors, including convenience, ease of device use, portability, the stigma of having asthma, and personal or peer preference for a specific device. The relative importance of these factors changes as children get older and so the choice of device should be reviewed frequently. Availability of drugs – Some drugs are only available in particular devices.# Evidence The systematic review included evidence on clinical effectiveness, ease of use, preference, compliance, and cost effectiveness. # Clinical effectiveness Because of the specificity of device and drug effect, evidence for one drug in one device cannot be generalised to other drugs. Therefore, only research comparing the same drug (e.g. salbutamol vs salbutamol) at an equivalent dose level in different devices was considered. Studies including children aged 5–15 years were included in the review. Since the appraisal concerns device choice, rather than whether to treat using inhaler devices, placebo comparisons were not included. All studies included in the consideration of clinical effectiveness were randomised controlled trials (RCTs). Evidence in this area is generally limited in quantity and quality. Only one relevant study comparing a breath-actuated device with other devices was found, and few studies considered devices delivering cromoglicates, long-acting ß2-agonists, or drugs in combination. Many of the available studies included fewer than 50 children, and were under-powered. The review found that studies claiming to demonstrate equivalence were often unable to do so, and that some studies used inappropriate dose comparators. Three in vitro studies of drug delivery were identified, but these do not provide a sufficiently reliable basis for generalisation to device performance in children with asthma in clinical practice. # Delivery of bronchodilators Twenty-three studies in the systematic review examined different devices in the delivery of bronchodilators. Seven studies compared press-and-breathe pMDIs with and without spacers. In the main these included children, and all had fewer than 50 participants. Two of the studies found a significant difference in lung function favouring the pMDI and spacer combination. These were randomised cross-over studies, involving a total of 30 children aged between 5 and 14 years, that compared the delivery of terbutaline from a pMDI with delivery from a pMDI plus 750 ml collapsible spacer.Thirteen studies compared press-and-breathe pMDIs (with or without spacer) with DPIs, and none demonstrated a statistically significant difference in lung function. Some of the studies used inappropriate dosing schedules, which may have biased their findings. Some studies included a high proportion of adults.Three studies comparing different DPIs were included. They found no significant difference in lung function or symptoms, and all were small or included few children. # Delivery of anti-inflammatory drugs Eight studies examined different devices for the delivery of corticosteroids. One used a filter method to compare a press-and-breathe pMDI in combination with one of two alternative spacers. It found significantly higher deposition of drug on the filters attached to a 250 ml metal spacer compared with a 750 ml plastic spacer. However, the study included only 16 children (aged 5 to 8 years), and found no difference in symptom scores between the two treatment groups. Five studies compared press-and-breathe pMDIs (with or without spacers) with DPIs. One large well-designed study reported equivalence of a pMDI with spacer and a DPI at half of the drug dose used in the pMDI. However, the authors of a systematic review concluded that this finding did not represent evidence of advantage of the DPI over the press-and-breathe pMDI and large-volume spacer as the device of choice for the delivery of corticosteroids in childhood asthma. In addition, a filter collection study comparing a press-and-breathe pMDI plus spacer with a DPI in children aged 5–15 years reported significantly higher deposition in the DPI group, though no differences in lung function were reported. The remaining studies were of poor quality or were likely to have included few children.Two adequately powered studies compared different DPIs, though neither reported a difference in effectiveness between devices.One study compared a press-and-breathe pMDI with a breath-actuated pMDI for cromoglicate. No differences were found in lung function, but the study was under-powered. # CFC-free devices The studies included in the review reported no evidence of difference in the effectiveness of devices using CFC-containing or CFC-free propellants in pMDIs. However, it is important to note that there are some reports of higher drug deposition of corticosteroids from HFA devices. Consequently it is possible that required doses may be different when transferring children from CFC to HFA inhalers. # Other influences on effectiveness Thirty-one studies on ease of use, preference or compliance were included in the systematic review. However their quality was generally poor, and many devices have not been studied. Many of the studies did not involve direct device comparison, had fewer than 100 participants, included adults, or did not examine the actual impact of these factors on disease outcomes. Only 11 of the studies were RCTs. A number of studies found that good individual (verbal) instruction was the key to correct inhaler technique, and two suggested that above age 5 or 6 years, this was the case regardless of the device. Studies on ease of use, adherence and preference are, however, of questionable value as the empirical value of these factors remains uncertain. Conclusions drawn from this body of research are likely to involve 'double counting', in that the effects of ease of use and preference may also contribute to compliance. # Cost effectiveness No robust cost-effectiveness or utility studies examining use of inhalers in children aged 5–15 years with asthma were identified by the systematic review. There are substantial differences in the acquisition costs of inhaler devices within the same drug dose range. For instance, in the delivery of one puff of salbutamol (ß2-agonist) a day, the lowest annual inhaler costs per device type are: press-and-breathe pMDI, £3.14; breath-actuated pMDI, £10.99; and DPI, £11.53. The highest cost for a DPI delivering salbutamol at this dose is £30.42. Similarly, in the delivery of a 200ug dose of beclometasone (corticosteroid) a day, the lowest annual inhaler costs per device type are: press-and-breathe pMDI, £28.73; breath-actuated pMDI £28.73; and DPI £38.51. The highest cost for a DPI delivering beclometasone at this dose is £69.06. The annual costs of suitable spacer devices available on NHS prescription range from £4.28 to £8.56. One study reported that the overall annual average cost of care for people with asthma who have not experienced an asthma attack in the past year was £108, compared with £381 for people who have had at least one attack over the same period. Higher costs in primary care contacts, hospital admissions and visits, and medication all contributed to the overall difference. An economic analysis considering differences in overall costs between devices found that only small improvements in asthma outcomes were needed for a device to be considered cost-effective compared with the cheapest available alternative for the delivery of the same drug at the same dose. Consequently if, after taking account of the factors specified in section 1.1, a clinician considers that a particular device would be more likely to achieve good asthma control in a particular child than cheaper ones available, then that device should be chosen. # Consideration The available evidence generally fails to distinguish adequately between devices to suggest significant advantage in clinical effectiveness for one single delivery system.However, a limited amount of evidence supports the use of press-and-breathe pMDIs with large-volume spacers compared to press-and-breathe pMDIs alone in the delivery of bronchodilators, whilst one study reported equivalence of a press-and-breathe pMDI and large-volume spacer with a DPI at half the dose used in the pMDI in the delivery of a corticosteroid.On balancing these findings, clinical opinion and pharmacological considerations, the Appraisal Committee concluded that press-and-breathe pMDIs and spacer devices have an important role to play in the delivery of corticosteroids in aiming to achieve optimal asthma control. Despite this, it was acknowledged that the effectiveness of any device depends on the willingness and ability of a child to use it and to adhere to an effective regimen. The aim should be to identify the most clinically appropriate device that the individual child will use, bearing in mind the need to minimise the systemic absorption of inhaled corticosteroids. Economic analysis suggests that no device should be excluded on grounds of cost effectiveness; however, when more than one device is felt to satisfy the considerations set out in 4.14 in an individual child, the device with the lowest overall cost (i.e. considering daily required dose and product price per dose) should be chosen. As there is limited evidence on the effectiveness of alternative spacers for a given inhaler, if a choice is available, the decision should be guided by information in the inhaler's Summary of Product Characteristics.# Implications for the NHS Overall budget impact is very sensitive to device prescribing patterns, since acquisition costs of inhalers delivering the same class of drug at the same dose vary substantially (as outlined in 4.11). However, with the exception of spacer devices, it is difficult to predict the impact of the guidance set out in section 1 on local inhaler prescribing patterns and costs. Consequently, an estimate of current inhaler prescribing patterns in primary care is set out below for England and Wales. These prescribing rates and costs can be used together with local information on inhaler use to calculate the likely local cost impact of the guidance. Estimates of the cost impact of the guidance as regards spacer devices are detailed in 5.5. Analysis of inhaler device prescribing in a large sample of older children treated in primary care shows that press-and-breathe pMDIs account for 60% of prescribed items, breath-actuated pMDIs account for 17%, and DPIs account for 23%. Applying the estimates in 5.2 to England and Wales as a whole suggests that the approximate current annual acquisition costs for devices prescribed to children aged 5–15 years in primary care are as follows: £11.2 million (£1499 per 1000 total population aged 5–15 years) for press-and-breathe pMDIs, £4.2 million (£562 per 1000) for breath-actuated pMDIs, and £21.7 million (£2898 per 1000) for DPIs. In addition, the analysis shows that in primary care, only 20% of children aged 5–15 prescribed a press-and-breathe pMDI delivering corticosteroids are currently prescribed a spacer attachment. The estimated total annual acquisition cost for spacer attachments is currently £233,000 (£31 per 1000) in England and Wales as a whole. If all children prescribed a press-and-breathe pMDI delivering corticosteroids in primary care were to be prescribed one spacer attachment per year, it is estimated that the total annual acquisition cost in England and Wales would increase to £1.2 million (£156 per 1000). Manufacturers generally recommend two spacers per year. In addition to any anticipated changes in device acquisition costs, it is also important that planning recognises the wider resource implications of implementing the guidance, including those set out in 1.4 and 7.3.# Further Research Given the scarcity of robust research comparing inhaler devices (including spacers) in older children, decision-making is likely to be substantially improved by adequately powered RCT equivalence studies. Ideally, these would include: treatment of a full spectrum of chronic asthma severity in generalisable clinical settings qualitative assessment of children's experience of devices and factors influencing adherence examination of clinically relevant outcome measures (e.g. symptoms, activities, time away from school) rather than short-term measures of lung function examination of differences in resource use epidemiological investigation of the determinants (e.g. social factors) of adherence, effectiveness and cost effectiveness of treatment. The Institute acknowledges that such studies would require large numbers of participants and present a significant challenge to manufacturers and other researchers. A parallel or alternative approach would be to undertake epidemiological and qualitative research on the factors influencing adherence and competence. Given that none of the currently available inhaler devices are completely satisfactory for children, manufacturers should consider research into novel inhalers that can be used effectively with greater ease by children.# Related guidance The Institute issued guidance on the use of inhalers in younger children (aged under 5 years) with chronic asthma in August 2000 Guidance on the use of inhaler systems (devices) in children under the age of 5 years with chronic asthma: NICE Technology Appraisal Guidance No.10. London: NICE, 2000..# Review of guidance Information on the review of the guidance on this technology is available on the NICE website. Andrew DillonChief ExecutiveMarch 2002# Appendix B. Sources of evidence . The following documentation and opinion was made available to the Appraisals Committee. a. Assessment Report: Prepared by School of Health Related Research (ScHARR), University of Sheffield, (Clinical and Cost Effectiveness of Inhaler Devices used in the Routine Management of Chronic Asthma in Older Children, August 2001). b. Manufacturer/sponsor submissions: M Health Care Ltd AstraZeneca UK Ltd Aventis Pharma Ltd Boehringer Ingelheim Celltech Pharmaceuticals Ltd GlaxoSmithKline Norton Healthcare Trinity Pharmaceuticals Yamanouchi Pharma Ltd c. Professional/specialist group, patient/carer group and trade association submissions: British Lung Foundation Royal College of Paediatrics and Child Health The General Practice Airways Group (GPIAG) British Thoracic Society National Asthma Campaign d. External expert and patient advocate attendance: Dr Mark Levy, Representative from GPIAG and Senior Lecturer (Clinical) Part Time, Dept of General Practice & Primary Care, Aberdeen University Trisha Weller, Head of Quality Assurance, National Asthma & Respiratory Training Centre Dr Mark Everard, Consultant in Paediatric Respiratory Medicine, Sheffield Children's Hospital Marsha Williams, Campaigns Manager, National Asthma Campaign Jack Barnes, Director of Research & Policy, National Asthma Campaign Dr Andrew Bush, on behalf of the British Lung Foundation, Reader in Paediatric Respirology, Royal Brompton Hospital# Appendix C. Guidance on the use of inhalers for the treatment of chronic asthma in older children (aged 5–15 years) – patient/carer information 'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.# Appendix D. Technical detail on the criteria for audit of the use of inhaler devices for treatment of asthma in older children Detail on criteria for audit of the use of inhaler devices for treatment of asthma in older children can be found in the PDF version of this guidance.# Changes after publication March 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "It is recommended that in addition to therapeutic need (including chosen drug and dose), the following factors be taken into account when choosing inhaler devices for individual children with chronic asthma:\n\nthe ability of the child to develop and maintain an effective technique with the specific device\n\nthe suitability of a device for the child's and carer's lifestyles, considering factors such as portability and convenience\n\nthe child's preference for and willingness to use a particular device.\n\nThe general recommendations in 1.1 should be taken into account when considering the following specific guidance:\n\nA press-and-breathe pressurised metered dose inhaler (pMDI) and suitable spacer device is recommended as the first-line choice for the delivery of inhaled corticosteroids as part of regular planned daily therapy, with the aim of maximising benefits of preventive therapy in attaining good asthma control, and minimising potential systemic absorption. Where clinicians believe that an individual child's adherence to the press-and-breathe pMDI and spacer combination is likely to be so poor as to undermine effective asthma control, other alternative devices (taking account of the factors outlined in 1.1 and evidence of equivalence of clinical effectiveness) should be considered, bearing in mind the need to minimise the risks of systemic absorption of corticosteroids.\n\nIn the case of other inhaled drugs, primarily bronchodilators, it is recommended that a wider range of devices be considered to take account of their more frequent spontaneous use, the greater need for portability, and the clear feedback that symptom response provides to the device user. In such circumstances the factors outlined in 1.1 are likely to be of greater importance in choosing a device.\n\nWhere more than one device satisfies the considerations outlined above in a particular child, it is recommended that the device with the lowest overall cost (taking into account daily required dose and product price per dose) should be chosen.\n\nOn selection of an inhaler device, it is important that consideration is given to other aspects of asthma care that influence the effective delivery of inhaled therapy, including:\n\nindividual practical training in the use of the specific device\n\nmonitoring of effective inhaler technique and adherence to therapy\n\nregular (i.e. no less than annual) review of inhaler needs, which may change over time with increasing age.", 'Clinical Need and Practice': 'Asthma is a chronic inflammatory disease affecting the lower airways, which manifests as reversible airway obstruction and mucosal inflammation, resulting in airway narrowing (bronchoconstriction). Children with asthma experience recurrent symptoms of cough, wheeze and breathlessness, and acute exacerbations/attacks. Symptoms can be caused by a variety of triggers principally infection, allergy, airborne chemicals, passive smoking, and exercise.\n\nAcute episodes may be experienced by children with any level of chronic asthma. While symptoms vary in individual cases, acute episodes may have the following characteristics: mild episodes – cough, audible wheeze, normal speech between breaths, and peak expiratory flow rate and forced expiratory volume above 75% of predicted values; severe episodes – severe distress, cyanosis (bluish lips), reduced ability to speak (often limited to only a few words between breaths), and being chair or bed bound.\n\nChildhood asthma is common – studies suggest that the prevalence of diagnosed childhood asthma is between 10% and 23% in England. However, not all cases are diagnosed or treated, and it is estimated that in England and Wales 12% of boys and 10% of girls aged 5–15 years are treated for asthma. These treatment rates are higher than in any other age group and in the overall population (for which the treatment rate is 7%).\n\nA steady rise in the diagnosis of childhood asthma is reported in England and Wales, with increases from 7% to 13% in girls and from 10% to 17% in boys aged 5–14 years between 1990 and 1998.\n\nChildhood asthma is a rare cause of death. However, the burden of the disease is considerable, in terms of physical and psychological morbidity (i.e. anxiety and stigma), reduced quality of life for children and their carers, and impact on schooling and social activities. Childhood asthma also presents an economic burden on health care resources.\n\nThe goals of asthma treatment are primarily the prevention of chronic symptoms, maintenance of near normal lung function and normal activity levels, and prevention of recurrent acute episodes (which may lead to hospitalisation), in order to maximise quality of life and satisfaction with the care being provided. It is likely that currently many asthma sufferers are achieving sub-optimal control of symptoms because of inadequate or inappropriate use of preventive therapy.\n\nA number of approaches to managing asthma are available, including non-pharmacological strategies (e.g. allergen and air pollutant avoidance), oral pharmacological therapy (e.g. corticosteroids, leukotriene receptor antagonists), and inhaled pharmacological therapy.\n\nInhaled therapy aims to reverse and prevent airway inflammation and constriction, in order to control acute symptoms and maximise respiratory flow. Where available as a therapeutic option, inhaled, rather than oral, administration is generally preferred, in order to reduce the total dose of drug required to produce a treatment effect, reduce the potential for systemic effects, and allow the drug to act in the lung as quickly as possible. Two therapeutic approaches are used, often in combination.\n\nBronchodilators (ß2-agonists, antimuscarinic bronchodilators) relieve symptoms of bronchoconstriction. Short-acting ß2-agonists deliver rapid relief, with a peak effect within 20 minutes. Long-acting ß2-agonists, which act for at least 12 hours, are used in conjunction with inhaled corticosteroids to treat children with more severe chronic asthma. Most children with chronic asthma are treated with inhaled bronchodilators.\n\nAnti-inflammatory agents (corticosteroids, cromoglicate and related compounds) act to prevent asthma symptoms. Three corticosteroid compounds are available: budesonide, beclometasone dipropionate, and fluticasone propionate. Sodium cromoglicate and nedocromil sodium are non-steroidal alternatives. Children with moderate or severe chronic asthma usually require inhaled anti-inflammatory treatment as well as bronchodilators.\n\nA guideline on the management of asthma in adults and children were issued by the British Thoracic Society (BTS) in 1997. These guidelines are the most commonly used in the UK, but are not explicitly evidence-based. They outline a five-step approach to managing asthma in adults and schoolchildren, usually starting with inhaled short-acting ß2-agonists, and introducing anti-inflammatory therapy, long-acting ß2-agonists and antimuscarinic bronchodilators if symptom control is not achieved. General guiding principles are set out regarding the appropriate selection of devices, though specific device recommendations are not made. The guideline is currently being updated in conjunction with the Scottish Intercollegiate Guidelines Network (SIGN).\n\nThe vast majority of chronic asthma care takes place in a primary care setting, often involving practice nurses. The aim is to maximise self-management of the disease. If symptom control is not achieved, drugs, doses, device suitability, inhaler technique and adherence should be reviewed. Doses of inhaled steroids and other drugs should be regularly monitored and slowly stepped down to the minimum dose required to maintain good control of symptoms.', 'The technologies': "Three main types of inhaler device are available: 'press-and-breathe' pressurised metered dose inhalers (pMDIs), breath-actuated pressurised metered dose aerosol inhalers, and dry powder inhalers (DPIs). In addition, press-and-breathe pMDIs can be used in conjunction with spacer systems, and pMDIs use either chlorofluorocarbon (CFC) or CFC-free, hydrofluoroalkane (HFA) propellants.\n\nOver 70 individual inhaler products (including different drugs and doses), together with at least five further spacer device attachments, are licensed in the UK for use by children aged 5–15 years. Innovation is continuing and new devices are emerging into the market. The majority of research on asthma therapy concentrates on the effect of drugs rather than that of the delivery device. Consequently there is a shortage of independent and evidence-based information for clinicians and patients choosing devices.\n\n# Press-and-breathe pMDIs\n\nAround 60% of childhood asthma inhaler medication is delivered by press-and-breathe pMDIs. These comprise a small plastic construction carrying a metal aerosol canister, often containing 200 doses. Both branded and generic press-and-breathe pMDIs are available. The inhaler is prepared by shaking. Users should remove the mouthpiece cap, breathe out, then take a slow deep breath through the mouth, actuating the device (i.e. pressing the canister) as inhalation begins, and then hold their breath.\n\nIndividuals may experience a number of problems with press-and-breathe pMDIs that can affect adherence to therapy and adequacy of delivery of drug to the lungs, and therefore effectiveness. It is estimated that at least 50% of press-and-breathe pMDI users have less than optimal technique. Problems include difficulty in co-ordinating device actuation and inhalation, oropharyngeal deposition of the drug, and, in the case of CFC devices, the 'cold freon effect', when the temperature of the propellant causes some individuals briefly to stop inhaling.\n\n# Spacer systems\n\nThe use of various spacer systems, which attach directly to the inhaler device, is one approach to alleviating some of the problems associated with pMDI use.\n\nTwo general types of spacer are available:\n\nDetachable chambers (small, medium or large volume): this type of spacer is attached to a press-and-breathe pMDI when required, and acts as a holding chamber for the aerosol and drug, allowing a number of breaths to be taken. Most spacers of this type incorporate a valve system, and inhalation techniques need to be taught. Five such spacers are currently available on NHS prescription.\n\nSmall-volume extended mouthpiece spacers: these provide increased distance between the point of aerosol release and the oropharyngeal area. They are available for use with some press-and-breathe and breath-actuated pMDIs.\n\nMany spacers are designed in conjunction with specific press-and-breathe pMDIs. However, some are designed to allow attachment to a wider range of press-and-breathe pMDIs, and in these cases there may be some uncertainty about their performance with different inhalers compared with those spacers designed for use with an individual inhaler.\n\nDetachable plastic spacers are prone to developing an electrostatic charge, which causes adhesion of the drug to their surface, so reducing delivery. Careful washing and air-drying (i.e. leaving to dry) of spacers at appropriate intervals reduces this problem. A metal spacer, which aims to avoid problems with electrostatic charge, has also been developed.\n\nOther shortcomings associated with spacers are portability and inconvenience, and feelings of stigma, which children may experience with their use.\n\n# Breath-actuated pMDIs\n\nBreath-actuated pMDIs also deliver a pressurised aerosol metered dose of drug, but are automatically actuated when the user inhales through the mouthpiece. Automatic actuation removes the difficulty of actuation-inhalation co-ordination that is associated with press-and-breathe pMDIs. However, the sound of some devices and the different sensation of automatic actuation may hamper use in some children. Oropharyngeal deposition can be a problem in breath-actuated pMDIs. Two breath-actuated pMDIs are currently available.\n\n# Dry powder inhalers (DPIs)\n\nDPIs deliver the micronised drug, and generally a carrier powder, using the individual's own inspiratory flow. This is another approach to overcoming the problem of actuation–inhalation co-ordination associated with pMDIs. Many newer DPIs also incorporate approaches to counting doses used or the amount of drug remaining, which can be used to aid monitoring of adherence to treatment.\n\nSome children (generally younger ones) may not reliably generate inspiratory flows that are high enough for effective delivery. These problems may present difficulty during acute exacerbations, and a press-and-breathe pMDI and spacer may be required for back-up.\n\nThere is greater variation in the design of DPIs than in other device types. A child may find one DPI device easier to use than another, or express a preference because of the appearance of a particular device. Seven DPIs are currently available for children.\n\n# Choosing suitable devices\n\nThe benefit gained from inhaled therapy is a unique combination of the drug, device and the individual (i.e. physical, cognitive, psychological and lifestyle characteristics). Consequently the following factors require consideration when choosing a device.\n\nInhaler technique – Poor technique, resulting either from poor training or from choosing a device poorly suited to the child, can significantly reduce the amount of drug delivered to the lungs and result in poor asthma control. Some children, especially the younger ones in the age range being considered, may have difficulty with actuation–inhalation co-ordination with a press-and-breathe pMDI, while others may have inconsistent inspiratory flow, which causes problems in using a DPI, or find the automatic actuation of some breath-actuated devices off-putting.\n\nAdherence to treatment – Even where good technique is possible, children may not use their devices appropriately. Device use may be influenced by a range of factors, including convenience, ease of device use, portability, the stigma of having asthma, and personal or peer preference for a specific device. The relative importance of these factors changes as children get older and so the choice of device should be reviewed frequently.\n\nAvailability of drugs – Some drugs are only available in particular devices.", 'Evidence ': "The systematic review included evidence on clinical effectiveness, ease of use, preference, compliance, and cost effectiveness.\n\n# Clinical effectiveness\n\nBecause of the specificity of device and drug effect, evidence for one drug in one device cannot be generalised to other drugs. Therefore, only research comparing the same drug (e.g. salbutamol vs salbutamol) at an equivalent dose level in different devices was considered. Studies including children aged 5–15 years were included in the review. Since the appraisal concerns device choice, rather than whether to treat using inhaler devices, placebo comparisons were not included. All studies included in the consideration of clinical effectiveness were randomised controlled trials (RCTs).\n\nEvidence in this area is generally limited in quantity and quality. Only one relevant study comparing a breath-actuated device with other devices was found, and few studies considered devices delivering cromoglicates, long-acting ß2-agonists, or drugs in combination. Many of the available studies included fewer than 50 children, and were under-powered. The review found that studies claiming to demonstrate equivalence were often unable to do so, and that some studies used inappropriate dose comparators.\n\nThree in vitro studies of drug delivery were identified, but these do not provide a sufficiently reliable basis for generalisation to device performance in children with asthma in clinical practice.\n\n# Delivery of bronchodilators\n\nTwenty-three studies in the systematic review examined different devices in the delivery of bronchodilators. Seven studies compared press-and-breathe pMDIs with and without spacers. In the main these included children, and all had fewer than 50 participants. Two of the studies found a significant difference in lung function favouring the pMDI and spacer combination. These were randomised cross-over studies, involving a total of 30 children aged between 5 and 14 years, that compared the delivery of terbutaline from a pMDI with delivery from a pMDI plus 750 ml collapsible spacer.Thirteen studies compared press-and-breathe pMDIs (with or without spacer) with DPIs, and none demonstrated a statistically significant difference in lung function. Some of the studies used inappropriate dosing schedules, which may have biased their findings. Some studies included a high proportion of adults.Three studies comparing different DPIs were included. They found no significant difference in lung function or symptoms, and all were small or included few children.\n\n# Delivery of anti-inflammatory drugs\n\nEight studies examined different devices for the delivery of corticosteroids. One used a filter method to compare a press-and-breathe pMDI in combination with one of two alternative spacers. It found significantly higher deposition of drug on the filters attached to a 250 ml metal spacer compared with a 750 ml plastic spacer. However, the study included only 16 children (aged 5 to 8 years), and found no difference in symptom scores between the two treatment groups. Five studies compared press-and-breathe pMDIs (with or without spacers) with DPIs. One large well-designed study reported equivalence of a pMDI with spacer and a DPI at half of the drug dose used in the pMDI. However, the authors of a systematic review concluded that this finding did not represent evidence of advantage of the DPI over the press-and-breathe pMDI and large-volume spacer as the device of choice for the delivery of corticosteroids in childhood asthma. In addition, a filter collection study comparing a press-and-breathe pMDI plus spacer with a DPI in children aged 5–15 years reported significantly higher deposition in the DPI group, though no differences in lung function were reported. The remaining studies were of poor quality or were likely to have included few children.Two adequately powered studies compared different DPIs, though neither reported a difference in effectiveness between devices.One study compared a press-and-breathe pMDI with a breath-actuated pMDI for cromoglicate. No differences were found in lung function, but the study was under-powered.\n\n# CFC-free devices\n\nThe studies included in the review reported no evidence of difference in the effectiveness of devices using CFC-containing or CFC-free propellants in pMDIs. However, it is important to note that there are some reports of higher drug deposition of corticosteroids from HFA devices. Consequently it is possible that required doses may be different when transferring children from CFC to HFA inhalers.\n\n# Other influences on effectiveness\n\nThirty-one studies on ease of use, preference or compliance were included in the systematic review. However their quality was generally poor, and many devices have not been studied. Many of the studies did not involve direct device comparison, had fewer than 100 participants, included adults, or did not examine the actual impact of these factors on disease outcomes. Only 11 of the studies were RCTs.\n\nA number of studies found that good individual (verbal) instruction was the key to correct inhaler technique, and two suggested that above age 5 or 6 years, this was the case regardless of the device. Studies on ease of use, adherence and preference are, however, of questionable value as the empirical value of these factors remains uncertain. Conclusions drawn from this body of research are likely to involve 'double counting', in that the effects of ease of use and preference may also contribute to compliance.\n\n# Cost effectiveness\n\nNo robust cost-effectiveness or utility studies examining use of inhalers in children aged 5–15 years with asthma were identified by the systematic review.\n\nThere are substantial differences in the acquisition costs of inhaler devices within the same drug dose range. For instance, in the delivery of one puff of salbutamol (ß2-agonist) a day, the lowest annual inhaler costs per device type are: press-and-breathe pMDI, £3.14; breath-actuated pMDI, £10.99; and DPI, £11.53. The highest cost for a DPI delivering salbutamol at this dose is £30.42. Similarly, in the delivery of a 200ug dose of beclometasone (corticosteroid) a day, the lowest annual inhaler costs per device type are: press-and-breathe pMDI, £28.73; breath-actuated pMDI £28.73; and DPI £38.51. The highest cost for a DPI delivering beclometasone at this dose is £69.06. The annual costs of suitable spacer devices available on NHS prescription range from £4.28 to £8.56.\n\nOne study reported that the overall annual average cost of care for people with asthma who have not experienced an asthma attack in the past year was £108, compared with £381 for people who have had at least one attack over the same period. Higher costs in primary care contacts, hospital admissions and visits, and medication all contributed to the overall difference.\n\nAn economic analysis considering differences in overall costs between devices found that only small improvements in asthma outcomes were needed for a device to be considered cost-effective compared with the cheapest available alternative for the delivery of the same drug at the same dose. Consequently if, after taking account of the factors specified in section 1.1, a clinician considers that a particular device would be more likely to achieve good asthma control in a particular child than cheaper ones available, then that device should be chosen.\n\n# Consideration\n\nThe available evidence generally fails to distinguish adequately between devices to suggest significant advantage in clinical effectiveness for one single delivery system.However, a limited amount of evidence supports the use of press-and-breathe pMDIs with large-volume spacers compared to press-and-breathe pMDIs alone in the delivery of bronchodilators, whilst one study reported equivalence of a press-and-breathe pMDI and large-volume spacer with a DPI at half the dose used in the pMDI in the delivery of a corticosteroid.On balancing these findings, clinical opinion and pharmacological considerations, the Appraisal Committee concluded that press-and-breathe pMDIs and spacer devices have an important role to play in the delivery of corticosteroids in aiming to achieve optimal asthma control. Despite this, it was acknowledged that the effectiveness of any device depends on the willingness and ability of a child to use it and to adhere to an effective regimen. The aim should be to identify the most clinically appropriate device that the individual child will use, bearing in mind the need to minimise the systemic absorption of inhaled corticosteroids.\n\nEconomic analysis suggests that no device should be excluded on grounds of cost effectiveness; however, when more than one device is felt to satisfy the considerations set out in 4.14 in an individual child, the device with the lowest overall cost (i.e. considering daily required dose and product price per dose) should be chosen.\n\nAs there is limited evidence on the effectiveness of alternative spacers for a given inhaler, if a choice is available, the decision should be guided by information in the inhaler's Summary of Product Characteristics.", 'Implications for the NHS': 'Overall budget impact is very sensitive to device prescribing patterns, since acquisition costs of inhalers delivering the same class of drug at the same dose vary substantially (as outlined in 4.11). However, with the exception of spacer devices, it is difficult to predict the impact of the guidance set out in section 1 on local inhaler prescribing patterns and costs. Consequently, an estimate of current inhaler prescribing patterns in primary care is set out below for England and Wales. These prescribing rates and costs can be used together with local information on inhaler use to calculate the likely local cost impact of the guidance. Estimates of the cost impact of the guidance as regards spacer devices are detailed in 5.5.\n\nAnalysis of inhaler device prescribing in a large sample of older children treated in primary care shows that press-and-breathe pMDIs account for 60% of prescribed items, breath-actuated pMDIs account for 17%, and DPIs account for 23%.\n\nApplying the estimates in 5.2 to England and Wales as a whole suggests that the approximate current annual acquisition costs for devices prescribed to children aged 5–15 years in primary care are as follows: £11.2 million (£1499 per 1000 total population aged 5–15 years) for press-and-breathe pMDIs, £4.2 million (£562 per 1000) for breath-actuated pMDIs, and £21.7 million (£2898 per 1000) for DPIs.\n\nIn addition, the analysis shows that in primary care, only 20% of children aged 5–15 prescribed a press-and-breathe pMDI delivering corticosteroids are currently prescribed a spacer attachment. The estimated total annual acquisition cost for spacer attachments is currently £233,000 (£31 per 1000) in England and Wales as a whole.\n\nIf all children prescribed a press-and-breathe pMDI delivering corticosteroids in primary care were to be prescribed one spacer attachment per year, it is estimated that the total annual acquisition cost in England and Wales would increase to £1.2 million (£156 per 1000). Manufacturers generally recommend two spacers per year.\n\nIn addition to any anticipated changes in device acquisition costs, it is also important that planning recognises the wider resource implications of implementing the guidance, including those set out in 1.4 and 7.3.', 'Further Research': "Given the scarcity of robust research comparing inhaler devices (including spacers) in older children, decision-making is likely to be substantially improved by adequately powered RCT equivalence studies. Ideally, these would include:\n\ntreatment of a full spectrum of chronic asthma severity in generalisable clinical settings\n\nqualitative assessment of children's experience of devices and factors influencing adherence\n\nexamination of clinically relevant outcome measures (e.g. symptoms, activities, time away from school) rather than short-term measures of lung function\n\nexamination of differences in resource use\n\nepidemiological investigation of the determinants (e.g. social factors) of adherence, effectiveness and cost effectiveness of treatment.\n\nThe Institute acknowledges that such studies would require large numbers of participants and present a significant challenge to manufacturers and other researchers. A parallel or alternative approach would be to undertake epidemiological and qualitative research on the factors influencing adherence and competence.\n\nGiven that none of the currently available inhaler devices are completely satisfactory for children, manufacturers should consider research into novel inhalers that can be used effectively with greater ease by children.", 'Related guidance': 'The Institute issued guidance on the use of inhalers in younger children (aged under 5 years) with chronic asthma in August 2000 Guidance on the use of inhaler systems (devices) in children under the age of 5 years with chronic asthma: NICE Technology Appraisal Guidance No.10. London: NICE, 2000..', 'Review of guidance': 'Information on the review of the guidance on this technology is available on the NICE website.\n\nAndrew DillonChief ExecutiveMarch 2002', 'Appendix B. Sources of evidence ': ". The following documentation and opinion was made available to the Appraisals Committee.\n\na. Assessment Report:\n\nPrepared by School of Health Related Research (ScHARR), University of Sheffield, (Clinical and Cost Effectiveness of Inhaler Devices used in the Routine Management of Chronic Asthma in Older Children, August 2001).\n\nb. Manufacturer/sponsor submissions:\n\nM Health Care Ltd\n\nAstraZeneca UK Ltd\n\nAventis Pharma Ltd\n\nBoehringer Ingelheim\n\nCelltech Pharmaceuticals Ltd\n\nGlaxoSmithKline\n\nNorton Healthcare\n\nTrinity Pharmaceuticals\n\nYamanouchi Pharma Ltd\n\nc. Professional/specialist group, patient/carer group and trade association submissions:\n\nBritish Lung Foundation\n\nRoyal College of Paediatrics and Child Health\n\nThe General Practice Airways Group (GPIAG)\n\nBritish Thoracic Society\n\nNational Asthma Campaign\n\nd. External expert and patient advocate attendance:\n\nDr Mark Levy, Representative from GPIAG and Senior Lecturer (Clinical) Part Time, Dept of General Practice & Primary Care, Aberdeen University\n\nTrisha Weller, Head of Quality Assurance, National Asthma & Respiratory Training Centre\n\nDr Mark Everard, Consultant in Paediatric Respiratory Medicine, Sheffield Children's Hospital\n\nMarsha Williams, Campaigns Manager, National Asthma Campaign\n\nJack Barnes, Director of Research & Policy, National Asthma Campaign\n\nDr Andrew Bush, on behalf of the British Lung Foundation, Reader in Paediatric Respirology, Royal Brompton Hospital", 'Appendix C. Guidance on the use of inhalers for the treatment of chronic asthma in older children (aged 5–15 years) – patient/carer information': "'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.", 'Appendix D. Technical detail on the criteria for audit of the use of inhaler devices for treatment of asthma in older children': 'Detail on criteria for audit of the use of inhaler devices for treatment of asthma in older children can be found in the PDF version of this guidance.', 'Changes after publication': 'March 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta38
26a901337f7fded467efd5aaa9c9a95c5f551247	nice	Guidance on the use of trastuzumab for the treatment of advanced breast cancer	Guidance on the use of trastuzumab for the treatment of advanced breast cancer Evidence-based recommendations on trastuzumab for treating advanced breast cancer in adults. # Guidance Trastuzumab in combination with paclitaxel (combination trastuzumab is currently only licensed for use with paclitaxel) is recommended as an option for people with tumours expressing human epidermal growth factor receptor 2 (HER2) scored at levels of 3+ who have not received chemotherapy for metastatic breast cancer and in whom anthracycline treatment is inappropriate. Trastuzumab monotherapy is recommended as an option for people with tumours expressing HER2 scored at levels of 3+ who have received at least two chemotherapy regimens for metastatic breast cancer. Prior chemotherapy must have included at least an anthracycline and a taxane where these treatments are appropriate. It should also have included hormonal therapy in suitable oestrogen receptor positive patients. HER2 levels should be scored using validated immunohistochemical techniques and in accordance with published guidelines. Laboratories offering tissue sample immunocytochemical or other predictive tests for therapy response should use validated standardised assay methods and participate in and demonstrate satisfactory performance in a recognised external quality assurance scheme.# Clinical Need and Practice Approximately 32,000 new cases of breast cancer were reported in England and Wales in 1996. In 1998, breast cancer caused over 11,000 deaths in England and Wales and was the leading cause of death in women aged 35 to 54 years. Advanced and metastatic breast cancer (MBC) are defined by clinical staging based on the tumour, node and metastasis staging system (stage III denotes locally advanced disease and stage IV indicates metastatic breast cancer). Between 16% and 20% of women initially presenting with breast cancer have advanced disease with distant metastases and around 50% of those presenting with early or localised breast cancer will eventually develop MBC. Some breast tumours contain an amplification of the human epidermal growth factor receptor (HER2), which causes overexpression of the HER2 protein and is associated with a poorer prognosis. Approximately 15%-20% of people with MBC overexpress HER2 at the 3+ level, measured by immunohistochemical techniques. The average period of survival after diagnosis of MBC is 18-24 months, but this is reduced by up to 50% for patients overexpressing HER2. First-line systemic therapy for advanced or metastatic breast cancer is chemotherapy for oestrogen receptor-negative patients (usually an anthracycline-containing regimen or sometimes a combination of cyclophosphamide, methotrexate and fluorouracil), and hormone manipulation therapy for oestrogen receptor-positive patients. However, the choice of therapy is influenced by the rate of progression and distribution of disease and by whether the drugs have already been administered as adjuvant therapies. Current NICE guidance states that docetaxel and paclitaxel should be available for the treatment of advanced breast cancer where initial cytotoxic chemotherapy (including an anthracycline) has failed or is inappropriate.# The Technology Trastuzumab is a recombinant humanised monoclonal antibody that specifically targets the HER2 protein. It is licensed for two indications for the treatment of MBC overexpressing HER2 at level 3+. Firstly, it is licensed in combination with paclitaxel for patients with MBC who have not received chemotherapy for metastatic disease and in whom an anthracycline is unsuitable. Secondly, it is licensed as a monotherapy for patients who have received at least two chemotherapy regimens for MBC; prior chemotherapy must have included at least an anthracycline and a taxane, unless these treatments are inappropriate; patients who are oestrogen receptor-positive must also have failed to respond to appropriate hormonal therapy. Trastuzumab is administered intravenously. Following an initial loading dose of 4 mg per kg body weight, patients receive a weekly dose of 2 mg per kg body weight until disease progression. Side-effects associated with trastuzumab have been noted to include cardiotoxicity and infusion-related reactions. The basic NHS price according to the British National Formulary (September 2001) for trastuzumab is £407 per 150 mg vial. For a typical patient, a 38-week course of combination therapy costs approximately £15,500 for trastuzumab and £9,600 for paclitaxel. The cost of a 12-week course of treatment with trastuzumab monotherapy is approximately £5,300. There are costs of testing a woman's suitability for treatment and of monitoring in addition to the cost of administering treatment. HER2 levels must be assessed in patients who are potentially eligible for treatment with trastuzumab, and patients receiving trastuzumab should have left ventricular ejection fraction measured before and during treatment.# Evidence # Clinical effectiveness ## Combination therapy One randomised controlled trial (RCT) (n=469) of first-line trastuzumab combination therapy was available. All individuals had HER2 overexpression at least at level 2+. Patients who had not previously received anthracyclines were randomised to an anthracycline in combination with cyclophosphamide with or without trastuzumab. Patients who had previously received an anthracycline as adjuvant therapy (n=188) were randomised to paclitaxel (n=96) or paclitaxel plus trastuzumab (n=92). The primary endpoint was time to progression and the median duration of follow-up was 30 (range 30-51) months. Patients in all arms of the trial were given the option of receiving trastuzumab monotherapy at the time of disease progression, meaning that allocation to this further treatment was non-random. When only the two relevant treatment arms involving paclitaxel were considered, there was no significant difference in overall survival between the group treated with trastuzumab plus paclitaxel and the group treated with paclitaxel alone (22 vs 18 months, p=0.17). However, the addition of trastuzumab resulted in longer median times to disease progression (7 vs 3 months, p<0.001), duration of response (11 vs 5 months, p<0.01) and time to treatment failure (6 vs 3 months, p<0.001). There was no statistically significant difference between the two treatments in terms of complete response (relative risk 3.65, 95% CI 0.89 to 15.22), but overall tumour response (RR 2.48, 95% CI 1.49 to 4.12), disease progression (RR 0.38, 95% CI 0.27 to 0.53) and treatment failure (RR 0.46, 95% CI 0.33 to 0.63) favoured treatment with trastuzumab. For patients with HER2 3+, trastuzumab and paclitaxel was associated with a longer median survival than paclitaxel alone (25 vs 18 months, no p-value provided). Quality of life, assessed using the pain and dyspnoea domains and the breast cancer module of the EORTC QLQ-C30 questionnaire, was higher in the group receiving trastuzumab plus chemotherapy than in the group receiving chemotherapy alone. The most important adverse event seen in the trial was cardiac dysfunction, which occurred in 27% of the group given an anthracycline, cyclophosphamide and trastuzumab, 8% of the group given an anthracycline and cyclophosphamide alone, 13% of the group given paclitaxel and trastuzumab, and 1% of the group given paclitaxel alone. The cardiotoxicity was potentially severe, and in some cases life threatening, but the symptoms were reported generally to improve with standard medical management. Although not originally observed during clinical trials, serious infusion-related reactions have been reported in 74 from a total of approximately 25,000 patients who received trastuzumab, with the reactions leading to the death of 15 patients. These reactions, which include anaphylaxis and severe dyspnoea, usually occur within 24 hours of the infusion, although delayed reactions have also been reported. Allergic or hypersensitivity reactions, haematological toxicity, hepatic and renal toxicity, diarrhoea and an increased risk of infections have also been noted. ## Monotherapy No comparative RCTs of trastuzumab monotherapy (i.e. versus systemic therapy without trastuzumab) were available. Of the studies that were identified, two were case-series of trastuzumab (H0551g, n=46; H0649g, n=222) and one was a RCT of trastuzumab monotherapy, which was concerned with an unlicensed indication and was essentially a dose ranging study (H0650g, n=113). Women in H0650g received first-line monotherapy with trastuzumab, which is an unlicensed indication. In H0649g, 4% of women experienced a complete response to treatment and 12% experienced a partial response. The overall response rate was 15%. Smaller proportions of women responded to treatment in study H0551g. The median duration of survival in H0649g was 13 months for all women and 16 months in a sub-group analysis of women overexpressing HER2 at 3+ levels. In the manufacturer's submission, survival reported in H0649g was indirectly compared with survival reported in two RCTs of vinorelbine monotherapy. Both RCTs contained a treatment arm consisting of vinorelbine monotherapy as second-line or salvage therapy for MBC. In one of these RCTs, 91% of participants had received prior treatment with anthracyclines for advanced breast cancer. The median duration of survival for people receiving vinorelbine monotherapy was 8 months. The reported median duration of survival in the other study was 10 months. Participants in these two RCTs were not selected on the basis of their HER2 status, which may suggest that their prognosis was better than those in H0649g. The manufacturer also submitted evidence from the Imperial Cancer Research Fund database at Guy's and St Thomas' Hospital NHS Trust on patients who had received third-line chemotherapy for MBC and who were not treated on the basis of their HER2 expression status. Analysis of these data showed that the median survival for these patients was 6.3 months. Trastuzumab monotherapy appeared to have a relatively low toxicity level. For study H0649g, the common adverse events (occurring in approximately 40% of people) were infusion-related fever and/or chills that usually occurred only during the first infusion. The most clinically significant adverse event was cardiac dysfunction, which occurred in 10 people (5%). However, only 1% of participants in this study discontinued treatment because of treatment-related adverse events. In study H0551g toxicity was reported as minimal, although two patients died as a result of cardiac dysfunction. In study H0650g the adverse events recorded were mainly mild to moderate in nature and were mostly associated with the higher dose regimen; only one person experienced cardiac dysfunction. # Cost-effectiveness ## Combination therapy The manufacturer evaluated the cost-effectiveness of trastuzumab in combination with paclitaxel versus paclitaxel alone for patients with HER2 3+, based on results from the RCT. Estimates of direct medical and social care costs were included in the evaluation, including the costs of HER2 testing (£21 for a single test) and cardiac testing (£520-£640 for four tests). The manufacturer estimated the incremental cost-effectiveness ratio to be £37,500 per Quality-Adjusted Life-Year (QALY) gained (and substantially less per life-year gained). This survival benefit used to estimate the QALY gain was based on a weighting of case-mix reflecting the selection of patients in the pivotal trial who, after the trial, crossed over to trastuzumab monotherapy. After extrapolating the trial results for this selection of patients, approximately 10 months mean survival advantage was imputed into the economic evaluation. A number of other sources, in particular two non-controlled studies that examined the use of taxane monotherapy as first-line treatment for metastatic breast cancer, suggest a survival advantage of combination therapy compatible, or even better, than this. ## Monotherapy One economic evaluation of monotherapy comparing trastuzumab with vinorelbine monotherapy was available to the Committee. Direct information relating to clinical effectiveness was unavailable (as there were no RCTs of trastuzumab other than a dose ranging study). Health outcomes were expressed in terms of life years and QALY by extrapolating survival from non-controlled studies. Direct medical and social care costs were included in the evaluation. Information on clinical effectiveness was imputed from H0649g and an RCT of vinorelbine versus melphalan that contained patients who were at an earlier stage of the disease and who were not selected on the basis of HER2 expression status. Patients who received vinorelbine in the RCT survived for approximately a median of 8 months. The manufacturer referenced two other non-controlled studies in an attempt to validate this period of survival for patients receiving vinorelbine. One of these studies examined median survival in patients at a similar disease stage who received vinorelbine monotherapy; in this study, median survival was approximately 6 months. The estimated incremental cost-effectiveness ratio was approximately £7,500 per life-year gained if trastuzumab was used instead of vinorelbine, when it was assumed that the additional survival attributable to trastuzumab monotherapy was 8 months. The manufacturers also provided a cost per QALY of approximately £19,000 by assuming that the 8 months of additional survival was equivalent to 2.6 quality-adjusted months. # Considerations ## Combination therapy Appraisal Committee considered that a survival gain of approximately 10 months used in the economic evaluation was likely to be an underestimate of the true survival gain attributable to combination therapy given that patients in the non-controlled studies of taxane monotherapy were not HER2 selected. The Appraisal Committee also concluded that the utility weights used to adjust survival for changes in quality of life were low. Based on these factors, the Appraisal Committee believed that trastuzumab combination therapy was likely to be lower than the estimate of £37,500 per QALY gained provided by the manufacturer. The Appraisal Committee also noted that improvements in survival of this magnitude due to therapeutic intervention have rarely been recorded in women with metastatic breast cancer. ## Monotherapy The evidence for the effectiveness of trastuzumab monotherapy was limited to two case-series and one RCT, which was concerned with an unlicensed indication and was essentially a dose ranging study. The report for the first case-series (H0551g) did not state the line of therapy being assessed or the length of follow-up. The second case-series (H0649g), which was relatively well reported, suggested that in terms of response rate trastuzumab monotherapy was an effective treatment in patients with MBC and HER2 overexpression at levels 3+. Although the Appraisal Committee had some reservations about the quality and robustness of the economic evaluation for trastuzumab monotherapy, as survival was not based on results from controlled studies, it was believed that these misgivings would not increase the ratio sufficiently to suggest that it is not cost-effective.# Implications for the NHS Patients who receive treatment with trastuzumab should be monitored for the possibility of cardiotoxicity. The manufacturer estimated the gross impact of providing trastuzumab plus paclitaxel instead of paclitaxel alone and trastuzumab monotherapy to be approximately £17 million per annum. This estimate is based on the following assumptions: HER2 status is assessed in 20,000 patients with metastatic disease at a cost of £21 per test; 1600 patients receive monotherapy at a cost of £5,300 per person; 450 patients receive combination therapy costing an additional £15,500 to provide trastuzumab and paclitaxel instead of paclitaxel alone; each person receives four cardiac tests at a cost of £580 for each set of four tests. (Overall calculation: + + + ).# Further Research Information linking side-effects associated with treatments with quality of life would enhance the comprehensiveness of future economic evaluations of treatments for advanced breast cancer.# Related Guidance The Institute issued guidance in September 2001 on the use of taxanes for the treatment of breast cancer: National Institute for Clinical Excellence (2001) Guidance on the use of taxanes for the treatment of breast cancer: NICE Technology Appraisal Guidance No. 30. London: National Institute for Clinical Excellence. # Review of Guidance Information on the review of the guidance on this technology is available on the NICE website. Andrew DillonChief ExecutiveMarch 2002# Appendix B. Sources of Evidence The following documentation and opinion was made available to the Appraisals Committee: a. Assessment Report: Prepared by The NHS Centre for Reviews and Dissemination (A rapid and systematic review of the clinical effectiveness and cost-effectiveness of trastuzumab and vinorelbine for breast cancer, February 2001) Prepared by The NHS Centre for Reviews and Dissemination (A rapid and systematic review of the clinical effectiveness and cost-effectiveness of trastuzumab for breast cancer, October 2001) b. Manufacturer/sponsor submissions: Roche c. Professional/specialist group submissions from: British Psychosocial Oncology Society Imperial Cancer Research Fund MRC Clinical Trials Unit National Cancer Research Institute Royal College of General Practitioners Royal College of Pathologists Royal College of Physicians d. Patient group submissions from: Breakthrough Breast Cancer, CancerBACUP and the UK Breast Cancer Coalition joint submission Breast Cancer Care Macmillan Cancer Relief e. Other group submissions from: Department of Health National Assembly for Wales f. External expert and patient advocate submissions from: Professor Robert Coleman, Professor of Medical Oncology, Cancer Research Centre,Weston Park Hospital, University of Sheffield Bernie Gardiner, Information Nurse Specialist, Breast Cancer Care Margaret King, Vice Chair, UK Breast Cancer Coalition# Appendix C. Guidance on the use of trastuzumab for the treatment of advanced breast cancer. Patient information 'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.# Changes after publication March 2014: implementation section updated to clarify that trastuzumab is recommended as an option for treating advanced breast cancer. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. The recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Trastuzumab in combination with paclitaxel (combination trastuzumab is currently only licensed for use with paclitaxel) is recommended as an option for people with tumours expressing human epidermal growth factor receptor 2 (HER2) scored at levels of 3+ who have not received chemotherapy for metastatic breast cancer and in whom anthracycline treatment is inappropriate.\n\nTrastuzumab monotherapy is recommended as an option for people with tumours expressing HER2 scored at levels of 3+ who have received at least two chemotherapy regimens for metastatic breast cancer. Prior chemotherapy must have included at least an anthracycline and a taxane where these treatments are appropriate. It should also have included hormonal therapy in suitable oestrogen receptor positive patients.\n\nHER2 levels should be scored using validated immunohistochemical techniques and in accordance with published guidelines. Laboratories offering tissue sample immunocytochemical or other predictive tests for therapy response should use validated standardised assay methods and participate in and demonstrate satisfactory performance in a recognised external quality assurance scheme.', 'Clinical Need and Practice': 'Approximately 32,000 new cases of breast cancer were reported in England and Wales in 1996. In 1998, breast cancer caused over 11,000 deaths in England and Wales and was the leading cause of death in women aged 35 to 54 years.\n\nAdvanced and metastatic breast cancer (MBC) are defined by clinical staging based on the tumour, node and metastasis staging system (stage III denotes locally advanced disease and stage IV indicates metastatic breast cancer).\n\nBetween 16% and 20% of women initially presenting with breast cancer have advanced disease with distant metastases and around 50% of those presenting with early or localised breast cancer will eventually develop MBC.\n\nSome breast tumours contain an amplification of the human epidermal growth factor receptor (HER2), which causes overexpression of the HER2 protein and is associated with a poorer prognosis. Approximately 15%-20% of people with MBC overexpress HER2 at the 3+ level, measured by immunohistochemical techniques. The average period of survival after diagnosis of MBC is 18-24 months, but this is reduced by up to 50% for patients overexpressing HER2.\n\nFirst-line systemic therapy for advanced or metastatic breast cancer is chemotherapy for oestrogen receptor-negative patients (usually an anthracycline-containing regimen or sometimes a combination of cyclophosphamide, methotrexate and fluorouracil), and hormone manipulation therapy for oestrogen receptor-positive patients. However, the choice of therapy is influenced by the rate of progression and distribution of disease and by whether the drugs have already been administered as adjuvant therapies.\n\nCurrent NICE guidance states that docetaxel and paclitaxel should be available for the treatment of advanced breast cancer where initial cytotoxic chemotherapy (including an anthracycline) has failed or is inappropriate.', 'The Technology': "Trastuzumab is a recombinant humanised monoclonal antibody that specifically targets the HER2 protein. It is licensed for two indications for the treatment of MBC overexpressing HER2 at level 3+. Firstly, it is licensed in combination with paclitaxel for patients with MBC who have not received chemotherapy for metastatic disease and in whom an anthracycline is unsuitable. Secondly, it is licensed as a monotherapy for patients who have received at least two chemotherapy regimens for MBC; prior chemotherapy must have included at least an anthracycline and a taxane, unless these treatments are inappropriate; patients who are oestrogen receptor-positive must also have failed to respond to appropriate hormonal therapy.\n\nTrastuzumab is administered intravenously. Following an initial loading dose of 4 mg per kg body weight, patients receive a weekly dose of 2 mg per kg body weight until disease progression. Side-effects associated with trastuzumab have been noted to include cardiotoxicity and infusion-related reactions.\n\nThe basic NHS price according to the British National Formulary (September 2001) for trastuzumab is £407 per 150 mg vial. For a typical patient, a 38-week course of combination therapy costs approximately £15,500 for trastuzumab and £9,600 for paclitaxel. The cost of a 12-week course of treatment with trastuzumab monotherapy is approximately £5,300.\n\nThere are costs of testing a woman's suitability for treatment and of monitoring in addition to the cost of administering treatment. HER2 levels must be assessed in patients who are potentially eligible for treatment with trastuzumab, and patients receiving trastuzumab should have left ventricular ejection fraction measured before and during treatment.", 'Evidence ': "# Clinical effectiveness\n\n## Combination therapy\n\nOne randomised controlled trial (RCT) (n=469) of first-line trastuzumab combination therapy was available. All individuals had HER2 overexpression at least at level 2+. Patients who had not previously received anthracyclines were randomised to an anthracycline in combination with cyclophosphamide with or without trastuzumab. Patients who had previously received an anthracycline as adjuvant therapy (n=188) were randomised to paclitaxel (n=96) or paclitaxel plus trastuzumab (n=92). The primary endpoint was time to progression and the median duration of follow-up was 30 (range 30-51) months. Patients in all arms of the trial were given the option of receiving trastuzumab monotherapy at the time of disease progression, meaning that allocation to this further treatment was non-random.\n\nWhen only the two relevant treatment arms involving paclitaxel were considered, there was no significant difference in overall survival between the group treated with trastuzumab plus paclitaxel and the group treated with paclitaxel alone (22 vs 18 months, p=0.17). However, the addition of trastuzumab resulted in longer median times to disease progression (7 vs 3 months, p<0.001), duration of response (11 vs 5 months, p<0.01) and time to treatment failure (6 vs 3 months, p<0.001). There was no statistically significant difference between the two treatments in terms of complete response (relative risk [RR] 3.65, 95% CI 0.89 to 15.22), but overall tumour response (RR 2.48, 95% CI 1.49 to 4.12), disease progression (RR 0.38, 95% CI 0.27 to 0.53) and treatment failure (RR 0.46, 95% CI 0.33 to 0.63) favoured treatment with trastuzumab. For patients with HER2 3+, trastuzumab and paclitaxel was associated with a longer median survival than paclitaxel alone (25 vs 18 months, no p-value provided).\n\nQuality of life, assessed using the pain and dyspnoea domains and the breast cancer module of the EORTC QLQ-C30 questionnaire, was higher in the group receiving trastuzumab plus chemotherapy than in the group receiving chemotherapy alone.\n\nThe most important adverse event seen in the trial was cardiac dysfunction, which occurred in 27% of the group given an anthracycline, cyclophosphamide and trastuzumab, 8% of the group given an anthracycline and cyclophosphamide alone, 13% of the group given paclitaxel and trastuzumab, and 1% of the group given paclitaxel alone. The cardiotoxicity was potentially severe, and in some cases life threatening, but the symptoms were reported generally to improve with standard medical management.\n\nAlthough not originally observed during clinical trials, serious infusion-related reactions have been reported in 74 from a total of approximately 25,000 patients who received trastuzumab, with the reactions leading to the death of 15 patients. These reactions, which include anaphylaxis and severe dyspnoea, usually occur within 24 hours of the infusion, although delayed reactions have also been reported. Allergic or hypersensitivity reactions, haematological toxicity, hepatic and renal toxicity, diarrhoea and an increased risk of infections have also been noted.\n\n## Monotherapy\n\nNo comparative RCTs of trastuzumab monotherapy (i.e. versus systemic therapy without trastuzumab) were available. Of the studies that were identified, two were case-series of trastuzumab (H0551g, n=46; H0649g, n=222) and one was a RCT of trastuzumab monotherapy, which was concerned with an unlicensed indication and was essentially a dose ranging study (H0650g, n=113). Women in H0650g received first-line monotherapy with trastuzumab, which is an unlicensed indication.\n\nIn H0649g, 4% of women experienced a complete response to treatment and 12% experienced a partial response. The overall response rate was 15%. Smaller proportions of women responded to treatment in study H0551g.\n\nThe median duration of survival in H0649g was 13 months for all women and 16 months in a sub-group analysis of women overexpressing HER2 at 3+ levels. In the manufacturer's submission, survival reported in H0649g was indirectly compared with survival reported in two RCTs of vinorelbine monotherapy. Both RCTs contained a treatment arm consisting of vinorelbine monotherapy as second-line or salvage therapy for MBC. In one of these RCTs, 91% of participants had received prior treatment with anthracyclines for advanced breast cancer. The median duration of survival for people receiving vinorelbine monotherapy was 8 months. The reported median duration of survival in the other study was 10 months. Participants in these two RCTs were not selected on the basis of their HER2 status, which may suggest that their prognosis was better than those in H0649g.\n\nThe manufacturer also submitted evidence from the Imperial Cancer Research Fund database at Guy's and St Thomas' Hospital NHS Trust on patients who had received third-line chemotherapy for MBC and who were not treated on the basis of their HER2 expression status. Analysis of these data showed that the median survival for these patients was 6.3 months.\n\nTrastuzumab monotherapy appeared to have a relatively low toxicity level. For study H0649g, the common adverse events (occurring in approximately 40% of people) were infusion-related fever and/or chills that usually occurred only during the first infusion. The most clinically significant adverse event was cardiac dysfunction, which occurred in 10 people (5%). However, only 1% of participants in this study discontinued treatment because of treatment-related adverse events. In study H0551g toxicity was reported as minimal, although two patients died as a result of cardiac dysfunction. In study H0650g the adverse events recorded were mainly mild to moderate in nature and were mostly associated with the higher dose regimen; only one person experienced cardiac dysfunction.\n\n# Cost-effectiveness\n\n## Combination therapy\n\nThe manufacturer evaluated the cost-effectiveness of trastuzumab in combination with paclitaxel versus paclitaxel alone for patients with HER2 3+, based on results from the RCT. Estimates of direct medical and social care costs were included in the evaluation, including the costs of HER2 testing (£21 for a single test) and cardiac testing (£520-£640 for four tests).\n\nThe manufacturer estimated the incremental cost-effectiveness ratio to be £37,500 per Quality-Adjusted Life-Year (QALY) gained (and substantially less per life-year gained). This survival benefit used to estimate the QALY gain was based on a weighting of case-mix reflecting the selection of patients in the pivotal trial who, after the trial, crossed over to trastuzumab monotherapy. After extrapolating the trial results for this selection of patients, approximately 10 months mean survival advantage was imputed into the economic evaluation. A number of other sources, in particular two non-controlled studies that examined the use of taxane monotherapy as first-line treatment for metastatic breast cancer, suggest a survival advantage of combination therapy compatible, or even better, than this.\n\n## Monotherapy\n\nOne economic evaluation of monotherapy comparing trastuzumab with vinorelbine monotherapy was available to the Committee. Direct information relating to clinical effectiveness was unavailable (as there were no RCTs of trastuzumab other than a dose ranging study). Health outcomes were expressed in terms of life years and QALY by extrapolating survival from non-controlled studies. Direct medical and social care costs were included in the evaluation. Information on clinical effectiveness was imputed from H0649g and an RCT of vinorelbine versus melphalan that contained patients who were at an earlier stage of the disease and who were not selected on the basis of HER2 expression status. Patients who received vinorelbine in the RCT survived for approximately a median of 8 months. The manufacturer referenced two other non-controlled studies in an attempt to validate this period of survival for patients receiving vinorelbine. One of these studies examined median survival in patients at a similar disease stage who received vinorelbine monotherapy; in this study, median survival was approximately 6 months.\n\nThe estimated incremental cost-effectiveness ratio was approximately £7,500 per life-year gained if trastuzumab was used instead of vinorelbine, when it was assumed that the additional survival attributable to trastuzumab monotherapy was 8 months. The manufacturers also provided a cost per QALY of approximately £19,000 by assuming that the 8 months of additional survival was equivalent to 2.6 quality-adjusted months.\n\n# Considerations\n\n## Combination therapy\n\nAppraisal Committee considered that a survival gain of approximately 10 months used in the economic evaluation was likely to be an underestimate of the true survival gain attributable to combination therapy given that patients in the non-controlled studies of taxane monotherapy were not HER2 selected. The Appraisal Committee also concluded that the utility weights used to adjust survival for changes in quality of life were low.\n\nBased on these factors, the Appraisal Committee believed that trastuzumab combination therapy was likely to be lower than the estimate of £37,500 per QALY gained provided by the manufacturer.\n\nThe Appraisal Committee also noted that improvements in survival of this magnitude due to therapeutic intervention have rarely been recorded in women with metastatic breast cancer.\n\n## Monotherapy\n\nThe evidence for the effectiveness of trastuzumab monotherapy was limited to two case-series and one RCT, which was concerned with an unlicensed indication and was essentially a dose ranging study. The report for the first case-series (H0551g) did not state the line of therapy being assessed or the length of follow-up. The second case-series (H0649g), which was relatively well reported, suggested that in terms of response rate trastuzumab monotherapy was an effective treatment in patients with MBC and HER2 overexpression at levels 3+.\n\nAlthough the Appraisal Committee had some reservations about the quality and robustness of the economic evaluation for trastuzumab monotherapy, as survival was not based on results from controlled studies, it was believed that these misgivings would not increase the ratio sufficiently to suggest that it is not cost-effective.", 'Implications for the NHS': 'Patients who receive treatment with trastuzumab should be monitored for the possibility of cardiotoxicity.\n\nThe manufacturer estimated the gross impact of providing trastuzumab plus paclitaxel instead of paclitaxel alone and trastuzumab monotherapy to be approximately £17 million per annum. This estimate is based on the following assumptions: HER2 status is assessed in 20,000 patients with metastatic disease at a cost of £21 per test; 1600 patients receive monotherapy at a cost of £5,300 per person; 450 patients receive combination therapy costing an additional £15,500 to provide trastuzumab and paclitaxel instead of paclitaxel alone; each person receives four cardiac tests at a cost of £580 for each set of four tests. (Overall calculation: [20,000 x £21] + [1,600 x £5,300] + [450 x £15,500] + [1,600 x £580]).', 'Further Research': 'Information linking side-effects associated with treatments with quality of life would enhance the comprehensiveness of future economic evaluations of treatments for advanced breast cancer.', 'Related Guidance': 'The Institute issued guidance in September 2001 on the use of taxanes for the treatment of breast cancer:\n\nNational Institute for Clinical Excellence (2001) Guidance on the use of taxanes for the treatment of breast cancer: NICE Technology Appraisal Guidance No. 30. London: National Institute for Clinical Excellence. [Replaced by NICE clinical guideline 81]', 'Review of Guidance': 'Information on the review of the guidance on this technology is available on the NICE website.\n\nAndrew DillonChief ExecutiveMarch 2002', 'Appendix B. Sources of Evidence ': 'The following documentation and opinion was made available to the Appraisals Committee:\n\na. Assessment Report:\n\nPrepared by The NHS Centre for Reviews and Dissemination (A rapid and systematic review of the clinical effectiveness and cost-effectiveness of trastuzumab and vinorelbine for breast cancer, February 2001)\n\nPrepared by The NHS Centre for Reviews and Dissemination (A rapid and systematic review of the clinical effectiveness and cost-effectiveness of trastuzumab for breast cancer, October 2001)\n\nb. Manufacturer/sponsor submissions:\n\nRoche\n\nc. Professional/specialist group submissions from:\n\nBritish Psychosocial Oncology Society\n\nImperial Cancer Research Fund\n\nMRC Clinical Trials Unit\n\nNational Cancer Research Institute\n\nRoyal College of General Practitioners\n\nRoyal College of Pathologists\n\nRoyal College of Physicians\n\nd. Patient group submissions from:\n\nBreakthrough Breast Cancer, CancerBACUP and the UK Breast Cancer Coalition joint submission\n\nBreast Cancer Care\n\nMacmillan Cancer Relief\n\ne. Other group submissions from:\n\nDepartment of Health\n\nNational Assembly for Wales\n\nf. External expert and patient advocate submissions from:\n\nProfessor Robert Coleman, Professor of Medical Oncology, Cancer Research Centre,Weston Park Hospital, University of Sheffield\n\nBernie Gardiner, Information Nurse Specialist, Breast Cancer Care\n\nMargaret King, Vice Chair, UK Breast Cancer Coalition', 'Appendix C. Guidance on the use of trastuzumab for the treatment of advanced breast cancer. Patient information': "'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.", 'Changes after publication': 'March 2014: implementation section updated to clarify that trastuzumab is recommended as an option for treating advanced breast cancer. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThe recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta34	Evidence-based recommendations on trastuzumab for treating advanced breast cancer in adults.
352cbaff7562a4170bd32949529f755f30dbdd09	nice	Guidance on the use of fludarabine for B-cell chronic lymphocytic leukaemia	Guidance on the use of fludarabine for B-cell chronic lymphocytic leukaemia # Guidance Oral fludarabine is recommended as second line therapy for B-cell chronic lymphocytic leukaemia (CLL) for patients who have either failed, or are intolerant of, first line chemotherapy, and who would otherwise have received combination chemotherapy of either: cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) cyclophosphamide, doxorubicin and prednisolone (CAP) or cyclophosphamide, vincristine and prednisolone (CVP) The oral formulation of fludarabine is preferred to the intravenous formulation on the basis of more favourable cost effectiveness. Intravenous fludarabine should only be used when oral fludarabine is contra-indicated.# Clinical Need and Practice Chronic lymphocytic leukaemia (CLL) is a malignant disorder of the white blood cells (lymphocytes). CLL causes abnormal lymphocytes to proliferate, thus impairing the production and function of red blood cells, platelets and normal lymphocytes. This in turn causes anaemia, failure of the blood to clot and increased susceptibility to infection. There are two main types of lymphocytes called B-cells and T-cells. B-cell CLL comprises about 95% of all CLL. Often, the disease goes undiagnosed either until it is well advanced, or until a chance test shows abnormally high levels of lymphocytes in the blood. CLL is a chronic, life-threatening and incurable disease. It is the most common form of leukaemia in the Western world, affecting about 2.7 people in every 100,000. Predominantly, it is a disease of older people, with 75% of those diagnosed being over the age of 60 years, although 6% are below the age of 50 years. Twice as many men as women are affected. Life expectancy depends on the stage at which the disease is diagnosed (see Table 2, Appendix D for definition of stages). For those in the early stages of the disease, median life expectancy is over 10 years, while for patients with advanced disease it is only 6 to 9 months. Other adverse prognostic factors include early age of onset. Despite the apparently better prognosis in early disease, there is no evidence that early treatment is beneficial, and it may indeed be harmful. Since many patients have limited disease, they do not require anything more than general observation, referred to as 'watchful waiting'. When the disease progresses, a hierarchy of treatments is used. There is a trade-off between the likelihood of halting or reversing progression of the disease and the side-effects of drug treatment. Response rates to chemotherapy of about 70% are seen in intermediate-stage disease, dropping to about 30% in later stages. In patients at intermediate or advanced stages of their disease an alkylating agent such as chlorambucil (with or without corticosteroids), cyclophosphamide or fludarabine (currently unlicensed in this indication) has been used as a first-line treatment. When patients relapse or fail to respond to one of the first-line treatments (usually chlorambucil or, occasionally, cyclophosphamide), either combination treatment (such as CHOP, CAP or CVP) or fludarabine monotherapy is employed. A single cycle of combination therapy usually consists of drugs given by both the intravenous route (day 1) and orally (for a further 4 days). Cycles are repeated monthly for up to six months. Fludarabine is sometimes used as third-line treatment after combination therapy has failed.# The Technology Fludarabine is a cytotoxic agent of the antimetabolite class. It is currently licensed for patients with B-cell CLL with sufficient bone marrow reserve and who have not responded to, or whose disease has progressed during or after, treatment with at least one standard alkylating-agent containing regimen. It is administered either as an intravenous infusion (over 30 minutes) or orally. This is repeated each day for 5 days, and this cycle is then repeated every 28 days for up to 6 cycles. The drug acquisition cost (for either intravenous or oral formulation) of a course of 6 cycles is about £3,900. Each intravenous infusion requires a day-case admission to hospital, while the oral preparation usually needs only a small number of hospital visits. Although the immediate side effects of fludarabine (nausea, vomiting, alopecia) are less troublesome than those of CHOP, there are frequent haematological adverse events (granulocytopenia, anaemia and thrombocytopenia), as well as other important long-term effects. Of these, the principal effect is T-cell immunosuppression, leading to a recommendation for prophylactic antibiotic treatment against Pneumocystis carinii pneumonia, and irradiation of all blood products given to the patient to prevent transfusion-related graft-versus-host disease. Concurrent corticosteroids increase this risk due to the additive lymphocytic activity and should therefore be avoided unless otherwise indicated. Additionally, autoimmune haemolytic anaemia is relatively common in patients with CLL. It occurs in about 1% to 5% of patients receiving fludarabine as a second line treatment. The haemolysis is often severe, may be difficult to treat, and is potentially fatal. Nevertheless, on a day-to-day basis, fludarabine is generally tolerated better than conventional second line chemotherapy regimens, particularly in patients currently considered too frail to withstand combination therapies.# Evidence # Clinical effectiveness There are two randomised controlled trials (RCT) evaluating intravenous fludarabine as a second line agent in CLL. In one of these, comparing fludarabine with cladribine, an unknown number of patients had B-cell CLL. It is not possible therefore to derive from this study, results relevant to the indication under consideration. The second RCT compared fludarabine with CAP. Only 96 of 196 patients studied had been previously treated with a first line agent. Response rates (RR) for these previously treated patients were 48% with fludarabine versus 27% with CAP (95% confidence interval on the difference of 21 percentage points was 2 to 40 percentage points). The fludarabine response rate was much higher than that seen in the case series (see below). Mostly, the responses were partial, with just 13% complete responses for fludarabine versus 6% for CAP (the difference is not statistically significant). Time to progression for previously treated patients (responders only) had a median of 324 days for fludarabine versus 179 days for CAP (the difference is not statistically significant). In addition there were 9 deaths in 48 patients with fludarabine compared with 3 out of 48 in the control arm (the difference is not statistically significant). No data on quality of life were collected as part of the trial. Adverse events, mostly haematological, were common in both arms of the trial. For intravenous fludarabine, six case series with an aggregate population size of almost 1000 were found. Response rates averaged 32%. The response rate appears to decline in patients who have been treated more heavily prior to treatment with fludarabine, and is generally lowest for patients for whom fludarabine is the treatment of last resort. Where reported, mild or moderate side effects were common although 72% of patients experienced severe haematological adverse events (based on laboratory results). The degree and length of response in these studies is greater than those of comparable studies for combination therapy, although it is not known whether there is an impact on length of survival. The quality of all such studies is lower than that of randomised controlled trials, due to the possibility of unrepresentative or biased patient selection, heterogeneity between studies, and placebo effects of unknown size. Quality of life data have not been formally collected as part of these studies. Some evidence, however, is available from the Lymphoma Association, whose survey showed that 74% of patients consider that they are in as good or better health during fludarabine treatment as they would have been with other chemotherapy. Recent data from the MRC-sponsored CLL3 study show that, for patients who failed to respond to first-line treatment with chlorambucil or chlorambucil plus epirubicin at 6 months, 80% responded to fludarabine (17% complete, 63% partial). This evidence is in general supportive of the use of fludarabine second line. It is, however, subject to the biases of being an uncontrolled case series, the difficulty in defining non-responders and the variation in times to recruitment into the study following 'failure' of first line treatment. Other evidence in the form of four randomised controlled trials for fludarabine alone against other chemotherapeutic agents for first line treatment (for which fludarabine is not currently licensed) shows that fludarabine gives higher rates of remission and longer remission than CAP, CHOP, or chlorambucil plus prednisolone, but no demonstrated survival advantage. For fludarabine against chlorambucil, one study favours fludarabine as above, but the other finds no difference between the two drugs. Assuming that a high positive correlation exists between the relative performance of fludarabine against its comparators in first and second line therapies, this evidence supports the case for the use of fludarabine in second-line therapy. For oral fludarabine, an open study of 78 previously treated patients with CLL showed that 46% of patients responded (20% complete and 26% partial remission). Evidence on the bioavailability of the oral formulation and equivalence of blood levels of oral fludarabine with those of the intravenous preparation indicates that orally administered fludarabine is likely to have similar clinical efficacy to the intravenously administered preparation. # Cost effectiveness No single piece of evidence is strong enough to establish whether fludarabine is a clinically effective agent for second line treatment of CLL. When the evidence is taken in aggregate, however, it is supportive of fludarabine as a clinically effective drug for this indication. The assessment of cost effectiveness, however, is also subject to considerable uncertainty, because reliable figures for the costs of dealing with adverse side effects are not available. Three sources have been used to examine the costs of overcoming adverse events in using fludarabine and CHOP. The first (described as the low estimate), submitted by the manufacturer, is based on very small numbers of patients, and is therefore subject to large sampling error. The second (described as the high estimate) was submitted by a different manufacturer for the treatment of a different type of lymphoma, and was also based on a small sample. This source yielded cost estimates over six times as high as the first source, much of which appears to be attributable to the disease having advanced much further, on average, in patients from the second source. The third was from the MRC trial CLL3, which may have included costs associated with the disease per se, as well as of side effects of fludarabine, yielded costs comparable with those of the high estimate. The cost effectiveness estimates have been examined separately for oral and intravenous fludarabine, and for both of these against the comparators of CHOP and of no treatment, for both high and low estimates of the cost of side effects. Oral fludarabine is less costly to administer than intravenous fludarabine. The estimated combined cost of acquisition and administration, based on an average of 4.1 cycles administered, is £3,000 for oral fludarabine (comprising £2,700 for acquisition and £300 for administration) against £5,300 for intravenous fludarabine (£2,700 acquisition, £2,600 administration). The mean cost per year of remission from CLL of oral fludarabine against no treatment is estimated to be £9,000 (low cost of treating side effects) or £21,000 (high cost of treating side effects); for intravenous fludarabine, the corresponding estimates are £14,000 and £28,000; and for CHOP are £22,000 and £67,000. The mean incremental cost-effectiveness ratio for oral fludarabine against CHOP is estimated to be £2,700 per year of remission (low cost of treating side-effects) and £200 per year of remission (high cost of treating side-effects) (the latter figure is smaller than the former because the cost of treating side-effects for CHOP is also much higher in the high-cost scenario). The corresponding estimates for intravenous fludarabine against CHOP are £10,600 and £10,500. Even if there is no increase in overall survival using fludarabine compared with that of CHOP, it is probable that oral fludarabine is cost effective against CHOP. In clinical practice it is likely that if fludarabine were not given, then patients who would otherwise have been prescribed it would be prescribed CHOP or an equivalent combination. In this situation oral fludarabine is both a more clinically effective and a more cost effective drug than its alternatives, as well as being more likely to be acceptable to patients.# Implications for the NHS This guidance is not expected to result in a net increase in NHS expenditure in England and Wales, because fludarabine is already in common use. Increases in drug acquisition costs are likely to be offset by the transfer to the oral formulation, and because the switch from combination therapies to fludarabine should reduce the costs of treating adverse side effects. (a) For each patient already being treated with fludarabine, it can be expected that cost savings in drug administration in switching from intravenous to oral fludarabine will be about £2,300 per course of an average 4 cycles (there was an average of 4 cycles of oral fludarabine given in one of the key trials).(b) For each patient new to fludarabine therapy who would otherwise have been prescribed combination chemotherapy (CHOP, CAP or CVP), the increased drug acquisition cost of fludarabine should be partially or fully offset by cost savings from avoiding the necessity of treating the side effects of combination drug therapy. For this group of patients, the net cost effect, on average, is likely to have a range of zero to £2,000, although this does not include the further costs of those who might subsequently also be treated with combination chemotherapy.(c) For each patient new to fludarabine therapy who would not have been able to tolerate combination chemotherapy, the additional costs are likely to be of the order of £6,000 to £9,000 per patient.# Further Research Further appropriately constructed clinical trials should assess impact on quality of life directly. Further research into fludarabine as a first line therapy, either singly or in combination with current first line drugs, would be of value. Recruitment of patients to the current CLL4 trial is recommended. More comprehensive research, in the form of an adequately powered randomised controlled trial, to determine with greater certainty whether oral fludarabine is as clinically effective as intravenous fludarabine, is required.# Review of guidance Information on the review of the guidance on this technology is available on the NICE website. Andrew DillonChief ExecutiveSeptember 2001# Appendix B. Sources of Evidence . The following documentation and opinion was made available to the Committee: a. Assessment Report prepared by the Department of Public Health and Epidemiology, University of Birmingham (Fludarabine as second line therapy for B-Cell chronic lymphocytic leukaemia, January 2001) Assessment Report Annexe prepared by the Department of Public Health and Epidemiology, University of Birmingham (Fludarabine as second line therapy for B-Cell chronic lymphocytic leukaemia: Effectiveness Annexe, May 2001) Assessment Report Cost- Effectiveness Annexe prepared by Dr A J Fischer, NICE Appraisals Team, May 2001 b. Manufacturer/Sponsor submissions: Schering Health Care Ltd c. Professional/Specialist Group, Patient/Carer Group and Trade Association submissions: British National Lymphoma Investigation and UK CCCR British Committee for Standards in Haematology (BCSH) CancerBACUP Lymphoma Association Macmillan Cancer Relief Royal College of Pathologists d. External expert and patient advocate submissions: Dr Andrew MacMillan, Oncologist, Mount Vernon Hospital Dr Peter Hoskin, Consultant Clinical Oncologist, Mount Vernon Hospital Dr Tracey Murray, Lecturer/Practitioner, St George's Healthcare NHS Trust Catriona Moore, Policy Officer, CancerBACUP Judith Brodie, Head of Cancer Support Services, CancerBACUP Catriona Gilmour Hamilton, Assistant Head of Information Services, The Lymphoma Association# Appendix C. Guidance on the use of fludarabine as second line therapy for B-cell chronic lymphocytic leukaemia 'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.# Appendix D. Staging Systems Rai Characteristics Median Survival Stage 0 Lymphocytosis in blood and bone marrow only years Stage I Lymphocytosis plus lymphadenopathy years Stage II Lymphocytosis plus splenomegaly or hepatomegaly Stage III Lymphocytosis plus anaemia (Hb < 110 g/L) < 1 year Stage IV Lymphocytosis plus thrombocytopenia (platelets < 100 x 109/L) Binet* Stage A < 3 sites involved, Hb > 100 g/L, platelets > 100 x 109/L years Stage B 3 sites involved, Hb > 100 g/L, platelets > 100 x 109/L years Stage C Hb 100 x 109/L years - Involved sites are liver, spleen and lymph nodes in inguinal, axilliary and cervical regions.# Changes after publication March 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2001. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Oral fludarabine is recommended as second line therapy for B-cell chronic lymphocytic leukaemia (CLL) for patients who have either failed, or are intolerant of, first line chemotherapy, and who would otherwise have received combination chemotherapy of either:\n\ncyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)\n\ncyclophosphamide, doxorubicin and prednisolone (CAP) or\n\ncyclophosphamide, vincristine and prednisolone (CVP)\n\nThe oral formulation of fludarabine is preferred to the intravenous formulation on the basis of more favourable cost effectiveness. Intravenous fludarabine should only be used when oral fludarabine is contra-indicated.', 'Clinical Need and Practice': "Chronic lymphocytic leukaemia (CLL) is a malignant disorder of the white blood cells (lymphocytes). CLL causes abnormal lymphocytes to proliferate, thus impairing the production and function of red blood cells, platelets and normal lymphocytes. This in turn causes anaemia, failure of the blood to clot and increased susceptibility to infection.\n\nThere are two main types of lymphocytes called B-cells and T-cells. B-cell CLL comprises about 95% of all CLL.\n\nOften, the disease goes undiagnosed either until it is well advanced, or until a chance test shows abnormally high levels of lymphocytes in the blood.\n\nCLL is a chronic, life-threatening and incurable disease. It is the most common form of leukaemia in the Western world, affecting about 2.7 people in every 100,000. Predominantly, it is a disease of older people, with 75% of those diagnosed being over the age of 60 years, although 6% are below the age of 50 years. Twice as many men as women are affected.\n\nLife expectancy depends on the stage at which the disease is diagnosed (see Table 2, Appendix D for definition of stages). For those in the early stages of the disease, median life expectancy is over 10 years, while for patients with advanced disease it is only 6 to 9 months. Other adverse prognostic factors include early age of onset.\n\nDespite the apparently better prognosis in early disease, there is no evidence that early treatment is beneficial, and it may indeed be harmful. Since many patients have limited disease, they do not require anything more than general observation, referred to as 'watchful waiting'.\n\nWhen the disease progresses, a hierarchy of treatments is used. There is a trade-off between the likelihood of halting or reversing progression of the disease and the side-effects of drug treatment.\n\nResponse rates to chemotherapy of about 70% are seen in intermediate-stage disease, dropping to about 30% in later stages. In patients at intermediate or advanced stages of their disease an alkylating agent such as chlorambucil (with or without corticosteroids), cyclophosphamide or fludarabine (currently unlicensed in this indication) has been used as a first-line treatment.\n\nWhen patients relapse or fail to respond to one of the first-line treatments (usually chlorambucil or, occasionally, cyclophosphamide), either combination treatment (such as CHOP, CAP or CVP) or fludarabine monotherapy is employed. A single cycle of combination therapy usually consists of drugs given by both the intravenous route (day 1) and orally (for a further 4 days). Cycles are repeated monthly for up to six months. Fludarabine is sometimes used as third-line treatment after combination therapy has failed.", 'The Technology': 'Fludarabine is a cytotoxic agent of the antimetabolite class. It is currently licensed for patients with B-cell CLL with sufficient bone marrow reserve and who have not responded to, or whose disease has progressed during or after, treatment with at least one standard alkylating-agent containing regimen.\n\nIt is administered either as an intravenous infusion (over 30 minutes) or orally. This is repeated each day for 5 days, and this cycle is then repeated every 28 days for up to 6 cycles. The drug acquisition cost (for either intravenous or oral formulation) of a course of 6 cycles is about £3,900. Each intravenous infusion requires a day-case admission to hospital, while the oral preparation usually needs only a small number of hospital visits.\n\nAlthough the immediate side effects of fludarabine (nausea, vomiting, alopecia) are less troublesome than those of CHOP, there are frequent haematological adverse events (granulocytopenia, anaemia and thrombocytopenia), as well as other important long-term effects. Of these, the principal effect is T-cell immunosuppression, leading to a recommendation for prophylactic antibiotic treatment against Pneumocystis carinii pneumonia, and irradiation of all blood products given to the patient to prevent transfusion-related graft-versus-host disease. Concurrent corticosteroids increase this risk due to the additive lymphocytic activity and should therefore be avoided unless otherwise indicated. Additionally, autoimmune haemolytic anaemia is relatively common in patients with CLL. It occurs in about 1% to 5% of patients receiving fludarabine as a second line treatment. The haemolysis is often severe, may be difficult to treat, and is potentially fatal.\n\nNevertheless, on a day-to-day basis, fludarabine is generally tolerated better than conventional second line chemotherapy regimens, particularly in patients currently considered too frail to withstand combination therapies.', 'Evidence ': "# Clinical effectiveness\n\nThere are two randomised controlled trials (RCT) evaluating intravenous fludarabine as a second line agent in CLL. In one of these, comparing fludarabine with cladribine, an unknown number of patients had B-cell CLL. It is not possible therefore to derive from this study, results relevant to the indication under consideration.\n\nThe second RCT compared fludarabine with CAP. Only 96 of 196 patients studied had been previously treated with a first line agent. Response rates (RR) for these previously treated patients were 48% with fludarabine versus 27% with CAP (95% confidence interval on the difference of 21 percentage points was 2 to 40 percentage points). The fludarabine response rate was much higher than that seen in the case series (see below). Mostly, the responses were partial, with just 13% complete responses for fludarabine versus 6% for CAP (the difference is not statistically significant). Time to progression for previously treated patients (responders only) had a median of 324 days for fludarabine versus 179 days for CAP (the difference is not statistically significant). In addition there were 9 deaths in 48 patients with fludarabine compared with 3 out of 48 in the control arm (the difference is not statistically significant). No data on quality of life were collected as part of the trial. Adverse events, mostly haematological, were common in both arms of the trial.\n\nFor intravenous fludarabine, six case series with an aggregate population size of almost 1000 were found. Response rates averaged 32%. The response rate appears to decline in patients who have been treated more heavily prior to treatment with fludarabine, and is generally lowest for patients for whom fludarabine is the treatment of last resort. Where reported, mild or moderate side effects were common although 72% of patients experienced severe haematological adverse events (based on laboratory results). The degree and length of response in these studies is greater than those of comparable studies for combination therapy, although it is not known whether there is an impact on length of survival. The quality of all such studies is lower than that of randomised controlled trials, due to the possibility of unrepresentative or biased patient selection, heterogeneity between studies, and placebo effects of unknown size.\n\nQuality of life data have not been formally collected as part of these studies. Some evidence, however, is available from the Lymphoma Association, whose survey showed that 74% of patients consider that they are in as good or better health during fludarabine treatment as they would have been with other chemotherapy.\n\nRecent data from the MRC-sponsored CLL3 study show that, for patients who failed to respond to first-line treatment with chlorambucil or chlorambucil plus epirubicin at 6 months, 80% responded to fludarabine (17% complete, 63% partial). This evidence is in general supportive of the use of fludarabine second line. It is, however, subject to the biases of being an uncontrolled case series, the difficulty in defining non-responders and the variation in times to recruitment into the study following 'failure' of first line treatment.\n\nOther evidence in the form of four randomised controlled trials for fludarabine alone against other chemotherapeutic agents for first line treatment (for which fludarabine is not currently licensed) shows that fludarabine gives higher rates of remission and longer remission than CAP, CHOP, or chlorambucil plus prednisolone, but no demonstrated survival advantage. For fludarabine against chlorambucil, one study favours fludarabine as above, but the other finds no difference between the two drugs. Assuming that a high positive correlation exists between the relative performance of fludarabine against its comparators in first and second line therapies, this evidence supports the case for the use of fludarabine in second-line therapy.\n\nFor oral fludarabine, an open study of 78 previously treated patients with CLL showed that 46% of patients responded (20% complete and 26% partial remission). Evidence on the bioavailability of the oral formulation and equivalence of blood levels of oral fludarabine with those of the intravenous preparation indicates that orally administered fludarabine is likely to have similar clinical efficacy to the intravenously administered preparation.\n\n# Cost effectiveness\n\nNo single piece of evidence is strong enough to establish whether fludarabine is a clinically effective agent for second line treatment of CLL. When the evidence is taken in aggregate, however, it is supportive of fludarabine as a clinically effective drug for this indication. The assessment of cost effectiveness, however, is also subject to considerable uncertainty, because reliable figures for the costs of dealing with adverse side effects are not available.\n\nThree sources have been used to examine the costs of overcoming adverse events in using fludarabine and CHOP. The first (described as the low estimate), submitted by the manufacturer, is based on very small numbers of patients, and is therefore subject to large sampling error. The second (described as the high estimate) was submitted by a different manufacturer for the treatment of a different type of lymphoma, and was also based on a small sample. This source yielded cost estimates over six times as high as the first source, much of which appears to be attributable to the disease having advanced much further, on average, in patients from the second source. The third was from the MRC trial CLL3, which may have included costs associated with the disease per se, as well as of side effects of fludarabine, yielded costs comparable with those of the high estimate.\n\nThe cost effectiveness estimates have been examined separately for oral and intravenous fludarabine, and for both of these against the comparators of CHOP and of no treatment, for both high and low estimates of the cost of side effects.\n\nOral fludarabine is less costly to administer than intravenous fludarabine. The estimated combined cost of acquisition and administration, based on an average of 4.1 cycles administered, is £3,000 for oral fludarabine (comprising £2,700 for acquisition and £300 for administration) against £5,300 for intravenous fludarabine (£2,700 acquisition, £2,600 administration).\n\nThe mean cost per year of remission from CLL of oral fludarabine against no treatment is estimated to be £9,000 (low cost of treating side effects) or £21,000 (high cost of treating side effects); for intravenous fludarabine, the corresponding estimates are £14,000 and £28,000; and for CHOP are £22,000 and £67,000.\n\nThe mean incremental cost-effectiveness ratio for oral fludarabine against CHOP is estimated to be £2,700 per year of remission (low cost of treating side-effects) and £200 per year of remission (high cost of treating side-effects) (the latter figure is smaller than the former because the cost of treating side-effects for CHOP is also much higher in the high-cost scenario). The corresponding estimates for intravenous fludarabine against CHOP are £10,600 and £10,500. Even if there is no increase in overall survival using fludarabine compared with that of CHOP, it is probable that oral fludarabine is cost effective against CHOP.\n\nIn clinical practice it is likely that if fludarabine were not given, then patients who would otherwise have been prescribed it would be prescribed CHOP or an equivalent combination. In this situation oral fludarabine is both a more clinically effective and a more cost effective drug than its alternatives, as well as being more likely to be acceptable to patients.", 'Implications for the NHS': 'This guidance is not expected to result in a net increase in NHS expenditure in England and Wales, because fludarabine is already in common use. Increases in drug acquisition costs are likely to be offset by the transfer to the oral formulation, and because the switch from combination therapies to fludarabine should reduce the costs of treating adverse side effects.\n\n(a) For each patient already being treated with fludarabine, it can be expected that cost savings in drug administration in switching from intravenous to oral fludarabine will be about £2,300 per course of an average 4 cycles (there was an average of 4 cycles of oral fludarabine given in one of the key trials).(b) For each patient new to fludarabine therapy who would otherwise have been prescribed combination chemotherapy (CHOP, CAP or CVP), the increased drug acquisition cost of fludarabine should be partially or fully offset by cost savings from avoiding the necessity of treating the side effects of combination drug therapy. For this group of patients, the net cost effect, on average, is likely to have a range of zero to £2,000, although this does not include the further costs of those who might subsequently also be treated with combination chemotherapy.(c) For each patient new to fludarabine therapy who would not have been able to tolerate combination chemotherapy, the additional costs are likely to be of the order of £6,000 to £9,000 per patient.', 'Further Research': 'Further appropriately constructed clinical trials should assess impact on quality of life directly.\n\nFurther research into fludarabine as a first line therapy, either singly or in combination with current first line drugs, would be of value. Recruitment of patients to the current CLL4 trial is recommended.\n\nMore comprehensive research, in the form of an adequately powered randomised controlled trial, to determine with greater certainty whether oral fludarabine is as clinically effective as intravenous fludarabine, is required.', 'Review of guidance': 'Information on the review of the guidance on this technology is available on the NICE website.\n\nAndrew DillonChief ExecutiveSeptember 2001', 'Appendix B. Sources of Evidence ': ". The following documentation and opinion was made available to the Committee:\n\na. Assessment Report prepared by the Department of Public Health and Epidemiology, University of Birmingham (Fludarabine as second line therapy for B-Cell chronic lymphocytic leukaemia, January 2001)\n\nAssessment Report Annexe prepared by the Department of Public Health and Epidemiology, University of Birmingham (Fludarabine as second line therapy for B-Cell chronic lymphocytic leukaemia: Effectiveness Annexe, May 2001)\n\nAssessment Report Cost- Effectiveness Annexe prepared by Dr A J Fischer, NICE Appraisals Team, May 2001\n\nb. Manufacturer/Sponsor submissions:\n\nSchering Health Care Ltd\n\nc. Professional/Specialist Group, Patient/Carer Group and Trade Association submissions:\n\nBritish National Lymphoma Investigation and UK CCCR\n\nBritish Committee for Standards in Haematology (BCSH)\n\nCancerBACUP\n\nLymphoma Association\n\nMacmillan Cancer Relief\n\nRoyal College of Pathologists\n\nd. External expert and patient advocate submissions:\n\nDr Andrew MacMillan, Oncologist, Mount Vernon Hospital\n\nDr Peter Hoskin, Consultant Clinical Oncologist, Mount Vernon Hospital\n\nDr Tracey Murray, Lecturer/Practitioner, St George's Healthcare NHS Trust\n\nCatriona Moore, Policy Officer, CancerBACUP\n\nJudith Brodie, Head of Cancer Support Services, CancerBACUP\n\nCatriona Gilmour Hamilton, Assistant Head of Information Services, The Lymphoma Association", 'Appendix C. Guidance on the use of fludarabine as second line therapy for B-cell chronic lymphocytic leukaemia': "'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.", 'Appendix D. Staging Systems': 'Rai\n\nCharacteristics\n\nMedian Survival\n\nStage 0\n\nLymphocytosis in blood and bone marrow only\n\nyears\n\nStage I\n\nLymphocytosis plus lymphadenopathy\n\nyears\n\nStage II\n\nLymphocytosis plus splenomegaly or hepatomegaly\n\nStage III\n\nLymphocytosis plus anaemia (Hb < 110 g/L)\n\n< 1 year\n\nStage IV\n\nLymphocytosis plus thrombocytopenia\n\n(platelets < 100 x 109/L)\n\nBinet\n\n\n\n\n\nStage A\n\n< 3 sites involved,\n\nHb > 100 g/L, platelets > 100 x 109/L\n\nyears\n\nStage B\n\n> 3 sites involved,\n\nHb > 100 g/L, platelets > 100 x 109/L\n\nyears\n\nStage C\n\nHb < 100 g/L, platelets > 100 x 109/L\n\nyears\n\n Involved sites are liver, spleen and lymph nodes in inguinal, axilliary and cervical regions.', 'Changes after publication': 'March 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2001. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta29
32c9c5e691d48301fd938979e42d4897c34ac711	nice	Guidance on the use of Riluzole (Rilutek) for the treatment of Motor Neurone Disease	Guidance on the use of Riluzole (Rilutek) for the treatment of Motor Neurone Disease # Guidance Riluzole is recommended for the treatment of individuals with the amyotrophic lateral sclerosis (ALS) form of Motor Neurone Disease (MND). Riluzole therapy should be initiated by a neurological specialist with expertise in the management of MND. Routine supervision of therapy should be managed by locally agreed shared care protocols undertaken by general practitioners.# Clinical Need and Practice Motor neurone disease (MND) is characterised by progressive degeneration of the motor neurones of the brain, brain stem or spinal cord. Depending on the site of the lesions, characteristic signs may include spasticity, muscle stiffness, brisk or diminished reflexes, muscle wasting and fasciculation, and both flaccid and/or spastic weakness. The classification and terminology used to describe the different Motor Neurone Disease syndromes are not always clear or consistent. This partly reflects uncertainties surrounding the underlying causes of MND and the mechanism of neuronal damage. There is also debate about the extent to which different syndromes are simply manifestations of the same disease process or whether there are several different disease mechanisms. The term 'Motor Neurone Disease' is used to describe variants of the disease – namely progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) which includes Progressive Bulbar Palsy (PBP). ALS, which is characterised by both upper and lower motor neurone signs, is the most common form of MND, accounting for 65% to 85% of all cases. Adult onset MND usually starts insidiously with symptoms and signs including stumbling, foot drop, weakened grip, slurred speech, cramp, muscle wasting, twitching and tiredness. Other symptoms of MND include muscle stiffness, paralysis, incoordination and impaired speech, swallowing and breathing. Most individuals die from ventilatory failure, resulting from progressive weakness and wasting of limb, respiratory and bulbar muscles within approximately 3 years of the onset of symptoms. The Institute was advised that, despite the terms of the product licence, it has been common clinical practice for riluzole to be used in all of the forms of MND referred to in paragraph 2.3. This may in part be because the mainland European and UK nomenclature for the disease differs. In mainland Europe, the terms MND and ALS are often used interchangeably. This document refers to ALS specifically in accordance with the terminology used in the current product licence for riluzole. There is no diagnostic test for MND. The diagnosis requires the demonstration of clinical signs affecting both the brain and spinal cord. Diagnosis is often delayed and can take more than 16 months from the onset of initial symptoms, which are commonly non-specific and include general fatigue. The incidence of ALS ranges from 1.8 to 2.2 per 100,000 population and prevalence ranges from 4.0 to 4.7 per 100,000 population in UK. Therefore at any one time about 2000 individuals per year in England and Wales are affected by ALS. There is a range of pharmacological interventions that provide symptomatic relief for people with MND. Surgical intervention may be necessary. Such interventions include percutaneous gastrostomy to enable feeding as the ability to swallow decreases and tracheostomy with or without ventilatory support to aid breathing as respiratory muscle weakness increases. Supportive and palliative care is currently available for people with MND. A wide range of multidisciplinary health and social services is required, particularly in the late stages of the disease, and need to be tailored to suit individual needs. NHS, personal social service and voluntary sector services needed include physiotherapy, occupational therapy, speech and language therapy and augmentative communication, mobility aids and district nursing support. In the later stages of the disease, the following interventions may also be required: enteral feeding (for severe dysphagia), domiciliary or hospice care, and ventilatory support, including mechanical ventilation and tracheostomy.# The Technology Riluzole (Rilutek) is currently the only drug licensed for treating ALS in the UK. The licensed indication of riluzole is to extend life or the time to mechanical ventilation for individuals with ALS. The Summary of Product Characteristics (SPC) recommends that riluzole should not be used in any other form of Motor Neurone Disease. The SPC also suggests that treatment should only be initiated by specialist physicians with experience in the management of Motor Neurone Disease. It is hypothesised that excessive stimulation of glutamate receptors on neurones may cause or play an important role in the destruction of motor neurones in MND. Glutamate is a neurotransmitter that tends to excite motor neurone cells. In vitro, riluzole inhibits the release of glutamate; decreases firing of motor neurones induced by glutamate receptor agonists and thus protects cells from glutamate-mediated damage. The main caution for use of riluzole is history of abnormal hepatic function. Regular blood testing (every month for 3 months, then every 3 months for a further 9 months and annually thereafter) is recommended to monitor hepatic function. Side effects include nausea, vomiting, weakness, tachycardia, somnolence, headache, dizziness, vertigo, pain, parasthesia and alterations in liver function tests. Side effects of dizziness or vertigo may affect the performance of skilled tasks such as driving. Riluzole is contraindicated in the presence of hepatic and/or renal impairment and during pregnancy and breast-feeding. The license dosage of riluzole is 100mg per day (50mg twice per day). The NHS list price (excluding VAT) of riluzole is £286 per treatment course, which amounts to an annual cost of £3718. An additional cost, incurred for monitoring liver enzymes, has been estimated to be a maximum of £24 per year, giving a total annual cost of treatment with riluzole of £3742.# Evidence Four randomised controlled trials (including a number of UK centres) in patients who fall within the diagnostic category of ALS have compared riluzole with placebo (a total of 1477 individuals). Three trials used riluzole at 100 mg/day and one used doses of 50, 100 and 200mg/day. Individuals were under 75 years, had a Forced Vital Capacity (FVC) ≥60% in three trials, with two of these also excluding patients who had suffered from MND for more than 5 years. The fourth trial recruited individuals who were older or who had a greater duration of disease (> 5 years) or who had a FVC<60%. All trials used tracheostomy-free survival as a primary outcome. Most individuals (in all four trials) were prevalent, rather than incident cases. The assessment report reviewed the results from all four of the trials identified and reported riluzole to be associated with a relative reduction in hazard ratio for tracheostomy-free survival at 18 months of 17% (i.e. hazard ratio of 0.88, 95% CI: 0.75- 1.02). There was some evidence of heterogeneity across the results of these four trials. When data on functional status were combined, a small reduction in the rate of deterioration of functional status was observed, although the statistical methods used to calculate changes were questionable. Furthermore it is not clear whether the estimated differences obtained using these methods were clinically significant. There was little evidence of a difference in adverse events between riluzole and placebo. There is strong clinical support for the use of riluzole in forms of MND other than ALS but the current licensed indications limit its use to ALS alone. The inclusion criteria for the published clinical trials has been restricted to a diagnosis of the ALS form of MND alone. Current estimates of the cost-effectiveness of riluzole must be viewed cautiously. Some of the key remaining uncertainties on benefits for the economic analysis concern the disease stage(s) in which the survival gain is experienced, the quality of life utility weights for ALS health states and the mean gain in life expectancy for individuals who take riluzole. Estimates from the two fully published trials suggest a gain in median tracheostomy free survival time of 2 months to 4 months. It is clear that riluzole is associated with a net increase in costs to the health service, though the magnitude of the increase is difficult to predict accurately. Using a published Markov model and 18 month trial follow up data, the manufacturer's submission provided a base case cost per quality adjusted life year (cost/QALY) estimate of £18,000 to £29,000 for riluzole. Based on a re-analysis of this Markov model using an alternative, more conservative, estimate of time-dependant probabilities, the assessment report derived discounted cost per QALY estimates for riluzole of between approximately £34,000 to £43, 500. These later estimates are consistent with the results obtained by the assessment report authors when using Weibull and Gompertz models to extrapolate survival over time. The Appraisal Committee considered the evidence of the clinical and cost effectiveness of this technology by reference to the Directions to the Institute issued by the Secretary of State. The Committee took account of the severity and relatively short life span of people with ALS and in particular, as directly reported to it, of the values which patients place on the extension of tracheostomy free survival time. With these considerations in mind, the Committee considered that the net increase in cost for the NHS of the use of riluzole in this indication was reasonable when set against the benefit, assessed as extended months of an acceptable (to patients) quality of life. The documentation and opinion available to the Appraisals Committee is set out in Appendix B.# Implications for the NHS It is estimated that the potential budget impact to the NHS in the England and Wales of making riluzole available to all individuals with ALS would be at maximum around £7.5 million per annum. Given an estimated current level of funding of riluzole for ALS of about £2 million per annum, this represents an additional cost to the NHS in England and Wales of about £5 million. However, there is considerable uncertainty about the proportion of patients who will take up this therapy. Moreover, these figures do not take into account the additional NHS costs of patient survival. A diagnosis of MND should be made or confirmed by a specialist physician with experience in the management of Motor Neurone Disease after appropriate investigations. In most cases, the specialist will be responsible for monitoring the progress of the disease and the safe use of riluzole. The needs of people with MND demand flexibility, and this monitoring role can be taken up by the general practitioner or by other physicians involved in providing shared care. In the latter stages of their disease, patients may wish to review their continued use of riluzole and they should be provided with the opportunity to discontinue treatment, if after discussion with the responsible clinician, they consider it appropriate.# Further research Further trials of riluzole are required to examine the relative effectiveness of differing dosing regimens. Methods for the early diagnosis of MND require development as they may enable earlier treatment and enhanced clinical outcomes.# Review of guidance Information on the review of the guidance on this technology is available on the NICE website Andrew DillonChief ExecutiveJanuary 2001# Appendix B: Sources of Evidence . The following documentation and opinion was made available to the Committee: a. Assessment Report Assessment report 'The clinical effectiveness and cost effectiveness of Riluzole in the Treatment of Motor Neurone Disease' by Stewart, Sandercock, Bryan, Hyde, Fry- Smith, Burls.West Midlands Development & Evaluation Service, University of Birmingham Update Assessment Report prepared by the West Midlands Development and Evaluation Service (The clinical effectiveness and cost-effectiveness of Riluzole for Motor Neurone Disease, August 2000) b. Manufacturer/Sponsor submissions: Aventis Pharma c. Professional/Specialist Group, Patient/Carer Group and Trade Association submissions: Association of British Neurologists & Royal College of Physicians Association for Palliative Medicine of Great Britain and Ireland Chartered Society of Physiotherapy Motor Neurone Disease Association Royal College of General Practitioners Royal College of Nursing Royal College of Speech and Language Therapists d. External expert and patient advocate submissions: Professor Pamela Shaw, Section of Neurology, Royal Hallamshire Hospital, Sheffield Ms. Julia Johnson, Speech and Language Therapist, King's College Hospital Mr. George Levvy, Chief Executive, MND Association Mr. Chris Davies, Member of MND Association.# Appendix C: Guidance on the use of Riluzole (Rilutek) for the Treatment of Motor Neurone Disease – patient information 'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.# Changes after publication March 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2001. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Riluzole is recommended for the treatment of individuals with the amyotrophic lateral sclerosis (ALS) form of Motor Neurone Disease (MND).\n\nRiluzole therapy should be initiated by a neurological specialist with expertise in the management of MND. Routine supervision of therapy should be managed by locally agreed shared care protocols undertaken by general practitioners.', 'Clinical Need and Practice': "Motor neurone disease (MND) is characterised by progressive degeneration of the motor neurones of the brain, brain stem or spinal cord. Depending on the site of the lesions, characteristic signs may include spasticity, muscle stiffness, brisk or diminished reflexes, muscle wasting and fasciculation, and both flaccid and/or spastic weakness.\n\nThe classification and terminology used to describe the different Motor Neurone Disease syndromes are not always clear or consistent. This partly reflects uncertainties surrounding the underlying causes of MND and the mechanism of neuronal damage. There is also debate about the extent to which different syndromes are simply manifestations of the same disease process or whether there are several different disease mechanisms.\n\nThe term 'Motor Neurone Disease' is used to describe variants of the disease – namely progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) which includes Progressive Bulbar Palsy (PBP). ALS, which is characterised by both upper and lower motor neurone signs, is the most common form of MND, accounting for 65% to 85% of all cases. Adult onset MND usually starts insidiously with symptoms and signs including stumbling, foot drop, weakened grip, slurred speech, cramp, muscle wasting, twitching and tiredness. Other symptoms of MND include muscle stiffness, paralysis, incoordination and impaired speech, swallowing and breathing. Most individuals die from ventilatory failure, resulting from progressive weakness and wasting of limb, respiratory and bulbar muscles within approximately 3 years of the onset of symptoms.\n\nThe Institute was advised that, despite the terms of the product licence, it has been common clinical practice for riluzole to be used in all of the forms of MND referred to in paragraph 2.3. This may in part be because the mainland European and UK nomenclature for the disease differs. In mainland Europe, the terms MND and ALS are often used interchangeably. This document refers to ALS specifically in accordance with the terminology used in the current product licence for riluzole.\n\nThere is no diagnostic test for MND. The diagnosis requires the demonstration of clinical signs affecting both the brain and spinal cord. Diagnosis is often delayed and can take more than 16 months from the onset of initial symptoms, which are commonly non-specific and include general fatigue.\n\nThe incidence of ALS ranges from 1.8 to 2.2 per 100,000 population and prevalence ranges from 4.0 to 4.7 per 100,000 population in UK. Therefore at any one time about 2000 individuals per year in England and Wales are affected by ALS.\n\nThere is a range of pharmacological interventions that provide symptomatic relief for people with MND. Surgical intervention may be necessary. Such interventions include percutaneous gastrostomy to enable feeding as the ability to swallow decreases and tracheostomy with or without ventilatory support to aid breathing as respiratory muscle weakness increases.\n\nSupportive and palliative care is currently available for people with MND. A wide range of multidisciplinary health and social services is required, particularly in the late stages of the disease, and need to be tailored to suit individual needs. NHS, personal social service and voluntary sector services needed include physiotherapy, occupational therapy, speech and language therapy and augmentative communication, mobility aids and district nursing support. In the later stages of the disease, the following interventions may also be required: enteral feeding (for severe dysphagia), domiciliary or hospice care, and ventilatory support, including mechanical ventilation and tracheostomy.", 'The Technology': 'Riluzole (Rilutek) is currently the only drug licensed for treating ALS in the UK. The licensed indication of riluzole is to extend life or the time to mechanical ventilation for individuals with ALS. The Summary of Product Characteristics (SPC) recommends that riluzole should not be used in any other form of Motor Neurone Disease. The SPC also suggests that treatment should only be initiated by specialist physicians with experience in the management of Motor Neurone Disease.\n\nIt is hypothesised that excessive stimulation of glutamate receptors on neurones may cause or play an important role in the destruction of motor neurones in MND. Glutamate is a neurotransmitter that tends to excite motor neurone cells. In vitro, riluzole inhibits the release of glutamate; decreases firing of motor neurones induced by glutamate receptor agonists and thus protects cells from glutamate-mediated damage.\n\nThe main caution for use of riluzole is history of abnormal hepatic function. Regular blood testing (every month for 3 months, then every 3 months for a further 9 months and annually thereafter) is recommended to monitor hepatic function. Side effects include nausea, vomiting, weakness, tachycardia, somnolence, headache, dizziness, vertigo, pain, parasthesia and alterations in liver function tests. Side effects of dizziness or vertigo may affect the performance of skilled tasks such as driving. Riluzole is contraindicated in the presence of hepatic and/or renal impairment and during pregnancy and breast-feeding.\n\nThe license dosage of riluzole is 100mg per day (50mg twice per day). The NHS list price (excluding VAT) of riluzole is £286 per treatment course, which amounts to an annual cost of £3718. An additional cost, incurred for monitoring liver enzymes, has been estimated to be a maximum of £24 per year, giving a total annual cost of treatment with riluzole of £3742.', 'Evidence': "Four randomised controlled trials (including a number of UK centres) in patients who fall within the diagnostic category of ALS have compared riluzole with placebo (a total of 1477 individuals). Three trials used riluzole at 100 mg/day and one used doses of 50, 100 and 200mg/day. Individuals were under 75 years, had a Forced Vital Capacity (FVC) ≥60% in three trials, with two of these also excluding patients who had suffered from MND for more than 5 years. The fourth trial recruited individuals who were older or who had a greater duration of disease (> 5 years) or who had a FVC<60%.\n\nAll trials used tracheostomy-free survival as a primary outcome. Most individuals (in all four trials) were prevalent, rather than incident cases.\n\nThe assessment report reviewed the results from all four of the trials identified and reported riluzole to be associated with a relative reduction in hazard ratio for tracheostomy-free survival at 18 months of 17% (i.e. hazard ratio of 0.88, 95% CI: 0.75- 1.02). There was some evidence of heterogeneity across the results of these four trials.\n\nWhen data on functional status were combined, a small reduction in the rate of deterioration of functional status was observed, although the statistical methods used to calculate changes were questionable. Furthermore it is not clear whether the estimated differences obtained using these methods were clinically significant.\n\nThere was little evidence of a difference in adverse events between riluzole and placebo.\n\nThere is strong clinical support for the use of riluzole in forms of MND other than ALS but the current licensed indications limit its use to ALS alone. The inclusion criteria for the published clinical trials has been restricted to a diagnosis of the ALS form of MND alone.\n\nCurrent estimates of the cost-effectiveness of riluzole must be viewed cautiously. Some of the key remaining uncertainties on benefits for the economic analysis concern the disease stage(s) in which the survival gain is experienced, the quality of life utility weights for ALS health states and the mean gain in life expectancy for individuals who take riluzole. Estimates from the two fully published trials suggest a gain in median tracheostomy free survival time of 2 months to 4 months. It is clear that riluzole is associated with a net increase in costs to the health service, though the magnitude of the increase is difficult to predict accurately.\n\nUsing a published Markov model and 18 month trial follow up data, the manufacturer's submission provided a base case cost per quality adjusted life year (cost/QALY) estimate of £18,000 to £29,000 for riluzole. Based on a re-analysis of this Markov model using an alternative, more conservative, estimate of time-dependant probabilities, the assessment report derived discounted cost per QALY estimates for riluzole of between approximately £34,000 to £43, 500. These later estimates are consistent with the results obtained by the assessment report authors when using Weibull and Gompertz models to extrapolate survival over time.\n\nThe Appraisal Committee considered the evidence of the clinical and cost effectiveness of this technology by reference to the Directions to the Institute issued by the Secretary of State. The Committee took account of the severity and relatively short life span of people with ALS and in particular, as directly reported to it, of the values which patients place on the extension of tracheostomy free survival time. With these considerations in mind, the Committee considered that the net increase in cost for the NHS of the use of riluzole in this indication was reasonable when set against the benefit, assessed as extended months of an acceptable (to patients) quality of life.\n\nThe documentation and opinion available to the Appraisals Committee is set out in Appendix B.", 'Implications for the NHS': 'It is estimated that the potential budget impact to the NHS in the England and Wales of making riluzole available to all individuals with ALS would be at maximum around £7.5 million per annum. Given an estimated current level of funding of riluzole for ALS of about £2 million per annum, this represents an additional cost to the NHS in England and Wales of about £5 million. However, there is considerable uncertainty about the proportion of patients who will take up this therapy. Moreover, these figures do not take into account the additional NHS costs of patient survival.\n\nA diagnosis of MND should be made or confirmed by a specialist physician with experience in the management of Motor Neurone Disease after appropriate investigations. In most cases, the specialist will be responsible for monitoring the progress of the disease and the safe use of riluzole. The needs of people with MND demand flexibility, and this monitoring role can be taken up by the general practitioner or by other physicians involved in providing shared care.\n\nIn the latter stages of their disease, patients may wish to review their continued use of riluzole and they should be provided with the opportunity to discontinue treatment, if after discussion with the responsible clinician, they consider it appropriate.', 'Further research': 'Further trials of riluzole are required to examine the relative effectiveness of differing dosing regimens.\n\nMethods for the early diagnosis of MND require development as they may enable earlier treatment and enhanced clinical outcomes.', 'Review of guidance': 'Information on the review of the guidance on this technology is available on the NICE website\n\nAndrew DillonChief ExecutiveJanuary 2001', 'Appendix B: Sources of Evidence': ". The following documentation and opinion was made available to the Committee:\n\na. Assessment Report\n\nAssessment report 'The clinical effectiveness and cost effectiveness of Riluzole in the Treatment of Motor Neurone Disease' by Stewart, Sandercock, Bryan, Hyde, Fry- Smith, Burls.West Midlands Development & Evaluation Service, University of Birmingham\n\nUpdate Assessment Report prepared by the West Midlands Development and Evaluation Service (The clinical effectiveness and cost-effectiveness of Riluzole for Motor Neurone Disease, August 2000)\n\nb. Manufacturer/Sponsor submissions:\n\nAventis Pharma\n\nc. Professional/Specialist Group, Patient/Carer Group and Trade Association submissions:\n\nAssociation of British Neurologists & Royal College of Physicians\n\nAssociation for Palliative Medicine of Great Britain and Ireland\n\nChartered Society of Physiotherapy\n\nMotor Neurone Disease Association\n\nRoyal College of General Practitioners\n\nRoyal College of Nursing\n\nRoyal College of Speech and Language Therapists\n\nd. External expert and patient advocate submissions:\n\nProfessor Pamela Shaw, Section of Neurology, Royal Hallamshire Hospital, Sheffield\n\nMs. Julia Johnson, Speech and Language Therapist, King's College Hospital\n\nMr. George Levvy, Chief Executive, MND Association\n\nMr. Chris Davies, Member of MND Association.", 'Appendix C: Guidance on the use of Riluzole (Rilutek) for the Treatment of Motor Neurone Disease – patient information': "'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.", 'Changes after publication': 'March 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2001. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta20
4883dd4a4b8a2ba7b430baa02492f45a18d6e602	nice	Guidance on the use of inhaler systems (devices) in children under the age of 5 years with chronic asthma	Guidance on the use of inhaler systems (devices) in children under the age of 5 years with chronic asthma # Guidance For children under the age of 5 years with chronic stable asthma both corticosteroids and bronchodilator therapy should be routinely delivered by pressurised metered dose inhaler (pMDI) and spacer system, with a facemask where necessary. Where this combination is not clinically effective for the child and depending on the child's condition, nebulised therapy may be considered and in the case of children aged 3 to 5 years, a dry powder inhaler (DPI) may also be considered. Choice of device to be made within the pMDI and spacer range should be primarily governed by specific individual need and the likelihood of good compliance. Once these factors have been taken into account, choice should be made on the basis of cost minimisation.# Clinical Need and Practice Asthma is a common disease that produces symptoms of wheezing and breathlessness. It affects the lower airways and results in narrowing (bronchoconstriction) of the airways with consequent reduction in the flow of gases between the airways and lung alveoli. It can be triggered by a variety of environmental factors such as infection, allergy, airborne chemicals and also exercise. There are a number of patterns of lower airways disease in early childhood that results in two predominant clinical patterns (acute wheezy episodes and recurrent day to day symptoms) that may occur separately or together in the child. The overall prevalence of asthma in England and Wales is around 8% to 10% although not all cases are currently being treated. In all children under the age of 5 years about 9% of boys and 6% of girls are prescribed inhalers. There is a strong genetic component in the aetiology of this disease. There is also wide geographical variation in prevalence, with asthma being more common in, for example, urban rather than rural communities. It has a wide range of severity, is the cause of considerable morbidity and a rare cause of death. The primary objective of asthma treatment is to achieve optimal control of the disease by reducing exacerbations, increasing lung function and limiting symptoms in order to maximise the quality of life of the child. This is currently best achieved by delivering both symptom relieving (bronchodilators – including ß2 agonists and anticholinergics) and preventive anti-inflammatory drugs (typically corticosteroids) by inhalation. In the UK, asthma treatment is strongly influenced by the 1997 guidelines of the British Thoracic Society (BTS), which promote step-wise management of increasingly severe asthma. The 1997 BTS guidelines are mainly based on a consensus of expert opinion. The estimated annual drug cost for asthma to the NHS in England and Wales in all age groups is approximately £115 million. In children under the age of 5 years this cost is about £8 million.# The Technology It is important to ensure that an inhaler device delivers the drugs to the airways consistently and in the appropriate quantity. There are a variety of inhaler devices that can be used in the management of asthma: hand held inhalers i.e. pressurised metered dose inhalers (pMDIs) (which can be breath activated or manual) and dry-powder inhalation systems (DPIs) and nebulisers. All the metered dose inhaler systems require co-ordination of activation and inhalation and may be difficult to use, particularly for younger children. For this reason a pMDI should be combined with a spacer device in young children. The purpose of the spacer device is to act as an intermediary chamber into which the pMDI can discharge the drug allowing the child to inhale over several breaths. The inhalation devices have different mechanical characteristics which, combined with child and carer factors, leads to variation in both the quantity of drug delivered by the device and the amount actually deposited in the lung. Using the appropriate inhalation device is important to ensure reproducibility and consistency of drug dosing, as well as compliance for which child and carer acceptability and education regarding device usage may also be major factors. The 1997 BTS Guidelines recommend the following device choices for children of under 5 years of age: Age Group st Choice Device nd Choice Device rd Choice Device Breath-actuated Dry-powder -2 years inclusive MDI + spacer + face mask MDI + spacer Nebuliser (rarely needed) Avoid Avoid -5 years inclusive MDI + spacer MDI + spacer + face mask Nebuliser (rarely needed) Not proven Possible use for ß2-agonist but not recommended for corticosteroids Interpretation of the evidence base for effectiveness of inhaler devices is influenced by a number of potential factors – the drug being delivered by the device, the severity of asthma, whether the condition is acute or chronic and the ability of the child/carer to effectively use the device. Moreover it is not possible to directly extrapolate to children under the age of five years, data collected in older children and adults, as the young child's anatomy and physiology may substantially alter the amount of drug delivered.# Evidence Delivery of corticosteriods by a hand held device The evidence base for pressurised metered dose inhalers (pMDIs) plus spacer versus dry-powder inhalation systems (DPI) for the delivery of corticosteriods in children with chronic asthma is relatively small and of poor quality. Two randomised controlled trials were identified, which recruited children of 5 years or under. These trials involved a total of 140 children, although the majority of these recruited children of 5 years or older. One of these trials was inadequately powered and compared a pMDI alone (not recommended by current BTS guidelines) versus DPI. The second and largest trial demonstrated no difference in steroid delivery via a pMDI plus spacer compared to DPI (at half MDI dosage). Delivery of ß agonists by a hand held device The evidence base for pressurised metered dose inhalers (pMDIs) alone or pMDI plus spacer compared to dry-powder inhalation systems (DPI) in children with chronic asthma is poor. Four randomised controlled trials were identified that recruited children of 5 years or less. These trials involved a total of 278 children, some of which were aged 5 years or more. The remaining three studies demonstrated no difference when comparing ß2 agonist delivery via pMDI plus spacer with ß2 agonist delivery by DPI. Delivery of ß agonists or anticholinergics by nebuliser The evidence for nebulised bronchodilators compared with bronchodilator delivery via hand held device in children with chronic asthma is also poor. Three randomised controlled trials which recruited children aged 5 years or less, were identified. These trials were small and involved a total of 51 children, although many of the children were aged 5 years or older. No differences were found between nebulisation, pMDIs or dry powder devices. These trials are likely to be of insufficient size to detect small differences between devices. Cost Effectiveness There is currently a wide range in the cost of drug/inhaler combinations. No cost effectiveness studies were identified that make direct comparison between asthma devices in children under the age of 5 years with chronic asthma. The documentation and opinion available to the Appraisal Committee is set out in Appendix B.# Implications for the NHS Where the 1997 BTS guidelines are currently being applied in practice, the guidance is unlikely to result in substantial change in NHS costs. The impact of referral patterns is difficult to predict. It is likely however to strengthen and improve the quality of primary care based asthma therapy, thereby reducing the need for admission or outpatient referral.# Further research At present there is insufficient evidence regarding the most clinically and cost effective spacer (e.g. small or large volume). This is reflected in the current lack of standardisation and variations in the usage of these devices. Further research in this area should be carried out in relation to optimising the reproducibility, consistency and acceptability of these delivery systems as well as their overall clinical and cost effectiveness. Well conducted community based trials in the management of asthma in young children and studies to investigate factors determining compliance (including health education and the acceptability of devices) in this group of children would enhance the future evidence base.# Review of Guidance Information on the review of the guidance on this technology is available on the NICE website Andrew DillonChief ExecutiveAugust 2000# Appendix B: Sources of Evidence i) The following documentation and opinion was made available to the Committee: a) Assessment Report The effectiveness of inhaler devices for young children with asthma; Prepared by Payne N & Beard S, Trent Institute for Health Services Research, School of Health & Related Research, University of Sheffield;Wright, Brocklebank,D & Ram F, Bradford Hospitals NHS Trust; Taylor RS, National Institute for Clinical Excellence. March 2000. b) Manufacturer/Sponsor submissions: i. AstraZeneca ii. Boehringer Inglheim Ltd. iii. Aventis Pharma (formerly Rhône-Poulenc Rorer) iv. Boehringer Inglheim Ltd. v. Glaxo Wellcome vi. 3M Health Care Ltd. vii. Norton Healthcare viii.Yamanouchi Pharma Ltd. c) Professional/specialist group, patient/carer group and trade association submissions; i. Association of British Health-Care Industries ii. British Medical Association iii. British Thoracic Society iv. National Asthma Campaign v. Royal College of Nursing vi. Royal College of Paediatrics & Child Health vii. Royal College of Physicians ii) The following experts were invited to make submissions to the Committee: a) Dr Andrew Bush, Reader in Paediatric Respirology & Honorary Consultant Paediatric Chest Physician, Royal Brompton Hospital, London. b) Dr C O'Callaghan, Senior Lecturer & Consultant Paediatrician,University of Leicester & Leicester Royal Infirmary Children's Hospital.# Appendix C: Guidance on inhalers for childhood asthma – patient information 'Understanding NICE Guidance' , a summary of this guidance for patients and carers can be found on our website.# Changes after publication March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2000. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "For children under the age of 5 years with chronic stable asthma both corticosteroids and bronchodilator therapy should be routinely delivered by pressurised metered dose inhaler (pMDI) and spacer system, with a facemask where necessary.\n\nWhere this combination is not clinically effective for the child and depending on the child's condition, nebulised therapy may be considered and in the case of children aged 3 to 5 years, a dry powder inhaler (DPI) may also be considered.\n\nChoice of device to be made within the pMDI and spacer range should be primarily governed by specific individual need and the likelihood of good compliance. Once these factors have been taken into account, choice should be made on the basis of cost minimisation.", 'Clinical Need and Practice': 'Asthma is a common disease that produces symptoms of wheezing and breathlessness. It affects the lower airways and results in narrowing (bronchoconstriction) of the airways with consequent reduction in the flow of gases between the airways and lung alveoli. It can be triggered by a variety of environmental factors such as infection, allergy, airborne chemicals and also exercise. There are a number of patterns of lower airways disease in early childhood that results in two predominant clinical patterns (acute wheezy episodes and recurrent day to day symptoms) that may occur separately or together in the child.\n\nThe overall prevalence of asthma in England and Wales is around 8% to 10% although not all cases are currently being treated. In all children under the age of 5 years about 9% of boys and 6% of girls are prescribed inhalers. There is a strong genetic component in the aetiology of this disease. There is also wide geographical variation in prevalence, with asthma being more common in, for example, urban rather than rural communities. It has a wide range of severity, is the cause of considerable morbidity and a rare cause of death.\n\nThe primary objective of asthma treatment is to achieve optimal control of the disease by reducing exacerbations, increasing lung function and limiting symptoms in order to maximise the quality of life of the child. This is currently best achieved by delivering both symptom relieving (bronchodilators – including ß2 agonists and anticholinergics) and preventive anti-inflammatory drugs (typically corticosteroids) by inhalation. In the UK, asthma treatment is strongly influenced by the 1997 guidelines of the British Thoracic Society (BTS), which promote step-wise management of increasingly severe asthma. The 1997 BTS guidelines are mainly based on a consensus of expert opinion.\n\nThe estimated annual drug cost for asthma to the NHS in England and Wales in all age groups is approximately £115 million. In children under the age of 5 years this cost is about £8 million.', 'The Technology': "It is important to ensure that an inhaler device delivers the drugs to the airways consistently and in the appropriate quantity. There are a variety of inhaler devices that can be used in the management of asthma: hand held inhalers i.e. pressurised metered dose inhalers (pMDIs) (which can be breath activated or manual) and dry-powder inhalation systems (DPIs) and nebulisers. All the metered dose inhaler systems require co-ordination of activation and inhalation and may be difficult to use, particularly for younger children. For this reason a pMDI should be combined with a spacer device in young children. The purpose of the spacer device is to act as an intermediary chamber into which the pMDI can discharge the drug allowing the child to inhale over several breaths.\n\nThe inhalation devices have different mechanical characteristics which, combined with child and carer factors, leads to variation in both the quantity of drug delivered by the device and the amount actually deposited in the lung. Using the appropriate inhalation device is important to ensure reproducibility and consistency of drug dosing, as well as compliance for which child and carer acceptability and education regarding device usage may also be major factors.\n\nThe 1997 BTS Guidelines recommend the following device choices for children of under 5 years of age:\n\nAge Group\n\nst Choice Device\n\nnd Choice Device\n\nrd Choice Device\n\nBreath-actuated\n\nDry-powder\n\n-2 years inclusive\n\nMDI + spacer + face mask\n\nMDI + spacer\n\nNebuliser (rarely needed)\n\nAvoid\n\nAvoid\n\n-5 years inclusive\n\nMDI + spacer\n\nMDI + spacer + face mask\n\nNebuliser (rarely needed)\n\nNot proven\n\nPossible use for ß2-agonist but not recommended for corticosteroids\n\nInterpretation of the evidence base for effectiveness of inhaler devices is influenced by a number of potential factors – the drug being delivered by the device, the severity of asthma, whether the condition is acute or chronic and the ability of the child/carer to effectively use the device. Moreover it is not possible to directly extrapolate to children under the age of five years, data collected in older children and adults, as the young child's anatomy and physiology may substantially alter the amount of drug delivered.", 'Evidence': 'Delivery of corticosteriods by a hand held device\n The evidence base for pressurised metered dose inhalers (pMDIs) plus spacer versus dry-powder inhalation systems (DPI) for the delivery of corticosteriods in children with chronic asthma is relatively small and of poor quality. Two randomised controlled trials were identified, which recruited children of 5 years or under. These trials involved a total of 140 children, although the majority of these recruited children of 5 years or older. One of these trials was inadequately powered and compared a pMDI alone (not recommended by current BTS guidelines) versus DPI. The second and largest trial demonstrated no difference in steroid delivery via a pMDI plus spacer compared to DPI (at half MDI dosage).\n\nDelivery of ß\n \n 2 \n \n agonists by a hand held device \n The evidence base for pressurised metered dose inhalers (pMDIs) alone or pMDI plus spacer compared to dry-powder inhalation systems (DPI) in children with chronic asthma is poor. Four randomised controlled trials were identified that recruited children of 5 years or less. These trials involved a total of 278 children, some of which were aged 5 years or more. The remaining three studies demonstrated no difference when comparing ß2 agonist delivery via pMDI plus spacer with ß2 agonist delivery by DPI.\n\nDelivery of ß\n \n 2\n \n agonists or anticholinergics by nebuliser \n The evidence for nebulised bronchodilators compared with bronchodilator delivery via hand held device in children with chronic asthma is also poor. Three randomised controlled trials which recruited children aged 5 years or less, were identified. These trials were small and involved a total of 51 children, although many of the children were aged 5 years or older. No differences were found between nebulisation, pMDIs or dry powder devices. These trials are likely to be of insufficient size to detect small differences between devices.\n\nCost Effectiveness \n There is currently a wide range in the cost of drug/inhaler combinations. No cost effectiveness studies were identified that make direct comparison between asthma devices in children under the age of 5 years with chronic asthma.\n\nThe documentation and opinion available to the Appraisal Committee is set out in Appendix B.', 'Implications for the NHS': 'Where the 1997 BTS guidelines are currently being applied in practice, the guidance is unlikely to result in substantial change in NHS costs. The impact of referral patterns is difficult to predict. It is likely however to strengthen and improve the quality of primary care based asthma therapy, thereby reducing the need for admission or outpatient referral.', 'Further research': 'At present there is insufficient evidence regarding the most clinically and cost effective spacer (e.g. small or large volume). This is reflected in the current lack of standardisation and variations in the usage of these devices. Further research in this area should be carried out in relation to optimising the reproducibility, consistency and acceptability of these delivery systems as well as their overall clinical and cost effectiveness.\n\nWell conducted community based trials in the management of asthma in young children and studies to investigate factors determining compliance (including health education and the acceptability of devices) in this group of children would enhance the future evidence base.', 'Review of Guidance': 'Information on the review of the guidance on this technology is available on the NICE website\n\nAndrew DillonChief ExecutiveAugust 2000', 'Appendix B: Sources of Evidence': "i) The following documentation and opinion was made available to the Committee:\n\na) Assessment Report The effectiveness of inhaler devices for young children with asthma; Prepared by Payne N & Beard S, Trent Institute for Health Services Research, School of Health & Related Research, University of Sheffield;Wright, Brocklebank,D & Ram F, Bradford Hospitals NHS Trust; Taylor RS, National Institute for Clinical Excellence. March 2000.\n\nb) Manufacturer/Sponsor submissions:\n\ni. AstraZeneca\n\nii. Boehringer Inglheim Ltd.\n\niii. Aventis Pharma (formerly Rhône-Poulenc Rorer)\n\niv. Boehringer Inglheim Ltd.\n\nv. Glaxo Wellcome\n\nvi. 3M Health Care Ltd.\n\nvii. Norton Healthcare\n\nviii.Yamanouchi Pharma Ltd.\n\nc) Professional/specialist group, patient/carer group and trade association submissions;\n\ni. Association of British Health-Care Industries\n\nii. British Medical Association\n\niii. British Thoracic Society\n\niv. National Asthma Campaign\n\nv. Royal College of Nursing\n\nvi. Royal College of Paediatrics & Child Health\n\nvii. Royal College of Physicians\n\nii) The following experts were invited to make submissions to the Committee:\n\na) Dr Andrew Bush, Reader in Paediatric Respirology & Honorary Consultant Paediatric Chest Physician, Royal Brompton Hospital, London.\n\nb) Dr C O'Callaghan, Senior Lecturer & Consultant Paediatrician,University of Leicester & Leicester Royal Infirmary Children's Hospital.", 'Appendix C: Guidance on inhalers for childhood asthma – patient information': "'Understanding NICE Guidance'\n , a summary of this guidance for patients and carers can be found on our website.", 'Changes after publication': 'March 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2000. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ta10
a4335d2e759656081858c293b07aeff2f0879eec	nice	Guidance on the Extraction of Wisdom Teeth	Guidance on the Extraction of Wisdom Teeth Evidence-based recommendations on removing wisdom teeth in adults. # Guidance The practice of prophylactic removal of pathology-free impacted third molars should be discontinued in the NHS. The standard routine programme of dental care by dental practitioners and/or paraprofessional staff, need be no different, in general, for pathology free impacted third molars (those requiring no additional investigations or procedures). Surgical removal of impacted third molars should be limited to patients with evidence of pathology. Such pathology includes unrestorable caries, non-treatable pulpal and/or periapical pathology, cellulitis, abscess and osteomyelitis, internal/external resorption of the tooth or adjacent teeth, fracture of tooth, disease of follicle including cyst/tumour, tooth/teeth impeding surgery or reconstructive jaw surgery, and when a tooth is involved in or within the field of tumour resection. Specific attention is drawn to plaque formation and pericoronitis. Plaque formation is a risk factor but is not in itself an indication for surgery. The degree to which the severity or recurrence rate of pericoronitis should influence the decision for surgical removal of a third molar remains unclear. The evidence suggests that a first episode of pericoronitis, unless particularly severe, should not be considered an indication for surgery. Second or subsequent episodes should be considered the appropriate indication for surgery.# Clinical Need and Practice Permanent molar teeth normally erupt from the age of six onwards, with the third molars (wisdom teeth) being the last to erupt, usually between the ages of eighteen and twenty four years. Wisdom teeth may erupt normally into correct dental alignment and function or conversely develop in non- or minimally functional positions. Impaction occurs when there is prevention of complete eruption due to lack of space, obstruction or development in an abnormal position. This may result in a tooth erupting partially or not at all. Wisdom teeth can also be impacted, either erupting partially or not at all. Impaction may be associated with pathological changes including pericoronitis, an increased risk of caries and periodontal disease in adjacent teeth, and orthodontic problems in later life. Removal of wisdom teeth is one of the most common surgical procedures performed in the UK. Current practice includes both the removal of impacted third molars causing pathological changes as well as the early prophylactic removal of pathology-free impacted third molars. Wide variations in the rates of this latter procedure across the country, which suggest that in the past, up to 44% of wisdom teeth removals and prophylactic surgery may have been inappropriate, have been reported. However, in recent years, changes in the practice of removal of wisdom teeth may have taken place in response to Faculty of Dental Surgery, Royal College of Surgeon's guidelines. Even so, some 22% of procedures may still be inappropriate. In 1994/95 there were approximately 36,000 inpatient and 60,000 day case admissions in England. More recent figures (1998/99) for Wales indicate that there were up to 3000 procedures. It is estimated that the total cost to the NHS in England and Wales of wisdom teeth extractions is up to £12 million per year. Current clinical practice and parameters of care: The management of patients with third molar teeth. Faculty of Dental Surgery of the Royal College of Surgeons September 1997. # Evidence There is no reliable research evidence to support a health benefit to patients from the prophylactic removal of pathology-free impacted third molar teeth. Every procedure for the removal of an impacted third molar carries risk for the patient, including temporary or permanent nerve damage, alveolar osteitis, infection and haemorrhage as well as temporary local swelling, pain and restricted mouth opening. There are also risks associated with the need for general anaesthesia in some of these procedures, including rare and unpredictable death. Such patients are therefore being exposed to the risk of undertaking a surgical procedure unnecessarily. A list of the source documentation and opinion made available to the Appraisal Committee is attached as appendix B.# Implications for the NHS Given the uncertainty in current rates of prophylactic removal of pathology-free impacted third molars, it is difficult to precisely quantify the budget impact of discontinuation of this practice. However, based on 1994/95 data, this could result in an opportunity to release capacity in the specialty with a value of up to £5 million (NHS in England & Wales) The number of patients waiting for this operation, in England and Wales might change, if waiting lists are reviewed using this guidance.# Further research There are two ongoing randomised controlled trials (in the United States and in Denmark) comparing prophylactic extraction of wisdom teeth with management by deliberate retention. The results of these trials will be reviewed by the Institute to establish whether they have a material impact on this guidance.# Review of Guidances Information on the review of the guidance on this technology is available on the NICE website. Andrew DillonChief ExecutiveMarch 2000# Appendix C. Wisdom Teeth Removal – Patient Notes # What is NICE guidance? The National Institute for Clinical Excellence (NICE) is a part of the NHS. It has a team of experts who produce guidance for both the NHS and patients on medicines, medical equipment and clinical procedures. When the Institute evaluates these things, it is called an appraisal. Each appraisal takes around 12 months to complete and involves the manufacturers of the technology, patient groups and professional organisations. NICE was asked to look at wisdom teeth removal and provide guidance to the NHS which will help dentists and surgeons decide when wisdom teeth should be removed. # What are Wisdom Teeth and why are they operated on? Adult teeth normally come through from the age of 6 upwards, with the wisdom teeth being the last to arrive (usually between the ages of 18 & 24 years). Sometimes, as wisdom teeth come through they cause problems. The term used to describe wisdom teeth that don't come through normally is impacted wisdom teeth. Two reasons for this are a lack of space, or other teeth being in the way. For most people, impacted wisdom teeth cause no problems at all, but some people can suffer problems such as inflammation of the surrounding gum, a higher risk of tooth decay, gum disease in other teeth, and possibly problems with teeth in later life. Removal of wisdom teeth is one of the most common operations carried out in the UK. Impacted wisdom teeth have sometimes been removed whether or not they were causing problems. There is no reliable evidence to suggest that operating on impacted wisdom teeth that are not causing problems has any benefit for the patient. In fact every operation has some risk. # What do NICE recommend about the removal of Wisdom Teeth? Based on the evidence, NICE has recommended to the NHS that: . Impacted wisdom teeth that are free from disease (healthy) should not be operated on. There are two reasons for this a) There is no reliable research to suggest that this practice benefits patients b) Patients who do have healthy wisdom teeth removed are being exposed to the risks of surgery. These can include: nerve damage damage to other teeth infection bleeding and, rarely, death Also, after surgery to remove wisdom teeth, patients may: have swelling and pain be unable to open their mouth fully . Patients who have impacted wisdom teeth that are not causing problems should visit their dentist for their usual check-ups. . Only patients, who have diseased wisdom teeth, or other problems with their mouth, should have their wisdom teeth removed. Your dentist or oral surgeon will be aware of the sort of disease or condition which would require you to have surgery. Examples include: untreatable tooth decay abscesses cysts or tumours disease of the tissues around the tooth if the tooth is in the way of other surgery # What should I do? If you or a member of your family or someone you care for are having problems with their wisdom teeth you should discuss this with your dentist or surgeon. # Will NICE review its guidance? Yes. The guidance will be reviewed in March 2003. There is further research underway in this area. The results of this will be reviewed by NICE to decide if this guidance needs to be updated before 2003. ISBN: 978-1-4731-3148-4	{'Guidance': 'The practice of prophylactic removal of pathology-free impacted third molars should be discontinued in the NHS.\n\nThe standard routine programme of dental care by dental practitioners and/or paraprofessional staff, need be no different, in general, for pathology free impacted third molars (those requiring no additional investigations or procedures).\n\nSurgical removal of impacted third molars should be limited to patients with evidence of pathology. Such pathology includes unrestorable caries, non-treatable pulpal and/or periapical pathology, cellulitis, abscess and osteomyelitis, internal/external resorption of the tooth or adjacent teeth, fracture of tooth, disease of follicle including cyst/tumour, tooth/teeth impeding surgery or reconstructive jaw surgery, and when a tooth is involved in or within the field of tumour resection.\n\nSpecific attention is drawn to plaque formation and pericoronitis. Plaque formation is a risk factor but is not in itself an indication for surgery. The degree to which the severity or recurrence rate of pericoronitis should influence the decision for surgical removal of a third molar remains unclear. The evidence suggests that a first episode of pericoronitis, unless particularly severe, should not be considered an indication for surgery. Second or subsequent episodes should be considered the appropriate indication for surgery.', 'Clinical Need and Practice': "Permanent molar teeth normally erupt from the age of six onwards, with the third molars (wisdom teeth) being the last to erupt, usually between the ages of eighteen and twenty four years. Wisdom teeth may erupt normally into correct dental alignment and function or conversely develop in non- or minimally functional positions. Impaction occurs when there is prevention of complete eruption due to lack of space, obstruction or development in an abnormal position. This may result in a tooth erupting partially or not at all. Wisdom teeth can also be impacted, either erupting partially or not at all. Impaction may be associated with pathological changes including pericoronitis, an increased risk of caries and periodontal disease in adjacent teeth, and orthodontic problems in later life.\n\nRemoval of wisdom teeth is one of the most common surgical procedures performed in the UK. Current practice includes both the removal of impacted third molars causing pathological changes as well as the early prophylactic removal of pathology-free impacted third molars. Wide variations in the rates of this latter procedure across the country, which suggest that in the past, up to 44% of wisdom teeth removals and prophylactic surgery may have been inappropriate, have been reported. However, in recent years, changes in the practice of removal of wisdom teeth may have taken place in response to Faculty of Dental Surgery, Royal College of Surgeon's guidelines. Even so, some 22% of procedures may still be inappropriate. In 1994/95 there were approximately 36,000 inpatient and 60,000 day case admissions in England. More recent figures (1998/99) for Wales indicate that there were up to 3000 procedures. It is estimated that the total cost to the NHS in England and Wales of wisdom teeth extractions is up to £12 million per year.\n\n \n Current clinical practice and parameters of care: The management of patients with third molar teeth. Faculty of Dental Surgery of the Royal College of Surgeons September 1997.\n\n", 'Evidence': 'There is no reliable research evidence to support a health benefit to patients from the prophylactic removal of pathology-free impacted third molar teeth.\n\nEvery procedure for the removal of an impacted third molar carries risk for the patient, including temporary or permanent nerve damage, alveolar osteitis, infection and haemorrhage as well as temporary local swelling, pain and restricted mouth opening. There are also risks associated with the need for general anaesthesia in some of these procedures, including rare and unpredictable death. Such patients are therefore being exposed to the risk of undertaking a surgical procedure unnecessarily.\n\nA list of the source documentation and opinion made available to the Appraisal Committee is attached as appendix B.', 'Implications for the NHS': 'Given the uncertainty in current rates of prophylactic removal of pathology-free impacted third molars, it is difficult to precisely quantify the budget impact of discontinuation of this practice. However, based on 1994/95 data, this could result in an opportunity to release capacity in the specialty with a value of up to £5 million (NHS in England & Wales)\n\nThe number of patients waiting for this operation, in England and Wales might change, if waiting lists are reviewed using this guidance.', 'Further research': 'There are two ongoing randomised controlled trials (in the United States and in Denmark) comparing prophylactic extraction of wisdom teeth with management by deliberate retention. The results of these trials will be reviewed by the Institute to establish whether they have a material impact on this guidance.', 'Review of Guidances': 'Information on the review of the guidance on this technology is available on the NICE website.\n\nAndrew DillonChief ExecutiveMarch 2000', 'Appendix C. Wisdom Teeth Removal – Patient Notes': "# What is NICE guidance?\n\nThe National Institute for Clinical Excellence (NICE) is a part of the NHS. It has a team of experts who produce guidance for both the NHS and patients on medicines, medical equipment and clinical procedures.\n\nWhen the Institute evaluates these things, it is called an appraisal. Each appraisal takes around 12 months to complete and involves the manufacturers of the technology, patient groups and professional organisations.\n\nNICE was asked to look at wisdom teeth removal and provide guidance to the NHS which will help dentists and surgeons decide when wisdom teeth should be removed.\n\n# What are Wisdom Teeth and why are they operated on?\n\nAdult teeth normally come through from the age of 6 upwards, with the wisdom teeth being the last to arrive (usually between the ages of 18 & 24 years).\n\nSometimes, as wisdom teeth come through they cause problems. The term used to describe wisdom teeth that don't come through normally is impacted wisdom teeth. Two reasons for this are a lack of space, or other teeth being in the way.\n\nFor most people, impacted wisdom teeth cause no problems at all, but some people can suffer problems such as inflammation of the surrounding gum, a higher risk of tooth decay, gum disease in other teeth, and possibly problems with teeth in later life.\n\nRemoval of wisdom teeth is one of the most common operations carried out in the UK. Impacted wisdom teeth have sometimes been removed whether or not they were causing problems. There is no reliable evidence to suggest that operating on impacted wisdom teeth that are not causing problems has any benefit for the patient.\n\nIn fact every operation has some risk.\n\n# What do NICE recommend about the removal of Wisdom Teeth?\n\nBased on the evidence, NICE has recommended to the NHS that:\n\n. Impacted wisdom teeth that are free from disease (healthy) should not be operated on. There are two reasons for this\n\na) There is no reliable research to suggest that this practice benefits patients\n\nb) Patients who do have healthy wisdom teeth removed are being exposed to the risks of surgery.\n\nThese can include:\n\nnerve damage\n\ndamage to other teeth\n\ninfection\n\nbleeding and, rarely, death\n\nAlso, after surgery to remove wisdom teeth, patients may:\n\nhave swelling and pain\n\nbe unable to open their mouth fully\n\n. Patients who have impacted wisdom teeth that are not causing problems should visit their dentist for their usual check-ups.\n\n. Only patients, who have diseased wisdom teeth, or other problems with their mouth, should have their wisdom teeth removed.\n\nYour dentist or oral surgeon will be aware of the sort of disease or condition which would require you to have surgery. Examples include:\n\nuntreatable tooth decay\n\nabscesses\n\ncysts or tumours\n\ndisease of the tissues around the tooth\n\nif the tooth is in the way of other surgery\n\n# What should I do?\n\nIf you or a member of your family or someone you care for are having problems with their wisdom teeth you should discuss this with your dentist or surgeon.\n\n# Will NICE review its guidance?\n\nYes. The guidance will be reviewed in March 2003.\n\nThere is further research underway in this area. The results of this will be reviewed by NICE to decide if this guidance needs to be updated before 2003.\n\nISBN: 978-1-4731-3148-4"}	https://www.nice.org.uk/guidance/ta1	Evidence-based recommendations on removing wisdom teeth in adults.
86d1c018b624d1f2e567f5fd9e286bf7482110c8	pubmed	EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta	EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta Osteogenesis imperfecta (OI) comprises a group of inherited disorders characterized by bone fragility and increased susceptibility to fractures. Historically, the laboratory confirmation of the diagnosis OI rested on cultured dermal fibroblasts to identify decreased or abnormal production of abnormal type I (pro)collagen molecules, measured by gel electrophoresis. With the discovery of COL1A1 and COL1A2 gene variants as a cause of OI, sequence analysis of these genes was added to the diagnostic process. Nowadays, OI is known to be genetically heterogeneous. About 90% of individuals with OI are heterozygous for causative variants in the COL1A1 and COL1A2 genes. The majority of remaining affected individuals have recessively inherited forms of OI with the causative variants in the more recently discovered genes CRTAP, FKBP10, LEPRE1,PLOD2, PPIB, SERPINF1, SERPINH1 and SP7, or in other yet undiscovered genes. These advances in the molecular genetic diagnosis of OI prompted us to develop new guidelines for molecular testing and reporting of results in which we take into account that testing is also used to 'exclude' OI when there is suspicion of non-accidental injury. Diagnostic flow, methods and reporting scenarios were discussed during an international workshop with 17 clinicians and scientists from 11 countries and converged in these best practice guidelines for the laboratory diagnosis of OI. # Introduction ## Classification of osteogenesis imperfecta Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders characterized by susceptibility to bone fractures with severity that ranges from death in the perinatal period to subtle increase in fracture frequency and in almost all cases presumed or proven defects in type I (pro)collagen biosynthesis. [bib_ref] Classification of osteogenesis imperfecta revisited, Van Dijk [/bib_ref] In 1979, David Sillence developed a four-type classification, which is still in use for classification according to clinical/radiological features: OI type I (mild OI with bone fragility and blue sclerae), II (perinatal lethal), III (progressive deforming) and IV (normal sclerae and mild deformity). 2,3 Dominant COL1A1/2 variants appeared to be causative in the majority of OI types. In 2004, OI types V and VI were added to this classification because of specific clinical/radiological and/or histological features, absence of abnormalities of type I (pro)collagen synthesis or structure on gel electrophoresis and absence of causative variants in the COL1A1/2 genes. [bib_ref] Type V osteogenesis imperfecta: a new form of brittle bone disease, Glorieux [/bib_ref] [bib_ref] Osteogenesis imperfecta type VI: a form of brittle bone disease with mineralization..., Glorieux [/bib_ref] With the discovery of rare recessive genetic causes of OI (see [fig_ref] Table 1: Genes in which sequence variants cause OI LRG sequences have been developed... [/fig_ref] , it was proposed to extend the classification with OI types VII and VIII. [bib_ref] Osteogenesis imperfecta, Rauch [/bib_ref] However, the classification and subdivision into different types of OI is still under discussion 1 because the phenotypic spectrum that results from mutations in some of these genes is almost as broad as that with mutations in type I collagen genes. There is also debate as to whether Bruck syndrome type I 7 and II, [bib_ref] Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of..., Ha-Vinh [/bib_ref] characterized clinically by bone fragility and congenital contractures of the large joints, should be classified as a type of OI. ## Biosynthesis of type i collagen Most individuals affected with OI are heterozygous for a causative variant in either of the two genes, COL1A1 or COL1A2, which encode the proa1(I) and proa2(I) chains of type I procollagen, respectively. Type I collagen is the major structural protein in bone, tendon and ligament. Recently, rare recessive genetic causes of OI have been described and, in all but one, the identified genes encode proteins involved in the biosynthesis of type I procollagen , [fig_ref] Table 1: Genes in which sequence variants cause OI LRG sequences have been developed... [/fig_ref]. [bib_ref] The zipper-like folding of collagen triple helices and the effects of mutations..., Engel [/bib_ref] [bib_ref] Osteogenesis imperfecta: translation of mutation to phenotype, Byers [/bib_ref] Genes, proteins and causative variants Autosomal dominant OI. The most common form of OI in most populations is OI type I. Cultured dermal fibroblasts from affected individuals produce about half the normal amount of type I procollagen molecules, which have normal structure. OI type I usually results from variants in one COL1A1 allele (frameshift, nonsense and splice-site alterations) that lead to mRNA instability and haploinsufficiency. In a small subset of individuals with OI type I, substitutions for glycine by small amino acids (cysteine, alanine and serine) near the amino terminal ends of the triple-helical domains of either COL1A1 or COL1A2 are found. In contrast, OI types II-IV are usually caused by sequence variants in either COL1A1 or COL1A2 that result in substitutions for glycine residues in the uninterrupted Gly-X-Y triplet repeat of the 1014-residue triple-helical domains encoded by each gene. Less common causative variants include splice-site alterations, variants in the carboxyl-terminal propeptide ## Figure 1 Critical steps in collagen type I biosynthesis and indication of genes known to be involved in OI. Type I collagen is the major structural protein in bone, tendon and ligament. It is first synthesized in the rough endoplasmic reticulum (rER) as type I procollagen, containing C-and N-terminal propeptides. In the rER, the two a1(I)-collagen chains encoded by COL1A1 and the one a2(I)-collagen chain encoded by COL1A2 comprising predominantly Gly-X-Y triplets, align and assemble in the C-to-N direction to form a triple helix. During folding, collagen is modified by, among others, specific enzymes that hydroxylate lysine and proline residues and glycosylate hydroxylysyl residues. This process is called post-translational modification and it stops when triple helix assembly is complete. The CRTAP/P3H1/CyPB complex encoded by the CRTAP, LEPRE1 and PPIB genes, is responsible for the 3-hydroxylation of P986 (p.P1164 counting from the methionine that initiates translation) but will most likely also act as a cis-trans isomerase and a molecular chaperone. FKBP65 encoded by FKBP10 also acts as a molecular chaperone for type I procollagen. The protein product of PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2) hydroxylates telopeptide lysines in the rER. HSP47 encoded by SERPINH1 is thought to maintain the stability of the triple helix. After folding, the procollagen molecules are transported through the Golgi apparatus and plasma membrane (PM) into the extracellular matrix (ECM) where cleavage of the N-and C-terminal propeptides occurs and collagen molecules aggregate to form fibrils. coding-domains or insertion/deletion events that lead to in-frame sequence alterations. Most of these variants result in synthesis of abnormal type I procollagen molecules characterized by post-translational over-modification of the triple-helical domain, which results in alterations visible by SDS-polyacrylamide gel electrophoresis. Loss of expression of either gene because of large-scale deletions appears to be rare. [bib_ref] Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele..., Willing [/bib_ref] [bib_ref] Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type..., Willing [/bib_ref] [bib_ref] Prenatal diagnosis of osteogenesis imperfecta type I by COL1A1 null-allele testing, Nuytinck [/bib_ref] [bib_ref] Complete COL1A1 allele deletions in osteogenesis imperfecta, Van Dijk [/bib_ref] More than 1000 distinct variants in the COL1A1 and COL1A2 genes have been identified that cause OI (R Dalgleish: Osteogenesis Imperfecta Variant Database (https://oi.gene.le.ac.uk, accessed 3 May 2011). [bib_ref] The human type I collagen mutation database, Dalgleish [/bib_ref] [bib_ref] The human collagen mutation database 1998, Dalgleish [/bib_ref] Autosomal recessive OI including Bruck syndrome In the last 5 years, candidate-gene approaches have identified several loci in which causative variants have been identified which result in the long-sought causes for recessively inherited forms of OI (see , [fig_ref] Table 2: Characteristics of recessive OI-related genes [/fig_ref]. We classify these genes in four groups-(i) one in which the genes encode proteins that contribute to the initial phase of chain recognition and propagation of molecular folding (CRTAP, LEPRE1 and PPIB) [bib_ref] Biochemical characterization of the prolyl 3-hydroxylase 1Ácartilage-associated proteinÁcyclophilin B complex, Ishikawa [/bib_ref] [bib_ref] Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta, Barnes [/bib_ref] [bib_ref] CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta, Morello [/bib_ref] [bib_ref] Null mutations in LEPRE1 and CRTAP cause severe recessive osteogenesis imperfecta, Marini [/bib_ref] [bib_ref] Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe..., Cabral [/bib_ref] [bib_ref] Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of..., Willaert [/bib_ref] [bib_ref] PPIB mutations cause severe osteogenesis imperfecta, Van Dijk [/bib_ref] [bib_ref] Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding, Barnes [/bib_ref] [bib_ref] Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and..., Pyott [/bib_ref] the second in which the genes encode proteins involved in the final quality control of type I procollagen (FKBP10 [bib_ref] Mutations in the gene encoding RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta, Alanay [/bib_ref] [bib_ref] Phenotypic heterogeneity or call for reclassification?, Shaheen [/bib_ref] [bib_ref] Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome, Kelley [/bib_ref] and SERPINH1 30 ), the third, which involves a gene encoding proteins involved in late modification and crosslink formation (PLOD2 [bib_ref] Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of..., Ha-Vinh [/bib_ref] [bib_ref] Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis, Van Der Slot [/bib_ref] and the fourth group, which involves recently recognized genes encoding proteins involved in bone cell differentiation (SP7 32 and possibly SERPINF1 33 ). ## Reasons for referral Prenatal. Prenatal ultrasounds showing abnormalities suggestive of OI (diminished mineralization of skull, platyspondyly or bowing, shortening and/or fractures of long bones) are an important reason for referral for molecular diagnostics of OI. Postnatal. Radiographs at birth suggestive of OI, recurrent and/or unexplained fractures with or without suspicion of non-accidental injury (NAI), primary (idiopathic) low bone mass, preferably with exclusion of secondary causes, a family history of OI and request for confirmation of the clinical diagnosis are all reasons for referral for molecular diagnostics of OI. However, in some cases dentinogenesis imperfecta or even blue sclerae might be the only reason for referral. As such, physicians from many specialties (gynaecologist, paediatrician, orthopaedic surgeon, clinical geneticist, general practitioner, dentist, ear nose throat specialist, endocrinologist, internist and ophthalmologist) might refer a patient for molecular analysis. Depending on the age of presentation, OI can be difficult to distinguish from some other genetic conditions, for example, Ehlers-Danlos syndrome arthrochalasis type (former EDS VIIA and B), isolated CRTAP forms a complex with the proteins encoded by LEPRE1 and PPIB. Apart from 3-prolyl hydroxylation activity, the complex appears to have cis-trans isomerase activity and is thought to act as a molecular chaperone initiating chain recognition and helical folding. Post-translational over-modification Osterix is an osteoblast-specific transcription factor which has been shown to be essential for bone formation in mice No post-translational over-modification IV a p.Pro1164 counting from the methionine that initiates translation. dentinogenesis imperfecta, blue sclerae and corneal fragility, hypophosphatasia, and non-genetic causes of fractures including NAI and idiopathic juvenile osteoporosis. [bib_ref] Genetic evaluation of suspected osteogenesis imperfecta (OI), Byers [/bib_ref] [bib_ref] Testing for osteogenesis imperfecta in cases of suspected non-accidental injury, Marlowe [/bib_ref] [bib_ref] Differentiation of child abuse from osteogenesis imperfecta, Ablin [/bib_ref] [bib_ref] Studies of collagen synthesis and structure in the differentiation of child abuse..., Steiner [/bib_ref] Non-accidental injury. Many referrals for OI diagnostics occur in the context of suspected NAI in an attempt to exclude a genetic cause of fractures. Fractures resulting from NAI occur in 24 per 10 000 children under 3 years of age whereas the OI prevalence is 1 per 10 000-20 000. [bib_ref] Testing for osteogenesis imperfecta in cases of suspected non-accidental injury, Marlowe [/bib_ref] The incidence of OI among children evaluated for NAI is 2-5%. [bib_ref] Testing for osteogenesis imperfecta in cases of suspected non-accidental injury, Marlowe [/bib_ref] Differentiation is aided by an experienced clinician and radiologist familiar with OI 36 as the nature and localization of fractures in OI and NAI can often be distinguished.However, because injuries may involve infants before many of the clinical features of OI are apparent, laboratory diagnostics for OI can certainly be helpful in this differentiation. # Materials and methods # Results Discussions focussed on diagnostic flow, methodologies, interpretation of results and reporting. Consensus guidelines were established. # Discussion ## The diagnostic flow The 'traditional' way to establish or confirm the diagnosis of OI is based on studies of collagens synthesized by cultured dermal fibroblasts. Previous studies 35 demonstrated that either quantitative or qualitative alterations can be identified in about 90% 38 of individuals with clinically confirmed OI. Biochemical analysis will separate individuals with quantitative defects (OI type I), from those with qualitative defects (OI types II-IV) because of causative variants in the COL1A1/2, CRTAP, LEPRE1, PPIB genes and those with no abnormalities detected. Electrophoretic analysis of type I procollagen may also identify other disorders that can mimic some aspects of OI: EDS kyphoscoliotic type (type VIA), EDS arthrochalasia type (types VIIA and VIIB) and EDS dermatosparaxis type (type VIIC).Also, cultured fibroblasts provides a resource for the analysis of RNA splicing and unclassified variants. However, biochemical analysis will not identify some quantitative defects of type I procollagen, certain causative variants that alter sequences in some coding regions of the COL1A1/COL1A2 genes and recessive forms of OI (including Bruck syndrome) that result from variants in FKBP10, PLOD2, SERPINF1, SERPINH1 or SP7. Furthermore, prenatal diagnosis by biochemical analysis is only possible in chorionic villus cells and is effective with qualitative alterations 9 but unsuitable for quantitative defects and delays time of diagnosis by 2-4 weeks compared with genetic analysis. In contrast, direct genomic analysis (sequencing) of the known genes should identify causative variants in 495% of affected individuals in most populations. [bib_ref] Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning..., Körkkö [/bib_ref] [bib_ref] Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen..., Sykes [/bib_ref] Next generation sequencing has gained importance in the laboratory diagnosis of OI -in part because of shorter time to diagnosis and in part because of the added value of the information as well as reduced costs, which is important for the precise determination of recurrence risk (autosomal dominant versus recessive), prenatal diagnosis and pre-implantation genetic diagnosis. Given these considerations and current facilities, the consensus of the EMQN Best Practice in OI meeting was to initiate laboratorybased diagnostic studies with direct genomic sequencing of the type I procollagen genes, COL1A1 and COL1A2. The approach to diagnosis is detailed in . It was agreed that the 'traditional' approach can still be used in the context in which genomic DNA sequencing is unavailable or the financial barriers are high. Moreover, analysis of proteins and mRNA/cDNA from cultured fibroblasts remain valuable tools for follow-up studies. ## Explanation of diagnostic work flow Sequencing of all type I procollagen gene exons. Procollagen type I gene sequencing should identify causative variants in 90% of affected individuals, [bib_ref] Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning..., Körkkö [/bib_ref] [bib_ref] Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen..., Sykes [/bib_ref] provided that the clinical diagnosis of OI is accurate. In some cases a follow-up study is needed to determine whether a variant is causative. This will often include genetic studies in the parents with correlation to the phenotype observed in the parent, or analysis of mRNA splicing and protein-based biochemical studies on cultured dermal fibroblasts. If no causative variant in the COL1A1/2 genes is identified by sequence analysis, the next step is to determine if a deletion or duplication of some or all of the coding regions of either gene has occurred. Strategies such as array-based analysis, MLPA or qPCR if properly validated are considered equivalent by the working group in their detection of such alterations. From currently available data in the represented laboratories, the added causative variants expected from this approach should be about 1-2%. In case of OI types II-IV, after identifying the causative variant in the index patient, determination of parental mosaicism by sequence analysis of DNA from blood from each parent will provide data for genetic counselling with respect to recurrence risk and care in subsequent pregnancies. Re-review of clinical data and the question of NAI. When no causative COL1A1/2 variant is found, clinical priorities should be re-considered. Failure to find a causative variant occurs if there is technical failure, or if no causative variant is present in these genes (because of causative variants in other (un)known genes or because the patient does not have OI). Therefore, referring physicians should be encouraged to provide a completed clinical checklist (Supplementary [fig_ref] Table 1: Genes in which sequence variants cause OI LRG sequences have been developed... [/fig_ref] and X-rays of the patient. This clinical/radiological information should be reviewed by a clinical geneticist or a clinician with experience in OI. This can help to determine the likelihood of OI in the particular patient. With clear evidence of OI, further analysis should proceed . However, if the primary reason for genetic study is to identify children with OI among the larger group suspected for NAI, analysis can reasonably stop after COL1A1/2 sequencing unless there is a strong suggestion of consanguinity or recessive inheritance. Justification of this decision rests on the following considerations. First, previous studies indicate that fewer than 5% of infants studied for suspicion of NAI are found to have OI by biochemical or DNA-based studies. [bib_ref] Testing for osteogenesis imperfecta in cases of suspected non-accidental injury, Marlowe [/bib_ref] Second, DNA-based analysis will identify a causative variant in 490% of all individuals with OI 39,40 so that the remaining risk that an infant has OI, will be about 0.5%. Third, at present all infants with recessive OI have obvious radiographic abnormalities fitting a diagnosis of OI and not of NAI. Identification and characterization of causative variants in autosomal recessive OI. Variants in the genes causing recessive OI are estimated to account for about 5 or 6% of individuals with OI. This represents the pooled estimates from all the laboratories represented at the workshop. Although laboratory context and clinical criteria may in some cases require otherwise, the preferred strategy is to analyse all genes at the same time to minimize turnaround time. If no, or only one, causative variant is identified by sequence analysis, the next step is to determine by array-based analysis, MLPA or qPCR if a deletion or duplication of some or all of the coding regions of either allele has occurred. Once recessive causative variants are identified, parental confirmation of carrier status should be completed, first to confirm that the causative variants in the index case are inherited in trans and, second, to exclude the possibility of uniparental disomy in the case of homozygosity in the infant. Analysis of proteins and mRNA/cDNA from cultured fibroblasts (functional analysis). By following the guidelines to this point, virtually all causative variants in type I procollagen genes and in the recessive OI-related genes will have been identified. However, in some cases analysis of proteins and mRNA/cDNA from cultured fibroblasts can have an additive value. First of all, mRNA/cDNA analysis provides a tool for studying the effect of unclassified variants suspected to alter splicing. Moreover, this approach can unravel the effect of deep intronic variants that alter the mRNA sequences usually by conversion of cryptic exons to active exons and which would not be detected by gDNA sequencing. In these cases, biochemical analysis of type I procollagen chains can detect quantitative defects if the new exon results in introduction of a premature stop codon and nonsensemediated mRNA decay, or qualitative defects if the mRNA is stable and translated into an abnormal protein. When OI type I is suspected, but genomic DNA sequencing is unavailable or too costly, COL1A1 null-allele 14 testing on cDNA can be used to confirm the diagnosis. However, this approach relies on the availability of informative markers and will not lead to the identification of the disease-causing variant. Analysis of remaining samples. Some diagnostic laboratories maintain research arms and the identification of the additional OI-related genes has profited from the repositories of cells and DNA samples from individuals with OI because of unknown genetic causes. This practice should continue and cells and DNA samples should be banked for future analysis. If the diagnostic laboratory does not maintain such a resource, banking with ones that do, should be considered. Laboratory diagnosis of OI Molecular analysis for OI. Molecular analysis for OI includes sequencing or mutation scanning and deletion/duplication testing for COL1A1 and COL1A2, followed by sequencing of recessive OI-related genes (see [fig_ref] Table 1: Genes in which sequence variants cause OI LRG sequences have been developed... [/fig_ref]. Preferred material for testing is genomic DNA from blood, but other sources can be used as well (see [fig_ref] Table 3a: Postnatal diagnostics for OIAbbreviation [/fig_ref]. For general issues regarding sample labelling and identification, sequence analysis and interpretation see 'Practice guidelines for Sanger Sequencing Analysis and Interpretation' (http://www.cmgs.org/BPGs/ pdfs%20current%20bpgs/Sequencingv2.pdf). gDNA and cDNA sequencing Current practices in sequencing of the type I collagen genes differ among laboratories in that some use exon-by-exon amplification followed by sequence determination [fig_ref] Table 3a: Postnatal diagnostics for OIAbbreviation [/fig_ref] and others use a multi-exon substrate for analysis. If properly validated, both will provide the same mutation capture probability and their use should be determined by local preferences. To identify splice variants, primer sequences for PCR used for direct sequencing should be designed far enough from intron-exon boundaries to allow reading of the branch sites, consensus splice donor and acceptor sites or UTR sequences of acceptable quality. With regard to sequence analysis of cDNA, large fragments should be analysed to allow detection of multi-exon deletions, because these could be missed when primers are located close to the exon junctions at multiple sites. The analysis of cDNA from fibroblasts is warranted when an unknown variant is found that might affect splicing. In addition, cDNA sequence analysis may detect null-alleles without a known cause (eg, an unknown variant in the promoter region) if care is taken to analyse regions in which coding sequence heterozygosity is known. Preferred diagnostic flow in OI. The approach to diagnosis is designed to maximize the likelihood that causative variants will be identified in all affected individuals or assign those without causative variants to research pools. This flow assumes that the clinical diagnosis of OI is well established according to the traditional diagnostic criteria. With clear evidence of OI from radiological and clinical examination, further analysis should proceed according to the proposed strategy. Functional analysis consists of analysis of proteins and mRNA/cDNA from cultured fibroblasts and also includes COL1A1 null allele testing in certain selected cases. ## Report # Quantitative analysis Quantitative analysis by MLPA (kits for COL1A1 and COL1A2 have been designed by MRC-Holland, available at http://www.mlpa.com) and qPCR is particularly important in cases without a detected molecular cause in which only genomic DNA is available and without heterozygous polymorphic variants detected by sequencing. Recently, complete COL1A1 allele deletions have been reported to cause OI type I. [bib_ref] Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type..., Willing [/bib_ref] For reliable quantitative testing (MLPA/qPCR) patient and control materials from the same source (eg, blood or fibroblasts) should be used for comparison and the same DNA purification protocol should be used for all samples within a test series. is used to detect quantitative and qualitative changes. The method used for this analysis is based on in vitro labelling of collagen in cultured fibroblasts, followed by electrophoresis on 2 M urea SDS-PAGE gels (the 2 M urea enhances chain separation) and autoradiography. [bib_ref] Cysteine in the triple-helical domain of one allelic product of the a1(I)..., Steinmann [/bib_ref] The analysis of procollagens is achieved by omitting the pepsin digestion step from the collagen protocol. Procollagen electrophoresis enhances detection sensitivity of quantitative type I (pro)collagen defects (OI type I), visualizes defects in type I (pro)collagen located in the N-terminal region of the type I collagen triple helix more clearly and distinguishes between EDS VIIC and EDS VIIA and B (if samples are analysed after labelling in the presence and absence of dextran sulphate to enhance proteolytic processing). [bib_ref] Assessment of procollagen processing defects by fibroblasts cultured in the presence of..., Bateman [/bib_ref] Prenatal diagnosis. Prenatal diagnosis is possible in case of identification of known disease-causing variant(s) both on genomic DNA extracted from chorionic villus sample (CVS) cells and amniocytes. 'Testing for Maternal Cell Contamination (MCC) in Prenatal Samples for Molecular Studies' (http://www.cmgs.org/BPGs/pdfs%20current%20 bpgs/MCC_08.pdf) should be applied. In those rare instances when post-translational over-modification of (pro)collagen type I is visible in, for example, cells from an affected sibling but no disease-causing variant(s) have been detected in the genes involved in OI, electrophoresis of type I (pro)collagen from cultured CVS cells can be used for prenatal diagnosis. Amniocytes are good sources of DNA but they do not make type I procollagen in sufficient abundance to permit prenatal diagnosis. ## Protein analysis. protein analysis of type i (pro)collagen (supplementary appendix ## Interpretation of performed diagnostics For the interpretation of an observed sequence variant it is essential to establish the causal role of the variant in the pathogenesis of the disease. Textboxes 1 and 2 include descriptions of variants in the genes involved in OI that are likely to be pathogenic or that should be considered as unclassified variants. ## Reporting General information on requirements for variant reporting can be found in the OECD Guidelines for Quality Assurance in Molecular Genetic Testing (http://www.OECD.org/dataoecd/43/6/38839788.pdf) and in the guidelines issued by the Swiss Medical Genetics Society (http://sgmg.ch/user_files/images/SGMG_Reporting_Guidelines.pdf). ## Reporting scenarios Finding a causative variant in the COL1A1/COL1A2 genes in an affected index case. The report should state that a causative variant has been detected and that this confirms the clinical diagnosis. The report should include a description of the reason why a particular variant is considered causative. Determination of the parental origin of the detected variant(s) should be advised. Testing of relatives at risk should be offered in conjunction with appropriate counselling. In the case of severe/lethal OI because of a causative variant in COL1A1 or COL1A2, the measured recurrence risk is 2% after the birth of one affected child. The recurrence risk is increased after the birth of two affected individuals, presumably because the proportion of germ cells that carry the mutation is higher. [bib_ref] Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between..., Pyott [/bib_ref] This information may be mentioned in the results letter. If parental mosaicism can be demonstrated in the father, the referring clinician could be encouraged to request a sperm sample from the father to clarify the risk. When the referring physician is not a clinical geneticist, it is recommended that the patient be referred to a clinical genetics centre for counselling. Referral to OI centres for therapy can be proposed if available. Not finding a causative variant in COL1A1 and COL1A2 genes in an affected index case. If no causative variant is detected in the COL1A1 and COL1A2 genes after gDNA analysis and screening for large gene deletions (eg, MLPA), an interim report can be made with the recommendation for review of the original patient diagnosis (detailed clinical information, eg, with use of the clinical checklist, radiographs, contact with the referring physician (see Supplementary Appendix [fig_ref] Table 1: Genes in which sequence variants cause OI LRG sequences have been developed... [/fig_ref]. This review of the clinical diagnosis should involve a clinician with expertise in diagnosis and classification of OI. The outcome of this review might indicate the desirability for testing of additional OI genes and cDNA and protein analysis of type I (pro)collagen. If applicable, a new request for additional testing should be sent by the referring physician to the laboratory. Laboratories that do not offer analysis of the recessive genes should suggest further analysis in another laboratory. In the case of doubtful pathogenicity of the identified variant, the 'Practice guidelines for the Interpretation and Reporting of Unclassified Variants (UV's) in Clinical Molecular Genetics' (http://www. cmgs.org/BPGs/pdfs%20current%20bpgs/UV%20GUIDELINES%20 ratified.pdf) should be applied. If the genetic testing procedure has identified an unclassified variant as the only sequence change, this should be reported as such. However, the report should clearly state that the clinical significance of the variant is unknown and that its identification does not provide an explanation for the clinical phenotype of the patient. Finding causative variants in the CRTAP, LEPRE1, PPIB, FKBP10, SERPINF1, SERPINH1, PLOD2, SP7 genes in an affected index case. The final report should state that causative variants have been detected. It is necessary to investigate the carrier status of the parents and siblings in order to determine whether a variant is causative. Testing of relatives at risk may be offered in conjunction with appropriate counselling. Such testing might be useful for prenatal diagnosis. Finding one causative variant in the CRTAP, LEPRE1, PPIB, FKBP10, SERPINF1, SERPINH1, PLOD2, SP7 genes in an affected index case. When one causative recessive variant has been detected, it cannot be excluded that a second causative variant has been missed, for example when it concerns a deep intronic variant. Dependent on the laboratory, a second interim report can be made indicating the desirability for cDNA and protein analysis of type I (pro)collagen in the case of one causative variant in the CRTAP, LEPRE1 or PPIB genes. When these additional tests are not informative or cannot be performed in the laboratory, the final report should state that it is not possible to confirm the clinical diagnosis OI by biochemical and/or molecular testing. Not finding causative variants in the CRTAP, LEPRE1, PPIB, FKBP10, SERPINF1, SERPINH1, PLOD2, SP7 genes in an affected index case. In the case of doubtful pathogenicity of the identified variants, the same procedure as described above for the COL1A1 and COL1A2 genes should be followed. In the case where no causative variants in the genes involved in recessive OI have been found, the final report should state that it is not possible to confirm the clinical diagnosis OI by biochemical and/or molecular testing. Not finding causative variant(s) in the genes known for autosomal dominant and autosomal recessive OI: type I (pro)collagen electrophoresis. Reports of these studies are necessarily more descriptive than the DNA-based results. They should list the types of genetic alterations that could not be identified. When low production or post-translational over-modification of type I (pro)collagen is observed, the diagnosis of OI can be confirmed and in the case of over-modification of type I (pro)collagen, prenatal diagnosis on chorionic villus cells is possible. In reports concerning cells and samples with no molecular and/or biochemical diagnosis of OI, it should be stated that it is not possible to confirm the clinical diagnosis OI. Prenatal or preimplantation genetic diagnosis Prenatal or preimplantation genetic diagnosis with the intention of terminating a pregnancy or not selecting embryos carrying the causative variant(s) is possible in the case of identification of known disease-causing variant(s). This service should only be offered in a clinical genetics service and must be accompanied by appropriate genetic counselling. Requests for prenatal or preimplantation diagnosis should always be referred and announced in advance to a clinical genetics service. In addition, the original result letter of the laboratory that identified the causative variant should accompany the request. # Conclusions Best practice guidelines have been established for the molecular genetic diagnosis of OI. The most noteworthy issue is that molecular analysis of the COL1A1/2 genes is recommended as the starting point in the diagnostic flow as opposed to protein analysis. It is to be expected that molecular genetic testing in OI will only gain in importance as new OI-genes are discovered and with the development of new technologies. However, in certain selected cases protein analysis will remain important. [table] Table 1: Genes in which sequence variants cause OI LRG sequences have been developed to provide a stable genomic reference for each gene region annotated with transcripts, proteins and other associated data.44 For some recently discovered genes in which sequence variation causes OI, no LRG is available yet. b The two transcripts of the SP7 gene are translated into identical proteins. [/table] [table] Table 2: Characteristics of recessive OI-related genes [/table] [table] Table 3b: Prenatal and preimplantation genetic diagnosis for OI [/table] [table] Table 3a: Postnatal diagnostics for OIAbbreviation: HRM, high-resolution melting. a Performing MLPA with DNA extracted from fibroblasts leads to unclear results in certain cases. [/table]	None	https://www.nature.com/articles/ejhg2011141.pdf	None
344928bb540d348cd2beff2990ce221cd4de6fdf	pubmed	Neuroanesthesia Practice During the COVID-19 Pandemic: Recommendations From Society for Neuroscience in Anesthesiology and Critical Care (SNACC)	Neuroanesthesia Practice During the COVID-19 Pandemic: Recommendations From Society for Neuroscience in Anesthesiology and Critical Care (SNACC) The pandemic of coronavirus disease 2019 has several implications relevant to neuroanesthesiologists, including neurological manifestations of the disease, impact of anesthesia provision for specific neurosurgical procedures and electroconvulsive therapy, and health care provider wellness. The Society for Neuroscience in Anesthesiology and Critical Care appointed a task force to provide timely, consensus-based expert guidance for neuroanesthesiologists during the COVID-19 pandemic. The aim of this document is to provide a focused overview of COVID-19 disease relevant to neuroanesthesia practice. This consensus statement provides information on the neurological manifestations of COVID-19, advice for neuroanesthesia clinical practice during emergent neurosurgery, interventional radiology (excluding endovascular treatment of acute ischemic stroke), transnasal neurosurgery, awake craniotomy and electroconvulsive therapy, as well as information about health care provider wellness. Institutions and health care providers are encouraged to adapt these recommendations to best suit local needs, considering existing practice standards and resource availability to ensure safety of patients and providers. T he novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first emerged in Wuhan, China, in December 2019, [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] and has since spread across the globe. On February 11, 2020, the World Health Organization named the disease caused by this virus COVID-19, and subsequently declared a pandemic on March 11, 2020. 2 COVID-19 is characterized by fever (89%), cough (58%), dyspnea (46%), myalgias (29%), lymphopenia, [bib_ref] Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis, Rodriguez-Morales [/bib_ref] and typical chest imaging features of bilateral ground glass opacities and consolidation. [bib_ref] Relation between chest CT findings and clinical conditions of coronavirus disease (COVID-19)..., Zhao [/bib_ref] Although symptoms can range from mild to severe, 20% of infected patients overall require admission to an intensive care unit. [bib_ref] Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis, Rodriguez-Morales [/bib_ref] Risk factors for severe disease or death include older age, smoking, chronic obstructive pulmonary disease, diabetes, hypertension, immunocompromise, and malignancy. [bib_ref] Comorbidity and its impact on 1590 patients with Covid-19 in China: a..., Guan [/bib_ref] [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] COVID-19 has several implications relevant to neuroanesthesiologists, including neurological manifestations of the disease, impact of anesthesia provision for specific neurosurgical procedures and electroconvulsive therapy (ECT), and health care provider wellness. ## Aim and scope The aim of this document is to provide a focused overview of the novel SARS-CoV-2 virus and COVID-19 disease relevant to neuroanesthesiologists. This statement provides information on the neurological manifestations of COVID-19, advice for neuroanesthesia clinical practice during emergent neurosurgery, interventional radiology (excluding endovascular treatment of acute ischemic stroke), transnasal neurosurgery, awake craniotomy and ECT, as well as information about health care provider wellness. Guidelines for the anesthetic management of endovascular therapy for acute ischemic stroke during the COVID-19 pandemic are available in separate guidance from the Society for Neuroscience in Anesthesiology and Critical Care (SNACC). [bib_ref] Anesthetic management of endovascular treatment of acute ischemic stroke during COVID-19 pandemic:..., Sharma [/bib_ref] The information provided in this document can be used to inform local and institutional policies and procedures. Information about COVID-19 will evolve as our knowledge about this virus increases over the coming months. The recommendations provided herein reflect expert consensus opinion based on the information available at the time of writing (April 2020) and are subject to change as knowledge increases. Finally, the recommendations can be adapted to regional and institutional resources and requirements, considering existing practice standards and resource availability, to ensure the safety of patients and providers. ## Writing group The authors of these consensus guidelines were appointed by SNACC, and chosen based on their clinical expertise in various aspects of neuroanesthesia practice and to represent a range of geographic locations (North America, Australia, Europe, China, and India) and clinical practice settings. The guidelines were made available to SNACC members for review and were approved by the Board of Directors of SNACC before publication. ## Neurological manifestations of covid-19 The neurological manifestations of COVID-19 have only recently been described. Preliminary unpublished evidence suggests that COVID-19-positive patients are at increased risk of acute ischemic stroke. A recent report from China suggests that neurological symptoms, such as dizziness, headache, hypogeusia, and hyposma, are common (36%) in patients with COVID-19.Encephalopathy and altered mental status have also been reported in patients infected with the SARS-CoV-2 virus. [bib_ref] Neurological complications of coronavirus disease (COVID-19): encephalopathy, Filatov [/bib_ref] Cerebrovascular disease is more common in severe COVID-19 disease; acute ischemic stroke has been reported in 5.7% and impaired consciousness in 15% of patients with severe disease.These results are consistent with another report of 221 patients from Wuhan, China, which found a 5% incidence of acute ischemic stroke and a 1% incidence of cerebral hemorrhage.In this cohort, patients with cerebrovascular complications were more likely to be older, have severe COVID-19 disease, and demonstrate evidence of hypercoagulability and inflammation. Ultimately, 38% of patients with cerebrovascular complications died. Together, these preliminary reports suggest that patients with COVID-19 could present more frequently for endovascular treatment of acute ischemic stroke and could also be at elevated risk of perioperative stroke if they require surgery during acute infection. Other coronaviruses with close similarity to SARS-CoV-2 have been shown to invade the central nervous system. The SARS-CoV and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) viruses are closely related to the SARS-CoV-2 virus in structure and infection pathway, and both have been shown to infect the central nervous system (CNS) in animal models; the brainstem was found to be heavily infected by both SARS-CoV 11 and MERS-CoV. [bib_ref] Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease..., Li [/bib_ref] Furthermore, CNS infection was closely related to high mortality rate, possibly due to dysfunction of the cardiorespiratory center in the brainstem. A predisposition to neuroinvasion is considered to be a common feature of the coronavirus family, and the SARS-CoV-2 virus should be presumed to have similar features. [bib_ref] The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory..., Li [/bib_ref] The alterations in smell observed with COVID-19, in particular, have been postulated to reflect the access of the virus to the brain through the transcribrial route as described in other pathogens [bib_ref] Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction,..., Baig [/bib_ref] ; although this remains to be proven for SARS-CoV-2. Overall, direct invasion of the CNS is plausible, and may account for some of the neurological symptoms reported by COVID-19-positive patients. [bib_ref] The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory..., Li [/bib_ref] ## Urgent neurosurgical procedures The COVID-19 pandemic has necessitated a reduction in elective surgeries to increase capacity and free up resources [bib_ref] Covid-19: all non-urgent elective surgery is suspended for at least three months..., Iacobucci [/bib_ref] ; this includes limitations on neurosurgical procedures. Nevertheless, some patients will continue to require emergent and urgent neurosurgical intervention for life-threatening conditions. The hard-hit region of Lombardy, Italy, described creating a centralized network of 3 "hub" hospitals that accepted all urgent neurosurgical referrals, whereas 1 additional center was designated for urgent oncological neurosurgery. [bib_ref] Neurosurgery during the COVID-19 pandemic: update from Lombardy, northern Italy, Zoia [/bib_ref] Urgent neurosurgery will require specific considerations during the pandemic [fig_ref] FIGURE 1: Summary of recommendations for the anesthetic management of urgent neurosurgical procedures during... [/fig_ref]. The diagnostic criteria for suspected or confirmed COVID-19 cases include epidemiological history, clinical manifestation, real-time quantitative fluorescence polymerase chain reaction (RT-qPCR) test, and COVID-19-specific IgM and IgG antibody test. RT-qPCR testing of respiratory specimens, [bib_ref] Detection of SARS-CoV-2 in different types of clinical specimens, Wang [/bib_ref] including nasopharyngeal swabs, bronchoalveolar lavage fluid, sputum, or bronchial aspirates, for SARS-CoV-2 RNA is currently widely used for case diagnosis. [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] Owing to the possibility of false-negative RT-qPCR test results, [bib_ref] Chest CT for typical 2019-nCoV pneumonia: relationship to negative RT-PCR testing, Xie [/bib_ref] RT-qPCR testing on 2 consecutive respiratory samples obtained at least 24 hours apart should be considered when resources allow. [bib_ref] Positive RT-PCR test results in patients recovered from COVID-19, Lan [/bib_ref] Together, typical clinical symptoms, chest imaging, and epidemiological history (travel or high-risk exposure) can be used to assess the risk of COVID-19 infection and indication for testing. The accepted criteria for the diagnosis of COVID-19 include 1 of the following: (1) RT-qPCR positive for COVID-19 nucleic acid; (2) the viral gene identified by gene sequencing is highly homologous with known COVID-19; or (3) presence of COVID-19-specified IgM and IgG antibodies. For patients requiring aerosol-generating procedures by providers, protection against viral aerosolization should be used for all patients using an N95 mask or powered, air-purifying respirator.Anesthesiologists should refer to detailed published recommendations for the perioperative management of COV-ID-19 patients, [bib_ref] Perioperative management of patients infected with the novel coronavirus: recommendation from the..., Chen [/bib_ref] [bib_ref] Recommendations for endotracheal intubation of COVID-19 patients, Orser [/bib_ref] [bib_ref] Expert recommendations for tracheal intubation in critically ill patients with noval coronavirus..., Zuo [/bib_ref] [bib_ref] Consensus guidelines for managing the airway in patients with COVID-19: guidelines from..., Cook [/bib_ref] which are summarized as follows: (1) To conserve personal protective equipment (PPE) and limit exposure, only essential personnel should be present for aerosol-generating procedures that occur during general anesthesia. Ideally, induction of anesthesia and intubation should be performed by an experienced provider in a negative-pressure environment, and intubation performed using rapid sequence induction with videolaryngoscopy while minimizing bag-mask ventilation. Extubation following general anesthesia should, if possible, also be performed in a negativepressure environment using airborne PPE. Coughing should be avoided during extubation. The patient should wear a surgical mask after extubation and high flow oxygen (ie, <6 L/min) avoided given the risk of aerosolization. [bib_ref] Evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and..., Simonds [/bib_ref] Finally, patient transportation also requires attention to safety and minimization of contamination. Extubated patients should receive oxygen via face mask and, if possible, an additional surgical mask placed on the patient underneath. [bib_ref] Perioperative management of patients infected with the novel coronavirus: recommendation from the..., Chen [/bib_ref] ## Transnasal neurosurgical procedures Transnasal endoscopic neurosurgery facilitates access to the sellar region and is most frequently employed for transsphenoidal hypophysectomy for pituitary tumors. The SARS-CoV-2 virus is believed to have a high degree of viral shedding from the nasal mucosa, [bib_ref] SARS-CoV-2 viral load in upper respiratory specimens of infected patients, Zou [/bib_ref] and early reports from Wuhan, China, have highlighted the propensity of nasal surgery, such as transsphenoidal hypophysectomy, to aerosolize virus with high potential for transmission.Early in the pandemic in China, before testing became widespread, emergency transsphenoidal hypophysectomy resulted in viral transmission to multiple health care workers within days of the surgery, even with appropriate PPE.As a result of widespread reports of infected colleagues, concern has rapidly escalated among otolaryngologists about the safety of nasal surgery.Despite these concerns, patients may still require urgent or emergent transsphenoidal hypophysectomy, such as for acute vision loss, severe pituitary apoplexy, or deteriorating level of consciousness. [bib_ref] UK guidelines for the management of pituitary apoplexy, Rajasekaran [/bib_ref] Recent guidance has highlighted the high risk of nasal surgery in patients infected with SARS-CoV-2, making recommendations to defer nonurgent surgery, to evaluate for SARS-CoV-2 via symptoms, radiologic imaging, and 2 COVID RT-PCR tests separated by [bib_ref] Perioperative management of patients infected with the novel coronavirus: recommendation from the..., Chen [/bib_ref] hours, and about the use of appropriate PPE. [bib_ref] Safety recommendations for evaluation and surgery of the head and neck during..., Givi [/bib_ref] Preoperative nasal decolonization could also be considered. [bib_ref] Perioperative COVID-19 defense: an evidence-based approach for optimization of infection control and..., Dexter [/bib_ref] If transsphenoidal hypophysectomy is required urgently, and rapid SARS-CoV-2 testing is not available, then identifying infected patients becomes problematic due to the high proportion of asymptomatic patients. As such, the minimum number of essential staff should be in the operating room and use appropriate PPE [fig_ref] FIGURE 1: Summary of recommendations for the anesthetic management of urgent neurosurgical procedures during... [/fig_ref]. An alternative surgical approach may also be considered when rapid SARS-CoV-2 testing is not available or the patient is confirmed to have COVID-19, that is craniotomy rather than the transnasal approach.These options should be considered on a case-by-case basis. ## Awake craniotomy An awake craniotomy requires the patient to be fully conscious in order to participate in neurocognitive testing during surgery, although the patient can be awake, sedated, or under general anesthesia before and after periods of intraoperative testing. [bib_ref] Anesthesia for awake craniotomy: a how-to guide for the occasional practitioner, Meng [/bib_ref] Awake craniotomy is typically used for brain tumor and epilepsy surgery when the lesion is in close proximity to eloquent areas of the brain, in order to facilitate surgeon's decision-making. [bib_ref] Awake craniotomy to maximize glioma resection: methods and technical nuances over a..., Sl [/bib_ref] During the COVID-19 pandemic, an awake craniotomy presents several challenges for neuroanesthesiologists, with little specific evidence available to guide practice. The following discussion primarily reflects the expert opinion of task force members. The role of awake craniotomy will be modified during the COVID-19 pandemic [fig_ref] FIGURE 1: Summary of recommendations for the anesthetic management of urgent neurosurgical procedures during... [/fig_ref]. First, in principle, an awake craniotomy should not be performed emergently given its relative complexity, although occasionally an urgent awake (vs. asleep) craniotomy may be indicated for surgical reasons and patient comorbidities. [bib_ref] Awake craniotomy in a patient with ejection fraction of 10%: considerations of..., Meng [/bib_ref] Secondly, awake craniotomy can offer unique benefits to patients, [bib_ref] The potential benefits of awake craniotomy for brain tumor resection: an anesthesiologist's..., Meng [/bib_ref] and should still be considered for selected patients during the pandemic. The relative risks and benefits must be carefully considered, as well as alternatives such as image-guided resection if available. Several steps are required to adequately prepare for awake craniotomy during the pandemic. Before the procedure, patients should be carefully screened for the presence of the SARS-CoV-2 virus through clinical assessment and RT-qPCR testing. If the patient presents with respiratory symptoms or hypoxemia preoperatively, the etiology should be investigated, and the patient tested for COVID-19. If the patient is positive for COVID-19, or remains symptomatic, an awake craniotomy is not recommended. Different awake craniotomy anesthetic techniques have been described: awake throughout without any sedation, conscious sedation or monitored anesthesia care, asleepawake technique, and asleep-awake-asleep technique. [bib_ref] Awake craniotomies without any sedation: the awake-awake-awake technique, Hansen [/bib_ref] The specific technique chosen should be familiar, while also minimizing the risk for urgent airway intervention. Whatever technique is chosen, during the COVID-19 pandemic coughing during awake craniotomy should be avoided to minimize the potential for contamination and aerosolization. This can be mitigated through the use of intravenous medications such as low dose lidocaine or remifentanil. [bib_ref] Different interventions in preventing opioid-induced cough: a meta-analysis, Shuying [/bib_ref] [bib_ref] Intubation and ventilation amid the COVID-19 outbreak: Wuhan's experience, Meng [/bib_ref] In addition, we advocate an approach that avoids airway instrumentation and uses only light sedation (ie, drowsy but arousable) before neurocognitive testing. Urgent airway intervention, including nasal airway insertion, is particularly detrimental during this pandemic. In addition, regional scalp blocks and/or local anesthetic infiltration are essential to provide analgesia and minimize sedation requirements. Given that individuals can potentially be infected by SARS-CoV-19 and remain asymptomatic, [bib_ref] Presumed asymptomatic carrier transmission of COVID-19, Bai [/bib_ref] patients should wear a surgical mask whenever possible, including during the procedure; the mask can be temporarily removed during neurocognitive testing. Supplemental oxygen (ie, face mask) can be placed over the surgical mask if needed. A microphone may facilitate intraoperative communication while using PPE, and maintain distance between the patient and the operating room team to lessen the chance of cross infection. ## Neurointerventional radiology procedures With the exception of endovascular therapy for acute ischemic stroke, most neurointerventional radiology procedures performed during the pandemic will be considered urgent, rather than emergent (eg, embolization of intracranial aneurysms, spine tumors). Therefore, any patients with suspected COVID-19 should be tested before undertaking the procedure (provided the results of testing is available in <24 h), and appropriate PPE implemented according to institutional policies. For cases where testing is not possible due to case urgency, the patient should be treated as presumed COVID-19 positive. Only essential personnel should be present during airway management and, ideally, intubation should be performed in an airborne isolation room with negative pressure relative to the surrounding area. [bib_ref] Turbulent gas clouds and respiratory pathogen emissions: potential implications for reducing transmission..., Bourouiba [/bib_ref] However, it is recognized that this may not be available near many interventional radiology suites, and that intubation will then need to occur in the radiology suite with only essential personnel present. Anesthesia for neurointerventional radiology procedures during the pandemic requires several other, unique, considerations [fig_ref] FIGURE 1: Summary of recommendations for the anesthetic management of urgent neurosurgical procedures during... [/fig_ref]. For example, anesthesia providers must ensure that lead protection is donned before PPE, as the anesthesia practitioner may be required to remain in the interventional radiology suite rather than the control room. Afterwards, the lead suits worn during the procedure require rigorous decontamination with disinfection wipes containing a quaternary ammonium compound and alcohol [bib_ref] Perioperative COVID-19 defense: an evidence-based approach for optimization of infection control and..., Dexter [/bib_ref] ; a top-down cleaning sequence may reduce bioburden. Locations for donning, doffing, and cleaning of lead will need to be established in close proximity to the interventional suite, and appropriate PPE made available in that location. Finally, given the remote location of many interventional radiology suites, a plan for extubation is required. Transport to a negative-pressure isolation room in another location for extubation should be considered. After extubation, as a minimum, caution must be taken to ensure that patients are transported without risk of urgent airway intervention or coughing during transit. ## Ect ECT is an effective treatment for a wide variety of neurological and psychiatric disorders. [bib_ref] Relapse following successful electroconvulsive therapy for major depression: a meta-analysis, Jelovac [/bib_ref] [bib_ref] Electroconvulsive therapy (ECT) in schizophrenia: a review of recent literature, Sanghani [/bib_ref] During and following the COVID-19 pandemic, we should prepare for a potential increase in demand for ECT procedures. Pandemics are likely to cause damaging effects on mental health. These include increases in suicide rates, particularly in survivors of the disease, health care providers, and previously healthy but isolated or quarantined populations. Of particular concern are those affected by the economic down fall; the suicide rate in the United States rose dramatically during the Great Depression. [bib_ref] Life and death during the Great Depression, Tapia Granados [/bib_ref] A previous outbreak of a related virus, SARS-CoV-1, in 2003 significantly impacted the mental health of SARS survivors and health care providers; 41% to 65% of SARS survivors suffered persistent psychological and/or psychiatric problems, predominantly posttraumatic stress disorder and depression. These symptoms often last as long as 30 months after recovery from SARS, including in health care providers who were infected and recovered. [bib_ref] Stress and psychological distress among SARS survivors 1 year after the outbreak, Lee [/bib_ref] [bib_ref] Quality of life and psychological status in survivors of severe acute respiratory..., Kwek [/bib_ref] Even healthy health care providers who were not infected experienced substantial psychological distress years after the outbreak. [bib_ref] Long-term psychological and occupational effects of providing hospital healthcare during SARS outbreak, Maunder [/bib_ref] At the time of writing (April 2020), the magnitude of the COVID-19 pandemic is at least 2 orders greater than that of SARS and a recent survey suggests that health care providers taking care of COVID-19 patients in China report high rates of distress, depression, anxiety, and insomnia. [bib_ref] Factors associated with mental health outcomes among health care workers exposed to..., Lai [/bib_ref] During the COVID-19 pandemic, the risks and benefits of ECT must be carefully assessed. ECT should be considered as an urgent or semiurgent intervention for suicidal ideation, severe depression, mania, and catatonia and should not be delayed. [bib_ref] Relapse following successful electroconvulsive therapy for major depression: a meta-analysis, Jelovac [/bib_ref] [bib_ref] ECT in a time of COVID-19, Tor [/bib_ref] However, when considering ECT, both the anesthesiologist and psychiatrist must ensure that all conservative interventions have been pursued and exhausted before administration of ECT as a "last resort" therapy. [bib_ref] Relapse following successful electroconvulsive therapy for major depression: a meta-analysis, Jelovac [/bib_ref] The patient population commonly undergoing ECT presents specific challenges during the COVID-19 pandemic. As ECT patients tend to be older [bib_ref] Association of electroconvulsive therapy with psychiatric readmissions in US hospitals, Slade [/bib_ref] and with comorbidities, they are at higher risk for both ECT-associated 54 and COV-ID-19-related morbidity and mortality. [bib_ref] Comorbidity and its impact on 1590 patients with Covid-19 in China: a..., Guan [/bib_ref] [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] Only those asymptomatic for COVID-19 disease should be considered for ECT, and each patient should be tested for SARS-CoV-2 virus close to the time of their procedure. SARS-CoV-2-positive patients should not be allowed to proceed with ECT. If asymptomatic, patients who test positive for SARS-CoV-2 but remain asymptomatic should be allowed to proceed only if subsequent testing 14 days later is negative, and ECT is considered a life-saving procedure. The conduct of anesthesia for ECT during the COVID-19 pandemic requires careful consideration . The most challenging aspect of anesthesia for ECT during the pandemic is airway management. The commonly used technique of bagmask ventilation and hyperventilation without an airway device represents significant risk of infection for health care providers, including anesthesiologists. [bib_ref] Practical recommendations for critical care and anesthesiology teams caring for novel coronavirus..., Wax [/bib_ref] To minimize risk of viral transmission, the following are recommended: (1) Since anesthesia management for ECT inevitably involves positive-pressure bag-mask ventilation with an unprotected airway, it should ideally be performed in a negativepressure single airborne suite, utilizing full PPE, restricted personnel, and careful disinfection (eg, minimum 75% alcohol 52 ) of the suite, allowing at least 30 minutes between patients 55,56 depending on institutional air exchange rate; (2) To minimize hypersalivation, glycopyrrolate 0.2 to 0.4 mg intravenously can be safely administered before induction of anesthesia 57 ; (3) To reduce coughing on emergence, remifentanil can be safely administered during the procedure and lidocaine (1 to 1.5 mg/kg of ideal body weight) can be administered intravenously after the seizure is completed 55,56 ; (4) Although hyperventilation using bag-mask ventilation can improve seizure quality, the evidence for this is weak [bib_ref] Hyperventilation and electroconvulsive therapy: a literature review, Gomez-Arnau [/bib_ref] and aerosolization is increased. Therefore, this strategy should be avoided during the COVID-19 pandemic unless adjustment to other measures to improve seizure quality is unsuccessful. Induction agents providing best possible quality of seizure should be employed; these include ketamine, etomidate, and methohexital 59 ; (5) Patients should be carefully preoxygenated before induction of anesthesia when bag-mask ventilation is minimized; consider apneic oxygenation with nasal prongs 55 ; (6) In cases requiring hyperventilation, a laryngeal mask airway allowing capnography 55 should be considered as an alternative to manual bag-mask ventilation; (7) Patients should be recovered in designated areas wearing surgical masks. 52,55 ## Wellness for health care providers During a pandemic, the concept of "duty to treat" by health care workers is a given, although many significant changes are observed in health care delivery and risks to health care providers. [bib_ref] Ethics, pandemics, and the duty to treat, Malm [/bib_ref] The notion of self-sacrifice is a grave mistake; success in controlling and ultimately eradicating a pandemic depends on availability of all resources, including personnel. [bib_ref] Wuhan and Hubei COVID-19 mortality analysis reveals the critical role of timely..., Zhang [/bib_ref] Physicians, nurses, and other health care workers may not realize that during a pandemic the nature of "the patient" changes from a single individual to a community. Thus, we reinforce the utmost importance of safety to preserve the human resources necessary to overcome the pandemic. The wellness of health care workers should encompass both physical and mental fitness . Physical wellness is a primary concern to maintain a sustainable workforce during a pandemic. In addition to the risks that general anesthesiologists face in becoming infected with the virus, including during airway management, neuroanesthesiologists have additional exposure risk due to their close proximity to patients and long surgical procedures. Wearing PPE for a prolonged time may cause excessive heat, pressure sores, and a need for frequent rehydration; neurointerventional procedures may be particularly uncomfortable due to the addition of lead protection under the PPE. It is essential that all steps of doffing should be thoroughly completed and meticulous hand washing performed before any consumption, and that all food or drink is consumed outside of any patient care area. Owing to these practice restrictions, neuroanesthesiology departments should ensure additional staffing is available to provide breaks and clinical support during cases. Psychological health is of critical importance. Anesthesiologists and intensivists are at the front line of the management of the target organs that the COVID-19 virus attacks and are faced with the task of rapidly reviewing and implementing continually evolving guidelines. In addition to the general anxieties felt during the pandemic, health care practitioners face substantial stress due to the challenges of remembering guideline recommendations and implementing them with minimal time to practice. A change (increase) in the number of work hours and assignments outside familiar environments and skill sets may be difficult for some. Physicians and other health care workers may also have concerns about transmitting the virus to their home environment. [bib_ref] Healthcare workers' attitudes towards working during pandemic influenza: a multi method study, Draper [/bib_ref] High levels of anxiety can arise during deviation from routine workflow and this anxiety, along with long hours of work, can negatively affect the immune system of health care workers. Healthy nourishment, adequate sleep, and scheduled breaks are ways to cope with stress in pandemic situations. Many hospitals have support systems for all front-line health care professionals managing patients during a high mortality pandemic. There should be counseling and designated areas for rest in accordance with social distancing rules. [bib_ref] Supporting the health care workforce during the COVID-19 global epidemic, Adams [/bib_ref] The American Medical Association has released resources for health care leadership to guide them in supporting providers during the COVID-19 pandemic, including sustaining physical and mental well-being.Ultimately, a pandemic is a battle; the well-being of the health care professionals who fight the battle is essential in ensuring victory. # Conclusions Since the novel SARS-CoV-2 virus first emerged in late 2019 in China, the COVID-19 pandemic has spread around the globe and caused massive disruptions to health care provision. Neuroanesthesiologists should be aware of several specific considerations related to anesthesia for urgent neurosurgical and neurointerventional procedures, as well as ECT. These recommendations will continue to evolve as the pandemic progresses, particularly as we gain further insights into the pathophysiology, clinical course, and treatment options for COVID-19. ## Table 1. wellness for health care providers During a pandemic, the physical and mental health of health care professionals is essential for sustainability Prolonged procedures, physical exhaustion, a high risk of contamination and psychological stress are common in neuroanesthesia practice Neuroanesthesiology departments should ensure additional staffing is available to provide breaks and clinical support during long cases, particularly when PPE is required Multiple specialty societies provide resources on strategies to relieve stress and improve wellness PPE indicates personal protective equipment. [fig] FIGURE 1: Summary of recommendations for the anesthetic management of urgent neurosurgical procedures during the COVID-19 pandemic. PAPR indicates powered, air-purifying respirator; PPE, personal protective equipment; RT-qPCR, real-time quantitative fluorescence polymerase chain reaction. [/fig]	None	None	The pandemic of coronavirus disease 2019 (COVID-19) has several implications relevant to neuroanesthesiologists, including neurological manifestations of the disease, impact of anesthesia provision for specific neurosurgical procedures and electroconvulsive therapy, and health care provider wellness. The Society for Neuroscience in Anesthesiology and Critical Care appointed a task force to provide timely, consensus-based expert guidance for neuroanesthesiologists during the COVID-19 pandemic. The aim of this document is to provide a focused overview of COVID-19 disease relevant to neuroanesthesia practice. This consensus statement provides information on the neurological manifestations of COVID-19, advice for neuroanesthesia clinical practice during emergent neurosurgery, interventional radiology (excluding endovascular treatment of acute ischemic stroke), transnasal neurosurgery, awake craniotomy and electroconvulsive therapy, as well as information about health care provider wellness. Institutions and health care providers are encouraged to adapt these recommendations to best suit local needs, considering existing practice standards and resource availability to ensure safety of patients and providers.
c07b5e0931a09daac2dbb2b21876c7cde6cc8fdc	pubmed	Prevention in Sports Dentistry	Prevention in Sports Dentistry [bib_ref] Nutrition et sant e bucco-dentaire du sportif, Hausswirth [/bib_ref] [bib_ref] Mouthguards in sport activities: history, physical properties and injury prevention effectiveness, Knapik [/bib_ref] [bib_ref] Effects of experimental horizontal mandibular deviation on stepping test of equilibrium function, Karasawa [/bib_ref] ## Scope This policy statement aims to provide information to promote the integration of oral care into sports medicine, to stress the importance for all athletes of achieving and maintaining optimal oral health, as well as to emphasise the role of dentists in oral health care and prevention. ## Definition Sports dentistry: An interest area of dentistry dealing with the promotion of oral health in sports and prevention and treatment of pathologies and injuries of the stomatognathic system related to sports and exercise. Stomatognathic system: The anatomic and functional system comprising the teeth, jaws, associated soft tissues, facial muscles, and temporomandibular joint. ## Principles Microbial or functional stomatognathic pathologies are often preventable. Therefore, promoting oral health and good oral hygiene practices in the earliest stages of sports practice (eg, in school, grassroots clubs, and sports academies) is essential. Regular dental or oral health screenings integrated with general health assessments of both elite and amateur athletes, no matter their skill level or classification, are highly valuable so that early detection of any oral issue can be fostered. ## Policy FDI has the following recommendations for sports organisations: Communicate the substantial evidence of the relationship between oral health and general health to all their members, from the most junior to the most senior. Communicate the importance of good oral health in order to maintain athletes' overall health and well-being. Encourage schoolchildren and amateur and elite athletes to adopt healthy oral hygiene, nutrition, hydration, regular dental checkups, and injury prevention behaviours. Encourage collaboration amongst sports clubs, federations, institutions, and sports medicine centres at local, national, regional, and international levels to promote prevention, research, surveillance, and monitoring of oral health and related health factors and to support education in the field of sports and dentistry. Stimulate interactions between their medical staff and dentists by encouraging regular medical and dental checkups amongst their members/athletes. Initiate common strategies with national and international sports federations, foster the integration of sports dentistry into sports medicine, and incorporate dentists as members of the sports medical team. ## Fdi recommends that dentists and sports physicians: Include questions related to the type of sports their patients are practising and how often in the medical questionnaire. Inform all athletes, elite or amateur, about the importance of good oral health for optimum performance, about the impact of sports on oral health, and about the relationship between oral health and general health. Collaborate when managing an athlete's health. Include oral health as part of the athlete's general health checkup and ensure they seek appropriate dental care. Systematically provide advice on prevention to all athletes, including oral hygiene and preventive measures, benefits of well-balanced diets, knowledge of the acidity of sports drinks and risk to oral health, regular oral health checkups, good nutrition, appropriate hydration, the use of customised mouthguards when participating in contact or combat sports, and the detriments of alcohol and tobacco consumption. Regularly update their knowledge of the metabolism of prescribed medicines and potential interactions that may result in the athlete's noncompliance with the World Anti-Doping Agency regulation. FDI recommends that all athletes (amateur and elite): Wear a custom-made mouthguard when engaging in contact and combat sports, even if only participating in the sport occasionally. Understand that poorly fitting mouthguards offer poor protection. Avoid consequences of sports activities on their oral health by following specific recommendations of oral health professionals. ## Disclaimer The information in this policy statement was based on the best scientific evidence available at the time. It may be interpreted to reflect prevailing cultural sensitivities and socioeconomic constraints.	None	None	None
660d0a1cacc2e8cfaea3242236af412bf56888b5	pubmed	Clinical practice guidelines for ultrasound-guided vacuum-assisted breast biopsy: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021	Clinical practice guidelines for ultrasound-guided vacuum-assisted breast biopsy: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021 ## Level of evidence and recommendation strength Level of evidence standard [bib_ref] Clinical practice guidelines for sentinel lymph node biopsy in patients with early-stage..., Ye [/bib_ref] Recommendation strength standard [bib_ref] Clinical practice guidelines for sentinel lymph node biopsy in patients with early-stage..., Ye [/bib_ref] Recommendation strength review committee There were 82 voting committee members for this guideline: 66 from breast surgery departments (80.5%), six from medical oncology departments (7.3%), four from medical imaging departments (4.9%), two from pathology departments (2.4%), two from radiotherapy departments (2.4%), and two epidemiologists (2.4%). ## Target audience Clinicians specializing in breast diseases in China.II A ## Recommendations # Discussion The expert group believes that ultrasound guided VABB is safe, fast, effective, economical, without radioactivity, and permits monitoring the location of the biopsy needle in real time. [bib_ref] Expert consensus and operation guidelines for ultrasound-guided vacuum-assisted breast biopsy surgery (2017)..., Fan [/bib_ref] [bib_ref] Image-guided breast biopsy and localisation: recommendations for information to women and referring..., Bick [/bib_ref] The VABB technique was approved by the US Food and Drug Administration (FDA) in April 1995. In 1999, the American Medical Association announced that image-guided VABB is a reliable diagnostic technique that replaces surgical biopsy. In 1999, the technique was approved by the China Food and Drug Administration for clinical use in China. In 2004, the US FDA approved VABB for "total excision of abnormalities found in imaging," that is, the technique can be applied to remove benign breast lesions.After VABB was introduced in China, because of the high cost, it was mainly used for treatment purposes and was extensively recognized by breast surgeons and patients. With the continuous upgrading of this technique, its applications are increasingly extensive, and it is currently used for diagnosis and treatment in breast surgery. According to previous reports, VABB is superior to core needle biopsy (CNB) in terms of the specificity of the histopathological diagnosis of lesion biopsy for diagnosis. The underestimation rates of VABB and CNB for ductal carcinoma in situ in a previous study were 9% and 38%, respectively, and the underestimation rates of these techniques for high-risk lesions were 11% and 25%, respectively. [bib_ref] Core Needle and Open Surgical Biopsy for Diagnosis of Breast Lesions: An..., Dahabreh [/bib_ref] According to the recommendations of the expert group, the indication of VABB for diagnostic purposes is ultrasound diagnosis of breast imaging reporting and data system (BI-RADS) classification ≥IV lesions, [bib_ref] The evolving role of vacuum assisted biopsy of the breast: a progression..., Bennett [/bib_ref] especially for lesions with small volumes (largest diameter <1.0 cm). VABB is also preferred for biopsy of lesions adjacent to the chest wall or a prosthesis. [bib_ref] Clinicopathological analysis of ultrasound-guided vacuum-assisted breast biopsy for the diagnosis and treatment..., Park [/bib_ref] [bib_ref] Core Needle and Open Surgical Biopsy for Diagnosis of Breast Lesions: An..., Dahabreh [/bib_ref] For lesions with inconsistent results by imaging evaluation and CNB, VABB can be performed again to enhance the diagnostic accuracy. [bib_ref] The evolving role of vacuum assisted biopsy of the breast: a progression..., Bennett [/bib_ref] For VABB used for diagnosis, the expert group recommends that a clip can be placed simultaneously to enhance the accuracy of lesion resection in subsequent open surgery, reduce the rate of secondary resection of the incision margins in breast-conserving surgery, and reduce recurrence. For patients receiving neoadjuvant treatment, positioning a clip can avoid difficulty in confirming the location of the original lesion after complete clinical remission, which can facilitate subsequent surgery. [bib_ref] Image-guided breast biopsy and localisation: recommendations for information to women and referring..., Bick [/bib_ref] [bib_ref] A clinical feasibility trial for identification of exceptional responders in whom breast..., Kuerer [/bib_ref] Chinese Medical Journal 2021;134 [bib_ref] Analysis of the efficacy and accuracy of two vacuum-assisted breast biopsy devices:..., Bozzini [/bib_ref] www.cmj.org VABB for treatment is indicated for BI-RADS classification III lesions with surgical indications. For BI-RADS classification III lesions measuring 2.0 cm, the complete resection rate of VABB is nearly 100%, while for lesions measuring >2.0 cm, the probability of residual lesions is positively correlated with the tumor size. [bib_ref] The evolving role of vacuum assisted biopsy of the breast: a progression..., Bennett [/bib_ref] [bib_ref] Clinicopathological analysis of ultrasound-guided vacuum-assisted breast biopsy for the diagnosis and treatment..., Park [/bib_ref] [bib_ref] Analysis of the efficacy and accuracy of two vacuum-assisted breast biopsy devices:..., Bozzini [/bib_ref] The expert group has not yet discussed VABB for treating gynecomastia, accessory breast, breast abscess, and early breast cancer because of the lack of evidence from prospective randomized controlled trials. Hematoma is a common complication after VABB, and small-volume hematomas do not require treatment. The expert group considers that surgery is necessary for hemostasis or debridement if a patient is suspected of having active bleeding or has a huge hematoma causing severe pain. [bib_ref] Feasibility and safety of imageguided vacuum-assisted breast biopsy: a PRISMA-compliant systematic review..., Fang [/bib_ref] High-risk breast lesions are composed of a group of heterogeneous lesions (atypical ductal hyperplasia, lobular neoplasia, flat epithelial atypia, radial scars, papillary lesions, phyllodes tumors, and others). The highest risk of these lesions for malignancy is 35% after total resection. ## Conflicts of interest The expert committee for these guidelines declares no conflict of interest. These guidelines are a reference for breast disease specialists in clinical practice. However, the guidelines are not to be used as the basis for medical evaluation, and do not play an arbitrating role in the handling of any medical disputes. The guidelines are not a reference for patients or non-breast specialists. The Chinese Society of Breast Surgery assumes no responsibility for results involving the inappropriate application of these guidelines and reserves the right to interpret and revise the guidelines. List of compiling committee members (In alphabetical order by surname followed by first name): Zhong-Wei Cao, De-Dian Chen, Yuan-Jia Cheng, Xue-Ning Duan,	None	None	Ultrasound-guided vacuum-assisted breast biopsy (VABB) is a common technique in breast surgery. To standardize this technique, the Chinese Society of Breast Surgery (CSBrS) re-evaluated the quality of evidence for clinical studies of VABB, referring to the grading of recommendations assessment, development, and evaluation, and developed the Clinical Practice Guidelines for Ultrasoundguided vacuum-assisted breast biopsy: CSBrS Practice Guidelines 2021, in accordance with the Expert Consensus andOperation Guidelines for Ultrasound-guided Vacuumassisted Breast Biopsy Surgery (2017) combined with data from clinical practice in breast surgery in China, providing a reference for breast surgeons in China.
7277ee135ed29207717dfee68db97dcbf8f66be4	pubmed	Recommendations from the Brazilian Society of Nephrology for approaching Covid-19 Diagnostic Testing in Dialysis Units	Recommendations from the Brazilian Society of Nephrology for approaching Covid-19 Diagnostic Testing in Dialysis Units # Abstract The Covid-19 pandemic brought several challenges to the healthcare system: diagnosis, treatment and measures to prevent the spread of the disease. With the greater availability and variety of diagnostic tests, it is essential to properly interpret them. This paper intends to help dialysis units concerning the use of clinical criteria and diagnostic tests for decision making regarding the discontinuation of isolation of patients with suspected or confirmed Covid-19, as well as the return to work activities for employees with suspected or confirmed Covid-19. ## Keywords: Covid A estratégia baseada em critérios clínicos pode ser utilizada nos casos com sintomatologia leve, baixa suspeição de Covid-19 ou se o teste laboratorial (sorologia ou RT-PCR) não estiver disponível 1 .	None	https://www.scielo.br/j/jbn/a/WgTXk8nNLQyXNGZjj9ssbyC/?lang=en&format=pdf	ABSTRACT The Covid-19 pandemic brought several challenges to the healthcare system: diagnosis, treatment and measures to prevent the spread of the disease. With the greater availability and variety of diagnostic tests, it is essential to properly interpret them. This paper intends to help dialysis units concerning the use of clinical criteria and diagnostic tests for decision making regarding the discontinuation of isolation of patients with suspected or confirmed Covid-19, as well as the return to work activities for employees with suspected or confirmed Covid-19.
8d120cb4299adf98920980ed7134ecef4a0e71d5	pubmed	SASLT Practice Guidelines for the Management of Hepatitis B Virus	SASLT Practice Guidelines for the Management of Hepatitis B Virus [bib_ref] Canadian Association for the Study of the Liver. Management of chronic hepatitis..., Coffin [/bib_ref] [bib_ref] APASL consensus statements and management algorithms for hepatitis C virus infection, Omata [/bib_ref] [bib_ref] Chronic Hepatitis B: Update 2009. AASLD Practice Guidelines, Lok [/bib_ref] [fig_ref] Table 1: Grading of recommendations [/fig_ref] ## Epidemiology The World Health Organization (WHO) estimates that approximately 2 billion people worldwide have been infected with HBV and approximately 350 million live with chronic infection. [bib_ref] Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention..., Lavanchy [/bib_ref] HBV was considered hyperendemic in Saudi Arabia according to the WHO classification. In the 1980s, various studies on the seroprevalence of hepatitis B surface antigen (HBsAg) were conducted in blood donors, pregnant women, and various outpatient populations. Pooling these data together revealed the prevalence of HBV infection to be 5.5%, 8.9%, and 9.6% in the central, southwestern, and eastern provinces of the Kingdom of Saudi Arabia, respectively. The overall average prevalence in the Kingdom was estimated to be 8.3%, making Saudi Arabia one of the most highly endemic areas of HBV infection in the world. [bib_ref] Hepatitis B infection in Saudi Arabia, Fz [/bib_ref] [bib_ref] Prevalance and acquisition rates of hepatitis BsAg in Riyadh Al-Kharj Hospital Programme, Al-Admawy [/bib_ref] [bib_ref] A twe-year survey of diagnostic virus laboratory services of King Saud University..., Jamjoom [/bib_ref] [bib_ref] Prevalence and subtype of hepatitis B surface antigen (HBsAg) in the Saudi..., Ramia [/bib_ref] [bib_ref] Prevalence of HBV markers in adult Saudis in relation to age and..., Takieddine [/bib_ref] [bib_ref] Vertical transmission of hepatitis B surface antigen in Saudi Arabia, Ramia [/bib_ref] [bib_ref] Hepatitis B markers in Saudi Arabia: A comparative study in different regions, El-Hazmi [/bib_ref] [bib_ref] Hepatitis B virus in Gizan, Saudi Arabia, Arya [/bib_ref] [bib_ref] Twenty-five month's epidemiological observations at King Faisal Military Hospital. Khamis Mushayt, Habayeb [/bib_ref] [bib_ref] Hepatitis B vaccination (letter to the editor), Habayeb [/bib_ref] [bib_ref] Hepatitis B virus among Saudi children in Gizan, Saudi Arabia, Parande [/bib_ref] [bib_ref] The prevalence of HBsAg in healthy subjects residing in the Eastern Province..., Fathalla [/bib_ref] [bib_ref] Prevalence of hepatitis B surface antigen among male Saudi Arabians, Talukder [/bib_ref] [bib_ref] Prevalence of viral hepatitis markers in patients with sickle cell gene, Fz [/bib_ref] These studies also revealed significant information on the prevalence of other HBV markers. The HBV exposure rate was very high, ranging between 20 and 80% in different regions of the Kingdom. [bib_ref] Prevalence of HBV markers in adult Saudis in relation to age and..., Takieddine [/bib_ref] [bib_ref] Hepatitis B markers in Saudi Arabia: A comparative study in different regions, El-Hazmi [/bib_ref] [bib_ref] Hepatitis B virus in Gizan, Saudi Arabia, Arya [/bib_ref] [bib_ref] Prevalence of viral hepatitis markers in patients with sickle cell gene, Fz [/bib_ref] [bib_ref] Epidemiology of viral hepatitis among the Saudi population: A study of viral..., El-Hazmi [/bib_ref] [bib_ref] Epidemiology of delta agent infection in Arabia: Geographical distribution and prevalence of..., El-Hazmi [/bib_ref] [bib_ref] Hepatitis B and A markers in children with thalassaemia and sickle-cell disease..., Babiker [/bib_ref] The highest exposure rate of 80% was registered in the city of Khaiber in the western province. [bib_ref] Epidemiology of viral hepatitis among the Saudi population: A study of viral..., El-Hazmi [/bib_ref] However, the prevalence of hepatitis B e antigen (HBeAg) positivity ranged from 8 to 26%. [bib_ref] Hepatitis B infection in Saudi Arabia, Fz [/bib_ref] [bib_ref] Hepatitis B markers in Saudi Arabia: A comparative study in different regions, El-Hazmi [/bib_ref] [bib_ref] Hepatitis B virus in Gizan, Saudi Arabia, Arya [/bib_ref] [bib_ref] Hepatitis B virus markers in male Saudi blood donors, Sheth [/bib_ref] [bib_ref] Seroepidemiology of hepatitis B virus infection in Saudi Arabian children: A baseline..., Al-Faleh [/bib_ref] These rates are much lower than the rates reported in different Asian countries, where the prevalence was found to range from 70 to 80%. [bib_ref] Hepatitis B infection in Saudi Arabia, Fz [/bib_ref] Horizontal transmission of the virus is the main route of transmission in Saudi Arabia. This finding is supported by the fact that infection acquired through close personal contact is far more common than that acquired through needle pricks or blood transfusions. [bib_ref] Transmission of hepatitis B virus, Francis [/bib_ref] Furthermore, prevalence studies in Saudi Arabia revealed a higher infection rate in children aged 1-12 years compared with infants less than 1 year of age. [bib_ref] Prevalance and acquisition rates of hepatitis BsAg in Riyadh Al-Kharj Hospital Programme, Al-Admawy [/bib_ref] [bib_ref] A twe-year survey of diagnostic virus laboratory services of King Saud University..., Jamjoom [/bib_ref] [bib_ref] Prevalence and subtype of hepatitis B surface antigen (HBsAg) in the Saudi..., Ramia [/bib_ref] [bib_ref] Prevalence of HBV markers in adult Saudis in relation to age and..., Takieddine [/bib_ref] [bib_ref] Vertical transmission of hepatitis B surface antigen in Saudi Arabia, Ramia [/bib_ref] [bib_ref] Hepatitis B markers in Saudi Arabia: A comparative study in different regions, El-Hazmi [/bib_ref] [bib_ref] Hepatitis B virus in Gizan, Saudi Arabia, Arya [/bib_ref] [bib_ref] Twenty-five month's epidemiological observations at King Faisal Military Hospital. Khamis Mushayt, Habayeb [/bib_ref] [bib_ref] Hepatitis B vaccination (letter to the editor), Habayeb [/bib_ref] [bib_ref] Hepatitis B virus among Saudi children in Gizan, Saudi Arabia, Parande [/bib_ref] [bib_ref] The prevalence of HBsAg in healthy subjects residing in the Eastern Province..., Fathalla [/bib_ref] A study assessing the prevalence of infection in preschool children born to HBsAg-positive mothers showed that the infection rate increased rapidly between the ages of 10 weeks and 5 years from 3.6 to 14.6%. [bib_ref] The prevalence of HBsAg in healthy subjects residing in the Eastern Province..., Fathalla [/bib_ref] These studies demonstrate the strong horizontal transmission of HBV infection. The low HBeAg positivity of HBsAg-positive mothers in Saudi Arabia makes vertical transmission a less important route compared with the relevant routes in other Asian populations. [bib_ref] Hepatitis B virus infection in 6,130 unvaccinated Korean-Americans surveyed between 1988 and..., Hann [/bib_ref] These accumulating data on the prevalence of HBV and the availability of a safe and efficacious vaccine triggered the governmental launching of a mass vaccination program in Saudi Arabia. In 1989, the HBV vaccine was integrated into the expanded program of immunization (EPI), through which all newborn children were vaccinated throughout the country. [bib_ref] Integration of hepatitis B vaccine into the expanded program on immunization: The..., Al-Faleh [/bib_ref] The vaccination schedule consisted of three pediatric doses of 10 μg SKF or 5 μg MSD recombinant HB vaccine administered intramuscularly at specified intervals (0, 1, and 5 months). Details of the vaccinations were recorded in the registries of the primary healthcare centers and on the children's EPI cards. One year later, a catch-up program was also initiated with the aim of vaccinating all children at school entry, expatriates, healthcare workers, and hemodialysis patients. As a result of these programs, all Saudi individuals aged 28 years or younger would potentially be vaccinated. To evaluate the efficacy of the vaccination program, three large post-vaccine follow-up studies were conducted. The first study was conducted 2 years after starting the program. In this study, none of the vaccinated children were positive for HBsAg. [bib_ref] Seroepidemiology of hepatitis B virus infection in Saudi Arabian children: A baseline..., Al-Faleh [/bib_ref] The second study was performed in 1997, eight years after initiation of the program. Saudi children aged 1-12 years were included. The prevalence of HBsAg positivity was 0.16% in children vaccinated at birth, compared with 0.7% in those vaccinated at school entry. [bib_ref] Seroepidemiology of hepatitis B virus infection in Saudi children 8 years after..., Al-Faleh [/bib_ref] The third study was conducted 18 years after starting the program. School students between the ages of 16 and 18 years from different regions of the Kingdom were included. In this study, no cases of HBsAg or anti-hepatitis B core antibody (anti-HBc) positivity were detected among the study population. Additionally, this study showed that 38% of the study population had protective anti-hepatitis B surface (anti-HBs) titers (≥10 ml U/ml). [bib_ref] Long-term protection of hepatitis B vaccine 18 years after vaccination, Al-Faleh [/bib_ref] These post-vaccination follow-up studies confirm the efficacy of the vaccination program. The decreasing prevalence of HBV infection in the country has also been shown in various other studies. For example, prevalence data from pregnant Saudi women showed a significantly lower infection rate in younger (<20 years) pregnant women, ranging from 0 to 0.5%, compared with older, non-vaccinated pregnant women (4%). [bib_ref] Screening of pregnant Saudi women for hepatitis B surface antigen, Al-Mazrou [/bib_ref] [bib_ref] Hepatitis B virus sero-prevalence among pregnant females in Saudi Arabia, Alrowaily [/bib_ref] [bib_ref] Serosurvey of hepatitis B surface antigen in pregnant Saudi women, Khalil [/bib_ref] Similar findings were also observed in various studies from different blood banks across the country. [bib_ref] Prevalence of seromarkers of HBV and HCV among blood donors in eastern..., Bashawri [/bib_ref] [bib_ref] Prevalence of Hepatitis B and C and blood donors, Mehdi [/bib_ref] [bib_ref] HIV-1, 2 and HTLV-I/II infections among blood donors in a teaching hospital..., El-Hazmi [/bib_ref] In January 2008, the Saudi Arabian health authority included mandatory testing for human immunodeficiency virus (HIV), HBV, and hepatitis C virus (HCV) in the premarital screening program. A cross-sectional descriptive study originating from this program, with the aim of studying the prevalence of viral hepatitis among this population (N = 74,662 individuals), was conducted. This study revealed a prevalence of 0.33% and 1.3% for HCV and HBV infections, respectively. They also showed that the infection prevalence was higher in older participants. [bib_ref] Is there a need to include HIV, HBV, and HCV viruses in..., Alawaidibfm [/bib_ref] Despite the significant decline in the prevalence of HBV infection in Saudi Arabia, HBV infection remains a significant cause of morbidity and mortality. Disease prevalence in older patients remains high, placing an extra burden on the healthcare system for the next few decades. Furthermore, recent genotype studies showed that genotype D is the most common genotype among infected Saudi patients; further studies on the natural history and treatment response of patients with this genotype are required. [bib_ref] Hepatitis B genotypes: Relation to clinical outcome in patients with chronic hepatitis..., Abdo [/bib_ref] ## Natural history of hbv An understanding of the natural history of chronic hepatitis B (CHB) is fundamental to the evaluation and management of CHB and plays a critical role in the assessment of patient status and in guiding decisions regarding candidacy for treatment and treatment endpoints. In Mediterranean countries, transmission of HBV usually occurs from person to person during childhood, as previously mentioned. In these populations, most children who are HBeAg positive have elevated alanine aminotransferase (ALT) levels, and seroconversion to anti-hepatitis B e (anti-HBe) is common near, or shortly after, the onset of puberty. [bib_ref] A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection..., Keeffe [/bib_ref] The natural history of CHB can be schematically divided into five phases, which are not necessarily sequential. The "immune tolerant phase" is characterized by HBeAg positivity, high levels of HBV replication [reflected by high levels of serum hepatitis B virus deoxyribonucleic acid (HBV DNA)], normal or low levels of aminotransferases, mild or no liver necroinflammation, and no or slow progression of fibrosis. [bib_ref] A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection..., Keeffe [/bib_ref] [bib_ref] Viral hepatitis in the third millennium, Rizzetto [/bib_ref] During this phase, the rate of spontaneous HBeAg loss is very low. This first phase is more frequent and more prolonged in subjects infected prenatally or in the first years of life. These patients are highly contagious. The "immune reactive phase" is characterized by HBeAg positivity, lower levels of replication (as reflected by lower serum HBV DNA levels), increased or fluctuating levels of The Saudi Journal of Gastroenterology aminotransferases, moderate or severe liver necroinflammation, and more rapid progression of fibrosis. [bib_ref] A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection..., Keeffe [/bib_ref] [bib_ref] Viral hepatitis in the third millennium, Rizzetto [/bib_ref] [bib_ref] Hepatitis B virus infection natural history and clinical consequences, Ganem [/bib_ref] This phase may last for several weeks to several years. In addition, the rate of spontaneous HBeAg loss is enhanced. This phase may occur after several years of immune tolerance and is more frequently reached in subjects infected during adulthood. The "inactive HBV carrier state" is characterized by very low or undetectable serum HBV DNA levels and normal levels of aminotransferases. As the infection is controlled, this state confers a favorable long-term outcome with a very low risk of cirrhosis or hepatocellular carcinoma (HCC) in the majority of patients. HBsAg loss and seroconversion to anti-HBs antibodies may occur spontaneously in 1-3% of cases per year, usually after several years of persistently undetectable HBV DNA. [bib_ref] Hepatitis B virus infection natural history and clinical consequences, Ganem [/bib_ref] The "HBeAg-negative CHB phase" may follow seroconversion from HBeAg to anti-HBe antibodies during the immune reactive phase and represents a later phase in the natural history of CHB. It is characterized by periodic reactivation with a pattern of fluctuating levels of HBV DNA and aminotransferases and active hepatitis. These patients are HBsAg negative and harbor HBV variants with nucleotide substitutions in the pre-core and/or basal core promoter regions unable to express or expressing low levels of HBeAg. HBeAg-negative CHB is associated with low rates of prolonged spontaneous disease remission. It is important and sometimes difficult to distinguish true inactive HBV carriers from patients with active HBeAg-negative CHB in whom phases of spontaneous remission may occur. The former patients have a good prognosis with a very low risk of complications, whereas the latter patients have active liver disease with a high risk of progression to advanced hepatic fibrosis, cirrhosis, and subsequent complications such as decompensated cirrhosis and HCC. [bib_ref] Hepatitis B virus-related cirrhosis: Natural history and treatment, Chu [/bib_ref] [bib_ref] Natural history and prognosis of hepatitis B, Fattovich [/bib_ref] "HBsAg-negative phase:" After HBsAg loss, low-level HBV replication may persist with detectable HBV DNA in the liver. [bib_ref] Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg..., Martinot-Peignoux [/bib_ref] Generally, HBV DNA is not detectable in the serum, whereas anti-HBc antibodies with or without anti-HBs are detectable. HBsAg loss is associated with improvement of the outcome with a reduced risk of cirrhosis, decompensation, and HCC. The clinical relevance of occult HBV infection [detectable HBV DNA in the liver with low level (<200 IU/ml) of HBV DNA in the blood] is unclear.Immunosuppression may lead to reactivation in these patients. [bib_ref] Hepatitis B e antigen-negative-chronic hepatitis B, Hadziyannis [/bib_ref] [bib_ref] Statements from the Taormina expert meeting on occult hepatitis B virus infection, Raimondo [/bib_ref] ## Hbv diagnosis The diagnosis of chronic HBV infection is based on the evaluation of serological and virological markers of HBV infection in serum and the evaluation of biochemical and histological markers of liver disease. HBsAg is the first serological marker to appear after infection. Its persistence for more than 6 months indicates chronic HBV infection. The presence of antibodies to HBsAg (anti-HBs), which are detectable following immunity conferred by hepatitis B vaccination, implies recovery and/or immunity to HBV. The presence of HBeAg indicates active replication of HBV. However, its absence cannot be assumed to imply the absence of viral replication because HBeAg is undetectable in patients with HBeAg-negative (pre-core or core promoter mutant) HBV infection. The presence of anti-HBe generally indicates HBeAg seroconversion, although it is also found in patients with pre-core or core promoter mutant HBV infection. HBeAg seroconversion has generally been considered the endpoint for HBV therapy in HBeAg-positive patients because it has been shown to be associated with a lower risk for disease progression. [bib_ref] A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection..., Keeffe [/bib_ref] However, this is not a true reflection of inflammation and should be used in conjunction with other markers, such as HBV polymerase chain reaction (PCR). Histological evaluation of liver biopsy specimens is a more sensitive and accurate indicator of liver disease assessment than ALT levels, and is useful for establishing the baseline status of liver histology at the initial evaluation before the initiation of therapy and to exclude other causes of liver disease. However, liver biopsy examination is not always used as a method of diagnosis and is resisted by some patients because of its invasive nature. [bib_ref] Hepatitis B e antigen-negative-chronic hepatitis B, Hadziyannis [/bib_ref] Recently, the upper limit of normal for serum ALT concentrations was redefined as 30 U/l for males and 19 U/l for females. [bib_ref] Updated definitions of healthy ranges for serum alanine aminotransferase levels, Prati [/bib_ref] [bib_ref] Estimation of the healthy upper limits for serum alanine aminotransferase in Asian..., Lee [/bib_ref] We assessed these new standards in our population by evaluating 175 consecutive healthy Saudi potential living liver donors with biopsy-proven normal liver histology who underwent a liver biopsy as part of a pre-liver donation workup. We concluded that the upper limit of normal should be lowered (33 IU/l for males and 22 IU/l for females). [bib_ref] Revising the upper limit of normal for levels of serum alanine aminotransferase..., Al-Hamoudi [/bib_ref] These new ALT standards should be utilized when assessing disease activity and when deciding whether to perform liver biopsies in infected patients. Although the universal vaccination program in Saudi Arabia is strictly enforced, high-risk populations should be screened for hepatitis B [ ## Hbv management The current aims of treating CHB with antiviral agents are to achieve sustained suppression of HBV replication and remission of the ongoing liver disease, with the ultimate goal of preventing cirrhosis and HCC. However, the current treatment options are far from ideal. The limitations of current treatments for chronic HBV are related to the unique abilities of HBV to chronically persist in host hepatocytes [due to the unique existence of covalently closed circular DNA (cccDNA) HBV] despite immune and therapeutic pressure. Based on this limitation, we need to be careful in interpreting the inconsistent definitions of responders to antiviral therapy (whether on-therapy or sustained off-therapy), primary non-responders, and on-therapy breakthroughs. Indicators of responses to antiviral treatment include biochemical normalization, viral suppression, HBeAg seroconversion, and histological improvement. Recently, some investigators have used HBsAg titers as another indicator of response; however, the value of this indicator is currently inconsistent and, accordingly, will not be included in these guidelines. [bib_ref] Correlation between hepatitis B surface antigen titers and HBV DNA levels, Alghamdi [/bib_ref] ## Pretreatment assessment Obtaining a complete history is essential before considering antiviral therapy initiation [ [fig_ref] Table 3: Pretreatment assessment AST [/fig_ref] ]. Specific information, such as family history of hepatitis B and HCC and history of jaundice and previous treatment, is important. Histories of high-risk behavior, such as intravenous drug use, are important, as individuals exhibiting such behavior may transmit the infection to the community. Vaccination history, especially for hepatitis A, should be addressed, as hepatitis A infection in CHB-infected patients could be fatal. Providing certain advice to patients during history-taking, such as advice regarding diet, alcohol intake, and avoidance of herbal medicine during antiviral therapy, is important. A detailed discussion about the risks and benefits of therapy, cost of treatment, and goal of therapy should be carried out before starting any antiviral therapy. All patients with CHB infection should be carefully assessed with a complete examination to look for the signs and stigmata of chronic liver disease and hepatosplenomegaly. A complete blood workup is essential in assessing the relationship between HBV and the severity of liver disease. Complete liver function tests (LFTs), including total bilirubin, prothrombin time (PT), and albumin; complete blood counts, including platelets; and assessment of biochemical markers, including aspartate aminotransferase (AST), ALT, gamma-glutamyltransferase (GGT), and alkaline phosphatase, should be performed. [bib_ref] Durability of HBeAg sero-conversion following antiviral therapy for chronic hepatitis B: Relation..., Van Nunen [/bib_ref] Hepatitis serology, including hepatitis e antigen and e antibody, is important for determining the immunological response to hepatitis B and for differentiating the hepatitis B wild-type from the pre-core mutant type. Hepatitis B DNA level measurement became a major cornerstone in deciding when to initiate therapy and plays an important role in patient follow-up during or following treatment. The standard tests are real-time PCR tests that should be standardized using international units (IU/ml). The same assay should be used consistently to assess the effectiveness of therapy. The HBV DNA level is very important for determining therapy indications and for assessing responses to therapy. [bib_ref] Rapid quantification of hepatitis B virus DNA by automated sample preparation and..., Stelzl [/bib_ref] [bib_ref] Characterization of a new sensitive PCR assay for quantification of viral DNA..., Thibault [/bib_ref] [bib_ref] Performance of the Cobas AmpliPrep/Cobas TaqMan real-time PCR assay for hepatitis B..., Chevaliez [/bib_ref] [bib_ref] Virologic monitoring of hepatitis B virus therapy in clinical trials and practice:..., Pawlotsky [/bib_ref] Ultrasound of the liver is mandatory to assess the signs of portal hypertension and to exclude any focal lesions before starting antiviral therapy. Liver biopsy is very helpful in determining the degree of inflammation and the degree of fibrosis. It is also very helpful in excluding other co-existing liver diseases such as steatosis, steatohepatitis, and autoimmune liver disease. Furthermore, liver biopsy can be very helpful in patients who do not clearly meet the treatment criteria. Hepatitis B patients, especially those older than 40 years, with mildly elevated ALT levels may have significant histological abnormalities and increased mortality from liver disease. Thus, the decision of whether to perform liver biopsy in specific patient groups should take into consideration age, the new upper-limit level of ALT, HBeAg status, and HBV DNA level. New noninvasive markers and FibroScan have become widely used for the assessment of patients with hepatitis B, but have not yet replaced the standard liver biopsy. [bib_ref] Noninvasive assessment of liver fibrosis by stiffness measurement in patients with chronic..., Marcellin [/bib_ref] [bib_ref] Transient elastography and other non-invasive tests to assess hepatic fibrosis in patients..., Castera [/bib_ref] [bib_ref] Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive..., Castera [/bib_ref] [bib_ref] The role of transient elastography in patients with hepatitis B viral disease, Fraquelli [/bib_ref] [bib_ref] Transient elastography in chronic viral hepatitis: A critical appraisal, Cardoso [/bib_ref] ## Goal of treatment The goal of treatment is to suppress hepatitis B replication and achieve sustained suppression of the virus to decrease the effect of the virus on the liver and reduce histological activity. There is substantial evidence that suppression of the virus will decrease the progression of liver disease and development of HCC and, thus, improve the quality of life and survival. [bib_ref] Prevention and surveillance of hepatitis B virus related hepatocellular carcinoma, Liaw [/bib_ref] The main parameters used to assess response to treatment are HBV DNA, ALT, and disappearance of the HBeAg, with or without development of the hepatitis B e antibody. Different types of responses to antiviral therapy have been proposed, namely, biochemical, virological, and histological responses. The response to therapy can be classified as a response while on therapy or a sustained response while off therapy. ## Endpoint of treatment A high level of HBV DNA has been associated with a worse outcome. [bib_ref] Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the..., Iloeje [/bib_ref] [bib_ref] Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B..., Chen [/bib_ref] [bib_ref] Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response..., Marco [/bib_ref] An effective antiviral treatment must reduce HBV DNA to the lowest level possible and ideally below the lower limit of detection (10-15 IU/ml). Reducing HBV DNA to a lower level should result in reducing the probability of viral resistance and in biochemical remission, histological improvement, and the reduction of complications such as cirrhosis, decomposition, and HCC. [bib_ref] The role of hepatitis B virus integrations in the pathogenesis of human..., Bonilla [/bib_ref] [bib_ref] Hepatocellular carcinoma: The point of view of the hepatitis B virus, Pollicino [/bib_ref] In general, sustained HBsAg loss with or without hepatitis B surface antibody is ideally the best outcome, as this scenario has been associated with improved long-term outcomes. The other alternative and acceptable endpoint is hepatitis e antibody seroconversion in HBeAg patients, as this has also been associated with improved outcomes. ## Treatment indications All patients with hepatitis B should be monitored and followed closely. The majority of patients are chronically inactive, have normal liver enzymes, and respond poorly to currently available antivirals. In general, elevated ALT is important in initiating antiviral treatment in HBeAg-positive or -negative patients, depending on the variable cut-off levels of HBV DNA. A careful assessment of liver injury indicators, including liver enzymes and hepatitis B DNA, with and without histological assessment of the liver tissue to assess the grade of inflammation and degree of fibrosis on certain occasions, is important for deciding which group of patients will benefit from treatment. Consideration of treatment with antiviral therapy is variable depending on HBeAg status and the presence or absence of cirrhosis [ [fig_ref] Figure 2: Algorithm for the management of hepatitis B e antigen [/fig_ref] ]. For example, patients with cirrhosis should be treated regardless of ALT level, HBeAg status, and HBV DNA level. Additionally, if patients have signs or symptoms of decompensation, antiviral therapy must be initiated immediately, along with early referral to a liver transplant center. [bib_ref] Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis, Shim [/bib_ref] [bib_ref] Tenofovir disoproxilfumarate (TDF), emtricitabine/ TDF, and entecavir in patients with decompensated chronic..., Liaw [/bib_ref] [bib_ref] Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients..., Liaw [/bib_ref] Immunotolerant patients (normal ALT and a high HBV DNA level of more than 10 7 copies/ml) without evidence of advanced liver disease or a family history of HCC or cirrhosis should not be treated, as the risk of drug resistance is very high in this group of patients. ## Monitoring of therapy It is very crucial to carefully monitor patients with hepatitis B after starting antiviral treatment. Periodic testing of liver enzymes, AST, ALT, HBeAg, HBV DNA, and liver function should be performed every 3 months. Patients on interferon (IFN) should have their complete blood count, electrolytes, thyroid function, and kidney function checked monthly. Patients on adefovir should also have their renal function and phosphate levels checked every 3 months. At the end of therapy, ALT and HBV DNA should be monitored monthly for the first 3 months and then every 3-6 months to detect early relapse. ## Response to therapy and treatment failure The response to therapy can be divided into biochemical, histological, serological, and virological responses. All clinical trials using antiviral agents address these responses individually or in combination. Different types of The Saudi Journal of Gastroenterology responses resulting from IFN or oral antiviral therapy have been identified, namely, complete response, partial response, non-response, and virological breakthrough. In IFN-based regimens, the quantitative HBsAg titer has been shown to predict response and could aid in deciding whether to continue or stop therapy. [bib_ref] Hepatitis B surface antigen: Association with sustained response to peginterferon alfa-2a in..., Piratvisuth [/bib_ref] [bib_ref] Neptune study: On-treatment HBsAg level analysis confirms prediction of response observed in..., Gane [/bib_ref] [bib_ref] Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigenpositive..., Sonneveld [/bib_ref] In HBeAg-positive patients treated with nucleoside or nucleotide agents, therapy can be stopped following the development of hepatitis e antibody and negative HBV DNA based on three consecutive measurements at two occasions 6 months apart. In HBeAg-negative patients, the optimal duration of therapy is unknown, and the decision to stop therapy should be individualized based on HBV DNA response and liver disease severity. [bib_ref] Lamivudine maintenance beyond one year after HBeAgseroconversion is a major factor for..., Lee [/bib_ref] [bib_ref] Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in..., Song [/bib_ref] [bib_ref] Durability of serologic response after lamivudine treatment of chronic hepatitis B, Dienstag [/bib_ref] The response to therapy may be variable in patients with hepatitis B treated with IFN, nucleos(t)ide, and nucleotide analogs. Virological response to IFN therapy is defined by a decrease in HBV DNA to less than 2000 IU/ml at week 24 of treatment, whereas virological response to nucleos(t)ide analogs (NAs) is defined as undetectable HBV DNA by the real-time PCR assay within 48 weeks. [bib_ref] Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B, Lau [/bib_ref] [bib_ref] Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic..., Janssen [/bib_ref] [bib_ref] Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients..., Marcellin [/bib_ref] For patients treated with IFN, the other important parameter associated with serological response is the development of hepatitis B e antibody in patients with HBeAg positivity. [bib_ref] Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic..., Janssen [/bib_ref] Primary non-response is the failure to obtain a decrease in HBV DNA of less than 1 log from baseline to 12 weeks of therapy following both IFN and oral antiviral therapy. Two other responses should be identified during oral antiviral therapy, namely, virological breakthrough and partial virological response. Partial virological response is defined as a decrease in HBV DNA of less than 1 log, but detectable DNA by real-time PCR. It is important to recognize partial response at week 24 of therapy to modify treatment according to the agents being used. Virological breakthrough is defined as an increase in the HBV DNA level of more than 1 log compared with the lowest level reached while undergoing therapy. It is usually preceded by biochemical breakthrough with an increase in ALT. The most common causes of virological breakthrough are non-adherence and drug resistance. Primary non-response can occur with adefovir, but rarely occurs with tenofovir, entecavir, telbivudine, or lamivudine. The appropriate action in cases of adefovir virological non-response is to switch to entecavir (preferably) or tenofovir. Identification of HBV-resistant mutations can be performed to plan rescue strategies and to aid in choosing appropriate antiviral agents. Partial non-response can occur with all nucleoside agents. It can occur with the use of lamivudine, adefovir, or telbivudine, and can be diagnosed with the assessment of HBV DNA at week 24. [bib_ref] Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to..., Lampertico [/bib_ref] [bib_ref] Hepatitis B virus resistance to nucleos (t) ide analogues, Zoulim [/bib_ref] Switching to more potent antivirals (tenofovir or entecavir) or adding another drug that does not share cross-resistance is another strategy (add tenofovir to lamivudine in cases of telbivudine resistance or add entecavir in cases of adefovir resistance). In cases of partial virological response to tenofovir or entecavir, many experts recommend adding another agent to prevent long-term resistance. Virological breakthrough should be diagnosed early and is mainly related to viral resistance. Viral resistance is increased in patients with high baseline DNA levels and patients previously treated with antiviral agents. Virological breakthrough should be expected in patients with a slow decline in DNA after therapy initiation. Early suspicion of virological breakthrough and appropriate detection of genetic mutations will aid in deciding which type of rescue therapy to utilize. When drug resistance develops, the most effective measure is to add a second antiviral agent without cross-resistance to the first agent to avoid multi-drug resistance [ [fig_ref] Table 4: Management of drug resistanceThe Saudi Journal of Gastroenterology >20,000 IU/ml and elevated... [/fig_ref] ]. [bib_ref] Entecavir treatment for up to 5 years in patients with hepatitis B..., Chang [/bib_ref] [bib_ref] HBsAg kinetics in patients with chronic hepatitis B (CHB) treated with tenofovir..., Marcellin [/bib_ref] [bib_ref] No detectable resistance to tenofovir disoproxil fumarate (TDF) following up to 240..., Marcellin [/bib_ref] In cases of lamivudine resistance, adding adefovir or switching to tenofovir is recommended. In cases of adefovir resistance, it is recommended to switch to entecavir or tenofovir or add lamivudine in the absence of previous lamivudine resistance. In N236 T mutation cases, adding lamivudine, entecavir, or telbivudine is an option. In A181 T/V mutation cases, adding entecavir is the best choice. In cases of entecavir and telbivudine resistance, the best choice is to switch to or add tenofovir. [bib_ref] Long-term efficacy of tenofovir monotherapy for hepatitis B virus monoinfected patients after..., Van Bommel [/bib_ref] [bib_ref] Antiviral effect of entecavir in chronic hepatitis B: Influence of prior exposure..., Reijnders [/bib_ref] [bib_ref] Tenofovir is effective alone or with emtricitabine in adefovir-treated patients with chronic-hepatitis..., Berg [/bib_ref] Recommendations 9. HBeAg-positive patients with HBV DNA levels ## Treatment of chb The promoter of liver disease in chronic HBV is continuous HBV replication; thus, effective sustained viral suppression is of paramount importance. [bib_ref] Lamivudine for patients with chronic hepatitis B and advanced liver disease, Liaw [/bib_ref] However, there are limitations to the current therapy for chronic HBV that are related to the unique abilities of HBV to chronically persist in host-infected hepatocytes (due to the unique existence of cccDNA HBV) despite immune and therapeutic pressures. [bib_ref] State of hepatitis B virus DNA in hepatocytes of patients with hepatitis..., Brechot [/bib_ref] [bib_ref] Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen:..., Brechot [/bib_ref] Indicators of antiviral treatment response include biochemical normalization, viral suppression, HBeAg seroconversion, and histological improvement [ [fig_ref] Table 5: Response categories [/fig_ref] ]. [bib_ref] Management of hepatitis B: Summary of a clinical research workshop, Hoofnagle [/bib_ref] To date, seven antiviral agents have been approved for the treatment of chronic HBV, and each of them will be discussed briefly [ [fig_ref] Table 6: Results of the main studies for the treatment of HBeAg-negative chronic hepatitis... [/fig_ref] ]. Antiviral agents can be categorized into two main groups: IFN-based agents and nucleos(t)ide analogs (NAs). The first type of agent is given for a definite period of time and is associated with well-recognized side effects, whereas the second type of agent is given for an indefinite duration. There are currently no reliable endpoints with which to determine the duration of NA treatment. With the long-duration use of NAs, a major concern of HBV antiviral-resistant mutations arises, which can make long-term HBV treatment challenging. [bib_ref] Antiviral drug-resistant HBV: Standardization of nomenclature and assays and recommendations for management, Lok [/bib_ref] Thus, chronic HBV patients with minimal disease (especially immune-tolerant HBeAg and inactive carriers) should not be treated with NAs, particularly if they are young (<30 years). Moreover, whenever possible, treatment should start with the most potent NA with the highest resistance barrier. ## Interferon IFNs are unique because they have antiviral, anti-proliferative, and immune-modulatory effects. However, their HBV suppression efficacy is limited to a small percentage after 1 year of treatment for various categories of HBV patients. [bib_ref] Management of hepatitis B: 2000-summary of a workshop, Lok [/bib_ref] Efficacy in various disease categories HBeAg-positive chronic HBV: This needs to be subcategorized into the following. - Normal ALT: This is the most common pattern of chronic HBV in Saudi Arabia among children and young adults based on the prevalent vertical transmission of HBV. The Saudi Journal of Gastroenterology Despite high viral replication in this category of chronic HBV, no antiviral treatment is indicated. This unique situation is related to the immune-tolerant phase of the natural course of the virus; thus, IFNs are not expected to work effectively as antiviral agents due to a lack of immune recognition of the virus. [bib_ref] Long-term follow-up in a randomized controlled trial of recombinant alpha 2-interferon in..., Lok [/bib_ref] - Persistently or intermittently elevated ALT: At different stages of the immune-tolerant phase, some patients may have elevated ALT, indicating the beginning of the immune system recognition of the virus. This is usually manifested by successive and variable-intensity immune system attacks on hepatocytes harboring HBV, leading to variable degrees of elevated enzymes and histological necroinflammatory activity. Because of this immune recognition of the virus, antiviral trials with IFN were found to be effective. Meta-analyses of randomized controlled trials revealed that a higher percentage of IFN-treated patients had a virological response, compared with untreated controls. High pretreatment ALT levels (greater than twice the upper limit of normal) and low levels of serum HBV DNA are the most important predictors of IFN therapy response. [bib_ref] Which patients with chronic hepatitis B virus infection will respond to alpha-interferon..., Brook [/bib_ref] The virological response is usually identified by suppression of the HBV viral load, seroconversion of HBeAg to HBe antibodies, and some degree of histological improvement. Although long-term studies indicate that IFN-induced HBeAg seroconversion is durable, it does not result in definite changes in chronic HBV disease, as only 5% of responders achieve HBsAg loss over the next 5 years. However, some studies have suggested favorable results in terms of reducing cirrhosis and HCC incidence over the following years in responding patients. - Children: The efficacy of IFN in children is similar to that in adults. However, most children have normal ALT levels, and less than 10% of children with intermittently elevated ALT levels who received IFN had achieved HBeAg seroconversion. [bib_ref] Placebo-controlled trial of recombinant alpha 2-interferon in Chinese HBsAg-carrier children, Lai [/bib_ref] - HBeAg-negative CHB: Most Saudi adults with chronic HBV reach this stage of the natural HBV course in their third or fourth decade of life, and can either be inactive carriers (if associated with a low viral load and normal ALT levels and histology) who require no treatment or progress to a pre-core mutant HBV state (due to immune pressure escape). The latter group of patients generally exhibits a broad spectrum of progressive disease and requires antiviral treatment. - Results of four randomized controlled trials of IFN-α showed virological response ranging from 38% to 90% occurring after 1 year of treatment, compared with only 0-37% response in controls. [bib_ref] A randomized, controlled trial of a 24-month course of interferon alfa 2b..., Lampertico [/bib_ref] The wide range of response rates is related to the different HBV genotypes that were found to affect the response rate; specifically, patients with genotypes A and B were found to respond better than those with genotypes C and D. Al Ashgar et al. conducted a study to determine the safety and efficacy of pegylated (PEG)-IFN α-2a in HBeAg-negative, genotype D-naive patients and to analyze the predictors of response. They concluded that HBeAg-negative genotype D-naive patients treated with PEG-IFN α-2a achieved sustained virological response (SVR) with rates of 23% (HBV < 400 copies/ml) and 57% (HBV < 20,000 copies/ml), which is a better response than previously reported and may be related to the absence of drug resistance in these naive patients. Pretreatment predictors of SVR were low body weight, high ALT levels, low HBV DNA levels, and low triglyceride levels. [bib_ref] Efficacy of peginterferon α-2a and predictors of response in HBeAg-negative, genotype D-naive..., Al-Ashgar [/bib_ref] However, approximately 70% of the responders relapse when therapies are discontinued, and relapses can occur up to 5 years post-therapy. Retreatment of patients who undergo such relapses or of non-responders was found to be of no benefit, but a longer treatment duration may increase the rate of sustained response - Decompensated or compensated cirrhosis: Approximately 20-40% of patients with HBeAg-positive CHB develop a spike in their ALT levels during IFN-α treatment. In patients with cirrhosis, the spike may precipitate hepatic decompensation. Two studies on IFN-α in patients with Child's class B or C cirrhosis reported minimal benefit. Similar outcomes have been observed in HBeAg-negative patients with established cirrhosis when they are treated with IFN-α. [bib_ref] Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection..., Perrillo [/bib_ref] and from 24 to 32%, respectively. [bib_ref] A randomized, controlled trial of combination therapy for chronic hepatitis B: Comparing..., Chan [/bib_ref] However, neither of these two viral response indicators is considered reliable. In fact, low levels of HBV DNA persist and are detectable (due to the persistence of cccDNA in hepatocytes) even following HBeAg seroconversion or viral suppression (400 copies/ml); thus, loss of HBsAg was considered to be a more reliable indicator. The long-term benefits of IFN treatment, as manifested by HBsAg loss, were variable between studies from North America and Europe (12-65%) compared with Asian studies (5-12%). This variability was attributed to the geographic variation of HBV; specifically, patients with genotypes A and B (common in North America and Western Europe) respond better to IFN compared with patients with genotypes C and D (common in Asia and the Middle East). In HBeAg-negative patients, relapse after the end of IFN treatment is frequent, with a sustained virological response rate of only 15-30%. ## Lamivudine (3tc) Lamivudine is an NA that acts by incorporating an active triphosphate into the growing HBV DNA chains, resulting in the premature termination of synthesis. ## Efficacy The initial enthusiasm that was present regarding the value of lamivudine in treating chronic HBV (in view of its low cost and minimal side effects) declined over time based on the high number of lamivudine-resistant HBV mutations that steadily increased with longer durations of drug exposure. The most common mutation involves substitution of methionine in the tyrosine-methionine-aspartateaspartate (YMDD) motif of the HBV DNA polymerase for valine or isoleucine rtM204V/I. Genotypic resistance can be detected in 14-32% of cases after 1 year of lamivudine treatment and increases with the duration of treatment to 60-70% after 5 years of treatment. In addition to a long treatment duration, a high pretreatment viral load and high HBV residual after 1 year of treatment are also associated with higher rates of lamivudine resistance. Different HBV genotypes were found to contribute very little to the slow suppression rate or resistance. [bib_ref] Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B...., Liaw [/bib_ref] [bib_ref] Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B, Perrillo [/bib_ref] ## Dose regimen, duration of treatment, and durability of response The recommended dose of lamivudine for adults with normal renal function (creatinine clearance > 50 ml/min) and no HIV coinfection is 100 mg orally daily. The recommended dose for children is 3 mg/kg/d, with a maximum dose of 100 mg/d. Dose reduction is necessary for patients with renal insufficiency. The endpoint of treatment for HBeAg-positive patients is HBeAg seroconversion. Liver enzymes should be monitored every 3 months and HBV DNA levels every 6 months while on therapy, and HBeAg and anti-HBe status should be tested at the end of 1 year of treatment and every 6 months thereafter. Treatment may be discontinued in patients who have confirmed HBeAg seroconversion (HBeAg loss and HbeAb detection), followed by approximately 1 year of consolidation treatment. Treatment may be continued in patients who do not achieve seroconversion, although the benefits of continued treatment should be balanced with the risk of developing resistance. HBV viral suppression after cessation of therapy is not maintained in up to 60% of patients, and major virological and clinical relapse can occur even after 1 year following lamivudine cessation; thus, patients should be carefully monitored every 3 months. The durability of HBeAg seroconversion is not more than that of IFN, and it can be as low as 30% within the first year and may continue to decrease thereafter. [bib_ref] Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in..., Song [/bib_ref] For HBeAg-negative patients, the endpoint of lamivudine treatment is not known, and post-treatment relapse (up to >90% in some trials) occurs even in patients with persistently undetectable HBV DNA throughout therapy. With the availability of newer therapies with a lower risk of drug resistance, lamivudine is not considered a first-line therapy. Furthermore, in patients previously treated with lamivudine, a switch to an alternative, more potent Volume 20, Number 1 Rabi Al-Awwal 1435H January 2014 The Saudi Journal of Gastroenterology treatment with a high genetic barrier must be considered, particularly in patients who have received lamivudine for more than 2 years. ## Long-term outcome Despite maintained virological and biochemical responses in lamivudine patients who do not develop resistance, histological and long-term fibrosis resolution benefits are hampered by YMDD mutation development and viral breakthrough, potentially causing major clinical and histological relapse. Accordingly, the long-term benefits of lamivudine are questionable. [bib_ref] Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos-(t)..., Papatheodoridis [/bib_ref] Adefovir Adefovir is a nucleotide analog that can inhibit both reverse transcriptase and DNA polymerase, causing chain termination and preventing HBV replication. It was found in clinical studies to suppress both wild-type and YMDD mutant viruses because of its different resistance pattern than that of lamivudine. ## Efficacy The HBeAg seroconversion rate after 1 year of treatment with 10 mg adefovir was reported as 12%, and the average HBV DNA reduction was reported to be 3.5 logs. In the same study, a 30-mg dose of adefovir yielded better results; however, this dose was associated with higher nephrotoxicity (defined as an increase in serum creatinine by > 0.5 mg/dl above baseline in two consecutive readings), and the only approved dose is 10 mg. Nephrotoxicity has also been reported in 3% of patients with compensated liver disease after 4-5 years of continued adefovir therapy, and in 12% of transplant recipients and 28% of patients with decompensated cirrhosis during the first year of therapy. Most patients with decompensated cirrhosis have some degree of renal insufficiency; thus, the use of alternative treatment is more appropriate in these patients. [bib_ref] Adefovirdipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B, Marcellin [/bib_ref] Some studies have reported that 20-50% of patients receiving the 10-mg dose of adefovir exhibit primary non-response, indicating that the approved dose of adefovir may be suboptimal. In the HBeAg-negative group of patients, clinical trials have reported a higher rate of viral suppression, with a 51% undetectable level at 1 year that increases up to 71% at 2 years. Adefovir was found to be of particularly great value in controlling lamivudine-resistant HBV that manifests as degrees of clinical and histological worsening. The "add-on policy" of adefovir on top of lamivudine was associated with a 3-4 log reduction in viral load, which was sustained throughout treatment and led to clinical improvements. This method is particularly valuable in post-liver transplant patients who need to be on long-term lamivudine for HBV suppression. Recent data showed that switching to adefovir in patients with lamivudine-resistant HBV was associated with a higher risk of adefovir resistance, compared with adding adefovir. [bib_ref] Adefovirdipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B, Hadziyannis [/bib_ref] Dose regimen, duration of treatment, and durability of response The recommended dose of adefovir for adults with normal renal function (creatinine clearance > 50 ml/min) is 10 mg orally daily. The dosing interval should be increased in patients with renal insufficiency. Adefovir has not been approved for use in children. In HBeAg-positive patients, adefovir can be stopped after approximately 1 year of consolidation treatment after HBeAg seroconversion. HBeAg seroconversion usually occurs after a long duration of adefovir therapy (more than 2 years) due to its associated low viral suppression potency. In patients who do not reach seroconversion, adefovir may be continued as long as HBV DNA remains suppressed. For HBeAg-negative patients, continued treatment is needed, but treatment duration is not clear. More importantly, viral relapse occurs in 92% of patients after 1 year of cessation of adefovir treatment. However, the majority of patients on long-term adefovir (up to 5 years) maintained their response, but with little increase compared with the response during the first year. Thus, adefovir is considered to have low viral suppression potency and is valuable primarily in suppressing lamivudine-or entecavir-resistant HBV. For this reason, for most patients with lamivudine-resistant HBV (especially patients with decompensated cirrhosis or recurrent HBV post-liver transplant), long-term use of adefovir is required indefinitely in combination with lamivudine. [bib_ref] Sustained hepatitis B e antigen seroconversion in patients with chronic hepatitis B..., Wu [/bib_ref] Resistance occurs at a slower rate with adefovir compared with lamivudine and can reach 29% at 5 years. However, resistance was observed more frequently in patients taking lamivudine who were shifted to adefovir monotherapy. [bib_ref] Week 48 resistance surveillance in two phase 3 clinical studies of adefovirdipivoxil..., Westland [/bib_ref] Entecavir Entecavir inhibits HBV replication in three different steps; thus, it is considered more potent than lamivudine and adefovir. This statement is true in the setting of wild-type HBV infection, whereas entecavir is less potent in lamivudine-resistant HBV. ## Efficacy In HBeAg-positive patients, 48 weeks of 0.5 mg entecavir resulted in higher biochemical, virological, and histological responses compared with those associated with lamivudine. However, HBeAg seroconversion Volume 20, Number 1 Rabi Al-Awwal 1435H January 2014 The Saudi Journal of Gastroenterology was similar between the two groups (21% vs. 18%), although this rate continued to increase with continued treatment. [bib_ref] A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B, Chang [/bib_ref] Comparable results were also noted in HBeAg-negative patients. [bib_ref] Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B, Lai [/bib_ref] Of particular importance is the finding that entecavir was highly efficacious in decompensated cirrhotic patients and in patients with recurrent HBV post-liver transplant. While patients with lamivudine-resistant HBV require higher doses of entecavir (1 mg), the ability of entecavir to suppress HBV replication is lower than its suppression ability in wild-type HBV. This finding is related to a similar resistance pattern between the two NAs and, accordingly, entecavir was found to be effective in suppressing resistance to adefovir only. [bib_ref] A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory..., Chang [/bib_ref] Dose regimen, duration of treatment, and durability of response The dose of entecavir is 0.5 mg p.o. once daily, and it needs to be increased to 1 mg once daily only in cases of resistant HBV. The dose needs to be adjusted in patients with a creatinine clearance of less than 50 ml/min. The duration of treatment is still controversial. HBeAg seroconversion is not maintained in more than 30% of patients, even after 1 year of consolidation therapy following seroconversion. Similarly, in HBeAg-negative patients, it seems that indefinite entecavir use is warranted to keep HBV under continuous suppression. [bib_ref] Clinical emergence of entecavirresistant hepatitis B virus requires additional substitutions in virus..., Tenney [/bib_ref] Entecavir resistance is rare in nucleoside-naive patients, reaching only 5% after 5 years of therapy. However, resistance reaches 16% within 2 years in cases of lamivudine-resistant HBV. The susceptibility of HBV to entecavir decreases with the increase in the number of resistant mutations for both lamivudine and entecavir. Accordingly, it is advisable to stop lamivudine and switch to entecavir if the decision is to treat these patients with entecavir. ## Safety Entecavir had a similar safety profile to that of other nucleosides. ## Tenofovir Tenofovir is a nucleotide reverse transcriptase inhibitor that is more potent than adefovir and is administered at a dose of 300 mg once daily. It was also found to be more potent in suppressing lamivudine-resistant HBV compared with adefovir. However, this potency is decreased 3-to 4-fold when treating adefovir-resistant HBV because of the partial cross-resistance between tenofovir and adefovir. Tenofovir has been repeatedly reported to achieve much higher biochemical, virological, and histological responses in both HBeAg-positive and -negative patients, compared with adefovir and lamivudine. The 7-year safety and efficacy data were presented at American Association for the Study of Liver Diseases (AASLD) 2013 as an abstract. Specifically, HBV DNA suppression to less than 400 copies/ml in 99% of HBeAg-positive and -negative patients undergoing treatment, HBeAg loss/seroconversion rates of 55%/40%, and a confirmed HBsAg loss of 12% (10% seroconversion) were reported. No resistance was detected throughout the 7-year study. Although tenofovir has been reported to cause renal insufficiency, Fanconi syndrome, and osteomalacia, no bone disease was detected at the 3-year follow-up. The 7-year data demonstrated renal side effects in 2% of patients who were manageable, although dose adjustment was required in patients with renal impairment. Tenofovir demonstrated safety and efficacy in patients with liver cirrhosis, and regression of cirrhosis during treatment with tenofovir was observed in 71 (74%) of 96 patients treated for 5 years. [bib_ref] Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis..., Marcellin [/bib_ref] Tenofovir was also found to be safe during pregnancy (category B). ## Telbivudine Telbivudine is an NA with antiviral activity against HBV. It is more potent than lamivudine; however, it is associated with a high rate of resistance that increases with time and is not notably different from lamivudine resistance. Therefore, it has a limited role in the treatment of HBV as a monotherapy. The approved dose of telbivudine is 600 mg once daily, although the dose must be adjusted in patients with renal insufficiency. Cases of myopathy and peripheral neuropathy have been reported. ## Combination therapies Although combination therapies have been proven to be of significant value in treating HIV and HCV based on their synergistic antiviral effects, such therapies have not been proven to be of clear benefit in treating HBV. Several combinations have been tested to date for HBV (PEG-IFN with NA or a different NA), and none of them were found to be superior to monotherapy. This limited value of combination therapy in HBV is likely related to our limited knowledge of the most effective combination. To date, the only proven benefit of using combinations of different NAs is the reduction of resistance in cases of drugs that have high resistance patterns when used alone. Volume 20, Number 1 Rabi Al-Awwal 1435H January 2014 The Saudi Journal of Gastroenterology The other disadvantages of combination therapies are increased cost, increased toxicity, and potential drug interactions. ## Treatment of hbv in special populations ## Hbv-hcv coinfection Infection with HBV and HCV may occur, as the two viruses share similar risk factors and modes of transmission, especially in regions of the world where both viruses are endemic and among injection drug users. Usually, one virus (generally HCV) dominates over the other. These infections are usually associated with more severe liver disease. Combination therapy with PEG-IFN and ribavirin is equally effective in patients with HCV mono-infection and in those with HBV/HCV coinfection with similar SVR. [bib_ref] Peg interferon alfa-2a plus ribavirinfor the treatment of dual chronic infection with..., Liu [/bib_ref] Because HCV is the dominating virus in most cases, patients should receive treatment for HCV. [bib_ref] The HEP-NET B/C co-infection trial: A prospective multicenter study toinvestigate the efficacy..., Potthoff [/bib_ref] HBV may be reactivated after HCV clearance and after achieving SVR; [bib_ref] Virological profiles in hepatitis B virus/hepatitis C virus coinfected patients under interferon..., Saitta [/bib_ref] thus, patients should be closely monitored and treated with NAs if needed. ## Hbv-hdv coinfection HDV is a defective virus, as it requires HBsAg to envelop its delta antigen. Thus, the virus simultaneously coinfects patients with HBV or causes a superinfection in patients already chronically infected with HBV. Active HDV infection is defined by the presence of HDV IgM and RNA in patients with an unexplained elevation of LFTs. The primary endpoint of treatment is the suppression of HDV replication. Based on available data, PEG-IFN for 1 year appears to have long-term beneficial effects in patients, although most patients had viral relapse after stopping therapy that was usually accompanied by normalization of ALT level and a decrease in necroinflammatory activity based on liver biopsy, which were maintained over the long term. [bib_ref] Long-term benefit of interferon alpha therapy of chronic hepatitis D: Regression of..., Farci [/bib_ref] [bib_ref] Efficacy of peginterferon alpha-2b in chronic hepatitis delta: Relevance of quantitative RT-PCR..., Castelnau [/bib_ref] NA monotherapy does not appear to affect HDV replication and related disease. [bib_ref] Lamivudine for chronic delta hepatitis, Lau [/bib_ref] ## Hbv-hiv coinfection The prevalence of CHB infection among HIV-infected individuals may be ten times or more than that in the background population because they share the same mode of transmission with an accelerated course to cirrhosis and HCC. The indications for therapy are the same as those in HIV-negative patients and are based on HBV DNA levels, serum ALT levels, and histological stages. Treatment regimens depend on the clinical status of both HIV and HBV, but monotherapy with an agent that is effective against both HIV and HBV should be avoided; otherwise, resistance to both HIV and HBV will rapidly occur. Because anti-retroviral regimens may include drugs with activity against HBV (lamivudine, emtricitabine, and tenofovir are NAs with activity against both HIV and HBV), [bib_ref] Efficacy of tenofovirdisiproxilfumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1..., Dore [/bib_ref] [bib_ref] Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency..., Benhamou [/bib_ref] it is reasonable to base HBV treatment decisions on whether HIV treatment is ongoing or planned. Patients who are not on highly active anti-retroviral therapy (HAART) and are not anticipated to require HAART in the near future should be treated with an antiviral therapy that does not target HIV, such as PEG-IFN-α or adefovir. [bib_ref] European AIDS Clinical Society guidelines for the clinical management and treatment of..., Rockstroh [/bib_ref] Although telbivudine does not target HIV, it should not be used in this circumstance due to high resistance in the long term. Patients in whom treatment for both HBV and HIV is planned should receive therapies that are effective against both viruses; lamivudine plus tenofovir or emtricitabine plus tenofovir is preferred. Patients who are already on effective HAART that does not include a drug active against HBV may be treated with PEG-IFN or adefovir (in patients with lamivudine resistance, tenofovir should be added). When HAART regimens are altered, drugs that are effective against HBV should not be discontinued without substituting another drug that has activity against HBV, unless the patient has achieved HBeAg seroconversion and has completed an adequate course of consolidation treatment [ [fig_ref] Table 7: Management of patients with HIV coinfection [/fig_ref] ]. ## Immunosuppressed patients Hepatitis B inactive carriers and patients undergoing immunosuppressive or cancer chemotherapy (especially regimens that include corticosteroids or rituximab) are at a 20-50% greater risk of HBV reactivation. These individuals are usually asymptomatic, but immunosuppression may lead to hepatic decompensation and death. [bib_ref] Systematic review: The effect of preventive lamivudine on hepatitis B reactivation during..., Loomba [/bib_ref] All patients undergoing immunosuppressive treatment or chemotherapy, even short-term courses, should be screened for HBsAg, anti-HBc, and anti-HBs (and HBV DNA if HBsAg is already positive). Prophylactic antiviral therapy is recommended for HBV-inactive carriers at the onset of cancer chemotherapy or after a finite course of immunosuppressive therapy, and if baseline HBV DNA is <2000 IU/ml, this prophylactic therapy should be continued for 6 months after the completion of chemotherapy or immunosuppressive therapy. Tenofovir or entecavir is preferred if a longer duration of treatment is anticipated, as lamivudine and telbivudine result in resistance with prolonged use. IFN should be avoided due to its bone marrow suppression effect, which may lead to a hepatitis flare. Active HBV-immunosuppressed patients should be treated in the same manner as immunocompetent individuals. In patients with isolated core antibodies, prophylactic antivirals should be considered, particularly in patients receiving a regimen containing high-dose steroids or rituximab. ## Recommendations ## Symptomatic acute hepatitis b Although more than 95-99% of adults with acute HBV infection recover spontaneously and exhibit anti-HBs antibody seroconversion without antiviral therapy, a small subset of patients may develop acute liver failure and, accordingly, may benefit from NA treatment. Treatment should be continued until HBsAg clearance is confirmed or indefinitely in those who undergo liver transplantation. IFN is contraindicated because of the risks of worsening hepatitis and the frequent side effects. ## Pregnant women Most women with chronic HBV infection have mild disease during pregnancy; however, hepatitis may flare up after delivery, so close monitoring is warranted. Based on the risk of teratogenicity as assessed during preclinical evaluation, the nucleos(t)ides' are listed by the US Food and Drug Administration (FDA) as pregnancy category C drugs (lamivudine, adefovir, and entecavir) and category B drugs (telbivudine and tenofovir). There is a considerable amount of safety data on pregnant HIV-positive women who have received tenofovir, lamivudine, and/or emtricitabine. [bib_ref] Treating chronic hepatitis B infection in patients, who are pregnant or are..., Terrault [/bib_ref] In these women, tenofovir is preferred because it has a better resistance profile and more extensive safety data when used during pregnancy. [bib_ref] Therapy in pregnancy, Bzowej [/bib_ref] Pregnant women should be treated with NAs in the third trimester after organogenesis. However, if patients discover they are pregnant while on antivirals, treatment should be continued if they are on tenofovir, lamivudine, or telbivudine, especially after the first trimester and in cases of advanced fibrosis. However, if patients are on adefovir, entecavir, or PEG-IFN, treatment should be stopped and switched to tenofovir. IFN-based therapy is contraindicated in pregnancy because of its anti-proliferative effect. Breastfeeding is generally not recommended while receiving antivirals because nucleos(t)ide analogs are present in breast milk. However, based on the existing data, tenofovir is safe because it is a pro-drug with low oral bioavailability. ## Recommendations ## Children The majority of children present with CHB in an immune-tolerant phase, causing benign disease. In these cases, children should not be treated. However, in patients with elevated ALT levels for >6 months and those with ensuing hepatic decompensation, conventional IFN-α, lamivudine, and adefovir, which have been shown to have a similar safety and efficacy to that found in adults, should be administered. [bib_ref] Safety, efficacy, and pharmacokinetics of adefovirdipivoxil in children and adolescents (age 2..., Jonas [/bib_ref] [bib_ref] International Pediatric Lamivudine Investigator Group. Long-term lamivudine treatment of children with chronic..., Jonas [/bib_ref] [bib_ref] Virological response during treatment of chronic hepatitis B with pegylated interferon alfa-2a..., Pawlowska [/bib_ref] ## Chronic renal failure and renal transplant patients Patients with chronic renal failure who are undergoing dialysis can be treated with NA, but the dosage needs to be adjusted based on renal function. Nucleosides (lamivudine and entecavir) [bib_ref] Efficacy and safety of lamivudine on replication of recurrent hepatitis B after..., Rostaing [/bib_ref] are a safer choice in these patients than nucleotide (adefovir and tenofovir) analogs because they yield better renal outcomes [ [fig_ref] Table 8: Dosage adjustments of nucleos [/fig_ref] ]. ## Prevention of recurrent hepatitis b after liver transplantation Patients with CHB and end-stage liver disease who are awaiting liver transplant should be treated with NAs, regardless of ALT and HBV DNA levels, to maintain an undetectable viral load at the time of transplantation. In addition, viral suppression rescues some patients with decompensated cirrhosis, thereby avoiding the need for a future transplant. [bib_ref] Determinants of early mortality in patients with decompensated chronic hepatitis B treated..., Fontana [/bib_ref] Therapy with a potent NA with a high barrier to resistance and or a combination of nucleos (t) ides should be administered to avoid resistance that may lead to disease flare-ups, which may lead to acute liver failure. [bib_ref] Management of hepatitis B in liver transplantation patients, Samuel [/bib_ref] [bib_ref] Adefovirdipivoxil for wait-listed and postliver transplantation patients with lamivudine-resistant hepatitis B: Final..., Schiff [/bib_ref] After transplantation, long-term combination treatment with NAs and HBIG reduces the risk of HBV re-infection of the graft. Recent evidence suggests the safety of early cessation of HBIG post-liver transplant in the era of new potent antiviral agents. Volume 20, Number 1 Rabi Al-Awwal 1435H January 2014 The Saudi Journal of Gastroenterology ## Compensated cirrhosis Treatment of patients with cirrhosis should not be based on ALT levels, as these may be normal in advanced disease. [bib_ref] Accuracy of international guidelines for identifying significant fibrosis in hepatitis B e..., Sanai [/bib_ref] [bib_ref] Predictors of significant fibrosis in chronic hepatitis B patients with low Viremia, Abdo [/bib_ref] The use of potent NAs with a very low risk of resistance (tenofovir or entecavir) and close monitoring of HBV DNA levels are important, and resistance must be prevented by adding a second drug without cross-resistance if HBV DNA is still detectable at week 48 of therapy. Patients with cirrhosis require long-term therapy with careful monitoring for resistance and flare-ups, as prolonged and adequate suppression of HBV DNA may stabilize patients and delay or even obviate the need for transplantation. [bib_ref] Lamivudine for patients with chronic hepatitis B and advanced liver disease, Liaw [/bib_ref] PEG-IFN-α 2a should be used with caution for the treatment of well-compensated cirrhosis because it places patients at increased risk of sepsis and decompensation. [bib_ref] Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients..., Buster [/bib_ref] ## Decompensated cirrhosis Patients with decompensated cirrhosis should be treated in a specialized liver unit because many of these patients may have progressed significantly and may not benefit from treatment, thus requiring transplantation. [bib_ref] Determinants of early mortality in patients with decompensated chronic hepatitis B treated..., Fontana [/bib_ref] Treatment is indicated even if the HBV DNA level is low, to prevent recurrent reactivation. Potent NAs with good resistance profiles (entecavir or tenofovir) should be used to avoid hepatic decompensation due to hepatic flare-ups when a resistant strain is selected. Although PEG-IFN-α 2a can be used for the treatment of compensated cirrhosis, albeit with some caution, it is definitely contraindicated in cases of decompensated cirrhosis. ## Occupational aspects of hbv in the ksa Provider-to-patient transmission of HBV has been well documented in the literature. The Centers for Disease Control and Prevention (CDC) reported 42 instances of provider-to-patient transmission of HBV involving 375 patients. [bib_ref] Preventing bloodborne pathogen transmission from health-care workers to patients: The CDC perspective, Bell [/bib_ref] Other studies reported 19 and 4 patients who acquired HBV from cardiothoracic and orthopedic surgeons, respectively, [bib_ref] Transmission of hepatitis B virus to multiple patients from a surgeon without..., Harpaz [/bib_ref] [bib_ref] Transmission of hepatitis B related to orthopedic surgery (abstract), Johnston [/bib_ref] and several other reports from the UK and USA confirmed these findings.HBV transmission is either parenteral or across mucus membranes, making the risk for transmission negligible during routine medical care. The risk is still very small even with invasive procedures, but it is clearly elevated compared with the risk associated with other routine medical care, necessitating a balance between patient safety and unnecessary exclusion of healthcare providers. ## Hbv international regulations Regulations related to HBV-infected healthcare workers vary. The US guidelines, published in 1991, recommend that "healthcare providers who perform exposure-prone procedures and who have HBV (and HBeAg positive) should not perform exposure-prone procedures unless they have sought counsel from an Expert Review Panel and been advised that they may continue to perform these procedures after informing their patients."In 2010, the Society for Healthcare Epidemiology of America (SHEA) used the HBV DNA level to stratify HBV-infected healthcare providers. According to this stratification, there are no restrictions imposed on healthcare providers if HBV is <10 4 genome equivalents (GE)/ml, whereas providers with HBV >10 4 GE/ml are allowed to perform category 1 and 2 procedures but not category 3 procedures. [bib_ref] SHEA guideline for management of healthcare workers who are infected with hepatitis..., Henderson [/bib_ref] In the UK, HBV-infected providers who are HBeAg positive may not perform exposure-prone invasive procedures; HBV-infected providers who are HBeAg negative but have HBV DNA levels greater than 10 3 GE/ml may not conduct exposure-prone invasive procedures; and HBV-infected providers who are HBeAg negative and have HBV DNA levels less than 10 3 GE/ml may conduct exposure-prone invasive procedures but must be retested at least every 12 months to ensure that the level of viremia remains below 10 3 GE/ml.More recently, authorities in the UK have allowed healthcare providers to perform such procedures if their viral loads decrease to below 10 3 GE/ml following treatment.In 2012, the CDC issued an update with a cut-off point of 1000 IU/ml (5000 GE/ml), regardless of HBeAg status.A European consortium used a cut-off level of 10 4 GE/ml, [bib_ref] Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in health..., Gunson [/bib_ref] whereas scientists from the Netherlands used a cut-off level of 10 5 GE/ml. [bib_ref] Doctor to patient transmission of hepatitis B virus: Implications of HBV DNA..., Buster [/bib_ref] In a comprehensive analysis, van der Eijk et al. [bib_ref] Hepatitis B virus DNA levels and the management of HBVinfected health care..., Van Der Eijk [/bib_ref] listed the challenges of standardizing recommendations for practice restrictions for HBV-infected providers, emphasizing that guidelines have to strike a balance between unnecessarily excluding providers and patient safety. ## The current national regulation In March 2006, the Ministry of Health Preventive Medicine Department within Saudi Arabia issued an updated regulation for HBV consisting of the following three main categories: 1. Visitors, tourists, and Hajj and Omra visitors are not required to be tested for HBV or HCV before obtaining a visa or after landing, except if they apply to change their visa status to a resident visa 2. New resident visa for work: - New expatriates, regardless of job title, are required to be tested for HBsAg in their country of origin, with repeated testing required after arriving in the Kingdom and before beginning work. Only HBsAg-negative individuals are allowed to work, with the exception of university professors in rare cases - Indeterminate results should be confirmed by PCR - Individuals who test negative should receive the vaccines. 3. Individuals currently working in Saudi Arabia are further divided into healthcare workers and non-healthcare workers. ## Healthcare workers - All healthcare workers who were not previously tested for HBsAg should be tested - HBsAg testing should be repeated every 2 years upon residency visa renewal for non-Saudi physicians and healthcare workers in surgery department, operating rooms, Ob/GYN clinic, intensive care unit, emergency department, neonatal intensive care unit, burn unit, dental clinic, HD unit, phlebotomy laboratory, or wound management clinics - Physicians and healthcare workers performing exposure-prone procedures, who test positive for HBsAg, should undergo HBV PCR. If the titer is >10 5 copies/ ml, they should stop performing these procedures, but can work in other departments - Individuals who are HBsAg positive with HBV DNA < 10 5 copies/ml in two consecutive tests can continue performing their exposure-prone procedures due to a lack of transmission risk, but annual testing is required. - Physicians and healthcare workers not performing exposure-prone procedures and who have HBsAg with HBV DNA <10 5 copies/ml can continue working, as they do not pose a risk to patients - Physicians and healthcare workers not performing exposure-prone procedures and who have HBsAg with HBV DNA >10 5 copies/ml can continue working, as they do not pose a risk to patients, but they must strictly follow the universal precautions for infectious control. ## Non-healthcare workers - HBsAg testing should be repeated every 2 years upon residency visa renewal for housemaids, drivers, babysitters, and barbers; those who test positive will not be allowed to work in these jobs, and their residency visa will not be renewed - Individuals with jobs not listed above and who test positive can continue to work.We have chosen a cut-off value of 1000 IU/ml to separate providers who can and cannot perform invasive procedures. This level was chosen in the absence of data associating a given level with either a clear risk for transmission or, more importantly, an absence of risk; nevertheless, this is the lowest HBV DNA level at which transmission from a healthcare worker to a patient occurred. ## Recommendations 24. All providers should follow the standard precautions (Grade A) 25. HBV-infected healthcare providers should not be prohibited from participating in patient care activities solely on the basis of their HBV infection status (Grade C) 26. Providers infected with HBV who have circulating viral burdens ≥ 1000 IU/ml should refrain from performing exposure-prone invasive procedures (Grade D) 27. Healthcare providers who have circulating HBV burdens [fig] Figure 2: Algorithm for the management of hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B infection. ALT, alanine aminotransferase; HBV, hepatitis B virus; ULN, upper limit of normal. Not considered as fi rst-line therapy due to high rates of resistance; °not recommended in this subgroup of patients [/fig] [fig] Figure 1: Algorithm for the management of hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B infection. ALT, alanine aminotransferase; HBV, hepatitis B virus; ULN, upper limit of normal. Not considered as fi rst-line therapy due to a high rate of resistance [/fig] [fig] 17: All patients undergoing chemotherapy or treatment with other immunosuppressive therapies should be screened for HBsAg and anti-HBc antibodies (Grade A) 18. Patients testing positive for HBsAg should receive antiviral prophylaxis starting as soon as possible before treatment and continuing for at least 6 months after the last dose of immunosuppressive drug with close monitoring during and after therapy (Grade B) 19. Patients with isolated anti-HBc who are immunosuppressed should have close HBV DNA monitoring, and should be considered for antiviral therapy (Grade C). [/fig] [table] Table 1: Grading of recommendations [/table] [table] Table 3: Pretreatment assessment AST: Aspartate aminotransferase, GGT: Gamma-glutamyltransferase, ALP: Alkaline phosphatase, PT: Prothrombin time, HCC: Hepatocellular carcinoma [/table] [table] Table 4: Management of drug resistanceThe Saudi Journal of Gastroenterology >20,000 IU/ml and elevated ALT for 3-6 months should be considered for treatment (Grade B) 10. HBsAg-negative patients with HBV DNA levels >2000 IU/ml and elevated ALT levels for 3-6 months should be [/table] [table] Table 5: Response categories [/table] [table] Table 6: Results of the main studies for the treatment of HBeAg-negative chronic hepatitis B at 6 months following [/table] [table] Table 7: Management of patients with HIV coinfection [/table] [table] Table 8: Dosage adjustments of nucleos (t) ide analogs according to creatinine clearance [/table]	None	None	Gastroenterology Unit, College of Medicine, King Saud University, Riyadh, Saudi ArabiaAAddress for correspondence:ddress for correspondence: Dr. Waleed Al-Hamoudi, Gastroenterology and Hepatology Unit (59), Department of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia. E-mail: walhamoudi@gmail.com
8fb96cdfaf1103d70bcaf20a2cf4bc0cbf57ae00	pubmed	None	ContextAlthough the principles of infection prevention and control remain unchanged, new technologies, materials, equipment and updated data require continuous evaluation of current infection control practices 1 and continuous education for the oral health team.ScopeThis policy statement provides the basic principles of infection prevention and control. More detailed information can be found in the references and in relevant legislation. ## Definitions Infection prevention and control (IPC): scientific approach and practical solution designed to prevent harm caused by infection to patients and health workers 2 Standard precautions: Guidelines for the prevention of transmittable diseases including nosocomial infections. Standard precautions combine universal precautions and body-substance precautions for all patients regardless of diagnosis or possible infectious status. 3 ## Principles It is the responsibility of dentists to establish a protocol that prevents or limits the spread of infection in dental practice for their patients, their staff and themselves. This can be accomplished by following the recommended infection control work practice procedures. ## Policy FDI supports the following statements: 1. Recommendations, guidelines and regulations should be developed in consultation with the dental profession. 2. Recommendations, guidelines and laws affecting standard precautions required of dental practices must be evidence-based or based on international best practices and receive adequate financial compensation for the additional costs that are incurred. 3. Local/regional dental associations should educate the public on the importance of proper infection control in the dental office, the effectiveness of such recommended procedures and consequently the absence of a significant risk of contracting transmittable diseases through the provision of dental care. 4. Dental educators must incorporate current infection prevention and control recommendations in healthcare settings into the curriculum and during clinical activities. This should include a blame-free critical incident reporting and learning system. ## Page 1 of 3 ## Infection prevention and control in dental practice Published on FDI World Dental Federation (https://www.fdiworlddental.org) ## General Members of the oral health team are obliged to keep their knowledge and skills up to date with regard to the diagnosis and management of infectious diseases that may be transmitted in the clinical setting, adhere to standard precautions and where necessary transmission-based precautions as set forth by the relevant authorities and to take appropriate measures to protect their patients and themselves against infections. These measures include: adopting the principles of cleanliness and disinfection of all exposed surfaces in the work environment; following protocols accepted and/or recommended by relevant authorities for the decontamination, disinfection, sterilization and reprocessing of reusable instruments and disposal of clinical waste 4 ; assuring that sterile instruments are protected from recontamination by using appropriate barrier packaging; using single-use instruments if sterilization is not possible 5 ; exercising special care with the use of sharps; removing them from the work area after use and disposing them in a clearly labelled puncture-resistant container; adopting disinfection principles for devices, prostheses, impressions, instruments and applicable items transported to and from the dental laboratory; handling biopsy specimens with care and placing them in leak-proof containers according to the recommended guidelines. ## Health professionals FDI urges oral health professionals to be physically protected (surgical masks, gloves, protective eye wear and outerwear) as appropriate for the care being provided; to be appropriately vaccinated against infectious diseases according to current guidelines issued by the relevant authorities; immediately to initiate appropriate postexposure prophylaxis for occupational exposure of blood-borne pathogens, including HBV, HCV and HIV 6 ; to be personally aware of signs and symptoms which indicate the possibility of blood-borne and other infectious diseases and undergo the necessary diagnostic tests when infection is suspected. FDI opposes any legislation that makes universal screening of oral health professionals for blood-borne pathogens mandatory; to comply with medical advice and relevant regulations regarding continuation of clinical practice if an infection is diagnosed. ## Patient FDI believes that all patients with communicable infections should disclose their status as part of their medical history. It is unethical for patients to be denied oral healthcare solely because of their blood-borne disease status. FDI urges all oral health professionals to be alert for signs and symptoms of blood-borne and other infectious diseases in their patients; to advise all patients with a relevant medical history or condition suggestive of infection to undergo appropriate evaluation and treatment in a supportive environment with full regard to privacy; to have an appropriate protocol, in accordance with applicable relevant laws, for the confidential handling of information about patients; to make patients aware of the privacy policy in all settings where dental care is delivered; to share information pertaining to the patient's medical condition with other health workers as permitted by relevant regulations and with the patient's consent. ## Disclaimer Published on FDI World Dental Federation (https://www.fdiworlddental.org)The information in this Policy Statement was based on the best scientific evidence available at the time. It may be interpreted to reflect prevailing cultural sensitivities and socio-economic constraints.	None	None	None
ac558deba35ad21acb94ba25b2c4a3a9a0f64ed3	pubmed	2019 update of the European AIDS Clinical Society Guidelines for treatment of people living with HIV version 10.0	2019 update of the European AIDS Clinical Society Guidelines for treatment of people living with HIV version 10.0 The European AIDS Clinical Society (EACS) Guidelines cover key aspects of HIV management with major updates every two years.Guideline highlightsThe 2019 Guidelines were extended with a new section focusing on drug-drug interactions and other prescribing issues in people living with HIV (PLWH). The recommendations for treatment-na€ ıve PLWH were updated with four preferred regimens favouring unboosted integrase inhibitors. A two-drug regimen with dolutegravir and lamivudine, and a three-drug regimen including doravirine were also added to the recommended initial regimens. Lower thresholds for hypertension were expanded to all PLWH and for cardiovascular disease prevention, the 10-year predicted risk threshold for consideration of antiretroviral therapy (ART) modification was lowered from 20% to 10%. Frailty and obesity were added as new topics. It was specified to use urine albumin to creatinine ratio to screen for glomerular disease and urine protein to creatinine ratio for tubular diseases, and thresholds were streamlined with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations. Hepatitis C virus (HCV) treatment recommendations were split into preferred and alternative treatment options. The algorithm for management of recently acquired HCV infection was updated and includes recommendations for early chronic infection management. Organization (WHO) recommendations, and new tables on immune reconstitution inflammatory syndrome, on when to start ART in the presence of opportunistic infections and on TB drug dosing were included. # Conclusions The EACS Guidelines underwent major revisions of all sections in 2019. They are available in four different formats including a new interactive web-based version and are translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish. Keywords: antiretroviral treatment, comorbidities, drug-drug interactions, European AIDS Clinical Society (EACS) Guidelines, hepatitis B virus, hepatitis C virus, HIV, opportunistic infections, prescribing in elderly patients The European AIDS Clinical Society (EACS) Guidelines As several countries are lacking or infrequently update national HIV guidelines, the EACS Guidelines have since 2005 provided recommendations that are independent of geographical region and levels of care. Acknowledging that HIV care extends far beyond antiretroviral treatment (ART), the EACS Guidelines also provide guidance on several other key aspects related to HIV management. In 2019, the EACS Guidelines underwent major revisions of all sections. One of the most essential changes includes a new panel focusing on drug-drug interactions (DDIs) and other prescribing issues in people living with HIV (PLWH) in acknowledgement of the increased ageing of PLWH and increasing risks of polypharmacy. Bictegravir (BIC) and doravirine (DOR) were released since the last major revision and have been included in all sections. In addition, older drugs that are now rarely used, including several older boosted protease inhibitors (PI/bs), didanosine and stavudine, were removed from most sections. To ensure easy access to the Guidelines, a new format in the form of an interactive web-based version was introduced (https://eacs.sanfordguide.com) in 2019. The Guidelines remain available in print as a booklet, online as a pdf (https://www.eacsociety.org/files/2019_guideline s-10.0_final.pdf) and as a free App for IOS and Android devices produced with the Sanford Group. The EACS Guidelines are translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish. ## The guideline review process The Guidelines undergo major revisions every second year, and minor revisions in the years in between, as previously described. Interim updates may be performed in the case of new key data emerging between scheduled updates. Meetings are held at regular intervals but can also be set up at short notice when necessary. Each of the Guideline sections is created by a panel of experts governed by a three-person leadership group. The Guidelines are managed by a Guidelines Chair and Coordinator; details have previously been described. As also previously reported, the recommendations provided in the EACS Guidelines are based on evidence whenever possible, and, in the rare instances where adequate evidence is unavailable, based on expert opinions. The Guidelines are extensively cross-reviewed by the panellists, and by representatives from the community and from Women Against Viruses in Europe (WAVE). Conflict of interest statements are required for all members and can be provided upon request. In the following, the most important changes made in version 10.0 for each section of the Guidelines are described. ## Art section In the 2019 version, the layout for initial ART regimens, treatment in pregnancy/women wishing to conceive and in persons coinfected with tuberculosis (TB) were made uniform to ensure consistency. Before initiating ART, it is recommended to consider if a woman is pregnant or wishes to conceive, and if the person has an opportunistic infection or any potential treatmentlimiting comorbidities. In addition, it is recommended to consider if the person is at risk of DDIs or if the person has swallowing difficulties. In all these instances, the Guidelines provide management recommendations. Among the recommended first-line regimens for ART-na€ ıve PLWH, EACS recommends four preferred options consisting of two nucleoside reverse transcriptase inhibitors [NRTIs; abacavir (ABC)/lamivudine (3TC), tenofovir alafenamide (TAF)/emtricitabine (FTC), tenofovir disoproxil fumarate (TDF)/TFC or TDF/3TC] in combination with an unboosted integrase strand transfer inhibitor [INSTI; dolutegravir (DTG), BIC or raltegravir (RAL)] [fig_ref] Table 1: Combination antiretroviral therapy [/fig_ref]. Among these preferred regiments, EACS favour those with a high genetic barrier (DTG or BIC) as a third agent. Other recommended first-line regimens include one two-drug combination with an NRTI (3TC) plus an INSTI (DTG), and three three-drug combinations with two NRTIs (TAF/FTC, TDF/FTC or TDF/3TC) plus a nonnucleoside reverse transcriptase inhibitor [NNRTI; DOR or rilpivirine (RPV)] or plus a boosted protease inhibitor [PI/b; cobicistat (COBI)-or ritonavir (RTV)-boosted darunavir (DRV/c or DRV/r)] [fig_ref] Table 1: Combination antiretroviral therapy [/fig_ref]. The alternative regimen recommendations to be used when none of the preferred regimens are available are shown in [fig_ref] Table 1: Combination antiretroviral therapy [/fig_ref]. The following two-drug combinations are recommended as possible switch strategies; 3TC with DTG, DRV/b or boosted atazanavir (ATV/b) or DTG plus RPV. Three new tables were included for pregnant women living with HIV or women wishing to conceive to specify which drugs are considered safe and which to avoid. EACS currently recommends not using DTG in women who wish to conceive because of the reported higher risk of neural tube defect if used preconception [bib_ref] Neural tube defects and antiretro-viral treatment regimens in Botswana, Zash [/bib_ref]. As a consequence of insufficient data on safety and efficacy in pregnancy, TAF, RAL once a day (qd), BIC and DOR are currently not recommended in women who become pregnant while on ART. In addition, COBI boosting has proved less robust than RTV boosting during pregnancy, and therefore COBI-boosted elvitegravir (EVG/c) is not recommended and ATV or DRV should be boosted only with RTV in women who become pregnant while on ART. The preferred initial options for ART-na€ ıve pregnant women include combinations of two NRTIs (ABC/3TC, TDF/FTC or TDF/3TC) plus an INSTI [DTG, which can be used after pregnancy week 8, or RAL twice a day (bid)]. The recommended regimens include two NRTIs (TDF/FTC or TDF/3TC) plus a PI/r (DRV/r). Alternative regimens to be considered consist of two NRTIs (ABC/3TC, TDF/FTC or TDF/3TC) plus an NNRTI [efavirenz (EFV) or RPV] or plus a PI/r (ATV/r or DRV/r). A section on labour and breastfeeding was further added. For PLWH coinfected with susceptible TB, the recommended ART regimens to be used with rifampicin include the combination of two NRTIs (TDF/FTC, TDF/3TC or ABC/3TC) plus an NNRTI (EFV), or for alternative regimens plus an INSTI (DTG bid or RAL bid). An updated table further describes the most relevant DDIs when ART is co-administered with rifampicin or rifabutin. For post-exposure prophylaxis (PEP), additional regimen combinations with TAF/FTC, RAL qd and BIC were included. For pre-exposure prophylaxis (PrEP), use of daily TAF/FTC was included as a possible alternative in men who have sex with men and transgender women. ## Section on ddis and other prescribing issues All DDI tables have been organized in a separate section devoted to issues related to prescribing ART and other co-medication in PLWH. The DDI tables each provide an overview of the interaction potential between individual antiretroviral drugs and the most commonly used comedications within a therapeutic area. Two new tables have been added on dose adjustment in renal impairment for commonly co-administered drugs Additional guidance: (I) ABC contraindicated if HLA-B57:01 positive. Even if HLA-B57:01 negative, counselling on hypersensitivity reaction risk still mandatory. ABC should be used with caution in persons with a high CVD risk (> 10%). (II) In certain countries, TDF is labelled as 245 mg rather than 300 mg to reflect the amount of the prodrug (tenofovir disoproxil) rather than the fumarate salt (tenofovir disoproxil fumarate). There are available generic forms of TDF, which instead of fumarate use phosphate, maleate, and succinate salts. They can be used interchangeably. When available, combinations containing TDF can be replaced by the same combinations containing TAF. TAF is used at 10 mg when coadministered with drugs that inhibit p-glycoprotein (P-gp), and at 25 mg when co-administered with drugs that do not inhibit P-gp. The decision whether to use TDF or TAF depends on individual characteristics as well as availability. So far, there are only limited long-term data on TAF. If the antiretroviral (ART) regimen does not include a booster, TAF and TDF have similar short-term risks of renal adverse events leading to discontinuation and bone fractures. TAF* should be considered as a first choice over TDF in individuals with: (1) established or high risk of chronic kidney disease (see Guideliness page 64); (2) co-administration of medicines with nephrotoxic drugs or prior TDF toxicity (see Guidelines page 65); (3) osteoporosis/progressive osteopenia, high fracture risk asessement tool score or risk factors (see Guidelines page 61); (4) history of fragility fracture (see Guidelines pages 61 and 63). There are limited data on use of TAF with estimated glomerular filtration rate (eGFR) < 30 mL/min; ***Expert opinion pending clinical data. in PLWH and a list of the top ten drugs to avoid in elderly PLWH to increase awareness of inappropriate drug administration and dosing. In addition, a new table was developed on the recommended drug dosages for hormone therapy when used at high doses for gender transitioning. Detailed information on DDIs can be found in the University of Liverpool website www.hiv-druginteractions.org. ## Comorbidity section The comorbidity section continues to be the largest section of the EACS Guidelines and provides screening and management recommendations for the most common comorbid conditions among PLWH and for conditions that require specific guidance. Given the increased prevalence of frailty in PLWH, a new table outlines definitions, recommended assessments and management to help identify those at frailty risk. For some comorbidities [e.g. hypertension, nonalcoholic fatty liver disease (NAFLD) and bone disease], different agespecific guidance for diagnosis [e.g. using dual-energy Xray absorptiometry (DEXA) scan and liver fibrosis scores] and management (e.g. for hypertension) is provided. Recommendations to lower blood pressure targets to systolic pressure < 130 mmHg and diastolic pressure < 80 mmHg were previously introduced (v9.0) for highrisk individuals; in 2019 (v10.0), these recommendations were further broadened to apply to all PLWH. Furthermore, antihypertensive drug sequencing was amended. The threshold for ART modification in relation to 10year predicted cardiovascular disease (CVD) risk has been lowered from 20% to 10%. Similarly, lipid targets have been lowered for both primary and secondary prophylaxis. As obesity and weight increase have become more frequent in PLWH, and this is a rapidly evolving field, an addition on diagnosis, risk factors and management of obesity was made to the existing chapter on lipoatrophy. New data on weight increase related to use of INSTIs and TAF were added to the table on potential adverse drug effects. In the liver section, a fourth step was added to the workup of persons with increased transaminases to include risk stratification using aspartate aminotrabsferase to platelet ratio (APRI), fibrosis-4 (FIB4), NAFLD fibrosis score and transient elastography. Similarly, the screening recommendation for hepatocellular carcinoma in noncirrhotic persons with chronic HBV coinfection was amended in collaboration with the viral hepatitis panel to include an age threshold acknowledging the higher risk in those older than 45 years [bib_ref] Incidence of hepatocellular carcinoma in HIV/HBV-coinfected patients on tenofovir therapy: relevance for..., Wandeler [/bib_ref]. The algorithm for surveillance for varices and primary prophylaxis was updated to incorporate transient elastography (where available) with platelet counts to determine indications for upper gastrointestinal endoscopy. Finally, the diagnostics flow-chart for NAFLD was revised to include the use of fibrosis scores. Finally, in the renal subsection, it was specified to use urine albumin to creatinine ratio to screen for glomerular disease (such as diabetes and HIV-related disease), and urine protein to creatinine ratio to screen for tubular diseases (i.e. ART drug toxicity). The cut-off values for albuminuria and proteinuria have further been streamlined with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations [bib_ref] Kidney disease in the setting of HIV infection: conclusions from a kidney..., Swanepoel [/bib_ref]. ## Viral hepatitis coinfection section This section was renamed Clinical management and treatment of viral hepatitis co-infections in PLWH. The overall structure of the section was also revised to improve readability. The first subsection contains general recommendations on viral hepatitis coinfections in PLWH and focuses on screening recommendations, measures of prevention and complications related to viral hepatitis. A new table on noninvasive liver fibrosis markers was introduced. Another subsection focuses on treatment and monitoring of PLWH coinfected with HBV and includes a part on HBV reactivation related to immunosuppressive treatment with monitoring and treatment recommendations stratified by type of immunosuppressive drugs. Awareness of the risk for HBV reactivation is particularly important in the era of ART simplification with regimens not containing NRTIs active against HBV. There were no new direct-acting antivirals (DAAs) licensed for the treatment of HCV since the last Guideline revision. The HCV treatment [fig_ref] Table 2: Preferred DAA HCV treatment options [/fig_ref] , 3). The recommendations for the management of DAA treatment failures were updated. Acute HCV infection was renamed "recently acquired HCV infection" in accordance with the recent European AIDS Treatment Network consensus conference (NEAT) statement. Lack of spontaneous clearance and progression to chronic infection can be predicted reliably by four weeks after diagnosis in those with less than a 2 9 log 10 reduction in HCV RNA [bib_ref] Fueling the epidemic: low rates of spontaneous clearance of acute HCV coinfection, Boesecke [/bib_ref]. Accordingly, this situation is considered as early chronic HCV infection and immediate DAA therapy is recommended. DAA treatment is recommended as in treatment-na€ ıve noncirrhotic individuals (except for those with pre-existing liver cirrhosis), as several trials failed to demonstrate noninferiority of shortened treatment courses. Finally, the recommendations on the management of viral hepatitis D and E in PLWH were expanded. ## Opportunistic infection (oi) section A new table is included at the start of the revised OI section, providing guidance on when to start ART in the presence of OIs and in particular TB, cryptococcal meningitis and cytomegalovirus (CMV) end-organ disease. Also added is a new table on immune reconstitution inflammatory syndrome (IRIS), including definitions of paradoxical and unmasking IRIS, along with recommendations on prevention and management. For the 2019 update, extensive revisions on how to manage drug-resistant TB in PLWH were made. The recommendations are in line with the most recent World Health Organization (WHO) recommendations to use four, preferably oral and presumed effective TB drugs for the first six months of intensive treatment, followed by treatment with three active drugs for 12-14 months depending on response . In addition, a new table on recommended TB drug doses and key adverse effects has been added. Also new is the addition of talaromycosis, which is relevant in PLWH who have lived in Asia. The table contains recommendations on diagnosis, treatment and secondary prophylaxis. Minor edits have been made to the other individual OIs, most importantly for Pneumocystis jiroveci pneumonia (PCP) and Toxoplasma gondii infection, where primary prophylaxis can now be stopped already at CD4 counts > 100 cells/lL and if viral load has been undetectable for > 3 months. For nontuberculous mycobacteria, primary prophylaxis in the case of a CD4 count < 50 cells/lL is no longer recommended if ART is started. # Conclusions The 2019 version of the EACS Guidelines has undergone substantial updates in all sections and has been expanded with new sections on DDIs and other prescribing issues in PLWH. The Guidelines are available in four different formats and translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish. [table] Table 1: Combination antiretroviral therapy (ART) regimens for treatment-na€ ıve adult people living with HIV (PLWH) TAF/FTC or TDF/FTC or TDF/3TC + ATV/c or ATV/r [/table] [table] Table 2: Preferred DAA HCV treatment options (except for persons pretreated with protease or NS5A inhibitors) [/table] [table] Table 3: DAA HCV treatment options (except for persons pretreated with protease or NS5A inhibitors) to be used if preferred option is not avaible [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/hiv.12878	The European AIDS Clinical Society (EACS) Guidelines cover key aspects of HIV management with major updates every two years.
b1c90f4554caa6da07a36716b42e3e28b91c220c	pubmed	Clinical Practice Guidelines on the Screening and Treatment of Precancerous Lesions for Cervical Cancer Prevention in Saudi Arabia	Clinical Practice Guidelines on the Screening and Treatment of Precancerous Lesions for Cervical Cancer Prevention in Saudi Arabia BACKGROUND: Cervical cancer is the third most common gynecological malignancy in Saudi women with an estimated incidence rate of 1.9 cases per 100 000 women-years. More than 40% of cervical cancer cases are diagnosed at advanced stages due to lack of a routine screening program in Saudi Arabia. Thus, national guidelines for routine screening and treatment of precancerous cervical lesions are needed. # Methods: The Saudi Centre for Evidence-Based Healthcare invited a panel of local experts and partnered them with a team from McMaster University in Canada for methodological support, to develop national clinical practice guidelines on the screening and treatment of precancerous lesions for cervical cancer. After the panel identified key clinical questions, the McMaster University working group updated existing systematic reviews that had been used for the 2013 WHO Guidelines for screening and treatment of precancerous lesions for cervical cancer prevention. Recommendations were based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. Those recommendations took into account the available evidence, patient values and preferences, and resource use in the Saudi context. The panel provided recommendations on two major issues: screening for precancerous lesions (cervical intraepithelial neoplasia 2 & 3) and treatment of those lesions to prevent cervical cancer in women who tested positive after screening. # Conclusions: The Saudi expert panel recommends using the HPV DNA test followed by colposcopy or cytology (Pap test) followed by colposcopy to screen for CIN2+ in women at risk of cervical cancer. The panel recommends cryotherapy or loop excision electrosurgery procedure (LEEP) over cold knife cone biopsy to treat women at risk of cervical cancer that tests positive for CIN2+. Universal screening for precancerous cervical dysplasia in women in Saudi Arabia is recommended using HPV testing and or cytology. Either cryotherapy or LEEP are preferred for treatment. LIMITATIONS: National studies on cervical cancer screening modalities and treatment of precancerous cervical lesions, including HPV prevalence and its association with cervical cancer, are scarce. A n estimated 1% to 2% of women develop cervical intraepithelial neoplasia grade 2 and 3 (CIN 2 and 3) each year worldwide.Those lesions could progress to cervical squamous cell carcinoma, which comprises 80% to 90% of cervical cancers. [bib_ref] Detection and typing of human papillomavirus DNA in uterine cervices with coexistent..., Agorastos [/bib_ref] Therefore, screening and treatment of CIN 2 and 3 (CIN2+) are important and successfully decrease cervical cancer incidence and mortality. [bib_ref] The effect of mass screening on incidence and mortality of squamous and..., Nieminen [/bib_ref] This reduction in mortality through established screening programs is attributed to 1) an increase in the detection of invasive cancer at early stages; and 2) the detection and treatment of precancerous lesions, which reduces the overall incidence of invasive cancer. [bib_ref] Cancer of the uterine cervix, Cannistra [/bib_ref] One of the main risk factors for cervical cancer is human papilloma virus (HPV). A retesting of HPV-negative cases in a worldwide epidemiological study showed that nearly 100% of cervical cancer cases test positive for high-risk HPV genotypes. [bib_ref] Human papillomavirus is a necessary cause of invasive cervical cancer worldwide, Walboomers [/bib_ref] Currently, one of the screening modalities for cervical cancer takes screening and detection of the HPV genotype into account. Cervical cancer is reported to be the third most common gynecological malignancy in Saudi women with an estimated incidence rate of 1.9 cases per 100 000 women-years. The number of new cervical cancer cases is 152 cases per year; 55 women die from cervical cancer per year. 7 A dramatic increase in the incidence of cervical cancer in Saudi Arabia is anticipated; the projected number of new cervical cancer cases and deaths in the year 2025 will be 309 and 117, respectively. Nonetheless, more than 40% of cervical cancer cases are diagnosed at advanced stages in Saudi women compared with 25% of cases in British Columbia, Canada. This is most probably attributed to the lack of national screening programs in Saudi Arabia. [bib_ref] Cervical cancer screening program in Saudi Arabia: action is overdue, Manji [/bib_ref] Additionally, screening and treatment modalities for precancerous cervical lesions are variable and it is important to identify the appropriateness and cost effectiveness of those modalities among women in Saudi Arabia. For these reasons, the Ministry of Health in Saudi Arabia has developed national clinical practice guidelines for cervical cancer screening and treatment. The objective of this paper is to provide concise guidance for clinicians based on the best current available evidence so as to reduce variability in clinical practice in the screening and treatment of precancerous cervical dysplasia (CIN2+). The target audience of these guidelines includes primary care physicians and gynecologists in Saudi Arabia. # Methods This clinical practice guideline was part of the larger initiative of the Saudi Arabia Ministry of Health to pro-vide guidance for clinicians to ensure high quality of care and reduce variability in clinical practice across the country. For this purpose, the Saudi Arabia Ministry of Health, through the Saudi Centre for Evidence-Based Healthcare, partnered with the McMaster University Working Group to provide methodological support and contacted a panel of national experts in the field of screening and treatment of cervical cancer. The detailed methodology is published online through the Saudi Arabian Ministry of Health website.The invited expert panel selected clinical questions using a formal prioritisation process. The McMaster University working group updated existing systematic reviews related to the clinical questions. The reviews had been used for the 2013 WHO Guidelines for screening and treatment of precancerous lesions for cervical cancer prevention.The group also conducted systematic searches for information specific to the Saudi context, including searches for information about patient values and preferences, and cost and resource use. Based on the updated systematic reviews, the panel prepared summaries of available evidence supporting each recommendation following the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. The panel assessed the quality of evidence using the system described by the GRADE working group. [bib_ref] GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables, Guyatt [/bib_ref] Evidence on the diagnostic accuracy of screening strategies, and the effects of screening and treatment strategies on critical and important health outcomes, was sought from randomized controlled trials; however, no such studies were found and it was necessary to use clinical decision modelling techniques to combine studies that reported separately on these two aspects and obtain estimates of the effects of the different screening and treatment strategies. The quality of evidence is classified as "high", "moderate", "low", or "very low" based on considerations of risk of bias, directness, consistency and precision of the available evidence for a specific health care problem. [bib_ref] GRADE guidelines: 3. Rating the quality of evidence, Balshem [/bib_ref] The definition of each category is as follows: 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. According to the GRADE approach, the strength of a recommendation is either strong or conditional (weak) and has explicit implications (see . Understanding the interpretation of these two gradeseither strong or conditional -of the strength of recommendations is essential for sagacious clinical decisionmaking. Based on this information and the input of Saudi Arabia panel members, the group prepared the evidence-to-recommendation tables that served the guideline panel in following the structured consensus process and transparently document all decisions made during the meeting. The guideline panel met in Riyadh on December 4, 2013 and formulated all recommendations during this meeting. Potential conflicts of interests of all panel members were managed according to the World Health Organisation (WHO) rules. ## Analysis of the evidence and recommendations The panel provided recommendations on two major issues; I: Screening for precancerous lesions to prevent cervical cancer (Questions 1-3) and II: Treatment of CIN2+ lesions for preventing cervical cancer in women who tested positive after screening (Questions 4-6). The recommendations were made taking into account the available evidence, resource use, and the Saudi context. The full document related to this guideline development and recommendations is available online.I. Screening for precancerous lesions to prevent cervical cancer Question 1: Should an HPV test followed by colposcopy be preferred over visual inspection with acetic acid (VIA) followed by colposcopy to screen for CIN2+ in asymptomatic women at risk of cervical cancer? Summary of findings: There was moderate quality evidence on the diagnostic accuracy of the screening strategies (5 cohort and cross-sectional studies, 8921 patients, [bib_ref] Comparison of Pap smear, visual inspection with acetic acid, human papillomavirus DNA-PCR..., Vuyst [/bib_ref] [bib_ref] Test characteristics of various screening modalities for cervical cancer: a feasibility study..., Sodhani [/bib_ref] [bib_ref] Shanxi Province Cervical Cancer Screening Study: a cross-sectional comparative trial of multiple..., Belinson [/bib_ref] [bib_ref] A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional..., Qiao [/bib_ref] and very low quality evidence on the effects of the screening strategies on health outcomes (clinical decision models were used to combine studies providing information on diagnostic accuracy and health outcomes.) Assuming a 2% probability of having CIN2+, HPV testing has the benefit of more true positives and fewer false negatives. Mortality due to cervical cancer, cervical cancer incidence, CIN2+ recurrence, and undetected CIN2+ rates are lower when patients are screened with the HPV test. The guideline panel agreed that the benefits of the HPV test over VIA are large. The HPV test followed by colposcopy results in fewer true negatives and more false positives. Adverse effects such as major bleeding, major and minor infections, and unnecessary treatments are slightly smaller after screening with VIA followed by colposcopy; however, the differences are not clinically significant for most of these outcomes. The guideline panel agreed that the harms of the HPV test followed by colposcopy compared with VIA followed by colposcopy are small. Values and Preferences: The guideline panel agreed that most women would prefer to be screened with the HPV test over VIA because the procedure takes less time to be administered. They also agreed that there is probably not important uncertainty and/or variability on women's values and preferences. Resource use: The guideline panel agreed that even though there are extra resources needed to screen . Interpretation of strong and conditional (weak) recommendations. ## Implications strong recommendation conditional (weak) recommendation For patients Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. The majority of individuals in this situation would want the suggests course of action, but many would not. ## For clinicians Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful helping individuals making decisions consistent with their values and preferences. For policy makers The recommendation can be adapted as policy in most situations. Policy making will require substantial debate and involvement of various stakeholders. women with HPV test over VIA (considering resources needed for implementation), these resources are probably small and are worth the benefits. Once the program is implemented, the HPV test would be cheaper. Other considerations: Health inequities would be reduced if the HPV test is implemented, and this would be an option acceptable to all key stakeholders. Since resources may be the only constraint for implementing HPV testing, and these are not perceived to be a problem in Saudi Arabia, the HPV screening is a feasible option to implement. On the other hand, VIA is not an acceptable option nor it is feasible to implement, and therefore, health inequities would increase if it were implemented. Implementation considerations: to implement this recommendation, the panel notes that resources such as equipment, maintenance, and trained professionals are needed. Also, there would be a need to implement a system to transport samples from villages to main centers. ## Recommendation 1: The Saudi Expert Panel recommends the use of the HPV test followed by colposcopy over VIA followed by colposcopy to screen for CIN2+ in women at risk of cervical cancer. (strong recommendation, moderate quality evidence for diagnostic test accuracy and very low quality evidence for health outcomes evidence). Remark: In settings where colposcopy is not available, cytology is an alternative for women who test positive on the HPV test (evidence not assessed). Question 2: Should the HPV test followed by colposcopy be preferred over cytology followed by colposcopy to screen for CIN2+ in asymptomatic women at risk of cervical cancer? Summary of findings: There was low quality evidence on the diagnostic accuracy of the screening strategies (11 cohort and cross-sectional studies, 39 050 patients), [bib_ref] Shanxi Province Cervical Cancer Screening Study: a cross-sectional comparative trial of multiple..., Belinson [/bib_ref] [bib_ref] A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional..., Qiao [/bib_ref] [bib_ref] Human papillomavirus testing for primary screening in women at low risk of..., Agorastos [/bib_ref] [bib_ref] The probability for a Pap test to be abnormal is directly proportional..., Bigras [/bib_ref] [bib_ref] The performance of human papillomavirus high-risk DNA testing in the screening and..., Cardenas-Turanzas [/bib_ref] [bib_ref] Efficiency of the hybrid capture 2 HPV DNA test in cervical cancer..., De Cremoux [/bib_ref] [bib_ref] BD-ProExC as adjunct molecular marker for improved detection of CIN2+ after HPV..., Depuydt [/bib_ref] [bib_ref] A comprehensive evaluation of the accuracy of cervical pre-cancer detection methods in..., Hovland [/bib_ref] [bib_ref] Comparison of human papillomavirus testing and cytology for cervical cancer screening in..., Mahmud [/bib_ref] [bib_ref] Evaluation of oncogenic human papillomavirus RNA and DNA tests with liquid-based cytology..., Monsonego [/bib_ref] [bib_ref] Inclusion of HPV testing in routine cervical cancer screening for women above..., Petry [/bib_ref] and very low quality evidence on the effects of the screening strategies on health outcomes (clinical decision models were used to combine studies providing information on diagnostic accuracy and health outcomes). Assuming a 2% probability of having CIN2+, HPV testing results in more true positives and fewer false negatives. Mortality due to cervical cancer, cervical cancer incidence, CIN2+ recurrence, and undetected CIN2+ rates are lower when patients are screened with the HPV test.The guideline panel agreed that the benefits of the HPV test followed by colposcopy over cytology followed by colposcopy are large. The HPV test followed by colposcopy results in fewer true nega-tives and more false positives. Adverse effects such as major bleeding, major and minor infections, and unnecessary treatments are slightly smaller after screening with cytology followed by colposcopy; however, the differences are not clinically significant for most of these outcomes. The guideline panel agreed that the harms of HPV testing followed by colposcopy compared with cytology followed by colposcopy are small. Values and Preferences: The guideline panel agreed that most women would prefer to be screened with the HPV test over cytology because the results of the HPV test can be obtained faster, there is no need to undergo a speculum exam and the procedure can be done by a nurse or the patient herself. They also agreed that there is probably not important uncertainty and/or variability in women's values and preferences. Resource use: The guideline panel agreed that patients may incur less costs if HPV testing is implemented since there would be no need to visit a gynaecologist to collect the sample. Resources may be needed for implementation of an HPV testing program, but the benefits are worth the costs. Other considerations: The fact that the screening could be done by health professionals other than gynecologists makes it easier to reach women in remote areas, which would reduce health inequities. HPV testing would be an option acceptable to all key stakeholders. Since resources may be the only constraint for implementing HPV testing, and these are not perceived to be a problem in Saudi Arabia, HPV screening is a feasible option to implement. Implementation considerations: To implement this recommendation, the panel notes that resources such as equipment, maintenance, and trained professionals are needed. Also, there would be a need to implement a system to transport samples from villages to main centres. ## Recommendation 2: The Saudi Expert Panel suggests using HPV testing followed by colposcopy over cytology followed by colposcopy to screen for CIN2+ in women at risk of cervical cancer. (conditional recommendation, low quality evidence for diagnostic test accuracy and very low quality evidence for health outcomes evidence). Remark: In settings where colposcopy is not available, cytology is an alternative for women who test positive on the HPV test (evidence not assessed). Question 3: Should VIA followed by colposcopy be preferred over cytology followed by colposcopy to screen for CIN2+ in asymptomatic women at risk of cervical cancer? ## Summary of findings: There was low quality evidence on the diagnostic accuracy of the screening strategies (11 cohort and cross-sectional studies, 12 089 patients), and very low quality evidence on the effects of the screening strategies on health outcomes (clinical decision models were used to combine studies providing information on diagnostic accuracy and health outcomes). The guideline panel agreed that the benefits of VIA over cytology are probably small, since benefits seem to be clinically insignificant when comparing both options. Assuming a 2% probability of having CIN2+, VIA followed by colposcopy results in fewer true negatives, fewer true positives, more false negatives and more false positives. Mortality due to cervical cancer, cervical cancer incidence, CIN2+ recurrence, and undetected CIN2+ rates are higher when patients are screened with VIA. Adverse effects such as major bleeding, major and minor infections, and unnecessary treatments are slightly smaller after screening with cytology followed by colposcopy; however, the differences are not clinically significant for most of these outcomes. The guideline panel agreed that the harms of VIA followed by colposcopy compared with cytology followed by colposcopy are large. ## Values and preferences: The guideline panel agreed that women would consider VIA an advantage of over cytology because of the the time needed to get results; however, when considering the procedure itself, cytology would be preferred. They also agreed that there is probably not important uncertainty and/or variability on women's values and preferences. Resource use: The guideline panel agreed that VIA followed by colposcopy is cheaper than cytology followed by colposcopy; however, since there are not benefits for VIA followed by colposcopy over cytology followed by colposcopy; costs are irrelevant. Other Considerations: VIA is not currently implemented in Saudi Arabia. All physicians would need to be trained to perform this screening test, which makes it infeasible to implement and would probably cause health inequities in terms of people who would have access to trained physicians. Therefore, this would not be an acceptable option from the point of view of key stakeholders. Implementation considerations: There is a need to expand the structure to perform cytology on a large scale in Saudi Arabia. ## Recommendation 3: The Saudi Expert Panel suggests using cytology followed by colposcopy over VIA followed by colposcopy to screen for CIN2+ in women at risk of cervical cancer (conditional recommendation, low quality evidence for diagnostic test accuracy and very low quality evidence for health outcomes evidence). II. Treatment of CIN2+ lesions for preventing cervical cancer in women who test positive after screening. Question 4: Should cryotherapy be preferred over cold knife conization (CKC) to treat women at risk of cervical cancer who test positive after screening? Summary of findings: There was very low quality evidence on the effects of the screening strategies on health outcomes (clinical decision models were used to combine studies providing information on diagnostic accuracy and health outcomes). After treatment with cryotherapy, there is a slightly higher mortality, cervical cancer incidence and CIN2+ recurrence rate; however, the guideline panel considered the differences clinically insignificant. After treatment with cryotherapy, there is a lower rate of major bleeding, major and minor infections and premature deliveries, irrespective of the screening strategy used (see tables in full version).The difference in these outcomes was considered to be clinically important, and thus the guideline panel agreed that the benefits of cryotherapy compared with CKC probably outweigh the harms. ## Values and preferences: The guideline panel agreed that most women would prefer to undergo treatment with cryotherapy because it can be done as an outpatient. The only disadvantage is an increase in watery vaginal discharge after treatment with cryotherapy, which may lead to a need further control visits. They also agreed that there is probably not uncertainty and variability in these values and preferences. Resource use: the guideline panel agreed that cryotherapy would be cheaper than CKC, and thus it would be a cost-saving alternative. Other considerations: The guideline panel agreed that inequities would be reduced if cryotherapy was implemented and that this is an option acceptable to all key stakeholders. Both options would be feasible to implement. ## Recommendation 4: The Saudi Expert Panel recommends using cryotherapy over CKC to treat women at risk of cervical cancer who tested positive for CIN2+. (strong recommendation, very low quality evidence for health outcomes evidence). ## Question 5: should loop electrical excision procedure (leep) be preferred over ckc to treat women at risk of cervical cancer who test positive after screening? Summary of findings: There was very low quality evidence on the effects of the screening strategies on health outcomes (clinical decision models were used to combine studies providing information on diagnostic accuracy and health outcomes) After treatment with LEEP, there is a slightly higher mortality, cervical cancer incidence and CIN2+ recurrence rate; however, the guideline panel considered the differences clinically insignificant (see tables in full version).After treatment with cryotherapy, there is a lower rate of major bleeding, minor infections and premature deliveries; and a higher rate of major infections irrespective of the screening strategy used (see tables in full version).The difference in these outcomes was considered clinically important, and thus the guideline panel agreed that the benefits of LEEP compared with CKC probably outweigh the harms. ## Values and preferences: The guideline panel agreed that most women would prefer to receive treatment with LEEP over CKC due to the lower rate of complications and the possibility of performing the procedure in an outpatient clinic. There is probably no uncertainty and variability in these values and preferences. Resource use: The guideline panel agreed that LEEP would be cheaper than CKC, and thus it would be a cost-saving alternative. Other considerations: The guideline panel agreed that inequities would be reduced if LEEP was implemented and that this is an option acceptable to all key stakeholders. Both options would be feasible to implement. ## Recommendation 5: The Saudi Expert Panel recommends using LEEP over CKC to treat women at risk of cervical cancer who test positive for CIN2+ (strong recommendation, very low quality evidence for health outcomes evidence). Question 6: Should cryotherapy be preferred over LEEP to treat women at risk of cervical cancer who tested positive after screening? Summary of findings: There was very low quality evidence on the effects of the screening strategies on health outcomes (clinical decision models were used to combine studies providing information on diagnostic accuracy and health outcomes). There are no differences in benefits after treatment with cryotherapy compared with LEEP. After treatment with cryotherapy, there is a lower rate of major bleeding and major infections. Differences in premature deliveries and minor infections are clinically insignificant irrespective of the screening strategy used. The guideline panel agreed that the benefits of cryotherapy compared with LEEP probably outweigh the harms. Values and Preferences: The guideline panel agreed that most women would prefer to undergo treatment with cryotherapy over LEEP; and that there is probably no uncertainty and variability in these values and preferences. Resource use: The guideline panel agreed that cryotherapy would be cheaper than LEEP, and thus it would be a cost-saving alternative. Other considerations: The guideline panel agreed that inequities would be reduced if cryotherapy was implemented and that this is an option acceptable to all key stakeholders. Both options would be feasible to implement. Implementation considerations: LEEP is a valid alternative particularly in settings where there are experienced physicians and the equipment is available. ## Recommendation 6: The Saudi Expert Panel suggests using cryotherapy over LEEP to treat women at risk of cervical cancer who test positive for CIN2+ (conditional recommendation, very low quality evidence for health outcomes evidence). # Discussion and implementation The main aim of cervical cancer screening is to prevent morbidity and mortality from cervical cancer. Thus, screening strategies should identify cervical cancer precursors likely to progress to invasive cancers (potentially maximizing the benefits of screening) and avoid the detection and unnecessary treatment of transient HPV infection and its associated benign lesions that will likely become cancerous (minimizing the potential harms associated with screening). Cytology (the Pap test) has been widely used as the sole screening method for precancerous lesions of the cervix. Incorporation of HPV testing into cervical cancer screening strategies has the potential to allow both increased disease detection (improving benefits) and decreasing harms such as the psychosocial impact of screening positive, additional clinical visits and procedures, and treatment of lesions that may resolve. In the development of these evidence-based guidelines, we considered the tradeoffs of desirable and undesirable consequences of screening while considering different screening modalities. These clinical practice guidelines are the result of an initiative of the Saudi Ministry of Health to promote the practice of evidence-based medicine across Saudi Arabia. The guidelines are expected to reduce practice variations and health inequities in Saudi Arabia. It should be noted that no guidelines or recommendations could take into account all unique features of individual clinical circumstances. Hence, clinicians, patients, third-party payers, institutional review committees, other stakeholders, or courts should never view these recommendations as dictates. Additionally, the values and preferences of individual patients should be taken into consideration in the diagnosis and treatment of CIN2+ lesions especially when considerable variability among patients is expected. Our guidelines may also alert the public and the appropriate government agencies to the prevalence of HPV and assist in the decision to recommend HPV screening, triage, and vaccination as well as aid in the prediction of the disease progression. The panel considers it necessary to perform periodic and formal evaluations of adherence to the recommendations of this guideline and any new evidence in this field. Finally, the panel considers it necessary to undertake local research on the values and preferences of the Saudi population related to such issues as well as the development of a national register of local data on the incidence and outcomes of CIN2+. # Limitations National studies on cervical cancer screening modalities and treatment of precancerous cervical lesions, including HPV prevalence and its association with cervical cancer in Saudi Arabia, are scarce. Moreover, future studies on the performance of different screening modalities should take into account patient acceptability, population uptake of screening, quality of screening, quality of the supportive services like pathology, and the cost of screening. # Conclusion Universal screening for precancerous cervical dysplasia in women in Saudi Arabia is recommended. It should be initiated within 3 years after marriage and up to 65 years of age; however, further research on the threshold age for screening in Saudi Arabia is warranted. HPV testing and or cytology are recommended as screening modalities. Either cryotherapy or the loop electrical excision procedure are preferred for treatment of CIN2+ lesions. A national registry with data on the incidence and treatment of cervical dysplasia and its progression to cancer is needed. # Funding This clinical practice guideline was funded by the Ministry of Health, Saudi Arabia. AcknowledgmentsThe authors would like to thank Dr Mohammed Zamakhshary, Dr Zulfa Alrayess, Dr Yaser Adi, and the members of the Saudi Centre for Evidence-Based Healthcare (EBHC), MoH, Saudi Arabia for their unlimited support.	None	https://www.annsaudimed.net/doi/pdf/10.5144/0256-4947.2016.313	BACKGROUND Cervical cancer is the third most common gynecological malignancy in Saudi women with an estimated incidence rate of 1.9 cases per 100 000 women-years. More than 40% of cervical cancer cases are diagnosed at advanced stages due to lack of a routine screening program in Saudi Arabia. Thus, national guidelines for routine screening and treatment of precancerous cervical lesions are needed. METHODS The Saudi Centre for Evidence-Based Healthcare invited a panel of local experts and partnered them with a team from McMaster University in Canada for methodological support, to develop national clinical practice guidelines on the screening and treatment of precancerous lesions for cervical cancer. After the panel identified key clinical questions, the McMaster University working group updated existing systematic reviews that had been used for the 2013 WHO Guidelines for screening and treatment of precancerous lesions for cervical cancer prevention. Recommendations were based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. Those recommendations took into account the available evidence, patient values and preferences, and resource use in the Saudi context. The panel provided recommendations on two major issues: screening for precancerous lesions (cervical intraepithelial neoplasia 2 & 3) and treatment of those lesions to prevent cervical cancer in women who tested positive after screening. CONCLUSIONS The Saudi expert panel recommends using the HPV DNA test followed by colposcopy or cytology (Pap test) followed by colposcopy to screen for CIN2+ in women at risk of cervical cancer. The panel recommends cryotherapy or loop excision electrosurgery procedure (LEEP) over cold knife cone biopsy to treat women at risk of cervical cancer that tests positive for CIN2+. Universal screening for precancerous cervical dysplasia in women in Saudi Arabia is recommended using HPV testing and or cytology. Either cryotherapy or LEEP are preferred for treatment. LIMITATIONS National studies on cervical cancer screening modalities and treatment of precancerous cervical lesions, including HPV prevalence and its association with cervical cancer, are scarce.
bbace774681d17071fd3faaae6805edcc08e61a5	pubmed	Peri‐operative management of the obese surgical patient 2015	Peri‐operative management of the obese surgical patient 2015 ## Recommendations 1 Every hospital should nominate an anaesthetic lead for obesity. 2 Operating lists should include the patients' weight and body mass index (BMI).Experienced anaesthetic and surgical staff should manage obese patients. 4 Additional specialised equipment is necessary.Central obesity and metabolic syndrome should be identified as risk factors. 6 Sleep-disordered breathing and its consequences should always be considered in the obese. 7 Anaesthetising the patient in the operating theatre should be considered. 8 Regional anaesthesia is recommended as desirable but is often technically difficult and may be impossible to achieve. 9 A robust airway strategy must be planned and discussed, as desaturation occurs quickly in the obese patient and airway management can be difficult. 10 Use of the ramped or sitting position is recommended as an aid to induction and recovery. 11 Drug dosing should generally be based upon lean body weight and titrated to effect, rather than dosed to total body weight. 12 Caution is required with the use of long-acting opioids and sedatives. 13 Neuromuscular monitoring should always be used whenever neuromuscular blocking drugs are used. 14 Depth of anaesthesia monitoring should be considered, especially when total intravenous anaesthesia is used in conjunction with neuromuscular blocking drugs. # Introduction The World Health Organization (WHO) uses a class system to define obesity [fig_ref] Table 1: World Health Organization classification of obesity[4] [/fig_ref]. Statistics for 2013 from the UK, Health and Social Care Information Centre show that in adults, 24% of men and 25% of women are classified as obese and over 3% have class-3 obesity. For an average UK district general hospital serving an adult population of 200 000, this equates to 52 000 obese and over 6000 class-3 obese patients. Obese patients are more likely to present to hospital because they are more prone to concomitant disease. , there was an eleven-fold increase in the number of patients (from 1019 to 11 736) of all ages admitted to NHS hospitals with a primary diagnosis of obesity [fig_ref] Figure 1: Adult trends in obesity [/fig_ref]. In 2007, the UK Government's Foresight Report predicted that 50% of the UK population would be clinically obese by 2050, costing the NHS an extra £45.5 billion (€61.5 billion; $70.1 billion) per year, but even this may be an underestimate [bib_ref] Executive summary: foresight ''Tackling Obesities: Future Choices'' project, Kopelman [/bib_ref]. This consensus guidance is a synthesis of expert opinion, current practice and literature review, designed to replace the 2007 editionand act as a guide to the delivery of safe anaesthesia to this clinically demanding group. ## Pathophysiology of obesity Fat distribution (patient shape) Not all fat within the body is identical. Unlike peripherally deposited fat, intra-abdominal fat is highly metabolically active and is known to be a contributor to several disease states [bib_ref] Intra-abdominal fat: is it a major factor in developing diabetes and coronary..., Kissebah [/bib_ref]. Patients with centrally distributed or 'visceral' fat are at greater peri-operative risk than those with peripherally distributed fat, and are far more likely to exhibit the metabolic syndrome, which consists of central obesity, hypertension, insulin resistance and hypercholesterolemia [bib_ref] Ignoring our evolution: the 'pandemic' of over-nutrition. Not simply a metabolic syndrome, Ball [/bib_ref] [bib_ref] Perioperative outcomes among patients with the modified metabolic syndrome who are undergoing..., Glance [/bib_ref]. Central obesity can be defined as a waist circumference greater than 88 cm in a woman and 102 cm in a man; or a waist-to-height ratio greater than 0.55 [bib_ref] Perioperative outcomes among patients with the modified metabolic syndrome who are undergoing..., Glance [/bib_ref] [bib_ref] Accuracy of anthropometric indicators of obesity to predict cardiovascular risk, Schneider [/bib_ref]. People who exhibit central, or visceral, obesity are often male and can be described as 'apple shaped', while those with a predominantly peripheral fat distribution are more likely to be female and are described as 'pear shaped'. ## Respiratory system Obesity results in reduced functional residual capacity (FRC), significant atelectasis and shunting in dependent lung regions [bib_ref] The effects of body mass on lung volumes, respiratory mechanics, and gas..., Pelosi [/bib_ref] , but resting metabolic rate, work of breathing and minute oxygen demand are increased. This combination means that, following the cessation of breathing, arterial oxygen levels decrease rapidly. Wheeze in the obese may be due to airway closure rather than asthma: 50% of patients diagnosed with asthma 'recover' with weight loss [bib_ref] Respiratory medication prescriptions before and after bariatric surgery, Sikka [/bib_ref]. Formal assessment of the effectiveness of bronchodilator therapy may be useful in differentiating the two conditions [bib_ref] Obesity is a risk for asthma and wheeze but not airway hyperresponsiveness, Schachter [/bib_ref]. ## Sleep-disordered breathing Sleep-disordered breathing describes the spectrum of conditions ranging from obstructive sleep apnoea (OSA) through obesity hypoventilation syndrome (OHS). Each of these conditions has a spectrum of severity, described according to the number and severity of oxygen desaturations occurring every hour and their impact upon the patient [bib_ref] Rules for scoring respiratory events in sleep: update of the 2007 AASM..., Berry [/bib_ref]. Severe OSA occurs in 10-20% of patients with BMI > 35 kg.m À2 and is often undiagnosed. Overall, a diagnosis of OSA is associated with a greater than doubling of the incidence of postoperative desaturation, respiratory failure, postoperative cardiac events and ICU admission [bib_ref] A matched cohort study of post-operative outcomes in obstructive sleep apnea, Mutter [/bib_ref]. The presence of multiple and prolonged oxygen desaturations increases the sensitivity to opioidinduced respiratory depression [bib_ref] Experimental pain and opioid analgesia in volunteers at high risk for obstructive..., Doufas [/bib_ref]. However, if identified pre-operatively and treated appropriately with continuous positive airway pressure (CPAP), the risk of complications is much reduced [bib_ref] Obstructive sleep apnoea and perioperative complications in bariatric patients, Weingarten [/bib_ref]. Increasing severity of OSA is associated with older age, cardiovascular disease secondary to heart strain, and the development of left ventricular dysfunction. It is also associated with a difficult airway and laryngoscopy. If untreated, OSA may progress to obesity hypoventilation syndrome, a triad of obesity (BMI > 35 kg.m À2 ), sleep-disordered breathing (usually OSA) and daytime hypercapnia (pCO 2 > 6 kPa) [bib_ref] Obesity hypoventilation syndrome: a state of the art review, Mokhlesi [/bib_ref]. The combination of chronic hypoxaemia and hypercapnia make this subgroup particularly susceptible to the effects of anaesthetic agents and opioids, which may precipitate acute and chronic hypoventilation and respiratory arrest in the early postoperative period. Formal diagnosis of sleep-disordered breathing is with polysomnography, but in the majority of cases, diagnosis can be made by overnight oximetry testing at home [bib_ref] Oxygen desaturation index from nocturnal oximetry, Chung [/bib_ref]. Nocturnal CPAP is the usual treatment in patients with significant degrees of OSA, but around 50% of patients are poorly compliant with CPAP therapy and thus will not obtain benefit, usually because of problems with the fitting of the mask. Seeking information on compliance during pre-operative assessment is advised. ## Cardiovascular system Obesity leads to increased blood pressure, cardiac output and cardiac workload. People with untreated OSA may have associated pulmonary hypertension and heart failure [bib_ref] Rules for scoring respiratory events in sleep: update of the 2007 AASM..., Berry [/bib_ref]. There is an increased incidence of arrhythmias, predominantly secondary to sino-atrial node dysfunction and fatty infiltration of the conducting system. This results in a relative risk of 1.5 for atrial fibrillation [bib_ref] Atrial fibrillation and obesity -results of a meta-analysis, Wanahita [/bib_ref] , and a markedly increased risk of sudden cardiac death [bib_ref] Obesity in adulthood and its consequences for life expectancy: a life-table analysis, Peeters [/bib_ref]. There is an increased incidence of prolonged QT interval with increasing BMI [bib_ref] Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss, Lavie [/bib_ref] , and therefore a potential increased risk with drugs such as ondansetron. Ischaemic heart disease and heart failure are more prevalent in the obese population, with heart failure the predominant risk factor for postoperative complications [bib_ref] Outcomes in heart failure patients after major noncardiac surgery, Hernandez [/bib_ref]. ## Thrombosis Obesity is a prothrombotic state and is associated with increased morbidity and mortality from thrombotic disorders such as myocardial infarction, stroke and VTE [bib_ref] Mechanisms of thrombosis in obesity, Blokhin [/bib_ref]. The postoperative incidence of VTE may be 10 times higher in obese women compared with their healthy-weight counterparts [bib_ref] Body mass index, surgery, and risk of venous thromboembolism in middle-aged women:..., Parkin [/bib_ref]. Previous VTE is an independent risk factor for patients having gastric bypass surgery [bib_ref] Obesity surgery mortality risk score: proposal for a clinically useful score to..., Demaria [/bib_ref]. A hypercoagulable state may extend beyond two weeks, warranting extended postoperative VTE prophylaxis depending on the type of surgery and the patient's BMI [bib_ref] Extended thromboprophylaxis reduces incidence of postoperative venous thromboembolism in laparoscopic bariatric surgery, Magee [/bib_ref]. ## Diabetes Obesity is strongly associated with increased insulin resistance [bib_ref] Obstructive sleep apnea and metabolic syndrome: alterations in glucose metabolism and inflammation, Tasali [/bib_ref]. Poor glycaemic control in the perioperative period is associated with increased morbidity, and good glycaemic control is recommended [bib_ref] Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac..., Frisch [/bib_ref]. Gastric bypass surgery causes a unique neurohumeral response, resulting in a rapid, dramatic reduction in insulin requirement, starting immediately after surgery. In this cohort of patients, cautious postoperative reintroduction of diabetic medication and frequent blood sugar monitoring are essential [bib_ref] Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery, Guidone [/bib_ref]. ## Pharmacology ## Body composition There are a number of terms used to describe the weight of a patient; the four most useful are shown in . ## Drug dosing There is limited information on the effect of obesity on the pharmacology of commonly used anaesthetic drugs. Much of the excess weight is fat, which has a relatively low blood flow. While lipophilic drugs will have a larger volume of distribution than hydrophilic ones, the current evidence indicates that changes in volume of distribution in the obese are drug-specific, so generalisations are difficult [bib_ref] Effect of obesity on the pharmacokinetics of drugs in humans, Hanley [/bib_ref]. For most anaesthetic agents, dosing to total body weight is rarely appropriate and increases the risk of relative overdose. Fortunately, most anaesthetic agents are dosed to affect, e.g. loss of eyelash reflex, nerve stimulator response or relief of pain. Given the paucity of information, the recommendation, based on current practice amongst experts in bariatric anaesthesia, is that lean or adjusted body weight are used as the scalars for calculating initial anaesthetic drug doses rather than total body weight [fig_ref] Table 3 Suggested: SeeTable 1for definitions/calculations [/fig_ref]. The fifth National Audit (NAP5) into accidental awareness under anaesthesia (AAGA) included a disproportionate number of obese patients who suffered AAGA. Half of the incidents of awareness occurred during the induction of anaesthesia and neuromuscular blocking drugs were used in 93% of these cases [bib_ref] The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia:..., Pandit [/bib_ref]. In the obese patient, after a bolus of anaesthetic induction agent, anaesthesia will occur before redistribution from the central compartment, and the induction dose required to produce unconsciousness correlates well with lean body weight [bib_ref] Lean body weight scalar for the anesthetic induction dose of propofol in..., Ingrande [/bib_ref]. However, more rapid redistribution of induction agents into the larger fat mass means that patients wake up more quickly than nonobese patients after a single bolus dose. With induction agents, a dose based on total body weight will last longer than one calculated using lean or adjusted body weight but is likely to result in significant hypotension. It is likely that in the cases of AAGA found in NAP5, small doses of induction agent based on lean or adjusted body weight were not quickly followed by the introduction of maintenance anaesthesia, thus raising the risk of AAGA. Thiopental is associated with a greater risk of awareness than propofol. It is strongly recommended that additional induction agent be given if there is a delay in commencing effective maintenance anaesthesia after induction. Hydrophilic drugs such as neuromuscular blocking drugs are distributed primarily in the central The four most useful terms for describing patients' weight. ## Total body weight (tbw) The actual weight of the patient Ideal body weight (IBW) What the patient should weigh with a normal ratio of lean to fat mass. Varies with age, and is usually approximated to a function of height and sex: [formula] IBW (kg) ¼ height (cm) À x (where x ¼ 105 [/formula] ## In females and 100 in malesþ Lean body weight (LBW) The patient's weight excluding fat. Many of the formulae for calculating lean body weight are complex but one of the most widely used is that of Janmahasatian et al. [bib_ref] Quantification of lean body weight, Janmahasatian [/bib_ref] : [formula] LBW (kg) ¼ 9270 Â TBW (kg) 6680 þ ð216 Â BMI (kg.m À2 ÞÞ ðmenÞ LBW (kg) ¼ 9270 Â TBW (kg) 8780 þ ð244 Â BMI (kg.m À2 ÞÞðwomenÞ [/formula] Regardless of total body weight, lean body weight rarely exceeds 100 kg in men and 70 kg in women [fig_ref] Figure 2: Relationship between total body weight and body mass index [/fig_ref] [bib_ref] Dose adjustment of anaesthetics in the morbidly obese, Ingrande [/bib_ref] Adjusted body weight (ABW) Takes into account the fact that obese individuals have increased lean body mass and an increased volume of distribution for drugs. It is calculated by adding 40% of the excess weight to the IBW [bib_ref] Pharmacokinetic concepts for TCI anaesthesia, Gepts [/bib_ref] : ABW (kg) = IBW (kg) + 0.4 (TBW (kg) À IBW (kg)) compartment and lean body weight is a suitable dosing scalar. A dose of rocuronium based on total body weight does not significantly shorten the onset time, but will markedly increase the duration of action [bib_ref] The pharmacodynamic effects of rocuronium when dosed according to real body weight..., Leykin [/bib_ref]. However, due to increased plasma cholinesterase activity, total body weight is appropriate for suxamethonium. Doses of neostigmine and sugammadex are related to the timing and total dose of neuromuscular blocking drugs to be reversed and can usually be titrated to effect. For opioids, the clinical effect is poorly related to the plasma concentration [bib_ref] Relationships between plasma concentrations of morphine, morphine-3-glucuronide, morphine-6-glucuronide, and intravenous morphine titration..., Hammoud [/bib_ref]. Dosing using lean body weight is therefore a sensible starting point until the patient is awake and titration to effect is possible. For target controlled infusions (TCI) of propofol, the Marsh and Schnider formulae become unreliable for patients weighing over 140-150 kg [bib_ref] The pharmacodynamic effects of rocuronium when dosed according to real body weight..., Leykin [/bib_ref]. Because of this, none of the commercially available pumps allow input of weights above 150 kg using the Marsh model, or BMI > 35 kg.m À2 (female) and 42 kg.m À2 (male) using the Schnider model. There is a lack of evidence as to the best weight scalar to use with TCI techniques, and when used with neuromuscular blocking drugs, awareness is a significant potential risk. In these situations, some form of depth of anaesthesia monitoring is strongly recommended [bib_ref] Pharmacokinetic models for propofol-defining and illuminating the devil in the detail, Absalom [/bib_ref]. ## Pre-operative preparation ## General considerations The vast majority of obese patients presenting for surgery are relatively healthy and their peri-operative risk is similar to that of patients of normal weight. The patients at high risk of peri-operative complications are those with central obesity and metabolic syndrome, rather than those with isolated extreme obesity [bib_ref] Perioperative outcomes among patients with the modified metabolic syndrome who are undergoing..., Glance [/bib_ref]. Particular attention should be focused on screening patients for sleep-disordered breathing and those at particularly high risk of VTE. A clear pathway for referral for specialist sleep studies should be identified. The Obesity Surgery Mortality Risk Stratification score (OS-MRS) [fig_ref] Table 4: The Obesity Surgery Mortality Risk Stratification score [/fig_ref] has been validated for patients undergoing gastric bypass surgery to identify the risk factors associated with mortality [bib_ref] Validation of the Obesity Surgery Mortality Risk score in a multicenter study..., Demaria [/bib_ref]. It includes features of metabolic syndrome and sleep-disordered breathing. Although only validated for bariatric surgical patients, it may be applicable to obese patients undergoing non-bariatric operations. Patients who score 4-5 on the OS-MRS are more likely to require closer postoperative monitoring. All patients should have their height and weight recorded and BMI calculated, and these should both be recorded on the operating list to inform the teams that additional time, equipment and preparation may be needed. There may be an advantage in estimating lean and adjusted body weight and recording these in the patient's records to aid the calculation of drug doses. Diagnostic testing should be based on the need to evaluate co-morbidity and the complexity of surgery, rather than merely as a result of the presence of obesity. In bariatric surgery, it is routine to initiate a preoperative 'liver shrinking' diet to reduce the size of the liver and make access to the stomach technically easier. There is evidence that 2-6 weeks of intense preoperative dieting can improve respiratory function and facilitate laparoscopic surgery, and may be worth considering in the higher risk patients [bib_ref] Preoperative 4-week low-calorie diet reduces liver volume and intrahepatic fat, and facilitates..., Edholm [/bib_ref]. Pre-operative discussion can promote smoking cessation, clarify the importance of thromboprophylaxis and early mobilisation, plan the management of medication before admission and remind relevant patients to bring their own CPAP machine into hospital. ## Respiratory assessment Clinical evaluation of the respiratory system and exercise tolerance should identify functional limitations and guide further assessment. It is helpful to assess patients' arterial saturation in the pre-assessment clinic. Spirometry is also often useful. The following features may indicate the presence of significant underlying respiratory disease and should prompt consideration of pre-operative arterial blood gas analysis [bib_ref] Respiratory complications of obesity, Mandal [/bib_ref] : - Arterial saturation < 95% on air - Forced vital capacity < 3 l or forced expiratory volume in 1 s < 1.5 l - Respiratory wheeze at rest - Serum bicarbonate concentration > 27 mmol.l À1 An arterial PCO 2 > 6 kPa indicates a degree of respiratory failure and consequently the likelihood of increased anaesthetic risk. It is essential to screen for sleep-disordered breathing. Of the several screening tools available, the STOP-BANG questionnaire is the best validated in obese patients. It is easy to calculate and has shown good correlation with the severity of postoperative apnoeas. A STOP-BANG score of 5 or greater indicates the possibility of significant sleep-disordered breathing and should prompt referral to a sleep physician if time allows [bib_ref] High STOP-BANG score indicates a high probability of obstructive sleep apnoea, Chung [/bib_ref] [bib_ref] Predictive performance of the STOP-BANG score for identifying obstructive sleep apnea in..., Chung [/bib_ref]. Even in the presence of a low STOP-BANG score, a history of marked exertional dyspnoea, morning headaches and ECG evidence of right atrial hypertrophy may indicate the presence of sleep-disordered breathing and should also prompt referral for assessment. Patients with undiagnosed OSA, or those unable to tolerate CPAP, are at the highest risk of perioperative respiratory and cardiovascular morbidity [bib_ref] Eliminating respiratory intensive care unit stay after gastric bypass surgery, Hallowell [/bib_ref] , while patients fully compliant with CPAP (usually indicated by symptomatic benefit) are at lower risk of peri-operative events. In general, patients with adequately treated sleep-disordered breathing do not have problems requiring high dependency care and may even be suitable for day surgery(see below). ## Airway assessment Obesity is associated with a 30% greater chance of difficult/failed intubation, although predictors for difficult laryngoscopy are the same as for the non-obese [bib_ref] High body mass index is a weak predictor for difficult and failed..., Lundstrøm [/bib_ref]. A large neck circumference is a useful additional indicator and when greater than 60 cm, is associated with a 35% probability of difficult laryngoscopy [bib_ref] Saidman LJ. Morbid obesity and tracheal intubation, Brodsky [/bib_ref]. The STOP-BANG screening questionnaire for obstructive sleep apnoea (adapted with permission [bib_ref] High STOP-BANG score indicates a high probability of obstructive sleep apnoea, Chung [/bib_ref] [bib_ref] Predictive performance of the STOP-BANG score for identifying obstructive sleep apnea in..., Chung [/bib_ref]. One point is scored for each positive feature; a score ≥ 5 is a significant risk. Bag-mask ventilation is also known to be more difficult in the obese [bib_ref] Predictions and outcomes of impossible mask ventilation: a review of 50,000 anesthetics, Kheterpal [/bib_ref] [bib_ref] Prediction of difficult mask ventilation, Langeron [/bib_ref]. Beards in particular can cause problems with bag-mask ventilation and are quite common in the obese male population. If time allows, it is recommended that all facial hair should be removed pre-operatively, or at the very least clipped short. ## Cardiovascular assessment Obese patients should be assessed in the same way as any other patient group. Features of the metabolic syndrome should be actively identified as there is a strong association with cardiac morbidity [bib_ref] Obesity and cardiovascular disease, Apovian [/bib_ref]. Assessment of exercise tolerance can be a valuable tool. The requirement for specific cardiac investigations should be based on: the degree of exercise tolerance; the presence of additional co-morbidity; and the site and extent of the anticipated surgery. Cardiopulmonary exercise testing (CPET) may predict those at high risk of postoperative complications and increased length of stay [bib_ref] Cardiorespiratory fitness and short-term complications after bariatric surgery, Mccullough [/bib_ref] [bib_ref] Cardiopulmonary exercise testing predicts postoperative outcome in patients undergoing gastric bypass surgery, Hennis [/bib_ref]. Standard CPET equipment may not be suitable and recumbent bikes are available for heavier patients. ## Planning postoperative care The planned postoperative management of most obese patients should resemble the enhanced recovery programmes of many surgical specialities. Obesity alone is not a clinical indication for highdependency postoperative care. Factors that warrant consideration for a level-2 or -3 setting include the following: - Pre-existing co-morbidities - Indicated high risk (e.g. OS-MRS 4-5 or limited functional capacity) - Surgical procedure - Untreated OSA plus a requirement for postoperative parenteral opioids - Local factors including the skill mix of ward staff An important consideration for all patients is the degree and site of surgery. If longer acting opioids (e.g. morphine) are necessary, then these patients will require closer monitoring, specifically watching for developing hypercapnia, and level-2 care may be indicated. ## Intra-operative care ## Preparation of patients Patients' dignity is important, so suitably sized theatre gowns and disposable underwear should be available. Antacid and analgesic premedication should be considered. As previously mentioned, it may be appropriate to ask male patients with beards to shave/trim them before surgery. ## Preparation of staff The specific peri-operative requirements of the obese patient should be included in the pre-operative team brief of the WHO surgical checklist to ensure the presence of appropriate equipment, including suitable operating tables, beds and trolleys (see below). Extra time should be allowed for positioning the obese patient and performing anaesthesia. Anaesthetists should recognise when additional personnel (another trained anaesthetist or additional operating department practitioners) are needed. The seniority of both the anaesthetist and the surgeon should be considered. Patients with an OS-MRS score > 3 should be discussed with a consultant, and those with a score of 4-5 should be anaesthetised by an anaesthetist experienced in the management of such patients. An experienced surgeon will reduce operative time and this will help to limit peri-operative morbidity. ## Regional anaesthesia Where possible, regional anaesthesia is preferred to general anaesthesia, although a plan for airway management is still mandatory [bib_ref] Influence of obesity on surgical regional anesthesia in the ambulatory setting: an..., Nielsen [/bib_ref]. There is a higher risk of failure of regional techniques in the obese, and appropriate patient counselling/consent is advised. [bib_ref] Regional anesthesia and obesity, Ingrande [/bib_ref] If sedation is required during regional anaesthesia, this should be kept to the minimum. Specific equipment such as extra-long spinal or epidural needles should be available and ultrasound might be a useful adjunct [bib_ref] Ultrasound imaging of the lumbar spine in the transverse plane: the correlation..., Balki [/bib_ref]. There are advantages to the patient (comfort) and practitioner (success rates) in using the sitting position for neuraxial techniques, and it may be helpful to tilt the bed towards the operator so the patient naturally leans forward [bib_ref] Parturient's posture during epidural puncture affects the distance from the skin to..., Hamza [/bib_ref]. To reduce epidural catheter migration, it is recommended that at least 5 cm catheter should be left in the epidural space [bib_ref] Appropriate length of epidural catheter in the epidural space for postoperative analgesia:..., Afshan [/bib_ref]. It is safer to calculate local anaesthetic drug dose using lean body weight. Despite the potential reduction in neuraxial volume due to adipose tissue, standard doses of local anaesthetic are recommended for central neuraxial blockade [bib_ref] ED(50) and ED(95) of intrathecal bupivacaine in morbidly obese patients undergoing cesarean..., Carvalho [/bib_ref]. The anaesthetist should be aware that hypotension following neuraxial anaesthesia may be more problematic in the obese as they are less tolerant of lying flat or in the Trendelenberg position. ## Induction of general anaesthesia Easily reversible drugs, with fast onset and offset, are the agents of choice for obese patients. Anaesthetising the patient in the operating theatre has the advantages of avoiding the problems associated with transporting an obese anaesthetised patient, and will also reduce the risk of arterial desaturation and AAGA associated with disconnection of the breathing system during transfer [bib_ref] The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia:..., Pandit [/bib_ref] [bib_ref] An observational study of practice during transfer of patients from anaesthetic room..., Broom [/bib_ref]. In addition, the patient can position him/herself on the operating table and can help identify pressure points for protection. There were a number of learning points from the fourth National Audit Project (NAP4) which looked at airway complications that are pertinent to the airway management of the obese patient [bib_ref] on behalf of the Fourth National Audit Project. Major complications of airway..., Cook [/bib_ref] : - There was often a lack of recognition and planning for potential airway problems - As a result of the reduced safe apnoea time, when airway complications occurred, they did so rapidly and potentially catastrophically - There was evidence that rescue techniques such as supraglottic airway devices and emergency cricothyroidotomy had an increased failure rate - Adverse events occurred more frequently in obese patients when anaesthetised by inexperienced staff Since the work of spontaneous breathing is increased in the obese patient, tracheal intubation with controlled ventilation is the airway management technique of choice. Use of supraglottic airway devices as the primary airway device should be reserved for highly selected patients undergoing short procedures and, where the patient can be kept head-up during surgery. The upper airway should be accessible at all times and there must be a plan for tracheal intubation if required. During induction of anaesthesia, the patient should be positioned in a ramped position with the tragus of the ear level with the sternum, and the arms away from the chest [fig_ref] Figure 3: Ramping position for obese patients [/fig_ref]. This will improve lung mechanics, thereby assisting oxygenation and ventilation and as a result, maximising the safe apnoea time. The addition of positive end-expiratory pressure (PEEP) may further facilitate pre-oxygenation [bib_ref] Positive end-expiratory pressure during induction of general anesthesia increases duration of nonhypoxic..., Gander [/bib_ref]. Minimising the time from induction to intubation will reduce the risk of oxygen desaturation should bagmask ventilation prove difficult. It has been demonstrated that ramping improves the view at laryngoscopy in the obese patient and this is therefore the recommended default position during induction in all obese patients [bib_ref] Laryngoscopy and morbid obesity: a comparison of the ''sniff'' and ''ramped'' positions, Collins [/bib_ref]. Any difficulty with/failure of direct laryngoscopy should be promptly managed in accordance with the Difficult Airway Society guidelines [bib_ref] Difficult Airway Society guidelines for management of the unanticipated difficult intubation, Henderson [/bib_ref]. Suxamethonium-associated fasciculations increase oxygen consumption and have been shown to shorten the safe apnoea time [bib_ref] Effect of suxamethonium vs rocuronium on onset of oxygen desaturation during apnoea..., Taha [/bib_ref] ; consequently, it is unlikely to wear off before profound hypoxia occurs, and so may not be the drug of choice for obese patients [bib_ref] Critical hemoglobin desaturation will occur before return to an unparalyzed state following..., Benumof [/bib_ref]. With the advent of sugammadex, aminosteroids could instead be considered the neuromuscular blocking drugs of choice. The use of rocuronium can minimise the apnoea time from cessation of spontaneous ventilation to control of ventilation via a secure airway if bag-mask ventilation is difficult. The dose of sugammadex for emergency reversal should be pre-calculated and be immediately available for preparation if required [bib_ref] Can sugammadex save a patient in a simulated 'cannot intubate, cannot ventilate'..., Bisschops [/bib_ref]. Ideal body weight should be used to size tracheal tubes and to calculate tidal volume during controlled ventilation. Tracheal diameter reduces slightly with increasing BMI [bib_ref] Does body mass index predict tracheal airway size?, D'anza [/bib_ref]. During controlled ventilation, no particular mode of controlled ventilation has been proven to be superior; however, greater tidal volumes for a given peak pressure can often be achieved using pressure-controlled, rather than volume-controlled, ventilation. The addition of sufficient PEEP and recruitment manoeuvres will reduce intra-and postoperative atelectasis [bib_ref] Oxygen transport and venous admixture in the extremely obese. Influence of anaesthesia..., Santesson [/bib_ref]. For laparoscopic surgery, flexion of the patient's trunk, i.e. a slight sitting position, allows increased abdominal excursion and slightly lower airway pressures [bib_ref] Impact of the patient's body position on the intraabdominal workspace during laparoscopic..., Mulier [/bib_ref]. As intravenous access is often difficult in the obese, it is prudent to site two intravenous cannulae while in theatre. Ultrasound may prove useful to help locate peripheral veins but consideration should be given to unusual sites for intravenous access such as the upper arm and anterior chest wall. Central venous access should only be used if peripheral access is impossible, or if specifically indicated. The 'SDB-safe' anaesthetic A simple and safe principle is to assume that all obese patients have some degree of sleep-disordered breathing (whether formally tested or not) and to modify the anaesthetic technique accordingly. Useful peri-operative strategies therefore include the following: - Avoidance of general anaesthesia and sedatives where possible - Use of short acting agents - Use of depth of anaesthesia monitoring techniques to limit anaesthetic load, particularly when neuromuscular blocking drugs and/or a total intravenous anaesthetic technique are utilised ## Maintenance of anaesthesia There is limited evidence at present to favour either TCI of propofol or volatile agents for maintenance of anaesthesia in the obese. However, due to the increased risk of AAGA in the obese, it is important that maintenance is commenced promptly after induction of anaesthesia [bib_ref] The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia:..., Pandit [/bib_ref]. Fat-insoluble volatile agents such as desflurane or sevoflurane have a faster onset and offset than isoflurane. There is evidence of faster return of airway reflexes with desflurane compared with sevoflurane in the obese [bib_ref] Effect of increased body mass index and anaesthetic duration on recovery of..., Mckay [/bib_ref]. Multimodal analgesia techniques, including local anaesthesia, enable opioid sparing and are strongly recommended. ## Emergence from anaesthesia Both NAP4 and NAP5 showed a high incidence of problems during extubation in the obese. An extubation plan must therefore be in place in accordance with the Difficult Airway Society extubation guidelines. Reversal of neuromuscular blockade should be guided by a nerve stimulator. The aim is to restore motor capacity before waking the patient [bib_ref] The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia:..., Pandit [/bib_ref]. Patients should have return of their airway reflexes and be breathing with good tidal volumes before tracheal extubation, which should be performed with the patient awake and in the sitting position. In those patients with confirmed OSA, the insertion of a nasopharyngeal airway before waking helps mitigate the partial airway obstruction that is commonly seen during emergence from anaesthesia. ## Postoperative care Immediate post-anaesthesia care Oxygen therapy should be applied to maintain pre-operative levels of arterial oxygen saturation and should be continued until the patient is mobile postoperatively. If the patient was using CPAP therapy at home, it should be reinstated on return to the ward or even in the PACU if oxygen saturation levels cannot be maintained by the use of inhaled oxygen alone. If supplemental oxygen is necessary, this can either be given via the patient's CPAP machine or via nasal specula under the CPAP mask. Before discharge from the PACU, all obese patients should be observed whilst unstimulated for signs of hypoventilation, specifically episodes of apnoea or hypopnoea with associated oxygen desaturation, which will warrant an extended period of monitoring in the PACU. Ongoing hypoventilation will require anaesthetic assessment to establish the need for further respiratory support and level-2 care. The patient is safe to return to the ward only when: - Routine discharge criteria are met - The respiratory rate is normal and there are no periods of hypopnea or apnoea for at least one hour - The arterial oxygen saturation returns to the preoperative values with or without oxygen supplementation ## Analgesia and ward care An enhanced recovery protocol is essential [bib_ref] Enhanced recovery after bariatric surgery (ERABS): clinical outcomes from a tertiary referral..., Awad [/bib_ref]. Early mobilisation is vital and most patients should be out of bed on the day of surgery. If possible, restricting the patient with a urinary catheter, intravenous infusions or other devices should be avoided. Calf compression devices can be disconnected for mobilisation. The intramuscular route of drug administration is to be avoided owing to unpredictable pharmacokinetics. The use of patient-controlled analgesia (PCA) systems needs careful consideration because of the increased risk of respiratory depression in those with undiagnosed sleep-disordered breathing. In those patients with suspected or poorly treated sleep-disordered breathing, increased postoperative monitoring in a level-2 unit is recommended if PCA is required. Subarachnoid block with an opioid adjunct is a useful technique resulting in reduced postoperative opioid requirements. Epidural infusions are associated with reduced postoperative mobility and may be counterproductive. In the ward, oxygen therapy should be continued until baseline arterial oxygen saturations are achieved, and pulse oximetry should continue until oxygen saturations remain at baseline without supplemental oxygen and parenteral opioids are no longer required. Postoperative tachycardia may be the only sign of a postoperative complication and should not be ignored (see below). ## Thromboprophylaxis Obesity per se is a risk factor for VTE and it is recommended that all obese patients, undergoing all but minor surgery, should receive VTE prophylaxis. Guidelines for postsurgical VTE prophylaxis were published by the National Institute for Health and Care Excellence in 2010. Strategies to reduce the risk of VTE include: early postoperative mobilisation; mechanical compression devices; thromboembolic device (TED) stockings; anticoagulant drugs; and vena caval filters. There is currently limited evidence to support the use of TEDs in obesity, but if used, it is essential that they be fitted correctly to avoid vascular occlusion. Current evidence does not support the routine use of venal caval filters in the obese population [bib_ref] Inferior vena cava filters for prevention of venous thromboembolism in obese patients..., Rowland [/bib_ref]. The mainstay of VTE prophylaxis in obesity is pharmacological, with the criteria for pharmacological prophylaxis including: prolonged immobilisation; total theatre time > 90 min; age > 60 years; BMI > 30 kg.m À2 ; cancer; dehydration; and a family history of VTE. Oral agents such as rivaroxiban and dabigatran are licensed for VTE prophylaxis following orthopaedic surgery, but there is limited evidence for their use in obesity. At present, dose adjustment for oral agents is not recommended for the obese. There is evidence regarding dose adjustments for low molecular weight heparins in obesity. The Haemostasis, Anticoagulation and Thrombosis (HAT) Committee published the dosing schedule reproduced in [fig_ref] Table 6: Dosing schedule for thromboprophylaxis[80] [/fig_ref] in April 2010. ## Rhabdomyolysis A rare but serious complication in the obese patient is rhabdomyolysis. Apart from obesity, pre-disposing risk factors include hypotension, immobility, prolonged operative procedures and dehydration. Rhabdomyolysis should be considered if the patient has postoperative deep tissue pain, classically in the buttocks. Serum creatinine kinase concentration should be measured promptly, and if rising, aggressive fluid resuscitation, diuretics and urinary alkalinisation may be required to prevent further acute kidney injury [bib_ref] Intraoperative fluid replacement and postoperative creatine phosphokinase levels in laparoscopic bariatric patients, Wool [/bib_ref]. ## Special circumstances Sedation Pre-operative evaluation for patients undergoing sedation should be similar to those having general anaesthesia. Patients with sleep-disordered breathing are likely to have airway obstruction with even minimal sedation. Obese patients are not suitable for solo operator-sedator procedures. ## Emergency surgery It is particularly important that obese patients requiring emergency surgery are managed by an anaesthetist experienced in the care of the obese, along with an experienced surgeon in order to minimise the operative time and the risk of complications. Postoperative level-2 nursing care is far more likely to be required owing to the much higher risk from emergency surgery complications. Obese patients can look deceptively well and abdominal examination can be notoriously difficult. Tachycardia, the new onset of abdominal pain or unexplained fever may be the only signs of intraabdominal sepsis and should be an indication for measuring arterial blood gases and serum lactate. ## Day surgery It is acceptable for obese patients to undergo surgery as a day case if: the management would not be modified if they were admitted as an inpatient; and being treated as a day case will not alter the peri-operative risk. The exclusion of obese patients from the advantages that day surgery may offer should not be made on the basis of weight alone. There is an increased risk of anaesthetic-related complications in obese patients in the day surgery environment, but these tend to occur on induction of anaesthesia, intraoperatively or in the early recovery phase [bib_ref] Pre-existing medical conditions as predictors of adverse events in day-case surgery, Chung [/bib_ref]. Obesity has no influence on the rate of unanticipated admission, postoperative complications, readmission or other unplanned contact with health professionals after home discharge [bib_ref] Obesity and daycase surgery, Davies [/bib_ref]. Current guidelines advocate automatic acceptance of patients with BMI < 40 kg.m À2 [bib_ref] Day case and short stay surgery: 2, Verma [/bib_ref] [bib_ref] Pushing the patient boundaries, Jones [/bib_ref]. A casenote review should be carried out by an anaesthetist to determine whether individualised discussion and assessment may be required before the day of surgery for those with co-morbidities or BMI > 40 kg.m À2 . A review and meta-analysis by the Society for Ambulatory Anesthesia provides useful advice on day surgery for patients with sleep-disordered breathing. Patients with a known diagnosis of OSA can be considered for day surgery: if they have, and are able to use, a CPAP device after discharge; if any co-morbid conditions are optimised; and if postoperative pain relief can be provided predominantly by non-opioid analgesics. Laparoscopic cholecystectomy and laparoscopic gastric banding are increasingly being performed as a day-case procedure [bib_ref] Laparoscopic adjustable gastric banding in an ambulatory surgery center, Watkins [/bib_ref] [bib_ref] Laparoscopic gastric banding for morbid obesity in the day surgical setting, Dunsire [/bib_ref] [bib_ref] Laparoscopic gastric banding is safe in outpatient surgical centers, Cobourn [/bib_ref]. ## Obstetrics Maternal obesity is recognised as one of the most commonly occurring risk factors seen in obstetrics, with outcomes for both mother and baby poorer than in the general population. The CMACE report and the Obstetric Anaesthetists' Association have made a number of recommendations regarding the care of obese pregnant women. Obese women have an increased risk of co- [bib_ref] The prevalence and impact of overweight and obesity in an Australian obstetric..., Callaway [/bib_ref] [bib_ref] Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies, Duckitt [/bib_ref]. Obesity and pregnancy are both significant risk factors for the development of VTE in pregnancy. Compared with a non-obese parturient, an obese woman is more likely to have her labour induced and require instrumental delivery [bib_ref] Siega-Riz AM. Maternal prepregnancy overweight and obesity and the pattern of labor..., Vahratian [/bib_ref] [bib_ref] Maternal obesity and risk of cesarean delivery: a meta-analysis, Chu [/bib_ref]. There is an increased risk of operative and postoperative complications, including increased rates of postpartum haemorrhage, prolonged operative times, and infective complications such as endometritis and wound infection [bib_ref] Obesity as an independent risk factor for infectious morbidity in patients who..., Myles [/bib_ref]. Fetal outcomes in obese pregnant women are poorer compared with the general population, with stillbirth rates in women with a BMI > 35 kg.m À2 twice as high as the national stillbirth rate. There is an increased risk of preterm delivery in pregnant obese women [bib_ref] Maternal obesity and risk of preterm delivery, Cnattingius [/bib_ref]. In addition, babies born to obese mothers are at increased risk of shoulder dystocia, brachial plexus lesions, fractured clavicle and congenital birth defects such as neural tube defects [bib_ref] Maternal obesity, mode of delivery, and neonatal outcome, Blomberg [/bib_ref]. Specific anaesthetic considerations are similar to those in the non-obstetric obese patient: - Obese patients are particularly vulnerable to aortocaval compression - Vascular access may be more difficult and should be established early in labour in a woman with a BMI > 40 kg.m À2- The provision of general anaesthesia and central neuraxial blockade is associated with increased difficulties [bib_ref] Obstetric anaesthesia outcome in obese and non-obese parturients undergoing caesarean delivery: an..., Bamgbade [/bib_ref] [bib_ref] Anesthetic and obstetric outcome in morbidly obese parturients, Hood [/bib_ref] [bib_ref] Massive maternal obesity and perioperative cesarean morbidity, Perlow [/bib_ref]. This can lead to an increased decision-to-delivery interval in women who require a category-1 or -2 caesarean section. The obese obstetric patient is particularly at risk of VTE and conversely, postpartum haemorrhage. The recommended dosing of anticoagulants is generally higher for pregnant women; the Royal College of Obstetricians and Gynaecologists' Green-top Guideline provides current recommendations. ## Critical care Outcomes of obese patients in critical care remain controversial. In several recent studies, obesity was not associated with increased mortality; however, it was associated with a prolonged requirement for mechanical ventilation, tracheostomy and prolonged length of stay in a critical care unit [bib_ref] Outcomes of morbidly obese patients receiving invasive mechanical ventilation: a nationwide analysis, Kumar [/bib_ref] [bib_ref] Effect of obesity on intensive care morbidity and mortality: a meta-analysis, Akinnusi [/bib_ref]. Airway interventions in the obese are associated with an increased risk of hypoxia and complications and should only be undertaken by appropriately skilled personnel. Many would advocate an early tracheostomy if long-term airway management is anticipated. Custom-made tracheostomy tubes with an adjustable flange may be required to ensure an adequate length to reach the trachea. Tracheostomies are usually performed in the intensive care unit using a percutaneous approach, but surgical placement may be considered, depending on the experience of the available medical staff. For mechanical ventilation, ideal body weight is used to calculate the initial recommended tidal volume of 5-7 ml.kg À1 , ensuring the peak inspiratory pressure remains < 35 cmH 2 O. Enteral absorption of drugs is not altered in the morbidly obese. However, owing to the altered pharmacokinetics, monitoring of serum levels is considered more important in this group of patients to ensure that drug levels remain within the therapeutic range [bib_ref] Effect of obesity on the pharmacokinetics of drugs in humans, Hanley [/bib_ref]. Prophylaxis against VTE is vitally important for the morbidly obese patient in critical care and should follow the guidelines given above. All critically ill patients are prone to develop protein malnutrition as a result of metabolic stress and despite having excess fat stores, the morbidly obese are no different. However, there is some evidence suggesting that hypocaloric feeding regimens can achieve adequate nitrogen balance with more favourable outcomes [bib_ref] high-protein nutrition therapy for critically ill patients with obesity, Dickerson [/bib_ref]. Early aggressive rehabilitation and physiotherapy should be undertaken as soon as is possible to encourage early mobilisation. Increased numbers of staff are needed to roll these patients to prevent formation of pressure sores. ## Cardiopulmonary resuscitation Morbid obesity presents additional problems during resuscitation. There may be delays caused by difficulties in placement of defibrillator pads, establishment of vascular access or securing an effective airway. Physical and biological factors related to obesity may affect the quality of chest compressions delivered, the efficacy of administered vasoactive drugs or the efficacy of defibrillator shocks applied, because none of these measures are standardised to a patient's BMI. The American Heart Association has concluded that no alterations to resuscitation have been shown to affect outcome [bib_ref] cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary..., Vanden Hoek [/bib_ref]. Inspiratory airway pressures will be higher than normal, and excessive leak with supraglottic airway devices may mean that chest compressions will have to be paused to enable ventilation (i.e. a standard 30:2 compression-ventilation ratio). The high airway pressures that can occur during resuscitation of very obese patients may impair coronary perfusion pressure and ultimately reduce the chance of survival [bib_ref] Death by hyperventilation: a common and life-threatening problem during cardiopulmonary resuscitation, Aufderheide [/bib_ref]. Chest compressions will be difficult to perform in many patients, simply because of suboptimal positioning of rescuers. A step or platform may be required, or compressions can be performed from the patients' head end. Recommended defibrillation energies remain unaltered in the morbidly obese, though there is evidence that the thoracic impedance is higher [bib_ref] Determinants of thoracic electrical impedance in external electrical cardioversion of atrial fibrillation, Fumagalli [/bib_ref]. If defibrillation remains unsuccessful, the defibrillator pads should be repositioned and the shock energy increased to the maximum setting. If intravenous access is difficult, the intraosseous route for drug delivery is recommended. The upper humerus is a well-established point of access, and drug delivery during resuscitation is effective via this route. Standard doses of adrenaline and amiodarone should be used. ## Patients with adjustable gastric bands in situ Laparoscopic adjustable gastric banding is a recognised treatment for obesity. However, patients with a gastric band in situ are at increased risk of pulmonary aspiration during general anaesthesia owing to oesophageal dysmotility and dilatation above the band. The dilatation may persist following band deflation. There are case reports of regurgitation of food even after prolonged fasting and a tracheal tube is recommended in all patients who have a gastric band [bib_ref] Esophageal dysmotility disorders after laparoscopic gastric banding-an underestimated complication, Naef [/bib_ref] [bib_ref] Airway management concerns in patient with gastric banding procedures, Koolwijk [/bib_ref]. Current advice is not to deflate the band before surgery; however, depending on the extent and type of surgery, a decision to deflate the band may be made on an individual basis. Discussion with the bariatric surgical team is advised. An important side note is that patients with gastric bands in situ who present with sudden onset of dysphagia or upper abdominal pain should be considered as having a band slippage until proved otherwise. This is a surgical emergency and should be treated by immediate deflation of the gastric band and referral to a competent general surgeon. Delay in deflating the band can lead to gastric infarction and perforation. For the management of other bariatric surgical emergencies, readers are referred to the American Society for Metabolic and Bariatric Surgery website (see below). ## Resources equipment A 2011 review of incidents related to obesity reported to the National Patient Safety Agency highlighted that many of these involved inadequate provision of suitable equipment. This is a clinical governance issue and hospitals need to invest in appropriate equipment to assist in the safe management of obese patients. A suggested but not exhaustive list of equipment to be considered is given in [fig_ref] Table 7: Equipment for managing obese surgical patients [/fig_ref] [bib_ref] Patient safety incidents associated with obesity: a review of reports to the..., Booth [/bib_ref]. An 'obesity pack' is useful; this can include specialised documentation, the SOBA single-sheet guidelines (see below) and smaller items of equipment plus a list of where the larger items are located. ## Staff All units managing obese surgical patients must have the ability to escalate care appropriately in the event of acute deterioration of patients. It is recommended that a single person in the anaesthetic department be nominated as the obesity lead. It would be his/her responsibility to ensure that equipment and training are up to standard and could act as a point of contact for advice. Theatre teams should have training in managing obese patients, which can be provided either internally or externally. In hospitals where there is a bariatric service, all staff should periodically observe practice in this area. Specific training on moving the morbidly obese patient should be provided. In ideal circumstances, all anaesthetic trainees should complete a module in bariatric anaesthesia to gain insight and hands-on experience in the management of the morbidly obese surgical patient. ## Ward equipment Specialised electrically operated beds that can raise a patient to standing without the need for manual handling with pressure-relieving mattresses Suitable bathrooms with floor-mounted toilets, suitable commodes Large blood pressure measuring cuffs Extra-large gowns Suitably sized compression stockings and intermittent compression devices Larger chairs, wheelchairs and trolleys, all marked with the maximal recommended weight Scales capable of weighing up to 300 kg On-site blood gas analysis Continuous positive airway pressure or high-flow oxygen delivery device for the post-anaesthesia care unit Patient hoist or other moving device (may be shared with other departments) Theatre equipment Bariatric operating table, able to incorporate armboards and table extensions, attachments for positioning such as leg supports for the lithotomy position, and shoulder and foot supports Gel pads and padding for pressure points Wide Velcro strapping to secure the patient to the operating table Ramping device/pillows Raised step for the anaesthetist Large tourniquets Readily available difficult airway equipment Anaesthetic ventilator capable of positive end-expiratory pressure and pressure modalities Portable ultrasound machine Hover-mattress or slide sheet Long spinal and epidural needles Long arterial lines if femoral access is necessary Neuromuscular blockade monitor Depth of anaesthesia monitoring to minimise residual sedation [fig] Figure 1: Adult trends in obesity (BMI ≥ 30 kg.m 2 ) in the UK male (○) and female (•) population, showing threeyearly averages. Redrawn from Health Survey England 2013 data (see http://www.hscic.gov.uk/catalogue/PUB16077) accessed 10/03/2015). [/fig] [fig] Figure 2: Relationship between total body weight and body mass index (BMI), showing how lean body mass effectively plateaus despite increasing BMI. A male of height 190 cm and ideal body weight (IBW) is indicated, demonstrating how IBW includes a normal 15% fat mass. [/fig] [fig] Figure 3: Ramping position for obese patients. Note the tragus of the ear level with the sternum. [/fig] [fig] •: Use of neuromuscular monitoring to maintain a level of block compatible with surgery and to ensure complete reversal of block before waking the patient Maximal use of local anaesthetic and multimodal opioid-sparing analgesia Maintaining the head-up position throughout recovery Monitoring of oxygen saturations until mobile postoperativelyIf long-acting opioids are required and the patient is not stabilised on CPAP pre-operatively, then the use of level-2 care is recommended. [/fig] [table] Table 1: World Health Organization classification of obesity[4]. [/table] [table] Table 3 Suggested: SeeTable 1for definitions/calculations. † See product literature. [/table] [table] Table 4: The Obesity Surgery Mortality Risk Stratification score: (a) risk factors; (b) risk of mortality[43]. [/table] [table] Table 6: Dosing schedule for thromboprophylaxis[80]. [/table] [table] Table 7: Equipment for managing obese surgical patients. [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/anae.13101	Guidelines are presented for the organisational and clinical peri‐operative management of anaesthesia and surgery for patients who are obese, along with a summary of the problems that obesity may cause peri‐operatively. The advice presented is based on previously published advice, clinical studies and expert opinion.
a63f67a20c6565f20462eeb55a8b8b54e51760e4	pubmed	The impact of the COVID-19 pandemic on the future of telehealth in primary care	The impact of the COVID-19 pandemic on the future of telehealth in primary care A B S T R A C TThis policy paper reviews the history, use and significance of telehealth in primary care. The emergence of telehealth as a primary strategy to continue to deliver value based, timely primary care during COVID-19 is discussed with recommendations for future applications, payment and preparation of providers to continue to provide quality care of clients in the future using telehealth. # Background The COVID-19 pandemic radically transformed the delivery of primary care in the United States (U.S). In the face of a highly contagious virus, the fragility of the nation's reliance on in-person primary care was dramatically revealed, with implications for patient access to primary care, cost, and the financial sustainability of providers and primary care practices. Thus, to facilitate access to primary care for people and address revenue streams in primary care after the initial severe disruption, telehealth services regulations, administrative rules, payer policies, and reimbursement were modified almost overnight. Providers quickly adapted, and more patients have become acquainted with primary health care offered in the comfort of their home, a care delivery model that eliminates travel time and time-consuming waits in primary care practices. Virtual care and other forms of technology-enabled interactions provided fresh approaches to primary care and have the potential to be efficient, collaborative, cost-effective, and patient-centered. Taken as a whole, the acceptance by both patients and providers of primary care services via telehealth suggests that telehealth in some form and configuration is here to stay. Thus, the purpose of this manuscript is to discuss the implications for telehealth in primary care, benefits and barriers for patients and providers, considerations and cautions, as well as reforms needed to ensure appropriate and equitable availability of telehealth services post-COVID 19 pandemic. But first, what, exactly is telehealth? ## Telehealth defined The Health Resources and Services Administration (HRSA) defines telehealth as the "use of electronic information and telecommunications technologies to support long-distance clinical health care, patient and professional health-related education, public health and health administration. Technologies include videoconferencing, the internet, store-and-forward imaging, streaming media and terrestrial and wireless communications. Telehealth is different from telemedicine. Telehealth refers to a broader scope of remote health care services than telemedicine. While telemedicine refers specifically to remote clinical services, telehealth can refer to remote nonclinical services, such as provider training, administrative meetings, and continuing medical education, in addition to clinical services" . ## An overview of the history of telehealth Today's telehealth finds its roots in telemedicine. Telemedicine spans nearly 100 years, beginning with the rudimentary idea of medical care being provided via radio with a television screen in 1924 [bib_ref] Creating a Framework to Support Measure Development for Telehealth. Department of Health..., Myers [/bib_ref]. In the early 1950s, telemedicine was formally introduced at the 1951 New York World's Fair. Subsequently, teleradiology was initiated in 1957 with tele-education, and tele-psychiatry following in 1959. Federal funding was provided to seven sites in the 1960s and 1970s for telemedicine research and development projects that were predominately in rural areas or targeted specific populations such as Native Americans in Arizona and Alaska . Telecommunications was implemented to manage the Mexico City disaster in 1985 employing satellite technology to support disaster recovery teams [bib_ref] Telecommunications systems in support of disaster medicine: Applications of basic information pathways, Garchnek [/bib_ref]. At the same time, the U.S. and the United Socialist Soviet Republic created an international telemedicine project to monitor the health of astronauts in space exploration. Another initiative, the Space Bridge Project was implemented for recovery efforts of the Armenian earthquake in 1988. Communication to the front-line was with four U.S. medical centers in Maryland, Houston, and Utah. These medical institutions provided real-time video consultation for sub-specialties in neurology, orthopedics, psychiatry, infectious diseases, and surgery [bib_ref] Telecommunications systems in support of disaster medicine: Applications of basic information pathways, Garchnek [/bib_ref]. These early projects established the technological basis for telemedicine, demonstrating that telecommunications could be utilized as a substitute for travel to obtain medical care, as well as to provide specialized care during emergency situations (e.g., telestroke, teleICU, teleNICU). Nurses were always part of the team of health care professionals using this technology . Now, the Internet has evolved into a nearly ubiquitous platform for health care. Internet-based services have expanded access to consumers for medical information, access to health care portals, use of an array of blue-tooth enabled devices and applications that download health information to personal websites or for sharing with health care professionals. The Internet provides a platform for researchers to collaborate, educate students and professionals of all educational backgrounds, and for medical professionals to conduct webbased visits with patients for consultation, preventive care, monitoring, diagnosis, and chronic condition management and support . Despite the history of the development of successful telehealth applications, particularly in primary care with hard-to-reach clients, the implementation of these technologies has been uneven. Arguably, one of the reasons they have not proliferated in primary care prior to the COVID-19 pandemic relates to the strong tradition of in-person interactions in primary care between provider and patient. This is how health professional students have been taught, what they observe in practice, and-as Hyman (2020) notes-may even be central to their professional identity. Patients have also learned this tradition as they have encountered care throughout their lifespan and may perceive such care as a hallmark of quality primary care. This delivery model has been reinforced by the historical lack of reimbursement by public and private payers for primary care delivered through video or telephone. The COVID-19 pandemic prompted Centers for Medicare and Medicaid (CMS) to adjust telehealth reimbursement rules, resulting in a significant increase in video and phone visits in primary care. This allowed many more patients to experience the convenience of web-based care. Compared to February 2019 through February 2020 when medical claims for health services employing telehealth rose 121% nationally, the rise between March 2019 to March 2020 showed a dramatic 4,347% increase indicating the rapid expansion of telehealth services [bib_ref] The Coronavirus pandemic and the transformation of telehealth, Gelburd [/bib_ref]. Today, consumer demand has begun to drive the change as will long-term change in reimbursement from CMS and other payers. ## The key benefits and barriers related to telehealth Every mode of patient care delivery has benefits and limitations or barriers. Telehealth is no different. [fig_ref] Table 1 -: Key Benefits and Barriers to the Use of TelehealthBenefits BarriersPatients can receive... [/fig_ref] reviews the primary strengths or benefits of telehealth as well as the barriers to effective patient care utilizing telehealth. ## Barriers Although any form of health care can be fraudulently deployed, telehealth provides ready opportunities for abuse because "unscrupulous providers . . .have much greater reach with telehealth" (Cohen, cited in Schulte, 2020, para 4). This reach includes "sham remote visits to increase the size and scale" of their criminal operations, states U.S. Health and Human Services Deputy Inspector General Christi Grimm (cited in Berry, 2021, para 8) resulting in "enormous losses to payers through Medicare fraud" (Berry, para 9). And, because Medicare is financed though taxes and premiums paid by Medicare beneficiaries, the balance between opening access to care and preventing financial abuse is complex, particularly given the popular support for telehealth by those who are not aware of the potential for abuse. The problem is not limited to governmental payers such as Medicare, but also includes private payer such as commercial insurance. Two current policy issues of contention can interact to accelerate fraud and excessive health care costs: 1) first dollar coverage of telehealth services, in which patients pay no cost sharing in the form of deductibles or copayments and thus have little incentive to question what is offered to them; and 2) providers being able to bill for telehealth for people they have never seen. Although both issues can increase access to needed care, they also create dramatic new openings for exploitation of taxpayer dollars through fraudulently billing of Medicare and Medicaid and manipulation of vulnerable, unsuspecting patients who cannot be aware that the services offered are a financial scheme rather than representing valuable services. Moreover, even outside of fraud, telehealth for some services has been found to be associated with more downstream use of health care services than in-person visits, which therefore limits telehealth cost effectiveness. This phenomenon suggest that these telehealth services were "additive" rather than "substantive," with the latter being a component of a value-oriented, postpandemic telemedicine regulation and payment orientation suggested by. Fragmentation of care is also a risk that can be associated with telehealth services. Single-purpose telehealth providers already offer virtual consultations and prescriptions for a variety of conditions. Patients may or may not disclose these prescriptions to their primary care provider, resulting in potential safety issues. Optimal payment policy that is focused on delivering timely and effective primary care to patients will spur the uptake of telehealth that adds value and prevents downstream costs rather than increasing low value, unnecessary care, with both provider payment and patient cost sharing aligned with this critical aim. Value-informed nurses can play a key role in deployment of high-quality telehealth services. ## Benefits Virtual care may offer particular opportunities for effective teamwork and a dramatically re-envisioned professional life. No longer geographically bound, the opportunities to live or relocate as one wishes to create virtual "warm hand-offs" between team members and disciplines along with work hours that are acceptable to patients and providers versus being limited by facilities/office hours are appealing. However, the roles and dimensions of team members in primary care must be developed just as they are for in-person teams. Best practices in virtual team building incorporate creating trust, clarifying work roles inclusive of expectations and boundaries, developing strategies for effective delegation and referral, and using appropriate software and technology. At this point, it is unclear if telework will enhance provider satisfaction or create new forms of burnout for primary care providers. Will truncating commuting and other geographic-related efforts enhance provider satisfaction or, instead, will "ZOOM fatigue" [bib_ref] What it feels like to experience ZOOM burnout and how to avoid..., Melsenzahl [/bib_ref] overwhelm any positive gains proffered by telework? ## Trends in telehealth payment The rapid and dramatic expansion of telehealth services in response to the COVID-19 pandemic could not have taken place without a concomitant willingness on the part of public payers, namely Medicaid and Medicare, to Patient's exposure to infectious disease is reduced and those who are immunocompromised are protected. 2. Inadequate broadband particularly in rural and remote areas to support access, connectivity and speed. Timely care between patient and providers, provider and specialty consultants and allied members of the health care team. . 3. Access and continuity of care influenced by licensure, payment parity, HIPAA, and provider preferences. N u r s O u t l o o k 7 0 ( 2 0 2 2 ) 3 1 5 À3 2 2 remove regulatory barriers at least during this public health emergency period. Given that CMS is particularly charged with caring for the elderly and the low income who were particularly vulnerable during the epidemic, this has great significance for the nation. Prior to the COVID-19 pandemic, Medicare allowed for several telehealth services, but they were limited by geography, provider type, and organizations. All of this changed in March 2020, when CMS issued waivers to its requirements; one of the first on March 17, 2020 allowed all beneficiaries to receive telehealth services in any location, including their homes. This was followed by a series of temporary waivers to make telehealth more readily accessible. Medicare reports that prior to the COVID-19 emergency, 13,000 beneficiaries in fee for service Medicare received a telemedicine service per week; this escalated to 1.7 million a week by the end of April. Medicaid, of course, sets policy and is regulated at the level of each state. States have broad flexibility to cover telehealth through Medicaid, including the methods of communication (such as telephonic and/or video technology commonly available on smart phones and other devices (United State Department of Health and Human Services, 2020b). The flexibility of allowing telephonic only services is significant in overcoming the "digital divide" that low income and vulnerable populations may face in accessing care via telehealth. Registered Nurses (RNs) are recognized for their ability to integrate traditional health care and person-centered approaches. They have been providing high quality telehealth services, utilizing telephone, internet, and remote patient monitoring technologies that focus on health promotion, chronic condition management, and coordination of care for many years. Studies have demonstrated effectiveness of RN interventions across populations, settings, and socioeconomic conditions [bib_ref] Care coordination: Roles of registered nurses across the care continuum, Swan [/bib_ref] , capacities they can effectively deploy in telehealth with enabling reimbursement. RN roles in primary care have corresponding practice incentives to improve quality, safety, cost-effectiveness, and convenience for patients. Value-based reimbursement models and financial reward programs for quality such as the Merit Based Incentive Pay System (MIPS) have highlighted the need for care that extends beyond a traditional physician visit. Currently, RNs can bill select in-person services such as Medicare annual wellness visits under the direct supervision of a primary care provider. At this time, however, RNs are not identified as eligible providers of reimbursable telehealth services and while they can temporarily bill for video services under Public Health Emergency Waivers, they are currently not included in either the Coronavirus Aid, Relief, and Economic Security (CARES) Act (Public Law 116À136) or the Creating Opportunities Now for Necessary and Effective Care Technologies (CONNECT) for Health Act of 2019 (H.R. 4932/S. 2741), despite reimbursement availability for similar services provided in face-to-face delivery [bib_ref] Primary care registered nurse telehealth policy implications, Watkins [/bib_ref]. Although reimbursement for RN services is not a new problem, it is more urgent as primary care patients become more complex. With the passage of The Patient Protection and Affordable Care Act (2010), substantial changes have occurred in the organization and delivery of primary care, emphasizing greater team involvement in care and expansion of the roles of each team member, including RNs [bib_ref] Registered nurses in primary care: Emerging new roles and contributions to team-based..., Flinter [/bib_ref]. Incorporating RNs as team members can increase access to care, improve care quality and coordination for chronic conditions, and reduce burnout among primary care practitioners by expanding primary care capacity [bib_ref] Nursing in a transformed health care system, Fraher [/bib_ref] [bib_ref] Share the care TM : Building teams in primary care practices, Ghorob [/bib_ref] [bib_ref] Policy agenda for nurse-led care coordination, Lamb [/bib_ref]. In primary care, early evidence suggests that RNs are effective in supporting chronic condition management, promoting health and wellness, coordinating care for high need, complex patients and managing transitions of care while reducing unnecessary utilization of health services [bib_ref] Registered nurses: Partners in transforming primary care, Bodenheimer [/bib_ref]. Findings from a 2013 study of The Primary Care Team: Learning from Effective Ambulatory Practices (LEAP) suggest that a large majority of LEAP primary care practices, regardless of practice type or corporate structure, use RNs as a key part of their care team model [bib_ref] The emerging primary care workforce: Preliminary observations from the primary care team:..., Ladden [/bib_ref]. This contrasts with a study of 496 practices in the CMS's Comprehensive Primary Care initiative [bib_ref] Staffing patterns of primary care practices in the comprehensive primary care initiative, Peikes [/bib_ref] that found that only 36 percent of practices had RNs on staff, compared with 77 percent of LEAP sites [bib_ref] Registered nurses in primary care: Emerging new roles and contributions to team-based..., Flinter [/bib_ref]. If final regulations preclude RNs from billing for telehealth services currently paid for in the in-person environment, it represents a step backward in already limited reimbursement options and a disincentive to employ RNs. ## Cost sharing Prior to the COVID-19 crisis, private insurance coverage for telehealth varied from payer to payer and differences between plans. Since then, several health plans announced that they would support telehealth services including no fee or copay for subscribers. Also of note, a Blue Cross and Blue Shield survey found that 75% of Americans with behavioral health conditions are still able to continue therapy due to the availability of telehealth services. However, 42% of Americans reported delaying routine healthcare (Blue. Unfortunately, the number of people affected by the pandemic still grows, variants emerge, and the need for social distancing continues. Vulnerable people may fear in-person medical visits and may be delaying routine and chronic disease maintenance care. Thus, there is a pressing need to continue the ability to have continued access to telehealth visits. ## Nursing education ## Entry level There is a recognized need for additional primary care capacity. To accommodate this "growing need for primary care providers, educators will have to increase coursework and student clinical experiences in primary care settings, which in turn could lead to more graduates choosing careers in primary care and ambulatory and community-based settings" . In response to these and other contemporary factors, the American Association Colleges of Nursing (AACN) has shifted toward a competency-based curriculum. As part of this effort, AACN published a new Essentials of Baccalaureate Education for Professional Nursing Practice (2021) that identifies 10 domains for nursing education. These domains include informatics and health care technologies. More specifically prelicensure nursing students are to be able to "identify the basic concepts of electronic health, mobile and effectively use electronic communication tools . Within these 10 domains are specific competencies that AACN believes are essential for nursing practice, including, engaging in effective partnerships, advancing equitable population health policy, demonstrating advocacy strategies, using information and communication technologies and informatics processes to deliver safe nursing care to diverse populations in a variety of settings, and using knowledge of nursing and other professions to address the health care needs of patients and populations (p.196). On a practical level, students in primary care will need grounding in the technical skills of telehealth as well as a framework to address ethical challenges that may arise within an interdisciplinary team and administration of services. Educational experiences can incorporate interprofessional learning in telehealth [bib_ref] Telehealth and eHealth in nurse practitioner training: Current perspectives, Rutledge [/bib_ref]. COVID-19 gives the opportunity for advanced practice students to work with providers who are actively using telemedicine visits. ## Graduate level Graduate level nurse abilities add to these core competencies to include care redesign; developing, maintaining and evaluating virtual teams; workflow optimization, and oversight of cost, quality, and value outcomes. For advanced practice registered nurses (APRN) and all licensed independent providers on the primary care team, the core challenge may well be developing the confidence and competence to be able to conduct the full visit, from history to physical exam, assessment, diagnosis(es), and treatment all in the context of virtual care, using new tools such as remotely monitoring devices. ## Preparation for providers As the COVID-19 crisis loomed, providers who had never used telehealth services were engaged in a steep learning curve in developing competency in telehealth visits. Going forward telehealth needs to be part of the competencies for all practicing RN's and advanced practice nurses. Clinicians should participate in telehealth service continuing education such as prevention education etiquette, how to deliver care via telehealth visits and navigate home monitoring data sharing (i.e., glucose, blood pressure, electrocardiogram) with technological devices. It is also important for clinicians to learn the regulatory aspects of telehealth, how to maintain standards of care, ethics, prevention of fraud, and the economics of telehealth. Education methods should include didactic content, but also telehealth experiences through simulation with standardized patients [bib_ref] Telehealth and eHealth in nurse practitioner training: Current perspectives, Rutledge [/bib_ref]. ## Licensure and regulation The National Council of State Boards of Nursing (NCSBN) plays an important role in nursing, including administration of initial practice (NCLEX) and other certification examinations, oversight of school curricula, and regulation of nursing practice. In order to ensure that the NCLEX accurately reflects entry level nursing practice, the NCSBN conducts both triennial and continuous practice analyses. These analyses include extensive literature review, input from new graduate nurses, and nurse leader interviews [bib_ref] Validating the NCLEX-RN test plan: Comparing practice analysis data, Williams [/bib_ref]. The dramatic changes heralded by COVID-19 reveal new essential, virtual competencies that must be urgently incorporated in school curricula and tested in NCLEX examinations to meet its mission of reflecting current practice and ensuring safe patient care. Nursing licensure is also regulated through the National Council of State Boards of Nursing (NCSBN). Recognizing that patient care does not always follow state lines, the NCSBN promotes the Nurse Licensure Compact (NLC). The NLC enables a nurse to have one multistate license allowing practice in both the home state and other compact states, facilitating the provision of telehealth services. An important aspect of the temporary Public Health Emergency Waiver was dropping the requirement for the provider to be licensed in the patient's state. Some state requirements still apply, but this opens patient access to specialty providers and eliminates patient problems with transportation over distances to get to providers in other states (Center for Connected Health Policy, 2020). ## Disparities The digital divide remains a concern. Both providers and patients need to have resources to properly conduct a telehealth visit. However, not everyone has access to required resources. According to U.S. 2015 census data, N u r s O u t l o o k 7 0 ( 2 0 2 2 ) 3 1 5 À3 2 2 89% of households had some sort of computer and internet. Differences exist based on age, ethnicity, socioeconomic status, and region. This means some people such as those over 65 years of age (47% with internet) have access deficits. One potential solution came with the April 30, 2020 Public Health Emergency Waiver. This opened telehealth visits to the use of both video and audio-only telehealth services in response to organized medicine efforts. CMS matched payments for audio-only telephone visits between Medicare patients and their providers to similar office and outpatient visits. As well, payments were retroactive to March of 2020 (American Medical Association, 2020). Health literacy is a concern in any patient encounter. However, in a telehealth encounter, clear communication practices with a plan for the patient to review their understanding of what has been communicated by the provider is essential. Universal precautions for health communication assumes that all patients are at risk for miscommunication and misunderstanding, regardless of education, socioeconomic status, or literacy skills; recognizes that patients may go to great lengths to conceal their lack of understanding [bib_ref] Shame and health literacy: The unspoken connection, Parikh [/bib_ref] ; and, acknowledges that healthcare professionals are poor at detecting when patients do not understand [bib_ref] Cross Blue, and Shield, Blue (2020a). 75% of Americans with behavioral health..., Coleman [/bib_ref]. All personnel should use simple language and clear communication practices to support lowering barriers to comprehension for all patients, whether communicating via telehealth or in-person. ## Ensuring health insurance portability and accountability act (hippa) compliance Privacy concerns exist in all of health care but have additional nuances in telehealth. Basic rules for following HIPPA include that both the patient and provider should be in private spaces such as the provider alone in an office and the patient in a quiet place at home. If this is not possible, other means of maintaining privacy such as low voices and lack of screen view should be practiced. The United States Department of Health and Human Services (2020a) provides guidance and a partial listing of "non-public facing" HIPAA-compliant video communication. The vendors of these communication products need to verify they are "HIPAA compliant and will enter into HIPAA business associate agreements (BAAs) in connection with the provision of their video communication products". Public-facing products such as a public chat room are not permissible because of wide, uncontrolled access. During the COVID pandemic, the "Office for Civil Rights (OCR) exercises enforcement discretion and waive penalties for HIPAA violations against health care providers that serve patients in good faith through everyday communications technologies, such as FaceTime or Skype" (Unites States Department of Health and Human Services, 2020a). ## Recommendations ## Policy The policy recommendations for the future are based on the evidence to date but will require ongoing monitoring and development of telehealth as it becomes more widespread and embedded into routine primary care. We recommend the following: 1. Payment policy should support provision of primary care services provided by RN's, APRNs and other members of the health care team, particularly those that replace other services, diminish low value and unnecessary care, and support costeffective, high-quality outcomes. 2. Patient cost sharing should be designed to maximize access to telehealth services that address patient needs and reduce use of expensive downstream care. 3. Primary care services delivered through telehealth should be subject to the same standards, regulations, and quality expectations as visits as in person visits. 4. Telehealth technology and platform must be subject to the same stringent privacy regulation as in person care. 5. Federal funding is essential to enable widespread broad band expansion with particular attention to rural, low income, and special needs populations. 6. Federal research funding should prioritize the use and effectiveness of telehealth in primary care addressing key national health priorities. ## Nursing education 1. Schools of Nursing should invest in telehealth resources for the provision of telehealth clinical learning experiences across the curriculum. 2. Current knowledge and practices in telehealth should be incorporated in nursing curriculum at the pre-licensure and advanced levels of nursing education, inclusive of the ethical obligation to prevent fraud and abuse. 3. Current Clinicians should have ongoing opportunities for learning of the latest telehealth applications for primary care. 4. Evidence-based frameworks for the evaluation of telehealth in nursing and health care practice need to be developed. 5. Telehealth has arrived, demonstrated acceptance from providers and patients, and now must be integrated into health policy, payment and nursing education to ensure long term viability and improve patient-centered care for all consumers and providers of primary care. 2012credentialing and privileging process for that distantly located institution. [table] Table 1 -: Key Benefits and Barriers to the Use of TelehealthBenefits BarriersPatients can receive most elements of preventive care, ongoing care, education, counseling, therapeutic services, care management and coaching without leaving their home 1. Economic disparities impacting access to equipment such as computers, tablets, and smart phones. [/table]	None	http://www.nursingoutlook.org/article/S002965542100227X/pdf	None
c5b532800e4d039c1c357ac58fcd32215c065a8c	pubmed	Guidelines: Anaesthesia in the context of COVID-19 pandemic☆☆☆	Guidelines: Anaesthesia in the context of COVID-19 pandemic☆☆☆ # Introduction The outbreak of COVID-19 (SARS-CoV-2) has been spreading globally outside the first Chinese outbreak since January 2020 and the World Health Organization (WHO) declared a pandemic situation on . The epidemic situation has led to a drastic reduction in hospital activities. The evolution of the pandemic allows us to resume some of these activities. Beyond this resumption, the persistence of the virus defines a new situation that will have to be taken into account for the care of patients in the coming months. The size and type of activities that will resume depend on many factors outside the organisation of care within our establishments. These factors include the availability of personal protective equipment, anaesthesia/critical care drugs, and critical care beds. Finally, it seems important to point out that the epidemic situation is fluctuating not only in time but also in space, so it will be necessary to modulate the recommendations according to the region of exercise and the incidence of COVID-19 cases. We need to organise access to this care by meeting a dual imperative: 1) providing access to quality care for patients whose procedures cannot (or can no longer) be postponed, and 2) limiting the risk of contamination of these patients and healthcare professionals. The choice of specific measures to be implemented for the management of a patient in this context will be guided by the risk associated with the patient and the risk associated with the procedure. The persons at risk of serious forms of COVID-19 are:  people aged 70 years and over (although people aged 50 to 70 years should be monitored more closely);  people with a history of cardiovascular disease: complicated high blood pressure, history of stroke or coronary artery disease, heart surgery, NYHA stage III or IV heart failure;  insulin-dependent diabetics who are unbalanced or have secondary complications;  people with chronic respiratory disease that may decompensate for a viral infection;  people with morbid obesity (body mass index > 30 kg/m 2 ).  Concerning the risk related to surgery, two situations have been identified:  surgery with a high risk of contamination of caregivers by aerosolisation of SAR-CoV-2 (intervention with opening or exposure of the airways: lung resection surgery, ENT surgery, neurosurgery of the base of the skull, rigid bronchoscopy);  major surgery, with a high risk of postoperative critical care stay, where the perioperative respiratory risk inherent to surgery and anaesthesia is likely to be increased by SAR-CoV-2 infection or even porting. ## Purpose of the recommendations The objective of these guidelines is to produce a framework to facilitate the partial and gradual resumption of intervention activity in the context of the COVID-19 pandemic. The group has endeavoured to produce a minimum number of recommendations to highlight the strengths to be retained in the 7 predefined areas. The basic rules of universal good medical practice in perioperative medicine were considered to be known and were therefore excluded from the recommendations. ## Fields of the recommendations The recommendations made concern 7 fields: to the drafting of the recommendations to adopt a format of expert opinion. The recommendations were then drafted using the terminology "experts suggest doing" or "experts suggest not doing". Proposed recommendations were presented and discussed one by one. The aim was not to necessarily arrive at a single, convergent expert opinion on all the proposals, but to identify points of agreement and points of divergence or indecision. Each recommendation was then evaluated by each of the experts and subjected to an individual rating using a scale ranging from 1 (complete disagreement) to 9 (complete agreement). The collective rating was based on a GRADE grid methodology. In order to validate a recommendation, at least 70 per cent of the experts had to express a favourable opinion, while less than 20 per cent expressed an unfavourable opinion. In the absence of validation of one or more recommendations, the recommendation(s) was/were reformulated and submitted again for scoring with the aim of reaching consensus. The experts' synthesis work resulted in 51 recommendations. After one round of scoring, a strong agreement was reached for 100% of the recommendations and algorithms. In order to protect them during this pandemic, strict safety measures should be implemented. These measures should be carried out all throughout the patient's healthcare pathway: preanaesthetic assessment, operating theatres, recovery rooms, intermediate care units and critical care units. These safety measures will be implemented directly by providing healthcare professionals with adequate PPE, but also indirectly by supplying patients with the right equipment. Administrative measures (patient information, preoperative laboratory testing, check-up modalities, anaesthesia modalities, dedicated healthcare pathways, patient and surgery selection), which also help protecting staff members, will be detailed in the following/other chapters. Staff members should apply strict social and physical distancing measures when not caring for patients (team rounds, discussions about patients, hand-offs, breaks, meals...): they must keep at least 1 to 2 meters apart from one another, especially during times when wearing a mask is not possible. ## Preanaesthetic assessment/check-up ## R1.2.1 -experts suggest that all patients coming in for a preanaesthetic assessment perform hand disinfection using alcohol-based hand sanitiser and put on a surgical mask type II/IIR when entering a hospital. This also applies to kids for whom fitted masks should be provided. ## R1.2.2 -during preanaesthetic assessment, experts suggest performing hand hygiene using Page 11 of 57 J o u r n a l P r e -p r o o f 11 alcohol-based hand sanitiser before and after every contact with the patient or his surroundings, in addition to wearing a surgical mask type II or IIR and eye protection (goggles) during any clinical examination which requires the patient to take off his mask.  Setting up a safety distance in addition to specific physical distancing devices (like temporary plexiglass barriers, interphones…) for those whose work position requires them to be in physical proximity to other people. These devices should be cleaned frequently, following the same cleaning procedures that are used on other surfaces;  Removing magazines, documents and other commonly used objects from waiting rooms and common areas, including children's toys; ## R1.2.3 -experts  Regularly cleaning surfaces (counters, computers, phones...) and equipment (blood pressure cuffs, pulse oximeter, stethoscopes…) after each patient. ## Rationale During this COVID-19 pandemic, every patient could potentially be contaminated and should therefore protect other patients and hospital staff by applying alcohol-based hand gel and wearing a surgical mask type II or IIR. [bib_ref] COVID-19 Infection: Implications for Perioperative and Critical Care Physicians, Greenland [/bib_ref] [bib_ref] Protecting health-care workers from subclinical coronavirus infection, Chang [/bib_ref] By blocking large droplets, surgical masks protect staff members from droplet and contact transmission.Surgical masks can provide protection for healthcare professionals against droplet transmission within a one-meter radius of the patient. Four RCTs compared the efficiency of N95 or FFP2 masks and surgical masks in healthcare workers performing non aerosol-generating procedures. 5-8 A meta-analysis including these studies reported no significant difference in the occurrence of viral respiratory infections (RC 1,06; 95% IC 0, [bib_ref] Presumed Asymptomatic Carrier Transmission of COVID-19, Bai [/bib_ref] between the 2 types of mask.Only one study specifically evaluated coronaviruses and reported no significant difference between the 2 types of masks in non-aerosol generating procedures. [bib_ref] A Randomized Clinical Trial of Three Options for N95 Respirators and Medical..., Macintyre [/bib_ref] 1.3. Operating theatre 12 R1.3.1 -Experts suggest that healthcare professionals involved in airway management (intubation, extubation, supraglottic airway insertion and/or removal…), or those who could be brought to do so in some given situations, wear a fit tested respirator mask (Respirator N95 or FFP2 standard, or equivalent) in addition to a disposable face shield or at least, in the absence of the latter, safety goggles, regardless of the patient's COVID-19 status [fig_ref] Table 1: Personal protective equipment [/fig_ref] ## Rationale There is a great risk of becoming infected during airway management. Therefore, strict safety measures should be applied during aerosol-generating procedures such as bag mask ventilation, endotracheal intubation, open/endotracheal suctioning and extubation. The use of a respirator FFP (filtering face piece mask) type 2 is recommended by the French Society of Hospital Hygiene (SF2H) and the French-Speaking Society of Infectious Disease for all healthcare professionals manipulating the airway. Respirators are tight fitting masks, designed to create a facial seal that protect the person wearing them from droplets and airborne particles inhalation. However, wearing this type of mask can bring more discomfort than wearing a surgical mask (overheating, Page 13 of 57 J o u r n a l P r e -p r o o f 13 respiratory resistance...). They have the advantage of blocking at least 94% of aerosol particles (total inward leaking < 8%) and are more effective than surgical masks type II/IIR in blocking < 5 µm particles.Nonetheless, a poorly fitted N95 or FFP2 respirator does not protect more than a surgical mask. A leak test must be performed systematically. Furthermore, a beard (even a stubble one) reduces the mask's adherence to the face and thus decreases its global efficiency. In case of N95 or FFP2 respirators shortage, some experts suggested using N99 or FFP3 respirators which block at least 99% of aerosol particles (total inward leaking < 2%). However, the problem with these respirators in that the air is most often exhaled through an expiratory valve without being filtered. They do not filter the wearer's exhalation, only the inhale. This one-way protection puts others around the wearer at risk, in a situation like COVID-19. COVID-19 can also be transmitted by aerosol contact with conjunctiva 12 and lead to a respiratory infection. [bib_ref] Ocular Tropism of Respiratory Viruses, Belser [/bib_ref] The fact that unprotected eyes increase the risk of transmission has been demonstrated with coronaviruses. 14 Face shields provide a barrier against high velocity aerosol particles and are commonly used as alternatives to safety goggles as they provide greater face protection.Using a droplets simulator loaded with influenza viruses (mean droplet diameter: 3.4 µm) and a breathing simulator, it was demonstrated/shown that the use of a face shield reduces the risk of aerosol inhalation by 70%. [bib_ref] Efficacy of Face Shields Against Cough Aerosol Droplets from a Cough Simulator, Lindsley [/bib_ref] When spraying fluorescent dye (particle diameter = 5 µm) from a distance of 50 cm towards a mannequin head equipped with an N95 respirator and a face shield, no contamination was noted in either nostrils nor eyes nor mouth folds. The same researchers found that using safety goggles in combination with an N95 respirator did not prevent some eye contamination.Face shields also contribute to sparing N95 or FFP2 respirators by limiting their contamination with aerosol projections. N95 or FFP2 respirators can be used for up to 8 hours. ## R1.4.4 -experts suggest maintaining a minimal one-meter distance between each patient in recovery rooms during the pandemic period, and a minimal distance of 7-8 meters if an extubation is performed in the recovery room. ## Rationale Whenever possible, in order to spare N95 or FFP2 respirators and to protect staff members and other patients, extubation should be performed in the operating theatre by the person who performed the intubation. If this is not possible, the same precautions should be taken in the recovery room for staff protection. In the latest World Health Organization (WHO) recommendations for COVID-19, health care personnel and other staff are advised to maintain a one-meter distance away from a person showing symptoms of disease.The Centre for Disease Control and Prevention recommends a two-meters separation.However, these distances are based on estimates of range that have not considered the possible presence of a high-momentum cloud carrying the droplets long distances Recent work has shown that exhalations, sneezes and coughs emit turbulent multiphase flows that can contain pathogen-bearing droplets of mucosalivary fluid. [bib_ref] Visualization of sneeze ejecta: steps of fluid fragmentation leading to respiratory droplets, Scharfman [/bib_ref] When sneezing or coughing, these droplets/gas clouds can travel in the air for up to 7 to 8 meters. [bib_ref] Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission..., Bourouiba [/bib_ref] This new understanding of respiratory emissions dynamics has implications on social distancing strategies during the COVID-19 pandemic. Similarly, swabs taken from air exhaust outlets in COVID+ patients' rooms were found to contain RNA fragments, suggesting that small virus-laden droplets may be displaced by airflows. However, in this study, no viral culture was done to demonstrate virus viability. For these reasons, extubation should remain exceptional in the recovery room, and giving out surgical masks type II/IIR to patients after their extubation is essential.  Administration of nebulised treatment by a device other than vibrating membrane nebulisers. R1.5.3 -When the patient's COVID-19 status is unknown, experts suggest using a closed suction system for tracheal suctioning. If this system is unavailable, it is necessary to interrupt the patient's ventilation during suctioning, ideally with the help of a second operator. ## Rationale Respiratory droplets are the main source of contamination in healthcare professionals. 2 During aerosol-generating procedures, there is a consensus on the efficiency of N95 or FFP2 respirators (see questions 1.3) and the wear of protective gear such as a fluid resistant long-sleeved gown or a combination of a conventional gown and a plastic apron. 10,The number of asymptomatic patients carrying the virus is high [bib_ref] Presumed Asymptomatic Carrier Transmission of COVID-19, Bai [/bib_ref] , which is why caregivers should systematically use protection during high-risk procedures. 10,24,25 1.6. Paediatric particularities R1.6.1 -Experts suggest allowing only one parent to be present during kids' preanaesthetic assessment. ## R1.6.2 -experts suggest that all clinical anaesthesia personnel wear a surgical mask type ii or iir, safety goggles and gloves, when performing any procedure with a high transmission risk, particularly when examining the oral cavity. R1.6.3 -Experts suggest wearing an N95 or FFP2 respirators, a head cap, a gown with an apron, gloves and a face shield or, failing that, protective goggles, when performing airway procedure in children who are awake in the recovery room, regardless of their COVID status. ## Rationale During this COVID-19 pandemic, applying enhanced safety measures for the paediatric population is justified due to the existence of a significant proportion of possibly asymptomatic COVID+ children (up to 16% depending on the series) and the likely difficulty in complying with social distancing and safety measures (difficulty of continuous wearing of the surgical mask) by children. [bib_ref] Coronavirus Infections in Children Including COVID-19: An Overview of the Epidemiology, Clinical..., Zimmermann [/bib_ref] [bib_ref] Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Children and Adolescents:..., Castagnoli [/bib_ref] [bib_ref] SARS-CoV-2 Infection in Children, Lu [/bib_ref] These findings imply that anaesthesia staff should wear a surgical mask type II/IIR, protective goggles (or a face shield) and gloves when performing any procedure with a high risk of transmission, and particularly when examining the oral cavity during anaesthesia consultation. ## Benefit and risk of operating, and patient information R2.1 -In asymptomatic patients, during a COVID-19 pandemic, experts suggest evaluating the benefit/risk ratio of the intervention according to criteria related to the patient, the pathology and the procedure [fig_ref] Table 2: Criteria for assessing the benefit / risk ratio of surgical intervention in... [/fig_ref]. ## Rationale The circulation of SARS-CoV-2 in the population and the existence of asymptomatic carriers affect the risk-benefit ratio of performing a planned surgical procedure during the COVID-19 pandemic and require rigorous evaluation. This consideration must integrate three types of criteria related to the patient, the pathology and the procedure. The data in the literature, although heterogeneous and with a low level of evidence, identify several patientrelated risk factors for serious forms of COVID-19 potentially associated with an increase in postoperative complications: ASA class, obesity, age (> 65 years, < 1 year), underlying respiratory (asthma, COPD, cystic fibrosis) or cardiovascular (hypertension, coronary artery disease and chronic heart failure) pathology, obstructive sleep apnoea syndrome, diabetes, and immunosuppression. [bib_ref] How to risk-stratify elective surgery during the COVID-19 pandemic?, Stahel [/bib_ref] [bib_ref] Medically Necessary, Time-Sensitive Procedures: Scoring System to Ethically and Efficiently Manage Resource..., Prachand [/bib_ref] This increase in perioperative risk is, however, offset by the potential deleterious effect of cancelling or postponing the procedure on the patient.The loss of chance in the absence of intervention must be estimated and the effectiveness and availability of therapeutic alternatives (curative or waiting) explored. Finally, two types of factors related to the surgical procedure must be considered: resource utilisation and the risk of transmission of CoV-2-SARS to the healthcare team. Surgical time and expected length of stay provide an indication of the staff and hospital resources required. For each intervention, the foreseeable use of postoperative management in a critical care area must be anticipated in order to adapt surgical activity to the supply available at the time. Transfusion needs must also be assessed due to the difficulties of public access to blood donation collection points. The number of personnel required must be taken into account as it increases the risk of contamination of the health care team due to the impossibility of complying with the recommendations for intraoperative distancing. Finally, the risk related to the type of anaesthesia and the type of surgery must be evaluated. Upper airway management has been identified as a high-risk event for potential transmission of the aerosolised airway secretion virus that persists several minutes after the procedure. [bib_ref] Aerosol Generating Procedures and Risk of Transmission of Acute Respiratory Infections to..., Tran [/bib_ref] [bib_ref] Risk Factors for SARS Transmission from Patients Requiring Intubation: A Multicentre Investigation..., Raboud [/bib_ref] The same risk is observed for upper aerodigestive tract and thoracic procedures. Finally, the risk related to the surgical site must take into account the probability of postoperative mechanical ventilation, the consequences of which could be aggravated in the context of an infection, or even portage, with SARS-CoV-2. ## R2.2 -experts suggest informing, orally and in writing, the patient and/or his legal representatives of the specific circumstances related to the covid-19 pandemic. in particular, information regarding the evaluation of the risk/benefit ratio related to the intervention and the anticipated patient path should be delivered. this information should be written in the patient's medical records (appendix #1, #2 and #3). ## Rationale During the preanaesthetic consultation, detailed information must be provided to the patient and/or his/her legal representative about the perioperative strategy decided regarding his specific situation in the context of COVID-19 pandemic. The message must be clear, objective and based on the currently available data, while trying to be reassuring for the patient and/or his legal representative. This message must be given orally during the consultation but also disseminated through a document (established and validated by each structure), which can be given to the patient and/or his legal representative during the preoperative consultation (surgical or preanaesthetic). This information must appear in the medical record. In the appendix, based on current data, we propose examples of model documents (Appendix 1, 2 and 3). In the event of cancellation or postponement of the intervention, it is essential to keep in touch with the patient, mostly through the surgical teams, and to reassess the possible alternatives and the feasibility of the procedure according to the evolution of the circumstances. If the decision of postponement or cancellation of the surgery is taken by the patient, it must be recorded in the medical record. ## Preoperative assessment and decision regarding surgery ## R3.1.1 -experts suggest using a standardised questionnaire to search for symptoms compatible with a sars- ## Cov-2 infection before any surgery in adults and children (appendices #4 and #5). ## Rationale The use of a standardised questionnaire increases the completeness of the symptom collection and the reproducibility of the medical examination. It is an appropriate tool for collecting accurate information from a large number of subjects. The data collected are easily quantifiable and traceable. The essential qualities of such a questionnaire are acceptability, reliability and validity. The questions must be formulated to be understood by the largest number of patients, without ambiguity, and be based on validated items. Because of the wide variety of symptoms attributable to the SARS-CoV-2, the questionnaire should be designed to look for the most frequent symptoms (fever, dry cough, etc.) and/or the most evocative ones (anosmia, ageusia, etc.), without however declining all the unusual symptoms that have been reported in the literature. An example of a standardised questionnaire distinguishing between major and minor symptoms is proposed for adults in the Appendix #4 and for children in the Appendix #5. ## R3.1.2 -in adults and children, the experts suggest searching systematically symptoms compatible with a sars- CoV-2 infection at the minimum during the preanaesthetic consultation/teleconsultation and during the preanaesthetic visit. Whenever possible, searching symptoms during a phone call with the patient or his legal representative 48-72 hours before the intervention is also recommended to avoid a last-minute postponement of surgery. ## Rationale Assessment of specific perioperative risk during the COVID-19 pandemic requires, as in the usual situation, the joint consideration of the surgical, patient and anaesthetic risks. In addition, searching usual and/or evocative symptoms of SARS-CoV-2 infection is an important time of the preanaesthetic consultation in the current pandemic context and during the first months following the easing of the lockdown. The presence of major (i.e., very frequent or relatively characteristic) and/or minor (i.e. more inconsistent and/or less specific) symptoms allows to orient the preoperative COVID-19 status assessment, and then to estimate the benefit/risk balance of maintaining or postponing the surgery, taking into account the risk of contamination of health personnel and others patients within the care structure. [bib_ref] Clinical and Transmission Characteristics of Covid-19 -A Retrospective Study of 25 Cases..., Li [/bib_ref] The integration of these different risks must be collectively weighed against the potential consequences of postponing or cancelling a scheduled intervention.This search for symptoms compatible with a SARS-CoV-2 infection must take place at the time of the preanaesthetic consultation in order to discuss the postponement of the intervention, if possible, and to anticipate the protective measures that should be applied for the health personnel, and the care circuit that should be used. The questionnaire can be completed by the patient himself, by a nurse just before the consultation or by the anaesthesiologist during the consultation. Then, it must be explained that the patient must immediately contact the anaesthesia team, without waiting for admission to the hospital, in case one or more symptoms compatible with a SARS-CoV-2 infection appear between the preanaesthetic consultation and the day of the intervention. It will also be necessary to explain the importance of the strictest compliance with protective measures, particularly hand-washing and wearing systematically a face mask outside home, between the preanaesthetic consultation and the day of the intervention. If the local organisation allows it, a contact with the patient 48 to 72 hours prior to its admission to the hospital, to ensure that no symptoms have appeared, can also be planned. This timeframe can be adapted locally, the objective of this contact being to have a PCR performed and its results available before coming to the hospital for surgery if the patient has become symptomatic since the preanaesthetic consultation. However, taking into account that the delay between the preanaesthetic consultation and the intervention may correspond to the incubation period of the disease, and that spontaneous reporting by the patient of the onset of symptoms since the consultation will not be systematic nor exhaustive, the search for these same symptoms must be systematically renewed during the "physical" preanaesthetic visit the day before or on the day of surgery. ## R3.1.3 -in adults and children ## Rationale Fever, although non-specific, is a very common symptom of symptomatic SARS-CoV-2 infections, present in 75% to 95% of cases. [bib_ref] Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia..., Chen [/bib_ref] [bib_ref] Clinical features of COVID-19 in elderly patients: A comparison with young and..., Liu [/bib_ref] [bib_ref] Sah R: Clinical, laboratory and imaging features of COVID-19: A systematic review..., Rodriguez-Morales [/bib_ref] The presence of fever is a major symptom and an important warning sign that should raise the suspicion of a possible SARS-CoV-2 infection during the current pandemic. However, since the sensation of fever is highly imperfectly correlated with the temperature objectively measured, [bib_ref] Accuracy of perception and touch for detecting fever in adults: a hospital-based..., Singh [/bib_ref] it is suggested that patient's temperature should be measured during the preanaesthetic consultation. In addition, antipyretic drug intake should also be systematically collected at the same time as the temperature measurement because acetaminophen (or even NSAIDs when taken as self-medication by the patient) can normalise the patient's temperature. As the delay between the pre-anaesthetic consultation and the intervention may correspond to the incubation period of the disease, an objective measurement of the patient's temperature must be renewed during the preanaesthetic visit the day before or on the day of the intervention. [fig_ref] 6. 1: Which specific pathway for the management of COVID+ patients? R6 [/fig_ref] for the preoperative COVID-19 status assessment and perioperative strategy before scheduled or emergency surgery. ## R3.1.4 -in adults, the experts suggest using the following 2 algorithms ## Rationale These 2 algorithms are the result of a work that tried to take into account a maximum number of clinical situations in a maximum number of structures, while trying to keep it simple. If local provisions, linked to access to diagnostic tests, to the typology of patients, to the prevalence of the virus in the geographical area concerned, or to an agreement between the different specialties at the local level, have led to propose a local algorithm different from those proposed, we suggest that the local algorithm may take precedence over those proposed here. If the patient presents with signs compatible with a SARS-CoV-2 infection but that the PCR is negative, the evocative paraclinical signs are absent, the CT-scan shows no signs of SARS-CoV-2 viral pneumonia, and the serology performed after at least 7-10 days of symptoms is negative, a differential diagnosis is then the most likely, and the intervention will be postponed until this other pathology has recovered. In a completely asymptomatic patient, a distinction should be made between: 1) surgeries with opening or exposure of the airways (ENT surgery, thoracic surgery, oral surgery, surgery of the base of the skull, rigid bronchoscopy, etc.) for which there is a significant risk of aerosolisation for the operating theatre staff, motivating the realisation of a PCR even in an asymptomatic patient as long as the virus is circulating in the population; and 2) surgeries for which a SARS-CoV-2 infection could have serious postoperative consequences, thus motivating PCR testing. These surgeries can probably be summed up as "major" surgeries (open-heart surgery, major abdominal or pelvic surgery, organ transplantation, etc.), particularly due to their frequent respiratory impact, since the risk of synergy between SARS-CoV-2 and perioperative lung injury is not known. To date, this preoperative screening for COVID-19 indicated by the type of surgery is based on PCR and there is no indication to perform a thoracic CT scan in this context. In these two situations, the PCR will ideally be performed in the 24 hours preceding the intervention, at most 48 hours, in order to have an idea of the viral carriage as close as possible to the high-risk procedure while taking into account the time required to obtain the results in each structure in order to have them available before the intervention. Finally, non-major surgeries in an asymptomatic patient can be performed in a conventional non-COVID-19 circuit.If possible, it is suggested that the close contacts of these patients (such as the immediate neighbours in the postoperative recovery room) should be traced to facilitate contact tracing if the patient develops symptoms consistent with SARS-CoV-2 infection in the days following surgery. It should be noted that if the presence of antibodies in the plasma of a convalescent patient 7 to 10 days after the onset of symptoms has been reported, the positivity of the serology is sometimes later (up to several weeks). In addition, the antibody titre and their neutralising character against SARS-CoV-2 may vary depending on the patient. [bib_ref] Haagmans BL: Severe Acute Respiratory Syndrome Coronavirus 2−Specific Antibody Responses in Coronavirus..., Okba [/bib_ref] [bib_ref] Diagnostic Testing for Severe Acute Respiratory Syndrome-Related Coronavirus-2: A Narrative Review, Cheng [/bib_ref] [bib_ref] Evolving status of the 2019 novel coronavirus infection: Proposal of conventional serologic..., Xiao [/bib_ref] [bib_ref] Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum..., To [/bib_ref] [bib_ref] Value of Diagnostic Testing for SARS-CoV-2/COVID-19, Patel [/bib_ref] Furthermore, diagnostic performances vary greatly depending on the type of kit used in the laboratory. Finally, the neutralising character of the detected antibodies depends on the viral antigens against which the detected antibodies are directed. [bib_ref] Haagmans BL: Severe Acute Respiratory Syndrome Coronavirus 2−Specific Antibody Responses in Coronavirus..., Okba [/bib_ref] [bib_ref] Diagnostic Testing for Severe Acute Respiratory Syndrome-Related Coronavirus-2: A Narrative Review, Cheng [/bib_ref] [bib_ref] Evolving status of the 2019 novel coronavirus infection: Proposal of conventional serologic..., Xiao [/bib_ref] [bib_ref] Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum..., To [/bib_ref] [bib_ref] Value of Diagnostic Testing for SARS-CoV-2/COVID-19, Patel [/bib_ref] Consequently, the only place of serology in the diagnostic strategy to date is in addition to a chest CT-scan and a new PCR sample if the first PCR in a symptomatic patient is negative and the symptoms have been evolving for at least 7 to 10 days. New data may change its place in the diagnostic algorithm in the future, especially if it allows the formal detection of patients who are genuinely cured and protected against re-infection, so that surgery can be performed without risk for the patient and staff. ## For emergency surgery (figures 2): By definition non-deferrable, the surgery has to take place. However, PCR sampling should be performed in symptomatic or mildly symptomatic patients who have had close contact with a COVID-19 patient within the last 15 days, or who themselves have risk factors for severe forms of COVID-19 or are operated from surgery with postoperative respiratory risk. Surgery is performed without waiting for the results. In the case of major surgery, a postoperative surveillance in the intensive care unit (potentially already justified by the complexity of the surgery and/or the patient's comorbidities) may be considered, especially in a symptomatic patient, as a risk of synergy between perioperative lung injury and infection/carry of SARS-CoV-2 cannot be excluded at this time. ## R3.1.5 -paediatric specificity: in children scheduled for a surgical procedure in a conventional hospital setting, given the large number of asymptomatic forms of cov-2-sars infection, experts suggest that a pcr screening test be routinely performed in the hours prior to the procedure (appendix 6). when the child is scheduled for an outpatient procedure, the experts suggest that the COVID-19 status should be sought, at a minimum by using the standardised questionnaire (paediatric version, Appendix 5) at the call on D-1. If the interview proves positive, the procedure is rescheduled at least 15 days later. If the questioning does not appear to be interpretable, the child will, depending on the degree of urgency of the procedure, either be rescheduled or hospitalised with a PCR screening test. ## Rationale Severe forms of COVID-19 are uncommon in children compared to adults, with an estimated incidence of resuscitation of 0.6% of symptomatic forms. [bib_ref] Systematic review of COVID-19 in children shows milder cases and a better..., Ludvigsson [/bib_ref] Clinical manifestations are generally limited to a mild form with fever, myalgia, dry (or productive) cough, runny nose and digestive disorders (nausea, vomiting, diarrhoea, abdominal pain) in 54% of cases. [bib_ref] Systematic review of COVID-19 in children shows milder cases and a better..., Ludvigsson [/bib_ref] [bib_ref] Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19)..., Qiu [/bib_ref] [bib_ref] Epidemiology of COVID-19 Among Children in China, Dong [/bib_ref] Finally, more specific to COVID-19 is the presence of anosmia and/or ageusia without nasal obstruction, which are strongly suggestive of this pathology. [bib_ref] COVID-19 Infection: Implications for Perioperative and Critical Care Physicians, Greenland [/bib_ref] The presence of skin signs such as pseudo frostbite or urticarial elements are also signs suggestive of COVID-19 in children and adolescents. In all cases, the majority of reported paediatric cases are familial in origin and a history of COVID-19 in the family environment should be considered a risk factor for this disease in children, even if the child is asymptomatic. [bib_ref] Pediatric anesthetic implications of COVID-19-A review of current literature, Lee-Archer [/bib_ref] [bib_ref] Pediatric Airway Management in COVID-19 patients -Consensus Guidelines from the Society for..., Matava [/bib_ref] Radiological signs are identical to those in adults but are inconsistently found (43% of cases on average) and therefore do not contribute much to the diagnosis in this population. [bib_ref] Pediatric anesthetic implications of COVID-19-A review of current literature, Lee-Archer [/bib_ref] [bib_ref] Pediatric Airway Management in COVID-19 patients -Consensus Guidelines from the Society for..., Matava [/bib_ref] The same limitation applies to pulmonary ultrasonography given the lack of studies in the paediatric population. [bib_ref] Proposal for International Standardization of the Use of Lung Ultrasound for Patients..., Soldati [/bib_ref] Biologically, the published series show lymphopenia or hyperlymphocytosis associated with increased CRP. [bib_ref] Pediatric anesthetic implications of COVID-19-A review of current literature, Lee-Archer [/bib_ref] It is important to note that recent studies conducted on cohorts of individuals on an epidemiological basis tend to show that for one person expressing the disease, 7 people are asymptomatic, which reflects the limitations of the clinic to screen all potentially contaminating patients (prepublication study 1) [9-10]. Taking into account these elements and the asymptomatic or paucisymptomatic nature of the disease, the problem of the preoperative assessment in paediatrics is above all that of diagnosing this pathology in children, given the risks incurred by caregivers (representing between 3 and 15% of COVID-19 infections) [bib_ref] A Randomized Clinical Trial of Three Options for N95 Respirators and Medical..., Macintyre [/bib_ref] , but also that of nosocomial contamination of other patients given the particularly high number of reproductions of this condition (between 2 and 3.5). [bib_ref] Pediatric anesthetic implications of COVID-19-A review of current literature, Lee-Archer [/bib_ref] [bib_ref] Pediatric Airway Management in COVID-19 patients -Consensus Guidelines from the Society for..., Matava [/bib_ref] In the same vein, ambulatory surgery should in theory be favoured in order to avoid cases of nosocomial contamination. It is therefore proposed to perform a PCR test for the virus for each paediatric patient before surgery. ## J o u r n a l p r e -p r o o f 23 In the context of the emergency department, PCR is carried out on admission of the child, but surgery can be performed before the results are obtained. ## Preanaesthetic patient assessment R4.1.1 -During COVID-19 crisis, the experts suggest that telemedicine is an alternative to face-to-face consultation and must be used to reduce patient in-visit. ## Rationale The current outbreak of COVID-19 has placed a heavy burden on global medical systems, particularly with regard to the preoperative assessment of patients for surgery. For all elective surgeries in France and in many countries for major surgery, preoperative physical assessment by physicians had become a standard of care. The current crisis has reduced this possibility because patients should not be exposed to potentially contagious structures. In For patients, prior agreement to carry out a telemedicine evaluation is a mandatory step. It is advisable to send beforehand a guide to prepare the teleconsultation (including: connection modalities, health questionnaire on current treatments, information documents...) to facilitate the smooth running of the consultation. If necessary, a person close to the patient or an interpreter may, if present during the TLC, assist the doctor in carrying data of the clinical examination within the limits of his or her competence. Not all patients desire remote evaluation, and the exact reasons for this have not been elucidated. Patient selection is an important step for virtual preoperative evaluation. For example, patients in whom arranging travel is complicated underwent successful telemedicine preoperative evaluation before oral and maxillofacial surgery with no complications, highlighting this patient population as one in whom remote evaluation may be beneficial. The use of telemedicine preoperative evaluation has been studied in a variety of patient populations. All types of surgery can be performed with telemedicine evaluation but major surgery (cardiac, vascular, thoracic, etc.) and patients with many comorbities or treatment are obstacles to the development of this technique. Similarly, patients must be able to connect to a platform and know how to use the software. Failure to undergo a preoperative anaesthesia evaluation may contribute to day of surgery cancellation, which has a negative financial impact on both patients and hospitals. Up to 25% of day of surgery cancellations are due to inadequate preoperative workup, and it is well established that preoperative clinics reduce risk of such cancellations and delays. With telemedicine, we found a 1.3% last minute cancellation rate, consistent with the international average, in patients who underwent telehealth evaluation as opposed to an in-person visit, thus suggesting an equivalent performance between the 2 evaluation options. Teleconsultation is carried out using tools that guarantee the security of patient data. It is carried out in conditions that must guarantee : Authentication of the healthcare professionals involved in the procedure; Identification of the patient; Access by healthcare professionals to the patient's medical data required to perform the procedure; Access by the patient to the patient's medical data required to perform the procedure. Informed consent is an important factor in surgery and telemedicine itself is no different. The evaluation of the practices is advised to optimise these new modalities. ## Modalities of anaesthesia and analgesia As stated in the introduction, in the context of the COVID-19 pandemic, the resumption of surgical activity is subject to several major limitations: the strain on the supply of certain anaesthesia drugs, the change in hospitalisation capacities, the risk of contamination of healthcare providers and patients and the application, throughout the patient's journey, of the "distancing" principle. In addition, some peculiarities of COVID-19 patients (risk of drug interactions, worsening of the condition, etc.) are to be taken into account. These limitations lead us to propose an adaptation of anaesthesia procedures. Favour strategies that reduce the exposure of health professionals to a risk of contamination while maintaining optimal safety conditions for the patient is one of the most important objectives. When safety conditions are met (especially for postoperative follow-up), outpatient management should probably be prioritised. ## Is it necessary to adapt the anaesthesia modalities? ## R5.1.1 -in a context of resumption of surgical activity and covid-19 pandemic, experts suggest that drug-saving anaesthetic strategies (for propofol, midazolam, myorelaxants) should be preferred in adults and children. R5.1.2 -Experts suggest giving priority whenever possible to regional anaesthesia. Regional analgesia and infiltration techniques should also be considered. ## Rationale Tensions on drug stocks and even shortages of drugs such as propofol, midazolam, atracurium, cisatracurium or rocuronium require the choice of anaesthesia protocol that spares these drugs, which are otherwise subject to quotas. To do so, the experts propose several principles: -Prefer regional anaesthesia (RA) for anaesthesia and analgesia, rather than general anaesthesia. In the context of -Peripheral and topical local anaesthesia allow postoperative follow-up directly in the room or in a dedicated space, without going through the recovery room in accordance with regulations. This facilitates compliance with distancing measures specific to the current epidemic context. [bib_ref] Use of cerebral monitoring during anaesthesia: Effect on recovery profile, White [/bib_ref] In children, since RA techniques are regularly associated with general anaesthesia or sedation, they do not make it possible to bypass the recovery room. -When GA is required, inhaled anaesthesia should probably be preferred in this context to intravenous targetcontrolled anaesthesia. -Monitoring of the depth of anaesthesia when possible, and of curarisation may be required in order to best adapt drug dosages.These recommendations apply to both elective and emergency care. In conjunction with the institution's pharmacy, it is important to monitor local stock trends. ## Are there any particularities for airway management? ## R5.2.1 -regarding airway management during intubation of a covid+ or highly suspicious patient, the experts refer to the "expert recommendations on the resuscitation management of patients during sars-cov-2 epidemics" published by the SRLF-SFAR and to the "airway management principle" sheet, which are also applicable in the operating theatre. ## Rationale During the COVID-19 pandemic period, the intubation of a COVID+ patient in the operating theatre is based on the same rules as those issued in critical care units, due to the risk of spraying of the virus during this risky procedure. In order to minimise the risk of aerosolisation and contamination of personnel, it is necessary to: -Limit the number of staff present in the operating theatre -Avoid ventilating the patient with a face mask during the preoxygenation phase. -Stop oxygen before removing the bag valve mask. -Intubate the patient by the most experienced senior using a video laryngoscope -Connect the ventilator after inflating the intubation tube balloon. ## R5.2.2 -experts suggest that rapid sequence induction is preferred for airway management of a covid+ or highly suspected patients. ## R5.2.3 -the experts suggest performing induction according to usual airway management for a non-covid patient. ## Rationale If general anaesthesia is required, the patient's clinical condition and COVID-19 status should be considered in the airway management strategy. -If the patient is COVID+ or highly suspected: the procedure described by SFARshould be followed with rapid sequence induction and intubation. Special attention should be paid to tracheal extubation with the same barrier precautions as for intubation. This applies to patients under emergency management when the COVID-19 status is unknown. Special attention should also be paid to hand hygiene. -If the patient is non-COVID or asymptomatic, there is no need to modify usual procedures because of the COVID-19 pandemic. Routine airway management is recommended. If intubation is chosen, conventional induction is recommended according to standard recommendations, with adaptation of the induction sequence according to haemodynamic conditions, drug contraindications, and compliance with fasting conditions and the patient's age. The frequency of anaphylaxis related to atracurium has been estimated to be 1/22451 administrations. The frequency of anaphylaxis due to fast-acting myorelaxant is about 10 times higher (succinylcholine: 1/2080 and J o u r n a l P r e -p r o o f 27 rocuronium: 1/2499). [bib_ref] Anaphylaxis Is More Common with Rocuronium and Succinylcholine than with Atracurium, Reddy [/bib_ref] The severe over-risk of allergy to the patient linked to a rapid sequence induction does not seem to be justified by the sole risk of SARS-CoV-2 contamination of the caregivers, this risk being low when protective measures are well respected (Cf. item 1). Readers are invited to refer to "Guidelines on muscle relaxants and reversal in anaesthesia".In a non-COVID patient, spontaneous ventilation anaesthesia or the use of supraglottic devices such as laryngeal masks is possible. We insist on the importance during the preoperative checklist to share with the operating theatre staff, in addition to the usual information, the COVID status of the patient which will determine his perioperative circuit and the strategy adopted by the anaesthesia team for airway management. ## Rationale ## Covid+ patients are likely to be treated with antivirals. a table of drug interactions with drugs used against sars- CoV-2 is available online from the University of Liverpool. 68 A summary is provided below for drugs frequently used in the perioperative period . The hydroxychloroquine has multiple cardiac adverse events, including significant QT prolongation. Combinations with other drugs that prolong the QT interval, frequently used in the perioperative period such as halogenated drugs, droperidol, ondansetron, or hypothermia related to surgery and anaesthesia may increase the risk of developing a serious arrhythmia, such as ventricular fibrillation. The combination of hydroxychloroquine and azithromycin, proposed by some, carries a risk of additive/synergistic QT interval prolongation. ECG monitoring is essential. In addition, the combination of lopinavir/ritonavir carries a risk of overdosage with amide type local anaesthetics (lidocaine, levobupivacaine, bupivacaine, prilocaine, mepivacaine, ropivacaine), ketamine, midazolam, sufentanil, oxycodone or tramadol due to ritonavir-related cytochrome P3A inhibition, but also to underdosage of propofol and morphine due to increased biotransformation of products metabolised by cytochrome P2C9 and P2C19 or by glucuronidation. Remdesivir, tocilizumab, and interferon beta do not show significant interactions with drugs normally used perioperatively, nor do they have cardiac effects. NSAIDs may be associated with worsening of symptoms during respiratory viruses, with an increased risk of empyema.Despite recent alerts, there is no scientific evidence to date linking NSAID use to the aggravation of SARS-CoV-2 infection. A precautionary principle applies.Thus, in a patient with an established or strongly suspected SARS-CoV-2 infection, the prescription of NSAIDs will be avoided. However, in asymptomatic patients, there appears to be no contraindication to their use if their benefit is established. [bib_ref] Misguided drug advice for COVID-19, Fitzgerald [/bib_ref] Discontinuation of corticosteroids is not recommended in patients on long-term therapy.Steroid treatment of patients with COVID-19 is controversial and is not currently recommended. [bib_ref] Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury, Russell [/bib_ref] The single intraoperative injection of dexamethasone, at the usual recommended doses, does not appear to present an over-risk in the asymptomatic patient. ## R5.5.3 -experts suggest avoiding nitrous oxide for obstetric labour analgesia during a covid-19 pandemic. ## R5.5.4 -experts suggest that neuraxial anaesthesia should be preferred for caesarean section. if general anaesthesia is indicated, experts suggest that rapid sequence anaesthesia be performed regardless of the patient's COVID-19 status. ## R5.5.5 -experts suggest avoiding the postpartum prescription of nsaids in covid+ or highly suspected women. ## Rationale In the context of COVID-19 pandemic, obstetric patients present two particularities. First, unlike scheduled surgical activities, obstetrical activity in essence cannot be postponed and therefore remained at its usual level at the peak of the pandemic. The organisation of care had to be adapted, with the establishment of specific care channels for women infected with SARS-CoV-2 or suspected of being infected, not only to optimise the care of these women, but also to avoid the contamination of other pregnant women and of caregivers working in maternity wards. These COVID-positive or suspected COVID-positive/non-COVID channels are logically maintained as long as the pandemic persists. ## Specific hospitalisation pathways The resumption of surgical activity during the COVID-19 outbreak exposes no-COVID-19 patients and healthcare workers to contamination. The following expert proposals should be discussed within each institution in a collegial manner (Extended Executive Board, Operating Theatre Committee, Healthcare Infection Control Practices Advisory Committee) and lead to protocols that take into account the specific characteristics of each institution (architectural constraints, recruitment) and the local incidence of COVID-19 infection. Appropriate signage has to be applied throughout the specific COVID-19 pathway. ## Rationale In the context of non-COVID patients management in the operating theatre, the aim of this guideline was to avoid both the occurrence of nosocomial SARS-CoV-2 infection 87 and the contamination of caregivers by asymptomatic patients. For any planned surgical procedure, the risk/benefit balance must be discussed in a multidisciplinary manner, given the probably high postoperative morbidity and mortality in this epidemic context.Management of "non-COVID" patients must be considered in a specific pathway. [bib_ref] Preparing for a COVID-19 pandemic: a review of operating room outbreak response..., Wong [/bib_ref] This pathway covers the entire patient's hospitalisation day: from the anaesthesia consultation to discharge from the hospital after surgery, following the guidelines for protection (chapter 1). ## R6.2.2 -experts suggest that for both adults and children, priority should be given to outpatient treatment and enhanced recovery after surgery as much as possible. ## Rationale In the context of COVID-19 outbreak, outpatient management should be considered and preferred to conventional hospitalisation when feasible. Outpatient management reduces the length of stay, thereby reduces the risk of patient exposure and the risk of contamination in case of asymptomatic infection. [bib_ref] The COVID-19: Role of Ambulatory Surgery Facilities in This Global Pandemic, Rajan [/bib_ref] Outpatient management of surgical emergencies should be considered whenever possible.Outpatient pathways for resumption of activity during the pandemic period need to consider several points: 1/ the planning and convocation schedules should be staggered to avoid waiting times and gathering of patient; 2/ the use of single or isolated rooms should be preferred to wait or exit lounges; 3/ Limit admissions in the postoperative recovery room must be applied as much as possible, in particular after performing locoregional anaesthesia. Depending on the local outpatient surgery units, this recommendation may limit the number of patients treated. Finally, waiting areas for companions should be arranged in order to respect the safe distances. [bib_ref] Guidelines for Ambulatory Surgery Centers for the Care of Surgically Necessary/Time-Sensitive Orthopaedic..., Dephillipo [/bib_ref] The number of companions should be limited to one person per patient (adult or child). In case of conventional hospitalisation, enhanced recovery after surgery should be preferred as far as possible in order to reduce, once again, the length of stay. In the same way, hospitalisation on the day of surgery should be considered if the healthcare institution ensures that there is no risk of infected patient by the COVID-19 (for example by a phone call the day before hospitalisation). ## Resumption of surgical activity after the covid-19 pandemic and the ## Rationale The rapidly changing COVID-19 pandemic situation requires a periodic review of the measures taken and an analysis of the clinical, social and economic context derived from each decision. The resumption of surgical activity will be gradual and spread over time. The objective is to summarise, as a priority and progressively, those activities that prove decisive in limiting the loss of chance for patients awaiting cancer or non-cancer surgery.The gradual deployment of surgical activity in a controlled number of operating theatres will make it possible to achieve efficiency in open operating theatres and facilitate compliance with reinforced hygiene rules to ensure the safety and protection of patients and caregivers. Experts suggest that public and private facilities agree to propose a common approach to the provision of care adapted to the population and regional conditions of the COVID-19 pandemic. The pace of rescheduling elective surgery in children and adults will vary according to geographical location, epidemiological pressure, and the possibility of redeploying staff from critical care to operating theatres. Elements to be evaluated for the resumption of surgical activity are the following:  Timing of resumption: There should be a sustained reduction in the rate of new COVID-19 cases in the geographical area concerned for at least 14 days before the resumption of elective surgery. Any resumption must be authorised by the relevant regional and national health authorities.  Facilities are able to safely treat all patients requiring hospitalisation without the need for a crisis care organisation.  The facility has an appropriate number of critical and non-critical non-COVID and COVID+ beds, PPE, ventilators, drugs, blood products and all necessary medical and surgical equipment. The facility has a number of trained and educated staff appropriate to the planned surgical procedures, the patient population and the facility resources. Health care staff fatigue and the impact of stress must be considered in order to perform planned procedures without compromising patient safety or staff safety and well-being. ## How to coordinate within each institution the resumption of surgical activity after the end of lockdown? (Role and operation of the regulation cell) [fig] : patients with chronic renal failure on dialysis;  patients with active cancer under treatment (excluding hormone therapy);  people with congenital or acquired immunosuppression: -drug: cancer chemotherapy, immunosuppressive therapy, biotherapy, -and/or immunosuppressive dose corticosteroid therapy, -uncontrolled HIV infection or with CD4 < 200/mm3, -following a solid organ or haematopoietic stem cell (HSC) transplant, -related to a malignant haemopathy being treated, patients with cirrhosis at least stage B of the Child-Pugh classification; [/fig] [fig] : Protection of staff and patients Benefit/Risk and Patient Information Preoperative assessment and decision on intervention Modalities of the preanaesthetic consultation Specificity of anaesthesia and analgesia Dedicated circuits Containment Exit Type of Interventions METHOD These recommendations are the result of the work of a group of experts brought together by the French Society of Anaesthesia and Intensive Care (SFAR). The approach used to draw up these recommendations was deliberately pragmatic and logical. Initially, the organising committee defined the issues to be addressed with the coordinators, and then designated the experts in charge of each of them. Due to the topic addressed, (perioperative organisation in the context of the resumption of surgical activity scheduled during the COVID-19pandemic), and the lack of evidence in the literature for a certain number of issues to date, it was decided prior [/fig] [fig] 18 1. 4: Recovery rooms R1.4.1 -Experts suggest performing extubation and supraglottic airway removal in the operating theatre, regardless of the patient's COVID-19 status. Extubation in recovery rooms should remain exceptional. R1.4.2 -Experts suggest giving out surgical masks type II/IIR to patients post-extubation and before leaving the operating theatre, regardless of their COVID-19 status.R1.4.3 -If an extubation or supraglottic airway removal should exceptionally be carried out in the recoveryroom, experts suggest wearing an N95 or FFP2 respirator, a head cap, disposable gloves, and a face shield or, failing that, safety goggles during the procedure. In other cases, experts suggest wearing a surgical mask type II/IIR. [/fig] [fig] 1. 5: Critical care units/ intermediate care units R1.5.1 -Experts suggest always/continuously wearing a surgical mask type II/IIR in common areas. Barrier measures should be followed strictly during medical and paramedical team rounds, hand-offs and breaks (opening additional spaces for lunch breaks). R1.5.2 -Experts suggest wearing an N95 or FFP2 respirator, a head cap, non-sterile disposable gloves, a face shield (which has the advantage of protecting the respirator) and/or safety goggles when performing aerosolgenerating procedures in patients whose COVID-19 status is unknown. A fluid resistant long-sleeved gown + a plastic apron or, failing that a surgical gown, should be added when dealing with a known or suspected case of COVID-19. Procedures at risk of aerosolisation are:  Endotracheal intubation and extubation;  Performing a tracheotomy;  Endotracheal suctioning without a closed suction system;  Caring for patients who are receiving non-invasive pressure ventilation or high-flow nasal oxygen therapy; [/fig] [fig] FOR: PLANNED SURGERY (Figures 1): In a symptomatic patient, it seems reasonable to postpone the intervention for 24-48 hours to obtain the results of the SARS-CoV-2 PCR performed on a nasopharyngeal swab. If the PCR is positive, COVID-19 infection requires postponing the intervention until patient's recovery, which is set for a period of at least 14 days after symptom onset, extended to at least 24 days in immunocompromised patients or patients with a severe form of COVID-19, in whom clearance of the virus may be longer. 40,41 At the end of this postponement period, the patient returns to the first line of the algorithm: recollection of a nasopharyngeal swab if symptoms persist or, in the absence of symptoms, in the case of surgery at risk.If the PCR is negative, and taking into account the existence of false negative results, if the clinical presentation is evocative, especially if it is reinforced by characteristic paraclinical signs (lymphopenia 35-70% of cases; eosinopenia 50-65 % of cases; high CRP with normal PCT 60-90% of cases[35][36][37][38]42 ), it should be considered that the patient has a proven SARS-CoV-2 infection. Then, the diagnostic probability may be reinforced, especially in the case of major surgery at risk of severe postoperative forms of COVID-19, by: 1) a thoracic CT-scan, which has a high negative predictive value to rule out COVID-19 in symptomatic patients (approximately 85-95%)43,44 ;2) a control of the PCR on a second sample, taking maximum care to ensure that the new oropharyngeal swab is performed by a team trained in the proper execution of swabbing; or 3) a COVID-19 serology, only if the symptoms have been present for at least 7 to 10 days. This serology will only be of value if it is positive, and it will only indicate that the patient has been in contact with the virus, without being able to date the infection or conclude on the possible protective nature of the antibodies detected (see explanations below).45 It is therefore advisable to be particularly vigilant if the serology is the only positive test, as the patient may have a history of SARS-CoV-2 infection and another current virus or pathology. [/fig] [fig] 5. 3: Are there any particularities for medication management in the perioperative period? R5.3.1 -In the perioperative period, the experts suggest a systematic evaluation of possible drug interactions, particularly in the case of treatment with antiviral drugs. [/fig] [fig] 5. 4: Are there any particularities for postoperative care, including outpatient care? R5.4.1 -Experts suggest applying the usual strategies for multimodal analgesia and prevention of nausea and vomiting, including outpatient treatment. possible in other cases. Rationale Pain and postoperative nausea and vomiting (PONV) are the most common complications of the ambulatory route. They are the source of medical consultations and hospitalisation, exposing the patient to a new risk of viral transmission. 69 [/fig] [fig] 5. 5: Are there any specific considerations for anaesthesia and analgesia in the obstetrical context? R5.5.1 -Experts suggest that analgesic management of obstetrical labour should not be modified in parturient who are not infected with SARS-CoV-2 or who have an asymptomatic infection. R5.5.2 -For women with a symptomatic condition, experts suggest eliminating thrombocytopenia prior to epidural analgesia. [/fig] [fig] 6. 1: Which specific pathway for the management of COVID+ patients? R6.1.1 -Experts suggest, for hospitals treating adults and paediatric patients COVID+, that a specific COVID+ pathway be implemented for their management, from the time they are admitted until they leave the operating theatre or the intensive care unit. This pathway must be secure (with adequate protective measures for patients and health workers); identified with visible signage; dimensioned to limit interference with conventional pathways; contain at least one identified postoperative room, in particular for intensive care unit(Figure 4).RationaleSurgery remains possible for COVID+ patients in case of emergency or decrease in prognosis. The infectiousness of COVID+ patients requires the establishment of dedicated pathway, using 5 concepts 80 :1. security: healthcare workers are among the people most at risk of contamination,3 and should be protected (cf. 1); similarly, other patients must be protected in the establishment by a specific pathway used for COVID+ patients;2. the signalling of the pathway with explicit and uniform signage warning the health workers the presence of a COVID+ patients in the interventional room;3. the optimisation of the pathway to isolate the COVID+ patients from others as much as possible using analysis of inflow and outflow of patients to avoid the crossing of COVID+ patients with others;4. the identification of one or more operating theatres dedicated to the care of COVID+ patients using dedicated materials;After surgery, postoperative care should be conducted in dedicated units for COVID+ patients in surgical unit or ICU unit using cohorting. 81R6.1.2 -Experts suggest that, in addition to the extubation of adult and paediatric COVID+ patients inthe operating theatre, their post-interventional care should be ensured, as far as possible, in the operating theatre or in another COVID+ dedicated protected area.RationaleCough frequently occurred following extubation, which is at high risk of spread of SARS-CoV-2, 82 explaining a dissemination until 8 meters22,83 . While some methods have been described to decrease the risk of dissemination during the extubation procedure,84,85 health workers should use PPE (especially N95 or FFP2 respirator and face shield). To protect other patients and health workers, it seems preferable to conduct the extubation and postinterventional care in the interventional room or in a dedicated protected area.86 A surgical mask should be placed on the face of adult patients following extubation while nasal oxygenation could be used. For paediatric COVID+ patients, the surgical mask use could be difficult.6.2. Which specific pathway for the management of non-COVID patients?R6.2.1 -Experts suggest that adult and paediatric non-COVID patients undergoing scheduled surgery (outpatient, conventional or heavy surgery requiring critical postoperative care) should be managed in an isolated pathway from the COVID+. The entire care pathway for these patients must comply with the protective measures mentioned above. [/fig] [fig] . 1: What is the timing and pattern of resumption of surgical activity after the end of lockdown? R7.1 -Experts suggest considering a timeline for the resumption of elective surgery when authorised by local agencies AND when the facility has an appropriate number of critical/intermediate care and conventional beds, protective equipment (PPE), ventilators, drugs, blood products, and staff trained to treat all elective patients without resorting to a crisis care organisation. [/fig] [table] Table 1: Personal protective equipment (PPE) depending on the place and the procedures that are performed in adult patients and healthcare professionals. gloves and a face shield (or failing that safety goggles). A dedicated COVID-19 operating theatre or an operating room that is well identified with poster on the entrance door. N95 or FFP2 respirator, head cap, fluid resistant long-sleeved gown (or failing that a surgical gown) + plastic apron, disposable gloves and a face shield (or failing that safety goggles). Setting up a closed suction system when the patient is intubated and if possible. for non-COVID patient Surgical mask type II/IIR. In the case of a body fluid exposition: head cap + face shield or safety goggles. [/table] [table] Table 2: Criteria for assessing the benefit / risk ratio of surgical intervention in a patient during the COVID-19 pandemic. Underlying respiratory (asthma, COPD, cystic fibrosis) or cardiovascular (hypertension, coronary artery disease and chronic heart failure) pathology Obstructive sleep apnea syndrome Diabetes Immunosuppression related to the disease Possible therapeutic alternatives Loss of luck in the absence of intervention Number of staff needed in the operating room Anaesthesia modality Surgery site on https://www.covid19-druginteractions.org/ J o u r n a l P r e -p r o o fDon't wait for results Discuss preoperative chest CT-scan Major surgery Post-anaesthesia recovery in the operating room* Transfer to the wards if no hypoxemia, polypnoea, dyspnoea Intervention Postoperative surveillance in the ICU for 24-48h Re-evaluation after PCR results Surgery at risk of aerosolisation?* Close contact with a suspected or confirmed Covid-19 patient within the last 15 days? OR Subject at risk of severe form of Covid-19? Standardized questionnaire before the surgery Non-major surgery Intervention Enhanced surveillance for 24-48h in the wards for non-major surgery, if not in the ICU Re-evaluation after PCR results * Post-anaesthesia recovery in the operating room if <60 min or dedicated space isolated from other patients in the recovery room with a facemask for the patient if >60 min * thoracic surgery with pulmonary resection, ENT surgery, endo-oral surgery, basal skull neurosurgery, rigid bronchoscopy, etc.COVID-19 PCRDon't wait for resultsSurgery with protective measures for the staff (Cf. 1rst area) Specific COVID-19 pathway (Cf. 6 th area) Prefer loco-regional anaesthesia and spontaneous ventilation if possible COVID+ pathway Intervention Postoperative surveillance in the ICU for24-48h Re-evaluation after PCR resultsCOVID-19 PCRNo Yes# ≥1 major symptom and/or ≥2 minor symptoms ## 1 single minor symptom as recommended by the French High Council of Public Health J o u r n a l P r e -p r o o f II or IIR Post-operative room in theatre (or specific area) Specific COVID+ pathway Temperature ± Blood count Rt-PCR ± CT-scan COVID survey Temperature ± Blood count Rt-PCR ± CT-scan During hospitalization Presential or Teleconsultation (depending on eligibiliy) [/table]	None	None	None
9d5d7f8a7b9da00654e12d5d9ae41530095a53f7	pubmed	Malignant tumours of the salivary glands	Malignant tumours of the salivary glands Malignant tumours of the salivary glands are relatively rare, with an estimated incidence of less than 1 per 100 000. They represent a little less than 5% of head and neck tumours. These are generally slow-growing tumours of varied histology, long doubling times and late locoregional and distant recurrences. Prolonged survival is possible, even with metastatic disease.These recommendations do not consider salivary gland lymphomas. They were validated in August 1999 and an update is planned for the year 2000.PROGNOSTIC FACTORSThe most important prognostic factors with respect to local control and survival are tumour size and clinical stage. Other independent factors are the histology, (low grade vs high grade) and the treatment (the quality of the surgical excision). Knowledge of these factors is part of initial staging, and allows the subsequent therapeutic strategy to be matched to the clinical situation. ## Diagnosis and staging Standard staging of malignant tumours of the salivary glands is based on clinical examination, imaging and histopathological examination. From clinical examination, the size of the lesion, locoregional extension, and any signs suggestive of malignancy (e.g. facial paralysis, trismus, cutaneous infiltration) can be determined. Endoscopic examination (often under general anaesthesia) is required to obtain biopsy samples and to complete the staging of tumours of the minor salivary glands (notably those in the pharynx and larynx). Clinical assessment of locoregional extension is based on examination of the neck. A total body examination is required to look for distant metastases. An assessment of performance status, nutritional status and of major organ function, using clinical and laboratory parameters, determines whether or not the patient has operable disease (standard). Standard imaging consists of a cervico-facial CT scan or highresolution ultrasound (level of evidence B). High-resolution ultrasonography must only be used by those teams trained in this method. For tumours under the maxilla, an orthopantogram is necessary to complete staging (standard). MRI imaging and sialograms are options. Further imaging is done according to symptoms and signs suggestive of malignant involvement and extraglandular spread. Histopathological examination is necessary to confirm a diagnosis of malignancy. An excision biopsy with frozen section is required for the major salivary glands (standard) and a simple biopsy for the minor salivary glands (standard). A preoperative diagnosis can be made by cytological analysis following fineneedle aspiration (option). ## Staging The TNM AJC/UICC classification is the most practical and the best adapted to treatment decision-making (standard). The histological classification differentiating the tumours according to grade (low vs high grade), is now universally recognized (standard). ## Treatment The basic treatment of salivary gland tumours is complete surgical excision (standard), with or without postoperative irradiation, according to the clinical stage and the histological grade. The combination of surgery and radiotherapy is the treatment of choice for high grade disease. Routine postoperative radiotherapy is indicated for stage II, III and IV high grade tumours and for low grade stage III and IV tumours (standard). It is also indicated in all cases in which surgery has been macro-or microscopically incomplete (standard). Neutron therapy alone, when possible, is the treatment of choice for inoperable tumours, whatever the stage and grade. To a lesser degree, neutron therapy provides an alternative treatment for locally advanced disease (stages III and IV) where surgery is likely to be difficult or to result in significant functional sequelae (option). This requires further evaluation. Postoperative neutron therapy is not indicated except in the case of large-volume residual disease (option, level of evidence C). The place of chemotherapy remains unclear. It should only be given within a multicentre therapeutic trial. Treatment is according to clinical stage and histological grade. ## Stage i, low grade / high grade: t1a t2a n0 m0 Complete surgical resection is the standard treatment for stage I tumours of the salivary glands . For tumours of the major salivary glands the gland must be completely excised (standard). For tumours of the minor salivary glands, a wide radical resection must be undertaken (standard). In all cases, the excision should be complete and in the case of encapsulated tumours, outside the capsule. If the resection is macroscopically and microscopically complete, there is no indication for adjuvant radiotherapy, even for high grade tumours (standard). If the excision is incomplete, or if histological examination has shown tumour at the excision margins, postoperative radiotherapy is indicated (standard). Postoperative irradiation should be with photons (±electrons) with standard fractionation (level of evidence A). Irradiation with neutrons can be given in cases of large-volume residual disease (option, level of evidence C). Routine ipsilateral nodal clearance is standard for T2 high grade tumours (standard, level of evidence B) and is an option for T1a tumours (option). If nodal involvement is detected at the time of surgery, ipsilateral neck dissection followed by routine postoperative radiotherapy is recommended (level of evidence B). ## Stage ii, t1b t2b t3a n0 m0 Low grade tumours Surgery alone, of variable extent, is the standard treatment [fig_ref] Figure 3: Treatment of stage II disease [/fig_ref]. If a complete resection is likely to result in a significant functional or cosmetic deficit, neutron therapy alone can be undertaken (option, level of evidence C). Postoperative radiotherapy must be undertaken if the surgical excision margins are involved (standard). In the case of positive nodes, extended surgical excision of the tumour and cervical nodes is followed by postoperative irradiation irrespective of whether the resection is macroscopically or microscopically complete (level of evidence B) or incomplete (level of evidence A). ## High grade tumours Surgery alone (complete excision, with or without subsequent extraglandular extension and ipsilateral neck dissection) is indicated for lesions limited to the gland (standard) . In the case of extension of the tumour to involve the facial nerve or crucial structures, the therapeutic options are extensive disfiguring surgery or neutron therapy alone. External irradiation (with neutrons) as first-line therapy can be considered for lesions judged to be incompletely resectable, or where extensive disfiguring surgery will be necessary with the risk of significant functional impairment (notably disease extending to the facial nerve, infratemporal fossa or the mandible) (option, level of evidence B). Routine postoperative external irradiation to tumour and nodes is standard when the excision has been incomplete (macro-and microscopically) or in the case of positive nodes (standard). It is recommended in cases of complete excision (option, level of evidence B). The role of chemotherapy, either as neoadjuvant or adjuvant treatment or with the aim of radiosensitization, must be evaluated in prospective therapeutic trials (it has no role as routine treatment). ## Stage iii, t3b t4a n0 m0 all t (except t4b) n1 m0 Low grade tumours Low grade stage III tumours are treated in the same way as high grade stage II tumours . If surgery has been complete, postoperative irradiation to the tumour and nodes remains the standard treatment. Neutron therapy alone is preferable in certain cases where surgery would be very extensive and disfiguring. The standard treatment of N1 lesions is primary tumour and nodal surgery with uni-or bilateral neck dissection (bilateral in the case of midline tumours), followed by postoperative irradiation (standard). The extent of nodal irradiation will depend on the histological findings following neck dissection. ## High grade tumours For stage III high grade tumours, two types of treatment can be considered: complete excision of the primary tumour and nodes, followed by radiotherapy, or neutron therapy alone to both tumour and nodes (option) . The place of chemotherapy must be evaluated within prospective trials (it has no role as routine treatment). ## Stage iv disease T4b low and high grade, all N, M0 There is no standard therapeutic approach for the management of patients presenting with stage 4b low or high grade node-positive stage IV disease . The therapeutic options are neutron therapy alone to tumour and nodes or extensive disfiguring surgery followed by radiotherapy (level of evidence B). Surgery should be radical and carried out by cancer specialists. The role of chemotherapy remains to be evaluated within prospective therapeutic trials. For T4b N0 M0 disease, neutron therapy alone is the technique of choice (level of evidence B). The role of chemotherapy must be evaluated within prospective therapeutic trials (no role in routine use). ## All t, n2 or n3 m0 disease If the primary lesion is easily resectable (T1-T2), the standard treatment is surgical excision of tumour and nodes. In all other cases, neutron therapy alone, when possible, is preferable to extensive disfiguring surgery (option) . ## All t, all n, m1 disease (distant metastases) In metastatic disease, the recommended therapeutic approach is palliative treatment (standard) and the evaluation of chemotherapy and/or surgery and/or radiotherapy within multicentre trials (option) . Elective surgical excision is the standard treatment for isolated pulmonary metastases. ## Inoperable disease In patients unfit for surgery, or with unresectable disease, the recommended treatment is neutron therapy alone where possible (option, level of evidence B) . Standard radiotherapy with photons, including those protocols using hyperfractionation or accelerated irradiation (which is still under evaluation in this condition) gives inferior results (level of evidence B). Incomplete surgery followed by radiotherapy with photons, is not recommended. The place of chemotherapy, especially in high grade tumours, must be evaluated within prospective trials. ## Loco-regional recurrence There is no standard therapeutic approach. This will depend largely on the type of recurrence and above all on the treatment that has previously been given to the primary tumour. In the case of relapse after surgery, further surgery followed by postoperative radiotherapy, or neutron therapy alone can be considered (options). For recurrent disease after radiotherapy alone or after surgery followed by radiotherapy, the treatment options are: repeat surgery if possible, neutron therapy at a dose limited by the previous irradiation, or chemotherapy within a prospective trial (especially for high grade disease) . For nodal relapses, uni-or bilateral nodal dissection (± postoperative irradiation), can be considered (options). If the recurrence is inoperable, neutron therapy alone, irradiation with photons combined with localized hyperthermia, or chemotherapy within a prospective trial (especially for high grade disease) are the treatment options. ## Follow-up Monthly surveillance is recommended during the first 6 months following treatment (3 months in the case of low grade tumours and stage I and II disease). Thereafter, follow-up can be 4-monthly, then 6-monthly for 3-4 years, then annually. The assessment should include a chest X-ray (AP and lateral) every 6 months initially, then every year. ## Internal reviewers C Alzieu (Institut Paoli Calmettes, Marseille), P Barrellier (Centre François Baclesse, Caen), G Dolivet (Centre Alexis Vautrin, Options · radical surgery followed by radiotherapy to tumour and nodes · neutron therapy alone to tumour and nodes · chemotherapy within a clinical trial Follow-up [fig] Figure 1, Figure 2: Treatment of stage I carcinoma of the salivary glands (low grade) Treatment of stage I disease (high grade) [/fig] [fig] Figure 3: Treatment of stage II disease (low grade) [/fig] [fig] Figure 6, Figure 7: Treatment · radiotherapy for palliation or tumour reduction · cytoreduction surgery · chemotherapy (high grade tumours) Treatment of stage IV metastatic disease [/fig]	None	https://www.nature.com/articles/6691762.pdf	Malignant tumours of the salivary glands are relatively rare, with an estimated incidence of less than 1 per 100 000. They represent a little less than 5% of head and neck tumours. These are generally slow-growing tumours of varied histology, long doubling times and late locoregional and distant recurrences. Prolonged survival is possible, even with metastatic disease. These recommendations do not consider salivary gland lymphomas. They were validated in August 1999 and an update is planned for the year 2000.
b52ec495ea7955b0ebc027dd0af7f44fb68fe78e	pubmed	Adult cardiac surgery and the COVID-19 pandemic: Aggressive infection mitigation strategies are necessary in the operating room and surgical recovery	Adult cardiac surgery and the COVID-19 pandemic: Aggressive infection mitigation strategies are necessary in the operating room and surgical recovery ## Central message Aggressive infection mitigation strategies are necessary to safeguard our patients and healthcare workers during the COVID-19 pandemic. The Centers for Disease Control and Prevention (CDC) recently published recommendations for the care of patients undergoing surgical procedures during the COVID-19 pandemic.Additional modifications provided by the American College of Surgeons offer further guidance for surgical patients and personnel.Both organizations have recommended significantly reducing or stopping elective cases and implementing logical, tiered general precautions. The Society of Thoracic Surgeons COVID-19 Task Force and the Workforce for Adult Cardiac and Vascular Surgery published tiered patient triage guidance. [bib_ref] on behalf of The Society of Thoracic Surgeons COVID-19 Task Force and..., Haft [/bib_ref] Other suggestions from the American College of Surgeons to enhance safety for healthcare workersin the context of COVID-19 include the following: 1. Consider nonoperative management whenever it is clinically appropriate for the patient. 2. Complete testing as close to the planned operative date (preferably <48 hours) to lessen the risk that a patient becomes positive while waiting for a surgical procedure. 3. Avoid emergency surgical procedures during off hours, when possible, due to limited team staffing and the potential lack of optimal specialty specific expertise. 4. Perform aerosol-generating procedures (AGPs) [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref] in confirmed or suspected COVID-19 patients while practicing enhanced droplet/contact precautions, including an N95 mask, eye protection, gown and gloves, or a powered air-purifying respirator. Examples of known and possible AGPs include: a. Intubation, extubation, bag mask ventilation, noninvasive ventilation (continuous positive airway pressure and bilevel positive airway pressure), airway suctioning, nebulizer therapies, bronchoscopy, chest tube insertion, thoracotomies, and pleural procedures b. Electrocautery of blood or any other body fluids 6 c. Endoscopy 5. Defer nonurgent cardiovascular testing. 6. Distinguishing COVID-19 from other respiratory infections will be challenging; therefore, interventions will need to be applied broadly and not limited to patients with confirmed COVID-19.While helpful, these guidelines do not provide the granular guidance needed to address important aspects of the surgical management of cardiac surgical patients. In particular, there will remain a certain volume of patients who will still require urgent and emergent operations during this pandemic. At time of writing this document, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus associated with COVID-19 disease, has been associated with at least a 6% mortality in the United States in those patients with a confirmed diagnosis.The virus is well equipped with several virologic, epidemiologic, and clinical features that have contributed to its ability to rapidly spread through a global population. Specifically, a substantial number of asymptomatic or presymptomatic infections, with or without mild symptoms, are key to its effective dissemination throughout populations, including to healthcare providers. [bib_ref] Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2), Li [/bib_ref] At times of documented or assumed community spread of COVID-19, it is reasonable to suspect that all patients could be carriers of the virus. As such, all patients should be considered COVID-19 suspects, regardless of testing availability or results, and all patients should be treated equally with precautions similar to those used in COVID-19-confirmed cases. This approach is similar to the concept of universal precautions. This level of safety may not be required if community transmission and the burden of cases is low in specific areas. However, to minimize infectious risk to healthcare providers of patients undergoing cardiac surgical procedures in the preoperative, intraoperative, and postoperative period, additional detailed protective strategies are suggested. These are guidance recommendations during a pandemic surge for all patients until the supply chain for personal protective equipment (PPE) is restored and local COVID-19 disease burden is substantially reduced. ## Guidance recommendations 1. Patients should be transferred directly to the operating room (OR), without stopping in the preoperative or postanesthesia care unit areas, to minimize exposure to other patients, staff, and other environments. 2. "COVID-19 precautions" signs should be posted on all doors to the OR suite to inform staff of potential risks and minimize exposure. 3. The OR should remain positive pressure, but the surrounding rooms (ie, anteroom[s]) must maintain a strict negative pressure ventilation system at more than À2.5 Pa at 12 or more air changes per hour. 9 4. All OR staff are required to practice enhanced droplet and contact precautions in the OR at all times. This includes the use of N95 respirator, eye protection, gown, and gloves. Given the possibility of false-negative testing (10%-30%), [bib_ref] Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and..., Yang [/bib_ref] [formula] Ig ¼ immunoglobulin OR ¼ operating room PPE ¼ personal protective equipment SARS-CoV-2 ¼ severe acute respiratory syndrome coronavirus 2 TEE ¼ transesophageal echocardiography [/formula] Anesthesiologists recommends that all anesthesia professionals should use PPE appropriate for AGPs for all patients during all diagnostic, therapeutic, and surgical procedures when working near the airway.We would broaden this recommendation to include all OR personnel. 5. If N95 masks are to be reused (though not optimal) the CDC recommends a 5-day period of drying 12 or preferably decontaminated using ultraviolet germicidal irradiation, vaporous hydrogen peroxide, or moist heat by autoclaving. 12,13 6. If a powered air-purifying respirator is used as an alternative to an N95 respirator and eye protection, practitioners should be cautioned that these devices may reduce the clarity of surgical loupes and positioning of headlights. 7. A donning-and-doffing-trained observeris highly recommended because most nosocomial spread of COVID-19 occurs during this critical period. [bib_ref] Self-contamination during doffing of personal protective equipment by healthcare workers to prevent..., Suen [/bib_ref] Ongoing donning-and-doffing simulation training should be regularly performed for continual refinement of safety processes. 8. Limit entry/exit to a single OR entrance. Keep all OR doors closed as much as possible, and limit staff entry/reentry to keep OR pressures and air exchanges regulated. 9. Before AGPs are performed, OR personnel must ensure that no more than the minimal number of staff required to safely achieve the procedure are present in the room. 10. During induction and endotracheal intubation, it is recommended that the anesthesiologist: a. Be the most experienced available operator with the highest probability of first-pass intubation. b. Limit the number of staff in the OR to the minimum needed to safely intubate (1 anesthesiologist plus 1 or 2 assistants). c. At the discretion of the anesthesiologist, video laryngoscopy may be chosen over direct visualization to decrease the risk of droplet transmission. d. Preoxygenate with 100% inspired oxygen and avoid bag-mask ventilation unless absolutely necessary. 11. After AGPs, including intubation, additional OR personnel should wait 30 minutes before entering the room (this is dependent on the efficiency of the air exchange in each OR suite; see point 3 above). 12. Intraoperative staffing for the surgical case should be minimized to the minimal number needed to safely and efficiently complete the procedure. [bib_ref] N95 mask decontamination using standard hospital sterilization technologies, Kumar [/bib_ref]. Staff relief for breaks should be provided only as necessary to preserve PPE and decrease the number of staff exposed and reentries. 14. Smoke evacuation of electrosurgical devices should be used to minimize staff exposure to surgical smoke. [bib_ref] Awareness of surgical smoke hazards and enhancement of surgical smoke prevention among..., Liu [/bib_ref] 15. Patients should preferably recover in a negativepressure isolation room when resources permit (in the postanesthesia care unit or intensive care unit). If negative-pressure isolation rooms are unavailable, consider early recovery in the OR before transfer to a single patient room. 16. After the patient has left the OR, the OR should be closed for an appropriate standoff period to achieve greater than 99.9% aerosol clearance. The amount of time that aerosols stay suspended in the air will depend on a number of factors, including the size of the room, the number of air changes per hour, how long the patient was in the room, whether the patient was coughing or sneezing, and whether an AGP was performed. General guidance on clearance rates under differing ventilation conditions is available from the CDC.17. After the standoff period, the OR suite must be cleaned using routine procedures with United States Environmental Protection Agency-approved hospital disinfectant. 18. Operations should be performed by the most experienced available surgeons and assistants to limit exposure time in the OR. Junior residents and other learners should not be exposed unless absolutely necessary. 19. Strong consideration to surgical approach and technique must be considered to optimize patient outcomes while minimizing exposure risk to providers. Use of laparoscopic or video-assisted thoracoscopic procedures should be avoided when possible due to risk of aerosolization from CO 2 insufflation systems with inadvertent lung injury. 20. Limit all routine preoperative and postoperative laboratory testing, imaging, and procedures to minimize personnel exposure. 21. COVID-19 repeat testing is only required in postoperative patients when symptoms or signs of COVID-19 develop. Rapid COVID-19 testing is preferred when available. 22. In the event of cardiac arrest or other medical emergency, all patients must continue to be treated as suspected or confirmed COVID-19 cases. This requires strict adherence to enhanced contact and droplet precautions. No patient interaction should be permitted before full PPE is donned. This likely represents an uncomfortable paradigm shift for surgeons accustomed to "jumping into lifesaving patient interactions with little regard to infectious risk." 23. For a cardiac arrest in the intensive care unit, only 1 provider should provide cardiopulmonary resuscitation while medications are administered. Cessation of advanced cardiac life support is at the discretion of the provider, but prolonged resuscitative efforts should be avoided due to futility and risk. [bib_ref] In-hospital cardiac arrest outcomes among patients with COVID-19 pneumonia in Wuhan, Shao [/bib_ref] 24. Transesophageal echocardiography (TEE) in an intubated, anesthetized patient has never been demonstrated to generate aerosols. However, many societies have classified TEE as an AGP. Clinicians should weigh the necessity of placing a TEE in each cardiac surgical patient against the theoretical concern of generating aerosols. If performed, all staff should wear an N95 mask. The most experienced echocardiographer should perform the examination, including probe insertion and removal. 18 ## Covid-19 testing There is accumulating evidence indicating that a substantial fraction of COVID-19-infected individuals are asymptomatic. [bib_ref] Evidence of SARS-CoV-2 infection in returning travelers from Wuhan, China, Hoehl [/bib_ref] A study of skilled nursing facility residents infected with COVID-19 demonstrated that half were asymptomatic or presymptomatic at the time of contact tracing evaluation and testing. [bib_ref] Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled..., Kimball [/bib_ref] In a population-based study in Iceland, 43% of the participants who tested positive reported having no symptoms. [bib_ref] Spread of SARS-CoV-2 in the Icelandic Population, Gudbjartsson [/bib_ref] A study of 215 pregnant women admitted for delivery in New York City found 15% were COVID-19 positive, 88% of whom were asymptomatic. [bib_ref] Universal screening for SARS-CoV-2 in women admitted for delivery, Sutton [/bib_ref] Virologic studies have demonstrated viral RNA and viable virus among persons with asymptomatic and presymptomatic infection. [bib_ref] Evidence of SARS-CoV-2 infection in returning travelers from Wuhan, China, Hoehl [/bib_ref] [bib_ref] Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled..., Kimball [/bib_ref] [bib_ref] SARS-CoV-2 viral load in upper respiratory specimens of infected patients, Zou [/bib_ref] If a high-fidelity, rapid point-of-care testing system is available, providers could consider screening preoperative patients immediately before a surgical procedure if time permits within a 24-hour window, particularly in areas of high COVID-19 disease burden. Positive screening tests should lead to reconsideration of the risks and benefits of proceeding with the planned surgical procedure. These patients may be in the presymptomatic or early symptomatic phase of infection and are likely at heightened risk of adverse outcomes after an operative procedure. In a retrospective cohort study of 34 patients who were unintentionally scheduled for elective operations during the incubation period of COVID-19, the mortality rate was 20%. [bib_ref] Clinical characteristics and outcomes of hospitalised patients with COVID-19 treated in Hubei..., Liang [/bib_ref] However, negative screening tests must be interpreted with caution, particularly in the setting of (1) low pretest probability, (2) typically low viral titers in the asymptomatic phase, and (3) the possibility of false-negative results. If clinical suspicion for COVID-19 remains due to exposure history, active symptoms, high prevalence of circulating community infections, or other clinical factors, repeat testing may be indicated during the postoperative course. ## Serologic immunity After viral infections, an immunoglobulin (Ig) M immune response occurs, which then diminishes within a few weeks. The IgG and IgA immune response occurs simultaneously, producing more specific and longer-acting immunity.Testing patients' serostatus could be an important tool to determine whether patients have mounted prior immunity from natural infection, reducing the likelihood of current COVID-19 colonization. The prospect of testing providers for serologic immunity to COVID-19 is also promising if the presence of antibodies confers immunity to future infection, because providers with acquired immunity could be selected to care for COVID-19 suspected or confirmed patients. Unfortunately, serologic testing and capacity are currently limited and require further scientific evidence to support their use in screening healthcare workers. Important studies are underway to determine the pattern of antibody development after COVID-19 infection, whether antibodies confer immunity to future infections, whether specific antibody titers determine the level of protection, and the duration of conferred immunity. Similar coronavirus outbreaks demonstrated that survivors developed robust immunity after natural infection. The 2003 severe acute respiratory syndrome outbreak elicited an immunity that was protective for up to 3 years. [bib_ref] Duration of antibody responses after severe acute respiratory syndrome, Wu [/bib_ref] Until more data emerge supporting the widespread adoption of antibody testing, 29 strict infection prevention and control policies are required to enhance the safety of patients and providers. # Conclusions At the present time, we urge all healthcare organizations providing cardiac surgical procedures in regional environments of widespread COVID-19 disease to consider adopting these aggressive mitigation strategies (1) to create a safe environment that protects our patients from acquiring or transmitting COVID-19 and (2) to protect members of our surgical and postoperative provider teams. We all look forward to the near future when elective surgical procedures can be resumed as the threat of this virus wanes and capacity permits. However, until that time, and in an effort to hasten its arrival, the aforementioned protocols should become standard of care. Rakesh C. Arora has received an unrestricted educational grant from Pfizer Canada Inc.	None	http://www.jtcvs.org/article/S0022522320310114/pdf	None
d5f15e33598066e8d74132c496f767e7d6806521	pubmed	Treatment and surveillance for non-muscle-invasive bladder cancer: a clinical practice guideline (2021 edition)	Treatment and surveillance for non-muscle-invasive bladder cancer: a clinical practice guideline (2021 edition) Non-muscle invasive bladder cancer (NMIBC) is a major type of bladder cancer with a high incidence worldwide, resulting in a great disease burden. Treatment and surveillance are the most important part of NIMBC management. In 2018, we issued "Treatment and surveillance for non-muscle-invasive bladder cancer in China: an evidence-based clinical practice guideline". Since then, various studies on the treatment and surveillance of NMIBC have been published. There is a need to incorporate these materials and also to take into account the relatively limited medical resources in primary medical institutions in China. Developing a version of guideline which takes these two issues into account to promote the management of NMIBC is therefore indicated. We formed a working group of clinical experts and methodologists. Through questionnaire investigation of clinicians including primary medical institutions, 24 clinically concerned issues, involving transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and intravesical immunotherapy of NMIBC, and follow-up and surveillance of the NMIBC patients, were determined for this guideline. Researches and recommendations on the management of NMIBC in databases, guideline development professional societies and monographs were referred to, and the European Association of Urology was used to assess the certainty of generated recommendations. Finally, we issued 29 statements, among which 22 were strong recommendations, and 7 were weak recommendations. These recommendations cover the topics of TURBT, postoperative chemotherapy after TURBT, Bacillus Calmette-Guérin (BCG) immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of carcinoma in situ, radical cystectomy, treatment of NMIBC recurrence, and follow-up and surveillance. We hope these recommendations can help promote the treatment and surveillance of NMIBC in China, especially for the primary medical institutions. # Background Bladder cancer is one of the most commonly diagnosed cancers worldwide, with more than 500 thousand newly diagnosed cases and 200 thousand deaths estimated globally in 2019 [1-3]. As one of the types of bladder cancer, non-muscle invasive bladder cancer (NMIBC) is the most common form of bladder cancer, comprising approximately 75% of cases . NMIBC is characterized by frequent recurrences and a high risk of disease progression, as reported the 5-year recurrence rates ranging from 50 to 70%, and 5-year progression rates ranging from 10 to 30% . Proper management can reduce the risk of recurrence and progression of the disease. The management of NMIBC includes transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and intravesical immunotherapy, and follow-up and surveillance of NMIBC patients . In China, as the medical resources are distributed unbalancedly, there is a need to strengthen the management of NMIBC. For example, in some areas, there is a shortage of the Bacillus Calmette-Guérin (BCG) for NMIBC immunotherapy in the primary medical institutions. Therefore, it is necessary to develop a version of guidelines for different grade hospitals, especially including primary medical institutions to promote the management of NMIBC which takes into account the conditions prevailing there. In 2018, we published a guideline for the treatment and surveillance of NMIBC in China . Considering the studies on the treatment and surveillance of NMIBC being published in recent years, and the need to promote the management of NMIBC including primary medical institutions, we updated and developed 2021 edition of the guidelines for the treatment and surveillance of NMIBC in China. This guideline includes eight sections: TURBT, postoperative chemotherapy after TURBT, BCG immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of carcinoma in situ (CIS), radical cystectomy, treatment of NMIBC recurrence, follow-up and surveillance. # Methods ## Target users The main users of the guideline are urologists, nursing staff, and general practitioners in different grade medical institutions that can provide NIMBC diagnosis and treatment services, especially at or below the county level. Other users include teachers and researchers working in the area of bladder cancer treatment. ## Target population Patients with NMIBC. The guideline panel was composed of a steering group, a working group, and an evidence search and synthesis group, which included 27 urological experts, 2 methodologists, and 16 clinical research assistants with evidence searching and assessment expertise. The external consultancy review group included 11 clinical experts and one methodologist. (See the Authors' Contributions). ## Composition of the guideline development group ## Selection and identification of clinical questions and outcomes The guideline working group designed a questionnaire for the selection and identification of clinical concerns and outcomes for the development of guideline through systematic retrieval of published guidelines and systematic reviews, stakeholder questionnaires, and conference discussions. It included 35 clinical questions on 8 topics: TURBT, postoperative chemotherapy after TURBT, BCG immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of CIS, radical cystectomy, treatment of NMIBC recurrence, follow-up and surveillance. Each topic consists of two parts: one was to investigate the status of the topic-related concerns in clinical practice; the other was to evaluate the feasibility and importance of the topic-related clinical questions. A Likert 5-level scoring method was used to assess the importance of clinical questions, with 1 representing very unimportant and 5 representing very important. From November 2020 to January 2021, a questionnaire survey was conducted using the designed questionnaires among 112 urologists in the county-level medical institutions, and the survey results were reported to the guideline development committee. After discussion, 11 clinical questions with an average score of less than 4, less application in clinical practice or duplication of contents were deleted, and a total of 24 clinical questions were included in the guidelines. The outcome indicators in the guidelines were: (1) key outcome indicators: progression-free survival (PFS), overall survival (OS), recurrence-free survival (RFS) and cancer-specific survival (CSS). (2) Important outcome indicators: recurrence rate, total mortality and diseasespecific mortality. (3) Adverse reactions: 1) adverse reactions related to adjuvant therapies, including: frequent urination, urodynia, pyuria, hematuria, dysuria, bladder irritation symptoms, cystitis, fever, allergic reaction, gastrointestinal reaction and general discomfort; 2) adverse reactions related to surgery operations: obturator nerve reflex, bladder perforation, urinary extravasation, bladder irritation symptoms, urinary tract infection and urinary tract stenosis. ## Evidence reviews Evidence was searched from multiple resources, including: Systematic review and meta-analysis published in professional medical journals were first considered for evidence synthesis. If there was no relevant systematic review or meta-analysis on the topic, we would consider formulating one based on the existing primary research. If there was no relevant primary research, we would look for the published guidelines, consensus, monographs and expert opinions. The quality of evidence of primary research was evaluated according to the relevant criteria [10]. ## Formation of recommendations The grade criteria for evidence and recommendation used in the EAU guideline [11] [fig_ref] Table 1: Levels of evidence and grades of the recommendation in EAU GuidelineEAU European... [/fig_ref] were chosen for the formation of recommendations. Strong recommendations mean that most informed patients should be given the recommended management and that clinicians can organize their interactions with patients accordingly. Weak recommendations mean that the management given to the patients will vary depending on their values and preferences, and clinicians must ensure that patient's care is in line with their values and preferences. We used the word "recommend" to introduce "strong recommendations", and used "suggest" or "consider" to describe "weak recommendations". Consensus principles for recommendation voting were as follows: if the number of votes for the strength of a recommendation was more than 50% of total voters, the direction (such as support or oppose an intervention) and strength of recommendations can be determined directly; if the above standards cannot be met, but the total number of votes in the same direction of recommendation exceeds 70%, the direction of the recommendations can be determined, the strength of recommendations depends on the highest number of votes; if the above two items cannot be met, the next stage of discussion shall be performed to reach an agreement. ## Classification criterion of nmibc The staging of NMIBC in this guideline was based on Tumor Node Metastasis (TNM) staging method (Additional file 1:was not excluded in the process of literature collection. The risk classification criterion for NMIBC in this guideline is shown in Additional file 1: . Additional file 1: shows the risk classification criterion of EAU guideline . # Results ## Section 1: clinical concerns related to the surgical treatment of nmibc question 1: what are the indications for turbt in nmibc patients? Recommendation: For patients with suspected NMIBC, TURBT is recommended as the diagnosis procedure and initial treatment measure. (Evidence level: 4; Strength of recommendation: Strong). Implementation consideration: If the conditions permit, remove all visible tumors through TURBT, and conduct a histological examination for pathological staging and grading. Evidence summary: We referred to the recommendations from the EAU guideline [11], AUA guideline, CUA guideline, and Chinese Guidelines for Diagnosis and Treatment of Urology and Andrology [7] (Additional file 2: Question 1). ## Question 2: what are the indications not to undergo turbt as the primary procedure for patients with nmibc? Recommendation: TURBT is not recommended for patients with insurmountable issues that hinder the implementation of TURBT and for patients who require radical cystectomy. (Evidence level: 4; Strength of recommendation: Strong). Implementation consideration: Insurmountable conditions hindering the implementation of TURBT include severe urinary tract stenosis, patients who cannot be placed in the lithotomy position due to skeletal or muscle disease. See Question 22 for indications for radical cystectomy. Evidence summary: We referred to the recommendations from the Standardization of Cancer Diagnosis and Treatment Series-bladder cancer and prostate cancer [8]: Patients with severe urethral stricture, bladder adenocarcinoma, squamous cell carcinoma, bladder diverticulum cancer and urachal cancer, or patients who cannot be placed in the lithotomy position due to bone or muscle diseases, or those who relapse rapidly after the first treatment cannot undergo TURBT. ## Question 3: what is the extent of initial turbt resection in nmibc patients? Recommendation: Endoscopically visible tumors should be resected deep into underlying detrusor muscle in the initial TURBT resection. Tumors with a diameter less than 1 cm could be resected along with part of the bladder wall under the tumor. For large tumors, it is recommended to resect the tumor in fractions until normal bladder wall muscle is exposed. The biopsy specimens sent for pathological examination should include the muscular tissue. ## Question 4: what are the indications for fluorescenceor narrow-band imaging-guided turbt in patients with nmibc? Recommendation: If the equipment and operators are available, TURBT guided by fluorescence or narrowband imaging can be used for patients suspected of having multiple tumors, CIS or high-grade tumors, or for patients with positive urine cytology but negative The advantages and disadvantages of interventions are uncertain or the evidence regardless of its quality shows that the advantages and disadvantages are equal ordinary cystoscopy. (Evidence level: 1a; Strength of recommendation: Weak). Implementation consideration: The commonly used photosensitizers in clinical practice during fluorescence guidance are 5-aminolevulinic acid (5-ALA) and hexaminolevulinate (HAL). Evidence summary: We referred to the recommendations from relevant systematic reviews, guidelines and monographs. (1) A systematic review [bib_ref] Novel visualization methods assisted transurethral resection for bladder cancer: an updated survivalbased..., Li [/bib_ref] (2) We also referred to the EAU guideline [11], NICE guideline, and Guidelines for Diagnosis and Treatment of Urology and Andrology in China [7] (Additional file 2: Question 4). ## Question 5: what are the indications for a repeat turbt in patients with nmibc? Recommendation: For the conditions of incomplete initial TURBT, no muscle tissue in the first resection specimen, high-risk tumors, T1 tumor, G3/high-grade tumor (except CIS), a repeat TURBT operation is recommended. (Evidence level: 1a; Strength of recommendation: Strong). Implementation consideration: For TaG1/low-grade tumors, even if there is no muscle tissue in the first resected specimen, a repeat TURBT is not an obligated choice. Evidence summary: We referred to the recommendations from a relevant systematic review, guidelines and monographs. (1) A systematic review [bib_ref] Repeat transurethral resection in non-muscle-invasive bladder cancer: a systematic review, Cumberbatch [/bib_ref] about repeat TURBT on NMIBC published in 2018 recruited 1 RCT and 30 non-RCTs, a total of 8409 patients with highgrade Ta or T1 NMIBC. 1) Residual tumor tissues were found in 17-67% of the patients with Ta stage tumor by a repeat TURBT; Residual tumor tissues were found in 20-71% of the patients with T1 stage tumor by repeat TURBT. 2) For Ta stage tumors, the disease recurrence rate was 16% for the patients who received repeat TURBT, and it was 58% in patients without receiving repeat TURBT; For T1 stage tumors, the recurrence rate was 45% in the patients who received repeat TURBT, and that was 49% in patients without receiving repeat TURBT. 3) The tumor progression rates in patients with Ta stage showed no significant difference between patients who received and not received repeat TURBT; For patients with T1 stage, after 26-66 months of followup, 5 of the 6 studies showed that the rate of tumor progression in the group without repeat TURBT was higher than that in the group with repeat TURBT. 4) Two studies have shown that repeat TURBT could slightly reduce the overall mortality on the basis of primary TURBT (22-30% vs. 26-36%). (2) We also referred to the EAU guideline [11], AUA guideline, CUA guideline, NICE guideline, NCCN guideline [18], Chinese Expert Consensus on Secondary Resection of Non-muscle-invasive Bladder Cancer [9], and Guidelines for Diagnosis and Treatment of Urology and Andrology in China [7] (Additional file 2: Question 5). ## Question 6: how long is the recommended interval between the initial and a second turbt for a nmibc patient? Recommendation: A second TURBT should be performed within 4-6 weeks after initial TURBT. (Evidence level: 4; Strength of recommendation: Strong). Evidence summary: We referred to the recommendations from the EAU guideline [11], AUA guideline, CUA guideline, NICE guidelineEvidence summary: We conducted two meta-analyses and referred to the recommendations from relevant systematic reviews, guidelines and monographs. (1) We performed a meta-analysis to compare the efficacy and safety of single intravesical infusion chemotherapy immediately after TURBT with TURBT alone in the treatment of NMIBC. A total of 8 RCTs (10 studies) [bib_ref] Single-dose versus multiple instillations of epirubicin as prophylaxis for recurrence after transurethral..., Ali-El-Dein [/bib_ref] [bib_ref] Immediate intravesical instillation of mitomycin C after transurethral resection of bladder tumor..., Barghi [/bib_ref] [bib_ref] Long-term experience with early single mitomycin C instillations in patients with low-risk..., De Nunzio [/bib_ref] [bib_ref] Should all patients with non-muscle-invasive bladder cancer receive early intravesical chemotherapy after..., Gudjónsson [/bib_ref] [bib_ref] Effect of intravesical instillation of gemcitabine vs saline immediately following resection of..., Messing [/bib_ref] [bib_ref] Two instillations of epirubicin as prophylaxis for recurrence after transurethral resection of..., Saika [/bib_ref] [bib_ref] Effectiveness of a single immediate mitomycin C instillation in patients with low..., Solsona [/bib_ref] were included, with a total sample size of 1531 cases and a maximum follow-up time of 108 months. Among these studies, two studies included 417 low-risk patients; one study included 219 patients with low and medium risk; one study included 86 high-risk patients; six studies included 1175 patients with unclear risk. Metaanalysis results showed that: in terms of effectiveness, compared with the TURBT alone group, the combination of TURBT and immediate postoperative intravesical infusion chemotherapy group reduced the 1-year recurrence rate (RR = 0.75, 95% CI 0.58-0.95), 2-year recurrence rate (RR = 0.76, 95% CI 0.63-0.92), 3-year recurrence rate (RR = 0.85, 95% CI 0.77-0.93), 4-year recurrence rate (RR = 0.78, 95% CI 0.66-0.93) and 5-year recurrence rate (RR = 0.91, 95% CI 0.85-0.98); The recurrence risk in the group receiving TURBT combined with immediate single intravesical infusion chemotherapy was 0.64 times of that in TURBT alone group (HR = 0.64, 95% CI 0.53-0.76), but there was no significant difference in the progression risk and overall survival between the two groups (HR = 0.74, 95% CI 0.42-1.28; HR = 0.68, 95% CI 0.37-1.27). In terms of safety, there was no significant difference in the incidence of hematuria (RR = 1.91, 95% CI 0.29-12.63), cystitis (RR = 3.88, 95% CI 0.63-24.14), fever (RR = 2.87, 95% CI 0.12-66.75) and allergy (RR = 2.12, 95% CI 0. between the two groups. There was no heterogeneity among the studies included in the above outcome indicators. (2) We performed another meta-analysis to compare the efficacy and safety between immediate single bladder perfusion chemotherapy combined with early maintenance perfusion chemotherapy after TURBT and early maintenance perfusion chemotherapy after TURBT in the treatment of NMIBC, which covered a total of 16 RCTs (18 studies) [bib_ref] CUA THP ® Immediate Instillations Study Group. Efficacy of immediate instillation combined..., Li [/bib_ref] [bib_ref] Adjuvant chemotherapy with early intravesical instillation of adriamycin and long-term oral administration..., Ueda [/bib_ref] [bib_ref] Effect on prophase intravesical instillation of pirarubicin for preventing recurrence of bladder..., Shen [/bib_ref] [bib_ref] The therapeutic effects of intravesical instillation of mitomycin C immediately after TURBT..., Chen [/bib_ref] [bib_ref] Comparison of THP high dose immediate perfusion and routine perfusion, Li [/bib_ref] [bib_ref] Clinical study of immediate postoperative perfusion combined with distilled water irrigation for..., Li [/bib_ref] [bib_ref] Clinical application of localization diagnosis and treatment in the early non-muscle invasive..., Li [/bib_ref] [bib_ref] Intravesical instillation of pirarubicin aftre transurethral resection of bladder for superficial bladder..., Wang [/bib_ref] [bib_ref] A therapeutic effect analysis of the comparative early intravesical instillation of pirarubicin..., Wang [/bib_ref] [bib_ref] Effect of early postoperative intravesical instillation of Pirarubicin on prevention of postoperative..., Wang [/bib_ref] [bib_ref] Intravesical instillation of mitomycin C at different time after transurethral resection for..., Xu [/bib_ref] [bib_ref] The action on the recurrence of non-muscleinvasive bladder carcinoma using immediate and..., Yu [/bib_ref] [bib_ref] Comparison of two different perfusion methods after resection of bladder tumor, Zhang [/bib_ref] [bib_ref] Clinical observation of postoperative bladder perfusion with pirarubicin for transurethral resection of..., Zhang [/bib_ref] [bib_ref] Intravesical instillation of THP immediately and regularly after transurethral resection of superficial..., Zhang [/bib_ref] [bib_ref] Clinical significance of instantly intravesical instillation of pirarubicin for preventing recurrence of..., Zhang [/bib_ref] , with a total of 1682 patients and a maximum follow-up time of 60 months. Results showed that in terms of effectiveness, TURBT combined with immediate single intravesical infusion chemotherapy after operation reduced the 1-year recurrence rate (RR = 0.51, 95% CI 0.35-0.75), 2-year recurrence rate (RR = 0.49, 95% CI 0.39-0.63) and 3-year recurrence rate (RR = 0.52, 95% CI 0.30-0.88) of NMIBC patients; there was no significant difference in the recurrence-free survival between the two groups (HR = 1.80, 95% CI 0. . In terms of the safety, there was no statistical difference between the two groups in the incidence of hematuria (RR = 1.34, 95% CI 0.59-3.07), bladder irritation (RR = 1.26, 95% CI 0.93-1.69), cystitis (RR = 0.80, 95% CI 0.22-2.85), fever (RR = 0.93, 95% CI 0.14-6.30) and allergy (RR = 3.95, 95% CI 0. . There was no heterogeneity among the studies included in the above outcome indicators. (3) We also referred to the EAU guideline [11], AUA guideline, CUA guideline, NICE guideline, NCCN guideline [18], and Guidelines for Diagnosis and Treatment of Urology and Andrology in China [7] (Additional file 2: Question 8). ## Question 9: do patients with low-risk tumors only need sic after turbt? Recommendation: Only SIC following TURBT is needed for patients with low-risk tumors. (Evidence level: 4; Strength of recommendation: Strong). Evidence summary: We referred to the recommendations from the EAU guideline [11], AUA guideline, CUA guideline, NICE guideline, NCCN guideline [18], and Guidelines for Diagnosis and Treatment of Urology and Andrology in China[7], summary of recommendations on chemotherapy for NMIBC patients with different risk levels are shown in Additional file 2: Table S1 (Additional file 2: Question 9). ## Question 10: what are the commonly used drugs and doses for the intravesical chemotherapy? Recommendation: Drugs, such as gemcitabine, pirarubicin, hydroxycamptothecin, mitomycin-C, doxorubicin and epirubicin, are recommended for intravesical chemotherapy. Under the premise of safe dosage and patients' tolerance, full-dose intravesical chemotherapy is recommended. (Evidence level: 1a; Strength of recommendation: Strong). Implementation consideration: Commonly used intravesical chemotherapy drugs and their common doses are: Gemcitabine (1000 mg), pirarubicin (30-50 mg), hydroxycamptothecin (10-20 mg), mitomycin-C (20-60 mg), doxorubicin (30-50 mg) and epirubicin (50-80 mg) per usage. Evidence summary: We conducted 5 meta-analyses and referred to the recommendations from relevant systematic reviews, guidelines and monographs. (1) To compare the efficacy and safety of gemcitabine and pirarubicin for the intravesical infusion chemotherapy of NMIBC, a total of 31 RCTs (32 studies) were included in the meta-analysis, with a total of 2182 patients and a maximum follow-up time of 36 months. Results showed that the 1-year recurrence rate (RR = 0.58, 95% CI 0.40-0.84), 2-year recurrence rate (RR = 0.58, 95% CI 0.48-0.70) and 3-year recurrence rate (RR = 0.51, 95% CI 0.31-0.84) of gemcitabine group were lower than those of pirarubicin group, but there was no significant difference in 1-year progression rate (RR = 0.60, 95% CI 0.35-1.02) and 3-year progression rate (RR = 0.50, 95% CI 0.05-5. [bib_ref] Novel visualization methods assisted transurethral resection for bladder cancer: an updated survivalbased..., Li [/bib_ref] between the two groups; The recurrence risk in gemcitabine group was 0.47 times of that in pirarubicin group (HR = 0.47, 95% CI 0.25-0.89). In terms of safety, the incidence of cystitis (RR = 0.35, 95% CI 0.14-0.86), bladder irritation (RR = 0.54, 95% CI 0.44-0.65) and hematuria (RR = 0.35, 95% CI 0.23-0.52) in gemcitabine group was lower than that in pirarubicin group. There was no significant difference in the incidence of fever (RR = 0.77, 95% CI 0.33-1.79) and allergic reaction (RR = 0.44, 95% CI 0.17-1.17) between the two groups. There was no heterogeneity among the included studies for the above outcome indicators. Subgroup analysis was carried out according to the dosages and medication schemes. The results showed that the conventional dose of gemcitabine (1000 mg) produced better outcome than the conventional dose group of pirarubicin (30-50 mg) in terms of efficacy indexes (1-year, 2-year and 3-year recurrence rate) and safety indexes (cystitis, bladder irritation sign and hematuria). Under the drug regimen of immediate combined induction and maintenance instillation after TURBT operation in both groups, gemcitabine group saw better outcome than pirarubicin group in terms of efficacy indexes (1-year and 2-year recurrence rate) and safety indexes (cystitis, bladder irritation sign and hematuria) (Additional file 3: [fig_ref] Table S1: of the Union for International Cancer Control [/fig_ref]. (2) To compare the efficacy and safety of pirarubicin and hydroxycamptothecin for the intravesical infusion chemotherapy of NMIBC, a total of 14 RCTs [bib_ref] Clinical effect of anticancer drug perfusion in preventing postoperative recurrence of superficial..., Zhang [/bib_ref] [bib_ref] Comparison of the therapeutic effect of three drugs by bladder instillation after..., Chen [/bib_ref] [bib_ref] The clinical investigation of different intravesical instillation of chemotherapy after transurethral resection..., Tu [/bib_ref] [bib_ref] Therapeutic comparison of bladder instillation with hydroxycamptothecine and pirarubicin on preventing the..., Guan [/bib_ref] [bib_ref] Efficacy of pirarubicin combined with hydroxycamptothecin in preventing recurrence after resection of..., Tao [/bib_ref] [bib_ref] Clinical effects of different intravesical instillation chemotherapies on non-muscle invasive bladder cancer..., Long [/bib_ref] [bib_ref] Clinical study of intravesical pirarubicin instillation for preventing postoperative recurrence of superficial..., Pu [/bib_ref] [bib_ref] Clinical efficacy of intravesical instillation of pirarubicin combined with Hydroxycamptothecin in the..., Mao [/bib_ref] [bib_ref] Clinical effect of the pirarubicin in the treatment of non-muscle invasive bladder..., He [/bib_ref] [bib_ref] Efficacy of TURBT combined with hydroxycamptothecin and pirarubicin intravesical perfusion in the..., Feng [/bib_ref] [bib_ref] THP and hydroxycamptothecin for prevention of postoperative superficial bladder cancer recurrence clinical..., Li [/bib_ref] [bib_ref] Comparison of therapeutic effects of different perfusion drugs after electroresection of superficial..., Wang [/bib_ref] [bib_ref] Comparison of efficacy of intravesical instillation of hydroxycamptothecin and pirarubicin in preventing..., Nan [/bib_ref] were included in the meta-analysis, with a total of 1284 patients and a maximum follow-up time of 60 months. Results showed that, in terms of effectiveness, there was no significant difference between the pirarubicin group and the hydroxycamptothecin group in the 1-year recurrence rate (RR = 0.79, 95% CI 0.58-1.07), 2-year recurrence rate (RR = 0.80, 95% CI 0.61-1.05), 3-year recurrence rate (RR = 0.84, 95% CI 0.37-1.91), 4-year recurrence rate (RR = 0.92, 95% CI 0.44-1.95) and 5-year recurrence rate (RR = 0.73, 95% CI 0.43-1.23). In terms of safety, there was no difference between the two groups in the incidence of total adverse reactions (RR = 1.38, 95% CI 0.71-2.70) and hematuria (RR = 0.99, 95% CI 0.60-1.62), but the incidence of bladder irritation (RR = 1.39, 95% CI 1.14-1.70) in pirarubicin group was higher than that in hydroxycamptothecin group. Except for the indicators of total adverse reaction, there was no heterogeneity among the studies included in the above outcome indicators. Subgroup analysis was carried out according to the dosages and medication schemes. The results showed that the 2-year recurrence rate and the incidence of bladder irritation in the pirarubicin (30-50 mg) group were lower than those in the hydroxycamptothecin (10-20 mg) group. There was no significant difference in these indicators between the two groups under different medication schemes (Additional file 3: [fig_ref] Table S1: of the Union for International Cancer Control [/fig_ref]. (3) To compare the efficacy and safety of pirarubicin and mitomycin-C for the intravesical infusion chemotherapy of NMIBC, a total of 25 RCTs [bib_ref] Clinical effect of anticancer drug perfusion in preventing postoperative recurrence of superficial..., Zhang [/bib_ref] [bib_ref] Effect of intravesical infusion of different chemotherapeutic drugs on preventing tumor recurrence..., Dong [/bib_ref] [bib_ref] Comparison of the therapeutic effect of three drugs by bladder instillation after..., Chen [/bib_ref] were included in the meta-analysis, with a total of 2026 patients and a maximum follow-up time of 75 months. Results showed that, in terms of effectiveness, the 1-year recurrence rate (RR = 0.50, 95% CI 0.36-0.68) and 2-year recurrence rate (RR = 0.45, 95% CI 0.36-0.57) of the pirarubicin group were lower than those of the mitomycin-C group, but there was no significant difference in the 3-year recurrence rate between the two groups (RR = 0.66, 95% CI 0.42-1.03). In terms of safety, the incidences of total adverse reactions (RR = 0.55, 95% CI 0.42-0.73), bladder irritation sign (RR = 0.60, 95% CI 0.48-0.76) and hematuria (RR = 0.53, 95% CI 0.30-0.94) in the pirarubicin group were lower than that in the mitomycin-C group. There was no significant difference in the incidence of cystitis between the two groups (RR = 0.94, 95% CI 0.37-2.39). Except for the indicators for total adverse reactions and cystitis, there was no heterogeneity among the included studies in other outcome indicators. Subgroup analysis was carried out according to the dosages and medication schemes. The results showed that when comparing the prognosis of patients under different doses of pirarubicin and mitomycin-C, the 2-year recurrence rates in the pirarubicin group were all lower than that in the mitomycin-C group. In the patients treated with induction and maintenance instillation, or combined induction and maintenance instillation immediately after TURBT, the 1-year and 2-year recurrence rates of the pirarubicin group were lower than those of the mitomycin-C group (Additional file 3: [fig_ref] Table S1: of the Union for International Cancer Control [/fig_ref]. (4) To compare the efficacy and safety of intravesical instillation chemotherapy with different doses of epirubicin in the treatment of NMIBC, a total of 8 RCTs (12 studies) [bib_ref] Effect of prophylactic treatment with intravesical epirubicin on recurrence of superficial bladder..., Kuroda [/bib_ref] [bib_ref] Randomized study of single instillation of epirubicin for superficial bladder carcinoma: longterm..., Liu [/bib_ref] [bib_ref] Intravesical chemotherapy with epirubicin: a dose response study, Masters [/bib_ref] [bib_ref] Single intravesical instillation of epirubicin for primary superficial bladder carcinoma: long-term results, Liu [/bib_ref] [bib_ref] Cost-effectiveness analysis of epirubicin bladder perfusion in preventing postoperative recurrence of superficial..., Lv [/bib_ref] [bib_ref] The clinical research on preventing the recurrence of superficial bladder cancer by..., Liang [/bib_ref] [bib_ref] Single or consecutive instillation of epirubicin or mitomycin C for the prophylaxis..., Zhang [/bib_ref] [bib_ref] Efficacy and safty of different dosages of intravesical epirubicin instillation for prevention..., Wu [/bib_ref] were included in the meta-analysis, with a total of 1114 patients and a maximum follow-up time of 60 months. Results showed that there was no significant difference in the efficacy (1-year and 2-year recurrence rate) and safety (total adverse reaction rate) between the groups of high-dose (> 80 mg) vs. common-dose (50-80 mg), high dose (> 80 mg) vs. low dose (< 50 mg), common dose (50-80 mg) vs. low dose (< 50 mg) of epirubicin in the treatment of NMIBC. (5) To compare the efficacy and safety of intravesical instillation chemotherapy with different doses of pirarubicin in the treatment of NMIBC, 2 RCTs (4 studies) [bib_ref] Effectiveness and safety of different doses of pirarubicin on preventing non-muscle invasive..., Deng [/bib_ref] [bib_ref] Single bladder pirarubicin perfusion to prevent the recurrence of superficial bladder carcinoma, Peng [/bib_ref] were included in the meta-analysis, with a total of 258 patients and a maximum follow-up time of 38 months. Results showed that the 2-year recurrence rate under pirarubicin treatment (RR = 0.35, 95% CI 0.18-0.68; RR = 0.44, 95% CI 0.22-0.89) was lower in 50 mg dosage group than that in the 30 mg or 40 mg dosage groups, but the incidence of bladder irritation (RR = 1.91, 95% CI 1. ; RR = 2.15, 95% CI 1.19-3.89) was higher in 50 mg pirarubicin group. There was no significant difference in the above indexes between the dose groups of pirarubicin at 40 mg and 30 mg. (6) A network meta-analysis published in 2020 evaluated the efficacy of mitomycin-C, doxorubicin, epirubicin, gemcitabine and thiotepa in the treatment of NMIBC, including 55 RCTs and 12,462 patients [bib_ref] Efficacy of intravesical therapies on the prevention of recurrence and progression of..., Lu [/bib_ref]. Results showed that compared with TURBT only, except doxorubicin (HR = 0.94, 95% CI 0.66-1.35) and cetidipine (HR = 0.36, 95% CI 0.10-1.26), the other three chemotherapeutic drugs could reduce the risk of disease progression, with a ranking of gemcitabine > mitomycin-C > epirubicin in their superiority of therapy. Except for cetidipine (HR = 0.69, 95% CI 0.41-1.14), the other four chemotherapeutic drugs could reduce the risk of recurrence, with a ranking of gemcitabine > mitomycin-C > epirubicin > doxorubicin in their superiority of therapy. Considering the combined results ofrecurrence and progression, gemcitabine was the most effective treatment regimen. In the subgroup analysis according to drug regimen, tumor characteristics and literature quality, the results are still stable. (7) We also referred to the EAU guideline [11], NICE guideline, NCCN guideline [18], and Guidelines for Diagnosis and Treatment of Urology and Andrology in China [7] (Additional file 2: Question 10). ## Question 11: how to improve the efficacy of intravesical chemotherapy? Recommendation: The efficacy of intravesical chemotherapy can be improved by reduction of fluid intake and urine excretion to maintain the drug concentration, instillation for 0.5-2 h (according to the drug instructions), or hyperthermic instillation. (Evidence level: 4; Strength of recommendation: Strong). Evidence summary: We referred to the recommendations from the EAU guideline Evidence summary: We referred to the recommendations from the Guidelines for Diagnosis and Treatment of Urology and Andrology in China [7]: Chemical cystitis, manifesting as bladder irritation symptoms and hematuria, is the main adverse reaction from intravesical chemotherapy, the severity of which is dependent on the dosage and frequency of instillation. If severe bladder irritation symptoms occur, the instillation should be delayed or stopped to avoid consequential bladder contracture. Most adverse reactions disappear spontaneously after discontinuation of instillation. ## Question 14: is intravesical bcg immunotherapy prior to intravesical chemotherapy in patients with nmibc? Recommendations: (1) For patients with high-risk tumors, intravesical BCG immunotherapy is recommended. (Evidence level: 1a-1b; Strength of recommendation: Strong). (2) For patients with intermediate-risk tumors, intravesical chemotherapy (Evidence level: 1a-1b; Strength of recommendation: Strong) or intravesical BCG immunotherapy (Evidence level: 1a-1b; Strength of recommendation: Weak) is recommended. Implementation consideration: Treatment schemes for intravesical BCG immunotherapy: starting intravesical BCG instillation within 2-4 weeks after TURBT; The patients should first be given BCG induction instillation for 6-8 weeks (once a week), followed by BCG maintenance instillation for 1-3 years (once for a week for 3 continuous weeks at 3 and 6 months after TURBT), and then repeat the treatment every 6 months (once a week for 3 continuous weeks). Evidence summary: We conducted a meta-analysis and referred to the recommendations from relevant systematic reviews, guidelines and monographs. The results from different systematic reviews varied due to the heterogeneous patient characteristics, follow-up times, drugs, medication schemes and other factors. However, most of the studies showed that BCG instillation can reduce the risk of tumor recurrence in the patients with high and medium-risk tumors. (1) We conducted a meta-analysis to compare the efficacy and safety between intravesical BCG immunotherapy and intravesical chemotherapy in the treatment of NMIBC. A total of 25 studies (35 studies) were included, with a total of 3820 patients with a maximum follow-up time of 80 months. Results showed that in terms of efficacy, the 2-year recurrence rate (RR = 0.60, 95% CI 0.38-0.96) of BCG group was lower than that of chemotherapy group, but there was no significant difference in the 3-year recurrence rate (RR = 0.69, 95% CI 0.44-1.07), 4-year recurrence rate (RR = 1.84, 95% CI 0.72-4.68) and 5-year recurrence rate (RR = 0.74, 95% CI 0.50-1.10) between the two groups. There was no significant difference in 1-year disease progression rate (RR = 0.69, 95% CI 0.20-2.37), 2-year disease progression rate (RR = 0.58, 95% CI 0.20-1.70) and 3-year disease progression rate (RR = 0.28, 95% CI 0.06-1.38) between the two groups, but the 5-year disease progression rate in BCG group was lower than that in chemotherapy group (RR = 0.58, 95% CI 0.36-0.91). There was no significant difference in the 5-year mortality between the two groups (RR = 0.80, 95% CI 0.59-1.08). The recurrence free survival in BCG group was 0.45 times that in chemotherapy group (HR = 0.45, 95% CI 0.32-0.63), but there was no significant difference in the overall survival between the two groups (HR = 0.90, 95% CI 0.71-1.. In terms of safety, the incidence of bladder irritation (RR = 2.41, 95% CI 1.57-3.69), hematuria (RR = 1.80, 95% CI 1.46-2.21), cystitis (RR = 2.29, 95% CI 1.72-3.05) and fever (RR = 4.70, 95% CI 3.09-7.14) in BCG group were significantly higher than those in chemotherapy group. Except for the 1-year recurrence rate, 4-year recurrence rate and hematuria index, there was no heterogeneity among the studies included in the outcome indicators mentioned above. 1) Subgroup analysis was conducted according to the BCG instillation time (≤ 1 year, > 1 year). When the instillation time was ≤ 1 year, the 2-year and 3-year recurrence rate of BCG group was lower than that of chemotherapy group, but the incidence of bladder irritation, hematuria, cystitis and fever was significantly higher than that of chemotherapy group. When the instillation time was > 1 year, the 5-year recurrence rate of BCG group was lower than that of chemotherapy group, and the safety index results of the two groups remained unchanged (Additional file 3: [fig_ref] Table 2: Management of BCG side effectsBCG Bacillus Calmette-Guérin, TURBT transurethral resection of bladder... [/fig_ref]. 2) Subgroup analysis was conducted according to the dosage of BCG. When the dosage of BCG was less than 80 mg, the 5-year recurrence rate of BCG group was lower than that of chemotherapy group, but there was no significant difference in the incidence of cystitis and allergy between the two groups. When the dose of BCG was 80-120 mg, the 2-year and 5-year recurrence rate of BCG group was lower than that of chemotherapy group, but the incidence of bladder irritation, hematuria, cystitis and fever were significantly higher than that of chemotherapy group. When the dose of BCG was > 120 mg, the 3-year recurrence rate of BCG group was lower than that of chemotherapy group, and the incidence of hematuria, cystitis and fever was significantly higher than that of chemotherapy group (Additional file 3: [fig_ref] Table 2: Management of BCG side effectsBCG Bacillus Calmette-Guérin, TURBT transurethral resection of bladder... [/fig_ref]. 3) Subgroup analysis was also conducted according to the BCG instillation scheme. For the induction plus maintenance instillation scheme, the 2-year and 5-year recurrence rate and the 5-year progression rate of BCG group were lower than those of chemotherapy group, but the incidence of bladder irritation, hematuria, cystitis and fever were higher than those of chemotherapy group (Additional file 3: [fig_ref] Table 2: Management of BCG side effectsBCG Bacillus Calmette-Guérin, TURBT transurethral resection of bladder... [/fig_ref]. 4) Since most of the included studies could not distinguish the risk levels of the included patients, subgroup analysis was not conducted according to the risk level of patients. (2) A network meta-analysis published in 2020 evaluated the efficacies of BCG, mitomycin-C, doxorubicin, epirubicin, gemcitabine and thiotepa in the treatment of NMIBC, including 55 RCTs and 12,462 patients [bib_ref] Efficacy of intravesical therapies on the prevention of recurrence and progression of..., Lu [/bib_ref]. Results showed that in terms of reducing the risk of recurrence, BCG was better than mitomycin-C, doxorubicin, epirubicin and cetiritin, but there was no statistical difference when compared with gemcitabine. The ranking in reducing the recurrence risk was as follows: Gemcitabine > BCG > mitomycin-C > epirubicin > cetiritin > doxorubicin. In terms of reducing the risk of progression, BCG was superior to doxorubicin and epirubicin, but there was no significant difference when comparing it with gemcitabine, mitomycin-C and cetidipine. The ranking was as follows: gemcitabine > BCG > mitomycin-C > cetidipine > epirubicin > doxorubicin. In the subgroup analysis according to drug regimen, tumor characteristics and literature quality, the results were still stable. (3) A systematic review published by the Cochrane library in 2020 evaluated the efficacy and safety of BCG and mitomycin-C in patients with high-risk Ta and T1 bladder cancer [bib_ref] Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer, Schmidt [/bib_ref]. It included a total of 12 RCTs and 2932 patients. Results showed that there was no significant difference between BCG and mitomycin-C in reduction of all-cause death (HR = 0.97, 95% CI 0.79-1.20), tumor recurrence (HR = 0.88, 95% CI 0.71-1.09) and tumor progression (HR = 0.96, 95% CI 0.73-1.26), and there was no significant difference between them in serious adverse reactions (RR = 2.31, 95% CI 0.82-6.52) too. The grade of evidence quality of the above indicators is classified as low level. (4) We also referred to the EAU guideline [11], AUA guideline, CUA guideline, NICE guideline, and Guidelines for Diagnosis and Treatment of Urology and Andrology in China [7] (Additional file 2: Question 14). ## Question 15: is a standard dose of bcg immunotherapy superior to a low dose of bcg immunotherapy for the patients with intermediate-risk and high-risk nmibc? Recommendations: (1) For patients with high-risk tumors, a standard dose of BCG immunotherapy is rec- Evidence summary: We conducted one meta-analysis and referred to the recommendations from relevant systematic reviews, guidelines and monographs. (1) We conducted a meta-analysis to compare the efficacy and safety of low-dose BCG and standard dose BCG in the treatment of NMIBC [bib_ref] Efficacy and safety of low dose and standard dose bacillus calmette guerin..., Li [/bib_ref]. A total of 13 RCTs (18 studies) were included, with a total of 2903 patients and the maximum follow-up time of 84 months. Results showed that in terms of efficacy, the recurrence risk was higher in low dose BCG treated patients than that in the standard dose GCG group (HR = 1.21, 95% CI 1.06-1.39), but there was no significant difference in the risk of progression between the groups with the two dosages (HR = 1.09, 95% CI 0.86-1.38). In terms of safety, the incidence of total adverse reactions (RR = 0.64, 95% CI 0.51-0.80), systemic adverse reactions (RR = 0.67, 95% CI 0.47-0.95) and serious adverse reactions (RR = 0.51, 95% CI 0.35-0.73) in the low-dose BCG group were lower than those in the standard-dose BCG group, but there was no significant difference in the incidence of local adverse reactions (RR = 0.92, 95% CI 0.79-1.07) between the two groups. There was no heterogeneity for the above efficacy indicators among the studies, but heterogeneity existed in the safety indicators among the studies included. 1) Subgroup analysis was performed according to the instillation scheme (simple induction, induction plus maintenance) (Additional file 3: . The analysis results showed that the efficacy outcomes of the two groups were consistent with the above conclusions, and the overall adverse reactions of the low-dose BCG group were less than that of the standard dose BCG group. Because the included literature mostly did not demonstrate the risk levels of the patients, subgroup analysis was not performed according to the risk level of the patients. 2) Among the included studies, the results of an RCT [bib_ref] Final results of an EORTC-GU cancers group randomized study of maintenance bacillus..., Oddens [/bib_ref] (n = 1349) showed that, for patients with high-risk tumors (multiple tumors, recurrence times ≥ 2, G3, CIS), the standard dose of BCG was advantageous over the 1/3 standard dose treatment in reducing the risk of disease recurrence. For patients with intermediate-risk tumors, there was no significant difference in reducing the risk of disease recurrence between the standard-dose and 1/3 standard-dose BCG groups. 3) The low doses of BCG used in these included studies were 27 mg, 40 mg, 45 mg and 60 mg, and the standard doses were 80 mg, 81 mg, 90 mg, 100 mg and 120 mg. In the meta-analysis conducted by the evidence synthesis group, the low dose of BCG was defined as < 80 mg, and the standard dose of BCG was defined as 80-120 mg. 4) According to the conclusions of the meta-analysis, it is suggested to stratify the recommendations per the risk levels of the patients, that is, standard dose of BCG immunotherapy is recommended for high-risk patients and low-dose BCG perfusion therapy is recommended for intermediate-risk ## Question 16: is bcg induction plus its maintenance instillation superior to bcg induction instillation alone in the patients with nmibc? Recommendation: BCG induction plus its maintenance instillation is recommended for NMIBC patients with intermediate-risk and high-risk tumors. (Evidence level: 1a; Strength of recommendation: Strong). Implementation consideration: The instillation scheme generally includes 6-8 weeks (once a week) of BCG induction instillation within 2-4 weeks after TURBT, and 1-3 years of BCG maintenance instillation. The 1-year maintenance instillation scheme can be considered: after the induction instillation, start the intensive instillation once 2 weeks for a total of 3 continuous times, followed by maintenance instillation once a month for a total of 10 times. For the patients with high-risk tumors, a 3-year maintenance instillation scheme can be considered: after induced instillation, start the continuous instillation for 3 weeks periodically at the 3rd, 6th, 12th, 18th, 24th, 30th and 36th months respectively. Evidence summary: We conducted a meta-analysis and referred to the recommendations from relevant systematic reviews, guidelines and monographs. (1) We conducted the meta-analysis to compare the efficacy and safety of BCG induction plus maintenance instillation and induction instillation alone in NMIBC patients [bib_ref] Efficacy of bacille Calmette-Guérin induction therapy and bacille Calmette-Guérin induction plus with..., Qin [/bib_ref]. Thirteen RCTs were included, with a total of 1625 patients and a maximum follow-up time of 120 months. Results showed that, in terms of efficacy, compared with BCG induction instillation alone, BCG induction plus maintenance instillation reduced the recurrence risk (HR = 0.53, 95% CI 0.42-0.65), progression risk (HR = 0.72, 95% CI 0.53-0.90) and overall rate of tumor recurrence and progression (RR = 0.78, 95% CI 0.62-0.98) In terms of safety, the incidences of frequent urination, dysuria, urinary pain, gross hematuria, fever and fatigue in the BCG induction plus maintenance group were higher than that in the simple induction group. There was no heterogeneity among the included studies for the indicators of recurrence risk and progression risk, but there was heterogeneity among the studies in the indicators of overall rate of recurrence and progression. 1) Among the 13 RCTs included, 10 RCTs were studied in NMIBC patients with intermediate-risk or high-risk tumors. When analysis was conducted for these patients with intermediate-risk or high-risk tumors, the results showed that compared with BCG induction instillation alone, BCG induction plus maintenance instillation reduced the recurrence risk, progression risk and the overall rate of recurrence and progression (Additional file 3: . 2) Among the 13 RCTs included, 6 RCTs focused on NMIBC patients with high-risk tumors. When analysis was conducted for these patients with high-risk tumors, the results showed that compared with BCG induction instillation alone, BCG induction plus maintenance instillation reduced the recurrence risk and the overall rate of recurrence and progression, but there is no significant difference in the progression risk (Additional file 3: . 3) Subgroup analysis was performed according to the time of maintenance instillation (< 2 years, ≥ 2 years) and BCG dosages (≤ 81 mg, > 81 mg) (Additional file 3: . The results showed that no matter whether the maintenance perfusion time was ≥ 2 years or < 2 years, the induction plus maintenance instillation had an advantage over simple induction instillation in reducing the recurrence risk. In the patients with the maintenance instillation dose ≤ 81 mg, the induction plus maintenance instillation had advantages over simple induction instillation in reducing the recurrence risk, the progression risk, and the overall rate of recurrence and progression. (2) We also referred to the EAU guideline [11], AUA guideline, CUA guideline, NICE guideline, and Guidelines for Diagnosis and Treatment of Urology and Andrology in China [7] (Additional file 2: Question 16). ## Question 17: for the patients with nmibc, is the 3-year bcg maintenance instillation superior to the 1-year maintenance instillation? Recommendations: (1) For patients with high-risk tumors, standard dose of BCG maintenance instillation for 1-3 years is recommended. Implementation consideration: The 3-year maintenance instillation scheme can be as follows: induction instillation for 6-8 weeks after TURBT (once/week), and then followed by the maintenance instillation for 3 weeks at the 3rd, 6th, 12th, 18th, 24th, 30th and 36th months. The 1-year maintenance instillation scheme can be the following: induction instillation for 6-8 weeks (once/ week), followed by intensive instillation once 2 weeks for a total of 3 continuous times, and then maintenance instillation once a month for a total of 10 times. Evidence summary: We referred to the recommendations from relevant systematic reviews, guidelines and monographs. (1) An RCT published in 2013 included 1355 patients and compared the therapeutic effects of 1-year maintenance instillation and 3-year maintenance instillation [bib_ref] Final results of an EORTC-GU cancers group randomized study of maintenance bacillus..., Oddens [/bib_ref]. The results showed that the 5-year recurrence-free rates resulted from the 1-year and 3-year maintenance instillation were 56.6% and 63.4% respectively. In the high-risk patients who received standarddose treatment, the 3-year maintenance instillation further reduced the recurrence risk compared with the 1-year maintenance instillation (HR = 0.62, 95% CI 0.43-0.88). For the intermediate-risk patients who received 1/3 standard-dose treatment, the 3-year maintenance instillation reduced the recurrence risk compared with the 1-year maintenance instillation (HR = 0.74, 95% CI 0.56-0.97). (2) We also referred to the EAU guideline [11], AUA guideline, CUA guideline, and NCCN guideline [18] (Additional file 2: Question 17). ## Question 18: what is the treatment option after the intravesical bcg immunotherapy failed? Recommendations: (1) For the patients with high-risk recurrences, (T1 stage, CIS, or high-grade tumor), radical cystectomy is recommended. (Evidence level: 4; Strength of recommendation: Strong). (2) For the patients with high-risk recurrences but not suitable for or refuse a radical cystectomy, bladder preservation strategies (comprehensive treatment, intravenous chemotherapy, etc.) can be offered. (Evidence level: 1b; Strength of recommendation: Weak). Implementation consideration: Recurrence of lowrisk tumors after BCG instillation is not considered treatment failure, and BCG instillation can be offered again. The treatment option for the recurrence of intermediate-risk tumors is between the intensity of options for low-risk and high-risk recurrence. The actual choice is to be determined through full discussion between doctors and patients. Evidence summary: We referred to the recommendations from relevant systematic reviews, guidelines and monographs. (1) A systematic review published in 2020 evaluated the efficacy of bladder-sparing therapies after BCG treatment failure, including 4 randomized controlled trials and 24 single arm studies [bib_ref] Evidence-based assessment of current and emerging bladdersparing therapies for non-muscle-invasive bladder cancer..., Kamat [/bib_ref]. The results showed that the 12-month response rates were 24% for the patients who received two or more prior courses of BCG and 36% for those who received one or more prior courses of BCG. (2) A systematic review published in 2020 including 42 studies with 24 treatment regimens and 2254 patients with NMIBC [bib_ref] Systematic review of the therapeutic efficacy of bladder-preserving treatments for non-muscle-invasive bladder..., Li [/bib_ref] also evaluated the efficacy of bladder-preserving therapies after BCG treatment failure. The results showed that the bladder-sparing treatments produced a median complete response rate of 26% at 6 months, 17% at 12 months and 8% at 24 months in the patients with CIS. In contrast, they produced the median recurrence-free rate of 67% at 6 months, 44% at 12 months and 10% at 24 months in the patients with bladder papilloma. (3) We also referred to the EAU guideline [11], AUA guideline, CUA guideline, NICE guideline, and Guidelines for Diagnosis and Treatment of Urology and Andrology in China[7] (Additional file 2: Question 18; Additional file 2: Tables S2, S3). ## Question 19: how to manage the side effects of intravesical bcg immunotherapy? Recommendation: The side effects of intravesical BCG immunotherapy include local and systemic side effects, and the corresponding managements are shown in [fig_ref] Table 2: Management of BCG side effectsBCG Bacillus Calmette-Guérin, TURBT transurethral resection of bladder... [/fig_ref]. (Evidence level: 4; Strength of recommendation: Strong). Evidence summary: We referred to the recommendations from the EAU guideline [11], CUA guideline, and Guidelines for Diagnosis and Treatment of Urology and Andrology in China [7] (Additional file 2: Question 19; Additional file 2: Tables S4, S5). ## Section 4: clinical concerns related to the combination therapy question 20: for the patients with nmibc, is the combination therapy (intravesical bcg immunotherapy combined with intravesical chemotherapy) superior to the intravesical bcg immunotherapy alone? Recommendation: For the BCG-unresponsive patients who are not suitable or refuse radical cystectomy, intravesical BCG immunotherapy combined with intravesical chemotherapy can be considered. (Evidence level: 1a-1b; Strength of recommendation: Weak). Implementation consideration: The following treatment scheme can be considered for intravesical BCG instillation combined with intravesical chemotherapy: Single postoperative instillation of intravesical chemotherapy should be offered immediately after TURBT. Next, the patients should be given maintenance chemotherapy 2-3 times (once a week) followed by BCG instillation immunotherapy (80-120 mg) 2-3 times (once a week), which should be started within 2-3 weeks after TURBT. Then the above intravesical chemotherapy and intravesical BCG instillation should be given alternately for a total of 2-3 months. After that, intravesical chemotherapy and intravesical BCG instillation are still offered alternately but the frequency should be changed to once a month. The whole course of combined treatment lasts for 10-12 months. Evidence summary: We conducted a meta-analysis and referred to the recommendations from relevant systematic reviews, guidelines and monographs. (1) We conducted a meta-analysis to compare the efficacy and safety of BCG combined chemotherapy (combined group) and BCG alone (BCG group) in the treatment of NMIBC [bib_ref] Bacille Calmette-Guérin alone in non-muscle invasive bladder cancer: a metaanalysis, Huang [/bib_ref]. A total of 13 RCTs were included, with a total of 1754 patients and a maximum follow-up time of 121 months. Results showed that, compared with BCG group, the combined group improved the recurrencefree survival (HR = 0.53, 95% CI 0.43-0.66), overall survival (HR = 0.66, 95% CI 0.50-0.86) and disease-specific survival (bladder cancer) (HR = 0.48, 95% CI 0.29-0.80), but there was no significant difference in the progression-free survival between the two groups (HR = 0.65, 95% CI 0.25-1.68). In terms of safety, the incidence of gastrointestinal reactions (RR = 2.54, 95% CI 0.61-10.60), cystitis (RR = 0.67, 95% CI 0.29-1.54) in the combined group were not significantly different from those in the BCG group. The incidence of fever (RR = 0.50, 95% CI 0.27-0.91), bladder irritation (RR = 0.69, 95% CI 0.52-0.90) and hematuria (RR = 0.50, 95% CI 0.28-0.89) were significantly decreased in the combined group compared to those in the BCG group. There was no heterogeneity among the studies for the above outcome indicators. 1) Subgroup analysis was conducted according to the geographical locations of the studies (China, non-China), chemotherapy drugs used in the combined group (pirarubicin, mitomycin-C, epirubicin), maintenance treatment duration (≤ 1 year, > 1 year), and the facts whether patients were encountered with the complication of CIS (with CIS and without CIS). The conclusion was consistent with the above results, that is, the combined treatment was more advantageous in reducing the risk of recurrence and progression than the BCG group alone. 2) Due to the data limitation, the comparative effects of different courses and frequencies of the combined therapy and the comparative effects of different chemotherapeutic drugs in the combined therapy could not be analyzed. 3) Considering the toxic reactions of BCG, and the facts that most of the patients included in this meta-analysis were intermediate-risk or high-risk patients, the latter making up more than half of the total samples, which limited the feasibility of the conclusion in low-risk patients. Therefore, the combination therapy is not recommended for the non BCG-unresponsive patients. (2) We also referred to the EAU guideline [11] and CUA guideline(Additional file 2: Question 20). ## Section 5: clinical concerns related to the treatment of nmibc cis question 21: is intravesical bcg immunotherapy superior to intravesical chemotherapy in the patients with cis? Recommendation: For the patients with CIS, the intravesical BCG immunotherapy is recommended after TURBT. (Evidence level: 1a-1b; Strength of recommendation: Strong). Implementation consideration: For the patients with CIS who underwent radical cystectomy, intravesical BCG immunotherapy is not required. Intravesical BCG instillation usually starts 2-3 weeks after TURBT. Firstly, 6 weeks of induction instillation (once a week) is to be offered. Then those who are responsive to the induction instillation should be given the maintenance instillation for 1-3 years (continuous instillation for 3 weeks at the 3rd, 6th, 12th, 18th, 24th, 30th and 36th months). Evidence summary: We conducted a meta-analysis and referred to the recommendations from relevant systematic reviews, guidelines and monographs. (1) We conducted a meta-analysis to compare the efficacy and safety of intravesical BCG immunotherapy and intravesical chemotherapy in the treatment of NMIBC CIS patients. A total of 9 RCTs (11 studies) [bib_ref] Bacillus Calmette-Guerin versus epirubicin for primary. Secondary or concurrent carcinoma in situ..., De Reijke [/bib_ref] [bib_ref] Thiotepa versus bacille Calmette-Guérin in non-muscle invasive bladder cancer, Fallah [/bib_ref] [bib_ref] A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for..., Lamm [/bib_ref] [bib_ref] Intravesical chemotherapy (mitomycin C) versus immunotherapy (bacillus Calmette-Guérin) in superficial bladder cancer, Rintala [/bib_ref] [bib_ref] Results of a randomised controlled trial comparing intravesical chemohyperthermia with mitomycin c..., Arends [/bib_ref] [bib_ref] Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk..., Stasi [/bib_ref] [bib_ref] Equivalent efficacy of mitomycin C plus doxorubicin instillation to bacillus Calmette-Guerin therapy..., Droller [/bib_ref] [bib_ref] Risk factors in carcinoma in situ of the urinary bladder, Van Gils-Gielen [/bib_ref] [bib_ref] Long-term follow-up of an EORTC randomized prospective trial comparing intravesical bacille Calmette-Guérin-RIVM..., Witjes [/bib_ref] were included, with a total of 1231 patients and a maximum follow-up time of 148.8 months. The 11 studies included 1333 patients with high-risk tumors. Results showed that, in terms of effectiveness, intravesical BCG immunotherapy significantly reduced the 72-month recurrence rate (RR = 0.70, 95% CI 0.56-0.89) and the 143-month recurrence rate (RR = 0.18, 95% CI 0.05-0.72) compared with intravesical chemotherapy, but there was no significant difference between the two groups in the 12-month recurrence rate, 22-69-month and 143-148.8-month progression rate and 143-148.8month mortality. In terms of safety, the incidence of dysuria (RR = 2.25, 95% CI 1. , local adverse reactions (RR = 3.20, 95% CI 1. and systemic adverse reactions (RR = 12.00, 95% CI 1. in BCG instillation group were significantly higher than those in intravesical chemotherapy group, but there was no significant difference in the incidence of fever, hematuria and cystitis. There was no heterogeneity among the studies for the above outcome indicators. As the included studies adopted different follow-up duration and the number of studies included in the meta-analysis of these indicators were limited, the results should be interpreted with caution. (2) We also referred to the EAU guideline [11], AUA guideline, CUA guideline, NICE guidelineImplementation consideration: For the patients with recurrent low-risk tumors and small papilloma after intravesical chemotherapy, a single immediate instillation of intravesical chemotherapy can be administered. Currently, there is no evidence supporting the need of intravesical chemotherapy maintenance, and it is still controversial whether to perform single immediate instillation of chemotherapy alone. The treatment schedule for medium-risk recurrent tumors is between the aggressivity of low-risk and high-risk recurrent diseases, and the final choice can be determined by the discussion between doctors and patients. Evidence summary: We referred to the recommendations from the EAU guideline [11], AUA guideline, CUA guideline, and Guidelines for Diagnosis and Treatment of Urology and Andrology in China [7] (Additional file 2: Question 23). ## Section 8: clinical concerns related to the follow-up of patients with nmibc question 24: how to manage the follow-up for the nmibc patients after turbt? Recommendations: (1) For the patients with low-risk tumors, the first cystoscopy should be performed in the third month after TURBT, followed by a cystoscopy in the 12th month, and then cystoscopy should be performed once a year from the second to the fifth years. (Evidence level: 4; Strength of recommendation: Strong). (2) For the patients with intermediate-risk tumors, the first cystoscopy and urine cytology should be performed in the third month after TURBT, followed by tests of cystoscopy and urine cytology in the 6th, 9th, 12th, 18th and 24th months. Then cystoscopy and urine cytology should be performed once a year from the third to fifth years. In the first year, baseline examinations by upper urography, abdominal and pelvic imaging should be conducted. (Evidence level: 4; Strength of recommendation: Strong). (3) For the patients with high-risk tumors, cystoscopy and urine cytology should be performed every 3 months after TURBT. From the third to fifth years, cystoscopy and urine cytology should be performed once every six months. After the 6th year, cystoscopy and urine cytology should be performed once a year. Baseline examinations of upper urinary tract imaging and imaging of chest, abdomen and pelvis should be conducted within the first year. Additionally, the upper urinary tract imaging examination should also be performed at the 12th month and every 1-2 years after that for 10 years. (Evidence level: 4; Strength of recommendation: Strong). (4) Integrated dual-channel bladder catheter is recommended for the cystoscopy, which is effective to prevent potential infection and reduce the damage of cystoscope. (Evidence level: 1b; Strength of recommendation: Weak). Implementation consideration: Upper urography examinations include: CT urography, MR urography, intravenous urography, ascending urography or ureteroscopy. Baseline examination represents that performed in the perioperative period. If it is performed before TURBT, it does not need to be repeated within 1 year after TURBT. Evidence summary: We referred to the relevant clinical trials and recommendations from relevant systematic reviews, guidelines. (1) The evidence synthesis group conducted a randomized, open-labeled controlled trial to compare the efficacy and safety of integrated dualchannel cystoscopy in 140 Chinese patients (Clinical Trial Registration No.: chictr180014256). The results showed that the integrated dual-channel bladder catheter was equipped with high-definition camera, and well-sealed and connected to the cystoscope. It was convenient and comfortable for doctors to operate [6]. (2) We also referred to the EAU guideline [11], AUA guideline, CUA guideline, NICE guideline, and NCCN guideline . The relevant recommendations in the existing guidelines are shown in Additional file 2: (Additional file 2: Question 24). # Discussion During this guideline development, we adopted rigorous search techniques for the evidence synthesis and guideline development methodology was strictly followed for the formulation of recommendations. The medical resources and conditions in the primary medical institutions were also taken into account to justify the recommendations. Meanwhile, attention should be paid to the following points in the future research or update of future guidelines: (1) Many clinical managements lack the support from research evidence or high-quality research evidence, such as the treatment measures of recurrent NMIBC. Meanwhile, the difference in the tumor characteristics, adopted drugs and drug regimens raised heterogeneity among the research results. Thus, high-quality clinical trials are needed to provide solid comparable evidence. (2) To meet the medical resources and conditions in primary medical institutions, researches conducted in the primary medical institutions can provide more appropriate evidence than studies conducted in other medical institutions for the recommendations targeting NMIBC patients in these institutions. However, few studies we searched met this condition. (3) The evidence from health economics is the factor to be considered in determining the recommendations, as economic burden is an important factor that influences the decision-making of the patients in primary medical institutions. However, at present, the economic evidence related to the use of TURBT, chemotherapy and immunotherapy in NMIBC patients is still lacking, such as the research on comparative health economics between TURBT and other surgical treatment devices, and that between chemotherapy and BCG immunotherapy, etc. (4) The anatomical proportion of Chinese people is different from that of European and American people. The comfort and adaptability of the imported TURBT equipment for the patients need to be studied. Additionally, it is valuable to compare the effect and safety of TURBT equipment in the treatment of NMIBC between domestic equipment and imported equipment to refine the application settings of medical devices. (5) Currently, there is little evidence on the application of immune checkpoint-targeting therapies such as PD-1/PD-L1-targeting therapy in the NMIBC patients, which is a new branch of applications to be investigated other than the intravesical chemotherapy and BCG immunotherapy. (6) Patient values/preferences are one of the three elements of evidence-based medicine. The development of this guideline did not investigate the influence of patient values/preferences, which also needs to be taken into account in the future. [fig] Question 8: Does immediate postoperative intravesical chemotherapy reduce the risk of recurrence of NMIBC? Recommendation: Except for those with the contraindications to immediate intravesical chemotherapy after operation, all patients with NMIBC should receive immediate postoperative intravesical chemotherapy within 24 h after TURBT. (Evidence level: 1a; Strength of recommendation: Strong). [/fig] [table] Table S1: of the Union for International Cancer Control (UICC)[12]. The histological grading of NMIBC was based on the WHO standard (2004/2016 version) (Additional file 1: Table S2) [13], but WHO/ International Society of Urology standard (1973 version) (Additional file 1:Table S2) [/table] [table] Table 1: Levels of evidence and grades of the recommendation in EAU GuidelineEAU European Association of Urology [/table] [table] Table 2: Management of BCG side effectsBCG Bacillus Calmette-Guérin, TURBT transurethral resection of bladder cancer, ICU Intensive Care Unit cease intravesical therapy, administer quinolone antibiotics or anti-tuberculous drugs. If symptoms persist, hormone therapy is feasible. Abscess incision drainage is also feasible when abscess occurs. If the treatments above are not effective, consider orchiectomy when necessary Urethral stricture Postpone the instillation, perform spasmolytic treatment. Continue the instillations when symptoms are relieved within a few days, and avoid drugs flowing into urethra during instillations. If the symptoms persist or worsen, urethral dilatation or urethrotomy is feasible Strictly follow the contraindications to BCG instillations. BCG should be started at least 2 weeks away after TURBT. When sepsis occurs, stop the BCG treatment immediately, transfer the patients to ICU for treatment, perform urine culture for bacteria and acid-fast bacilli, administer broad-spectrum antibiotics, anti-tuberculosis and hormone drugs. For severe cases without renal failure, consider giving oral cycloserine and strengthening the monitoring of its blood concentration. BCG instillation is no longer recommended after the patient's condition improves Allergic reactions (1) Postpone the instillations, or suspend the instillations if symptoms worsen (2) Administer antihistamines and anti-inflammatory agents, and increase the dosage of antibiotics or utilize the antituberculosis drugs, if necessaryOther rare adverse reactions Most rare adverse reactions are considered to be autoimmune reactions such as arthritis, hepatitis, pneumonia, bone marrow suppression, etc. Non-steroidal anti-inflammatory, cortisol, quinolones or anti-tuberculosis drugs are feasible [/table]	None	https://mmrjournal.biomedcentral.com/counter/pdf/10.1186/s40779-022-00406-y	None
a732195a8f6a3cfa140b38524c1617a4c5ddb925	pubmed	None	A high standard of medical practice is a prerequisite of good medical care and clinical governance is the means for ensuring that a high standard is maintained. In February of this year the College issued the following report to its Fellows and Members. The report states unequivocally the College's position on clinical governance and self-regulation and what it expects of individual physicians and their employers in implementing them. Some of the proposals have already been acted upon and are set in train; others will require additional resources and the commitment of the Department of Health and the Trusts. \| Self-regulation has long been a central tenet of medical prac tice and with the passing of the first Medical Act of 1859, developed a legal framework. Hitherto, the responsibility for that self-regulation rested on central mechanisms of the Gen eral Medical Council, supported by the ethical responsibil ities of individual doctors. The public and the profession now have expectations of consistent very high standards of prac tice and behaviour, with less variability than has sometimes been the case. Towards meeting these expectations, the GMC has published Good Medical Practice' and Maintaining Good Medical Practice1, and the government has obliged hospital trusts to establish systems of clinical governance. The first annual report is due by 1 April 2000.The General Medical Council stresses that to maintain a good standard of professional work it is necessary to have in place the following: - clear standards wherever possible - effective quality assurance, especially in clinical directorates - sound professional arrangements for dealing with concerns about particular doctors. This approach to individual and team practice has already been encouraged by the Royal College of Physicians with its several initiatives in fostering and producing guidelines and audit materials, and with its supportive advice for physi cians contained in the publications Consultant Physicians Responding to Change* and Consultant Physicians Working for Patient^.Further action is demanded however as we are now required to demonstrate clearly good, effective practice not just assert it. This report outlines the steps the College wishes to take over the next two years to ensure the maintenance of high standards of practice by physicians in England and Wales. ## Definition of clinical governance Clinical Governance is the acceptance of the responsibility by individual physicians to work in a way which is consis tent with the values and strategic objectives of the organisa tion which employs them. Within this there is a responsibil ity to maintain good medical practice and achieve high standards. The responsibility of the organisation (Trust) is to provide appropriate facilities for medical work and to sup port the professional development of physicians and clinical teams on a continuing basis. ## The need for clinical governance The Royal College of Physicians has always been involved in maintaining standards in clinical practice through many activities: more recently these have included the MRCP(UK) examination; educational initiatives; the approving of train ing posts in hospitals; representation on Advisory Appoint ment Committees, and many publications giving leadership in good medical practice. Physicians look to the College for advice about good practice and it is necessary and impor tant for the College to make public pronouncements about what consititues good medical practice and to criticise actions of government and other organisations when they adversely affect standards. Through its committees and administrative structure, both in London and in the regions, the College provides advice and support to physicians which enables them to be aware of the various require ments for their practice of medicine and the maintenance of high standards. The College and its Members and Fellows must now discuss and introduce new ways whereby they not only improve the quality of their practice but demonstrate to the public, themselves and their colleagues that they can continue to maintain high standards. In introducing and encouraging new methods of assess ment of clinical practice, and demonstrating maintenance of standards, the College is aware that such assessments create extra work on top of already heavy and onerous schedules. However, clinical governance and regulation by physicians working with management will identify inadequacies in facilities for good practice. This whole process should be seen as a dual responsibility: of the physician to maintain good standards; of management to provide adequate resources. The College will meanwhile continue to press for the additional consultant staff required to make clinical governance a feasible and useful proposition. A few physicians perform below standard, and thus their patients are at risk. In the past, doctors who have recog nised failings of colleagues have not always taken effective action. Therefore, together with the concepts of clinical governance and self-regulation, must go a change of attitude and culture, in which colleagues who are not managing their work adequately can be helped. Physicians should be able to regard this is a helpful necessity rather than distasteful recrimination. ## Role of and action by the royal college of physicians towards implementing clinical governance ## Standards committee A new committee, reporting to the Clinical Affairs Board, has been established to lead change and to oversee all matters concerning standards of practice, including the establishment of explicit standards, their measurement and methods of assessment. An urgent priority will be the publi cation of Good Medical Practice for Physicians,6 based on the GMC's Good Medical Practice.1 ## Specialties Appropriate standards (and methods of monitoring) will vary between specialties. The College will collaborate with specialist societies in developing standards for all 25 specialties represented by the College. ## Annual appraisal This is a key component of clinical governance and is a Trust responsibility. It must include an annual review of the job plan to ensure that physicians are working appropri ately. The College, through its Standards Adviser, will give guidance on the detailed content of the job plan. The Appraisal based on the job plan is the single most important method of identifying the effectiveness of individual physicians, (see Working for Patients Part 2).5 ## Guidelines and clinical audit The College's Research Unit has been re-modelled and has become the Clinical Effectiveness and Evaluation Unit. In collaboration with the Standards Committee and specialist societies, it will continue the work of producing evidence based guidelines. It will also serve as a clearing house for guidelines relevant to medical specialties. The best objective test of clinical practice standards is appropriate audit, including outcome measures (with proper allowance for case mix and other potential confounding factors). The Clinical Effectiveness and Evaluation Unit will develop the necessary tools. It will also help to identify reliable outcome data, or process measures when outcome data are not avail able. In all this there will be close collaboration with the National Institute for Clinical Excellence (NICE). Clinical audit cannot be carried out effectively without good data management to specified standards and appro priate information technology. Indeed, clinical audit should not be attempted if the basic data are not available in a suitable form. We wish to draw attention to the present inadequate provision of information technology in many hospital Trusts. While local audits are possible in many areas, participation in national audit through improved information management and IT systems is the ultimate goal. ## Peer assessment and service accreditation Assessment of individual practitioners or clinical teams by other clinicians or groups (peer assessment) can be invalu able but is costly in resources and manpower. In addition, subjective value judgements may be misleading and, if adverse, might lead to complaints or even legal action. External peer assessment using explicit standards is time and resource-consuming, both for the assessors and the assessed. For example, if the aim was to assess each specialist unit at five-year intervals, a Trust with all 25 medical sub-specialties would have one medical visiting team every two months; add to that surgical and other specialties and the prospect is dauntingbut nonetheless may be essential. Some specialtiessuch as thoracic medicine, cardiology and nephrologyhave already intro duced peer assessment and the College is working closely with other Colleges and specialty societies to test different systems of team assessment. The College intends to pilot schemes involving multidisciplinary assessment and using explicit criteria to yield measurable outcomes which can serve as comparators with other similar services. Lay representation in the assessment process will be introduced. Less rigorous assessment might be possible by extending the brief of existing visits related to training. If the teams were asked to make some observations about the adequacy of trainers' clinical practice, involvement in audit and CME, etc, it might give an early indication of weak practice. This might provide an interim measure whilst resources are identified to enable the introduction of the full system. ## Continuing professional development Central to maintaining and improving standards is the concept of continuing professional development (CPD) and self-assessment. Most physicians in fact keep themselves up to date on medical practice but they are now expected also to demonstrate their state of knowledge. Whilst they have accepted the need for keeping records of their continuing medical education (CME) activities, it is generally accepted that filling in a diary of educational activities has limited value. Innovative and interactive CME programmes are therefore being developed, in which self-assessment will be built-in. These programmes will ultimately enable users to link to the College via the Internet, so providing evidence that self-assessment is being undertaken, sending an early warning when results are consistently poor and demonstrat ing the need to update in certain areas. Adequate funding for CME must be provided but this funding cannot be the responsibility of the College (although the College's CME Unit is actively developing such programmes and will publish details separately). When adequate resources are available and structures are in place, CPD and CME will become mandatory for all career-grade physicians. ## Improving performance Should physicians become aware that their knowledge or performance in some areas is below standard, it is their professional responsibility to remedy such deficiencies. They may not however, be able to do so unaided. In these circumstances, their employer has a responsib ility to assist by providing time and resources for whatever educational processes are needed, and the College will always be prepared to give appropriate advice and, where necessary, help with any practical arrangements. In the occasional instances where a physician's perfor mance is so defective that he/she has to stop practising either by suspension, or by a GMC decision to withold registration, there is no available method of resourcing the required professional rehabilitation. The College Standards Committee will seek ways to find methods to support this desirable process and, if funds are provided by the Depart ment of Health or Trusts, will establish relevant procedures and construct appropriate programmes. ## The college network The RCP now has a substantial network of physicians with specific responsibilities for implementing College policy in their own areas, and who are in regular communication with the College. These are: - For each Deanery Regional Advisers; Deputy Regional Advisers; CME Advisers; 22 Regional Specialty Advisers - For each Trust or group of Trusts Trust Tutors; Assistant Trust Tutors; Standards Advisers are plarmed. The Standards Adviser will be a new post designed specifically to assist colleagues in matters pertaining to clinical governance and, importantly, independent of the Trust clinical governance machinery, although inevitably in contact with the latter when required. The role of the Standards Adviser is to act as an independent adviser to individual physicians, and the Trust, on all matters affecting clinical governance. The postholder will encourage physicians in their approach to CPD, advise them about job plan preparation and career development as well as inform Trust Chief Executives and Medical Directors about RCP recommendations on clinical standards, CPD and career development. ## Election to frcp Advancement to FRCP has always depended on evidence of a good professional reputation and performance, but this has customarily been obtained by subjective reports from a few senior colleagues. Work will proceed to ensure more direct evidence of adequate performance before admission to Fellowship, such as assessment of CME and an indication of involvement in clinical audit: for example, no-one will be elected to the Fellowship if they are not up to date with their CME. Maintenance of the Fellowship may also become dependent on continued participation in these programmes. ## Consultant advisory appointment committees The College representatives on AACs have always been relied upon to indicate whether a candidate's experience and training was adequate for the post for which he/she has applied. The selection of these College representatives is being overhauled and instructions are being revised to ensure that this important task is performed well. ## Service review The College has always been willing to respond to requests from managers, Trust Boards or physicians to send a suit able team to review a service and make recommendations when it seems that there may be some weakness or failure of service provision. This will continue under the direction of the Clinical Vice-President. The speed of response will be determined by the circumstances, but the College will always try to act quickly in the interest of patient safety. ## Local initiatives Clinical governance, as currently formulated, is intended to operate at local level, and is a responsibility of the Chief Executive of NHS Trusts. The vast majority of physicians work in the National Health Service at local Trust hospitals but, of course, the principles formulated in this document apply also to those working in other areas such as private hospitals, prisons, hospices, etc. Discussions are therefore underway to introduce similar systems into the private sector. ## The job plan This should be regarded as a two-way tool. A physician should have a detailed discussion annually about the job plan with the Clinical or Medical Director. This is an oppor tunity for the Clinical Director (and therefore the Trust) to identify any deficiencies in resources and facilities, as well as an opportunity for the Clinical Director to appraise the work of the physician, raising any points of criticism that may have been made in the course of the past year. Such appraisal of working ability and performance is now the norm in many occupations and should be accepted by physicians as an essential part of their professional life. For the physician, this will be the opportunity for an annual discussion on continuing professional development and any plans for a change in working patterns; no longer is it accept able for all physicians to be appointed to a consultant post and then work to the same pattern for up to thirty years. The opportunity to discuss new patterns of practice, changing competencies and developing ambitions of physicians must be regarded as professionally desirable. Not all physicians will wish to alter their job plan, but they should have the oppor tunity to discuss the possibility of change. The listed items in the job plan are: - ward rounds - clinics - procedures (endoscopy, catheters, etc) - cover arrangements and post-take ward rounds - teaching (undergraduate and postgraduate) - CPD/CME - clinical governance and audit - administration - managerial work - national work - research (in some cases). It is self-evident that to take on all the above duties is beyond the ability of a physician within his/her contracted hours. Unless an annual appraisal of physician's work and workload is carried out, management will never be under sufficient pressure to provide adequate facilities and the requisite personnel to allow the majority of these tasks to be carried out. Indeed, it will become apparent that since an individual physician cannot carry out all these tasks, more physicians will be necessary. So while the physician is openly accepting inspection and assessment of his work, he/she should require that there is adequate information technology for audit, good funding for CME and an allowance of time for teaching, research, learning and managerial duties. ## Clinical teams All physicians in modern medical care work in teams, whether those teams are formally identified as such or not. Many aspects of governance and assessment are easier to achieve when the team is regarded as the unit of medical work. Quoting the GMC document Good Medical Practice1' . Most doctors today practise in medical and clinical teams. As well as being responsible for their own perfor mance and conduct, they should share the responsibility for the quality of care provided by their team. Medical teams are usually organised around Clinical Direc torates in hospitals. Clinical teams include colleagues in other health professions. The GMC goes on to state that medical and clinical teams must be well led and managed, and must: - have a positive attitude to patients and listen to their wishes and needs - make themselves aware of what patients think about the quality of their services - have a clear understanding of their professional values, standards and purpose. Team members must be: - willing to learn - committed to providing good quality service and effective clinical practice - open and honest about professional performance, both together and separately. To help maintain quality, clinical teams will normally use: - an active and supportive approach to the professional development of each member - the standards set by a professional organisation - recommended clinical guidelines - detailed performance records - internal and external medical and clinical audit - regular review of individual members' performance - suitable procedures for looking into complaints, and avoiding unnecessary risk. Mutual respect between team members is essential. Pro fessionals working in teams are skilled, highly qualified and as committed to good patient care as the medical profession and should be respected as such. Finally, if a team is working wellor is to work wellno individual within it is likely to be performing badly, but if they are they should be identified and their performance discussed. This emphasises the value of assessment of teams rather than just individuals. ## Identifying poor performance Failure to identify a poorly performing colleague is now regarded as a deficiency which could lead to disciplinary action. The public requires assurance that we have developed effective methods for identifying poor perform ance and that offending physicians are removed from practiceeither temporarily for retraining, or permanently. However, having accepted that such a change in culture and behaviour is now necessary, consideration must be given to how it could work sensitively and efficiently. The Standards Committee will continue to give advice on behalf of the College about ways of dealing with matters of poor performance. Concern about possible poor perform ance should normally be addressed to the Trust's Medical Director, who has a clearly defined responsibility for clinical governance. If a clinician is uncertain about setting such a formal investigation in train, he/she may prefer first to discuss the matter with the College's Standards Adviser, who will have specific responsibility for advising on RCP recommendations and processes. ## Critical incident reporting A highly effective method of identifying deficiencies in clinical management has been developed by the Royal College of Surgeons by means of the Confidential Enquiry into Perioperative Death. Such methods are more easily carried out in the surgical area than in medicine, particularly in relation to chronic conditions. However, we recommend that consideration be given to a system of critical incident reporting in medical wards; such a system is already in oper ation in some hospitals. Definition of a critical incident will have to be carefully considered. The possibility of a Confi dential Enquiry into deaths of emergency admissions under the age of 50 is under discussion with NICE. # Conclusion The long established mechanisms for regulating the medical profession are no longer good enough. The public, the profession and the government all expect a much greater degree of accountability, with less variation in standards of practice and behaviour. It is up to us to demonstrate as clearly as possible, through clinical governance and self-regulation, good and effective practice. Clinical governance imposes a responsibility on physicians to maintain good medical practice and to strive for the highest standards. At the same time it places a responsibility on the employer to ensure that the appropri ate resources and facilities are in place to allow this. For many years the College has been involved in standard setting through a range of activities, including the MRCP(UK) examination, the approval of training posts and the publication of guidelines. However the College must now introduce new ways to improve the quality of practice and to demonstrate publicly its commitment to the maintenance of the highest possible standards. The College will do this in two ways: introducing a number of initiatives aimed at encouraging physicians to aspire realistically to the highest standards of clinical practice; persuading the Government and employing Trusts to put in place adequate resources and manpower to allow clinical governance to bring real benefits to patients. Some of these initiatives can be put in place immediately, while others will inevitably require more time to enable sufficient resources to be identified. What is essential is widespread recognition of the key components of clinical governance: appraisal, CPD/CME, national audit, personal development plans and peer-led service review. The following steps towards a system of clinical governance can be taken in the immediate future: - Annual, thorough two-way job plan review and appraisal of performance with a Clinical or Medical Director. The RCP has prepared outline job plans for most specialties6 - Introduction of regular CME of an interactive nature, based on a personal development plan, with assessment programmes being followed as they develop - Involvement in local or national audit of clinical out come and process, with evidence of action resulting if required - Introduction of a Royal College of Physicians Standards Adviser for each Trust or group of Trusts to assist in all of the above - Piloting of multi-disciplinary peer assessment service reviews of clinical teams. The following recommended initiatives require further exploration and will need to be costed: Special service reviews at the request of Trusts and Health Authorities. [fig] •: Development of standards in the clinical specialties in conjunction with specialist societies Establishment and introduction of evidence based clinical guidelines of effectiveness and management Provision of audit tool kits Identification of poor performance in colleagues Election to and maintenance of the FRCP, dependent on the satisfactory fulfillment of all components of clinical governance and self-regulation Critical incident reporting as a further component of clinical governance Development of processes for Continuing Professional Development Development of programmes for training in assessment, appraisal and educational supervision Development of retraining programmes. [/fig]	None	None	None
da5c48d46dfc877254cb5012700242bbc6b425ac	pubmed	European Resuscitation Council COVID-19 guidelines executive summary	European Resuscitation Council COVID-19 guidelines executive summary Coronavirus disease 2019 has had a substantial impact on the incidence of cardiac arrest and survival. The challenge is to find the correct balance between the risk to the rescuer when undertaking cardiopulmonary resuscitation (CPR) on a person with possible COVID-19 and the risk to that person if CPR is delayed. These guidelines focus specifically on patients with suspected or confirmed COVID-19. The guidelines include the delivery of basic and advanced life support in adults and children and recommendations for delivering training during the pandemic. Where uncertainty exists treatment should be informed by a dynamic risk assessment which may consider current Resuscitation j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / r e s u s c i t a t i o n risks for those providing treatment. These guidelines will be subject to evolving knowledge and experience of COVID-19. As countries are at different stages of the pandemic, there may some international variation in practice. # Introduction The World Health Organization has declared COVID-19 a pandemic. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is highly contagious. These coronavirus disease 2019 (COVID-19) guidelines focus specifically on patients with suspected or confirmed COVID-19. For resuscitation of those who are low risk or confirmed negative for COVID-19, the reader is directed to the standard resuscitation guidelines for adults and children. Where uncertainty exists treatment should be informed by a dynamic risk assessment which may consider current COVID-19 prevalence, the patient's presentation (e.g. history of COVID-19 contact, COVID-19 symptoms), likelihood that treatment will be effective, availability of personal protective equipment (PPE) and personal risks for those providing treatment. These guidelines will be subject to evolving knowledge and experience of COVID-19. As countries are at different stages of the pandemic, there may some international variation in practice The number of out-of-hospital cardiac arrests in the Lombardy region of Italy increased by 58% during the COVID-19 pandemic in comparison with a similar period in 2019; 77% of the increase in these cardiac arrests were among those with suspected or confirmed COVID-19. [bib_ref] Out-of-Hospital Cardiac Arrest during the Covid-19 Outbreak in Italy, Baldi [/bib_ref] In Paris and surrounding suburbs, the incidence of out of hospital cardiac arrest doubled in parallel with an increase in hospital admissions for COVID-19. [bib_ref] Out-of-hospital cardiac arrest during the COVID-19 pandemic, Marijon [/bib_ref] In the Parisian study only 33% of the increase in the incidence was explained by patients with suspected or confirmed COVID- [bib_ref] Risk factors for SARS infection among hospital healthcare workers in Beijing: A..., Liu [/bib_ref]. This suggests that a significant proportion of the excess cardiac arrests were not directly attributable to Whether this is explained by fear and anxiety delaying presentation for non-COVID-19 related illnesses, deteriorating mental health increasing self-harm or other reasons requires further research.In both studies the proportion of cardiac arrests which occurred at home increased, likely related to the lock-down. Importantly the rate of bystander CPR and public access defibrillation fell as did overall survival. These worrying observations highlight the importance of practical guidance to enable members of the community and healthcare professionals to continue to provide effective resuscitation to the several hundred thousand people who sustain a cardiac arrest each year in Europe. [bib_ref] Survival after out-of-hospital cardiac arrest in Europe -Results of the EuReCa TWO..., Grasner [/bib_ref] Among 136 patients with severe COVID-19 pneumonia and inhospital cardiac arrest at a tertiary hospital in Wuhan, China, 119 (87.5%) had a respiratory cause for their cardiac arrest. [bib_ref] In-hospital cardiac arrest outcomes among patients with COVID-19 pneumonia in Wuhan, Shao [/bib_ref] In this series of patients, the initial cardiac arrest rhythm was asystole in 122 (89.7%), pulseless electrical activity in 6 (4.4%) and ventricular fibrillation/ pulseless ventricular tachycardia (VF/pVT) in 8 (5.9%). Cardiovascular manifestations of COVID-19 include elevation of cardiac biomarkers, cardiac arrhythmia, arterial and venous thromboembolism, cardiogenic shock and cardiac arrest.In a case series of 138 hospitalised COVID-19 patients, [bib_ref] COVID-19 in cardiac arrest and infection risk to rescuers: A systematic review, Couper [/bib_ref].7% of patients developed arrhythmias and 7.2% had acute cardiac injury. [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref] Thus, although most cardiac arrests in these patients are likely to present with a non-shockable rhythm caused by hypoxaemia (although dehydration, hypotension, sepsis coagulation activation and pulmonary embolism may also contribute), some will have a shockable rhythm, which may be associated with drugs causing prolonged-QT syndrome (e.g. chloroquine, azithromycin) or caused by myocardial ischaemia. In the series of 136 cardiac arrests from Wuhan, four (2.9%) patients survived for at least 30 days but only one of these had a favourable neurological outcome. [bib_ref] In-hospital cardiac arrest outcomes among patients with COVID-19 pneumonia in Wuhan, Shao [/bib_ref] Risks associated with cardiopulmonary resuscitation (CPR) in patients with COVID-19 ## Mechanisms of transmission of sars-cov-2 The main mechanism of disease transmission of SARS-CoV-2 is by respiratory secretions either directly from the patient or by touching contaminated surfaces. Viable virus is detectable on some surfaces for up to 72 h. [bib_ref] Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1, Van Doremalen [/bib_ref] Respiratory secretions are called either droplets (> 5 À10 microns in diameter) or airborne particles (< 5 microns). Droplets fall onto surfaces within 1À2 m of the patient's respiratory tract while airborne particles can remain suspended in the air for prolonged periods. The International Liaison Committee on Resuscitation (ILCOR) has undertaken a systematic review addressing three questions: [bib_ref] COVID-19 in cardiac arrest and infection risk to rescuers: A systematic review, Couper [/bib_ref] 1 Is the delivery of chest compressions or defibrillation an aerosolgenerating procedure? 2 Do the delivery of chest compressions, defibrillation or CPR (all CPR interventions that include chest compressions) increase infection transmission? 3 What type of PPE is required by individuals delivering chest compressions, defibrillation or CPR in order to prevent transmission of infection from the patient to the rescuer? The evidence addressing these questions is scarce and comprises mainly retrospective cohort studies [bib_ref] SARS among critical care nurses, Loeb [/bib_ref] [bib_ref] Risk factors for SARS transmission from patients requiring intubation: a multicentre investigation..., Raboud [/bib_ref] and case reports. In most cases, delivery of chest compressions and defibrillation are lumped together with all CPR interventions, which means that there is considerable confounding in these studies. Aerosol generation by chest compressions is plausible because they generate small but measurable tidal volumes. [bib_ref] Does compression-only cardiopulmonary resuscitation generate adequate passive ventilation during cardiac arrest?, Deakin [/bib_ref] Chest compressions are similar to some chest physiotherapy techniques, which are associated with aerosol generation. [bib_ref] Evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and..., Simonds [/bib_ref] Furthermore, the person performing chest compressions is close to the patient's airway. The ILCOR systematic review did not identify evidence that defibrillation generates aerosols. If it occurs, the duration of an aerosol generating process would be brief. Furthermore, the use of adhesive pads means that defibrillation can be delivered without direct contact between the defibrillator operator and patient. The ILCOR treatment recommendations are listed in [fig_ref] Table 1 -: ILCOR treatment recommendations for cardiopulmonary resuscitation [/fig_ref]. The values, preferences and Task Force insights summarise the rationale for recommendations for lay persons and health care professionals. ## Personal protective equipment (ppe) Recommendations for PPE are summarised in [fig_ref] Table 2 -: Recommendations for Personal Protective Equipment [/fig_ref]. Some healthcare systems are facing shortages of personnel and equipment. The position of the European Resuscitation Council (ERC) is that health systems should prioritise the protection of healthcare personnel and ensure adequate PPE is available to those who are expected to provide treatment for cardiac arrest. Safety is paramount and the safety priorities are: (1) self; (2) colleagues and bystanders; (3) the patient. The time required to achieve safe care is an acceptable part of the resuscitation process. Basic life support for adults with suspected or confirmed COVID-19 For patients with confirmed or suspected COVID-19 the European Resuscitation Council recommends the following changes to basic life support (BLS) based on the recent ILCOR evidence review and commentary: [bib_ref] COVID-19 in cardiac arrest and infection risk to rescuers: A systematic review, Couper [/bib_ref] [bib_ref] International Liaison Committee on Resuscitation: COVID-19 consensus on science, treatment recommendations and..., Perkins [/bib_ref] Basic life support in adults by lay persons Cardiac arrest is identified if a person is unresponsive and not breathing normally. Responsiveness is assessed by shaking the person and shouting. When assessing breathing, look for normal breathing. In order to minimise the risk of infection, do not open the airway and do not place your face next to the persons' mouth / nose. Call the emergency medical services if the person is unresponsive and not breathing normally. During single-rescuer resuscitation, if possible, use a phone with a hands-free option to communicate with the emergency medical dispatch centre during CPR. Lay rescuers should consider placing a facemask or cloth/towel over the person's mouth and nose before performing chest compressions and public-access defibrillation. This may reduce the risk of spreading the virus during chest compressions.Lay rescuers should follow instructions given by the emergency medical dispatch centre. After providing CPR, lay rescuers should, as soon as possible, wash their hands thoroughly with soap and water or disinfect their hands with an alcohol-based hand gel and contact the local health authorities to enquire about screening after having been in contact with a person with suspected or confirmed COVID-19. ## Emergency medical dispatch staff For untrained rescuers, provide compression-only instructions. Guide additional rescuers to the nearest automated external defibrillator (AED) when available. The risk of COVID-19 should be assessed by emergency medical dispatch as early as possible; if there is a risk of infection, the responding healthcare personnel should be alerted immediately to enable them to take precautions such as donning airborneprecaution PPE. First responders or trained volunteers who are dispatched or alerted to cardiac arrests in patients with suspected or confirmed We suggest that chest compressions and cardiopulmonary resuscitation have the potential to generate aerosols (weak recommendation, very low certainty evidence). We suggest that in the current COVID-19 pandemic lay rescuers consider compression-only resuscitation and public-access defibrillation (good practice statement). We suggest that in the current COVID-19 pandemic, lay rescuers who are willing, trained and able to do so, may wish to deliver rescue breaths to children in addition to chest compressions (good practice statement). We suggest that in the current COVID-19 pandemic, healthcare professionals should use personal protective equipment for aerosol-generating procedures during resuscitation (weak recommendation, very low certainty evidence). We suggest that it may be reasonable for healthcare providers to consider defibrillation before donning aerosol generating personal protective equipment in situations where the provider assesses the benefits may exceed the risks (good practice statement). COVID-19 should have access to and training in the use of airborne precaution PPE. In making this recommendation the BLS writing group is of the opinion that first responders have a professional duty to respond and therefore their employer must provide adequate PPE. Trained volunteers who are dispatched to a cardiac arrest also have the right to be protected adequately against the risk of infection with SARS-CoV-2. Basic life support in adults by healthcare personnel Teams responding to cardiac arrest patients (both in-and out-ofhospital) should be comprised only of healthcare personnel with access to, and training in the use of airborne-precaution PPE. Recognise cardiac arrest by looking for the absence of signs of life and the absence of normal breathing. Applying defibrillator pads and delivering a shock from an AED/ defibrillator is unlikely to be an aerosol-generating procedure and can be undertaken with the healthcare provider wearing dropletprecaution PPE (fluid-resistant surgical mask, eye protection, short-sleeved apron and gloves. Healthcare personnel should always use airborne-precaution PPE for aerosol-generating procedures (chest compressions, airway and ventilation interventions) during resuscitation. Perform chest compressions and ventilation with a bag-mask and oxygen at a 30:2 ratio, pausing chest compressions during ventilations to minimise the risk of aerosol. BLS teams less skilled or uncomfortable with bag-mask ventilation should not provide bag-mask ventilation because of the risk of aerosol generation. These teams should place an oxygen mask on the patient's face, give oxygen and provide compression-only CPR. Use two hands to hold the mask and ensure a good seal for bagmask ventilation. This requires a second rescuer À the person doing compressions can squeeze the bag when they pause after each 30 compressions. Use a high-efficiency particulate air (HEPA) filter or a heat and moisture exchanger (HME) filter between the self-inflating bag and the mask to minimise the risk of virus spread. Apply a defibrillator or an AED and follow any instructions where available. ## Advanced life support for adults with suspected or confirmed covid-19 In-hospital cardiac arrest Identify as early as possible any patients with a COVID-19 like illness, who are at risk of acute deterioration or cardiac arrest. Take appropriate steps to prevent cardiac arrest and avoid CPR without appropriate PPE. Use of physiological track-and-trigger systems will enable early detection of acutely ill patients. For those for whom resuscitation would be inappropriate, decisions must be made and communicated. Patients with severe COVID-19 respiratory failure who would not be deemed suitable for tracheal intubation and mechanical ventilation or multiple organ support are extremely unlikely to survive attempted resuscitation after cardiac arrest. For such patients, a do not attempt CPR (DNACPR) decision is appropriate. If a patient is unresponsive and not breathing normally shout for help/pull emergency bell. Check for signs of life/pulse. DO NOT listen for breaths or place your cheek near to the patient's face. Send someone to place a COVID cardiac arrest call (2222 or equivalent local number), and to bring a defibrillator. Chest compressions have the potential to generate aerosols and airway interventions are aerosol-generating procedures (AGPs). Healthcare staff should therefore don (put on) airborne-precaution PPE before starting chest compressions and /or airway interventions; as a minimum a FFP3 mask (FFP2 or N95 if FFP3 not available), eye and face protection, long-sleeved gown, and gloves before undertaking these procedures. Applying defibrillator pads and delivering a shock from an AED/ defibrillator is unlikely to be an aerosol-generating procedure and can be undertaken with the healthcare provider wearing a fluid-resistant surgical mask, eye protection, short-sleeved apron and gloves. If a defibrillator is immediately available, switch it on, apply the defibrillator pads and deliver a shock if the rhythm is ventricular fibrillation/ pulseless ventricular tachycardia (VF/pVT If not on the patient already, place an oxygen mask and give oxygen. Leave the mask on the patient until a bag-mask device arrives. Once a bag-mask device arrives, proceed with a compression: ventilation ratio of 30:2. Manual ventilation with a bag-mask should be minimised and be performed only by experienced staff using a 2-person technique because an ill-fitting mask/poor seal will generate an aerosol. The person doing compressions can pause to squeeze the bag. Ensure there is a viral filter (HME filter or HEPA filter) between the self-inflating bag and airway (mask, supraglottic airway, tracheal tube) to filter exhaled breaths. Experienced airway staff should insert a supraglottic airway or intubate the trachea early so that the period of bag-mask ventilation is minimised. Consider videolaryngoscopy for tracheal intubation by providers familiar with its use À this will enable the intubator to remain further from the patient's mouth. If a supraglottic airway has been inserted, use a 30:2 chest compression ventilation ratio, pausing the chest compressions to enable ventilation. This will minimise the risk of aerosol generation caused by gas leaking from the seal between the supraglottic airway and larynx. Consider stopping CPR early if treatable reversible causes of cardiac arrest have been addressed. If there is a need for prolonged CPR, consider the use of a mechanical chest compression device in those settings that are familiar with its use. Ensure the safe removal ('doffing') of PPE to prevent selfcontamination. Undertake a team debrief. ## Resuscitation in intubated patients at the time of cardiac arrest Resuscitation team members should wear airborne-precaution PPE. In the event of cardiac arrest in an intubated and mechanically ventilated patient, do not disconnect the ventilator circuit when starting CPR to avoid aerosol generation. Increase the FiO 2 to 1.0 and set the ventilator to deliver 10 breaths a minute. It may be necessary to use a volume control mode and to increase the pressure limits. Quickly check the ventilator and circuit to ensure that they have not contributed to the cardiac arrest, e.g. blocked filter, breath-stacking with high auto-PEEP, or mechanical failure. Follow local guidance regarding ventilator disconnection to minimise aerosol generation e.g. clamping the tube prior to disconnection, use of viral filters etc. ## Resuscitation in patients in the prone position COVID-19 patients are often managed in the prone position because this can improve oxygenation.Most of these patients will be intubated, but in some cases awake unintubated COVID-19 patients may also be nursed in the prone position. In the event of cardiac arrest in the unintubated, prone patient, whilst wearing the correct PPE, immediately turn the patient supine before starting chest compressions. In the event of cardiac arrest in an intubated patient who is prone, it is possible to deliver chest compressions by pressing the patient's back. This can provide some perfusion of vital organs while a team prepares to turn the patient supine, as follows: 1 Resuscitation team members should wear airborne-precaution PPE. 2 Compress between the scapulae (shoulder blades) at the usual depth and rate (5À6 cm at 2 compressions per second). 3 Turn patient supine if: a ineffective compressions À look at arterial line and aim for diastolic pressure greater than 25 mmHg b interventions require the patient supine, e.g. for airway problems c unable to restore a circulation rapidly (minutes) 4 Turning the patient supine requires additional help À plan this early. 5 Defibrillator pad placement options in the prone position include: a Anterior-posterior (front and back), or b Bi-axillary (both armpits). ## Out-of-hospital cardiac arrest Most of the principles described for the management of inhospital cardiac arrest in adults with confirmed or suspected COVID-19 also apply to ALS for such patients in cardiac arrest out-of-hospital. In the context of COVID-19, early recognition of cardiac arrest by the dispatcher will enable emergency medical services (EMS) staff to put on airborne-precaution PPE as soon as possible. Paediatric basic and advanced life support with suspected or confirmed COVID-19 Children are susceptible to COVID-19 but often seem to have only mild disease. 33À39 Very young children and children with co-morbid diseases may be more prone to severe illness. [bib_ref] Epidemiology of COVID-19 Among Children in China, Dong [/bib_ref] [bib_ref] Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan:..., Sun [/bib_ref] In approximately 70% of paediatric out-of-hospital cardiac arrests, rescuers are likely to be family members and therefore, if the child is infected with SARS-CoV-2, they are likely to have had previous exposure to the virus. They might also consider their personal risk far less important than the potential benefit for the child. This is unlikely to be true for random bystanders. Healthcare providers may also value the benefit for the child higher than their personal risk, but they should be aware of their responsibility towards their relatives, colleagues and the wider community as well. [bib_ref] Code Blue During the COVID-19 Pandemic, Chan [/bib_ref] Basic life support for children Check for responsiveness -in an unresponsive child, assess breathing visually (chest rise). Do not approach the child's mouth or nose at this stage. Cardiac arrest is defined by 'being unresponsive and not breathing normally'. Untrained lay rescuers will likely have called the EMS dispatcher (112/national emergency number) at the start; trained providers should do so before starting chest compressions. In cases where there are two or more rescuers, a second rescuer should call the EMS immediately. Once cardiac arrest is identified, rescuers should provide at least compression-only CPR. Place a surgical mask or other face mask (if available) over the child's mouth and nose before commencing chest compressions. The routine use of a cloth as an alternative is not advised because of the potential risk of airway obstruction and/ or restriction of passive air movement (due to compressions). However, when a surgical mask or face mask is not available, and if this cloth encourages rescuers to provide support where otherwise they would not, they should use it (lightly draped over mouth and nose). Unless a primary cardiac origin is likely, those rescuers who are willing and able should also open the airway and provide rescue breaths. This is likely to increase the risk of infection (if the child has COVID-19) but can significantly improve the outcome. When an AED is readily available, trained providers should use it as soon as feasible. An AED should primarily be advised as part of dispatcher-assisted CPR in those cases where the likelihood of a primary shockable rhythm is sufficiently high: in cases of sudden witnessed collapse; for children with a specific 'cardiac' history; or for children older than 1y of age without any identifiable noncardiac cause of arrest. Communicate the child's COVID-19 status to all providers involved. ## Foreign body airway obstruction (fbao) in children The existing guidelines for the management of FBAO are applicable regardless of the presumed COVID-19 status. [bib_ref] Resuscitation Council Guidelines for Resuscitation 2015: Section 6. Paediatric life support, Maconochie [/bib_ref] Advanced life support for children Pre-hospital EMS or in-hospital ALS teams must wear airborneprecaution PPE before arriving at the child's side, unless COVID-19 has been ruled out, even if it delays commencing or continuing CPR. Protocols should be in place to facilitate this and to minimise delays. Keep teams as small as possible but without compromising efficacy. Personnel wearing only droplet-precaution PPE may consider providing initial defibrillation before putting on airborneprecaution PPE in children with an identified shockable rhythm. If a defibrillator is immediately available, switch it on, apply the defibrillator pads and deliver a shock if the rhythm is VF/pVT. If the child remains in VF/pVT, and if wearing airborne-precaution PPE, start chest compressions and follow the 2015 algorithms. Do not delay CPR in order to secure an invasive airway. Provide initial ventilations with a bag-mask following the same principles as described in adults above. If not wearing airborne-precaution PPE, give up to two additional shocks (if indicated) while other healthcare workers are putting on airborne-precaution PPE. Early identification and proper treatment of any reversible causes during CPR is important. Some of these reversible causes demand 'advanced' resuscitation techniques: consider early transport to a centre capable of performing this for children. There is insufficient evidence to advocate for or against the use of extracorporeal life support for children with COVID-19. In settings where this facility is available, providers should balance the use of such advanced resources with the likelihood of a good outcome for the individual patient. ## Newborn life support Case series suggest the risk of vertical transmission of SARS-CoV-2 at birth is unlikely and that there is a low risk of babies being infected at birth even if born to a confirmed COVID-19 positive mother. [bib_ref] Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine..., Chen [/bib_ref] [bib_ref] An Analysis of 38 Pregnant Women with COVID-19, Their Newborn Infants, and..., Schwartz [/bib_ref] Maternal infection with COVID-19 does not appear to increase the risk of spontaneous preterm labour (35a) but may increase the risk of premature delivery. [bib_ref] Coronavirus disease 2019 in pregnant women: a report based on 116 cases, Yan [/bib_ref] There is a tendency for more deliveries to be via caesarean section with foetal compromise cited as an indication. [bib_ref] Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies, Zaigham [/bib_ref] Concerns about maternal health may also prompt a decision to deliver. [bib_ref] Infants Born to Mothers With a New Coronavirus (COVID-19), Chen [/bib_ref] [bib_ref] Neonatal Resuscitation and Postresuscitation Care of Infants Born to Mothers with Suspected..., Chandrasekharan [/bib_ref] Factors including the necessary obstetric precautions against viral exposure may increase the time taken to deliver compromised babies by caesarean section. However, the presence of maternal COVID-19 does not appear to compromise babies further at birth. [bib_ref] Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies, Zaigham [/bib_ref] The indications for the attendance of a neonatal team in advance, and the clinical factors which might prompt resuscitation remain unchanged whatever the maternal COVID-19 status. The sequence of assessment and any subsequent resuscitation/ stabilisation remain unchanged and follow standard newborn life support (NLS) principles. [bib_ref] European Resuscitation Council Guidelines for Resuscitation 2015 Section 7 Resuscitation and Support..., Wyllie [/bib_ref] Changes to the standard approach should be made to reduce the risk of COVID-19 cross infection for staff and the baby. Departments should have clear local guidelines on the prevention of COVID-19 transmission and suitable personal protective equipment (PPE) must be available in all birthing areas. Staff must be familiar with the guidelines and trained in the appropriate use of PPE. Local recommendations may take into account the regional prevalence of COVID-19. Where maternal COVID-19 is not clinically suspected, staff should follow local or national guidelines for PPE, which may include the routine use of droplet-precaution PPE for any attendance. Where maternal COVID-19 is suspected or confirmed, staff must attend in full airborne-precaution PPE. ## Delivery area Significant numbers of asymptomatic mothers may be infected with COVID-19 at the time of childbirth. [bib_ref] Universal Screening for SARS-CoV-2 in Women Admitted for Delivery, Sutton [/bib_ref] Whilst it is recommended that mothers with suspected or confirmed COVID-19 should deliver their babies in a designated area, it may not be feasible to segregate all such mothers. Therefore, take appropriate precautions and wear PPE when attending all deliveries. Ideally, delivery of a baby from a mother with suspected or confirmed COVID-19 should take place in a negative-pressure room, but these facilities may not be available in all delivery or operating rooms. As a minimum precaution, resuscitation of the baby should ideally take place at least 2 m from the mother in order to minimise the risk of droplet spread (the risk from airborne spread still exists). [bib_ref] Personal protective equipment during the coronavirus disease (COVID) 2019 pandemic -a narrative..., Cook [/bib_ref] Provision of a mask for the mother may reduce droplet spread. Consider a partition or locating the resuscitation area separate from the delivery area. [bib_ref] Neonatal Resuscitation and Postresuscitation Care of Infants Born to Mothers with Suspected..., Chandrasekharan [/bib_ref] Operating rooms are associated with a higher risk of droplet or airborne spread because of aerosol-generating procedures carried out on the mother (airway management, diathermy etc.). ## Pre-delivery discussions with suspected or confirmed covid-19 positive parents Droplet-precaution PPE is required for face-to-face consultation. Video consultation may be an alternative to reduce contact. If the neonatal team is unable to counsel the family then the obstetric/midwifery team may need to undertake such discussions. ## Neonatal team attending in advance (for suspected or covid-19 positive mother) Check and prepare the resuscitation area before the mother is in the room. Where a neonatal team is called in advance, careful planning is required to minimise the number who enter the room. The team should include someone experienced in newborn resuscitation and interventional procedures. Additional team members may be required to help with PPE. Ensure that there are facilities for safely putting on and taking off PPE. Handling PPE may incur delays. Full airborne-precaution PPE is required for anyone entering the room. Team members should put on PPE in advance although they may choose to leave off their masks/visors until it is clear they are required to attend the baby. ## Delivery There are no changes to the immediate management of the baby following delivery in the presence of suspected or confirmed COVID-19 infection. Delayed cord clamping should still be considered. Initial assessment of the newborn may take place on the perineum provided extra care is taken. [bib_ref] Neonatal Resuscitation and Postresuscitation Care of Infants Born to Mothers with Suspected..., Chandrasekharan [/bib_ref] The baby should only be passed to the neonatal team if intervention is needed; babies doing well stay with mother and the neonatal team may be able to avoid exposure. Neonatal team called after delivery (of a suspected or confirmed COVID-19 positive mother) Staff attending any delivery need to be able to initiate the resuscitation of a compromised baby before the neonatal team arrives. Call for help early because there may be a delay as the neonatal team puts on full airborne-precaution PPE. ## Approach to resuscitation and stabilisation The approach to resuscitation and stabilisation follows standard NLS recommendations. [bib_ref] European Resuscitation Council Guidelines for Resuscitation 2015 Section 7 Resuscitation and Support..., Wyllie [/bib_ref] Take measures to minimise potential COVID-19 exposure. A wet towel must be considered contaminated and removed with care. A viral filter (HME filter or HEPA filter) between the T-piece/selfinflating bag and mask might be considered. If a filter is used ensure that it is appropriate for the size of the baby and that ventilation is not compromised. Two-person airway support reduces mask leakage and is preferred where enough staff with appropriate PPE are available. Minimise potential aerosol-generating procedures (AGPs) such as suction and ensure that the most experienced team member carries out any advanced airway manoeuvres. [bib_ref] Neonatal Resuscitation and Postresuscitation Care of Infants Born to Mothers with Suspected..., Chandrasekharan [/bib_ref] ## Neonatal post resuscitation care Decisions to separate a COVID-19 positive mother and her baby should follow local guidance. Generally, a baby should stay with their mother if she is well enough. Skin-to-skin care and breast feeding may be possible if adequate precautions are taken including strict hand hygiene and a fluid-resistant surgical mask for the mother to reduce the risk of droplet spread.Should the baby require admission to a neonatal intensive care unit we recommend that transfer takes place in a closed incubator. Minimise exposure of the incubator to the contaminated area; it may be kept out of the delivery area/operating room if the resuscitation area is in the same room and the baby carried to it. Staff escorting the baby to the neonatal unit should consider wearing full airborne-precaution PPE where they might need to intervene during the transfer. If possible, avoid AGPs outside controlled areas such as the neonatal unit. Following resuscitation, isolate the baby until its COVID-19 status is known. A team debrief will support staff and improve future performance. ## Postnatal deterioration and resuscitation Where the cause of a deterioration or collapse is unknown, consider the possibility of infection with COVID-19. A high local incidence of disease or confirmed COVID-19 infection in the mother should prompt a higher index of suspicion. Any resuscitation should take place in a designated area to minimise the risk of cross-infection. Assessment and resuscitation follow standard NLS principles regardless of circumstances Those undertaking initial assessment and support should as a minimum use droplet-precaution PPE. Any staff attending subsequently should wear full airborne-precaution PPE as it may be necessary to undertake AGPs. If intubation is necessary, consider videolaryngoscopy. Ideally respiratory support should not be delayed. Mask ventilation and cardiac compressions are considered AGPs in all age groups outside the immediate newborn period. [bib_ref] COVID-19 in cardiac arrest and infection risk to rescuers: A systematic review, Couper [/bib_ref] [bib_ref] Personal protective equipment during the coronavirus disease (COVID) 2019 pandemic -a narrative..., Cook [/bib_ref] [bib_ref] International Liaison Committee on Resuscitation: COVID-19 consensus on science, treatment recommendations and..., Perkins [/bib_ref] There is no published evidence that resuscitative measures during postnatal collapse are associated with increased risk of infection. Nevertheless, due to the heightened concerns of cross infection, full airborne-precaution PPE should be used whenever possible if attending a postnatally collapsed baby in these circumstances. Decisions on providing breathing support in the absence of full airborne-precaution PPE need to be made with the understanding that there may be a small, but undefined, risk of COVID-19 exposure. ## Resuscitation education and covid-19 This educational guidance considers the infection risk for instructors and candidates during a pandemic. Minimising the risk of infection during courses is paramount À distance learning, self-directed learning, augmented and virtual learning will become much more important in CPR teaching. ## General guidance for education in cpr during the pandemic Life support teaching programmes must include specific interventions for COVID-19 patients focusing on infection prevention whilst being adaptable for local needs and requirements. Self-protection against infection (equipment and procedures) must be part of CPR education. Basic courses during the COVID-19 pandemic ## Bls education for laypeople During the pandemic BLS training should conform to local government advice on social distancing and mass gatherings. Hands-on BLS teaching for laypeople is important because bystander CPR saves lives. Self-learning stations with proper infection precautions and cleaning by the course organiser as well as use of individual (blow-up) manikins are valid means of teaching BLS skills. During the pandemic, for BLS education for laypeople the ERC recommends individual self-directed learning, apps and virtual reality resources for BLS À they are readily available and are effective for teaching chest compressions and the use of an AED. Self-directed learning or distance learning will reduce the infection risk for both candidates and instructors. Internet-based tutorials and video instruction are a suitable alternative. Whilst their effectiveness for learning BLS is less certain, they provide a readily accessible medium for people to access training. The focus of BLS education for laypeople during the pandemic is on chest compressions and the use of an AED while minimising the risk of infection. They should be taught to look for normal breathing but not to open the airway and not to place their face close to the victim's mouth/nose. No mouth-to-mouth ventilation will be taught. ## Bls education for professionals For professionals, self-directed learning or distance learning is feasible and effective and has the potential to reduce the infection risk for both candidates and instructors. The ERC suggests self-directed learning for those professionals who have a duty to respond but who rarely treat cardiac arrest patients. For this group of rescuers, the educational focus is on chest compressions, use of an AED, and the donning (putting on) and doffing (taking off) of PPE. Professionals who provide BLS regularly should be educated in the donning and doffing of PPE, chest compression, use of an AED, and bag-mask ventilation with a heat and moisture exchange (HME) filter or high-efficiency particulate air (HEPA) filter between the mask and bag. ## Ethics and end-of-life decisions during the covid-19 pandemic During a pandemic many concomitant risks might put further pressure on the already strained healthcare system and potentially lead to excess mortality: [bib_ref] Code Blue During the COVID-19 Pandemic, Chan [/bib_ref] [bib_ref] Responding to Covid-19: How to Navigate a Public Health Emergency Legally and..., Gostin [/bib_ref] [bib_ref] CPR in the Covid-19 Era -An Ethical Framework, Kramer [/bib_ref] During a pandemic, the demand for resources (e.g. critical care beds, ventilators, medicines, test materials and PPE) may significantly exceed resource availability. Healthcare workers are at an increased risk of contracting COVID-19, creating additional challenges in providing adequate staffing for both direct patient care and support work. Disruptions to the healthcare system (because of insufficient resources, decreased delivery of non-COVID related care and, importantly, exaggerated fear) will also affect the care for patients with other medical problems, both acute and chronic. Eventually this could lead to more morbidity and mortality than caused by COVID-19 itself. [bib_ref] COVID-19 in Italy: momentous decisions and many uncertainties, Lazzerini [/bib_ref] Any temporary modifications to existing guidelines should be interpreted within the context of each healthcare system, taking into consideration the prevalence of COVID-19 and available resources. Our knowledge about COVID-19 is still limited and guidelines may need to be updated as more data become available. [bib_ref] Code Blue During the COVID-19 Pandemic, Chan [/bib_ref] The general principles of ethics in resuscitation remain valid. Where possible, advance care planning should be considered. [bib_ref] European Resuscitation Council Guidelines for Resuscitation 2015: Section 11. The ethics of..., Bossaert [/bib_ref] This may be particularly challenging in the context of the current COVID-19 pandemic due to knowledge gaps, social distancing measures, etc. Implementation of criteria for withholding or withdrawing resuscitation will depend on the local context (legal, cultural and organisational). Healthcare teams should carefully assess for each individual patient their chances of survival and/or good long-term outcome and their expected use of resources; such evaluation should be reviewed regularly. Categorical or blanket criteria (e.g. age thresholds) should not be used to determine the eligibility of a patient to receive resources or treatments. [bib_ref] CPR in the Covid-19 Era -An Ethical Framework, Kramer [/bib_ref] The principal challenge with resuscitation during the COVID-19 pandemic is the difficulty of reliably balancing the risk for the provider and the potential benefit for the patient. Whilst doing their best for an individual patient, healthcare providers should also be aware of their responsibility towards their relatives, colleagues, and the wider community. Healthcare providers (including first responders) should use PPE for all patients with confirmed or suspected COVID-19. The type of PPE should be defined at system level, proportionate to the presumed risk of transmission. Protocols may need to be adjusted locally to reflect the evolving pandemic and resources. ## First aid during the covid-19 pandemic There are only a few changes to the current recommended first aid protocols, most of which relate to the prevention or minimisation of the risk of virus transfer: A casualty with COVID-19 may be asymptomatic and yet still be a virus carrier. If the casualty is a household contact of the care provider and infected with COVID-19, that provider has likely already been exposed and may be willing to provide direct first aid. If the casualty is not a household contact: o Follow national advice on social distancing and the use of PPE wherever possible. o The use of PPE (gloves, masks, eye-protection, etc) may not be applicable to all first aid, but care should always be taken to protect the casualty and the first aid provider. o Those key workers with a duty of care should put on the appropriate PPE and provide first aid without further delay. o If the casualty is responsive and able to follow selfcare advice, provide first aid advice from a safe (2 m) distance. If the casualty has a face cover/mask available, encourage them to wear it while being cared for. Family members, if willing, may be coached to provide direct first aid. It may also be necessary to provide dressings, bandages, etc. from outside the immediate contact area. o If the casualty is unresponsive or unable to provide selfcare then it may be necessary to provide direct care. However, the casualty and the first aid provider must be aware of the risk of virus transfer. Sequence of actions for bystander care of a casualty outside of the household: o Call for medical assistance immediately. o Where possible, wear gloves when touching or handling the casualty. o Wear a face cover/mask if available and consider placing a face cover/mask over the face of the casualty. o Only handle/touch what is essential, remembering that all surfaces in and around the casualty may be contaminated with the virus. o Only provide essential direct first aid in order to limit your exposure time. This may include controlling significant bleeding, applying a dressing, use of an adrenaline autoinjector, assessing for responsiveness by shaking the person and shouting, and positioning of a casualty. Following completion, it is essential to: o remove and dispose of any PPE; o wash your hands thoroughly with soap and water for at least 20 s; o wash all your clothing as soon as practicable; o be prepared to self-isolate and follow national guidance if you develop COVID-19 symptoms after providing direct first aid. ## Conflict of interest [table] Table 1 -: ILCOR treatment recommendations for cardiopulmonary resuscitation (CPR) in patients with COVID-19. [/table] [table] Table 2 -: Recommendations for Personal Protective Equipment. 94%, and 99%. The US National Institute for Occupational Safety and Health (NIOSH) classifies particulate filtering facepiece respirators into nine categories based on their resistance to oil and their efficiency in filtering airborne particles. N indicates not resistant to oil; R is moderately resistant to oil; and P is strongly resistant to oil À 'oil proof'. The letters N, R or P are followed by numerical designations 95, 99, or 100, which indicate the filter's minimum filtration efficiency of 95%, 99%, and 99.97% of airborne particles (<0.3 microns).29,30 . [/table]	None	http://www.resuscitationjournal.com/article/S030095722030232X/pdf	None
72648b7d7eedf2f6a22b33af02252458f4ca40f1	pubmed	ASE Statement on Protection of Patients and Echocardiography Service Providers During the 2019 Novel Coronavirus Outbreak	ASE Statement on Protection of Patients and Echocardiography Service Providers During the 2019 Novel Coronavirus Outbreak Duke University, Durham, North Carolina (M.S.).Notice and Disclaimer:This statement reflects recommendations based on expert opinion, national guidelines, and available evidence. Our knowledge with regard to COVID-19 continues to evolve, as do our institutional protocols for dealing with invasive and non-invasive procedures and practice of personal protective equipment. Readers are urged to follow national guidelines and their institutional recommendations regarding best practices to protect their patients and themselves. These reports are made available by ASE as a courtesy reference source for its 2 American Society of Echocardiography ASEcho.org members. The reports contain recommendations only and should not be used as the sole basis to make medical practice decisions or for disciplinary action against any employee. The statements and recommendations contained in these reports are primarily based on the opinions of experts, rather than on scientifically-verified data. ASE makes no express or implied warranties regarding the completeness or accuracy of the information in these reports, including the warranty of merchantability or fitness for a particular purpose. In no event shall ASE be liable to you, your patients, or any other third parties for any decision made or action taken by you or such other parties in reliance on this information. Nor does your use of this information constitute the offering of medical advice by ASE or create any physician-patient relationship between ASE and your patients or anyone else. ## American society of echocardiography ASEcho.org members. The reports contain recommendations only and should not be used as the sole basis to make medical practice decisions or for disciplinary action against any employee. The statements and recommendations contained in these reports are primarily based on the opinions of experts, rather than on scientifically-verified data. ASE makes no express or implied warranties regarding the completeness or accuracy of the information in these reports, including the warranty of merchantability or fitness for a particular purpose. In no event shall ASE be liable to you, your patients, or any other third parties for any decision made or action taken by you or such other parties in reliance on this information. Nor does your use of this information constitute the offering of medical advice by ASE or create any physician-patient relationship between ASE and your patients or anyone else. ## Page 3 of 21 # Background The 2019 novel coronavirus, or severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that results in coronavirus disease-2019 (COVID-19), has been declared a pandemic and is severely affecting the provision of healthcare services all over the world.Healthcare workers are at higher risk since this virus is very easily spread, especially through the kind of close contact involved in the performance of echocardiographic studies. The virus carries relatively high mortality and morbidity risk, particularly for certain populations (the elderly, the chronically ill, the immunocompromised and, possibly, pregnant women). [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] Given the risk of cardiovascular complications in the setting of COVID-19, including pre-existing cardiac disease, acute cardiac injury, and drug-related myocardial damage, [bib_ref] COVID-19 and the cardiovascular system, Zheng [/bib_ref] echocardiographic services will likely be required in the care of patients with suspected or confirmed COVID-19. Consequently, echo providers will be exposed to SARS-CoV-2. Sonographers, nurses, advance practice providers and physicians have a duty to care for patients and are at the frontlines in the battle against disease. We are at high risk, particularly when we participate in the care of patients who are suspected or confirmed to have highly contagious diseases. While dedication to patient care is at the heart of our profession, we also have a duty to care for ourselves and our loved ones and to protect all of our patients by preventing the spread of disease. This means reducing our own risk while practicing judicious use of personal protective equipment (PPE). ASE is committed to the health, safety and wellbeing of our members and the patients we serve. This statement addresses triaging and decision pathways for handling echocardiographic requests, as well as indications and recommended procedures to be followed for an echocardiographic assessment of cardiovascular function in suspected or confirmed COVID-19 cases. In addition, we list measures recommended to be used in the echo lab for prevention of disease spread. Secondly, there are cases in which the indication for echocardiography is appropriate or may be appropriate, but the exam is unlikely to yield clinically important information in the short termAmerican Society of Echocardiography ASEcho.org with the added risk of potential disease transmission. There are two ways to identify these studies. ## Whom to image? ## Review of indications - Determine which studies are "elective" and reschedule them, performing all others. - Identify "non-elective" (urgent/emergent) indications and to defer all others. In cases considered for deferral, there is no significant risk to patients in terms of morbidity or mortality and no expected benefit in terms of avoiding the use of medical resources (such as emergency department visits or hospitalizations). These tests should be postponed. Next, it is important to determine the clinical benefit of echocardiography for symptomatic patients whose SARS-CoV-2 status is unknown. Knowing the status of a patient allows for the appropriate application of personal protective equipment (PPE) and its conservation when not needed, in addition to reducing the exposure risk to echocardiography personnel. TEEs carry a heightened risk of spread of the SARS-CoV-2 since they may provoke aerosolization of a large amount of virus due to coughing or gagging that may result during the examination. TEEs therefore deserve special consideration in determining when and whether they should be performed, and under what precautions (described below Depending on the trajectory of the outbreak, some institutions may face a crisis state with reduced availability of trained staff and/or equipment. In this setting, triage by indication may be necessary, deciding which appropriate and urgent/emergent echocardiograms will be performed and which will not, or deciding which will be performed first. This prioritization of indications will need to be done on a case-by-case basis, while accounting for many patient-level factors such as current indication, current clinical status, past medical history and the results of other tests. Involving referring physicians in the triage process is therefore essential. ## Where to image? The portability of echocardiography affords a clear advantage in imaging patients without having to move them and risk virus transmission in the clinic or hospital. All forms of echocardiography interpretive assistance from more experienced echocardiographers. Archiving these images for review should help to focus future imaging studies and provide comparisons of cardiac structure and function over time. In some cases, review of these images by a consulting cardiovascular specialist may obviate the need for an echocardiogram (and therefore reduce staff exposure), as pertinent clinical questions will be answered (e.g. etiology of hypotension). In other cases, they will indicate the need for more advanced imaging (e.g. wall motion and quantitative valvular assessment). Therefore, these images should be saved and archived whenever possible. Some devices use a camera that allows a sonographer or other imaging expert to remotely guide probe placement. Along the same lines, echocardiographic studies performed on patients with suspected or confirmed COVID-19 should be as focused as necessary to obtain diagnostic views but should also be comprehensive enough to avoid the need to return for additional images. Each study should be tailored to the indication and planned in advance, after review of images from past exams and other imaging modalities. Complete exams may be necessary in some circumstances. Plans for ultrasound enhancing agent (UEA) utilization should be made in advance in order to prevent a sonographer having to wait for the agent to be delivered or having to use more personal protective equipment to exit the patient's room to obtain the agent. While the safety of UEAs specifically in COVID-19 cases has not yet been determined, they have been used and proved safe in ICU patients. The use of UEAs may therefore be considered in such cases as long as the benefits in terms of diagnostic yield and scan time are favorable. [bib_ref] Multimodality imaging of left atrium in patients with atrial fibrillation, Guglielmo [/bib_ref] American Society of Echocardiography ASEcho.org Regardless of the type of study (UAPE, POCUS, CCE or comprehensive echo), prolonged scanning can expose these clinicians to added risk. An additional consideration when performing a limited transthoracic echo exam is the limitations that may be posed by layers of protective equipment on image quality. Therefore, these studies should not be performed by a sonography student or any other novice/inexperienced practitioner, in order to minimize scanning time while obtaining images of the highest possible quality. Finally, the results of the exam should be rapidly reviewed and key findings recorded immediately on the patient's record and communicated to the primary care team to allow hemodynamic management to be optimized. The group therefore recommends the following: - Echocardiographic exams be planned ahead, based on indications, clinical information, laboratory data and other imaging findings to allow for a focused sequence of images that help with management decisions. - The use of UEAs should be considered prior to the exam to avoid the need to prolong scan time while awaiting preparation of the agent. - Scan times should be minimized by excluding students or novice practitioners from performing imaging. - Imaging team should ensure rapid review and reporting of key findings in the patient's record and communicating them with the primary care team.American Society of Echocardiography ASEcho.org ## Protection ## Personnel Imaging should be performed according to local standards for the prevention of virus spread. Meticulous and frequent hand washing is crucial. In some institutions, the level of PPE required may depend on the risk level of the patient with regard to COVID-19 (minimal risk=not suspected, moderate risk=suspected, high risk=confirmed). In some institutions, suspected and confirmed cases are treated similarly. The types of PPE can be divided into levels or categories (see . - Standard care involves handwashing or hand sanitization and use of gloves. The use of a surgical face mask in this setting may also be considered. - Droplet precautions include gown, gloves, headcover, facemask and eye shield. - Airborne precautions add special masks (e.g. N-95 or N-99 respirator masks, or powered air purifying respirator -PAPR systems), and shoe covers. The local application of each component of PPE can vary according to level or type of risk for TTEs and stress echo exams, but airborne precautions are required during a TEE for suspected and confirmed cases, due to the increased risk for aerosolization. A surgical face mask for patients is recommended for those who are symptomatic, undergoing surface echo examination provided institutional resources allow this strategy for source control.It is important to reiterate that the type of PPE to be used on specific cases will depend on local institutional policy and resources. The US Centers for Disease Control (CDC) provides updated guidelines for PPE use for healthcare workers. (AIUM) has specific guidelines for disinfection of ultrasound equipment.Role of learners ## Other considerations In addition to limiting the number of echocardiography practitioners involved in scanning, consideration should be given to limiting the exposure of staff who may be particularly susceptible to severe complications of COVID-19. Staff who are >60 years old, have chronic conditions, are immunocompromised or are pregnant may wish to avoid contact with patients suspected or confirmed to have COVID-19, depending on local procedures. The risk of transmission also occurs in reading rooms. Keyboards, monitors, mice, chairs, phones, desktops, and door knobs should be frequently cleaned, and ventilation provided wherever possible. In some institutions the echo lab reading room is a place where many clinical services congregate to review images. In the current environment, it may be advisable to ask 13 American Society of Echocardiography ASEcho.org these services to review images remotely while speaking with the echocardiographer-consultant by phone, or review images together via a webinar. # Conclusion The provision of echocardiographic services remains crucial in this difficult time of the SARS-CoV-2 outbreak. Working together, we can continue to provide high quality care while minimizing risk to ourselves, our patients and the public at large. Carefully considering 'Whom to Image', 'Where to Image' and 'How to Image' has the potential to reduce the risks of transmission.	None	None	None
194f55b2a8646ef36a6084d57b4a0e3a3de5c4ae	pubmed	Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with prostate cancer	Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with prostate cancer # Introduction In 2020 an estimated 19.3 million new cases of cancer were diagnosed and almost 10 million cancer-related deaths recorded, worldwide. [bib_ref] Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for..., Sung [/bib_ref] Of these, prostate cancer accounted for 7.3% (1 414 259) of new cases and 3.8% (375 304) of cancer deaths, representing 14.5% of new cases of cancer and 6.8% of cancer deaths in men worldwide. Prostate cancer is the second most frequently diagnosed cancer in men after lung cancer and the fifth most common cause of cancer death worldwide. [bib_ref] Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for..., Sung [/bib_ref] Asia historically has been considered to have a low incidence of prostate cancer, but the incidence of and mortality from prostate cancer is increasing rapidly. [bib_ref] Epidemiology and genomics of prostate cancer in Asian men, Zhu [/bib_ref] However, the age-standardised rates for prostate cancer incidence in Western Asia, South-Eastern Asia and South-Central Asia were 28.6, 13.5 and 6.3 per 100 000 men, respectively, in 2020, compared with 73 per 100 000 for North America. [bib_ref] Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for..., Sung [/bib_ref] Both the incidence as well as the mortalityto-incidence ratio are associated with the human development index. [bib_ref] Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for..., Sung [/bib_ref] The lower incidence of prostate cancer in Asian men compared with Western men may also be due to less prostate-specific antigen (PSA) screening. Studies in both Japan [bib_ref] Prostate-specific antigen-based population screening for prostate cancer: current status in Japan and..., Kitagawa [/bib_ref] and Taiwan [bib_ref] Increasing incidence of prostate cancer in Taiwan: a study of related factors..., Lin [/bib_ref] have shown the incidence of prostate cancer to increase with PSA testing. In the case of the Japanese study, [bib_ref] Prostate-specific antigen-based population screening for prostate cancer: current status in Japan and..., Kitagawa [/bib_ref] PSA screening was associated with a reduction in the proportion of advanced prostate cancers detected. However, another reason for the difference in the incidence of prostate cancer may be due to the fact that the genomic features of prostate cancer differ between Asian and Western populations and also vary between different regions and countries in Asia. [bib_ref] Epidemiology and genomics of prostate cancer in Asian men, Zhu [/bib_ref] A recent study has shown the Han Chinese, Korean and Japanese populations to have distinct genetic profiles. [bib_ref] Genetic structure, divergence and admixture of Han Chinese, Japanese and Korean populations, Wang [/bib_ref] Asian studies have also shown men with diabetes to be at a higher risk of developing prostate cancer than their non-diabetic counterparts. [bib_ref] History of diabetes mellitus and the risk of prostate cancer: the Ohsaki..., Li [/bib_ref] [bib_ref] The association of diabetes mellitus with liver, colon, lung, and prostate cancer..., Lee [/bib_ref] [bib_ref] Prostate cancer mortality in Taiwanese men: increasing age-standardized trend in general population..., Tseng [/bib_ref] [bib_ref] Diabetes and risk of prostate cancer: a study using the National Health..., Tseng [/bib_ref] Thus, differences in genetics, environment, lifestyle, diet and culture are all likely to influence the management of prostate cancer in Asia, as demonstrated by a comparison of the epidemiology, incidence, mortality and risk factors for prostate cancer in Eastern Asia, South-Eastern Asia and South-Central Asia with those for Western countries. [bib_ref] The incidence, mortality and risk factors of prostate cancer in Asian men, Chung [/bib_ref] Guidelines and recommendations for the treatment and management of patients with prostate/advanced prostate cancer in Asia have been published for the Asia Pacific region, [bib_ref] Management of patients with advanced prostate cancer in the Asia Pacific region:..., Chiong [/bib_ref] China,Japan, [bib_ref] NCCN Asia Consensus Statement prostate cancer, Hinotsu [/bib_ref] [bib_ref] Evidenced-based clinical practice guideline for prostate cancer (summary: Japanese Urological Association, 2016..., Kakehi [/bib_ref] India, [bib_ref] Expert Group consensus opinion on prostate cancer diagnosis and management in India..., Ghose [/bib_ref] [bib_ref] Prostate cancer research in India: a scientometric analysis of publications output during..., Gupta [/bib_ref] Korea, [bib_ref] Korean guidelines for the management of metastatic prostate cancer, Kim [/bib_ref] Singapore [bib_ref] Guidelines on management of prostate cancer, Sim [/bib_ref] and Taiwanand are important for the standardisation of both diagnostic and treatment approaches, with the aim of optimising clinical outcomes for what is an increasing health care problem in Asia. The European Society for Medical Oncology (ESMO) guidelines for the diagnosis, treatment and follow-up of patients with prostate cancer were published in 2020, [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] and a decision was taken by ESMO and the Singapore Society of Oncology (SSO) that these guidelines should be adapted for patients of Asian ethnicity. Consequently, representatives of SSO, ESMO, the Chinese Society of Clinical Oncology (CSCO), the Indian Society of Medical and Paediatric Oncology (ISMPO), the Japanese Society of Medical Oncology (JSMO), the Korean Society for Medical Oncology (KSMO), the Malaysian Oncological Society (MOS) and the Taiwan Oncology Society (TOS) convened for a virtual, 'face-to-face', working meeting on 20 November 2021, hosted by SSO, to adapt the recent ESMO Clinical Practice Guidelines for patients with prostate cancer. This manuscript summarises the Pan-Asian adapted guidelines, developed before and finalised during the meeting, accompanied by the level of evidence (LoE), grade of recommendation (GoR) and percentage consensus reached for each recommendation. The main focus was on the scientific acceptability of each recommendation, independent of the availability, reimbursement and practical challenges that may be associated with it, in certain Asian countries. # Methodology This Pan-Asian adaptation of the current ESMO Clinical Practice Guidelines for prostate cancer, [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] together with any relevant data updates from the ESMO 2021 Annual Meeting, was prepared in accordance with the principles of ESMO standard operating procedures (http://www.esmo. org/Guidelines/ESMO-Guidelines-Methodology) and was an SSOeESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and TOS. An international panel of experts was selected from the SSO (n ¼ 6), the ESMO (n ¼ 5) and two experts from each of the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS) and Taiwan (TOS). Only two of the six expert members from the SSO (AW and MLKC) were allowed to vote on the recommendations together with the experts from each of the six other Asian oncology societies (n ¼ 14). Of the 14 voting experts, 4 were urologists [YZ (CSCO), QZ (CSCO), YSP (TOS) and HK (JSMO)] and the remainder oncologists. A modified Delphi process was used to review, accept or adapt each of the individual recommendations in the latest ESMO Clinical Practice Guidelines. [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] The 14 Asian experts were asked to vote YES or NO (one vote per society) on the 'acceptability' (agreement with the scientific content of the recommendation) and 'applicability' (availability, reimbursement and practical challenges) of each of the ESMO recommendations in a pre-meeting survey (see Supplementary Methodology, available at https://doi.org/10.1016/j.esmoop. 2022.100518). For recommendations, where a consensus was not reached, the Asian experts were invited to modify the wording of the recommendation(s) at the 'face-to-face' virtual meeting using rounds of voting in order to determine the definitive acceptance or rejection of an adapted recommendation and discuss the applicability challenges. The 'Infectious Diseases Society of America-United States Public Health Service Grading System' (Supplementary [fig_ref] Table 1: Summary of Asian recommendations mpMRI should be used to confirm the indication... [/fig_ref] , available at https://doi.org/10.1016/j.esmoop. 2022.100518) [bib_ref] Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell..., Dykewicz [/bib_ref] was used to define the LoE and strength (grade) of each recommendation. Any modifications to the initial recommendations were highlighted in bold text in a summary table of the final Asian recommendations and in the main text, if and as applicable. A consensus was considered to have been achieved when !80% of experts voted that a recommendation was acceptable. # Results In the initial pre-meeting survey, the 14 Asian experts reported on the 'acceptability' and 'applicability' of the 50 recommendations for the diagnosis, treatment and followup of patients with prostate cancer based on the most recent ESMO Clinical Practice Guidelines 20 A lack of agreement (no consensus) in the pre-meeting survey was established for 'recommendations 2b and c, 6a, 12a and 13c', in terms of 'acceptability', leading to their discussion during the 'face-to-face' meeting. In addition, no consensus was established for 'recommendations 1b, 2a-d, 6a, 7d, 8a, 10a, 11a, 12a-d, 13c and 14b' in terms of 'applicability' , available at https://doi.org/10.1016/j.esmoop.2022.100518). Of the latter, three recommendations ('recommendations 7d, 12b and 14b') were discussed due to the fact that comments relating to scientific acceptability were made under applicability. A further three recommendations ('recommendations 4f, 5b and 9a') needed to be updated and two new recommendations ('recommendations 11g and 12e') added due to the emergence of new data. For the purposes of these guidelines, the following general definitions apply: Early prostate cancerdlocalised prostate cancer without evidence of lymph node involvement or distant metastases. Locally advanced prostate cancerd!T3b prostate cancer with or without lymph node involvement within the pelvis. Metastatic prostate cancerdprostate cancer with lymph node invasion beyond the pelvis and/or bone or visceral spread. Castration-resistant prostate cancerdprostate cancer that no longer responds to androgen deprivation therapy (ADT) despite adequate castration evidenced by serum testosterone levels <0.50 ng/ml; typically, three consecutive rises in PSA >0.2 ng/ml. The majority of prostate cancers are adenocarcinomas, and for the purposes of this guidelines manuscript, the term prostate cancer refers to adenocarcinomas, unless otherwise specified. 1. Screening and early detectiondrecommendations 1a-c In Western countries, population-based screening of middle-aged men using PSA testing has increased early diagnosis and decreased prostate cancer mortality. [bib_ref] Screening and prostate cancer mortality: results of the European Randomised Study of..., Schroder [/bib_ref] [bib_ref] Strategy for detection of prostate cancer based on relation between prostate specific..., Vickers [/bib_ref] [bib_ref] Recent trends in prostate cancer mortality show a continuous decrease in several..., Bouchardy [/bib_ref] Although a meta-analysis of data from five randomised controlled trials (RCTs) showed PSA testing not to decrease prostate cancer mortality, [bib_ref] Screening for prostate cancer, Ilic [/bib_ref] the European Randomised Study of Screening for Prostate Cancer (ERSPC) reported a significant 27% reduction in prostate cancer-specific mortality in men aged between 55 and 69 years, after 13 years of follow-up. [bib_ref] Screening and prostate cancer mortality: results of the European Randomised Study of..., Schroder [/bib_ref] As a consequence, the American (AUA) and European (EAU) Urological Associations state, respectively, that well-informed men aged 55-69 years cannot be denied PSA testing [bib_ref] Early detection of prostate cancer: AUA Guideline, Carter [/bib_ref] and that PSA testing should be offered to wellinformed men aged >50 years with a life expectancy of at least 10-15 years. [bib_ref] EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment..., Heidenreich [/bib_ref] The Japanese Urological Association (JUA) recommends PSA-based screening.However, in Asia, the level of PSA testing is low compared with Western countries. Despite this, the Pan-Asian panel of experts agreed with and accepted completely (100% consensus) the ESMO recommendations on Screening and early detection, 'recommendations 1a-c' below and [fig_ref] Table 1: Summary of Asian recommendations mpMRI should be used to confirm the indication... [/fig_ref]. However, in terms of applicability, 'recommendation 1b' is not yet implemented in ## Diagnosis and pathologydrecommendations 2a-d The risk of being diagnosed with and developing clinically significant prostate cancer is related to age, ethnicity, family history, PSA level, free/total PSA ratio and findings on digital rectal examination. [bib_ref] Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial, Thompson [/bib_ref] Physicians are encouraged to consider these factors for risk calculations. Until recently, transrectal (TR) ultrasound-guided prostate biopsy was the standard for detecting prostate cancer in patients with elevated PSA levels. However, several studies suggest that multi-parametric magnetic resonance imaging (mpMRI) should be carried out before biopsy, 30-32 including a systematic review and meta-analysis of mpMRI for the diagnosis of prostate cancer conducted in China, [bib_ref] Accuracy of multiparametric magnetic resonance imaging for diagnosing prostate Cancer: a systematic..., Zhen [/bib_ref] which showed mpMRI to be a sensitive tool for the diagnosis and detection of prostate cancer. According to the ESMO guidelines, 20 when mpMRI is positive [i.e. Prostate ImagingeReporting and Data System (PI-RADS) !3], a targeted biopsy, plus or minus systematic biopsies, should be carried out. When mpMRI is negative (i.e. PI-RADS 2), and clinical suspicion of prostate cancer is low, the biopsy can be omitted in well-informed patients. An algorithm for the diagnostic work-up and staging of prostate cancer, taken from the ESMO guidelines, 20 is presented in . In addition, a Korean study has shown biparametric magnetic resonance imaging (bpMRI) to have similar efficacy to mpMRI in the detection of prostate cancer and clinically significant prostate cancer. [bib_ref] Comparison of multiparametric and biparametric MRI in first round cognitive targeted prostate..., Lee [/bib_ref] More recently, comparison of bpMRI with mpMRI in combination with PSA density (PSAD) in the detection of clinically significant prostate cancer showed bpMRI combined with PSAD to achieve a better detection rate than mpMRI in Asian patients. [bib_ref] MRI combined with PSA density in detecting clinically significant prostate cancer in..., Han [/bib_ref] Diffusionweighted imaging as part of mpMRI techniques has recently been investigated in a Japanese study for the detection of clinically significant prostate cancer in patients with elevated PSA levels, [bib_ref] Diffusion-weighted imaging in prostate cancer, Tamada [/bib_ref] and further refinement to the use of these techniques in Asia is likely to be forthcoming. Thus, the Pan-Asian experts agreed with and 'accepted' completely (100% consensus) the ESMO 'recommendation 2a' below without change, although in terms of 'applicability' MRI may not be available/reimbursed in some Asian countries (see However, there was considerable discussion around ESMO 'recommendations 2b and c' with a lack of consensus in terms of acceptability and applicability in the premeeting survey , available at https://doi.org/10.1016/j.esmoop.2022.100518). Prostate cancer risk calculation tools provide quantitative guidance for decision making regarding whether or not to carry out a biopsy. It was emphasised during discussions Transperineal prostate (TP) biopsy is emerging as one of the options for prostate cancer diagnosis, and when compared with TR prostate biopsy it offers a non-inferior cancer detection rate, [bib_ref] Transperineal prostate biopsy: the modern gold standard to prostate cancer diagnosis, Ortner [/bib_ref] with a lower infection rate. A systematic comparison of TR and TP prostate biopsies in terms of efficacy and complications in the detection of prostate cancer in Asian studies showed no significant difference in prostate cancer detection rate and complications between the TR and TP approaches, [bib_ref] The results of transperineal versus transrectal prostate biopsy: a systematic review and..., Shen [/bib_ref] [bib_ref] Comparison between transrectal and transperineal prostate biopsy for detection of prostate cancer:..., Xue [/bib_ref] with the TP approach shown, in a meta-analysis conducted in China, to have a lower risk of fever and rectal bleeding. [bib_ref] Transperineal versus transrectal prostate biopsy in the diagnosis of prostate cancer: a..., Xiang [/bib_ref] Thus, in the case of 'recommendation 2c' below, the original text was revised for the sake of clarification (with the changes highlighted in bold text below and [fig_ref] Table 1: Summary of Asian recommendations mpMRI should be used to confirm the indication... [/fig_ref] ## Staging and risk assessmentdrecommendations 3a-c Patients should be assessed with regard to their general health and comorbidities, and those who are not suitable for treatment with curative intent, by virtue of poor general health, do not normally require staging investigations. MRI provides tumour staging information. [bib_ref] The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge..., Amin [/bib_ref] The Gleason score is recommended for pathological grading of prostate adenocarcinomas and comprises a system of primary and secondary scores. [bib_ref] Grading of prostate cancer: a work in progress, Kweldam [/bib_ref] The degree of differentiation is defined/ determined by the sum of the two scores. Thus, patients with localised disease can be classified as outlined in [bib_ref] Meta-analysis of (11)C-choline and (18)Fcholine PET/CT for management of patients with prostate..., Von Eyben [/bib_ref] or the emerging prostate-specific membrane antigen (PSMA)-PETeCT. Gallium PSMA-PETeCT has been shown to have value as a diagnostic and clinical decisionmaking tool in Asian patients with rapid biochemical recurrence. [bib_ref] 68 Gallium-labelled PSMA-PET/CT as a diagnostic and clinical decision-making tool in Asian..., Tan [/bib_ref]. Where possible, patients should be treated within a multidisciplinary team environment which should include both urologists and radiation oncologists as well as medical oncologists. Prostate cancer can be slow growing and may never cause patients any problems during their lifetime. Thus, 'watchful waiting' is an option for those patients with other health problems who may be unsuitable for or unwilling to undergo treatment with curative intent such as surgery [bib_ref] Radical prostatectomy or watchful waiting in prostate cancer -29-year follow-up, Bill-Axelson [/bib_ref] [bib_ref] Radical prostatectomy versus observation for localized prostate cancer, Wilt [/bib_ref] or radiotherapy (RT). It generally applies to patients with shorter life expectancies (<10 years). Active surveillance, on the other hand, involves careful patient monitoring such as PSA testing, repeat biopsies and MRI, to avoid patients having unnecessary treatment, and is for patients with slow-growing tumours who would benefit from curative treatment if required. [bib_ref] Guidelines on management of prostate cancer, Sim [/bib_ref] [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] Curative options for these low-risk patients include external beam RT (EBRT), low-dose rate brachytherapy and radical prostatectomy (RP) [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] improve survival over RT alone [bib_ref] Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer:..., Warde [/bib_ref] [bib_ref] Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/..., Widmark [/bib_ref] [bib_ref] Recent trend of androgen deprivation therapy in newly diagnosed prostate cancer patients:..., Lim [/bib_ref] [fig_ref] Figure 3: High-risk localised and locally advanced prostate cancer treatment algorithm [/fig_ref]. More recently, combination therapy with abiraterone acetate plus prednisone/prednisolone (AAP) has been shown to be associated with significantly higher rates of metastasis-free survival compared with ADT alone in patients with high-risk localised disease meeting the STAMPEDE trial criteria. [bib_ref] Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate..., Attard [/bib_ref] RP plus pelvic lymphadenectomy is also an option for high-risk disease [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] [fig_ref] Figure 3: High-risk localised and locally advanced prostate cancer treatment algorithm [/fig_ref] and Supplementary For patients relapsing after RT, local salvage using highintensity focused ultrasound (HIFU), high-dose rate brachytherapy or RP may be required. Observation with delayed ADT may be appropriate for those patients with biochemical relapse and symptomatic local disease, proven metastases or a PSA doubling time of <3 months [fig_ref] Figure 3: High-risk localised and locally advanced prostate cancer treatment algorithm [/fig_ref] , and also Section 8 below.). For those patients who have undergone RP, RT to the prostate bed plus or minus pelvic nodes may be required or observation with delayed ADT [fig_ref] Figure 3: High-risk localised and locally advanced prostate cancer treatment algorithm [/fig_ref]. These patients, however, often require postoperative RT plus or minus ADT. All the Asian experts agreed completely with 'recommendations 4a and b' below, in terms of acceptability (100% consensus) and applicability, without change. 4a. Watchful waiting with delayed ADT is an option for patients with localised or locally advanced disease who are not suitable for, or unwilling to have, radical treatment [bib_ref] United in Fight against prOstate cancer (UFO) registry: first results from a..., Uemura [/bib_ref] All the Asian experts accepted completely (100% consensus) 'recommendations 4d-f and 4h' below, in the pre-meeting survey without change. However, 'recommendation 4f' was updated at the virtual 'face-to-face' meeting and a new recommendation 4g added (as denoted by the bold text below and in [fig_ref] Table 1: Summary of Asian recommendations mpMRI should be used to confirm the indication... [/fig_ref] ## Relapse after radical therapy Salvage RT to prostate bed +/-pelvic nodes Consider ADT for 6 months or bicalutamide for 2 years ## Esmo open 4h. RP plus pelvic lymphadenectomy is an option for selected men with high-risk disease [bib_ref] Outcomes of pathologically localized high-grade prostate cancer treated with radical prostatectomy, Heo [/bib_ref] [bib_ref] Comparison of clinical outcomes of radical prostatectomy versus IMRT with long-term hormone..., Shih [/bib_ref] [III, B]. ## Neoadjuvant and adjuvant hormone treatmentd recommendations 5a-c The benefit of neoadjuvant and concurrent ADT together with RT has been established in RCTs 67,68 for men with highrisk localised and locally advanced prostate cancer. [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] Furthermore, RCTs in patients with unfavourable intermediate-risk prostate cancer risk [primary Gleason score 4, !50% positive biopsy scores or !2 intermediaterisk factors (cT2b-c, Gleason score 7, PSA 10-20 ng/ml)], and therefore an anticipated poorer outcome, showed longcourse (18-36 months) adjuvant ADT after RT to improve overall survival in those patients. [bib_ref] Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of..., Bolla [/bib_ref] [bib_ref] Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction..., Hanks [/bib_ref] [bib_ref] Duration of androgen deprivation therapy in high-risk prostate cancer: a randomized phase..., Nabid [/bib_ref] All the Asian experts agreed completely with 'recommendations 5a and b' below in terms of both acceptability (100% consensus) and applicability in the pre-meeting survey. However, as for 'recommendation 4f' above, new data from the phase III STAMPEDE trial [bib_ref] Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate..., Attard [/bib_ref] showing the addition of 2 years of AAP to improve both metastases-free survival (P ¼ 3.2 Â 10 À7 ) and overall survival (P ¼ 0.0005) in patients with very-high-risk M0 disease also necessitated an update to 'recommendation 5b', and a new recommendation 5c added (as denoted by the bold text below and in [fig_ref] Table 1: Summary of Asian recommendations mpMRI should be used to confirm the indication... [/fig_ref] 7. Post-operative RTdrecommendations 7a-e RT can be administered post-operatively as either adjuvant or salvage therapy, 20 but it is unclear which is more appropriate for patients with localised or locally advanced prostate cancer following RP. Adjuvant RT (ART) had been shown to improve biochemical control but not overall survival. [bib_ref] Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy..., Wiegel [/bib_ref] A prospectively planned, systematic review and meta-analysis of event-free survival (EFS) data for 2153 patients from three trials comparing immediate ART (n ¼ 1075) with early salvage RT (SRT, n ¼ 1078) (the ARTISTIC collaboration) [bib_ref] Adjuvant or early salvage radiotherapy for the treatment of localised and locally..., Vale [/bib_ref] showed no evidence that ART improved EFS over SRT (HR 0.95; 95% CI 0.75-1.21; P ¼ 0.70). ART was associated with bladder and bowel morbidity but not with any proven benefit in terms of biochemical progression-free survival (PFS). Thus, observation followed by SRT in the case of PSA failure is the current standard in Europe and Asia after RP, with better outcomes achieved when a patient's PSA is <0.5 ng/ml. [bib_ref] Prognostic value of biochemical recurrence following treatment with curative intent for prostate..., Van Den Broeck [/bib_ref] [bib_ref] Outcomes and prediction models for exclusive prostate bed salvage radiotherapy among patients..., Tseng [/bib_ref] ART may be offered to selected patients with positive resection margins or extracapsular extension. [bib_ref] Systematic review and meta-analysis of trials evaluating the role of adjuvant radiation..., Bhindi [/bib_ref] Comparison of SRT with SRT plus either 6 months of ADT or 24 months of bicalutamide showed 24 months of bicalutamide to reduce the rate of prostate cancer death (HR 0.77; 95% CI 0.59-0.99; P ¼ 0.04) and improve overall survival (HR 0.49; 95% CI 0.32-0.73; P < 0.001). [bib_ref] Radiation with or without antiandrogen therapy in recurrent prostate cancer, Shipley [/bib_ref] The randomised phase III GETUG-AFU 16 trial showed ADT to improve metastasis-free survival (HR 0.73; 95% CI 0.54-0.98; P ¼ 0.034), but not overall survival. [bib_ref] Interest of short hormonotherapy (HT) associated with radiotherapy (RT) as salvage treatment..., Carrie [/bib_ref] In a United States study, comparison of pelvic node RT plus 6 months of ADT with prostate bed-only RT or prostate bed RT plus 6 months of ADT showed the addition of pelvic RT to improve freedom from failure and freedom from metastases compared with prostate bed-only RT (HR 0.52; 95% CI 0.30-0.92; P ¼ 0.014). [bib_ref] Short term androgen deprivation therapy without or with pelvic lymph node treatment..., Pollack [/bib_ref] Thus, all the Asian experts accepted completely (100% consensus) 'recommendations 7a-e' below. some Asian countries, ADT is not routinely offered following salvage RT, as patients are referred for early salvage RT when their PSA levels are <1.0 ng/ml, and the benefit of ADT in these patients is less certain. ## Treatment of relapse after radical local treatmentdrecommendations 8a-d For patients with biochemically recurrent prostate cancer, PSMA-PET imaging is replacing conventional imaging, based on its superior sensitivity and specificity, in terms of diagnosis. [bib_ref] Gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer-updated diagnostic..., Perera [/bib_ref] There are three treatment approaches for patients who relapse after radical local treatment and these are (i) local salvage therapy, (ii) metastasis-directed therapy and (iii) systemic therapy. [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] Since the natural history of PSA recurrence following treatment is long, life expectancy needs to be taken into account when considering local treatment options. [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] In the case of patients with local recurrence, in the absence of metastases, the local treatment options in Europe include salvage RP, HIFU, cryoablation and brachytherapy, and typically only provide temporary control. Early detection of recurrence theoretically provides the opportunity to selectively ablate metastases with the possibility of prolonging survival. Recently, a European trial has shown metastasis-directed therapy to improve biochemical progression and the time to palliative ADT, [bib_ref] Surveillance or metastasisdirected therapy for oligometastatic prostate cancer recurrence: a prospective, randomized,..., Ost [/bib_ref] while another trial conducted in Canada, the Netherlands, Scotland and Australia, in different solid tumour types (of which 16% were prostate cancer) showed the addition of stereotactic body RT to standard of care to improve overall survival. [bib_ref] Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with..., Palma [/bib_ref] Systemic ADT is not routinely recommended for patients with biochemical relapse unless they have a rapid PSA doubling time, symptomatic local disease or proven metastases. Early administration of ADT has been shown to confer no survival benefit [bib_ref] Systematic review of the diagnosis and management of malignant extradural spinal cord..., Loblaw [/bib_ref] and is associated with an adverse effect on quality of life. [bib_ref] Timing of androgendeprivation therapy in patients with prostate cancer with a rising..., Duchesne [/bib_ref] Intermittent ADT when compared with continuous ADT had a more favourable toxicity profile with no difference in overall survival (HR 1.02; 95% CI 0.86-1.21). [bib_ref] Intermittent androgen suppression for rising PSA level after radiotherapy, Crook [/bib_ref] Thus, all the Asian experts accepted completely (100% consensus) 'recommendations 8a-d' below, with a revision to the text of 'recommendation 8b' for clarification. 8a. For patients with a local recurrence following RP and no distant metastases, the pros and cons of local salvage therapy should be discussed, taking into account life expectancy and the long natural history of isolated local recurrences [III, C]. 8b. Patients with biochemical relapse after radical RT who may be candidates for local salvage or metastasisdirected treatment should undergo imaging with next generation imaging tools such as [bib_ref] Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate..., Roach M 3rd [/bib_ref] to ADT. This benefit was seen particularly in M1 patients, in combination with ADT, and also in combination with zoledronic acid, in the STAMPEDE trial, [bib_ref] Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy..., James [/bib_ref] and in patients with high-volume disease in the CHAARTED trial. [bib_ref] Chemohormonal therapy in metastatic hormone-sensitive prostate cancer, Sweeney [/bib_ref] The GETUG-AFU 15 trial showed docetaxel (75 mg/m 2 every 21 days for 9 cycles) added to ADT to improve PSA PFS and radiographic PFS but not overall survival. However, a metaanalysis of the data from these three trials confirmed the benefit of the addition of docetaxel to ADT regardless of disease volume (HR 0.77; 95% CI 0.68-0.87). [bib_ref] Docetaxel versus surveillance after radical radiotherapy for intermediate-or high-risk prostate cancer-results from..., Kellokumpu-Lehtinen [/bib_ref] [bib_ref] Addition of docetaxel or bisphosphonates to standard of care in men with..., Vale [/bib_ref] The benefit of the addition of AAP to ADT was demonstrated in the randomised phase III LATITUDE trial, 97 a subgroup analysis of the LATITUDE trial in Japanese patients [bib_ref] Efficacy and safety of abiraterone acetate plus prednisone in Japanese patients with..., Fukasawa [/bib_ref] and in the STAMPEDE 99 trial. However, recent data from the phase III PEACE-1 trial showed the addition of AAP to ADT plus docetaxel to improve both radiographic PFS (HR 0.50; 99.9% CI 0.34-0.71; P < 0.0001) and overall survival (HR 0.75; 95% CI 0.59-0.95; P ¼ 0.017). In patients with high-volume disease (at least four bone metastases including at least one in the peripheral skeleton, or visceral metastasis), the survival medians were 5.14 and 3.47 years, respectively, for those patients receiving abiraterone versus those receiving docetaxel ADT (HR 0.72; 95% CI 0.55-0.95; P ¼ 0.019). [bib_ref] Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de..., Fizazi [/bib_ref] The randomised phase III TITAN trial showed the addition of apalutamide to ADT to improve overall survival in patients with mHNPC. [bib_ref] Apalutamide for metastatic, castration-sensitive prostate cancer, Chi [/bib_ref] The benefit of adding enzalutamide to ADT for the treatment of patients with mHNPC has been shown in the phase III ARCHES 102 and ENZAMET 103 trials. The randomised HORRAD [bib_ref] Effect on survival of androgen deprivation therapy alone compared to androgen deprivation..., Boeve [/bib_ref] and STAMPEDE 105 trials have compared ADT alone (docetaxel was allowed in addition to ADT in both arms of the STAMPEDE trial) or in combination with RT to the prostate in patients with mHNPC. RT improved time to PSA progression in the HORRAD trial, [bib_ref] Effect on survival of androgen deprivation therapy alone compared to androgen deprivation..., Boeve [/bib_ref] and time to treatment failure in the STAMPEDE trial. [bib_ref] Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE):..., Parker [/bib_ref] The Asian experts agreed and accepted completely 'recommendations 9a-d' in the pre-meeting survey The treatment recommendations for mHNPC are presented in [fig_ref] Figure 4: Metastatic prostate cancer treatment algorithm [/fig_ref]. ## Non-metastatic castration-resistant prostate cancerd recommendation 10a According to the EAU-ESTRO-SIOG guidelines, patients are classified as castration-resistant if their disease progresses during ADT with serum testosterone at castrate levels. [bib_ref] EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and..., Cornford [/bib_ref] The phase III SPARTAN trial has shown apalutamide to significantly increase median metastasis-free survival (40.5 versus 16.2 months, HR 0.28; 95% CI 0.23-0.35) and time to symptomatic progression (HR 0.45; 95% CI 0.32-0.63) when compared with placebo. [bib_ref] Apalutamide treatment and metastasis-free survival in prostate cancer, Smith [/bib_ref] Similarly in the PROSPER trial in patients with high-risk CRPC, enzalutamide has been shown to be superior to placebo in terms of median metastasisfree survival (36.6 versus 14.7 months, HR 0.29; 95% CI 0.24-0.35), and the key secondary end points of median time to PSA progression (37.2 versus 3.9 months; HR 0.07; 95% CI 0.05-0.08) and time to subsequent antineoplastic therapy (39.6 versus 17.7 months; HR 0.21; 95% CI 0.17-0.26). [bib_ref] Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer, Hussain [/bib_ref] Median overall survival was 67.0 (95% CI 64.0-not reached) months in the enzalutamide group and 56.3 (95% CI 54.4-63.0) months in the placebo group (HR 0.73; 95% CI 0.6-0.89; P ¼ 0.001). [bib_ref] Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer, Sternberg [/bib_ref] The phase III ARAMIS trial has shown darolutamide to significantly increase median metastasis-free survival (40.4 versus 18.4 months, HR 0.41; 95% CI 0.34-0.50). [bib_ref] Darolutamide in nonmetastatic, castration-resistant prostate cancer, Fizazi [/bib_ref] Darolutamide also significantly improved overall survival (HR 0.69; 95% CI 0.53-0.88; P ¼ 0.003) and significantly delayed time to deterioration of prostate cancer-specific quality of life and disease-related symptoms versus placebo. [bib_ref] Nonmetastatic, castrationresistant prostate cancer and survival with darolutamide, Fizazi [/bib_ref] Bicalutamide and low-dose corticosteroids have both shown a benefit in patients with mCRPC in terms of PSA and symptomatic responses. [bib_ref] Prostate specific antigen levels and clinical response to low dose dexamethasone for..., Storlie [/bib_ref] [bib_ref] A randomised phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate..., Venkitaraman [/bib_ref] Abiraterone plus prednisone has been shown to significantly improve overall survival (HR 0.79; 95% CI 0.66-0.96) in patients with chemotherapynaïve asymptomatic/mildly symptomatic mCRPC in the COU-AA-302 trial. [bib_ref] Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with..., Ryan [/bib_ref] In the PREVAIL trial, [bib_ref] Enzalutamide in metastatic prostate cancer before chemotherapy, Beer [/bib_ref] enzalutamide was shown to be superior to placebo in terms of overall survival (HR 0.71; 95% CI 0.60-0.84). The phase III TAX-327 117 and SWOG-9916 118 trials showed docetaxel (75 ng/m 2 every 21 days) combined with prednisone, and docetaxel (60 mg/m 2 every 21 days) combined with estramustine and prednisone to improve overall survival, compared with mitoxantrone plus prednisone, with HRs of 0.76 (95% CI 0.62-0.94) 117 and 0.80 (95% CI 0.67-0.97), [bib_ref] Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate..., Petrylak [/bib_ref] respectively, while the ALSYMPCA trial showed radium 223 (Ra-223) to significantly increase overall survival (HR 0.70; 95% CI 0.55-0.83) and time to first symptomatic skeletal event (HR 0.66; 95% CI 0.0.53-0.83) in patients with symptomatic, bone-predominant mCRPC. [bib_ref] Alpha emitter radium-223 and survival in metastatic prostate cancer, Parker [/bib_ref] In Japan, a study of Ra-223, in a real-life setting, showed Ra-223 to be well tolerated in all groups. However, the incidences of serious or ! grade 3 treatment-emergent adverse events (TEAEs)/drug-related TEAEs and ! grade 3 haematological TEAEs were numerically higher in the prior-chemotherapy group than in the no prior-chemotherapy group. The safety and effectiveness of Ra-223 in patients without concomitant use of ADT were encouraging, and similar to those in the overall population. [bib_ref] Real-world safety and effectiveness of radium-223 in Japanese patients with castrationresistant prostate..., Uemura [/bib_ref] However, due to the fact that Ra-223 has been associated with an increased incidence of fractures in combination with AAP in the ERA trial, 121 its use in Europe has been restricted to patients who have received at least two lines of systemic therapy for CRPC (abiraterone/ enzalutamide and docetaxel) or who are ineligible to receive these therapies.Administration of Ra-223 in combination with AAP is not permitted. [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] For patients who had previously received docetaxel chemotherapy, cabazitaxel improved overall survival (HR 0.70; 95% CI 0.59-0.83) when compared with mitoxantrone in the TROPIC trial, [bib_ref] Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after..., De Bono [/bib_ref] AAP improved overall survival (HR 0.74; 95% CI 0.64-0.86) compared with placebo plus prednisone in the COU-301 trial [bib_ref] Abiraterone and increased survival in metastatic prostate cancer, De Bono [/bib_ref] and enzalutamide improved overall survival (HR 0.63; 95% CI 0.53-0.75) compared with placebo in the AFFIRM trial. [bib_ref] Increased survival with enzalutamide in prostate cancer after chemotherapy, Scher [/bib_ref] However, the optimal sequencing of these agents is still being investigated with evidence to suggest that there may be cross-resistance between the androgen receptor inhibitors abiraterone and enzalutamide. More recently, cabazitaxel has been shown to improve both median radiographic PFS (HR 0.54; 95% CI 0.40-0.73; P < 0.001; 8.0 versus 3.7 months) and median overall survival (HR 0.64; 95% CI 0.46-0.89; P ¼ 0.008; 13.6 versus 11.0 months) compared with AAP or enzalutamide in patients with mCRPC pre-treated with docetaxel and one of the 'novel' androgen receptor pathway inhibitors, and who progressed within 12 months. [bib_ref] Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer, De Wit [/bib_ref] Also, an international, open-label, phase III trial has been conducted to evaluate 177 Lutetium (Lu)-PSMA-617 (Lu-PSMA) plus standard of care versus standard of care alone in patients who had PSMA-positive mCRPC previously treated with at least one androgen receptor pathway inhibitor and one or two taxane regimens. Standard of care excluded chemotherapy, immunotherapy, Ra-223 and investigational drugs. The addition of Lu-PSMA to standard of care improved both median radiographic PFS (HR 0.40; 99.2% CI 0.29-0.57; P < 0.001; 8.7 versus 3.4 months) and median overall survival (HR 0.62; 95% CI 0.52-0.74; P < 0.001; 15.3 versus 11.3 months) compared with standard of care alone in pre-treated patients with mCRPC. [bib_ref] Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer, Sartor [/bib_ref] All 14 Asian experts accepted completely (100% consensus) the 'recommendations 11a-f' below in the premeeting survey However, based on the publication of the new data on the potential sequencing of agents in the treatment of patients with mCRPC outlined above, [bib_ref] Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer, De Wit [/bib_ref] [bib_ref] Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer, Sartor [/bib_ref] the new recommendation, 'recommendation 11g' below, was discussed and voted on at the virtual meeting and added below and in [fig_ref] Table 1: Summary of Asian recommendations mpMRI should be used to confirm the indication... [/fig_ref] ## Precision medicinedrecommendations 12a-e Tissue-based molecular assays may be used in conjunction with all clinico-pathological factors for treatment decision making in patients with localised prostate cancer. Potentially actionable somatic or germline events have been identified in w90% of patients with mCRPC. [bib_ref] Integrative clinical genomics of advanced prostate cancer, Robinson [/bib_ref] The BRCA2 gene is commonly altered and prostate tumours associated with a germline BRCA2 mutation have a high Gleason score, nodal and distant metastases at the time of diagnosis and poor survival. [bib_ref] Germline BRCA mutations are associated with higher risk of nodal involvement, distant..., Castro [/bib_ref] Approximately 20% of metastatic prostate cancers have mutations and alterations involved in DNA damage and repair (DDR) genes 128 with w30% metastatic prostate cancer patients carrying a germline DDR mutation found not to have a previous family history Thus, in Europe, the recommendation is that germline testing for BRCA2 and other DDR gene changes should be offered to all patients with a family history and should be considered for all patients with metastatic prostate cancer. [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] There was a lack of consensus amongst the Asian experts with regard to 'recommendation 12a' in the pre-meeting survey However, there was considerable discussion around 'recommendation 13c' with regard to the limited access to MRI especially for asymptomatic patients. Also, the Asian experts considered that there was little point in conducting MRI, if they were not going to use RT in the treatment of asymptomatic patients. Thus, the original 'recommendation 13c' below was revised to cover a more individual approach to the palliative treatment of patients, depending on the individual patient situation, with experts maybe electing to start with a bone-targeting agent or change the existing anticancer treatment depending on the general condition of the patient. Thus, the wording of the initial recommendation was revised to make the use of MRI optional as indicated by the bold text below and 14. Follow-up and long-term implicationsd recommendations 13a and b The increase in survival times for patients with prostate cancer means that patients spend longer receiving ADT. ADT may cause hot flushes, lethargy, mood swings and significantly osteoporosis. The latter, together with the adverse effects on bone health of abiraterone, enzalutamide, steroids and Ra-223, means that bone health in patients with prostate cancer has become a more important issue. Thus, lifestyle measures to improve bone health are recommended and patients starting long-term ADT should either be offered an oral bisphosphonate or be offered a bone density dual-energy X-ray absorptiometry (DEXA) scan and be treated according to the ESMO guidelines for CTIBL. [bib_ref] Bone health in cancer: ESMO Clinical Practice Guidelines, Coleman [/bib_ref] A management manual exists for CTIBL in Japan. [bib_ref] Management manual for cancer treatment-induced bone loss (CTIBL): position statement of the..., Fukumoto [/bib_ref] There was some discussion about access to and costs of bone-targeting agents and the interpretation of DEXA scans in relation to 'recommendation 14b', but all 14 Asian experts accepted 'recommendations14a and b' without change (i.e. 100% consensus Recently, pembrolizumab monotherapy has shown promising antitumour activity, with an acceptable safety profile, in a small cohort of patients with bone-predominant mCRPC (mostly with MSI disease) previously treated with docetaxel and targeted endocrine therapy, [bib_ref] Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199..., Antonarakis [/bib_ref] and has been included in Supplementary [bib_ref] Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Parker [/bib_ref] Following the virtual 'face-to-face' discussions, the revisions were made to the wording of 'recommendations 2b and c, 4f, 6a and 9a' and two new recommendations added, recommendations 11g and 12e [fig_ref] Table 1: Summary of Asian recommendations mpMRI should be used to confirm the indication... [/fig_ref] , and resulted in a 100% consensus in terms of acceptability being achieved for all the recommendations listed in [fig_ref] Table 1: Summary of Asian recommendations mpMRI should be used to confirm the indication... [/fig_ref]. Thus, the recommendations listed in [fig_ref] Table 1: Summary of Asian recommendations mpMRI should be used to confirm the indication... [/fig_ref] can be considered to constitute the consensus clinical practice guidelines for the treatment of patients with prostate cancer in Asia. As mentioned previously, the acceptance of each recommendation by each of the Asian experts was based on the available scientific evidence and was independent of the approval and reimbursement status of certain procedures and drugs in their individual countries. A summary of the availability of the recommended treatment modalities and recommended drugs, as of November 2021, is presented for each participating Asian country in [fig_ref] Table S6 ,: available at https [/fig_ref] , available at https://doi.org/10. 1016/j.esmoop.2022.100518, and will obviously impact some of the disease and patient management strategies that can be adopted by certain countries. vendor Globewerks for their assistance in the execution of the virtual 'face-to-face' meeting of experts. Dr A. Kinsella of Cancer Communications and Consultancy Ltd, Cheshire, UK is acknowledged for her contribution to the preparation of the manuscript. Mrs N. Latino, ESMO Head of Scientific Affairs, is acknowledged for her contribution in the completion of the ESMO-MCBS table. # Funding No external funding has been received for the preparation of these guidelines. Production costs have been covered by SSO from central funds. # Disclosure RK declares institutional payments from Pfizer, MSD, BMS, Eisai, Amgen, Astellas, J&J, Novartis and Merck and support for meeting attendance or travel from Pfizer, MSD, BMS, Eisai, Amgen, Astellas, J&J, Novartis and Merck. EC declares an institutional grant from Janssen, consulting fees from Astellas, AstraZeneca, Bayer, MSD and Pfizer, fees and honoraria for lectures, presentations from Astellas, Astra-Zeneca, Bayer, Janssen, MSD and Pfizer and support for attending meetings or travel from AstraZeneca and Janssen. AW declares personal fees from MS, MSD, Pfizer, Eisai and IPSEN and participation on a data safety monitoring or advisory board for BMS, MSD, Pfizer, Eisai and IPSEN. KF declares institutional honoraria for participation in advisory boards and talks for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Janssen, MSD, Novartis/AAA, Pfizer and Sanofi, and personal honoraria for participation to advisory boards for CureVac and Orion. MLKC declares payments or honoraria from ImmunoScape, IQVIA, Telix, Atsellas, AstraZeneca, Bayer, Illumina, Janssen, MSD, Pfizer and Varian, participation on a data safety monitoring or advisory board for AstraZeneca, Astellas, Bayer Pharma, Illumina, Janssen Pharma, MSD Oncology and Varian, a grant from Ferring, stock option in Digital Life Line, a role with the F1000dHead and Neck Cancer Section, Singapore Society of Oncology and Head Neck Caner International Group and other financial interests in Medlever and Varian. HM declares personal fees from CIPLA, Novartis, AstraZeneca, Roche, Eli Lilly, Merck, Pfizer, MSD, CADILA, Bard India and Somex Research. YM declares payments or honoraria from BMS, MSD and Takeda, participation on an advisory board for Chugai Pharmaceutical and Takeda and local PI, institutional, financial interest from MSD. JLL declares institutional grants or contracts from Pfizer, Novartis BMS, Janssen, MSD, Roche/Genetech, AstraZeneca/MedImmune, Seagen Astellas, Bayer, Schering Pharma, Lilly and Merck and participation on a data safety monitoring or advisory board from Pfizer Korea, Astella Korea, BMS, Merck, MSD, AstraZeneca, stocks or stock options from Myovant Sciences, Amgen, Johnson and Johnson and Merck. YSP declares honoraria and consulting fees from MSD, Roche, Merck, Ipsen, BMS/ONO, Novartis, Pfizer, Astellas, Janssen and GSK and support for attending meetings and/or travel from Ipsen, BMS/ONO, Novartis, Pfizer, Astellas and Janssen. MS declares research grants from Johnson and Johnson, payments or honoraria from Johnson and Johnson, AstraZeneca, Amgen and CIPLA, support for meeting attendance from Astellas, fees for participation in data monitoring or advisory boards from Johnson and Johnson, Amgen and AstraZeneca and receipt of equipment/materials for a compassionate programme for drugs/drug samples from Johnson and Johnson, AstraZeneca and Astellas. HJL declares participation on a data safety monitoring or advisory board for Astellas Korea. HK declares payments or honoraria from Astellas, AstraZeneca, Janssen, Sanofi and Takeda and payment for expert testimony and participation in an advisory board for Janssen. KP declares institutional [fig] Figure 3: High-risk localised and locally advanced prostate cancer treatment algorithm. AAP, abiraterone acetate plus prednisolone/prednisone; ADT, androgen deprivation therapy; EBRT, external beam radiotherapy; HDR, high-dose rate; HIFU, highintensity focused ultrasound; PC, prostate cancer; PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiotherapy. a For men with biochemical relapse and symptomatic local disease, proven metastases or a PSA doubling time of <3 months. [/fig] [fig] Figure 4: Metastatic prostate cancer treatment algorithm. AAP, abiraterone acetate plus prednisolone/prednisone; ADT, androgen deprivation therapy, ECOG PS, Eastern Cooperative Oncology Group performance status; PC, prostate cancer; RT, radiotherapy. [/fig] [table] Table 1: Summary of Asian recommendations mpMRI should be used to confirm the indication for a biopsy in men with elevated PSA, where available [I, A]. 100% 2c. Transperineal ultrasound-guided biopsies are recommended, over transrectal biopsies due to lower infection rates. [III, B]. 100% 2d. Each biopsy should be reported individually and evaluated using the ISUP consensus recommendations [II, B]. 100% Recommendation 3: Staging and risk assessment 3a. Localised disease should be classified as low-, intermediate-or high-risk as a guide to prognosis and therapy [III, A]. 100% 3b. Patients with intermediate-risk disease should be staged for metastases using MRI or CT of the abdomen and pelvis and bone scans [III, B]. Primary ADT alone is not recommended as standard initial treatment for non-metastatic disease [I, D]. 100% 4f. External beam RT plus ADT is recommended for patients with high-risk or locally advanced prostate cancer [I, B]. 100% 4g. External beam RT plus ADT plus AAP (24 months) is recommended for patients with high-risk or locally advanced prostate cancer, as defined by the STAMPEDE trial criteria [I, B]. 100% 4h. RP plus pelvic lymphadenectomy is an option for selected patients with high-risk disease [III, B]. 100% Recommendation 5: Neoadjuvant and adjuvant hormone treatment 5a. Patients receiving radical RT for intermediate-risk disease should be offered a short course of ADT for 4-6 months [I, A]. 100% 5b. Patients receiving radical RT for high-risk disease should have a long course of ADT (18-36 months) [I, A]. 100% 5c. Patients receiving radical RT for high-risk disease who fit the STAMPEDE trial criteria should have a long course of ADT Adjuvant post-operative RT after RP is not routinely recommended. Selected patients with positive surgical margins or extracapsular extension after RP may be offered adjuvant RT [I, B]. Patients having salvage RT to the prostate bed may be offered pelvic nodal RT [I, C]. 100% Recommendation 8: Treatment of relapse after radical treatment 8a. For patients with a local recurrence following RP and no distant metastases, the pros and cons of local salvage therapy should be discussed, taking into account life expectancy and the long natural history of isolated local recurrences [III, C]. ADT alone is recommended as first-line systemic treatment for mHNPC in patients who are unfit for abiraterone, apalutamide, enzalutamide and docetaxel [III, A]. Non-metastatic castrate-resistant prostate cancer 10a. Apalutamide [ESMO-MCBS v1.1 score 3], darolutamide [ESMO-MCBS v1.1 score 3] or enzalutamide [ESMO-MCBS v1.1 score 3] should be considered as options for patients with M0 CRPC and a high risk of disease progression [I, B]. [/table] [table] Table S6 ,: available at https://doi.org/10. 1016/j.esmoop.2022.100518. The results of the voting by the Asian experts both before and after the 'face-to-face' meeting showed >80% concordance (Supplementary Tables S2 and S3, available at https://doi.org/10.1016/j.esmoop.2022.100518) with the ESMO recommendations for the treatment of patients with prostate cancer. [/table]	None	http://www.esmoopen.com/article/S2059702922001387/pdf	None
9be6275ccc4d9a6fd5704287564a81afda622ed0	pubmed	Standards for the management of cancer‐related pain across Europe—A position paper from the EFIC Task Force on Cancer Pain	Standards for the management of cancer‐related pain across Europe—A position paper from the EFIC Task Force on Cancer Pain Background and objective:Pain is a common symptom in patients who survive cancer and in those who live with progressive advanced disease. Evidence from meta-analyses suggests that pain remains poorly controlled for a large proportion of patients; barriers to good management include poor assessment of pain, inadequate support for patient self-management and late or inadequate access to strong opioid analgesia in those with advanced disease.Methods: The European Pain Federation (EFIC) established a Task Force in 2017which convened a European group of experts, drawn from a diverse range of relevant clinical disciplines, to prepare a position paper on appropriate standards for the management of cancer-related pain. The expert panel reviewed the available literature and made recommendations using the GRADE system to combine quality of evidence with strength of recommendation. The panel took into account the desirable and undesirable effects of the management recommendation, including the cost and inconvenience of each when deciding the recommendation. Results and conclusions: The 10 standards presented are aimed to improve cancer pain management and reduce variation in practice across Europe. The Task Force believes that adoption of these standards by all 37 countries will promote the quality of care of patients with cancer-related pain and reduce unnecessary suffering. Significance: Pain affects up to 40% of cancer survivors and affects at least 66% of patients with advanced progressive disease, many of whom experience poor pain control. These 10 standards are aimed to improve cancer pain management, promote the quality of care of patients and reduce variation across Europe.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. # \| introduction Each year, approximately 3.45 million Europeans are diagnosed with cancer of whom 66% will survive for at least 5 years and 40% will be alive more than 10 years after their diagnoses [bib_ref] Cancer incidence and mortality patterns in Europe: estimates for 40 countries in..., Ferlay [/bib_ref] [bib_ref] Pain in cancer survivors, Glare [/bib_ref]. Pain is the commonest symptom of cancer at diagnosis [bib_ref] Cancer-related pain: A pan-European survey of prevalence, treatment, and patient attitudes, Breivik [/bib_ref] and rises in prevalence throughout and beyond cancer treatment (van den . Between 33% and 40% of cancer survivors (persons with cancer whose curative treatment was completed) suffer from chronic pain [bib_ref] Persistent pain in cancer survivors, Boland [/bib_ref] [bib_ref] Chronic treatment-related pain in cancer survivors, Paice [/bib_ref] [bib_ref] Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and..., Seretny [/bib_ref]. In contrast, 1.7 million European cancer patients die from their disease each year of whom at least 66% will experience pain before death and 55% will experience moderate-to-severe intensity pain [bib_ref] Cancer incidence and mortality patterns in Europe: estimates for 40 countries in..., Ferlay [/bib_ref]. It is more than 30 years since the publication of the WHO method or guidelines for cancer pain relief . Despite this and the publication of European guidelines [bib_ref] Adult cancer pain, Swarm [/bib_ref] , there remain barriers to good control of cancer-related pain [bib_ref] A systematic review on barriers hindering adequate cancer pain management and interventions..., Oldenmenger [/bib_ref]. At least one-third of patients are undertreated which is often due to inadequate attention to pain during regular oncological treatment, and inequitable or delayed access to opioids [bib_ref] Patterns of community-based opioid prescriptions in people dying of cancer, Gagnon [/bib_ref] [bib_ref] Quality of cancer pain management: An update of a systematic review of..., Greco [/bib_ref] [bib_ref] Pain is not systematically registered in Dutch medical oncology outpatients, Boveldt [/bib_ref] [bib_ref] Standards for the management of cancer-related pain across Europe-A position paper from..., Ziegler [/bib_ref]. Uncontrolled or undertreated pain may become physically and emotionally disabling, leading to increased suffering and reduced quality of life (Te . A Task Force was sourced by the European Pain Federation (EFIC) in 2017. In line with other standards development groups, a panel of international experts was instituted, chaired by EE and MB. Experts from European countries were invited by email to participate, explaining the rationale for the process, and aiming for broad geographical representation within Europe. EFIC recognizes that improving the experience of patients with cancer-related pain requires actions that focus on patients, clinicians and healthcare providers or systems. The EFIC Task Force on cancer-related pain reviewed existing evidence-based guidelines and reached a consensus on the standards for the management of cancer-related pain across all 37 European countries that are members of the European Pain Federation (EFIC). This paper describes 10 standards that EFIC member countries should institute or be working towards. The standards do not specify which healthcare professional(s) should conduct assessments, agree management plans, provide tailored treatment and support, or refer for more specialized advice and treatment. The Task Force considered that all services involved in the care of patients with cancer should consider how best to meet these standards considering local expertise and resources. These standards may also prompt greater collaboration between clinicians in pain medicine, palliative care and oncology to meet the needs of patients with cancer-related pain. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to determine recommendations for each standard based on quality of evidence and strength of recommendation [bib_ref] GRADE: An emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref]. Recommendations were judged by the Task Force based on weighing up the desirable and undesirable effects of the management recommendation, including the cost and inconvenience of each. Each Task Force member was asked to assign a recommendation for each standard, and the final recommendation was based on majority consensus where agreement was not unanimous (Box 1). 2 \| STANDARDS 2.1 \| Standard 1. Patients with a history of cancer should be routinely screened for pain at every engagement with a healthcare professional. ## [grade 1b] Supporting patients with cancer-related pain requires systematic screening for pain symptoms for both patients in remission and those with ongoing disease [bib_ref] Adult cancer pain, Swarm [/bib_ref] [bib_ref] Routine screening for pain combined with a pain treatment protocol in head..., Williams [/bib_ref]. Patients are often reluctant to disclose pain as they do not perceive healthcare professionals are interested or have the time, and these attitudes are often consolidated because healthcare professionals rarely ask about pain routinely [bib_ref] What do patients with advanced incurable cancer want from the management of..., Gibbins [/bib_ref]. Screening for pain can be achieved by using routine questions in consultations; for example "Have you experienced pain that interferes with daily activities?," or by use of paper or electronic questionnaires in clinics or on hospital wards, such as Numerical Rating Scales (NRS) or Visual Analogue Scales (VAS). ## Box 1 grade recommendations (guyatt et al., 2008) ## Grade recommendations 1A. Strong recommendation, high-quality evidence 1B. Strong recommendation, moderate-quality evidence 1C. Strong recommendation, low-quality evidence 2A. Weak recommendation, high-quality evidence 2B. Weak recommendation, moderate-quality evidence 2C. Weak recommendation, low-quality evidence 2.2 \| Standard 2. Patients identified with cancer-related pain should receive a pain assessment when seen by a healthcare professional, which at a minimum classifies the cause of pain based on proposed ICD-11 taxonomy and establishes the intensity and impact on quality of life of any pain that they report. ## [grade 1b] Cancer-related pain has multiple aetiologies including the cancer itself (cancer pain) and cancer treatments, particularly surgery, chemotherapy (including hormonal, biological and immune therapies) and radiotherapy [bib_ref] Mechanism-based cancer-pain therapy, Bennett [/bib_ref]. It can originate from visceral, bone or nerve tissues and can have nociceptive, neuropathic or inflammatory mechanisms [bib_ref] Pain and nociception: mechanisms of cancer induced bone pain, Falk [/bib_ref] [bib_ref] Classification of pain in cancer patients -a systematic literature review, Knudsen [/bib_ref]. It also varies in its temporal characteristics: it can be acute or chronic and may have continuous or episodic features [bib_ref] An international survey of cancer pain characteristics and syndromes. IASP Task Force..., Caraceni [/bib_ref]. Persistent cancer pain can lead in some individuals to the development of chronic widespread pain induced by plastic changes in the somatosensory nervous system) [bib_ref] Do we need a third mechanistic descriptor for chronic pain states?, Kosek [/bib_ref]. Pain may also be caused by comorbid conditions unrelated to cancer, and this aetiology accounts for around 10%-20% of pains in cancer patients [bib_ref] Assessment of cancer pain: a prospective evaluation in 2266 cancer patients referred..., Grond [/bib_ref]. Therefore, pain in a cancer patient is not synonymous with cancer-related pain; a clinical assessment must distinguish between cancer pain, cancer treatment pain and pain from comorbid conditions. Often, patients experience mixed types of pain simultaneously, or pain that changes over time. A detailed diagnostic assessment that must be repeated at appropriate intervals is therefore often required to guide treatment strategies. A bedside assessment can determine the intensity, aetiology, character and underlying mechanisms of pain leading to improvements in pain outcomes. The new proposed ICD-11 classification for cancer-related pain will enable a standardized taxonomy for clinical practice and research and should be used widely [bib_ref] A classification of chronic pain for ICD-11, Treede [/bib_ref]. The Brief Pain Inventory provides a summary of the severity and impact of the pain on the patient's daily activities [bib_ref] Pain assessment: Global use of the Brief Pain Inventory, Cleeland [/bib_ref]. Additionally, conditions which can amplify pain expression such as distress, anxiety and depression [bib_ref] Quality of life in patients with advanced cancer: Differential association with performance..., Laird [/bib_ref] , delirium or effects of alcohol and mis-used drugs, should be incorporated in a structured pain assessment . ## \| standard 3. a multimodal pain management plan should be agreed with the patient who explains the causes of their pain and its likely prognosis, the need for further investigations, the multimodal treatment options, and includes the patient's preferences and goals for treatment. [grade 1c] Cancer patients with pain are keen to understand the cause of their pain, what to expect, options for pain control, and how to cope with cancer pain including talking with others and finding help [bib_ref] What patients with cancer want to know about their pain: a qualitative..., Bender [/bib_ref]. Longitudinal interview studies reveal that pain is very dynamic and complex for patients and that pain control is often a trial and error process that requires continuous work [bib_ref] Patient and caregiver perspectives on managing pain in advanced cancer: A qualitative..., Hackett [/bib_ref]. Cognitive and other side effects of analgesia for cancer-related pain impact on quality of life [bib_ref] Side effects of analgesia may significantly reduce quality of life in symptomatic..., Sloot [/bib_ref]. Patients often try to manage by reducing interference from both pain and these side effects to maintain as much function as possible. This "trading-off" between pain and side effects can impact on medication adherence and should be acknowledged within the pain management plan [bib_ref] The use of morphine to treat cancer-related pain: A synthesis of quantitative..., Flemming [/bib_ref] [bib_ref] Exploring interference from analgesia in patients with cancer pain: a longitudinal qualitative..., Manzano [/bib_ref]. The goals of cancer-related pain management should therefore be to reduce the pain and its impact on daily living though tailored treatment, and to increase each patient's ability for self-management [bib_ref] Mechanism-based cancer-pain therapy, Bennett [/bib_ref] [bib_ref] What do patients with advanced incurable cancer want from the management of..., Gibbins [/bib_ref]. Helping patients to achieve this balance and identifying realistic expectations of treatments (for example that pain may be controlled to an acceptable degree rather than relieved completely) are important for improved patient outcomes. The care of many patients with cancer may be provided by different healthcare professionals simultaneously, for example a surgeon, oncologist or primary care physician. It is therefore essential that all healthcare professionals who are involved in the care of patients with cancer-related pain be appropriately trained to complete this assessment, to initiate evidence-based treatment and to refer to a competent specialist when needed (see standard 7). However, most patients can be adequately treated at a nonspecialized care level and on an outpatient basis. Proper coordination is required between the different healthcare professionals to ensure consistent and quality care. ## \| standard 4. patients should receive tailored multimodal treatment which reduces the pain and its impact on daily living and that may include a combination of medicines, nonpharmacological treatments, oncological interventions, physical rehabilitation and psychosocial or spiritual support. [grade 1a] Patients must have access to drugs and other interventions which are tailored to them. This means that the treatments are believed to be effective in their type of cancer-related pain, and that they are consistent with the patient's preferences and goals for treatment. Analgesic medication that is appropriate for the patient and their pain should be available within 24 hr of a pain assessment where indicated; this must include access to a prescriber as well as access to a dispensed prescription . Prescribers should adhere to regional or national protocols or evidence-based guidelines for cancer-related pain [bib_ref] Adult cancer pain, Swarm [/bib_ref] as this improves outcomes for patients [bib_ref] Does an oral analgesic protocol improve pain control for patients with cancer?..., Cleeland [/bib_ref]. Although analgesic medications are a cornerstone in the management of cancer-related pain, the use of other modalities and procedures can often improve outcomes. Access to opioid analgesia is critical for pain related to advanced and progressing cancer. For patients with cancer-related pain who are in the last weeks or days of life, a tailored treatment plan is especially important and should anticipate analgesic needs . Medications aimed to treat opioid-related side effects such as laxatives, peripheral opioid antagonists and antiemetics should be readily available. Opioid analgesia may not always be suitable for long-term management of pain related to cancer treatments (chemotherapy or surgery) in the context of disease that has been cured or is in remission [bib_ref] Persistent pain in cancer survivors, Boland [/bib_ref] Access to oncological and surgical management options to control pain should be available regionally within each country. For example, radiotherapy for bone metastases, spinal stabilization, surgical fixation of pathological fractures, vertebroplasty or palliative debulking of tumour. ## \| standard 5. support and advice for selfmanagement should be provided [grade 1a] Self-management is the capability of a patient to manage their pain, their analgesic treatments and the physical and psychological consequences of living with cancer-related pain [bib_ref] An exploration of self-management support in the context of palliative nursing: a..., Johnston [/bib_ref]. This involves a number of skills and activities including getting the right information, managing practical tasks and emotions, solving problems and knowing what to do when symptoms get worse or more help is needed [bib_ref] Pain medication management processes used by oncology outpatients and family caregivers part..., Schumacher [/bib_ref]. Most patients want help to manage themselves, but their ability to do this is influenced by their emotional state and their physical health. Addressing concerns about pain and strong opioids, and providing strategies that help patients though provision of educational materials, improve patient outcomes and should be routine practice [bib_ref] How effective are patients-based educational interventions in the management of cancer pain?..., Bennett [/bib_ref] [bib_ref] A systematic review of the effectiveness of patient-based educational interventions to improve..., Oldenmenger [/bib_ref] [bib_ref] Meta-analysis of psychosocial interventions to reduce pain in patients with cancer, Sheinfeld Gorin [/bib_ref]. This information must cover how to take analgesia, the likely effectiveness of this, how to monitor side effects, plans for further follow-up, and how to get help especially out of hours. All members of the healthcare team have a role in supporting self-management including doctors, nurses pharmacists and others. ## \| standard 6. the pain management plan should be reviewed regularly to assess outcomes and plan longer-term care [grade 1b] Although patients understandably express that they want to be pain free, in general, they do not actually expect their pain to go completely [bib_ref] What do patients with advanced incurable cancer want from the management of..., Gibbins [/bib_ref]. Most patients seem to determine whether their pain is controlled by whether or not they can perform activities or tasks and maintain relationships with family or friends. The outcome in terms of the balance of residual pain and functioning is individually determined. Patients should know who is responsible for reviewing their pain management plan, when this review is expected to take place and whether this can be done face-to-face, by telephone or digital technology [bib_ref] What are the current challenges of managing cancer pain and could digital..., Adam [/bib_ref]. Contact information for out of hours support should be easily accessible. Telephone support from a nurse or pharmacist integrated with electronic symptom monitoring is an effective method of follow-up for pain and analgesia [bib_ref] Effect of telecare management on pain and depression in patients with cancer:..., Kroenke [/bib_ref] [bib_ref] A combined pain consultation and pain education program decreases average and current..., Oldenmenger [/bib_ref]. ## \| standard 7. patients should be referred for more specialist advice and treatment if pain is not improving within a short time or if they are experiencing intolerable side effects of analgesia [grade 1c] Patients should be referred for specialist support if pain is not well controlled despite initial management or the pain has been identified as complex. Specialist support must be available regionally within each country in the form of specialist multidisciplinary pain services, oncology services including radiotherapy and palliative care services. Access to specialist services for pain that is insufficiently responding to standard care should be readily available regionally within one week . This includes access to advanced pain management techniques such as intrathecal pumps and neuro-ablative techniques [bib_ref] Intrathecal therapy for cancer-related pain, Bruel [/bib_ref] [bib_ref] Randomized clinical trial of an implantable drug delivery system compared with comprehensive..., Smith [/bib_ref]. Early referral to specialist services is needed when pain is complex or not responding to initial treatment, rather than waiting until all conventional approaches have been exhausted and the patient is too unwell for advanced pain management intervention. Patients who present with severe uncontrolled pain, significant drug related adverse events or extreme psychological distress should also be referred urgently to a specialized care facility . Healthcare professionals should be aware of appropriate specialized care facilities with specific and targeted multidimensional expertise in the management of cancer pain nationally. Established referral pathways should exist between oncology, pain and palliative care services to coordinate care while taking into account patient and family expectations. With improved early cancer diagnosis and enhanced treatments, many patients are now living with cancer as a chronic disease. Increasing numbers of patients experience cure or prolonged remission and are regarded as cancer survivors. Some of these patients will continue to experience pain which negatively affects their quality of life [bib_ref] Pain in cancer survivors, Glare [/bib_ref]. Some patients may continue to use high doses of opioid, previously required for adequate pain control, but which are no longer needed while causing side effects. These patients require more specialist help which is likely to include long-term self-management plans, medication weaning plans and pain rehabilitation and occupational therapy interventions [bib_ref] Management of chronic pain in survivors of adult cancers, Paice [/bib_ref]. Such plans are typically offered by chronic pain management programs and pain clinicians with a special interest in opioid management. Each country should have national guidance on managing and referring patients with long-term pain from cancer treatments. ## \| standard 8. healthcare professionals who treat patients with cancer should receive ongoing education and training in order to undertake basic pain assessment, initiate basic management, and learn about correctly referring for more specialist support [GRADE 1C] Significant gaps in knowledge on cancer pain diagnosis and management by healthcare professionals are well documented in the medical literature, leading to inadequate relief in a substantial number of patients with cancer pain [bib_ref] A systematic review on barriers hindering adequate cancer pain management and interventions..., Oldenmenger [/bib_ref]. Proper education and training is therefore essential. EFIC recommends its chapters to develop educational programs on cancer pain at undergraduate level (medical and nursing schools), postgraduate level for all healthcare professions who are involved in the care of patients with cancer, and finally within specialized programs within training in pain and palliative medicine. An example of the contents of such educational programs can be found in EFIC's Core Curriculum for Pain Management (European Pain Federation, 2017). ## \| standard 9. regular review of service outcomes for all patients with cancer pain should be in place [grade 1c] Regular review of outcomes for patients enables services to identify areas for improvement, focusing on safety and efficacy data of various methods of pain control. Novel methods for supporting patients to complete outcome measures are needed, for example using electronic or digital technology [bib_ref] What are the current challenges of managing cancer pain and could digital..., Adam [/bib_ref]. ## \| standard 10. each efic chapter should have national evidence or consensusbased guidelines in place for cancer-related pain [grade 1c] Many international and national guidelines on cancer pain assessment and treatment are available but they may not be suitable for all countries [bib_ref] Treatment for neuropathic pain in patients with cancer: Comparative analysis of recommendations..., Piano [/bib_ref]. EFIC recommends that its chapters should produce an appropriate treatment guideline for cancer-related pain that is valid for the circumstances according to each country's needs acknowledging variations in access to drugs and other treatments, and respecting social and cultural identity. Such guidelines can be adapted from existing international or national guidelines in other countries. Production of lay versions which can be understood by nonhealthcare professionals should be considered. We recommend that each country will develop a mechanism, by either professional organizations or through regulatory authorities, to monitor and assess the implementation and usage of national guidelines and European standards. ## \| summary The 10 standards presented are aimed to improve cancer pain management and reduce variation across Europe. We believe that adoption of these standards by all 37 countries will promote the quality of care of patients with cancer-related pain and reduce unnecessary suffering. EFIC will continuously support enhancing the quality of cancer pain management through its pain schools, special sessions in conferences and reviewing and when necessary revising this document in the future.	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ejp.1346	Pain is a common symptom in patients who survive cancer and in those who live with progressive advanced disease. Evidence from meta‐analyses suggests that pain remains poorly controlled for a large proportion of patients; barriers to good management include poor assessment of pain, inadequate support for patient self‐management and late or inadequate access to strong opioid analgesia in those with advanced disease.
b8dfc7ad58e8a5dd88d3e13f228e1df1068ce9d5	pubmed	Multidisciplinary consensus on the criteria for fertility preservation in cancer patients	Multidisciplinary consensus on the criteria for fertility preservation in cancer patients Infertility is one of the main sequelae of cancer and its treatment in both children and adults of reproductive age. It is, therefore, essential that oncologists and haematologists provide adequate information about the risk of infertility and the possibilities for its preservation before starting treatment. # Introduction The survival of patients with cancer has increased in recent years and is expected to continue improving [bib_ref] Cancer statistics, 2020. CA Cancer, Siegel [/bib_ref]. Five percent of cancer survivors are under the age of 40 years. The assessment of long-term side effects in this population is important to provide the best quality of life for these survivors. Infertility is one of the main sequelae of cancer, and its treatment in both children and adults of reproductive age has a great impact on quality of life. Oncologists and haematologists must adequately inform patients about the potential risk of infertility and the current possibilities for preserving fertility before starting treatment. The prospect of preserving fertility has beneficial psychological effects for patients, helping to boost their confidence in the treatment and project positive personal goals into the future [bib_ref] Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer, Saito [/bib_ref]. While many international clinical guidelines address fertility preservation in cancer patients, this document is the first Spanish multidisciplinary guideline in paediatric and adult oncological patients. For this reason, the Spanish Society of Medical Oncology (SEOM), the Spanish Fertility Society (SEF), the Spanish Society of Haematology and Haemotherapy (SEHH), the Spanish Society of Paediatric Haematology and Oncology (SEHOP) and the Spanish Society of Radiation Oncology (SEOR) have collaborated to review the current evidence on this issue in paediatric, adolescent, and adult patients with cancer, and to develop a multidisciplinary consensus. ## Gametogenesis ## Ovarian reserve At birth, the ovaries have a limited number of oocytes that constitute the ovarian reserve. The follicular pool has around 7 million follicles in the 20th week of gestation, and this number decreases progressively until menopause. Only approximately 300 follicles will reach maturity during reproductive life. Ovarian ageing results in a loss of fertility, reducing the likelihood of both spontaneous conception and pregnancy through assisted reproduction techniques. This is mainly due to the progressive decrease of the initial follicular pool (quantitative decrease), but also to the loss of oocyte quality, which increases the percentage of meiosis alterations (qualitative decrease) and results in aneuploid embryos. The concept of ovarian reserve, therefore, encompasses both the quantity and quality of a woman's oocytes. Currently, it is difficult to predict a woman's reproductive capacity. Several markers are used to estimate ovarian reserve, such as antral follicle count (AFC) and anti-Müllerian hormone (AMH) levels; however, their value for predicting pregnancy remains uncertain. Nonetheless, these markers are useful for predicting ovarian responsiveness to stimulation in an in vitro fertilisation cycle. Although the normal range of AMH in the general population is wide, in patients under 20 years of age the predictive value is lower; consequently, there is not a well-defined normal value for these patients. Therefore, when considering the indications for and performance of fertility preservation, both the age of the patient and her ovarian reserve must be assessed. AMH levels before gonadotoxic treatment may correlate with subsequent ovarian function; however, their relationship with reproductive capacity after treatment is controversial. Fertility assessments must, therefore, be based on markers (AMH and AFC) together with age. ## Spermatogenesis Spermatogenesis occurs in the seminiferous tubules of the testes and is the process by which the male primordial germ cells, spermatogonia, produce spermatozoa. It begins in puberty and persists throughout adult life. Spermatogonia differentiate to initiate meiosis, producing haploid spermatids and then spermatozoa, after complete differentiation. The maturation of sperm is completed in the epididymis. The entire process is controlled by Sertoli cells, which surround germ cells and promote their progression in response to testosterone, follicle-stimulating hormone (FSH), and multiple regulatory proteins. Spermatogonia are susceptible to apoptosis induced by ionising radiation and cytostatics [bib_ref] Effects of chemotherapy and radiotherapy on spermatogenesis in humans, Meistrich [/bib_ref]. Spermatids are more resistant but have no DNA repair mechanisms. Tubular lesions are reflected by elevated serum FSH and are accompanied by a decrease in testicular volume and consistency due to germ cell depletion. Chemotherapy can also damage Leydig cells and temporarily or permanently decrease steroidogenesis, leading to elevated luteinising hormone (LH) levels [bib_ref] The effects of Hodgkin's disease and combination chemotherapy on gonadal function in..., Whitehead [/bib_ref]. Testicular volume, semen analysis and gonadotropin levels are the most useful tools for assessing the degree of testicular injury associated with gonadotoxic treatment. ## Gonadotoxicity of current treatments In the adult population, gonadal damage is difficult to predict accurately. This damage can be caused by surgery, radiotherapy, chemotherapy or all of these factors together. Overall gonadotoxicity figures after paediatric cancer range between 8 and 30%, although they can increase to 70-90% in high-risk subgroups. describes the risk of infertility associated with anticancer treatments in adults, and [fig_ref] Figure 2: Risk of infertility associated with antineoplastic treatment in paediatric and adolescent patients [/fig_ref] describes the risk in children and adolescents. ## Surgery The surgeries that are necessary to treat some tumours compromise or remove the reproductive organs, diminishing or eliminating the fertility of affected patients [bib_ref] SEOM Clinical Guideline of fertility preservation and reproduction in cancer patients, Munoz [/bib_ref]. The need for bilateral gonadal excision as part of cancer treatment in the paediatric population is rare. However, on occasion, the hypothalamic-pituitary stalk can be affected by surgical treatment for some brain tumours, producing an alteration in gonadotropins and potentially affecting fertility. ## Radiotherapy The impact of radiotherapy on fertility is variable, and sometimes it is impossible to establish a prognosis. Intensitymodulated radiotherapy should always be used to preserve reproductive tissues, and radiotherapy doses received by the reproductive organs must be assessed when planning a future pregnancy . Radiotherapy impacts the fertility of children and young people with acute leukaemia, lymphomas, Wilms tumours, pelvic sarcomas and brain and nasopharyngeal tumours. In adults, it affects patients with rectal, sigmoid and anal cancer, cervical and uterine cancer, sarcomas, leukaemia, lymphomas and brain and nasopharyngeal tumours. In women, radiation can alter fertility by inducing damage at three levels: (i) the pituitary axis, which can be affected by both cranial and total body irradiation, causing infertility, miscarriage, delayed puberty and hypogonadotropic hypogonadism; replacement therapy and ovulation induction with gonadotropins will be required if there is a desire for pregnancy; (ii) the ovaries, where the damage depends on the dose of radiation and whether it is combined with chemotherapy and causes menstrual irregularities, acute ovarian failure, decreased ovarian reserve, infertility, miscarriage, early menopause and delayed puberty; damage to the ovaries results from pelvic, spinal, total abdominal and total body irradiation (similarly for uterine damage) and the dose that causes ovarian failure varies according to age, with adult patients being more sensitive to radiation than adolescents or children; the dose that produces a 50% decrease in ovarian reserve is ≤ 2 Gy; (iii) uterine damage, which is associated with infertility, miscarriage, preterm delivery, low birth weight, abnormal placental implantation, foetal malposition and intrauterine and perinatal death, as well as increased rates of diabetes, hypertension and eclampsia during pregnancy; depending on the administered doses, different degrees of blood supply alteration, decreased uterine size and elasticity, myometrial fibrosis and necrosis and endometrial atrophy with the replacement of tissue by dense collagen depositions can occur; the cervix becomes atrophic and loses elasticity (mainly in adults); additionally, implantation is hindered, and although the dose that prevents pregnancy is unknown, pregnancy has been considered unviable at doses > 25 Gy. In men, radiotherapy affects the testicular germinal epithelium, including Sertoli cells and, to a lesser extent, Leydig cells, which may impair spermatogenesis; it does not usually cause hypogonadism, but the effects on spermatogenesis depend on the dose and the regimen used (doses ≥ 1.2 Gy are associated with azoospermia, which is permanent at doses > 6 Gy) [bib_ref] Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer..., Skinner [/bib_ref]. ## Hormone therapy Although hormone therapy is not gonadotoxic per se, increased treatment duration may increase the risk of infertility due to the decrease in ovarian reserve with age. Patients should be informed of this risk when starting endocrine therapy, and the duration of the treatment should be considered [bib_ref] Role of endocrine responsiveness and adjuvant therapy in very young women (below..., Colleoni [/bib_ref] [bib_ref] Incidence of chemotherapy-induced, long-term amenorrhea in patients with breast carcinoma age 40..., Fornier [/bib_ref] [bib_ref] Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment:..., Petrek [/bib_ref] [bib_ref] Incidence and time course of bleeding after long-term amenorrhea after breast cancer..., Sukumvanich [/bib_ref] [bib_ref] Impact of taxanes, endocrine therapy, and deleterious germline BRCA mutations on anti-Mullerian..., Lambertini [/bib_ref]. Ovarian suppression with luteinising hormone-releasing hormone (LHRH) analogues combined with tamoxifen or aromatase inhibitors is an adjuvant treatment for patients with hormone receptor-positive breast cancer. Published data estimate that ovarian function usually recovers approximately 3 months after treatment is completed. Androgen deprivation therapy causes hypogonadism and low testosterone levels; consequently, it can be associated with oligospermia and azoospermia and cause transient sterility. ## Chemotherapy Chemotherapy, especially with alkylating agents, produces gonadotoxicity in both sexes. The risk of gonadal toxicity depends on the type of treatment received , the accumulated dose, the state of the gonads before treatment begins and, in particular, the patient's age when chemotherapy is administered [bib_ref] American Society of Clinical Oncology recommendations on fertility preservation in cancer patients, Lee [/bib_ref]. Chemotherapy affects the germinal epithelium more than the Leydig cells; consequently, men receiving chemotherapy may have oligospermia, azoospermia or partial or compensated hypogonadism. Chemotherapy can affect primordial follicles but may also reduce the number of growing follicles, where a "burn-out" effect may occur because of accelerated follicular recruitment which can lead to premature ovarian failure. Since the ovarian reserve decreases with age, the risk of permanent ovarian failure increases in older women. Additionally, vascular damage, stromal injury or fibrosis may occur. ## Immunotherapy and other targeted therapies Available data on the infertility risk associated with biological treatments are scarce and heterogeneous [bib_ref] Infertility risk and teratogenicity of molecularly targeted anticancer therapy: a challenging issue, Lorenzi [/bib_ref]. Imatinib does not cause infertility in men or women. Data on nilotinib and dasatinib suggest that they do not affect gonadal function. However, data from the Summary of product characteristics (SmPC) and clinical trials confirm that the use of tyrosine kinase inhibitors (TKI) is contraindicated during pregnancy. Although angiogenesis plays a crucial role in gonadal development, preclinical studies show that male and female fertility is only moderately affected by sunitinib and other TKIs with antiangiogenic activity, such as sorafenib or pazopanib. There are no preclinical studies on the effect of bevacizumab on fertility. A clinical trial of the addition of bevacizumab to adjuvant chemotherapy in colon cancer found that the incidence of ovarian failure in premenopausal women was 3% when bevacizumab was not administered and 39% when it was. However, at the end of treatment with bevacizumab, 86% of patients regained ovarian function [bib_ref] Initial safety report of NSABP C-08: a randomized phase III study of..., Allegra [/bib_ref]. Trastuzumab and lapatinib do not confer an increased risk of infertility after chemotherapy [bib_ref] Adjuvant Anti-HER2 therapy, treatmentrelated amenorrhea, and survival in premenopausal HER2-positive early breast..., Lambertini [/bib_ref]. In preclinical models with other EGFR TKIs, such as erlotinib or gefitinib, a decrease in fertility parameters was observed, although the effect in humans is unknown. The only clinical study with gefitinib shows suppression of androgen levels in both men and women. Clinical studies evaluating the effect of everolimus on gonadal function have been conducted in men who have undergone kidney transplant, but not in cancer patients. These studies show that everolimus produces a decrease in testosterone levels and disrupts spermatogenesis. According to preclinical data, crizotinib can cause infertility in men and women. Clinical data indicate crizotinib lowers testosterone levels, which should be monitored in males receiving this treatment. There is very little evidence regarding the possible gonadal toxicity of immunomodulatory drugs, including immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab and durvalumab. Therefore, the risk of gonadotoxicity remains unknown [bib_ref] It is time to talk about fertility and immunotherapy, Duma [/bib_ref]. Some patients will develop immunity-related adverse events, such as hypothyroidism or hypophysitis, which can cause ovarian failure and decreased testosterone levels. ## Fertility preservation techniques Currently, there are several techniques for preserving fertility, such as conservative surgery of the reproductive organs in the early stages of disease and cryopreservation techniques (of embryos, oocytes, ovarian cortex, semen and testicular tissue). The paediatric population is particularly vulnerable, and practical, ethical and legal factors must be considered in addition to strictly biological factors before applying these procedures [bib_ref] Cancer treatment and gonadal function: experimental and established strategies for fertility preservation..., Anderson [/bib_ref] [bib_ref] Fertility preservation for young patients with cancer: who is at risk and..., Wallace [/bib_ref]. [fig_ref] Table 1: Indications for offering fertility preservation in paediatric, adolescent and adult patients with... [/fig_ref] describes the main indications for fertility preservation in paediatric, adolescent and adult patients with cancer. ## Surgical techniques Ovarian transposition or oophoropexy is a surgical procedure indicated when pelvic radiotherapy is administered without chemotherapy or with a low-gonadotoxic one. This technique has been used in cases of cervical and rectal cancer, lymphomas and other tumours. Transposition above the iliac crests is recommended to move the ovary away from the radiation field; this procedure can preserve ovarian function in 50-80% of cases. Ovarian transposition can be combined with other techniques, such as ovarian cortex or oocyte preservation, since its effectiveness may be limited and can hinder subsequent assisted reproduction techniques [bib_ref] The relationship between ovarian function and ovarian limited dose in radiotherapy postoperation..., Du [/bib_ref] [bib_ref] Diminished utilization of in vitro fertilization following ovarian transposition in cervical cancer..., Salih [/bib_ref]. ## Oocyte cryopreservation Oocyte cryopreservation is currently the fertility preservation technique of choice. The ideal number of mature oocytes that should be retrieve for vitrification is a controversial issue. Cryopreservation of between 10 and 15 oocytes is recommended as the probability of pregnancy is higher with a greater number of oocytes; however, this correlation is not so clearly observed after the age of 35 years due to the effect of age on oocyte quality and the increase in aneuploidies. Ovarian hormonal stimulation using gonadotropins is required and usually lasts between 10 and 12 days, at the end of which a transvaginal ovarian puncture with follicular aspiration is performed under sedation for oocyte retrieval. Subsequently, the patient can start chemotherapy without delay. Random-start stimulation may be initiated at any time during the patient's ovarian cycle [bib_ref] Oocyte cryopreservation for fertility preservation in women with cancer, Domingo [/bib_ref]. In cases of low response, if the start of chemotherapy allows, several stimulation or double stimulation cycles can be performed in the same cycle (DuoStim) to increase oocyte availability [bib_ref] Safety and feasibility of performing two consecutive ovarian stimulation cycles with the..., Turan [/bib_ref]. The complications of this procedure are the same as those associated with oocyte retrieval: hemoperitoneum, ovarian torsion, infection or hyperstimulation syndrome (minimal with the use of GnRH agonists to achieve ovulatory discharge), although these are rare (< 1%) in the absence of risk factors (e.g., coagulation alterations, etc.). In adolescent patients, oocyte cryopreservation is physiologically feasible starting at puberty, considering the particularities of this population. ## Ovarian tissue cryopreservation This experimental technique is indicated for patients who must urgently start chemotherapy, prepubertal patients and patients with hormone-dependent cancers with contraindications for hormonal stimulation. It is more effective in patients under 35 years of age [bib_ref] Oocyte vitrification versus ovarian cortex transplantation in fertility preservation for adult women..., Diaz-Garcia [/bib_ref]. Ovarian tissue cryopreservation requires a double surgical procedure. The extraction (partial oophorectomy, total oophorectomy, decortication) and reimplantation (in the contralateral ovary or pelvic wall) techniques are not standardised. Histopathological analysis should be routinely performed to rule out the possibility of micrometastases. The loss of functional capacity of the tissue occurs mainly after reimplantation due to ischaemia and subsequent follicular burn-out. More than 100 live births conceived spontaneously or through assisted reproduction have been reported as a result of this technique. Ideally, the patient should not have undergone any previous chemotherapy regimen; however, the possibility of ovarian cryopreservation can be assessed even if the gonadotoxic risk is very high [bib_ref] Cancer treatment and gonadal function: experimental and established strategies for fertility preservation..., Anderson [/bib_ref] [bib_ref] Fertility preservation in young females with hematological malignancies, Shapira [/bib_ref]. Among the main limitations of this technique are the theoretical risk of reinserting tumour cells; therefore, it is contraindicated in patients with leukaemia or central nervous system tumours and is still considered an experimental technique in some countries. In prepubertal patients, it is the only fertility preservation option available. It could potentially be used from birth, but there are few data in children under 5 years of age, although some groups offer it for patients older than 1 year [bib_ref] Fertility preservation in young females with hematological malignancies, Shapira [/bib_ref]. Because it is experimental, it is important to perform it with an alternative anaesthetic procedure. ## Semen cryopreservation Semen freezing should be performed as soon as possible after ejaculation once liquefaction and semen evaluation have been completed. Rapid freezing (−50 °C per minute) is performed manually by depositing the containers in the nitrogen vapour phase for 30 min and then quickly immersing the straws/vials in liquid nitrogen. Sperm vitrification is an alternative cryopreservation method for which limited reports of clinical experiences are available. It is indicated for low-volume samples with a low sperm count and poor sperm quality, as it seems to preserve vitality and DNA integrity better than classical cryopreservation [bib_ref] Human sperm vitrification: a scientific report, Schulz [/bib_ref]. Sperm cryosurvival is assessed by measuring the degree of sperm motility in an aliquot after thawing and comparing the results to fresh-sample motility. For patients with anejaculation, available alternatives include penile vibratory stimulation, transrectal electroejaculation under general anaesthesia, epididymal aspiration and testicular biopsy. The latter technique is also indicated for azoospermic patients and those without any sperm mobility in the cryosurvival test. Semen cryopreservation should be offered before starting any therapy. Patients who are referred to a semen bank after they have started treatment may find that freezing is no longer an option due to the absence of sperm in the ejaculate or very poor semen quality. Acute effects of genotoxic treatments include genetic mutation, sperm DNA fragmentation, chromosome breakage and sperm aneuploidy. With alkylating agents, the risk of genetic damage is greatest at day one of treatment and persists for at least one spermatogenic cycle (75 days). In the case of radiotherapy, the maximum risk occurs one week after the start of the doses, but it persists for up to 2 months. Topoisomerase II inhibitors act mainly on meiosis; consequently, the greatest damage occurs between 30 and 50 days after administration [bib_ref] Risks of genetic damage in offspring conceived using spermatozoa produced during chemotherapy..., Meistrich [/bib_ref]. These circumstances, as well as the inevitable effect of the underlying disease (hormonal or paracrine dysregulation in testicular tumours, fever in lymphomas or leukaemia, radiation exposure from diagnostic tests) are individual risk factors that should be included in the consent form. ## 3 In young people who have entered puberty and are at Tanner stage > 2 and have a testicular volume > 8-10 mL, it is possible to find mature sperm in semen. However, these patients can be very sensitive to the pressure of their environment (e.g., from family or professionals) during this period of the beginning of their sexual activity. In patients with unclear pubertal development (10-12 years), it is advisable to perform a hormonal assessment and a physical examination or ultrasound to estimate testicular volume. Examination of nocturnal urine for sperm (spermaturia) can be used as a non-invasive indicator of sexual maturity. If ejaculate collection is not possible and the examination suggests that pubertal development is advanced, a testicular biopsy may be performed. ## Gnrh analogues The use of GnRH analogues is an experimental technique, and their possible protective mechanism is unknown. Various mechanisms have been proposed, such as the inhibition of FSH secretion, a decrease in utero-ovarian blood flow [bib_ref] Preserving fertility when choosing chemotherapy regimens-the role of gonadotropin-releasing hormone agonists, Blumenfeld [/bib_ref] and the activation of GnRH receptors. There are numerous studies with conflicting results, most of which do not have good study design or adequate sample size. The main advantage of this technique is the simplicity of administering it along with cancer treatment, without a need to postpone treatment. The main medical societies-the American Society of Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), European Society of Human Reproduction and Embryology (ESHRE) and SEOM-do not recommend the use of GnRH analogues as the only fertility preservation technique [bib_ref] SEOM Clinical Guideline of fertility preservation and reproduction in cancer patients, Munoz [/bib_ref] [bib_ref] Fertility preservation in patients with cancer: ASCO clinical practice guideline update, Oktay [/bib_ref] [bib_ref] ESHRE guideline: female fertility preservation, Eggoff [/bib_ref] given the low level of evidence regarding their effectiveness. This technique may be an option for patients with hormone receptor-negative breast cancer for whom other techniques are not considered or for the preservation of ovarian function. ## Other experimental techniques ## Techniques for female patients In vitro oocyte maturation In vitro maturation (IVM) is an alternative method that can help to avoid delays in the administration of oncological treatment. It is a viable option for patients with cancer since it consists of the punctureaspiration of an unstimulated ovary and subsequent in vitro oocyte maturation. There are few data on children born after the use of this technique. IVM can cause several undesirable effects at the oocyte level and should, therefore, be considered an experimental technique [bib_ref] ESHRE guideline: female fertility preservation, Eggoff [/bib_ref]. In vitro development of primordial follicles A dynamic multi-step culture system is necessary to support each of the follicle transition stages. This in vitro follicular growth approach must fulfil the changing requirements of the developing oocyte and its surrounding granulosa cells to maintain the interactions among these cells. This technique presents many challenges, such as the determination of the competence of the developing oocyte and the associated genomic imprinting [bib_ref] In vitro follicle growth supports human oocyte meiotic maturation, Xiao [/bib_ref]. ## Techniques for male patients Fertility preservation in children and adolescents who have not entered puberty is still in the research and development stage and is far from achieving effective results in humans [bib_ref] Testicular biopsy in prepubertal boys: a worthwhile minor surgical procedure?, Faure [/bib_ref]. The most promising approach involves the autologous transplantation of spermatogonia of the immature testicular tissue, with the aim of colonising the seminiferous tubules by reimplantation through the rete testis and thus partially restoring spermatogenesis in vivo. The culture must be free of infiltration by malignant cells [bib_ref] Cryopreservation of testicular tissue or testicular cell suspensions: a pivotal step in..., Onofre [/bib_ref]. An alternative is the grafting of testicular tissue fragments. In this way, and under the appropriate environmental conditions, the architecture and paracrine interactions of the seminiferous tubules can be maintained. The third strategy is in vitro spermatogenesis from spermatogonia or even from embryonic stem cells or somatic cells undergoing cell reprogramming using artificial co-culture systems that mimic the structure of the original testis [bib_ref] Current state regarding fertility cryopreservation in pre-pubertal boys, Medrano [/bib_ref]. ## Indications for fertility preservation ## Paediatric and adolescent patients with cancer (<16 years) After the initial diagnosis, patients and their families should receive an individualised assessment of the gonadotoxic risk of the treatment to be given and information about available fertility preservation options. During this process, both intrinsic factors (tumour type, location and stage, and patient age, gonadal function, pubertal stage before treatment and overall health status) and extrinsic factors (type of treatment, dose, time available, availability of qualified centres, parental consent, etc.) should be considered. [fig_ref] Figures 3: and 4 show the decision-making algorithms to preserve fertility in female and... [/fig_ref] Decision-making algorithm to preserve fertility in female patients with cancer or haematological disease. FP fertility preservation; CT chemotherapy; RT radiotherapy. Re-grafting is contraindicated in diseases with a high risk of ovarian metastasis, such as leukaemia, neuroblastomas or Burkitt's lymphoma ◂ [fig_ref] Table 1: Indications for offering fertility preservation in paediatric, adolescent and adult patients with... [/fig_ref] outlines the main indications for fertility preservation in this population subgroup, in which the main and most complex factor is the calculation of the gonadotoxic risk associated with treatment [fig_ref] Figure 2: Risk of infertility associated with antineoplastic treatment in paediatric and adolescent patients [/fig_ref]. Usually, this calculation takes into account the classification of [bib_ref] Fertility preservation for young patients with cancer: who is at risk and..., Wallace [/bib_ref] based on treatment intensity, which classifies infertility risk groups as low (< 20%), medium (21-80%) or high (> 80%) [bib_ref] Fertility preservation for young patients with cancer: who is at risk and..., Wallace [/bib_ref]. Over time, this classification has been modified according to long-term follow-up data, resulting in changes to some international strategies that encourage the selection of less gonadotoxic treatments, such as a procarbazine substitution, or avoiding radiotherapy if an adequate and rapid initial response is observed [bib_ref] Cancer treatment and gonadal function: experimental and established strategies for fertility preservation..., Anderson [/bib_ref]. SEHOP, through the experience gained in the last 10 years with specific fertility preservation programmes in paediatric populations, has reclassified the risk subgroups by adding an intermediate category, resulting in the following classification: low < 20%, low-intermediate 20-50%, intermediate-high 50-75%, and high > 75%. This reclassification is based on the protocols used in Spain and was undertaken to provide a consensus and to standardise the offer of fertility preservation techniques to all patients with an infertility risk > 50% [fig_ref] Figure 2: Risk of infertility associated with antineoplastic treatment in paediatric and adolescent patients [/fig_ref]. In any case, it should be noted that the risk of gonadal insufficiency for each specific case can be difficult to calculate, and some researchers propose a somewhat lower limit when considering the use of such techniques (> 30%) [bib_ref] Recommendations for fertility preservation in patients with lymphoma, leukemia, and breast cancer, Committee [/bib_ref] , especially for patients in the older age groups. Additionally, when using the proposed classifications, differences according to patient sex should be considered, and the classifications should be updated when there are substantial changes in the regimens used. In very high-risk patients, it is important to consider the possibility of using the experimental options described (IVM of primordial follicles) in the mediumto long-term, as in these cases, there is enough time for tissues to fully develop, thus potentially avoiding the need for ovarian tissue reimplantation. Fertility preservation techniques, particularly oocyte vitrification, may be considered during follow-up for young women who have completed their treatment and in whom premature depletion is expected, even if they still have an ovarian reserve. In general, fertility preservation techniques are firstline treatments, although they can also be applied to young patients in relapse if they have maintained a good gonadal reserve and have good curative expectations. ## Adult patients with cancer ## Solid tumours The treatment of non-metastatic colon cancer requires surgery and adjuvant chemotherapy at stage III. The treatment of rectal cancer also includes radiotherapy as an adjuvant or neoadjuvant treatment with chemotherapy. In principle, colon cancer surgery has no impact on fertility; however, pelvic surgery for rectal cancer can affect women's fertility [bib_ref] Female fertility and colorectal cancer, Spanos [/bib_ref]. Chemotherapy with 5-fluorouracil or capecitabine has no severe effect on fertility; however, oxaliplatin has a moderate effect. In women, the technique of choice for preserving fertility is oocyte cryopreservation. If the need for treatment does not allow time for this technique, ovarian cortex cryopreservation is indicated. If only pelvic radiotherapy is performed, ovarian transposition may be considered, although an alternative preservation technique is recommended as this technique is not always safe. In men, the indicated fertility preservation method is semen cryopreservation. Ablative therapy with I 131 may be necessary for the treatment of thyroid cancer. I 131 produces oligomenorrhea in > 20% of women but has no long-term effects; therefore, it is not necessary to recommend any fertility preservation technique. In men, the administration of a single ablative dose of I 131 (3 GBq, equivalent to an absorbed testicular dose < 0.1 Gy) has transient effects on spermatogenesis or male fertility. However, gonadal damage may be cumulative when multiple administrations are required, and therefore cryopreservation is advised in male patients with metastases or pelvic involvement, who can receive up to 1 Gy [bib_ref] Cancer treatment-related infertility: a critical review of the evidence, Poorvu [/bib_ref] [bib_ref] Gonadal effect of radiation from 131I in male patients with thyroid carcinoma, Krassas [/bib_ref]. Surgery is the primary treatment for sarcomas. Radiotherapy may be indicated for high-grade or locally advanced tumours. Because the most common locations are the limbs, pelvis and retroperitoneum, the reproductive organs are included or close to the irradiation field in many cases. Chemotherapy with alkylating agent regimens is the main treatment for many sarcomas [bib_ref] Oncofertility in sarcoma patients, Lopategui [/bib_ref]. Therefore, in women, oocyte cryopreservation is recommended if time allows, and, if not, ovarian cortex cryopreservation may be considered along with ovariopexy, when possible. In men, the best option is semen cryopreservation. The initial treatment for testicular cancer is orchiectomy. Adjuvant treatment with platinum-based chemotherapy or radiotherapy reduces the risk of relapse and is recommended based on risk assessment. Currently, chemotherapy is the treatment of choice, and semen cryopreservation is recommended before its initiation, either before or after orchiectomy. Semen quality decreases due to testicular cancer itself, and unilateral orchiectomy can further reduce sperm count. Breast cancer is the most common neoplasm during reproductive age [bib_ref] The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/ European..., Cibula [/bib_ref]. The choice of neo-or adjuvant Decision-making algorithm to preserve fertility in male patients with cancer or haematological disease. FP fertility preservation; ART assisted reproductive techniques; ITT immature testicular tissue. Considered experimental ◂ treatment depends on the tumour subtype and the risk of relapse. Chemotherapy is the treatment with the greatest effect on fertility. The fertility effects of different chemotherapy protocols is variable, as shown in . Oocyte vitrification is the technique of choice to preserve fertility if there is time for ovarian stimulation. No increased risk of relapse has been observed after ovarian stimulation with gonadotropins, simultaneously with letrozole or tamoxifen, although there are few published reports [bib_ref] Long-term safety of letrozole and gonadotropin stimulation for fertility preservation in women..., Kim [/bib_ref]. Ovarian cortex cryopreservation is indicated in cases in which there is no time for stimulation. When hereditary cancer is suspected, the use of this technique is more controversial; it should be performed when no other technique is possible, and graft excision should occur once pregnancy is achieved and before the age of 40. When previously described options cannot be undertaken, other options of an experimental nature for which results are available include the use of GnRH agonists or in vitro oocyte maturation. As previously mentioned, adjuvant hormone therapy in breast cancer does not compromise fertility, but the duration of this therapy means that some patients have no chance of pregnancy after its completion. The results of the POSITIVE study, which examines whether temporarily interrupting adjuvant endocrine therapy to allow for pregnancy increases the risk of relapse in young patients with luminal breast cancer, will elucidate whether this strategy is possible. In epithelial ovarian cancer, surgery involves hysterectomy and bilateral salpingo-oophorectomy. Fertility-sparing surgery (unilateral oophorectomy with correct staging) can be considered in cases of (i) stage IA tumours with lowgrade histology (G1-G2) and (ii) borderline tumours [bib_ref] The safety of fertility and ipsilateral ovary procedures for borderline ovarian tumors, Lou [/bib_ref] , and it can be individually considered in (iii) patients with stage 1C1 tumours with intraoperative rupture of the tumour capsule and negative peritoneal cytology. Subsequently, a thorough follow-up should be performed and, after the patient's reproductive goals have been achieved, salpingooophorectomy should be performed. In stages III and IV, conservative surgery is contraindicated. Oocyte vitrification is indicated in stage IA and borderline tumours due to the possibility of recurrence or bilaterality and the need to remove the contralateral ovary. Other indications are a diagnosis of low ovarian reserve, patient age, or cases in which adjuvant chemotherapy is proposed. Ovarian cortex cryopreservation is not recommended because of the potential risk of tumour cell reimplantation. In malignant ovarian germ cell tumours, unilateral salpingo-oophorectomy is the treatment of choice for young patients with early-stage tumours and may be considered in selected cases of advanced disease. Oocyte cryopreservation is indicated for patients who will be receiving chemotherapy. In cases of cervical cancer, conservative surgical treatment (conisation and radical trachelectomy) can be considered for [bib_ref] The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/ European..., Cibula [/bib_ref] [bib_ref] Radical trachelectomy for early stage cervical cancer: a case series and literature..., Wu [/bib_ref] (i) stage IA1 microinvasive carcinoma without lymphovascular involvement and (ii) clinical stage IA1 epidermoid tumours and adenocarcinomas with lymphovascular invasion up to IB1 (< 2 cm), once high-grade histology has been ruled out; (iii) in some cases with stage IB2 (> 2 cm), neoadjuvant chemotherapy to reduce tumour size followed by radical trachelectomy and pelvic lymphadenectomy may be considered, although this is not a standard procedure, and long-term safety studies are lacking. Oocyte vitrification is indicated for patients who will receive chemotherapy. Endometrial cancer is treated with surgery (hysterectomy and bilateral adnexectomy). In patients with endometrioid carcinomas, stage IA G1 tumours without myometrial invasion, and if pregnancy is desired, high doses of oral medroxyprogesterone (400-600 mg/day) or megestrol acetate (160 mg) and a levonorgestrel IUD may be proposed to preserve fertility, with close follow-up [bib_ref] Prognostic factors of oncologic and reproductive outcomes in fertility-sparing management of endometrial..., Koskas [/bib_ref] and surgery after the patient's reproductive desire is fulfilled. Assisted reproduction techniques can facilitate and shorten the time required to achieve pregnancy, given the high incidence of obese and anovulatory patients. Letrozole may be added during the stimulation treatment. ## Haematological tumours Patients with haematological diseases require a specific approach to fertility preservation since (i) the incidences of acute lymphoblastic leukaemia (ALL) and Hodgkin's lymphoma (HL) are very high in adolescents and young adults; (ii) many patients present with medical complications that prevent the use of standard fertility preservation techniques and, in some cases, contraindicate them; (iii) many patients will undergo haematopoietic stem cell transplantation (HSCT), which is associated with a high risk of infertility. Among cancer therapies, alkylating agents, platinum and radiotherapy carry an increased risk of infertility. In women, infertility risk is correlated with age at the time of treatment. In Hodgkin's lymphoma, the two most commonly used first-line treatment regimens are the combination of Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) and, to a lesser extent, the escalated combination of bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine (Oncovin ® ), procarbazine and prednisone (BEACOPP). The ABVD regimen rarely produces permanent sterility [bib_ref] Fertility among female Hodgkin lymphoma survivors attempting pregnancy following ABVD chemotherapy, Hodgson [/bib_ref]. A small study in women treated with ABVD and radiotherapy showed no ovarian failure in women younger than 25 years and transient amenorrhea in 33% of women under 45 years of age [bib_ref] Treatment of early-stage Hodgkin's disease with four cycles of ABVD followed by..., Brusamolino [/bib_ref]. Male patients treated with ABVD who develop oligospermia recover spermatogenesis completely after 18 months [bib_ref] Gonadal toxicity after combination chemotherapy for Hodgkin's disease. Comparative results of MOPP..., Viviani [/bib_ref]. In acute leukaemia, most polychemotherapy regimens produce low gonadotoxicity. In acute myeloid leukaemia (AML), the risk of infertility is lower than in ALL. Infertility will depend on whether patients receive HSCT; therefore, fertility preservation should be considered in patients who are candidates for HSCT [bib_ref] Severe adverse impact on sexual functioning and fertility of bone marrow transplantation,..., Watson [/bib_ref]. In terms of chronic myeloid leukaemia (CML), several retrospective studies show that in male patients treated with imatinib, there is no risk of infertility or teratogenicity. However, in women, there is an absolute indication to discontinue treatment in case of pregnancy, since clinical trials have shown the drug is teratogenic due to its off-target effect [bib_ref] Pregnancy outcome among partners of male patients receiving imatinib, dasatinib or nilotinib..., Carlier [/bib_ref]. Therefore, in women who desire pregnancy, a deep and sustained major molecular response (MMR) must be achieved for 18-24 months to allow the discontinuation of TKIs, which should take place three months before conception and throughout pregnancy. When HSCT is performed, the risk of infertility varies depending on the underlying disease, the treatment type and dose received before HSCT, the conditioning treatment administered and the patient's age at the time of HSCT. Most conditioning treatments based on chemotherapy and radiotherapy cause infertility. The development of graft-versushost disease can also lead to infertility. ## Subsequent follow-up and pregnancy Currently, there are no robust data associating cancer diagnosis and treatment with an increase in complications during pregnancy. In female cancer survivors, no significant increase in miscarriage or congenital or chromosomal abnormalities has been demonstrated [bib_ref] Pregnancy outcomes in females after treatment for childhood cancer, Chiarelli [/bib_ref] [bib_ref] Fertility of male survivors of childhood cancer: a report from the Childhood..., Green [/bib_ref]. However, in a subgroup of patients who have received holocranial and especially pelvic radiotherapy, an increased likelihood of miscarriage [bib_ref] Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer..., Skinner [/bib_ref] , second-trimester pregnancy loss, preterm delivery and low birth weight has been observed [bib_ref] Pregnancy outcomes in females after treatment for childhood cancer, Chiarelli [/bib_ref] [bib_ref] Fertility of male survivors of childhood cancer: a report from the Childhood..., Green [/bib_ref] [bib_ref] Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood..., Reulen [/bib_ref] [bib_ref] Pregnancy outcomes in female childhood and adolescent cancer survivors: a linked cancer-birth..., Mueller [/bib_ref]. Among patients diagnosed with and treated for cancer during childhood, the impact of treatment on pregnancy complications such as increased metabolic risk, gestational diabetes, and hypertension remains controversial and there are conflicting results [bib_ref] Pregnancy outcomes in female childhood and adolescent cancer survivors: a linked cancer-birth..., Mueller [/bib_ref] [bib_ref] Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors, Haggar [/bib_ref] [bib_ref] Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in..., Taskinen [/bib_ref]. Regarding the association between the administration of anthracyclines and the development of cardiotoxicity, only patients with altered cardiac function showed a non-significant postpartum worsening on echocardiography and worse perinatal outcomes, including more admissions to the intensive care unit (ICU), longer hospital stays, and higher rates of labour induction, and it may be advisable to monitor these patients before pregnancy or in the first trimester. When the study population comprised women, who were diagnosed and treated in early adulthood, higher rates of late miscarriage, caesarean section, preterm delivery, low birth weight, neonatal distress and admission to the neonatal ICU were observed. However, no increase in congenital anomalies, perinatal death, antepartum haemorrhage, premature rupture of membranes or failure of labour to progress was observed [bib_ref] Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult..., Haggar [/bib_ref]. The effect of pregnancy on cancer is particularly complex in cases of breast cancer, especially in patients with hormone receptor-positive tumours. The current belief is that there is no association between pregnancy and the risk of recurrence or increased mortality in these patients, regardless of their hormone receptor status [bib_ref] Safety of pregnancy following breast cancer diagnosis: a metaanalysis of 14 studies, Azim [/bib_ref]. In 2015, Goldrat et al. published a retrospective multicentre study in which they observed no differences in disease prognosis between patients who conceived spontaneously and those who did so through assisted reproduction techniques [bib_ref] Pregnancy following breast cancer using assisted reproduction and its effect on long-term..., Goldrat [/bib_ref]. In men undergoing semen cryopreservation, it is advisable to use contraceptive measures from the beginning of cancer treatment until 18-24 months after its completion. Clinical and analytical follow-up (semen analysis, FSH, LH, testosterone) is recommended until the resolution of the underlying disease; additional recommendations include informing the attending physicians of the patient's underlying disease and making an epicrisis report on residual fertility 3-5 years after the end of treatment. The degree of fertility recovery will determine whether the semen should be kept or cryopreservation can be ended. If there is a reproductive desire and the semen quality has returned to normal, natural reproduction can be allowed. If the patient has become azoospermic or severely oligozoospermic, the use of cryopreserved semen with assisted reproduction techniques appropriate for the quality of the semen can be considered. The decision to use cryopreserved gametes or those produced after successful treatment should be individualised according to the initial quality of the gametes and the clinical circumstances at the time of freezing compared to the current situation and parameters. The analysis of sperm DNA fragmentation and/or aneuploidy can contribute to the most favourable decision. ## Regulatory issues ## Specific criteria for access to fertility preservation techniques The current legal framework is set out in Royal Decree 1030/2006. In the field of gamete or pre-embryo preservation for deferred autologous use according to medical indications with the aim of preserving fertility in situations associated with particular disease processes, the general criteria for access to assisted human reproduction (AHR) treatments must be met, except for factors addressed in the specific criteria for this technique, which will prevail over general criteria. The common portfolio of AHR services (Order SSI/2065/2014, of 31 October) states that fertility preservation techniques will be performed in patients with a possible risk of loss of their reproductive capacity associated with exposure to gametotoxic treatments or pathological processes with a proven risk of premature ovarian failure or primary testicular failure. The transfer of cryopreserved gametes or pre-embryos will be performed in women under 50 years of age as long as they do not have any condition for which pregnancy could entail a serious and uncontrollable risk to both their health and that of their possible offspring. At present, techniques are to be performed exclusively based on the medical indications in the public service portfolio and are not to be provided only in cases of the patient's request for deferred use. Gametes may be cryopreserved in authorised gamete banks for at least the duration of the donor's lifetime, so a priori, there is no time limit for their conservation. The samples will remain at the disposal of the sperm and oocyte bank if the donors cannot be contacted after two years have elapsed since the samples were deposited. ## Information and consent The freezing of semen and oocytes entails obligations and conditions of which patients must be informed, and specific consent must be obtained from patients with a medical indication who express interest in fertility preservation. In minors, the consent of the child and his or her parents or legal guardians is required. A signed request is required to remove cryopreserved samples and to destroy them. Although such discussions may generate some apprehension on the part of the doctor, it is necessary to inform patients of the legal conditions regulating the use of their gametes in the event of death. In such cases, for semen to be used to fertilise the patient's wife or partner, there must be prior consent in a public deed or will, and the semen must be used within twelve months of the patient's death. In the case of a married man, the birth of a child conceived in the indicated manner shall produce the legal effects derived from the marital affiliation. In the case of an unmarried man, such consent shall serve as the basis to initiate proceedings under article 49 of the Civil Registry Law (for the registration of natural filiation) without prejudice of legal action to establish paternity. Consent is presumed to have been given when an assisted reproduction process is initiated prior to the death of a male partner. # Conclusions With the improvements in diagnosis, treatment and survival rates in patients with cancer that have been attained in recent years, quality of life is becoming increasingly important. Reduction or loss of fertility as a result of cancer or cancer treatment impairs the quality of life of survivors. The development of various fertility preservation techniques has made it possible to offer reproductive counselling to these patients. This counselling must be carried out in a multidisciplinary way in specialised centres. The degree of gonadotoxicity and, in the case of women, the patient's age and state of her ovarian reserve, are decisive factors for the indication of a specific fertility preservation procedure. Moreover, it should always be considered that in patients with cancer, the fertility preservation procedure is subject to assessments of the patient's prognosis and functional status. Oocyte vitrification is currently the technique of choice in most cases. However, the most appropriate technique depends on the patient's characteristics, disease and treatment, and an individualised approach is mandatory. In adult and young males with advanced pubertal development, the usual technique is semen cryopreservation. The continuous development of different techniques results in the establishment of new experimental procedures. It is thus necessary to create international registries of the outcomes and follow-up data for each technique. Ethical approval (research involving human participants and/or animals) The study has been performed in accordance with the ethical standards of the Declaration of Helsinki and its later amendments. This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent For this type of study, formal consent is not required. 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/. [fig] Figure 1: Risk of infertility associated with antineoplastic treatment in adult cancer patients. Azoospermia likely when given with other highly sterilizing agents. ABVD doxorubicin (Adriamycin ® ), bleomycin, vinblastine and dacarbazine; AC doxorubicin (Adriamycin ® ) and cyclophosphamide; AC-T doxorubicin (Adriamycin ® ), cyclophosphamide and paclitaxel (Taxol ® ); BEA-COPP bleomycin, etoposide, doxorubicin (Adriamycin ® ), cyclophosphamide, vincristine (Oncovin ® ), procarbazine and prednisone; BEP bleomycin, etoposide and platinum; CHOP cyclophosphamide, doxorubicin (Adriamycin ® ), vincristine and prednisone; CT chemotherapy; FAC fluorouracil, doxorubicin (Adriamycin ® ) and cyclophosphamide; FEC fluorouracil, epirubicin and cyclophosphamide; FOLFOX fluorouracil, leucovorin and oxaliplatin; HCT haematopoietic cell transplantation; TAC docetaxel (Taxotere ® ), doxorubicin (Adriamycin ® ) and cyclophosphamide; TBI total body irradiation; TC docetaxel (Taxotere ® ) and cyclophosphamide [/fig] [fig] Figure 2: Risk of infertility associated with antineoplastic treatment in paediatric and adolescent patients. ALL acute lymphoblastic leukaemia; AML acute myeloid leukaemia; CNS central nervous system; CNS3 CNS with cerebrospinal fluid 5 ≥ leukocytes/µl and blast positives Colli et al., 205; CYP cyclophosphamide; GCTs germ cell tumors; HL Hodgkin lymphoma; HCT hematopoietic cell transplantation; HSCT hematopoietic stem cell transplantation; LBL lymphoblastic lymphoma; NHL non-Hodgkin lymphoma; PMBCL primary mediastinal B-cell lymphoma; PNET primitive neuroectodermal tumour; RMS rhabdomyosarcoma; RT radiotherapy; TBI total body irradiation. To calculate the gonadotoxic risk [70-72], the patient should receive an equivalent dose of CFM (cyclophosphamide equivalent dose, CED) according to the formula of Green et al.: > 6000-8000 mg/ m 2 in women and > 4000 mg/m 2 in men, ovarian or testicular RT or HSCT (73). The following equivalences were used (CFM = 1; ifosfamide × 0.244; procarbazine × 0.857; chlorambucil × 14.28; BCNU × 16; melphalan × 40; thiotepa × 40; nitrogen mustard × 100; busulfan × 8.82). In women, considered: low risk (CED < 4000 mg/ m 2 ), low-intermediate risk (CED between 4000 and 6000 mg/ m 2 ), intermediate-high risk (CED between 6000 and 10,000 mg/ m 2 ), high risk (CED > 10,000 mg/m 2 ). In men, considered: low risk (CED < 2000 mg/m 2 ), low-intermediate risk (CED between 2000 and 4000 mg/m 2 ), intermediate-high risk (CED between 4000 and 8000 mg/m 2 ), high risk (CED > 8000 mg/m 2 ). Depending on the dose of alkylating agent used. Risk calculated by cumulative dose of platinums (gonadotoxic potential not agreed). *Pelvic RT (> 15 Gy in prepubertal and > 10 Gy in postpubertal) or total abdominal RT. Craniospinal RT if the ovaries (> 2 Gy) or testes are included in the field (0.1-1.2 Gy) ◂ [/fig] [fig] Figures 3: and 4 show the decision-making algorithms to preserve fertility in female and male patients with cancer or a haematological disease. [/fig] [table] 1: Risk of infertility associated with antineoplastic treatment in adult cancer patients. FOLFOX fluorouracil, leucovorin and oxaliplatin; HCT haematopoietic cell transplantation; TAC docetaxel (Taxotere ® ), doxorubicin (Adriamycin ® ) and cyclophosphamide; TBI total body irradiation; TC docetaxel (Taxotere ® ) and cyclophosphamide [/table]	None	https://link.springer.com/content/pdf/10.1007/s12094-021-02699-2.pdf	None
1e26fa7e462eb237d52aa16b084eb97706dbabff	pubmed	Diagnostic approach to the congenital muscular dystrophies	Diagnostic approach to the congenital muscular dystrophies Congenital muscular dystrophies (CMDs) are early onset disorders of muscle with histological features suggesting a dystrophic process. The congenital muscular dystrophies as a group encompass great clinical and genetic heterogeneity so that achieving an accurate genetic diagnosis has become increasingly challenging, even in the age of next generation sequencing. In this Open access under CC BY-NC-ND license. document we review the diagnostic features, differential diagnostic considerations and available diagnostic tools for the various CMD subtypes and provide a systematic guide to the use of these resources for achieving an accurate molecular diagnosis. An International Committee on the Standard of Care for Congenital Muscular Dystrophies composed of experts on various aspects relevant to the CMDs performed a review of the available literature as well as of the unpublished expertise represented by the members of the committee and their contacts. This process was refined by two rounds of online surveys and followed by a three-day meeting at which the conclusions were presented and further refined. The combined consensus summarized in this document allows the physician to recognize the presence of a CMD in a child with weakness based on history, clinical examination, muscle biopsy results, and imaging. It will be helpful in suspecting a specific CMD subtype in order to prioritize testing to arrive at a final genetic diagnosis. # Introduction The congenital muscular dystrophies (CMDs) and the congenital myopathies (nondystrophic myopathies with characteristic histological and histochemical findings) constitute the two most important groups of congenital onset muscle disease. The CMDs are defined as early onset muscle disorders in which the muscle biopsy is compatible with the presence of a dystrophic process (even if not fully developed) without histological evidence of another neuromuscular disease [bib_ref] A clinical and histological study of Ullrich's disease (congenital atonic-sclerotic muscular dystrophy), Nonaka [/bib_ref] [bib_ref] Congenital muscular dystrophy: clinical and pathologic study of 50 patients with the..., Kobayashi [/bib_ref]. However, it has become clear that there is overlap between the CMDs and and the congenital myopathies on the clinical, morphological and genetic level. For example, mutations in RYR1 and SEPN1 can cause both core disorders (belonging to the congenital myopathies) as well as CMD-like presentations. The clinical as well as genetic complexity of the disorders subsumed under the CMDs has resulted in different genetic as well as clinical classification schemes [bib_ref] Congenital muscular dystrophy. Part I: a review of phenotypical and diagnostic aspects, Reed [/bib_ref] [bib_ref] Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives, Reed [/bib_ref] [bib_ref] The ever-expanding spectrum of congenital muscular dystrophies, Mercuri [/bib_ref]. Also, the genetic nomenclature used is not always consistent. For instance MDC1A (muscular dystrophy, congenital, type 1A) refers to disease caused by mutations in LAMA2, but this nomenclature system has not been systematically carried forward for all CMDs. lists most currently used names and symbols for reference. Gene symbols in this review are not italicized. We have used the gene or protein name annotated by "-related dystrophy (-RD)" or "-related myopathy (-RM)" for several of the CMD phenotypic classes to reflect the type of pathology that is more typically encountered in a biopsy for the subtype while allowing for a broad phenotypic and histopathological spectrum associated with the respective primary gene. If we are referring specifically to the congenital onset dystrophy without including later onset presentations we use "-related CMD". Myopathy here is meant to reflect a pathology without clear evidence of degeneration and regeneration in the majority of cases, although such features may be evident in some cases. The conditions designated as "related myopathy" are also those that may have presentations as more typical congenital myopathies. The incidence and prevalence of CMD in various populations is not sufficiently known and may have been underestimated in early published CMD surveys owing to more limited diagnostic means available. Point prevalence in early studies ranges from 0.68 to 2.5 per 100,000 [bib_ref] Genetic epidemiology of congenital muscular dystrophy in a sample from north-east Italy, Mostacciuolo [/bib_ref] [bib_ref] The prevalence of inherited neuromuscular disease in Northern Ireland, Hughes [/bib_ref] [bib_ref] Neuromuscular disorders in childhood: a descriptive epidemiological study from western Sweden, Darin [/bib_ref] [bib_ref] Prevalence of genetic muscle disease in Northern England: in-depth analysis of a..., Norwood [/bib_ref]. The relative frequency of individual types also varies in different populations. In Japan, the most commonly diagnosed CMD subtype is Fukuyama CMD caused by a founder mutation in the fukutin gene, followed by COL6-RD [bib_ref] Mild muscular dystrophy due to a nonsense mutation in the LAMA2 gene..., Blasi [/bib_ref] , while fukutin mutations are very rare in other populations [bib_ref] Primary collagen VI deficiency is the second most common congenital muscular dystrophy..., Okada [/bib_ref] [bib_ref] Variable penetrance of COL6A1 null mutations: implications for prenatal diagnosis and genetic..., Peat [/bib_ref]. Individual CMD forms are rare so that only highly specialized centers have the combined diagnostic experience and technology to cover all subtypes. It thus frequently falls on the primary pediatric, neuromuscular provider or pathologist caring for a patient with suspected CMD to coordinate and interpret data and results from different disciplines and laboratories in an effort to achieve a diagnosis for an individual patient. Establishing a molecular diagnosis however is of importance for genetic and prenatal counseling, prognosis and anticipatory management, and also for future stratification for clinical trials and treatment approaches that are specific for an individual subtype or even are mutation-specific. In an effort to arrive at consensus guidelines for achieving a specific genetic diagnosis in an individual patient, an international group involving the majority of experts in the field have participated in working groups and meetings to summarize currently available data and literature, unpublished experience, and individual expertise to develop a rational and comprehensive approach to the specific diagnosis of the heterogeneous disorders currently subsumed under CMD. ## General clinical findings in the congenital muscular dystrophies ## Initial presentation and its differential diagnosis When presenting in infancy there are certain clinical signs that point towards or are compatible with a CMD diagnosis, while other presenting features make a diagnosis of CMD much less likely (specific clinical findings will be discussed under diagnostic aspects of the CMD subtypes below). The most important differential diagnostic considerations for the hypotonic and weak infant outside of CMD (and excluding systemic metabolic and acquired conditions) are the congenital myopathies, congenital myasthenic syndromes, congenital metabolic myopathies, very early SMA and amongst the non-neuromuscular genetic conditions in particular Prader-Willi syndrome. contains a diagnostic schematic for infants <2-3 years starting with clinical findings and linking them to the diagnostic subtype considerations within the CMD and also to differential diagnostic considerations outside of CMD. ## Presentation at an older age and its differential diagnosis It is not infrequent that a patient may present for diagnosis at an older age either because a definitive CMD diagnosis has not yet been established despite congenital onset or because symptom onset or symptom recognition had been delayed. Several clinical clues help to arrive at a clinical and finally a molecular diagnosis. B and C cover clinical findings in the older child and adult, similarly starting from clinical observations such as the distribution of weakness and linking them to diagnostic subtype considerations as well as to differential diagnostic considerations outside of CMD. ## Initial testing available CK levels can be normal in SEPN1-RM and is often normal or only mildly elevated in COL6-RD, however, it is consistently elevated in LAMA2-RD and elevated most of the time (but not in 100% of patients) in αDG-RD. Brain MRI can help support the clinical diagnosis in the αDG-RD and LAMA2-RD (see below). While EMG/nerve conduction testing findings are not diagnostic in CMD they often show myopathic features (in LAMA2-RD they commonly also show peripheral motor and sensory neuropathy of lower extremities [bib_ref] Demyelinating peripheral neuropathy in merosin-deficient congenital muscular dystrophy, Shorer [/bib_ref] [bib_ref] EMG and nerve conduction studies in children with congenital muscular dystrophy, Quijano-Roy [/bib_ref] [bib_ref] Dysmyelinating sensory-motor neuropathy in merosin-deficient congenital muscular dystrophy, Muzio [/bib_ref]. A typical decremental response on repetitive stimulation is not compatible with a CMD diagnosis and should suggest a congenital myasthenic syndrome. ## Diagnostic aspects of specific subtypes ## Lama2-cmd-rd (laminin α 2 related cmd, merosin deficient cmd, mdc1a) Diagnostic considerations-Laminin α2 related CMD is caused by mutations in the LAMA2 gene, encoding the α2 heavy chain of the laminin 211 isoform (α 2/β1/γ1), also known as merosin [bib_ref] Congenital muscular dystrophy with merosin deficiency, Tomé [/bib_ref] [bib_ref] Expression of laminin subunits in congenital muscular dystrophy, Sewry [/bib_ref] [bib_ref] Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular..., Helbling-Leclerc [/bib_ref] [bib_ref] Genetics of laminin alpha 2 chain (or merosin) deficient congenital muscular dystrophy:..., Guicheney [/bib_ref]. In the genetic nomenclature, this CMD subtype is also referred to as MDC1A. Complete absence of laminin α2 staining on muscle (or skin biopsy) is more common and in general associated with a more severe non-ambulatory phenotype compared to a partial laminin α2 deficiency [bib_ref] Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2..., Geranmayeh [/bib_ref]. Patients [fig_ref] Figure 2: A [/fig_ref] , F) with complete laminin α2 deficiency present at birth with significant hypotonia and weakness of the extremities, which may worsen in the first few weeks of life in some infants. There may be contractures in the hands and feet at birth (arthrogryposis). In patients with complete deficiency the degree of muscle weakness usually precludes independent ambulation, although patients may get to a standing position and rarely achieve independent ambulation (2/33 patients in one series) [bib_ref] Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2..., Geranmayeh [/bib_ref]. Partial laminin α2 deficiency due to mutations in LAMA2 tends to present with milder and more variable phenotypes, including LGMD-like proximal weakness, and an Emery-Dreifuss like contracture phenotype, although manifestations may also be as severe as in the complete deficient patient [bib_ref] Mild muscular dystrophy due to a nonsense mutation in the LAMA2 gene..., Blasi [/bib_ref] [bib_ref] Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2..., Geranmayeh [/bib_ref] [bib_ref] Exon skipping mutations in collagen VI are common and are predictive for..., Lampe [/bib_ref] [bib_ref] Congenital muscular dystrophy with primary partial laminin alpha2 chain deficiency: molecular study, He [/bib_ref] [bib_ref] Variable clinical phenotype in merosin-deficient congenital muscular dystrophy associated with differential immunolabelling..., Sewry [/bib_ref]. In LAMA2-RD, particularly in the first 2 years of life, the CK is typically elevated more than five times normal. Typical findings on brain MRI [fig_ref] Figure 3: Fig. 3. [/fig_ref] , B) include high signal in the white matter on T2 weighted and FLAIR images and are seen in all patients but are most obvious in patients greater than 6 months of age. The internal capsule, corpus callosum, and other dense fiber tracts are usually spared, but there may be subcortical cyst formation. White matter changes once evident do not require further imaging. White matter abnormalities on MRI are also seen in patients with incomplete deficiency, while patients with very late adulthood onset my have normal brain MRI. A smaller percentage (about 5%) of patients shows more obvious brain structural abnormalities, including a particular occipital cortical dysgenesis with a subcortical band of heterotopia and cerebellar hypoplasia [bib_ref] Merosin-deficient congenital muscular dystrophy: the spectrum of brain involvement on magnetic resonance..., Philpot [/bib_ref]. Seizures occur in about 30% of all patients with LAMA2-RD, including in those with no obvious evidence for a cortical malformation on imaging. Selected genotype-phenotype correlations-Most mutations resulting in typical complete laminin α2 deficiency are functionally null mutations leading to the absence of the laminin α2 protein on immunostaining and a more severe non-ambulatory phenotype. 55% of mutations in one series were located in exons . Compound heterozygosity for a null mutation and an in-frame deletion or exon skipping mutations may lead to a milder phenotype with partial deficiency of laminin α2 [bib_ref] Mild muscular dystrophy due to a nonsense mutation in the LAMA2 gene..., Blasi [/bib_ref]. In contrast, in-frame deletions affecting the N-terminal G-domain, critical for binding of laminin isoforms to αdystroglycan and various integrins, affect the function of this molecule profoundly, leading to a severe phenotype, even though laminin α2 may be partially present in the basement membrane by immunohistological exam [bib_ref] Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225, LAMA2 gene coding for..., Allamand [/bib_ref]. Rare homozygous missense mutations have been associated with laminin α2 deficiency [bib_ref] Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2..., Geranmayeh [/bib_ref]. Affected siblings may demonstrate intrafamilial variability for onset and severity of clinical manifestations and degree of laminin α2 deficiency noted on muscle biopsy immunostaining. ## Alpha dystroglycan related dystrophies (αdg-rd) Diagnostic considerations-The αDG-RDs, are characterized by reduced O-mannosyl and LARGE-dependent glycosylation of α-dystroglycan, a sarcolemmal membrane structural protein. This is the result of mutations in the currently 13 genes directly or putatively involved in the glycosylation pathway (POMT1, POMT2, POMGnT1, FKRP, Fukutin, LARGE, ISPD, GTDC2, B3GALNT2, B3GNT1, TMEM5, GMPPB, SGK196) [bib_ref] Muscular dystrophies due to glycosylation defects: diagnosis and therapeutic strategies, Muntoni [/bib_ref] [bib_ref] The o-mannosylation pathway: glycosyltransferases and proteins implicated in congenital muscular dystrophy, Wells [/bib_ref]. A single mutation in dystroglycan (DAG1) that specifically interferes with its glycosylation can lead to an αDG-RD [bib_ref] A dystroglycan mutation associated with limbgirdle muscular dystrophy, Hara [/bib_ref]. Mutations in the dolichyl-phosphate mannosyltransferase subunit genes DPM1, DPM2 and DPM3 cause overlap syndromes of muscular dystrophy with under-glycosylated αDG in the muscle [bib_ref] Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital..., Yang [/bib_ref] [bib_ref] Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie, Imbach [/bib_ref] [bib_ref] Congenital muscular dystrophy with defective alphadystroglycan, cerebellar hypoplasia, and epilepsy, Messina [/bib_ref] , while mutations in the dolichol kinase DOLK are a cause of dilated cardiomyopathy [bib_ref] Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan..., Lefeber [/bib_ref]. αDG-RD classifications have been proposed to accommodate the very broad clinical spectrum, ranging from syndromic CMD forms with very severe brain involvement (including WWS, FCMD and Muscle-Eye-Brain disease) to the LGMD spectrum [bib_ref] The ever-expanding spectrum of congenital muscular dystrophies, Mercuri [/bib_ref] [bib_ref] Congenital muscular dystrophies: 1997 update, Voit [/bib_ref] [bib_ref] An ancient retrotransposal insertion causes Fukuyamatype congenital muscular dystrophy, Kobayashi [/bib_ref] [bib_ref] Muscular Dystrophy and Neuronal Migration Disorder Caused by Mutations in a Glycosyltransferase, Yoshida [/bib_ref] [bib_ref] Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital..., Brockington [/bib_ref] [bib_ref] Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy..., Brockington [/bib_ref] [bib_ref] Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study, Mercuri [/bib_ref] [bib_ref] Mutations in the O-Mannosyltransferase Gene POMT1 Give Rise to the Severe Neuronal..., Beltran-Valero De Bernabe [/bib_ref] [bib_ref] Mutations in the human LARGE gene cause MDC1D, a novel form of..., Longman [/bib_ref] [bib_ref] POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker Warburg syndrome, Van Reeuwijk [/bib_ref] [bib_ref] Dystroglycanopathies: coming into focus, Godfrey [/bib_ref]. It may be difficult to unequivocally classify patients with transitional milder CNS abnormalities including microcephaly, cerebellar hypoplasia with or without cysts or patients with learning disability with normal appearing MRI presenting with either CMD or LGMD like age of symptom onset with or without achieved ambulation as it may be difficult to assign a delay in acquisition of motor milestones to the global developmental delay as opposed to muscle weakness. Normal cognitive abilities have been encountered in patients with FKRP, FKTN, and ISPD mutations while cognitive impairment which ranges from profound mental retardation to mild learning disability has been observed in patients with mutations in all 17 genes (DAG1, POMT1, POMT2, POMGnT1, LARGE, FKRP, FKTN, ISPD, GTDC2, B3GNT1, B3GALNT2, GMPPB, TMEM5, SGK196, DPM1, DPM2, DPM3). In the αDG-RDs, the spectrum of the muscle involvement is broad for all subtypes, ranging from prenatal onset weakness precluding ambulation, to Duchenne and Becker-like severities [fig_ref] Figure 2: A [/fig_ref] , I). The distribution of muscle weakness is proximal with a tendency for muscle hypertrophy and pseudohypertrophy in both upper and lower extremities. Scapular winging, lumbar lordosis and a Trendelenburg gait can be present. Some patients have experienced myositis-like rapid decline in function that was partially responsive to steroid treatment [bib_ref] Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy, Godfrey [/bib_ref] [bib_ref] Inflammation and response to steroid treatment in limb-girdle muscular dystrophy 2I, Darin [/bib_ref] [bib_ref] Severe muscle damage following viral infection in patients with Fukuyama congenital muscular..., Murakami [/bib_ref]. Dilated cardiomyopathy is most commonly found in αDG patients due to FKRP and FKTN mutations, especially in those patients at the LGMD end of the clinical spectrum, and less commonly in POMT1 mutations. However, echocardiographic surveillance has to be considered in any dystroglycanopathy patient [bib_ref] Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness, Murakami [/bib_ref] [bib_ref] Variable cardiac involvement in Tunisian siblings harboring FKRP gene mutations, Kefi [/bib_ref]. The hallmark of central nervous system involvement in the αDG-RD on brain MRI [fig_ref] Figure 3: Fig. 3. [/fig_ref] is represented by the cobblestone complex, ranging from complete lissencephaly (type II) to more focal pachygyria or polymicrogyria showing a frontal predominance. Similar to LAMA2-RD there may also be an occipital cortical dysplasia with a smooth appearing cortex and an underlying heterotopic band of neurons. Characteristic infratentorial findings may include midbrain hypoplasia, a relatively thick tectum, fused colliculi, a pontomesencephalic kink, ventral pontine cleft, pontocerebellar hypoplasia, abnormalities of cerebellar foliation and cerebellar cysts, which are frequently observed in POMGnT1, and FKRP mutations and have recently been described in POMT2 and LARGE patients [bib_ref] Brain involvement in muscular dystrophies with defective dystroglycan glycosylation, Clement [/bib_ref] [bib_ref] Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion,..., Clarke [/bib_ref]. Some patients may only have frontal polymicrogyria without infratentorial involvement (seen in POMT1, POMT2 and LARGE), while some may only have infratentorial involvement (ISPD) [bib_ref] ISPD gene mutations are a common cause of congenital and limb-girdle muscular..., Cirak [/bib_ref]. MRI findings may also include hydrocephalus, and occipital encephalocele. There may be high signal in the white matter on FLAIR or T 2 -weighted images showing patchy or more confluent involvement. In contrast to LAMA2-RD, these white matter abnormalities can regress over time [bib_ref] Brain involvement in muscular dystrophies with defective dystroglycan glycosylation, Clement [/bib_ref] [bib_ref] Four Caucasian patients with mutations in the fukutin gene and variable clinical..., Vuillaumier-Barrot [/bib_ref] [bib_ref] Brain MRI abnormalities in muscular dystrophy due to FKRP mutations, Quijano-Roy [/bib_ref] , and are not typically observed in dystroglycanopathy patients with preserved intelligence. Selected genotype-phenotype correlations-The number of αDG-RD diagnosis without a mutation in one of the currently known genes is not entirely clear, but it is still significant and additional genes will likely be found. While point mutations are the most common mutation type in all genes, genomic deletions or deletion-insertions have been reported in particular POMT2 and LARGE [bib_ref] Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion,..., Clarke [/bib_ref] [bib_ref] POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental..., Yanagisawa [/bib_ref] [bib_ref] Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome, Van Reeuwijk [/bib_ref]. Mutations in POMGnT1 showed the highest correlation with the typical MEB phenotype [bib_ref] Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study, Mercuri [/bib_ref] [bib_ref] Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan, Godfrey [/bib_ref]. Patients homozygous for the ancestral Japanese mutation (insertion of a retrotransposon) in FKTN have a comparatively milder phenotype (FCMD), while the disease severity increases towards the MEB and WWS range in patients who are compound heterozygous for this ancestral mutation and a more severe loss-of-function mutation on the other allele [bib_ref] Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular..., Kondo-Iida [/bib_ref]. Homozygous null mutations in the human FKTN gene have resulted in a WWS-like phenotype [bib_ref] A new mutation of the fukutin gene in a non-Japanese patient, Silan [/bib_ref]. FKRP, FKTN and ISPD mutations are associated with the broadest clinical spectrum to date ranging from WWS to a Becker-like limb girdle muscular dystrophy [bib_ref] Four Caucasian patients with mutations in the fukutin gene and variable clinical..., Vuillaumier-Barrot [/bib_ref] [bib_ref] Phenotypic spectrum associated with mutations in the fukutin-related protein gene, Mercuri [/bib_ref] [bib_ref] ISPD gene mutations are a common cause of congenital and limb-girdle muscular..., Cirak [/bib_ref] [bib_ref] Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome, Beltran-Valero De Bernabe [/bib_ref]. The c.826C>A (p.Leu276Ile) mutation in the FKRP gene is particularly common in LGMD2I patients, but can be associated with a more severe phenotype in the compound heterozygous state depending on second mutation [bib_ref] Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy..., Brockington [/bib_ref] [bib_ref] Phenotypic spectrum associated with mutations in the fukutin-related protein gene, Mercuri [/bib_ref]. In contrast, most of the CMD associated FKRP mutations are unique to individual patients. In the POMT1 and POMT2 genes, mutations leading to severe functional defects appear to be associated with severe WWS or MEB phenotypes [bib_ref] POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental..., Yanagisawa [/bib_ref] , whereas less disruptive missense changes result in milder phenotypes such as CMD or even LGMD with mental retardation and normal MRI [bib_ref] POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker Warburg syndrome, Van Reeuwijk [/bib_ref] [bib_ref] Expanding the clinical spectrum of POMT1 phenotype, D'amico [/bib_ref] [bib_ref] POMT1 and POMT2 mutations in CMD patients: a multicentric Italian study, Messina [/bib_ref] [bib_ref] Whole body muscle MRI protocol: pattern recognition in early onset NM disorders, Quijano-Roy [/bib_ref]. New genes associated with alphaDG-RD are continuously added reducing the percentage of patients in the alphaDG spectrum without genetic basis: Recessive mutations in the ISDP (isoprenoid synthase domain containing protein) have recently been identified as a novel cause for WWS [bib_ref] Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan, Roscioli [/bib_ref] [bib_ref] ISPD loss-of-function mutations disrupt dystroglycan Omannosylation and cause Walker-Warburg syndrome, Willer [/bib_ref] , but ranging to the milder spectrum with isolated cerebellar involvement and LGMD like presentations without cognitive involvement [bib_ref] ISPD gene mutations are a common cause of congenital and limb-girdle muscular..., Cirak [/bib_ref]. Mutations in CTDC2 were found in consanguineous WWS families [bib_ref] Exome sequencing and functional validation in zebrafish identify GTDC2 mutations as a..., Manzini [/bib_ref] , while TMEM5 mutations have been identified in aborted fetuses with severe cobblestone lissencephaly typical of aDGpathy [bib_ref] Identification of mutations in TMEM5 and ISPD as a cause of severe..., Vuillaumier-Barrot [/bib_ref] and in WWS and MEB [bib_ref] Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry, Jae [/bib_ref]. β-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2) mutations were shown to cause CMD with brain and eye abnormalities consistent with the alpha DG-RD spectrum [bib_ref] Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan, Stevens [/bib_ref] , while mutations in GDP-mannose pyrophosphorylase B (GMPPB) were associated with a spectrum from severe CMD with brain involvement to milder LGMD [bib_ref] Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb-girdle muscular dystrophies associated..., Carss [/bib_ref] , and SGK196 mutations in one family with WWS [bib_ref] Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry, Jae [/bib_ref]. The congenital disorders of glycosylation associated with mutations in the DPM1, DPM2 and DPM3 [bib_ref] Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital..., Yang [/bib_ref] [bib_ref] Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie, Imbach [/bib_ref] [bib_ref] Congenital muscular dystrophy with defective alphadystroglycan, cerebellar hypoplasia, and epilepsy, Messina [/bib_ref] while showing reduced alpha-dystroglycan and elevated CK, also present with cognitive impairment, microcephaly, cerebellar hypoplasia, feeding difficulties and notably severe myoclonic epilepsy. Recessive mutations in DOLK so far present mostly as a dilated cardiomyopathy [bib_ref] Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan..., Lefeber [/bib_ref]. ## Collagen vi related dystrophies (col6-rd) Diagnostic considerations-Collagen VI is an important component of the muscle extracellular matrix where it interacts with the basement membrane of all muscle fibers. Mutations in one of the three collagen 6 alpha genes (COL6A1, COL6A2, COL6A3) can have recessive as well as dominant modes of action and inheritance patterns, leading to the COL6-RD spectrum, ranging from early onset, severe Ullrich CMD (UCMD) to an intermediate severity phenotype to milder Bethlem myopathy (BM). (For reviews see [bib_ref] The collagen VI-related myopathies: muscle meets its matrix, Bonnemann [/bib_ref] [bib_ref] Collagen type VI and related disorders: Bethlem myopathy and Ullrich scleroatonic muscular..., Bertini [/bib_ref] [bib_ref] Collagen VI related muscle disorders, Lampe [/bib_ref] [bib_ref] Early onset collagen VI myopathies: genetic and clinical correlations, Brinas [/bib_ref] UCMD [fig_ref] Figure 2: A [/fig_ref] typically presents in the newborn period with striking distal joint hypermobility of the hands and often feet with prominent calcanei, while talipes equinovarus can also occur [bib_ref] A clinical and histological study of Ullrich's disease (congenital atonic-sclerotic muscular dystrophy), Nonaka [/bib_ref]. Congenital hip dislocation is frequently present. Proximal elbow and knee contractures, kyphoscoliosis, and torticollis may be also present at birth and may improve initially with physical therapy and orthopaedic treatment. Later in life, joint contractures return and progress, in particular in the long finger flexors, shoulders, elbows, knees and hips, and spine becomes stiff with risk of kyphoscoliosis. While some UCMD patients may not achieve the ability to walk, more commonly walking is achieved for some years, and then is lost again in the late first or early second decade of life due to combined progressive hip contractures and increasing weakness. A steady decline in percent predicted forced vital capacity is observed in virtually all Ullrich patients, leading to predominantly night-time respiratory insufficiency [bib_ref] Natural history of Ullrich congenital muscular dystrophy, Nadeau [/bib_ref] [bib_ref] Rapidly progressive scoliosis and respiratory deterioration in Ullrich congenital muscular dystrophy, Yonekawa [/bib_ref] [bib_ref] Natural history of pulmonary function in collagen VIrelated myopathies, Foley [/bib_ref] in which the diaphragm is disproportionally affected [bib_ref] Diaphragmatic dysfunction in Collagen VI myopathies, Quijano-Roy [/bib_ref]. In the allelic Bethlem phenotype onset may either be as early as the congenital period but with few conspicuous findings in early childhood such as mild weakness and some degree of joint hypermobility, or clinical recognition may be later. Contractures of the Achilles tendons, pectoralis muscle, elbows and long finger flexors develop progressively. The weakness itself is slowly progressive. Respiratory compromise is also less conspicuous in the Bethlem phenotype, although weakness may progress in adulthood [bib_ref] Natural history of Ullrich congenital muscular dystrophy, Nadeau [/bib_ref] [bib_ref] Respiratory muscle involvement in Bethlem myopathy, Haq [/bib_ref]. Clinical phenotypes that are intermediate between these two classic presentations include patients with early presentation who are ambulating to late teenage years or young adulthood but still presenting progressive respiratory failure, even while still ambulating [bib_ref] Natural history of pulmonary function in collagen VIrelated myopathies, Foley [/bib_ref] [bib_ref] Diaphragmatic dysfunction in Collagen VI myopathies, Quijano-Roy [/bib_ref] [bib_ref] Consensus statement on standard of care for congenital muscular dystrophies, Wang [/bib_ref] , Characteristic skin findings are diagnostically helpful and include a tendency for keloid or atrophic scar formation, striae, soft velvety skin on palms and soles and hyperkerotosis pilaris [bib_ref] Ullrich congenital muscular dystrophy: connective tissue abnormalities in the skin support overlap..., Kirschner [/bib_ref]. Cognition is normal and often advanced for age. CK is normal or mildly elevated. Differential diagnostic considerations for milder COL6-RD phenotypes with prominent joint contractures include LAMA2-RD with partial deficiency, LMNA-RD as well as other Emery-Dreifuss muscular dystrophies. In contrast to LMNA-RD and Emery-Dreifuss muscular dystrophy and FHL1-related disorders, the COL6-RD do not develop cardiac involvement. For patients with very prominent joint hypermobility, the relevant differential diagnostic considerations are kyphoscoliotic Ehlers-Danlos syndromes (type VI) and the hypermobile type caused by mutations in tenascin X [bib_ref] Ehlers-Danlos syndrome due to tenascin-X deficiency: muscle weakness and contractures support overlap..., Voermans [/bib_ref]. Recently recognized EDS/ myopathy overlap syndromes to consider in the differential diagnosis include a form with severe kyphoscoliosis and myopathy due to FKBP14 mutations [bib_ref] Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis,..., Baumann [/bib_ref] and forms due to mutations in collagen XII ranging from severe and precluding ambulation to milder presentations [bib_ref] Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome..., Zou [/bib_ref] [bib_ref] Mutations in the Collagen XII gene define a new form of extracellular..., Hicks [/bib_ref]. Analysis of collagen VI in dermal fibroblast cultures may add sensitivity to the biochemical testing [bib_ref] Early onset collagen VI myopathies: genetic and clinical correlations, Brinas [/bib_ref] [bib_ref] A comparative analysis of collagen VI production in muscle, skin and fibroblasts..., Jimenez-Mallebrera [/bib_ref] [bib_ref] A refined diagnostic algorithm for Bethlem myopathy, Hicks [/bib_ref] [bib_ref] Flow cytometry analysis: a quantitative method for collagen VI deficiency screening, Kim [/bib_ref]. The availability of fibroblast cultures also allows for genetic testing and confirmation of splice mutations on fibroblast derived cDNA. This type of analysis is currently only available in research laboratories and is often needed to confirm a molecular diagnosis given the important role of splice mutations. Selective genotype-phenotype correlations-Even though two new collagen VI related genes have been identified in humans (COL6A5 and COL6A6 [bib_ref] Three novel collagen VI chains with high homology to the alpha3 chain, Gara [/bib_ref] [bib_ref] Three novel collagen VI chains, alpha4(VI), alpha5(VI), and alpha6(VI), Fitzgerald [/bib_ref] , all cases of COL6-RD identified to date are related to mutations in the original COL6A1-3 genes with genotype-phenotype correlations established in larger published cohorts of similar mutations [bib_ref] Primary collagen VI deficiency is the second most common congenital muscular dystrophy..., Okada [/bib_ref] [bib_ref] Exon skipping mutations in collagen VI are common and are predictive for..., Lampe [/bib_ref] [bib_ref] Early onset collagen VI myopathies: genetic and clinical correlations, Brinas [/bib_ref] [bib_ref] Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity, Pace [/bib_ref] [bib_ref] Dominant collagen VI mutations are a common cause of Ullrich congenital muscular..., Baker [/bib_ref]. Mutations underlying the severe end of the spectrum are typically recessive loss of function mutations that prevent any chains from assembling [bib_ref] Exon skipping mutations in collagen VI are common and are predictive for..., Lampe [/bib_ref] , occasional recessive missense mutations [bib_ref] Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of..., Zhang [/bib_ref] , and importantly de novo dominant negative mutations [bib_ref] Exon skipping mutations in collagen VI are common and are predictive for..., Lampe [/bib_ref] [bib_ref] Dominant collagen VI mutations are a common cause of Ullrich congenital muscular..., Baker [/bib_ref]. Dominant negatively acting mutations are usually in-frame exon skipping mutations or glycine missense mutations of the collagenous Gly-X-Y motif at the Nterminal end of the triple helical domain, allowing them to be carried forward in the assembly [bib_ref] Exon skipping mutations in collagen VI are common and are predictive for..., Lampe [/bib_ref] [bib_ref] Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity, Pace [/bib_ref] [bib_ref] Dominant collagen VI mutations are a common cause of Ullrich congenital muscular..., Baker [/bib_ref] [bib_ref] Kinked collagen VI tetramers and reduced microfibril formation as a result of..., Lamande [/bib_ref] [bib_ref] Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and..., Butterfield [/bib_ref]. Bethlem myopathy is typically caused dominantly acting mutations with less severe functional impact, [bib_ref] Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity, Pace [/bib_ref] [bib_ref] Kinked collagen VI tetramers and reduced microfibril formation as a result of..., Lamande [/bib_ref] , while recessive mutations are less common [bib_ref] Autosomal recessive inheritance of classic Bethlem myopathy, Foley [/bib_ref] [bib_ref] Autosomal recessive Bethlem myopathy, Gualandi [/bib_ref]. In particular dominantly acting glycine missense mutations are associated with a phenotypic range that extends from typical Ullrich CMD to Bethlem, and are also responsible for large number of patients in the intermediate severity group discussed earlier [bib_ref] Early onset collagen VI myopathies: genetic and clinical correlations, Brinas [/bib_ref] [bib_ref] Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity, Pace [/bib_ref]. Large exonic or even the whole gene deletions that will not be recognized by exon sequencing based testing can occur in COL6A1 and COL6A2 in particular [bib_ref] Identification of a deep intronic mutation in the COL6A2 gene by a..., Bovolenta [/bib_ref] [bib_ref] Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy, Foley [/bib_ref]. ## Sepn1 related myopathy (sepn1-rm) Diagnostic considerations-SEPN1-RM is a congenital muscle disorder caused by autosomal recessive mutations of the SEPN1 gene, which encodes selenoprotein N (SelN) and plays a key role in protecting human cells against oxidative stress [bib_ref] Oxidative stress in SEPN1-related myopathy: from pathophysiology to treatment, Arbogast [/bib_ref] [bib_ref] Selenoprotein N is required for ryanodine receptor calcium release channel activity in..., Jurynec [/bib_ref]. Poor or delayed head control in the first months of life is the most common presenting sign, although almost all patients continue to acquire motor milestones and achieve independent ambulation often at a normal age. Neonatal respiratory failure, severe feeding difficulties, congenital contractures or major joint hyperlaxity would be highly unusual presenting features. During later infancy and childhood, muscle weakness and slenderness remain more marked in axial groups, particularly in neck flexors and sometimes extensors (dropped head) [bib_ref] Mutations of the selenoprotein N gene, which is implicated in rigid spine..., Ferreiro [/bib_ref] [bib_ref] The phenotype and long-term follow-up in 11 patients with juvenile selenoprotein N1-related..., Schara [/bib_ref] [bib_ref] SEPN1-related myopathies: clinical course in a large cohort of patients, Scoto [/bib_ref]. In contrast, limb strength and therefore walking ability are usually preserved, although difficulties climbing stairs, walking long distances and easy fatiguability are common. Marked progression has been observed in several cases after the fourth decade. Other characteristic features are a relative atrophy of the inner thigh muscles, mild hyperlaxity of hands and wrists and mild facial weakness with a typical nasal voice. Mild ophthalmoparesis is uncommon but can be seen particularly in severe cases. In a series of patients with hirsutism, signs of insulin resistance were detected [bib_ref] SEPN1: associated with congenital fiber-type disproportion and insulin resistance, Clarke [/bib_ref]. Joint contractures are absent or mild but they are severe in the spine leading to a spinal stiffness which may appear around 5-6 years of life or even earlier. Later on, thoracic lordoscoliosis with lateral translation is a frequent complication [fig_ref] Figure 2: A [/fig_ref]. Progressive restrictive respiratory failure frequently manifests by the end of the first decade of life as nocturnal hypoventilation even in children with fairly preserved vital capacity. As in Ullrich patients, diaphragmatic failure may be observed and most patients require non-invasive ventilation while still ambulant, at an average age of 13.9 years with a range of 1 to 33 years, suggesting that respiratory surveillance should be initiated at diagnosis [bib_ref] SEPN1-related myopathies: clinical course in a large cohort of patients, Scoto [/bib_ref]. CK is normal or mildly elevated (less than 4-fold). SEPN1-RM needs to be differentiated from other conditions with prominent spinal rigidity, particularly Emery-Dreifuss muscular dystrophy, FHL1 related myopathies, Pompe disease, COL6-RD (UCMD, Bethlem myopathy), and some cases of RYR1 related core disease. Joint contractures are not typical of SEPN1 and this is a differential feature with most of these entities, but this complication may not be present at young ages. Drop head and spinal rigidity are also observed in LMNA-RD, but CK levels are usually higher in LMNA-RD and muscle weakness distribution in the limbs is different (proximal in upper extremities and distal in lower limbs in LMNA-RD). Selective genotype-phenotype correlations-Mutations are distributed along the whole gene, except exon 3 and the majority are nonsense mutations, microdeletions or insertions leading to frameshifts, as well as splice-site mutations leading to aberrant pre-mRNA splicing (reviewed in Lescure et al., [bib_ref] Selenoprotein function and muscle disease, Lescure [/bib_ref] [bib_ref] Oxidative stress in SEPN1-related myopathy: from pathophysiology to treatment, Arbogast [/bib_ref] [bib_ref] SEPN1-related myopathies: clinical course in a large cohort of patients, Scoto [/bib_ref] [bib_ref] Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy, Foley [/bib_ref]. Interestingly, several mutations affect the cis sequences (3' UTR SECIS element, Sec codon redefinition element (SRE)) required for selenocysteine insertion which needs to be evaluated if Sanger sequencing of coding exons does not reveal a mutation [bib_ref] A single homozygous point mutation in a 3' untranslated region motif of..., Allamand [/bib_ref] [bib_ref] Ex vivo correction of selenoprotein N deficiency in rigid spine muscular dystrophy..., Rederstorff [/bib_ref] [bib_ref] A mutation in the SEPN1 selenocysteine redefinition element (SRE) reduces selenocysteine incorporation..., Maiti [/bib_ref]. ## Recessive ryr1-related myopathy (ryr1-rm) presenting as cmd (ryr1-cmd) Patients with recessive mutations in the RYR1 gene coding for the sarcoplasmic reticulum calcium release channel may present with a distinct CMD like presentation (RYR1-CMD) which falls into the larger context of recessive RYR1-RM that now includes centronuclear (CNM), central core, multi-minicore, and fiber type disproportion histological presentations [bib_ref] Clinical and genetic findings in a large cohort of patients with ryanodine..., Klein [/bib_ref] [bib_ref] Severe congenital RYR1-associated myopathy: The expanding clinicopathologic and genetic spectrum, Bharucha-Goebel [/bib_ref]. RYR1-CMD lacks evidence for typical core formation on muscle biopsy staining with NADH and other oxidative stains, but presents with a histological and clinical picture most suggestive of CMD. Like SEPN1 mutations, RYR1 mutations can present as disorders sharing features of both a congenital myopathy and a CMD. There is evidence to suggest common aspects to the pathogenesis in both of these disorders and that they may physically interact [bib_ref] Selenoprotein N is required for ryanodine receptor calcium release channel activity in..., Jurynec [/bib_ref]. Clinically, patients with RYR1-CMD may present with significant congenital onset hypotonia, including facial weakness and early onset severely progressive scoliosis. Nocturnal ventilatory support due to pulmonary insufficiency and gastrostomy due to feeding and swallowing difficulties may be required. Although not frequent, CK can be mildly elevated. Ophthalmoplegia/paresis as seen in the the centronuclear and multiminicore presentations of recessive RYR1 mutations may be absent in the CMD like presentation of RYR1-CMD. ## Lmna related cmd (lmna-cmd) Mutations in the lamin A/C (LMNA) gene, cause a wide range of genetic disorders in humans, including muscular dystrophies (LMNA-RD) [bib_ref] The laminopathies: a clinical review, Rankin [/bib_ref] [bib_ref] Diseases of the nuclear envelope, Worman [/bib_ref]. The typical neuromuscular disorder associated with lamin A/C mutations is Emery-Dreifuss muscular dystrophy (EDMD), characterized by scapuloperoneal muscle weakness, contractures of elbows, heel cords and spine, scoliosis, cardiomyopathy and cardiac arrhythmias. More recently mutations in LMNA have also been identified in patients with an early onset CMD form (LMNA-CMD) [bib_ref] Extreme variability of phenotype in patients with an identical missense mutation in..., Mercuri [/bib_ref] [bib_ref] De novo LMNA mutations cause a new form of congenital muscular dystrophy, Quijano-Roy [/bib_ref]. In LMNA-CMD, weakness becomes evident in infancy, sometimes including a brief phase of more rapid progression during the first 24 months of age with loss of early motor milestones. Characteristic weakness of axial and neck muscles (flexors and extensors) causes the clinical phenomenon of head-drop or "dropped head syndrome" [fig_ref] Figure 2: A [/fig_ref] [bib_ref] De novo LMNA mutations cause a new form of congenital muscular dystrophy, Quijano-Roy [/bib_ref] [bib_ref] Two patients with 'Dropped head syndrome' due to mutations in LMNA or..., D'amico [/bib_ref] [bib_ref] Novel LMNA mutation presenting as severe congenital muscular dystrophy, Prigogine [/bib_ref] , due to very weak neck extensors. In addition there is pronounced lumbar hyperlordosis at a very early age, arm and hand weakness as well as peroneal predominant weakness while hip flexors are better preserved demonstrating good antigravity strength. Thus, weakness resembles an early axial-scapulo-peroneal pattern in addition to the early and severe axial weakness. Contractures manifest in the Achilles tendon, knees, hips and spine with considerable spinal rigidity, with less contractures in the elbows and finger flexors or extensors when compared to classic Emery-Dreifuss phenotype and COL6-RD. In the most severe cases, sitting and head support may never be achieved. More commonly, walking ability is acquired but it is lost later in life, often after a short period of time. Night-time respiratory insufficiency with hypoventilation and hypercapnea may manifest early [bib_ref] De novo LMNA mutations cause a new form of congenital muscular dystrophy, Quijano-Roy [/bib_ref]. Similar to Emery-Dreifuss phenotype, cardiac involvement in LMNA-CMD may take the form of an initially atrial arrhythmogenic cardiomyopathy with conduction block, and also ventricular tachyarrhythmias, necessitating the use of an AICD. Cognition is unaffected. CK levels can be mildly to moderately elevated. The most important differential diagnostic consideration is SEPN1-RM (see section 3.4.). Selective genotype-phenotype correlations-All identified mutations so far have been heterozygous de novo mutations that act in a dominant negative way [bib_ref] Extreme variability of phenotype in patients with an identical missense mutation in..., Mercuri [/bib_ref]. Some mutations seem unique to LMNA-CMD, while other mutations also occur in patients at the severe end of the spectrum of the Emery-Dreifuss phenotype [bib_ref] De novo LMNA mutations cause a new form of congenital muscular dystrophy, Quijano-Roy [/bib_ref] [bib_ref] Phenotypic clustering of lamin A/C mutations in neuromuscular patients, Benedetti [/bib_ref]. ## Mutations in metabolic pathway genes presenting as cmd Several genetic causes for CMD like presentations have been described recently and involve mutations in genes that are involved in metabolic pathways (see [fig_ref] Table 2: Summary of currently recognized Congenital Muscular Dystrophies [/fig_ref]. CHKB-related CMD-Mutations in choline kinase B, which is involved in phosphatidylcholine biosynthesis, cause a congenital onset muscular dystrophy with large appearing mitochondria (megacolonial or giant mitochondria) on oxidative stains and ultrastructure [bib_ref] A new congenital muscular dystrophy with mitochondrial structural abnormalities, Nishino [/bib_ref]. Affected patients in addition show cognitive impairment but normal brain MRI findings and also skin findings including acanthosis nigricans like lesions with intense pruritus. This clinical constellation together with the biopsy findings is diagnostic [bib_ref] Congenital muscular dystrophy: clinical and pathologic study of 50 patients with the..., Kobayashi [/bib_ref]. ## Paraclinical diagnosis of cmd ## Muscle pathology- The careful evaluation of the muscle biopsy often is essential to suggest or support a genetic diagnosis. Proper performance, handling, and processing of the biopsy specimen need to be assured. The muscle biopsy should be obtained from a skeletal muscle that is clinically affected but not to a degree that makes it unsuitable for diagnosis due to near complete replacement of muscle by connective and fatty tissue. Although the degree of involvement of the muscle can be suspected on clinical grounds, it may be very helpful to utilize muscle imaging (MRI, ultrasound, or CT) to estimate the degree of involvement. It is important to anticipate the need for future analysis of biological materials and assure proper storage of muscle fixated for ultrastructural analysis, frozen muscle, genomic DNA and if possible fibroblast culture. When available, establishment of a myoblast culture may be useful for future studies in unclear CMD presentations. Correlation with the clinical picture is often required to arrive at a correct biopsy interpretation given the variability of possible compatible morphologic findings [bib_ref] Congenital muscular dystrophy: clinical and pathologic study of 50 patients with the..., Kobayashi [/bib_ref] [bib_ref] Muscle histochemistry in congenital muscular dystrophy with central nervous system involvement, Nonaka [/bib_ref] [bib_ref] Congenital muscular dystrophy. A histochemical study with morphometric analysis on biopsied muscles, Kihira [/bib_ref] , the possible variability inherent in performance and interpretation of the commercial antibodies used to evaluate specific protein deficiencies by immunohistochemistry [bib_ref] Dystroglycan: from biosynthesis to pathogenesis of human disease, Barresi [/bib_ref] , and the lack of the specific stains in certain CMD subtypes. One of the most immediate uses of a muscle biopsy is to recognize or exclude other disorders that are important in the differential diagnosis of CMD. Lack of any morphological changes could indicate the presence of a central nervous system disorder causing significant hypotonia, and does not exclude a metabolic problem. On the Hematoxylin and Eosin (H&E) stain, CMD is usually characterized by abnormal variation in fiber size for age without obvious grouping. The fiber shape may be rounded, and there is an increase in internalized nuclei (but not usually central nuclei as seen in the centronuclear myopathies). RYR1-RM in particular may have high numbers of centralized nuclei as can congenital DM1 as an important differential diagnosis. There is a variable increase in endomysial connective and adipose tissue, while the width of perimysium is increased (but note that it is wider in general in neonates) [bib_ref] Congenital muscular dystrophy: clinical and pathologic study of 50 patients with the..., Kobayashi [/bib_ref] [bib_ref] Predominant fiber atrophy and fiber type disproportion in early ullrich disease, Schessl [/bib_ref]. There may be necrosis, which however may not be readily apparent on H&E so that its absence does not exclude a CMD diagnosis. The presence of basophilic fibers suggests regenerative activity, but not all basophilic fibers are regenerating fibers. The analysis of neonatal and foetal myosins might be very helpful in these cases. In addition, foci of inflammatory cells may be present. Other fiber abnormalities that may be seen occasionally and which are still consistent with a CMD diagnosis include various types of vacuoles (however, these are never a prominent finding in the biopsy), whorled and/or split fibers and hyper-contracted fibers (though fewer compared to the dystrophinopathies). In neonates, the observation of some large Wohlfart B fibers is considered normal. In addition, the modified Gömöri Trichrome (mGT) stain may be helpful in recognizing other conditions such as rods in nemaline myopathy and ragged red fibers in mitochondrial myopathy. The mGT stain also reveals the degree and distribution of fibrosis present in the biopsy. The oxidative stains as well as ATPase stains reveal fiber typing. Fiber type 1 predominance is common in the CMDs but is not specific for any particular diagnosis. Fiber typing can be indistinct, particularly in neonates. In this case myosin heavy chain immunofluorescence can be helpful. Absent clear typing is referred to as fiber type uniformity and could suggest a RYR1-RM. Fibertype grouping (of both types) is not a feature in the CMDs and suggests the presence of a neurogenic disorder. Cores can be diagnosed if observed on all oxidative stains: COX, SDH and NADH-TR stains. The presence of large and longitudinally extended cores would usually suggest the presence of a RYR1-RM or RYR1-CMD. However, unevenness in staining is more common and can even be seen in COL6-RM. The presence of multiple minicores (in particular in longitudinal section) suggests the presence of either a SEPN1-RM or RYR1-RM, but if infrequent is not a very specific finding. Peripheral aggregation of mitochondria sometimes resembling lobulated fibers may occur in UCMD, although true lobulated fibers are not usually a feature in children with any neuromuscular disorder. The presence of COX negative and/or COX negative SDH positive fibers suggest a mitochondrial cytopathy. Very large mitochondria, in particular towards the periphery of fibers, is indicative of a phosphatidylcholine defect (CHKB) [bib_ref] A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de..., Mitsuhashi [/bib_ref]. The size of mitochondria, degree of glycogen and lipid accumulation can vary for a variety of reasons, including diet and type of feed in nasogastric fed neonates. Electron microscopy is sometimes helpful to interpret the significance of subtle loss of oxidative stains as it can differentiate the myofibrillar abnormalities found in myofibrillar myopathies from the disruption associated with typical core lesions. ## Subtype specific findings- The immunohistochemical examination is of particular importance in the pathological workup of a patient with suspected CMD [bib_ref] From proteins to genes: immunoanalysis in the diagnosis of muscular dystrophies, Barresi [/bib_ref]. There is a basic panel of antibodies that need to be available for comprehensive evaluation of the biopsy (see . In the following section we briefly summarize the general and immunohistochemical findings for the CMD forms in which this analysis can be diagnostic: Laminin α2 related dystrophy (LAMA2-RD): General histology may show a particularly pronounced buildup of fibrosis and fatty replacement, as well as sometimes prominent presence of inflammatory cells, along with evidence for degeneration and regeneration. These findings are present early. On immunostaining typically there will be a complete absence or near absence of laminin α2 immunostaining from all muscle fibers and nerves. In cases of a partial deficiency, there will be a reduction on some muscle fibers while the staining on nerves may appear normal. Partial laminin α2 deficiency can be seen in both primary LAMA2-RD and αDG-RD. If the deficiency is subtle, confirmation with a second laminin α2 antibody to the 300 kDa fragment (or one that behaves similar to it) and review of the clinical presentation to determine consistency with a diagnosis of LAMA2-RD versus αDG-RD are required. Fibers that are deficient in laminin α2 immunostaining will show a compensatory upregulation of laminin α5 immunofluorescence [bib_ref] Expression of laminin subunits in congenital muscular dystrophy, Sewry [/bib_ref] [bib_ref] From proteins to genes: immunoanalysis in the diagnosis of muscular dystrophies, Barresi [/bib_ref]. Upregulated laminin α5 can also be seen on regenerating fibers, thus, those will have to be excluded from this assessment. Laminin α2 immunostaining in skin from a patient with LAMA2-RD will show absence of laminin α2 from the epidermal/dermal junction, the sensory nerves and all other components seen in skin (e.g. sebaceous glands). Intramuscular nerves typically will also be negative for laminin-α2 in LAMA2-RD, while the staining is preserved in αDG-RD. ## Alpha-dystroglycanopathy related dystrophy (αdg-rd): General histology shows dystrophic features with degeneration, necrosis and regeneration and fibrofatty replacement that are most similar to those seen in the dystrophinopathies and the sarcoglycanopathies. In contrast to LAMA2-CMD in neonatal or very early biopsies dystrophic features may be subtle. Immunohistochemical findings on muscle biopsy in the αDG-RD are similar irrespective of the primary gene involved. The degree of deficiency can be variable and does not necessarily correlate with the severity of the clinical phenotype. It is important to utilize an antibody raised against the glycosylated form of α-dystroglycan and not against the core protein. This glycoepitope-sensitive antibody will show absence, near absence, or reduced labeling on most or some of the fibers. In less pronounced cases, there may just be uneven labeling on some fibers, in which case it may be difficult to clearly recognize the findings as a primary deficiency. Western-blot analysis for glycosylated α-dystroglycan may be helpful by showing a reduction as well as a downward shift of the broad band of glycosylated αdystroglycan. Normal labeling of β-dystroglycan on all fibers will help recognize a secondary α-dystroglycan deficiency seen in the dystrophinopathies (DMD, BMD). Commercially available antibodies to glycosylated α-dystroglycan have to be validated carefully by comparing established disease controls with normal samples as they may produce variable results. Laminin α2 reduction (with preservation of laminin β1, γ1) will be seen as a secondary change in primary α-dystroglycan deficiency (αDG-RD). As degeneration and regeneration is seen early on in this group of conditions, several fibers will be positive for developmental and/or neonatal myosin labeled regenerating fibers. ## Collagen vi myopathy (col6-rd): Muscle biopsy findings in the COL6-RD are quite variable and depend on the disease severity and stage. In very young children and very mildly affected patients there may only be minimal myopathic changes or features of fiber type disproportion [bib_ref] Predominant fiber atrophy and fiber type disproportion in early ullrich disease, Schessl [/bib_ref]. Later in the disease, myopathic findings become more pronounced and dystrophic features more apparent. Core-like lesions may also be present [bib_ref] Myopathy with lobulated fibers, cores, and rods caused by a mutation in..., Claeys [/bib_ref]. In cases with recessive null mutations, an overall deficiency or absence of collagen VI immunofluorescence in the muscle will be apparent (including sarcolemma, endomysium, epimysium and perimysium), although some may still be seen around blood vessels. In patients with dominantly acting mutations, collagen VI immunoreactivity will be absent from the sarcolemma/basement membrane specifically, while there may be no discernible deficiency in the interstitial connective tissue of the endomysium, epimysium and perimysium [bib_ref] New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion..., Pan [/bib_ref] [bib_ref] Ullrich disease due to deficiency of collagen VI in the sarcolemma, Ishikawa [/bib_ref]. For proper recognition of this phenomenon in particular in partial deficiencies it is necessary to co-label the sarcolemma/basement membrane with a second basement membrane antibody (i.e. perlecan, collagen type IV) using two color double immunofluorescence technique. While many Bethlem cases also show a recognizable sarcolemmal specific deficiency, in mild cases in particular in the mild Bethlem myopathy range, the collagen VI immunoreactivity in the biopsy may appear normal in amount and localization. Degenerating and regenerating fibers are not a prominent feature early on in biopsies from patients with COL6-RD, however, there may be fibers present that stain for developmental and/or neonatal myosin. A sarcolemmal reduction of laminin β1 may be seen in some adult or adolescent cases of Bethlem myopathy but is not specific to collagen VI disorders. Immunohistochemical examination of skin sections (as opposed to fibroblasts in culture) is only helpful if there is a complete absence of collagen VI immunoreactivity, although more recently the application of techniques such as FACS may allow to appreciate more subtle reduction in collagen VI expression [bib_ref] Flow cytometry analysis: a quantitative method for collagen VI deficiency screening, Kim [/bib_ref]. ## Sepn1-rm and ryr1-rm: The muscle pathology spectrum of SEPN1-RM is broad and includes most but not all cases of Rigid Spine Muscular Dystrophy (RSMD1) [bib_ref] Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive..., Moghadaszadeh [/bib_ref] , classic multi-minicore disease [bib_ref] Mutations of the selenoprotein N gene, which is implicated in rigid spine..., Ferreiro [/bib_ref] , desmin-related myopathy with Mallory body-like inclusions [bib_ref] Desmin-related myopathy with mallory bodylike inclusions is caused by mutations of the..., Ferreiro [/bib_ref] and in a small percentage of congenital fiber type disproportion (CFTD) cases [bib_ref] SEPN1: associated with congenital fiber-type disproportion and insulin resistance, Clarke [/bib_ref]. Most SEPN1-RM muscle biopsies show small focal areas of mitochondria depletion and sarcomere disorganization (minicores) on oxidative stains in muscle fibers, together with type 1 fiber predominance and variable atrophy, protein aggregates and/or endomysial fibrosis. Necrosis and/or regeneration are less frequent but may be present. There currently is no immunohistochemical diagnostic stain for SEPN1-RM yet. In RYR1-RM cases presenting as CMD histological findings are extremely variable [bib_ref] Severe congenital RYR1-associated myopathy: The expanding clinicopathologic and genetic spectrum, Bharucha-Goebel [/bib_ref]. Extreme fiber atrophy, frequent central nucleation, fiber type uniformity, irregular oxidative enzyme stains including core-like areas are all features. Overt degeneration and regeneration is not conspicuous while fatty-fibrous replacement can be prominent. ## Lmna-cmd: The histological appearance of the muscle biopsy is variable, ranging from a myopathic appearing biopsy with mostly type 1 atrophic fibers to more overtly dystrophic findings, mainly reflected as increased fibrosis and less so by overtly necrotic fibers. Findings may be different between sections in a given biopsy and between different muscles. Conspicuous cellular infiltration suggesting inflammation is a feature in some biopsies and may provide rational for anti-inflammatory steroid therapy [bib_ref] Inflammatory changes in infantile-onset LMNAassociated myopathy, Komaki [/bib_ref]. Immunohistochemical examination for LMNA in the biopsy will be normal as there is no appreciable deficiency or mislocalization of lamin A/C even in the presence of a mutation causing severe disease. LMNA-CMD shows no characteristic protein deficiencies by immunohistochemical analysis. ## Muscle imaging (ultrasound and magnetic resonance imaging)-imaging techniques, such as computed tomography or resonance magnetic imaging, and ultrasound [bib_ref] Sensitivity and specificity of qualitative muscle ultrasound in assessment of suspected neuromuscular..., Brockmann [/bib_ref] [bib_ref] Muscle ultrasound in neuromuscular disorders, Pillen [/bib_ref] have assumed increasing importance in the diagnostic approach for patients with muscle disease and show specificity for several genetic entities [bib_ref] Whole body muscle MRI protocol: pattern recognition in early onset NM disorders, Quijano-Roy [/bib_ref] [bib_ref] Muscle magnetic resonance imaging involvement in muscular dystrophies with rigidity of the..., Mercuri [/bib_ref] [bib_ref] Differentiating Emery-Dreifuss muscular dystrophy and collagen VI-related myopathies using a specific CT..., Deconinck [/bib_ref] [bib_ref] Muscle imaging in clinical practice: diagnostic value of muscle magnetic resonance imaging..., Mercuri [/bib_ref]. Within the diagnostic work up of CMDs they have proved to be particularly useful when suspecting a COL6-RD, SEPN1-RM, LMNA-CMD and RYR1-CMD [bib_ref] Whole body muscle MRI protocol: pattern recognition in early onset NM disorders, Quijano-Roy [/bib_ref] [bib_ref] Muscle MRI findings in a three-generation family affected by Bethlem myopathy, Mercuri [/bib_ref] [bib_ref] Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem myopathy, Mercuri [/bib_ref] [bib_ref] Muscle ultrasound in bethlem myopathy, Bonnemann [/bib_ref]. MRI should be regarded as a gold standard technique. Standardized T1 weighted spin echo sequences of the lower limb, particularly of the thigh muscles are probably the most informative and should be favored when time and resources are limited. Whole body MRI has also been successfully used for the purpose of pattern recognition, in particular when lower limbs are not specific enough or if the myopathy has selective involvement in other parts of the body [bib_ref] Whole body muscle MRI protocol: pattern recognition in early onset NM disorders, Quijano-Roy [/bib_ref] [bib_ref] Muscle imaging in congenital myopathies, Quijano-Roy [/bib_ref]. The acquisition of images is generally easy to accomplish in conventional imaging units. However, the identification of a specific pattern of muscle involvement requires a high level of expertise and one should consider sending the images for advice to international centers of CMD expertise. In COL6-CMD [fig_ref] Figure 3: Fig. 3. [/fig_ref] , muscle MRI shows a characteristic pattern with diffuse involvement of fatty infiltration within thigh muscles with relative sparing of sartorius, gracilis, adductor longus. Localization of fatty infiltration typically takes the form of a rim of hypodensity at the periphery of muscles particularly in vasti muscles, with a relative sparing of the central part indicative of endomysial fibrosis tracking along the muscle fascia. In the rectus femoris muscle fatty infiltration occurs along the central fascia specifically with a centrally located abnormal signal denoted as a "central shadow sign" on ultrasound [bib_ref] Muscle MRI findings in a three-generation family affected by Bethlem myopathy, Mercuri [/bib_ref] [bib_ref] Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem myopathy, Mercuri [/bib_ref] [bib_ref] Muscle ultrasound in bethlem myopathy, Bonnemann [/bib_ref]. In SEPN1-RM [fig_ref] Figure 3: Fig. 3. [/fig_ref] , selective involvement of sartorius, semimembranous and great adductor muscles with sparing of the gracilis is very suggestive of the diagnosis [bib_ref] Congenital muscular dystrophy with rigid spine syndrome: a clinical, pathological, radiological, and..., Flanigan [/bib_ref]. This pattern may overlap with RYR1 at the thigh level but using WBMRI, selective axial involvement with striking hypotrophy of neck flexors will allow differential diagnosis [bib_ref] Whole body muscle MRI protocol: pattern recognition in early onset NM disorders, Quijano-Roy [/bib_ref]. A useful imaging based differential diagnosis of rigid spine myopathies is provided by Mercuri et al. [bib_ref] Muscle magnetic resonance imaging involvement in muscular dystrophies with rigidity of the..., Mercuri [/bib_ref]. LMNA-RD in ambulatory patients shows vastus lateralis and gastrocnemius medialis selective initial involvement. In the congenital forms with severe weakness, muscle imaging is informative by regarding the pattern of relatively spared muscles, (cranial, psoas and forearm muscles) [bib_ref] Muscle imaging in congenital myopathies, Quijano-Roy [/bib_ref]. Muscle imaging is less used for diagnostic purposes in the CMD types with central nervous system involvement or increased CK levels (LAMA2-RD and αDG-RD), since diagnosis is usually oriented by other complementary tests (brain MRI, immunohistochemistry). ## Diagnostic algorithm schematics The subtype specific schematics (Supplemental Figs. A-E) aim to guide the diagnostic workup starting from a clinical suspicion of CMD with a prioritization of possible subtype involvement to genetic confirmation of a CMD diagnosis. Although it is advantageous (less invasive) and sometimes possible to go directly to genetic testing for a suspected CMD diagnosis, the algorithms proposed here favor inclusion of a muscle biopsy (provided that it can be expertly done, interpreted and stored). However, given a strong clinical suspicion, difficult access to quality biopsy services and easier access to genetic services, a muscle biopsy can sometimes be skipped. The algorithm can also be used in reverse order -i.e. when a genetic change is found on panel genetic testing the algorithm can be followed backwards to assess whether the gene the mutation was found in is plausible as a cause of the phenotype in the patient. ## Final practical considerations and pitfalls ## Interpretation of molecular genetic results The interpretation of the results of mutation analysis can be quite straightforward if the pathogenicity of the mutations is obvious and the mutations are consistent with the known pattern(s) of inheritance in a given condition. In the following we address three of the more likely scenarios and pitfalls that occur in the genetic confirmation of CMD. "Missing" second allele-Lack of detection of a second allele using current methods may occur in particular in LAMA2-RD, with upwards of 25% of LAMA2-RD patients having a gene rearrangement (deletion/duplication of one or more exons) not identified on standard Sanger sequencing [bib_ref] Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2..., Geranmayeh [/bib_ref]. Access to quantitative allele assessment (including MLPA and comparative genomic array technology) will be important to appropriately detect this type of mutation in order to complete the genetic workup. Similar types of genomic mutations may be found in COL6-RD, however given the multiple inheritance patterns of COL6-RD one must carefully evaluate a single variant found on one allele for its potential to act dominantly before suspecting a missing allele. Also, in both LAMA2-RD and COL6-RD cases with only a single allele identified, there should be clear diagnostic evidence for the presence of the disease (such as unequivocal deficiency of immunostaining for laminin α2 or collagen VI in the muscle biopsy) before suspecting a missing allele. It is also important to confirm apparent homozygous mutations by parental analysis. If only one of the parents carries the mutation it is possible that the patient is in fact hemizygous for the initially detected mutation because of the presence of a larger deletion on the other allele. Other important possibilities for a "missing" second allele are mutations in regulatory regions of the gene as well as deep intronic mutations that could influence splicing but elude mutation analysis based on exonic sequencing alone. In such situations research laboratory based analysis of cDNA from muscle or from dermal fibroblast cultures (for COL6-RD, αDG-RD, SEPN1-RM and LMNA-CMD analysis) can be helpful to detect additional deep intronic mutations that may affect splicing of exons. In SEPN1 it is important to not forget to include the SECIS sequence located in the 3'UTR [bib_ref] A single homozygous point mutation in a 3' untranslated region motif of..., Allamand [/bib_ref]. Recognizing dominantly acting mutations-Autosomal dominant mutations are required to be co-inherited with the phenotype in families with a positive family history, or confirmed as dominant "sporadic" and de novo confirmed by parental testing. The possibility of somatic and germline mosaicisim in dominant de novo mutations should always be considered and has been reported in LMNA-CMD and COL6-RM, with obvious implications on genetic counseling. All hitherto recognized LMNA-CMD mutations are dominantly acting. In COL6-RD, mutations acting in a dominant fashion are common in Ullrich, intermediate and Bethlem phenotypes, but recessive mutations can also cause all three phenotypes. For accurate genetic counseling and disease recurrence risk for family planning it is thus essential to decide whether a single detected mutation would be expected to act in a dominant manner, or whether only one of two recessive mutations has been detected (missing allele). Clearly dominantly acting mutations have been identified as such with solid supporting evidence and are usually annotated in genetic reports. Genomic deletions and deep intronic mutations may also lead to dominantly acting exon skipping (see earlier discussion for COL6-RD). Missense mutations elsewhere in the collagen VI genes that have not been previously convincingly reported as pathogenic are much harder to interpret and one cannot automatically assume the mechanism of its action and counsel for recurrence risk. ## Unclear pathogenicity of identified sequence changes (variant of unknown Significance, VOUS)-To reduce the chance of having to deal with sequence changes of unclear significance it is best to focus the sequence analysis on the gene(s) that is most likely to be responsible for the disease phenotype in the patient, using clinical and paraclinical analysis outlined above. Undirected shot-gun approaches to genetic testing, as in parallel sequencing array platforms and whole exome or genome sequencing will result in a number of VOUS potentially confusing genetic confirmation for the individual patient. Testing parents for the variant is important to establish whether the change follows the pattern of inheritance predicted for a mutation in the suspected CMD subtype, including de novo occurrence in the patient or co-inheritance with the disease from an affected parent for forms with a possible dominant mechanism (COL6-RD, LMNA-CMD). Finding a single variant initially detected in both a sporadic patient and in unaffected family members suggests a benign sequence variant under consideration of a dominant mechanism, or, under consideration of a recessive mechanism, that the required other allele has not been detected. Literature review to identify additional publications describing the variant in question and in silico analysis should be performed by the testing laboratory to determine the presumed variant's effect based upon the secondary protein structure and degree of evolutionary conservation of the affected amino acid. An innocent appearing missense mutation or even a synonymous change (a mutation that does not change an amino acid) could still be pathogenic by interfering with an exonic splice enhancer, thereby leading to exon skipping. In silico analysis can also be performed for this type of change but is imperfect at such predictions. However, cDNA analysis in muscle or in fibroblast culture may provide a direct answer by confirming the presence or absence of an abnormal splicing event. Helpful ancillary investigations may include additional stainings on the muscle biopsy, and dermal fibroblast analysis to assess collagen VI matrix formation in the case of COL6-RD. For the αDG-RDs, fibroblasts or lymphoblasts [bib_ref] Protein O-mannosyltransferase activities in lymphoblasts from patients with alpha-dystroglycanopathies, Manya [/bib_ref] can be used for direct assays of enzymatic activity for POMT1, POMT2 and POMTGnT1. It is also possible to assess fibroblast αDG glycosylation and perform complementation assays directed at pinpointing the defective gene in selected situations [bib_ref] ISPD loss-of-function mutations disrupt dystroglycan Omannosylation and cause Walker-Warburg syndrome, Willer [/bib_ref] [bib_ref] Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan, Stevens [/bib_ref]. It is equally important to keep track of patients with convincing clinical and paraclinical phenotypes but without genetic confirmation (i.e. mutation analysis was performed but was negative or inconclusive) as new genes can be expected to be discovered in the future, eventually allowing for a diagnosis in such patients. Massive parallel sequencing of groups of disease genes and whole exome sequencing as the primary diagnostic tool-Next generation based sequencing will be increasingly available in the diagnosis of the CMDs [bib_ref] Assessment of target enrichment platforms using massively parallel sequencing for the mutation..., Valencia [/bib_ref]. This can take the form of targeted massively parallel re-sequencing of groups of disease implicated genes, or be based of whole exome sequencing. These technologies can be very beneficial in that they can lead efficiently and directly to the genetic diagnosis, provided the mutation found are clear and unequivocal. Even in those situations it is mandatory to compare the sequencing results with the ascertained clinical and morphological phenotype as outlined here to make sure the genetic and clinical results are congruent. A more challenging situation arises if potentially pathogenic variants are detected in more than one relevant disease gene, a relatively common occurrence. In these scenarios it will be very helpful to carefully follow the algorithms outlined here to arrive at the most likely genetic diagnosis from a clinical point of view. With clinical direction it will be considerably easier to weigh the changes found on next generation sequencing. Finally, if the clinical analysis strongly suggests a specific diagnosis that is not reflected in the results obtained from next generation sequencing it is important to interrogate the genetic platform used for types of mutation that could have been missed because of poor coverage of certain exons, insensitivity to larger deletions and genomic rearrangements and lack of detection of deep intronic changes. A careful clinically informed approach to the diagnosis of the CMDs thus will not become obsolete but only gain in importance in conjunction with the application of next generation genetic technology. # Supplementary material Refer to Web version on PubMed Central for supplementary material. A-D: Differential diagnostic considerations for various clinical findings in infancy (A) and beyond infancy (B and C), as well as for various laboratory findings that may be available at the outset of the diagnostic encounter (D). Note: The most important tools in the clinical differential diagnosis are: EMG/NCV to diagnose neurogenic involvement, muscle biopsy, and selective biochemical and genetic testing. The differential diagnostic considerations are not exhaustive but highlight a few of the more relevant conditions to consider with a given clinical picture. To save space we are only using the gene/protein symbols to indicate specific diagnosis. A and B: T2-weighted brain MR images in LAMA2-CMD. Note extensive signal abnormalities of the cerebral white matter while the corpus callosum and the internal capsule are spared (arrows). C: Tl weighted brain MRI in αDG-RD (POMT2).Note thinning of the corpus callosum, the relatively flat pons (arrow) and atrophic and dysplastic cerebellar vermis (arrow head). D and E: T2-weighted MR images in αDG-RD. Note thin corpus callosum, extremely small pons, relatively thick tectum (arrow head), and small and dysplastic cerebellar vermis on the sagittal cut (D). Frontal polymicrogyria (arrow) and abnormal white matter signal is evident on the axial cut (E). F: Tl-weighted MR images in αDG-RD. Note abnormal configuration of the pons and corticospinal tracts and dysplastic cerebellum with cerebellar cysts (arrow) and small vermis (arrow head)). G: Tl-TSE weighted thigh MR images in a COL6-RD, a patient with typical phenotypic UCMD presentation. Note in particular the striated aspect of vastus lateralis caused by outer rim of increased signal (arrow) and increased signal around the central fascia of the rectus femoris (arrow head) (courtesy of Dr. R Carlier). H: Tl-TSE weighted thigh MR images in SEPN1-RM. Note selective involvement of sartorius (arrow), biceps femoris and adductor magnus and sparing of the gracilis (arrow head). Brief CMD classification overview (underlined: abbreviated nomenclature used in this paper). ## Subtype and alternate nomenclatures associated genes ## Associated phenotypic spectrum Collagen VI related dystrophies [fig] Figure 2: A: Hand of a patient with COL6-RD. Note the significant hyperlaxity even in the most distal interphalangeal joints. B: Foot of an infant with COL6-RD. Note the ability to dorsiflex the foot back to the shin, the soft palmar skin, the pes planus (loss of arch) and the prominent calcaneus. C: Patient with COL6-RD. Note flexible fingers and round face with facial erythema. He also has contractures in the elbows and knees. D: Patient with LMNA-CMD. Note the dropped head, hyperlordosis and adducted foot indicative of peroneal weakness, and overall thinness. E: Patient with SEPN1-RM, note atrophy of inner thigh muscles and lateral deviation of spine (status after surgical rod placement). F: Twins with LAMA2-CMD. Note hypotonic posture with splayed legs ("frog leg" posture), weak arms, flexed fingers and foot contractures. G: Patient with LAMA2-CMD. Note facial weakness and foot contracture. She has no antigravity strength in the upper extremity. H: Patient with αDG-RD (POMT1). Note weak sitting posture, hypotonic lower face with open mouth characteristic of congenital myopathic disorders. I: Same patient with αDG-RD (POMT1) at an older age, note calf and quadriceps hypertrophy and mild forearm hypertrophy. [/fig] [fig] Figure 3: Fig. 3. [/fig] [fig] ▪▪: Ullrich congenital muscular dystrophy (UCMD) -severe nonambulant and transient ambulant ▪ Intermediate phenotype ▪ Bethlem myopathy (BM, milder disease course) Non-ambulant typically correlates with absent laminin α2 staining on muscle biopsy and ambulant with partial deficiency (with exeptions) αDystroglycan related dystrophy (αDG-RD, also alpha dystroglycanopathy, αDGpathy) FKRP, FKTN, POMT1, POMT2, POMGnT1, LARGE, ISPD, GTDC2, DAG1, TMEM5, B3GALNT2, B3GNT1, GMPPB, SGK196 (DPM1, DPM2, DPM3, DOLK) ▪ Walker-Warburg syndrome ▪ Muscle-eye-brain disease; Fukuyama CMD; Fukuyama-like CMD ▪ CMD with cerebellar involvement; cerebellar abnormalities may include cysts, hypoplasia, and dysplasia ▪ CMD with mental retardation and a structurally normal brain on imaging; this category includes patients with isolated microcephaly or minor white matter changes evident on MRI ▪ CMD with no mental retardation; no evidence of abnormal cognitive development ▪ Limb-girdle muscular dystrophy (LGMD) with mental retardation (milder weakness, maybe later onset) and a structurally normal brain on imaging ▪ LGMD without mental retardation (milder weakness, maybe later onset) SEPN1 related myopathy (SEPN1-RM, also rigid spine CMD, RSMD1) SEPN1 ▪ Consistent rigid spine early respiratory failure phenotype ▪ despite variable histological presentations as multiminicore disease, desmin positive Mallory body inclusions, congenital fiber-type disproportion, mild CMD, or nonspecific myopathy RYR1 related myopathy (RYR1-RM, includes RYR1-CMD) RYR1 ▪ RYR1 related myopathies (RYR1-RM) include central core, multi-mini-core, centronuclear and nonspecific pathologies. which can assume CMD like characteristics ▪ Clinically significant for early scoliosis and absent or limited ambulation LMNA related dystrophy (LMNA-RD, includes LMNA-CMD, L-CMD, and Emery Dreifuss) LMNA ▪ CMD presentation: Dropped head syndrome, axial and scapuloperoneal involvement, absent or early loss of ambulation ▪ Milder presentations fuse with early-onset Emery-Dreifuss muscular dystrophy CMD without genetic diagnosis ▪ Congenital onset weakness with CMD compatible histology and variable clinical features, without confirmed genetic diagnosis, despite testing for currently known genes [/fig] [table] Table 2: Summary of currently recognized Congenital Muscular Dystrophies. [/table]	None	None	None
a6d6c420f43fce95dd44dca5886301ecd515a3a9	pubmed	Guideline for diagnosis and treatment of subacromial pain syndrome	Guideline for diagnosis and treatment of subacromial pain syndrome Treatment of "subacromial impingement syndrome" of the shoulder has changed drastically in the past decade. The anatomical explanation as "impingement" of the rotator cuff is not sufficient to cover the pathology. "Subacromial pain syndrome", SAPS, describes the condition better. A working group formed from a number of Dutch specialist societies, joined by the Dutch Orthopedic Association, has produced a guideline based on the available scientific evidence. This resulted in a new outlook for the treatment of subacromial pain syndrome. The important conclusions and advice from this work are as follows:(1) The diagnosis SAPS can only be made using a combination of clinical tests. (2) SAPS should preferably be treated non-operatively.(3) Acute pain should be treated with analgetics if necessary. (4) Subacromial injection with corticosteroids is indicated for persistent or recurrent symptoms. (5) Diagnostic imaging is useful after 6 weeks of symptoms. Ultrasound examination is the recommended imaging, to exclude a rotator cuff rupture. (6) Occupational interventions are useful when complaints persist for longer than 6 weeks. (7) Exercise therapy should be specific and should be of low intensity and high frequency, combining eccentric training, attention to relaxation and posture, and treatment of myofascial trigger points (including stretching of the muscles) may be considered. (8) Strict immobilization and mobilization techniques are not recommended. (9) Tendinosis calcarea can be treated by shockwave (ESWT) or needling under ultrasound guidance (barbotage). (10) Rehabilitation in a specialized unit can be considered in chronic, treatment resistant SAPS, with pain perpetuating behavior. (11) There is no convincing evidence that surgical treatment for SAPS is more effective than conservature management. (12) There is no indication for the surgical treatment of asymptomatic rotator cuff tears.  Shoulder problems are common. Between 7% and 34% of adults have shoulder pain at times(Reilingh et al. 2008). Treatment of "subacromial impingement syndrome" of the shoulder has changed drastically in the past decade. The anatomical explanation as "impingement" of the rotator cuff is not sufficient to cover the pathology. "Subacromial pain syndrome", SAPS, describes the condition better. A working group formed from a number of Dutch specialist societies, joined by the Dutch Orthopedic Association, has produced a guideline based on the available scientific evidence. This resulted in a new outlook for the treatment of subacromial pain syndrome. The important conclusions and advice from this work are as follows: (1) The diagnosis SAPS can only be made using a combination of clinical tests. (2) SAPS should preferably be treated non-operatively. (3) Acute pain should be treated with analgetics if necessary. (4) Subacromial injection with corticosteroids is indicated for persistent or recurrent symptoms. (5) Diagnostic imaging is useful after 6 weeks of symptoms. Ultrasound examination is the recommended imaging, to exclude a rotator cuff rupture. (6) Occupational interventions are useful when complaints persist for longer than 6 weeks. (7) Exercise therapy should be specific and should be of low intensity and high frequency, combining eccentric training, attention to relaxation and posture, and treatment of myofascial trigger points (including stretching of the muscles) may be considered. (8) Strict immobilization and mobilization techniques are not recommended. (9) Tendinosis calcarea can be treated by shockwave (ESWT) or needling under ultrasound guidance (barbotage). (10) Rehabilitation in a specialized unit can be considered in chronic, treatment resistant SAPS, with pain perpetuating behavior. (11) There is no convincing evidence that surgical treatment for SAPS is more effective than conservature management. (12) There is no indication for the surgical treatment of asymptomatic rotator cuff tears.  Shoulder problems are common. Between 7% and 34% of adults have shoulder pain at times [bib_ref] Course and prognosis of shoulder symptoms in general practice, Reilingh [/bib_ref]. The incidence of shoulder pain in primary care in the Netherlands is estimated to be 19 per 1,000 person-years-highest in women over 45 years and lower in young adults [bib_ref] prevalence, and consultation rates of shoulder complaints in general practice, Greving [/bib_ref]. In the Netherlands, the orthopedic diagnosis of "supraspinatus tendinitis" is made 50,000-60,000 times a year (source Prismant). The course, independent of the chosen therapy, appears to be unfavorable in terms of resumption of previous work, and after 1 year, a third of the patients still have some kind of restriction and/or pain [bib_ref] Course and prognosis of shoulder symptoms in general practice, Reilingh [/bib_ref] [bib_ref] prevalence, and consultation rates of shoulder complaints in general practice, Greving [/bib_ref].developed the concept of "impingement syndrome". This can be caused or aggravated by contact between the acromion and the rotator cuff while lifting the arm. However, this hypothesis cannot be substantiated with improved imaging and arthroscopic techniques. More value is placed nowadays on the role of degeneration of the rotator cuff tendons, eventually giving rise to the development of tears [bib_ref] Published evidence relevant to the diagnosis of impingement syndrome of the shoulder, Papadonikolakis [/bib_ref]. A direct relationship between the anatomical substrate, functional load and pain is not always explicitly present. Naming this condition "subacromial pain syndrome", abbreviated to SAPS, describes the condition better. SAPS is defined as all non-traumatic, usually unilateral, shoulder problems that cause pain, localized around the acromion, often worsening during or subsequent to lifting of the arm. The different clinical and/or radiological names, such as bursitis, tendinosis calcarea, supraspinatus tendinopathy, partial tear of the rotator cuff, biceps tendinitis, or tendon cuff degeneration are all part of SAPS. As patients come into contact with various healthcare providers, it was deemed necessary-following the Dutch General practitioners guideline for shoulder complaints, and to supplement the Dutch Physical Therapists Guideline for aspecific complaints of arm, neck and shoulder (KNGF 2012) and the KNGF Evidence Statement for subacromial shoulder pain [bib_ref] KNGF evidence statement subacromiale klachten, Jansen [/bib_ref] -to create a guideline for the treatment of SAPS. # Methods ## Literature search The group conducted an exploratory search for existing international guidelines in Medline (OVID), the databases of the Guidelines International Network (GIN), the Quality Dome and Artsennet, and systematic reviews in Medline (OVID) and the Cochrane Library. Next, for each clinical question based on specific search terms, a search was conducted for published scientific studies in electronic databases. The searches were limited to literature in English, Dutch, French, and German. Additional studies were searched for on the basis of the reference lists of the articles selected. Search filters were used based on the filters used by the Scottish Intercollegiate Guideline Network (SIGN) to identify possible systematic reviews and randomized clinical trials. ## Grading of study quality The working group members selected articles based on criteria established in advance [fig_ref] Table 1: GRADE evidence levels of intervention studies [/fig_ref]. From these data, the level of the recommendations was defined [fig_ref] Table 3: Level-of-evidence strength of the conclusion, based on the literature underlying the conclusion... [/fig_ref]. In general, the studies showed great heterogeneity in study populations, factors examined, duration of follow-up, and outcome measures. There were also confounders due to the definition Observational studies with large effects and without severe limitations. Low RCTs with extremely severe limitations. Observational studies without severe limitations. Very low RCTs with extremely severe limitations and inconsistent results. Observational studies with severe limitations. Non-systematic clinical observations (e.g. case series and case reports). of shoulder complaints, as the difference between subacromial complaints and general pain in the shoulder and/or neck was not always clear. The working group formulated recommendations on each of the questions following the highest level of evidence. When a scientific basis was not possible, consensus of the working group was obtained on the recommendation. # Results ## Clinical question 1: what is known about the prognosis of saps? Scientific evidence level 1: There is an association between a longer duration of shoulder pain (> 3 months) and poorer outcome [bib_ref] Systematic review of prognostic cohort studies on shoulder disorders, Kuijpers [/bib_ref] [bib_ref] Predictors of outcome in neck and shoulder symptoms: A cohort study in..., Bot [/bib_ref] [bib_ref] Two pragmatic trials of treatment for shoulder disorders in primary care: Generalisability,..., Thomas [/bib_ref] [bib_ref] Course and prognosis of shoulder symptoms in general practice, Reilingh [/bib_ref]. There is an association between being middle-aged (45-54 years) and worse outcome [bib_ref] Systematic review of prognostic cohort studies on shoulder disorders, Kuijpers [/bib_ref]. Level 2: Psychosocial factors appear to have a greater association with the course and prognosis of chronic shoulder pain (> 3 months) than with that of shorter-term shoulder pain (< 6 weeks) [bib_ref] Course and prognosis of shoulder symptoms in general practice, Reilingh [/bib_ref]. Level 3: There are indications that a worse outcome is associated with a worse score at the start, longer duration of symptoms, and type II or III acromion morphology [bib_ref] Outcome predictors in nonoperative management of newly diagnosed subacromial impingement syndrome: A..., Taheriazam [/bib_ref]. ## Considerations There is consistent evidence that a longer duration of symptoms (> 3 months) is a poor prognostic factor. There is evidence that psychosocial factors play a role in chronic complaints. ## Recommendation The working group recommends being aware of the effect of symptom duration on prognosis (> 3 months) and distinguishing between acute symptoms and chronic symptoms when deciding on interventions for SAPS. ## Clinical question 2: what measures are effective in preventing saps? Scientific evidence level 1: There are associations between the occurrence of SAPS and (1) repetitive movements of the shoulder or hand/wrist during work, (2) work that requires much or prolonged strength of the upper arms, (3) hand-arm vibration (high vibration and/or prolonged exposure) at work, (4) working with a poor ergonomic shoulder posture, and (5) a high psychosocial workload. Psychosocial factors associated with prolonged shoulder complaints are high psychological demands, low control, low social support, low job satisfaction, and high pressure to perform (van Rijn et al. 2010). Level 2: There is evidence that regular sporting activities (> 3 h per week for at least 10 months a year) have a preventive effect on the risk of neck and shoulder complaints and (long-term) illness [bib_ref] The effect of physical activity in leisure time on neck and upper..., Van Den Heuvel [/bib_ref]. ## Considerations There were fewer modifiable factors found in studies on psychosocial risks than in studies on physical factors. In one study [bib_ref] Current concepts for shoulder training in the overhead athlete, Kennedy [/bib_ref] , influencing the entire kinematic chain is mentioned as the starting point for prevention and treatment of sports-related shoulder pain. However, there have been no studies on the effects of these interventions. ## Recommendations The working group recommends early intervention to modify repetitive movements of the shoulder or hand/wrist during work, work that demands much or prolonged power of the upper arms, hand-arm vibration (high vibration and/or prolonged exposure) during work, and work in a non-ergonomic shoulder position. An approach based on the "biopsychosocial model", focusing on early return to work, has the best chance of success [bib_ref] Shoulder pain at the workplace, Shanahan [/bib_ref]. [bib_ref] Physical examination tests of the shoulder: A systematic review with meta-analysis of..., Hegedus [/bib_ref] [bib_ref] Most clinical tests cannot accurately diagnose rotator cuff pathology: A systematic review, Hughes [/bib_ref]. The inter-rater reliability of the most common tests varies greatly. Inter-rater reliability of active abduction and abduction trajectory pain is moderate [bib_ref] Reliability of physical examination tests used in the assessment of patients with..., May [/bib_ref]. Level 2: The combination of a number of tests increases the post-test probability of the diagnosis of SAPS. [bib_ref] Diagnosis of rotator cuff tears, Murrell [/bib_ref] [bib_ref] Diagnostic accuracy of clinical tests for the different degrees of subacromial impingement..., Park [/bib_ref] [bib_ref] Reliability and diagnostic accuracy of 5 physical examination tests and combination of..., Michener [/bib_ref]. ## Considerations As one physical sign cannot sufficiently differentiate between the various shoulder disorders, or give a clear distinction regarding the status of the rotator cuff, a combination of multiple tests increases post-test probability of a diagnosis of SAPS. ## Recommendations To determine SAPS, a combination of the Hawkins-Kennedy test, the painful arc test, and the infraspinatus muscle strength test should be used; and for a rotator cuff tear, the drop-arm test and the infraspinatus and supraspinatus muscle strength tests should be used. ## Clinical question 4: what is the added value of imaging tests for diagnosis of saps? Scientific evidence level 1: The sensitivity and specificity of ultrasound and conventional MRI are not significantly different in the detection of partial-or full-thickness rotator cuff tears [bib_ref] The effectiveness of diagnostic tests for the assessment of shoulder pain due..., Dinnes [/bib_ref]. MR arthrography is an accurate method to rule out partial rotator cuff injuries [bib_ref] Accuracy of MRI, MR arthrography, and ultrasound in the diagnosis of rotator..., De Jesus [/bib_ref]. Level 2: It is likely that ultrasound is an accurate method for the detection or exclusion of rotator cuff tendinopathy, subacromial bursitis, biceps tendon rupture, and tendinosis calcarea . The interobserver variability of ultrasound with respect to detection of rotator cuff injuries is low, as the results are very similar [bib_ref] Ultrasound detection of rotator cuff tears: Observer agreement related to increasing experience, Rutten [/bib_ref] [bib_ref] Detection and quantification of rotator cuff tears with ultrasonography and magnetic resonance..., Sipola [/bib_ref]. Level 3: There is evidence that ultrasound is not sufficiently reliable to differentiate between an intact rotator cuff and partial lesions [bib_ref] Detection and quantification of rotator cuff tears with ultrasonography and magnetic resonance..., Sipola [/bib_ref]. ## Considerations Ultrasound of the shoulder is a sensitive and specific method. The diagnostic accuracy is good and comparable to that of conventional MRI for identification and quantification of complete (full-thickness) rotator cuff injuries. There are conflicting results about the value of ultrasonography in partial rotator cuff tears and tendinopathies. For optimal sonographic analysis of the shoulder, standardized examination and expertise as well as high-quality equipment (7.5-to 20-MHz linear trans-ducers) should be available. When repair of a rotator cuff tear is intended, MRI provides useful information on size, retraction, and matching atrophy and fatty infiltration. For the detection of partial articular side cuff injuries (PASTA lesions), MR arthrography may be considered because of its high sensitivity and specificity. It is preferable to perform a series in abduction/ external rotation position (ABER). Although a correlation has been described between the shape of the acromion (type III, angled) and the presence of rotator cuff injuries [bib_ref] Acromial structure and tears of the rotator cuff, Toivonen [/bib_ref] , this association is not significant in patients over 50 [bib_ref] The relative importance of acromial morphology and age with respect to rotator..., Gill [/bib_ref]. ## Recommendations Ultrasound is advised as the most valuable and cost-effective diagnostic imaging if a first period of non-operative treatment fails. This can be combined with conventional radiography of the shoulder to determine osteoarthritis, osseous abnormalities, and presence/absence of calcium deposits. MRI of the shoulder is indicated when reliable ultrasound is not at hand or inconclusive, and should be used in patients who are eligible for surgical repair of a cuff tear to assess the degree of retraction and atrophied fatty infiltration. An MRI study with intra-articular contrast can be considered if any intra-articular abnormality or a partial rotator cuff injury have to be ruled out. It is preferable for a study in abduction and external rotation (ABER) to be part of an MR arthrography protocol. ## Clinical question 5: which instruments are most suitable for measuring the outcome of treatment of saps? Scientific evidence level 2: Measurements of ROM using instruments (in goniometry and inclinometry) are more reliable than those based on visual assessment [bib_ref] Inter-rater reliability for measurement of passive physiological range of motion of upper..., Van De Pol [/bib_ref]. The Dutch Shoulder Disability Questionnaire seems to be responsive (van der [bib_ref] The responsiveness of the shoulder disability questionnaire, Van Der Windt [/bib_ref] [bib_ref] Shoulder disability questionnaire design and responsiveness of a functional status measure, Van Der Heijden [/bib_ref]. Levels 2/3: The internal consistency and test-retest reliability of the Dutch Simple Shoulder Test seem high and the construct validity moderate to good (van Kampen et al. 2012 ). Level 3: There is insufficient inter-rater reliability of visual estimation of ROM [bib_ref] Rating the methodological quality in systematic reviews of studies on measurement properties:..., Terwee [/bib_ref]. There are indications that the inter-rater reliability of ROM measured using a digital inclinometer for individual patients is poor, with differences in ROM of less than 20-25 degrees being indistinguishable from measurement error [bib_ref] Inter-observer reproducibility of measurements of range of motion in patients with shoulder..., De Winter [/bib_ref]. The DASH-DLV has excellent internal consistency, reasonable test-retest reliability, and reasonable criterion validity . The English Oxford Shoulder Score has a high test-retest reliability, high internal consistency, and a weak-to-moderate criterion validity [bib_ref] Validation of the dutch version of the oxford shoulder score, Berendes [/bib_ref]. The Dutch Shoulder Rating Questionnaire has high internal consistency, high testretest reliability, moderate-to-good criterion validity, and is an appropriate instrument to demonstrate clinical differences [bib_ref] Translation, adaptation and validation of the shoulder rating questionnaire (SRQ) into the..., Vermeulen [/bib_ref]. Level 4: It is possible that isokinetic muscle strength measurements using a dynamometer have good reliability at group level and poor reliability at individual level . ## Considerations Visual assessment of the ROM is appropriate only for distinguishing between the affected and the contralateral side. Even when using a goniometer, which can increase the reliability of the measurements, the measurement error remains high. In selecting an outcome instrument, it is important for the instrument to have been validated in the Dutch language. The Simple Shoulder Test and the Oxford Shoulder Score are instruments with relatively few questions and are easy to use. The Dutch Shoulder Disability Questionnaire with 16 questions is a medium-length questionnaire and is also easy to use. The Shoulder Rating Questionnaire is more detailed, has a more complex calculation of the sum score, and for certain items it misses answers quite often. ## Recommendations Visual estimates of the range of motion can only serve to distinguish between the affected and the contralateral shoulder. Instruments to assess the effects of treatment of SAPS, validated in the Dutch language, are: Disabilities of the Arm, Shoulder and Hand (DASH), English Oxford Shoulder Score (DOSS), Dutch Simple Shoulder Test (DSST), and Shoulder Disability Questionnaire (SDQ-NL). ## Clinical question 6: which non-operative treatment is most effective for patients with saps? - corticosteroid injections Scientific evidence level 1: In the first 8 weeks, corticosteroid injections are more effective than placebo injections, physiotherapy, or no treatment in reducing pain and improving shoulder function. Corticosteroid injections in the short term are no more effective than NSAIDs in reducing pain. The effect of corticosteroids in the long term (≥ 3 months) is unclear [bib_ref] Corticosteroid injections for shoulder pain, Buchbinder [/bib_ref] [bib_ref] Corticosteroid injections for painful shoulder: A meta-analysis, Arroll [/bib_ref] [bib_ref] Efficacy and safety of steroid injections for shoulder and elbow tendonitis: A..., Gaujoux-Viala [/bib_ref]. ## - extracorporeal shockwave therapy (eswt) Level 1: High-energy extracorporeal shockwave therapy (ESWT) is more effective than low-energy ESWT or placebo in reducing pain and improving shoulder function in patients with tendinosis calcarea. ESWT (all forms) is no more effective than placebo or other treatments in reducing pain or in improving shoulder function of patients without calcium deposition in the tendons ). ## - exercise therapy Levels 1-2: Exercise therapy is more effective than no treatment in reducing pain and improving function of the shoulder [bib_ref] Role of physiotherapy in the treatment of subacromial impingement syndrome: A prospective..., Dickens [/bib_ref]. There appears to be no difference in effectiveness between exercise therapy and home exercises [bib_ref] Self-training versus conventional physiotherapy in subacromial impingement syndrome, Werner [/bib_ref] [bib_ref] The subacromial impingement syndrome of the shoulder treated by conventional physiotherapy, self-training,..., Walther [/bib_ref]. Exercises specifically focused on rotator cuff and scapular stabilizers appear to be more effective than general exercise therapy [bib_ref] Effect of specific exercise strategy on need for surgery in patients with..., Holmgren [/bib_ref]. Manual joint mobilizations have no added benefit to a program of active exercises in reducing pain and improving shoulder function [bib_ref] The effect of therapeutic exercise and mobilization on patients with shoulder dysfuction:..., Brudvig [/bib_ref]. Level 2: Massage (myofascial trigger points in the shoulder muscles, or soft tissue) appears to be more effective than placebo or no treatment in reducing pain and improving shoulder function in patients with shoulder pain [bib_ref] Chronic shoulder pain of myofascial origin: A randomized clinical trial using ischemic..., Hains [/bib_ref] [bib_ref] Treatment of myofascial trigger points in patients with chronic shoulder pain: A..., Bron [/bib_ref] [bib_ref] Effects and predictors of shoulder muscle massage for patients with posterior shoulder..., Yang [/bib_ref] ## ) - other interventions Level 3: Oral NSAIDs appear to be more effective than placebo in reducing pain in the first 1-2 weeks [bib_ref] Treatment of acute shoulder syndrome with flurbiprofen, Mena [/bib_ref] [bib_ref] Celecoxib effectively treats patients with acute shoulder tendinitis/bursitis, Petri [/bib_ref]. Laser treatment (of all types) appears to be more effective than placebo or ultrasound treatment in reducing pain after 2-4 weeks [bib_ref] Low power laser therapy of shoulder tendonitis, England [/bib_ref] [bib_ref] Laser therapy in the treatment of some bone and joint pathology, Taverna [/bib_ref] [bib_ref] The efficacy of low level laser therapy in supraspinatus tendinitis, Saunders [/bib_ref] [bib_ref] A doubleblind study of the effectiveness of low level laser treatment of..., Vecchio [/bib_ref] [bib_ref] Short-term effects of high-intensity laser therapy versus ultrasound therapy in the treatment..., Santamato [/bib_ref]. Ultrasound treatment is no more effective than placebo, no treatment, physiotherapy, or exercise therapy [bib_ref] Ultrasound therapy for calcific tendinitis of the shoulder, Ebenbichler [/bib_ref] [bib_ref] Treatment of myofascial trigger-points with ultrasound combined with massage and exercise--a randomised..., Gam [/bib_ref] [bib_ref] Adding ultrasound in the management of soft tissue disorders of the shoulder:..., Gursel [/bib_ref] [bib_ref] Pulsed ultrasound treatment of the painful shoulder a randomized, double-blind, placebo-controlled study, Nykanen [/bib_ref]. Electrical stimulation has not been shown to be more effective than placebo [bib_ref] Pulsed electromagnetic field therapy of persistent rotator cuff tendinitis. A double-blind controlled..., Binder [/bib_ref] [bib_ref] Trattamento della periartrite calcarea di spalla con campi magnetici pulsanti: Studio controllato, Dal Conte [/bib_ref] [bib_ref] Therapeutic effect of pulsed electromagnetic field in conservative treatment of subacromial impingement..., Aktas [/bib_ref]. Acupuncture treatment appears to be no more effective than placebo and exercise therapy [bib_ref] Acupuncture for shoulder pain, Green [/bib_ref]. ## Considerations Much research has been done on the effect of non-operative therapies for various subacromial and shoulder pain syndromes. There is a great diversity of interventions and methods, and many studies use the terms shoulder pain and SAPS interchangeably. Also, any co-interventions and complications often remain unnamed. There is no literature on the effectiveness of behavioral counseling, but it is unlikely that therapy is given without behavioral counseling. The effectiveness of such advice (ranging from absolute rest to passive mobilization beyond the pain threshold) is unclear. ## Recommendations A non-operative treatment algorithm for SAPS starts with a recommendation of relative rest in the acute phase, if necessary combined with a prescription of NSAIDs for 1 or 2 weeks. This should be followed by gradually expanding activities. Corticosteroid injections may be used for severe pain, if possible under ultrasound guidance, in the first 8 weeks. The use of corticosteroid injections as single long-term therapy is not recommended. Use of high-energy ESWT can be considered for proven subacromial calcium deposits. ESWT is not recommended in the acute phase. Movement within the pain threshold is desirable. Neither strict immobilization nor passive joint mobilization in SAPS is recommended. Exercise should preferably be performed at low intensity and high frequency, within the pain threshold, and focusing on eccentric training. Scapular stabilization training and relaxation with proper posture should be part of the regime. Treatment of myofascial trigger points (including stretching of the muscles) may be considered. Rehabilitation can be considered for chronic, treatment-resistant SAPS, where pain-perpetuating behavior plays a role. ## Clinical question 7: when is surgical treatment for saps indicated, and which technique is preferred? - Interventions with an intact rotator cuff Scientific evidence level 2: It has not been shown that surgical treatment of SAPS is more effective than non-operative management to improve shoulder function or reduce pain [bib_ref] Surgery for rotator cuff disease, Coghlan [/bib_ref] [bib_ref] Conservative or surgical treatment for subacromial impingement syndrome? A systematic review, Dorrestijn [/bib_ref]. No difference in outcome (shoulder function, complications) has been shown between an arthroscopic approach and an open approach. A bursectomy is likely to give the same clinical outcome as a bursectomy with acromioplasty [bib_ref] Treatment of impingement syndrome: A systematic review of the effects on functional..., Faber [/bib_ref] [bib_ref] Arthroscopic versus open acromioplasty: A systematic review, Barfield [/bib_ref] [bib_ref] Surgery for rotator cuff disease, Coghlan [/bib_ref] [bib_ref] Arthroscopic versus open acromioplasty: A meta-analysis, Davis [/bib_ref] [bib_ref] Arthroscopic subacromial decompression: Acromioplasty versus bursectomy alone--does it really matter? A systematic..., Donigan [/bib_ref]. Level 3: An open decompression may lead to longer hospital stay and a delayed return to work compared to arthroscopic surgery for SAPS [bib_ref] Arthroscopic versus open acromioplasty: A meta-analysis, Davis [/bib_ref]. ## - interventions to repair a torn rotator cuff Level 3: There are indications that there is no difference between single-row and double-row fixation technique in terms of the final clinical outcome (shoulder function, reruptures) in surgical treatment of rotator cuff tears [bib_ref] Does the literature support double-row suture anchor fixation for arthroscopic rotator cuff..., Nho [/bib_ref]. There are indications that there is a greater chance of anatomical recovery (tendon adhesion to the footprint) in the double-row fixation technique than in the single-row fixation technique [bib_ref] Outcomes of single-row and double-row arthroscopic rotator cuff repair: A systematic review, Saridakis [/bib_ref]. There are indications that the chance of re-ruptures is smaller in the double-row fixation technique in tears larger than 1 cm [bib_ref] Which method of rotator cuff repair leads to the highest rate of..., Duquin [/bib_ref]. There are indications that there is no difference between an open, mini-open, or arthroscopic approach with regard to final clinical outcome in the surgical treatment of rotator cuff tears [bib_ref] Arthroscopic versus mini-open rotator cuff repair: A comprehensive review and metaanalysis, Morse [/bib_ref] [bib_ref] Systematic review: Nonoperative and operative treatments for rotator cuff tears, Seida [/bib_ref]. There are indications of worse outcome after arthroscopic rotator cuff repair measured after 1-2 years of follow-up associated with simultaneous procedures on the biceps, simultaneous procedures on the acromioclavicular joint, preoperative fatty degeneration of the m. supraspinatus, sex (women have worse outcomes than men), and age (the risk of poorer outcome increases with age) [bib_ref] Prospective analysis of arthroscopic rotator cuff repair: Prognostic factors affecting clinical and..., Nho [/bib_ref] [bib_ref] Prognostic factors affecting anatomic outcome of rotator cuff repair and correlation with..., Oh [/bib_ref] [bib_ref] Singlerow versus double-row arthroscopic rotator cuff repair: A prospective randomized clinical study, Grasso [/bib_ref] [bib_ref] Does an arthroscopic suture bridge technique maintain repair integrity?: A serial evaluation..., Park [/bib_ref]. ## - biceps tendon tenotomy or tenodesis Level 3: A biceps tenotomy leaves more cosmetic defects; a biceps tenodesis gives more pain . ## Considerations There is no convincing evidence that surgical treatment is more effective than non-operative treatment. No clear preference for surgical technique can be indicated either. There is no indication for surgical treatment of asymptomatic rotator cuff tears (AAOS. 2010). If rotator cuff repair is indicated, performing an open, a mini-open, or an arthroscopic approach makes no difference in end-results. There is moderate evidence for fewer re-ruptures in tears larger than 1 cm (measured backward) with a double-row fixation, but any effect on clinical outcome has not been demonstrated. Comparison between ESWT, barbotage (needling of the calcium deposit guided by fluoroscopy or ultrasound), and surgical removal shows no obvious preference for one of these interventions [bib_ref] Calcific tendinitis of the shoulder, Diehl [/bib_ref] in the treatment of tendinosis calcarea. The only difference between a biceps tendon tenotomy and biceps tenodesis is cosmetic . Recommendations SAPS should preferably be treated non-operatively. If the patient does not respond to exhaustive non-operative treatment and does not qualify for a rehabilitation treatment, bursectomy can be considered. A mini, mini-open, or arthroscopic approach is associated with shorter hospital stay and faster return to work. When surgical repair of symptomatic rotator cuff tears is indicated, the condition of the muscles as well as age and activity level of the patient play a role in the decision. Surgical treatment of tendinosis calcarea is not recommended, given the availability of equivalent alternatives. ## Clinical question 8: what advice can be given to patients with saps, argued from the patient's point of view? considerations There is little research on the patient's point of view. From the few existing studies, it can be tentatively concluded that dissatisfaction with the outcome of treatment is more common in women than in men. There are indications that after a course of treatment, two-thirds of patients are still looking for one or more subsequent treatments, either in the medical sector or in alternative sectors. # Conclusion Patients with shoulder pain who are often part of the working population come into contact with various healthcare providers. The collected recommendations from all disciplines in this guideline provide treatment advice based on the bestavailable evidence. The "do's" in this treatment algorithm are: 1 A diagnosis of SAPS can only be made after a combination of tests; the Hawkins-Kennedy test, the painful arc test, and the infraspinatus muscle strength test are advisable. 2. It is preferable to treat SAPS non-operatively. 3. Treat acute pain with advice, explanation, and possibly analgesics (NSAIDs) for a maximum of 2 weeks. 4. If symptoms persist longer than 6 weeks, take steps in the workplace to prevent development of a chronic syndrome. 5. Prescribe therapy or home exercises of low intensity and high frequency, combining eccentric training with stabilization training of the scapula and focusing on relaxation and proper posture. 6. Treatment of myofascial trigger points (including stretching of the muscles) can support exercise therapy. 7. For persistent symptoms, subacromial injection with corticosteroids is an effective treatment. 8. If symptoms persist longer than 6 weeks, ultrasound can be performed to rule out cuff rupture-if indicated, supplemented by conventional radiographic examination. 9. MRI is indicated when ultrasound examination is inconclusive, or to measure the size of the tear and the condition of the muscles when rotator cuff repair is being considered. 10. For tendinosis calcarea, ESWT or barbotage can be used. 11. Rehabilitation in a specialized center can be considered for chronic, treatment-resistant SAPS, in which pain-perpetuating behavior plays a role. 12. The indication for surgical repair of a symptomatic rotator cuff tear depends on the size of the tear, the condition of the muscles, and the age and activity level of the patient. The "don'ts" in this algorithm are: 1. Strict immobilization. 2. No active intervention to prevent overload in work or sports and to address psychosocial factors. 3. Limiting imaging to conventional radiographic examination. 4. Ultrasound examination with suboptimal technique and experience. 5. ESWT in the acute phase, and in absence of tendinosis or bursitis calcarea. 6. Surgical treatment without exhaustive non-operative treatment. The production of this guideline was supported by Ms S. B. Muller-Ploeger and Ms N. van Veen of the Knowledge Institute of the Netherlands Medical Specialists Association. [table] Table 1: GRADE evidence levels of intervention studies [/table] [table] Table 2: EBRO evidence levels of diagnostic accuracy research or research into etiology and prognosis [/table] [table] Table 3: Level-of-evidence strength of the conclusion, based on the literature underlying the conclusion Level Conclusion based on 1For therapeutic intervention studies: high-quality studies. For diagnostic accuracy research or prognosis, etiology or side effects: A1-level study or at least 2 independently conducted A-2 level studies. 2For therapeutic intervention studies: moderate-quality studies. For diagnostic accuracy research or prognosis, etiology or side effects: one A2-level study or at least 2 independently conducted B-level studies. 3For therapeutic intervention studies: low-quality studies. For diagnostic accuracy research or prognosis, etiology or side effects: one B-level study or at least 2 independently conducted C-level studies. 4For therapeutic intervention studies: very low-quality studies. For diagnostic accuracy research or prognosis, etiology or side effects: one C-level study. Question 3: Which physical diagnostic tests are most accurate, sensitive and specific for subacromial pain syndrome of the shoulder? Scientific evidence level 1: No single test is sufficiently accurate to diagnose SAPS [/table]	None	https://europepmc.org/articles/pmc4062801?pdf=render	Treatment of “subacromial impingement syndrome” of the shoulder has changed drastically in the past decade. The anatomical explanation as “impingement” of the rotator cuff is not sufficient to cover the pathology. “Subacromial pain syndrome”, SAPS, describes the condition better. A working group formed from a number of Dutch specialist societies, joined by the Dutch Orthopedic Association, has produced a guideline based on the available scientific evidence. This resulted in a new outlook for the treatment of subacromial pain syndrome. The important conclusions and advice from this work are as follows: (1) The diagnosis SAPS can only be made using a combination of clinical tests. (2) SAPS should preferably be treated non-operatively. (3) Acute pain should be treated with analgetics if necessary. (4) Subacromial injection with corticosteroids is indicated for persistent or recurrent symptoms. (5) Diagnostic imaging is useful after 6 weeks of symptoms. Ultrasound examination is the recommended imaging, to exclude a rotator cuff rupture. (6) Occupational interventions are useful when complaints persist for longer than 6 weeks. (7) Exercise therapy should be specific and should be of low intensity and high frequency, combining eccentric training, attention to relaxation and posture, and treatment of myofascial trigger points (including stretching of the muscles) may be considered. (8) Strict immobilization and mobilization techniques are not recommended. (9) Tendinosis calcarea can be treated by shockwave (ESWT) or needling under ultrasound guidance (barbotage). (10) Rehabilitation in a specialized unit can be considered in chronic, treatment resistant SAPS, with pain perpetuating behavior. (11) There is no convincing evidence that surgical treatment for SAPS is more effective than conservature management. (12) There is no indication for the surgical treatment of asymptomatic rotator cuff tears.
bad61f5cf2bc152492675dfd9662779ee68bd379	pubmed	Cardiopulmonary Considerations for High School Student-Athletes During the COVID-19 Pandemic: NFHS-AMSSM Guidance Statement	Cardiopulmonary Considerations for High School Student-Athletes During the COVID-19 Pandemic: NFHS-AMSSM Guidance Statement [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] [bib_ref] Association of cardiac injury with mortality in hospitalized patients with COVID-19 in..., Shi [/bib_ref] [bib_ref] Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19), Inciardi [/bib_ref] [fig_ref] Figure 1: COVID-19 supplemental questionnaire [/fig_ref] [bib_ref] The resurgence of sport in the wake of COVID-19: cardiac considerations in..., Baggish [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Myocarditis in athletes is a challenge: diagnosis, risk stratification, and uncertainties, Eichhorn [/bib_ref] [bib_ref] Cardiac involvement in recovered COVID-19 patients identified by magnetic resonance imaging, Huang [/bib_ref] ## \| \| Any "close contact" (ie, family or household member) with confirmed COVID-19 infection \| \| Student-athletes with underlying medical conditions that place them at higher risk of severe COVID-19 illness, such as uncontrolled or moderate to severe asthma, a serious heart condition, obesity, diabetes, chronic kidney or liver disease, or a weakened immune system 8 \| \| Student-athletes with prior symptoms suggestive of (but not confirmed) COVID-19, especially if symptoms were severe or required hospitalization new Covid-19 infeCtions - - Schools should consider a daily tracking tool to confirm student-athletes are appropriately self-monitoring and have not developed symptoms of COVID-19. In addition, it is suggested that schools establish a COVID-19 response team to help develop and implement policies and procedures for a safe return to sport in their school and to assist in COVID-19 symptom screening, reporting, and contact tracing. - - Student-athletes should not attend school, sports practices, or competitions if feeling ill and should be referred to their medical provider for possible COVID-19 testing if they present with any of the following symptoms: fever, new cough, difficulty breathing, shaking chills, chest pain, gastrointestinal symptoms (nausea, vomiting, or diarrhea), loss of taste or smell, sore throat, or an unusual rash or painful discoloration of fingers or toes. - - Student-athletes who test positive for COVID-19 with or without symptoms should be isolated per public health guidelines. No exercise is recommended for at least 14 days from diagnosis and 7 days after all symptoms have resolved. - - After symptom resolution and prior to sports participation, student-athletes should be evaluated by a medical provider to assess for residual symptoms and the need for additional testing. Written medical clearance prior to sports participation is recommended. ## Emergency action plan Every school is reminded to have a well-rehearsed emergency action plan (EAP) for every sport at every venue to facilitate a coordinated and efficient response to SCA. [bib_ref] The inter-association task force for preventing sudden death in secondary school athletics..., Casa [/bib_ref] [bib_ref] Design and implementation of an emergency action plan for sudden cardiac arrest..., Pelto [/bib_ref] [bib_ref] Sudden cardiac arrest on the field of play: turning tragedy into a..., Siebert [/bib_ref] - - Every school should maintain an on-site automated external defibrillator (AED) program that allows retrieval and use of an AED within 3 minutes of collapse at school athletic venues and buildings. - - Potential first responders to SCA, including coaches, are encouraged to be trained in cardiopulmonary resuscitation (CPR), the recognition of SCA, and use of an AED. - - Each school should conduct and document an annual EAP practice drill for SCA among anticipated first responders (ie, athletic trainers, school nurses, coaches, and administrators). - - AED devices should be maintained according to manufacturer guidelines, including monthly readiness checks and scheduled battery or lead replacement. [fig] Figure 1: COVID-19 supplemental questionnaire. [/fig]	None	https://journals.sagepub.com/doi/pdf/10.1177/1941738120941490	SARS-CoV-2, the novel coronavirus that causes COVID-19 illness, presents unique health issues that should be considered in student-athletes prior to a return to sports and exercise. While the vast majority of young persons afflicted with the coronavirus have mild symptoms or remain asymptomatic, the infection can cause direct injury or inflammation to the heart and lungs, especially in patients ill enough to require hospitalization. Cardiopulmonary concerns from COVID-19 arise from data in severely ill adult patients, where approximately 1 in 5 hospitalized patients suffers from cardiac or thromboembolic (clotting) complications. However, evidence on the prevalence and risks of these complications in adolescents and in individuals who have had a milder form of the illness remains limited. An expert task force was formed from the National Federation of State High School Associations (NFHS) and the American Medical Society for Sports Medicine (AMSSM) to provide guidance for the medical assessment of student-athletes with prior COVID-19 illness before sports participation. The task force recommends that schools consider a supplemental questionnaire addressing medical issues specific to COVID-19 (Figure 1). Any positive response from the survey should trigger an evaluation by a medical provider prior to sports participation.
6d8e7c9d68b49126a8dfff550ccf4eca0165ef6d	pubmed	Consensus of the Liaison-Psychiatry Committee of the Colombian Psychiatric Association on the diagnosis and treatment of delirium in the context of the COVID-19 pandemic	Consensus of the Liaison-Psychiatry Committee of the Colombian Psychiatric Association on the diagnosis and treatment of delirium in the context of the COVID-19 pandemic publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. r e v c o l o m b p s i q u i a t . 2 0 2 2;5 1(3):245-255 ## A b s t r a c t The pandemic caused by the new coronavirus named SARS-CoV-2 poses unprecedented challenges in the health care. Among them is the increase in cases of delirium. The severe SARS-CoV-2 disease, COVID-19, has common vulnerabilities with delirium and produces alterations in organs such as the lungs or the brain, among others, which have the potential to trigger the mental disorder. In fact, delirium may be the first manifestation of the infection, before fever, general malaise, cough or respiratory disturbances. It is widely supported that delirium increases the morbidity and mortality in those who suffer from it during hospitalization, so it should be actively sought to carry out the relevant interventions. In the absence of evidence on the approach to delirium in the context of COVID-19, this consensus was developed on three fundamental aspects: diagnosis, non-pharmacological treatment and pharmacological treatment, in patients admitted to the general hospital. The document contains recommendations on the systematic use of diagnostic tools, when to hospitalize the patient with delirium, the application of non-pharmacological actions within the restrictions imposed by COVID-19, and the use of antipsychotics, taking into account the most relevant side effects and pharmacological interactions. La pandemia por el nuevo coronavirus denominado SARS-CoV-2 plantea retos sin precedentes en la atención de la salud. Entre ellos se cuenta el aumento en los casos de delirium. La enfermedad grave por SARS-CoV-2, COVID-19, tiene vulnerabilidades comunes con el delirium y produce alteraciones en órganos como el pulmón o el cerebro, entre otros, que tienen potencial para precipitar el trastorno mental; de hecho, este puede ser la primera manifestación de la infección, antes de la fiebre, el malestar general, la tos o las alteraciones respiratorias. Está ampliamente sustentado que el delirium incrementa la morbilidad y la mortalidad de quienes lo padecen durante una hospitalización, por lo que se debe buscar activamente para realizar las intervenciones pertinentes. Ante la ausencia de evidencia sobre el abordaje del delirium en el contexto de la COVID-19, se elaboró este consenso sobre tres aspectos fundamentales: diagnóstico, tratamiento no farmacológico y tratamiento farmacológico, en pacientes ingresados en el hospital general. El documento contiene recomendaciones sobre uso sistemático de herramientas diagnósticas, cuándo hospitalizar al paciente con delirium, la aplicación de acciones no farmacológicas dentro de las restricciones que impone la COVID-19 y la utilización de antipsicóticos teniendo en cuenta los efectos secundarios más relevantes y las interacciones farmacológicas. © 2020 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España, S.L.U. Todos los derechos reservados. ## Statement of the problem Coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 was declared a pandemic by the World Health Organization (WHO) on 11 March 2020.The first case in Colombia had been reported on 6 March 2020, and as of the latest update to this manuscript, on 14 September 2020, the Colombian Ministry of Health and Social Protection and the Colombian National Institute of Health had reported 716,319 confirmed cases, 22,924 deaths and 599,385 recoveries in that country (which has a population of 48,258,498), despite the public health measures adopted, including population lockdown and a clinical management protocol for positive cases.The virus, with a tropism for angiotensin converting enzyme II receptors -which are present in the lungs, heart, kidneys, gastrointestinal system and brain, among other organs -causes a broad spectrum of symptoms, including malaise, pneumonia, impairment of various systems and death. [bib_ref] Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins..., Lu [/bib_ref] [bib_ref] Coronavirus 2019 disease (COVID-19), systemic inflammation, and cardiovascular disease, Inciardi [/bib_ref] Although other modes of transmission have not been ruled out, COVID-19 is spread in a manner similar to influenza. [bib_ref] Coronavirus: update related to the current outbreak of COVID-19, Gabutti [/bib_ref] According to the WHO, it has a basic reproduc-tion number of 2-4, 15% of cases are serious, 5% are critical and the global gross mortality rate is 7%.The risk of having a serious/critical case or dying increases with age or if one suffers from cardiovascular disease, respiratory disease, diabetes or cancer. [bib_ref] Why the elderly appear to be more severely affected by COVID-19: The..., Kadambari [/bib_ref] [bib_ref] Vascular risk factors, Framingham risk score, and COVID-19: community-based cohort study, Batty [/bib_ref] [bib_ref] Covid-19 transmission, outcome and associated risk factors in cancer patients at the..., Rogado [/bib_ref] Lines of research on COVID-19 treatment include searching for a vaccine and studying the plasma of recovered patients. [bib_ref] Vaccines for COVID-19: the current state of play, Koirala [/bib_ref] [bib_ref] Therapeutic plasma exchange: a potential management strategy for critically ill COVID-19 patients, Tabibi [/bib_ref] While awaiting more high-quality empirical evidence, proposed treatment regimens include public healthmeasures such as population lockdown, isolation of positive cases and drugs ranging from symptomatic treatment to antiviral agents. [bib_ref] Evidence based management guideline for the COVID-19 pandemic -review article, Nicola [/bib_ref] Staff who care for patients with the disease must follow strict protective measures, and the need to have these measures in place at institutions as well as the possibility of transmission in said staff have placed restrictions on medical care.Delirium is acute brain failure triggered by health conditions that cause inflammation, abnormalities in cell homeostasis or central neural activity and other changes. 14 Patients with delirium have cortical and deep-structure dysfunction related to consciousness, which may be reflected in the onset of cognitive symptoms, abnormalities in executive function, changes in circadian rhythm and frontal release signs. [bib_ref] Discriminant performance of dysexecutive and frontal release signs for delirium in patients..., Franco [/bib_ref] It is not a categorically "present" or "absent" disorder; rather it is an altered mental state on a spectrum from mild changes to very serious changes. [bib_ref] Delirium subsindrómico en pacientes ancianos: revisión sistemática, Velilla [/bib_ref] To understand the causes of delirium, both individual vulnerability and precipitating factors must be taken into account. [bib_ref] A predictive model for delirium in hospitalized elderly medical patients based on..., Inouye [/bib_ref] Several conditions increase vulnerability, such as major neurocognitive disorder and other predisposing factors, [bib_ref] Predisposing and precipitating factors for delirium in hospitalized older patients, Inouye [/bib_ref] [bib_ref] Factores de riesgo y mortalidad hospitalaria de los pacientes quirúrgicos y no..., Restrepo [/bib_ref] largely coinciding with those stated for serious/critical SARS-CoV-2 infection, which for its part has the potential to precipitate mental disorder, as a result of abnormalities caused in various systems. [bib_ref] COVID-19-associated hyperactive intensive care unit delirium with proposed pathophysiology and treatment: a..., Sher [/bib_ref] Several mechanisms account for the novel virus's capacity to precipitate delirium. Regarding central nervous system (CNS)-specific impairment, the virus likely gains access to the brain parenchyma through the olfactory nerve, and gets as far as the thalamus and brainstem, which are directly involved in the pathophysiology of delirium. [bib_ref] The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory..., Li [/bib_ref] Other abnormalities caused by SARS-CoV-2 that affect both the CNS and other systems include excessive cytokine production, clot formation and hypoxia, all with the potential to alter consciousness. [bib_ref] Neurobiology of COVID-19, Fotuhi [/bib_ref] [bib_ref] Encephalopathy in patients with COVID-19: a review, Garg [/bib_ref] Under normal conditions, delirium already affects one out of every five hospitalised patients, [bib_ref] Delirium in an adult acute hospital population: predictors, prevalence and detection, Ryan [/bib_ref] and in Colombia more than 30% of geriatric patients will ultimately get it. [bib_ref] Delírium en pacientes mayores de 60 años en un hospital público de..., Sánchez [/bib_ref] [bib_ref] Incidence of confusional syndrome (delirium) in adult patients hospitalized at a university..., Oviedo [/bib_ref] Since COVID-19 features a confluence of vulnerabilities and precipitating factors, to which must be added the pharmacological interventions required in serious/critical cases, an increase in the prevalence of delirium has been observed. [bib_ref] Collaborative delirium prevention in the age of COVID-19, Lahue [/bib_ref] [bib_ref] Neurologic manifestations of hospitalized patients with coronavirus disease, Mao [/bib_ref] [bib_ref] A complication of coronavirus disease 2019: delirium, Cipriani [/bib_ref] [bib_ref] Neurological features of COVID-19 and their treatment: a review, Orsucci [/bib_ref] In fact, the disorder may be the first sign of COVID-19. [bib_ref] Delirium as the first clinical presentation of the coronavirus disease 2019 in..., Soysal [/bib_ref] [bib_ref] A unique presentation of delirium in a patient with otherwise asymptomatic COVID-19, Alkeridy [/bib_ref] This is concerning because delirium usually has low detection and treatment rates, [bib_ref] Prevalence, detection and treatment of anxiety, depression, and delirium in the adult..., Rincon [/bib_ref] and furthermore lengthens stays and increases care costs, morbidity, functional/cognitive difficulties upon discharge and mortality in those who suffer from it;to date there is a dearth of specific evidence on how to address it in the context of the pandemic. ## Scope of the consensus Taking the above considerations into account, the Comité de Psiquiatría de Enlace [Liaison Psychiatry Committee] of the Asociación Colombiana de Psiquiatría [Colombian Psychiatry Association] developed this consensus on three essential aspects of clinical treatment of delirium in relation to the current pandemic: a) diagnosis; b) general measures and nonpharmacological interventions; and c) drug treatment. To this end, a member of the committee prepared the initial version and sent it to the other authors for critical analysis and comments in two rounds before a final consensus was reached. The context of this document is a general hospital, and it is intended for general physicians, psychiatrists, specialists in other areas and nurses responsible for treating adults with suspected or confirmed COVID-19. It must be stressed that these are not guidelines for treating delirium in general; rather, they are a specific consensus on care for the disorder in the scenario caused by infection with the novel SARS-CoV-2 virus. There is not enough high-quality evidence on the treatment of delirium under these specific circumstances, and this article emphasises the relevant points taking into account variability in resources and interventions in the infection. [fig_ref] Table 1 -: Consensus of the Comité de Psiquiatría de Enlace [Liaison Psychiatry Committee] of... [/fig_ref] features the consensus recommendations and the subsequent sections show the detailed discussion. [fig_ref] Table 2 -: Profile of particularly significant side effects in the context of COVID-19 of... [/fig_ref] offers instructions on antipsychotic use and the section on drug treatment includes online sources, where updates can be found. ## Diagnosis Given the importance of timely diagnosis of delirium, physicians and nurses lacking in-depth knowledge of psychiatric disease must use screening instruments or, better yet, instruments for provisional diagnosis, which ideally can also be used in patients who lack the capacity to give verbal responses due to intubation or limitations on communication. In Colombia, the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Delirium Diagnostic Tool-Provisional (DDT-Pro) are validated. [bib_ref] Instrumentos para el diagnóstico de delirium en hispanohablantes: artículo de revisión, Velásquez Gaviria [/bib_ref] The former is an algorithm to screen for delirium on intensive care units (ICUs), [bib_ref] Evaluation of delirium in critically ill patients: validation of the Confusion Assessment..., Ely [/bib_ref] and the latter is the first tool developed for provisional diagnosis of delirium in the absence of an expert to verify it. [bib_ref] Initial validation of a brief provisional diagnostic scale for delirium, Kean [/bib_ref] The CAM-ICU has four items that can be evaluated even in the absence of a verbal response from the patient: a) acute change or fluctuating course; b) inattention; c) disorganised thinking; and d) level of consciousness according to the Richmond Agitation Sedation Scale (RASS). It is scored as positive or negative for delirium. A patient is positive if they have abnormalities in the first and second item plus failures in either of the other two items. The Colombian version has very good interevaluator agreement ( = 0.8), with 93% sensitivity and 87% specificity for people on ventilation and delirium according to the DSM-IV-TR. [bib_ref] Versión en español del método para la evaluación de la confusión en..., Toro [/bib_ref] Since the prevalence of delirium in critically ill and intubated patients can exceed 80% and the condition can develop at any time during ICU admission, [bib_ref] Intensive care unit delirium: a review of the literature, Kalabalik [/bib_ref] the consensus recommendation is to use the CAM-ICU at least every 12−24 hours in patients with COVID-19. Those positive for delirium should be periodically assessed and it should be determined whether they cease to be positive once treatment measures are instated. The CAM-ICU validated in Colombia is available online (https://n9.cl/sbad). The DDT-Pro has three items that can be evaluated even in the absence of verbal responses: a) comprehension, b) vigilance and c) sleep-wake cycle. Each is scored from 0 (serious abnormality) to 3 (no abnormality). The total score ranges from 0 to 9. The Colombian version was validated in patients admitted to internal medicine and its subspecialisations. Agreement between a physician and a nursing professional is very good (intraclass correlation index = 0.9) and is not affected in major neurocognitive disorder. Diagnostic accuracy for delirium according to the DSM-V is 94%. A cut-off point ≤6 is the one recommended as indicative of a diagnosis of delirium. DDT-Pro scores are sensitive to changes in clinical stages, and therefore serve to monitor the patient's course. [bib_ref] Validation of the Delirium Diagnostic Tool-Provisional (DDT-Pro) with medical inpatients and comparison..., Franco [/bib_ref] Given the needs for staff isolation and protection in accident and emergency departments and hospitalisation departments with large numbers of admissions, and Association] on the diagnosis and treatment of delirium related to SARS-CoV-2 infection and COVID-19. ## Diagnosis of delirium - Implement guidelines for delirium treatment at all centres with hospital services, articulating the actions of all professionals according to their role - Use screening instruments or instruments for provisional diagnosis of delirium validated in Colombia, without neglecting to screen for other common disorders such as anxiety and depression - On the ICU: -The CAM-ICU algorithm is recommended; intensivists and nurses can use it in patients with or without the ability to give verbal responses -The CAM-ICU should be used at least every 12−24 hours in patients with confirmed or suspected COVID-19 -Patients screened as positive for delirium should be periodically assessed with the CAM-ICU to determine whether they remain positive -The version in Spanish of the CAM-ICU can be downloaded at: https://uploads ssl.webflow.com/5b0849daec50243a0a1e5e0c/5bb41b525e9306c1d636d785 CAM ICU training Spanish.pdf - In other hospital departments: -The DDT-Pro is recommended; it can be used by physicians or nurses, even in patients who cannot give verbal responses or have major neurocognitive disorder -The DDT-Pro should be used in all patients with recent alteration of their behaviour/mental state -If delirium is diagnosed, the DDT-Pro should be used at least once daily to evaluate the seriousness or resolution of the case -The version in Spanish of the DDT-Pro can be downloaded at: https://n9.cl/sbad -Although no known data validate the general CAM in Colombia, those who are already using it should not switch instruments during the pandemic and should consider the instructions provided -To use the general CAM, the patient must be able to give verbal responses -To use the general CAM, it is necessary to register at: https://help.agscocare.org/chapter abstract/chapter/H00101/H00101 PART001 002 General measures and non-pharmacological interventions - Delirium prevention: -Maintain proper patient hydration and, depending on their possibilities and restrictions, allow mobility, promote sleep hygiene and care for cognitive function - Decision to hospitalise a patient with delirium from the accident and emergency department: -When the patient's delirium symptoms are serious -When the patient's clinical condition is progressively declining -When the aetiologies of the delirium have not been identified or if it is suspected or confirmed that the disorder may be in some way related to COVID-19 -When in-home care or outpatient follow-up cannot be ensured or when delirium overlaps with a known cognitive disorder - General non-pharmacological actions for the care of patients with delirium: -Tolerate, anticipate and not agitate(TANA): tolerate minor behavioural disturbances, anticipate fall and injury risk, and evaluate risk of aggression -When behavioural disturbances are present, verbal behavioural interventions are initially used - Only for patients in whom it is strictly necessary, mechanical restraint: -If, despite other non-pharmacological and pharmacological interventions, the risk that they will harm themselves or that their behaviour will interfere with their treatment persists -Always bear in mind that mechanical restraint itself can cause agitation -Whenever this measure is necessary, strict records of the patient's condition and the continuity of the indication for restraint must be kept -Always as brief as possible - Specific non-pharmacological actions for delirium treatment: -Considering restrictions that come with patient isolation and possible limitations on staff and space, communication with the patient must be maintained -Circumstances and characteristics of the centre, specific department and patient permitting, electronic means should be used to maintain frequent contact with the patient -The use of any eyeglasses or hearing equipment that the patient may require is allowed, whenever possible -Orientate and give frequent, clear explanations, insofar as is possible: where you are, who is caring for you, what procedure/treatment is being performed, etc. - Although involving companions in delirium care is beneficial, the pandemic restricts the possibility of doing so regularly Drug treatment - Preventive prescription of medicines intended to prevent the onset of delirium related to COVID-19 is not recommended - For all patients, with or without delirium, a rational drug prescription must be made, and this must be reviewed daily - It is necessary to investigate causes of delirium and behavioural abnormalities in the context of COVID-19 and to intervene in those that can be treated - In investigating causes, vulnerability factors and specific precipitating factors must be analysed in each case in order to rationalise interventions to the extent possible - As the pandemic restricts some non-pharmacological interventions, an increase in drug treatment for delirium is anticipated - When delirium in the context of COVID-19 does not resolve with the other actions described, it is recommended that an antipsychotic be administered at the minimum effective dose - The most important side effects of antipsychotics used to treat delirium in the context of COVID-19 are: -Extrapyramidal effects, especially with typical antipsychotics -Effects on metabolism, especially with atypical antipsychotics, which may appear at the start and be more significant in at-risk populations ## -table 1 (continued) -Cardiovascular and cerebrovascular effects, especially in patients with risk factors for QT prolongation and the geriatric population with neurocognitive disorders -Gastrointestinal effects (among them, constipation is significant in inpatient settings and may worsen delirium) - In the context of COVID-19, cardiovascular abnormalities may occur due combining antipsychotics with drugs to manage viral disease - Decision-making as to which antipsychotic to administer must be personalised based on the patient's clinical characteristics and the medicines that the patient is already taking (see [fig_ref] Table 2 -: Profile of particularly significant side effects in the context of COVID-19 of... [/fig_ref] - Treatment with antipsychotics should be as brief as possible, depending on the patient's clinical course and comorbidities - Benzodiazepines should not be administered as a first-line pharmacological option in the treatment of delirium in patients with COVID-19 -Lorazepam should only be used for timely control of behavioural changes when it is not possible to prescribe an antipsychotic, and it should always be used at low doses with monitoring of respiratory function Does not significantly interact with chloroquine, tocilizumab, dexamethasone, interferon beta, remdesivir, lopinavir, ritonavir, favipiravir, ribavirin or amisulpride * The decision to administer a specific antipsychotic depends on the individual risk of serious side effects and on whether the patient is taking a drug associated with significant interactions. Outside of what is specified herein, antipsychotics have other side effects, as well as other drug interactions. Although hydroxychloroquine and lopinavir/ritonavir do not reduce mortality from COVID-19, the WHO leaves open the possibility of using and evaluating them in patients exposed to the virus; hence, their interactions with antipsychotics are reviewed. Some online sources that can be checked for updates on drug interactions between antipsychotics and the drugs reviewed or other antivirals or drugs that may be used in patients with COVID-19 are: https://www.drugs.com/ and https://www.covid19-druginteractions.org/. given that delirium should be suspected in all patients with acute or subacute changes in behaviour while in hospital, [bib_ref] Quality indicators for in-hospital geriatric co-management programmes: a systematic literature review and..., Van Grootven [/bib_ref] it is advisable to use the DDT-Pro in any patient with recent alteration in their behaviour/mental state and, if delirium is diagnosed, continue using it at least once daily during treatment to assess the course. The DDT-Pro validated in Colombia can be downloaded online (https://www.dropbox.com/s/2bahekw4679wf8d/DDT-Pro Spanish.pdf?dl=0). Finally, we are not aware of any validations in Colombia of the CAM algorithm for general use. It is a screening instrument with items similar to those of the CAM-ICU, which requires prior training and verbal responses from the patient. It was constructed according to the criteria of the DSM-III-R and is very well known. [bib_ref] Clarifying confusion: the Confusion Assessment Method. A new method for detection of..., Inouye [/bib_ref] Its adaptation in Spain has very good agreement as it is applied by physicians ( = 0.9) and has 90% sensitivity and 100% specificity. [bib_ref] Instrument for detection of delirium in general hospitals: adaptation of the Confusion..., González [/bib_ref] Although quantitative data on the performance of the CAM in the country are unknown, it is recommended that those with experience not switch instruments and that they use this in the context of the pandemic with patients who are able to give verbal responses, according to the recommendations mentioned for accident and emergency departments and hospitalisation departments. To download the CAM in Spanish, it is necessary to register beforehand (https://help.agscocare.org/chapter-abstract/chapter/H00101 /H00101 PART001 002). ## General measures and non-pharmacological interventions Non-pharmacological measures for preventing delirium are widely used.The most important ones are care for baseline cognition, promotion of sleep hygiene, mobilisation according to the patient's circumstances and hydration. [bib_ref] Effectiveness of multicomponent nonpharmacological delirium interventions: a meta-analysis, Hshieh [/bib_ref] The fourth should always be done, and the first through third can be done to some degree, given the need for isolation of COVID-19 cases and potential staff and space restrictions. On the accident and emergency department, a decision should be made as to whether a patient with delirium should be hospitalised. Patients with delirium who visit accident and emergency departments and are not hospitalised are at higher risk of dying and hospitalisation is the best option when delirium symptoms are serious, clinical status is declining, outpatient care or follow-up cannot be ensured, or underlying neurocognitive disorder is present. [bib_ref] Delirium in the emergency department: an independent predictor of death within 6..., Han [/bib_ref] Although the decision to hospitalise or not hospitalise should be personalised, the recorded evidence indicates that the best option is to hospitalise patients with delirium of indeterminate cause or suspected or confirmed to be related to COVID-19. It should be borne in mind that delirium may be the only clinical sign of the infection.Non-pharmacological interventions are among first-line treatment options. In any case of delirium, the "tolerate, anticipate and not agitate" (TANA) strategy should be used. Minor behavioural abnormalities can be tolerated, fall and injury risk must be anticipated and risk of self-aggression or heteroaggression must be evaluated. [bib_ref] Altered mental status in older patients in the emergency department, Han [/bib_ref] Although most disruptive or dangerous behaviours can be reduced with verbal interventions, behavioural measures or pharmacological interventions (see the following section), mechanical restraint may be required in specific cases: if there is a risk of self-harm on the part of the patient or if the behaviours are interfering with treatment. Whenever this measure is necessary, it should be applied according to each institution's protocols, with recording of clinical status and the continuity of the indication to use it, endeavouring to keep it as brief as possible. Mechanical restraint can cause agitation in itself. [bib_ref] Preventing falls in hospitalized patients, Lelaurin [/bib_ref] The guidelines of the National Institute for Heath and Care Excellence recommend maintaining communication with the patient, who insofar as is possible should be wearing any required eyeglasses or hearing aids. For example, it should be explained to the patient: where they are, who is caring for them and what procedure is being performed. In addition, efforts should be made to calm them; to this end, under normal conditions, families and carers can be involved.Unfortunately, indications for isolation and staff and space restrictions limit the possibility of including companions. Since non-pharmacologic preventive and therapeutic measures may be restricted, prescription of medicines for managing delirium can be anticipated to increase during the pandemic. ## Drug treatment There are no clear instructions on the preventive use of drugs for delirium; there is not even agreement on whether they decrease its duration or reduce its incidence, or on identification of patients who would benefit from it. [bib_ref] Debate article: antipsychotic medications are clinically useful for the treatment of delirium, Meagher [/bib_ref] It is not possible to recommend this strategy for those affected by COVID-19. On the other hand, there is a unanimous agreement on the need to identify and treat the cause of delirium. This also involves rationalising the various pharmacological interventions in patients (this rationalisation being preventive and therapeutic). [bib_ref] A systematic review of implementation strategies for assessment, prevention, and management of..., Trogrlić [/bib_ref] In the context of COVID-19, it is necessary to analyse the factors of vulnerability to delirium that a given patient has, as well as specific precipitating factors, among which drug treatment plans must be considered, [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] in order to maximise personalisation of interventions in mechanisms of brain failure. Traditionally, drug treatment of delirium has been based on antipsychotics at the lowest possible doses. Although research is inconclusive and debate persists, 51 the drugs with the most empirical support are haloperidol, quetiapine, risperidone and olanzapine. [bib_ref] Acute brain failure: pathophysiology, diagnosis, management, and sequelae of delirium, Maldonado [/bib_ref] According to a survey on delirium treatment in Colombia, these same drugs, in that order, are the most commonly used ones in that country, with the fifth most common option being aripiprazole. [bib_ref] Encuesta a psiquiatras y residentes de psiquiatría en Colombia sobre sus prácticas..., Franco [/bib_ref] Although there is less evidence on aripiprazole, there are reports on it, as well as amisulpride, indicating that they are effective. [bib_ref] Study on the efficacy and tolerability of amisulpride in medical/surgical inpatients with..., Pintor [/bib_ref] [bib_ref] Antipsychotic medications for the treatment of delirium: a systematic review and meta-analysis..., Kishi [/bib_ref] Antipsychotics should be used with caution if other measures have not worked, especially when there is increased motor activity, and they should be used only as long as strictly necessary.Special care should be taken with: a) extrapyramidal effects, especially, but not exclusively, with typical antipsychotics; b) effects on metabolism, especially with atyp-ical agents; c) cardiac/cerebrovascular effects, with virtually all antipsychotics, in people with risk factors for QT interval prolongation and in geriatric patients with neurocognitive disorders; d) gastrointestinal effects (among them, constipation can worsen delirium); and e) in the current situation, drug interactions with drugs to treat viral disease. [fig_ref] Table 2 -: Profile of particularly significant side effects in the context of COVID-19 of... [/fig_ref] describes recommendations for antipsychotic use according to the five sources of caution listed. Relevant side effect recommendations are based on the Stahl Prescriber's Guide (https://n9.cl/9qe7k), and remarks on interactions are based on the widely recognised websites https://www.drugs.com/ and https://www.covid19druginteractions.org/, which are regularly updated. It should be clarified that we are not offering a categorical recommendation as to which drug to use; guidelines are presented according to patients' demographic, clinical and pharmacological profiles. That is, the decision to administer or not administer an antipsychotic depends on individual risk factors for side effects and on whether antivirals or other drugs are being administered. Regarding antipsychotic interactions, [fig_ref] Table 2 -: Profile of particularly significant side effects in the context of COVID-19 of... [/fig_ref] describes the safety and risks of concomitant administration of antivirals such as remdesivir, lopinavir, ritonavir, favipiravir, ribavirin and atazanavir, which are being used and studied in the context of COVID-19. [bib_ref] An overview of the safety, clinical application and antiviral research of the..., Wang [/bib_ref] [bib_ref] Antiviral therapy in management of COVID-19: a systematic review on current evidence, Yousefifard [/bib_ref] Although the WHO announced that, according to the Solidarity trial, neither hydroxychloroquine nor a combination of lopinavir/ritonavir reduces mortality, it left open the option of using and evaluating them as prophylaxis against exposure to SARS-CoV-2. 60 Therefore, as it is possible to encounter patients who are taking them, their interactions are described. The safety of tocilizumab, dexamethasone and interferon beta, used in the treatment of the inflammatory response to the virus, is also reviewed. [bib_ref] A comprehensive review on tocilizumab in COVID-19 acute respiratory distress syndrome, Khiali [/bib_ref] [bib_ref] Dexamethasone in hospitalized patients with COVID-19 -preliminary report, The Recovery Collaborative [/bib_ref] [bib_ref] Efficacy and safety of interferon ␤-1a in treatment of severe COVID-19: a..., Davoudi-Monfared [/bib_ref] On the other hand, the risk of side effects must not be overestimated. The best evidence available in 2019 in relation to delirium treatment indicated that, although those who took antipsychotics tended to experience cardiac side effects, mortality did not increase and it could not be confirmed that taking them for short periods negatively impacted other systems. [bib_ref] Antipsychotics for treating delirium in hospitalized adults, Nikooie [/bib_ref] Except when delirium is due to central nervous system depressants, routine use of benzodiazepines is not recommended. [bib_ref] Effect of early and focused benzodiazepine therapy on length of stay in..., Lee [/bib_ref] Although they have a sedative effect, they alter sleep architecture, attention, memory and motor skills, and their anticholinergic effects and effects on GABA worsen the prognosis of delirium. In geriatric patients and patients with lung disease, in combination with other central depressants, they cause respiratory complications. [bib_ref] Benzodiazepine use in older adults: dangers, management, and alternative therapies, Markota [/bib_ref] Even so, the British Geriatrics Society, the European Delirium Association and the Royal College of Psychiatrists recommend lorazepam in patients with COVID-19, when antipsychotics cannot be administered, always with monitoring of respiratory function.Information on other first-line and adjuvant drugs in the treatment of delirium is less conclusive, so no instructions can be given on using or not using them.The recommendation in the context of COVID-19 is not to supply them without first weighing the reasons for doing so and the risks in each case. # Conclusions Given the large numbers of cases of delirium related to COVID-19 and environmental factors of isolation and potential restrictions on human and technical resources, systematic detection and monitoring of the disorder should be structured with validated tools. In all cases, the aetiology must be actively sought in order to intervene, and non-pharmacological interventions must be adapted to suit the resources available. When pharmacological interventions for delirium are necessary, adverse effects should be taken into account in light of patient profiles and drug interactions. ## Conflicts of interest José G. Franco coordinated the validation in Colombia of the Confusion Assessment Method-Intensive Care Unit and the Delirium Diagnostic Tool-Provisional. He co-owns the copyright for the Delirium Diagnostic Tool-Provisional. He also worked with the team that validated the Confusion Assessment Method for general use in Spain. He receives no remuneration for the use of any of these instruments. Gabriel Fernando Oviedo Lugo has sat on Janssen's advisory board. Liliana Patarroyo Rodriguez has been a speaker for Lundbeck. The other authors declare that they have no conflicts of interest. r e f e r e n c e s [fig] © 2020 Asociación: Colombiana de Psiquiatría. Published by Elsevier España, S.L.U. All rights reserved.Consenso del Comité de Psiquiatría de Enlace de la Asociación Colombiana de Psiquiatría sobre el diagnóstico y tratamiento del delirium en el contexto de la pandemia por COVID-19 [/fig] [table] Table 1 -: Consensus of the Comité de Psiquiatría de Enlace [Liaison Psychiatry Committee] of the Asociación Colombiana de Psiquiatría [Colombian Psychiatric [/table] [table] Table 2 -: Profile of particularly significant side effects in the context of COVID-19 of antipsychotics used to treat delirium.* [/table]	None	None	None
7f2370f646a46e5a4caaffcf56eafa60ecf61562	pubmed	Guidance for cardiac electrophysiology during the COVID-19 pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Associat	Guidance for cardiac electrophysiology during the COVID-19 pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Associat [bib_ref] Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref] [bib_ref] SARS-CoV-2 viral load in upper respiratory specimens of infected patients, Zou [/bib_ref] [bib_ref] Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1, Van Doremalen [/bib_ref] ## Impact of covid-19 on cardiac arrhythmias Patients infected with COVID-19 can exhibit a wide range of clinical manifestations, ranging from an asymptomatic state to severe disease with hypoxia and acute respiratory distress syndrome-type lung injury. [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan [/bib_ref] [bib_ref] First case of 2019 novel coronavirus in the United States, Holshue [/bib_ref] In the setting of hypoxemic respiratory failure, ground-glass opacification on chest imaging is found in .50%. [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan [/bib_ref] Because the majority of patients will experience only mild symptoms, including fever, cough, headache, anorexia, diarrhea, and malaise, it can be difficult to distinguish COVID-19 from the common cold. COVID-19 has the potential to cause myocardial injury, with at least 17% found to have an elevated troponin and 23% noted to have heart failure in a study of 191 inpatients from Wuhan, China. [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] Cases of fulminant myocarditis with cardiogenic shock have also been reported, with associated atrial and ventricular arrhythmias. [bib_ref] Cardiovascular considerations for patients, health care workers, and health systems during the..., Driggin [/bib_ref] Given that hypoxia and electrolyte abnormalities that are common in the acute phase of severe illness can potentiate cardiac arrhythmias, the exact arrhythmic risk related to COVID-19 in patients with less severe illness or those who recover from the acute phase of the severe illness is currently unknown. Improved understanding of this is critical, primarily in guiding the need for additional arrhythmia monitoring (eg, mobile cardiac telemetry) after discharge and whether an implantable cardioverter defibrillator (ICD) or wearable cardioverter defibrillator will be needed in those with impaired left ventricular function thought to be secondary to COVID-19. ## Triage of procedures based on screening and ppe The experiences in China, Italy, South Korea, and Taiwan have informed the need to quickly test and triage patients with suspected infection. It is important for all electrophysiologists to have a high degree of suspicion for COVID-19 in any patient they interact with in the electrophysiology laboratory, hospital, or outpatient setting. A thorough travel history and assessment of contact with individuals or family members who were sick or received hospitalization is mandatory. Patients with fever, cough, and upper respiratory tract symptoms deserve special attention and should be immediately isolated. Testing for severe acute respiratory syndrome coronavirus 2, along with other respiratory viruses (eg, influenza, respiratory syncytial virus) should be pursued. ## Ppe In patients with suspected COVID-19 infection, it is recommended that all clinicians and healthcare providers don PPE, which include a face mask, protective eyewear, gown, and gloves. Initial PPE recommendations in these patients included the use of fitted N95 or powered air-purifying respirator masks, protective eyewear, gloves, and gowns. However, because of a shortage of N95 masks and increased understanding of droplet and airborne transmissibility during routine care of patients with suspected and positive COVID-19, substitution with a surgical mask with a face shield combination or other protective eyewear during routine nonprocedural care has been recommended by the US Centers for Disease Control and Prevention (CDC). Recommendations related to PPE may continue to change on the basis of supply chain, contingency, and crisis capacity status. Consultation with the hospital infection control team is strongly recommended. Appropriate donning and doffing procedures should be followed as outlined by the CDC (see the Useful Links section). It is also important to know how to report potential COVID-19 cases or exposure to public health authorities; local or hospital COVID-19 hotlines can be useful in this regard. ## Guidance for managing invasive and noninvasive electrophysiology procedures, clinic visits, and cied interrogation Because of the increased numbers of COVID-19 cases and the anticipated impact on healthcare resources (eg, hospital and intensive care unit beds, ventilators, PPE, and the blood supply), it is recommended, and increasingly mandated, to postpone or cancel nonurgent, elective procedures. The definition of what constitutes an elective or nonurgent case should be based on individualized risk assessment, informed by the patient's clinical status. In general, it is reasonable to consider deferring any test or procedure that is unlikely to directly impact clinical care or outcomes over the next several months. The rationale for delaying nonurgent or elective procedures should ideally be discussed with the patient and documented in the medical record [fig_ref] Figure 1: Guidance on EP procedures for urgent, semiurgent, or nonurgent procedures in the... [/fig_ref]. In contrast, semiurgent, urgent, or emergent procedures include those in which there is (1) threat to the patient's life if the procedure is not performed urgently, (2) threat of permanent dysfunction of an extremity or organ system, or (3) risk of rapidly worsening to severe symptoms. ## Urgent or emergent procedures Procedures are considered urgent or emergent if they substantially decrease the risk of clinical decompensation, hospitalization, or death [fig_ref] Figure 1: Guidance on EP procedures for urgent, semiurgent, or nonurgent procedures in the... [/fig_ref]. Screening for COVID-19 should be performed if it is suspected, and a high level of suspicion for COVID-19 infection should be maintained. 1. Ventricular tachycardia ablation for medically uncontrolled electrical storm in a hemodynamically compromised patient 2. Catheter ablation of incessant, hemodynamically significant, severely symptomatic tachycardia (supraventricular tachycardia/atrial fibrillation/atrial flutter) not responding to antiarrhythmic drugs, rate control, and cardioversion 3. Catheter ablation for Wolff-Parkinson-White syndrome or preexcited atrial fibrillation with syncope or cardiac arrest 4. Lead revision for malfunction in a pacemaker-dependent patient or patient with an ICD receiving inappropriate therapy 5. Generator change in pacemaker-dependent patients who are at elective replacement indicator or at device end of life 6. Pacemaker or ICD generator change with minimal battery remaining, depending on specific clinical situations 7. Secondary prevention ICD 8. Pacemaker implant for complete heart block, Mobitz II atrioventricular block, or high-grade atrioventricular block with symptoms or severe symptomatic sinus node dysfunction with long pauses 9. Lead/device extraction for infection, including patients not responding to antibiotics, or for endocarditis, bacteremia, or pocket infection 10. Cardiac resynchronization therapy in the setting of severe refractory heart failure in guideline-indicated patients 11. Cardioversion for highly symptomatic atrial arrhythmias or rapid ventricular rates not controlled with medications 12. Transesophageal echocardiogram for patients who need urgent cardioversion (further guidance on this issue from the American Society of Echocardiography). ## Semiurgent procedure Some electrophysiology procedures are not emergent yet clinically may need to be performed in a timely manner because of clinical circumstances [fig_ref] Figure 1: Guidance on EP procedures for urgent, semiurgent, or nonurgent procedures in the... [/fig_ref]. Often, the decision of when to schedule a procedure will depend on the clinical judgement of the electrophysiology physician, in partnership with the patient and the associated healthcare teams. As noted previously, appropriate PPE and a high level of suspicion for COVID-19 infection is required. 1. Ventricular tachycardia ablation for medically refractory recurrent ventricular tachycardia 2. Supraventricular tachycardia ablation, in patients with medically refractory supraventricular tachycardia resulting in emergency department visits 3. CIED generator replacement for elective replacement indicator battery status that is not urgent or emergent 4. Primary prevention ICD in patients at particularly high risk of life-threatening ventricular arrhythmia. ## Nonurgent or elective procedures Procedures are considered nonurgent or elective if they do not meet the aforementioned criteria for semiurgent, urgent, or emergent procedures [fig_ref] Figure 1: Guidance on EP procedures for urgent, semiurgent, or nonurgent procedures in the... [/fig_ref]. It may be reasonable to delay the following procedures for several weeks or months - Screen all EP procedure paƟents for fever, COVID-19 symptoms and high-risk exposures - CoordinaƟon with anesthesia and ICU team is essenƟal for procedure planning on COVID-19-posiƟve paƟents *In locaƟons with community spread and/or limited tesƟng availability, it may be prudent to consider at least droplet precauƟons for all EP procedures For patients with suspected COVID-19 requiring electrophysiology procedures, it is optimal to await confirmation of COVID-19 test status to avoid unnecessary use of resources. PPE including N95 or powered air-purifying respirator masks should be used by healthcare personnel treating patients with suspected or confirmed COVID-19 requiring conscious sedation (which carries a risk for aerosolization with high-flow oxygen) or intubation. Close coordination between anesthesia and the electrophysiology laboratory teams is required. For general anesthesia cases, consideration should be given to elective intubation in the intensive care unit or a negative-pressure room before entering the electrophysiology laboratory. Because the care team is restricted to the laboratory or procedure room until the procedure has finished, staff should pay particular attention to having all supplies and equipment in the room at the start of the case. Consideration can also be given to performing procedures on patients with confirmed or suspected COVID-19 in a negative-pressure operating room. [bib_ref] Anesthetic management of patients with COVID-19 infections during emergency procedures, Zhao [/bib_ref] It is important for hospitals to review the ventilation system of their electrophysiology laboratories to determine whether there is sharing of an air return that might require disinfection of other rooms. Where possible, procedure time should also be minimized. For example, among patients undergoing ventricular tachycardia ablation, extensive ventricular tachycardia induction and activation mapping may be minimized to reduce risk. Same-day discharges after device implantation should be considered to minimize the patient's risk of nosocomial infection. To minimize the transport of infected patients, direct-current or chemical cardioversions can be performed at the bedside in the intensive care unit with suitable anesthesia support. When feasible, patients with confirmed or suspected COVID-19 infection should be scheduled as the last case of the day, given the extensive cleaning required after the procedure. The CDC's recommendations for environmental cleaning and disinfection should be followed (see the link later in this article). ## Limit clinic visits to those considered time-sensitive or urgent Where possible, in-person clinic visits should be avoided. Instead, telehealth or virtual visits (secure Internet, phone, or video) should be adopted to minimize unnecessary exposure. The majority of incision site inspections after CIED implantation or catheter ablation can be managed through telehealth by inspecting the site using a video conference or by asking the patient to send a picture in a secure email message. Similarly, many of the clinic follow-ups and some new consults can be performed through telehealth, leveraging electronic medical record data and obtaining vital signs and ECG tracings by using digital wearables where available. As the number of application-based technologies evolves, they will continue to be an integral part of telehealth. Examples of low-risk patients for whom in-person visits could be deferred include asymptomatic patients with satisfactory CIED battery longevity, patients who are not dependent on a pacemaker, and patients who have primary prevention ICDs without symptoms suggesting worsening of heart failure or arrhythmia burden. Patients on antiarrhythmic drugs, such as dofetilide, that require QTc and laboratory monitoring may need to defer testing if prior values and their clinical condition have remained stable and if no new drugs that may prolong the QTc have been added. Patients with borderline values may need continued access to ECGs and laboratory testing. Although several studies have evaluated the use of mobile ECG devices for QTc monitoring, none of the currently available single-and 6-lead mobile ECG devices have been cleared by the US Food and Drug Administration for such purposes. However, regulations are evolving quickly in this area. Other urgent or semiurgent clinical indications can be evaluated in person on an individualized basis. Select patients with worsening heart failure or arrhythmia symptoms or for whom there is a need for device reprogramming may warrant office evaluation. These include but are not limited to patients who have atrial fibrillation with worsening heart failure, patients who have an ICD with recent shocks or syncope, patients with a CIED who have recent symptoms suggesting possible device malfunction (eg, syncope or heart failure exacerbation), or suspected device infection. A limited physical examination may well be appropriate on the basis of their clinical presentation. When possible, inperson visits and procedures should be coordinated on the same day to minimize multiple exposures for the patient. In patients coming for outpatient visits, measures should be taken to screen patients for concerning symptoms (eg, fever, cough) before they present to clinic. If suggestive symptoms or a fever are present, patients should be redirected to an appropriate screening clinic or facility, with appropriate measures taken [fig_ref] Figure 2: Guidance on nonprocedural care in outpatient clinic visits and CIED monitoring in... [/fig_ref]. ## Limit in-person cied interrogation to those considered urgent or time-sensitive To minimize exposure of electrophysiology staff and device manufacturer representatives to patients with suspected or confirmed COVID-19 infection, it is prudent to perform inperson CIED interrogations only as follows. It is important to note that device interrogation programmers, cables, and wands should be disinfected between all patients. Clinically actionable abnormality of CIED noted on remote monitoring, telemetry, or ambulatory monitoring ICD shocks, presyncope, or syncope concerning for an arrhythmic event, to perform programming changes Evaluation of symptoms suspicious for arrhythmia or abnormal device function in patients who are not enrolled in remote monitoring Identified need for reprogramming of the device For patients with CIED who need urgent or emergent magnetic resonance imaging scanning, consider performing a computerized tomography scan instead, if possible (to minimize the need for additional healthcare provider or device manufacturer representative contact); if not urgent, delay the magnetic resonance imaging Patients in the emergency department where remote monitoring is not available; remote monitoring should be used wherever possible Cardiac electrophysiologists have a responsibility to protect patients, their families, other caregivers, and themselves. This includes resource stewardship, keeping themselves safe while delivering care, and collaboration with other healthcare professionals on the front lines . ## Remote device monitoring A substantial number of electrophysiology patients with a CIED have remote monitoring, which remains a powerful tool for off-site cardiac rhythm management. Current guidelines give remote monitoring a class I recommendation for routine use in patients with CIEDs. [bib_ref] HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable..., Slotwiner [/bib_ref] Despite its effectiveness, remote monitoring is significantly underused because of a variety of patient-and system-based issues. Amid the pandemic, remote monitoring should be used in most circumstances to reduce the need for nonurgent clinic visits. When feasible, remote monitoring should be reconsidered in patients who are currently not enrolled. ## Resource conservation and training for all personnel As the pandemic spreads and affects more individuals, resource conservation becomes even more important. Accordingly, it is critical to conserve valuable resources, such as PPE, medical, and ancillary staff, by minimizing ## Minimizing clinical covid-19 exposure for cardiac electrophysiology teams and paɵents -nonprocedural care ## Outpaɵent clinic ## Cied clinic Telehealth/E-Visits Although there are limited published data currently available on arrhythmia management in patients with COVID-19, such data will be forthcoming. The number of personnel in the room of a patient experiencing cardiac arrest with confirmed or suspected COVID-19 during resuscitation efforts should be minimized. All participants should don PPE before entering the patient's room. Because of the risk of viral aerosolization, consideration should be given to early intubation along with the use of external mechanical compression devices and airborne precautions during intubation. At the time of this writing, it is unclear what medications may be beneficial for patients with COVID-19. Off-label use of some medications is currently being investigated. Although we are not recommending any specific treatment, safety guidance for clinicians using hydroxychloroquine may be requested of electrophysiology providers. Hydroxychloroquine is known to block Kv11.1 (HERG) and can cause drug-induced long QT. [bib_ref] Inhibition of hERG K1 currents by antimalarial drugs in stably transfected HEK293..., Traebert [/bib_ref] The clinical arrhythmic toxicity (syncope and torsade de pointes) is largely limited to chronic use (because of its long half-life of 40 days), use of multiple concomitant QT-prolonging medications (eg, azithromycin), Role of an electrophysiologist in being an important solution in managing a pandemic such as COVID-19. One has responsibility to self, family, patients, other healthcare professionals and to be a good steward for resource conservation. COVID-19 5 coronavirus disease 2019; PPE 5 personal protective equipment. metabolic derangements, renal failure, or in the setting of an acute overdose. [bib_ref] The hazards of chloroquine self prescription in West Africa, Demazi Ere [/bib_ref] [bib_ref] Cardiac toxicity secondary to long term treatment with chloroquine, Cervera [/bib_ref] To date, it has been widely tolerated in most populations as an antimalarial and has been safely used in the rheumatoid arthritis and systemic lupus erythematosus populations without ECG monitoring. [bib_ref] The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a..., Haeusler [/bib_ref] Because the proposed hydroxychloroquine therapy for COVID-19 is relatively short (eg, 5-10 days), the risk of arrhythmic toxicity is likely quite low. However, there are specific precautions to be considered for select patients, however: [formula] - [/formula] ## Cardiac electrophysiologists Patients with known congenital long-QT syndrome Patients with severe renal insufficiency should have the dose reduced (50% for CrCl ,10 mL/min) Patients on QT-prolonging drugs Electrolyte imbalances (eg, hypokalemia, hypomagnesemia) must be corrected before use, with regular monitoring None of these conditions is an absolute contraindication if use of hydroxychloroquine is warranted. It is reasonable to temporarily stop class III antiarrhythmic drugs, with use of a reasonable alternative if there is evidence of QT prolongation. It is important to note that aggressive electrolyte correction can mitigate arrhythmic toxicity. ECG monitoring should be considered for patients on multiple QT-prolonging medications and avoidance or careful monitoring may be required for patients with congenital long-QT syndrome. Additional guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of pharmacotherapies for COVID-19 has been recently published. [bib_ref] Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential..., Giudicessi [/bib_ref] # Concluding statements At this unprecedented time, it is important for patients to feel that physicians and healthcare systems are not abandoning them. Many patients with arrhythmias are among the sickest of those with cardiovascular disease. To protect patients (many of whom are at high risk because of coexisting comorbidities) and healthcare teams from COVID-19 exposure, preserve resources, and maintain access to necessary cardiovascular care, it is important that nonessential encounters, tests, and procedures be postponed. Although electrophysiology is uniquely suited to leverage virtual care and remote monitoring, it is important to assure patients that they have our full support, and we are ready and able to provide care as necessary. [fig] Figure 1: Guidance on EP procedures for urgent, semiurgent, or nonurgent procedures in the hospital setting. See text for details. AF 5 atrial fibrillation; AFL 5 atrial flutter; AV 5 atrioventricular; AVB 5 atrioventricular block; CHB 5 complete heart block; CIED 5 cardiac implantable electronic device; COVID-19 5 coronavirus disease 2019; CRT 5 cardiac resynchronization therapy; ED 5 emergency department; EOS 5 end of service; EP 5 electrophysiology; ERI 5 elective replacement indicator; HF 5 heart failure; ICD 5 implantable cardioverter defibrillator; ICU 5 intensive care unit; LAA 5 left atrial appendage; LBBB 5 left bundle-branch block; PAPR 5 powered air-purifying respirator; PM 5 permanent pacemaker; PPE 5 personal protective equipment; PUI 5 patient under investigation for COVID-19; PVC 5 premature ventricular contraction; RVR 5 rapid ventricular rate; SND 5 sinus node dysfunction; SVT 5 supraventricular tachycardia; TEE 5 transesophageal echocardiography; VT 5 ventricular tachycardia; WPW 5 Wolff-Parkinson-White. [/fig] [fig] Figure 2: Guidance on nonprocedural care in outpatient clinic visits and CIED monitoring in the outpatient and inpatient settings. CDC 5 Centers for Disease Control and Prevention; CIED 5 cardiac implantable electrical device; COVID-19 5 coronavirus disease 2019; ED 5 emergency department; ICD 5 implantable cardioverter defibrillator; PAPR 5 powered air-purifying respirator; PPE 5 personal protective equipment; PUI 5 patient under investigation for COVID-19. [/fig] [table] TABLE OF CONTENTS: Potential Risks of Exposure to Patients, Physicians, Allied Healthcare Staff, Industry Representatives, and Hospital Administrators [/table]	None	http://www.heartrhythmjournal.com/article/S1547527120302897/pdf	None
dd3cb93d21b61037a8fbdbdb03b2399a41a83143	pubmed	Carcinoma of the oesophagus	Carcinoma of the oesophagus Cancer of the oesophagus has an estimated incidence of 4600-5600 new cases per year in France and ranks third in frequency among digestive tract cancers after colon and gastric cancer. It is responsible for 3.9% of cancer deaths and is the fourth commonest cause of death after lung, colon, rectum and prostate cancer. The prognosis is very poor; the French registry shows a 5-year survival of only 3-6%. These recommendations concern only squamous (epidermoid) and adenocarcinomas of the oesophagus and none of the other rarer histological types. ## Diagnosis and initial assessment The diagnosis of cancer of the oesophagus is based on the histopathological study of biopsies taken by oesophagogastric fibroscopy. Staining with Toluidine blue or Lugol can be used to define more clearly the extent of the primary tumour and/or demonstrate a second site of disease (defined as a lesion more than 5 cm away from the primary lesion). Assessment of the extent of disease spread should include (standard) a complete clinical examination (including nutritional state), as well as fibreoptic bronchoscopy to exclude the presence of tracheo-bronchial mucosal extension or a synchronous primary lesion. A formal head and neck examination should be done to look for a synchronous lesion in the oropharynx. Other assessments include an analysis of respiratory function (blood gas analysis) as well as cardiological, hepatic and renal function (standard). Thoraco-abdominal CT scan or abdominal ultrasound, sub-clavicular ultrasound, oesophagogram and oesophageal echo-endoscopy are all options depending on the results of initial staging examinations. ## Classification There is no standard for the pre-therapeutic classification of oesophageal cancers. The us-TNM classification based on echoendoscopy is an option. The standard post-surgical classification is the pTNM classification of the UICC (1997). ## Treatment modalities ## Surgery The standard technique for curative surgery is a subtotal transthoracic oesophagectomy with concurrent nodal clearance and gastroplasty if possible. Surgical treatment is a recommended for stages I and II (disease localized to the oesophagus). This treatment remains an option for tumours extending beyond the oesophageal wall (involving the adventitia (T3) or involving nodes (NI)). Surgery is not recommended for tumours involving mediastinal organs (T4) or with distant metastases (M). The inclusion of patients in therapeutic trials is recommended especially for T3, N0-1 tumours. ## Radiotherapy If chemotherapy is contra-indicated, radiotherapy alone is recommended for the treatment of advanced or inoperable cancers of the oesophagus. Pre-or postoperative radiotherapy is not recommended for the treatment of oesophageal cancers (option). ## Chemotherapy Chemotherapy for the adjuvant treatment of oesophageal cancer is not recommended (option, level of evidence B). Therapeutic trials in which surgery alone is the control should be undertaken. Chemotherapy for the treatment of advanced oesophageal cancer is an option, but this must be considered case by case, and be given when possible within a trial context. ## Chemoradiation therapy Combined modality therapy with radiotherapy and chemotherapy is superior to radiotherapy alone for the non-surgical treatment of cancer of the oesophagus (level of evidence B). The RTOG schedule (four cycles of 5-FU-cisplatin (weeks 1, 5, 8, 11) and radiotherapy 50 Gy 25 fractions spread over 5 weeks, from week 1 to week 5) can be considered standard treatment for inoperable cases. It is superior to accelerated high dose per fraction (split course) radiotherapy (level of evidence B). Combined chemoradiation therapy is an alternative to surgery in operable disease that penetrates the wall of the oesophagus to involve the adventitia (T3) or nodes (N1) and also for T1 or T2 tumours (in certain institutions only). A formal comparison between surgery and chemoradiation therapy alone has never been undertaken. Preoperative chemoradiation therapy has not been proven to be superior to surgery alone in operable subjects with stage I and II epidermoid cancer of the thoracic oesophagus (level of evidence B). This treatment remains an option; further trials are necessary. In operable adenocarcinomas of the oesophagus or the oesophagogastric junction, the combination of chemoradiation therapy is efficacious when given preoperatively (level of evidence B). This treatment constitutes a therapeutic option but should still be given within randomized controlled trials. ## Endoscopic therapy This represents the standard for patients unfit for other treatments. Formal comparisons with other therapy in prospective trials are necessary to evaluate the impact on quality of life. ## Therapeutic strategy ## T1 n0-1 m0, t2 n0-1 m0 disease There is no standard treatment in operable patients . Surgical excision (level of evidence C) and combination ## Figure 2 Treatment of advanced stage disease chemoradiation therapy are options. Surgical resection is recommended. Preoperative chemoradiation therapy must be reevaluated within therapeutic trials. For patients with inoperable disease, chemoradiation therapy is the standard treatment. If chemotherapy is contra-indicated, radiotherapy alone is a therapeutic option. ## Us t3 n0-1 m0 disease There is no standard. Surgical excision, chemoradiation therapy (or radiotherapy alone if chemotherapy is contra-indicated) and chemoradiation therapy followed by surgery are the therapeutic options . Patients should be included in prospective randomized trials. ## Us t4 n0 and t4 n1 disease without invasion of the tracheal mucosa There is no standard. Palliative surgery, chemoradiation therapy or radiotherapy alone (if chemotherapy is contra-indicated) are options . Patients should be included in prospective randomised trials. US T4 N0 and T4 N1 disease with involvement of the tracheal mucosa a) Patients without oesophageal-respiratory tract fistulae. There is no standard. Endoscopic treatments for dysphagia and respiratory compromise or radiotherapy (using small doses per fraction) with or without chemotherapy for patients of reasonable performance status are therapeutic options. b) Patients with oesophageal-respiratory tract fistulae. The placement of an oesophageal and/or tracheo-bronchial stent constitutes standard treatment. ## Metastatic oesophageal cancer a) Coeliac axis and cervical node metastases (M1). There is no standard treatment. Chemotherapy, combination chemoradiation therapy and endoscopic treatments are therapeutic options. [fig_ref] Figure 3: Treatment of metastatic disease [/fig_ref] Visceral metastases. If the primary oesophageal tumour has not been resected, and if the patient is of good performance status (PS1 or 2), there is no standard. Combination chemoradiation therapy followed by chemotherapy alone (if there is evidence of an objective response), endoscopic treatment for dysphagia and/or chemotherapy are therapeutic options. If the oesophageal tumour has not been resected and if the patient is of poor performance status (PS3 or 4) the standard therapy is endoscopic therapy for the palliation of dysphagia. If the primary oesophageal tumour has been resected and if the patient has a good performance status (PS1 or 2) there is no standard. Chemotherapy, preferably within the context of a therapeutic trial is an option. If the oesophageal tumour has been resected and if the patient is of poor performance status, symptomatic treatment is standard. ## Non-metastatic adenocarcinoma of the cardiooesophageal junction If the patient has operable disease, surgical excision is standard. Preoperative chemoradiation therapy, preferably within a clinical trial is a therapeutic option. If the patient does not have operable disease, combination chemoradiation therapy is standard. When chemotherapy is contra-indicated, radiotherapy alone and/or endoscopic treatments are therapeutic options. ## Follow-up The follow-up of patients with oesophageal cancer relies on clinical examination focusing on dysphagia, nutritional status and the sites of likely nodal relapse. There is no consensus as to the interval between assessments (3-6 months). Paraclinical followup (i.e. by imaging and blood tests) is an option, especially if patients are entered into therapeutic trials. A formal head and neck examination should be undertaken 12-18 months after initial treatment in patients without recurrence. [fig] Figure 3: Treatment of metastatic disease [/fig]	None	https://europepmc.org/articles/pmc2408850?pdf=render	Cancer of the oesophagus has an estimated incidence of 4600‐ 5600 new cases per year in France and ranks third in frequency among digestive tract cancers after colon and gastric cancer. It is responsible for 3.9% of cancer deaths and is the fourth commonest cause of death after lung, colon, rectum and prostate cancer. The prognosis is very poor; the French registry shows a 5-year survival of only 3‐6%. These recommendations concern only squamous (epidermoid) and adenocarcinomas of the oesophagus and none of the other rarer histological types. These guidelines were validated in April 2000 and an update is planned for late 2000. The diagnosis of cancer of the oesophagus is based on the histopathological study of biopsies taken by oesophagogastric fibroscopy. Staining with Toluidine blue or Lugol can be used to define more clearly the extent of the primary tumour and/or demonstrate a second site of disease (defined as a lesion more than 5 cm away from the primary lesion). Assessment of the extent of disease spread should include (standard) a complete clinical examination (including nutritional state), as well as fibreoptic bronchoscopy to exclude the presence of tracheo-bronchial mucosal extension or a synchronous primary lesion. A formal head and neck examination should be done to look for a synchronous lesion in the oropharynx. Other assessments include an analysis of respiratory function (blood gas analysis) as well as cardiological, hepatic and renal function (standard). Thoraco-abdominal CT scan or abdominal ultrasound, sub-clavicular ultrasound, oesophagogram and oesophageal echo-endoscopy are all options depending on the results of initial staging examinations.
ea3cce96baafcd8a8502036b2a77c87c8661d5df	pubmed	Hepatocellular carcinoma	Hepatocellular carcinoma The incidence of hepatocellular carcinoma (HCC) has been rising steadily and varies between 2 and 5 per 100 000 per year in Europe and the USA. These tumours are associated with cirrhosis in 80% of cases.The major goals in this disease are to clarify the natural history of HCC, to evaluate the efficacy of a wide range of treatments and to carry out controlled trials in order to define which treatments are best in terms of risk and benefit.These recommendations relate to the management of primary hepatocellular carcinoma and its variants (e.g. fibrolamellar, clear cell and giant cell carcinoma) in both cirrhotic and normal livers.These guidelines were validated in June 1999 by the working group and an update is planned for 2001. ## Diagnosis With the exception of the cirrhotic patient with an alphafetoprotein (AFP) level greater than 500 mg ml -1 , the diagnosis of hepatocellular carcinoma (HCC) is based on the histopathological examination of one or more liver sample. These are obtained at open surgery, by laparoscopy or by ultrasound or CT scan-guided biopsy (standard). Fine-needle aspiration for cytology is an option for the diagnosis of HCC and can be considered if a liver biopsy is not possible. The ease of diagnosis depends on the quality and nature of the biopsy specimens and the histologic type of the lesions. If the level of AFP is normal in a cirrhotic patient, the level of gamma-carboxyprothrombin (in patients without a Vitamin K deficiency) can be measured (option). ## Staging Assessment of locoregional extension depends on clinical examination, liver ultrasonography and hepatic CT scanning (standard). MRI of the liver is an option. Standard investigations to assess distant spread include a chest X-ray (CXR), a spiral CT and a bone scan if this is clinically indicated. If a liver transplant is planned and the CXR is normal, a thoracic CT scan should be done. The evaluation of hepatic function depends on liver enzyme levels, serum albumin and a coagulation screen (standard). Endoscopy must be undertaken in the case of hepatic cirrhosis to exclude the presence of oesophagogastric varices (standard). In the case of diagnostic difficulty in differentiating an adenoma, a cholangiocarcinoma or a metastatic lesion, immunohistochemical staining to identify keratin subtypes and/or reticulin staining can be considered. ## Classification Primary HCC is classified according to the WHO classification (standard). There is no standard classification for the differentiation or grade of HCC. This can be done according to the grading of Edmonson or following the recommendations of the WHO (option). The standard classification for patients having a surgical resection is the TNM classification, where multiple tumours, large-diameter tumours and the invasion of vasculature and nodes are adverse prognostic factors. The associated pathological standard is the classification of Child-Pugh. For non-operable patients, the clinical classification system of Okuda can be used. This is useful but not without problems. ## Treatment modalities Resection is indicated for HCC in a cirrhotic liver when the tumour is single and non-metastatic and if there is no portal invasion (level of evidence C). The liver function must allow for the type of excision necessary according to the localization and size of the tumour. The majority of teams will undertake liver transplantation for unifocal HCC of less than 3 cm in diameters that is secondary to cirrhosis and has been discovered by chance. In the case of HCC in a healthy liver, excision by partial hepatectomy is the only surgical modality to be considered. It should be undertaken where there is no vascular involvement, no extrahepatic spread and when the tumour is uni-focal. Elective incomplete excision should be avoided. Percutaneous techniques (intratumoral injections of absolute alcohol or acetic acid) or ultrasonic thermo-ablation are alternatives when surgery is not possible (level of evidence C). Randomized studies are necessary to determine the exact place of these techniques in the treatment of HCC as compared to surgery and other techniques of local treatment. Chemo-embolization is not recommended for the treatment of HCC (option, level of evidence B). This therapy has no proven benefit with respect to survival over no therapy or systemic chemotherapy. This technique must be evaluated within randomized trials of adjuvant or neoadjuvant treatment. 'In situ' radiotherapy is an option for the treatment of inoperable patients with portal thrombosis (level of evidence C). Chemotherapy represents an area of research for the treatment of inoperable HCC, but the results to date are inferior to those of other treatment modalities. Immunotherapy is an option for the treatment of inoperable hepatocellular carcinoma (level of evidence C). It has questionable efficacy when compared to systemic chemotherapy. It place as adjuvant treatment within complex therapeutic strategies must be evaluated in randomized trials. Hormone therapy represents an option for palliative treatment in patients with inoperable or metastatic hepatocellular carcinoma in whom neither percutaneous techniques, chemo-embolization, nor in situ radiotherapy are possible (level of evidence C). The place of somatostatin must be confirmed by prospective randomized trials. ## Therapeutic strategy ## Hcc in a cirrhotic liver The objective of treatment in these patients is to improve survival and/or to provide palliation. There are no standard therapeutic approaches. Unifocal HCC (Single lesion HCC <5 cm maximum diameter) Child-Pugh A disease Surgical excision, hepatic transplantation and percutaneous techniques can be considered (options) . It is recommended that surgical excision be undertaken if at all possible and within a specialist setting (level of evidence C). The role of adjuvant treatment remains to be established. Child-Pugh B disease Hepatic transplantation, percutaneous techniques, the use of radioactive lipioidal or chemo-embolization can be considered (option) . It is recommended that the place of hepatic transplantation be evaluated within a formal protocol. Any surgery must be undertaken within a specialist setting (level of evidence C). In the case of a Child-Pugh B lesion of small size, percutaneous techniques are recommended (level of evidence C). Child-Pugh C disease Hepatic transplantation, hormone therapy or best supportive care can be considered (option). ## Unifocal hcc (single lesion hcc > 5 cm maximum diameter) Child-Pugh A and B disease Liver resection, chemoembolization (± alcohol injection) and radioactive lipioidal can be considered. If at all possible, resection should be undertaken within a specialist centre (level of evidence C). Child-Pugh C disease The objective of treatment is palliation. There is no standard therapy. Hormone therapy or best supportive care can be considered (option). ## Multifocal hcc without portal thrombosis Child-Pugh A and B If there are less or equal to three lesions of less than 5 cm in diameter, surgical resection, transplantation and percutaneous procedures can be considered . In other cases, chemo-embolization or radioactive lipioidal injections can be considered (option). Surgical excision is recommended for peripheral tumours (level of evidence C), hepatic transplantation for central tumours and percutaneous techniques for microtumours (tumours of less than 5 cm diameter) (level of evidence C). Child-Pugh C disease The objective of treatment in the management of these patients is palliation. Hormone therapy or symptomatic management alone can be considered (option) . ## Multifocal hcc with portal thrombosis Child-Pugh A and B disease These patients have inoperable disease. Radioactive lipioidal, chemo-lipioidal (without embolization) and external-beam irradiation (for lateral tumours) can be considered (option). Child-Pugh C disease The objective of treatment is palliation. Hormone therapy or symptomatic care can be considered (option). ## Metastatic hcc Child-Pugh A and B disease The objective of treatment is palliation. Chemotherapy, hormone therapy or symptomatic care can be considered (option) . Inclusion in ongoing therapeutic trials is recommended. Child-Pugh C disease The objective of treatment is palliation. Hormone therapy or symptomatic care can be considered (option). ## Hcc in a non-cirrhotic liver Single peripheral lesions Surgical excision by partial hepatectomy is standard treatment [fig_ref] Figure 4: Multifocal HCC in a non-cirrhotic liver [/fig_ref]. ## Single central lesions Surgical excision by partial hepatectomy is standard treatment [fig_ref] Figure 4: Multifocal HCC in a non-cirrhotic liver [/fig_ref]. ## Multifocal disease There is no standard treatment. Percutaneous techniques, chemoembolization or radioactive lipoidal can be considered (option) [fig_ref] Figure 4: Multifocal HCC in a non-cirrhotic liver [/fig_ref]. ## Metastatic hcc There is no standard treatment . Chemotherapy, highdose interferon, hormone therapy, surgical excision (if feasible) or symptomatic treatment alone can be considered (option) ## Follow-up There is no consensus regarding the pattern or modalities of follow-up in HCC apart from clinical examination. Hepatic ultrasonography, measurement of alpha-fetoprotein, abdominal CT scan, CXR and MRI imaging are all options. Surveillance should be planned according to the treatment given. ## Multifocal non-metastatic hcc in [fig] Figure 4: Multifocal HCC in a non-cirrhotic liver [/fig]	None	https://www.nature.com/articles/6691769.pdf	The incidence of hepatocellular carcinoma (HCC) has been r steadily and varies between 2 and 5 per 100 000 per year in E and the USA. These tumours are associated with cirrhosis in of cases. The major goals in this disease are to clarify the natural his of HCC, to evaluate the efficacy of a wide range of treatments to carry out controlled trials in order to define which treatments best in terms of risk and benefit. These recommendations relate to the management of pri hepatocellular carcinoma and its variants (e.g. fibrolamellar, c cell and giant cell carcinoma) in both cirrhotic and normal liver These guidelines were validated in June 1999 by the wor group and an update is planned for 2001.
1e152d8f4f193772064e2ecf960e708e7bfb9b49	pubmed	Techniques of biliary drainage for acute cholecystitis: Tokyo Guidelines	Techniques of biliary drainage for acute cholecystitis: Tokyo Guidelines # Introduction Biliary drainage used to be a surgical procedure consisting of external biliary drainage done under local anesthesia -called "percutaneous cholecystostomy". With the popularization of ultrasonography, percutaneous transhepatic gallbladder drainage (PTGBD), which is an interventional procedure, has become a standard method. The usefulness of PTGBD as a drainage method for high-risk patients is endorsed by many case-series studies (level 4), 1-8 but its superiority over conventional treatment has not been proven by randomized controlled trials (RCTs) based on the highest level of evidence (level 2b). [bib_ref] Treatment of acute cholecystitis by direct-puncture bile aspiration with ultrasound image control, Mizumoto [/bib_ref] Percutaneous transhepatic gallbladder aspiration (PTGBA), is an alternative biliary drainage method in which the gallbladder contents are punctureaspirated without placing a drainage catheter. The usefulness of PTGBA has been reported only in case-series studies (level 4). [bib_ref] Treatment of acute cholecystitis in non-critically ill patients at high surgical risk:..., Chopra [/bib_ref] [bib_ref] Acute cholecystitis in high-risk patients: percutaneous cholecystostomy vs conservative treatment, Hatzidakis [/bib_ref] [bib_ref] Effectiveness of ultrasound-guided percutaneous transhepatic gallbladder aspiration (PTGBA) for acute calculous cholecystitis, Kutsumi [/bib_ref] Acalculous cholecystitis is known to occur in elderly or high-risk patients with poor systemic condition, and it can be treated by biliary drainage alone (level 4). [bib_ref] Percutaneous cholecystostomy in acute cholecystitis in high-risk patients: an analysis of 69..., Kiviniemi [/bib_ref] [bib_ref] Is percutaneous cholecystostomy the optimal treatment for acute cholecystitis in the very..., Sugiyama [/bib_ref] [bib_ref] Acute acalculous cholecystitis, Babb [/bib_ref] [bib_ref] Surgical treatment of biliary tract infections, Lillemoe [/bib_ref] This article describes the details of drainage procedures used for acute cholecystitis, and indicates the grades of recommendation for the procedures established by the Guidelines. # Abstract The principal management of acute cholecystitis is early cholecystectomy. However, percutaneous transhepatic gallbladder drainage (PTGBD) may be preferable for patients with moderate (grade II) or severe (grade III) acute cholecystitis. For patients with moderate (grade II) disease, PTGBD should be applied only when they do not respond to conservative treatment. For patients with severe (grade III) disease, PTG-BD is recommended with intensive care. Percutaneous transhepatic gallbladder aspiration (PTGBA) is a simple alternative drainage method with fewer complications; however, its clinical usefulness has been shown only by case-series studies. To clarify the clinical value of these drainage methods, proper randomized trials should be done. This article describes techniques of drainage for acute cholecystitis. ## Procedures for gallbladder drainage ## Percutaneous transhepatic gallbladder drainage (ptgbd) PTGBD is an essential technique for nonoperative gallbladder drainage. After ultrasound-guided transhepatic gallbladder puncture is done with an 18-G needle, a 6to 10-Fr pigtail catheter is placed in the gallbladder, using a guidewire under fl uoroscopy (Seldinger technique; . The advantage of the technique is its simplicity. However, although bile aspiration and lavage are easily performed by this technique, it has disadvantages in that the drainage tube cannot be extracted until a fi stula forms around the tube (around 2 weeks) and there is a risk of dislocation of the tube. The superiority of PTGBD over conservative treatment has not be proven by RCTs (level 2b) [bib_ref] Acute cholecystitis in high-risk patients: percutaneous cholecystostomy vs conservative treatment, Hatzidakis [/bib_ref] Only the mandolin is removed and the external cylinder remains. c Backfl ow of bile is confi rmed. d A guidewire is inserted into the gallbladder. e After removal of the external cylinder, a drainage tube is passed over the guidewire into the gallbladder. The guidewire is then withdrawn, and the tube is fi xed to the skin ment 3 and less restriction of the patient's activity of daily living (ADL), but an RCT (level 2b) 12 has indicated that the drainage is less effective [fig_ref] Table 2: Comparisons of results for PTGBA and PTGBD [/fig_ref]. However, as it is known that the effect of drainage is enhanced when PTGBA is performed two times or more (level 4), [bib_ref] Effectiveness of ultrasound-guided percutaneous transhepatic gallbladder aspiration (PTGBA) for acute calculous cholecystitis, Kutsumi [/bib_ref] [bib_ref] Treatment of acute cholecystitis by direct-puncture bile aspiration with ultrasound image control, Mizumoto [/bib_ref] an RCT should be performed to confi rm the effect of PTGBA by comparing it with PTGBD not only in terms of drainage but also in terms of other outcomes, including complications and the effects on patients' ADL. ## Percutaneous transhepatic gallbladder aspiration (ptgba) PTGBA is a method to aspirate bile via the gallbladder with a small-gauge needle under ultra sonographic guidance ; it is an easy low-cost bedside-applicable procedure, without X-ray guidance. It has various advantages as compared with PTGBD, such as the absence of complications, including those caused by tube displacement, as it requires no drainage tube manage- [bib_ref] Treatment of acute cholecystitis by direct-puncture bile aspiration with ultrasound image control, Mizumoto [/bib_ref] PTGBA, 58 98% 81% (94% a ) 2.5% -* P < 0.05 a PTGBA was performed twice or more Through the ERCP catheter, a hydrophilic guidewire was passed beyond the obstruction. c A radiofocus guidewire was inserted into the gallbladder. d An ENG-BD catheter was inserted into the gallbladder for drainage For PTGBA, considering the potential for bile leakage into the peritoneal cavity, a transhepatic puncture route is chosen, and the gallbladder contents should be completely aspirated until the gallbladder collapses, as shown by ultrasound-guided checking of the needle tip . The use of a large-gauge (18-G) needle is convenient for aspirating highly viscous bile containing infl ammatory products and biliary sludge, but we should be careful to prevent bile leakage after removing the needle. While a small-gauge (21-G) needle has a lower risk of leakage after removal, aspiration of highly viscous bile is diffi cult with such needles and should be conducted while washing with saline containing antibiotics. Many stadies (level 2b, 4) 10-12 report the use of 21-G needles. ## Endoscopic nasogallbladder drainage (engbd) ENGBD is an external drainage procedure done by placing a 5-to 7-Fr tube, using a guide-wire technique, after selective cannulation into the gallbladder . ENGBD can be used for patients with severe comorbid conditions, especially those with end-stage liver disease, in whom the percutaneous approach is diffi cult to perform. However, because it requires a diffi cult endoscopic technique, and relevant case-series studies have been conducted only at a limited number of institutions (level 4), [bib_ref] Effi cacy of endoscopic retrograde cholecystoendoprosthesis (ERCCE) for cholecystitis, Tamada [/bib_ref] [bib_ref] Drainage of the gallbladder in patients with acute acalculous cholecystitis by transpapillary..., Johlin [/bib_ref] [bib_ref] Endoscopic transpapillary gallbladder drainage (ETGBD) for the treatment of acute cholecystitis, Nakatsu [/bib_ref] [bib_ref] Endoscopic stenting of the gallbladder for symptomatic gallbladder disease in patients with..., Shrestha [/bib_ref] [bib_ref] Endoscopic naso-gallbladder drainage in the treatment of acute cholecystitis: alleviates infl ammation..., Toyota [/bib_ref] ENGBD has not been established as a standard method. The Guidelines established the following grades of recommendation for gallbladder drainage, based on the currently available evidence. ## Q1. what procedure should be chosen when gallbladder drainage is required in acute cholecystitis? by the Japanese Ministry of Health, Labour, and Welfare. We also truly appreciate the panelists who co operated with and contributed signifi cantly to the International Consensus Meeting, held in Tokyo on April 1 and 2, 2006. [fig] Fig: 1a-e. Percutaneous transhepatic gallbladder drainage (PTGBD) procedure. a A hollow needle (external cylinder with a mandolin) is inserted into the gallbladder. b [/fig] [table] Table 2: Comparisons of results for PTGBA and PTGBD [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs00534-006-1155-8.pdf	None
39d67918ea78a03129ab25d3ccffbc6d57c89fea	pubmed	Assessment of acute myocardial infarction: current status and recommendations from the North American society for cardiovascular imaging and the European society of cardiac radiology	Assessment of acute myocardial infarction: current status and recommendations from the North American society for cardiovascular imaging and the European society of cardiac radiology There are a number of imaging tests that are used in the setting of acute myocardial infarction and acute coronary syndrome. Each has their strengths and limitations. Experts from the European Society of Cardiac Radiology and the North American Society for Cardiovascular Imaging together with other prominent imagers reviewed the literature. It is clear that there is a definite role for imaging in these patients. While comparative accuracy, convenience and cost have largely guided test # Introduction In order to improve the accuracy of the diagnosis of myocardial infarction (MI) for clinicians and clinical scientists, multinational task forces met in 1999-2000 under the auspices of the European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the World Heart Federation (WHF) in order to develop a simple, clinically oriented, universal definition for MI that could be employed both in daily clinical practice and in clinical investigation. The report of the original task force was published simultaneously in the European Heart Journal and the Journal of the American College of Cardiology in 2000 and later updated by a joint ESC/ACCF/AHA/WHF task force . A consensus report the British Cardiovascular Society developed the definition into three clinical categories [6] (a) Acute Coronary Syndrome (ACS) with clinical myocardial infarction in which there is a raised troponin greater than 1 ng/ml± raised CK-MB or AccuTn1 greater than 0.5 ng/ml. These patients usually have a complete coronary occlusion, evidence of left ventricular dysfunction and ECG changes of ST elevation, ST depression, or T wave inversion and the risk of death in this syndrome is 12-15%. (b) The patient may have an acute coronary syndrome with myocardial necrosis in which case the troponin although elevated is less than 1 ng/ml. The patient usually has intracoronary thrombus and some evidence of left ventricular dysfunction, the risk of death in this intermediate state is 8-12%. The third syndrome is (c) acute coronary syndrome with unstable angina. In this syndrome the troponin and/or other biomarkers are not raised and the ECG changes of ST depression or elevation may be transient. This syndrome has a reduced risk of death and usually is not associated with left ventricular dysfunction. Coronary plaque disruption and partial coronary occlusion may be present. After the onset of insufficient myocardial oxygneation, it takes several hours before larger amounts of cell death occur and myocardial necrosis can be identified by macroscopic or microscopic post-mortem examination. Complete necrosis of all myocardial cells within the area at risk requires at least 2-4 h or longer depending on the presence of collateral circulation to the ischemic zone, persistent or intermittent coronary arterial occlusion, the sensitivity of the myocytes to ischemia, pre-conditioning, and/or, finally, individual demand for myocardial oxygen and nutrients. However, in terms of clinical therapy it is essential that the diagnosis of an acute coronary syndrome should be established quickly and accurately as therapy has to be instigated to limit myocardial necrosis. The concepts of 'door to needle time' for thrombolysis and 'door to balloon time' have been established for primary percutaneous coronary artery interventions (PCI) . In patients presenting with acute myocardial infarction (AMI) present with ST elevation (STEMI) , delays in primary PCI increase mortality. The tight window for STEMI allows very little time for additional diagnostic steps including imaging with the exception of the pre PCI coronary angiogram and an emergency room diagnostic cardiac ultrasound. Myocardial infarction without ST elevation presents a different clinical situation. It is essential that the diagnosis is established correctly in order that appropriate treatment can be commenced. In these acute cases the ECG changes may include left bundle branch block or signs of ischemia on the ECG. Myocardial infarction may be ''silent.'' In the Framingham study, over 30 years 1 in 4 myocardial infarcts were detected because of routine biannual ECG examinations and several recent magnetic resonance trials have demonstrated a significant proportion of unrecognized myocardial infarction. Patients may also present atypically whilst undergoing myocardial infarction and in these cases imaging may play a significant role. Myocardial infarctions are usually classified by size: microscopic (focal necrosis), small (\10% of the left ventricular myocardium),moderate (10-30% of the LV myocardium), and large ([30% of the LV myocardium), and by location . The pathological identification of myocardial necrosis is made without reference to morphological changes in the coronary arterial tree or to the clinical history. The ''universal'' definition of myocardial infarction of the ESC/ACCF/AHA/WHF task force included the use of imaging tests and cardiac biomarkers . The imaging evidence of a new loss of myocardium or new regional wall motion abnormality is now a key part of the definition of myocardial infarction. This widened definition offers the opportunity for the use of a range of imaging tests. This paper from the European Society of Cardiac Radiology and the North American Society for Cardiovascular Imaging aims to discuss the use and context of these tests in the diagnosis of acute myocardial infarction and to widen the guidelines for imaging in the light of these new developments. ## Physiologic assessment of myocardial infarction ## Ecg ## St elevation myocardial infarction (stemi) Myocardial infarction is stratified according to the presence or absence of elevation of the ST-segment. The presence of ST-segment elevation denotes total occlusion of a coronary artery and identifies patients who would benefit from reperfusion therapy, either with the administration of thrombolytic agents or preferably by primary percutaneous coronary intervention . By definition, in order to diagnose a STEMI, STsegment elevation of greater than 0.1 mV should be present in at least two contiguous limb or precordial leads, with the exclusion of aVR, which ''sees'' the left ventricular cavity. However, in leads V1-V4, a higher ST-segment elevation of greater than 0.2 mV has greater specificity and diagnostic accuracy. There are two situations where there is total occlusion of an artery causing an AMI, and would benefit from early reperfusion therapy, in which ST-segment elevation may not be present in the 12-lead ECG; AMI of the posterior wall and the new presence of left bundle branch block (LBBB). True posterior AMI is suspected when there is marked ST-segment depression in leads V1-V4 along with tall R waves and upright T waves in right precordial leads. In these cases, posterior leads V7 and V8 should demonstrate STsegment elevation and lead to the correct diagnosis. Patients with new or presumably new LBBB caused by AMI are at high risk; however, the presence of LBBB may lead to delays in diagnosis and management. Three characteristics have been associated with new MI in the presence of LBBB, and, when present, prompt for urgent management; ST elevation greater than or equal to 0.1 mV in leads with a positive QRS, ST depression greater than or equal to 0.1 mV in V1-V3, and ST elevation greater than or equal to 0.5 mV in leads with a negative QRS . It should be mentioned that in the hyperacute phase (during the first 2-30 min) of an AMI the ECG may occasionally demonstrate hyperacute T waves instead of ST-segment elevation. These T waves should be distinguished from the peaked T waves caused by hyperkalemia. Furthermore, it should be emphasized that the presence of ST-segment elevation does not necessarily denote myocardial infarction. Over 90% of healthy young men have at least 0.1 mV of ST-segment elevation in at least one precordial lead, a normal finding designed as a male pattern . This prevalence declines with age, reaching 30% in men 76 years of age or older. Other ECG mimics of acute myocardial infarction include early repolarization, acute pericarditis, myocarditis, hyperkalemia, Brugada syndrome, paced rhythm, apical left ventricular ballooning syndrome, and left ventricular aneurysm. The presence of reciprocal changes on the 12 lead ECG may help distinguish Int J Cardiovasc Imaging (2011) 27:7-24 9 true acute myocardial infarction from the mimics of acute myocardial infarction. The contour of the ST segment may also be helpful, with a straight or upwardly convex (non-concave) ST segment favouring the diagnosis of acute myocardial infarction. ## Estimation of infarct size and reperfusion therapy The ECG may be helpful in the estimation of size of myocardium at risk for necrosis. The number of leads showing ST-segment deviation (elevation or depression) and the magnitude of the ST-segment deviation are associated with the size of the ischemic myocardium and with prognosis. The final infarct size, however, also depends on the timing and the efficacy of the reperfusion therapy. ECG has been for long used to assess the efficacy of reperfusion. be a sign of extend of ischemia and provide important prognostic information independent of other predictors, such as clinical markers and cardiac biomarkers. The presence of ST-segment depression in at least 3 ECG leads and maximal ST-segment depression of at least 0.2 mV in patients with chest pain is associated with greater likelihood of NSTEMI . Furthermore, the presence of ST-segment deviation is associated with poorer prognosis than isolated T-wave changes . The presence of greater than or equal to 0.2 mV symmetrical precordial T-wave inversion is associated to acute ischemia due to a critical stenosis of the left anterior descending coronary artery (LAD) and it is associated with poor prognosis . NSTEMI that is associated with the above changes will usually be caused by thrombus in a coronary artery, which may unlike a STEMI not be totally occlusive. ## Cardiac biomarkers For patients with a moderate or high probability of ACS, physicians usually perform assays of markers of myocardial injury such as the cardiac troponins T or I (cTnT or cTnI) or creatinekinase-MB [3, 21]. The ideal serum marker for myocardial injury would be specific to myocardium, highly sensitive and quantitative with rapidly increased serum levels for early diagnosis. Troponins now are the 'gold standard' method for diagnosis of myocardial infarction [20-23]. Cardiac troponin I and troponin T are proteins that regulate the calcium-dependent interactions between actin and myosin and have been shown to be very sensitive and specific markers of myocardial cell injury. Different genes encode troponins T and I in cardiac muscle, slow skeletal muscle, and fast skeletal muscle; hence, the assays for cardiac troponins are more specific than CK-MB for myocardial injury. They start to rise approximately 4-6 h after the onset of ACS and peak at approximately 24 h. Troponin measurements remain elevated for 7-14 days after the onset of the pain, giving long diagnostic window. An increased value of elevated troponin is assessed as a measurement exceeding the 99th percentile of a normal specificity for AMI. In addition, troponin I provides a higher degree of test specificity than troponin T. Blood samples should be taken on the first hours of the pain onset, 6-9 h later and another sample between 12 and 24 h if the previous measurements were not elevated but the clinical suspicion was high . Even low-level increases of cardiac troponin are associated with an increased rate of recurrent cardiovascular events. ## Catheter based angiography With the rapid development of primary angioplasty catheter angiography and percutaneous intervention have become central to the diagnostic and treatment of myocardial infarction. Primary PCI (percutaneous coronary intervention) is superior to fibrinolytic therapy in reducing the rates of death, reinfarction, intracranial bleeding, reocclusion of the infarct artery, and recurrent ischemia (even when interhospital transport to a PCI-capable center is required) when performed in a timely fashion by experienced centres . If a primary angioplasty protocol is being followed after an ECG based diagnosis of STEMI, the patient is transferred within the door-to-balloon time to a cardiac catheter laboratory. Imaging studies after PCI for STEMI have the possibility of adding value by defining risk stratification. The feasibility and safety of performing cardiac magnetic resonance (CMR) in the hyperacute phase of STEMI was recently verified in a series of 64 patients after PPCI (primary percutaneous coronary intervention) . If primary angioplasty is not available, thrombolysis is the next treatment of choice following which if there is incomplete resolution of the chest pain and ECG changes, 'rescue angioplasty' is often undertaken. On a world wide basis fibrinolytic therapy is the most common treatment for STEMI . However, approximately 20% of patients who suffer STEMI are not suitable for thrombolysis. Many of these patients, however, do not have access to coronary angioplasty. There are two general exceptions to the rule that patients who suffer STEMI should undergo primary PCI as the preferred option. These are: (1) patients with STEMI presenting greater than 12 h from symptom onset without ongoing symptoms of ischemia or clinical instability; and (2) after successful treatment of the culprit artery by PCI or fibrinolysis, revascularization of non-culprit arteries before hospital discharge in patients without clinical instability, with no evidence of recurrent or provokable ischemia, and with a normal LVEF [32]. There is almost certainly a role for non-invasive imaging in these groups of patients who either do not require or do not have access to PCI and catheter angiography. If the patient suffers a NSTEMI, the patient may also be transferred acutely to the catheter lab as myocardial necrosis also occurs in this condition. The catheter lab therapy follows similar protocols to the treatment of STEMI. Infarct size as measured by acute CMR techniques has been found to smaller in NSTEMI than STEMI [33]. ## Spect imaging Myocardial perfusion imaging in acute coronary syndrome Acute rest myocardial perfusion SPECT has also been shown to reduce health care costs and length of hospital stay in two randomized studies . Stowers et al. reported a median hospital costs of $1,843 less for patients in the imaging-guided arm, in which the SPECT imaging results were available to the ED physician. A prospective, randomized study (ERASE Chest Pain) conducted in 7 institutions enrolled 2,475 ED patients who were randomized to either routine management in the ED or a management strategy that included acute rest myocardial perfusion SPECT. Hospitalization was reduced from 52% with routine management strategy to 42% with imagingguided strategy. Logistic hurdles have constrained the widespread use of acute rest myocardial perfusion SPECT. The radiotracer injection should take place during symptoms or within few hours of the last chest pain episode for optimal diagnostic value of the test. There should be around the clock availability of the radiopharmaceutical and radiation safety trained staff in the ED. Patients with a previous history of myocardial infarction or coronary intervention are not good candidates for acute rest myocardial perfusion SPECT because a perfusion defect, if present, may represent an old myocardial infarction. The INSPIRE study was a prospective multinational clinical trial [42-44] designed to evaluate the role of myocardial perfusion SPECT as a risk assessment tool in stable patients within 10 days after acute myocardial infarction. One-day nitrateenhanced rest and adenosine stress myocardial perfusion SPECT was performed in 728 patients with either ST-elevation or non-ST-elevation myocardial infarction. The INSPIRE trial demonstrated that coronary angiography can be safely avoided in stable acute myocardial infarction patients with small (\20%) total defect size, minimal ischemia (\10%), and preserved LV function. These patients had a low (\2%) death/reinfarction event rate at considerably lower associated costs and shorter length of hospital stay compared with the higher-risk patients. ## Rb-82 pet/ct in the assessment of myocardial infarction Hospitals with chest pain observation units have developed alternative methods to triage chest pain patients. After myocardial infarction has been excluded by ECG and biomarkers, stress or rest/ stress myocardial perfusion imaging is performed. A complete rest/stress imaging protocol is best used in patients with a previous history of myocardial infarction and/or revascularization. Rubidium myocardial perfusion positron emission tomography (PET) is an attractive approach in chest pain unit patients. Rubidium is always available because in contrast to other PET perfusion tracers (such as N-13 ammonia and O-15 water) that require an in-house cyclotron for production, rubidium is generator produced. Overall rubidium PET allows better diagnostic accuracy and higher patient throughput when compared to any SPECT protocol. In a retrospective study 1,177 patients who presented with chest pain to the ED were referred for rest/stress rubidium myocardial perfusion PET . Of the 1,177 patients, 95.4% had normal images and 4.6% had abnormal images. Of the abnormal group, 52% had obstructive CAD at coronary arteriography while 41% were deemed to have ACS by clinical assessment. ## Ischemic memory imaging in acute coronary syndrome Following an ischemic episode, restoration of coronary blood flow precedes normalization of myocardial metabolism by many hours. This process of metabolic alteration is described as ischemic memory or metabolic stunning. Metabolically stunned myocardium preferentially uses glucose rather than free fatty acids as its primary source of energy. This metabolic phase can be used to evaluate patients in whom the chest pain has subsided upon arrival to the ED. Radioactive glucose (FDG) imaging demonstrates selective tracer uptake in stunned myocardium if the patient is injected at a fasting state [46-48]. Ischemic memory imaging has also been tested with I-123 BMIPP, a free fatty acid analogue . I-123 BMIPP SPECT images are the mirror images of FDG: normal myocardium concentrates I-123 BMIPP whereas stunned myocardium does not. Two clinical studies by Kawai et al. have shown the potential use of I-123 BMIPP ischemic memory imaging in the ED. The first report [51] included a total of 111 patients who presented with acute coronary syndrome. All patients underwent I-123 BMIPP SPECT and coronary angiography within one to 4 days. The sensitivity for obstructive coronary disease or spasm at angiography was 74% and the specificity was 92%. An ongoing clinical trial in the United States will better define the value of I-123 BMIPP in ED patients. ## Echocardiography Each year in the United States, about 4 million people undergo evaluation at the Emergency Department for acute chest pain and more than 50% are admitted to the hospital. Accurate evaluation of patients with chest pain without electrocardiographic changes and no elevation of serum levels of cardiac enzymes is difficult because of the low specificity of clinical variables . Echocardiography is used not only to triage patients with suspected myocardial infarction, but it is also used in the acute phase of myocardial infarction (MI) as a diagnostic and prognostic tool. Evaluation of patients with acute chest pain in the emergency room comprises a frequent and sometimes difficult to resolve problem. Echocardiography has an important role in establishing the diagnosis, location, and extent of AMI, diagnosing possible associated mechanical complications of the AMI, and can provide prognostic information that is important for risk stratification. The American Heart Association, and the American Society of Echocardiography (ACC/AHA/ASE) gave a class I recommendation to the use of echocardiography in the diagnosis of suspected acute ischemia or infarction not evident by standard means [bib_ref] ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography-summary article: a..., Cheitlin [/bib_ref]. Echocardiographic changes in AMI, occur before the onset of electrocardiographic changes or the development of symptoms. Within seconds from the occlusion of the coronary artery, severe ischemia produces regional wall motion abnormalities that can be visualized by cardiac ultrasound [bib_ref] Myocardial perfusion imaging for detection of silent myocardial ischemia, Beller [/bib_ref]. Furthermore the effects of the acute myocardial injury in the diastolic function of the left ventricle are important and can be determined by Echocardiography. Echocardiography can determine the location and extent of the AMI, can access the left ventricular segments involved, the severity of the wall motion abnormality of the segments involved, calculate the wall motion score index (WMSI) and can detect possible mechanical complications. The availability and use of echo-contrast agents have resulted in better left ventricular opacification and better visualization of the left ventricular endocardium making it easier to access segmental wall motion abnormalities as well as with special protocols visualize myocardial perfusion. The use of contrast has expanded the capability of conventional 2D echocardiography in the assessment of left ventricular function. Echocardiography is very helpful in determining the presence or not of a thrombus in the left ventricle and makes it easier to differentiate the thrombus from an artifact or trabeculations especially in dealing with difficult images. Myocardial contrast echocardiography (MCE) correlates with angiographic methods of perfusion assessment such as myocardial blush grade after thrombolysis [bib_ref] Myocardial perfusion assessed by contrast echocardiography correlates with angiographic perfusion parameters in..., Tomaszuk-Kazberuk [/bib_ref]. After acute myocardial infarction, low dose dobutamine stress echo can be performed safely in stabilized patients who did not undergo coronary revascularization-under some strict indications: electrical stability, absence of symptoms, no signs of severe cardiac failure, negative enzymes-in order to assess risk stratification, global and regional ventricular function and the presence and extent of residual myocardial ischemia. Especially in patients with low EF due to ischemic cardiomyopathy dobutamine stress echocardiography (DSE) can predict cardiac death, a strong end point in patients who did not undergo early revascularization [bib_ref] Comparison of intravenous myocardial contrast echocardiography and low-dose dobutamine echocardiography for predicting..., Hillis [/bib_ref] [bib_ref] American Society of Echocardiography recommendations for performance, interpretation, and application of stress..., Pellikka [/bib_ref]. DSE can also localize restenosis or graft occlusion and assess adequacy of revascularization after acute coronary syndrome [bib_ref] American Society of Echocardiography recommendations for performance, interpretation, and application of stress..., Pellikka [/bib_ref] [bib_ref] Prognostic value of dobutamine stress echocardiography in patients with previous coronary revascularisation, Bountioukos [/bib_ref] [bib_ref] American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society..., Douglas [/bib_ref]. The extent of myocardium at risk, affects the benefit from reperfusion strategies. In the presence of transmural acute myocardial infarction (ST elevation AMI), cardiac echo will show akinesia or dyskinesia of the myocardial segments, and early reperfusion may lead to the reversal of this effect. Sequential echocardiograhic examinations have shown that the improvement of the myocardial contraction is visible within 24-48 h from reperfusion therapy if the reperfusion is performed early after the event. The persistent akinesia does not indicate failure of thrombolysis. If the reperfusion therapy does not achieve perfusion of [75% of the transmural thickness of the myocardial wall, the myocardial segments may remain akinetic. In case that akinesia remains but viability exists, low dose dobutamine stress echo (DSE) will result in a biphasic response with increase in contractility of the previously akinetic myocardial segment with low dose dobutamine. In case of absence of viability, low dose of dobutamine will have no effect on the wall motion of the affected segment. Furthermore, in survivors of a first AMI, DSE allows effective risk stratification on the basis of the presence, severity, and extent the induced ischemia [bib_ref] Pharmacologic stress echocardiography predicts total mortality early after acute myocardial infarction, Sicari [/bib_ref]. It is feasible and safe early after uncomplicated myocardial infarction and allows effective risk stratification on the basis of the presence, severity, extent and timing of the induced ischemia. In particular, the risk of death doubles in patients who develop ischemia at high doses of Dobutamine infusion and almost quadruples in patients with ischemia at low doses (early stages of the dobutamine stress echo protocol) [bib_ref] Prognostic value of dobutamine-atropine stress echocardiography early after acute myocardial infarction. Echo..., Sicari [/bib_ref]. ## Cardiac magnetic resonance imaging The assessment of myocardial necrosis by the method of late gadolinium enhancement (LGE) imaging is based on essentially two premises, which were initially established in experimental studies of acute myocardial infarction. The loss of myocyte membrane or sarcolemmal integrity during myocardial ischemia is recognized to be tantamount to the loss cell-viability, and myocardial viability. All available evidence suggests that myocytes can not recover from this disruption of the sarcolemma [bib_ref] The cell biology of acute myocardial ischemia, Jennings [/bib_ref] [bib_ref] Myocyte swelling and plasmalemmal integrity during early experimental myocardial ischemia in vivo, Sage [/bib_ref]. The extracellular contrast agents, once they can enter the intra-cellular space, can cause significantly higher contrast enhancement than in normal, viable myocardium, if sufficient time is allowed for the contrast agent to reach an infarct zone after contrast injection. Post-infarct tissue remodeling leads subsequently to a significant increase of the interstitial space. Animal studies comparing Gd-DTPA enhanced MR with the standard of reference 99 m Tc-DTPA autoradiography showed widely different distribution volumes for extracellular contrast agents in viable and necrotic myocardium, both in acute and chronic myocardial infarction [bib_ref] Measurement of the distribution volume of gadopentetate dimeglumine at echo-planar MR imaging..., Arheden [/bib_ref] [bib_ref] Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and..., Kim [/bib_ref]. The distribution volume for Gd-based contrast agents in normal myocardium is on the order of 25%, compared to 70% or higher in necrotic myocardium [bib_ref] Determining the extent to which delayedenhancement images reflect the partition-coefficient of Gd-DTPA..., Thornhill [/bib_ref]. However, the difference of contrast agent concentrations between the different compartments (infarct, viable tissue, blood) is not constant due to complex wash-in and wash-out kinetics. Consequently, the techniques used for LGE imaging have to take into consideration both the time evolution of contrast enhancement of infarcted, normal myocardium, and possibly the blood pool, and also maximize this contrast through the pulse sequence parameters and contrast dosage. Initial studies had focused on validating the LGE technique in animal models of acute myocardial infarction. A time delay of approximately 20 min between contrast injection and LGE image acquisition was considered optimal for the detection of myocardial infarction and yielded good agreement with histology [bib_ref] Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and..., Kim [/bib_ref]. Delivery of the contrast agent to the infarct zone is generally limited by blood flow to the infarct zone for the first couple of minutes after contrast injections, in particular in the absence of recanalization. Despite this, a more recent study by the original pioneers of the LGE technique established that a time delay as short as 5 min post injection may be sufficient for a reliable detection of acute myocardial infarcts, provided the contrast settings for the image acquisition are adjusted [bib_ref] Effects of time, dose, and inversion time for acute myocardial infarct size..., Wagner [/bib_ref]. In a recent multicenter trial with a Gd-based contrast agent in patients with acute and chronic infarctions the authors reported that images acquired at 10-and 30-min after contrast injection appeared to yield equal performance for the detection of MI [bib_ref] Performance of delayed-enhancement magnetic resonance imaging with gadoversetamide contrast for the detection..., Kim [/bib_ref]. LGE disappears as the contrast agent is eliminated from the blood pool, with a half time in the blood pool on the order of 30 min for the Gd-based contrast agents. Contrast delivery can be impaired during an early phase by microvascular obstruction, which is a result of the blockage of the microcirculation in the infarct zone due to physical obstruction of capillaries by leukocytes, compression of capillaries and hemorrhage. Microvascular obstruction is generally most pronounced at the core of a myocardial infarct. Microvascular obstruction has a clear signature in MRI as a core zone in an infarct that does initially not enhance after contrast injection, but is surrounded within the LV wall by non-viable myocardium with sufficient up-take of contrast agent to show hyperenhancement [bib_ref] Magnitude and time course of microvascular obstruction and tissue injury after acute..., Rochitte [/bib_ref] [bib_ref] Quantification and time course of microvascular obstruction by contrastenhanced echocardiography and magnetic..., Wu [/bib_ref]. The initially dark infarct core then slowly fills in with contrast over a couple of minutes. A typical LGE image of a patient with microvasvcular obstruction after a recent acute myocardial infarction is illustrated in [fig_ref] Figure 1: Example of a 76 year old male patient with an acute myocardial... [/fig_ref]. The exact mode of contrast delivery in areas with microvascular obstruction remains poorly understood but may be related to diffusive rather than convective transport of the contrast agent to the infarct core. The hypoenhancement lasts for approximately 10 min or less after injection of Gd-based contrast agents, and eventually the core of the infarct also enhances [bib_ref] Regional heterogeneity of human myocardial infarcts demonstrated by contrast-enhanced MRI. Potential mechanisms, Lima [/bib_ref]. First pass perfusion imaging may be an even more sensitive method to detect microvascular obstruction [bib_ref] Use of cardiovascular magnetic resonance imaging in acute coronary syndromes, Lockie [/bib_ref]. Myocardial edema has been shown to accompany acute myocardial infarction following cellular swelling and increased intracellular osmolarity. The signal intensity of T2-weighted MR techniques have been shown to correlate with the amount of myocardial water content in experimental infarcts and have proven to reliably visualize myocardial edema in AMI [bib_ref] Delayed enhancement and T2-weighted cardiovascular magnetic resonance imaging differentiate acute from chronic..., Abdel-Aty [/bib_ref] [bib_ref] Regional myocardial blood flow, edema formation, and magnetic relaxation times during acute..., Brown [/bib_ref] [bib_ref] Black blood'' T2-weighted inversion-recovery MR imaging of the heart, Simonetti [/bib_ref] [bib_ref] Effects of transient coronary ischemia and reperfusion on myocardial edema formation and..., Slutsky [/bib_ref] [bib_ref] Characterization of the peri-infarction zone using T2-weighted MRI and delayed-enhancement MRI in..., Stork [/bib_ref]. In patients with chronic myocardial infarction (CMI) no increase in SI is exhibited in T2weighted imaging [bib_ref] Cardiovascular magnetic resonance of acute myocardial infarction at a very early stage, Schulz-Menger [/bib_ref]. The extent of the myocardial edema in AMI though not only delineates the infarcted area itself, but also the threatened periinfarct regions the so-called ''area at risk'' [bib_ref] Characterization of the peri-infarction zone using T2-weighted MRI and delayed-enhancement MRI in..., Stork [/bib_ref] [bib_ref] Retrospective determination of the area at risk for reperfused acute myocardial infarction..., Aletras [/bib_ref] [bib_ref] Value of t2-weighted magnetic resonance imaging early after myocardial infarction in dogs:..., Dymarkowski [/bib_ref]. Based on its high accuracy ([95%) T2 weighted MR imaging is the current MR approach to identify and differentiate acute from chronic myocardial infarction [bib_ref] Characterization of the peri-infarction zone using T2-weighted MRI and delayed-enhancement MRI in..., Stork [/bib_ref]. It also allows visualizing the effect of revascularization, as most of the area at risk will subsequently become necrotic, if no revascularization is performed. As the image quality of SE or FSE based MR techniques may be subject to major variation and these techniques also result in a significant time effort recent technical developments further improve and push the application of T2 weighted techniques in infarction assessment [bib_ref] Retrospective determination of the area at risk for reperfused acute myocardial infarction..., Aletras [/bib_ref]. A timely and reliable diagnosis of MI is required for proper treatment of patients in the acute setting, to improve the patients' outcome and to reduce the rate of re-events. A considerable number of patients, though may experience silent MI without noticing and thus during routine checkup there might be no evidence of MI in serum enzymes tests or even ECG [bib_ref] Comparison of prevalence of unrecognized myocardial infarction and of silent myocardial ischemia..., Deluca [/bib_ref] [bib_ref] The prevalence and prognosis of unrecognized myocardial infarction and silent myocardial ischemia..., Feringa [/bib_ref]. In a diabetic population in up to 28% of the patients LGE may be present without any clinical evidence of previous MI [bib_ref] Incidence and prognostic implication of unrecognized myocardial scar characterized by cardiac magnetic..., Kwong [/bib_ref]. However, these patients would also substantially benefit from This indicates almost no myocardial salvage after successful revascularization of the LAD. b shows the T2* image at TE = 15 ms and d the T2* imaging map of the T2* mapping. The central dark area (white arrow) represents pixels with a T2* decay \20 ms indicating postreperfusionhemorrhage aggressive secondary prevention measures as for patients with known history of MI. Especially subtle silent subendocardial infarction may be missed by lab testing, ECG or even nuclear medicine tests [bib_ref] Contrastenhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging..., Wagner [/bib_ref]. In patients presenting with symptoms of acute MI the delineation of possible previous MI is also of major importance and may contribute to further patient triage. Several recent clinical studies have indicated the multi-faceted approach by CMR can characterize the spectrum of disease in patients with acute coronary syndromes with high accuracy. A resting study that consists of myocardial perfusion, cine function, and LGE performed in the emergency room can detect acute coronary syndromes at a high sensitivity and specificity [bib_ref] Detecting acute coronary syndrome in the emergency department with cardiac magnetic resonance..., Kwong [/bib_ref]. The addition of T2weighted imaging of area-at-risk improves the specificity to detecting acute coronary syndrome by assessing the acuteness of the ischemic event [bib_ref] Cardiac magnetic resonance with T2-weighted imaging improves detection of patients with acute..., Cury [/bib_ref]. Adding stress perfusion enhances the test's sensitivity [bib_ref] Assessment of non-ST-segment elevation acute coronary syndromes with cardiac magnetic resonance imaging, Plein [/bib_ref] and has been shown to be a powerful risk stratifying tool to adverse cardiac events within 12 months after hospital presentation [bib_ref] Prognosis of negative adenosine stress magnetic resonance in patients presenting to an..., Ingkanisorn [/bib_ref]. Areas initially involved in acute myocardial infarctions do undergo a steady process of change in their composition within the first days and weeks. This process includes resorption and scar tissue formation with possible ventricular remodeling that may further deteriorate global cardiac function. In the acute setting infarct areas consistently exhibit cell necrosis as well as a considerable myocardial edema; areas of microvascular obstruction (MVO or ''noreflow''-zones) resulting from capillary obstruction, edema and endothelial swelling may also be present and are found in a large percentage of ST-segment elevating AMI. In the setting of chronic MI the initially necrotic myocardium is replaced by scar tissue formation with a large extracellular space and less dense cell distribution than in normal myocardium [bib_ref] Assessment of myocardial viability by cardiovascular magnetic resonance imaging, Mahrholdt [/bib_ref]. With the resorption process the size of the infarcted area typically shows a 20-40% reduction in the overall volume but also a reduction in its transmural extent although there may be larger variations [bib_ref] Infarct involution and improved function during healing of acute myocardial infarction: the..., Choi [/bib_ref] [bib_ref] Autologous bone marrow stem cell mobilization induced by granulocyte colony-stimulating factor after..., Engelmann [/bib_ref] [bib_ref] Prediction of left ventricular remodeling and analysis of infarct resorption in patients..., Lund [/bib_ref] [bib_ref] Determination of regional ejection fraction in patients with myocardial infarction by using..., Masci [/bib_ref]. These changes on the morphology of the infarcted area as well as the change in its functional and metabolic status provide the basics for differentiation of acute from chronic by means of non-invasive imaging modalities. Recent clinical evidence indicates that detection of MVO has important prognostic value beyond infarct size in patients who suffered an acute MI [bib_ref] Sequelae of acute myocardial infarction regarding cardiac structure and function and their..., Hombach [/bib_ref]. O 0 Regan et al. [bib_ref] Reperfusion hemorrhage following acute myocardial infarction: assessment with T2 mapping and effect..., O'regan [/bib_ref] examined 15 patients after acute PCI in acute myocardial infarction using a T2* mapping technique and demonstrated that patients with hemorrhage after revascularization had lower LVEF, lower myocardial salvage [bib_ref] Retrospective determination of the area at risk for reperfused acute myocardial infarction..., Aletras [/bib_ref] greater infarct size and more MVO [fig_ref] Figure 1: Example of a 76 year old male patient with an acute myocardial... [/fig_ref]. Areas with wall motion abnormalities but less than 50% transmural hyperenhancement are generally regarded as having a high likelihood for functional recovery after revascularization [bib_ref] The use of contrastenhanced magnetic resonance imaging to identify reversible myocardial dysfunction, Kim [/bib_ref] [bib_ref] Nonstress delayed-enhancement magnetic resonance imaging of the myocardium predicts improvement of function..., Schvartzman [/bib_ref]. In these areas the remaining myocardium is not necrotic, but in a ''stunned'' or ''hibernating'' state. Stunned myocardium is myocardium, which has suffered from severe ischaemia, consequently stopped contracting, but has not been irreversibly damaged. Blood flow to these areas has been restored by revascularization. If this situation becomes chronic as no revascularization has been performed, these areas become hibernating, just preserving their cellular integrity, but not contributing to cardiac function. Low dose dobutamine CMR may be a better predictor of recovery of function following revascularization [bib_ref] Magnetic resonance low-dose dobutamine test is superior to SCAR quantification for the..., Wellnhofer [/bib_ref] mainly in patients with intermediate transmurality of myocardial necrosis. But there are also studies available, which show a better prediction of functional recovery after revascularization procedures by using the LGE technique compared to low dose dobutamine stress [bib_ref] Myocardial viability assessment in patients with highly impaired left ventricular function: comparison..., Gutberlet [/bib_ref]. demonstrated in 20 patients examined before and 6 months after successful revascularization, that LGE showed the best results for predicting functional recovery compared to low-dose dobutamine stress, wall thickness and also SPECT imaging. The combination of LGE with dobutamine CMR may improve the diagnostic accuracy [bib_ref] Usefulness of a comprehensive cardiovascular magnetic resonance imaging assessment for predicting recovery..., Bodi [/bib_ref] although this concept is controversial [bib_ref] Prediction of myocardial recovery by dobutamine magnetic resonance imaging and delayed enhancement..., Barmeyer [/bib_ref]. Dysfunctional myocardium not uncommonly has associated thrombus. A study by Srichi et al. showed that CMR is more sensitive than either transthoracic or transesophageal echocardiography for the detection of ventricular thrombus in patients with ischemic heart disease. Given the risk of embolization in these patients, CMR has a distinct advantage over other techniques. Furthermore, CMR with the use of edema and inflammation sensitive sequences and LGE allows for the differential diagnosis of myocarditis [bib_ref] Cardiovascular magnetic resonance in myocarditis: a JACC White Paper, Friedrich [/bib_ref] [bib_ref] Suspected chronic myocarditis at cardiac MR: diagnostic accuracy and association with immunohistologically..., Gutberlet [/bib_ref] , tako-tsubocardiomyopathy (TTC) [bib_ref] Takotsubo cardiomyopathy or myocardial infarction? Answers from delayed enhancement magnetic resonance imaging, Eitel [/bib_ref] [bib_ref] Prognostic significance and magnetic resonance imaging findings in aborted myocardial infarction after..., Eitel [/bib_ref] [bib_ref] Inflammation in takotsubo cardiomyopathy: insights from cardiovascular magnetic resonance imaging, Eitel [/bib_ref] and acute myocardial infarction, which is crucial because all three can present with similar acute symptoms, ECG-changes, focal wall motion abnormalities and elevated troponin levels, but demonstrate in MRI with different typical features. Acute MI demonstrates with edema and typically subendocardial to transmural LGE [fig_ref] Figure 1: Example of a 76 year old male patient with an acute myocardial... [/fig_ref] , myocarditis also demonstrates with edema but a usually subepicardial LGE and TTC can also appear with edema, but no LGE and shows usually total recovery of ventricular function after a few weeks . In summary, CMR is well suited to detect wall motion abnormalities (stunning, hibernation, necrosis), area at risk (with T2 imaging), irreversible damage (necrosis, by LGE), microvascular obstruction (as an independent risk factor), and thrombus in a single examination [bib_ref] Use of cardiovascular magnetic resonance imaging in acute coronary syndromes, Lockie [/bib_ref]. Ischemia imaging has no role in patients with acute coronary syndromes but is a strong component of the work up of patients presenting with chest pain . ## Cardiac ct Cardiac CT has already been established as a highly useful adjunct to percutaneous intervention [bib_ref] Applications of multislice coronary computed tomographic angiography to percutaneous coronary intervention: how..., Hecht [/bib_ref]. With the development of high-speed CT systems, cardiac CT is becoming a first line diagnostic modality in the evaluation of chest pain of unknown origin. This includes atypical presentations of myocardial infarction and presentations that do not result in ECG changes. Arterial phase imaging is mainly dedicated to coronary CT angiography with identification of possible coronary artery stenoses of coronary plaque formation. A detailed analysis of the myocardial A T2-STIR B T1-w PSIR late Gd-enh C T1-w IR-GRE LGE oedema scar scar density can give more precise information on possible myocardial perfusion deficits and infarction [fig_ref] Figure 1: Example of a 76 year old male patient with an acute myocardial... [/fig_ref]. Kachenoura et al. found improved diagnostic accuracy for CCTA in a group of 84 patients when myocardial perfusion was also assessed [bib_ref] Combined assessment of coronary anatomy and myocardial perfusion using multidetector computed tomography..., Kachenoura [/bib_ref]. A significantly lower attenuation level of infarcted myocardium (any age; acute and chronic) in comparison to normal myocardium has been observed [bib_ref] Comparison of MDCT and MRI in the detection and sizing of acute..., Choe [/bib_ref] [bib_ref] Differentiation of recent and chronic myocardial infarction by cardiac computed tomography, Nieman [/bib_ref] [bib_ref] Assessment of myocardial infarctions using multidetector-row computed tomography, Nikolaou [/bib_ref] [bib_ref] Assessment of myocardial perfusion and viability from routine contrastenhanced 16-detector-row computed tomography..., Nikolaou [/bib_ref]. In regard to the differentiation of acute vs. chronic infarctions, some studies showed a tendency to lower attenuation of chronic infarctions compared to acutely injured myocardium [bib_ref] Differentiation of recent and chronic myocardial infarction by cardiac computed tomography, Nieman [/bib_ref] [bib_ref] Assessment of myocardial infarctions using multidetector-row computed tomography, Nikolaou [/bib_ref] while others could hardly tell a difference [bib_ref] Comparison of MDCT and MRI in the detection and sizing of acute..., Choe [/bib_ref]. Inherent differences in CT technology and injection protocols may explain discrepant results. In the acute setting the underlying principle of hypo-attenuation in arterial phase cardiac CT is most likely related to a decreased perfusion while the even lower densities in a chronic infarct setting may be based in changes of the myocardial wall texture with scar tissue development and also possible fatty replacement [bib_ref] Differentiation of recent and chronic myocardial infarction by cardiac computed tomography, Nieman [/bib_ref]. Within recent years the principle of ''delayed enhancement'' imaging as used in MRI has also been systematically been evaluated in cardiac CT. In fact, the principle of ''delayed enhancement'' has initially been described based on CT imaging in the late 1970s [bib_ref] Evaluation of myocardial ischemic damage of various ages by computerized transmission tomography...., Higgins [/bib_ref]. Recent animal studies have confirmed the ability to accurately evaluate acute and chronic infarctions by means of this technique [bib_ref] Characterization of acute and chronic myocardial infarcts by multidetector computed tomography: comparison..., Gerber [/bib_ref] [bib_ref] Contrastenhanced multidetector computed tomography viability imaging after myocardial infarction: characterization of myocyte..., Lardo [/bib_ref] [bib_ref] Characterization of peri-infarct zone heterogeneity by contrast-enhanced multidetector computed tomography: a comparison..., Schuleri [/bib_ref] and confirmed in patient studies [bib_ref] Characterization of acute and chronic myocardial infarcts by multidetector computed tomography: comparison..., Gerber [/bib_ref] [bib_ref] Multidetector computed tomography in reperfused acute myocardial infarction. Assessment of infarct size..., Jacquier [/bib_ref]. CT does not allow to accurately differentiate acute from chronic infarctions solely based on this feature. The accuracy for detection and size of MI appears to be roughly comparable to CMR [bib_ref] Comparison of MDCT and MRI in the detection and sizing of acute..., Choe [/bib_ref]. Delayed enhancement imaging is realized 5-7 min after injection in acute settings, and later for visualisation of a fibrotic, chronic scar. Low kilovoltage settings (80 kV for patients under 80 kg of weight, 100 kV above) are recommended to enhance iodine attenuation and lower radiation dose delivery. Thick MPR images of 5-8 mm are adequate to visualize myocardium using short-axis, 2 and 4 chambers views. Transmural infarction appears as hyperenhanced myocardium. A central hypoenhanced area, surrounded by contrast enhancement (central core of the infarction) may be observed. This feature corresponds to the no-reflow phenomena, which is also associated with poor recovery of the contractile function. Compared to transmural enhancement, subendocardial changes may be more difficult to detect due to similar contrast between the damaged myocardium and left ventricular cavity, the latter being still partially enhanced 10 min after iodine injection. Delayed enhancement imaging seems more challenging is case of chronic MI when compared to acute MI. Contrast uptake appears to be weaker compared to acute myocardial infarction. Optimal timing may be different from acute MI because of difference of contrast distribution in case of fibrosis: there is at present time no recommendation for Example of acute MI due to occlusion of an obtuse marginal artery [bib_ref] Sixteen-slice computed tomography after acute myocardial infarction: from perfusion defect to the..., Paul [/bib_ref]. First pass MSCT shows local hypoenhancement of the antero-lateral wall. This perfusion defect was leading to find the culprit lesion in a 3 vessel disease patient Post-angioplasty MSCT without reinjection of contrast medium, showing transmuralantero-septal contrast uptake, involving papillary muscle (asterisk). This finding predicts poor recovery of the antero-septal wall optimal visualisation of chronic scar. Thrombus detection in the left ventricle may be facilitated by delayed enhancement imaging, by a better differentiation between enhanced left ventricle wall and nonenhanced thrombus. Recently, use of cardiac CT just after a coronary angioplasty has been proposed, without needs for reinjection of iodine. This procedure has been shown to be safe and easy to perform. Intra-arterial iodine injected during the angioplasty may be indeed also used as a marker of myocardial damage . The first study on this topic showed that the transmural pattern of contrast uptake within the myocardium was closely linked to absence of functional recovery (absence of viability) using low-dose dobutamine echocardiography for comparison [bib_ref] Acute myocardial infarction early viability assessment by 64-slice computed tomography immediately after..., Habis [/bib_ref]. In addition, CT findings were found well correlated to MR realized 8 days after [bib_ref] Assessment of acute myocardial infarction using MDCT after percutaneous coronary intervention: comparison..., Boussel [/bib_ref]. A third paper showed that transmural damage observed just after coronary stenting without reinjection of contrast was able to predict LV remodelling or heart failure at 6 months [bib_ref] Early validation study of 64-slice multidetector computed tomography for the assessment of..., Sato [/bib_ref]. It does appear possible to detect ischemia with CT perfusion using adenosine perfusion [bib_ref] Cardiac myocardial perfusion imaging using dual source computed tomography, Blankstein [/bib_ref] [bib_ref] Multidetector computed tomography myocardial perfusion imaging during adenosine stress, George [/bib_ref]. In combination with delayed enhanced imaging, it may be possible to provide a comprehensive evaluation for coronary artery stenosis and its functional significance in concert with infarct imaging. Such an approach has not yet been evaluated but may become feasible as radiation dose decreases with more modern CT technology. # Conclusions ECG remains the first line test for myocardial infarction together with the use of biomarkers in the acute setting. Catheter based coronary angiography is used for the diagnosis and treatment of acute coronary syndrome. The role for non-invasive imaging in the acute setting is in patients for which the diagnosis is uncertain, for assessment of resulting mechanical causes of heart failure and for risk assessment. Echo because of its portability can offer critical information very early in AMI. PET has traditionally been regarded as the reference standard for myocardial viability. Its place has been challenged recently by CMR, which can detect smaller myocardial infarctions that can be prognostically important with no radiation. Together with its ability to detect ventricular thrombus, edema and inflammation, CMR is a compelling alternative test and furthermore, allows monitoring of revascularization procedures 0 success. Currently there exist more software tools to quantitate and display scar burden by PET but we can anticipate that this advantage will rapidly evaporate since this is now a focus of activity of software development. Intracellular contrast agents currently under investigation may more readily identify areas with reversible ischemia by CMR. Ischemia and infarct imaging by CT is now becoming feasible with the latest generation CT equipment. This technology needs to be assessed and compared with standard tests. The combination of coronary anatomy and myocardial abnormalities is only possible by CMR and CT. Coronary anatomy visualization is currently more robust with CT and easier to obtain. We anticipate that myocardial imaging with CT will be an active area of research for the next few years. In addition to accuracy, the costs of tests affect their utilization. PET is relatively expensive in this regard. Nevertheless, the bar has been raised by the Centers for Medicare and Medicaid Services (CMS) in the US for the acceptance of new technologies. In order for a new test to be reimbursed by CMS, the test needs to demonstrate that its use positively improves patient outcomes particularly in the form of randomized controlled trials. There is currently the strongest outcome data in the echo and nuclear imaging literature although there is a growing body of supporting literature for CMR. It is likely that most countries will similarly require outcome data for acceptance. Thus we anticipate that more outcome studies will be a focus of future research. [fig] Rest: Tc-99 m sestamibi myocardial perfusion single photon emission computed tomography (SPECT) has been used to exclude acute coronary syndrome in ED patients presenting with chest pain syndrome [34-41]. The negative predictive value of acute rest myocardial perfusion SPECT for ruling out myocardial infarction in the ED is greater than 99% [34-36, 39, 41]. Kontos et al. [37] studied patients who presented to the ED within 6 h of symptoms. Only two of 361 patients (0.6%) with a negative test had an acute myocardial infarction within 5 days of admission. Heller et al. [34] showed that only 2 of 204 patients (1%) with normal images had an acute myocardial infarction during hospitalization in a study involving 6 centers. The negative predictive value of acute rest myocardial perfusion SPECT for future adverse cardiac events is greater than 97% [34, 39-41]. Udelson et al. [40] prospectively evaluated 1,215 ED patients of 7 different hospitals who were injected with Tc-99 m sestamibi during or within 3 h of last chest pain episode. [/fig] [fig] Figure 1: Example of a 76 year old male patient with an acute myocardial infarction (STEMI) of the anterior wall after acute PCI of the occluded LAD with stent implantation (pain-toballoon time 150 min.). a The water sensitive T2-STIR image demonstrates the edema in the anterior wall (white arrows), c the LGE images demonstrate an almost transmural myocardial infarction (white arrows) with central MVO (asterisk). [/fig] [fig] Figure 2, Figure 3: CMR of a 20 year old man with biopsy proven acute myocarditis. a Demonstrates the typical finding of a subepicardialedema (white arrows) and LGE, b, c indicating acute myocardial inflammation and irreversible cell death Cine CMR images of a 40 year old female patient during diastole (a) and systole (b) acquired at acute phase of takotsubocardiomyopathy (TTC) demonstrating apical ballooning (black arrows) in the absence of LGE (c). A repeated Cine CMR 3 months later (d) showed complete normalization of systolic ventricular function [/fig]	None	https://link.springer.com/content/pdf/10.1007/s10554-010-9714-0.pdf	None
eb400326889a0fa7ebbf0925160e8b19c14af9e1	pubmed	New clinical guidelines on the spinal stabilisation of adult trauma patients – consensus and evidence based	New clinical guidelines on the spinal stabilisation of adult trauma patients – consensus and evidence based Traumatic spinal cord injury is a relatively rare injury in Denmark but may result in serious neurological consequences. For decades, prehospital spinal stabilisation with a rigid cervical collar and a hard backboard has been considered to be the most appropriate procedure to prevent secondary spinal cord injuries during patient transportation. However, the procedure has been questioned in recent years, due to the lack of high-quality studies supporting its efficacy. A national interdisciplinary task force was therefore established to provide updated clinical guidelines on prehospital procedures for spinal stabilisation of adult trauma patients in Denmark. The guidelines are based on a systematic review of the literature and grading of the evidence, in addition to a standardised consensus process. This process yielded five main recommendations: A strong recommendation against spinal stabilisation of patients with isolated penetrating trauma; a weak recommendation against the prehospital use of a rigid cervical collar and a hard backboard for ABCDE-stable patients; and a weak recommendation for the use of a vacuum mattress for patient transportation. Finally, our group recommends the use of our clinical algorithm to ensure good clinical practice. # Background Traumatic spinal cord injury (TSCI) is a relatively rare injury. The overall annual incidence in Denmark during 1990-94 to 2010-12 was 10.2 per million person-years at risk and varied from 8.3 to 11.8 [bib_ref] Incidence of traumatic spinal cord injury in Denmark, Noe [/bib_ref]. However, despite its rarity, the consequences of TSCI are serious, and may lead to a substantial handicap. In order to prevent secondary spinal cord injuries under transportation and medical treatment of trauma patients, it was postulated in the mid-1960s, that this risk might be reduced by stabilisation of the patient using a rigid cervical collar and a hard backboard. This strategy was adopted by many prehospital medical services worldwide as well as on trauma courses such as Prehospital Trauma Life Support (PHTLS®) and Advanced Trauma Life Support (ATLS®) [bib_ref] American College of Surgeons' committee on trauma, international ATLS working group. Spine..., Subcommittee [/bib_ref]. This change occurred despite a lack of high-quality study data to suggest clear benefits [bib_ref] Spinal immobilisaton in pre-hospital and emergency care: a systematic review of the..., Hood [/bib_ref] [bib_ref] The definite risks and questionable benefits of liberal pre-hospital spinal immobilisation, Purvis [/bib_ref]. On the contrary, a growing body of evidence during recent years indicates that the use of the rigid cervical collar and the hard backboard might indeed have harmful effects. The two most important studies are presented below. A study published by Hauswald et al. in 1998 described a 5-year retrospective chart review at two university hospitals (University of Malaya, Malaysia and University of New Mexico, USA) where the effect of emergency spinal stabilisation was examined in relation to neurological outcome for patients with blunt traumatic spinal injuries. All patients with acute blunt TSCI who were transported directly from the injury site to the hospital were included. The two hospitals were comparable with respect to physician training and clinical resources. None of the 120 patients examined at the University of Malaya underwent spinal stabilisation during patient transportation, whereas all 334 patients examined at the University of New Mexico did. The study found that there were fewer neurologic disabilities sustained in the Malaysian patients who did not undergo spinal stabilisation and concluded that there was less than a 2% chance that spinal stabilisation had any beneficial effect on neurologic outcomes in patients with blunt TSCI. In 2010, Haut et al. published a study based on a retrospective analysis of penetrating trauma patients in the US American National Trauma Data Bank . They studied more than 45,000 cases and their results showed that only 30 (0.01%) had incomplete spinal cord injury and underwent surgical spinal fixation. The number needed to treat (NNT) with spinal stabilisation to potentially benefit one patient was 1032. Conversely, the number needed to harm (NNH) with spinal stabilisation to potentially contribute to one death was 66. The authors concluded that prehospital spinal stabilisation was associated with a higher mortality risk in patients with penetrating trauma and therefore should not be routinely used in patients with penetrating trauma. Numerous studies were published in recent years which reveal further possible hazardous effects of spinal stabilisation, including pain [bib_ref] The definite risks and questionable benefits of liberal pre-hospital spinal immobilisation, Purvis [/bib_ref] [bib_ref] The effects of neutral positioning with and without padding on spinal immobilization..., Lerner [/bib_ref] [bib_ref] Prehospital spinal immobilisation: an initial consensus statement, Connor [/bib_ref] [bib_ref] To board or not to board: an evidence review of prehospital spinal..., Freauf [/bib_ref] [bib_ref] Cervical spine immobilization in athletes-to immobilize or not? A systematic review, Taub [/bib_ref] , the development of pressure ulcers [bib_ref] The effects of neutral positioning with and without padding on spinal immobilization..., Lerner [/bib_ref] [bib_ref] To board or not to board: an evidence review of prehospital spinal..., Freauf [/bib_ref] [bib_ref] Cervical spine immobilization in athletes-to immobilize or not? A systematic review, Taub [/bib_ref] , elevated intracranial pressure [bib_ref] To board or not to board: an evidence review of prehospital spinal..., Freauf [/bib_ref] , prolonged intrahospital length of stay [bib_ref] The OPALS Major Trauma Study: impact of advanced life-support on survival and..., Stiell [/bib_ref] , an increased number of radiological examinations [bib_ref] Effect of spineboard and headblocks on the image quality of head CT..., Hemmes [/bib_ref] [bib_ref] Emergency Radiology: Radiation exposure as a consequence of spinal immobilization and extrication, Stevens [/bib_ref] [bib_ref] Maintaining immobilisation devices on trauma patients during CT: a feasibility study, Stokkeland [/bib_ref] , an increased difficulty of clinical examination [bib_ref] The definite risks and questionable benefits of liberal pre-hospital spinal immobilisation, Purvis [/bib_ref] , prolonged prehospital on-scene time [bib_ref] To board or not to board: an evidence review of prehospital spinal..., Freauf [/bib_ref] [bib_ref] Cervical spine immobilization in athletes-to immobilize or not? A systematic review, Taub [/bib_ref] , difficulty in intubation [bib_ref] Redesign of a spine board: proof of concept evaluation, Nemunaitis [/bib_ref] and a risk of spinal fracture displacement in elderly patients [bib_ref] Cervical spine immobilization in the elderly population, Rao [/bib_ref]. The strength of the evidence in the aforementioned studies was either low or very low according to the GRADE-tool (Grading of Recommendations Assessment, Development and Evaluation) [bib_ref] GRADE handbook for grading quality of evidence and strength of recommendations, Schünemann [/bib_ref]. Based on this growing body of evidence, we have recently published new national guidelines for the spinal stabilisation of adult trauma patients in Danish language through the Danish National Board of Health, which are presented here in English language to allow a broader international audience access to our guidelines. # Methods A systematic review of the literature was performed involving grading of the strength of the evidence, clinical judgment and a consensus process. In order to involve all relevant stakeholders, an interdisciplinary working group was established consisting of representatives from eight different Medical Associations in Denmark, representatives from the Danish ATLS, PHTLS and International Trauma Life Support (ITLS) chapters, medical directors from the four largest Danish ambulance providers as well as representatives from all five Danish Emergency Medical Services (EMS) [fig_ref] Table 1: Members of the Danish interdisciplinary working group Members of the Danish interdisciplinary... [/fig_ref]. The working group also included two research methodologists contributing in the systematic evidence work (EJ and MAR). The scope of the guideline was defined based on five clinical key questions relating to the population, intervention, comparator/control and outcomes (PICO) [fig_ref] Table 2: The PICO questions [/fig_ref]. We defined the target population as trauma patients aged 18 years or above, who experienced spinal trauma within 48 h, and were at risk of developing a spinal cord injury. This definition was based on practical constraints rather than research evidence. The initial searches of existing guidelines were performed on October 19th, 2017, and included the following resources: Guidelines International Network (G-I-N), National Institute for Health and Care Excellence (NICE, UK), National Guideline Clearinghouse, Scottish Intercollegiate Guidelines Network (SIGN), UK National Institute for Health Research's Health Technology Assessment database (NIHR-HTA), Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU), Swedish National Board of Health and Welfare (Socialstyrelsen), Norwegian Directorate of Health (Helsedirektoratet), Norwegian Institute of Public Health (Kunnskapssenteret), and the Australian Physiotherapy Evidence Database (PEDRO). A Norwegian guideline of best practice which covered literature from 1966 to 2015 was also identified and included in the scoping search [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref]. The search strategy from this guideline was extended to include articles from January 2015 to October 2017. The search strategy is described in full in the Additional file 1. A research librarian conducted the systematic search for systematic reviews and primary studies in the databases of MEDLINE, EMBASE, CINAHL and the Cochrane Library. We searched for a combination of subject terms and text words to identify Two reviewers independently screened titles and abstracts of all articles identified in the searches for inclusion (EJ and MAR). Any discrepancy was resolved through discussion and consensus in our interdisciplinary working group. We read the full-texts and critically reviewed and included them, if relevant according to the PICO questions. For completeness, we identified additional articles by scanning the reference lists of the included studies and the authors' contributing papers known to them. We used the Critical Appraisal Skills Program (CASP) checklist for critical appraisal of observational studies and the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool for included guidelines [bib_ref] AGREE II: advancing guideline development, reporting and evaluation in health care, Brouwers [/bib_ref]. The critical appraisal of all studies was done by EJ in cooperation with the working group. As no randomized controlled studies or large observational studies were identified, we systematically reviewed all relevant published material, regardless of the study design. Case reports and cadaver studies were excluded due to the high risk of bias in case studies often involving only one patient and the low generalisability relating to cadaver studies.. The strength of the evidence and strength of recommendations were assessed using the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach [bib_ref] GRADE handbook for grading quality of evidence and strength of recommendations, Schünemann [/bib_ref]. The strength of the evidence was rated as high, moderate, low or very low. When assessing the strength of recommendations, we considered two factors and integrated them in a working group consensus process: benefit versus harm and quality of the evidence. The strength of the recommendations was graded as strong or weak or as good clinical practice. Our group evaluated the final national clinical guidelines (from June 2018) in a Delphi/consensus process utilising the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool / Danish National Board of Health's handbook of methods. A preliminary version of the new guidelines was sent out to all relevant medical associations and the other respective institutions via their representatives from our working group. The chairman of our group or the groups' representatives answered all comments and questions during two public hearing processes. After each public hearing process our group re-discussed and adapted the guidelines accordingly. ## Implementation and meetings These guidelines were implemented in Denmark by 1st March 2019. They were first published on 9th October 2018 on the public internet site of the Danish National Board of Healthand were shortly after available through several Danish Medical Societies' homepages. The guidelines were also available publicly via an indepth Danish podcast. In order to facilitate both pre-and in-hospital implementation, the five Danish Regions funded the production of several open-source videos. These videos were published in December 2018 and are publicly available. Since January 2019, the guidelines form part of the education, certification and recertification of all pre-hospital personnel, both via internal education and through incorporation in the Danish chapters' PHTLS®-, ATLS®-and ITLS®-courses. In April 2019, we published a short "heads-up" notice about our guidelines in "Der Notarzt", a German language medical paper. The guidelines have been presented in Denmark, at the 8th Danish Emergency Medical Conference (DEMC8) 2018, the Annual meeting of the Danish Society of Anesthesiology and Intensive Care Medicine (DASAIM) 2018, the Copenhagen Critical Symposium 2019, and the European EMS Congress 2019 in Madrid, Spain. # Results A total of 6484 titles and abstracts were identified in the systematic review. Of these, four observational studies of moderate and high methodological quality were included, in addition to the included Norwegian guideline with included references. The search process is shown in [fig_ref] Figure 1: Prisma flow-chart depicting the literature search and selection of included and excluded... [/fig_ref]. Following main recommendations for spinal stabilisation of adult trauma patients were given based on the identified studies, clinical judgment and consensus decisions made in the interdisciplinary working group [fig_ref] Table 3: Summary of main recommendations, quality of evidence and strength of recommendation [/fig_ref]. ## 1.) clinical question 1 Should adult trauma patients with risk of a secondary spinal cord injury undergo spinal stabilisation with a rigid cervical collar? ## Recommendation There is a weak recommendation against the use of a rigid cervical collar as a spinal stabilisation measure in adult trauma patients. ## Level of evidence Very low ## Evidence and rationale No published high-quality studies were found. The published studies were of very low evidence according to GRADE, mostly due to the fact, that the data was extrapolated from either cadaver studies or studies with healthy volunteers [bib_ref] Spinal immobilisaton in pre-hospital and emergency care: a systematic review of the..., Hood [/bib_ref]. We did not find any study proving the efficacy of rigid cervical collars with regards to a better neurological outcome or mortality [bib_ref] Spinal immobilisaton in pre-hospital and emergency care: a systematic review of the..., Hood [/bib_ref] [bib_ref] The definite risks and questionable benefits of liberal pre-hospital spinal immobilisation, Purvis [/bib_ref] [bib_ref] Prehospital spinal immobilisation: an initial consensus statement, Connor [/bib_ref] [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref] [bib_ref] Effects of prehospital spinal immobilization: a systematic review of randomized trials on..., Kwan [/bib_ref] [bib_ref] Cervical spine immobilization during extrication of the awake patient: a narrative review, Cowley [/bib_ref] [bib_ref] Cervical collars are insufficient for immobilizing an unstable cervical spine injury, Horodyski [/bib_ref] [bib_ref] The effect of soft and rigid cervical collars on head and neck..., Barati [/bib_ref]. However, several publications describe the efficacy of a rigid cervical collar with regards to the reduction of range of motion in the cervical spine, and all note that the effect on the range of motion in the neck is very limited [bib_ref] The effect of soft and rigid cervical collars on head and neck..., Barati [/bib_ref] [bib_ref] Efficacy of cervical spine immobilization methods, Podolsky [/bib_ref] [bib_ref] Comparison of the effectiveness of different cervical immobilization collars, Mccabe [/bib_ref] [bib_ref] Prehospital Spinal Immobilization: Effect of Effort on Kinematics of Voluntary Head-neck Motion..., Pryce [/bib_ref]. In 2013, a joint committee from The American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons published new guidelines for the management of acute cervical spine and spinal cord injuries [bib_ref] prehospital cervical spinal immobilization after trauma, Theodore [/bib_ref]. These guidelines still recommend the use of a rigid cervical collar for the spinal stabilisation of the cervical spine. However, the authors concluded that this recommendation is based on anatomical and mechanical considerations rather than on evidence. Furthermore, they found that the variety of techniques used and the lack of evidence to advocate a uniform device for spinal stabilisation made spinal stabilisation technique and device recommendations difficult. In line with previous publications, additional publications proposing possible harmful effects were found. For example, longer stay in the emergency room [bib_ref] Cervical spine collar clearance in the obtunded adult blunt trauma patient: a..., Patel [/bib_ref] , decreased lung function [bib_ref] cervical collar effect on pulmonary volumes in patients with trauma, Ala [/bib_ref] , development of pressure ulcers [bib_ref] Pressure ulcer development in trauma patients with suspected spinal injury; the influence..., Ham [/bib_ref] , impeded airway management [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref] , worsening of existing cervical injury [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref] , severe neurological deterioration in patients with ankylosing spondylitis [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref] , triggering of non-compliance or agitation and even increased spinal movement due to pain or discomfort [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref] as well as possible elevation of intracranial pressure [bib_ref] Increase in intracranial pressure by application of a rigid cervical collar: a..., Maissan [/bib_ref]. The weak recommendation is given due to a low prevalence of secondary TSCI as well as the limited efficacy of the rigid cervical collar regarding to the movement in the cervical spine and other existing methods of spinal stabilisation. Moreover, there was a lack of studies demonstrating a positive effect on both survival and neurological outcomes and the increasing evidence for possible harmful side effects when applying a rigid cervical collar. Instead of using the rigid cervical collar for spinal stabilisation where indicated, we recommend using manual inline stabilisation of the head (the MILS-maneuver), head blocks, or a or a vacuum mattress reaching up over the head [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref] [bib_ref] Value of a rigid collar in addition to head blocks: a proof..., Holla [/bib_ref] [bib_ref] Comparison of the Vacuum Mattress versus the Spine Board Alone for Immobilization..., Prasarn [/bib_ref]. According to GRADE it is not possible to give a stronger recommendation against the use of rigid cervical collars due to the lack of high-quality studies regarding their use. ## 2.) clinical question 2 Should adult trauma patients with risk of a secondary spinal cord injury undergo spinal stabilisation on a hard backboard? ## Recommendation There is a weak recommendation against the use of a hard backboard as a spinal stabilisation measure in case of ABCDE-stable patients. Should adult trauma patients with risk of a secondary spinal cord injury undergo spinal stabilisation on a vacuum mattress? ## Level of evidence ## Very low ## 3.) clinical question 3 ## Recommendation There is a weak recommendation for the use of a vacuum mattress as a spinal stabilisation measure for ABCDE-stable patients with neurologic deficit and / or osseous pain on examination. ## Level of evidence ## Very low Evidence and rationale for clinical question 2 and 3: Our group did not find any published high-quality studies covering the efficacy of a rigid backboard for spinal stabilisation. The strength of evidence in all published studies was very low according to GRADE, mostly due to the fact that the data was extrapolated from either cadaver studies or studies with healthy volunteers [bib_ref] Spinal immobilisaton in pre-hospital and emergency care: a systematic review of the..., Hood [/bib_ref]. Besides the lack of studies supporting improved patient outcome when transporting trauma patients on a hard backboard, there are two studies highlighting the previous mentioned adverse effects. This includes the possible development of significant discomfort and moderate to severe pain after a short time on the hard backboard, possible voluntary spinal movement and even the possible development of pressure ulcers after prolonged exposure [bib_ref] The definite risks and questionable benefits of liberal pre-hospital spinal immobilisation, Purvis [/bib_ref] [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref]. Furthermore, the efficacy of the hard backboard with regards to restriction of lateral movement under ambulance transport compared to a simple ambulance stretcher is also questionable [bib_ref] The long spine board does not reduce lateral motion during transport-a randomized..., Wampler [/bib_ref]. Several studies favor the use of soft surface stretcher systems, e.g. the vacuum mattress. This in order to reduce the above mentioned possible adverse effects of the hard surface stretcher systems and at the same time maintain the principle of a minimal handling strategy [bib_ref] Redesign of a spine board: proof of concept evaluation, Nemunaitis [/bib_ref] [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref] [bib_ref] on-scene treatment of spinal injuries in motor sports, Kreinest [/bib_ref] [bib_ref] A new Craniothoracic mattress for immobilization of the cervical spine in critical..., Holla [/bib_ref]. Moreover, some studies suggest that the vacuum mattress may provide either a similar or even superior degree of spinal stabilisation compared to the hard backboard [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref] [bib_ref] Comparison of the Vacuum Mattress versus the Spine Board Alone for Immobilization..., Prasarn [/bib_ref]. Because of this, we recommend the use of a vacuum mattress over the use of a hard backboard for patient transportation of adult trauma patients undergoing spinal stabilisation. ## 4.) clinical question 4: Should patients with isolated penetrating injuries undergo spinal stabilisation? ## Recommendation There is a strong recommendation against the effort of a spinal stabilization in patients with isolated penetrating injuries. ## Level of evidence ## Moderate ## Evidence and rationale Patients with penetrating injuries may be ABCDEunstable and in need of time-critical surgical intervention. In 2010, Haut et al. published a retrospective analysis of the National Trauma Data Bank, studying 45,284 patients with isolated penetrating trauma . They compared outcomes between patients who received spinal stabilisation and patients who did not. The results showed that unadjusted mortality was twice as high in the patients who underwent spinal stabilisation (14.7% vs. 7.2%, p < 0.001) compared to the patients that did not. The odds ratio of death for patients undergoing spinal stabilisation was 2.06 (95% CI: 1.35-3.13) compared to the patients that did not, probably due to the prolonged prehospital time used in the spinal stabilisation of the patients. Out of the 45,284 patients only 30 (0.01%) patients had incomplete spinal cord injury and underwent subsequent spinal surgery. The NNT with spinal stabilisation to potentially benefit one patient was 1032, whereas the NNH was 66 . Due to the study's effect size and the high number of patients studied, the study was upgraded to a moderate level of evidence according to GRADE. ## 5.) clinical question 5: Should the decision, whether and how to perform spinal stabilisation on an adult trauma patient be facilitated by a clinical triaging tool? ## Recommendation It is good clinical practice to use our clinical triaging tool to determine whether and how to perform spinal stabilisation on an adult trauma patient. ## Level of evidence ## None. good clinical practice ## Evidence and rationale It is very unlikely that all patients with a spinal injury need spinal stabilisation in order to prevent them from developing a secondary spinal injury. But how can we determine, which patients need spinal stabilisation and which do not? Studies have shown that prehospital triaging tools based on mechanisms of injury instead of clinical findings are inferior with regards to accuracy and lead to over-triage [bib_ref] Prehospital clinical findings associated with spinal injury, Domeier [/bib_ref] [bib_ref] The reliability of prehospital clinical evaluation for potential spinal injury is not..., Domeier [/bib_ref] [bib_ref] Comparison of three prehospital cervical spine protocols for missed injuries, Hong [/bib_ref]. Several EMS systems around the world are already using different triaging tools facilitating the decision whether to perform spinal stabilisation [bib_ref] The Norwegian guidelines for the prehospital management of adult trauma patients with..., Kornhall [/bib_ref] [bib_ref] A statewide, prehospital emergency medical service selective patient spine immobilization protocol, Burton [/bib_ref]. Most of these triaging tools are traditionally based on decision aids like the National Emergency X-radiography Utilisation Study (NEXUS) tool or the Canadian C-Spine Rule criteria (CCR). Originally, these decision aids were developed to help clinicians to decide whether a patient needs radiographic imaging in order to diagnose spinal injuries [bib_ref] Accuracy of the Canadian C-spine rule and NEXUS to screen for clinically..., Michaleff [/bib_ref] [bib_ref] Validity of a set of clinical criteria to rule out injury to..., Hoffman [/bib_ref]. In order to further reduce over-triage, our group modified these earlier published triaging tools and developed a new clinical decision tool illustrated in [fig_ref] Figure 2: Algorithm for a clinical handling strategy with spinal trauma Maschmann et al [/fig_ref]. We recommend assigning adult trauma patients to one out of three groups: ## 1) no efforts of spinal stabilisation 2) spinal stabilisation on a vacuum mattress 3) time-critical spinal stabilisation In line with earlier publications we agree that alert and ABCDE-stable patients will seek to stabilise their spine themselves and in the most comfortable position for them as possible automatically. We do also recommend that patients being affected by alcohol or drugs should be treated like all other non-intoxicated patients, since it is clinically difficult to differentiate between clinical findings resulting from intoxication or from other more critical injuries such as intracranial hemorrhage [bib_ref] Cervical spine evaluation and clearance in the intoxicated patient: a prospective Western..., Martin [/bib_ref]. Furthermore, we recommend that patients with socalled "distracting injuries" and a GCS of 15 should be treated like all other alert patients. It has been seen that a so-called distracting injury does not affect the sensitivity of an examination of the cervical spine [bib_ref] The Presence of Nonthoracic Distracting Injuries Does Not Affect the Initial Clinical..., Konstantinidis [/bib_ref] [bib_ref] Femur fractures should not be considered distracting injuries for cervical spine assessment, Dahlquist [/bib_ref] [bib_ref] Thoracolumbar spine clearance: clinical examination for patients with distracting injuries, Cason [/bib_ref]. When it comes to the clinical examination of the spine, we recommend using the interpretation of the patient's face expression as a marker of pain, rather than asking the patient directly. Our concern was overtriage by overestimation of symptoms through the use of leading questions [bib_ref] Comparative analysis of the independent medical examination reports and legal decisions in..., Nahm [/bib_ref] [bib_ref] The General History and Physical Exam, Chow [/bib_ref]. In general, our group still supports a minimal handling strategy, but acknowledges potentially life-threatening injuries that might demand immediate intervention. In these instances, we therefore recommend a so-called time-critical spinal stabilisation, which must not delay other life-saving procedures or transportation. Our group cannot recommend a standard procedure of a timecritical spinal stabilisation, since it should be based on the individual patient's situation and other factors, such as the availability of stabilisation-and transportation tools. Therefore, a time-critical spinal stabilisation might consist of the use of a vacuum mattress, a hard backboard, a scoop stretcher or a simple ambulance stretcher, as well as the MILS maneuver; depending on the most appropriate solution for the given situation. With respect to the transportation of unconscious, non-intubated trauma patients, our group supports the use of the novel lateral trauma position (LTP) or other positioning maneuvers like the HAINES-maneuver (high-arm-IN-endangeredspine) for time-critical spinal stabilisation. This is in line with previous studies, which suggest that these maneuvers do not produce more movement in the unstable spine than the traditional log-rolling maneuver [bib_ref] Eliminating log rolling as a spine trauma order, Conrad [/bib_ref] [bib_ref] Is the supine position associated with loss of airway patency in unconscious..., Hyldmo [/bib_ref] [bib_ref] Safety of the lateral trauma position in cervical spine injuries: a cadaver..., Hyldmo [/bib_ref] [bib_ref] Does the novel lateral trauma position cause more motion in an unstable..., Hyldmo [/bib_ref]. As with prior studies, our group recommends limiting the use of the log-roll-maneuver to those situations where inspecting the back of a trauma patient may have immediate consequences for the treatment of the patient. This includes situations where a patient is found in a prone position and has to be rolled over onto a transportation device. Some studies suggest there is significantly more motion in the unstable spine by using the log-roll maneuver compared to alternative maneuvers like the straddle lift and slide, 6 + lift and slide or the scoop stretcher [bib_ref] Eliminating log rolling as a spine trauma order, Conrad [/bib_ref] [bib_ref] Does the novel lateral trauma position cause more motion in an unstable..., Hyldmo [/bib_ref] [bib_ref] What is the purpose of log roll examination in the unconscious adult..., Tveit [/bib_ref]. ## Key issues for future investigations As mentioned by previous authors, well-designed, prospective studies, including randomized controlled trials to elucidate the efficacy of spinal stabilisation and the preferred techniques are warranted [bib_ref] Should suspected cervical spinal cord injury be immobilised?: A systematic review, Oteir [/bib_ref]. However, ethical, consent and potential medico-legal and practical issues are recognized as barriers which may limit such studies in the prehospital settings. Large, international cohort studies and / or comparative studies may also yield a better understanding of the various spinal.stabilisation measures and their potential harms and benefits. # Conclusion The evidence for spinal stabilisation of trauma patient is sparse. Based on a systematic review of the existing literature, grading of the strength of the evidence, clinical judgment and a consensus process, our Danish working group formulated the following recommendations for spinal stabilisation of adult trauma patients: a strong recommendation against the efforts of spinal stabilisation in case of patients with isolated penetrating injuries, a weak recommendation against the use of the rigid cervical collar as well as the hard backboard, and a weak recommendation for the use of a vacuum mattress in case of ABCDE-stable patients. Lastly, our working group suggests our algorithm should be adopted based on the clinical findings rather than the mechanisms of injury to guide clinical practice. ## Additional file Additional file 1: Search strategy for "spinal stabilisation of adult trauma patients". (DOCX 31 kb) ## Acknowledgements Our group would like to thank Britta Tendal and Henriette Callesen, both employed at the Danish National Board of Health, for their invaluable help in the development of these guidelines. Moreover, we would like to thank the chief librarian Conni Skrubbeltrang from Aalborg University Hospital for her professional help and guidance in performing the literature search. Our appreciation goes as well to graphic designer Astrid Andersen for the graphic composition of our clinical algorithm and Dr. Gethin Hodges, MD, who provided assistance with translation for the English manuscript. Author's contribution CM is the main author of this manuscript. EJ and MAR have screened all studies and all authors have participated in the research and the consensus process as well as contributing to the drafting and approval of the final version of the manuscript. # Funding The development of these clinical guidelines was supported by funding from the Danish Finance Act under the management of the Danish Health Authority. ## Availability of data and materials We have submitted our detailed search vocabulary as supplementary material. Ethics approval and consent to participate This is not applicable as this manuscript is a literature review and a national clinical guideline. ## Consent for publication This manuscript contains no individual person's data in any form. ## Competing interests The authors declare that they have no competing interests. [fig] Figure 1: Prisma flow-chart depicting the literature search and selection of included and excluded studies Maschmann et al. [/fig] [fig] Figure 2: Algorithm for a clinical handling strategy with spinal trauma Maschmann et al. [/fig] [table] Table 1: Members of the Danish interdisciplinary working group Members of the Danish interdisciplinary working group • Danish Society for Emergency Medicine -DASEM (chairman) • Danish Neurosurgical Society -DNKS • Danish Society for Spinal Surgery -DRKS • Danish Orthopaedic Society -DOS • Danish Orthopaedic Trauma Society -DOTS • Danish Society for Anesthesiology and Intensive [/table] [table] Table 2: The PICO questions [/table] [table] Table 3: Summary of main recommendations, quality of evidence and strength of recommendation [/table]	None	https://sjtrem.biomedcentral.com/track/pdf/10.1186/s13049-019-0655-x	None
cace32300e99ffed3c1e4b9521541da33d15f96f	pubmed	ASCI 2010 contrast media guideline for cardiac imaging: a report of the Asian Society of Cardiovascular Imaging cardiac computed tomography and cardiac magnetic resonance imaging guideline working group	ASCI 2010 contrast media guideline for cardiac imaging: a report of the Asian Society of Cardiovascular Imaging cardiac computed tomography and cardiac magnetic resonance imaging guideline working group The use of contrast media for cardiac imaging becomes increasing as the widespread of cardiac CT and cardiac MR. A radiologist needs to carefully consider the indication and the injection protocol of contrast media to be used as well as the possibility of adverse effect. There are several guidelines for contrast media in western countries. However, these are focusing the adverse effect of contrast media. The Asian Society of Cardiovascular Imaging, the only society dedicated to cardiovascular imaging in Asia, formed a Working Group and created a guideline, which summarizes the integrated knowledge of contrast media for cardiac imaging. In cardiac imaging, coronary artery evaluation is feasible by non-contrast MR angiography, which can be an alternative examination in high risk patients for the use of iodine contrast media. Furthermore, the body habitus of Asian patients is usually smaller than that of their western counterparts. This necessitates modifications in the injection protocol and in the formula for calculation of estimated glomerular filtration rate. This guideline provided fundamental information for the use of contrast media for Asian patients in cardiac imaging. protocol of contrast media to be used as well as the possibility of adverse effect. There are several guidelines focusing the adverse effect of contrast media. However, there is no guideline, which summarizes the integrated knowledge of contrast material for cardiac imaging, especially for patients of Asian origin. In cardiac imaging, coronary artery evaluation is feasible by non-contrast MR angiography, which can be an alternative examination in high risk patients for the use of iodine contrast media. Furthermore, the body habitus of Asian patients is usually smaller than that of their western counterparts. This necessitates modifications in the injection protocol and in the formula for calculation of estimated glomerular filtration rate (eGFR) [bib_ref] Revised equations for estimated GFR from serum creatinine in Japan, Matsuo [/bib_ref] [bib_ref] Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney..., Ma [/bib_ref]. The major purpose of this manual is to provide fundamental information for the use of contrast media for Asian patients in cardiac imaging. For the usage of contrast material, the basic knowledge for contrast material injection is very important to obtain optimal contrast images. The knowledge for adverse reaction is inevitable for the safe patient care. Among several adverse reactions, contrast induced nephropathy (CIN) is almost specific to iodinated contrast media, while nephrogenic systemic fibrosis (NSF) is specific to gadolinium contrast media. On the other hands, adverse reactions other than CIN and NSF is similar in both iodinated and gadolinium contrast material. Thus, this guideline consists of four chapters; (1) general rule for contrast material injection, (2) adverse reaction of iodinated and gadolinium contrast material, (3) contrast induced nephropathy and (4) nephrogenic systemic fibrosis. 2 General rule for contrast material injection ## Computed tomography contrast material Contrast enhancement in a given patient is determined by 3 factors: contrast material flow rate (ml/s), contrast material volume (ml) and contrast material iodine concentration (mg/ml) [bib_ref] Optimal vascular and parenchymal contrast enhancement: the current state of the art, Fleischmann [/bib_ref]. The overall contrast volume is calculated as the injection rate multiplied by the injection duration. Warming of contrast agent prior to injection decreases viscosity and allows higher injection rates at lower injection pressures. Accurate timing of the scan with respect to the arrival of the intravenous (IV) contrast in the target structures is necessary. Thus, the usage of either bolus tracking or a test bolus protocol is recommended. ## Coronary ct angiography - The injection flow rate mainly determines the enhancement (fast dynamic peak). The contrast material volume also affects the enhancement [bib_ref] Aortic and hepatic peak enhancement at CT: effect of contrast medium injection..., Bae [/bib_ref] [bib_ref] Parameters affecting bolus geometry in CTA: a review, Cademartiri [/bib_ref]. - Optimal images require high intraarterial opacification of more than 250 Hounsfield units (HU) [bib_ref] Optimal contrast application for cardiac 4-detector-row computed tomography, Becker [/bib_ref]. Higher intracoronary attenuation value will improve the diagnostic accuracy of coronary artery stenosis [bib_ref] Higher intracoronary attenuation improves diagnostic accuracy in MDCT coronary angiography, Cademartiri [/bib_ref] [bib_ref] Influence of intra-coronary enhancement on diagnostic accuracy with 64-slice CT coronary angiography, Cademartiri [/bib_ref]. - High iodine concentration contrast agents are preferred to achieve greater contrast-to-noise ratios [bib_ref] Intravenous contrast material administration at helical 16-detector row CT coronary angiography: effect..., Cademartiri [/bib_ref] [bib_ref] Contrast bolus optimization for cardiac 16-slice computed tomography: comparison of contrast medium..., Rist [/bib_ref]. - The injection duration should be as long as or slightly longer than the estimated scan duration. For very short scans, the injection duration should be at least 10 s [bib_ref] Optimal vascular and parenchymal contrast enhancement: the current state of the art, Fleischmann [/bib_ref]. - A biphasic injection protocol using dual-head pumps is preferable [bib_ref] Improved uniformity of aortic enhancement with customized contrast medium injection protocols at..., Fleischmann [/bib_ref] [bib_ref] Reduction of contrast material dose and artifacts by a saline flush using..., Haage [/bib_ref]. It consists of a first injection of contrast at a rate of 3-6 ml (volume depends on scan length) and a second injection of approximately 20-40 ml of saline at the same injection rate. - A body weight tailored injection protocol is recommended to decrease the total contrast material volume in Asian patients. The use of 0.7 ml/kg of contrast material injected at a fixed duration of 10 s followed by 20 ml of saline is feasible [bib_ref] Reduction of the total injection volume of contrast material with a short..., Tatsugami [/bib_ref] [bib_ref] Feasibility of low-volume injections of contrast material with a body weight-adapted iodine-dose..., Tatsugami [/bib_ref]. ## Other protocols - In CT angiography (CTA) protocols, the right heart typically appears washed out. In some clinical settings, it may be desirable to have some opacification of the right heart. - For the right heart opacification, the saline flush may be replaced by a mixture of contrast and saline, or a triphasic injection protocol may be used [bib_ref] Triphasic contrast bolus for whole-chest ECG-gated 64-MDCT of patients with nonspecific chest..., Mitsumori [/bib_ref] [bib_ref] ECG-gated chest CT angiography with 64-MDCT and triphasic IV contrast administration regimen..., Litmanovich [/bib_ref] [bib_ref] What is the best contrast injection protocol for 64-row multi-detector cardiac computed..., Lu [/bib_ref]. - Triphasic protocols consist of an initial high flow rate contrast injection (3-6 ml/s), followed by a second injection of either a mixture of contrast and saline (3-6 ml/s) or a contrast injection at lower injection rate (e.g., 2 ml/s), followed by a third injection of a smaller volume of saline. - Regarding the protocol for the evaluation of delayed enhancement, further studies are required. ## Magnetic resonance contrast material Gadolinium based contrast media (GBCM) shorten T1 relaxation times and thus lead to higher signal intensity on T1-weighted images. Although first-pass kinetics and late distribution of GBCM are similar to those of iodinated contrast materials for CT; there are two distinct characteristics in GBCM compared to iodinated contrast materials. First, the signal intensities are not proportional to GBCM concentration due to substantial signal loss caused by T2-shortening effect at high concentrations of GBCM. Therefore, the concentration of GBCM in the blood pool or myocardium cannot be calculated directly from the signal intensity on MRI [bib_ref] Cardiovascular MR imaging: physical principles to practical protocols, Lee [/bib_ref]. Second, due to the much smaller contrast volume required for first-pass imaging, improving effect of high injection rate on bolus profile is limited for MRI compared to CT [bib_ref] Absolute blood contrast concentration and blood signal saturation on myocardial perfusion MRI:..., Ishida [/bib_ref]. For example, when you administer a single dose of GBCM to a patient with 50 kg body weight (i.e. 10 ml), increasing injection rate from 4 to 5 ml/s shortens the injection duration only slightly (i.e. 0.5 s). The injection protocol for myocardial perfusion MRI is usually used as a dose of 0.05-0.1 mmol/kg with injection rate of 3-7 ml/s, followed by at least 30 ml saline flush (5-7 ml/s). For delayed gadolinium enhancement MRI, a total dose of 0.1-0.2 mmol/ kg is administered. 3 Adverse effects of iodinated and gadolinium contrast medium ## Patient selections and preparation strategies Before the administration of contrast media, the referring physician and the radiologist should consider the following issues: (1) Assessment of patient risk versus potential benefit of the contrast-assisted examination. (2) Imaging alternatives that would provide the same or better diagnostic information. (3) Prevention of adverse events. ## Risk factors for adverse intravenous contrast material reactions - The history obtained should focus on identification of factors that may indicate either a contraindication to contrast media use or an increased likelihood of a reaction. - Severe, life-threatening reactions, although rare, can occur in the absence of any specific risk factors with any type of media. - Risk factors for adverse reactions to contrast media are summarized in [fig_ref] Table 1: Risk factors for adverse intravenous contrast material reactions [/fig_ref]. - In pregnant patients, it is unclear how iodinated or gadolinium contrast agents will affect the fetus, these agents should be administered only with extreme caution. Free iodine in radiographic contrast medium given to the mother has the potential to depress fetal/neonatal thyroid function. Neonatal thyroid function should be checked during the 1st week if iodinated contrast media have been given during pregnancy. No effect on the fetus has been seen after gadolinium contrast media [bib_ref] Members of Contrast Media Safety Committee of European Society of Urogenital Radiology..., Webb [/bib_ref]. - In lactating patients, breast feeding may continue normally when iodinated or gadolinium agents are given to the mother [bib_ref] Members of Contrast Media Safety Committee of European Society of Urogenital Radiology..., Webb [/bib_ref]. ## Preparation strategies - For patients at increased risk of reaction, consider an alternative test not requiring the agent. For the evaluation of coronary artery, non-contrast MR angiography can be an alternative examination [bib_ref] Detection of coronary artery stenosis with whole-heart coronary magnetic resonance angiography, Sakuma [/bib_ref]. - There is no concrete clinical evidence on the effectiveness of use of premedication in patients undergoing contrast enhanced CT or MRI examinations. - However, the premedication is preferable in patients at higher risk for an acute allergic-like reaction. - If the radiologists does intend to use premedication then a useful option can be prednisolone 30 mg orally, given 12-2 h before the contrast medium. - Preliminary intradermal skin testing with contrast agents is not predictive of adverse reactions, may itself be dangerous, and is not recommended [bib_ref] Prediction of severe adverse reactions to ionic and nonionic contrast media in..., Yamaguchi [/bib_ref] [bib_ref] Mechanisms of severe, immediate reactions to iodinated contrast material, Laroche [/bib_ref]. ## At the time of examination A general category that deserves attention is emotional state. There is anecdotal evidence that severe adverse effects to contrast media or to procedures can be mitigated at least in part by reducing anxiety. It may be useful, therefore, to determine whether a patient is particularly anxious and it is important to reassure and calm that patient before contrast injection [bib_ref] The effect of informed consent on the level of anxiety in patients..., Hopper [/bib_ref]. ## To reduce the risk of adverse reactions - Some of the strategies to avoid contrast media induced adverse events are listed in. ## Extravasation ## Frequencies - The reported incidence of IV contrast media extravasation related to power injection for CT has ranged from 0.1% to 0.9% (1/1,000 patients to 1/106 patients) [bib_ref] Frequency and effects of ionic and nonionic CT contrast media during rapid..., Federle [/bib_ref]. - The frequency of extravasation is not related to the injection flow rate [bib_ref] Contrast media reactions and extravasation: relationship to intravenous injection rates, Jacobs [/bib_ref]. ## Risk factors - Inappropriate injection site (small vessels), - High volume of contrast media or high osmolar contrast media. - Use of power injectors. ## Type of injuries - Most injuries are minor. - In severe cases, ulceration, soft tissue necrosis or compartment syndrome may be observed. - A compartment syndrome is more likely to occur after extravasation of larger volumes of contrast media [bib_ref] Frequency, management, and outcome of extravasation of nonionic iodinated contrast medium in..., Wang [/bib_ref] ; however, it also has been observed after extravasation of relatively small volumes, especially when this occurs in less capacious areas (such as over the ventral or dorsal surfaces of the wrist). To reduce the risk - Use appropriate sized plastic cannula placed in a suitable vein to handle the flow rate. - A test injection with normal saline. - Use non-ionic iodinated contrast medium as far as possible. ## Treatment - Conservative management (limb elevation, use of ice packs) is adequate in most cases. - Close clinical follow-up for several hours is essential for all patients in whom extravasations occur, since the severity and prognosis of a contrast medium extravasation injury are difficult to determine on initial evaluation of the affected site. - An immediate surgical consultation is indicated for any patient in whom one or more of the following signs or symptoms develops: progressive swelling or pain, altered tissue perfusion as evidenced by decreased capillary refill at any time after the extravasation has occurred, change in sensation in the affected limb, and skin ulceration or blistering. ## Type of adverse reactions Adverse reactions are classified into acute and delayed reactions. Acute reactions are those that occur up to 1 h after the administration of CM. The majority of the delayed reactions occur between 1 and 72 h after the administration of contrast media. Subsequently occurring reactions are rare; the maximum interval is 7 days [2]. ## Acute adverse reaction - The classification of severity of reactions to contrast media has been shown in [fig_ref] Table 3: Classification of severity of reactions to contrast media [/fig_ref]. - The majority of adverse side effects are mild nonlife-threatening events that require only observation and supportive treatment. - Severe adverse side effects, however, may have a mild or moderate prodrome. Nearly all lifethreatening reactions occur immediately or within the first 3 h after contrast media injection [bib_ref] The risks of death and of severe nonfatal reactions with high-vs lowosmolality..., Caro [/bib_ref]. - Prediction of occurrence or severity is impossible, although there are some known risk factors, and anticipation and vigilance are critical [bib_ref] Acute reactions to intravascular contrast media: types, risk factors, recognition, and specific..., Bush [/bib_ref]. - Mild reactions do not require treatment, but, as noted, they may presage or evolve into a more severe reaction. Any patient with any reaction should, therefore, be observed for 20-30 min, or as necessary, to ensure clinical stability and recovery. - Moderate adverse events, by definition, are not immediately life-threatening (although they may progress to be so) but often require treatment. - Severe adverse events are potentially or immediately life-threatening. - Historically, adverse effects have occurred in 5-15% of all patients who receive ionic, highosmolality contrast media (HOCM) [bib_ref] Incidence and severity of acute allergic-like reactions to i.v nonionic iodinated contrast..., Dillman [/bib_ref]. One study in Asia reported the frequency of adverse effects was 12.66% with HOCM [bib_ref] Adverse reactions to ionic and nonionic contrast media. A report from the..., Katayama [/bib_ref]. - Use of low-osmolality ionic nonionic contrast media (LOCM) is associated with an overall incidence of adverse events of 0.2-0.7% [bib_ref] Trends in adverse events after IV administration of contrast media, Cochran [/bib_ref] [bib_ref] Frequency, outcome, and appropriateness of treatment of nonionic iodinated contrast media reactions, Wang [/bib_ref]. In Asia, this is reported to be 3.13% [bib_ref] Adverse reactions to ionic and nonionic contrast media. A report from the..., Katayama [/bib_ref]. - Serious contrast reactions are rare and have occurred in 1 or 2 per 1,000 (0.1-0.2%) intravascular injections of HOCM and in 1 or 2 per 10,000 (0.01-0.02%) IV injections of LOCM. In a report from Asia, this frequency was 0.22% of intravascular injections of ionic and 0.04% of non-ionic IV injections [bib_ref] Adverse reactions to ionic and nonionic contrast media. A report from the..., Katayama [/bib_ref]. - The adverse event rate for gadolinium based contrast agents can range from 0.5 to 2.5% [bib_ref] Clinical safety of gadopentetate dimeglumine, Nelson [/bib_ref] [bib_ref] Clinical safety and diagnostic value of the gadolinium chelate gadoterate meglumine (Gd-DOTA), Herborn [/bib_ref] [bib_ref] Assessment of adverse reaction rates to a newly approved MRI contrast agent:..., Bleicher [/bib_ref]. - The management for acute adverse reactions is the same with generalized anaphylactoid reaction. This is summarized in. - b-blockers may impair the response to treatment of bronchospasm induced by contrast medium. ## Delayed reactions - An adverse reaction which occurs 1 h to 1 week after contrast medium injection. - The incidence of delayed adverse cutaneous reactions has been reported to range from 0.5 to 2% [bib_ref] Delayed allergy-like reactions to X-ray contrast media: mechanistic considerations, Christiansen [/bib_ref]. - The main types of delayed reactions are given in. - Relatively common symptoms are nausea, vomiting, drowsiness, headache, and pruritus without urticaria, all of which are self-limited and many of which are self limiting and do not require any therapy [bib_ref] Delayed allergy-like reactions to X-ray contrast media: mechanistic considerations, Christiansen [/bib_ref]. - Skin reactions are true late adverse reactions. They are usually mild to moderate and self limiting. Delayed cutaneous reactions are not, however, associated with other acute adverse events such as bronchospasm or laryngeal edema. - The management of late adverse reactions is identical to that of other drug induced skin reactions. - Delayed cardiopulmonary arrest has also been reported, but this and other severe systemic reactions are probably related to etiologies other than the contrast media. - Currently, very late reactions to gadolinium media in the form of nephrogenic systemic fibrosis (NSF) are a major concern, and are dealt with in detail in chapter D. ## Contrast-induced nephropathy (iodinated contrast medum) Contrast medium nephrotoxicity (renal adverse reactions) is mostly associated with iodinated contrast media. The risk of nephrotoxicity is very low when gadolinium contrast media are used in approved doses. The risk of nephrotoxicity is related to the degree of pre-existing renal disease and hydration. Clinically significant nephrotoxicity after administration of iodinated contrast media is highly unusual in patients with normal renal function. There is no standard definition for reporting contrast-induced nephrotoxicity (CIN). Definitions used have included percent change in the baseline serum creatinine (e.g., a 20-50% rise in serum creatinine) and absolute elevation from baseline (0.5-2.0 mg/dl) [bib_ref] Radiologic contrastinduced nephropathy, Berkseth [/bib_ref] [bib_ref] Contrast media for angiography: effect on renal function, Cruz [/bib_ref]. The clinical course of CIN depends on baseline renal function, coexisting risk factors, degree of hydration, and other factors. Serum creatinine usually begins to rise within the first 24 h following IV contrast media administration, peaks within 96 h (4 days), and usually returns to baseline within 7-10 days [bib_ref] Radiologic contrastinduced nephropathy, Berkseth [/bib_ref]. It is unusual for patients to develop permanent renal failure, and this usually occurs in the setting of multiple risk factors. ## Risk factors for adverse intravenous contrast medium induced nephropathy - The major risk factors for CIN is given in [fig_ref] Table 6: Risk factors for contrast medium induced nephropathy [/fig_ref]. - Serum creatinine values should be measured within 7 days of contrast media administration. - There is no universally agreed upon threshold of serum creatinine elevation (or degree of renal [bib_ref] Prediction of creatinine clearance from serum creatinine, Cockcroft [/bib_ref] [bib_ref] Modification of diet in renal disease (MDRD) estimated glomerular filtration rate (eGFR)..., Hafez [/bib_ref]. - However, these equations are less accurate for Asians, with greater bias at estimated GFR (eGFR) less than 60 ml/min/1.73 m 2 [bib_ref] Revised equations for estimated GFR from serum creatinine in Japan, Matsuo [/bib_ref]. This difference would be accounted for by the difference in muscle mass. African-American people probably have a greater muscle mass than Asian. Interestingly, the correction coefficients for the modification of the MDRD Study equation were considerably different even among patients of Asian origin. For example, the correction coefficient for patients of Chinese origin was 1.233 [bib_ref] Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney..., Ma [/bib_ref] and that for patients of Japanese origin 0.808 [bib_ref] Revised equations for estimated GFR from serum creatinine in Japan, Matsuo [/bib_ref]. - The establishment of GFR-estimating formulae specific for patients of different race is required. For example, in Japan, new formula is recommended as follows; eGFR (ml/min/1.73 m 2 ) = 194 9 Serum creatinine -1.094 9 Age -0.287 9 0.739 (if female) [bib_ref] Revised equations for estimated GFR from serum creatinine in Japan, Matsuo [/bib_ref]. - Metformin is excreted unchanged in the urine. In the presence of renal failure, either pre-existing or induced by iodinated contrast medium, metformin may accumulate in sufficient amounts to cause lactic acidosis. Depending on serum creatinine level, metformin will have to be stopped either before or at the time of contrast medium administration. ## Prevention or amelioration - Consider an alternative imaging method not using iodinated contrast media. For the evaluation of coronary artery, non-contrast MR angiography can be an alternative examination [bib_ref] Detection of coronary artery stenosis with whole-heart coronary magnetic resonance angiography, Sakuma [/bib_ref]. - Stop nephrotoxic drugs, mannitol and loop diuretics at least 24 h before [bib_ref] Effects of saline, mannitol, and furosemide to prevent acute decreases in renal..., Solomon [/bib_ref]. - Start hydration. A suitable intravenous regime is 100 ml/h of normal saline beginning 12 h before and continuing 12 h after examinations. In hot climates the volume should be increased [bib_ref] Cardiac angiography in renally impaired patients (CARE) study: a randomized double-blind trial..., Solomon [/bib_ref]. - Stop metformin from the time of contrast medium administration or 48 h. Only restart metformin if serum creatinine remains normal or unchanged 48 h after contrast medium. - The efficacy of N-acetylcysteine (Mucomyst) or sodium bicarbonate to reduce the incidence of CIN is controversial [bib_ref] A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID..., Baker [/bib_ref] [bib_ref] Acetylcysteine and non-ionic isosmolar contrast-induced nephropathy-a randomized controlled study, Ferrario [/bib_ref] [bib_ref] Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning, Kanter [/bib_ref]. ## At the time of examination - Use low or iso-osmolar contrast media. - Use the lowest dose of contrast medium consistent with a diagnostic result. - Continue hydration for at least 6 h [bib_ref] Prevention of contrast induced nephropathy: recommendations for the high risk patient undergoing..., Schweiger [/bib_ref]. - In patients suffering from end-stage renal disease, there is no need for urgent dialysis [bib_ref] Dialysis is not indicated immediately after administration of nonionic contrast agents in..., Younathan [/bib_ref]. - Correlation of time of the contrast medium injection with the hemodialysis session in dialysis patients is unnecessary [bib_ref] Dialysis is not indicated immediately after administration of nonionic contrast agents in..., Younathan [/bib_ref]. ## Nephrogenic systemic fibrosis (gadolinium contrast media) Nephrogenic systemic fibrosis (NSF) is recently reported adverse effect specific to gadolinium contrast media. Fewer cases of NSF have been reported in Asia, as compared to the US or Europe. NSF is a severe, usually progressive, potentially fatal, systemic fibrotic disease, affecting the dermis, subcutaneous fasciae and striated muscles. In 2006 several groups noted a strong association between gadolinium-based contrast media (GBCM) administration and the disease [bib_ref] Gadolinium-a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic..., Grobner [/bib_ref]. In many cases, affected patients had been injected with more than one type of GBCM prior to symptoms onset. However, it must be emphasized that the frequency with which NSF has been associated with different GBCM may also have been affected if the agents were used at higher doses compared to what is recommended in their package inserts. It is advisable to use the GBCM agents within their prescribed dosages and not to overdose the patient. Risk factors for nephrogenic systemic fibrosis are given in [fig_ref] Table 7: Risk factors for contrast medium induced Nephrogenic Systemic Fibrosis [/fig_ref]. The etiology of NSF is still unknown but is thought to be multifactorial. The prevailing theory regarding gadolinium and NSF is that gadolinium (Gd 3? ) ions are released from the Gd-chelate complex of MRI contrast agents and accumulate in tissues such as skin, thereby initiating what some have described as a ''toxic'' reaction. The precise pathomechanism is not yet known [bib_ref] Current status of gadolinium toxicity in patients with kidney disease, Perazella [/bib_ref]. It is estimated that patients with eGFR \ 30 ml/ min/1.73 m 2 have a 1-7% chance of developing NSF after exposure to GBCM [bib_ref] Gadolinium-a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic..., Grobner [/bib_ref] [bib_ref] Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic..., Marckmann [/bib_ref]. All patients should be questioned for a history of renal disease. The measurement of an eGFR within 6 weeks of the GBCM study is recommended in patients with renal disease in anyone over 60 years of age, or in patients with hypertension, diabetes mellitus. ## Preparation strategies - In patients with already being dialyzed. Non-contrast MR angiography is recommended for the evaluation of coronary artery. The use of CT angiography is also possible. If a contrast-enhanced MRI examination must be performed such as for the evaluation of perfusion or delayed enhancement, avoidance of the use of those GBCM that have been most frequently associated with NSF [gadodiamide (Omniscan Ò ), gadopentetate dimeglumine (Magnevist Ò ) and gadoversetadmide (OptiMARK Ò ]) is recommended. Also, use of the lowest possible dose needed to obtain a diagnostic study is suggested. GBCM-enhanced MRI exams is recommended to be performed shortly before dialysis, as prompt post-procedural dialysis may reduce the likelihood that NSF will develop, although this has not been proved definitively to date [bib_ref] Incidence of nephrogenic systemic fibrosis at two large medical centers, Prince [/bib_ref]. - In patients with eGFR \ 30 ml/min/1.73 m 2 , who are not on chronic dialysis. It is recommended that any contrast media administration be avoided if at all possible. If MRI contrast media administration is absolutely essential, judicious use of the lowest possible doses of selected GBCM (avoidance of the use of those GBCM that have been most frequently associated with NSF) is probably safest [bib_ref] Incidence of nephrogenic systemic fibrosis at two large medical centers, Prince [/bib_ref]. To the best of our knowledge this is the first comprehensive guide on use of contrast media amongst Asians for cardiac imaging. In summary this manual provides basic information for the use of contrast media for Asian patients in cardiac imaging. In addition to general principles of contrast material injection we have also discussed associated adverse events like contrast induced nephropathy and nephrogenic systemic fibrosis. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. [table] Table 1: Risk factors for adverse intravenous contrast material reactions [/table] [table] Table 3: Classification of severity of reactions to contrast media [/table] [table] Table 6: Risk factors for contrast medium induced nephropathy [/table] [table] Table 7: Risk factors for contrast medium induced Nephrogenic Systemic Fibrosis (NSF) [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs10554-010-9691-3.pdf	None
780eb0b38006ec73ff6b71163c2a5d996b199994	pubmed	The use of preoperative radiotherapy in the management of patients with clinically resectable rectal cancer: a practice guideline	The use of preoperative radiotherapy in the management of patients with clinically resectable rectal cancer: a practice guideline Background: This systematic review with meta-analysis was designed to evaluate the literature and to develop recommendations regarding the use of preoperative radiotherapy in the management of patients with resectable rectal cancer.Methods: TheResults: Two meta-analyses of preoperative radiotherapy versus surgery alone, nineteen trials that compared preoperative radiotherapy plus surgery to surgery alone, and five trials that compared preoperative radiotherapy to alternative treatments were obtained. Randomized trials demonstrate that preoperative radiotherapy followed by surgery is significantly more effective than surgery alone in preventing local recurrence in patients with resectable rectal cancer and it may also improve survival. A single trial, using surgery with total mesorectal excision, has shown similar benefits in local recurrence.Conclusion:For adult patients with clinically resectable rectal cancer we conclude that:- Preoperative radiotherapy is an acceptable alternative to the previous practice of postoperative radiotherapy for patients with stage II and III resectable rectal cancer;- Both preoperative and postoperative radiotherapy decrease local recurrence but neither improves survival as much as postoperative radiotherapy combined with chemotherapy. Therefore, if preoperative radiotherapy is used, chemotherapy should be added postoperatively to at least patients with stage III disease. # Background Adenocarcinoma of the rectum is a common malignancy that originates in the last 15 cm of the large bowel where most of its external surface is not covered by peritoneum but rather is directly surrounded by connective-adipose tissue. Resection of the rectum and surrounding tissues can cure approximately 50% of patients. The other half will eventually die of the disease. Surgical failure is related to distant micro metastases that are not apparent and / or incomplete local resection. Local recurrences increase in frequency and survival decreases as the tumor penetrates through the rectal wall and extends to regional lymph nodes [bib_ref] Cancer of the rectum, Cohen [/bib_ref]. These prognostic factors form the basis for the tumor, node, metastases (TNM) staging system widely used to advise therapy (see Additional file 1). Meticulous dissection of perirectal tissues en bloc with total mesorectal excision (TME) decreases local relapse [bib_ref] Mesorectal excision for rectal cancer, Macfarlane [/bib_ref]. Preoperative and postoperative radiotherapy (RT) has also been used to reduce local recurrence, which is associated with pelvic pain and rectal obstruction, and to prevent disease dissemination from the local site, thereby improving survival. Other goals of RT are to convert inoperable tumors into resectable cases, to preserve the anal sphincter and to avert a colostomy [bib_ref] Radiation: The preoperative adjuvant strategy, Mohiuddin [/bib_ref]. The advantages and disadvantages of preoperative and postoperative RT have been well described [bib_ref] Radiation: The preoperative adjuvant strategy, Mohiuddin [/bib_ref]. The principal advantage of postoperative RT is that it is given only to patients at high risk of recurrence according to well-investigated prognostic factors [pathological stages II and III (B2 and C)]. Major incentives for preoperative RT originate from a variety of perspectives. Biologically, a tumor with an undisturbed circulation and oxygenation has a better chance for full radiation effects. Moreover, a tumor reduced in size and with the surrounding tissues sterilized facilitates surgery and reduces potential tumor dissemination. A more practical incentive is the possibility of using an equally effective five-day course of high dose fraction preoperative RT instead of a 25 -30 day standard postoperative course of RT. Another practice guideline by the Gastrointestinal Cancer Disease Site Group (DSG) first developed in 1997 and updated in 2001 reviewed the effects of postoperative RT and / or chemotherapy in resected stage II / III rectal cancer [bib_ref] Cancer Disease Site Group: Post-operative adjuvant radiotherapy or chemotherapy for resected stage..., Figueredo [/bib_ref]. This guideline recommended the combined use of postoperative radiation and chemotherapy as the preferred treatment for resected stage II and III rectal cancer. This combined treatment improved the local recurrence rate by 50% and the five-year survival rate by 42%. The same guideline discouraged the use of RT alone as adjuvant treatment because it only decreased local recurrence rates. For the present report, we initially reviewed only the effect of RT given before definitive surgery on survival and local recurrence. Following advice received from practi-tioner feedback and from our resource group, we have also included a discussion of preoperative RT compared with postoperative combined RT plus chemotherapy. This report does not consider the use of preoperative RT to convert locally advanced, initially unresectable rectal cancer into resectable cases, to preserve the anal sphincter, or to delay the need for colostomy. # Methods This practice guideline was developed by the Cancer Care Ontario Practice Guidelines Initiative (CCOPGI), using the methodology of the Practice Guidelines Development Cycle [bib_ref] The practice guidelines development cycle: a conceptual tool for practice guidelines development..., Browman [/bib_ref]. Evidence was selected and reviewed by four members of the CCOPGI's Gastrointestinal Cancer DSG and methodologists. This practice guideline report is a convenient and up-to-date source of the best available evidence on preoperative RT for clinically resectable rectal cancer, developed through systematic reviews, evidence synthesis and input from practitioners in Ontario. External review by Ontario practitioners was obtained through a mailed survey consisting of items that address the quality of the draft practice guideline report and recommendations, and whether the recommendations should serve as a practice guideline. Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee (PGCC). The report is intended to promote evidence-based practice. The Practice Guidelines Initiative is editorially independent of Cancer Care Ontario and the Ministry of Health and Long-Term Care. The CCOPGI has a formal standardized process to ensure the currency of each guideline report. This consists of periodic review and evaluation of the scientific literature, and where appropriate, integration of this literature with the original guideline information. were searched with no language restrictions. "Rectal neoplasms" (Medical subject heading [MeSH]), "colorectal neoplasms" (MeSH) and the text word "rectal cancer" were combined with "radiotherapy" (MeSH) and the following phrases used as text words: "preoperative"; "neoadjuvant"; "radiotherapy"; "radiation"; "irradiation". These terms were then combined with the search terms for the following study designs or publication types: practice guidelines, meta-analyses, and randomized controlled trials. The proceedings of the 1998 to 2002 annual meetings of the American Society of Clinical Oncology (ASCO) and the 1999 to 2002 annual meetings of the American Society for Therapeutic Radiology and Oncology (ASTRO) were searched for reports of new or ongoing trials. Rele-vant articles and abstracts were selected and reviewed and the reference lists from these sources were searched for additional trials. A search of personal reprint files was also conducted. ## Examination of the evidence ## Study selection criteria Trials of preoperative RT in resectable rectal cancer are characterized by multiple methodological problems because two treatments are combined (RT and surgery) to affect a heterogeneous condition (various populations and stages of rectal carcinoma) and to achieve a variety of goals (downstaging, improving resectability, decreasing local and possibly distant recurrences and improving survival). Cummings [bib_ref] A critical review of adjuvant pre-operative radiation therapy for adenocarcinoma of the..., Cummings [/bib_ref] detailed many of the pitfalls that marred early trials, including deficiencies in trial design, eligibility criteria, treatment standardization and reporting of results. We used this critique to develop standard criteria for the selection of trials of preoperative RT for rectal cancer. Studies were included in this systematic review of the evidence if they met all of the following criteria: 1. Patients were randomly assigned to preoperative RT versus surgery alone or an alternative treatment. 2. The study population was well defined. Studies preferably included only rectal carcinoma, defined by tumors located within 15 cm of the pectinate line or anal verge on sigmoidoscopy, or rectosigmoid tumors. Patients were screened for metastases and co-morbidity by clinical and imaging procedures and were assessed as surgically resectable for cure. 3. Treatments were described clearly, including RT dose, fractionation, duration, field size and portals of irradiation. Timing of surgery after completion of RT was clearly set. General surgical principles were described. [bib_ref] Cancer Disease Site Group: Post-operative adjuvant radiotherapy or chemotherapy for resected stage..., Figueredo [/bib_ref]. Compliance with treatments and follow-up were described. 5. Treatment outcomes were reported for overall survival and / or local failure. Other outcomes such as adverse effects (morbidity and mortality), downstaging (decrease in the proportion of cases with stage III disease), and resectability (total and curative) were recorded if available. ## Synthesizing the evidence Trials of preoperative RT versus surgery alone were pooled using Review Manager 4.2.1 ( © Update Software), which is available through the Cochrane Collaboration. Overall mortality, local failure, tumor resectability, tumor downstaging, and adverse effects were pooled in separate analyses for all studies, where data was available. Reported figures or estimates obtained from tables or graphs were used. For calculation of survival and local failure, all eligible patients were considered in the denominator, based on intention to treat. All deaths at the time of reporting, regardless of cause, were included in survival calculations. Patients with local failure included those with nonresected as well as those with recurrent disease. Only resected cases were considered in the calculation of downstaging. Data were pooled using the random effects model as the more conservative estimate of effect [bib_ref] Meta-analysis in clinical trials, Dersimonian [/bib_ref]. Results were expressed as relative risk ratios (RR) with 95% confidence intervals (CI), where a RR less than 1.0 favors preoperative RT and a RR greater than 1.0 favors surgery alone. Odds ratios (OR) and absolute risk differences (RD) were also calculated. Heterogeneity of results among trials was expected in view of the different treatments used and populations tested, as well as the wide time interval and geography across which these trials were conducted. For example, the RT prescription may affect the results. RT doses greater than are considered necessary and pelvic fields are as effective as extended fields. Moreover, the use of three or more RT beams will lessen toxicity and short delays of surgery after RT will not demonstrate downstaging. Thus, these factors were investigated with sensitivity analyses to see whether there was an impact on results. Outcomes of predetermined groups of patients were examined initially by the graphic method described by L'Abbe et al. [bib_ref] Meta-analysis in clinical research, L'abbe [/bib_ref] and RR calculated. For sensitivity analyses the following factors were examined: Treatment effects: - Biologically effective dose (BED) of RT (less than 30 Gy 10 versus equal to or greater than 30 Gy 10 ). BED was calculated using the linear quadratic formula [bib_ref] The linear-quadratic formula and progress in fractionated radiotherapy, Fowler [/bib_ref] and the parameters suggested for time correction [bib_ref] Radiotherapy in addition to radical surgery in rectal cancer: evidence for a..., Glimelius [/bib_ref] : [formula] BED time = nd (1+d/α/β) -γ/α (T -Tk) [/formula] where n = number of fractions, d = dose per fraction, α/β = 10 for tumor effect and acute reactions and α/β = 3 for late reactions, γ/α = repair rate set at 0.6 Gy/day, T = total treatment time and Tk = initial delay time set at 7 days; - RT fraction size (standard fractions up to 2.5 Gy/day versus high fractions of 5 Gy/day); - Contemporary RT prescription, defined as studies employing multiple-field technique and target volume confined to the pelvis (i.e. excluding studies employing parallel pair arrangements or including para-aortics); and - Delay of surgery after completion of RT (less than seven days versus eight or more days). Population effects: - Studies including a range of rectal cancer cases versus those including only advanced disease. Sensitivity analyses were also performed for all five of the meta-analyses (overall survival, local failure, tumor resectability, downstaging, and adverse effects) considering only trials with high design quality. The quality of the 14 eligible randomized trials of preoperative RT versus surgery alone in operable rectal cancer was scored independently. Five assessors assessed each trial using the Detsky instrument [bib_ref] Incorporating variations in the quality of individual randomized trials into meta-analysis, Detsky [/bib_ref]. This questionnaire addresses five domains of study quality: randomization process, outcomes measure, patient eligibility, treatment description, and statistical procedures. The 14 questions on the Detsky instrument can be answered "adequate", "inadequate", or "partial" and scored 1, 0, or 0.5, respectively. The final score of each trial is a ratio of the observed points divided by the total number of questions answered. The results from the five assessors were averaged for a final score. Trials with Detsky instrument scores greater than 0.5 were considered to be of high quality. # Results # Literature search results The literature search identified 24 trials. Nineteen of these trials compared preoperative RT plus surgery to surgery alone [bib_ref] Preoperative roentgen therapy for cancer of the rectum and rectosigmoid, Stearns [/bib_ref] [bib_ref] Preoperative irradiation of rectosigmoid carcinoma including its regional lymph nodes, Kligerman [/bib_ref] [bib_ref] Preoperative irradiation in operable cancer of the rectum: report of the Toronto..., Rider [/bib_ref] [bib_ref] Preoperative radiation and surgery for cancer of the rectum, Higgins [/bib_ref] [bib_ref] Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a..., Dahl [/bib_ref] [bib_ref] Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a..., Gérard [/bib_ref] [bib_ref] A comparison of nonoperative vs. preoperative radiotherapy in rectal carcinoma. A 10-year..., Reis-Neto [/bib_ref] [bib_ref] Local recurrence of rectal cancer following preoperative irradiation, Illényi [/bib_ref] [bib_ref] Longterm results of a randomized trial of short-course low-dose adjuvant pre-operative radiotherapy..., Goldberg [/bib_ref] [bib_ref] Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective,..., Marsh [/bib_ref] [bib_ref] Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer, Kapiteijn [/bib_ref]. Five trials compared preoperative RT to alternative treatments [bib_ref] Pre-or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized..., Pahlman [/bib_ref] [bib_ref] Evaluation of preoperative radiation therapy in operable colorectal cancer, Sause [/bib_ref] [bib_ref] Final results of a randomized trial on the treatment of rectal cancer..., Boulis-Wassif [/bib_ref] [bib_ref] Influence of the interval between preoperative radiation therapy and surgery on downstaging..., Francois [/bib_ref]. Two meta-analyses of preoperative RT versus surgery alone were found in a recent search update [bib_ref] Preoperative radiotherapy for resectable rectal cancer. A meta-analysis, Cammà [/bib_ref]. ## Preoperative rt versus surgery alone Four of the 19 trials of preoperative RT compared with surgery alone were excluded from the review [bib_ref] Preoperative roentgen therapy for cancer of the rectum and rectosigmoid, Stearns [/bib_ref]. Preliminary results of one trial have been reported in Russian, but the report and results were difficult to interpret. This trial was excluded until more mature results are available and it is clear that the trial meets the inclusion criteria. Three trials [bib_ref] Preoperative roentgen therapy for cancer of the rectum and rectosigmoid, Stearns [/bib_ref] had major violations to the inclusion criteria. The Memorial Hospital trial included both randomized as well as non-randomized patients in the analysis [bib_ref] Preoperative roentgen therapy for cancer of the rectum and rectosigmoid, Stearns [/bib_ref]. The Veterans Administration Surgical Oncology Group (VASOG) Trial I included patients who may have had apparent metastases and did not allow for an analysis excluding this group of patients. The Essen trial was described in summary form and was a failed trial of preoperative plus postoperative RT treatment due to difficulties with compliance. The remaining 15 trials are shown in [fig_ref] Table 1: Randomized trials of preoperative RT versus surgery alone in resectable rectal cancer [/fig_ref]. The significant trial coordinated by the Dutch Colorectal Cancer Group report results after a median follow-up of 24.9 months, much shorter than other trials, and numbers of patients with events cannot be determined [bib_ref] Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer, Kapiteijn [/bib_ref]. Therefore this trial is not included in the meta-analysis. This study, which included patients with rectal cancer not fixed or amenable to local excision, standardized surgery with total mesorectal excision. Patients were randomized to surgery alone or surgery preceded by RT (bottom row, [fig_ref] Table 1: Randomized trials of preoperative RT versus surgery alone in resectable rectal cancer [/fig_ref] [bib_ref] Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer, Kapiteijn [/bib_ref]. The recurrence rate was significantly lower in patients receiving preoperative RT (2.4% vs. 8.2%; p < 0.001) but overall survival was the same for both treatment groups. In a multivariate subgroup analysis, tests for interaction between tumor location, TNM stage and treatment were not significant, suggesting that treatment effect was similar for all the subgroups analyzed. This left 14 trials of preoperative RT compared with surgery alone [bib_ref] Preoperative irradiation of rectosigmoid carcinoma including its regional lymph nodes, Kligerman [/bib_ref] [bib_ref] Preoperative irradiation in operable cancer of the rectum: report of the Toronto..., Rider [/bib_ref] [bib_ref] Preoperative radiation and surgery for cancer of the rectum, Higgins [/bib_ref] [bib_ref] Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a..., Dahl [/bib_ref] [bib_ref] Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a..., Gérard [/bib_ref] [bib_ref] A comparison of nonoperative vs. preoperative radiotherapy in rectal carcinoma. A 10-year..., Reis-Neto [/bib_ref] [bib_ref] Local recurrence of rectal cancer following preoperative irradiation, Illényi [/bib_ref] [bib_ref] Longterm results of a randomized trial of short-course low-dose adjuvant pre-operative radiotherapy..., Goldberg [/bib_ref] [bib_ref] Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective,..., Marsh [/bib_ref]. One trialcontributed to two comparisons (single fraction preoperative RT versus surgery alone; multiple fractions preoperative RT versus surgery alone). One trialincluded 316 patients who were also included in another trial; neither report described results for these patients separately from those who were included in only one of the two trials. Reports of three trials [bib_ref] Preoperative irradiation in operable cancer of the rectum: report of the Toronto..., Rider [/bib_ref] [bib_ref] A comparison of nonoperative vs. preoperative radiotherapy in rectal carcinoma. A 10-year..., Reis-Neto [/bib_ref] [bib_ref] Local recurrence of rectal cancer following preoperative irradiation, Illényi [/bib_ref] did not provide data on compliance with treatment. Where results have been reported or updated in more than one publication, only the most recent publication is listed. All trials included patients with resectable rectal cancer. Two trials also included patients with rectosigmoid tumors [bib_ref] Preoperative irradiation of rectosigmoid carcinoma including its regional lymph nodes, Kligerman [/bib_ref] [bib_ref] Preoperative radiation and surgery for cancer of the rectum, Higgins [/bib_ref]. Some trials excluded patients with small tumorsor were limited to those with locally advanced tumors [bib_ref] Local recurrence of rectal cancer following preoperative irradiation, Illényi [/bib_ref] [bib_ref] Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective,..., Marsh [/bib_ref] or those requiring abdomino-perineal resection [bib_ref] Preoperative radiation and surgery for cancer of the rectum, Higgins [/bib_ref]. Patients excluded were those with evidence of distant metastases, previous malignancy or previous RT. Surgery was performed from a few hours up to 40 days following the preoperative RT course, but most surgeries were done within one to four weeks of preoperative RT. The description of surgical procedures was very general except for the distinction between palliative and curative procedures. Radiation was delivered mostly by anterior and posterior portals. Only recent trials used three or four radiation portals [bib_ref] Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective,..., Marsh [/bib_ref]. Radiation fields were mostly pelvic but some trials used extended guitar-shaped fields up to L2 [bib_ref] Preoperative irradiation of rectosigmoid carcinoma including its regional lymph nodes, Kligerman [/bib_ref] [bib_ref] Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a..., Dahl [/bib_ref] [bib_ref] Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a..., Gérard [/bib_ref]. The total radiation dose and the fractionation schedules were quite different across studies, ranging from 5 Gy in a single treatment to over 50 Gy in five weeks. Compliance with treatments was generally well described. Follow-up data were collected prospectively in all but one trial [bib_ref] Preoperative irradiation in operable cancer of the rectum: report of the Toronto..., Rider [/bib_ref]. The follow-up schedule was described for all trials except one [bib_ref] Preoperative irradiation of rectosigmoid carcinoma including its regional lymph nodes, Kligerman [/bib_ref]. The rate of patients lost to follow-up was 16% in one trial [bib_ref] Longterm results of a randomized trial of short-course low-dose adjuvant pre-operative radiotherapy..., Goldberg [/bib_ref] , but most other trials seemed to have had greater than 90% compliance with follow-up. The median follow-up at the time of the trial report was five years or more in most trials. ## Pooled results of trials comparing preoperative rt to surgery alone Overall survival Survival was reported for all trials except one [bib_ref] Local recurrence of rectal cancer following preoperative irradiation, Illényi [/bib_ref]. Survival results for only resected cases were reported for one trial. The overall mortality risk ratio favored preoperative RT (RR, 0.94; 95% CI, 0.89 to 0.99; p = 0.02), results that correspond to an absolute risk difference of 4% (95% CI, 0.7% to 7.5%; p = 0.018). There was significant heterogeneity across trials (X 2 = 20.59; p < 0.10). As observed in , most heterogeneity derived from a study from Brazil [bib_ref] A comparison of nonoperative vs. preoperative radiotherapy in rectal carcinoma. A 10-year..., Reis-Neto [/bib_ref] ; removal of this study resulted in non-significant heterogeneity and the results were similar (RR, 0.95; 95% CI, 0.91 to 0.99; p = 0.012). Survival benefit was observed only for trials using BED > 30 but there was significant heterogeneity detected. ## Local failure Local failure rate was calculated for all trials as the number of patients unable to have tumor removal as well as those with recurrent disease after resection. The overall relative risk ratio favored preoperative RT (RR, 0.71; 95% CI, 0.57 to 0.89; p = 0.0025) with an absolute risk reduction of 8.6% (95% CI, 3.1% to 14.2%; p = 0.0024). There was significant heterogeneity when local failure rates were pooled across trials (X 2 = 61.72; p < 0.001). displays the local failure risk ratios with the trials arranged in ascending order of the RT dose (BED) used. There was no treatment effect in the analysis of three trials of preoperative RT using doses of 7.5 to 26.8 BED (RR, 0.95; 95% CI, 0.79 to 1.11; p = 0.58) while trials using doses greater than or equal to 30 BED had evidence of reduced local failures (RR, 0.63; 95% CI, 0.48 to 0.83; p = 0.0011) with significant heterogeneity being detected. ## Tumor resectability Total tumor resectability between the treatment arms was not significantly different when 12 trials (14 comparisons) involving 5 923 patients were pooled (RR, 1.00; 95% CI 0.99 to 1.00; p = 0.36). Pooling of 14 trials (16 comparisons) involving 6 816 patients detected no significant difference in curative resections for preoperative RT compared with surgery alone (RR, 0.99; 95% CI, 0.98 to 1.01; p = 0.59). There was no significant heterogeneity among trials in either pooled analysis. , number of treatment fields, target volume (G, guitarshaped; P, pelvic). † 0 indicates per cent of patients receiving no treatment; <1, percent receiving less than planned treatment; >1, percent receiving more than planned treatment. ‡ Based on independent assessment by five reviewers using the Detsky instrument 10 . § 5% of patients also received RT over >7 days, and 8% of patients received radiation through a two portal beam. ## Downstaging There was an overall significant decrease in the incidence of stage III rectal cancer among patients randomized to preoperative RT compared with surgery alone, but there was significant heterogeneity among the pooled results (X 2 = 38.57; p < 0.001) . Neither radiation dose or its fractionation, nor timing of surgery affected results. Meta-analysis examining preoperative RT for patients with resectable rectal cancer: overall mortality Meta-analysis examining preoperative RT for patients with resectable rectal cancer: overall mortality. Results were reported for only the eligible or evaluable patients for Norway [bib_ref] Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a..., Dahl [/bib_ref] trial. Results were reported for only the eligible patients undergoing surgery for the Swedentrial. Meta-analysis examining preoperative RT for patients with resectable rectal cancer: local failure Meta-analysis examining preoperative RT for patients with resectable rectal cancer: local failure. Results were reported for only the eligible or evaluable patients for the Norway [bib_ref] Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a..., Dahl [/bib_ref] trial. ## Adverse effects Preoperative RT did not significantly increase 30-day postoperative mortality compared with surgery alone (RR, 1.33; 95% CI, 0.87 to 2.05; p = 0.19). These results showed significant heterogeneity of trial results (X 2 = 23.35; p < 0.05) . Results were not affected by radiation dose. Postoperative morbidity was similar across trials and consisted mainly of delay of perineal wound healing and infection. The pooled results for postoperative morbidity also demonstrated significant heterogeneity (X 2 = 62.74; p < 0.001) . Results were not different for patients receiving high or low dose RT or delay to surgery of < 7 or > 8 days. Meta-analysis examining preoperative RT for patients with resectable rectal cancer: incidence of stage III tumors Meta-analysis examining preoperative RT for patients with resectable rectal cancer: incidence of stage III tumors. Meta-analysis examining preoperative RT for patients with resectable rectal cancer: 30-day postoperative mortality Meta-analysis examining preoperative RT for patients with resectable rectal cancer: 30-day postoperative mortality. ## Sensitivity analyses Sensitivity analyses were conducted to test the robustness of the conclusions of the five pooled analyses above (overall survival, local failure, tumor resectability, downstaging, adverse effects) when excluding the three studies with quality scores of less than 0.5 [bib_ref] Preoperative irradiation of rectosigmoid carcinoma including its regional lymph nodes, Kligerman [/bib_ref] [bib_ref] A comparison of nonoperative vs. preoperative radiotherapy in rectal carcinoma. A 10-year..., Reis-Neto [/bib_ref] [bib_ref] Local recurrence of rectal cancer following preoperative irradiation, Illényi [/bib_ref]. Results of the pooled analyses of the best quality studies were not different from the results considering all studies (data not shown). Details of the quality assessment results using the Detsky instrument can be found in Additional file 2. ## Published meta-analyses After completing our analysis, two literature-based metaanalyses of trials comparing preoperative RT to surgery alone for resectable rectal cancer were published [bib_ref] Preoperative radiotherapy for resectable rectal cancer. A meta-analysis, Cammà [/bib_ref]. The Camma et al. [bib_ref] Preoperative radiotherapy for resectable rectal cancer. A meta-analysis, Cammà [/bib_ref] meta-analysis followed a method-ology similar to ours. In the analysis, however, there was also an investigation of patient subgroups (Dukes' stages A, B and C, and male sex) and a regression analysis for overall survival (but not for other outcomes). The following regression variables were used: BED, stage of disease, male sex, study publication year, study size, allocation concealment and handling of withdrawals. This metaanalysis considered 14 published trials [bib_ref] Preoperative irradiation of rectosigmoid carcinoma including its regional lymph nodes, Kligerman [/bib_ref] [bib_ref] Preoperative irradiation in operable cancer of the rectum: report of the Toronto..., Rider [/bib_ref] [bib_ref] Preoperative radiation and surgery for cancer of the rectum, Higgins [/bib_ref] [bib_ref] Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a..., Dahl [/bib_ref] [bib_ref] Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a..., Gérard [/bib_ref] [bib_ref] A comparison of nonoperative vs. preoperative radiotherapy in rectal carcinoma. A 10-year..., Reis-Neto [/bib_ref] [bib_ref] Longterm results of a randomized trial of short-course low-dose adjuvant pre-operative radiotherapy..., Goldberg [/bib_ref] [bib_ref] Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective,..., Marsh [/bib_ref] : it included the VASOG-I trial, which we excluded, and it did not include a trial from Hungary [bib_ref] Local recurrence of rectal cancer following preoperative irradiation, Illényi [/bib_ref] or the single-fraction RT arm from the MRC-I trial. All comparisons were made using odds ratios. Camma et al. [bib_ref] Preoperative radiotherapy for resectable rectal cancer. A meta-analysis, Cammà [/bib_ref] detected a significant reduction in overall mortality with preoperative RT [fig_ref] Table 2: Results of three meta-analyses of preoperative RT versus surgery alone in resectable... [/fig_ref]. In a subgroup analysis, the decrease in mortality occurred in patients with Dukes' stages B and C but not in patients with stage A disease. No interaction was found between RT dose and survival (BED Meta-analysis examining preoperative RT for patients with resectable rectal cancer: postoperative morbidity Meta-analysis examining preoperative RT for patients with resectable rectal cancer: postoperative morbidity. < 30 or > 30; p = 0.53). In the regression analysis none of the factors used as variables had a significant impact on survival. Cancer-specific mortality and local recurrences were also reduced by the use of preoperative RT [fig_ref] Table 2: Results of three meta-analyses of preoperative RT versus surgery alone in resectable... [/fig_ref] but not distant metastases. The overall rate of post-operative adverse events was higher in patients receiving preoperative RT (57.4% versus 42.4%; p < 0.001). The 30-day postoperative mortality was not significantly different between patients receiving preoperative RT and those having only surgery. Camma et al. [bib_ref] Preoperative radiotherapy for resectable rectal cancer. A meta-analysis, Cammà [/bib_ref] concluded that preoperative RT reduced overall and cancer-specific mortality rates, and particularly local recurrence rates, while not affecting distant metastases. Postoperative mortality was not affected by the use of preoperative RT in spite of a higher rate of adverse events in patients. The Colorectal Cancer Collaborative Group (CCCG)identified trials of adjuvant preoperative and postoperative RT started before January 1 st , 1987. The CCCG search yielded 19 trials of preoperative RT which included five trials not included in our review: two trials using preoperative plus postoperative RT [bib_ref] Evaluation of preoperative radiation therapy in operable colorectal cancer, Sause [/bib_ref] , one trial including patients with metastatic disease, another combining RT with 5-fluorouracil (5-FU) administration [bib_ref] Final results of a randomized trial on the treatment of rectal cancer..., Boulis-Wassif [/bib_ref] and a Japanese trial published in 1989. Analysis was done by the log-rank method for overall and disease-specific mortality and for all and isolated recurrences. The overall yearly death rate was 5.6% (standard error ± 3.3). All recurrences and isolated recurrences were significantly decreased by preoperative RT at 5 years (45.9% vs. 52.9% and 12.5% vs. 22.2%, respectively) and at 10 years (55.1% vs. 60.8% and 16.7% vs. 25.8%, respectively). There was significant heterogeneity between the results of the 12 trials analyzed (p = 0.002), which was explained by the greater efficacy of RT at higher biologically effective doses . The reduction in local recurrence was proportionally similar for the various stages of the disease, and not affected by either sex or age. A multivariate analysis was not done. The results of the published meta-analyses [bib_ref] Preoperative radiotherapy for resectable rectal cancer. A meta-analysis, Cammà [/bib_ref] and the one conducted for this systematic review are shown in [fig_ref] Table 2: Results of three meta-analyses of preoperative RT versus surgery alone in resectable... [/fig_ref]. ## Preoperative rt versus alternative treatments preoperative rt versus postoperative adjuvant rt in high-risk cases In a multi-institutional randomized trial in Sweden, patients with operable rectal cancer were randomized to preoperative RT or selective postoperative RT if the pathological stage was II or III [bib_ref] Pre-or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized..., Pahlman [/bib_ref] [bib_ref] Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results..., Frykholm [/bib_ref]. Overall survival was the same for both treatment groups. When only patients with radical resection were considered, local recurrence was less likely for those receiving preoperative RT (11% vs. 22%; p = 0.02) [fig_ref] Table 3: Randomized trials of preoperative RT compared to alternative treatments in rectal cancer [/fig_ref]. Postoperative complications, both early [bib_ref] Pre-or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized..., Pahlman [/bib_ref] and late [bib_ref] Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results..., Frykholm [/bib_ref] , were significantly more frequent after higher-dose postoperative RT. The investigators emphasized that a short course of high fraction preoperative RT is preferable to a standard course of postoperative RT. Preoperative RT was better in reducing local recurrence rates and was associated with lower morbidity. Two other randomized trials have investigated the benefit of preoperative RT given to patients who also received postoperative RT if the pathological stage was II or III [bib_ref] Evaluation of preoperative radiation therapy in operable colorectal cancer, Sause [/bib_ref] [fig_ref] Table 3: Randomized trials of preoperative RT compared to alternative treatments in rectal cancer [/fig_ref]. In a study by the Radiation Therapy Oncology Group (RTOG), investigators randomized patients to a single dose of 5 Gy preoperatively and gave 45 Gy postoperatively to all high-risk patients [bib_ref] Evaluation of preoperative radiation therapy in operable colorectal cancer, Sause [/bib_ref]. After more than five years of follow-up, survival and local failure were similar in patients with or without preoperative RT. The preoperative RT dose in this trial was very small and has been shown to be ineffective [bib_ref] Preoperative irradiation in operable cancer of the rectum: report of the Toronto..., Rider [/bib_ref]. German investigators performed a similar but smaller trial using a higher preoperative RT dose. Patients were randomized to immediate surgery or to receive 16.5 Gy in 5 fractions preoperatively. After surgery, patients at high risk of local recurrence (T4 stage, R1-2 or intraoperative tumor perforation) also received 41.4 Gy if they had preoperative RT and 59.8 Gy if they did not have preoperative RT. In a multivariate analysis of local recurrence, the only significant variable was staging (International Union Against Cancer [UICC]; p = 0.0003) while preoperative RT and T4 stage had non-significant effects (p = 0.08 and 0.07, respectively). In a similar analysis of survival, three variables were significant: age (p = 0.0003), UICC stage (p = 0.001) and residual disease status (p = 0.01). Preoperative RT had a non-significant effect (p = 0.078). These trials [bib_ref] Evaluation of preoperative radiation therapy in operable colorectal cancer, Sause [/bib_ref] indicate that selective postoperative RT annuls any potential positive effect of preoperative RT in low dose. ## Preoperative rt alone versus preoperative rt plus chemotherapy An early randomized trial by the European Organization for Research and Treatment of Cancer (EORTC) [bib_ref] Final results of a randomized trial on the treatment of rectal cancer..., Boulis-Wassif [/bib_ref] compared preoperative RT with or without chemotherapy. 5-FU by bolus injection was given for four days during the first week of the radiation course. The trial was marred by many difficulties, with 27% of the cases being ineligible or not evaluable. The combined treatment did not reveal any advantage over RT alone [fig_ref] Table 3: Randomized trials of preoperative RT compared to alternative treatments in rectal cancer [/fig_ref]. Of interest was a marginally significant decrease in liver metastases for patients receiving preoperative combined treatment (p = 0.06). ## Preoperative rt with surgery at different intervals One trial by French investigators tested whether the delay of surgery after the completion of preoperative RT is important [bib_ref] Influence of the interval between preoperative radiation therapy and surgery on downstaging..., Francois [/bib_ref] [fig_ref] Table 3: Randomized trials of preoperative RT compared to alternative treatments in rectal cancer [/fig_ref]. Operable patients with rectal tumors accessible to digital rectal examination (stage T2-3, NX, M0) received preoperative RT (39 Gy in 13 fractions over 17 days through 3 fields) and were randomized to surgery after a short (two-week) or a long (six-to eightweek) interval. The only significant difference in outcomes, favoring the long over the short delay, was the higher proportion of patients with a clinical tumor response (partial plus complete) (53.1% versus 71.7%; p = 0.007) and pathological downstaging (10.3% versus 26%; p = 0.005). The three-year local failure and survival rates were not significantly different. # Discussion Results of three meta-analyses [fig_ref] Table 2: Results of three meta-analyses of preoperative RT versus surgery alone in resectable... [/fig_ref] indicate that preoperative RT compared to surgery alone significantly decreases the risk of local failure and overall mortality. The absolute reduction in local failure is 8.6% (95% CI, 3.1% to 14.2%) while the absolute reduction in overall mortality at five years is 3.5% (95% CI, 1.1% to 6.0%). Early results of the Dutch trial [bib_ref] Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer, Kapiteijn [/bib_ref] confirm the decrease in local recurrence with preoperative RT even after optimal surgery with total mesorectal excision. The improved results of recent trials can be explained by better patient selection and radiation prescription. Swedish investigators, comparing the results of the Stockholm-Iand Stockholm-IItrials of preoperative RT, showed that the overall survival of patients is significantly affected by the 60-day postoperative mortality rate [bib_ref] Adjuvant preoperative radiotherapy in patients with rectal carcinoma, Holm [/bib_ref]. This early fatality rate is due to an excess of infectious, cardiovascular and thromboembolic causes. This excess in mortality is attributed to the delivery of similar radiation doses to larger versus smaller volumes and by two rather than multiple radiation portals, and to patient characteristics such as evidence of ischemia by ECG and poor performance status. An increase in morbidity was also observed and consisted of venous thromboembolism, femoral neck and pelvic fractures, and intestinal obstruction. A subgroup of patients who participated in the Swedish trialcompleted a questionnaire about anorectal dysfunction. Bowel disturbances led to social restrictions in 30% of patients who received preoperative RT compared with 10% of patients who received surgery alone (p < 0.01). The abnormalities included more frequent bowel movements, urgency and incontinence. No single factor could be identified to explain the complications, but the authors postulated the radiation effect on the anal sphincter itself or on its nerve supply [bib_ref] Preoperative irradiation affects functional results after surgery for rectal cancer. Results from..., Dahlberg [/bib_ref]. Similar anorectal dysfunction has been reported after postoperative RT combined with chemotherapy [bib_ref] The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel..., Kollmorgen [/bib_ref] [bib_ref] Morbidities of adjuvant chemotherapy and radiotherapy for resectable rectal cancer: an overview, Ooi [/bib_ref]. Preoperative RT in high fractions has been compared with standard low-fraction postoperative adjuvant RT [bib_ref] Pre-or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized..., Pahlman [/bib_ref]. The overall survival was the same for both treatment groups but the local recurrence rate was lower and the morbidity less for preoperative RT. While preoperative RT was given to all cases, postoperative RT was given only to high-risk cases (Dukes' stages B2 and C), a group equal to half the number of cases treated with the preoperative approach. The increased morbidity of the postoperative RT must be related in part to the higher radiation dose given. In a retrospective analysis of preoperative and postoperative RT trials, Glimelius et al. [bib_ref] Radiotherapy in addition to radical surgery in rectal cancer: evidence for a..., Glimelius [/bib_ref] observed that for a similar reduction in local failure the dose of radiation must be higher in the postoperative than in the preoperative setting. The use of preoperative RT in small doses did not decrease the indications for postoperative adjuvant RT [bib_ref] Evaluation of preoperative radiation therapy in operable colorectal cancer, Sause [/bib_ref]. Patients who received four bolus injections of 5-FU during the preoperative RT in one old trial increased postoperative mortality and decreased overall survival [bib_ref] Final results of a randomized trial on the treatment of rectal cancer..., Boulis-Wassif [/bib_ref]. The cause for this toxicity is not known and has not been observed in subsequent trials of combined therapy. The delay of surgery after preoperative RT for more than two weeks decreased the rate of stage III disease but had no impact on resectability, local recurrence or survival [bib_ref] Influence of the interval between preoperative radiation therapy and surgery on downstaging..., Francois [/bib_ref]. ## Development of a clinical practice guideline gastrointestinal cancer dsg consensus When presented with the reviewed evidence, the discussion of the Gastrointestinal Cancer DSG focused on results from recent trials of preoperative RT in Europe that demonstrated significant improvements in local failure and survival rates. These results, achieved with a short course of radiation (five fractions) and with less toxicity than standard longer courses of radiation, have prompted the widespread use of this treatment modality in Europe and more recently in North America. Some treatment centers in Ontario have started phase II studies of preoperative RT, in some cases with concurrent chemotherapy. There are, however, some concerns about the widespread use of preoperative RT. Some potential risks of the treatment seem preventable. The use of radiation given to smaller volumes and multiple fields, instead of the past practice of two fields, has been shown to decrease both early postoperative morbidity and mortality. The exclusion of patients with poor performance status and those with ischemic changes in the electrocardiogram (ECG) [bib_ref] Adjuvant preoperative radiotherapy in patients with rectal carcinoma, Holm [/bib_ref] reduced both mortality and morbidity in the first two months. More difficult to predict is the long-term anorectal dysfunction, which restricts the social life of one third of survivors in some series following both preoperative and postoperative adjuvant RT [bib_ref] Preoperative irradiation affects functional results after surgery for rectal cancer. Results from..., Dahlberg [/bib_ref] [bib_ref] Morbidities of adjuvant chemotherapy and radiotherapy for resectable rectal cancer: an overview, Ooi [/bib_ref]. Another concern is that some of the preoperatively irradiated patients would not have required this treatment based on the postoperative staging of the disease. Furthermore, the prognostic value of the postoperative staging of irradiated patients remains uncertain, although downstaging does not occur after the short course of preoperative RT. The postoperative pathological staging is important to determine the need for adjuvant chemotherapy, which improves survival and reduces local recurrence [bib_ref] Cancer Disease Site Group: Post-operative adjuvant radiotherapy or chemotherapy for resected stage..., Figueredo [/bib_ref]. Should preoperative RT be recommended for adjuvant treatment in resectable rectal cancer? The common practice in North America for patients with resected stages II and III rectal cancer has been postoperative RT plus chemotherapy. In a previous guideline, it was demonstrated that this combined treatment significantly reduced local failure by 50% (95% CI, 8% to 73%) and improved patient survival by 42% (95% CI; 8% to 63%) for patients with stage II and III rectal cancer when compared to postoperative RT alone [bib_ref] Cancer Disease Site Group: Post-operative adjuvant radiotherapy or chemotherapy for resected stage..., Figueredo [/bib_ref]. In similar patients, postoperative RT alone compared to observation after surgery decreased local recurrences by 27% (95% CI, 4% to 45%) but did not improve survival. Postoperative RT alone has been, therefore, discouraged [bib_ref] Cancer Disease Site Group: Post-operative adjuvant radiotherapy or chemotherapy for resected stage..., Figueredo [/bib_ref]. Preoperative RT alone, when compared to surgery, has been shown to decrease local failure by approximately 50% and to improve survival by approximately 15% [fig_ref] Table 2: Results of three meta-analyses of preoperative RT versus surgery alone in resectable... [/fig_ref]. The improvement in local recurrence has occurred after optimal surgery with TME [bib_ref] Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer, Kapiteijn [/bib_ref]. In a single trial [bib_ref] Pre-or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized..., Pahlman [/bib_ref] [bib_ref] Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results..., Frykholm [/bib_ref] , preoperative short-course RT has induced less local recurrence (11% versus 22%; p = 0.02) and less morbidity than conventional postoperative RT alone. From these results it can be inferred that preoperative RT is a better treatment choice than postoperative RT with less local failures and less morbidity. A comparison of preoperative RT followed by postoperative chemotherapy versus combined postoperative RT plus chemotherapy is presently being investigated in clinical trials but mature results are not yet available for review. Based on the evidence from the Swedish and Dutch trials [bib_ref] Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer, Kapiteijn [/bib_ref] and the meta-analyses data, preoperative RT (followed by chemotherapy for at least patients with stage III) is an alternative to our previous recommendation for combined postoperative RT plus chemotherapy for resected patients with stage II and III rectal cancer. Patients must be made aware of the potential benefits and drawbacks of both approaches. Benefits of short-course preoperative RT are lower local failure and less treatment morbidity. Local failure is an important outcome in rectal cancer as recurrences are associated with significant disability. Drawbacks are the need to use preoperative RT in more patients compared to RT administered according to postoperative staging and the possibility that patients not requiring radiation may develop treatment associated complications. Physicians should encourage patients to participate in clinical trials of the primary treatment of rectal cancer. These trials should require the best possible surgery, the confirmation of the accuracy of clinical staging versus pathological staging, and the use of measures of quality of life. Patients must also be clearly advised of the differences between treatment approaches. ## External review Practitioner feedback was obtained through a mailed survey. The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommenda-tions should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Gastrointestinal Cancer DSG reviewed the results of the survey. ## Summary of main findings Written comments provided by practitioners varied. Several respondents expressed concern with the statement in the draft recommendations that "Postoperative radiotherapy for patients with stage II / III rectal cancer is as effective in prolonging survival as preoperative radiotherapy for all rectal cancer patients regardless of stage of disease". These respondents noted that preoperative versus postoperative RT was not the topic of this guideline and randomized trials addressing this issue are still ongoing. Other respondents also questioned the recommendation that "postoperative radiotherapy combined with chemotherapy should remain the standard treatment". They argued that if the results of the on-going trials demonstrate that preoperative and postoperative RT are equally effective, then one treatment should not be recommended over the other as the standard treatment. Several respondents raised the question of the role of total mesorectal excision. ## Modifications or actions Practitioner feedback indicated a need to clarify the role of preoperative RT in the context of the companion guideline [bib_ref] Cancer Disease Site Group: Post-operative adjuvant radiotherapy or chemotherapy for resected stage..., Figueredo [/bib_ref] recommending postoperative RT plus chemotherapy for stage II and III rectal cancer. In this context, the magnitude of benefits and drawbacks of preoperative and postoperative RT with and without chemotherapy are further discussed in the Gastrointestinal Cancer DSG Consensus section. ## Practice guidelines coordinating committee approval process The guideline was circulated to 11 members of the Practice Guideline Coordinating Committee. Seven members returned ballots; five approved the guideline report as written, and two members approved the guideline conditional on the Gastrointestinal Cancer DSG addressing suggestions for revision. The suggestions referred to the recommendations and the meta-analyses. Changes were made to the guideline based on these suggestions, and a revised version was resubmitted to the PGCC for further consideration. The practice guideline was approved with one dissenting vote. # Conclusions This practice guideline reflects the integration of a review of the evidence, the Gastrointestinal Cancer DSG draft recommendations and the feedback obtained from the external review process. It has been approved by the Gastrointestinal Cancer DSG and the Practice Guidelines Coordinating Committee. ## Target population These recommendations apply to adult patients with clinically resectable rectal cancer. This report does not consider the use of preoperative RT to convert locally advanced, initially unresectable rectal cancer to resectable cases, to preserve the anal sphincter, or to delay the need for colostomy. ## Recommendations Preoperative RT is an acceptable alternative to the previous practice of postoperative RT for patients with stage II and III resectable rectal cancer. Both preoperative and postoperative RT decrease local recurrence but neither improves survival as much as postoperative RT combined with chemotherapy. Therefore, if preoperative RT is used, chemotherapy should be added postoperatively to at least patients with stage III disease. # Qualifying statement Patients must be made aware of the potential benefits and drawbacks of both approaches. Benefits of short-course preoperative RT are lower local failure and less treatment morbidity. Local failure is an important outcome in rectal cancer as recurrences are associated with significant disability. Drawbacks are the need to use preoperative RT in more patients compared to RT administered according to postoperative staging and the possibility that patients not requiring radiation may develop treatment associated complications. ## List of abbreviations used TNM, tumor, node, metastases (the staging system of the UICC); RT, radiotherapy; DSG, disease site group; [table] Table 1: Randomized trials of preoperative RT versus surgery alone in resectable rectal cancer. Note: EORTC indicates European Organization for Research and Treatment of Cancer; ICRF-UK, Imperial Cancer Research Fund United Kingdom; MRC, Medical Research Council; NW-UK, Northwest Region Rectal Cancer Group United Kingdom; VASOG, Veterans Administration Surgical Oncology Group. * Total dose in Gy, number of fractions, (duration of treatment in days) [/table] [table] Table 2: Results of three meta-analyses of preoperative RT versus surgery alone in resectable rectal cancer. [/table] [table] Table 3: Randomized trials of preoperative RT compared to alternative treatments in rectal cancer.Note: NS indicates not statistically significant; RTOG, Radiation Therapy Oncology Group. * Radiation given only to high-risk cases (stages B2 and C). † 3-year survival rate. [/table] [table] 1: Number surveyed: 155 practitioners in Ontario (30 medical oncologists, 21 radiation oncologists, 100 surgeons, and four gastroenterologists). 2. Return rate: 63% 3. Written comments attached: 54% 4. Agreement with the summary of the evidence: 87% 5. Agreement with the recommendation: 85% 6: Approval of the recommendation as a practice guideline: 68% [/table]	None	https://bmcmedicine.biomedcentral.com/track/pdf/10.1186/1741-7015-1-1	None
02802af3db1ead11fe84b5227e74f14824db0bd8	pubmed	From randomized trials to the clinic: is it time to implement individual lung-cancer screening in clinical practice? A multidisciplinary statement from French experts on behalf of the french intergroup (IFCT) and the groupe d'Oncologie de langue française (GOLF)	From randomized trials to the clinic: is it time to implement individual lung-cancer screening in clinical practice? A multidisciplinary statement from French experts on behalf of the french intergroup (IFCT) and the groupe d'Oncologie de langue française (GOLF) Background: Despite advances in cancer therapy, mortality is still high except in early-stage tumors, and screening remains a challenge. The randomized National Lung Screening Trial (NLST), comparing annual low-dose computed tomography (LDCT) and chest X-rays, revealed a 20% decrease in lung-cancer-specific mortality. These results raised numerous questions. The French intergroup for thoracic oncology and the French-speaking oncology group convened an expert group to provide a coherent outlook on screening modalities in France.Methods: A literature review was carried out and transmitted to the expert group, which was divided into three workshops to tackle specific questions, with responses presented in a plenary session. A writing committee drafted this article.Results: The multidisciplinary group favored individual screening in France, when carried out as outlined in this article and after informing subjects of the benefits and risks. The target population involves subjects aged 55-74 years, who are smokers or have a 30 pack-year smoking history. Subjects should be informed about the benefits of quitting. Screening should involve LDCT scanning with specific modalities. Criteria for CT positivity and management algorithms for positive examinations are given. † This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Conclusions: Individual screening requires rigorous assessment and precise research in order to potentially develop a lung-cancer screening policy. introduction Lung cancer is the leading cause of cancer-related deaths worldwide. Most patients are diagnosed with advanced-stage tumors, precluding curative-intent treatment. Lung-cancer screening is aimed at decreasing lung-cancer-associated mortality and improving prognosis by detection at an early stage, especially stage I, which has the highest long-term survival rates (up to 90%) following surgical resection [bib_ref] Survival of patients with stage I lung cancer detected on CT screening, Henschke [/bib_ref] [bib_ref] Natural History of Stage I Non-Small Cell Lung Cancer: Implications for Early..., Raz [/bib_ref] [bib_ref] Long-term prognosis of patients with lung cancer detected on low-dose chest computed..., Nawa [/bib_ref]. While lung-cancer screening trials using chest radiography have reported inconsistent findings [bib_ref] Early lung cancer detection: results of the initial ( prevalence) radiologic and..., Frost [/bib_ref] [bib_ref] Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up, Marcus [/bib_ref] [bib_ref] Screening by Chest Radiograph and Lung Cancer Mortality: The Prostate, Lung, Colorectal,..., Oken [/bib_ref] , several studies using low-dose computed tomography (LDCT) scans have led to a re-evaluation of screening programs. However, increases in the proportion of stage I cancers and survival rates after diagnosis have not sufficiently demonstrated the efficacy of screening, as these outcomes are subject to bias. Screening benefits can only be demonstrated by comparing specific mortality with and without screening in randomized trials. The randomized, controlled National Lung Screening Trial (NLST)recently demonstrated a reduction in lung-cancer-related and overall mortality of 20.0% [95% confidence interval (CI), 6.8-26.7; P = 0.004] and 6.7% (95% CI, 1.2-13.6; P = 0.02), respectively, when using LDCT instead of chest radiography. In recent months, these results have received substantial media coverage in the medical and general communities. In routine practice, patients, especially smokers, have increasingly questioned physicians about individual lung-cancer screening. Given this context, the French intergroup for thoracic oncology [Intergroupe Francophone de Cancérologie Thoracique (IFCT)] and the French-speaking oncology group [Groupe d'Oncologie de Langue Française (GOLF)] invited a group of thoracic oncologists, respiratory specialists, radiologists, surgeons, methodologists, and general practitioners (GPs) to join a multidisciplinary taskforce. Our main objective was to discuss how recent data from lungcancer screening randomized trials might be implemented on the individual level. Based on available evidence, this article provides physicians and patients with practical information and recommendations for individual lung-cancer screening. methodology Following the publication of the NLST, the experts of the taskforce were invited to participate in a workshop on 17 February 2012 in Paris, [fig_ref] Table 1: Comparison of protocol characteristics in the main lung-cancer screening trials [/fig_ref] , available at Annals of Oncology online). The taskforce was sponsored by an unrestricted grant from Roche SA France, who played no role in data collection, interpretation, discussion, or manuscript writing. Before the meeting, a core workgroup (FB, EL, BMi, and GZ) undertook a comprehensive literature review, selecting and distributing key publications to the group. It should be emphasized that this is not a systematic review of the literature following usual recommendation for guidelines edition. The following keywords were used for the literature review on the Medline database: 'lung cancer', 'screening', 'randomized, controlled trial', 'nodule', 'CT scan', 'low-dose CT', and 'tobacco'. The bibliography was completed with references to the retrieved articles and with articles suggested by each expert in its proper field. The core workgroup first listed a number of questions usually asked by patients and colleagues in their daily practice. This list was then sent to the whole group for afterthought. At the meeting, the first plenary session was dedicated to edit the final question list that was approved by showing hands. Each pack of question was then discussed in three workgroups (supplementary [fig_ref] Table 2: Comparison of positive screening test results in the different studies [/fig_ref] , available at Annals of Oncology online) based on available evidence in order to formulate multidisciplinary statements, which were further refined after discussions by the whole group. Finally, this paper was edited by a writing committee (FB, AC, SC, NG, VG, LGr, EL, BMe, BMi, and GZ), and the draft was reviewed and amended by some experts from the taskforce. to whom should CT screening be proposed? The NLST results(20% decrease in lung-cancer-specific mortality) appear sufficient to support individual screening. Individual screening may be carried out on a physician's recommendation or at a subject's request once informed of the potential benefits and risks. Participation must be voluntary. To be eligible, subjects must fulfill certain criteria in line with those previously published studies [bib_ref] A randomized study of lung cancer screening with spiral computed tomography: three-year..., Infante [/bib_ref] [bib_ref] Baseline results of the Depiscan study: a French randomized pilot trial of..., Blanchon [/bib_ref] [bib_ref] Lung cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian (PLCO)..., Hocking [/bib_ref] (cf. [fig_ref] Table 1: Comparison of protocol characteristics in the main lung-cancer screening trials [/fig_ref] -aged between 55 and 74 years; -at least 30 pack-year tobacco exposure; -active smoker or quit during the last 15 years; -no serious progressive disease (history of cancer other than non-melanoma skin cancer or carcinoma in situ over the past 5 years 1 ; severe co-morbidity, including respiratory insufficiency contraindicating invasive chest examination; prior hemoptysis; unexplained weight loss over 10% over the past 12 months); -no pulmonary infection over the 12 past weeks; -accepts repeated scans or additional investigations in the case of abnormal findings; -accepts considering help to quit smoking (active smokers). With the help from the attending physician, the prescribing physician should systematically propose helping subjects quit smoking, referring them to health care professionals and suggesting anti-smoking organizations (http://www.tabac-infoservice.fr; http://www.ofta-asso.fr; http://cancer.gov/cancertopics/ tobacco/smoking). Subjects, particularly those continuing to smoke, should be reminded of the benefits of quitting at each visit. [bib_ref] Survival of patients with stage I lung cancer detected on CT screening, Henschke [/bib_ref] Screening does not apply to these patients, since they require specific management and monitoring. Subjects wishing to undergo LDCT scans for cancer screening should receive detailed information, notably about the risks of detecting abnormalities [fig_ref] Table 2: Comparison of positive screening test results in the different studies [/fig_ref] and the probability of complementary examinations or surgical procedures leading to the diagnosis of malignant or benign conditions (one-third of cases). In the NLST, for over 17 000 positive examinations, 457 invasive procedures (surgery, bronchoscopy, and needle puncture) were carried out in subjects not diagnosed with a malignancy (2.6% 'useless' investigations). Of these, 413 (90.4%) were completed without any complications, while major complications occurred in 44 (0.24%). By comparison, in COSMOS (an Italian cohort study with 5201 subjects incorporating TEP scan in nodule management) 13 useless surgeries were carried out after baseline and first round screening accounting for 0.13% of all positive screening CT scan [bib_ref] Lung cancer screening with low-dose computed tomography: a non-invasive diagnostic protocol for..., Veronesi [/bib_ref] [bib_ref] Difficulties encountered managing nodules detected during a computed tomography lung cancer screening..., Veronesi [/bib_ref]. In the NELSON study [bib_ref] Management of lung nodules detected by volume CT scanning, Van Klaveren [/bib_ref] (incorporating volume doubling time of the nodule in its management), 324 of the 7557 participating subjects had a positive CT screening after two rounds. From those, 162 underwent useless examinations, mainly with an invasive procedure (1.1% of all screening CT scan-follow-up scan at 3 months for indeterminate nodule excluded). Subjects must be reminded of the risk of diagnosing tumors that would probably never have led to clinical symptoms (over diagnosis risk) or impacted survival (rare indolent forms). Finally, physicians should mention the radiation exposure risks related to repeated scanning, including evaluation of positive screening, even at low doses. During this information session, subjects should be reminded that quitting smoking is always beneficial, regardless of age and tobacco exposure, and that screening only makes sense when combined with smoking cessation. Information should be provided orally and accompanied by written documents. Health care professionals involved in screening, namely GPs, radiologists, and pulmonologists, should also receive written information reminding the target population of screening its expected benefits, notably in terms of cancer-specific and overall mortality reduction, and its risks. Moreover, these professionals should be aware that repeated examinations may detect lesions whose management requires referral to specialists, such as pulmonologists, radiologists, surgeons, and pathologists. Finally, chronic obstructive pulmonary disease should be investigated in all subjects even if the scan is normal, in the case of respiratory symptom or symptoms reported by screening participants. [bib_ref] A randomized study of lung cancer screening with spiral computed tomography: three-year..., Infante [/bib_ref] [bib_ref] The Danish randomized lung cancer CT screening trial-overall design and results of..., Pedersen [/bib_ref] [bib_ref] Design, recruitment and baseline results of the ITALUNG trial for lung cancer..., Lopes Pegna [/bib_ref] [bib_ref] UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen..., Baldwin [/bib_ref] [bib_ref] Risk-based selection from the general population in a screening trial: Selection criteria,..., Van Iersel [/bib_ref] [bib_ref] Abstract SS03-03: The ITALUNG study and the state of art of randomized..., Paci [/bib_ref]. what is the optimal follow-up duration and screening interval? Little prospective data are available regarding the optimal follow-up duration. However, the New York's ELCAP cohort was compared with another cohort of smoker with no screening intervention (CARET). In this paper, it appears clearly that discontinuation of screening is associated with an increase of lung-cancer mortality rate [bib_ref] Assessment of lung-cancer mortality reduction from CT Screening, Henschke [/bib_ref]. showed that the lung-cancer detection rate among a long duration annual screening cohort was stable over time [bib_ref] Long-term outcomes of a pilot CT screening for lung cancer, Veronesi [/bib_ref]. Overall, a minimum of three scans carried out 1 year apart seems advisable, as in the NLST protocol. Finally, considering that (collective) screening programs only make sense on an ongoing basis, carrying out LDCT scans annually appears justified, especially compared with other cancer screening programs, such as breast or colon cancer, although the optimal frequency remains undetermined. Continued screening seems all the more relevant since in all screening studies, cancers were detected at each round. The benefits of continued screening in patients over 75 years of age (having undergone at least three initial scans) and subjects with over 15 years' smoking abstinence are not known. The optimal interval between two rounds of CT is unknown. The MILD trial compares an annual schedule versus a biennial schedule. Ground-glass opacities were not considered in this study until a solid component appears. Although the paper reports intermediate and underpowered results, the cumulative incidence of lung cancer increases in the annual group but without any shift to higher stage in the biennial arm [bib_ref] Annual or biennial CT screening versus observation in heavy smokers: 5-year results..., Pastorino [/bib_ref]. The mortality rate seems higher in the annual than in the biennial arm, although nonsignificant. Moreover, there was no difference in the number of lung cancers detected from CT screening in each arm. Another approach might be to propose a personalized screening interval according to the individual risk factors and radiological findings at baseline CT. This model if validated will allow us to save costs and radiation exposure by increasing the screening interval in low-risk population [bib_ref] Lung cancer risk prediction to select smokers for screening CT--a model based..., Maisonneuve [/bib_ref]. what are the technical screening modalities? Screening modalities include technical recommendations on how LDCT scan should be carried out according to the 230 available literature, and recommendations on CT reading and interpretation [bib_ref] Management of lung nodules detected by volume CT scanning, Van Klaveren [/bib_ref] [bib_ref] Guidelines for the use of spiral computed tomography in screening for lung..., Henschke [/bib_ref] [bib_ref] International association for the study of lung cancer computed tomography screening workshop..., Field [/bib_ref] [bib_ref] Multidetector computed tomography chest examinations with low-kilovoltage protocols in adults: effect on..., Kim [/bib_ref] [bib_ref] Use of BMI guidelines and individual dose tracking to minimize radiation exposure..., Manowitz [/bib_ref] [bib_ref] Pulmonary nodule detection on MDCT images: evaluation of diagnostic performance using thin..., Jankowski [/bib_ref] [bib_ref] Detection of pulmonary nodules at multirow-detector CT: effectiveness of double reading to..., Wormanns [/bib_ref] [bib_ref] No benefit for consensus double reading at baseline screening for lung cancer..., Wang [/bib_ref] [bib_ref] Using radiation risk models in cancer screening simulations: important assumptions and effects..., Kong [/bib_ref] [bib_ref] Dose exposure in the ITALUNG trial of lung cancer screening with low-dose..., Mascalchi [/bib_ref]. The patient should be supine, with the arms above the head. A multi-detector row CT scanner should be used without contrast medium injection. Acquisition is performed in volumetric mode, during apnea at the end of the inspiration, from the apices to the pleural recesses. Native slice thickness should be ≤1.25mm with a 30% overlap reconstruction, allowing for volumetric analysis [bib_ref] Management of lung nodules detected by volume CT scanning, Van Klaveren [/bib_ref] [bib_ref] Guidelines for the use of spiral computed tomography in screening for lung..., Henschke [/bib_ref] [bib_ref] International association for the study of lung cancer computed tomography screening workshop..., Field [/bib_ref]. The examination is then reconstructed with two reconstruction algorithms (i.e. soft tissues and highresolution). There is no consensus on low-dose scanning. To avoid variability, voltage was not limited, but dose-length product 2 (DLP) had an upper limit of 150 mGy.cm for an adult of average weight (70 kg) [bib_ref] Multidetector computed tomography chest examinations with low-kilovoltage protocols in adults: effect on..., Kim [/bib_ref] , with adjustment according to weight [bib_ref] Use of BMI guidelines and individual dose tracking to minimize radiation exposure..., Manowitz [/bib_ref]. The DLP should appear on the imaging report. Ultra-low-dose scanning is not recommended, so as to avoid altering image quality. Noise level reduction software may be used. CT reading should be performed on workstation using native slices in the axial plane and multi-planar reconstruction. Five to eight millimeters maximum-intensity-projection (MIP) slabs should be analyzed for improving the detection of pulmonary nodules. Currently, computer-assisted diagnosis is not recommended in this indication [bib_ref] Pulmonary nodule detection on MDCT images: evaluation of diagnostic performance using thin..., Jankowski [/bib_ref]. Software that measures nodule volume is necessary for follow-up [bib_ref] Management of lung nodules detected by volume CT scanning, Van Klaveren [/bib_ref]. As regards individual scanning, a systematic second reading is not justified [bib_ref] Detection of pulmonary nodules at multirow-detector CT: effectiveness of double reading to..., Wormanns [/bib_ref] [bib_ref] No benefit for consensus double reading at baseline screening for lung cancer..., Wang [/bib_ref]. Interpretation of these examinations should ideally be undertaken by radiologists who specialize in thoracic imaging or have undergone specific training. Two-dimensional measurement of nodules should be obtained on axial images using lung parenchyma window settings (window level of −600 to −700 HU, window around 1500 UH), while volumetric measurement should be performed using images obtained with a standard reconstruction algorithm. When available, previous chest scans must be systematically reviewed. The screening scan should first be interpreted alone and then in comparison with all prior CT scans, including the oldest, in order to assess abnormality change. Each non-calcified nodule must be characterized as prevalent (discovered at first screening) or incidental (appearing between two examinations). Every detected abnormality must be described and detailed in the report, as should nodule characteristics, notably anatomical position (lateralization, lobe, segment), slice number, dimension (largest axial transverse diameter and volumetric measurement), contour characteristics (regular, spiculated, poorly defined, and indeterminate), doubling time in the case of previous examinations, and attenuation (solid, part-solid, or pure ground-glass nodules). The native slices should be stored on a CD-ROM in DICOM format along with the native slices. Subjects are invited to undergo repeated examinations in the same center or, failing that, to present the CD-ROM of the previous CT examination. All French centers with CT scanner equipments able to respond to the technical and organizational constraints described above should be able to perform lung cancer screening CT scans. Radiation protection in diagnostic radiography requires setting an upper DLP limit. In the NLST, the mean dose was 1.5 mSv. Mean natural radiation exposure in France is 3.7 mSv per year, while a chest X-ray carries a dose of 0.05 mSv. Patients need to be informed that screening CT scan is equivalent to less than 6 months' natural radiation exposure or 50 chest X-rays. The risk of developing radiationinduced cancers should not be understated. However, in screening, this risk is low, impacting very little on the magnitude of survival benefit [bib_ref] Using radiation risk models in cancer screening simulations: important assumptions and effects..., Kong [/bib_ref]. Recently, the ITALUNG study team published follow-up results for doses given during the trial. For the entire study duration (initial scan followed by annual scans for 4 years), the mean individual cumulative dose ranged from 6.2 mSv to 6.8 mSv. Overall, 77.4% of the radiation dose was linked to CT screening, and the remaining 22.6% to other examinations due to positive results. The individual dose effectively delivered by screening scans was low in this study [bib_ref] Dose exposure in the ITALUNG trial of lung cancer screening with low-dose..., Mascalchi [/bib_ref]. what is positive screening? Only nodules and masses observed in screening results are considered. Other radiological abnormalities on CT should be referred for specific management. With multiple nodules, the appropriate strategy is that suited to the most suspicious nodule. ## Solid nodules The solid nodule size is determined by measuring largest diameter. Volumetric measurements are also used, particularly for comparison. The management algorithm proposed for solid nodules detected on CT is presented in [fig_ref] Figure 1: Management algorithm for the interpretation of scans showing a solid nodule [/fig_ref]. The characteristics of CT-detected nodules allow examination results to be classified into three categories: positive (abnormality requiring further exploration), indeterminate (abnormality justifying a control CT scan), and negative (no abnormalities or abnormality not requiring specific follow-up besides annual screening). Examinations are considered negative when: -The nodule is entirely calcified or shows central calcification on two orthogonal reformations, regardless of size (calcified nodule) [bib_ref] CT of the pulmonary nodule: a cooperative study, Zerhouni [/bib_ref] ; -The nodule size is <5 mm. If there is an incidental nodule (not found on previous low-dose scanning), a low-dose control scan is carried out 1 year later; -The criteria for 'probably benign' nodules are: - fat attenuation (−40 to −120 Hounsfield units, standard deviation included) within the nodule; ## Reviews - characteristics suggestive of intrapulmonary lymph nodes: nodules <10 mm with angular shape at a distance of <10 mm from the pleura and situated below the carina [bib_ref] Perifissural Nodules Seen at CT Screening for Lung Cancer, Ahn [/bib_ref]. The technical difficulty of measuring small nodule attenuation, coupled with the limited data on intrapulmonary nodes, supports characterizing such nodules as probably benign and repeating the low-dose scan after 1 year. Examinations are considered indeterminate when the greatest nodule diameter is between 5 and 10 mm (approximate volume of 50-500 mm 3 ), justifying a low-dose control CT scan after 3 months (cf. [fig_ref] Figure 2: Management of solid indeterminate nodules [/fig_ref]. The working group supported the follow-up proposed in the NELSON study [bib_ref] Nodule management protocol of the NELSON randomised lung cancer screening trial, Xu [/bib_ref]. The CT reading is subsequently based on doubling time estimations using volumetric measurements: -If the doubling time is ≥400 days, the test is negative. A CT scan is systematically carried out 1 year after initial examination. -If the doubling time is <400 days (∼25% volume increase), the test is positive, and the subject is referred to a specialist. Examinations are considered positive when either: -at least one solid nodule of >10 mm at largest diameter (approximate volume 500 mm 3 ); or -initially indeterminate, but the 3month-CT follow-up demonstrates that the nodule doubling time is <400 days. ## Ground-glass nodules ( pure ground-glass and part-solid) Volumetric measurement is poorly suited to ground-glass nodules [bib_ref] Subsolid pulmonary nodules and the spectrum of peripheral adenocarcinomas of the lung:..., Godoy [/bib_ref]. These are, therefore, monitored using onedimensional largest-diameter measurements. Pure ground-glass nodules of <5 mm in diameter require no specific follow-up (it is negative screening and screening continues annually) as they are highly correlated with localized atypical adenomatous hyperplasia [bib_ref] Subsolid pulmonary nodules and the spectrum of peripheral adenocarcinomas of the lung:..., Godoy [/bib_ref] which is a premalignant lesion of adenocarcinoma with a long doubling time of 988 ± 470 days as showed by Takashima et al. [bib_ref] Indeterminate solitary pulmonary nodules revealed at population-based CT screening of the lung:..., Takashima [/bib_ref]. Ground-glass nodules with solid components and pure ground-glass nodules of ≥5 mm in diameter require probabilistic antibiotic treatment and a new scan after 3 months [fig_ref] Figure 3: Management of ground-glass opacity nodule [/fig_ref]. After 3 months, management can vary: -For resolving nodules, the test is negative and screening resumes without modification. -If the nodule size increases by at least 2 mm or if a solid component appears, the test is positive, and the subject is referred to a specialist. -If a pure ground-glass nodule is stable, the test is indeterminate, and management is subjected to multidisciplinary discussion. how should positive subjects be investigated? histology As far as screening in particular is concerned, conventional bronchofiberscopy is low-performing in anatomic pathology diagnoses, with 13.5% sensitivity and a negative predictive value of 47.6% [bib_ref] The role of the 18 ffluorodeoxyglucose-positron emission tomography scan in the Nederlands..., Van't Westeinde [/bib_ref]. Accordingly, negative examinations are not cause to discontinue investigation. New methods of fibroscopic sampling are being developed (radial endoscopic ultrasound, electromagnetic navigation), although their place in diagnosis after screening has yet to be defined. Transthoracic puncture has excellent sensitivity and specificity in pulmonary parenchymal nodules. However, this examination includes an approximately 20% risk of pneumothorax with a minority of cases requiring drainage. Nonetheless, its being negative does not totally exclude a cancer diagnosis. ## Positron emission tomography (pet) For screening populations at high risk of cancer, PET is irrelevant. The absence of hyper-metabolic nodule activity upon examination is insufficient to conclude benignity. PET's negative predictive value is only 81% [bib_ref] The role of conventional bronchoscopy in the work-up of suspicious CT screen..., Van 't Westeinde [/bib_ref]. That said PET must be performed in staging work-ups or before locoregional treatment, as recommended, when cancer is diagnosed or suspected. Other investigations, particularly cerebral imagery, should also be conducted according to current recommendations. ## Therapeutic and diagnostic options of solid nodules The following two strategies are proposed: -immediate surgical excision following pre-therapeutic assessment with no contraindications, for diagnostic and potentially therapeutic purposes, especially when malignity is highly probable. Subjects must be fully informed of the risk of "useless" excision of a benign nodule; -initially obtaining anatomic pathology evidence by transthoracic puncture as explained above. Subjects must be fully informed of the risk of false-negative histology (invasive cancer with negative puncture). The surgical excision of confirmed malignant nodules would then be the same as in the previous strategy. The choice between these two options should be made at a multidisciplinary meeting after informing the subject and taking into account the individual benefits and risks of each strategy. ## Therapeutic and diagnostic options of pure ground-glass nodules For positive pure ground-glass nodules, diagnosis cannot be confirmed by biopsy [bib_ref] International Multidisciplinary Classification of Lung Adenocarcinoma, Travis [/bib_ref]. Similarly, the value of extemporaneous examination to distinguish in situ from invasive adenocarcinomas is not proven. Diagnostic strategy therefore involves surgical resection. However, the risk of synchronous or metachronous multifocal lesions is high, entailing minimal surgical resection. Peripheral pure groundglass nodules in particular should be considered for sublobar resection [bib_ref] Sublobar resection for lung cancer, Rami-Porta [/bib_ref]. For indeterminate pure ground-glass nodules, the probability of in situ or minimally invasive adenocarcinoma (CT cannot differentiate) is high (over 75%), which may lead to surgical resection. However, given these tumors' usually show slow growth, annual follow-up CTs for at least 5 years may be considered as an alternative [bib_ref] Subsolid pulmonary nodules and the spectrum of peripheral adenocarcinomas of the lung:..., Godoy [/bib_ref]. surgery Recommendations differ depending on nodule type, i.e., pure ground-glass or solid: -Tumor ≥2 cm: the preferred techniques are lobectomy and complete mediastinal lymph node dissection performed according to recommendations (48); -Tumor <2 cm and full nodule: the standard is lobectomy and complete mediastinal lymph node dissection, although anatomic segmentectomy with node resection is an option; -Tumor <2 cm with pure ground-glass opacity: atypical resection is initially recommended. The definitive anatomic pathology analysis (invasive lepidic adenocarcinoma or in situ carcinoma) will determine subsequent surgical management. The use of video-assisted thoracoscopic surgery is encouraged, as this therapeutic option is recognized in national recommendations for surgical practice in the treatment of early-stage lung cancer. # Discussion Our group's results support the implementation of individual screening in France after informing the subject of the benefits and risks and in accordance with the conditions detailed in this article. Subjects should be between 55 and 74 years, smoke at least 30 pack-years and voluntarily agree to participate in the screening. They should be given information about quitting smoking, the main elements of which have already been formalized. Screening should be carried out using a LDCT scan according to specific technical modalities. Positivity criteria and management algorithms for positive tests are detailed in this article. The responses currently given by French physicians to individual requests for screening are diverse. While some accept prescribing CT scans, usually standard and non-lowdose scans (although no specific rules have been established), others refuse because no national program has yet been implemented. The members of this working group considered that the magnitude of the benefit observed in the NLST was such that it was not possible to refuse subjects who requested individual screening spontaneously, and that it even appeared acceptable to propose it. Theoretically, the NLST is the only prospective randomized study to have observed this benefit, and it would be valuable to confirm the efficacy of screening in another study. However, this comparative randomized study with high statistical power gave the highest level of evidence, and the trial was well conducted. Still, this study presents some methodological features which could be discussed. First, there is no true control arm considering the non-interventional arm is annual chest X-ray. However, the randomized PLCO study, recently carried out on >150 000 individuals showed that annual screening with chest radiograph did not reduce lungcancer mortality compared with no screening, the so-called bona fide control arm [bib_ref] Screening by Chest Radiograph and Lung Cancer Mortality: The Prostate, Lung, Colorectal,..., Oken [/bib_ref]. Second, attention should be paid to the fact that the results of the NLST trial were prematurely reported, according to the recommendations of the independent data and safety monitoring committee. So it could carry a risk of over-emphasizing the true benefit of intervention. However, as mentioned in the seminal paper, 'the efficacy boundary for the primary end-point had been crossed, and that there was no evidence of unforeseen screening effects that warranted acting contrary to the trial's prespecified monitoring plan'. Finally, the NLST trial included a high proportion of former smokers (around 50% in each arm) comparatively with other randomized study (around 25 to 40%). So it could be a recruiting bias as former smokers have better life expectancy than current smokers. However, this high proportion is well balanced in both the arms and cannot explain the observed significant differences. It could be interesting to perform a sub-group analysis which would explore whether the benefit of screening is similar in current or former smokers. Moreover, the NLST results are consolidated by a number of nonrandomized trials, which have evaluated the mortality benefit using statistical models and showing positive results [bib_ref] Assessment of lung-cancer mortality reduction from CT Screening, Henschke [/bib_ref] [bib_ref] Long-term outcomes of a pilot CT screening for lung cancer, Veronesi [/bib_ref]. On the other hand, several randomized studies are currently ongoing (see [fig_ref] Table 1: Comparison of protocol characteristics in the main lung-cancer screening trials [/fig_ref] but most will probably lack power to confirm the follow-up results obtained in the NLST study [bib_ref] Abstract SS03-03: The ITALUNG study and the state of art of randomized..., Paci [/bib_ref] [bib_ref] Annual or biennial CT screening versus observation in heavy smokers: 5-year results..., Pastorino [/bib_ref] [bib_ref] Nodule management protocol of the NELSON randomised lung cancer screening trial, Xu [/bib_ref] [bib_ref] LUSI: the german component of the european trial on the efficacy of..., Becker [/bib_ref] [bib_ref] CT screening for lung cancer brings forward early disease. The randomised Danish..., Saghir [/bib_ref]. From those, two have recently reported no benefit of CT screening on lungcancer mortality, although they both obviously lack of power [bib_ref] Annual or biennial CT screening versus observation in heavy smokers: 5-year results..., Pastorino [/bib_ref] [bib_ref] CT screening for lung cancer brings forward early disease. The randomised Danish..., Saghir [/bib_ref]. Indeed, the primary objective of the DLCST trial [bib_ref] The Danish randomized lung cancer CT screening trial-overall design and results of..., Pedersen [/bib_ref] [bib_ref] CT screening for lung cancer brings forward early disease. The randomised Danish..., Saghir [/bib_ref] was to assess a 25% difference in lung-cancer specific mortality. The trial was statistically powered to highlight this difference in addition with the NELSON study effective and 10 years after randomization. The 5ive-year results of DLCST alone reported a significant higher rate of cancer in the screening group and a nonsignificant higher lung-cancer and global mortality rate in this arm but with evident lack of power. The Italian MILD study [bib_ref] Annual or biennial CT screening versus observation in heavy smokers: 5-year results..., Pastorino [/bib_ref] also shows (5-year results) a higher mortality rate (both lung cancer specific and global) in the screening groups. Nonetheless, this trial suffers from limitations due to the lack of comparability between groups and differential attrition bias. In addition, initially powered for detecting a 30% difference in lung-cancer mortality, 10 000 participants were needed for a 10-year period of screening. Unfortunately, only 4104 peoples were recruited. The implementation of individual screening is only conceivable if a large amount of information is given to prescribing physicians. In fact, the difference between the trials and routine clinical practice lies in the sharing of information and individual discussion of the risks and benefits (among other things) [bib_ref] Uninformed compliance or informed choice? A needed shift in our approach to..., Stefanek [/bib_ref]. This information is not currently available. A survey conducted in the United States showed that physicians sometimes poorly interpret the findings of clinical trials on screening. This observation justifies expert work to explain these results and help transpose them into practice [bib_ref] Do physicians understand cancer screening statistics? A national survey of primary care..., Wegwarth [/bib_ref]. The working group of the International Association for Study on Lung Cancer recently provided a summary of the literature, but this offered few solutions to individual requests, particularly in a European health system [bib_ref] International association for the study of lung cancer computed tomography screening workshop..., Field [/bib_ref]. More recently, experts from the American National Comprehensive Cancer Network (NCCN) published their recommendations for clinical practice [bib_ref] Lung cancer screening, Wood [/bib_ref]. As in our group, they proposed implementing individual screening for at-risk subjects. Investigators of ongoing European lung-cancer screening trials were more cautious in their statement, underlying that 'several questions need to be answered in the near future, before considering implementation of low-dose CT screening for lung cancer'. The authors from a recent systematic literature review concluded that 'there are substantial uncertainties regarding how to translate that conclusion into clinical practice' [bib_ref] Benefits and harms of CT screening for lung cancer: a systematic review, Bach [/bib_ref]. Nevertheless, our work is therefore part of an overall effort to propose the standardization and organization of screening and its consequences in a different geographical and social context to that in which the NLST was conducted. Indeed, the populations and health care systems of North America and Europe are different. It is also a question of transposing the conditions that yield certain trial results into actual clinical practice [bib_ref] Prevalence of cancer screening in older, racially diverse adults: still screening after..., Bellizzi [/bib_ref]. The benefit of screening in terms of mortality is thus demonstrated in an American population subjected to some selection based mostly on motivation to participate in a longterm clinical trial, and including current or former smokers aged between 55 and 74 years and consuming at least 30 packyears. It would evidently be hazardous to extrapolate these results to another population, and thus, to the population targeted by screening, outside the setting of a clinical trial. Adherence to screening is essential. In the NLST, compliance with repeated examinations was excellent (95%). In contrast, in the Italian DANTE study with 2811 subjects [bib_ref] A randomized study of lung cancer screening with spiral computed tomography: three-year..., Infante [/bib_ref] , the adherence rate for the third scan was only 44% (20% for the fourth). In the French DEPISCAN study with 765 subjects, 19% of included patients were not compliant [bib_ref] Baseline results of the Depiscan study: a French randomized pilot trial of..., Blanchon [/bib_ref]. However, this was a prospective controlled study, suggesting that in 'real life' even greater deviations could be observed. These findings are in line with the observations made in France in relation to organized breast cancer screening, in which the patients' participation rate is sometimes low [bib_ref] Breast cancer screening in women aged 50-74 years: is there room for..., Morère [/bib_ref] [bib_ref] Socioeconomic and healthcare supply statistical determinants of compliance to mammography screening programs:..., Pornet [/bib_ref]. One of the factors favorably influencing adherence to screening programs is higher socioeconomic level. In both the NLST and DEPISCAN trials (data not published), subjects largely came from affluent segments of the population, [bib_ref] Baseline results of the Depiscan study: a French randomized pilot trial of..., Blanchon [/bib_ref] [bib_ref] Baseline characteristics of participants in the randomized national lung screening trial, Aberle [/bib_ref] , whereas the low socioeconomic level is a known risk factor in lung cancer [bib_ref] The impact of socioeconomic status on stage of cancer at diagnosis and..., Booth [/bib_ref]. Data from [fig_ref] Table 1: Comparison of protocol characteristics in the main lung-cancer screening trials [/fig_ref] show that the studies published on screening are heterogeneous in terms of subject selection, particularly with regards to the level of tobacco intoxication. Selecting participants for the screening program is crucial for increasing its cost-effectiveness. In this way, several models have been proposed, whereas only one has been built on a screening population. In their paper, showed that the use of a mathematical model (taking into account the presence of nodule, nodule characteristics and the presence of emphysema) seems suitable for selecting a higher risk population [bib_ref] Lung cancer risk prediction to select smokers for screening CT--a model based..., Maisonneuve [/bib_ref]. Another original approach is used in the UKLS study [bib_ref] UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen..., Baldwin [/bib_ref]. This study uses the Liverpool Lung project questionnaire [bib_ref] The LLP risk model: an individual risk prediction model for lung cancer, Cassidy [/bib_ref] to calculate the risk of lung cancer related to tobacco use, but also to personal and family cancer history, professional exposure, and pneumonia history. Nevertheless, the NLST study was the only randomized study which clearly demonstrates any benefit in terms of mortality, and thus for the moment, any possible screening policy should follow these inclusion criteria. Finally, NCCN guidelines recommend to select individuals at risk according several criteria including tobacco history and also other exposure to carcinogen such as occupational or second hand smoking [bib_ref] Lung cancer screening, Wood [/bib_ref]. Any individual or collective policies for lung-cancer screening must be accompanied by an anti-smoking program in order to be effective, including from a medico-economic point of view [bib_ref] Cost-effectiveness of computed tomography screening for lung cancer in the United States, Mcmahon [/bib_ref]. It is certain that screening visits offer a valuable opportunity to address complete and permanent smoking cessation [bib_ref] A pilot test of a combined tobacco dependence treatment and lung cancer..., Ferketich [/bib_ref] [bib_ref] The impact of a lung cancer computed tomography screening result on smoking..., Van Der Aalst [/bib_ref]. For this reason, our working group drafted information aimed at GPs and people wishing to participate in a screening program. Our proposals are based on expert's advice. However, many questions remain unresolved. It is, therefore, necessary to rapidly develop clinical research programs in this field. First, our group was unanimously in favor of a rigorous evaluation and follow-up of these proposals' implementation, of lungcancer incidence, and of positive subjects' change in time. Overdiagnosis (i.e. cancers discovered by screening which would not have led to clinical symptoms during the patient's lifetime) must be studied, as must the real efficacy of screening in terms of specific and overall mortality, and finally the frequency and results of examinations conducted after positive screening. Five other themes based on currently unresolved issues were identified as priorities by our group: (i) medicoeconomic evaluation of individual screening in the French health care system is essential in order to calculate the costbenefit ratio of screening, and this evaluation must include compliance and smoking cessation, possibly in relation to subjects' sociodemographic characteristics. (ii) The frequency and optimal duration of screening need to be studied. (iii) The value of CT scan double-reading and computer-aided nodule diagnosis should be evaluated, since such software does not seem efficient when used for the initial reading [bib_ref] Pulmonary nodule detection on MDCT images: evaluation of diagnostic performance using thin..., Jankowski [/bib_ref]. Furthermore, breast cancer screening programs with systematic double reading have shown that this practice is cost-effective [bib_ref] Effectiveness and cost-effectiveness of double reading of mammograms in breast cancer screening:..., Dinnes [/bib_ref] [bib_ref] Second reading of screening mammograms increases cancer detection and recall rates. Results..., Ciatto [/bib_ref]. However, the NLST did not include systematic CT double reading [bib_ref] CT quality assurance in the Lung Screening Study Component of the National..., Gierada [/bib_ref] , and the value of this practice was challenged in the NELSON study [bib_ref] No benefit for consensus double reading at baseline screening for lung cancer..., Wang [/bib_ref]. (iv) Studying benignity criteria for intra-thoracic nodules may reduce unnecessary investigations. These criteria are based on retrospective data from a small series of 234 nodules in 98 subjects [bib_ref] Perifissural Nodules Seen at CT Screening for Lung Cancer, Ahn [/bib_ref]. (v) Finally, it would be useful to evaluate other screening techniques. The discovery of a plasma microRNA signature predictive of malignity appears promising [bib_ref] MicroRNA signatures in tissues and plasma predict development and prognosis of computed..., Boeri [/bib_ref] [bib_ref] A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with..., Bianchi [/bib_ref]. All future studies should, therefore, take plasma biomarkers into account. In conclusion, lung-cancer screening using LDCT scans was shown to substantially decrease lung-cancer-specific mortality. These data deserve recognition and justify the work at hand, which will need to be updated with findings from other ongoing trials. ## Acknowledgement The authors thank Dr Gabrielle Cremer for expert English editing. [fig] Figure 2: Management of solid indeterminate nodules. [/fig] [fig] Figure 1: Management algorithm for the interpretation of scans showing a solid nodule. [/fig] [fig] Figure 3: Management of ground-glass opacity nodule. [/fig] [table] Table 1: Comparison of protocol characteristics in the main lung-cancer screening trials [/table] [table] Table 2: Comparison of positive screening test results in the different studies [/table]	None	https://academic.oup.com/annonc/article-pdf/24/3/586/13788697/mds476.pdf	Background Despite advances in cancer therapy, mortality is still high except in early-stage tumors, and screening remains a challenge. The randomized National Lung Screening Trial (NLST), comparing annual low-dose computed tomography (LDCT) and chest X-rays, revealed a 20% decrease in lung-cancer-specific mortality. These results raised numerous questions. The French intergroup for thoracic oncology and the French-speaking oncology group convened an expert group to provide a coherent outlook on screening modalities in France. Methods A literature review was carried out and transmitted to the expert group, which was divided into three workshops to tackle specific questions, with responses presented in a plenary session. A writing committee drafted this article. Results The multidisciplinary group favored individual screening in France, when carried out as outlined in this article and after informing subjects of the benefits and risks. The target population involves subjects aged 55–74 years, who are smokers or have a 30 pack-year smoking history. Subjects should be informed about the benefits of quitting. Screening should involve LDCT scanning with specific modalities. Criteria for CT positivity and management algorithms for positive examinations are given. Conclusions Individual screening requires rigorous assessment and precise research in order to potentially develop a lung-cancer screening policy.
a09a5b94abff5b5d3fc073528137237650a917a1	pubmed	Guidelines on the management of ascites in cirrhosis	Guidelines on the management of ascites in cirrhosis The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and metaanalysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the 'Grading of Recommendations Assessment, Development and Evaluation (GRADE)' system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years' time. 13.7. The cost-effectiveness and the effect of automated lowflow ascites pumps on the quality of life of patients with refractory ascites should be evaluated. 13.8. Effectiveness and safety of long-term abdominal drains should be assessed in RCTs for the palliative care of patients with cirrhosis and refractory ascites. ## Patient summary These guidelines have been produced on behalf of the British Society of Gastroenterology (BSG) in collaboration with the British Association for the Study of the Liver (BASL). These guidelines are aimed at healthcare professionals who look after patients with cirrhosis and ascites. Ascites is the build-up of fluid in the belly (abdomen). This occurs when the liver gets irreversibly scarred, a condition known as cirrhosis. Ascites is the most common complication of cirrhosis. All patients with a new onset of ascites should have the fluid tested. This involves inserting a small needle into the abdomen and removing about two tablespoons of ascitic fluid. The fluid is then analysed for protein and white cell count. Protein count can help differentiate whether the cause of ascites is cirrhosis or whether the ascites is due to other causes like heart disease or cancer. The white cell count indicates whether there is an infection in the ascitic fluid. If infection is present, this is treated with a short course of antibiotics. Infection of ascites should be ruled out at every hospital admission as it carries a high risk of death and should therefore be diagnosed and treated promptly. After this initial treatment, patients are given long-term antibiotics to prevent repeat infections. No salt should be added at the table to food. The total amount of salt in food per day should not be more than the equivalent of one teaspoon. Patients should read labels on prepared foods to confirm their daily salt intake is within the limit of 5 g of salt. The initial treatment for patients with ascites involves taking medication, commonly known as 'water tablets' (diuretics). These drugs are begun at a small dose, which is gradually increased until the ascites is treated. Diuretics can have side effects such dehydration, confusion, abnormal levels of sodium and potassium and kidney damage. Therefore patients should be monitored while taking these tablets. As the liver disease progresses the ascites may no longer respond to medication. This is known as untreatable or refractory ascites. This requires the patient to come into hospital every few weeks to have a temporary drain inserted into the abdomen and the ascitic fluid drained. If more than 5 L of fluid is removed, patients are also given a protein solution into the vein to prevent dehydration. In patients with untreatable ascites, alternatives to repeated hospital drainage include placing a small tube (stent) in the liver. # Introduction Contemporary data from an NHS hospital serving a population of 700 000, found 164 adults with a new diagnosis of ascites over a period of 5 years. Of these, 55% had cirrhosis (alcohol-related liver disease 58, non-alcoholic fatty liver disease 21, chronic viral hepatitis 4, autoimmune liver diseases 3 and cryptogenic cirrhosis 4), 29% had malignancies (gynaecological 12, gastrointestinal 25 and others 11), 6% cardiac failure (CF), 3% end-stage renal disease (ESRD) and 7% other aetiologies. Development of ascites is an important milestone in the natural history of cirrhosis. About 20% of patients with cirrhosis have ascites at their first presentation, and 20% of those presenting with ascites die in the first year of the diagnosis. [bib_ref] The rate of decompensation and clinical progression of disease in people with..., Fleming [/bib_ref] The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. ## Pathogenesis A detailed description of the pathogenesis of ascites formation is beyond the scope of this article, but two key factors involved in the pathogenesis of ascites formation are portal hypertension and retention of sodium and water. This is summarised in figure 1. An elevated sinusoidal pressure is essential for the development of ascites, as fluid accumulation does not develop at portal pressure gradient below 8 mm Hg, and rising corrected sinusoidal pressure correlates with decreased 24-hour urinary excretion of sodium. Architectural changes associated with advanced fibrosis are clearly the primary mechanism underlying increased intrahepatic resistance to the portal flow in cirrhosis. In addition, phenotypic changes in hepatic stellate cells and liver sinusoidal endothelial cells contribute to the pathophysiology. Activated stellate cells become contractile, and their recruitment around newly formed sinusoidal vessels increases the vascular resistance. Reduction in the production/bioavailability of nitric oxide (NO) in the cirrhotic liver adds further to the rise in vascular tone. Overall, vasoconstriction has been estimated to account for about 25% of the increased resistance within the liver. [bib_ref] Pathophysiology of portal hypertension, Iwakiri [/bib_ref] Increased portal pressure is sensed by intestinal microvasculature that generates angiogenic factors such as vascular endothelial growth factor, 5 and these stimulate the development of portosystemic collaterals through the opening of pre-existing vessels or new vessel formation. When the portal pressure rises further, induction of endothelial nitric oxide synthase and over production of NO leads to splanchnic arterial vasodilatation. This, in turn, increases portal blood flow, thus exacerbating portal hypertension. Portosystemic collaterals also permit vasodilators such as NO, prostacyclin and endocannabinoids 6 to enter the systemic circulation leading to a state of 'effective hypovolaemia'. [bib_ref] Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium..., Schrier [/bib_ref] This activates sympathetic nervous system stimulating reabsorption of sodium in proximal, distal tubules, loop of Henle and collecting duct as well as the renin-angiotensin-aldosterone system, leading to sodium absorption from distal tubule and collecting duct. [bib_ref] Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of..., Cárdenas [/bib_ref] Renal sodium retention and eventual free water clearance due to non-osmotic release of arginine-vasopressin and its action on V2 receptor in the collecting duct underlie the fluid retention associated with oedema and ascites in cirrhosis. [bib_ref] Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of..., Cárdenas [/bib_ref] More recently, it has been hypothesised that bacterial translocation associated with portal hypertension in cirrhosis and related pathogen-associated, molecular pattern activated innate immune responses lead to systemic inflammation. [bib_ref] Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation..., Bernardi [/bib_ref] This is associated with vasodilatation as well as release of proinflammatory cytokines, reactive oxygen and nitrogen species, contributing to organ dysfunction. ## Guidelines ## Definitions The terms used in this article have been defined by the International Ascites Club 10 ## Uncomplicated ascites Ascites that is not infected and which is not associated with the development of the hepatorenal syndrome (HRS). Ascites can be graded as mild when ascites is detectable only by ultrasound examination, moderate when it causes moderate symmetrical distension of the abdomen and large when it causes marked abdominal distension. ## Refractory ascites Ascites that cannot be mobilised or the early recurrence of which (ie, after therapeutic paracentesis) cannot be satisfactorily prevented by medical treatment. This includes two different subgroups. ## Diuretic-resistant ascites Ascites that is refractory to dietary sodium restriction and intensive diuretic treatment. ## Diuretic-intractable ascites Ascites that is refractory to treatment owing to the development of diuretic-induced complications that preclude the use of an effective diuretic dosage. ## Evaluation of patients with ascites Clinical evaluation should include history of exposure to risk factors for cirrhosis and physical examination to look for evidence to support chronic liver disease or an alternative diagnosis. Shifting dullness is detectable when about one and a half litres of free fluid accumulate in the abdomen; the physical sign has 83% sensitivity and 56% specificity in detecting ascites. However, in the presence of obesity or smaller amount of fluid, imaging such as ultrasound or CT is necessary to confirm the presence of ascites. ## Diagnostic paracentesis in new-onset ascites Aspiration of ascitic fluid and its laboratory analysis is an essential step in the management of patients with newly diagnosed ascites. In cirrhosis, hepatic sinusoids are less permeable owing to fibrous tissue deposition, resulting in ascites with low protein content. It is important to estimate total protein level in ascites fluid; a concentration below 1.5 g/dL (or 15 g/L) is a risk factor for the development of spontaneous bacterial peritonitis. In addition, serum ascites albumin gradient (SAAG) should be estimated routinely. A cut-off point of 1.1 g/dL (or 11 g/L) differentiates between causes of ascites with high sensitivity, [bib_ref] The serum-ascites albumin gradient is superior to the exudate-transudate concept in the..., Runyon [/bib_ref] [bib_ref] Superiority of the serum-ascites albumin difference over the ascites total protein concentration..., Rector [/bib_ref] [bib_ref] Diagnosing ascites: value of ascitic fluid total protein, albumin, cholesterol, their ratios,..., Gupta [/bib_ref] [bib_ref] Serum-ascites albumin concentration gradient: a physiologic approach to the differential diagnosis of..., Paré [/bib_ref] [bib_ref] Usefulness of serum-ascites albumin difference in separating transudative from exudative ascites. another..., Mauer [/bib_ref] [bib_ref] Does this patient have bacterial peritonitis or portal hypertension? How do I..., Wong [/bib_ref] although alternative causes should be considered based on the clinical scenario . Hepatic sinusoids are normally permeable in heart failure, which allows for leakage of protein-rich lymph into the abdominal cavity and therefore, total protein concentration in ascitic fluid is high (>2.5 g/dL) in combination with a high SAAG. In such a situation, measurement of brain natriuretic peptide (BNP) in the serum±ascites is useful. Total protein concentrations >2.5 g/dL within the ascites and serum BNP >364 ng/L are suggestive Grouping of aetiology of ascites based on serum albumin ascites gradient (SAAG) The pathogenesis of ascites in cirrhosis. of underlying or additional cardiac disease, whereas serum protein values <182 ng/L rule out cardiac disease. [bib_ref] Serum B-type natriuretic peptide in the initial workup of patients with new..., Farias [/bib_ref] In low SAAG states, clinical context and imaging should guide the investigational approach. The yield for positive cytology in the context of malignancy is variable, ranging from 0% to 96.7%, in part determined by the site of the tumour. Combining cytology with tumour markers in the ascitic fluid may increase the positive predictive value (PPV), specifically the use of carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), CA 15-3 and CA 19-9. [bib_ref] Evaluation of tumor markers for the differential diagnosis of benign and malignant..., Liu [/bib_ref] However, CA 125 in the serum or ascites has no role as a discriminator and will commonly be elevated by the presence of ascites from any cause. [bib_ref] CA 125 serum levels in patients with nonneoplastic liver diseases. A clinical..., Collazos [/bib_ref] Where peritoneal TB is considered plausible, ascites can be sent for acid-fast bacilli smear and culture, although culture positivity occurs in <50% and smear-positive ascites is rare. [bib_ref] Diagnostic features of tuberculous peritonitis in the absence and presence of chronic..., Shakil [/bib_ref] Adenosine deaminase is more useful to distinguish between peritoneal TB and carcinomatosis, with an area under the receiver operating characteristic curve of 0.98; adenosine deaminase levels of <40 IU/mL are used to exclude TB. Pancreatic ascites is a rare complication of pancreatitis, although more common when a pseudocyst is present. In pancreatic ascites, the amylase level in the ascitic fluid is typically >1000 IU/L or greater than six times the serum amylase, with mean values exceeding 4000 IU/L in a recent cohort of 80 patients. [bib_ref] Percutaneous drainage versus peritoneal lavage for pancreatic ascites in severe acute pancreatitis:..., He [/bib_ref] Raised polymorphonuclear leucocytes (PMN) count may also be found in pancreatic ascites. [bib_ref] Unexplained ascites, Hernaez [/bib_ref] The ascitic fluid samples required from the diagnostic paracentesis is summarised in figure 2. ## Recommendations ## Spontaneous bacterial peritonitis (sbp) Spontaneous bacterial peritonitis is the development of bacterial infection of ascites in the absence of any intra-abdominal surgically treatable source of infection. The prevalence of SBP in outpatients is 1.5-3.5% and approximately 10% in hospitalised patients. [bib_ref] Spontaneous bacterial peritonitis in asymptomatic outpatients with cirrhotic ascites, Evans [/bib_ref] A recent European study detected a prevalence of 11.3% among inpatients. [bib_ref] Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver..., Fernández [/bib_ref] When first described, mortality associated with SBP exceeded 90%, but, in-hospital mortality has been reduced to approximately 20% with early diagnosis and prompt treatment. [bib_ref] The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: results of a..., Piano [/bib_ref] In an observational study, each hour of delay in diagnostic paracentesis after admission was associated with a 3.3% increase of in-hospital mortality after adjusting for model for end-stage liver disease (MELD) score. [bib_ref] Delayed paracentesis is associated with increased in-hospital mortality in patients with spontaneous..., Kim [/bib_ref] Long-term survival remains poor; 1-year survival after hospitalisation with SBP in a UK study was found to be 34%. [bib_ref] Long-term outcomes after hospitalization with spontaneous bacterial peritonitis, Lim [/bib_ref] Patients recovering from an episode of SBP should always be considered as potential candidates for liver transplantation if they have not already been assessed. ## Diagnosis of sbp The diagnosis of SBP is confirmed when ascitic neutrophil count is >250 cells/mm 3 in the absence of an intra-abdominal and surgically treatable source of sepsis. A cut-off point of 250 neutrophils/mm 3 has the greatest sensitivity, although a cut-off point of 500 neutrophils/mm 3 has greater specificity. [bib_ref] Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International..., Rimola [/bib_ref] A metaanalysis of primary data from 14 prospective trials has defined the positive and negative likelihood ratios of SBP at different thresholds for total white cell count (WCC) and PMN in ascitic fluid. WCC >1000 cells/µL or PMN ≥500 cells/µL are most accurate and yield positive likelihood ratios of 9.1 (95% CI 5.5 to 15.1) and 10.6 (95% CI 6.1 to 18.3), respectively. Likelihood ratios for WCC >500 cells/µL (5.9; 95% CI 2.3 to 15.5) and PMN >250 cells/µL (6.4; 95% CI 4.6 to 8.8) support routine clinical practice of using lower thresholds, where the greater risk lies with underdiagnosing SBP. [bib_ref] Does this patient have bacterial peritonitis or portal hypertension? How do I..., Wong [/bib_ref] Historically, ascitic neutrophil counts have been performed by manual microscopy, but, this is time and cost intensive. Automated counts, based on flow cytometry for counting and differentiating cells, are now used in most centres. This technique has been shown to have sensitivity and specificity close to 100%, allowing a tube containing ethylenediamine tetra-acetate (EDTA; as used for plasma full blood count) to be inoculated with ascitic fluid and processed on a standard blood count analyser. Reagent strips have insufficient sensitivity for reliable use in this context [bib_ref] Diagnostic accuracy of the Multistix 8 SG reagent strip in diagnosis of..., Nousbaum [/bib_ref] and hence cannot be recommended to replace cell count to diagnose SBP. ## Ascitic fluid culture Ascites culture is essential to help guide antibiotic therapy. Patients with 'culture-negative neutrocytic ascites' (PMN count >250 cells/mm 3 ) have a similar presentation to those with culture-positive SBP. As both groups of patients have significant morbidity and mortality, they should be treated in a similar manner. Some patients have 'bacterascites' in which cultures are positive, but, ascitic neutrophil count is <250 cells/mm 3 . In some patients, bacterascites represents a transient and spontaneously reversible colonisation of ascites, in others, particularly those who are symptomatic, it may represent the first step in the development of SBP. [bib_ref] Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International..., Rimola [/bib_ref] Discussion with microbiologists about the organism cultured can help differentiate the above two scenarios, and when a positive culture is obtained a repeat tap should be sent to guide management. Although the identification of pathogen(s) is essential for the management of infectious diseases, ascites fluid cultures often fail to provide positive results, even when using ascites samples Guidelines from patients who develop clinical manifestations of SBP. Bacterial DNA detection and sequencing have been applied to the diagnosis of several infectious diseases, and molecular techniques can detect small amounts of bacterial DNA within a few hours. These promising techniques have yet to be introduced into routine clinical practice. [bib_ref] Amplification of bacterial genomic DNA from all ascitic fluids with a highly..., Enomoto [/bib_ref] Fungal peritonitis is a rare, less studied complication and observational data suggest a worse prognosis. [bib_ref] Spontaneous fungal peritonitis: a rare but severe complication of liver cirrhosis, Gravito-Soares [/bib_ref] In a large multicentre study of 2743 cirrhotic inpatients, of whom 1052 had infections, 12.7% of infected patients had evidence of fungal infections with a case fatality of 30%. The majority of these were urinary, but the highest mortality was seen with fungaemia and peritonitis (case fatality >50%). 41 ## Secondary bacterial peritonitis A small proportion of patients with cirrhosis may develop peritonitis secondary to perforation or inflammation of an intraabdominal organ, known as secondary bacterial peritonitis. In a small retrospective analysis, secondary peritonitis represented 4.5% of all peritonitis in cirrhotic patients. [bib_ref] Secondary bacterial peritonitis in cirrhosis: a retrospective study of clinical and analytical..., Soriano [/bib_ref] This should be suspected in those who have localised abdominal symptoms or signs, very high ascitic neutrophil count, the presence of multiple organisms on ascitic culture or in those with inadequate response to treatment. [bib_ref] Secondary bacterial peritonitis in cirrhosis: a retrospective study of clinical and analytical..., Soriano [/bib_ref] Cross-sectional imaging, such as CT, should be performed with early consideration of surgery in this scenario. ## Antibiotic therapy The most common organisms isolated in patients with SBP include Escherichia coli, Gram-positive cocci (mainly streptococcus species) and enterococci. Empirical antibiotic therapy must be initiated immediately after the diagnosis of SBP. [bib_ref] Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International..., Rimola [/bib_ref] In the 1990s, cefotaxime, a third-generation cephalosporin, was extensively investigated in patients with SBP because it was found to cover 95% of organisms and high ascitic fluid concentrations could be achieved. The take home message from these studies is that matching an effective antibiotic to the cultured organism is key to successful treatment, rather than any apparent superiority of one drug over another. Since these studies, the landscape of bacterial resistance has significantly changed with an increase in antimicrobial resistant organisms, [bib_ref] Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide, Piano [/bib_ref] and therefore recommending a specific single empirical antibiotic is challenging. Thus, it is crucial to separate community-acquired SBP from healthcare-associated SBP (nosocomial -defined as infection >48 hours after hospital admission) [bib_ref] CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types..., Horan [/bib_ref] and to consider both the severity of infection and the local resistance profile in order to decide the empirical antibiotic treatment of SBP.Over recent years there has been a significant increase in the number of infections caused by multidrug-resistant organisms, defined by an acquired non-susceptibility to at least one agent in three or more antimicrobial categories. [bib_ref] Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim..., Magiorakos [/bib_ref] It is also important to highlight the shift to extensively drug resistant bacteria, defined by nonsusceptibility to at least one agent in all but two or fewer antimicrobial categories, or to pan-drug resistance bacteria, defined by non-susceptibility to all agents in all antimicrobial categories. [bib_ref] Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim..., Magiorakos [/bib_ref] A second diagnostic tap should be considered at 48 hours from starting treatment, to check the efficacy of antibiotic therapy in patients who have an apparently inadequate response. If ascitic fluid neutrophil count fails to decrease to less than 25% of the pretreatment value, this should raise suspicion of antibiotic resistance or the presence of 'secondary peritonitis'. Specialist microbiology links should be developed within each trust to help guide local policy and patient management and, in addition, de-escalation of anti-microbial agents according to susceptibility of positive cultures is recommended. The evidence for the use of human albumin solution and recommendations for its use in SBP are discussed in a separate section below. ## Prophylactic therapy for sbp Three groups at high risk of developing SBP have been identified: (i) patients with acute gastrointestinal (GI) haemorrhage; (ii) patients with a low ascitic protein concentration and no prior history of SBP (primary prophylaxis) and (iii) patients with a previous episode of SBP (secondary prophylaxis). [bib_ref] Antibiotic prophylaxis in cirrhosis: good and bad, Fernández [/bib_ref] Although antibiotic prophylaxis to prevent further infection in patients presenting to hospital with upper GI bleeding is established in clinical practice, [bib_ref] Meta-analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding -an updated..., Chavez-Tapia [/bib_ref] [bib_ref] Antibiotic prophylaxis for spontaneous bacterial peritonitis in cirrhotic patients with ascites, without..., Cohen [/bib_ref] [bib_ref] guidelines on the management of variceal haemorrhage in cirrhotic patients, Tripathi [/bib_ref] there remains uncertainty over prophylaxis in other circumstances. Additional studies related to this area after the Cochrane review 53 are summarised in online supplemental table 1. ## Primary prophylaxis Primary prophylaxis is a controversial area and broad recommendations are not straightforward. In 2016 the National Institute for Health and Care Excellence (NICE) recommended offering prophylactic oral ciprofloxacin or norfloxacin for people with cirrhosis and ascites and no history of SBP with an ascitic protein of ≤15 g/L (1.5 g/dL), until the ascites has resolved. [bib_ref] Assessment and management of cirrhosis in people older than 16 years: summary..., Harrison [/bib_ref] Six studies were included in their analyses. [bib_ref] Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites: a..., Grangé [/bib_ref] [bib_ref] Ciprofloxacin and long-term prevention of spontaneous bacterial peritonitis: results of a prospective..., Rolachon [/bib_ref] [bib_ref] Selective intestinal decontamination prevents spontaneous bacterial peritonitis, Soriano [/bib_ref] [bib_ref] Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: a randomized, placebo-controlled study, Terg [/bib_ref] [bib_ref] Primary prophylaxis with ciprofloxacin in cirrhotic patients with ascites: a randomized, double..., Téllez-Ávila [/bib_ref] [bib_ref] Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival..., Fernández [/bib_ref] The European Association for the Study of Liver (EASL) recommend primary prophylaxis with norfloxacin (400 mg/day) in patients with Child-Pugh score ≥9 and serum bilirubin ≥3 mg/dL, with either impaired renal function or hyponatraemia and ascitic fluid protein lower than 15 g/L.The American Association for the Study of Liver Diseases (AASLD) also suggest that antibiotics for primary prophylaxis of SBP should be considered for people at high risk of developing this complication, which was defined as an ascitic fluid protein <1.5 g/dL together with impaired renal function or liver failure. [bib_ref] Introduction to the revised American Association for the Study of Liver Diseases..., Runyon [/bib_ref] In contrast, in a large placebo-controlled randomised clinical trial, the NORFLOCIR trial, norfloxacin did not reduce 6-month mortality in patients with advanced cirrhosis, with >95% of patients included having no history of prior SBP. [bib_ref] Effects of long-term norfloxacin therapy in patients with advanced cirrhosis, Moreau [/bib_ref] In post-hoc analyses, norfloxacin, appeared to increase survival of patients with low ascites fluid protein concentrations. However, other data have failed to replicate an association of incidence of SBP in patients with pre-existing low total ascitic fluid protein concentration in three large cohorts of hospitalised patients with cirrhosis and ascites. Furthermore, there are concerns about the potential consequences of long-term oral antibiotic therapy, including resistance, increased risk of Clostridium difficile associated diarrhoea, adverse reactions and drug interactions. In 2019 the Medicines and Healthcare products Regulatory Agency (MHRA) issued updated guidance on new restrictions and precautions for use of fluoroquinolone antibiotics following a detailed EU review of very rare reports of disabling and potentially longlasting or irreversible side effects affecting the musculoskeletal and nervous systems. Although SBP prophylaxis was not specifically considered, renal impairment is considered to increase this risk, and therefore healthcare professionals and patients should be vigilant during treatment with fluoroquinolone antibiotics and discontinue treatment at the first sign of tendon pain or inflammation. Finally, norfloxacin is not widely available in the UK. In view of the uncertainties outlined above, we advocate primary prophylaxis is offered to patients considered at high risk, as defined by an ascitic protein count <1.5 g/dL. However, it is important that the potential risks and benefits and existing uncertainties are communicated to patients. It is expected that a large ongoing multicentre UK trial (European Union Drug Regulating Authorities Clinical Trials Database Registration Number: 2019-000581-38) to investigate the efficacy of long-term co-trimoxazole compared with placebo as primary prevention for SBP may deal with these uncertainties. ## Secondary prophylaxis In patients who survive an episode of SBP, the cumulative recurrence rate at 1 year is approximately 70%. [bib_ref] Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International..., Rimola [/bib_ref] Probability of survival at 1 year after an episode of SBP is 30-50% and falls to 25-30% at 2 years. There is only one randomised, doubleblind, placebo-controlled trial of norfloxacin (400 mg/day) in patients who had a previous episode of SBP [bib_ref] Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind,..., Ginés [/bib_ref] ; treatment reduced the probability of recurrence of SBP from 68% to 20%. A recent systematic review with meta-analysis concluded that rifaximin may be effective for both primary and secondary SBP prophylaxis compared with systemically absorbed antibiotics and compared with no intervention. [bib_ref] Systematic review with meta-analysis: rifaximin for the prophylaxis of spontaneous bacterial peritonitis, Goel [/bib_ref] However, additional prospective studies are required before a change in clinical practice can be recommended. It has been suggested that proton pump inhibitor use may increase the risk for the development of SBP and indications for long-term use should be carefully assessed. [bib_ref] Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis..., Min [/bib_ref] [bib_ref] Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous..., Dam [/bib_ref] We therefore recommend norfloxacin 400 mg once a day as secondary prophylaxis, although in view of limited availability in the UK, many centres use once daily ciprofloxacin 500 mg once a day as an alternative. ## Recommendations ## Dietary salt restriction There is little evidence to support salt restriction in patients with cirrhosis in absence of ascites. In patients with cirrhosis and ascites, seven RCTs and one cross-sectional survey have examined the role of salt restriction (online supplemental table 2). [bib_ref] Advantages of treatment of ascites without sodium restriction and without complete removal..., Reynolds [/bib_ref] [bib_ref] Comparison of six treatments of ascites in patients with liver cirrhosis. A..., Descos [/bib_ref] [bib_ref] Salt or no salt in the treatment of cirrhotic ascites: a randomised..., Gauthier [/bib_ref] [bib_ref] Efficacy and safety of the stepped care medical treatment of ascites in..., Bernardi [/bib_ref] [bib_ref] The effect of dietary sodium restriction on energy and protein intake in..., Soulsby [/bib_ref] [bib_ref] Effect of a diet with unrestricted sodium on ascites in patients with..., Gu [/bib_ref] [bib_ref] Preservation of nutritional-status in patients with refractory ascites due to hepatic cirrhosis..., Sorrentino [/bib_ref] [bib_ref] Adherence to a moderate sodium restriction diet in outpatients with cirrhosis and..., Morando [/bib_ref] One of the studies has only been published as an abstract. [bib_ref] The effect of dietary sodium restriction on energy and protein intake in..., Soulsby [/bib_ref] Four of the earlier RCTs 72-75 found no difference in ascites control in those with and without salt restriction. Two recent RCTs found that a salt unrestricted diet (5-6.5 g/day) in contrast to a salt restricted diet (<5 g/day), resulted in ascites disappearance in a larger proportion (45% vs 16%) over a shorter time period and also significantly reduced the need for large volume paracentesis (LVP). Additionally, five of the eight above-mentioned studies reported significant adverse events with salt restriction, including hyponatraemia, reduced caloric intake, higher risk of renal impairment (0% vs 14%), [bib_ref] Effect of a diet with unrestricted sodium on ascites in patients with..., Gu [/bib_ref] hepatic encephalopathy (HE), hepatorenal syndrome (HRS), SBP [bib_ref] Preservation of nutritional-status in patients with refractory ascites due to hepatic cirrhosis..., Sorrentino [/bib_ref] and mortality. In a study by Sorrentino et al, [bib_ref] Preservation of nutritional-status in patients with refractory ascites due to hepatic cirrhosis..., Sorrentino [/bib_ref] 1-year mortality was 45-60% (salt unrestricted diet) versus 82.5% (salt restricted diet). Thus salt restricted diets (<5 g m of salt, <85 mmol sodium/ day) in patients with cirrhosis and ascites do not improve ascites control and, on the contrary, can result in complications. Additionally, such diets are difficult to comply with, especially since the average European ingests about 10 g of salt/day. [bib_ref] Global, regional and national sodium intakes in 1990 and 2010: a systematic..., Powles [/bib_ref] [bib_ref] Sodium and potassium urinary excretion and dietary intake: a cross-sectional analysis in..., Gonçalves [/bib_ref] [bib_ref] To salt or not to salt?-That is the question in cirrhosis, Haberl [/bib_ref] A crosssectional survey [bib_ref] Adherence to a moderate sodium restriction diet in outpatients with cirrhosis and..., Morando [/bib_ref] indicated that only about a third of cirrhotic patients were compliant with salt restriction, with an additional 45% incorrectly stating that they were. Based on these data, patients with cirrhosis and ascites should have a moderately salt restricted diet, with daily salt intake of no more than 5-6.5 g (87 mmol-113 mmol sodium). This translates to a no added salt diet with avoidance of precooked meals. An ongoing systematic review is assessing the role of salt restriction in patients with ascites due to cirrhosis. 83 ## Recommendations ## Guidelines diuretics Diuretics remain the main stay in management of ascites, though do not modify its natural history, providing only symptomatic benefit.Secondary aldosteronism plays a major role in renal sodium retention in patients with cirrhosis. [bib_ref] Hepatorenal disorders: role of the reninangiotensin-aldosterone system, Bernardi [/bib_ref] Spironolactone is a specific pharmacological aldosterone antagonist, acting primarily through competitive binding of receptors at the aldosteronedependent sodium-potassium exchange site in the distal convoluted renal tubule. [bib_ref] Importance of plasma aldosterone concentration on the natriuretic effect of spironolactone in..., Bernardi [/bib_ref] Its hydrophilic derivative is potassium canrenoate. They are usually the first-line diuretics used, either alone or in combination with a loop diuretic such as furosemide (causing sodium to flood more distal nephron sites). [bib_ref] Update in diuretic therapy: clinical pharmacology, Brater [/bib_ref] Spironolactone appears to be more effective (response rate of 95%) than furosemide (response rate of 52%) in non-azotemic patients with cirrhosis and ascites. Spironolactone has a long elimination half-life, allowing once a day dosing [bib_ref] New insights into the pharmacokinetics of spironolactone, Overdiek [/bib_ref] [bib_ref] Compartmentalization of ascites and edema in patients with hepatic cirrhosis, Shear [/bib_ref] ; dose changes should occur no more frequently than every 3-4 days. [bib_ref] Update in diuretic therapy: clinical pharmacology, Brater [/bib_ref] In those who are intolerant to spironolactone an alternative diuretic is amiloride (acts in the collecting duct). However it is not as effective, an earlier RCT showing response rates of 35% vs 70% in those receiving amiloride versus potassium canrenoate, respectively. [bib_ref] Randomized clinical study of the efficacy of amiloride and potassium canrenoate in..., Angeli [/bib_ref] Other diuretics which have been used in patients with cirrhosis and ascites include bumetanide [bib_ref] spironolactone and a combination of the two, in the treatment of ascites..., Sarin [/bib_ref] and torasemide. ## Sequential versus combined therapy Three RCTs assessing the role of sequential therapy (spironolactone followed by furosemide) or combination therapy (spironolactone plus furosemide) have given conflicting results . In the first study, [bib_ref] Diuresis in the ascitic patient: a randomized controlled trial of three regimens, Fogel [/bib_ref] onset of diuresis was faster in the combination group than in the sequential group. The second RCT mostly included those with first presentation of ascites and found no difference in sequential versus combined therapy for the rapidity of ascites mobilisation and incidence of complications. However, a need for dose reductions was significantly higher in the combination group (68% vs 34%). [bib_ref] Spironolactone alone or in combination with furosemide in the treatment of moderate..., Santos [/bib_ref] The third RCT included almost two-thirds of patients with prior ascites. [bib_ref] Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis:..., Angeli [/bib_ref] It reported shorter mean time for ascites resolution, lower risk of adverse events (especially hyperkalaemia), lower treatment failures (24% vs 44%), with ascites resolving in a higher percentage without need for diuretic dose change (76% vs 56%) in the combination versus sequential group, respectively. [bib_ref] Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis:..., Angeli [/bib_ref] These conflicting results are explained by the heterogeneous patient population as studies by Angeli et al [bib_ref] Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis:..., Angeli [/bib_ref] and Fogel et al [bib_ref] Diuresis in the ascitic patient: a randomized controlled trial of three regimens, Fogel [/bib_ref] included those with more advanced disease, explaining the lower response to spironolactone monotherapy. Others have also reported the likelihood of response to spironolactone monotherapy (vs no response) if a first occurrence (56% vs 37%) rather than recurrent (44% vs 63%) or large ascites (16% vs 58%). [bib_ref] A pathophysiological interpretation of unresponsiveness to spironolactone in a stepped-care approach to..., Gatta [/bib_ref] Since in non-azotemic cirrhotic patients with ascites, the distal tubule reabsorbs almost all the sodium delivered, it is unsurprising that the administration of spironolactone alone results in a good natriuretic response in most. Another advantage of spironolactone monotherapy is its modest diuretic effect, [bib_ref] Update in diuretic therapy: clinical pharmacology, Brater [/bib_ref] as patients with cirrhosis are sensitive to compromises in their intravascular volume. [bib_ref] Compartmentalization of ascites and edema in patients with hepatic cirrhosis, Shear [/bib_ref] Therefore, in patients with first presentation of moderate ascites, starting treatment with spironolactone monotherapy (starting dose 100 mg, increased to 400 mg) is reasonable. In those with persistent or severe ascites, and if faster diuresis is needed (for example, if hospitalised), it may be prudent to use combination therapy with spironolactone and furosemide (starting dose 40 mg, increased to 160 mg). Although maximal daily recommended doses of spironolactone and furosemide are 400 mg and 160 mg respectively, these are rarely achieved. In the largest study until now, which recruited about 2000 patients with ascites, at the time of discharge, mean diuretic units (one unit being 40 mg furosemide and 100 mg spironolactone) varied from 2.5+0.2 to 2.7+0.3. [bib_ref] Peritoneovenous shunting as compared with medical treatment in patients with alcoholic cirrhosis..., Stanley [/bib_ref] Based on evidence from an earlier RCT, it is recommended that diuretic-induced weight loss should not exceed 0.5 kg/day in patients without peripheral oedema, and 1 kg in the presence of peripheral oedema. [fig_ref] Figure 3: Approach to the use of diuretics in the management of ascites in... [/fig_ref] summarises the stepped-up 98 approach to diuretic treatment. ## Adverse reactions to diuretics All patients initiating diuretics should be monitored for adverse events, the prevalence of which ranges from 19% 96 to 33%. Almost half with adverse events require diuretic discontinuation or dose reduction. [bib_ref] Diuresis in the ascitic patient: a randomized controlled trial of three regimens, Fogel [/bib_ref] In hospitalised patients treated with diuretics, hepatic encephalopathy is seen in up to 25% 102 and renal impairment in 14-20%, especially in the absence of peripheral oedema. [bib_ref] Rapid diuresis in patients with ascites from chronic liver disease: the importance..., Pockros [/bib_ref] Renal impairment is usually of moderate severity and is reversible on discontinuing diuretics. [bib_ref] Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis...., Arroyo [/bib_ref] Hyponatraemia occurs in 8-30% and is related to impaired ability of the kidneys to excrete free water. Hypokalaemia is also a frequent side effect of loop diuretics. [bib_ref] Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis...., Arroyo [/bib_ref] Similarly hyperkalaemia can occur in up to 11%. [bib_ref] Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis:..., Angeli [/bib_ref] Gynaecomastia is commonly seen with spironolactone, especially with higher doses. [bib_ref] Update in diuretic therapy: clinical pharmacology, Brater [/bib_ref] It occurs less frequently with potassium canrenoate (53% vs 100%). [bib_ref] Gynaecomastia after spironolactone and potassium canrenoate, Bellati [/bib_ref] Eplerenone can also relieve the gynaecomastia. A causal relation is found between cirrhosis and muscle cramps, especially in advanced cirrhosis, with prevalence varying between 26% and 72%,. [bib_ref] Overlooked muscle cramps in patients with chronic liver disease: in relation to..., Murata [/bib_ref] [bib_ref] Cirrhosis and muscle cramps: evidence of a causal relationship, Angeli [/bib_ref] [bib_ref] Symptom prevalence and quality of life of patients with end-stage liver disease:..., Peng [/bib_ref] The cirrhosis-induced arterial underfilling probably plays a role in the pathogenesis of cramps. [bib_ref] Cirrhosis and muscle cramps: evidence of a causal relationship, Angeli [/bib_ref] Diuretics accentuate this reduction in effective plasma volume, thereby increasing the prevalence of cramps. [bib_ref] Cirrhosis and muscle cramps: evidence of a causal relationship, Angeli [/bib_ref] An earlier systematic review (including only three RCTs) assessed various interventions for muscle cramps, including zinc, 1-α-hydroxyvitamin D, vitamin E, branched chain amino acids, taurine, intravenous albumin and quinidine. Improvements occurred with most interventions with the exception of vitamin E. [bib_ref] Systematic review: the treatment of muscle cramps in patients with cirrhosis, Vidot [/bib_ref] Recent RCTs have reported beneficial effects with methocarbamol, 110 taurine 111 and baclofen. 112 ## Monitoring of diuretics The aim of diuretic therapy is to ensure that urinary sodium excretion exceeds 78 mmol/day (88 mmol intake per day -10 mmol non-urinary excretion per day). A random spot urine sodium:potassium ratio between 1.8 and 2.5 has a sensitivity of 87.5%, specificity of 56-87.5% and accuracy of 70-85% in predicting a 24-hour urinary sodium excretion of 78 mmol/day. Hyponatraemia Recent guidelines define hyponatraemia as a serum sodium <135 mmol/L, with 130-135 mmol/L, 125-129 mmol/L and <125 mmol/L, constituting mild, moderate and severe hyponatraemia, respectively. A prospective population survey among patients with cirrhosis found serum sodium <130 mmol/L in 21.6%. [bib_ref] Hyponatremia in cirrhosis: results of a patient population survey, Angeli [/bib_ref] Hyponatraemia has been associated with higher prevalence of refractory ascites, hepatic encephalopathy, SBP, HRS and mortality. [bib_ref] Hyponatremia in cirrhosis: results of a patient population survey, Angeli [/bib_ref] [bib_ref] Severe hyponatremia is a better predictor of mortality than MELDNa in patients..., Sersté [/bib_ref] [bib_ref] Hyponatremia and mortality among patients on the liver-transplant waiting list, Kim [/bib_ref] Acknowledging this, the Model for End Stage Liver Disease (MELD) score now incorporates serum sodium (MELD-Na). [bib_ref] Evidence-based incorporation of serum sodium concentration into MELD, Biggins [/bib_ref] Those with cirrhosis and chronic hyponatraemia are often asymptomatic and seldom need treatment. [bib_ref] Introduction to the revised American Association for the Study of Liver Diseases..., Runyon [/bib_ref] Both hypovolaemic and hypervolaemic hyponatraemia is observed in cirrhosis.Hypovolaemic hyponatraemia results from overzealous diuretic therapy, being characterised by a prolonged negative sodium balance with marked loss of extracellular fluid. Its management requires expansion of plasma volume with normal saline and cessation of diuretics.Most hepatologists would discontinue diuretics if serum sodium is <125 mmol/L. A number of studies (which include four RCTs and a retrospective cohort study) have assessed role of intravenous (IV) human albumin solution (HAS) in patients with hyponatraemia (online supplemental table 4). [bib_ref] Intravenous albumin infusion is an effective therapy for hyponatraemia in cirrhotic patients..., Mccormick [/bib_ref] [bib_ref] Albumin [232] infusion for severe hyponatraemia in patients with refractory ascites: a..., Jalan [/bib_ref] [bib_ref] Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in..., Ginès [/bib_ref] [bib_ref] Total therapeutic paracentesis (TTP) with and without intravenous albumin in the treatment..., García-Compeán [/bib_ref] [bib_ref] Beneficial effects of intravenous albumin infusion on the hemodynamic and humoral changes..., Luca [/bib_ref] [bib_ref] The impact of albumin use on resolution of hyponatremia in hospitalized patients..., Bajaj [/bib_ref] These studies did not strictly stratify patients as having hypovolaemic hyponatraemia and mostly included those with Child C cirrhosis and refractory ascites undergoing LVP. There were differences in baseline serum sodium levels, use of diuretics, and degree of salt and fluid restriction. Therefore not unsurprisingly results have been conflicting. An earlier meta-analysis that included three of the above RCTs [bib_ref] Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in..., Ginès [/bib_ref] [bib_ref] Total therapeutic paracentesis (TTP) with and without intravenous albumin in the treatment..., García-Compeán [/bib_ref] [bib_ref] Beneficial effects of intravenous albumin infusion on the hemodynamic and humoral changes..., Luca [/bib_ref] reported that use of IV HAS versus no IV HAS reduced occurrence of hyponatraemia (3.9% vs 16.5%) but did not affect mortality. [bib_ref] Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials, Bernardi [/bib_ref] A later meta-analysis (IV HAS vs no IV HAS) which included only two RCTs found no beneficial effects on hyponatraemia or mortality. [bib_ref] Insufficient evidence of benefit regarding mortality due to albumin substitution in HCC-free..., Kütting [/bib_ref] In the retrospective cohort study among hospitalised patients with hyponatraemia (only 42% requiring inpatient LVP), those receiving IV HAS were more likely to have resolution of hyponatraemia than those who did not (85.41% vs 44.78%). [bib_ref] The impact of albumin use on resolution of hyponatremia in hospitalized patients..., Bajaj [/bib_ref] Hyponatraemia resolution was an independent predictor of 30-day survival, even after adjustment for admission sodium and glomerular filtration rate. At present, however, there is insufficient evidence to routinely recommend IV HAS outside of a LVP setting in patients with cirrhosis and ascites and hypovolaemic hyponatraemia. Hypervolaemic hyponatraemia is more common in cirrhosis, occurring owing to non-osmotic hypersecretion of vasopressin and enhanced proximal nephron sodium reabsorption with impaired free water clearance, both being caused by effective hypovolaemia. Impaired free water clearance is observed in about 60% of patients with cirrhosis. [bib_ref] Role of vasopressin in abnormal water excretion in cirrhotic patients, Bichet [/bib_ref] Hypervolaemic hyponatraemia requires a negative water balance.Many hepatologists do recommend fluid restriction of between 1 and 1.5 L/day in presence of severe hyponatraemia (serum sodium <125 mmol/L). However, there are few data to support the level of serum sodium at which to initiate fluid restriction and how much fluid to restrict. It is sodium restriction and not fluid restriction that results in weight loss as fluid passively follows the sodium. [bib_ref] Introduction to the revised American Association for the Study of Liver Diseases..., Runyon [/bib_ref] Although fluid restriction may be helpful in preventing further decrease in serum sodium, it only rarely improves it. This is because on a practical level, fluid restriction to <1 L /day is not tolerated. [bib_ref] Hyponatremia in patients with cirrhosis of the liver, Bernardi [/bib_ref] Water restriction should be reserved for those who are clinically hypervolaemic Guidelines with severe hyponatraemia (serum sodium <125 mmol/L) with normal serum creatinine and not currently receiving diuretics. These recommendations are based on our consensus and consistent with our earlier guidelines. [bib_ref] Guidelines on the management of ascites in cirrhosis, Moore [/bib_ref] It is also our consensus that fluid restriction is unnecessary in absence of hyponatraemia. Hypertonic sodium chloride (3%) administration may improve hyponatraemia at the cost of worsening fluid overload. It is best reserved for those with severely symptomatic acute hyponatraemia, especially if a transplant is imminent.To prevent rapid increase in serum sodium and the risk of developing central pontine myelinolysis, [bib_ref] Changing picture of central nervous system complications in liver transplant recipients, Vizzini [/bib_ref] guidelines recommend a serum sodium increase of up to 5 mmol/L in the first hour with a limit of 8-10 mmol/L every 24 hours thereafter until the serum sodium concentration reaches 130 mmol/L. ## Vaptans Vaptans are vasopressin antagonists that competitively bind and block the V2-receptors of arginine vasopressin in the renal collecting ducts and induce a highly hypotonic diuresis without affecting the excretion of electrolytes. [bib_ref] Non-peptide arginine-vasopressin antagonists: the vaptans, Decaux [/bib_ref] In three RCTs involving 1200 patients, satavaptan was no more effective than placebo in controlling ascites and need for LVPs, though it improved serum sodium concentration in those with hyponatraemia. [bib_ref] Satavaptan for the management of ascites in cirrhosis: efficacy and safety across..., Wong [/bib_ref] Two of the studies were terminated owing to an increase in serum bilirubin, higher mortality (31% vs 22%), mostly due to increased cirrhosis complications and other adverse events. [bib_ref] Satavaptan for the management of ascites in cirrhosis: efficacy and safety across..., Wong [/bib_ref] Two metaanalyses on vaptans in cirrhosis reported improved serum sodium levels and ascites mobilisation, but without a beneficial effect on cirrhosis-related complications or mortality (RR=1.06, 95% CI 0.90 to 1.26). Current evidence does not support routine use of vaptans in cirrhosis. ## Midodrine Portal hypertension and splanchnic vasodilatation are major contributors to the development of ascites. [bib_ref] Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium..., Schrier [/bib_ref] In fact, mean arterial pressure and plasma norepinephrine are two of the best predictors of prognosis in ascites. [bib_ref] Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in..., Llach [/bib_ref] Therefore, vasopressors such as midodrine, an α-adrenergic agonist, have been used in nonazotemic patients with ascites, resulting in significant increase in mean arterial pressure and urine sodium excretion and significant decreases in plasma renin and aldosterone. [bib_ref] Effects of a 7-day treatment with midodrine in non-azotemic cirrhotic patients with..., Kalambokis [/bib_ref] A small RCT in patients with refractory ascites (midodrine 7.5 mg three times a day vs standard medical therapy) showed that at 3 months 94% versus 50% had a complete/partial ascites control, with a trend for a survival benefit in the midodrine group. [bib_ref] Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized..., Singh [/bib_ref] In another small RCT (midodrine vs placebo), significant reduction in body weight and abdominal girth was observed after 2 weeks of midodrine therapy. [bib_ref] Clinical study on the therapeutic role of midodrine in non azotemic cirrhotic..., Ali [/bib_ref] Though larger RCTs are needed to confirm these findings, it may be appropriate to consider use of midodrine in refractory ascites on a case-by-case basis. ## Recommendations ## Large volume (therapeutic) paracentesis Large volume paracentesis (LVP) is the standard of care for managing large volume ascites both in conjunction with diuresis to relieve symptoms of a tense abdomen, as well as in the management of refractory ascites, when diuretics become ineffective or the side effects preclude their continued use. Development of refractory ascites is of prognostic significance, 144 therefore, at its onset, suitability of liver transplantation should be considered and assessed as a priority. ## Performance standards An efficient LVP service can be provided safely in a day case or outpatient setting and non-physician healthcare providers such as GI endoscopy assistants [bib_ref] Performance standards for therapeutic abdominal paracentesis, Grabau [/bib_ref] and specialist nurses [bib_ref] Implementing a nurse-led paracentesis service to improve patient care and experience in..., Chivinge [/bib_ref] can be trained to perform therapeutic paracentesis and lead the service effectively. Exemplar training programmes indicate that 10 supervised procedures would be optimal for training to achieve competence in performing therapeutic paracentesis; mean duration of LVP was 97±24 min, and the mean volume of ascitic fluid removed was 8.7±2.8 L. [bib_ref] Performance standards for therapeutic abdominal paracentesis, Grabau [/bib_ref] Patients should provide informed consent before the procedure. In 52 patients (15% obese) with ascites due to cirrhosis, ultrasound demonstrated that the left lower quadrant abdominal wall was thinner and depth of ascites greater, therefore, a suitable site for drain insertion. [bib_ref] Choosing the location for non-image guided abdominal paracentesis, Sakai [/bib_ref] To minimise the risk of injury to the inferior epigastric artery (and avoid the liver and spleen) during paracentesis, point of puncture should be at least 8 cm from the midline and 5 cm above the symphysis 148-150 [fig_ref] Figure 4: Anatomical landmarks for the safe performance of paracentesis [A] and performance of... [/fig_ref]. All ascitic fluid should be drained to dryness in a single session as rapidly as possible over 1-4 hours assisted by gentle mobilisation of the cannula or turning the patient onto their side, if necessary. After the paracentesis, the patient should lie on the opposite side for 2 hours if there is leakage of any remaining ascitic fluid, and/or a suture (ideally purse-string) inserted around the site of drainage. These steps help to minimise the risk of ascitic fluid leakage. ## Adverse events A systematic review of adverse events that can result from a paracentesis reported an overall rate of significant bleeding ranging from 0% to 2.7%, ascitic fluid leak in 0% to 2.35%, perforation in 0.83%, residual catheter tip fragment in 0.41% and death in 0% to 17% among studies that were heterogeneous. [bib_ref] Does this patient have bacterial peritonitis or portal hypertension? How do I..., Wong [/bib_ref] In a retrospective study published in abstract form, of consecutive 3116 ultrasound guided LVPs, the mean international normalised ratio (INR) was 2.1 (range 1.0-7.0) and MELD score 24 (range 6-40) for inpatients, and 1.5 (range 1-5-5) and 16 (range 5-40) for outpatients, respectively. With no patients receiving fresh frozen plasma (FFP) before the procedure, a total of six patients (0.19%) had post-LVP bleeding requiring blood transfusion (one inpatient, five outpatients) and one required angiography with embolisation of a bleeding abdominal wall vessel. No patient died. [bib_ref] Ultrasound imaging guidance and large volume paracentesis: an analysis of safety, cost-effectiveness,..., Rowley [/bib_ref] In another study where GI endoscopy assistants performed 1100 large volume paracenteses, with a preprocedure mean INR of 1.7 (range 0.9-8.7) and the mean platelet count was 50.4×10 9 /L (range, 19-341×10 9 /L), there were no significant procedure-related complications. [bib_ref] Performance standards for therapeutic abdominal paracentesis, Grabau [/bib_ref] Risk factors for haemorrhagic complications after paracentesis in three studies (which included patients with acute on chronic liver failure) were high MELD and Child-Pugh scores and renal impairment. [bib_ref] Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease, Pache [/bib_ref] [bib_ref] Acute kidney injury, but not sepsis, is associated with higher procedure-related bleeding..., Hung [/bib_ref] [bib_ref] Hemorrhagic complications following abdominal paracentesis in acute on chronic liver failure: a..., Lin [/bib_ref] In a study by Hung et al, acute kidney injury at he time of paracentesis was the only independent predictor of post-paracentesis haemoperitoneum, independent of MELD score, large volume paracentesis, sepsis, platelets, INR and haemoglobin levels. [bib_ref] Acute kidney injury, but not sepsis, is associated with higher procedure-related bleeding..., Hung [/bib_ref] While some patients with bleeding complications after paracentesis have low platelet counts, elevated INR and low fibrinogen levels, this is invariably accompanied with high MELD scores (>25) and/or renal impairment. Ultrasound guidance Use of ultrasound guidance may reduce the adverse events related to LVP. [bib_ref] Recommendations on the use of ultrasound guidance for adult abdominal paracentesis: a..., Cho [/bib_ref] In a study involving 1297 procedures, 723 (56%) with ultrasound guidance and 574 (44%) without where the indications for paracentesis were similar between the two groups, the incidence of adverse events was lower in the ultrasound-guided procedures. [bib_ref] Evaluation of hospital complications and costs associated with using ultrasound guidance during..., Patel [/bib_ref] In another retrospective cohort study, 0.8% of 565 patients undergoing paracentesis experienced bleeding complications. After adjustment, ultrasound guidance was associated with lower risk of bleeding complications by 68%. 157 ## Recommendations ## Use of human albumin solution (has) plasma expansion after paracentesis One study evaluating haemodynamic and neurohumoral responses in 12 patients after a single, 5 L total paracentesis concluded that it was safe to omit albumin in these patients. [bib_ref] Cardiovascular, renal, and neurohumoral responses to single large-volume paracentesis in patients with..., Peltekian [/bib_ref] However, a subsequent study including 80 patients with acute on chronic liver failure (ACLF) found that albumin significantly reduced complications (renal impairment, hyponatraemia and death) following <5 L paracentesis compared with no administration of fluid. [bib_ref] Paracentesis-Induced circulatory dysfunction with modest-volume paracentesis is partly ameliorated by albumin infusion..., Arora [/bib_ref] Thus in <5 L paracentesis we recommend that plasma expansion is not necessary, unless there is evidence of ACLF. This recommendation is based on consensus rather than evidence and is consistent with other international guidance.Plasma volume expansion should always be used for LVP with >5 L of ascites removed. Serial paracenteses with and without albumin replacement have been evaluated in patients with tense ascites. There was a higher rate of renal impairment, fall in serum sodium levels, and a marked activation of the renin-angiotensin-aldosterone system in those not treated with albumin. However, the pooled risk ratio from these studies, which are more than 25 years old, showed only a tendency toward benefit of albumin (pooled RR=0.23, 95% CI 0.03 to 1.64) (online supplemental table 5). The consensus is that volume expansion Guidelines should be used with LVP. We recommend large volume paracentesis in one session and discourage repeated low volume paracentesis, which offers no additional benefits and carries a higher risk of procedure-related complications. Some debate remains over the use of albumin or artificial plasma expanders for volume expansion. Pooled analysis of 10 studies [bib_ref] Randomized trial comparing human albumin and hydroxyethyl starch 6% as plasma expanders..., Abdel-Khalek [/bib_ref] [bib_ref] Randomized comparative multicenter study of hydroxyethyl starch versus albumin as a plasma..., Altman [/bib_ref] [bib_ref] Impact on the energetic-proteic nutritional status of total paracentesis combined with infusion..., Bertrán [/bib_ref] [bib_ref] Paracentesis with dextran 70 vs. paracentesis with albumin in cirrhosis with tense..., Fassio [/bib_ref] [bib_ref] Treatment of cirrhotic tense ascites with dextran-40 versus albumin associated with large..., García-Compean [/bib_ref] [bib_ref] Paracentesis Masiva Con Reposician de dextran 70 vs Albumina en Pacientes cirrhotics..., Pérez [/bib_ref] [bib_ref] Comparison of outcome in patients with cirrhosis and ascites following treatment with..., Moreau [/bib_ref] [bib_ref] Dextran-70 versus albumin as plasma expanders in cirrhotic patients with tense ascites..., Planas [/bib_ref] [bib_ref] Randomized comparative study of hemaccel vs. albumin infusion after total paracentesis in..., Salerno [/bib_ref] [bib_ref] Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory..., Sola-Vera [/bib_ref] found that cirrhotic patients undergoing paracentesis who received albumin were no less likely to develop renal dysfunction than patients undergoing paracentesis that received an alternative plasma expander (pooled RR=1.11, 95% CI 0.58 to 2.14) (online supplemental table 5). Analysis from two other independently conducted systematic reviews is consistent with these findings. Pooled analysis from eight studies found that cirrhotic patients undergoing paracentesis who received albumin were no less likely to die than those who received an alternate plasma expander (pooled RR=0.83, 95% CI 0.61 to 1.12) (online supplemental table 6), which is supported by two systematic reviews. However, when all comparators to albumin (including control and vasoconstrictor alone) are pooled (16 RCTs) the RR is 0.77 (95% CI 0.57 to 1.00). This translates to 57 to 100 fewer patients per 1000 dying after LVP when HAS is used (online supplemental table 6). Less clinically important outcomes have been shown to improve in patients treated with HAS versus other plasma expanders. There is a decreased incidence of post-paracentesis-induced circulatory dysfunction (defined as a decrease in plasma renin) in patients undergoing LVP treated with albumin compared with an alternative plasma expander in a meta-analysis containing eight RCTs 127 (OR=0.34, 95% CI 0.23 to 0.51), and a pooled decrease in hyponatraemia in nine RCTs (OR=0.61, 95% CI 0.40 to 0.93). [bib_ref] Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials, Bernardi [/bib_ref] Both are supported in a second independently conducted systematic review. [bib_ref] Insufficient evidence of benefit regarding mortality due to albumin substitution in HCC-free..., Kütting [/bib_ref] Most of the plasma expanders used in the described studies are no longer in use and have been restricted by the European Medicines Agency (eg, polygeline carries risk of prion transmission, dextran the risk of allergic reaction and hydroxyethyl starch association with renal impairment and deranged coagulation). Therefore, consensus is that volume expansion should be with HAS due to availability, familiarity of use and suggested benefits in the available studies. Two small prospective RCTs compared standard dose (6-8 g/L of ascites drained) albumin after LVP with low-dose albumin (2-4 g/L). Pooled results from 70 patients suggested no difference in post-paracentesis-induced circulatory dysfunction (RR=2.97, 95% CI 0. and no development of renal dysfunction (no events in either group). A larger retrospective review of 935 patients found no increase in renal dysfunction when adherence to guidance (8 g/L after 5 L drained) was implemented, 173 but significant cost savings were made because less HAS was used. Potential cost savings have been proposed in relation to length of hospital stay in patients with ascites undergoing LVP who are treated with HAS as compared with an alternative plasma expander. [bib_ref] Comparison of outcome in patients with cirrhosis and ascites following treatment with..., Moreau [/bib_ref] However, HAS is more expensive than alternatives and is in worldwide shortage, therefore it should be prescribed according to recommended guidance based on the available evidence. [bib_ref] How albumin administration for cirrhosis impacts on hospital albumin consumption and expenditure, Mirici-Cappa [/bib_ref] There have been no cost-effectiveness analyses in the UK. Until further studies are undertaken to compare efficacy of albumin against clinically available artificial plasma expanders, we would recommend that albumin remains the preferred plasma expander when paracentesis is undertaken. Albumin (as 20% or 25% solution) should be infused after paracentesis of >5 L is completed at a dose of 8 g albumin/L of ascites removed. ## Albumin infusion in sbp Renal impairment develops in up to 30% of patients with SBP and is one of the strongest predictors of mortality, alongside progressive liver dysfunction. Three studies [bib_ref] Effect of intravenous albumin on renal impairment and mortality in patients with..., Sort [/bib_ref] [bib_ref] Effect of albumin infusion on preventing the deterioration of renal function in..., Hp [/bib_ref] [bib_ref] Effect of intravenous albumin on endotoxin removal, cytokines, and nitric oxide production..., Chen [/bib_ref] have compared albumin with no intervention, and one RCT 179 compared albumin with a plasma expander in order to prevent the development of renal impairment in patients with SBP. Cirrhotic patients with SBP treated with albumin were 72% less likely to develop renal dysfunction than patients with SBP who did not receive albumin (288 patients, pooled RR=0.28, 95% CI 0.16 to 0.50) (online supplemental table 7). There was also a decrease in mortality in patients with SBP treated with albumin, with patients 47% less likely to die than those not receiving albumin (334 patients, pooled RR=0.53, 95% CI 0.36 to 0.79) (online supplemental table 8). Therefore, we recommend the use of albumin in patients with SBP to prevent the development of renal dysfunction and decrease mortality. Although patients with SBP have a higher risk of post-drain renal dysfunction, LVP is not contraindicated. Therefore, if LVP is indicated in a patient with SBP then this should proceed with HAS support. The dose of albumin in original studies was 1.5 g albumin per kg body weight within 6 hours of diagnosis and 1.0 g/kg on day 3, using estimated dry weight, which is often difficult in cirrhotic patients. Some small studies have suggested that lower doses of albumin are as effective in preventing renal dysfunction and mortality in SBP, and one retrospective review including 88 patients with SBP suggested that doses of HAS in excess of 87.5 g (>4×100 mL 20% HAS) are associated with a worse outcome, possibly secondary to fluid overload. [bib_ref] The efficacy and safety profile of albumin administration for patients with cirrhosis..., Afinogenova [/bib_ref] Fluid overload has been reported in prospective studies of albumin in patients with cirrhosis and non-SBP infection. Therefore, if patients have an increased serum creatinine or a rising serum creatinine, we recommend 1.5 g albumin/kg within 6 hours of diagnosis, followed by 1 g/kg on day 3. ## Long term regular outpatient has therapy Improving morbidity and mortality by long-term administration of albumin to patients with decompensated cirrhosis and ascites has been explored in six studies with three recent RCTs, in contrasting patient groups, with contradictory findings (online supplemental table 9). [bib_ref] Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial, Caraceni [/bib_ref] [bib_ref] Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting..., Solà [/bib_ref] [bib_ref] Albumin improves the response to diuretics in patients with cirrhosis and ascites:..., Gentilini [/bib_ref] [bib_ref] Diuretic and natriuretic effects of long-term albumin infusion in patients with cirrhosis..., Vizzutti [/bib_ref] [bib_ref] Long-term albumin infusion improves survival in patients with cirrhosis and ascites: an..., Romanelli [/bib_ref] [bib_ref] Long-term administration of human albumin improves survival in patients with cirrhosis and..., Pascoli [/bib_ref] In the ANSWER 185 study, 431 patients with uncomplicated ascites receiving diuretics were randomised to weekly outpatient HAS infusions or no additional intervention (standard medical therapy). The study had a pragmatic approach and was unblinded. Overall 18-month survival was significantly higher in the standard therapy plus HAS than in the standard medical therapy group (Kaplan-Meier estimates 77% vs 66%; p=0.028), resulting in a 38% reduction in the mortality hazard ratio (0.62, 95% CI 0.40 to 0.95). There were additional benefits with lower incidence rate ratio (IRR) for infection (SBP and non-SBP) and renal dysfunction. However, unlike the standard therapy group, the HAS group had weekly medical professional contact when IV albumin was administered which could possibly have caused a confounding effect by improving standard of care in this group. In the MACHT 186 study, a double-blind, placebo-controlled trial, patients with advanced cirrhosis (MELD score [bib_ref] Usefulness of serum-ascites albumin difference in separating transudative from exudative ascites. another..., Mauer [/bib_ref] [bib_ref] Does this patient have bacterial peritonitis or portal hypertension? How do I..., Wong [/bib_ref] awaiting liver transplantation received outpatient fortnightly treatment with midodrine and albumin. This slightly suppressed vasoconstrictor activity but did not prevent complications of cirrhosis or improve survival. However, only nine patients were treated for the entire year, the median length of treatment was only 80 days and the mortality rate in both arms was very low due to patients undergoing timely liver transplantation. Perhaps, therefore, a greater dose of albumin or longer duration of treatment is required to benefit patients and should be targeted at those who are not close to receiving a liver transplant. Di Pascoli et al 190 most recently published outcomes of a study of 45 patients with refractory ascites undergoing regular LVP who accepted 20 g twice weekly albumin plus diuretics and sodium restriction versus 25 patients who did not (non-randomised, single centre, not blinded). Cumulative incidence of mortality was 41.6% in the albumin group versus 65.5% in the standard of care group. Albumin-treated patients had a lower probability of hospitalisation. There were no differences in the number of LVPs performed. Follow-up was 400 days in the albumin group and 318 in the standard of care group. Although the study was nonrandomised (patient choice to treatment arm) it does provide some additional evidence that using albumin in a longer-term outpatient setting may be beneficial, as in the ANSWER study, even in patients with very advanced disease. Two older studies support the use of outpatient albumin therapy in decreasing hospital admissions and LVP requirement with conflicting results on mortality. We expect these studies to stimulate further investigation to determine whether long-term albumin administration is feasible, efficacious and cost-effective in patients with cirrhosis and ascites within the NHS. Further research is required to determine which patients could benefit most from treatment, which seems to be those with less advanced disease who could receive treatment for at least 12 months. At present it is not possible to recommend the use of outpatient albumin administration in patients with ascites due to cirrhosis. ## Recommendations ► Albumin (as 20% or 25% solution) should be infused after paracentesis of >5 L is completed at a dose of 8 g albumin/L of ascites removed. (Quality of evidence: high; Recommendation: strong) ► Albumin (as 20% or 25% solution) can be considered after paracentesis of <5 L at a dose of 8 g albumin/L of ascites removed in patients with ACLF or high risk of postparacentesis acute kidney injury. (Quality of evidence: low; Recommendation: weak) ► In patients with SBP and an increased serum creatinine or a rising serum creatinine, infusion of 1.5 g albumin/kg within 6 hours of diagnosis, followed by 1 g/kg on day 3, is recommended. (Quality of evidence: low; Recommendation: weak) ## Transjugular intrahepatic portosystemic stent shunt (tipss) TIPSS decompresses the portal system by creating an artificial communication between the portal and the hepatic vein. TIPSS results in an increase in cardiac output and decrease in systemic vascular resistance in the short term. [bib_ref] Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in..., Wong [/bib_ref] [bib_ref] The mechanism of the initial natriuresis after transjugular intrahepatic portosystemic shunt, Wong [/bib_ref] [bib_ref] Transjugular intrahepatic portal-systemic shunt in the treatment of refractory ascites: effect on..., Quiroga [/bib_ref] Consequently, TIPSS leads to improvement in effective hypovolaemia and renal function, resulting in increased urinary sodium excretion. [bib_ref] Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in..., Wong [/bib_ref] [bib_ref] The mechanism of the initial natriuresis after transjugular intrahepatic portosystemic shunt, Wong [/bib_ref] [bib_ref] Transjugular intrahepatic portal-systemic shunt in the treatment of refractory ascites: effect on..., Quiroga [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and..., Lebrec [/bib_ref] [bib_ref] Long-term renal sodium handling in patients with cirrhosis treated with transjugular intrahepatic..., Wong [/bib_ref] The increase in urinary sodium correlates with the reduction in plasma renin activity. The efficacy of TIPSS in the management of ascites has been compared with LVP in seven RCTs (online supplemental table 10). The first six trials used bare metal stents. Shunt dysfunction due to stent stenosis or thrombosis is a common complication of bare stents and develops in up to 80% of patients. The use of polytetrafluoroethylene (PTFE)-covered stents has significantly increased the long-term patency of the stent to 92% at 1 year and 89% at 2 years. [bib_ref] Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients..., Bureau [/bib_ref] [bib_ref] Expanded polytetrafluoroethylene-covered stent-grafts for transjugular intrahepatic portosystemic shunts in cirrhotic patients: long-term..., Geeroms [/bib_ref] [bib_ref] Covered vs. uncovered stents for transjugular intrahepatic portosystemic shunt: a randomized controlled..., Perarnau [/bib_ref] TIPSS controls ascites better than LVP. Patients treated with TIPSS are more likely to be free of recurrent ascites than those treated with LVP at 12 months. [bib_ref] Tips improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an..., Bai [/bib_ref] However, the impact of TIPSS on survival is less consistent. The initial trial by showed a better survival with LVP mainly due to the detrimental effect of TIPSS in Child-Pugh C patients. The subsequent three studies did not show any difference in survival between TIPSS and LVP, [bib_ref] A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with..., Rössle [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in..., Ginès [/bib_ref] [bib_ref] The North American study for the treatment of refractory ascites, Sanyal [/bib_ref] whereas the most recent three studies have shown improved survival with TIPSS. [bib_ref] Randomized controlled study of tips versus paracentesis plus albumin in cirrhosis with..., Salerno [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunt versus paracentesis plus albumin in patients with refractory..., Narahara [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients..., Bureau [/bib_ref] In the two meta-analyses of the six trials using bare stent grafts, Bai et al [bib_ref] Tips improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an..., Bai [/bib_ref] reported an improved transplant-free survival with TIPSS but this was limited to patients with recurrent ascites and not refractory ascites in the other study. [bib_ref] Prophylactic use of transjugular intrahepatic portosystemic shunt AIDS in the treatment of..., Chen [/bib_ref] All the six trials with bare metal stents consistently showed that TIPSS resulted in higher incidence of hepatic encephalopathy than with LVP. PTFE-covered stents are now standard of care, and hence the results of the historical RCTs using bare stents are less relevant. Only the most recent RCTs compared PTFE-covered stent with LVP in patients with recurrent ascites. It demonstrated improved 1-year survival with TIPSS without any increased incidence of hepatic encephalopathy. [bib_ref] Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients..., Bureau [/bib_ref] TIPS has also been shown to improve the quality of life and nutritional status in patients with refractory ascites, [bib_ref] Quality of life in refractory ascites: transjugular intrahepatic portal-systemic shunting versus medical..., Campbell [/bib_ref] [bib_ref] Improved quality of life in patients with refractory or recidivant ascites after..., Gülberg [/bib_ref] [bib_ref] Effects of ascites resolution after successful tips on nutrition in cirrhotic patients..., Allard [/bib_ref] but the improvement was dependent on the resolution of ascites. ## Tipss technique A controlled study comparing TIPSS with 8 mm and 10 mm covered stent was stopped early as the 8 mm stent was not effective in controlling portal hypertensive complications (variceal bleeding and ascites). [bib_ref] Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with..., Riggio [/bib_ref] The rate of hepatic encephalopathy was equal between the two groups. However, in another study of variceal bleeding, 8 mm stents were as effective as 10 mm stents in preventing rebleeding, with a 50% reduction in the incidence of encephalopathy with 8 mm stents. [bib_ref] Eight millimetre covered tips does not compromise shunt function but reduces hepatic..., Wang [/bib_ref] Nonetheless, the applicability of these data in patients with refractory ascites is unclear, and evidence suggests that stent diameter increases over time. [bib_ref] The underdilation of nitinol stents at tips implantation: solution or illusion?, Mollaiyan [/bib_ref] In a retrospective study of patients with refractory ascites, 10 mm covered stent led to better control of ascites than an 8 mm stent, without any increase in encephalopathy. [bib_ref] Transjugular intrahepatic portosystemic shunts in patients with cirrhosis with refractory ascites: comparison..., Miraglia [/bib_ref] Data from recent TIPSS registry in Germany reported an improved survival with 8 mm than with 10 mm covered stent. [bib_ref] Smaller-diameter covered transjugular intrahepatic portosystemic shunt stents are associated with increased survival, Trebicka [/bib_ref] The optimal diameter of covered TIPS stent in refractory ascites remains unclear. The volume of TIPSS being performed in an individual hospital influences outcomes. Inpatient mortality was significantly lower in centres performing more than 20 TIPS procedures per year. 215 ## Patient selection Careful selection of patients with refractory ascites to be treated with TIPSS is vital to maximise the benefits and reduce the harmful effects of the treatment. The exclusion criteria for the insertion of TIPSS in the seven RCTs are reported in online supplemental table [bib_ref] Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis...., Arroyo [/bib_ref]. Patients with advanced stages of cirrhosis have been excluded from the trials as indicated by serum bilirubin, [bib_ref] A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with..., Rössle [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in..., Ginès [/bib_ref] [bib_ref] The North American study for the treatment of refractory ascites, Sanyal [/bib_ref] [bib_ref] Randomized controlled study of tips versus paracentesis plus albumin in cirrhosis with..., Salerno [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunt versus paracentesis plus albumin in patients with refractory..., Narahara [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients..., Bureau [/bib_ref] prolonged prothrombin time, renal dysfunction and Child-Pugh score. [bib_ref] Randomized controlled study of tips versus paracentesis plus albumin in cirrhosis with..., Salerno [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunt versus paracentesis plus albumin in patients with refractory..., Narahara [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients..., Bureau [/bib_ref] Presence of chronic hepatic encephalopathy was an exclusion criterion in all the RCTs; the presence of pre-TIPS encephalopathy has been shown to be a predictor of poor outcome following TIPSS. [bib_ref] Analysis of prognostic variables in the prediction of mortality, shunt failure, variceal..., Jalan [/bib_ref] [bib_ref] Pre-transjugular intrahepatic portosystemic shunts (tips) prediction of post-TIPS overt hepatic encephalopathy: the..., Berlioux [/bib_ref] [bib_ref] Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt insertion: a decade of experience, Masson [/bib_ref] In retrospective studies, patients with advanced disease had a worse outcome following TIPS insertion. The MELD score Guidelines was originally developed to predict survival following TIPSS and included serum creatinine, bilirubin, INR and aetiology of cirrhosis. [bib_ref] A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic..., Malinchoc [/bib_ref] The MELD score has now evolved into a prognostic score in patients with cirrhosis. [bib_ref] Accuracy of MELD scores in predicting mortality in decompensated cirrhosis from variceal..., Sibae [/bib_ref] Among patients with refractory ascites treated with TIPSS with covered stent, 1-year survival is 84% in those with MELD score <15 compared with 54% for MELD score >18. [bib_ref] Tips for refractory ascites: a 6-year single-center experience with expanded polytetrafluoroethylene-covered stent-grafts, Bercu [/bib_ref] In refractory ascites, a simple model of serum bilirubin and platelet count has been shown to predict 1-year survival. [bib_ref] Serum bilirubin and platelet count: a simple predictive model for survival in..., Bureau [/bib_ref] The survival rate of patients with serum bilirubin >50 µmol/L or platelet count of <75×10 9 /L was only 31.2% compared with 73.1% in patients with serum bilirubin <50 µmol/L and platelet count of >75×10 9 /L. The exact survival rate quoted here has to be interpreted cautiously as earlier patients in the cohort were treated with a bare metal stent before the introduction of a PTFE-covered stent. Hyponatraemia has also been shown to be related poor survival following TIPSS, 223 but subsequent studies have not reproduced this finding. Up to 50% of patients with decompensated cirrhosis have sarcopenia, which in turn negatively affects clinical outcome in these patients. However, the direct impact of sarcopenia on outcomes following TIPSS is unclear. Sarcopenia has been shown to be independently associated with development of post-TIPSS encephalopathy, but this study included patients with refractory ascites and uncontrolled variceal bleeding. [bib_ref] Sarcopenia is risk factor for development of hepatic encephalopathy after transjugular intrahepatic..., Nardelli [/bib_ref] A recent retrospective study published in abstract form on patients undergoing TIPSS for refractory ascites reported no impact of sarcopenia on outcomes after TIPSS. [bib_ref] SAT-016-Impact of sarcopenia in patients undergoing transjugular intrahepatic portosystemic shunt insertion for..., Benmassaoud [/bib_ref] Furthermore, they reported an improvement in muscle mass following TIPSS insertion. Although increasing age has been associated with poorer survival following TIPSS, the mean age in these studies was between 54 and 57 years. Patients above the age of 70 were generally excluded from the previously mentioned RCTs. There is a lack of data in the literature for clinical outcome following TIPS in older patients (>70 years). Interestingly, functional disability as measured by patient-reported activities of daily living predicts post-TIPSS mortality adjusted for MELD score. [bib_ref] A standardized assessment of functional disability predicts 1-year mortality in patients undergoing..., Grunwald [/bib_ref] The management of hepatic encephalopathy after TIPSS is beyond the scope of this document and is discussed in the recent BSG/BASL TIPSS guidelines. ## Recommendations ## Management of umbilical hernia in patients with ascites In the cirrhotic patient, the incidence of abdominal wall hernia is 16% and reaches 24% in the presence of ascites; more than half of these are umbilical hernias. [bib_ref] Assessment of risk for non-hepatic surgery in cirrhotic patients, Bhangui [/bib_ref] These progressively enlarge and are prone to complications, including ulceration of the overlying skin, incarceration, strangulation, and rupture. Nonoperative management of complicated hernias with antibiotics and dressing changes might result in mortality rates in the range of 60-88%. [bib_ref] Management of spontaneous umbilical hernia disruption in the cirrhotic patient, Lemmer [/bib_ref] On the other hand, hernia repair in cirrhosis has often been avoided due to high postoperative morbidity and mortality. Emergency surgery (OR=10. [bib_ref] Long-term outcomes after hospitalization with spontaneous bacterial peritonitis, Lim [/bib_ref] [bib_ref] The abdominal wall hernia in cirrhotic patients: a historical challenge, Salamone [/bib_ref] A recent retrospective series of 102 patients, who underwent surgical repair of the umbilical hernia in the presence of ascites, included 45 patients having emergency surgery (24 with incarceration, 12 with rupture of the hernia sac, and nine with skin ulceration or necrosis). Morbidity and mortality rates of 37.2% and 3.9%, respectively, were observed. [bib_ref] Surgical repair of umbilical hernia in cirrhotic patients with ascites: is it..., Elshoura [/bib_ref] Optimising management of ascites, including LVP and TIPSS perioperatively, could reduce the risk of wound dehiscence and recurrence of hernia. [bib_ref] Umbilical hernia in patients with liver cirrhosis: a surgical challenge, Coelho [/bib_ref] Recommendations ► Suitability and timing of surgical repair of umbilical hernia should be considered in discussion with the patient and multidisciplinary team involving physicians, surgeons and anaesthetists. (Quality of evidence: low; Recommendation: strong) ## Hepatic hydrothorax Hepatic hydrothorax (HH) is accumulation of transudative fluid in the pleural space in the absence of cardiac, pulmonary or pleural disease, affecting approximately 5-12% of patients with advanced liver disease. [bib_ref] Pulmonary contraindications, indications and MELD exceptions for liver transplantation: a contemporary view..., Krowka [/bib_ref] The first-line management of hydrothorax is based on controlling ascites with diuretics and/ or LVP as discussed previously. However, pleural effusion can persist despite successful treatment of ascites, defined as refractory hydrothorax.Therapeutic thoracentesis is required to provide symptomatic relief from dyspnoea but the effect is transient. Repeated procedures increase the risks of complications, including pneumothorax, bleeding and pleural infection. [bib_ref] Outcomes of patients with chest tube insertion for hepatic hydrothorax, Orman [/bib_ref] TIPSS has been suggested either as a definitive treatment or as a bridge to transplantation in patients with refractory hydrothorax. Metaanalysis of six retrospective studies with a total of 198 patients reported a response rate of 56%. [bib_ref] Transjugular intrahepatic portosystemic stent shunt for medically refractory hepatic hydrothorax: a systematic..., Ditah [/bib_ref] Mortality within 45 days of TIPSS placement was 18%, mainly related to older age and the severity of liver disease. However, without any data on comparison with standard treatment, it is difficult to interpret the impact of TIPSS on survival. It is also worth noting that only one of these studies reported on patients treated with PTFEcovered stents. [bib_ref] Transjugular intrahepatic portosystemic shunt for symptomatic refractory hepatic hydrothorax in patients with..., Dhanasekaran [/bib_ref] In patients with contraindications to TIPSS or liver transplant, a permanent indwelling pleural catheter can be considered in conjunction with the patient and the multidisciplinary team taking into account the infection risk. ## Recommendation ## Non-selective beta-blockers and ascites The portal pressure-lowering effects of non-selective betablockers (NSBB) have been known to be beneficial in patients with ascites for three decades. Lebrec's group demonstrated back in 1991 in a meta-analysis of trial data that NSBB reduce the likelihood of first variceal haemorrhage in the ascites subgroup, while in Child's Pugh B and C cirrhosis the addition of NSBB to band ligation results in less variceal rebleeding and superior survival. Proven haemodynamic response to NSBB (drop in hepatic venous pressure gradient (HVPG) of ≥10-20% from baseline, or to <12 mm Hg) has been linked with a lower probability of the development of ascites; and in patients already with ascites, a lower probability of refractory ascites and hepatorenal syndrome. However, it remains possible that non-response in this context is simply a surrogate marker for disease severity. In recent years, there has been increasing recognition that the benefits of NSBB in patients with cirrhosis may not be exclusively explained by the reduction in portal pressure. NSBB reduce markers of intestinal permeability, bacterial translocation, systemic inflammation and the incidence of spontaneous bacterial peritonitis independently of haemodynamic response, suggesting a direct effect, potentially via intestinal transit time or on the bowel mucosal integrity. [bib_ref] Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats..., Pérez-Paramo [/bib_ref] [bib_ref] β-Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis, Senzolo [/bib_ref] [bib_ref] Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and..., Reiberger [/bib_ref] Given the mounting evidence that bacterial translocation and the systemic inflammatory response contribute to the downward spiral of circulatory dysfunction in cirrhosis, it follows that NSBB may also reduce non-bleeding related mortality. Despite all this, Lebrec et al [bib_ref] Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and..., Lebrec [/bib_ref] introduced controversy to the beta-blocker story in 2010 when his team reported that patients with refractory ascites receiving NSBB had greater all-cause mortality during long-term follow-up. [bib_ref] Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory..., Sersté [/bib_ref] The window hypothesis has since been proposed, which postulates that refractory ascites represents the tipping point in portal hypertension when the cardio-inhibitory effects of NSBB compromise organ perfusion. [bib_ref] The window hypothesis: haemodynamic and non-haemodynamic effects of β-blockers improve survival of..., Krag [/bib_ref] Krag and coauthors suggest that the 'window' of benefit from NSBB opens when grade 2 oesophageal varices develop and closes with the development of refractory ascites. Yet, concerns have been raised about the methodology of the original observational study; and many subsequent studies, including five metaanalyses and three with propensity risk score matching, have shown either similar or superior survival in patients with refractory ascites receiving NSBB. [bib_ref] Nonselective β blockers increase risk for hepatorenal syndrome and death in patients..., Mandorfer [/bib_ref] Of relevance is that the Lebrec data observed patients receiving a relatively high dose of NSBB compared with many of the other cohorts studied, and the NSBB type (carvedilol vs propranolol) may be important. [bib_ref] Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory..., Sersté [/bib_ref] [bib_ref] Beta-blockers in patients with cirrhosis and ascites: type of beta-blocker matters, Njei [/bib_ref] We conclude that, until randomised high-quality data are available, the current evidence supports the use of NSBB when indicated in patients with refractory ascites (online supplemental ## Automated low-flow ascites pump (alfapump) The ALFApump system consists of a subcutaneously implanted battery-powered programmable pump. It is connected to catheters that transfer ascites from the peritoneal cavity to the bladder, from which it is eliminated with urine. Initially, two multicentre safety and efficacy studies reported substantial reduction of the number and volume of paracenteses in patients with advanced cirrhosis and refractory ascites. However, adverse effects directly related to the device occurred in up to 39% of cases. In a multicentre RCT in patients with refractory ascites, the ALFApump significantly reduced the need for paracentesis and was associated with significantly improved chronic liver disease questionnaire, nutritional parameters such as hand-grip strength and body mass index. [bib_ref] Alfapump® system vs. large volume paracentesis for refractory ascites: a multicenter randomized..., Bureau [/bib_ref] Meta-analysis of the data from the RCT and several case series showed that 62% of the patients did not require LVP following pump insertion. [bib_ref] Systematic review with meta-analysis: automated low-flow ascites pump therapy for refractory ascites, Lepida [/bib_ref] Pooled estimate rates were 30% for acute kidney injury, 27% for bacterial peritonitis and 20% for urinary tract infection. The device had no effect on survival. Currently, NICE recommends that the ALFApump should be used only with special arrangements for clinical governance, consent and audit or research. 259 ## Recommendation ► Automated low-flow ascites pump should be considered only in special circumstances with robust arrangements of clinical governance, audit or research. (Quality of evidence: low; Recommendation: weak) ## Hepatorenal syndrome Patients with cirrhosis and ascites can develop a specific form of renal dysfunction, which is termed hepatorenal syndrome (HRS). Traditionally HRS was thought to be due to the altered haemodynamic alterations with hyperdynamic circulation as well as overactive endogenous vasoactive system which results in renal hypoperfusion. [bib_ref] Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis, Salerno [/bib_ref] It is now recognised that systemic inflammation also plays an important role in the pathophysiology of HRS. The traditional classification of HRS-1 and HRS-2 has recently been revised by the International Club of Ascites. [bib_ref] News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond..., Angeli [/bib_ref] HRS-1, which reflects a rapid reduction in renal function, has been proposed to be changed to HRS-acute kidney injury (HRS-AKI). The new definition of HRS-AKI includes an increase in serum creatinine of ≥0.3 mg/dL (27 µmol/L) within 48 hours or ≥50% from baseline, without necessitating a final cut-off value of 1.5 mg/dL (133 µmol/L). This allows treatment to be started earlier. HRS-2, which represents renal dysfunction that does not progress rapidly, has been proposed to be changed to HRS-NAKI (non-AKI). [bib_ref] News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond..., Angeli [/bib_ref] The mainstay of treatment of HRS-AKI involves HAS and vasoconstrictors, particularly terlipressin. Combination of terlipressin and HAS has been shown in RCTs to significantly improve renal function in HRS-AKI and improve short-term mortality (online supplemental table 12). [bib_ref] Terlipressin versus other vasoactive drugs for hepatorenal syndrome, Israelsen [/bib_ref] [bib_ref] Terlipressin versus placebo or no intervention for people with cirrhosis and hepatorenal..., Allegretti [/bib_ref] [bib_ref] Editorial: treating hepatorenal syndrome-a window and the views, Palaniyappan [/bib_ref] Higher baseline serum creatinine is an independent predictor of failure to respond to vasoconstrictor treatment. A full review of HRS is beyond the scope of this guideline. ## Palliative care Palliative care is integral to the management of advanced non-cancer conditions, such as cardiac, respiratory and renal disease, often supported by practice guidelines. [bib_ref] Decision making in advanced heart failure: a scientific statement from the American..., Allen [/bib_ref] [bib_ref] An official American Thoracic Society clinical policy statement: palliative care for patients..., Lanken [/bib_ref] [bib_ref] Clinical practice guideline on shared decision-making in the appropriate initiation of and..., Galla [/bib_ref] Patients with cirrhosis and ascites often report a poor quality of life, [bib_ref] Patient experience of non-malignant ascites and its treatment: a qualitative study, Day [/bib_ref] this being an independent predictor of 12-month mortality. [bib_ref] Quality of life measures predict mortality in patients with cirrhosis and severe..., Macdonald [/bib_ref] However, only a minority of patients with advanced cirrhosis receive timely palliative care and this has been discussed in recent reviews. A British study indicated that from 2013 to 2015, of the 45 000 cirrhosis-related deaths, about a third required LVP in the last year of their life, overall healthcare costs being over £21 000 per person. [bib_ref] Cirrhosis with ascites in the last year of life: a nationwide analysis..., Hudson [/bib_ref] Substantial literature supports the use of palliative tunnelled long-term abdominal drains (LTAD) in individuals with refractory ascites due to malignancy, including NICE medical technology guidance. [bib_ref] Indwelling catheters for the management of refractory malignant ascites: a systematic literature..., Fleming [/bib_ref] [bib_ref] PleurX peritoneal catheter drainage system for vacuumassisted drainage of treatment-resistant, recurrent malignant..., White [/bib_ref] [bib_ref] Drainage of malignant ascites: patient selection and perspectives, Stukan [/bib_ref] [bib_ref] Chronic peritoneal indwelling catheters for the management of malignant and nonmalignant ascites, Caldwell [/bib_ref] These drains are inserted in hospital and Guidelines allow drainage of small amounts of ascites 2-3 times a week at home. Potential advantages over LVP include symptom-guided drainage and avoidance of repeated hospitalisations. A recent systematic review on LTAD in cirrhosis showed that the majority of patients could be managed in the community. [bib_ref] Permanent indwelling peritoneal catheters for palliation of refractory ascites in end-stage liver..., Macken [/bib_ref] Results from a recent feasibility RCT comparing palliative LTAD with LVP in refractory ascites due to cirrhosis have just been published (REDUCe study). [bib_ref] Randomised clinical trial: palliative long-term abdominal drains vs large-volume paracentesis in refractory..., Macken [/bib_ref] In this 3-month study, 36 patients were randomised, 19 to LVP and 17 to LTAD. All patients received prophylactic antibiotics for the study duration. Following randomisation, the median number (IQR) of hospital ascitic drains for LTAD versus LVP groups were 0 (0, 1) versus 4 (3, 7), respectively. Only two patients allocated to LTAD required hospital admissions specifically for ascites drainage. Self-limiting cellulitis/leakage occurred in 41% (7/17) in the LTAD vs 11% (2/19) in the LVP group; peritonitis incidence being 6% (1/17) vs 11% (2/19), respectively. Median (IQR) fortnightly community/hospital/social care ascites-related costs were lower in the LTAD group than in the LVP group, £329 (253, 580) versus £843 (603, 1060), respectively. Qualitative data (currently only published as a summary) indicate that LTAD could transform the care pathway. [bib_ref] Randomised clinical trial: palliative long-term abdominal drains vs large-volume paracentesis in refractory..., Macken [/bib_ref] The REDUCe study demonstrates feasibility, with preliminary evidence of LTAD acceptability, effectiveness and safety and reduction in health resource use. Future trials should assess LTAD as a palliative intervention for refractory ascites in cirrhosis. ## Recommendations ► Patients with refractory ascites who are not undergoing evaluation for liver transplant should be offered a palliative care referral. Besides repeated LVP, alternative palliative interventions for refractory ascites should also be considered. (Quality of evidence: weak; Recommendation: strong) # Conclusions The development of ascites is a landmark in the natural history of cirrhosis. Therefore, it should be considered an important time point at which an individual patient's suitability for liver transplantation which is a definitive treatment of ascites and its complications, should be determined. Over the years, there has been a substantial improvement in care of patients with cirrhosis, including those with ascites. A study involving over 780 000 hospitalisations of patients with cirrhosis demonstrated an improvement in inpatient survival over a decade despite higher age and more medically complex disease. [bib_ref] Decreasing mortality among patients hospitalized with cirrhosis in the United States from, Schmidt [/bib_ref] This was remarkably consistent across several cirrhosis complications, suggesting improved cirrhosis care beyond general improvements in inpatient care. Future research should focus on areas of need and questions where there is no high-quality evidence to guide the management of ascites. ## Research recommendations ► Randomised controlled trials (RCTs) with large sample size should evaluate the role of antibiotics in the secondary prophylaxis for SBP in ascites secondary to cirrhosis. ► Large RCTs should assess the role of midodrine in the management of ascites. ► Cost-effectiveness of long-term administration of HAS to patients with decompensated cirrhosis and ascites should be evaluated. ► Role of nutritional interventions in the management of ascites should be evaluated. ► Large RCT of long-term carvedilol versus no carvedilol in patients with refractory ascites without large oesophageal varices should be carried out. ► Role of TIPSS in the management of hepatic hydrothorax should be compared with other therapeutic interventions. ► The cost-effectiveness and the effect of automated low-flow ascites pumps on the quality of life of patients with refractory ascites should be evaluated. ► Effectiveness and safety of long-term abdominal drains should be assessed in RCTs for the palliative care of patients with cirrhosis and refractory ascites. [fig] Figure 2: The ascitic fluid samples required from diagnostic paracentesis. *These investigations should be considered based on pretest probability of specific diagnosis. BNP, brain natriuretic peptide. [/fig] [fig] ►: Patients with cirrhosis and ascites should have a moderately salt restricted diet with daily salt intake of no more than 5-6.5 g (87 mmol-113 mmol sodium). This translates to a no added salt diet with avoidance of precooked meals.(Quality of evidence: moderate; Recommendation: strong) Patients with cirrhosis and ascites should receive nutritional counselling on the sodium content in the diet. (Quality of evidence: weak; Recommendation: strong) [/fig] [fig] Figure 3: Approach to the use of diuretics in the management of ascites in patients with cirrhosis. [/fig] [fig] Figure 4: Anatomical landmarks for the safe performance of paracentesis [A] and performance of ascites drainage in patients with large ascites [B]. [/fig] [table] Author affiliations 1: NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK [/table]	None	https://gut.bmj.com/content/gutjnl/70/1/9.full.pdf	The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and meta-analysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE)’ system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years’ time.
4995e1207aff7fed4993d68d4bd499daf6f297b4	pubmed	A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)	A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version) In December 2019, a new type viral pneumonia cases occurred in Wuhan, Hubei Province; and then named "2019 novel coronavirus (2019-nCoV)" by the World Health Organization (WHO) on 12 January 2020. For it is a never been experienced respiratory disease before and with infection ability widely and quickly, it attracted the world's attention but without treatment and control manual. For the request from frontline clinicians and public health professionals of 2019-nCoV infected pneumonia management, an evidence-based guideline urgently needs to be developed. Therefore, we drafted this guideline according to the rapid advice guidelines methodology and general rules of WHO guideline development; we also added the first-hand management data of Zhongnan Hospital of Wuhan University. This guideline includes the guideline methodology, epidemiological characteristics, disease screening and population prevention, diagnosis, treatment and control (including traditional Chinese Medicine), nosocomial infection prevention and control, and disease nursing of the 2019-nCoV. Moreover, we also provide a whole process of a successful treatment case of the severe 2019-nCoV infected pneumonia and experience and lessons of hospital rescue for 2019-nCoV infections. This rapid advice guideline is suitable for the first frontline doctors and nurses, managers of hospitals and healthcare sections, community residents, public health persons, relevant researchers, and all person who are interested in the 2019-nCoV. # Background In December 2019, the 2019 novel coronavirus (2019-nCoV) was discovered and identified in the viral pneumonia cases that occurred in Wuhan, Hubei Province, China; And then was named by the World Health Organization (WHO) on 12 January 2020. In the following month, the 2019-nCoV quickly spreading inside and outside of Hubei Province and even other countries. What's more, the sharp increase of the case number caused widespread panic among the people. Medical professionals require an up-to-date guideline to follow when an urgent healthcare problem emerging. In response to the requests for reliable advice from frontline clinicians and public healthcare professionals managing 2019-nCoV pandemics, we developed this rapid advance guideline, involving disease epidemiology, etiology, diagnosis, treatment, nursing, and hospital infection control for clinicians, and also for public health workers and community residents. # Guideline methodology This guideline was prepared in accordance with the methodology and general rules of WHO Guideline Development and the WHO Rapid Advice Guidelines. ## Composition of the guideline development group This guideline development group is multidisciplinary and composed of individuals from health professionals and methodologists. Health professionals included frontline clinical doctors, nurses who work in departments of respiratory medicine, fever clinic, critical medicine, emergency, infectious disease, and experts of respiratory infectious disease and hospital management board. The methodologists included methodologists of guideline development, systematic review, and literature searching professionals. ## The end-user of the guideline This guideline is suitable for frontline doctors and nurses, managers of hospitals and healthcare sections, healthy community residents, personnel in public healthcare, relevant researchers, and all persons who are interested in the 2019-nCoV management. ## The target population of the guideline This guideline is aimed to serve the healthcare professionals to tackle the suspected 2019-nCoV infected cases, confirmed 2019-nCoV infected cases, clustered 2019-nCoV infected cases, and those with close contacts or suspicious exposure to 2019-nCoV infected cases. ## A survey of conflict of interests Oral inquiry for financial interests of relevant personal was conducted at the first meeting while to start this guideline. Relevant financial as well as nonfinancial interests were surveyed and disclosed and subsequently assessed in consensus conference in order to minimize potential bias in guideline development. Finally, there is no conflict of interests for all the personnel participating to prepare this guideline. ## Guideline's structural setup and refining the topics and coverage of this guideline This guideline is a rapid guideline to responding to the emerging infectious disease of 2019-nCoV. Due to the urgent need and tight work schedule, we conducted no wide-range survey but a discussion meeting with front-line clinicians who managed patients with 2019-nCoV infections to finalize guideline topics and key questions. 2.6 Literature searching and preparation of evidence profiles 2.6.1 General notes Considering the lack of direct evidence for this newly identified 2019-nCoV infection, we searched and referred to the guidelines that related to the SARS (Severe Acute Respiratory Syndrome), MERS (Middle East Respiratory Syndrome), and influenza. We also referred to the guidelines which were newly-issued by the National Health Commission of People's Republic of China and WHO for 2019-nCoV. In addition, we have an independent literature searching team to search available indirect evidence from systematic reviews and/or RCTs (randomized controlled trials), which were for the treatment and/ or chemoprophylaxis of SARS, MERS, or other influenza virus infections. If the existing evidence addressed topics or questions covered by the guideline, then its quality should be assessed. If there is a lack of higher-level quality evidence, our panel considered observational studies and case series. Because of the limited time, we did not perform new systematic review. We identified relevant literature up to 20 January 2020. ## Search resources We searched the bibliographic databases: PubMed, Embase, and Cochrane library. We also searched following websites: the WHO (https://www.who.int/), CDC (Centers for Disease Control and Prevention, https://www.cdc.gov/), NICE (National Institute for Health and Clinical Excellence, https://www.nice.org.uk/), National Health Commission of the People's Republic of China (http://www.nhc.gov. cn/), and National Administration of Traditional Chinese Medicine (http://www.satcm.gov.cn/). ## Frontline data collection and summary As the 2019-nCoV is a newly identified pathogen responsible for the outbreak of the pandemic disease, there is no sufficient evidence to reveal the whole nature of this virus. In these situations, obtaining evidence from the experts who fighting the disease on the frontline can be efficient and the main source. Until to 24:00 on 29 January 2020, 11,500 persons were screened, and 276 were identified as suspected infectious victims, and 170 were diagnosed (including 33 in critical condition) for 2019-nCoV infection in Zhongnan Hospital of Wuhan University. During this process, frontline clinicians and nurses have accumulated valuable experience in the diagnosis, treatment and nursing for 2019-nCoV infected patients. Hence, these experiences were assessed and then used as "Expert Evidence" for our guideline development. We took interviews and group surveys to collect information on treatment evidence during the guideline panel's meeting, so that it could be integrated into the guideline panel in the summary of findings (see Additional files 1 and 2). Experts' evidence can be solicited by the description of case reports, summaries, and reports of topics or questions of all cases they management. ## Grading the evidences and recommendations We accorded to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) basic approaches and rules, and particularly considered experts' evidence to assess the quality of a body of evidence to make recommendations. The quality of evidence reflects whether the extent to which our confidence estimating the effect is adequate to support a particular recommendation. The level of evidence was categorized as "high quality", "moderate quality", "low quality", or "very low quality"; Recommendations were classified as "strong" or "weak." The strong recommendation does not always mean there is sufficient intervention effectiveness. Besides the effectiveness of intervention, the forming of recommendations is based on the severity of the disease, patient willingness, safety, and economics. See. ## Forming the recommendations Before meetings, experts' evidence was collected systematically and available to panel members. Once the evidence has been identified and assessed, recommendations were formulated based on the evidence by a face-to-face meeting of panel members and supplemented by experts participating in the panel meeting. Experts' evidence was highly valued in this guideline development. During the consensus process, if the evidence was agreed on by more than 70% frontline clinicians in the consensus meeting, it is considered as highquality evidence. In specific recomendations, we used "should" or "strongly recommend" for strong recommendations; whereas, "suggest" or "consider" was used for weak ones. ## Drafting and publishing the guideline This guideline was published in both Chinese and English versions at the same time. Due to space limitations, the current standard revision does not include evidence descriptions. The full revision will be published in New Medicine (Chinese name: Yixue Xinzhi; http://www. jnewmed.com/), Volume 30 and Issue 1 2020. ## Epidemiological characteristics ## Scope of the 2019-ncov infection outbreak Since December 2019, multiple cases occurring unexplainable pneumonia were successively reported in some hospitals in Wuhan city with a history of exposure to a large Hua'nan seafood market in Wuhan city, Hubei province, China. It has been confirmed to be an acute respiratory infection caused by a novel coronavirus. So far, the number of cases without a history of the Hua'nan seafood market exposure is increasing. In addition, clustered cases and confirmed cases without a history of travel to Wuhan emerged. Also, confirmed cases without clear exposure to the Wuhan seafood market have been found in many foreign countries or regions. At 24:00 on 26 January 2020, the National Health Commission of the People's Republic of China has recorded a total of 2744 confirmed cases of pneumonia with 2019-nCoV infection from 30 provinces (districts and cities), including 461 severe cases and 80 deaths. A total of 51 cases have been cured and discharged. At present, 5794 suspected cases were recorded, 32,799 with close contacts to the confirmed patients have been tracked, 583 people were released from medical observation that day, and 30,453 people were still undergoing medical observation. A total of confirmed cases were reported from Hong Kong, Macao and Taiwan of China: 8 cases in Hong Kong, 5 cases in Macao, and 4 cases in Taiwan. In addition, confirmed cases had been reported from abroad: 7 in Thailand, 4 in Australia, 4 in Singapore, 3 in France, 3 in Japan, 3 in Korea, 3 in ## Host and reservoir Wild animal, batsis the most possible host of the 2019-nCoV. It requires further confirmation whether pneumonia infected by the 2019-nCoV is transmitted directly from bats or through an intermediate host. It is believed that clarifying the source of the virus will help determine zoonotic transmission patterns. ## Route of transmission Up to present, the main infection source was the patients who with pneumonia infected by the 2019-nCoV. Respiratory droplet transmission is the main route of transmission, and it can also be transmitted through contact. Although many details, such as the source of the virus and its ability to spread between people remain unknown, an increasing number of cases show the signs of human-tohuman transmission. ## Etiology and pathogenesis The 2019-nCoV isolated from the lower respiratory tract of patients with unexplainable pneumonia in Wuhan, and it is a novel coronavirus belonging to the β genus. The 2019-nCoV has an envelope; its particles are round or oval, often polymorphic, with a diameter from 60 nm to 140 nm. Its genetic characteristics are significantly different from SARSr-CoV (SARS related coronaviruses) and MERSr-CoV (MERS related coronaviruses). Current research shows it has more than 85% homology with SARSr-CoV (bat-SL-CoVZC45). 2019-nCoV can be found in human respiratory epithelial cells 96 h after in vitro isolation and culture, while it takes about 6 days in VeroE6 or Huh-7 cell lines. The source of the virus, the time span of the patients discharging infective virus, and the pathogenesis are still not clear. ## Molecular epidemiology No evidence of viral mutation has been found so far. It is necessary to obtain much more clinically isolated viruses with time and geographical variety to assess the extent of the virus mutations, and also whether these mutations indicate adaptability to human hosts. ## Incubation and contagious period Based on currently epidemiological survey, the latency period is generally from 3 to 7 days, with a maximum of 14 days. Unlike SARSr-CoV, 2019-nCoV is contagious during the latency period. The evidence agreed on by more than 70% frontline clinicians in consensus meeting is viewed as high-quality evidence ## Prognostic factors The population is generally susceptible to the virus. The elderly and those with underlying diseases show more serious conditions after infection, and children and infants also get infected by the 2019-nCoV. From current knowledge of the cases, most patients have a good prognosis, the symptoms of children are relatively mild, and a few patients are in critical condition. Death cases are more frequently seen in the elderly and those with chronic underlying diseases. The newest study including the first 41 confirmed cases admitted to Wuhan between 16 December 2019 and 2 January 2020 showed the median age of patients was 49 years; and the main underlying diseases were diabetes, hypertension, and cardiovascular diseases. Of them, 12 cases experienced acute respiratory distress syndrome (ARDS), 13 cases were admitted to the intensive care unit (ICU), and 6 cases died. Patients with any 2 of the following clinical features and any epidemiological risk: (1) clinical features: fever, imaging features of pneumonia, normal or reduced white blood cell count, or reduced lymphocyte count in the early stages of the disease onset. (2) epidemiologic risk: a history of travel to or residence in Wuhan city, China or other cities with continuous transmission of local cases in the last 14 days before symptom onset; contact with patients with fever or respiratory symptoms from Wuhan city, China or other cities with continuous transmission of local cases in the last 14 days before symptom onset; or epidemiologically connected to 2019-nCoV infections or clustered onsets. ## Confirmed case Those with one of the following pathogenic evidence is the confirmed case: (1) positive for the 2019-nCoV by the real-time PCR test for nucleic acid in respiratory or blood samples. 2) viral gene sequencing shows highly homogeneity to the known 2019-nCoV in respiratory or blood samples. ## Clustered cases Suspected clustering cases are defined when one confirmed case and at the same time, one or more cases of fever or respiratory infection are found in a small area (such as a family, a construction site, a unit, etc.) within 14 days. Under the above circumstances, 2 or more confirmed cases are found, and there is the possibility of human-tohuman transmission due to close contact or infection due to co-exposure, then it is determined as a clustered case. ## Close contacts Those who have one of the following contacts after the onset of confirmed cases in the absence of effective protection: (1) those who live, study, work, or have close contact with the confirmed cases, or other close contacts such as working closely with or sharing the same classroom or living in the same house with the confirmed case. (2) medical and nursing staffs and their family members living with them, who treated, nursed or visited the confirmed case, or other personnel who have similar close contact with the case, such as providing direct treatment or care of the case, visiting the case or staying in a closed environment where the cases are located; other patients or caregivers in the same room with the case. (3) people who have close contact with the patients in a same transport vehicle, including those who had taken care of the patients on the vehicle; the person who had companied the patients (family members, colleagues, friends, etc.); other passengers and traffic staff considered having likely close contact with the patients by investigation and evaluation. (4) other circumstances considered to be closely contacted with the person with close contact with the patients by the professional investigation and evaluation. ## Suspicious exposure Persons with suspicious exposure are those who are exposed without effective protection to processing, sales, handling, distributing, or administrative management of wild animals, materials, and the environments that are positive for the 2019-nCoV test. ## Prevention ## Persons with close contacts and suspicious exposure Persons with close contacts and suspicious exposure should be advised to have a 14-day health observation period, which starts from the last day of contact with the 2019-nCoV infected patients or suspicious environmental exposure. Once they display any symptoms, especially fever, respiratory symptoms such as coughing, shortness of breath, or diarrhea, they should reach out for medical attention immediately. Contact surveillance should be carried out for those who had exposed to accidental contact, low-level exposure to suspected or confirmed patients, i.e. checking any potential symptoms when carrying out daily activities. Seefor details. ## Patients with suspected 2019-ncov infection Patients with a suspected infection should be isolated, monitored, and diagnosed in hospital as soon as possible. Doctors should make recommendations based on the patient's situation. Patients with mild symptoms and suspected infection may consider in-home isolation and home care (weak recommendation). Suspected infected with severe symptoms and those who need to stay in hospital for observation by doctor's judgment should follow the isolation guidelines for suspected patients (seefor details). It should also be noted that: (1) whether the suspected patients should be given in-home isolation and care or not requires careful clinical evaluation and safety assessment by professionals.if the suspected patients do not get improvement in the symptoms or even worsened in condition during home care, they need to go to the doctor for treatment. (3) during the period of home care, the patients' medication and symptoms should be closely recorded and their caregivers should also monitor their body temperature daily. Throughout the period of home care, healthcare personnel should perform regular (e.g., daily) follow-up through face-to-face visits or phone interviews (ideally, if feasible) to follow the progress of symptoms and, if necessary, specific diagnostic tests should be conducted. ## Prevention for travellers (strong recommendation) International visitors should take routine precautions when entering and leaving the affected areas, including avoiding close contacts with people with acute respiratory infection, washing hands frequently, especially after contacting with the sick or their surrounding environment; following appropriate coughing etiquette; and avoiding close contact with live or dead farming animals or bats or other wild animals. Passengers should avoid unnecessary travel as possible. If they had travelled to Hubei Province (especially Wuhan city) in the past 14 days and is in fever, cough or difficulty in breathing, they should: (1) see a doctor immediately;call the doctor about his/her recent trips and symptoms before going to the doctor's office or emergency room; (3) avoid contact with others; (4) not to travel around; (5) cover mouth and nose with a tissue or sleeve (not hands) when coughing or sneezing; and (6) wash hands with soap and water for at least 20 s. If soap and water are not available, use alcohol-based hand sanitizers. ## Diagnosis of the 2019-ncov cases ## Clinical manifestation The 2019-nCoV infected cases have symptoms like fever, fatigue, dry cough, dyspnea etc., with or without nasal congestion, runny nose or other upper respiratory symptoms. Despite the atypical symptoms were reported, Nan-Shan Zhong, the academician of Chinese Academy of Engineering in an exclusive interview with Xinhua News Agency on 28 January 2020, pointed out that fever is still the typical symptom of 2019-nCoV infection. ## Physical examination Patients with mild symptoms may not present positive signs. Patients in severe condition may have shortness of breath, moist rales in lungs, weakened breath sounds, dullness in percussion, and increased or decreased tactile speech tremor, etc. ## Imaging examination 5.3.1 ct imaging (strong recommendation) The imaging findings vary with the patient's age, immunity status, disease stage at the time of scanning, underlying diseases, and drug interventions. When walking on the road or waiting in the hospital, try to stay away from other people (at least 1 m away) and wear a mask. ## Strong 7 The family members accompanying those for inspection should immediately follow the monitoring recommendations to close contacts, keep the respiratory hygiene and clean their hands properly. ## Strong 8 The community or street hospital should be informed before the suspected contacts to the hospital. The vehicle used should be cleaned and disinfected with 500 mg/L chlorine-containing disinfectant, and the window should be opened for ventilation. The imaging features of lesions show: (1) dominant distribution (mainly subpleural, along the bronchial vascular bundles); (2) quantity (often more than three or more lesions, occasional single or double lesions); (3) shape (patchy, large block, nodular, lumpy, honeycomblike or grid-like, cord-like, etc.); (4) density (mostly uneven, a paving stones-like change mixed with ground glass density and interlobular septal thickening, consolidation and thickened bronchial wall, etc.); and (5) concomitant signs vary (air-bronchogram, rare pleural effusion and mediastinal lymph nodes enlargement, etc.). ## Strong ## Clinical data from zhongnan hospital of wuhan university Typical CT/X-ray imaging manifestation, including (1) Multiple, patchy, sub-segmental or segmental groundglass density shadows in both lungs. They were classified as "paving stone-like" changes by fine-grid or small honeycomb-like thickening of interlobular septa. The thinner the CT scan layers, the clearer the ground-glass opacity and thickening of interlobular septa were displayed. A slightly high-density and ground-glass change with fuzzy edge in the fine-grid or small honeycomb-like thickening of interlobular septa were presented by the high-resolution computed tomography (HRCT),cases, 54.2% in a total of 83 cases). The resolution of X-ray was worse lower than that of CT in the resolution, which was basically manifested as ground-glass When coughing or sneezing, it is necessary to wear a medical mask, or cover with a paper towel and bent elbow, and clean hands immediately after coughing and sneezing. Strong 10 N95 masks should be worn in the same room with patients (preferred strategy). ## Strong 11 Disposable surgical mask (alternative strategy). Use the mask in strict accordance with the instruction manual. ## Weak 12 After washing hands with running water, dry them with a paper towel (preferred strategy). ## Strong 13 Dry with a towel, and wash and disinfect the towel daily (alternative strategy). ## Weak Home caregivers 1 Clean and disinfect hands after contact with the patient, before leaving patient's room or the house, before and after eating, after using the toilet and after entering house from outside (for visible contaminant on hands, wash hands with running water then use hand disinfection). ## Strong 2 Avoid direct contact with patient's secretions or discharges, especially oral or respiratory discharges; avoid direct contact with patient's feces. (2) Multiple, patchy or large patches of consolidation in both lungs, with a little grid-like or honeycombshaped interlobular septal thickening, especially in the middle and lower lobescases, 31.3% in a total of 83 cases). It was more common in the elderly or severe condition patients. ## Strong Atypical CT/X-ray imaging manifestation, including (1) Single, or multiple, or extensive subpleural grid-like or honeycomb-like thickening of interlobular septum, thickening of the bronchial wall, and tortuous and thick strand-like opacity. Several patchy consolidations, occasionally with a small amount pleural effusion or enlargement of mediastinal lymph nodes, can be seen: 6 cases, 7.2% in a total of 83 cases). This is mostly seen in the elderly. (2) Single or multiple solid nodules or consolidated nodules in the center of lobule, surrounded by ground-glass opacities: 5 cases, 6.2% in a total of 83 cases). Stage based on CT image The CT imaging demonstrates 5 stages according to the time of onset and the response of body to the virus, including: (1) Ultra-early stage. This stage usually refers to the stage of patients without clinical manifestation, negative laboratory test but positive throat swab for 2019-nCoV (2) Early stage.This stage refers to the period of 1-3 days after clinical manifestations (fever, cough, dry cough, etc.). The pathological process during this stage is dilatation and congestion of alveolar septal capillary, exudation of fluid in alveolar cavity and interlobular interstitial edema. It showed that single or multiple scattered patchy or agglomerated ground-glass opacities, separated by honeycomb-like or grid-like thickened of interlobular septa: 45 cases, 54.2% in a total of 83 cases). ## Differential diagnosis It mainly should be distinguished from other known viral virus of pneumonia, such as influenza viruses, parainfluenza virus, adenovirus, respiratory syncytial virus, rhinovirus, human metapneumovirus, SARSr-CoV, etc.; and also from mycoplasma pneumonia, chlamydia pneumonia, and bacterial pneumonia. In addition, it should be distinguished from non-infectious diseases, such as vasculitis, dermatomyositis, and organizing pneumonia. ## Techniques for laboratory tests ## Hematology examination In the early stage of the disease, the total number of leukocytes decreased or keeps normal, with decreased lymphocyte count or increased or normal monocytes. High attention should be paid on the situation where the absolute value of lymphocyte is less than 0.8 × 10 9 /L, or the numbers of CD4 and CD8 T cells are significantly decreased, which generally recommend rechecking the blood routine changes after 3 days. ## Detection of pathogens in respiratory tract (1) Flu antigens. At present, routinely detected flu antigens are A, B, and H7N-subtypes. Sampling of throat swabs is conducive to early rapid screening for flu because of the fast test, but it has a relatively high false negative rate. (2) Respiratory virus nucleic acid. The detection of respiratory virus nucleic acid is commonly used to ## Clinical data from zhongnan hospital of wuhan university In the early stage of this disease, the total number of leukocytes in peripheral blood was normal or decreased, and the lymphocyte count decreased. In some patients, liver enzyme (transaminase), creatine kinase (CK) and myoglobin increased. CRP, ESR, and IL-6 increased, and PCT was normal in most patients. The increased Ddimer occurred in severe cases. Compared with 120 healthy check-ups, the absolute value of lymphocyte (0.87 vs 2.13) × 10 9 /L, lymphocyte percentage (19.5% vs 33.7%), eosinophil percentage (0.13% vs 2.16%), and absolute value (0.0061 vs 0.1417) × 10 9 /L in 2019-nCoV patients were significantly reduced (P < 0.05). The absolute number (4.2 vs 3.7) × 10 9 /L and the percentage (72.0% vs 57.0%) increased in 2019-nCoV patients (P < 0.05). The percentage of monocytes increased slightly (8.1% vs 6.8%), while the absolute number of monocytes did not change significantly (0.38 vs 0.44) × 10 9 /L. ## Other early diagnosis methods The next generation sequencing (NGS) and electron microscope technology play a role in the early diagnosis, but their diagnostic values have been weakened by the discovery of specific nucleic acid detection technology. In addition, NGS detection can tell whether the pathogen has mutated or not. ## Treatment and control ## Principles Suspected and confirmed cases need to be treated in designated hospitals with effective isolation and protection conditions. Suspected cases need to be treated separately in single room, confirmed cases are admitted to a same ward, and critical cases should be admitted to ICU as soon as possible. ## Treatment plans (1) The patient should rest in bed, being monitored for vital signs (heart rate, pulse oxygen saturation, respiratory rate, blood pressure) and given supportive treatment to ensure sufficient energy intake and balance for water, electrolytes, acidbase levels and other internal environment factors (Strong recommendation). (2) The patient should be monitored for blood routine, CRP, PCT, organ function (liver enzyme, bilirubin, myocardial enzyme, creatinine, urea nitrogen, Urine volume, etc.), coagulation function, arterial blood gas analysis and chest imaging (Strong recommendation). First, oxygen therapy is the choice for patients with severe respiratory infections, respiratory distress, hypoxemia or shock. The initial flow rate is 5 L/min, and the titration flow rate is to reach the target oxygen saturation (adults: SpO 2 ≥ 90% in non-pregnant patients, SpO 2 ≥ 92-95% in pregnant patients; children: SpO 2 ≥ 94% in children with obstructive dyspnea, apnea, severe respiratory distress, central cyanosis, shock, coma or convulsions, and ≥ 90% in other children). Second, respiratory support should be given to patients with hypoxic respiratory failure and acute respiratory distress syndrome. HFNO or NIV can be selected when nasal cannula or mask oxygen therapy was ineffective or the patient had hypoxic respiratory failure. However, when patients had hypercapnia (acute exacerbation of chronic obstructive pulmonary disease, cardiogenic pulmonary edema), hemodynamic instability, multiple organ failure, and abnormal mental status HFNO oxygen is not the routinely adopted measure. If respiratory failure cannot be improved or worsens continuously within a short time (1 h) after using HFNO or NIV, intubation should be performed immediately. Low tidal volume (4-8 ml/kg) and low suction pressure (platform pressure < 30cmH 2 O) are used for invasive mechanical ventilation. It is suggested that positive endexpiratory pressure (PEEP) with high positive endexpiratory pressure should be used in patients with moderate or severe acute respiratory distress syndrome, and PEEP should be titrated according to FiO 2 to maintain SpO 2 , in order to improve alveolar atelectasis and reduce alveolar hyper-expansion and pulmonary vascular resistance at the end of inspiration. For severe patients with ARDS, it is recommended to ventilate in prone position for more than 12 h/d. ## (4) extracorporeal membrane oxygenation (ecmo) should be considered for the patients with refractory hypoxemia that is difficult to be corrected by protective lung ventilation. (Strong recommendation). ## Drug treatment 6.3.1 antiviral treatment (1) At present, there is no evidence from RCT to support specific drug treatment against the new coronavirus in suspected or confirmed cases. (2) The α-interferon atomization inhalation can be considered (5 million U per time for adults in sterile injection water, twice a day) (Weak recommendation); lopinavir/ritonavir orally, 2 capsules each time, twice a day, can be also considered (Weak recommendation). Low-level evidences included retrospective cohort, historically controlled studies, case reports, and case series revealed that lopinavir/ritonavir alone or in combination with antivirals produced certain benefits in the treatment of SARS and MERS, such as reducing the incidence or mortality of ARDS. A recently systematic review showed that lopinavir/ritonavir's anti-coronavirus effect was mainly seen in its early application, for reducing patient mortality and reduced glucocorticoid consumption. However, if the early treatment window is missed, there will be no significant effect in their late application. Real-world study stills need to further explore the clinical effects of its early use in 2019-nCoV infected pneumonia. The effectiveness of the combined use of antivirals is still controversial. ## Antibiotic therapy (1) Principles. Avoid blind or inappropriate use of antibacterial drugs, especially the combination of broad-spectrum antibacterial drugs. Enhancement of bacteriological surveillance should be performed and promptly given appropriate antibacterial drugs when it occurs secondary bacterial infection. (2) According to the clinical manifestations of patients, if the accompanying bacterial infection cannot be ruled out, mild patients can take antibacterial drugs against community-acquired pneumonia, such as amoxicillin, azithromycin, or fluoroquinolones; empirical antibacterial treatment in severe patients should cover all possible pathogens, deescalating therapy until the pathogenic bacteria are clarified. ## Corticosteroid therapy The use of corticosteroids for severe ARDS is controversial; therefore, systemic use of glucocorticoids needs to be cautious. Methylprednisolone can be used as appropriate for patients with rapid disease progression or severe illness. According to the severity of the disease, 40 to 80 mg of methylprednisolone per day can be considered, and the total daily dose should not exceed 2 mg/kg (Weak recommendation). SARS management related researches showed that timely use of non-invasive continuous positive airway pressure and corticosteroids is an effective strategy for increased lung shadows and increased dyspnea. Appropriate use of glucocorticoids is able to significantly improve the clinical symptoms of patients with SARS, reduce the degree of disease progression, and accelerate the absorption of lung lesions; but it cannot shorten the length of hospital stay. Be cautious that hormone therapy has some incidence of adverse reactions. ## Other medications (1) Symptomatic treatment of fever. When the temperature is higher than 38.5 ℃, ibuprofen can be used for Treat the patient based on syndrome differentiation individually. Prevention before illness is better than treatment after getting diseased. ## Prevention (1) Community. Implement relevant national regulations and take great effort to keep away from contaminated materials, disinfect the environment, and improve the healthcare management. i Fumigation with moxa in the room, 1-5 g/m 2 for 30 min per day. ii Wearing perfumed Chinese herb bags (clove, fineleaf schizonepeta herb, Perilla frutescens, atractylodes lancea, cinnamon, biond magnolia flower, asarum sieboldii, and Elettaria cardamomum, 2 g for each, crushed into powder and put it into bags for external use, change a new one every 10 days). iii Prescription of Chinese herbs for feet bath (vulgaris 10 g, carthamus 10 g, and dried ginger 6 g) Soaking the herbs in boiling water and bath the feet into the medical liquid when the temperature is suitable. Soak feet for about 20 min. iv Prescription of Chinese herbs for prophylaxis: Astragalus mongholicus 12 g, roasted rhizoma atractylodis macrocephalae 10 g, saposhnikovia divaricata 10 g, Cyrtomium fortunei 10 g, honeysuckle 10 g, dried tangerine or orange peel 6 g, eupatorium 10 g, and licorice 10 g. Taking the medicine above yielded decoction once a day for adults, and for 5 days as a treatment course. If for children, cutting the dose to half. v Medical tea: perilla leaf 6 g, agastache leaf 6 g, dried tangerine or orange peel 9 g, stewed amomum tsao-ko 6 g, and 3 slices of ginger. Soak the herbs in hot water and drink the water just like enjoying the tea. vi Chinese patent medicine: Huoxiang Zhengqi capsule or Huoxiang Zhengqi Shui (in half dose). ## Treatment [12] In medical observation period There are two clinical symptoms in this period, including: (1) Clinical symptoms 1: hypodynamia accompanied by gastrointestinal upset. And the recommended Chinese patent medicine is the Huoxiang Zhengqi capsules (ball, liquid, or oral liquid). (2) Clinical symptoms 2: hypodynamia and fever. And the recommended Chinese patent medicines is the Jinhua Qinggan granules, Lianhua Qingwen capsules (granules), Shufeng Jiedu capsules (granules), or Fangfeng Tongsheng pills (granules). Clinical treatment period This period involving 7 stages, including: (1) Early-stage, characterized as exterior syndrome of cold-dampness. In this stage, the clinical manifestations presents as follow: aversion to cold without sweating, headache and generalized heaviness, limb pain, glomus and fullness in the chest and diaphragm, thirst with no desire to drink, ungratifying loose stool, yellow urine, frequent micturition and yellow urine. The therapeutic logic is to dissipate cold and eliminate dampness. And the recommended prescription is the Huoxiang Zhengqi powder (Yin dampness injuring superficies case from the National Famous Traditional Chinese Medical Doctor Medical Cases); which comprises of perilla leaf 10 g, atractylodes lancea 15 g, radix angelicae dahuricae 10 g, dried tangerine or orange peel 10 g, notopterygium root 10 g, agastache rugosus 10 g (end addition), mangnolia officinalis 10 g, saposhnikovia divaricata 10 g, poria peel 15 g, and Tetrapanax papyriferus 10 g above yielded decoction. In addition, the recommended Chinese patent medicine is Huoxiang Zhengqi capsules or Huoxiang Zhengqi Shui. (2) Early-stage, characterized as cold-dampness obstructing lung. In this stage, the clinical manifestations presents as follow: aversion to cold with or without fever, dry cough, dry throat, fatigue and hypodynamia, oppression in chest, epigastric fullness, or nausea, loose stool. The tongue is pale or reddish, the tongue fur is slimy white, and soggy pulse. Hence, the therapeutic logic is to dissipate cold and resolve obstruction. And the recommended prescriptions comprises of atractylodes lancea 15 g, dried tangerine or orange peel 10 g, mangnolia officinalis 10 g, agastache rugosus 10 g (end addition), amomum tsao-ko 6 g, ephedra herb 6 g, notopterygium root 10 g, ginger 10 g, areca-nut 10 g (end addition), periostracum cicada 10 g, bombyx batryticatus 10 g, and rhizoma curcumae longae 10 g above yielded decoction. (3) Middle-stage, characterized as epidemic toxin blocking the lung. In this stage, its clinical manifestations includes persistent fever or alternating cold and heat, cough with less phlegm, or yellow phlegm, abdominal distension and constipation; oppression in chest with anhelation, cough with wheezes, panting on exertion; or red tongue, slimy yellow fur or yellow dry fur, slippery and rapid pulse. Therefore, the therapeutic logic is clearing heat and detoxicating. And the recommended prescription comprises of almond 10 g, gypsum 30 g (predecoction), trichosanthes kirilowii 30 g, rhubarb 6 g (end addition), ephedra with honey fried 6 g, semen lepidii 10 g, peach kernel 10 g, amomum tsao-ko 6 g, arecanut 10 g, and atractylodes lancea 10 g above yielded decoction. In addition, the recommended Chinese patent medicine is Xiyanping injection or Xuebijing injection. (4) Severe stage, characterized as heat toxin generating stasis. In this stage, the clinical manifestations is known as high fever, oppression in chest with anhelation, purple-black facial complexion, lips dark and swollen, obnubilation, crimson tongue, yellow dry fur, surging and fine rapid stringlike pulse. Thus, its therapeutic logic is detoxicating and dispersing blood stasis. The recommended prescription is three Yellows and Gypsum decoction, Shang Jiang Powder, and Toxin-Resolving Blood-quickening decoction. Its composition comprises of ephedra with honey fried 10 g, almond 10 g, gypsum 20-30 g, periostracum cicada 10 g, bombyx batryticatus 10 g, rhizoma curcumae longae 10 g, rhubarb stir-fried with wine 10 g, scutellaria baicalensis 10 g, coptis chinensis 5 g, phillyrin 15 g, angelica sinensis 10 g, peach kernel 10 g, radix paeoniae rubra 15 g, and rhizome of rehmannia 15 g above yielded decoction. The recommended Chinese patent medicines is the Xiyanping injection, Xuebijing injection, Qingkailing injection, or Angong Niuhuang pills. (5) Severe-stage, characterized as inner blocking causing collapse. In this stage, the clinical manifestations include dyspnea, panting on exertion or need assisted ventilation, accompanied by coma, and agitation, cold limbs with cold sweating, dark purple tongue, thick or dry thick tongue fur, floating and rootless pulse. The thrapeutic logic is rescuing from collapse by restoring Yang. Hence, the recommended prescription comprises of ginseng 15 g, aconitine 10 g (predecoction), and Cornus officinalis 15 g above yielded decoction, and both taken with fluid Suhexiang pills or Angong Niuhuang pills. The recommended Chinese patent medicines is Xuebijing injection, Shenfu injection, or Shengmai injection. (6) Recovery-stage, presents as lung and spleen Qi deficiency. Its clinical manifestations include shortness of breath, fatigue and hypodynamia, anorexia, nausea and vomiting, glomus and fullness, weak stools, ungratifying loose stool, pale tender-soft enlarged tongue, slimy white tongue fur. Therefore, therapeutic logic is to supplement the spleen and lung. The recommended prescription comprises of rhizoma pinellinae praeparata 9 g, dried tangerine or orange peel 10 g, Codonopsis pilosula 15 g, radix astragali preparata 30 g, poria cocos 15 g, agastache rugosus 10 g, and fructus amomi 6 g (end addition) above yielded decoction. In addition, the recommended Chinese patent medicines is pill of costus and amomum with six noble ingredients. (7) Recovery-stage, characterized as deficiency of Qi and Yin. The clinical manifestations of this stage is generalized heat with sweating, chest heat vexation, Qi counterflow with retching and vomiting, shortness of breath and lassitude of essence-spirit, red tongue and thin tongue fur, vacuous pulse. Hence, the therapeutic logics is boost Qi and nourish Yin. The recommended prescription is Zhuye Shigao decoction with cogongrass rhizome and rhizoma phragmitis; and the composition of this prescription includes bamboo leaf 15 g, gypsum 15 g (predecoction), Codonopsis pilosula 15 g, radix ophiopogonis 10 g, pinellia ternate 9 g, cogongrass rhizome 15-30 g, rhizoma phragmitis 20 g, licorice 10 g, and polished round-grained rice 30 g above yielded decoction. The recommended Chinese patent medicine: Shengmaiyin. 6.5 Treatment of severe patients 6.5.1 Hypoxemic respiratory failure and ARDS treatments Treatment principle: treat the patients to improve the symptoms and underlying diseases, actively prevent potential complications and secondary infection; provide timely measures to support organ function. (1) Hypoxic respiratory failure and severe ARDS. Give oxygen therapy immediately to patients with ARDS, and closely monitor them for signs of clinical deterioration, such as rapidly progressive respiratory failure. Consider severe hypoxemic respiratory failure when standard oxygen therapy fails. Conservative fluid management can be adopted for ARDS patients without tissue hypoperfusion. Use vasoactive drugs to improve microcirculation. Empirical antibiotics targeting the suspected potential infection should be used as soon as possible, blind or improper combination of broad-spectrum antibiotics should be avoided. Unless for special reasons, the routine use of corticosteroids should be avoided. Glucocorticoids can be used in a short time according to the degree of dyspnea and the progress of chest imaging if appropriate and the recommended dose is not more than the equivalent to 1-2 mg/kg methylprednisone per day. Provide intensive standard supportive care to the critically ill patients, including prevention of deep vein thrombosis and stress-induced gastrointestinal bleeding, blood glucose control and so on. Enteral nutrition can be provided. Supplemental nutrition with omega-3 fatty acids and antioxidants is not recommended. Inhaled or intravenous beta-adrenergic agonists are not recommended to promote alveolar fluid clearance and resolution of pulmonary edema. ## Treatment of septic shock (1) Recognize the septic shock. When infection is suspected or confirmed, and on the basis of full fluid resuscitation, vasoconstrictor drugs are still needed to maintain mean arterial pressure (MAP) ≥65 mmHg with lactate ≥2 mmol/L, the existence of septic shock should be considered. If lactate cannot be monitored for some reasons, the following three manifestations (changes in mental state, oliguria, poor peripheral perfusion and prolonged capillary filling time) should be considered as signs of a combination of infection and hypoperfusion. (2) In resuscitation from septic shock in adults, at least 30 ml/kg of isotonic crystalloid was considered for adults in the first 3 h. In resuscitation from septic shock in children, give 20 ml/kg as a rapid bolus and up to 40-60 ml/kg in first aid. (3) Isosmotic crystal solution is recommended for resuscitation. Do not use hypotonic crystalloids, starches, or gelatins for resuscitation in the first hour. Albumin may be considered as a resuscitation fluid, but this recommendation was based on low-quality evidence under certain conditions. (4) Administer vasoconstrictor is suggested when shock persists after fluid resuscitation, noradrenaline as the first choice. The initial blood pressure target is MAP ≥65 mmHg in adults and age-appropriate targets in children. can also be administered via intraosseous needles. 6.6 Condition evaluation and treatment effect evaluation 6.6.1 Criteria to withdraw ECLS (1) Remove VV-ECMO. The oxygen concentration of the ECMO air-oxygen mixer has dropped to 21%, the air flow rate has dropped to 0, and the ventilator is not strong enough. Lasting for 2-3 h, the respiratory rate is within 25 breaths/min, SpO 2 > 92%, PaCO 2 is normal, and withdrawal from VV-ECMO may be considered. (2) Remove VA-ECMO. The blood flow rate is reduced to the rate of (0.2 to 0.5 L / min) every 5 to 6 h from 3 L/min, and the hemodynamic condition is stable. The blood flow rate is reduced to 1.5 L/min within 24 h. If there is a bridging tube, the arteriovenous end can be connected with a bridging tube to form an ECMO circuit for self-circulation, so that the body's hemodynamics is driven by the heart. If hemodynamics is stable for at least 6 h, consider removing the machine. ## Criteria for removing invasive breathing When the patient is well aware, cough reflexes are obvious when sucking the sputum, the hemodynamics is stable, and the ventilator parameters are close to offline parameters, the spontaneous breathing test (SBT) is performed. After the SBT is passed, invasive breathing can be considered to remove the endotracheal tube. ## Standards of transfer out of icu Patients do not need advanced respiratory support (HFNO, NIV, MV, ECLS, etc.); stable hemodynamics and tissue perfusion; no significant impairment of organ function; and no need for organ support treatment (CRRT, artificial liver, etc.). Consider transferring the patient out of ICU procedure. ## Discharge standards The body temperature returned to normal for more than 3 days; respiratory symptoms improved significantly; inflammation of the lungs showed obvious signs of absorption; and respiratory nucleic acid was negative for two consecutive times (one-day sampling time interval at least); and the patient can be released from isolation. 7 Prevent and control nosocomial infection 7.1 Restriction and isolation guidelines for patient/ suspected patients See. (Strong recommendation). ## Personal protection guidelines According to the principles of standard prevention and tertiary protection, all personnel entering various zones should be evaluated using individual inventory tables according to the exposure risk level. Chose personal protective equipment of various levels is necessary. Personal protective equipment should be worn strictly in accordance with the instructions and only used for one time ( The patient's home isolation scheme is shown in. Patients should monitor their body temperature and illness at home. If your body temperature continues to be higher than 38 ℃, or your breath is getting worse, you should seek medical treatment timely. In addition to taking protective measures, the home caregivers also should monitor their body temperature closely. ## Nursing the patients 8.2.1 nursing of oxygen therapy Mild patients generally use a nasal catheter and a mask for oxygen. Adjust the oxygen flow as appropriate according to the patient's condition and doctor's instruction, and Requirements to the medical staff request 6. Medical personnel enter the isolation area with proper self-protection through designated channels. 6.1 Medical staff should perform the personal protection practice under the Personal Protection Guidelines inclosely monitor the patient's breathing and blood oxygen saturation. If oxygen therapy fails to reach the expected effect, the nurse should analyze the cause comprehensively and be vigilant to notify the doctor. ## Nursing of medication Mild patients generally use antiviral drugs, antibacterial drugs (when bacterial infection exists), and symptomatic treatment. The doctor's advice should be followed accurately and timely. The adverse reactions of oseltamivir mainly include nausea, vomiting, diarrhea, abdominal pain and bronchitis, cough, etc. The adverse reactions of interferon are mainly flu-like symptoms such as fever, fatigue, myalgia, and headache, followed by mild suppression of bone marrow. Attention should be paid to identify the change of clinical manifestations or adverse drug reactions. ## Nutritional support According to the patients' condition, provide highprotein, high-vitamin, carbohydrate-containing diets (e.g. eggs, fish, lean meat, milk, etc.) for enough nutrition to improve physical condition. ## Psychological nursing Take good care of the patient and respond to the patient's question timely. Positively encourage patients to reduce their anxiety and fear. ## Nursing of critically illed patients 8.3.1 condition monitoring Dynamically monitor patients' vital signs, waterelectrolytes balance, acid-base balance, and functions of various organs, monitor patients' infection indicators, and determine the occurrence of complications such as acute respiratory distress syndrome, septic shock, stress ulcers, and deep vein thrombosis. ## Sequential oxygen care The critically illed patients mainly use oxygen therapy such as HFNO, NIV and invasive mechanical ventilation. When using various oxygen treatments in a sequential manner, the airway and breathing circuit need to be kept open, and the effect of oxygen treatment needs to be monitored dynamically. At the same time, skincare products need to be used reasonably to avoid damage to the nose, face and lips by pressure. When using a high-flow nasal catheter to inhale oxygen, the oxygen flow and temperature and humidity should be adjusted appropriately. When using non-invasive mechanical ventilation, patient should receive relevant health education. Patients are instructed to inhale through the nose. The pressure is set from low to high and gradually reaches the target value. The human-machine coordination is maximized. The patient's consciousness and respiratory function are closely observed. Patients with artificial airway established should use a closed suction tube to reduce virus spread. Nurses should wear goggles or a face shield to avoid occupational exposure. ## Special treatment nursing If the patient develops moderate to severe ARDS, invasive mechanical ventilation combined with a prone position need to be adopted. Standard operating procedure for prone position needs to be followed. At the same time, be cautious to prevent pressure ulcers, falling bed, tube slippage, and eye damage by pressure and other complications. Patients treated with ECMO should be monitored for the performance of the oxygenator. If the oxygenator changes its color to darker, indicating the possibility of coagulation, the doctor should be notified to adjust the heparin dose as necessary. The oxygenator should be replaced if necessary. The coagulation function need to be monitored dynamically, including the whole set of coagulation and DIC (disseminated intravascular coagulation), and the time of activating partial thromboplastin, etc., the patient should be closely observed for signs of bleeding, such as bruising on the skin and mucous membranes, bleeding in the nasal cavity, oral cavity, bloody sputum, hematuria, blood in the stool, swelling of the abdomen, moving dullness, and the size of bilateral pupils. Make sure that the ECMO pipelines are tightly connected and firmly fixed to prevent air embolism and pipeline slippage. ## Infection prevention Perform oral care and skin care, assist the patient to use toilet, and take eyes on the indwelling tubes. Rules and regulations for aseptic operation and isolation should be strictly followed to prevent ventilator-related pneumonia, catheter-related sepsis, urinary catheter related urinary tract infections and other secondary infections. ## Nutrition support Dynamically assess the patients' nutritional risks and timely nutritional support can be given if needed. For the patients who can eat, the diet rich in protein and carbohydrates is recommended. Those patients who cannot eat but are compatible with enteral nutrition should be given enteral nutrition as soon as possible. For the patients incompatible with enteral nutrition, parenteral nutrition should be given timely to meet energy requirement. ## Psychological nursing Psychological and humanistic care should be performed in high priority especially for the awake patients. Psychological techniques like mindfulness -based stress reduction can be adopted to relieve the patients' anxiety and panic by building up their optimistic confidence in overcoming the disease. ## Limitations of this guideline Our guideline has three major limitations: Firstly, time is so limited that we cannot fully consider all clinical issues for this emergency disease. Secondly, many evidences came from data search is indirect. Thirdly, because some recommendations are based on the evidence from existing guidelines and experts' experience, there are situations where strong recommendations were produced on the base of low-quality evidence or very low-quality evidence, so high-quality evidence, when they appear, is likely to change current recommendations. ## Supplementary information Supplementary information accompanies this paper at https://doi.org/10. 1186/s40779-020-0233-6. Additional file 1. A successful treatment case of the severe 2019-nCoV infected pneumonia patient. Additional file 2. Experience and lessons in hospital rescue for 2019-nCoV infections. TB: tuberculosis; TNF: Tumor Necrosis Factor; WBC: White blood cells; WHO: World Health Organization	None	https://mmrjournal.biomedcentral.com/counter/pdf/10.1186/s40779-020-0233-6	None
a6f798fabaf412c198f1fae7db6bddd22343c54d	pubmed	Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative	Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative We present clinical practice recommendations for the treatment of children with Alport syndrome who are not enrolled in clinical trials. Our goal is to promote early initiation of a standard therapeutic approach that will facilitate assessment of the safety and efficacy of the protocol. The treatment protocol is based on the reduction of proteinuria, intraglomerular pressure, and renal fibrosis via interference with the renin-angiotensin-aldosterone system. # Introduction Investigation of Alport syndrome (AS) has elucidated the roles of type IV collagen in basement membranes and described the consequences of type IV collagen mutations for renal, cochlear, and ocular structure and function. Research studies employing animal models of AS have suggested interventions that may delay or reverse the renal effects of type IV collagen mutations, but these approaches have yet to be prospectively examined in human subjects with the disease. While we wait for clinical trials to be organized, funded, and carried to completion, children and adults with AS continue to progress towards end-stage renal disease (ESRD). What can nephrologists offer in the meantime, and what can we learn from clinical practice about the efficacy and safety of common treatment approaches? The Alport Syndrome Research Collaborative, currently comprising investigators in Canada, China, France, Germany, and the United States, has developed clinical practice recommendations aimed at standardizing therapy for people with AS who are not enrolled in clinical trials. It is our hope that adoption of a consistent approach to therapy will allow pooling and analysis of data about treatment responses and efficacy. ## Disclaimer These are general clinical practice recommendations for offlabel therapy with inhibitors of the renin-angiotensin-aldosterone system (RAAS) and may not be appropriate for all children with AS. It is expected that practitioners will carefully consider a child's baseline renal function in applying these guidelines, will appropriately monitor for adverse effects of therapy, and will adjust or discontinue therapy as needed. Natural history of untreated Alport syndrome ## Genetics and genotype-phenotype correlations Alport syndrome can be transmitted as an X-linked, autosomal recessive or autosomal dominant disorder. About 80% of individuals with AS have X-linked disease (XLAS) due to mutations in the COL4A5 gene. Males with XLAS progress inexorably to ESRD, with ESRD risks of 50% by age 25, 90% by age 40, and nearly 100% by age 60 [bib_ref] X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in..., Jais [/bib_ref]. Age at ESRD is strongly correlated with COL4A5 genotype in males with XLAS [bib_ref] X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in..., Jais [/bib_ref] [bib_ref] Genotype-phenotype correlation in X-linked Alport syndrome, Bekheirnia [/bib_ref] ; risk of ESRD by age 30 is 90% for deletions and nonsense mutations of COL4A5, 70% for splicing mutations, and 50% for missense mutations. The known strong genotype-phenotype correlation provides a rationale for using COL4A5 genotype data to guide the timing and intensity of intervention. In most families with XLAS, age at ESRD is fairly similar among affected males. In the absence of COL4A5 genotype data, timing of ESRD can be predicted for a young affected male on the basis of ESRD timing in older affected male relatives. The effects of COL4A5 genotype on age at ESRD are not observed in females with XLAS, likely due to the overwhelming influence of X-inactivation [bib_ref] Xinactivation modifies disease severity in female carriers of murine X-linked Alport syndrome, Rheault [/bib_ref]. In XLAS females, the timing and intensity of intervention should be guided by risk factors for progression to ESRD: proteinuria, gross hematuria, and hearing loss [bib_ref] Renal prognosis in women with hereditary nephritis, Grunfeld [/bib_ref] [bib_ref] X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women..., Jais [/bib_ref]. Autosomal recessive AS (ARAS) accounts for about 15% of individuals with the disease and arises from mutations in both alleles of either COL4A3 or COL4A4. Genotypephenotype data for ARAS is relatively sparse. In general, individuals with ARAS carry a high risk of ESRD by age 30. Only about 5% of individuals with AS have autosomal dominant disease (ADAS). As ADAS tends to progress at a relatively slow velocity [bib_ref] Renal prognosis in Alport's and related syndromes: influence of the mode of..., Pochet [/bib_ref] , there is less urgency to consider initiation of intervention in childhood. ## Clinicopathological correlations In general, AS is characterized by genetically determined dysfunction of the glomerular filter, mainly caused by mutations in the collagens assembling the glomerular basement membrane (GBM). In consequence, the earliest sign of GBM filter dysfunction is hematuria followed by albuminuria and subsequent nonselective proteinuria in increasing magnitude. Ultimately, not the GBM damage per se but the pro-inflammatory and pro-fibrotic consequences both in the tubulointerstitium and in the glomeruli resulting from progressive proteinuria, eventually lead to the development of ESRD [bib_ref] Treatment of Alport syndrome: beyond animal models, Gross [/bib_ref]. Overt proteinuria is typically absent in infant males with XLAS. Age at identification of overt proteinuria shows interfamilial variability and ranges from early childhood to adolescence. In dogs with XLAS, a period of microalbuminuria precedes the development of overt proteinuria and quantitative increases in interstitial volume due to tubular atrophy and fibrosis [bib_ref] The effect of progressive glomerular disease on megalinmediated endocytosis in the kidney, Vinge [/bib_ref]. Dogs with XLAS exhibit increased proximal tubular epithelial cell uptake of albumin, a process that has been linked to cellular injury [bib_ref] The effect of progressive glomerular disease on megalinmediated endocytosis in the kidney, Vinge [/bib_ref]. Preliminary data from the Alport Syndrome Treatments and Outcomes Registry (ASTOR) indicates that boys with AS also exhibit a transitional stage of microalbuminuria before overt proteinuria becomes established (manuscript in preparation). It has yet to be demonstrated that suppression of microalbuminuria has antifibrotic effects in AS, although this is a reasonable hypothesis. Measurements of cortical interstitial volumes in AS males have shown that interstitial fibrosis is unusual before age 10 [bib_ref] Chronology of renal scarring in males with Alport syndrome, Kashtan [/bib_ref]. Cortical interstitial volumes become abnormal in many AS males during the second decade of life, and are inversely correlated with glomerular filtration rates [bib_ref] Chronology of renal scarring in males with Alport syndrome, Kashtan [/bib_ref]. These observations suggest that, (1) as in other chronic glomerulopathies, interstitial fibrosis is a significant contributor to loss of renal function, and (2) prevention of interstitial fibrosis in AS males may require intervention during childhood. Therapeutic studies Several therapies improve outcomes in animal models of AS, including angiotensin-converting enzyme (ACE) inhibition [bib_ref] Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout..., Gross [/bib_ref] [bib_ref] Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine..., Gross [/bib_ref] , AT1-receptor blockade (ARB) [bib_ref] Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout..., Gross [/bib_ref] [bib_ref] Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine..., Gross [/bib_ref] , inhibitors of TGF-β1, matrix metalloproteinases, vasopeptidase A or HMG-CoA reductase [bib_ref] Role for transforming growth factor-beta 1 in Alport renal disease progression, Sayers [/bib_ref] [bib_ref] Nephroprotection by antifibrotic and antiinflammatory effects of the vasopeptidase inhibitor AVE7688, Gross [/bib_ref] [bib_ref] Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease, Zeisberg [/bib_ref] [bib_ref] Nephroprotective effect of the HMG-CoA-reductase inhibitor cerivastatin in a mouse model of..., Koepke [/bib_ref] ; chemokine receptor 1 blockade [bib_ref] Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with..., Ninichuk [/bib_ref] , BMP-7 [bib_ref] Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two..., Zeisberg [/bib_ref] , stem cells [bib_ref] Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression..., Ninichuk [/bib_ref] [bib_ref] Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney..., Sugimoto [/bib_ref] [bib_ref] Stem cell therapy for Alport syndrome: the hope beyond the hype, Gross [/bib_ref] [bib_ref] Stem cell therapies benefit Alport syndrome, Lebleu [/bib_ref] , and irradiation [bib_ref] Irradiation prolongs survival of Alport mice, Katayama [/bib_ref]. However, none of these approaches has been prospectively studied in human AS populations. In ARAS mice, initiation of ACE inhibitor therapy before onset of proteinuria suppressed proteinuria and azotemia and doubled length of survival [bib_ref] Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout..., Gross [/bib_ref] , a therapeutic benefit that has yet to be exceeded by any other intervention. A smaller but still significant improvement in outcome was achieved when ACE inhibition was started after onset of proteinuria [bib_ref] Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout..., Gross [/bib_ref]. ACE inhibitor therapy begun before onset of proteinuria lengthened survival in canine XLAS [bib_ref] Treatment of X-linked hereditary nephritis in Samoyed dogs with angiotensin-converting enzyme inhibitor, Grodecki [/bib_ref]. Retrospective analysis of registry data strongly suggests that ACE inhibition delays ESRD and improves life expectancy in AS patients in a time-dependent manner [bib_ref] Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves..., Gross [/bib_ref]. This observation highlights the importance of early and accurate diagnosis of AS, including specific genotyping whenever feasible (for information on diagnostic methods in AS, please see www.genereviews.org). Besides the beneficial effects of RAAS blockade on outcomes in experimental and human AS, there are additional compelling reasons to recommend RAAS blockade in AS patients until a superior therapy is identified. First, ACE inhibitor therapy at doses that achieve suppression of proteinuria has been used with a high degree of safety in children with chronic kidney disease [bib_ref] Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure, Wuhl [/bib_ref] [bib_ref] Strict blood-pressure control and progression of renal failure in children, Wuhl [/bib_ref]. Further, these agents are widely available and relatively inexpensive, making this therapy accessible to AS patients worldwide. ## Clinical trials We recognize that a randomized clinical trial would be the best way to evaluate the efficacy of ACE inhibition or any other intervention in children with AS. We also recognize that widespread adoption of our recommendations may reduce the pool of children who are eligible for clinical trials of potential therapies for AS. Nevertheless, we encourage eligible subjects and their families to consider participation in clinical trials wherever and whenever possible. For example, by the time this document is published, a clinical trial of ACE inhibition in AS will be recruiting subjects residing in Germany, or willing and able to travel to Germany (contact: studie@alport.de; for information and to download flyer see www.alport.de/EARLY_PRO-TECT). The goal of this trial is to clarify if an early start of therapy (in patients with isolated hematuria or microalbuminuria) delays renal failure even more effectively than later onset of therapy (in proteinuric patients) and above all if therapy at early stages of AS is safe. For those subjects unable to take part in clinical trials, we believe that valuable efficacy and safety data can be collected if these subjects are treated according to a standardized protocol. Currently, many children with AS are receiving ACE inhibitor therapy in a non-standardized fashion, and information about treatment responses is not being centrally collected or analyzed. We believe that this represents a wasted opportunity. ## Treatment recommendations Retrospective registry data strongly suggests that in subjects with AS ACE inhibitor therapy initiated once proteinuria has developed but while glomerular filtration rate is well preserved delays ESRD [bib_ref] Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves..., Gross [/bib_ref]. Similarly, in mice and dogs with AS, interventions that delay the onset of proteinuria or reduce established proteinuria prolong renal survival [bib_ref] Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout..., Gross [/bib_ref] [bib_ref] Treatment of X-linked hereditary nephritis in Samoyed dogs with angiotensin-converting enzyme inhibitor, Grodecki [/bib_ref]. Based on these observations, and on the general consensus that suppression of intraglomerular pressure and proteinuria is an important component of the management of chronic glomerular diseases, treatment of proteinuric AS patients with medications that diminish proteinuria is recommended. Proteinuria in children is defined as urine protein-creatinine ratio persistently greater than 0.2 mg/mg in children over 2 years of age, or urinary protein excretion greater than 4 mg/m 2 /h in a timed collection [bib_ref] Simplified quantification of urinary protein excretion in children, Elises [/bib_ref] [bib_ref] Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from..., Hogg [/bib_ref]. Cortical interstitial volume fraction (VvI/C) is a measure of interstitial fibrosis and tubular atrophy [bib_ref] Renal interstitial expansion in insulin-dependent diabetes mellitus, Lane [/bib_ref]. There is a strong inverse correlation between VvI/C and creatinine clearance in boys with AS [bib_ref] Chronology of renal scarring in males with Alport syndrome, Kashtan [/bib_ref]. In these boys, VvI/C is typically within the normal range during the first decade of life, when creatinine clearance is also normal, but often begins to increase during adolescence concurrent with declining creatinine clearance. We presume that COL4A5 mutations associated with relatively rapid progression to ESRD, such as deletions, nonsense, and splicing mutations, result in earlier onset and more aggressive development of interstitial fibrosis and tubular atrophy. In dogs and mice with AS, the onset of proteinuria precedes measurable increases in interstitial fibrosis. In light of these observations, we recommend that in boys with AS who have deletion, nonsense or splicing mutations, or who have a family history of ESRD before age 30, monitoring of urine protein excretion should begin early in life and that an aggressive approach to initiating and escalating proteinuriasuppressing therapies should be followed. Based on these principles, we make the following recommendations aimed at preventing renal tubular epithelial cell injury and suppressing fibrogenic processes in the renal interstitium (see : ## 1. Monitoring for microalbuminuria and proteinuria should be initiated by age 1 year in at risk children, or as soon as a diagnosis of Alport syndrome is established, and repeated at least annually. 2. Affected individuals with overt proteinuria (urine proteincreatinine ratio persistently greater than 0.2 mg/mg, or urinary protein excretion greater than 4 mg/m 2 /h in a timed collection) should receive treatment. 3. Treatment should be considered in affected boys with microalbuminuria in whom the risk of ESRD by age 30 is high, such as those with COL4A5 deletions, nonsense or splicing mutations, or a history of ESRD before age 30 in affected male relatives . We recognize that access to molecular genetic testing for Alport syndrome, and coverage by insurers, is variable. We recommend that the Alport genotype be determined whenever feasible, to facilitate identification of those at high risk of ESRD by age 30. ## Target The optimal target for lowering of urine protein levels is uncertain. Our recommendations are based upon an arbitrary goal of a urine protein:creatinine ratio of less than 0.5 mg/mg if the baseline value is greater than 1.0 mg/mg, or a 50% reduction if the baseline value is greater than 0.2 but less than 1.0. When therapy is initiated in subjects with microalbuminuria, we recommend a target microalbumin:creatinine ratio of less than 50-100 mg/g creatinine. Proteinuria may persist at levels that exceed these targets, despite maximum dosing of first-and second-line agents. In these cases, we recommend continuing therapy, with adjustment of dosing as indicated by growth and by renal function. ## Agents First line We chose angiotensin-converting enzyme (ACE) inhibition as first-line therapy for several reasons. First, ACE inhibition is the choice of most nephrologists for initial nonimmunologic therapy of proteinuric glomerular disease. Consequently, practitioners have extensive experience with dosing these agents and are familiar with their adverse effects. ACE inhibitors are widely available and relatively inexpensive. The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial demonstrated that ACE inhibition with ramipril is associated with very low frequencies of adverse events in children with chronic kidney disease and at least transient reductions in proteinuria [bib_ref] Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure, Wuhl [/bib_ref] [bib_ref] Strict blood-pressure control and progression of renal failure in children, Wuhl [/bib_ref]. Because of the ESCAPE experience, we chose ramipril as the reference ACE inhibitor, and suggest equivalent doses of other ACE inhibitors in [fig_ref] Table 2: First-line therapy [/fig_ref]. Finally, ramipril therapy started before or after onset of proteinuria significantly prolonged survival in mice with autosomal recessive Alport syndrome, and its effects were superior to those of candesartan [bib_ref] Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout..., Gross [/bib_ref] [bib_ref] Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine..., Gross [/bib_ref]. In the ESCAPE trial, reduction in proteinuria and preservation of glomerular filtration rate were correlated with ramipril's antihypertensive effect [bib_ref] Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure, Wuhl [/bib_ref] [bib_ref] Strict blood-pressure control and progression of renal failure in children, Wuhl [/bib_ref]. Many of the Alport subjects in whom therapy is initiated when they have developed microalbuminuria or mild proteinuria will be normotensive. If the renoprotective properties of ACE inhibitors are primarily due to their antihypertensive effects, the impact on Alport subjects may be insignificant. However, ramipril delays proteinuria and prolongs survival in normotensive autosomal recessive Alport syndrome mice, indicating that other effects of ACE inhibition are important in this model [bib_ref] Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout..., Gross [/bib_ref] [bib_ref] Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine..., Gross [/bib_ref]. Second line We propose two alternatives for second-line therapy, angiotensin receptor blockade (ARB) and aldosterone inhibition. For those nephrologists with experience combining an ACE inhibitor with an ARB, ARB may be the more comfortable, familiar approach. We suggest losartan as the reference ARB, based on published experience in children with chronic kidney disease [bib_ref] Antihypertensive and renoprotective efficacy and safety of losartan, Ellis [/bib_ref]. In a recent study of 30 proteinuric children with AS, losartan was found to reduce proteinuria to a greater extent than placebo or amlodipine [bib_ref] Efficacy and safety of losartan in children with Alport syndrome -results from..., Webb [/bib_ref]. We recommend a relatively low starting dose, given that the ARB will be added to ACE inhibition [fig_ref] Table 3: Second-line therapy [/fig_ref]. If an ARB is used instead of an ACE inhibitor, for example because a patient tolerates ACE inhibition poorly, a higher starting dose for the ARB would be appropriate. There are a limited number of published reports regarding the use of combination therapy with an ACE inhibitor and an ARB in children with chronic proteinuric renal diseases. Ten children with chronic kidney disease and persistent proteinuria, despite maximal doses of an ACE inhibitor, exhibited a sustained reduction in proteinuria after addition of losartan, with no significant changes in blood pressure or glomerular filtration rate [bib_ref] Angiotensin receptor blocker reduces proteinuria independently of blood pressure in children already..., Seeman [/bib_ref]. In another small study of ten children with chronic kidney disease and proteinuria that employed a cross-over design, combination therapy with an ACE inhibitor and an ARB reduced proteinuria to a significantly greater extent than either agent alone [bib_ref] Renal and cardiovascular effects of angiotensinconverting enzyme inhibitor plus angiotensin II receptor..., Lubrano [/bib_ref]. In a small group of patients with AS, combined therapy with an ACE inhibitor and spironolactone suppressed proteinuria to a greater extent than the combination of an ACE inhibitor with an ARB [bib_ref] The effect of aldosterone blockade in patients with Alport syndrome, Kaito [/bib_ref]. Hyperkalemia was not encountered in this small group of patients. Increased aldosterone levels (aldosterone escape) may contribute to persistent proteinuria in Alport patients receiving ACE inhibitor therapy [bib_ref] Role of aldosterone in the progression of chronic kidney disease and potential..., Ku [/bib_ref]. Aldosterone inhibition could be used as the initial second-line agent, or as an alternative to ineffective ARB therapy [fig_ref] Table 4: Second-line therapy [/fig_ref]. ## Potential adverse effects of therapy Potential adverse effects of the therapeutic approach described above include orthostatic hypotension, fetopathy in ovulating females, hyperkalemia, reversible decline in glomerular filtration rate, and gynecomastia. In the ESCAPE trial, only three of 352 children who received ramipril for at least 6 months required discontinuation of therapy because of orthostatic hypotension or hyperkalemia [bib_ref] Treatment of X-linked hereditary nephritis in Samoyed dogs with angiotensin-converting enzyme inhibitor, Grodecki [/bib_ref]. ACE inhibitors and ARBs should be used with caution in ovulating females in order to avoid fetal injury. In the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study, the combination of ramipril and telmisartan resulted in increased risk of adverse renal outcomes (doubling of serum creatinine and requirement for dialysis), hypotensive symptoms, syncope, and hyperkalemia, compared to ramipril monotherapy [bib_ref] Telmisartan, ramipril, or both in patients at high risk for vascular events, The [/bib_ref]. Subjects who received combination therapy also had an increased risk of mortality, although not statistically significant [bib_ref] Telmisartan, ramipril, or both in patients at high risk for vascular events, The [/bib_ref]. The relevance of the results of the ONTARGET study, in which study subjects had a mean age of 66 years and were at high risk for cardiovascular events due to vascular disease or diabetes, to children and young adults with Alport syndrome is unclear. Chronic administration of spironolactone is associated with an increased incidence of serum potassium greater than 5.5 mEq/l (about 3% of subjects participating in clinical trials), gynecomastia (about 5% of patients), and acute renal insufficiency (1-5% of subjects) [bib_ref] Spironolactone management of resistant hypertension, Marrs [/bib_ref]. We recommend regular monitoring of serum potassium and creatinine levels in treated Alport patients, especially those receiving combination therapy. ## Reporting of treatment experience We are in the process of developing an online reporting tool that will allow practitioners to upload de-identified information regarding treatment responses to a secure site. Once the tool is in place, we will assist interested practitioners in obtaining local IRB approval for participation. We will use listservs and blast e-mails from the Alport Syndrome Treatments and Outcomes Registry to announce the availability of the site. In the meantime, we encourage practitioners to share treatment experiences via e-mail with Dr. Kashtan. [table] Table 2: First-line therapy (angiotensin-converting enzyme inhibitor) [/table] [table] Table 3: Second-line therapy (angiotensin receptor blocker) [/table] [table] Table 4: Second-line therapy (aldosterone antagonist) [/table]	None	https://link.springer.com/content/pdf/10.1007/s00467-012-2138-4.pdf	None
b4479e48441add766b0242218cdb3df752d9bb6e	pubmed	Guidelines for the Use of Radioiodine in the Management of Hyperthyroidism: A Summary	Guidelines for the Use of Radioiodine in the Management of Hyperthyroidism: A Summary Radioiodine (131I) therapy is indicated in patients with nearly all causes of hyperthyroidism. It may safely be given to patients of all age groups but is less often given to children under 10 years old. It is completely contraindicated in pregnancy and while breast feeding, but there is no increased risk of thyroid cancer, leukaemia or solid tumours. Administration of radioiodine must conform to regulations and definitions laid down by ARSAC and POPUMET. Medical staff authorising therapy must hold an ARSAC licence. The recommended strategy is to give an activity sufficient to render the patient rapidly euthyroid and maintain that state or achieve no more than a low rate of hypothyroidism in subsequent years. A range of activity (300-800 MBq) is suggested depending on the clinical state. Antithyroid drugs may be given before or after (or both) radioiodine if necessary. Full written information should be given to the patient and written consent obtained. A structured follow-up should be used ensuring regular measurement of TSH or FT4. Close cooperation with the patient's general practitioner is recommended throughout the assessment, treatment and follow-up. Shared care with a computer based follow-up system is recommended.Radioiodine (iodine-131) has been used in therapy for hyperthyroidism for more than 50 years. It is indicated in cases of hyperthyroidism due to Graves' disease or toxic nodular goitre (solitary toxic adenomas or multinodular goitre) and is effective in curing hyperthyroidism in virtually all cases given single or multiple doses. Radioiodine is almost always not an appropriate treatment for thyrotoxicosis secondary to thyroiditis or for thyrotoxicosis associated with iodine excess. The total number of treatments in the UK is approximately 10,000 per annum.Factors that influence the decision to proceed to radioiodine therapy include patient age, gender, diagnosis, severity of hyperthyroidism, the presence of other medical conditions, access to radioiodine, and patient and doctor preference.Pregnancy represents an absolute contraindication to radioiodine treatment. In female patients of reproductive age, their plans for pregnancy must be taken into consideration. Pregnancy should be avoided for 4 months after treatment owing to the risk of concentration of residual radioiodine in the fetus. If a patient is keen to achieve pregnancy, it may be necessary to postpone radioiodine treatment (and continue with medical treatment), even in relapsed disease, until breast feeding has ended. Recent surveys of thyroid specialists have revealed marked differences in preference for antithyroid drug (ATD) therapy or radioiodine therapy in different parts of the world. However, there has been no large scale randomised trial comparing the three modes of treatment (ATD, surgery and radioiodine therapy) over the long term. In Europe, including the United Kingdom, radioiodine therapy is less readily considered the treatment of choice in young patients with Graves' hyperthyroidism than it is in the United States, though this situation is changing.Radioiodine is most readily provided in clinics held jointly by endocrinologists and radiotherapists or specialists in nuclear medicine, or where the endocrinologist is licensed to administer radioiodine. Patients can be given clear advice regarding the time of therapy, omission of ATD, counselling regarding contraception, and follow-up arrangements.Although thyroid cancer has been described in occasional patients treated With radioiodine, no relationship between radioiodine and thyroid cancer has been found in several large studies. There is, similarly, no evidence for an increase in leukaemia or solid tumours, with the possible exception of gastric cancer in one report. It should be noted that these studies included relatively small numbers of patients (<11,000) followed up for less than 40 years, determining that it is important to continue long-term followup of populations treated with radioiodine to ensure the accumulation of further evidence in support of its safety. Less direct information than for cancer risk is available regarding risks of congenital abnormality. There is no evidence of increased abnormality in small studies of the offspring of women treated with radioiodine. The risk in women and men has been estimated at 0.005%; not surprisingly, such a risk has not been identified in clinical studies.As radioiodine therapy does not normally require This summary was prepared on behalf of the Radioiodine Audit Subcommittee and the Research Unit of the Royal College of Physicians by: patients with nearly all causes of hyperthyroidism. It may safely be given to patients of all age groups but is less often given to children under 10 years old. It is completely contraindicated in pregnancy and while breast feeding, but there is no increased risk of thyroid cancer, leukaemia or solid tumours. Administration of radioiodine must conform to regulations and definitions laid down by ARSAC and POPUMET. Medical staff authorising therapy must hold an ARSAC licence. The recommended strategy is to give an activity sufficient to render the patient rapidly euthyroid and maintain that state or achieve no more than a low rate of hypothyroidism in subsequent years. A range of activity (300-800 MBq) is suggested depending on the clinical state. Antithyroid drugs may be given before or after (or both) radioiodine if necessary. Full written information should be given to the patient and written consent obtained. A structured follow-up should be used ensuring regular measurement of TSH or FT4. Close cooperation with the patient's general practitioner is recommended throughout the assessment, treatment and follow-up. Shared care with a computer based follow-up system is recommended. Radioiodine (iodine-131) has been used in therapy for hyperthyroidism for more than 50 years. It is indicated in cases of hyperthyroidism due to Graves' disease or toxic nodular goitre (solitary toxic adenomas or multinodular goitre) and is effective in curing hyperthyroidism in virtually all cases given single or multiple doses. Radioiodine is almost always not an appropriate treatment for thyrotoxicosis secondary to thyroiditis or for thyrotoxicosis associated with iodine excess. The total number of treatments in the UK is approximately 10,000 per annum. Factors that influence the decision to proceed to radioiodine therapy include patient age, gender, diagnosis, severity of hyperthyroidism, the presence of other medical conditions, access to radioiodine, and patient and doctor preference. Pregnancy represents an absolute contraindication to radioiodine treatment. In female patients of reproductive age, their plans for pregnancy must be taken into consideration. Pregnancy should be avoided for 4 months after treatment owing to the risk of concentration of residual radioiodine in the fetus. If a patient is keen to achieve pregnancy, it may be necessary to postpone radioiodine treatment (and continue with medical treatment), even in relapsed disease, until breast feeding has ended. Recent surveys of thyroid specialists have revealed marked differences in preference for antithyroid drug (ATD) therapy or radioiodine therapy in different parts of the world. However, there has been no large scale randomised trial comparing the three modes of treatment (ATD, surgery and radioiodine therapy) over the long term. In Europe, including the United Kingdom, radioiodine therapy is less readily considered the treatment of choice in young patients with Graves' hyperthyroidism than it is in the United States, though this situation is changing. Radioiodine is most readily provided in clinics held jointly by endocrinologists and radiotherapists or specialists in nuclear medicine, or where the endocrinologist is licensed to administer radioiodine. Patients can be given clear advice regarding the time of therapy, omission of ATD, counselling regarding contraception, and follow-up arrangements. Although thyroid cancer has been described in occasional patients treated With radioiodine, no relationship between radioiodine and thyroid cancer has been found in several large studies. There is, similarly, no evidence for an increase in leukaemia or solid tumours, with the possible exception of gastric cancer in one report. It should be noted that these studies included relatively small numbers of patients (<11,000) followed up for less than 40 years, determining that it is important to continue long-term followup of populations treated with radioiodine to ensure the accumulation of further evidence in support of its safety. Less direct information than for cancer risk is available regarding risks of congenital abnormality. There is no evidence of increased abnormality in small studies of the offspring of women treated with radioiodine. The risk in women and men has been estimated at 0.005%; not surprisingly, such a risk has not been identified in clinical studies. As radioiodine therapy does not normally require This summary was prepared on behalf of the Radioiodine Audit Subcommittee and the Research Unit of the Royal College of Physicians by: JOHN H LAZARUS, md, frcp, Department of Medicine, University of Wales College of Medicine, Cardiff. the patient to be hospitalised, the cost is relatively low and comparable to that of ATD therapy; this is substantially less than the cost of surgical treatment which usually requires a stay of 3-5 days in hospital. Regulations for administration of radioiodine ? Those clinically managing thyrotoxic patients may request radioiodine therapy, but only medical staff who hold an appropriate Administration of Radioactive Substances Advisory Committee (ARSAC) certificate may authorise its administration. The Ionising Radiation Regulations (Protection of Persons Undergoing Medical Examination or Treatment) 1988 (POPUMET) indicate that the person clinically directing the exposure (ie the ARSAC certificate holder) is responsible for ensuring that everyone else complies with legislation, and that administration of radioactive substances is in accordance with accepted therapeutic practice. The person who administers the radioiodine to the patient is physically directing the treatment and must have been trained in the core of knowledge required by POPUMET. Both the ARSAC and the POPUMET regulations require a physicist to liaise with the certificate holder and ensure that radioactive substances are administered safely. This function is distinct from that of Radiation Protection Adviser although it may be carried out by the same person. ? Radioactive iodine may be dispensed only in premises that have Her Majesty's Inspectorate of Pollution (HMIP) registration and authorisation in relation to the keeping and use of radioactive materials, and disposal thereof, in accordance with the Radioactive Substances Act 1993. If inpatients from another hospital are treated, notification of the administered activity should be sent to the RPA of the referring hospital; this is to ensure that each hospital remains within exemption limits or within any authorisation granted by HMIP. ? Local rules must be written that explain how the department will implement the Ionising Radiation Regulations 1985 and its approved code of practice. ? Administration of radioiodine must take place within a 'controlled area', the requirements of which are set out in the Ionising Radiation Regula- An activity sufficient to render the patient rapidly euthyroid within 3-4 weeks and preferably to maintain that state or to limit the incidence of hypothyroidism in subsequent years to a low level. An activity large enough to render the patient rapidly hypothyroid within 3-4 weeks of therapy. In many centres there may be considerable variation in activity to achieve this outcome. Administration of very small activities of radioiodine together with an ATD. The second of these strategies may be regarded as less than optimal since all patients will be required to take thyroxine replacement therapy. Administration of small activities usually results in inadequate treatment of the hyperthyroid state; this is undesirable, especially in the elderly, because of the adverse effects of excess thyroid hormones on the cardiovascular system. There is no evidence that precision dosimetry leads to an improved clinical outcome. The recommendation is to administer enough radioiodine to achieve euthyroidism with the acceptance of a moderate rate of hypothyroidism, eg 15-20% at 2 years and 1-3% per annum thereafter. Although the ablative strategy may be more cost-effective than a 'middle of the road' approach, consideration should be given to the health gain value of remaining euthyroid. ## Recommended activity It is clear that there are wide variations in current practice. The following activities are recommended as broad guidelines. It is considered essential to establish the aetiology of the hyperthyroidism using standard diagnostic tests and criteria before radioiodine is administered. ? 'Standard' case of hyperthyroidism A further dose of radioiodine may be given 2 months or more after the first one. ## ? The maximum permitted activity for outpatient treatment is 800 MBq. Hospitalisation is necessary if a greater activity is used. ## Pregnancy and breast feeding No patient in whom there is any chance of pregnancy may receive radioiodine therapy; if necessary, a pregnancy test should be performed. Women are advised not to become pregnant for 4 months after receiving radioiodine. If pregnancy occurs sooner than 4 months after treatment a termination is not mandatory but advice should be sought. There is no evidence of any fetal or maternal risk in pregnancy or its outcome in women who receive radioiodine provided the above guidelines are followed. A person living in the same house as a pregnant woman may receive radioiodine therapy provided there is no close or prolonged contact with the woman [fig_ref] Table 1: Number of days for which patients should take special precautions, according to... [/fig_ref]. No patient may continue to breast feed once radioiodine has been administered to her. Antithyroid drug administration ATD should be discontinued at least 2 days prior to radioiodine administration since their effect lasts for 24 hours or more. Where antithyroid medication is to be continued, it may be recommenced 3 days after radioiodine treatment without significantly affecting the delivered radiation dose. Compounds that contain iodine, such as amiodarone, may block iodine uptake for several months following cessation of therapy; iodine uptake measurements may be helpful in this instance in determining the activity required and the timing of radioiodine therapy. Allergy to iodine; this is not normally a problem as the amount of iodine in radioiodine preparations is minute. Assessing the patient for radioiodine therapy At the initial consultation, the clinician should record certain information: Personal or social factors that would determine the need for special advice concerning the administration of radioactive substances. The person clinically directing radioiodine therapy or his/her deputy must always see the patient prior to radioiodine administration. Where radioiodine administration takes place more than 7 days after the initial consultation, the person clinically directing therapy should see the patient again in order to be certain that the relevant clinical features (see above) have not changed. A deterioration in the patient's clinical state might place him/her at greater risk of developing thyroid storm or further exacerbation of hyperthyroidism following radioiodine treatment. The person clinically directing the radioiodine treatment should ensure that a follow-up plan has been agreed to be undertaken either by the person clinically directing the therapy or by the referring clinician. ## Patient information and consent At the initial consultation the patient should be advised of treatment effectiveness, with particular regard to the slow onset of action of radioiodine, the probability of persistent/recurrent hyperthyroidism or of hypothyroidism, and the need for regular follow-up to detect hypothyroidism. Before treatment, the patient should be advised of recommendations for protection from unnecessary radiation and informed of the implications of radioiodine treatment in relation to work, travel and contact with the family [fig_ref] Table 1: Number of days for which patients should take special precautions, according to... [/fig_ref]. The patient is advised to remain away from work and to avoid prolonged close contact with children and with pregnant women for a period of time related to the activity of radioiodine received, and there may be similar restrictions on travel. A premenopausal woman must be informed about the rules concerning radioiodine therapy and pregnancy. An information sheet should be given to patients following the initial consultation. On the day of radioiodine administration, the patient should sign a consent form indicating that he/she understands the advice concerning radiation protection and (where appropriate) that she is neither pregnant nor breast feeding. Following radioiodine administration, the patient should be given a coloured warning card clearly stating the date on which the radioiodine was taken, the total activity, and the duration for which special precautions are necessary; the card should be carried by the patient during this time. A telephone contact number should also be given on the card. ## Management following radioiodine therapy In the first 2 weeks following administration of radioiodine the patient should be warned that he/she may experience palpitations or other exacerbations of thyrotoxic symptoms, especially if not euthyroid prior to treatment. This is particularly relevant in the elderly and patients with heart failure, for whom admission to hospital over the period of the therapy should be considered. Prior to treatment the patient should be made aware of the importance of follow-up thyroid function tests. These may be carried out at the hospital where the radioiodine therapy has been administered, by the referring clinician or by the general practitioner. If the patient is not receiving an ATD it is rare for hypothyroidism to develop within the 8 weeks following treatment; the first blood test should therefore be carried out after about 6 weeks. Levels of free hormone and thyroid stimulating hormone (TSH) should ideally be measured to determine accurately the results of therapy. Persistent suppression of the TSH level may continue for several months. High levels of TSH suggest the development of hypothyroidism; this will be useful in determining the frequency of further follow-up. In patients who are biochemically euthyroid at 6-8 weeks a further set of thyroid function tests should be performed at 12 weeks after radioiodine therapy. In patients in whom large doses of radioiodine therapy are used, evidence of developing biochemical hypothyroidism may become apparent at this stage. Patients should be warned to report recurrence of thyrotoxic symptoms or alternatively the development of symptoms of hypothyroidism. They should be advised to report sudden changes in symptoms as soon as they occur rather than wait for their planned appointment, as hypothyroidism may sometimes develop rapidly. In patients who remain hyperthyroid or become biochemically hyperthyroid following therapy, ATD treatment should be recommenced. These drugs should be gradually withdrawn 3-4 months after therapy to assess the late efficacy of radioiodine treatment. If thyroid hormone levels remain elevated on withdrawal of antithyroid medication, repeat radioiodine therapy should be instituted. Patients who remain euthyroid following therapy should continue to be followed up, at lengthening intervals, and again should be warned to report sudden alterations in symptoms. Patients who become hypothyroid in the first 6-12 weeks following radioiodine treatment should be monitored carefully to ensure that it is not a transient phenomenon. Continuing rise in TSH levels with concomitant fall in free thyroxine levels suggests developing thyroid failure in these patients, so thyroxine replacement therapy should be commenced, increasing incrementally to an adequate replacement dose. Patients who required digoxin prior to radioiodine therapy, for management of atrial fibrillation, should have an ECG performed when biochemically euthyroid, as sinus rhythm is frequently restored and digoxin may then be discontinued. Patients should be reminded to avoid pregnancy for 4 months following radioiodine therapy, and contraceptive advice should be explicitly given if necessary. Monitoring and follow-up Regular monitoring, in general practice, of patients who have undergone radioiodine treatment for hyperthyroidism is essential for the timely detection of developing complications. To aid this process it is recommended that a computer based purposedesigned form be completed at the time of treatment. This should record essential details and serve as a reliable method of patient identification. The prevalence of hypothyroidism in post-treatment patients has Journal of the Royal College of Physicians of London Vol. 29 No. 6 November/December 1995 been estimated as 24?90% over the patient's lifetime. However, unnecessary review of low-risk patients, at a specialist level, is a waste of resources and causes inconvenience and expense to the patient. It is recommended that a fail-safe system be adopted that supports regular patient monitoring with standardised follow-up intervals and, possibly, investigation protocols. The extremes of unnecessary follow-up and of patients 'dropping through the net' will thus be avoided. Such a system will also provide information for the assessment and maintenance of the quality of care. The responsibility for life-long follow-up should not rest solely with the general practitioner; the patient has an important role to play, and the specialist has a legitimate interest in long-term follow-up. Shared care is a management strategy that facilitates joint responsibility in cost-effective follow-up. Communication between specialist, GP and patient After leaving the clinic, patients may think of questions that they would have liked to ask. In these circumstances it is not uncommon for the patient to seek further advice from the general practitioner who should be aware of the proposed treatment and should be told what advice to give the patient. This should be done within 1 week of the patient's visit to the clinic at which the decision was taken. Following the administration of radioiodine, a standard letter indicating the activity given and the form of treatment should be received by the general practitioner within 1 week. The letter from the specialist to the general practitioner should include a management plan outlining the clinical and biochemical data that should be determined and the intervals for reviews. The cooperation of general practitioners in helping to trace non-attenders should be obtained. The role of patients in being responsible for their own well-being should not be overlooked; support and advice may be needed to ensure this involvement. Patients requiring long-term follow-up should be aware of the need for regular review of their condition. They should be provided with an information sheet indicating the frequency of review appropriate to their condition, and the appropriate content of such a review. ## Follow-up intervals Follow-up intervals of 6-12 months are recommended, depending on clinical state. Longer intervals are recommended only for stable patients, supported by a fail-safe follow-up system. Intervals of 6-12 months are fairly arbitrary but systematic collection of follow-up data will provide the basis on which to review the recommendations. ## Recommended investigations T4 or FT4 measurements may offer the cheapest and most cost-effective approach in all post-treatment patients; they may not be as sensitive as TSH measurements but may be a useful indicator to investigate further. If TSH levels are high, consider more frequent review; if low, consider less frequent review. # Monitoring methods Computerised clinical systems have been claimed to improve records and communication, provide useful clinical and administrative information, create organisational structure, assist quality assurance and support long-term follow-up. Such systems have been used for a number of years in the care of radioiodine treated patients and have provided the basis for the development of shared care. Shared care for other chronic disease has been shown to be cost-effective in a rigorous evaluation; it operates in several centres in the UK. The advantages of shared care for thyroid disease are reduced loss to follow-up, improved adherence to therapy, improved detection of hypothyroidism, cost-effectiveness compared with alternative methods of follow-up, and increased opportunity for audit and evaluation of care. The way forward is a unified approach with linked general practice and specialist records and a greater role for patients in their own care. A manual system could be used if a computerised system is not currently considered feasible, but both should have similar characteristics. There should be an effective audit procedure to ensure quality of both information and the follow-up care provided by the system used. # Conclusions Radioiodine therapy is safe and effective for most causes of hyperthyroidism. It is essential to adhere to the current regulation for administration of radioiodine in order to protect the environment as well as health care workers and other contact persons from radiation. Following therapy, adequate arrangements must be made for continuing follow-up and assessment. Initially this may be performed in hospital but usually after 1 year a dedicated follow-up system is recommended. Cooperation with the patient's general practitioner is essential at all stages of therapy and long-term follow-up. Regular audit of treatment and monitoring procedures is suggested. [table] Table 1: Number of days for which patients should take special precautions, according to the activity of [/table]	None	None	Radioiodine (131I) therapy is indicated in patients with nearly all causes of hyperthyroidism. It may safely be given to patients of all age groups but is less often given to children under 10 years old. It is completely contraindicated in pregnancy and while breast feeding, but there is no increased risk of thyroid cancer, leukaemia or solid tumours. Administration of radioiodine must conform to regulations and definitions laid down by ARSAC and POPUMET. Medical staff authorising therapy must hold an ARSAC licence. The recommended strategy is to give an activity sufficient to render the patient rapidly euthyroid and maintain that state or achieve no more than a low rate of hypothyroidism in subsequent years. A range of activity (300–800 MBq) is suggested depending on the clinical state. Antithyroid drugs may be given before or after (or both) radioiodine if necessary. Full written information should be given to the patient and written consent obtained. A structured follow-up should be used ensuring regular measurement of TSH or FT4. Close cooperation with the patient's general practitioner is recommended throughout the assessment, treatment and follow-up. Shared care with a computer based follow-up system is recommended.
ecc984ac1a549361bd18ce36be9e69c2fb270e2f	pubmed	SEOM clinical guidelines for the treatment of head and neck cancer (2020)	SEOM clinical guidelines for the treatment of head and neck cancer (2020) Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m 2 in the adjuvant setting, new approaches for HPV-related oropharyngeal cancer and new treatments with immune-checkpoint inhibitors in recurrent/metastatic disease. # Introduction Squamous cell carcinomas of the head and neck (SCCHN) are defined as malignant tumors arising from mucosal surfaces located in the upper aerodigestive tract (paranasal sinuses, nasopharynx, oropharynx, hypopharynx, larynx, oral cavity, nostrils). In Spain, SCCHN represents 5% of all new cancer diagnoses in adults, being the sixth neoplasm (fifth in men), similar to the European median, and a mortality rate of three points below compared to the European median. The most important risk factor in our region continues to be tobacco and alcohol use, but human papillomavirus (HPV) infection is a key etiological factor in oropharyngeal cancer burden, which is rising worldwide. Despite the majority patients with early-stage SCCHN can be cured with surgery or radiation, those with aggressive disease and those with locally advanced stages, that represents two-thirds of new diagnosis, are more likely to recur (50% 5-year overall survival). A multidisciplinary team, bringing together all professionals who specialize in the diagnosis and treatment of these patients, will make the decision to establish the best sequence of individualized treatment for each patient. Within what is known as SCCHN, each location has a clinical presentation, staging, prognosis and different therapeutic approach. As this is a general guide, the particularities of each subsite will not be dealt with in depth. Nasopharyngeal cancer with a different epidemiological, pathological and natural history will not be included in this guide. # Methodology SEOM guidelines have been developed with the consensus of ten oncologists from the Spanish Group for the Treatment of Head and Neck Tumors (TTCC) and SEOM. To assign a level and quality of evidence and a grade of recommendation to the different statements of this treatment guideline, the Infectious Diseases Society of America-US Public Health Service Grading System for Ranking Recommendations in Clinical Guidelines was used. The final text has been reviewed and approved by all authors. ## Diagnosis and staging It is essential to start the diagnostic process with a good clinical history, including toxic and sexual habits and a methodical physical examination, with special attention to the head and neck area (inspection, indirect mirror examination or direct endoscopy and palpation of primary sites and neck). To explore tumor extension, diagnosis imaging is needed: -Imaging diagnosis before a large biopsy avoids false diagnosis from anatomy distortion. -Cervical computed tomography (CT) or magnetic resonance (MR). Imaging MRI is superior to CT for evaluation of tongue, perineural spread, skull base invasion and intracranial extension. Regarding lymphatic dissemination, defining extracapsular nodal extension is of prognostic value. -CT of chest preferably, or X-ray in early stages. -Positron emission tomography-CT (PET-CT) is very useful in diagnosis of node (N) and metastases (M) and synchronous primary tumors. It is recommended in patients with stage III-IV disease when definitive treatment is indicated or in those with equivocal findings on CT or MRI scan. -Esophageal-gastric contrast study or esophagoscopy in case of dysphagia. -Histological diagnosis is mandatory by primary tumor biopsy or fine needle aspiration (FNA) of lymph nodes (biopsy is always better than FNA). If a node biopsy is needed, complete nodal resection is preferable to prevent extracapsular metastatic spread. Accurate staging is crucial for coordinating and tailoring therapy to each individual patient. The 8th edition of TNM classisfication was implemented from January, 2018:-The most important introduction is an independent classification for p16-positive oropharyngeal tumors: in the T category, T4a and T4b were pooled as T4, and N category was reclassified. As a consequence, there is a downstaging. -T category (T1-T3) of lip and oral cavity includes the extent of depth invasion. -N3 category for non-HPV related tumors has been subdivided into N3a and N3b according to extranodal extension (in N1 and N2 categories lack of extranodal extension is specified). -Perineural invasion or deep invasion is included within squamous cell carcinomas of the skin. ## Early disease (clinical stage i-ii) treatment Surgery, 3D conformal radiotherapy (RT) and brachytherapy provide similar locoregional control and survival outcomes, but they have not been compared in randomized trials. A multidisciplinary team should choose according to the characteristics and wishes of the patient and the potential functional outcomes, a single modality to avoid morbidity. Transoral resection is preferred over RT in oral cavity because of the decreased long-term morbidity (II, B). In oropharyngeal carcinoma, minimally invasive transoral surgery such as robot (TORS) or laser (TLM), in selected patients, should be prioritized over open surgery (II, B). Alternative RT seems to have less tendency to long-term dysphagia (II, B). In both locations, cervical lymph nodes should be treated with prophylactic radiation or elective neck dissection (bilaterally in tumors that arise in or near the midline and guided by location and depth in oral carcinoma) (II, B). Recent data recommend treatment based on sentinel node biopsy for oral cavity and oropharynx tumors (T1-2 N0), since it obtains the same neck-relapse-free survival at 2 years than the neck dissection, with less morbidity during first year post-surgery (I, A). When cervical dissection is indicated, we would recommend elective neck dissection over therapeutic neck dissection due to similar efficacy with less morbidity associated (I,A). In the choice of treatment for hypopharyx and larynx carcinomas, laryngeal functional results will be considered in addition to survival. Conservative laryngeal surgery (TLM or supraglottic or supracricoid laryngectomy) will be priorized over open surgery, and considerer RT treatment in case of requiring extensive surgical resection. Elective treatment of the neck in hypopahrynx and supraglottic cancer is recommended (II, B), but not in glottic neoplasm (III, C). If the pathological staging is superior to the clinical staging or there are poor prognosis factors, complementary treatments should be used (I, A) including the re-resection. ## Locally advanced disease (clinical stages iii, iva, ivb) treatment In all cases there must be a multidisciplinary assessment to decide the best combined treatment option for each patient either based on surgery or RT as the key treatment (I-A) Given its special interest, we will introduce a special section for larynx preservation and HPV-related oropharyngeal cancer treatments. ## Surgery-based treatment There is no universally accepted definition of unresectability in SCCHN, but some anatomical criteria are considered unequivocal and classified as T4b tumors (involvement of skull base, cervical vertebrae, prevertebral muscles, brachial plexus, mediastinal spread, involvement of nasopharynx, fixed tumor to collarbone, vascular encasement). Multidisciplinary Tumor Boards can exclude patients for surgery: few chances of achieving adequate margins, unacceptable functional and/or esthetic sequelae, little expectation of cure or due to patients' comorbidities. For patients with T3-4aN0 tumors an ipsilateral or bilateral neck dissection is an option (except oral cavity where it is mandatory). When neck nodes are palpable, all nodal levels should be dissected. 40 mg/m 2 cisplatin can be non-inferior alternative with better safety profile (IB). ## Specific recommendations in special circumstances -Oral cavity: in clinically node-negative cases, elective ipsilateral node dissection is recommended more than watchful waiting approach (I-A). -Unfit patients not candidate for platinum: consider administration of RT alone (I-A). There is no evidence for using agents such as cetuximab or carboplatin in the adjuvant setting. ## Radiotherapy-based treatment CCRT is preferred for patients that are not candidates for or refuse radical surgery (IA). -RT technique: IMRT is preferred (IA): with similar overall survival compared with conventional RT, it has shown reduction in xerostomia (IA)and probably shorter duration of feeding tube placement (V). be equivalent to high-dose cisplatin (IIB). Concomitant cetuximab is an alternative treatment (400 mg/ m 2 at initial dose day -8 followed by 250 mg/m 2 weekly concurrent) for patients with some contraindication for cisplatin such as neuropathy, nephropathy, heart disease and hearing loss (IA). Sequential therapy with induction chemotherapy (ICT) followed by CCRT or RT alone is an option for locally advanced tumors (IIB). Factors such as patients' comorbidities, high tumor volume and rapid tumor growth will influence its indication by a multidisciplinary team. ICT has not demonstrated improvement in overall compared with concurrent CRT but increase the response rate. Its limitation is the potential toxicity that could compromise the posterior CRT compliance. The most recommended induction regimen is TPF schedule (three-weekly Cisplatin 75 mg/m 2 , Docetaxel 75 mg/m 2 , 5-Fluorouracil 750 mg/m 2 /d continue infusion 96 h) (IA). After ICT, there is no consensus for locoregional treatment (RT, chemoradiotherapy or RT plus cetuximab) (IIB). Decision should be made according to the response and tolerance to previous ICT. Salvage neck dissection should be considered in patients with residual lymph node disease and a complete response in the primary tumor. ## Organ preservation (larynx and hypopharynx) All patients should have a multidisciplinary evaluation regarding their suitably for a larynx-preservation approach. Organ-preservation surgery, CRT and ICT, all with further surgery reserved for salvage, offer the potential for larynx preservation without compromising overall survival. Selection of a treatment option will depend on patient factors, including age, comorbidities, preferences, socioeconomic factors, local expertise and the availability of appropriate support and rehabilitation services. For selected patients with extensive T3 or large T4a lesions and/or poor pretreatment laryngeal function, better survival rates and quality of life may be achieved with total laryngectomy rather than with organ-preservation approaches and may be the preferred approach (IA). CCRT offers a significantly higher chance of larynx preservation than RT alone or ICT followed by RT alone (IA). The best available evidence supports the use of high-dose cisplatin as the drug of choice in this setting. There is insufficient evidence to indicate that survival or larynx-preservation outcomes are improved by the addition of ICT before concurrent treatment. However, in the setting of operable cancer with the goal of larynx preservation, response to ICT serves as a surrogate predictive biomarker for successful organ preservation with subsequent RT plus cisplatin. Three options could be considered: Three options could be considered: 1.Surgical resection (total versus partial laryngectomy + neck dissection) followed by RT (IA) - Specially in T4a (IA). - For the most part of subglottic tumors (IA). Non-surgical organ preservation alternatives are showed in2.CRT with three-weekly cisplatin is recommended if patient refuses surgery (IA). If cisplatin cannot be administered, consider cetuximab concurrent to RT (IA). 3.ICT with TPF schedule: - If complete response of the primary tumors (without lymph node progression) → RT(IA). - If partial response (50% reduction of primary tumor without lymph nose progression) → RT (IA) or concomitant RT (with cisplatin or cetuximab)(IIB). - If stable disease (primary tumor) or progression → total laryngectomy (including neck dissection) followed by RT (IA) or CRT (IIB) based on histopathological results. ## Hpv-related oropharyngeal cancer: a new biological and clinical entity HPV status has widely been described as an independent predictor of improved outcomes in squamous cell oropharyngeal cancer (OPSCC) patients, proving a 58% reduction in the risk of death for patients with HPV-related OPC as compared HPV-negative tumors. ## Diagnosis and staging p16 INK4a over-expression is a surrogate marker of HPV involvement and it is the most widely implemented technique in the clinical setting. Nevertheless, a recent study highly recommends confirming HPV relatedness in p16-positive patients with an HPV specific biomarker such us HPV DNA (IIA). Double testing for oropharyngeal HPV-related patients is especially important in our geographical area. Importantly, HPV-related oropharyngeal cancer patients' staging should be done following AJCC TNM 8th edition, whereas clinical decision-making should follow AJCC TNM 7th edition. ## Early disease Minimally invasive surgery (TORS or TLM) or IMRT monotherapies are both validate techniques for early stages (IA). Importantly patient characteristics and wishes, functional outcomes and expertise of the treating team should be considered. ## Locally advanced (la) disease The good prognosis has led the scientific community to develop de-escalation clinical trials for LA HPV-related OPSCC patients. Two phase III de-escalation clinical trials have maintained cisplatin (100 mg/m 2 every 3 weeks) in combination with RT (70 Gy in 35 fractions) as the standard of care (IA). Deintensification protocols should be undertaken only within the context of clinical trials. ## Recurrent or metastatic (r/m) disease Surgery or re-irradiation should always be assessed by the multidisciplinary team for oligometastasic patients. If a radical approach is not possible, the clinical management of R/M HPV-related oropharyngeal patients does not differ from R/M HPV-negative HNSCC, except for patients included on specific clinical trials (IA). ## R/m disease treatment The multidisciplinary team will assess the benefit of salvage surgery or re-irradiation. In the presence of oligometastatic disease, treatment with curative intent should also be discussed. Systemic treatment will be considered in all other patients. All subjects should be recommended including in clinical trials if available. ## First-line treatment Decisions will be made based on Eastern Cooperative Oncology Group (ECOG) performance status (PS) comorbidities, symptom burden and PD-L1 expression (in archival or newly tumor samples and characterized by the combined positive score (CPS)). 1. Chemotherapy-naïve patients or patients with progressive disease more than 6 months after locoregional treatment with cisplatin : (a) Pembrolizumab alone is preferred in patients with PS 0/1, CPS ≥ 20 and low symptom load (IA). (b) The combination of Pembrolizumab plus chemotherapy might be preferred for patients whose symptom burden indicates a greater importance of objective response. (IA). immunotherapy protocol EXTREME (combination based on platinum plus 5-FU plus cetuximab) (IA)or TPEX (combination based on cisplatin plus docetaxel plus cetuximab if there is any contraindication to 5-FU) only in PS 0/1 patients able to receive cisplatin (IIB)* are the best option. (e) Best supportive care is the treatment of choice in patients with PS 2. In these patients and those with comorbidities that could not receive platinum the combination ERBITAX (paclitaxel plus cetuximab) should be considered (IIB). (f) The treatment of choice for patients with PS 3/4 is best supportive care. 2. Patients who have received chemotherapy at least 200 mg/m2 of cisplatin for locoregional disease within 6 months after last cisplatin dose should not receive cisplatin or carboplatin. The first option will be Nivolumab (IA)or Pembrolizumab in those patients with a tumor positive score (TPS) >/=50% (IIA). According to PS or symptom burden treatment with ERBITAXcould be an alternative . ## Second and subsequent line treatment With the paradigm switch at the frontline we can find new treatment settings: 1. After platinum-based therapy: immunotherapy with Nivolumab (IA)Pembrolizumab in those patients with tumor positive score (TPS) PDL1 ≥ 50% (IIA)2. After pembrolizumab alone: combination EXTREME is preferred or ERBITAX according to PS (IIIC apy, ERBITAX combination of paclitatel and cetuximab, EXTREME combination of platinum, 5-Fluorouracil and cetuximab, TPEX combination of cisplatin, docetaxel and cetuximab drugs with small sample sizes and patient heterogeneity which makes the evaluation of the relative efficacy of each drug challenging. There is no evidence of higher efficacy among the different drugs in the meta-analyses performed. Informed consent For thus type of study formal consent is not required. 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e4af120d1ba0c3023eed2650492358b0b57001fd	pubmed	Antibiotic prophylaxis is not indicated prior to dental procedures for prevention of periprosthetic joint infections	Antibiotic prophylaxis is not indicated prior to dental procedures for prevention of periprosthetic joint infections [table] Table 4: Bias assessment of the studies included, according to the GRADE method [/table] [table] Table 5: An overview of international recommendations AAOS: American Academy of Orthopaedic Surgeons; ADA: American Dental Association; AFSSAPS/ANSM: French health authorities; BASC: British Society for Antimicrobial Chemotherapy; BOA: British Orthopaedic Association; DE: dentists; IN: infectiologists; NZDA: New Zealand Dental Association; MI: microbiologists; OMFS: oral and maxillofacial surgeons; OS: orthopedic surgeons; SGINF: Swiss Society for Infectious Diseases. [/table]	None	https://www.tandfonline.com/doi/pdf/10.1080/17453674.2017.1340041?needAccess=true	Background and purpose — To minimize the risk of hematogenous periprosthetic joint infection (HPJI), international and Dutch guidelines recommended antibiotic prophylaxis prior to dental procedures. Unclear definitions and contradictory recommendations in these guidelines have led to unnecessary antibiotic prescriptions. To formulate new guidelines, a joint committee of the Dutch Orthopaedic and Dental Societies conducted a systematic literature review to answer the following question: can antibiotic prophylaxis be recommended for patients (with joint prostheses) undergoing dental procedures in order to prevent dental HPJI? Methods — The Medline, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs), reviews, and observational studies up to July 2015. Studies were included if they involved patients with joint implants undergoing dental procedures, and either considered HPJI as an outcome measure or described a correlation between HPJI and prophylactic antibiotics. A guideline was formulated using the GRADE method and AGREE II guidelines. Results — 9 studies were included in this systematic review. All were rated “very low quality of evidence”. Additional literature was therefore consulted to address clinical questions that provide further insight into pathophysiology and risk factors. The 9 studies did not provide evidence that use of antibiotic prophylaxis reduces the incidence of dental HPJI, and the additional literature supported the conclusion that antibiotic prophylaxis should be discouraged in dental procedures. Interpretation — Prophylactic antibiotics in order to prevent dental HPJI should not be prescribed to patients with a normal or an impaired immune system function. Patients are recommended to maintain good oral hygiene and visit the dentist regularly.
730bb5075a5e398df109bdb50a293f5adf5a4277	pubmed	Conventional radiography in juvenile idiopathic arthritis: Joint recommendations from the French societies for rheumatology, radiology and paediatric rheumatology	Conventional radiography in juvenile idiopathic arthritis: Joint recommendations from the French societies for rheumatology, radiology and paediatric rheumatology Background Juvenile idiopathic arthritis (JIA) can cause structural damage. However, data on conventional radiography (CR) in JIA are scant. Objective To provide pragmatic guidelines on CR in each non-systemic JIA subtype. Methods A multidisciplinary task force of 16 French experts (rheumatologists, paediatricians, radiologists and one patient representative) formulated research questions on CR assessments in each non-systemic JIA subtype. A systematic literature review was conducted to identify studies providing detailed information on structural joint damage. Recommendations, based on the evidence found, were evaluated using two Delphi rounds and a review by an independent committee. Results 74 original articles were included. The task force developed four principles and 31 recommendations with grades ranging from B to D. The experts felt strongly that patients should be selected for CR based on the risk of structural damage, with routine CR of the hands and feet in rheumatoid factor-positive polyarticular JIA but not in oligoarticular non-extensive JIA. Conclusion These first pragmatic recommendations on CR in JIA rely chiefly on expert opinion, given the dearth of scientific evidence. CR deserves to be viewed as a valuable tool in many situations in patients with JIA. # Introduction Juvenile idiopathic arthritis (JIA) is a heterogeneous group of chronic inflammatory joint conditions that can cause structural damage [bib_ref] Juvenile idiopathic arthritis, Prakken [/bib_ref]. Seven mutually exclusive subtypes of JIA are defined in the 2001 Edmonton classification developed by the International League Against Rheumatism (ILAR) [bib_ref] International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second..., Petty [/bib_ref]. This classification has been challenged and modifications suggested, such as exclusion of systemic-onset JIA (sJIA) due to its similarity to autoinflammatory diseases [bib_ref] It is time to rethink juvenile idiopathic arthritis classification and nomenclature, Martini [/bib_ref] [bib_ref] Juvenile idiopathic arthritis: Definition and classification, Deslandre [/bib_ref]. The prevalence of joint damage among patients with JIA has been estimated at 8-27 % in extended oligoarticular JIA (oJIA), 35-67 % in polyarticular JIA (pJIA) and up to 80 % in rheumatoid factor (RF)-positive pJIA [bib_ref] Radiographic progression in children with polyarticular juvenile rheumatoid arthritis: a pilot study, Mason [/bib_ref] [bib_ref] Early predictors of outcome in juvenile idiopathic arthritis, Ravelli [/bib_ref]. The main treatment objectives in JIA are to control the pain and to prevent structural damage. Joint space narrowing (JSN), bone erosions and demineralization are radiographic findings shared between JIA and adult rheumatoid arthritis (RA). Changes specific to the paediatric population are early growth plate closure, epiphyseal deformity and growth asymmetry [bib_ref] Juvenile idiopathic arthritis: clinically relevant imaging in diagnosis and monitoring, Southwood [/bib_ref]. Conventional radiography (CR), magnetic resonance imaging (MRI) and ultrasound (US) are the imaging modalities most often used to evaluate joint inflammation or structural damage [bib_ref] Imaging approaches for evaluating peripheral joint abnormalities in juvenile idiopathic arthritis, Breton [/bib_ref]. MRI and US hold considerable promise but are still under evaluation in JIA. CR remains the most readily available imaging technique for detecting and monitoring structural damage. However, potential limitations of CR in JIA include the risk of radiationinduced harm to the patient, interpretation difficulties raised by skeletal immaturity, and the delayed development of structural joint damage. Furthermore, because JIA is rare, little is known about the potential effects of synthetic or biological disease-modifying anti-rheumatic drugs (DMARDs) on structural joint damage [bib_ref] Preliminary evidence that etanercept may reduce radiographic progression in juvenile idiopathic arthritis, Nielsen [/bib_ref] [bib_ref] Effects of methotrexate on radiologic progression in juvenile rheumatoid arthritis, Harel [/bib_ref] [bib_ref] Radiologic progression in patients with juvenile chronic arthritis treated with methotrexate, Ravelli [/bib_ref]. Thus, whereas recommendations based on large studies are available for the radiographic assessment of chronic inflammatory joint disease in adults [bib_ref] Ability of oblique foot radiographs to detect erosions in early arthritis: results..., Devauchelle-Pensec [/bib_ref] [bib_ref] Recommendations of the French Society for Rheumatology for managing rheumatoid arthritis, Gaujoux-Viala [/bib_ref] , no similar guidelines have been developed for JIA. A task force was recently convened by the European League Against Rheumatism (EULAR) -Paediatric Rheumatology European Society (PReS) to develop recommendations about imaging studies for diagnosing and managing JIA [bib_ref] EULAR recommendations for the use of imaging of the joints in the..., Colebatch [/bib_ref]. Although this undertaking acknowledged, for the first time, that an assessment of imaging studies in JIA was needed, the task force neither focussed on CR nor provided specific guidance for everyday practice. We established a multidisciplinary task force to develop guidelines on the use of CR for the diagnosis and follow-up of each JIA subtype in everyday practice. Our project was supported by the French Society for Rheumatology (SFR), French Society for Paediatric Rheumatology and Internal Medicine (SOFREMIP), French Society for Paediatric and Prenatal Imaging (SFIPP), French Society for Radiology (SFR), and largest non-profit paediatric rheumatology patient organisation in France (KOURIR). # Methods ## Field of research We considered the following situations, at diagnosis and during follow-up, in each of the following five subtypes of JIA (oJIA, pJIA with and without RF and/or anti-citrullinated peptide antibody (ACPA), juvenile psoriatic arthritis (jPsA), and enthesitis-related arthritis (ERA)) Undifferentiated arthritis, as a heterogeneous subset related to one or several subtypes, and systemic JIA, having a peculiar articular course and structural prognosis, were left aside. Experts also focused on juvenile monoarthritis. Special attention was directed to the cervical spine, hip and temporo-mandibular joints (TMJs). ## Recommendation development process The task force comprised 16 JIA experts (eight rheumatologists, five paediatricians, two paediatric radiologists experienced in skeletal disease and one patient organisation representative). We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method [bib_ref] Grading quality of evidence and strength of recommendations in clinical practice guidelines..., Brożek [/bib_ref] for elaborating, evaluating, disseminating and implementing recommendations elaborated by the EULAR and the Outcome Measures in Rheumatology (OMERACT) group [bib_ref] EULAR standardised operating procedures for the elaboration, evaluation, dissemination, and implementation of..., Dougados [/bib_ref] [bib_ref] Update of the EULAR standardised operating procedures for EULARendorsed recommendations, Van Der Heijde [/bib_ref] , and the Population, Intervention, Comparison, Outcome (PICO) process to frame the research questions. We considered structural radiographic abnormalities: JSN, erosions, pseudo-joint space widening for sacro-iliac joint [bib_ref] Spondyloarthritis in a pediatric population: risk factors for sacroiliitis, Stoll [/bib_ref] [bib_ref] Early predictors of juvenile sacroiliitis in enthesitis-related arthritis, Pagnini [/bib_ref] and ankylosis [bib_ref] Ability of oblique foot radiographs to detect erosions in early arthritis: results..., Devauchelle-Pensec [/bib_ref]. A research fellow (PM) assisted by two experts in systematic review methodology (CGV, methodologist; and VDP, convenor) performed a systematic literature review by searching PubMed, Scopus/Elsevier, and the Cochrane Library. Original articles including clinical trials, retrospective cohort studies, other retrospective studies, and case-control studies published between 1980 and December 2016 were identified. The following indexing was used: 'juvenile idiopathic arthritis' OR 'juvenile rheumatoid arthritis' OR 'juvenile chronic arthritis' OR 'juvenile psoriatic arthritis' O R ' e n t h e s i t i s -r e l a t e d a r t h r i t i s ' O R ' j u v e n i l e spondyloarthritis' AND 'radiography' OR 'X-ray' (see Appendix 1 for details). The quality of evidence and grades of recommendation were determined according to the standards of the Oxford Centre for Evidence-Based Medicine . Recommendations were graded A to D depending on the level of the underlying evidence (from 1A to 4) [bib_ref] Update of the EULAR standardised operating procedures for EULARendorsed recommendations, Van Der Heijde [/bib_ref]. The task force debated and formulated a preliminary set of recommendations based on the systematic literature review supplemented, when necessary, by their expert opinion. This set was then evaluated by a panel of 14 independent Frenchspeaking experts. Modifications were debated by the task force. The final recommendations were then rated on a 10point scale by the task force and independent panel through a Delphi process. # Results ## Systematic literature review Of the 118 publications identified by the literature search, 74 original articles, as well as one abstractand one online recommendation, were included . ## Recommendations The experts elaborated four overarching principles and 31 recommendations. [fig_ref] Table 2: Routine CR of the wrists, hands, and forefeet is strongly recommended at... [/fig_ref] lists the recommendations. ## Overarching principles Radiation exposure was taken into account (principle B), according to French Society for Radiology recommendations(Appendix 2). Much of the cartilage is still radiotransparent in children younger than 5 years of age. In this age group, the need for CR must be evaluated with great care (principle C) [bib_ref] Development of the long bones in the hands and feet of children:..., Laor [/bib_ref]. Other imaging modalities such as US and MRI are increasingly used in JIA. Although promising, they are not discussed herein. They will be the focus of specific recommendations (principle D). Oligoarticular JIA (oJIA) 1. CR should not be performed routinely as a diagnostic investigation in oJIA. The literature review identified ten studies in which CR was performed, even in patients younger than 4 years. Among them, one focussed specifically on oJIA [bib_ref] Longterm outcome and prognosis in oligoarticular-onset juvenile idiopathic arthritis, Guillaume [/bib_ref] and nine investigated several JIA subtypes but reported data separately for oJIA . The usefulness of CR is limited by the incomplete ossification of the epiphyses, most notably in the youngest age groups [bib_ref] Use of the Sharp and Larsen scoring methods in the assessment of..., Rossi [/bib_ref]. Therefore, when the diagnosis is definitive, CR is not recommended. 2. and 3. During follow-up, CR should be performed on affected joint(s) that remain symptomatic after 3 months. By 'symptomatic joints', we mean painful and/or swollen joints and/or joints that are limited in motion. In patients with persistently symptomatic joints, the reiteration of CR during follow-up is at the discretion of the physician. Several studies showed evidence of radiographic progression early in the natural history of oJIA [bib_ref] Antinuclear antibody-positive patients should be grouped as a separate category in the..., Ravelli [/bib_ref] [bib_ref] Anticitrullinated protein antibodies and radiological progression in juvenile idiopathic arthritis, Lipinska [/bib_ref] [bib_ref] Longterm outcome and prognosis in oligoarticular-onset juvenile idiopathic arthritis, Guillaume [/bib_ref] [bib_ref] Radiologic outcome and its relationship to functional disability in juvenile rheumatoid arthritis, Oen [/bib_ref]. [bib_ref] Juvenile idiopathic arthritis: Definition and classification, Deslandre [/bib_ref]. In patients with clinically inactive disease (CID), CR should not be performed routinely. The diagnosis of CID relies on physician judgement, aided by validated tools [bib_ref] American College of Rheumatology provisional criteria for defining clinical inactive disease in..., Wallace [/bib_ref] [bib_ref] Validity of a three-variable Juvenile Arthritis Disease Activity Score in children with..., Mcerlane [/bib_ref] [bib_ref] Development and validation of a composite disease activity score for juvenile idiopathic..., Consolaro [/bib_ref]. No data are available on radiographic disease progression in clinically silent joints in patients with oJIA. [bib_ref] Radiographic progression in children with polyarticular juvenile rheumatoid arthritis: a pilot study, Mason [/bib_ref]. In patients with extended oJIA, the recommendations for pJIA should be applied. The number of affected joints is strongly associated with structural damage in oJIA [bib_ref] Longterm outcome and prognosis in oligoarticular-onset juvenile idiopathic arthritis, Guillaume [/bib_ref]. [bib_ref] Early predictors of outcome in juvenile idiopathic arthritis, Ravelli [/bib_ref]. In patients with structural damage, the selection and timing of specific imaging techniques to further assess the damaged joint during follow-up is guided by clinical considerations. Joints with structural damage must undergo specific CR evaluations during the patient's growth. Polyarticular JIA (pJIA) 7. and 8. Routine CR of the wrists, hands and forefeet is strongly recommended at the diagnosis of polyarticular JIA with positive RF/ACPA. CR of other joints than wrists, hands and forefeet, is recommended at the diagnosis for symptomatic jointsonly. Prospective studies were reviewed, with special attention to early pJIA. Erosions and JSN occurred preferentially at the hands, wrists and feet [bib_ref] Radiologic progression in patients with juvenile chronic arthritis treated with methotrexate, Ravelli [/bib_ref] [bib_ref] Radiologic features in juvenile idiopathic arthritis: a first step in the development..., Van Rossum [/bib_ref] , joints that were sometimes asymptomatic [bib_ref] Radiologic features in juvenile idiopathic arthritis: a first step in the development..., Van Rossum [/bib_ref] CR at the diagnosis provides a reference for assessing disease progression. It is supported by 'adult' recommendations [bib_ref] Recommendations of the French Society for Rheumatology for managing rheumatoid arthritis, Gaujoux-Viala [/bib_ref] for rheumatoid arthritis, which has a similar structural evolution. 9. and 10. In new-onset RF/ACPA-negative pJIA with adverse prognostic factors, CR at diagnosis should be performed as for RF/ACPA-positive pJIA. Box 1 lists the factors of adverse prognostic significance in pJIA [bib_ref] Radiologic features in juvenile idiopathic arthritis: a first step in the development..., Van Rossum [/bib_ref]. These factors are associated with a pattern of joint damage over time similar to that seen in RF/ACPA-positive pJIA [bib_ref] Radiologic outcome and its relationship to functional disability in juvenile rheumatoid arthritis, Oen [/bib_ref]. Box 1: Factors of adverse prognostic significance in polyarticular juvenile idiopathic arthritis (pJIA) Early involvement of wrists Symmetric arthritis Distal, small-joint arthritis Elevated ESR/CRP Pre-existing radiographic abnormalities ESR, erthrocyte sedimentation rate; CRP, serum C-reactive protein level [bib_ref] Radiologic progression in patients with juvenile chronic arthritis treated with methotrexate, Ravelli [/bib_ref]. In new-onset, RF/ACPA-negative pJIA without adverse prognostic factors, at diagnosis, CR should be confined to symptomatic joints. This recommendation is based on expert opinion. 12. In RF/ACPA-positive pJIA, CR of the hands, wrists and forefeet is strongly recommended 1 year after disease onset, and when transitioning from paediatric to adult healthcare. At other time points, the use of CR during follow-up is at the discretion of the physician. Prospective studies found evidence of joint damage even in asymptomatic joints [bib_ref] Radiologic features in juvenile idiopathic arthritis: a first step in the development..., Van Rossum [/bib_ref]. Patients with long-standing disease had high prevalences of joint erosions (30-70 % in historical studies) [bib_ref] Radiographic progression in children with polyarticular juvenile rheumatoid arthritis: a pilot study, Mason [/bib_ref] [bib_ref] Radiographic and clinical outcome in early juvenile rheumatoid arthritis and juvenile spondyloarthropathy:..., Selvaag [/bib_ref] [bib_ref] Radiologic outcome and its relationship to functional disability in juvenile rheumatoid arthritis, Oen [/bib_ref] [bib_ref] Health status of patients with juvenile rheumatoid arthritis at 1 and 5..., Bowyer [/bib_ref] , close to those in adults with RA [48]. In RA, joint destruction at asymptomatic sites is a major predictor of adverse outcomes [bib_ref] Recommendations of the French Society for Rheumatology for managing rheumatoid arthritis, Gaujoux-Viala [/bib_ref] [bib_ref] Presence of significant synovitis in rheumatoid arthritis patients with diseasemodifying antirheumatic drug-induced..., Brown [/bib_ref]. However, radiographic progression with erosions in asymptomatic joints is not well documented in JIA and may have been underestimated. In a study of 471 joints in 67 patients with polyarticular JIA, radiographs showed erosions at the hands and feet in 36 % and 39 % of [bib_ref] Radiologic features in juvenile idiopathic arthritis: a first step in the development..., Van Rossum [/bib_ref]. Our literature review identified some data on the best times for CR. One study suggested a higher risk of radiographic progression within the first year after disease onset . The experts felt that CR contributed to ease the transition from paediatric to adult healthcare [bib_ref] EULAR/PReS standards and recommendations for the transitional care of young people with..., Foster [/bib_ref]. [bib_ref] Recommendations of the French Society for Rheumatology for managing rheumatoid arthritis, Gaujoux-Viala [/bib_ref]. Routine CR of other joints is not recommended. No data were found on which to base specific recommendations. 14. During the follow-up of RF/ACPA-negative pJIA with adverse prognostic factors, CR should be performed as for RF/ACPA-positive pJIA (see recommendation #12). [bib_ref] Grading quality of evidence and strength of recommendations in clinical practice guidelines..., Brożek [/bib_ref]. During the follow-up of RF/ACPA-negative pJIA without adverse prognostic factors, the use of CR is at the discretion of the physician. No scientific data were available on which to base specific recommendations.. and 17. CR can be repeated in patients who remain symptomatic* longer than 3 months. In patients with structural damage, the selection and timing of specific imaging techniques during follow-up is guided by clinical considerations. The experts emphasised the need for careful attention to joints with active disease. In prospective studies, the time interval separating CR assessments of the same joints ranged from 8 months to 24 years. The 3-month interval in this recommendation was based on expert opinion. # Enthesitis-related arthritis (era) 18. In patients with axial ERA, CR of the spine and hip joints should be performed only when needed for the differential diagnosis. Axial manifestations may arise at the spine, hips and sacro-iliac joints. A radiographic view specifically designed to assess the sacro-iliac joints is not recommended, as the results are not interpretable in skeletally immature patients and radiation exposure is significant [bib_ref] Early predictors of juvenile sacroiliitis in enthesitis-related arthritis, Pagnini [/bib_ref]. In patients with axial inflammatory pain, MRI (for both sacro-iliac and hip joints) and US (for the hip joint) may be more relevant [bib_ref] Assessment of Sacroiliitis at Diagnosis of Juvenile Spondyloarthritis by Radiography, Magnetic Resonance..., Weiss [/bib_ref]. [bib_ref] Spondyloarthritis in a pediatric population: risk factors for sacroiliitis, Stoll [/bib_ref]. During the follow-up of axial ERA, CR should be considered only for the hip joints, depending on the clinical course and availability of US and/or MRI. ERA is associated with a high prevalence of hip joint arthritis [bib_ref] The influence of patient characteristics, disease variables, and HLA alleles on the..., Flatø [/bib_ref]. MRI or US are non-irradiating methods capable of detecting hip joint effusion; in addition, MRI can detect bone oedema. Therefore, in the future, MRI and US may deserve consideration as first-line imaging techniques. CR, however, is appropriate for monitoring known structural damage and deformities. 20. and 21. CR is not recommended for multifocal enthesitis. In patients with isolated enthesitis, CR can be JIA juvenile idiopathic arthritis, CR conventional radiography, oJIA oligoarticular juvenile idiopathic arthritis, pJIA polyarticular juvenile idiopathic arthritis, RF rheumatoid factor, ACPA anti-citrullinated protein antibody, ERA enthesitis-related arthritis, TMJ temporo-mandibular joint Symptomatic joints: swollen and/or painful joints, and/or joints with motion range limitation considered as a tool for establishing the differential diagnosis. When isolated enthesitis is suspected, CR may contribute to the differential diagnosis (e.g. with post-traumatic changes or osteochondritis); otherwise, CR is unhelpful for assessing peri-articular manifestations. Psoriatic juvenile arthritis (jPsA) ## 22. No specific recommendation can be made about CR in juvenile psoriatic arthritis. Scientific data are scarce [bib_ref] Comparison of patients with juvenile psoriatic arthritis and nonpsoriatic juvenile idiopathic arthritis:..., Butbul [/bib_ref] [bib_ref] Juvenile psoriatic arthritis: longterm outcome and differentiation from other subtypes of juvenile..., Flatø [/bib_ref] [bib_ref] Patterns of joint involvement at onset differentiate oligoarticular juvenile psoriatic arthritis from..., Huemer [/bib_ref] [bib_ref] Clinical comparison of early-onset psoriatic and non-psoriatic oligoarticular juvenile idiopathic arthritis, Stoll [/bib_ref] [bib_ref] Psoriatic juvenile idiopathic arthritis: a tale of two subgroups, Stoll [/bib_ref] [bib_ref] Positive family history of psoriasis does not affect the clinical expression and..., Tsitsami [/bib_ref]. The definition of this entity is still debated [bib_ref] Positive family history of psoriasis does not affect the clinical expression and..., Tsitsami [/bib_ref]. Traditionally, two subtypes are described, an axial inflammatory disease resembling axial ERA and a peripheral joint disease resembling oJIA [bib_ref] Psoriatic juvenile idiopathic arthritis: a tale of two subgroups, Stoll [/bib_ref]. 23. Guidance may be taken from the recommendations above, depending on the clinical presentation, or from recommendations issued for adults. ## Situations of specific interest Monoarthritis 24. At the diagnosis of acute monoarthritis, CR of the involved joint should be performed, with two perpendicular views. The French Society for Radiologystrongly recommends CR of any site of focal bone pain in paediatric patients, with the goal of excluding a tumour, osteomyelitis, or a haematological malignancy [bib_ref] Predictive plain X-ray findings in distinguishing early stage acute lymphoblastic leukemia from..., Tafaghodi [/bib_ref] [bib_ref] Monoarthritis; remember to ask the child, Rayen [/bib_ref]. [bib_ref] Radiographic Progression of Patients With Psoriatic Arthritis Who Achieve Minimal Disease Activity..., Kavanaugh [/bib_ref]. At the diagnosis of acute monoarthritis, comparative CR of the contralateral joint is unnecessary. Because cartilage thickness varies within individuals, comparison to the healthy contra-lateral joint is uninformative [bib_ref] Useful measurements in the evaluation of hand radiographs, Poznanski [/bib_ref] [bib_ref] Use of the Sharp and Larsen scoring methods in the assessment of..., Rossi [/bib_ref]. Cervical spine 26. In patients with persistent neck pain related to JIA, MRI is preferable over CR. 27. When MRI is unavailable, CR is recommended only for the cervical spine and should consist only of a lateral view. 28. In patients with JIA who have neurological symptoms of spinal cord compression and neck pain, cervical MRI must be performed, on an emergency basis. In a cohort study of oJIA, 2.4 % of patients had cervical spine damage at the diagnosis [bib_ref] Longterm outcome and prognosis in oligoarticular-onset juvenile idiopathic arthritis, Guillaume [/bib_ref]. Cervical spine erosions and ankylosis are common in advanced pJIA [bib_ref] Disease course, outcome, and predictors of outcome in a populationbased juvenile chronic..., Bertilsson [/bib_ref] [bib_ref] Subaxial cervical vertebrae in patients with juvenile idiopathic arthritis-something special?, Endén [/bib_ref]. Evidence-based data are too scarce to recommend any specific pattern of radiological follow-up. Atlanto-axial diastasis may be normal in paediatric patients, and dynamic CR is therefore irrelevant. MRI is the most sensitive imaging technique, and is mandatory when spinal cord compression is suspected [bib_ref] Radiological evaluation of cervical spine involvement in rheumatoid arthritis, Joaquim [/bib_ref]. Temporomandibular joints 29. CR of the TMJs is not recommended when cross-sectional imaging is available. TMJ damage is common in JIA, with the prevalence ranging across studies from 17 % to 87 % [bib_ref] Temporomandibular involvement in juvenile idiopathic arthritis, Twilt [/bib_ref]. The TMJ cartilage is thin and condylar erosions therefore develop early. The panoramic radiograph is often normal at disease onset. Cross-sectional imaging offers better diagnostic performance. Imaging of the TMJs is not usually performed on a routine basis but is required in the event of pain, mouth-opening limitation or audible cracking of the TMJs . MRI is considered the best imaging technique, although distinguishing the normal appearance from abnormal changes can be challenging [bib_ref] Contrastenhanced MRI of the temporomandibular joint: findings in children without juvenile idiopathic..., Kottke [/bib_ref] [bib_ref] MRI thresholds for discrimination between normal and mild temporomandibular joint involvement in..., Ma [/bib_ref]. Cone-beam computed tomography allows three-dimensional reconstructions [bib_ref] Change in condylar and mandibular morphology in juvenile idiopathic arthritis: Cone Beam..., Farronato [/bib_ref]. The usefulness of US TMJ imaging is under debate [bib_ref] Early diagnosis of temporomandibular joint involvement in juvenile idiopathic arthritis: a pilot..., Müller [/bib_ref] [bib_ref] Sonographic evaluation of the temporomandibular joints in juvenile idiopathic arthritis(, Melchiorre [/bib_ref]. Hip joint 30. Routine CR of the hip joint is not recommended in patients with pJIA. 31. When CR of a symptomatic hip joint is performed, a single view should be obtained, i.e. either an antero-posterior view or a frog leg view. In RF/ACPA-positive pJIA, hip joint damage is common [48] but CR of the hip joint is associated with a high level of ionising radiation exposure, so the hip is not among the joints for which routine CR is recommended .When available, MRI should be performed instead of, or in addition to, CR. If CR is performed, either an antero-posterior or a frog leg view is recommended, to visualise both hip joints and to allow the detection of bone erosions and/or avascular necrosis. # Discussion CR is the most widely available imaging procedure worldwide. In paediatric patients, this advantage should be weighed against the heightened risks of radiation exposure and difficulty in interpreting joint radiographs before skeletal maturity is achieved. In addition, in JIA, radiographically visible joint damage takes time to develop, limiting the usefulness of CR. Specific recommendations about CR in paediatric patients are therefore needed, a fact that prompted the present work. Obstacles to the development of recommendations about CR in JIA included the paucity of strong evidence about structural disease progression in JIA and the pooling of JIA subtypes in many studies. The low incidence of JIA contributes to explain the dearth of data. To maximise the usefulness of our recommendations to all physicians caring for patients with JIA, we focussed on CR and separated the five non-systemic, nonundifferentiated subtypes of JIA. Importantly, these recommendations are based not only on recently published data, but also, in many cases, on expert opinion, due to the paucity of paediatric studies. As a result, many of our recommendations are low grade, and in some cases obtaining guidance from recommendations for adults would seem to be the only option. However, the level of agreement among the multidisciplinary experts sitting on our panel was high. Structural damage requires evaluation in JIA, especially in pJIA and extended oJIA, which carry the highest risk of adverse outcomes. In the treatment plans for pJIA developed by the CARRA, CR changes are considered an important outcome and their yearly assessment is suggested . However, the risk associated with exposure to ionising radiation during CR is of major concern, as pointed out by the representative of the patient organisation during our study. Little evidence is available on which to base an objective quantification of this risk. Our experts considered that the risk was substantial for CR of the pelvis and lumbar spine but was too small at peripheral sites to constitute an argument against using CR. To minimise radiation exposure, the experts recommended having CR performed at centres with expertise in paediatric radioprotection. Research is needed in a broad range of areas to fill the knowledge gaps we identified when developing our recommendations (Box 2). More specifically, most paediatric clinical trials failed to assess potential treatment effects on structural damage. Also, data on structural damage just before the transition to adult healthcare are needed, since treatment recommendations for adults are based on structural damage. Box 2: Research agenda We considered neither MRI nor US, both of which are under evaluation in JIA. Both are non-irradiating, and US is also widely available and inexpensive, although it requires specific training. US is now performed almost routinely in adults with joint disease. In paediatric patients, however, differentiating normal from abnormal findings by MRI and US can be challenging [bib_ref] MRI thresholds for discrimination between normal and mild temporomandibular joint involvement in..., Ma [/bib_ref] [bib_ref] MRI of the wrist in juvenile idiopathic arthritis: erosions or normal variants?..., Muller [/bib_ref]. Furthermore, very few physicians are specifically trained in paediatric US. The OMERACT and Health-e-Child Radiology groups are currently working together to standardise MRI protocols and interpretation in JIA [bib_ref] MRI Protocol for the Assessment of Juvenile Idiopathic Arthritis of the Wrist:..., Nusman [/bib_ref] [bib_ref] Current Status of Efforts on Standardizing Magnetic Resonance Imaging of Juvenile Idiopathic..., Nusman [/bib_ref] [bib_ref] Preliminary definitions for the sonographic features of synovitis in children, Roth [/bib_ref]. In conclusion, CR still appears relevant in many situations in patients with JIA. CR is a widely available and inexpensive investigation that has an acceptable safety profile and can provide essential information about the structural course of the disease. Until validation studies of other imaging techniques, such as MRI and US, are completed, CR will remain the investigation of reference for assessing structural joint damage in patients with JIA. Statistics and biometry No complex statistical methods, were necessary for this paper. Ethical approval Institutional Review Board approval was not required; the methodology entirely relies on literature review and expert opinion. Informed consent Informed consent was not required because no human subjects were involved. [table] Table 2: Routine CR of the wrists, hands, and forefeet is strongly recommended at the diagnosis of polyarticular JIA with positive RF/ACPA. CR of other joints than wrists, hands, and forefeet, is recommended at the diagnosis for symptomatic joints only. In new-onset RF/ACPA-negative pJIA with adverse prognostic factors, CR at diagnosis should be performed as for RF/ACPA-positive pJIA (recommendation #7). At other time points, the use of CR during follow-up is at the discretion of the physician. During the follow-up of RF/ACPA-negative pJIA with adverse prognostic factors, CR should be performed as for RF/ACPA-positive pJIA (recommendation #12). [/table]	None	https://link.springer.com/content/pdf/10.1007/s00330-018-5304-7.pdf	None
12c07578361b0b8e393861cf4aa7c8858db86119	pubmed	COVID-19 FAQs in paediatric and congenital cardiology: AEPC position paper	COVID-19 FAQs in paediatric and congenital cardiology: AEPC position paper The COVID-19 pandemic has had a huge influence in almost all areas of life, affecting societies, economics, and health care systems worldwide. The paediatric cardiology community is no exception. As the challenging battle with COVID-19 continues, professionals from the Association for the European Paediatric and Congenital Cardiology receive many questions regarding COVID-19 in a Paediatric and Congenital Cardiology setting. The aim of this paper is to present the AEPC position on frequently asked questions based on the most recent scientific data, as well as to frame a discussion on how to take care of our patients during this unprecedented crisis. As the times are changing quickly and information regarding COVID-19 is very dynamic, continuous collection of evidence will help guide constructive decision-making.It is now more than a half year since the COVID-19 pandemic started to influence almost all areas of life, affecting societies, economics, and healthcare worldwide and it is likely that we will have to endure this for a long time ahead.Many questions have arisen regarding patients with CHD, with respect to increased susceptibility to the coronavirus, the risk of more severe disease in the presence of CHD, the value of testing, and regarding recent reports on the inflammatory disease with some Kawasaki features.The aim of this paper is to present the AEPC position on frequently asked questions regarding COVID-19 in a Paediatric and Congenital Cardiology setting, based on continuous monitoring and evaluation of scientific papers. It should be kept in mind that times are changing fast and this paper has been written with the best evidence available at the time of writing. The AEPC position will be updated in the future according to further evidence in the literature.Methods: This manuscript has been reviewed and approved by the AEPC Council for publication in Cardiology in the Young as an official position paper of AEPC. Which paediatric and grown-up CHD groups are at major risk for COVID-19 infection? Despite the large number of cases with COVID-19, little is known about the risk and effects in children as well as adults with CHD. However, it seems that children have a substantially better prognosis than adults with cardiovascular risk factors. According to a recent multicentre cross-sectional study from 46 centres within The United States of America and Canada, the overall ICU mortality of COVID-19 in children is less than 5%, compared with published mortalities of 50-62% in adults admitted to the ICU. These conclusions were drawn from 48 critically ill children with COVID-19, of whom more than 80% had significant comorbidities including CHD. [bib_ref] Characteristics and outcomes of children with Coronavirus Disease 2019 (COVID-19) infection admitted..., Shekerdemian [/bib_ref] Data from China suggests the same tendency towards better survival and outcomes from critical illness in infants and children than reported for adult patients. [bib_ref] Epidemiology of COVID-19 among children in China, Dong [/bib_ref] [bib_ref] SARS-CoV-2 infection in children, Lu [/bib_ref] The British Congenital Cardiac Association has published recommendations for precautions for some groups with other infections in CHD patients, based on existing knowledge from diseases, which have been extrapolated to the COVID-19 situation. According to the British Congenital Cardiac Association recommendations, the following CHD patient groups are estimated to be at high risk for a severe disease course with an increased risk for a negative outcome and should be particularly strict in following the social distancing and hygiene measures: - Single-ventricle patients. - Infants under 1 year with unrepaired CHD requiring surgery or catheter intervention. - Patients with chronic cyanosis (oxygen saturations <85% persistently). - Patients with severe cardiomyopathies. - Patients with CHD on medication for heart failure. - Patients with pulmonary hypertension. - Patients after heart transplantation. - Patients with CHD and significant comorbidities, e.g., chronic kidney disease, chronic lung disease. 12 - Grown-up CHD patients with Down's syndrome have a 4fold increased risk to be admitted to hospital and a 10-fold increased risk for COVID-19-related death. [bib_ref] COVID-19 mortality risk in down syndrome: results from a cohort study of..., Clift [/bib_ref] What is known about a potential cardiac pathology related to COVID-19 in children? To date, cardiac pathology in children has been described in very few cases beyond the systemic inflammatory disease, and in general cases, fatality is low. Tissue damage to lungs, heart, and other organs caused by SARS-CoV-2 is induced by binding of the virus with its surface spike glycoprotein to the host angiotensin-converting enzyme 2 receptor. In the human heart, the receptors are localised at the pericytes and their injury can lead to secondary capillary endothelial dysfunction, which is responsible for cardiac pathology. 14 Amongst several theories of protective mechanisms in the paediatric age group, the lower number and immaturity of angiotensin-converting enzyme 2 in children has been speculated to be one of the reasons for the milder nature of COVID-19. [bib_ref] A pneumonia outbreak associated with a new coronavirus of probable bat origin, Zhou [/bib_ref] Clinical symptoms of myocardial damage in adults affected with COVID-19 are rhythm disorders, hypotension, and cardiogenic shock. Biomarkers like troponin, creatine kinase, and lactate dehydrogenase are elevated. Acute myocarditis has been suspected in adults as myocardial interstitial oedema and diffuse late gadolinium enhancement could be documented. [bib_ref] Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19), Inciardi [/bib_ref] It remains obscure whether all cardiac pathologies are related to the primary viral attack on cardiomyocytes or whether it is the result of proinflammatory cytokines and systemic inflammatory response. Fulminant acute myocardial necrosis and mononuclear cell infiltration have been described, but only rarely have virus particles been demonstrated in myocardial tissue. [bib_ref] Myocardial localization of coronavirus in COVID-19 cardiogenic shock, Tavazzi [/bib_ref] Together with a timely delayed presentation of symptoms (10-15 days), these findings might be interpreted in favour of inflammation-mediated myocardial injury rather than induced by the cytopathic effect of the virus. [bib_ref] COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment..., Guzik [/bib_ref] Hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy are reported to contribute to increased severity of COVID-19, not only in respiratory but also in cardiac failure. [bib_ref] Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for..., Henry [/bib_ref] In this context, impaired cardiac function, vasculitis, and septic shock as well as features of a Kawasaki disease shock syndrome have also been described in children, with distinct differences in inflammatory markers. While coronary involvement was variable, depressed left ventricular function, pericardial effusion, and arrhythmia were the main findings. [bib_ref] Hyperinflammatory shock in children during COVID-19 pandemic, Riphagen [/bib_ref] [bib_ref] An outbreak of severe Kawasaki-Like disease at the Italian epicentre of the..., Verdoni [/bib_ref] The special characteristics of the delayed immune response after COVID-19, named MIS-C are provided in question 4. It was recently published that SARS-CoV-2 could be isolated from cardiac tissue in a child that died within a COVID-19-related multisystem inflammatory syndrome. [bib_ref] SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome, Dolhnikoff [/bib_ref] The timeline of the symptoms, in that case, does not rule out completely that the patient was in the acute phase of COVID-19 rather than MIS-C when myocardial evidence of the virus was detected. What are the possible inflammatory heart diseases related to COVID-19 in the paediatric age group? In the frame of the actual COVID-19 pandemic, an increasing number of children were admitted for clinical symptoms of the condition termed multisystem inflammatory syndrome (also referred to as paediatric multisystem inflammatory syndrome, paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2, paediatric hyperinflammatory syndrome, or paediatric hyperinflammatory shock). [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] These reports came specifically from countries with a high number of SARS-CoV-2 infections, such as Italy, Spain, the United Kingdom, and the United States of America. Understanding of COVID-19 infection and multisystem inflammatory syndrome is evolving. Guidance has been issued and consistently renewed by the World Health Organization and the Centers for Disease Control and Prevention. An association to a SARS-CoV-2 infection or a secondary reaction has been discussed and according to the most recent literature, multisystem inflammatory syndrome manifests temporarily in association with SARS-CoV-2, appearing about 3-4 weeks after the acute infection. [bib_ref] Multisystem inflammatory syndrome in U.S. children and adolescents, Feldstein [/bib_ref] [bib_ref] COVID-19-associated multisystem inflammatory syndrome in Children -United States, Godfred-Cato [/bib_ref] This may explain why many children had positive antibodies to SARS-CoV-2, but a negative reverse transcription-polymerase chain reaction on swab analysis at the time of multisystem inflammatory syndrome evaluation. Severe manifestation of COVID-19 in the paediatric age group is, in general, rare. The described severe cases do not present the first line with pulmonary symptoms, but with an untypical inflammatory reaction and gastrointestinal complaints. The cardiovascular system is affected by a vasculitis and in some cases by myocardial dysfunction. The clinical presentation shows overlapping features of a toxic shock syndrome and Kawasaki syndrome (or atypical one), and the criteria for Kawasaki disease do not apply fully for diagnosis. Clinical data on multisystem inflammatory syndrome provide evidence that although multisystem inflammatory syndrome and Kawasaki disease seem to be based on an increased inflammatory reaction, multisystem inflammatory syndrome differs from other paediatric inflammatory syndromes. [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] Some patients are described who have presented with a refractory vasodilatory shock syndrome with normal cardiac function. Not uncommonly children can present with septic or cardiogenic shock and impaired cardiac function (mainly left ventricular). Different organisations, such as the World Health Organization, the Centers for Disease Control and Prevention, and the Royal College of Paediatrics and Child Health have published definitions of the multisystem inflammatory syndrome, which are in slight variance from each other. [bib_ref] Hyperinflammatory shock in children during COVID-19 pandemic, Riphagen [/bib_ref] [bib_ref] An outbreak of severe Kawasaki-Like disease at the Italian epicentre of the..., Verdoni [/bib_ref] As a reference, [fig_ref] Table 1: WHO and CDC definitions of the multisystem inflammatory syndrome in children [/fig_ref] summarises the definitions for MIS-C of the WHO and CDC. The definitions of multisystem inflammatory syndrome in children from the World Health Organization 25 and Centers for Disease Control and Prevention 24 are summarised in this table. The CDC also comments that some individuals may fulfil full or partial criteria for Kawasaki disease, but should be reported if they meet the case definition for MIS-C. MIS-C should be considered in any paediatric death with evidence of SARS-CoV-2 infection. It seems that important differences occur in clinical and laboratory findings, which distinguish multisystem inflammatory syndrome from other paediatric inflammatory syndromes, such as Kawasaki disease, Kawasaki disease shock syndrome, and toxic shock syndrome. [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] The following major laboratory findings are described to characterise a potential multisystem inflammatory syndrome in comparison to Kawasaki disease 29 : - anaemia, lymphopenia, - elevated leucocytes and neutrophils, - normal or low platelets, - elevated fibrinogen and ferritin, - elevated troponin, N-terminal pro-b-type natriuretic peptide, - decreased albumin, - elevated interleukin 6, C-reactive protein, - lymphocytic myocarditis. Patients with the suspected multisystem inflammatory syndrome should undergo recommended diagnostic blood, urine, virology, bacteriology, serology, echocardiography, and sonography tests at admission. [fig_ref] Figure 1: Summarises the indicated diagnostic investigations and the potentially considered ones depending on... [/fig_ref] shows a diagnostic algorithm. Treatment strategies of the multisystem inflammatory syndrome are as follows: - Anti-inflammatory treatment: steroids, intravenous immunoglobulin, aspirin, and possibly interleukin 6 inhibitors. - Shock: inotropes, management of cardiac dysfunction. - Anti-platelet and anti-coagulation therapy: enoxaparin and others. The aetiology is not yet conclusive and might be in accordance with the inflammatory reaction seen with a delay in adults. Similar to the results of genetic analysis in Kawasaki research, the origin of the inflammation might be associated with genes that regulate the rate of production of T-cells or antibody responses or the clearing of antibody and immune complexes. [bib_ref] Hyperinflammatory shock in children during COVID-19 pandemic, Riphagen [/bib_ref] [bib_ref] An outbreak of severe Kawasaki-Like disease at the Italian epicentre of the..., Verdoni [/bib_ref] What is known about the potential management of arrhythmia syndromes and anti-arrhythmic medications in children? SARS-CoV-2 infection may occur in patients with channelopathies, e.g., congenital long QT syndrome, Brugada syndrome, 3. Clinical signs of multisystem involvement (at least two of the following): 3. Clinical presentation consistent with MIS-C, including all of the following: Rash or bilateral non-purulent conjunctivitis, or mucocutaneous inflammation signs (oral, hands, or feet). Evidence of clinically severe illness requiring hospitalisation, with multisystem (>2) organ involvement. Hypotension or shock. Cardiovascular, renal, neurologic, haematologic, gastrointestinal, or dermatologic system. Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated troponin/NT-proBNP). 4. Laboratory incidence of inflammation including, but not limited to any of the following: Evidence of coagulopathy (prolonged prothrombin time or partial thromboplastin time, elevated D-dimer). Elevated: C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, interleukin 6, neutrophils. catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome, with a risk of pro-arrhythmia. [bib_ref] SARS-CoV-2, COVID-19, and inherited arrhythmia syndromes, Wu [/bib_ref] In the setting of long QT syndrome with COVID-19, the QT interval should be monitored closely because the combination of drugs (Hydroxychloroquine and Azithromycin) and stress factors (electrolyte disturbances and kidney dysfunction) may further prolong QT.Fever-triggered malignant ventricular arrhythmia is the major concern in Brugada syndrome with COVID-19, therefore, fever should be aggressively treated with paracetamol. [bib_ref] COVID-19 Infection Unmasking Brugada Syndrome, Chang [/bib_ref] In patients with catecholaminergic polymorphic ventricular tachycardia and COVID-19, beta-blockers and flecainide should be continued with monitoring of drug interactions with the above-mentioned drugs.Is there an increased patient risk for cardiac surgery/ cardiac intervention/heart transplantation during the COVID-19 pandemic? The incidence of COVID-19 remains low in children. Numbers are quoted to be between 2 and 12% (depending on testing), with a generally milder course, but with variable symptoms that may mask the viral infection and cause a delay in making the diagnosis. Despite common-sense judgement that pre-existing cardiac diseases should impose children with CHD to a higher risk, this has only rarely been demonstrated to date. [bib_ref] Zeichner SL COVID-19 in Children: initial characterization of the pediatric disease, Cruz [/bib_ref] The following strategies should minimise the risk of cardiac surgery during the COVID-19 pandemic: - Prioritisation of cardiac surgery, leaving the surgical activity to urgent and emergency procedures. - Full personal protective equipment should be mandatory for staff who is performing a cardiac intervention for COVID-19positive patients. Paediatric heart catheterisation and intervention in COVID-19 patients have been required in exceptional circumstances. Elective cases have, in general, been postponed from the beginning of the pandemic. Meanwhile, as the numbers of affected children remain low, it seems reasonable to activate the programmes while continuing to use personal protective equipment and following institutional flow algorithms for COVID-19 patients, including switch to a negative pressure environment in the catheter laboratory if possible. A comprehensive guidance paper addresses most aspects of decision-making and resource allocation. [bib_ref] Resource allocation and decision making for pediatric and congenital cardiac catheterization during..., Morray [/bib_ref] The subgroup of adults with CHD are likely to have the highest risk within patients with CHD 6 as, at least in complex cases, premature ageing of the heart may be present together with limited cardiac reserve, thus lacking the advantage of children that are, in general, less susceptible to symptomatic SARS-CoV-2 infections. Heart transplantation/immunosuppression: while immunosuppression, in general, enhances the risk for viral infections and increased severity, as has been described for younger children with influenza, there's no supporting evidence in SARS-CoV-2. Data from solid organ transplantation do not show that immunosuppression during the COVID-19 pandemic leads to a less favourable outcome. Immunocompromised children, for example, those treated for cancer, only rarely needed modifications of their treatment. Accepting that not all patients are tested for COVID-19 at least symptomatic worsening has not been observed. [bib_ref] SARS-CoV-2 disease and children under treatment for cancer, Terenziani [/bib_ref] Nevertheless, transmission precautions are of paramount importance and should be strictly followed until further knowledge of SARS-CoV-2 impact on the immune system is available. 35 What is known about possible fetal COVID-19 transmission? Impact of postnatal testing and treatment especially in the setting of critical CHD? Currently, criteria for vertical transmission have not been developed. Based on limited data, viremia rates in patients with COVID-19 appear to be low and transient, suggesting placental seeding and vertical transmission are unlikely. [bib_ref] Detection of SARS-CoV-2 in different types of clinical specimens, Wang [/bib_ref] In a few recent review articles on pregnant women with COVID-19, no cases of vertical transmission have been registered. [bib_ref] An analysis of 38 pregnant women with COVID-19, their newborn infants, and..., Schwartz [/bib_ref] [bib_ref] Coronavirus disease 2019 during pregnancy: a systematic review of reported cases, Gatta [/bib_ref] [bib_ref] Coronavirus disease 2019 in pregnancy, Qiancheng [/bib_ref] A few newborn COVID-19 cases have been reported based on elevated immunoglobulin M levels and/or pneumonia on days 1 or 2 of life, with either negative or not performed COVID-19 testing on fetal blood, amniotic fluid, and placenta. [bib_ref] Association of COVID-19 with pregnancy outcomes in health-care workers and general women, Khan [/bib_ref] [bib_ref] Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn, Dong [/bib_ref] [bib_ref] Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with..., Zeng [/bib_ref] [bib_ref] Antibodies in infants born to mothers with COVID-19 pneumonia, Zeng [/bib_ref] However, it is not reliable to diagnose congenital COVID-19 based only on immunoglobulin M detection because immunoglobulin M assays can be false-positive and cross-reactivity may occur. The most likely cause of positive immunoglobulin M in many of those cases could be related to early infant infection due to postnatal contact with infected parents rather than fetal transmission. [bib_ref] CoV-2 infection be acquired in utero? More definitive evidence is needed, Kimberlin [/bib_ref] Even though there is no reliable data to confirm vertical COVID-19 transmission, the Centers for Disease Control and Prevention recommend that newborns born to mothers with known COVID-19 at the time of delivery should be considered to have suspected COVID-19 and should be tested and isolated from other healthy infants.It is equally important to ensure that a neonate with critical CHD born to a mother with COVID-19 is managed in a timely manner and that testing for COVID-19 does not prolong or delay transfer to a tertiary centre with a neonatal CHD ICU able to deliver high quality and timely management of critical CHD. Which groups of medication are thought to be potentially effective for COVID-19 treatment in paediatric age group? There is a lack of data supporting the efficacy of antiviral agents for the treatment of COVID-19 in children, though there are recommendations available from multicentre initial guidance on the use of antiviral agents in children. [bib_ref] Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2, Chiotos [/bib_ref] [bib_ref] A call for pediatric COVID-19 clinical trials, Campbell [/bib_ref] Given the typically mild course of paediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. Antiviral therapy generally should be reserved only for symptomatic children or those with underlying conditions with a high risk of disease progression. ## Antiviral drugs Remdesivir inhibits ribonucleic acid-dependent ribonucleic acid polymerase and has activity against coronaviruses. According to a multicentre panel, Remdesivir is preferred to other antiviral agents due to its better tolerance and beneficial effects in adults with COVID-19. Hence, the same assumption is being made for children, even though data regarding the benefits of Remdesivir for children with COVID-19 are lacking. On 22 October, 2020, the United States of America Food and Drug administration has approved Remdesivir to treat COVID-19 for use in adults and children 12 years of age and older and weighing at least 40 kg requiring hospitalisation. Lopinavir/Ritonavir is not recommended for children due to the absence of efficacy and unfavourable pharmacodynamics and negative clinical trial data. [bib_ref] A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19, Cao [/bib_ref] ## Immune modulators for adjunctive therapy The benefits and risks of immune modulators (e.g., glucocorticoids, interleukin 6 inhibitors, interferon-beta 1b) and of convalescent plasma from recovered COVID-19 patients in the treatment of children with COVID-19 are uncertain. The use of these medications is referred only on a case-by-case basis according to disease severity. The routine use of COVID-19 patients is not recommended. The cytokine profiles of serum from some patients with moderate-to-severe COVID-19 overlap with those seen in macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis. Thus, interleukin 6 and interleukin 1 blockades and Janus kinase inhibition has been proposed as an approach to treat the systemic inflammation associated with severe COVID-19 illness. [bib_ref] COVID-19: consider cytokine storm syndromes and immunosuppression, Mehta [/bib_ref] Corticosteroids are reserved only for critically ill patients with COVID-19. There is insufficient evidence for or against systemic corticosteroids for mechanically ventilated patients with acute respiratory distress syndrome (CI), and for adults with COVID-19 and refractory shock. The National Institutes of Health recommends using low-dose corticosteroid therapy (BII).The safety and effectiveness of dexamethasone for paediatric COVID-19 treatment have not been sufficiently evaluated as the Recovery trial did not include a significant number of children. According to the recent National Institutes of Health statement, dexamethasone is not generally recommended for children who require only low levels of oxygen support. On the other hand, dexamethasone may be beneficial in difficult cases where mechanical ventilation is required. Additional studies are needed to evaluate the use of steroids for the treatment of COVID-19 in children, including for multisystem inflammatory syndrome in children. [bib_ref] Dexamethasone in hospitalized patients with Covid-19 -preliminary report, Group [/bib_ref] Anticoagulation Patients with MIS-C are at risk of experiencing thrombotic complications. Especially in the setting of severe LV dysfunction, there is a higher risk for apical LV thrombus. And those with Kawasaki disease who have large or giant CA aneurysms are at risk for myocardial infarction. Additionally, hypercoagulability is associated with COVID-19, thus patients may be at risk for venous thromboembolism. A minimum required treatment for Kawasaki disease includes low-dose aspirin. Systemic anticoagulation may be used for patients with moderate-to-severe LV dysfunction. VTE prophylaxis should be recommended for older children and adolescents hospitalised with moderate-to-severe MIS-C only with calculated low bleeding risk. There is evidence that low-molecular-weight heparins appear to be associated with better prognosis in patients with moderate-to-severe COVID-19-induced coagulopathies or elevated D-dimer levels. A weak recommendation of subcutaneous enoxaparin use in mild to high risk of VTE was recommended in COVID-19 PICU guidelines. [bib_ref] COVID-19 PICU guidelines: for highand limited-resource settings, Kache [/bib_ref] Anticoagulation therapy should be coordinated with paediatric intensivists, haematologists, and paediatric interventional cardiologists. [bib_ref] COVID-19 anticoagulation recommendations in children, Loi [/bib_ref] There is no available data on the use of vitamin A for COVID-19; however, it is recommended to be used as an adjunctive agent for COVID-19 patients due to its effect on decreased morbidity and mortality from measles-associated pneumonia. [bib_ref] A randomized, controlled trial of vitamin A in children with severe measles, Hussey [/bib_ref] *Rating of Recommendations: A = Strong; B = Moderate; C = Optional. Rating of Evidence: I = One or more randomised trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, non-randomised trials or observational cohort studies; III = Expert opinion. ## Cardiology in the young Are there medications to be avoided in paediatric and adult CHD patients that might worsen the outcome of COVID-19? The potential experimental therapies for COVID-19 have important cardiovascular side effects and toxicities. Data for these side effects are extrapolated from patients treated for autoimmune diseases (Chloroquine/Hydroxychloroquine, Rocilizumab), hepatitis (Ribavarin, Interferon alfa), or human immunodeficiency virus infection (Lopinavir/Ritonavir). [bib_ref] COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment..., Guzik [/bib_ref] Azithromycin, Hydroxychloroquine, and Lopinavir/Ritonavir can cause conduction disorders, especially QT prolongation. The combination of Hydroxychloroquine and Azithromycin is not recommended due to a synergistic effect increasing the risk of severe arrhythmia and deleterious impact on the cardiovascular system.The QT interval should be monitored closely, especially in the setting of long QT syndrome with COVID-19.Other adverse cardiac events related to these drugs are less common, but include the following: ventricular hypertrophy, hypokinesia, heart failure, pulmonary arterial hypertension, and valvular dysfunction. Irreversible myocardial damage is seen in 12.9%, death in 30.8%, however, cardiac function normalises in the majority of patients (44.9%) upon withdrawal of Chloroquine and Hydroxychloroquine. [bib_ref] COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment..., Guzik [/bib_ref] [bib_ref] Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the..., Chatre [/bib_ref] On 17 June, 2020, the World Health Organization announced to stop the use of Hydroxychloroquine for COVID-19 patients, which was based on data from Solidarity and the Recovery trials. Both showed that Hydroxychloroquine does not result in the reduction of mortality of hospitalised COVID-19 patients, when compared with standard care.Lopinavir/Ritonavir may interact with antiplatelets, oral anticoagulants, digoxin, statins, and many others as it is a potent liver enzyme (CYP3A4) inhibitor.Tocilizumab has been shown to influence lipid metabolism in rheumatoid arthritis patients. However recently, the ENTRACE clinical trial supported the cardiovascular safety of Tocilizumab in these patients. [bib_ref] Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled..., Giles [/bib_ref] Interleukin 6 targeting has not been tested for secondary prevention in cardiovascular disease. There is no evidence that angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor neprilysin inhibitors or low-dose acetylsalicylic acid worsen outcomes in patients with confirmed or suspected COVID-19 or increase susceptibility to COVID-19. COVID-19 is not an indication to stop angiotensin-converting enzyme inhibitors/ Angiotensin II receptor blockers/angiotensin receptor neprilysin inhibitors or low-dose acetylsalicylic acid as stopping these medications may cause worsening of patient's heart condition, unless symptomatic hypotension or shock, acute kidney injury, or hyperkalemia appears.This applies to children, adolescents, and adults. According to the British Congenital Cardiac Association, the Canadian Cardiovascular Society, and other organisations, patients with heart failure and hypertension should preferentially choose acetaminophen over non-steroidal anti-inflammatory drugs for fever or pain to avoid decompensation of these cardiovascular conditions; however, there is yet no firm evidence.Fever-triggered malignant ventricular arrhythmia is the major concern in Brugada syndrome with COVID-19 infection, therefore, fever should be aggressively treated with paracetamol. [bib_ref] COVID-19 Infection Unmasking Brugada Syndrome, Chang [/bib_ref] In patients with catecholaminergic polymorphic ventricular tachycardia and COVID-19, beta-blockers and flecainide should be continued with monitoring of drug interactions with antiviral drugs.Preventive measures for CHD-patients? Should CHD patients of any age group be kept in strict and extensive isolation? What is the progress of COVID-19 vaccine development? The British Congenital Cardiac Association has suggested that adults and children with CHD, within the groups mentioned in the answer of question 1, should be considered more vulnerable to COVID-19 and other infections, and should therefore be particularly strict in following the social distancing and hygiene measures.Based on definitions of social distancing, this would exclude the attendance of such individuals at nurseries, school, college, or universities. Socialising with family, going to restaurants, and children's parties should be avoided as well. Children who do not fall into the mentioned groups should not be more likely to become infected with COVID-19 and there is no evidence of higher risk of complications, thus general rules of preventive measures should be applied.On 22 September, 2020 the World Health Organization made an announcement of approximately 38 COVID-19 vaccines in clinical trials and 149 in preclinical evaluation.What limitations are paediatric cardiologists facing in terms of CHD diagnostics and treatment in the presence of symptomatic COVID-19? Not only have non-invasive cardiological diagnostic procedures been limited to urgent and emergency situations, but also paediatric/congenital catheterisation laboratories have dramatically reduced case volumes by postponing elective procedures. [bib_ref] Resource allocation and decision making for pediatric and congenital cardiac catheterization during..., Morray [/bib_ref] Hence, availability of catheterisation is limited in the vast majority of centres. Cardiac centres in regions with greater COVID-19 prevalence are more likely to delay urgent, but not emergency case types. The decision regarding urgent cardiac surgery is expected to be based on a multidisciplinary team decision and if possible, surgery should be delayed until the patient's symptoms have improved and/or testing has been repeatedly negative. [bib_ref] COVID-19 FAQ's in pediatric cardiac surgery, Levy [/bib_ref] Summary The data regarding the COVID-19 crisis is being updated constantly. However, there is a scarce number of publications addressing the management of children with cardiac pathology. Hence, AEPC officers have been frequently asked various questions related to COVID-19 and patients with CHD. This led to the publication of FAQs and expert answers based on the most recent available literature sources. The goal of this document is to frame a discussion on how to take care of children with cardiac pathology in the setting of COVID-19 during this unprecedented crisis. As the times are changing quickly and information regarding COVID-19 is very dynamic, continuous collection of evidence will help guide constructive decision-making. [fig] •: Avoid the delay of urgent cardiac surgery. CHD patients planned for cardiac surgery if not an emergency should have tested negative for SARS-Cov-2 reverse transcription-polymerase chain reaction. Test-and symptom-based precautions to avoid transmission: separation of positive-tested COVID-19 patients from non-COVID-19 patients irrespective of symptoms. Staff working in rotations. [/fig] [fig] Figure 1: Summarises the indicated diagnostic investigations and the potentially considered ones depending on the clinical presentation in patients with suspicion of the multisystem inflammatory syndrome. [/fig] [table] Table 1: WHO and CDC definitions of the multisystem inflammatory syndrome in children.MIS-C definition of WHO MIS-C definition of CDCRequired: all six criteria Required: all four criteria 1. Children's age 0-19 years. 1. Age <21 years. 2. Fever for ≥3 days. 2. Fever: documented >38.0°C ≥ 24 hours or reported subjective fever lasting ≥24 hours. [/table]	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/4F4C18B09B9D62A22B6972CB12457323/S1047951120005028a.pdf/div-class-title-covid-19-faqs-in-paediatric-and-congenital-cardiology-aepc-position-paper-div.pdf	The COVID-19 pandemic has had a huge influence in almost all areas of life, affecting societies, economics, and health care systems worldwide. The paediatric cardiology community is no exception. As the challenging battle with COVID-19 continues, professionals from the Association for the European Paediatric and Congenital Cardiology receive many questions regarding COVID-19 in a Paediatric and Congenital Cardiology setting. The aim of this paper is to present the AEPC position on frequently asked questions based on the most recent scientific data, as well as to frame a discussion on how to take care of our patients during this unprecedented crisis. As the times are changing quickly and information regarding COVID-19 is very dynamic, continuous collection of evidence will help guide constructive decision-making.
7dfee99f7790a29cf6a2078ffa298922ad929358	pubmed	Saudi Oncology Society clinical management guideline series	Saudi Oncology Society clinical management guideline series King Fahad Specialist Hospital, Dammam, and the Department of Oncology (Al-Shehri) 11211. 2014 MBBSbazarbashi@gmail.com MBChB, FRCRMDPhDMBChB, FRCPCMDMBChBMBBS, FRCSCPhDMBBCh, FRCP (UK)MBBSMDMD, FRCPCKing Fahad Specialist Hospital, Dammam, and the Department of Oncology (Al-Shehri) Princess Nora Oncology Center, King Abdulaziz Medical City Jeddah, Kingdom of Saudi Arabia; Riyadh335411442393511211. 2014Received 15th July 2014. Accepted 13th October 2014.Address correspondence and reprint request to: Dr. Shouki N. 1538 C olorectal cancer ranked first in incidence among Saudi males and third among Saudi females for the last several years according to Saudi Cancer Registry data.A total of 1033 cases accounting for 10.4% of all newly diagnosed cases were reported in 2010.The overall age standardized rate (ASR) was 9.6/100,000 with ASR of 9.9/100,000 for males and 9.2/100,000 for females. The median age at diagnosis was 60 years for males (range 2-100 years) and 55 years for females (range 13-100 years).A committee of experts in the medical and surgical treatment of colorectal cancer was established under the supervision of the Saudi Oncology Society (SOS). The evidence adopted in these guidelines is rated at 3 levels: 1) Evidence level-1 (EL-1) (highest level) evidence from phase III randomized trials or meta-analyses; 2-EL-2 (intermediate-level) evidence from good phase II trials or phase III trials with limitations; and 3-EL-3 (low-level) from retrospective or observational data and/or expert opinion. This easy-to-follow grading system is convenient for the reader and allows accurate assessment of the applicability of the guideline in individual patients.Ultimately, it was agreed that all colorectal cancer cases are preferably seen or discussed in a multidisciplinary form In case of violation of any of the above, surgery should be offered. If surgery is not an option, adjuvant chemoradiotherapy should be offered (EL-3) 4.2.3. All clinically T3-4 or N positive lesions will receive pre-operative concurrent chemoradiotherapy. The irradiation will consist of 5040 cGy in 28 fractions and the chemotherapy will consist of capecitabine or infusional 5-Fluorouracil 16 (EL-1). Surgery will be performed 6-8 weeks after the end of radiation therapy. Short course radiation 2500 cGy in 5 fractions with surgical resection in one week can be considered if sphincter saving is not an option 17 (EL-1) [bib_ref] Capecitabine as adjuvant treatment for stage III colon cancer, Twelves [/bib_ref]	None	None	OPEN ACCESS C olorectal cancer ranked first in incidence among Saudi males and third among Saudi females for the last several years according to Saudi Cancer Registry data. 1 A total of 1033 cases accounting for 10.4% of all newly diagnosed cases were reported in 2010. 1 The overall age standardized rate (ASR) was 9.6/100,000 with ASR of 9.9/100,000 for males and 9.2/100,000 for females. The median age at diagnosis was 60 years for males (range 2-100 years) and 55 years for females (range 13-100 years). 1 A committee of experts in the medical and surgical treatment of colorectal cancer was established under the supervision of the Saudi Oncology Society (SOS). The evidence adopted in these guidelines is rated at 3 levels: 1) Evidence level-1 (EL-1) (highest level) evidence from phase III randomized trials or meta-analyses; 2-EL-2 (intermediate-level) evidence from good phase II trials or phase III trials with limitations; and 3-EL-3 (low-level) from retrospective or observational data and/or expert opinion. This easy-to-follow grading system is convenient for the reader and allows accurate assessment of the applicability of the guideline in individual patients. 4 Ultimately, it was agreed that all colorectal cancer cases are preferably seen or discussed in a multidisciplinary form 1. Pre-treatment evaluation: 1.1. Clinical examination, including rigid proctosigmoidoscopy for rectal cancer 1.2. Blood count, liver, and renal function tests 1.3. Chest x-ray 1.4. Carcinoembryonic antigen (CEA) level 1.5. CT scan of abdomen and pelvis (including chest in rectal cancer cases) 1.6. Full length colonoscopy 1.7. Transrectal ultrasound and magnetic resonance imaging (MRI) for rectal cancer Rectal cancer will be defined as tumors within 15 cm from the anal verge on rigid proctosigmoidoscopy, and below the sacral promontory on computed tomography (CT) scan.
6669d688503eaa92ffcc0b2573c4b2750be567f8	pubmed	Clinical practice guideline for diagnosis and treatment of hyperplasia of the mammary glands: Chinese Society of Breast Surgery (CSBrS) practice guideline 2021	Clinical practice guideline for diagnosis and treatment of hyperplasia of the mammary glands: Chinese Society of Breast Surgery (CSBrS) practice guideline 2021 ## Level of evidence and recommendation strength Level of evidence standardRecommendation strength standardRecommendation strength review committee There were 85 voting committee members for this guideline, including 71 breast surgeons (83.5%), four oncologists (4.7%), four radiologists (4.7%), two pathol-ogists (2.4%), two radiation therapists (2.4%), and two epidemiologists (2.4%). ## Target audience Clinicians specializing in breast diseases in China. ## Recommendations Recommendation 1: Definition. ## Definition ## Level of evidence # Strength of recommendation Non-inflammatory and non-tumorous lesions of the mammary glandsII Strong Breast radiography,x I A 3.5 Breast magnetic resonance imaging,jj I A 3.6 Histopathological examinations, ¶ I A * Patient history includes the following: breast symptoms, other concomitant symptoms, duration of symptoms, factors associated with aggravation/relief of symptoms, past history of breast or ovarian diseases, family history of breast cancer, and history of intake of reproductive hormones/oral contraceptives. In patients with breast pain, the following information is needed: type, duration, location, and severity of pain and its relationship to menstruation. History of reproductive hormones/ contraceptive use. † The breast examination should consist of inspection and palpation and be performed in both the upright and supine positions. ‡ Ultrasonography is much better than breast radiography for resolving nodes, cysts, and solid tumors in dense breasts. x Radiography is an important modality for detecting early carcinoma and microcarcinoma, and effective for revealing microcalcifications. jj Breast magnetic resonance imaging (MRI) is more sensitive but with a higher false positive rate than ultrasonography and breast radiography, so it should be used as a supplementary examination for high-risk patients. ¶ Breast biopsy techniques include core needle biopsy (CNB), vacuum-assisted breast biopsy (VABB), and excisional biopsy. Non-medical treatments such as including psychological counseling and counseling on changes in diet and lifestyleI A 4.3 Symptomatic treatmentsII A # Discussion HMG shows diverse, complicated, and non-specific histopathology findings, which have led to confusing definitions and terminology. After discussion, the expert panel voted to recommend the term "hyperplasia of the mammary glands (HMGs)." It defined "HMG" as a type of non-inflammatory and non-tumorous lesion of the mammary gland that is a structural disorder of the mammary glands associated with mammary parenchymal and stromal hyperplasia with subinvolution of different degrees.The major signs/symptoms of HMG are as follows: cyclical/non-cyclical breast pain, nodular breast or nodular breast mass, with nipple discharge in some patients.A nodular breast includes the following: granular nodules, striped nodules, solitary mass, or locally or diffusely thickened breast. Palpation of a unilateral breast or bilateral breasts reveals solitary or multiple firm nodules which have an unclear boundary and demonstrate cyclic changes in their nature and size over the menstrual cycle. The diagnosis of HMG is based on exclusion of other conditions, detailed history and systematic examination, clinical manifestations, auxiliary examinations, and histopathological examination of a biopsy specimen.Recommendations of Imaging and Pathological Diagnosis Methods were showed in the Supplementary file, http:// links.lww.com/CM9/A559. Imaging is an important step in the diagnosis of HMG, and aims to exclude other relevant diseases, especially breast cancer. On ultrasonography, HMG manifests as thickened and enhanced echoes, internal hypoechoic nodes with irregular and unclear margins, or no attenuation or slight enhancement of posterior echoes; color Doppler ultrasonography only reveals a few punctiform or short rod-like blood-flow signals.In more than 50% of patients with HMG and obvious masses on palpation, radiography has revealed massive high-density shadows or nodular shadows without visible borders that are sometimes accompanied by calcifications.However, dense breast tissues reduce the sensitivity of breast radiography for detecting lesions, especially malignant lesions, and the dense tissue may obscure miniature suspicious foci. Breast MRI can be used as a supplementary examination for women who are unsuitable for breast ultrasonography or radiography or at a high risk of breast cancer with negative findings on breast ultrasonography and radiography.HMG manifests complicated and diverse histopathology findings, which leads to controversy in its classification. According to the literature, HMG is classified into the following 2 categories: (1) mastopathy, including lobular hyperplasia, fibro-adenosis, and sclerosing adenosis; (2) fibrocystic mastopathy, including cyst, ductal epithelial hyperplasia, blunt duct adenosis, and adenosis with apocrine metaplasia. The above subtypes may be present solitarily or multiply in the mammary lobules of the same patients, but the hyperplastic development of various lobules is not completely consistent. The different histopathological manifestations of HMG show different breast risks of breast cancer.The rate of malignant transformation fibrocystic mastopathy ranges from 1% to 5%, and only fibrocystic mastopathy atypical ductal hyperplasia (ADH), as confirmed by a histopathological examination of a biopsy specimen, carries a significantly increased risk of breast cancer.Therefore, the treatment of HMG should focus on different clinical and histopathological manifestations. Regular follow-up examinations and non-medical treatment are the major recommendations for patients with HMG. Patients with mild to moderately painful HMG are mainly treated by psychological counseling and lifestyle interventions; medications are considered for patients with permanent, severe breast pain.The literature indicates Chinese Medical Journal 2021;134www.cmj.org that bromocriptine,danazol,and tamoxifen are effective against severe breast pain. However, there is little evidence to support the use of drugs to reverse the histopathological changes of HMG. Therefore, the side effects of medications should be thoroughly considered when weighing their risks and benefits. No high-level evidence is available for the clinical use of traditional Chinese medicine for treating HMG, and therefore no recommendations pertaining to traditional medicine appear in these guidelines. Since HMG is often diffuse, local surgical resection is inappropriate. HMG is not an indication for surgical treatment, and any surgical intervention, including puncture biopsy or resection, is aimed to avoid a misdiagnosis or missed diagnosis of breast cancer. Patients at high risk of breast cancer are those who present with ADH or whose first-degree relative(s) has/have a history of breast cancer. For these patients, physicians should implement preventive strategies, which include careful follow-up examinations, medications, and surgical interventions. With the continuous discovery of new evidence-based information, the concept of HMG is continually being updated, with subsequent effects on clinical practice. The establishment of a standardized diagnosis of and treatments for HMG can prevent the risk of the mistaking benign disease for malignant disease, thus avoiding the improper treatment of misdiagnosed patients, waste of medical resources, and unnecessary physical and mental harm to patients. List of compiling committee members (In alphabetical order by surname)	None	None	Hyperplasia of the mammary glands (HMG) is a nonogists (2.4%), two radiation therapists (2.4%), and two inflammatory and non-tumorous lesion. It is a structural disorder of the mammary glands due to different degrees of hyperplasia and subinvolution of the mammary parenchyma and stroma. In the literature, HMG is also called mastopathy, fibroadenosis, fibrocystic breast disease, mastalgia, fibrocystic change, benign mammary dysplasia, or sclerosing adenosis.
97dcebe3b35d4dc65fa8773676c05280963b1d9f	pubmed	7th Brazilian Guideline of Arterial Hypertension: Chapter 1 - Concept, Epidemiology and Primary Prevention	7th Brazilian Guideline of Arterial Hypertension: Chapter 1 - Concept, Epidemiology and Primary Prevention [bib_ref] Diferenças regionais na transição da mortalidade por doenças cardiovasculares no Brasil, Guimarães [/bib_ref] ## Prevalence of arterial hypertension The prevalence of HA in Brazil varies according to the population studied and the assessment method [fig_ref] Table 1 -: Prevalence of AH according to different approaches [/fig_ref]. In the meta-analysis by Picon et al., the 40 cross-sectional and cohort studies included showed a reduction trend in AH prevalence in the last three decades, from 36.1% to 31.0%. [bib_ref] Trends in prevalence of hypertension in Brazil: a systematic review with meta-analysis, Picon [/bib_ref] A study with 15,103 government employees from six Brazilian capitals has reported a 35.8% AH prevalence, with predominance of men (40.1% vs 32.2%). [bib_ref] Prevalence, awareness, treatment and influence of socioeconomic variables on control of high..., Chor [/bib_ref] Data from VIGITEL (2006 to 2014) indicate that the self-reported AH prevalence among individuals aged 18 years and over, living in the capitals, ranged from 23% to 25%, respectively, with no difference in the period assessed, not even regarding sex. The self-reported AH prevalence varied among adults according to age groups as follows: 18 -29 years, 2.8%; 30 -59 years, 20.6%; 60 -64 years, 44.4%; 65 -74 years, 52.7%; and ≥ 75 years, 55%. The Southeastern region showed the highest self-reported AH prevalence (23.3%), followed by the Southern (22.9%) and West-Central (21.2%) regions. The Northeastern and Northern regions had the lowest rates, 19.4% and 14.5%, respectively.In 2014, the Brazilian National Health Survey (PNS) measured the BP of selected dwellers from drawn residences, using calibrated digital semi-automated devices. Three BP measurements were taken at two-minute intervals, considering the mean of the last two measurements, inserted in smartphone. The overall prevalence of BP ≥140/90 mm Hg was 22.3%, with predominance among men (25.3% vs 19.5%), ranging from 26.7% in Rio de Janeiro to 13.2% in Amazonas, with predominance in the urban area as compared to the rural one (21.7% vs 19.8%). ## Knowledge, treatment and control A review 7 has shown a wide variation of BP knowledge (22% to 77%), treatment (11.4% to 77.5%) and control (10.1% to 35.5%) rates, depending on the population studied [fig_ref] Table 2 -: Blood pressure knowledge, treatment and control in 14 Brazilian population-based studies published... [/fig_ref]. ## Prehypertension Prehypertension (PH) is characterized by systolic BP (SBP) between 121 and 139 and/or diastolic BP (DBP) between 81 and 89 mm Hg.The world prevalence of PH has ranged from 21% to 37,7% in population-based studies, except for Iran (52.1%) [fig_ref] Figure 4 -: Prevalence of prehypertension [/fig_ref]. 14 Prehypertension associates with a higher risk of developing AH [bib_ref] Incidence of hypertension in Porto Alegre, Brazil: a population-based study, Moreira [/bib_ref] [bib_ref] Asia Pacific Cohort Studies Collaboration. Effects of prehypertension and hypertension subtype on..., Arima [/bib_ref] and cardiac abnormalities. [bib_ref] Prehypertension is associated with abnormalities of cardiac structure and function in the..., Santos [/bib_ref] Approximately one third of the cardiovascular (CV) events attributed to BP elevation occur in individuals with PH. [bib_ref] Impact of lower range of prehypertensionon cardiovascular events in a general population:..., Fukuhara [/bib_ref] Meta-analyses of the incidence of CVD, IHD and stroke in prehypertensive individuals have shown a higher risk among those with BP levels between 130 and 139 or 85 and 89 mm Hg than among those with BP levels between 120 and 129 or 80 and 84 mm Hg [fig_ref] Figure 5 -: Meta-analysis of the risk of the incidence of cardiovascular disease [/fig_ref]. [bib_ref] Prehypertension-prevalence, health risks, and management strategies, Egan [/bib_ref] The clinical implication of that epidemiological evidence is that the BP of prehypertensive individuals should be monitored closely, because a significant proportion of them will develop AH and its complications. 2 ## Risk factors for arterial hypertension ## Age There is a direct and linear association between aging and AH prevalence related to the increase: i) in life expectancy of the Brazilian population, currently 74.9 years; ii) in the elderly population ≥ 60 years in the past decade (2000 to 2010), from 6.7% to 10.8%.A meta-analysis of studies performed in Brazil including 13,978 elderly has shown a 68% AH prevalence. 20 ## Sex and ethnicity The 2013 Brazilian National Health Survey (PNS) showed a self-reported AH prevalence statistically different between sexes, being higher among women (24.2%) and black ## Overweight and obesity In Brazil, the 2014 VIGITEL data revealed, between 2006 and 2014, an increase in the prevalence of overweight (BMI ≥ 25 kg/m 2 ), 52.5% vs 43%. In that same period, obesity (BMI ≥ 30 kg/m 2 ) increased from 11.9% to 17.9%, predominating among 35-to-64-year-old individuals and women (18.2% vs 17.9%), but remained stable from 2012 to 2014. ## Salt intake The excessive consumption of sodium, one of the major RF for AH, associates with CV and renal events. [bib_ref] Dietary factors associated with hypertension, Zhao [/bib_ref] [bib_ref] Reducing population salt intake worldwide: from evidence to implementation, He [/bib_ref] In Brazil, data of the Survey on Family Income (POF), collect from 55,970 dwellings, have shown home availability of 4.7g of sodium/person/day (adjusted for the consumption of 2,000 kcal), exceeding more than twice the maximum recommended consumption (2 g/day), lower in the urban area of the Southeastern region, and higher in the rural area of the Northern region. [bib_ref] Alcohol consumption and risk of hypertension in men and women: a systematic..., Briasoulis [/bib_ref] The impact of the sodium-rich diet estimated in the 2014 VIGITEL data showed that only 15.5% of the individuals interviewed acknowledged high or extremely high salt content in their meals. 12 ## Alcohol intake A chronic and high consumption of alcoholic beverages increases BP consistently. A meta-analysis of 2012, including 16 studies with 33,904 men and 19,372 women compared the consumption intensity between non-drinkers and drinkers. [bib_ref] Prevalência de hipertensão arterial autorreferida na população brasileira: análise da Pesquisa Nacional..., Andrade [/bib_ref] For women, there was a protective effect with doses lower than 10g of alcohol/day, and risk for AH with a consumption of 30-40g of alcohol/day. For men, the increased risk for AH became consistent from 31g of alcohol/day onwards. The 2006-2013 VIGITEL data showed that abusive alcohol consumption -at least four doses for women, or at least five doses for men, of alcoholic beverages on the same occasion, within the past 30 days -is stable in the adult population, around 16.4% (24.2% for men and 9.7% for women). For both sexes, abusive alcohol consumption was more often among youngsters, and increased with schooling. 25 ## Sedentary lifestyle A population-based study in the city of Cuiabá, Mato Grosso State, (n = 1,298 adults ≥ 18 years) has revealed a 75.8% overall prevalence of sedentary lifestyle (33.6% during leisure time; 19.9% at work; 22.3% during both). A significant association of AH was observed with age, male sex, overweight, central adiposity, sedentary lifestyle during leisure time and work, less than 8 years of schooling, per capita income < 3 minimum wages. [bib_ref] Hipertensão arterial e atividade física em uma capital brasileira, Scala [/bib_ref] Brazilian National Health Survey (PNS) data indicate that insufficiently active individuals (adults not practicing at least 150 minutes per week of physical activity including leisure, work and displacement time) represent 46.0% of the adults, the percentage being significantly higher among women (51.5%). The frequencies of insufficiently active individuals differed between age groups, mainly among the elderly (62.7%) and the adults with no formal education and those with incomplete elementary education (50.6%). 27 ## Socioeconomic factors Adults with lower schooling (no formal education or incomplete elementary education) have a higher prevalence of self-reported AH (31.1%). The proportion decreases among those with complete elementary education (16.7%), being 18.2% among those with complete higher education. [bib_ref] Hipertensão arterial e atividade física em uma capital brasileira, Scala [/bib_ref] However, the ELSA Brazil Study, performed with employees of six Brazilian universities and university-affiliated hospitals with higher schooling, has shown a 35.8% AH prevalence, higher among men. 11 ## Genetics Brazilian studies assessing the impact of genetic polymorphisms in the quilombola population could not identify a more prevalent pattern, showing the strong impact of miscegenation, and hindering the identification of a genetic pattern for the elevation of BP levels. [bib_ref] Multilocus family-based association analysis of seven candidate polymorphisms with essential hypertension in..., Kimura [/bib_ref] [bib_ref] Genomic ancestry of rural African-derived populations from Southeastern Brazil, Kimura [/bib_ref] Strategies for the implementation of preventive measures The strategies for preventing the development of AH comprise public policies for health in combination with action from the medical societies and communication media. They should be aimed at stimulating early diagnosis, continuous treatment, control of BP and associated RF, by use of lifestyle changes and/or regular use of medications. [fig] Figure 1 -: Mortality rate in Brazil due to cardiovascular diseases (CVD) and distribution according to cause in 2013. IHD: ischemic heart disease; CbVD: cerebrovascular disease; HD: hypertensive disease; CHF: congestive heart failure. Arq Bras Cardiol 2016; 107(3Suppl.3):1-83 [/fig] [fig] Figure 2 -Figure 3 -: Mortality rate in Brazil due to CVD from 2000 to 2013. Source: Information System on Mortality. Health Surveillance Secretariat, Brazilian Ministry of Health. Hospitalization rate in Brazil per 100,000 inhabitants, per geopolitical region, from 2010 to 2012. [/fig] [fig] Figure 5 -: Meta-analysis of the risk of the incidence of cardiovascular disease (CVD) in individuals with prehypertension (PH). [/fig] [fig] Figure 4 -: Prevalence of prehypertension (PH). Arq Bras Cardiol 2016; 107(3Suppl.3):1-83 [/fig] [table] Table 1 -: Prevalence of AH according to different approaches [/table] [table] Table 2 -: Blood pressure knowledge, treatment and control in 14 Brazilian population-based studies published from 1995 to 2009. 7 [/table]	None	None	Concept Arterial hypertension (AH) is a multifactorial clinical condition characterized by sustained elevation of blood pressure (BP) levels ≥ 140 and/or 90 mm Hg. It is often associated with metabolic disorders, functional and/or structural changes in target organs, being worsened by the presence of other risk factors (RF), such as dyslipidemia, abdominal obesity, glucose intolerance and diabetes mellitus (DM).1,2 It is independently associated with events such as sudden death, stroke, acute myocardial infarction (AMI), heart failure (HF), peripheral arterial disease (PAD) and fatal and non-fatal chronic kidney disease (CKD).1-4
7adc1af6d3cc0232c17b57bb61044022c30dd7df	pubmed	Korean Society for Laboratory Medicine Practice Guidelines for the Molecular Diagnosis of Middle East Respiratory Syndrome During an Outbreak in Korea in 2015	Korean Society for Laboratory Medicine Practice Guidelines for the Molecular Diagnosis of Middle East Respiratory Syndrome During an Outbreak in Korea in 2015 # Introduction Middle East respiratory syndrome (MERS) is a viral respiratory disease caused by a novel coronavirus (MERS-CoV) that was first identified in Saudi Arabia in 2012 [bib_ref] Isolation of a novel coronavirus from a man with pneumonia in Saudi..., Zaki [/bib_ref]. , the Korean version of guideline was required in the unexperienced situation of the nationwide outbreak, which developed rapidly by intra-hospital and inter-hospital spread of an imported deadly virus. This outbreak was beyond national capacity of laboratory preparedness for emerging infectious diseases. Therefore, the KSLM MERS-CoV LR-TF decided to provide the clinical laboratories with the laboratory practice guidelines of national standard for the molecular diagnosis of MERS-CoV. On behalf of the Central MERS-CoV Control Office in Korea, organized by the Korean Ministry of Health and Welfare (KMHW), the first version of the KSLM laboratory practice guidelines was issued on This updated version of the KSLM laboratory practice guidelines for the molecular diagnosis of MERS-CoV is based on interim recommendations for MERS-CoV laboratory testing by the WHO, the laboratory testing guidelines for MERS-CoV by the Centers for Disease Control and Prevention of United States (US CDC) , and other available resources [bib_ref] Assays for laboratory confirmation of novel human coronavirus (hCoV-EMC) infections, Corman [/bib_ref] [bib_ref] Detection of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction, Corman [/bib_ref]. The guidelines provided here focus on the molecular diagnosis of MERS-CoV from case definition to interpretation and reporting as well as laboratory safety. ## Case definition of mers-cov infection The WHO, US CDC, and Saudi Arabia each has its own case definitions according to the purpose of use. WHO case definitions are for classification and reporting; as such, they should not be used for recommendations of when and whom to test. The case definitions of the US CDC are used to classify patients who should be evaluated for MERS-CoV infection in consultation with state and local health departments. Saudi Arabia also uses its case definitions for surveillance purposes. The following case definitions are for classification and reporting to the Korean Centers for Disease Control and Prevention (KCDC). Confirmed case: A person with laboratory confirmation of MERS-CoV infection by KCDC is regarded as a confirmed case irrespective of clinical signs and symptoms. Detection of viral nucleic acid by real-time reverse transcription polymerase chain reaction (rRT-PCR) is the method of choice for laboratory confirmation. Detailed protocols for rRT-PCR and interpretation of the results are described later in these guidelines. Although seroconversion assays were not used in the 2015 Korean outbreak, serological confirmation of a case requires the demonstration of seroconversion in two serum samples, ideally taken at least 14 days apart, on the basis of enzyme immunoassay or immunofluorescent assay as a screening and a neutralization assay. Suspect case: A person with febrile acute respiratory illness of any severity plus either a history of travel to the Middle East or a direct epidemiological link with a confirmed MERS-CoV case within 14 days before symptom onset is regarded as a MERS-CoV suspect case. The Middle East countries include Bahrain, Iraq, Iran, Israel, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, Syria, the United Arab Emirates (UAE), and Yemen. A direct epidemiological link with a confirmed MERS-CoV case showing relevant symptoms includes: with or without adequate personal protective equipment (PPE) plus one of 1) staying or living in the same room with a confirmed case; 2) healthcareassociated exposure that includes providing care for MERS-CoV cases; 3) working with healthcare workers infected with MERS-CoV; and/or 4) direct contact with the respiratory secretion of confirmed cases. Probable case: In addition to the case definitions of confirmed and suspect cases, the KSLM MERS-CoV LR-TF members agree that a case definition for a "probable case" is needed. A probable case can be defined as a suspect case with negative, indeterminate, or equivocal rRT-PCR results. In addition, an individual with preliminary positive rRT-PCR results from clinical laboratories but without confirmed results by KCDC can be defined as a probable case. Repeat testing for MERS-CoV is recommended for probable cases. ## Indications for testing The KMHW approved the emergency use of rRT-PCR assays for MERS-CoV diagnosis in clinical laboratories with KSLM guarantee of good laboratory practice from June 6, 2015 to the end of the outbreak. The KMHW defined the following indications to go for a MERS-CoV rRT-PCR test: 1) confirmation of a suspect case, 2) screening for a case with a direct epidemiological link, 3) differential diagnosis of a patient with fever and communityacquired pneumonia or acute respiratory distress syndrome, and/or 4) criteria for releasing confirmed cases from quarantine. The KSLM recommends the testing for other respiratory patho-gens such as influenza viruses, parainfluenza viruses, and respiratory syncytial virus, but emphasizes that there should not be any delay in testing for MERS-CoV because of those testing. ## Specimen type and protocols for specimen collection Lower respiratory specimens such as sputum, tracheal aspirates, and bronchoalveolar lavage are preferred for the detection of MERS-CoV; however, collection of upper respiratory specimens is recommended in addition to lower respiratory specimens whenever possible [fig_ref] Table 1: Specimen types, sample containers, and transport conditions for molecular detection of Middle... [/fig_ref]. Specimen collection is guided that nasopharyngeal and oropharyngeal swabs are collected from the nasopharyngeal and oropharyngeal walls, respectively, not just from the nostril or mouth. Nasopharyngeal and oropharyngeal swabs could be placed in the same viral transport medium. Synthetic fiber flocked swabs with plastic shafts should be used to increase virus yield. Calcium alginate swabs or swabs with wooden shafts are not recommended because they may contain substances that inactivate some viruses and inhibit PCR reactions. In asymptomatic individuals, induced sputum or forced coughing may help collect lower respiratory tract specimens. The rRT-PCR of serum samples can be helpful for detecting MERS-CoV, but these assays are not recommended for the routine diagnostic process in MERS-CoV outbreaks. While serological testing is impractical for clinical purposes during MERS-CoV outbreaks, it has incomparable importance for epidemiologic investigations. On the basis of WHO interim recommendations, serological testing for MERS-CoV can be used to identify confirmed MERS cases that can be reported under the International Health Regulations, to survey popula-tion-based seroprevalence and to investigate past exposures. Because a total of 16,693 people were self-quarantined owing to contact history with confirmed MERS-CoV cases, investigation of seroprevalence in this population is necessary in order to understand the epidemiology and pathophysiology of MERS-CoV infection. It is recommended that serum samples be collected during the acute stage of the disease, preferably during the first week after illness onset and again during convalescence, at least 14 to 21 days after the acute stage sample was collected. If the acute stage sampling is missed, it should be collected at least 14 days after the onset of symptoms. All specimen types for routine testing from symptomatic confirmed/suspect/probable cases should be collected by trained healthcare workers wearing PPE. In addition, further precautions for infection control and prevention in hospitals should be followed when exposure to aerosols such as tracheal intubation, bronchoalveolar lavage, and expectoration is expected as below. 1. Indications for additional precautions: expectoration of sputum, tracheal aspiration, bronchoscopy, intubation, and extubation. 2. Personal protection -Restrict the number of healthcare workers in the room to avoid unnecessary exposure. -All healthcare workers should wear PPE, including N95 masks, gloves, long-sleeved gowns, and eye protection equipment such as goggles or face shields. -Use hand hygiene before and after patient contact and after PPE removal. 3. Environmental control -An isolation room with a ventilation system that generates negative pressure is recommended. If unavailable, a single room ventilated with 6 to 12 air changes per hour (through ## Specimen packing and transport Double package systems can be used for transportation within an institution. All specimens must be packaged in a leak-proof plastic primary container with a screw cap. Primary containers that are decontaminated with 70% alcohol swabs and placed in a clear re-sealable zipper bag with absorbents must be packaged with a secondary container for transfer. Accurate labeling or the attachment of barcodes, including at least two patient identifiers on all specimens as well as on the package, is essential to avoid specimen mix-ups and contamination. For transportation outside an institution, triple package systems must be used according to the KCDC guidelines. Similar to within-an-institution transfer, all specimens must be packed in double containers. The secondary containers are packed with the associated information sheets such as request forms or information forms in the tertiary container, which is consistent with infectious substance shipping guidance by KCDC [bib_ref] Disease Control and Prevention, The guideline for safe transportation of infectious substances, Center For [/bib_ref]. ## Specimen handling and nucleic acid extraction All specimens should be stored at 2-8°C up to 72 hr before nucleic acid extraction. If nucleic acid extraction cannot be performed within 72 hr after collection, specimens should be stored at -70°C or lower as soon as possible after collection. MERS-CoV RNA should be extracted by using appropriate manual or automated nucleic acid extraction methods. For example, the QIAamp DSP Viral RNA Mini kit (QIAGEN GmbH, Hilden, Germany) is one of the most widely used manual extraction methods, and the NucliSENS easyMAG (bioMérieux, Durham, NC, USA), MagNA Pure 96 System (Roche, Basel, Switzerland), and QIAcube (QIAGEN) are commonly used automated nucleic extraction methods. Nucleic acid extraction from sputum, tracheal aspirates, bronchoalveolar lavage, nasopharyngeal or oropharyngeal swabs, or blood should be performed according to the manufacturers' instructions. RNA samples should be stored at -70°C or lower. Practically, rRT-PCR assays targeting upE are recommended for screening [fig_ref] Figure 1: rRT-PCR is recommended for the molecular detection of MERS-CoV RNA [/fig_ref]. If the upE screening assay is positive, an independent, confirmatory rRT-PCR assay targeting ORF1a should be performed. Laboratory developed tests and commercial kits for rRT-PCR assay should be used with provision of positive control and validation by LR-TF. ## Molecular detection of mers-cov rna A heterologous internal control to identify possible rRT-PCR inhibition and to confirm the integrity of the reagents of the kit is essential. Each run of rRT-PCR reaction should include both positive and negative controls in parallel. It is mandatory for all clinical laboratories to participate in the external quality control assessment organized by the KSLM LR-TF. ## Results interpretation and reporting The first step of interpretation of MERS-CoV rRT-PCR is verification of the internal control [fig_ref] Figure 1: rRT-PCR is recommended for the molecular detection of MERS-CoV RNA [/fig_ref]. Negative reactions in the internal control indicate a failure of the amplification process owing to either the presence of PCR inhibitors or other reasons. In this case, retesting the same sample is required after processing it to eliminate the inhibitory effect, including re-extraction of the nucleic acids or dilution of the extracted nucleic acids. When the internal control is properly amplified, the results can be classified as screen-negative, -indeterminate, or -positive according to the cycle threshold (Ct) values and whether the upE gene was amplified. Screen-positive specimens should be confirmed by amplification of ORF1a or other targets. When indeterminate or equivocal results are obtained in suspect cases, the results should be reported immediately to infection control units in each hospital. A series of negative results in the cases which have definite contact history should not rule out MERS-CoV infection, and factors that can cause false negatives such as poor specimen quality, too early or late stage specimens, inappropriate handling or specimen transport, and inherent testing problems should be investigated by obtaining an additional specimen (especially a lower respiratory specimen), by the verification of an internal control, or by retesting the sample at another facility for confirmation. ## Laboratory safety Diagnostic laboratory work and rRT-PCR analysis on clinical specimens from suspect, confirmed, or probable cases of MERS-CoV should be conducted in clinical laboratories with BSL-2 facilities. Appropriate PPE should be worn, and all technical procedures should be performed in a way that minimizes the formation of aerosols and droplets in class II biosafety cabinets with current certification. After completion of daily work, the workspace is cleaned with 70% alcohol, and all PPEs are removed. Hand hygiene is necessary whenever PPEs are removed and before exit from laboratories. All wastes and remaining specimens should be discarded by legislative regulation of medical wastes, but clinical specimens positive for MERS-CoV rRT-PCR should be discarded after sterilization such as autoclaving. The dilution or aliquot procedures of the potentially infectious substances, including the procedures for bacterial or fungal cultures, should be performed within a biological safety cabinet. # Conclusions These guidelines reflect our current understanding of MERS-CoV at the time of publication and the unique situation of the Korean MERS-CoV outbreak. When a clinical laboratory is to perform molecular testing for MERS-CoV, each laboratory should prepare its own protocols according to these guidelines and other available resources. In addition, laboratory layouts and facilities that are not covered in these guidelines should be checked in order to prevent contamination during PCR procedures and also to provide a safe environment for all laboratory staff. In conclusion, KSLM has established the practice guidelines for the molecular diagnosis of MERS-CoV during an outbreak in Korea in 2015. To prepare laboratory response to prevent and control public health crisis by emerging infectious diseases in future, practice guidelines for laboratory diagnosis of other possible agents should be prepared with preemptive risk assessment in cooperation with public and private sectors. [fig] Figure 1: rRT-PCR is recommended for the molecular detection of MERS-CoV RNA. Laboratory confirmation of MERS-CoV infection re-Laboratory process for the diagnosis of Middle East respiratory syndrome-coronavirus infection in Korea. Abbreviations: upE, upstream of the E gene; ORF1a, open reading frame 1a; ORF1b, open reading frame 1b; Ct, cycle threshold; KCDC, Korea Centers for Disease Control and Prevention. [/fig] [table] Table 1: Specimen types, sample containers, and transport conditions for molecular detection of Middle East respiratory syndrome coronavirus (MERS-CoV) After procedures, the room should be cleaned and evacuated for 30 minutes (in the case of 12 air changes). -Access to the room during procedures should be minimized. [/table]	None	https://www.annlabmed.org/journal/download_pdf.php?doi=10.3343/alm.2016.36.3.203	For two months between May and July 2015, a nationwide outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) occurred in Korea. On June 3, 2015, the Korean Society for Laboratory Medicine (KSLM) launched a MERS-CoV Laboratory Response Task Force (LR-TF) to facilitate clinical laboratories to set up the diagnosis of MERS-CoV infection. Based on the WHO interim recommendations, the Centers for Disease Control and Prevention of United States guidelines for MERS-CoV laboratory testing, and other available resources, the KSLM MERS-CoV LR-TF provided the first version of the laboratory practice guidelines for the molecular diagnosis of MERS-CoV to the clinical laboratories on June 12, 2015. The guidelines described here are an updated version that includes case definition, indications for testing, specimen type and protocols for specimen collection, specimen packing and transport, specimen handling and nucleic acid extraction, molecular detection of MERS-CoV, interpretation of results and reporting, and laboratory safety. The KSLM guidelines mainly focus on the molecular diagnosis of MERS-CoV, reflecting the unique situation in Korea and the state of knowledge at the time of publication.
04a0097252e6d1d249037d21f8eb975d512ad0a9	pubmed	Pathological aspects of the assessment of head and neck cancers: United Kingdom National Multidisciplinary Guidelines	Pathological aspects of the assessment of head and neck cancers: United Kingdom National Multidisciplinary Guidelines This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It introduces the current best practice in histopathology and cytopathology as it pertains to head and neck and thyroid cancers.Recommendations- Accurate diagnosis of the type of malignancy is a key component of effective management. (R) - Surgeons and oncologists should understand the scope and limitations of cellular pathology in order to inform multidisciplinary discussions. (R) - A clinically suspected diagnosis of malignancy should be confirmed by biopsy or cytology before operation. (R) - Cytopathological diagnoses should be discussed with surgeons and radiologists to maximise the information gained from each modality of investigation. (R) - Pathological investigations are the basis for accurate cancer staging and stratification of clinical outcomes. (R)Definitive operative specimen Specimens should be submitted in an adequate amount of 10 per cent neutral buffered formalin (at least three times the volume of the specimen) unless there is prior agreement with the laboratory. 2 The site and nature of each specimen should be clearly described on the request form and should be appropriately orientated. The form must include the clinical indication for the operation, the duration of signs and symptoms, pre-operative radiotherapy (RT) or chemotherapy, and details of previous biopsies or # Introduction This paper is an overview of the use of laboratory investigations and focuses on the important elements of cancer pathology reports that clinicians should use when discussing the implications of a diagnosis and management options with patients and with colleagues in a multidisciplinary setting. The recommendations for pathology practice are based on published evidence; key references are provided in the World Health Organisation (WHO) Classification of Tumours 1 and in the series of Histopathology Datasets published by the Royal College of Pathologists.Pathologists have critically important roles in confirming or excluding specific diseases on the basis of cytology or diagnostic biopsy, in assessing the adequacy of treatment, recognising key predictive and prognostic factors, and in contributing evidence-based criteria for the appropriate stratification of clinical outcomes. ## Use of cellular pathology services Frozen section Patient management should be guided primarily by preoperative biopsy and/or fine needle aspiration (FNA) cytology. Intra-operative frozen sections have a limited role and are appropriately used for the assessment of surgical excision margins when there is clinical doubt as to adequacy.Frozen sections are occasionally used to confirm the diagnosis of branchial cleft cysts in older people, of papillary, medullary or anaplastic thyroid carcinomas 5 or to identify lymph node involvement in thyroid cancers; they should not be used to differentiate follicular thyroid carcinoma from adenoma or follicular variant papillary carcinoma. It should be appreciated that the quality of frozen sections is not as good as paraffin sections and that important information may be missed or destroyed through inappropriate use of frozen sections, particularly if small pieces of tissue are submitted for examination. cytological investigations, and relevant biochemistry (particularly for thyroid diseases). ## Lymph node specimens The site of origin of lymph nodes should be recorded, and formal neck dissections should clearly state which nodal groups are included and should be clearly orientated, preferably with a diagram. [bib_ref] Lymph node metastases in head and neck malignancies: assessment in practice and..., Woolgar [/bib_ref] The optimal handling of biopsies for suspected lymphoma should be discussed with the laboratory; it is often useful to collect fresh tissue in a transport medium for possible cytogenetic and molecular studies. The predictive value of sentinel node biopsy is now recognised and is becoming established practice, particularly for the early-stage oral carcinoma. [bib_ref] Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in..., Schilling [/bib_ref] The pathological assessment of sentinel nodes is highly demanding of laboratory time and expertise, involving multiple sections and immunocytochemistry. [bib_ref] Sentinel node biopsy for early-stage oral cavity cancer: the VU University Medical..., Toom [/bib_ref] This should only be undertaken if appropriately resourced. ## Resection specimens including bone When cancer resection specimens contain bone, it is often possible to obtain a preliminary report on the soft tissue components of the specimen while the bone is decalcified before processing the tissues to assess the extent of bone invasion and bony margins. Decalcification may take several days or weeks depending on the density of the bone. Immunocytochemistry and molecular pathology Immunocytochemistry plays an important role in the correct diagnosis of primary head and neck cancers, particularly for the less common entities. The prognostic value of assessing oropharyngeal carcinomas for evidence of human papilloma virus infection (HPV) is established, with current guidance recommending a combination of immunocytochemistry for p16 protein overexpression and in situ hybridisation for high-risk HPV DNA. Morphologically similar poorly differentiated carcinomas arising in the oropharynx and nasopharynx, and their nodal metastases may be distinguished by the presence of HPV and Epstein-Barr virus DNA, respectively. In patients with metastatic malignancy in cervical lymph nodes without evidence of primary disease, the morphological features of the metastatic tumour may be useful, e.g. thyroid and salivary neoplasms. Immunocytochemical investigation of FNA or biopsy material does not reliably distinguish between primary sites of squamous cell carcinomas (SCCs) but may be helpful in identifying adenocarcinomas arising in the gastrointestinal tract, lungs or prostate. Clinicians should note that immunocytochemical markers are very rarely specific for particular tissues and that opinions on likely primary sites are based on the assessment of a panel of different markers and the balance of probabilities. Clinical features, such as the pattern of nodal disease, and imaging studies should be incorporated into the multidisciplinary assessment of these patients. Molecular genetic profiling of head and neck cancers is not currently recommended outside the research setting. [bib_ref] Gene expression profiling in head and neck squamous cell carcinoma, Braakhuis [/bib_ref] [bib_ref] Molecular diagnostic alterations in squamous cell carcinoma of the head and neck..., Hunt [/bib_ref] Multidisciplinary team working Cellular pathologists are core members of cancer MDTs and are essential to the provision of a successful service. The MDT should have a risk-based approach to developing its policy on pathology review, particularly for patients who have had diagnostic biopsies in other hospitals. Pathological review is essential for thyroid cancers and is good practice for other situations. ## Malignancies of the upper aerodigestive tract ## Squamous cell carcinoma The initial diagnosis may be obvious clinically on the basis of an irregularly infiltrating mass with ulceration, but should always be confirmed by biopsy as some inflammatory diseases, e.g. tuberculosis and sarcoidosis, can mimic carcinomas clinically and other mucosal malignancies, e.g. lymphoma, may require consideration of other treatment options. Practical problems that may preclude definitive diagnosis on diagnostic biopsies include poor orientation, necrotic or inflammatory debris, small samples containing few cells and crush artefact. The edges of laser resection specimens often show thermal artefacts, making detailed interpretation impossible. Patients who have been treated with RT and/or chemotherapy may have biopsies or resections to assess any residual or recurrent disease at primary or nodal sites. Extensive scarring, radiation-associated nuclear atypia and loss of the normal anatomical landmarks may make assessment of these specimens difficult. A good chemotherapeutic response may leave a mass of necrotic tissue containing degenerate keratinocytes; viable carcinoma may not be identified even after extensive histological sampling. Morphological variants of SCC. Some variants of SCC are associated with particular difficulties in diagnosis and clinical assessment but should be managed, stage for stage, in line with classical carcinomas. Papillary SCC is typified by an exophytic growth pattern with fronds of fibrovascular tissue covered by squamous epithelium showing in situ carcinoma; areas of invasive carcinoma are often small and limited in extent. Diagnostic biopsies may show only in situ carcinoma despite a bulky tumour. The prognosis is relatively good due to the limited invasive component. Verrucous SCC has an exophytic growth and is formed by extremely well-differentiated squamous epithelium with minimal atypia and abundant surface keratin. Diagnostic biopsies may not show invasion and the minimal cellular atypia makes pathologists reluctant to diagnose malignancy. Repeated biopsies and appreciation of the discrepancy between a clinically obvious carcinoma and minimal microscopic atypia are often needed to make a diagnosis of carcinoma. Spindle cell carcinomas typically present as polypoid tumours with an ulcerated surface and are formed by sheets of atypical spindle cells, often raising the possibility of sarcoma. Sarcomas of mucosal origin are extremely rare in adults, but a definitive diagnosis of spindle cell carcinoma may only be possible on resection specimens when small areas of in situ or more typical invasive carcinoma are identified. Immunohistochemistry only identifies squamous epithelial differentiation in about 60-70 per cent of cases. Oropharyngeal SCCs are usually related to high-risk HPV infection. Typical HPV-associated carcinomas are non-keratinising (basaloid) carcinomas, but may be of any histological type. Information that should be provided in histopathology reports. The information available from diagnostic biopsies is limited but should normally include whether any carcinoma is invasive or in situ and, for invasive carcinomas, should provide a provisional estimate of the degree of differentiation and the growth pattern. In the oral cavity, the depth of invasion or tissues involved (mucosa, muscle) may guide the extent of surgery. Resection specimens provide sufficient tissue to describe the full range of prognostic information 2,11 (Box I); the basis in evidence for this information is provided in guidelines published by the Royal College of Pathologists and varies between anatomical sites. [fig_ref] TABLE I GRADING: SYSTEMS FOR PRECURSOR LESIONS OF SQUAMOUS EPITHELIAL MALIGNANCIES [/fig_ref] and, although different criteria are used, each seeks to place a particular abnormality in a continuous spectrum of appearances from mild to severe atypia. There is no UK consensus 12 on which grading system should be recommended, although a majority of pathologists probably use the WHO dysplasia system but regard severe dysplasia and in situ carcinoma as indistinguishable. A proposed consensus system for laryngeal lesions based on the Ljubljana classification 13 is gaining recognition, but its translation to UK practice is limited. Management decisions should take account of the microscopic severity of the lesion and its clinically assessed extent. ## Other mucosal malignancies Adenocarcinomas. This may be of surface or salivary type. Those derived from surface epithelium of the nose and sinuses may resemble intestinal carcinomas and have a relatively poor prognosis compared with other low grade adenocarcinomas. Sinonasal undifferentiated (anaplastic) carcinoma. This is a rare, clinically aggressive neoplasm composed of cells that are undifferentiated on routine stains but which show varying degrees of neuroendocrine differentiation on immunocytochemistry. These carcinomas often result in bone destruction and extension into the orbit or cranial cavity and have a poor prognosis despite aggressive surgery and chemoradiotherapy. Olfactory neuroblastoma (esthesioneuroblastoma). This presents as a polypoid mass high in the nasal cavity. The histological features are characteristic and immunocytochemistry is positive for neuroendocrine markers. Morphological grading systems are of limited prognostic value. Despite spread to regional nodes and more Malignant melanoma. This most often arises in the nasal cavities and less often in the sinuses, presenting in adults over 50 years as polypoid, friable haemorrhagic masses. Histologically there is a wide range of appearances with very variable melanin production (30 per cent are amelanotic). Survival is poor with death due to widespread metastasis and/or extensive local recurrence. Lymphomas. This may present as primary mucosal malignancies in the sinonasal tract and tonsils. Almost all are non-Hodgkin's lymphomas with natural killer/ T-cell lymphomas mainly affecting the sinonasal tract and B-cell lymphomas arising in the tonsils. ## Nasopharyngeal carcinoma. this includes keratinising sccs and non-keratinising differentiated and undifferentiated carcinomas and is usually related to epstein-barr virus infection. the synonym of 'lymphoepithelioma' should not be used. Keratinising carcinomas are more radioresistant than non-keratinising and undifferentiated carcinomas. ## Diagnosis and management of neck lumps Fine needle aspiration Fine needle aspiration (FNA) of tissue by a well-trained operator is an essential part of the diagnostic assessment of patients with neck or thyroid lumps and as part of staging procedures for patients with the known head and neck cancer. [bib_ref] Fine needle aspiration cytology of head and neck diseases: advantages and limitations, Smith [/bib_ref] High-quality preparations are essential for an effective service. Either rapidly airdried slides or needle washings into preservative solution may be required depending on the clinical circumstance. The cytological diagnosis of metastatic SCC in cervical nodes is usually straightforward, but cystic metastases can be difficult to distinguish from benign cystic lesions containing squamous cells such as branchial cleft cysts; a high degree of clinical suspicion for malignancy is required in older patients with cystic lesions containing squamous cells. Haemorrhage into cystic neck nodes may conceal underlying malignancy, particularly metastatic papillary carcinoma from the thyroid. Multidisciplinary correlation of findings is of fundamental importance. FNA cytology is the method of choice for monitoring patients known to have lymphoma as cytology can document disease recurrence and can indicate transformation from low to high grade disease. The primary diagnosis of lymphoma can be made from FNA specimens if the laboratory repertoire includes molecular techniques and flow cytometry. FNA cytology is an effective method to triage patients into those in whom significant disease can be excluded, those in whom a definitive diagnosis of benign disease or metastatic malignancy can be made, and those with possible lymphoma who need lymph node biopsy. Where malignancy is identified, additional immunocytochemical and molecular testing for planning management is possible with appropriate specimen collection procedures. ## Neck dissections The presence or absence of nodal metastasis is a key component of tumour-node-metastasis (TNM)staging and determines further management. The pathological assessment of nodes in resection specimens verifies pre-operative imaging studies and identifies small volume nodal disease that is beyond the resolution of current imaging techniques. The terminology of possible nodal involvement by carcinoma includes: [formula] - [/formula] ## Salivary neoplasms Most tumours arising in the major or minor salivary glands are benign (although the proportions vary from site to site), but pre-operative suspicion of malignancy may be raised on clinical examination, from imaging studies or from pre-operative FNA cytology. All tumours of the major salivary glands should have preoperative FNA cytology to guide treatment, which can usually accurately diagnose pleomorphic salivary adenoma and Warthin's tumour with confidence, differentiate benign neoplasms from malignant in 81-98 per cent of cases, but which is less good at establishing a specific type of carcinoma. The main categories of salivary carcinoma are well defined, but these tumours have many morphological variants and precise histological diagnosis often requires a specialist opinion. Many salivary neoplasms have characteristic genetic translocations 17 which aid diagnosis and may lead to targeted therapeutics. The core pathological data from salivary resections for neoplasia are shown in Box III. ## Box iii prognostic information derived from salivary gland resections The histological type of neoplasm (according to the WHO Classification) The grade of malignancy (see text) The distance to the resection margins The presence or absence of peri-neural or vascular invasion The presence or absence of lymph node involvement Grading of the degree of malignancy is prognostically useful for some salivary carcinomas. Grading of mucoepidermoid carcinomas relates to metastatic potential and survival, whichever grading system is used. Acinic cell carcinomas are usually circumscribed but incompletely encapsulated; grading on the basis of cytological features is not generally useful, except for rare tumours showing dedifferentiation. Assessment of Ki-67 (MIB1) labelling is of prognostic value, and acinic cell carcinomas with indices of >5 per cent behaving more aggressively. The growth pattern of adenoid cystic carcinoma is related to metastatic potential, with 0-4 per cent of cribriform, hyaline and tubular carcinomas, and 33 per cent of solid (basaloid) carcinomas metastasising to local lymph nodes. Distant metastasis is more common in solid tumours. Salivary duct carcinoma is a high-grade malignancy morphologically resembling ductal carcinoma of the breast. About 70 per cent express androgen receptors and 15 per cent express HER-2 (human epithelial growth factor receptor 2); features which may influence therapy. Carcinomas arising in pleomorphic adenomas may be of any or mixed histological type; the extent of invasion is prognostically useful as invasion more than 5-6 mm from the capsule of the residual adenoma is associated with a high risk of local recurrence and distant metastasis. Non-invasive or minimally invasive carcinomas ex pleomorphic adenoma are true malignancies, but have a very low rate of disease progression. ## Thyroid cancers Most lesions will have had FNA before surgery. Immediate assessment of the adequacy of aspirates may be helpful. The descriptive cytology report informs clinical decisions on management and should incorporate a categorical summary [fig_ref] TABLE I GRADING: SYSTEMS FOR PRECURSOR LESIONS OF SQUAMOUS EPITHELIAL MALIGNANCIES [/fig_ref]. For all malignant thyroid tumours, the national dataset for histopathology reports 3 defines core data items of prognosis importance that will allow TNM stagingPapillary carcinoma A single papillary microcarcinoma (≤10 mm diameter) discovered incidentally in a resection performed for another disease is not thought to have a significant risk of recurrence or metastasis. Some microcarcinomas are potentially more aggressive including those with multifocal disease, extrathyroid extension and lymphatic invasion. Tall cell and columnar variants of papillary carcinoma may be more aggressive, while the outcome of the diffuse sclerosing variant is a matter of debate. Diagnosis of the follicular variant of papillary carcinoma (FVPC) may be difficult and require specialist opinion. The non-encapsulated invasive FVPC has a metastatic potential similar to that of classical papillary carcinoma, while encapsulated FVPC has metastatic potential related to the number of foci of vascular invasion. ## Medullary carcinoma The diagnosis should be confirmed by calcitonin immunoreactivity, although some poorly differentiated carcinomas only express carcinoembryonic antigen (CEA). Although there are variations in the cellular pattern and presence of amyloid these are unimportant prognostically compared with the tumour stage and completeness of excision. In the syndromes of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma, medullary carcinoma is often multifocal and preceded and/or accompanied by C-cell hyperplasia. Genetic testing for RET mutations will detect familial syndromes. ## Poorly differentiated carcinoma This group is defined as follicular or papillary carcinoma with necrosis and/or a mitotic count of five or more in ten high-power microscopic fields. The growth pattern may be insular, trabecular or solid. Poorly differentiated carcinomas have a poorer prognosis than differentiated carcinomas with variable response to radio-iodine treatment. Undifferentiated/anaplastic carcinoma Anaplastic carcinoma is diagnosed where a follicular or papillary carcinoma shows even a minor undifferentiated (anaplastic) component. Most undifferentiated tumours will be diagnosed by FNA cytology, core or open biopsy and will not have a surgical resection. The report should describe how immunocytochemistry has been used to exclude other poorly differentiated malignancies, especially lymphoma. ## Lymphoma The diagnosis of thyroid lymphoma is usually made on core or open biopsy rather than resection specimens and may require extensive immunocytochemical and molecular testing. It is important to distinguish between primary thyroid lymphoma and involvement of the thyroid by lymphoma as part of a wider disease. ## Recommendations - Accurate diagnosis of the type of malignancy is a key component of effective management (R). - Surgeons and oncologists should understand the scope and limitations of cellular pathology in order to inform multidisciplinary discussions (R) - A clinically suspected diagnosis of malignancy should be confirmed by biopsy or cytology before operation (R) - Cytopathological diagnoses should be discussed with surgeons and radiologists to maximise the information gained from each modality of investigation (R) - Pathological investigations are the basis for accurate cancer staging and stratification of clinical outcomes (R) [table] TABLE I GRADING: SYSTEMS FOR PRECURSOR LESIONS OF SQUAMOUS EPITHELIAL MALIGNANCIES [/table] [table] TABLE II CATEGORISATION: OF THYROID FNAS WITH LIKELIHOOD OF MALIGNANCY (LOM) (RCPATH AND BSCC GUIDELINES) PATHOLOGICAL ASPECTS OF THE ASSESSMENT OF HEAD AND NECK CANCERS: UK GUIDELINES Follicular carcinoma A follicular neoplasm is defined as carcinoma on the basis of capsular and/or vascular invasion. Minimally invasive follicular carcinomas show only focal microscopic vascular and/or capsular invasion. Tumours showing only capsular invasion have a minimal risk of metastasis. The risk of metastasis increases with vascular invasion, but no significance is attached to the number of foci of vascular invasion. Widely invasive follicular carcinoma shows obvious gross invasion or extensive microscopic infiltration of thyroid parenchyma, vessels or extrathyroidal tissues. The number of foci of vascular invasion should be described but is not prognostically significant. [/table]	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/6F2E77B3E9E41639D31D72E546830162/S0022215116000451a.pdf/div-class-title-pathological-aspects-of-the-assessment-of-head-and-neck-cancers-united-kingdom-national-multidisciplinary-guidelines-div.pdf	Abstract This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It introduces the current best practice in histopathology and cytopathology as it pertains to head and neck and thyroid cancers. Recommendations • Accurate diagnosis of the type of malignancy is a key component of effective management. (R) • Surgeons and oncologists should understand the scope and limitations of cellular pathology in order to inform multidisciplinary discussions. (R) • A clinically suspected diagnosis of malignancy should be confirmed by biopsy or cytology before operation. (R) • Cytopathological diagnoses should be discussed with surgeons and radiologists to maximise the information gained from each modality of investigation. (R) • Pathological investigations are the basis for accurate cancer staging and stratification of clinical outcomes. (R)
73d17ec439dbc2bdcb01feef025dc53e4060b34e	pubmed	COVID-19 PICU guidelines: for high- and limited-resource settings	COVID-19 PICU guidelines: for high- and limited-resource settings # Introduction In early December 2019, a novel coronavirus causing pneumonia was first reported in Wuhan, China and rapidly spread globally. Given the pathogenicity, high transmission, asymptomatic carrier rates, and global lack of human immunity to this virus, the World Health Organization pronounced a pandemic on . Despite the aggressive nature of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), children have been minimally affected by the disease. At the time of publication, 8.4 million infections have been confirmed and 450,835 total deaths have been reported.The epidemiology of infection rates by age and mortality are difficult to identify globally, but pediatric cases have been relatively few. Two large studies, from China and the United States, have the best pediatric data to date. The largest pediatric review reported 2143 children from China (34.1% laboratory confirmed and 65.9% suspected cases as of February 7, 2020), 5.6% children had severe respiratory disease, 0.6% developed acute respiratory distress syndrome (ARDS), and 1 died.In contrast, 18.5% of adults had developed severe or critical illness.In the United States, pediatric patients made up only 1.7% of total cases from February 12 to April 2; only 20% of these required hospitalization, 2% required intensive care unit (ICU) admissions and three died.Both studies noted that patients under 1 year of age were at greatest risk of hospitalization and males accounted for 57% of cases.For those patients where data were recorded, nearly a quarter of patients had an underlying medical condition.Factors associated with worse outcomes included younger age, underlying pulmonary conditions, and immunocompromised states.The median age of children in China was 7 years 2,5 and in the United States was 11 years, 3 suggesting regional differences in age distribution. Most children therefore are asymptomatic or have mild to moderate symptoms and the case fatality rate (CFR, 0-0.2%) in children is much lower as compared to adults (CFR 2.3%).Common signs and symptoms among pediatric patients include fever, cough, myalgias, sore throat, rhinorrhea, headache, shortness of breath, diarrhea, vomiting, tachypnea, and tachycardia.Gastrointestinal symptoms of vomiting and diarrhea appear to be more common in pediatric patients as compared to adults.Adult patients that progress to severe disease often develop dyspnea 8 days after disease onset and within 48 h can progress to ARDS and multisystem organ dysfunction.Other findings in critically ill patients include shock, encephalopathy, myocardial dysfunction, heart failure, coagulopathy, and acute renal injury.Patients with severe COVID-19 appear to have a cytokine storm profile similar to hemophagocytic lymphohistiocytosis.Recently, a Multisystem Inflammatory Syndrome in Children (MIS-C) has also been described and patient presentations range from mild inflammation to severe shock with multiorgan involvement. The progression of this pandemic in the ensuing months is unclear and pediatric intensivists globally will need to be aware of signs, symptoms, and treatments for COVID-19. The objective of this international collaboration is to present management strategies for critically ill pediatric patients infected with COVID-19 in both high-and limited-resource settings. Evaluation of minimal disease burden in children Why are children relatively protected from COVID-19 illnesses? Several theories have been proposed although scientific knowledge in this regard is still evolving. SARS-CoV-2 spike protein binds to angiotensin-converting enzyme II (ACE2) receptor to infect cells.ACE2 is expressed in the type II alveolar epithelial cells in the lungs, myocardial cells, esophageal, and ileocolic epithelial cells, and may also play a role in the coagulation system.The organotypic expression of this receptor may explain the presenting signs and symptoms of patients with COVID-19. An interplay between the renin-angiotensin system (RAS) and various proteins may increase or decrease inflammation in lung injury.Prevalent use of ACE-inhibitors (ACEi) or angiotensin-receptor blockers (ARB) in adults increases ACE2 expression, which may allow SARS-CoV-2 entry into type II alveolar cells leading to worsening lung disease.Conversely, other studies suggest that ACEi and ARBs diminish Angiotensin II production which in turn attenuates lung inflammation and injury.Relative absence of ACE2 expression in children is currently touted as one theory why children are protected from severe COVID-19 disease.Animal models demonstrate that levels of ACE2 receptor vary with development and by sex.Children from 4 to 18 years of age also have higher ACE activity than adults,which may be protective. Age-based differences in immunity and inflammatory responses across the lifespan could also explain these outcomes. Specifically, lymphopenia occurred in only 3% of pediatric patientsbut 80% of critically ill adults.Similar inferences about inflammatory markers such as C-reactive protein or procalcitonin are more difficult to draw at this time. Lymphopenia may contribute to the inability to clear SARS-CoV-2 infection. Another hypothesis is the antioxidant effects of melatonin to attenuate the inflammatory injury occurring from viral infections.Although melatonin may not decrease viral replication, it indirectly regulates ACE2 and may impact the ability of SARS-CoV-2 to enter, infect, and replicate.Ultimately, melatonin may prolong a patient's survival allowing the individual's immune system to eradicate the virus. Similar to ICU supportive care, melatonin affords the patient time to recover. Interestingly, the nighttime concentrations of melatonin in children are significantly higher than adults.Thus, the direct antioxidant effects of melatonin coupled with its effects on ACE2 receptors may play a protective effect in pediatric patients. Understanding why children are relatively protected from severe SARS-CoV-2 infection may help us develop targeted drugs for symptomatic adult and pediatric patients. # Methods Pediatric intensivists with many years of clinical experience and academic backgrounds were invited from across the globe to develop these guidelines. Authors from both high-and limitedresource settings and all regions of the world (except Oceania) are represented. All contributing authors were assigned to various recommendation sections along with writing the specific section for their global region. Given the paucity of data in pediatric patients to date, a systematic review with meta-analysis of multiple studies and case series could not be used to evaluate the strength of each recommendation. The authors therefore have identified relevant adult and pediatric studies along with management guidelines from other leading organizations, e.g. the World Health Organization, and have extracted the best current evidence and guidelines to support their recommendations. Each guideline is followed by a Strong, Weak, Best practice, or Insufficient evidence recommendationand the rationale for each recommendation is included in the body of the manuscript. Recommendations could not be formulated using the Evidence to Decision framework (EtD) due to the paucity of relevant evidence regarding COVID-19 in pediatric patients and the rapidly changing landscape of this disease. ## Recommendations ## Respiratory support Clinical presentation Mild respiratory disease: Pediatric patients presenting with mild illness can be discharged and monitored at home. The family should be advised to strictly adhere with quarantine guidelines, use acetaminophen or paracetamol as a first-line agent for fever control (see "Pharmacologic treatment" section for further discussion), and to monitor the progression of clinical symptoms. Severe respiratory disease: WHO defines severe respiratory distress in children presenting with tachypnea and any of the following: central cyanosis or hypoxemia (oxygen saturation [SpO 2 ] < 90%), grunting, inability to breastfeed or drink, lethargy, unconsciousness, or convulsions.Age-specific tachypnea definitions are respiratory rate ≥ 60/min in children < 2 months of age, ≥50/min in children 2-11 months of age, ≥40/min in children 1-5 years of age.Acute respiratory distress syndrome: Worsening respiratory symptoms 1 week after disease onset due to SARS-CoV-2 with new opacities on chest imaging not explained by cardiac failure or volume overload and with a partial pressure of oxygen (PaO 2 ) to fraction of inspired oxygen (FiO 2 ) ratio ≤ 300 mmHg, or an SpO 2 / FiO 2 < 264 during noninvasive ventilation, or an oxygenation index > 4, or an oxygen saturation index (OSI) > 5 during invasive mechanical ventilation are concerning for ARDS. Oxygen saturation index can be calculated based on pulse oximeter information COVID-19 PICU guidelines: for high-and limited-resource settings S Kache et al. Rationale. Patients with respiratory distress should be treated when oxygen saturations are <90%.HFNC or NIPPV are safe and efficacious modes of respiratory support in pediatric patients and may provide adequate respiratory support to prevent the need for invasive mechanical ventilation. At a time when there is a global shortage of ventilators, particularly in resource-limited settings, alternative methods of respiratory support such as bCPAP should be considered. WHO recommends the use of bubble CPAP for treatment of COVID-19-infected children with hypoxemia, severe pneumonia and/or ARDS based on trials in Bangladesh and Ghana.These studies demonstrate improved outcomes in pediatric patients treated with locally developed bCPAP devices. Thus, in situations where mechanical ventilation might not be available, bCPAP may be used for newborns and children with severe hypoxemia, and may more readily be available in resourcelimited settings.A recent systematic review revealed that the use of HFNC and bCPAP in children with severe pneumonia decreased the need for intubation and mechanical ventilation; younger children in particular had a greater benefit from the use of bCPAP.It is imperative that patients treated with either HFNC or NIPPV should be closely monitored for clinical deterioration. Finally, since all forms of respiratory support are at risk of aerosolization, health-care providers must assure airborne precautions and proper personal protective equipment is used. Treatment recommendations for invasive mechanical ventilation. 3. Children with COVID-19 failing NIPPV should be escalated to invasive mechanical ventilation (Strong recommendation). 4. In children with COVID-19 requiring intubation, the procedure should be done by a trained and skilled health-care provider (Strong recommendation). 5. Children with COVID-19 requiring intubation should be intubated with a cuffed endotracheal tube (Strong recommendation). 6. For children with COVID-19 requiring intubation, use of video laryngoscopy should be considered for intubation (Weak recommendation). 7. Personal protective equipment (PPE) should be worn for intubation and extubation of all children with COVID-19 (Strong recommendation). 8. For children with COVID-19 requiring mechanical ventilation, tidal volumes should be limited to 6 ml/kg (Weak recommendation). 9. For children with COVID-19 requiring mechanical ventilation, positive end expiratory pressure (PEEP) titration should be individualized to each patient and their phase of ARDS (Weak recommendation). 10. For children with COVID-19 requiring mechanical ventilation, prone position should be considered in patients with ARDS and severe hypoxemia (Weak recommendation). 11. For children with COVID-19 requiring mechanical ventilation with refractory hypoxemia, use of inhaled nitric oxide is not recommended (Insufficient evidence). 12. For children with COVID-19 requiring mechanical ventilation, high-frequency oscillatory ventilation (HFOV) is not recommended for routine application but may be considered in select cases (Insufficient evidence). Rationale. Patients with progressive hypoxemia, altered mental status, or continued increased work of breathing on NIPPV should undergo endotracheal intubation (e.g. evolving ARDS). Multiple intubation attempts can result in poorer outcomes for the patientand place the provider at greater risk of exposure to COVID-19; therefore, intubation by the most-skilled provider is recommended. Before endotracheal intubation, bag-mask respiratory assistance may become an aerosol-generating procedure; therefore, rapid sequence intubation (RSI) using muscle relaxant is recommended. Pre-oxygenation with 100% oxygen (unless contraindicated, e.g. cyanotic heart lesion patients) is recommended to minimize hypoxia with RSI; children are at great risk of hypoxia due to a smaller functional residual capacity. Video laryngoscopy, if available, can be used to increase the distance between the patient and provider.Once the patient is intubated, the endotracheal tube cuff must be inflated immediately to prevent aerosolization. Endotracheal intubation is an aerosol-generating procedure; the provider therefore requires full PPE to protect himself/herself. PPE includes disposable fluid-resistant longsleeved gowns, goggles or disposable full-face shields, and N95 masks. If available, a powered air-purifying respirator (PAPR) can be used in place of an N95 mask. Disposable operating room caps should be worn to reduce contaminating hairs by droplets.In order to provide further protection of health-care workers, other procedures have also been introduced, including an acryl intubation box,plastic drapes,as well as mask-over-tube technique.Use of hydrophobic viral filters placed at the ventilator outlets and inline closed suction are suggested to minimize the risk of transmission. Extubation is also an aerosolgenerating procedure; therefore, PPE must be worn. General management guidelines or protocolsfor mechanical ventilation in ARDS can be applied to the COVID-19 patients with respiratory failure. A low tidal volume, 4−6 ml/kg for ideal body weight, lung protective strategy is usually recommended.However, larger tidal volumes are frequently used in pediatric intensive care units (PICU) around the world; therefore, it is advised to continue to use tidal volumes familiar to each institution. A meta-analysis of observational studies in children did not demonstrate a survival benefit by reducing tidal volumesand a retrospective analysis of ARDS patients at a single center also did not show a relation between tidal volumes and outcomes.Regarding the PEEP level, the experience in adult COVID-19 patients in Italy does not advise the use of higher PEEP routinelywhich varies from previous recommendations of PEEP use in ARDS.In the early phase of respiratory failure with COVID-19, the majority of patients exhibit critical hypoxemia due to increased intrapulmonary shunt fraction; however, the lung compliance is relatively maintained.In this situation, applying high PEEP may have detrimental effects, and applying relatively low PEEP and accepting lower oxygen saturations (80s to 90s) may be advised if the patient has single organ failure of the lungs. In the later phase, the pathophysiology may change to typical ARDS 39 requiring a higher PEEP. Individualized titration of PEEP is recommended and the patient's hemodynamics must be monitored closely with increasing PEEP. Studies have demonstrated that prone positioning can improve oxygenation.However, this strategy should be implemented only by teams that routinely prone patients. Inhaled nitric oxide may improve oxygenation, but no studies to date have demonstrated a survival benefit.High-frequency oscillatory ventilation (HFOV) can be considered for refractory respiratory failure, but no clear data exist to support its use in COVID-19 patients. Hence, conventional mechanical ventilation using individualized PEEP is advised; patients with preserved compliance may not require high PEEP whereas those with low lung compliance will benefit from more PEEP. Finally, although not listed as a recommendation, a conservative fluid strategy should be used in patients with ARDS if the patient's hemodynamics will allow fluid restriction. If available, extracorporeal membrane oxygenation (ECMO) may be considered in patients with continued severe hypoxemia despite maximal support (see "ECMO considerations" section). Hemodynamic support Clinical presentation. Clinical presentation of children with COVID-19 can range from tachycardia to classic signs of shock and heart failure. The presence of tachycardia varies from 6 to 42%.Reports in adult patients indicate that patients with myocardial injury may have arrhythmias and myocarditis. The presence of myocardial injury and increased cardiac biomarkers are associated with worse outcomes with a tenfold increase in mortality.Cardiac injury can be detected by elevated cardiac biomarkers, such as troponin, creatine kinase (CK), and its isoenzyme MB, electrocardiogram (EKG) and echocardiographic abnormalities. Cardiac enlargement can be evidenced in chest X-ray or CT scan.Pediatric patients at risk of developing myocarditis include those with comorbidities, such as heart disease, or those who progress to the severe hyperinflammatory phase. Rationale. The need for bolus fluid administration should be guided by frequent clinical assessments (heart rate, blood pressure, capillary refill, level of consciousness, urine output), serial serum lactate levels, and advanced hemodynamic monitoring when available. In the presence of fluid overload, (signs of pulmonary edema and/or hepatomegaly), fluid resuscitation should be reassessed. In settings with advanced supportive care availability, recent studies show no difference in mortality between the restrictive and permissive fluid resuscitation strategies.The FEAST trial done in Africa evaluating fluid resuscitation in limited-resource settings demonstrates the need to be cautious of aggressive fluid resuscitation.Studies demonstrate no outcome benefits for patients resuscitated with crystalloid over colloid solutions. Crystalloid solutions are recommended based on lower cost, greater availability, and the transfusion risk associated with colloid use. Although blood lactate is not considered a direct measure of tissue perfusion, high lactate is associated with worse outcomes in children.Additionally, adult data demonstrated significantly lower mortality and improvement in other outcomes when resuscitation was guided by serial lactate measurements.Persistently elevated blood lactate levels may indicate incomplete hemodynamic resuscitation and should trigger efforts to restore adequate tissue perfusion and establish hemodynamic stability. For inotropic support, epinephrine or norepinephrine should be chosen as the first-line vasoactive infusion guided by clinical preferences, individual patient physiology, and local system factors. Both have inotropic and vasopressor effects and are effective in treating children with fluid refractory shock. Epinephrine should be considered as the first-line agent in patients with myocardial dysfunction and norepinephrine for patients with low systemic vascular resistance, as recommended in Surviving Sepsis Campaign (SSC) guidelines.Institutional practices and the availability of vasopressin should determine if and when it can be initiated. Although there are no RCTs for inodilators in children with shock, they should be considered in patients with myocarditis or low cardiac output syndrome. Glucocorticoids could also be considered for patients with refractory shock (see "Pharmacologic treatment" section for further discussion). For patients with signs of myocarditis, in addition to supportive treatment, some anecdotal reports in adult patients with COVID-19 and myocarditis suggest IVIG therapy.Adjuvant therapy Clinical presentation. In this section, we discuss several important supportive therapies that may be applicable in critically ill children with COVID-19. Many of these therapies are described in critically ill adults but their description in the pediatric population remains limited. These therapies include the management of the prothrombotic state that occurs frequently in adult patients with COVID-19, convalescent plasma infusion, nutritional therapy, and renal replacement therapies. Treatment recommendations.However, use of plasma exchange therapy in children with COVID-19 has not been reported to date. ## Consider anticoagulation therapy for children with covid In previous pandemics (e.g., SARS, H1N1 2009, MEWRS-CoV), convalescent plasma treatments were utilized as part of the management strategies.Because convalescent plasma can potentially suppress viremia in COVID-19,there is increasing description of convalescent plasma treatment, albeit mainly as case reports and case series. To date, there are no specific nutrition guidelines for critically ill children with COVID-19. The Society of Critical Care Medicine together with American Society for Parenteral and Enteral Nutrition have provided some guidance on the nutrition therapy for critically ill adult patients.Current available evidence from critically ill adults with COVID-19 found that acute kidney injury (AKI) is not a common phenomenonand no recommendations were made in the adult COVID-19 surviving sepsis guidelines.To date, there are no specific data on the incidence of AKI in critically ill children with COVID-19. Cardiopulmonary resuscitation (CPR) Clinical presentation. In pediatric patients infected with COVID-19 that are pulseless due to asystole, pulseless electrical activity (PEA), ventricular fibrillation, or pulseless ventricular tachycardia, the following recommendations should be considered. Change mode to Pressure Control Ventilation and limit pressure as needed to generate adequate chest rise. c. Adjusting the trigger to Off will prevent the ventilator from auto-triggering with chest compressions and may prevent hyperventilation. d. Adjust respiratory rate to 10/min for adults and children. e. Adjust PEEP level to balance lung volumes and venous return. f. If return of spontaneous circulation is achieved, set ventilator settings as appropriate to patient's clinical condition. 33. Patients in prone position at the time of cardiac arrest without an advanced airway should be placed supine. Intubated patients however can remain prone and CPR can be initiated while the patient is prone (Best practice recommendation). 34. For children with COVID-19 that require PICU admission, address the goals of care with the parents or proxy as lifesustaining therapies are being escalated (Best practice recommendation). Rationale. The American Heart Association (AHA) has modified conventional guidelinesand released the following general principles when administering CPR to patients with suspected COVID-19. The guidelines have been modified to protect healthcare providers and reduce COVID-19 exposure. All rescuers must don PPE to guard against both airborne and droplet particles. Limiting personnel in the room is recommended. If available, use of mechanical CPR devices on young adolescents instead of manual chest compressions is recommended to protect rescuers. To lower the aerosolization risk of COVID-19, patients should be intubated with a cuffed endotracheal tube and connected to a ventilator with an inline suction catheter and a high efficiency COVID-19 PICU guidelines: for high-and limited-resource settings S Kache et al. particulate air (HEPA) filter in the path of exhaled gas. If possible, an HEPA filter should be attached to all manual or mechanical ventilation devices (see "Ventilation" section regarding intubation). For patients that are already intubated at the time of arrest, they should remain on the ventilator with the HEPA filter to minimize aerosolization. General ventilator principles are to optimize oxygenation and venous return while minimizing hyperinflation.Patients who are prone at the time of arrest without an advanced airway, the recommendation is to place them supine and continue resuscitation. While the effectiveness of CPR in the prone position is not completely known, for proned patients with an advanced airway, avoid turning the patient to the supine position unless able to do so without risk of equipment disconnections and aerosolization. Instead, consider placing defibrillator pads in the anterior-posterior position and provide CPR with the patient remaining prone with hands in the standard position over the T7/10 vertebral bodies.Consider the appropriateness of starting and continuing CPR in COVID-19 patients. It is reasonable to consider age, comorbidities, and severity of illness in determining the appropriateness of resuscitation and balance the likelihood of success against the risk to rescuers and patients from whom resources are being diverted. It is recommended to address the goals of care with parents (or proxy) prior to an arrest situation. ## Ecmo considerations Clinical presentation. In PICU patients with SARS-CoV-2 that develop refractory hypoxemia or hypotension despite maximal medical support, ECMO may be considered. Treatment recommendations. ## Ecmo should be considered in covid-19-infected pediatric patients to manage ARDS and/or cardiac failure (myocarditis, arrhythmias, pulmonary embolism) (Strong recommendation). ## Strict selection criteria for both veno-arterial (va) and Veno-Venous (VV) ECMO should be applied in order to utilize ECMO for those patients most likely to benefit from the procedure (Strong recommendation). Rationale. The WHO,the Society of Critical Care Medicineand Extracorporeal Life Support Organization 87 have all recommended the potential use of ECMO in severe cases of COVID-19. However, at the time of submitting this publication, specific indications and contraindications for its use in COVID-19 are scarce and outcome data derived from China are not encouraging.However, preliminary positive experiences in South Korea and Japan suggest the use of ECMO to manage SARS-CoV-2-induced ARDS and/or cardiac failure (myocarditis, arrhythmias, pulmonary embolism) unresponsive to maximal medical therapy.Initiation and patient selection for both VA and VV ECMO should not deviate from the existing guidelines.Early ECMO deployment is suggested to avoid progression to multiorgan failure. Older age, presence of more than two comorbidities, immunocompromised state (lymphopenia) are not absolute contraindications; however, each case should be evaluated on an individual basis.In a pandemic, ECMO should be initiated only at an experienced center, but even in such centers the availability of equipment and human capital should be considered prior to deployment of such a resource-intensive intervention. Extracorporeal cardiopulmonary resuscitation (eCPR) should not be initiated in less experienced centers or centers without an existing eCPR program prior to the pandemic. As disease burden increases, selection criteria for both respiratory and cardiac ECMO will become more stringent in order to utilize ECMO for those patients most likely to benefit. Given the pathophysiology of SARS-CoV-2 in humans, children may have better outcomes than adult patients and therefore may be a population in which ECMO resources should be invested. ## Pediatric multisystem inflammatory syndrome-children (misc-c) Clinical presentation/case definition. Potential presenting signs for MIS-C are fever, fatigue, altered mental status, neck pain, respiratory difficulty, chest pain, vomiting, diarrhea, abdominal pain, rash, and conjunctivitis. Specifically, case definition of MIS-C per the Center for Disease Control include the following 93 : - Patient < 21 years of age presenting with fever (≥38.0°C for ≥ 24 h, or report of subjective fever lasting ≥24 h), altered inflammations markers (C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, or IL-6, elevated neutrophils, reduced lymphocytes, low albumin), and clinically severe illness requiring hospitalization, with two or more organs being involved (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND It must be noted that patient's severity of illness in the hospital may range from mild to severe. Multisystem Inflammatory Syndrome should be considered in any pediatric death with evidence of SARS-CoV-2 infection. Treatment recommendations for patients with concern for MIS-C. ## Supportive management and advanced monitoring should be provided (see "Hemodynamic support" section).serology suggesting a pathogenic link between SARS-CoV-2 and MIS-C. The potential mechanism for the inflammation and mediated organ damage is unclear at present. Given the novelty of MIS-C, treatment recommendations and best practices are based on treatments used in other aggressive inflammatory disease processes. Institutions with high number of MIS-C cases have developed institutional protocols regarding drug dosing and regimens based on patient's severity of illness, but no definitive data exist to date. Pharmacologic treatments There is insufficient evidence to date to make any definitive recommendations on pharmacologic therapies for pediatric patients with SARS-CoV-2. Children are protected from COVID-19 in part because they have low ACE2, which are entry points for the COVID-19 spike protein to attach and enter the host. Treatment of fever with acetaminophen or paracetamol is prudent since the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on children with COVID-19 is unclear and being investigated. Because children account for <0.1% of deaths from SARS-CoV-2, information on COVID-19-specific pharmacologic treatments is extrapolated from the adult Chinese, French, and Italian experience. The first report from Wuhan, China on hospitalized adult patients with SARS-CoV-2 revealed hyperferritinemic sepsis 98 in those who died. Fever developed on day 1, sepsis on day 10, ICU admission on day 12 (for ARDS), and death at 19 days. Hyperferritinemia on days 4 and 7 predicted mortality long before development of sepsis and ICU admission. Progression to death was marked by increasing ferritin, C-reactive protein, IL-6, LDH, and D-dimer levels. Pharmacologic approach presently under study in adults 99 has been conceived to target a first phase of viral infection (antiviral strategies), and then a second phase of hyperinflammatory (corticosteroid and biologic strategies) and prothrombotic (antithrombotic strategies) host responses. Repurposed antiviral strategies for SAR-CoV-2. Repurposed antiviral agents include remdesivir (ebola), and lopinavir/ritinovir (HIV); and repurposed immune-enhancing therapies include type I interferons (multiple sclerosis), and passive immunization with convalescent plasma. Effectiveness of these antiviral agents is best when given early in the course of infection before day 4 of symptoms. Use of immune-enhancing interferons is also likely to have benefit when given before need of hospitalization. For practical reasons, convalescent plasma should be reserved for hospitalized patients. Unfortunately, the ongoing adult clinical trials investigating the potential effectiveness of these therapies mostly do not adhere to these biologically plausible timelines. It is unlikely that their full benefit, if present, will be revealed in the present ongoing adult studies. Pediatric dosing experience exists for use of lopinavir/ritonavir (HIV), and type 1 interferons (chronic active hepatitis). Repurposed anti-inflammatory strategies. These strategies can be considered when there is bedside evidence for hyperinflammation. Adult studies are presently using some combination of ferritin levels > 500, LDH > 300, and D-dimers > 1000 to identify eligible patients. Anti-inflammatory agents with minimal immunesuppressive effects that are under study include corticosteroids (methylprednisone), interleukin 1 receptor antagonists, and interleukin 6 receptor inhibitors. Use of these agents are more likely to be beneficial if started when hyperferritinemia occurs, which started at day 4 in the Wuhan experience. Therefore, monitoring ferritin should begin at day 4 of illness and the therapies are given before day 7 if hyperferritinemia occurs, and optimally before requiring intensive care at day 12. It is important to note that the hyperinflammatory response occurs in a minority of COVID-19 patients but is associated with the highest mortality. Unlike antivirals, these anti-inflammatory therapies should be reserved only for patients with hyperferritinemic inflammation. Pediatric dosing experience exists with corticosteroids and interleukin 1 receptor antagonist protein (Systemic Juvenile Arthritis induced Macrophage Activation Syndrome) and interleukin 6 inhibitors (CAR T-cell therapy induced Cytokine Releasing Syndrome). These therapies can and should also be considered for patients with MIS-C. ## Regional experience Several databases have recently begun tracking pediatric patients affected by SARS-CoV-2 globally, but the authors gathered data from best available resources for their respective regions. ## Africa Due to limited testing and difficulty in tracking cases, the data from Africa are limited. But data that can be identified are listed here. In Uganda, as of April 23, 63 cases have been confirmed, 9 of which are children ≤19 years of age.It is unclear how many of those patients may have required hospitalization. In Zimbabwe, 203 total cases have been confirmed and the number of pediatric cases is unknown as they did not require ICU admission as of June 2. With widespread antibody screening now being initiated in the country, more accurate numbers of infected persons should be available. Based on National Institute for Communicable Diseases (NICD) data from South Africa, as of April 19, 219 persons under 20 years of age were infected with COVID-19 but PICU admission data were not available (communication with Dr. Felicity Gumbo). ## Asia As of April 17, 82,000 cases of COVID-19 cases were confirmed in China. Wuhan city has reported 50,333 cases with 600 of those being pediatric patients.Only a small proportion of the pediatric cases required PICU admission.Many patients that developed critical illness had underlying pathologies, e.g. congenital heart disease, malnutrition.From the initial experience described in China, pediatric patients were mainly linked to family clusters, and almost all of them had epidemiological links to adult patients.Outside of China, pediatric COVID-19 data from Asia are limited at the time of writing these guidelines. To the best of our knowledge, there are no critically ill children in countries such as Japan and Singapore. In India, children under 12 years of age constituted about 5.6% (1378 out of 24,586) of the total COVID-19 cases reported from the state of Tamil Nadu. In a limited screening of hospitalized children with severe acute respiratory illness, 0.5% were diagnosed with Critical illness is rare though a few deaths have been reported in young infants. The Institute of Epidemiology Disease Control and Research in Bangladesh reports 102,292 confirmed COVID-19 cases in the country with 3% being children under 10 years of age, 7% children 11−20 years of age, and with this age group accounting for 2.3% of the total deaths in the country. No data on hospitalizations are available.Europe In Spain to date, of the 250,287 reported cases, 1399 children under 15 years of age (0.6%) have tested COVID-19 positive, and 52 (3.7%) of those children required PICU admission.No pediatric mortalities have occurred directly due to COVID-19, but in 3 infected children SARS-CoV-2 may have contributed to their death (Communication from Spanish Society of Pediatric Intensive Care, SECIP, Registry for SARS-CoV-2 as of April 21, 2020). In Italy, at the time of manuscript submission, of the 162,004 reported cases, 1.7% are children 0−18 years of age. Among the pediatric patients, 18.2% were younger than 2 years of age and the 65.3% were older than 6 years. Only 6.3% of the pediatric patients required hospital admission with rare PICU admissions.In France, as of April 23, 556 pediatric patients (ages 0-14 years) have required hospitalization, 20 of which have required PICU admission, and 11 patients had underlying comorbidities. To date, five deaths (ages 0-19 years) have been reported.North America In North America, the Virtual PICU Systems (VPS) dashboardcaptures data for the United States and Canada from 183 PICUs. As of June 18, VPS reports 653 COVID-19-positive pediatric patients have required PICU admission and have in total required 4192 PICU days. The mortality rate is reported to be <1%. Of the patients requiring PICU admission, 15% of patients were under 2 years of age, 27% were 2-12 years old, and 37% were 12-18 years old with the remainder being adult patients admitted to the PICUs. Of the patients with data on discharge, 45% were previously healthy children with no comorbid conditions. Since the VPS data are self-reported by PICUs, there may be inaccuracies inherent to this dataset. Data from Mexico were not available. South America Similar to other regions of the world, definitive pediatric data were difficult to identify. In South America, Brazil has been the most affected country to date, followed by Peru, Chile, Ecuador, Colombia, and Argentina. Data from Ministry of Health of Brazil report, as of April 27, 27 deaths from COVID-19 in pediatric patients (0-19 years old). with the search criteria COVID-19, Children, and selecting for "Child (birth-17)" under Eligibility Criteria. Among the 377 identified trails, 115 are interventional, 256 observational, and 43 are registries. Studies are being conducted in all regions of the planet; pediatricians and intensivists caring for children with COVID-19 and its sequalae are encouraged to identify regional studies and registries for enrolling patients. As this is a rapidly evolving disease entity, understanding the demographics, clinical presentation, diagnostic findings, biomarker profiles, and potentially effective treatments will be beneficial for the global community of health-care providers. # Conclusion This manuscript was developed to provide guidelines for managing COVID-19-infected critically ill pediatric patients in both high-and limited-resource settings. We also discuss the available regional pediatric data, which may be of particular interest given the limited pediatric COVID-19 data at present. SARS-CoV-2 has had a devastating impact on the adult population. Children comprise a small fraction of those impacted by this disease. We propose a set of initial guidelines to manage critically ill pediatric patients with COVID-19. These guidelines were based on the best available evidence, extrapolation of clinical evidence from adults, and the best practices where the evidence is lacking. As the COVID-19 pandemic evolves, implementing the proposed guidelines will help to reduce morbidity and mortality in pediatric patients. Updating these guidelines will be necessary based on additional data and the new evidence from ongoing clinical trials.	None	https://www.nature.com/articles/s41390-020-1053-9.pdf	None
e3b6ee468718f3f5b042653a084ed9f4184aca98	pubmed	Guideline of the Brazilian Society of Cardiology on Telemedicine in Cardiology - 2019	Guideline of the Brazilian Society of Cardiology on Telemedicine in Cardiology - 2019 ## Owns stocks in industry Alexandre ## Presentation In due time, the Brazilian Society of Cardiology decided to create a guideline on telemedicine applied to cardiology, also known as telecardiology. According to the Pan American Health Organization (PAHO) and the World Health Organization (WHO), telemedicine is "The delivery of health care services, where distance is a critical factor, by all health care professionals using information and communication technologies for the exchange of valid information for diagnosis, treatment, and prevention of disease and injuries, research and evaluation, and for the continuing education of health care providers, all in the interests of advancing the health of individuals and their communities." Such a seemingly simple and altruistic definition carries a wide range of potential implications at various levels, from an ethical point of view to a potential impact on clinical practice and outcomes. Hence, the importance of guidelines, organized by the medical community through scientific societies, in offering to all of those involved in the process a reference based, as much as possible, on expert opinion, current scientific evidence, and on respect for medical ethical and deontological values. Considering that cardiovascular diseases are the main cause of morbidity and mortality in the 21st century in Brazil and worldwide, the opportunity to use instruments to allow more effective actions in the prevention, diagnosis, treatment, and follow-up of these diseases paves the way to very relevant perspectives of better care for the populations and communities that we serve. At the same time, bioethical aspects and consequences should never be neglected, as they can (and should) undermine programs that, disguised as "medical," fail to meet these ethical requirements. Therefore, regulated operating models based on guidelines organized by medical-scientific authorities are fundamental in striking a balance. The introduction and implementation of new digital technologies are favoring the emergence of new methodologies (many still experimental) aimed at improving the capacity of intervention on individual patients and allowing for more customized care. We are experiencing what Eric Topol 1 in his latest book, "Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again," called the "Fourth Industrial Age" comprising artificial intelligence, robotics, and big data that will have a great impact on the way we live and see ourselves as human beings. If this is very positive at first sight, it is also true that it is not devoid of risk, particularly in the way that we approach or will approach the patient. Therefore, one must not forget the Hippocratic principle: "It is far more important to know what person the disease has than what disease the person has." In fact, when we are sick, we all want to have our doctor -and not a computer -taking care of us and offering us a word of comfort and confidence. Therefore, we must think smartly about how to apply to human benefit this impressive array of elements that have opened up frontiers that were unfathomable just a few years ago. Telemedicine -or telecardiology -can indeed play a very important role, particularly when this may be the only available resource. However, its use must be properly delineated to prevent abuse and misuse. The present document and guideline was prepared for this purpose. This complete document offers a detailed review of the regulation of telemedicine in Brazil, defines the meaning of a geographically remote area, and describes the fundamentals of telemedicine and the secure grounds for its transmission. This document also offers up-to-date information on current evidence and applications of so-called teleconsultation, telediagnosis, and telemonitoring, and reflects on how telemedicine can provide technology-based medical services, with artificial intelligence playing a key role. The document also includes the economic assessment and budgetary impact of incorporating telemedicine in cardiology in Brazil and telemedicine in supplementary health, and -in one of the most important chapters -presents the ethical and legal aspects of telemedicine. Finally, the document includes a set of recommendations intended to be practical and adapted to the Brazilian perspective. The result is a guideline perfectly aligned with the WHO guidelines on the principle that the implementation of telemedicine must be properly planned and should predict situations like the feasibility of network coverage for technology access in remote locations, construction of a legal and judicial structure for the implementation, budgetary impact and cost-effectiveness assessment of the implementation of each stage of the project, and development of indicators of the clinical continuum of applicability for user safety. As the president-elect of the World Heart Federation, I see this as a model document in terms of how it was planned and implemented, as well as in its content, reflecting the current evidence and perspective of the main scientific players in the area. As such, I think it will become a historical document, a milestone in the responsible introduction of telemedicine-telecardiology in clinical practice, in this case, applied to Brazil, but which can serve as an example for others globally, contributing to decrease the burden of cardiovascular diseases worldwide. Lisbon, June 2019. # Introduction For more than 26 years now, starting after the publication of the Consensus on Severe Heart Disease in 1993,the Brazilian Society of Cardiology (SBC) has been regularly issuing guidelines on most diverse topics, guiding the practice of cardiology in Brazil. In 1999, the Brazilian Federal Council of Medicine (CFM) 3 partnered with the Brazilian Medical Association (AMB) and, aiming to support medical decision making and optimize patient care, started a process along with specialty societies for the development of Medical Guidelines based on current scientific evidence. Thus, the commitment of SBC precedes the initiative by AMB and fulfills one of the society's objectives, described in the society's bylaws. passed by the CFM to preserve the autonomy of the physician, defined that, in their relationship with physicians and beneficiaries, health insurance and group medical companies, medical cooperatives, selfmanagement companies, and other companies offering direct care or care mediated by medical-hospital services should only adopt medical guidelines or protocols prepared by Brazilian specialty societies along with the AMB. Within this context, 5 the CFM initiated discussions in 2018 to update the regulations of telemedicine. Telemedicine can be defined as the application of information and communication technologies to health care with the goal of offering, in a broad concept, health-related services ranging from primary care to robotic surgery and education, expanding coverage to remote areas in a country with continental dimensions. The Pan American Health Organization (PAHO) and the WHO define telemedicine as "The delivery of health care services, where distance is a critical factor, by all health care professionals using information and communication technologies for the exchange of valid information for diagnosis, treatment, and prevention of disease and injuries, research and evaluation, and for the continuing education of health care providers, all in the interests of advancing the health of individuals and their communities." The PAHO estimates that one third of the population in the Americas has no access to health care and that 800,000 additional health care professionals would be needed to meet the needs in the region.If applied in its broad context, telemedicine could allow access and reduce inequality for this population by providing supposedly cost-effective quality services, especially considering the increased prevalence and mortality from chronic noncommunicable diseases (NCDs) in low-and middle-income countries like Brazil. Added to this context is the aging and increasing disease rate of the Brazilian population, which makes telemedicine an ideal tool to face the contemporary challenges of universal health care systems.Beyond the vast possibilities and applications of telemedicine, rigorous evaluations of telemedicine projects must be undertaken, not only because all health care systems face financial sustainability challenges beyond investments in health care interventions, but also because of the limited clinical evidence available, especially in the current order of valuebased medicine. This topic of utmost importance has been the subject of several publications by the WHO. Examples of that include the Digital Health Atlas,a global virtual platform to support governments in monitoring and coordinating digital health activities; "BeHe@lthy, BeMobile" (BHBM), 9 for the prevention and control of NCDs; and mHealth Assessment and Planning for Scale (MAPS), a manual for digital health monitoring and evaluation 10 to enhance digital health research and implementation; among others. These documents culminated in the publication by the WHO of the first guideline on digital health interventions on April 17, 2019.In addition to updating the guideline on telemedicine applicable to cardiology published in 2015, the main objective of the present guideline is to answer the following questions: Is there legal and ethical support for the application of telemedicine in Brazil? Are there technical conditions for the application of telemedicine in the country? What is the priority of incorporating telemedicine into the health care system? For which modalities is there good quality scientific evidence to support this practice? For modalities supported by solid evidence, does cost effectiveness justify this application? What would be the budgetary impact? Is the Brazilian health care system prepared to provide comprehensive care? This guideline, which is in line with the WHO guidelines,advocates that the implementation of telemedicine should be a planned process that provides feasibility of the network coverage in remote locations, elaboration of the legal and judicial bases for its implementation, budgetary impact and cost-effectiveness assessment of each stage of the project, and development of clinical continuum indicators of the applicability for the safety of the beneficiaries. Telemedicine can be a potential tool in improving health care services but is not exempt from risks and challenges related to its implementation and from the evaluation of the real impact of its benefits. In the final chapter, the authors present a summary of recommendations based on current evidence, in an attempt to guide the discussions that will certainly permeate the democratization of comprehensive health care services, especially the actions involving telemedicine as a tool to expand the universality and integrality of the Brazilian Unified Health System (SUS), recommendations that also extend to supplementary health care. Brazil, June 2019. ## Innovation in digital health and telehealth Innovation in digital health is transversal to telehealth initiatives and seeks to explore via ICT new ideas to solve chronic problems with difficult solutions by usual methods. It must start with the population's health care needs. ## Teleconsulting Registered consultation between health care workers, professionals, and managers using two-way telecommunication instruments in order to answer questions about clinical procedures, health care actions, and suggestions related to the work process in health care. Teleconsulting can occur in real time or by offline messaging. ## Telediagnosis Autonomous service using ICT to deliver diagnostic support services (e.g., remote evaluation of diagnostic tests) to facilitate access to specialized services. The use of telediagnosis seeks to reduce the time to diagnosis by enabling treatment for predictable complications through early diagnosis. ## Telemonitoring Remote monitoring of patients' health and/or disease parameters through ICT. Monitoring may include clinical data collection, transmission, processing, and management by a health care professional using an electronic system. ## Teleregulation Set of actions in regulatory systems for evaluation of adequate responses to existing demands, promoting equity and access to services, and enabling health care access. Teleregulation also includes the evaluation and planning of actions to provide regulatory operational intelligence to management teams. The objective of teleregulation is to potentiate primary health care services, thus enabling the qualification and reduction of wait for specialized care. ## Tele-education Availability of interactive educational materials on healthrelated topics delivered remotely through ICT and focused on professional education across activity areas. ## Types of intervention in telehealth Synchronous video conference: modality of remote interaction via live conference between primary care and medical specialty services. Asynchronous video conference ("store and forward"): use of a storage system to forward diagnostic images, vital signs, and/or video clips along with patients' data for later review by a specialist. Provides diagnostic and treatment support for the primary care system. Remote monitoring: use of equipment to remotely collect and forward patients' data to a hospital or monitoring center for interpretation. These (wearable) devices monitor remotely a variety of indicators ranging from specific vital signs (heart rate, blood pressure , and blood glucose) to other indicators. Mobile health (mHealth): defined as a medical and public health care practice supported by mobile devices like cell phones, monitoring devices, personal digital assistants (PDAs), and other wireless devices.The goals of telemedicine include: - Remote assistance: teleconsultation, telediagnosis or diagnostic telemonitoring, remote patient monitoring and/ or treatment; - Administrative management of patient care: request of diagnostic tests, medical prescriptions, and actions related to service reimbursement; - Remote qualification of human resources to facilitate continuing education programs; - Network collaborative clinical research: use of ICT to share and disseminate best practices and generate knowledge. ## Safe bases for data transmission Information safety is fundamental for data transmission, and two immediate effects must be considered: a) understanding of the critical value of data storage and use, and b) possible implications for individuals and organizations of violating safety and compliance standards. The European General Data Protection Regulation (GDPR) and the Brazilian General Data Protection Act (Lei Geral de Proteção de Dados, LGPD) impose heavy fines and sanctions for improper access to information under their custody. The following sections list the main requirements for establishing appropriate safety policies. ## Data protection and confidentiality For proper information protection, the safety of the systems must be ensured, reducing vulnerabilities and preventing improper access and breach of confidentiality. Authorizations and hierarchical levels for access to information must be clearly determined.The policy related to information access and confidentiality must be reported in a document signed by the users defining the a) scope of data that can be accessed and b) legal implications and sanctions eventually applied to users in case of violation of the agreed rules. Misuse of technological installations is directly related to the safety of the environments under the responsibility of ICT teams. Strict policies must be adopted in terms of access to physical facilities, data networks, operating systems, and databases and their applications. A valuable framework to provide an understanding of the control of these environments can be found in the document "Access Control Example Policy" (Health and Social Care Information Centre, 2017).The recommended standard for data transmission in Brazil follows the set of rules determined by the Health Insurance Portability and Accountability Act (HIPAA). 17 This set of norms has proven robust enough to ensure the safety of the transferred data and is recommended as the benchmark for data transfer practices. The CFM Resolution 2.227/2018, now revoked, set the standard that would meet the desirable requirements: "Use of a proprietary or an open-source electronic/digital information registration system that captures, stores, presents, transfers, or prints digitally identifiable health information and is fully compliant with the requirements of Safety Assurance Level 2 (Nível de Garantia de Segurança 2, NGS2) and the ICP-Brazil standard." According to these standards, stored data ("at rest"; "in transit") must be encrypted for transfer. One of the essential practices for data security is to maintain the tools required to encrypt and decrypt information in environments other than the original storage locations.In addition to ensuring information security, HIPAA rules offer extensive documentation for data encryption and transfer, facilitating the work of development teams. Of note, national public data cannot be stored in cloud systems hosted outside the country. 21-22 # Bioethical aspects Initiatives to provide remote health care through telemedicine date back to the 19th century. Cardiology was a pioneer in this initiative, with the description by Einthoven in 1906 of a transtelephonic electrocardiographic transmission from the academic hospital to the physiology laboratory at Leiden University, a few miles away.The big boost in the development of telemetry was by the North American Space Agency (NASA) in astronaut monitoring.However, the incorporation of telemedicine, as currently conceived, is contemporaneousand linked to the traditional notion that the preservation of the social value of medicine depends on content flow. Any modality of telecommunication holds both constructive and destructive potentials that trigger contradictions in terms of values and rules of moral code related to bedside medical practice. Ambivalence is welcome in medicine, which according to , is the science of uncertainty and the art of probability.Telemedicine is not immune to the pendular movements of the variety of methods addressing health needs. Bedside practice faces dilemmas inherent to the diversity of the human condition.Physicians and patients face external and/or internal challenges without a single and simple solution. Any option to be considered must be judiciously expressed, clarified, and adjusted to be validated for the conceptual and individual context of the clinical circumstance. Applied technology has attributed a sense of real progress to medicine.The contemporary emphasis on ICTs in health care must be critically observed by society. Bioethics has the required competence to evaluate the effects of telemedicine on the integration of health sciences, health care professionals, patients/relatives, health institutions, and health care system. The benefit of telemedicine should be considered more as a non-presential complementation of usual care rather than a replacement for face-to-face care. Telemedicine should be practiced with security and for a period relevant to the clinical circumstance (expiration dates proportional to the legitimate interests involved).An additional ethical aspect is that certain unavoidable perspectives of abuse of a technique should not adversely affect the beneficial use of the technique. Therefore, any ethical and legal considerations regarding the still young telemedicine, especially for application in a continental, multiethnic, and multicultural country like Brazil, cannot fail to recognize that it is difficult for a health care professional to define comprehensively and in depth his or her set of responsibilities, considering that the scope of telemedicine demands an A-to-Z range of intertwining requirements, decisions, and provisions regarding: a. involvement with fundamentals of current ethics, prudence, and zeal regarding complex issues like elderly care, comfort of vulnerable individuals, decrease in hospitalizations, and prompt guidance; b. impartial judgment about covering the patient's real needs and constraint of secondary gains and conflicts of interest, including the potential for political (mis)use and power; o. appreciation of the value of face-to-face relationships immediately or long before the online connection; p. creation of a mood of confidence despite the distance; q. conceptual and event-driven alerts about non-presential limitations; r. individual assessment of the level of competence for the required care at the moment; s. assessment of the completeness of the required information; t. concern with the continuity of the care provided; u. promotion of adherence to the recommended management; v. respect for professional confidentiality; w. "passport adjustments" related to the state geographical limitation of the physician's registration in the medical council; x. continued research for reliable evidence of advantages and disadvantages; y. interface with consumerism in health care, including due and undue expectations about the possibility of immediate care; z. valuing the contribution of bioethics to the harmonization between classic, innovative, and novelty. Therefore, in light of the existing ethical-normative bases of the current legislation and the bioethical principles that guide physician-patient relationships, we can establish the following guidelines for the use of telemedicine in cardiology: 1. Cardiologists should use caution, and prior to using telemedicine applied to cardiology (or simply telecardiology), they should maintain a fruitful relationship with their patients based on the Code of Medical Ethics. 2. The free and informed consent form is the document that obtains authorization from the patient for the use of telecardiology when the alternative of direct teleconsultation is considered. 3. Procedures for the remote monitoring of vital signs should be previously consented by the patient, with proper guidance and training regarding its use. 4. Medical companies providing telecardiology services must be registered with the Regional Medical Council (Conselho Regional de Medicina, CRM) and have a cardiologist as a technical manager, who will be in charge of overseeing the procedures performed, especially regarding the technological tools available to professionals. ## 5. Respect for the patients' autonomy of will and protection of privacy regarding health data are the basis of telemedicine applied to cardiology. ## Legislation and regulation in brazil The Brazilian Internet Civil Framework (Federal Law No. 12.965, dated April 23, 2014) ## The brazilian internet civil framework The Brazilian Internet Civil Framework (Decree 8.771, dated establishes the principles, guarantees, rights, and duties of users of the World Wide Web in Brazil. The Brazilian Internet Civil Framework recognized legal relations in the virtual world and their effects on Brazilian order. In addition to establishing the neutrality of the web, it also excelled in safeguarding freedom of expression and privacy protection but failed to address important aspects related to personal data, leading to the development of the LGPD. 34 I. Personal data -information related to an identified or identifiable natural individual; ## General law data protection law II. Anonymized data -data related to a holder that cannot be identified by reasonable technical means available at the time of processing; III. Sensitive personal data -racial or ethnic origin; religious belief; political opinion; union affiliation or membership in religious, philosophical, or political organizations; healthor sex-related data; and genetic or biometric data, when linked to a natural individual. According to the legislation, access to the Internet is essential to the exercise of citizenship, and inviolability of intimacy, privacy, and communications established through the Internet must be ensured to users. Safety and confidentiality measures and procedures must be clearly informed by the service provider and should meet the standards set by regulations, respecting the right of confidentiality related to business privacy. Regarding telemedicine, the need to deal with a large amount of sensitive data (patient registration, health complaints, prior and current disease history, test requests and results, diagnostic hypotheses, therapeutic plan, clinical follow-up, and opinions, among others) makes LGPD an object of significant interest. In 2007, the Brazilian Ministry of Health established the National Telehealth Program to improve the quality of primary health care in the Unified Health System (SUS) and support the Family Health Strategy program. Ordinance 2.546, dated October 2011, expanded, redefined, and renamed the program to Brazilian National Telehealth Network Program, which governs the services of synchronous or asynchronous teleconsultation, telediagnosis, second formative opinion, and health tele-education. ## Regulation of telemedicine by the federal council of medicine According to CFM Resolution 1.643/2002,telemedicine is the practice of medicine through the use of interactive audiovisual and data communication methodologies, with the objective of health care, education, and research. Additionally, the following relevant aspects should be highlighted: - The services provided must have appropriate technological infrastructure and should comply with the CFM technical standards related to data storage, handling, transfer, confidentiality, and privacy, and must ensure professional secrecy. - The professional responsibility for the care lies with the patient's attending physician. Others involved in the process will be jointly liable to the extent to which they contribute to the eventual damage. - Entities providing telemedicine services must be registered in the Entities Register of the Regional Council of Medicine of the state of their location along with a physician regularly registered in the Council assigned as a technical manager and a list of all physicians participating as staff members. Since then, technological innovations and the democratization of Internet access have allowed several innovations that still lack proper regulation, such as: - new means of physician-patient relationship; - emergence of data and service agents and providers; - discussion of a new format for the free and informed consent form under strict safety rules to guarantee information confidentiality and integrity. This scenario prompted a need to update the regulation of telemedicine practice in Brazil. Based on that, the CFM issued Resolution 2.227/2018, which was later repealed. However, an update of the Resolution is urgently needed to provide legal security within the perspective of telemedicine emerging as a vector of health transformation.In this guideline, we adopt the denomination of the services offered within the scope of telemedicine, according to the Ministry of Health Ordinance 2.546, dated October 2011, and current CFM regulation. ## Applicability in brazil In a country with continental proportions like Brazil, telemedicine represents a perspective to ensure the implementation of public policies conceived when the SUS was established, which have not been entirely fulfilled due to existing unassisted or remote areas lacking health care professionals, among other reasons. Thus, infrastructure conditions must be established to deliver available resources using health-related ICTs to these areas. To understand the applicability of telemedicine in Brazil, it is important to discuss concepts related to remote areas and to know the country's medical demography. ## Concept of urban and rural territories and remote area The definition of territory goes beyond that of physical space since it generally has a strong relationship with the sociocultural context of the area. The division between urban and rural spaces is not abrupt; both have flexible boundaries and similar characteristics.Territorial occupation is evidently unequal in many regions, as it is also the access to goods and services offered in different forms of human settlements. In general, modes of transport and accessibility to urban and rural areas differ from one location to another, thus the importance of defining a classification for urban and rural concepts.According to the Organization for Economic Cooperation and Development (OECD), spaces are classified according to the population density, the proportion of the population living in large centers, and accessibility, defined as the commuting time between urban centers and rural areas. A rural area is classified as remote by the OECD when 50% of the local population requires at least 45 to 60 minutes of travel in motor vehicle to reach a center with a population of at least 50,000 inhabitants.In Brazil, the classification of occupied rural or urban spaces was established in 1938 by Decree No. 311/1938. The 2014 Territorial Base Manual, by the Brazilian Institute of Geography and Statistics (IBGE),considers the access by national road or waterway network from rural areas to urban centers to classify rural areas according to their degree of proximity and access to large urban centers, creating a sense of isolation. The 2014 Transportation Logistics Map classified municipalities as adjacent or remote if the travel time from the municipal headquarters to a center of influence was longer or shorter, respectively, than the national average..1 shows the distribution of municipalities across the national territory based on the classification of isolation by IBGE.More than 65% of the municipalities considered to be remote are located in the North and Midwest regions of the country. These two regions concentrate 5 million inhabitants or 72% of the country's residents living in remote municipalities (almost 7 million individuals live in areas considered remote by the IBGE). Also in the North and Midwest regions, the population in remote municipalities represents 20% and 12% of the total population, respectively. .1 shows the proportion of urban population in Brazilian municipalities. ## Medical demography The ratio of physicians per inhabitant in Brazil (2.1 physicians per thousand inhabitants) is significantly lower than the average ratio in OECD countries (3.4 physicians per thousand inhabitants). In addition to the absolute shortage of professionals, the country also has relative shortages due to large regional inequalities in the distribution of the existing medical workforce. Recent studies point out to a large concentration of medical professionals in the South and Southeast, with the proportion of specialists following this trend..2 shows the distribution of physicians by country region, divided according to specialization as generalists, with some type of specialty (specialists), ratio per thousand inhabitants, and distribution of cardiologists by region and per inhabitant. In the North and Northeast regions, some Federation units have a physician/inhabitant ratio below 1.00, like Resi dents i n urban per total resi dents Municipalities Data from the National Register of Health Establishments (Cadastro Nacional de Estabelecimentos de Saúde, CNES), provided by the Ministry of Health, ## Ehealth strategy The International Telecommunication Union (ITU),an agency of the United Nations (UN), has been working in collaboration with the WHO to create a global environment for eHealth strategy implementation, especially in telemedicine.The eHealth strategy is particularly important in the control of chronic noncommunicable diseases like hypertension, diabetes, heart diseases, and age-related diseases. The implementation of eHealth and telemedicine has progressed substantially in recent years,but a recent systematic review on the cost effectiveness of eHealth implementation found shortage of studies and could not assess the impact of the strategy on health systems or social aspects, although most studies showed the strategy to be efficacious and cost effective. 49 ## Telecommunications and data infrastructure Up to 95% of the world's population is estimated to have access to mobile telephony; in Brazil, this coverage may exceed 98%. Access to mobile phone services has progressed remarkably in Brazil, and the use of mobile phone equipment per inhabitant has increased from 2009 to 2019, 50,51 followed by a downward trend since then In terms of optical fiber coverage, the concentration is also greater in the Brazilian South and Southeast regions. .5 shows the distribution of optical fiber backhaul in Brazilian municipalities. Backhaul is the portion of a hierarchical network (like cellular mobile communication networks) that is responsible for connecting the main network and the subnets. As shown in the map in .5, the concentration of optical fiber networks is lower in municipalities of the North region, which also concentrates the largest proportion of isolated municipalities. Data from figures 1.4 and 1.5 show a trend of concentration of cardiologists in areas with a higher concentration of enabled mobile devices. The correlation coefficient of this relationship is 0.67, which indicates that the availability of cardiologists correlates highly with access to mobile phones. These data indicate a greater challenge to the implementation of telemedicine in remote areas, considering that the shortage of physicians follows the same distribution of the deficient telecommunications infrastructure in Brazil. A detailed analysis of the costs and benefits of this expansion should direct incentives to this area. ## Artificial intelligence Artificial intelligence (AI) is a complex framework of sophisticated mathematical-computational models that allows the construction of algorithms to emulate various human tasks. AI encompasses an increasing number of subareas translating into different combined or complementary methodologies and approaches. Some examples include artificial neural networks (particularly deep learning models and convolutional networks), support vector machines, evolutionary algorithms, and natural language processing. The elaboration of analytical algorithms derived from large databases allows for interactive interpretation and apprehension, recognition of hidden patterns of combined information not obtained with traditional statistical methods, and assistance in more accurate decision making. The availability of this huge amount of data and new analytical techniques -big data analytics -opens up new scientific possibilities and AI applications, such as machine learning and data mining, which are already widely applied in telecardiology to diagnose combinations of multiple modalities of images, biobanks, electronic cohorts, on-site and distance clinical monitoring sensors, electronic health records, genomes and other molecular techniques, among others.The implementation of these applications in clinical cardiology has grown exponentially 55 and has prognostic features, like the use of an algorithm derived from magnetic resonance based on three-dimensional patterns of right ventricular systolic function to assess with high accuracy the outcomes in pulmonary arterial hypertension,identification of phenotypic patterns in heart failure with preserved ejection fraction and unfavorable prognosis confirmed by heterogeneous patterns of ventricular repolarization on electrocardiogram, 57 prediction of cardiovascular risk in large cohorts,and prediction of urgent revascularization in emergency patients with chest pain, 59 among others. However, AI studies are generally based on observational data from administrative databases or clinical records, which potentially have different types of biases and confounding factors.AI applications in telemedicine are promising but still very limited.In the area of telediagnosis, efforts for automated classification and diagnosis in electrocardiography and cardiovascular imaging 61 are promising but still incipient. As for cardiovascular interventions, a recent review 62 found 8 studies incorporating machine learning in a real-life research setting, of which only three were evaluated in a randomized controlled trial. Of the 8 interventions, 6 (75%) showed statistical significance (at a p level of 0.05) in health outcomes. Some of these interventions are directly related to telecardiology and assessed interventions for weight loss, stress control, smoking cessation, and personalized nutrition based on glycemic response. Most studies had small sample sizes and short duration, reflecting a need for investments and further studies exploring the potentialities in the area. In a recent review, Topolhighlighted the presuppositions that will guide the future of AI in medicine: the patient must be considered the center for the implementation of any new technology, the incorporation of these new technologies for diagnosis and treatment should occur after robust validation of their clinical effectiveness, the use of digital tools and decision algorithms by patients should be an option for those who feel empowered to do so, and interdisciplinary training must involve health care professionals, engineers, computer scientists, and bioinformaticians. These minimum conditions Cell phones/100 inhab. Cardiologists/1000 inhab. Cardiologists/1000 inhab. Cell phones/100 inhab. Cardiologists/1000 inhab. Cell phones/100 inhab. presuppose the steps to incorporate AI into clinical practice and minimize implementation challenges. However, many aspects of health care practice will continue to depend on other dimensions, such as political, economic, and cultural ones, and on the ability of the health care professionals to interact with patients and community so that AI can truly benefit the patients, given that the issue of unequal access to health care is still critical in Brazil and will require large investments and reorganization of the health care system.Thus, potential strategies for incorporation and planning of implementation and adoption must be aligned with the possibility and challenges of offering cardiology care centered on the patient and the final value aggregated to the line of cardiology care. There is a need to identify the best technology to incorporate and define in which part of the medical work process such technology can add value to both the process and the patient's health. Additionally, it is necessary to plan the incorporation and design the journey of digital transformation in cardiology to ensure a high technological level. The incorporation of these technologies into clinical practice must, at first, involve rigorous evaluation of their performance and their ultimate value for the patient. This evaluation should respect and follow the current evaluation process of incorporation of new health technologies by the Ministry of Health, considering all aspects, norms, and regulations. The incorporation should also be based on scientific evidence on the generation of ultimate value to the patient's health from the perspective of an individual exposed to technology. It should be made clear that AI, once incorporated, works by increasing the professionals' capabilities and never by replacing them, and that all civil and criminal responsibilities, as well as all responsibilities related to the patient and his or her health problem, remain with the attending physician.Training should be multiprofessional, interdisciplinary, and focused on building services dedicated to generating the ultimate value for the patient. The medical curriculum in the cardiology area should include contents related to technical knowledge, competence development, and use of AI techniques, while cardiology services should structure a continuous program for professional qualification and human resources training in managing incorporation, training, and adoption of new digital health technologies. At present, there is no specific regulation on the use of AI in health care, although countries like Canada, United Kingdom, and the United States have begun the first phases of planning and implementing AI regulation in this area. Also, the European Union has published a document on the ethical aspects of AI in health care.The fast-paced digital transformation has led to reflections on how to balance the adoption of technology and emerging digital systems with ethical, moral, emotional, and social values, particularly values related to patients' safety. ## Uses and application of telemedicine in cardiology 2.1 telemedicine in brazil With the development of the Information Society in the late 20 th century as a result of globalization and widespread use of ICT, the emergence of organizational, social, political, and economic innovations of the society became pressing issues, requiring new ways to learn, teach, and work. The world began to worry about the principles of equal opportunity, participation, and integration so that everyone could access and benefit from the applications of the Information Society. In health care, telemedicine has made substantial progress worldwide, as it is classically viewed as a set of actions with great potential to improve access to health care services and to care quality and effectiveness at a lower cost.As a mark of the new millennium, we highlight the aging of the population, the increase in chronic noncommunicable diseases, and the consequent need to provide health care services for a longer time, which increases health-related costs. Therefore, it is essential to incorporate innovative, efficient, and effective solutions like telemedicine and biotechnology to promote universality and comprehensiveness in health care. Several actions in telemedicine are currently present in all continents and must be planned according to local needs in order to be successful. According to Bashshur et al.,the success of these actions depends on three pillars: access, quality, and cost.In developed countries, telemedicine is an alternative to traditional methods and is already present as an option to supplementary health or to address gaps in the health care system, but always aiming at integral care. In developing countries, access is the main pillar, since telemedicine can be the only option in regions where traditional specialized care is not available. In Brazil, the systematic development of telemedicine and telehealth in the public health system started in 2006, with investments from the Ministry of Health, State Health Secretariats, and Municipal Health Secretariats. The main objective was to support primary care, particularly the Family Health Strategy in remote municipalities, through teleconsulting, telediagnosis, and tele-education. If applied on a large scale, these strategies could decrease the referral of patients to large centers and consequently improve the population's access to specialized care and reduce health care costs.Therefore, telemedicine in the Brazilian public system has been anchored from the outset in the basic principles of universality, equity, and integrality of the SUS. Based on the universality principle, health is everyone's right, and it is up to the state to ensure it. Equity targets the reduction of inequalities or increased investment in areas where it's most needed. Integrality considers the individual as a whole to meet all his or her needs.Telecardiology, one of the most developed domains in telemedicine, has multiple actions in promoting health, disease prevention, diagnosis, treatment, and rehabilitation with an impact on the quality of life. It can be considered an important ally of the public, supplementary, or private health care system in promoting comprehensive and high-quality health care. ## In primary care Primary Health Care (PHC) involves integrated and multidisciplinary care and is the foundation to achieve universal health, according to the PAHO, which also advocates for other health determinants like education, food, housing, financial protection, clean water, and safe environments.To achieve universal health, health care systems must be transformed, especially by making PHC efficient, integrated, and organized, placing the patient at the center of the system. The PAHO also estimates that about one third of the population in the Americas has no access to health care and that 800,000 additional health care professionals would be necessary to meet the needs in the region. Telemedicine plays an important role in the qualification of the PHC, with clinical, human, organizational, educational, administrative, technical, and social benefits.The application of telemedicine to support PHC brings benefits to the population served, including (i) improved access to specialized services, (ii) increased solvability to the basic level, (iii) decreased number of patients referred to other municipalities for specialized care, (iv) more qualified referrals and faster hospitalization decisions, (v) better training of local health care professionals, with consequently better qualified clinical care, (vi) reduced time to diagnosis, with decreased risk of complications, (vii) diagnosis of diseases at earlier stages, (viii) cost and time savings for the patient, (ix) improved quality of life, (x) fewer hospitalizations and visits to emergency units, (xi) improved clinical care continuum, (xii) reduced risk factors and complications from chronic diseases, and (xiii) savings for the health care system. 70-74 ## Applications in health promotion and prevention In cardiology, health promoting actions and primary and secondary prevention of cardiovascular diseases translate into significant cost savings by reducing specialized consultations, hospitalizations for clinical complications, and admissions to the emergency room.Telemedicine can be useful in controlling risk factors for coronary artery disease; improving blood pressure control; 75-78 reducing glycosylated hemoglobin levels in patients with diabetes mellitus; 79-81 improving lipid profile; 82,83 reducing weight, body mass index (BMI), or waist circumference in obese individuals; 77,84-86 and increasing the success of smoking cessation programs.Several modalities of telemedicine can be applied in this regard, including cell phone text/audio messaging systems, which have positive results in improving medication adherence, changing eating habits, and increasing physical activity among patients with hypertension, diabetes, and obesity, or after acute myocardial infarction (AMI).,24-hour monitoring systems on cell phones or monitoring center services have become more frequent due to the development of specialized equipment with direct communication with telemedicine systems such as stethoscopes, scales, thermometers, digital devices, blood pressure equipment, remote monitoring of vital signs and implantable electronic devices.Simple watches have been transformed into monitoring systems equipped with technology to report heart rate, stress level (skin humidity and temperature), optical BP, and physical activity, among other parameters.Several applications are available to guide the health care team and/or patients, including applications focused on self-care. ## Decision support systems Clinical decision support systems (DSSs) provide knowledge and information from individual patients to physicians and other health care professionals, or to the patients themselves, to improve care quality and clinical outcomes. These systems are recommended by the Community Preventive Services Task Force (CPSTF) in the prevention of cardiovascular diseases despite being based on moderate-to poor-quality evidence.Applications that have shown benefits include those improving screening for cardiovascular risk factors, prescription of aspirin for primary prevention, and counseling on healthy diet, physical activity, and smoking cessation.Due to that, these applications may have wide applicability in PHC. Still, they have shown no evidence of reducing emergency visits, hospitalizations, or cardiovascular events, although additional studies are still needed. A study reported a lower mortality rate with an educational strategy for health care professionals associated with DSS alerts compared with educational strategy alone.DSSs have been evaluated in pilot studies in Brazilian Basic Health Units (Unidades Básicas de Saúde, UBS) in multifaceted interventions. This tool was proven feasible in PHC in patients with hypertension and diabetes and for cardiovascular risk management, with good satisfaction reported by the professionals and perceived ease of use,although the number of questionnaire fields filled in by the professionals was low.This may be related to the incipient implantation of electronic medical records in UBSs, generating duplicate work, a factor that was inversely related to the successful implementation of the DSS.New initiatives are underway to assess the impact on clinical outcomes of the control of patients with hypertension and diabetes in the Mucuri Valley, in Minas Gerais, and the management of patients on warfarin, still the most widely used anticoagulant in the SUS. ## Teleconsulting Teleconsulting systems have great applicability in PHC in terms of supporting health care professionals in remote areas and qualifying and reducing the time to diagnosis and treatment. As a tool with the important potential of increasing PHC solvability, teleconsulting should be incorporated into the care process in health care units as an integral part of the regulatory process of the municipality. This is an efficient way to reduce the long wait for in-person consultations with a cardiologist. Although teleconsultation has been extensively studied in our country,only a few studies have evaluated in our population the impact of teleconsultation on traditional health outcomes, like risk and mortality. A systematic review by Liddy et al.reported that teleconsulting systems were highly accepted by patients and health care professionals and improved access to specialized care. A randomized trial in cardiology assessed adverse events (including death, AMI, urgent or emergent cardiac catheterization and/or angioplasty, and emergency room visits) in patients referred to teleconsultation versus patients receiving a traditional referral. The group referred to teleconsultation was more likely to have an appointment with the cardiologist and had fewer visits to the emergency department. 101 ## Teleregulation The demand for specialized care has been growing worldwide and surpassing the supply of services while meeting limited access to specialists and long waiting times.Interventions in telehealth, particularly involving teleconsultation for regulation, have shown a great impact in reducing waiting time with the qualification of access to specialists, avoiding unnecessary referrals, and at a lower cost. In Brazil, the experience of teleconsultation for regulation (or teleregulation) has also reduced the waiting time for specialized consultation, qualifying the access and optimizing the use of resources, in addition to providing users with greater comfort and lower impact on their routine.Teleregulation also enables the classification of the risk of the demand for specialized care. Protocols to guide health care have been established, and the final decision regarding referral is defined along with the attending and teleconsulting physicians. In addition to the mentioned gains from the user's perspective, there is the process of continuing education and professional qualification, increasing solvability in primary care. 101-104 ## Telediagnosis Tele-electrocardiography, the most common activity in telecardiology, is a simple and low-cost technology for easy transfer of a small file using an Internet connection with limited bandwidth. Thus, it can be easily incorporated into the PHC routine for its great applicability and suitability for the infrastructure of PHC facilities in remote and poor areas.Tele-electrocardiography is widespread in both public and private settings in Brazil, with several companies in the country delivering reports around the clock. In 2017, the Ministry of Health launched the National Offer of Telediagnosis Project (Projeto Oferta Nacional de Telediagnóstico, ONTD) to expand the diagnostic services of tests conducted remotely in the most deprived areas of the country. Tele-electrocardiography was the first modality of telediagnosis offered nationwide by a telehealth team specialized in telecardiology. This project is an innovation in the management of a large-scale national telemedicine project model, and the good results obtained have shown its easy applicability and suitability for remote areas.The application of AI to the large databases of diagnostic tests improves the ease of the process of reporting and increases the accuracy of the tests.In telecardiology, tele-echocardiography is a promising strategy for rationalization of the access to complementary propaedeutics, early diagnosis, prioritization of referrals, and organization of waiting lists. Initial evidence of teleechocardiography application derive from population-based screening studies, for example, a study conducted in rural India, where more than 1,000 echocardiograms were performed in about 11 hours and transferred to a cloud computing system for expert analysis using telemedicine.The strategy proved feasible and showed good agreement between preliminary field diagnoses and the reports by experts (k = 0.85), and an alarming 16% rate of major abnormalities (including 32.9% of valvular defects). Even in high-income regions like the UK, evidence has shown echocardiographic screening in primary care by nonspecialists to be an attractive strategy, with clinically significant (moderate to severe) valvular disease observed in 6.4% of the asymptomatic population aged ≥ 65 years and associated with socioeconomic factors.The strategy may be especially useful in Brazil, which has a presumably high burden of undiagnosed cardiovascular disease and limitations in the provision of specialized tests, including conventional echocardiography. The tele-echocardiography strategy was first tested in Brazil in a program for screening of rheumatic heart disease (the Rheumatic Valvular Disease Screening Program study; Programa de RastreamentO da VAlvopatia Reumática -PROVAR). The study established, at a research level, a routine for the acquisition of simplified imaging protocols using portable and ultraportable devices by non-physicians (nurses and technologists), which were uploaded to dedicated cloud computing systems for storage and remote expert interpretation.In addition to remote diagnosis, telemedicine was also used to train health care professionals on basic echocardiographic principles through interactive online modules. After training, health care professionals with different backgrounds were able to diagnose rheumatic heart disease with accuracy.The project reported a high prevalence of subclinical rheumatic heart disease (4.2%), which is quite significant considering the current impact of the disease on public health.A similar strategy was subsequently applied in primary care. Professionals (physicians, nurses, nurse technicians) from health care centers located in low-income regions of metropolitan areas of Belo Horizonte and Montes Claros received online and in-person training for the acquisition of a simplified echocardiographic protocol with ultraportable devices and support by the project's field team. Echocardiography was performed in asymptomatic individuals of three age groups (17-20, 35-40, and 60-65 years) as a screening method and in patients on a waiting list to undergo echocardiography or who had this test requested by the family health care team. The results showed that a) the strategy is feasible for the conditions found in Brazil and has the potential to be expanded to other scenarios; b) the prevalence of echocardiographic abnormalities in asymptomatic populations was high (above 20%) in general; c) among patients on a waiting list for echocardiography, more than 50% had no significant abnormalities on screening echocardiography; and d) the correlation with conventional echocardiography was satisfactory.A prediction score was developed from these findings, incorporating clinical data and variables from the simplified echocardiogram.Thus, tele-echocardiography may be a strategy for early diagnosis but is mainly an instrument to prioritize and organize waiting lists in health care systems with limited availability of tests and specialized consultations. However, the incorporation of this model into Brazilian health policies depends on broad regulatory discussions involving authorities, professional councils, and medical societies -especially regarding simplified image acquisition by non-physicians. The adoption of tele-echocardiography for the care of disadvantaged remote communities has potential advantages, but this method still lacks robust scientific validation with prospective controlled studies confirming its benefits to patients' health and cost-effectiveness, among other challenges. ## Tele-education Remote educational activities in cardiology for health care professionals, offering courses, lectures, and learning tools on clinical issues and care management, have the added benefit of improving the quality of care. Educational activities for patients should be encouraged for their health empowerment. In remote municipalities with small populations, PHC is often the only level of local health care, while their health care units receive patients with acute cardiovascular diseases. Thus, telecardiology in PHC not only should qualify the care of chronic diseases but should also support urgent care for ischemic diseases and arrhythmias. Due to the myriad of applications of simple telemedicine tools, cardiology can be considered one of the specialties most sensitive to the use of ICTs. The triad teleconsulting, ## Lack of guidelines for training of operators ## Medical-legal uncertainties Legislative issues related to licensing, data storage, privacy, and confidentiality telediagnosis, and tele-education integrally applied to PHC and associated with tools like DSS can make a difference in the quality of care for cardiovascular diseases, especially hypertension, atrial fibrillation, heart failure, and AMI. Finally, teleregulation can offer support to PHC, in terms of solvability at this level, improving access to specialty care. ## In specialized care ## Heart failure Extensive literature has examined the use of telemedicine strategies to monitor patients with heart failure with the objective of reducing hospitalizations associated with increased morbidity, mortality, and costs and improving patients' adherence and participation. The interventions range from the application of traditional technologies like structured telephone support, telemonitoring using innovative technologies with implantable or wearable devices, DSS, and machine learning to predict complications.The results are variable, but most demonstrate benefits. However, the use of these strategies in clinical practice is still very limited due to regulatory, logistics, and financial issues.Telemonitoring may be invasive or noninvasive. Sensors are tools capable of detecting, recording, and responding to specific information, e.g., patients' vital signs, and are increasingly embedded in smartphones and other mobile devices. Sensor logging can generate large data sets that may be transmitted in real time to health care professionals.Since multiprofessional intervention programs often have geographical, economic, and bureaucratic barriers, telemonitoring can be a solution to promote care for patients with heart failure.Evidence about structured telephone support and noninvasive telemonitoring in patients with heart failure has been summarized in a Cochrane systematic review of 41 studies. Structured telephone support reduced allcause mortality (RR 0.87, 95%CI 0.77-0.98; n = 9,222) and heart failure-related hospitalizations (RR 0.85, 95%CI 0.77-0.93; n = 7,030), both with moderate-quality evidence. Telemonitoring reduced all-cause mortality (RR 0.80, 95%CI 0.68-0.94; n = 3,740) and heart failure-related hospitalizations (RR 0.71, 95%CI 0.60-0.83; n = 2,148), both with moderate-quality evidence.Another meta-analysis 120 of 26 studies with 2,506 patients undergoing telemonitoring (including the transmission of vital signs) observed a time-dependent effect. Short-term follow-up (up to 180 days) had better results for hard outcomes (like mortality), which were not maintained during longer follow-up (1 year). Regardless of the follow-up duration, the strategy was unable to reduce hospitalization. An increase in emergency visits in the telemonitoring group raises the question of how an intervention that does not reduce hospitalization could reduce the mortality rate. Perhaps the early detection of signs of decompensation encourages a more frequent search for care and prompt treatment with diuretics and vasodilators without requiring intensive therapy. In the publication of one of its Clinical Protocols and Guidelines on Heart Failure,the Ministry of Health analyzed several studies evaluating the benefits of telemonitoring based on telephone follow-up, recommending for health care services to consider follow-up using telephone support for patients with New York Heart Association (NYHA) functional class III to IV heart failure after hospital discharge. The analysis showed an 18% reduction in overall mortality with remote monitoring compared with usual care (RR 0.82, 95%CI 0.73-0.93). Telemonitoring also reduced by 23% (RR 0.77, 95%CI 0.68-0.88) the risk of hospitalization due to heart failure. Of note, this recommendation should be directed to patients with the potential of most benefits. There is no consensus on the intensity and frequency of monitoring, but they should be performed focused on clinical and educational guidance. Evidence regarding the duration of hospital stay is more fragile and controversial. Of seven studies on structured telephone support and nine on telemonitoring, only one on each type of intervention reported significantly decreased hospital stay. Additionally, nine of 11 studies on structured telephone support and five of 11 studies on telemonitoring reported significant improvements in quality of life. Three of nine studies on structured telephone support and one of six studies on telemonitoring reported reductions in cost, while two studies on telemonitoring reported increased costs due to expenses related to the intervention and increased medical management. Seven of the nine studies that assessed heart failure knowledge and self-care noted significant improvements. Despite acceptance by 76-97% of the participants, decreased adherence to the intervention over time can be challenging, and was reported in the review at 55.1-65.8% with structured telephone support and 75-98.5% with telemonitoring.Machine learning techniques can be potentially valuable in remote monitoring of patients at high risk of heart failure. Individual characteristics of these patients obtained from the analysis of a large number of electronic medical records may help identify those at greatest risk of unfavorable outcomes who could benefit from individualized medical treatment.The Seattle Heart Failure Model (SHFM), for example, is a machine learning framework for the calculation of mortality risk in heart failure. The model considers various clinical aspects obtained from electronic medical records to predict the prognosis of the disease and incorporates the potential impact of therapies on patients' outcomes. This DSS was shown to be potentially useful in identifying patients with heart failure at higher risk of unfavorable outcomes, but met implementation barriers, as it was time consuming, expensive, required familiarity of the physician with computers, and failed to take into account other clinical variables that were not included in the collected data.Evidence of the benefits of telemonitoring in heart failure has been recently confirmed with the publication of the Telemedical Interventional Management in Heart Failure II (TIM-HF2) study. This was a prospective, randomized, multicenter clinical trial including 1,571 patients with NYHA class II or III heart failure hospitalized due to heart failure within 12 months before the randomization and with an ejection fraction of 45% or lower. The patients were then randomized to remote management or usual care and followed up for up to 393 days.The percentage of days lost due to unplanned cardiovascular hospitalizations and death from all causes was 4.88% in the remote patient management group and 6.64% in the usual care group (p = 0.04). Patients assigned to remote management lost an average of 17.8 days/year compared with 24.2 days/year among patients assigned to usual care. The hazard ratio (HR) for all-cause mortality was 0.70 (95%CI 0.50-0.96; p = 0.0280) in favor of the teleconsultation group, but cardiovascular mortality was not significantly different between both groups (HR 0.671, 95%CI 0.45-1.01; p = 0.0560).New devices to monitor intracardiac pressure present the most compelling evidence for the application of telemonitoring and use more advanced technologies. CardioMEMS is a device that is percutaneously implanted in the pulmonary artery to transmit central pressure values to a platform. When the pressure levels of the pulmonary artery rise above a certain threshold, the physician receives an alert and a statement indicating congestion or low output. Other devices for implantation in the right ventricle are being used experimentally. The study CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) 125 evaluated patients with NYHA functional class III heart failure across 64 centers in the US. The patients were randomized by a centralized electronic system to a group of management by CardioMEMS or to a control group. In the monitoring group, the physicians used daily data from pulmonary artery pressure measurements to guide treatment. After a follow-up of 15 months, the monitoring group had a 37% reduction in hospitalizations related to heart failure compared with the control group. The long-term follow-up of this study, in which the control group was switched to receive pulmonary pressure monitoring, showed that these results remained significant and clinically relevant over time. ## In hypertension Telemonitoring strategies can also be applied for BP control, but they overlap the self-monitoring approach. In the TASMINH4 trial, 1,182 patients were randomized (1:1:1) to general titration of antihypertensive medication based on clinical readings by a generalist (usual care group), selfmonitoring (self-monitoring group), or self-monitoring along with telemonitoring (telemonitoring group). The study found that the use of BP self-monitoring to titrate antihypertensive therapy in poorly controlled hypertension in primary care resulted in lower systolic BP without increasing the workload of the clinical team. After 1 year, patients who had the medications adjusted based on self-monitoring with or without telemonitoring had significantly lower systolic BP than those who had the treatment adjusted based on BP measured during consultations. The BP values in the telemonitoring group that received medication titration became lower faster (at 6 months) than in those in the self-monitoring group, an effect that is likely to further reduce cardiovascular events and improve long-term control.Several studies also show that strategies for hypertension telemonitoring involving a clinical pharmacist lead to a beneficial impact on BP control in the short and medium term. Margolis et al.evaluated the durability of the effect of such intervention after a follow-up of 54 months in a randomized cluster study among 16 primary care clinics and 450 patients (228 receiving telemonitoring and 222 on usual care). Intensive intervention based on telemonitoring maintained the effects for up to 24 months (12 months after the end of the intervention), but lost efficacy in the long term.A prospective observational cohort study monitored the BP levels before and after an educational intervention and introduction to home BP monitoring (HBPM). In the intervention group, 484 patients were instructed to track their BP levels using a smartphone three to seven times a week. The mean BP levels improved from 42% to 67% among patients on HBPM compared with 59% to 67% among controls (p < 0.01).The INTERACT study was a randomized clinical trial in which 303 patients using BP and/or lipid-lowering medications were randomized to receive or not receive text messages. The group that received text messages improved medication adherence at 6 months compared with the group that did not receive messages. The overall improvement in medication adherence was 16%.A Cochrane systematic review 132 sought to establish the effectiveness of mobile phone-based interventions in improving adherence to medications prescribed for primary prevention of cardiovascular disease in adults. The participants in the trials were recruited from communitybased primary care or outpatient clinics in high-income (Canada, Spain) and upper-to middle-income countries (South Africa, China), but the interventions varied widely. One trial evaluated an intervention focused on adherence to BP medication delivered exclusively by text messaging, while another trial involved BP monitoring combined with feedback delivered via smartphone. The authors considered the body of evidence for the effect of cell phone-based interventions on objective outcomes (BP and cholesterol) having a low quality. Of two studies that evaluated medication adherence along with other lifestyle modifications, one reported a small beneficial effect on lowering low-density lipoprotein cholesterol while the other found no benefit. Another trial (1,372 participants) on an intervention based on text messaging showed a small reduction in systolic BP in a group that delivered information-only text messages, but uncertain evidence of benefit in a second intervention group that provided additional interactivity. One study examined the effect of BP monitoring combined with smartphone text messaging and reported moderate intervention benefits to systolic and diastolic BP. There was conflicting evidence from trials targeting medication adherence along with lifestyle advice using multicomponent interventions. Another study found large benefits on BP levels, while another study showed no such effect. The authors of this Cochrane review concluded that there is low-quality evidence related to the effects of interventions delivered via mobile phone in increasing adherence to medications prescribed for primary prevention. The conclusion based on this review is that there is current uncertainty about the effectiveness of such interventions. ## Emergency services Brazil has a geographically distributed health care system in which UBSs, emergency care units (ECUs), secondary hospitals, and ambulances are scattered across the country, often at remote locations. Specialized centers are located in advanced care units, like tertiary hospitals, located in major cities. In this context, telemedicine tools can improve emergency management.Telemedicine has different applications in emergency services, ranging from electrocardiographic transmissions associated or not with synchronous teleconsultations to assist in the early diagnosis and management of cases of acute coronary syndrome (ACS); clinical DSSs to help with the diagnosis, management, and prediction of cardiac complications in patients with ACS; 133 transmission of bedside ultrasonographic images before hospital admissions;and image transmission and support in the diagnosis and management of patients with acute stroke.The use of DSSs could increase the adherence to guideline recommendations in the management of patients with ACS, but evidence on its impact on clinical outcomes in this context is still limited. 135 ## In systems of care for acute myocardial infarction Systems of care for AMI integrate preadmission services, hospitals, and hemodynamic services comprising the care of patients with AMI in a given region in order to optimize the management of clinically suspected patients. The proposal of these systems is to delineate the patients' care flow involving early diagnosis, preadmission care, initial treatment, use of thrombolytic agents, referral to a specialized hospital, and post-event follow-up. They target high-quality, effective, safe care for patients with AMI by optimizing resources and reducing disparities in their access to care.Telemedicine services may play a crucial role in AMI systems of care, as they facilitate the communication between a physician in an emergency unit, low-complexity hospital, or pre-hospital admission with cardiologists at the hub or hospital with a hemodynamic center that will receive the patient. Cardiologists can assist in (i) analyzing and interpreting electrocardiograms for accurate and early diagnosis of STsegment elevation AMI,(ii) guiding the best course of action, including the administration or not of thrombolytic agents and other medications, through synchronous teleconsultations, i.e., real-time communication between the on-site professional and the remote specialist,and (iii) monitoring the patient's clinical condition through telemonitoring, with synchronous data transmission.The incorporation of telemedicine strategies in systems of care for AMI is a worldwide trend. A recent meta-analysis including studies conducted in Europe (11), North America (8), South America (5), Asia (9), and Australia (2), with a total of 16,960 patients, found consistent moderate-quality evidence that telemedicine strategies associated with usual care in this context reduce in-hospital mortality by 37% (RR 0.63, 95%CI 0.55-0.72), with a number needed to treat (NNT) of 29 (95%CI 23-40) when compared with usual care without telemedicine. The study also found poor quality evidence that this intervention can reduce door-to-balloon time (mean difference 28 minutes, 95%CI -35 to -20 minutes) and 30-day (RR 0.62, 95%CI 0.43-0.85) and long-term (RR 0.61 95%CI 0.40-0.92) mortality.In Brazil, Belo Horizonte, Campinas, Salvador, São Paulo, and the Northern Region of Minas Gerais (encompassing 89 municipalities) have published initiatives in this area.Decreased system delays and increased reperfusion rates have been observed in cases of ST-segment elevation AMI, with evidence of reduced hospital mortality.A typical telemedicine system comprises a specialized center (hub) and multiple remote care units distributed within a geographic region (spoke centers) connected bidirectionally by a communication channel. The specialized center may be a referral hospital in cardiology, the operation center of an Emergency Mobile Care Service (Serviço de Atendimento Móvel de Urgência, SAMU), or a telemedicine center. Some systems of care for AMI comprise more than one specialized center, each with specific remote units for regional coverage.The 2015 Telemecardiology Guideline for the Care of Patients with Acute Coronary Syndrome and Other Heart Diseases details models of care using telemedicine systems for the care of patients with ACS. ## In controlling the use of anticoagulants The strategy of self-management of anticoagulants has been associated with a significantly lower risk of ischemic stroke and all-cause mortality compared with direct treatment with oral anticoagulants, while no significant differences were observed for major bleeding and mortality. However, decreased surveillance is a potential problem for the detection of patients who are unable to take care of their own treatment. A structured education program is required for patients and/ or caregivers and for involved professionals in health care and quality control. ## Cardiac rehabilitation Guidelines recommend that patients should undergo cardiac rehabilitation after AMI, percutaneous coronary intervention (PCI), or myocardial revascularization. However, rehabilitation is still underused, with participation of only 14-31% of all eligible patients. Patients' inability to attend the sessions and costs are important barriers.Telehealth interventions using ICTs to enable remote rehabilitation programs can overcome common barriers to rehabilitation access while preserving clinical supervision and prescription of individualized exercise.In a systematic review of 11 studies, the types of intervention were variable and included the use of mobile or computer applications, biosensors, and interventions delivered by landline phone lines. The interventions involved prescription and/or monitoring of the participants' performance and adherence. All interventions included feedback, education, psychosocial support, and/or behavioral changes via landline phone communications, mobile messaging, e-mail, website use, online tutorial, or online chat.The level of physical activity was higher in the intervention group compared with the usual care group. Compared with face-to-face rehabilitation, the intervention with telehealth was more effective in improving the level of physical activity, exercise adherence, diastolic BP, and LDL-cholesterol, with poor-to moderate-quality evidence. Telehealth rehabilitation was similar to face-to-face rehabilitation in maximal aerobic exercise capacity and other modifiable cardiovascular risk factors.The Telehab III study was a prospective, randomized, multicenter controlled trial with patients undergoing cardiac rehabilitation. In all, 140 patients were randomized to a conventional rehabilitation group or a 24-week Internetbased telerehabilitation group associated with conventional rehabilitation. The additional telerehabilitation program showed improvement in physical fitness and quality of life and induced persistent health benefits.A clinical trial conducted in China randomized 98 patients with NYHA I-III functional class heart failure to an 8-week home-based teleconsultation exercise training program or usual outpatient follow-up. Statistically significant improvements were observed in the experimental group in terms of quality of life and result in the 6-minute walking distance test compared with the control group. These results confirm that physical training via teleconsultation is an effective alternative method for cardiac rehabilitation.The noninferiority, randomized controlled trial REMOTE-CR tested the effects and costs of cardiac rehabilitation by real-time teleconsultation in 162 patients with heart failure and demonstrated this to be a cost-effective alternative that can enhance the scope of rehabilitation.Home-based cardiac rehabilitation is an alternative to increase patients' engagement in the program by presenting greater flexibility and activity options, offering choices based on the patients' values and preferences, and allowing the implementation according to the patients' daily routine.The association of cardiac rehabilitation with conventional rehabilitation has been shown to be more effective and efficient compared with a conventional rehabilitation program alone, as it reduced the rates of readmission due to cardiovascular causes and improved quality of life during the study period. ## Remote monitoring by implantable devices Pacemaker telemonitoring has not significantly improved quality of life and number of cardiovascular events, but provided early detection and treatment of events, reducing hospital admissions and visits (routine and emergency) at lower costs compared with hospital follow-up.Implantable cardiac defibrillators (ICDs) or resynchronization defibrillators are another type of implantable monitoring systems. Some of these devices may be equipped with software for multiparametric monitoring of, for example, thoracic impedance and right ventricular filling pressure with measurements captured by a right ventricular lead. A groundbreaking study published in 2008 showed their clinical benefits in patients with NYHA functional class III heart failure.The IN-TIME trial later tested a similar strategy using multiparametric monitoring devices (ICDs and resynchronization defibrillators). The parameters evaluated in the trial included events like ventricular and atrial tachyarrhythmia, low percentage of biventricular pacing, increased frequency of ventricular extrasystoles, decreased patient activity, and abnormal intracardiac electrogram. Abnormalities in these parameters triggered a structured phone contact. The group allocated to telemonitoring had a significant reduction in combined clinical outcomes and total mortality.Other similar studies have also shown a reduction in combined clinical outcomes, often related to a decreased need for face-to-face visits.Results from an unselected population cohort study also indicated benefits of remote monitoring with information from ICD/cardiac resynchronization therapy (CRT) on mortality.However, a meta-analysis 162 of 11 randomized trials evaluating 5,703 patients showed no consistent results on clinical outcomes. The meta-analysis showed that device telemonitoring was associated with a reduction in the total number of planned, unplanned, and emergency room visits (RR 0.56, 95%CI 0.43-0.73, p < 0.001). However, rates of cardiac-related hospitalization (RR 0.96, 95%CI 0.82-1.12, p = 0.60), the composite endpoints of emergency visits, unplanned hospital visits, or hospitalizations (RR 0.99, 95%CI 0.68-1.43, p = 0.96), and total and cardiac mortality were also similar between groups. ## Atrial fibrillation Patients with atrial fibrillation (AFib) comprise a special group, considering that, among other things, AFib has been accounted for approximately 60% of pacemaker and CRT/ defibrillator (CRT-Ds) alerts and nearly 10% of all ICD alerts in a worldwide database.Remote monitoring has excellent sensitivity (95%) in detecting AFib, a feature that becomes even more important, considering that 90% of the detected episodes were asymptomatic.The potential benefits of remote monitoring include detection and early reaction (e.g., drug therapy, device reprogramming, or electrical cardioversion) to prevent atrial remodeling and serious adverse events related to AFib. The IMPACT trial has shown that the detection of asymptomatic AFib via remote monitoring considerably shortened the time to anticoagulation initiation (3 days versus 54 days) but was not associated with reduced rates of stroke, systemic embolism, and bleeding.In the preclinical phase of an arrhythmia, telemedicine screening may detect asymptomatic AFib.In a pilot study, the daily transmission of electrocardiographic data by phone facilitated the diagnosis of asymptomatic paroxysmal AFib.In large cohorts, telecardiology services improved the management of patients with AFib and detected new cases of arrhythmia.Support by telemedicine can improve the diagnosis of silent AFib.Bilgi et al.demonstrated that home-based electrocardiographic assessment supported by telecardiology increased the sensitivity of the diagnosis of AFib in elderly individuals and was useful in identifying individuals with AFib and atypical symptoms at home.The electrocardiogram (ECG) was recorded and transmitted by a smartphone to a 24/7 telecardiology center and evaluated by a cardiologist. The telecardiology support increased two times (40 years), four times (60 years), and seven times (70 years) the rate of AFib diagnosed at home. The SEARCH-AF study has shown that the use of an ECG lead (DI) on an iPhone ECG (iECG, AliveCor KardiaMobile) accurately diagnosed AFib, making this technology feasible for the screening of subclinical AFib in primary care and in the community.In the REHEARSE-AF study, a randomized trial of AFib screening involving 1,001 participants aged ≥ 65 years and with CHA 2 DS 2 -VASc ≥ 2, 171 the participants were randomized to screening with AliveCor KardiaMobile (iECG) twice a week for 12 months (and additional ECG in case of symptoms) or usual routine. The use of iECG increased by almost four times the diagnosis of AFib (HR 3.9, p = 0.007). Smartphones, apps, and cloud storage technology have the potential to change the practice of medicine and the way decisions are made. On smartphone platforms, medical or health care applications can analyze a range of vital signs through built-in sensors, interconnected devices, or peripherals.The transfer of ECG images by multimedia messaging can be a practical, low-cost procedure in telecardiology.These new technologies may increase the detection of arrhythmias, but the real value of these new methods has yet to be evaluated in rigorously conducted studies. ## Channelopathies Inherited electrical syndromes are less frequent indications for ICD implantation. However, their management can be challenging because these devices are then implanted in patients who are often younger and less likely to comply with the required follow-up.Electrical abnormalities may occur in these diseases, predisposing the patient to unnecessary shocks and requiring careful programming.The pediatric population, which often has implanted epicardial electrodes, is specifically more vulnerable. In such patients, telemonitoring may be particularly useful for surveillance, early detection, and preventive programming.In the multicenter Brugada registry, the number of outpatient visits was significantly lower in a telemonitoring group compared with a control group (p < 0.001), and there was a trend suggesting that the number of inappropriate shocks was also reduced. ## Tachycardia and ventricular fibrillation Remote patient monitoring can be valuable for prompt assessment of the appropriateness of the detection and the efficacy of the administered therapy. If shock is appropriate, and clinical condition is stable, the physician can reassure the patient without requiring a hospital visit. In a multicenter pilot study, 81% of the episodes of ventricular tachyarrhythmia were analyzed remotely, and in 85% of the cases, no further action was required.The TRUST study demonstrated that remote monitoring allows early detection of ventricular tachyarrhythmias compared with standard follow-up (1 day versus 36 days for ventricular fibrillation and 1 day versus 28 days for ventricular tachycardia, p < 0.001).Other potential benefits of remote monitoring include the prevention of inadequate shocks and appropriate but unnecessary shocks. Inadequate detection due to supraventricular tachyarrhythmias (or T-wave oversensing) may lead to the patient receiving a notification for in-hospital reprogramming or other interventions.Proper delivery of ICD shock for slow, stable ventricular tachycardia may lead to device reprogramming with broader use of painless antitachycardia therapies. Recurrent and self-limited asymptomatic rapid ventricular tachycardia occurring in the ventricular fibrillation window (triggering alerts in some systems, regardless of the administered therapy), can be detected early and, with appropriate intervention, be programmed to prevent electrical storms. In addition, timely treatment of tachycardias may prevent early battery depletion caused by recurrent loads and shock administration. 176,181 ## Congenital heart disease Tele-echocardiography can establish an early diagnosis of congenital heart diseases to guide therapeutic management.A North American multicenter study in 338 paired infants (with and without access to telemedicine) with or without minor heart disease showed a statistically significant reduction in the percentage of infants transferred to a tertiary hospital (10% versus 5%), as well as in total hospital stay and intensive care unit (ICU) stay.Telemedicine increases the ability of pediatric cardiologists to provide higher quality care to a greater number of patients, although high-quality studies evaluating the impact of this intervention are still limited. ## Cardiovascular teletomography and teleresonance Despite the apparent similarity between teleimaging and local diagnostic services, divergences between both occur in one fifth of the cases. Specifically, divergences with clinical impact occur in up to 1 to 3% of the cases. We can hypothesize that the reasons for these divergences may be inadequate imaging quality, unavailability of patients' clinical data (like current and past history and physical examination), limited access to patients' laboratory tests and other imaging evaluations, fatigue, and simple interobserver variation. The workflow of imaging diagnosis in local hospitals and in telediagnosis may be difficult to distinguish. Generated images are stored in imaging systems (picture archiving and communication system -PACS, for example) and then analyzed by the radiology department (and other specialties working with imaging tests, like cardiology and obstetrics). In teleimaging, the image is transmitted to an external center and analyzed the same way that it would be done locally. Further studies are needed to compare the diagnostic performance of teleimaging versus local imaging. Both may even be assumed to have the same performance, but evidence is critical to confirm our assumptions and can determine not only whether teleimaging can be performed, but also the optimal conditions to be carried out safely and cost-effectively without harm to the patient. ## Dicom standard A new group of services developed in previous years was introduced in 1993, the Digital Imaging and Communications in Medicine (DICOM) standard. The objective was to standardize data and information obtained by imaging methods, normalizing the rules for transmission and storage of medical information. This group of services uses a digital format that associates images with metadata-type information with the ability to optimize search and exchange of information and the use of images by specific software programs. DICOM specifications are updated from time to time without losing sight of previously established functionalities. ## Mri, ct, and telemedicine Contrast-enhanced magnetic resonance imaging (MRI) and computed tomography (CT) scanning bear additional complexities, requiring specific care at centers performing these tests. These range from the scheduling of the tests -in which there is a need to define its precise indication, e.g., pharmacological stress test (dipyridamole, adenosine, dobutamine), evaluation of myocardial ischemia, viability, valvular heart disease, specific cardiomyopathies, among others -to the need of on-site physicians due to frequent use of contrast and medications, nursing technicians to obtain an adequate venous access, and biomedical doctors and technologists with specific training and experience in the acquisition and postprocessing of MRI and CT scan images using software dedicated for these analyses. The images should be read by experienced specialized physicians with specific training in that particular area of diagnostic imaging. Such training usually requires 2 years and is not widely available nationwide, limiting the number of trained specialists for appropriate MRI and CT scanning. The complexity of performing MRI and CT scans with remote guidance and reading, together with the need for specialists to analyze the images and the possibility of the test being performed at any given time, depending on the clinical indication, makes telemedicine increasingly important for this activity. ## The federal council of medicine and tele-ct/tele-mri In 2014, the CFM updated the rules for tele-CT/tele-MRI practice in Brazil.These rules are valid for the transmission of patients' images between different locations to produce a medical report, a second expert opinion, or a clinical imaging review. The rules related to the topic of this document are listed below: - Clinical data -The transmission of tests by tele-CT/tele-MRI should be accompanied by necessary clinical data of the patient, collected by the requesting physician, for the preparation of the report. - Patient authorization -The patient must authorize on an informed consent form the transmission of images and data. - Local and remote specialist -The responsibility for the remote transmission of tests and reports must be assigned to a specialist in MRI and CT scanning. - Limits for remote practice -In the case of noncontrast imaging (e.g., calcium score -CS), and in the absence of a specialist physician at the health care facility, the attending physician may ask the specialist for appropriate remote diagnostic support. - Specialist required -A specialist physician must be present in centers where contrast imaging tests -including MRI and CT scans -are performed. - Shared responsibility -The professional responsibility for the care lies with the specialist physician caring for the patient undergoing the test. The specialist issuing the remote report shares this responsibility. - Headquarters in Brazilian territory -Legal entities providing services in tele-CT/tele-MRI must be headquartered in Brazilian territory and be registered with the CRM of their jurisdiction. If the provider is an individual, he or she must be a physician trained in MRI and CT scanning. - Operating standards -This is beyond the scope of this document, but specific information can be found in another document on operating standards and minimum requirements for the transmission and handling of remote imaging diagnostic reports. - Image compression and transmission -Communication protocols, file formats, and compression algorithms should comply with current DICOM and HL7 standards. The specialist physician is responsible for evaluating the compression ratio. - Image visualization and processing -The specialist physician is responsible for ensuring the technical characteristics of remote workstations, monitors, and ergonomic conditions in order to avoid compromising the diagnosis. - Safety and privacy -Computerized systems used for the transmission and handling of clinical data and diagnostic imaging reports and for sharing of image and information must comply with CFM regulations. Specifically, tele-CT/ tele-MRI, systems must meet the mandatory requirements of the "Level of Safety Assurance 2 (Nível de Garantia de Segurança 2, NGS2)" established in the current Certification Manual for Electronic Health Registration Systems issued by the CFM and the Brazilian Society of Health Informatics (Sociedade Brasileira de Informática em Saúde, SBIS). ## Imaging transmission Imaging transmission must comply with CFM standards regarding quality and security. However, MRI and CT images are generally larger, requiring an infrastructure with adequate data bandwidth for transmission. Importantly, the specialist physician responsible for the report must download the images. Thus, the choice of important sequences after image acquisition and the method of compression are fundamental for a smooth flow. ## Postprocessing software and workstations Ranging from ECG images to three-dimensional coronary angiotomography (TCA) images and the wide variety of MRI sequences, several imaging parameters must be evaluated, most requiring specific software. Assessment of CS -CS is assessed with software programs installed in workstations, which are usually purchased with the CT equipment, or with other independent programs or plugins. The report usually informs the amount of calcification in each artery along with the total CS value and percentile for the patient's gender and age, based on several population studies, of which the most used and recommended is the MESA (MultiEthnic Study of Atherosclerosis) study.Other data such as arterial age and the patient's overall cardiovascular risk variation based on the ECG can also be described. Evaluation of TCA -After the appropriate acquisition phase, aiming at the best temporal and spatial resolution of the coronary arteries, and editing of the ECG, which is usually done directly in the CT equipment, other applications are helpful in establishing a diagnosis. Until the requesting physician is able to obtain a clear view, the interpretation of the findings may be helped by software programs that extend the coronary arteries in a single plane (curved planar reconstruction -CPR), visualization of threedimensional rendered images (using a 3D-volume-rendering technique), visualization of bidimensional images with multiple oblique planes (multiplanar reconstruction -MPR), and the characterization of coronary plaques, as well as the objective measurement of stenoses.Evaluation with MRI -As one of the most versatile imaging methods available, MRI is able to produce images of almost any anatomical plane and provide a wide range of pulse sequences to generate images with specific characteristics, allowing assessments that range from the evaluation of ventricular function to myocardial tissue characterization.Several software applications are available for this purpose, including applications for: - assessment of volume, ventricular mass, and right and left cardiac function; - analysis of intracardiac flow to measure QP-QS, shunts, and valvular dysfunction; - magnetic resonance angiography postprocessing with measurement of vascular diameters; - tissue characterization to quantify perfusion, necrotic/ fibrotic mass, iron deposition by T2* evaluation, and parametric maps of T1, T2, and T2* values. The strategy of using software programs in MRI and CT imaging is strongly recommended and can improve the time required to read the images, the accuracy of the reading, and the clarity of the report of the findings. ## Database, communication, and image archiving The integration between radiological information system (RIS) and PACS enables the assignment of a unique registration for each patient. This optimizes the information by combining images with clinical data and making the process faster and more secure. This format has been increasingly used in health care centers and often enables remote access, facilitating the use of tele-CT/tele-MRI and improving administrative procedures and communication. Several solutions are available in this regard, including cloud-based web solutions. Remote access to images and the ability to distribute reports via a standard universal system are helpful for the workflow. A report is nothing more than a type of communication with the main objective of transmitting the assessment of images analyzed by an expert to another physician who needs such information to make decisions. The more complete and clear the transmitted information is, the more important the requested test becomes. The development of structured reports linking written information to tables, figures, and photos to make the information as clear and accurate as possible is an ongoing trend. As described earlier, reports may be made available through advanced systems like RIS, but other forms of transmission, including instant messaging applications like WhatsApp, may be used. According to the CFM,WhatsApp and similar platforms can be used for communication between physicians and patients, as well as privately between physicians for transmission of data or questions, or in closed group chats between specialists or clinical staff of an institution or chair, provided that all information transmitted is absolutely confidential, remain within the group, and is not circulated to recreational groups, even if these are composed only of physicians. ## Clinical indications for mri and ct Interestingly, no studies in the literature have assessed the clinical impact of the application of tele-MRI or tele-CT. Thus, clinical recommendations in this guideline are based on level C evidence, including expert consensuses, and in the absence of studies evaluating cost-effective outcomes. Aware of this limitation, we cite at the end of this document the main indications for the application of tele-CT/tele-MRI in this subarea of cardiovascular imaging.The use of MRI and CT imaging has been increasing, and characteristics of these imaging methods make their use very interesting in telemedicine, particularly in countries with continental proportions like Brazil and in those with a limited number of available MRI/CT specialists. The possibility of having a specialist potentially accessible at any moment can be helpful in patient management and in lowering health care costs by optimizing the time of available specialists and expediting reports of hospitalized patients, which can shorten their hospital stay, and in other applications related to this medical progress. ## Telerobotics applied to cardiology ## Robotic telesurgery The concept of telesurgery was introduced in the early 1970s by NASA.The objective of the original project was to provide medical care to astronauts during remote missions. Robotic telesurgery devices are applications in which the surgeon controls remotely a robot that executes the surgical procedure. The da Vinci® system (da Vinci® surgical system; Intuitive Surgical, Sunnyvale, CA, USA), the most widely used robotics platform today, follows this approach. The surgeon works on a console separated from the surgical field, and the movement of his or her hands is perceived and transmitted to the instruments close to the patient. This technique yields great ergonomic benefit to the surgeon, incorporates functions like hand tremor cancellation, and broadens (in three dimensions) the view of the field that the surgeon is interested in. However, these platforms lack much automation and require continuous involvement of a human operator (surgeon) for regulatory reasons. ARTEMIS was the first surgical robot used for cardiac procedures.Designed as a telesurgery and telepresence system for cardiac procedures, it was used for training and planning and to perform minimally invasive procedures. Currently, robotic cardiac surgery has been used primarily for mitral valve repair and myocardial revascularization, following approval by the Food and Drug Administration (FDA) in 2002 and 2000, respectively. Newer techniques assist in cardiac manipulation procedures by compensating heart movements. However, large-scale implementation of this technique is hampered by its high cost 195 and the absence of randomized studies demonstrating its superiority over traditional minimally invasive techniques, with or without hybrid procedures.The first robotic mitral valve heart surgery was performed in 1998 by Carpentier, in France, and Mohr, in Germany. That same year, Carpentier conducted the first coronary artery bypass surgery in Paris, while Reichenspurner performed revascularization surgery with the voice-controlled ZEUS Robotic Surgical System (Computer Motion, Goleta, CA) in Munich.Since then, this technique has become popular as it is associated with less surgical aggression, reduced cardiopulmonary bypass and aortic clamping duration, and shorter hospital stay compared with the conventional open technique.The da Vinci® robotic system has allowed improved visualization of the surgical field with three-dimensional capture and ten-fold magnification, resulting in greater precision in the surgical procedure and smaller incisions following a learning curve.It has also reduced the rates of all complications (particularly infection), blood transfusion, and time to return to work activities, with an impact on the total costs of the procedure. This has been observed especially among patients at high risk (like elderly individuals) and those with ejection fraction lower than 20%, diabetes of difficult control, and severe chronic obstructive pulmonary disease.This robotics system has also benefited hybrid surgeries, angioplasty, and minimally invasive procedures in patients with multilateral obstructive coronary artery disease.Both computer-integrated surgery and telemedicine are becoming popular in the developed world. Advancements in robotic technology and information technology, like the Internet of Things, allow robotic arms to be controlled remotely, enabling robotic telesurgery. With telesurgery, surgeons can perform surgical procedures in remote locations, away from the patients, improving the access to medical treatment and, potentially, the quality of the treatment. As with other telemedicine applications, telesurgery can broaden the access to interventions in remote areas or centers where specialists in particular types of surgery are not present, for example. The importance of telemedicine, telesurgery, and remote surgery is not restricted to their ability to perform medical procedures in areas where these procedures are not available and can be extended to telementoring, which involves the training of medical professionals to perform these procedures.In this area, telesurgery could also benefit patients requiring infrequent, highly complex interventions, in which the medical-surgical expertise is not widely available. The acquisition of new technology expertise by specialists has been accompanied by mentoring programs (proctors). In robotic surgery, telemedicine can provide training with remotely connected proctors (telementoring), expanding the access to innovative technologies.Outcomes of robotic surgeries still lack long-term analyses of hard outcomes like all-cause mortality, cardiovascular death, fatal AMI, stroke, need for repeat revascularization, and vascular graft patency. As in traditional surgeries, patient selection is essential, and the goal should be complete revascularization, bearing in mind that CO 2 insufflation decreases venous return by increasing intrathoracic pressure and may compromise hemodynamic parameters in patients with left ventricular dysfunction and in those with chronic obstructive disease, who would benefit more from minimally invasive surgery. Case series have been reported totaling about 110 patients and showing 90% of surgical success within 30 days without open surgery and a maximum follow-up of 5 years.The largest experience in this area has been published by Cavallaro et al.,who reported rates of morbidity and mortality with robotic myocardial revascularization surgery in 2,582 patients between 2008 and 2010. The authors reported lower rates of postoperative complications in selected patients but concluded that these benefits decreased in patients requiring multiple bypass grafts.Approximately 1,700 robotic heart surgeries are performed annually in the US, including 35.5% for mitral valve repairs.In 2011, the FDA introduced a post-marketing surveillance plan known as the Medical Device Epidemiology Network initiative, leveraging AI to real-world data analysis, including international registries and electronic medical record data, to bridge the gap in evidence gathering concurrent with the implementation of technological innovation without compromising patient safety.In Brazil, none of the robotic surgical techniques have been included in the public policy list or in the List of Procedures and Events in Health of the National Health Agency.In this sense, the CFM, through Resolution 2.227/2018, which was later repealed, had regulated robotic telesurgery, precisely anticipating the expansion of the benefits of the technique and facilitating the follow-up of the learning curve by proctors in remote locations. Thus, robotic surgery in Brazil can be remotely assisted by a specialist at a large center in another country. Although the CFM allowed the use of robotic telesurgery in Brazil, it restricted the method to professionals qualified to practice medicine in the country.Of note, mentoring/proctoring programs in Brazil have not been widely regulated, except in the State of Paraíba, where the CRM, through Resolution CRM-PB 182/2018, defined rules that regulate and legally secure the practice to the medical act.In addition to the information presented above, synchronization between the vast potential of these technologies and the existing ethical and legal apparatus is also lacking. Unlike a comprehensive national policy, there is a general scenario of fragmentation characterized by different norms and standards issued by different agencies and with a different focus.Even if a single instrument could hardly achieve these objectives, fragmentation would be yet another obstacle to overcome to reach the potential that telemedicine and telesurgery have in our country. Among other barriers to their practical use are the scarcity of resources and technical knowledge, as well as infrastructure issues. Brazil is a country of unequal regional distribution in terms of broadband availability.This means that the infrastructure of the broadband data network is one of the most limiting factors for the expansion of telemedicine in general and telesurgery in particular, especially in rural areas of the country. ## Robotic angioplasty PCI can be considered a highly predictable, safe, and minimally invasive therapy. However, this manual and operator-dependent procedure must be executed in person, demanding physical action by the physician. Full proficiency can only be achieved in high-volume environments with scenarios involving highly complex and technological interventions. Coronary angioplasty also exposes both professional and patient to ionizing radiation. As a result, the potential risks are high for occupational health damage arising not only from the radiation but also from the need of individual protection 211-213 (e.g., a 7-kg lead apron). Robot-assisted coronary interventions have recently been developed as an alternative to reduce the reliance on manual operation, 214-224 potentially reducing damage from radiation exposure.Clinical studies have demonstrated the safety and efficacy of the robotic system, which has already been approved for routine application in the US and the European Union. Even though the current set of scientific evidence is encouraging, it is also recent and limited to the number of patients treated, hindering further consideration of possible risks and benefits of the technique, especially when it comes to particularities of its application in subgroups of clinical interest. ## Telemedicine for provision of services and in supplementary health ## Provision of services Over 60% of all health care facilities and between 40-50% of all US hospitals are currently estimated to use some form of digital data transmission.In 2016, a US health care facility reported that communication of digital health data (e-mail, phone, and video) exceeded the number of inperson consultations.However, it is important to note that despite new modes and means of communication transmission between physicians and patients, ethical and legal responsibilities remain the same as those governing the traditional physician-patient relationship.Cardiologists must inform their patients about telemedicine services and their limitations, the possibility of late follow-up, by encouraging regular reporting to their attending physicians, and how they can receive electronic health-promoting information. Reimbursement is a key determinant of the success of clinical interventions. The movement toward value-based reimbursement rather than payment for service, which provides incentives for care in lower-cost settings, along with the identification and interaction with high-risk individuals before disease onset, and the efficient use of integrated care teams, provide incentives for telemedicine expansion. Understanding the effect of reimbursement within the context of alternative payment models is a priority. While the path of value-based reimbursement is uncertain, the efficiency of care will inevitably be a priority in any scenario. Ensuring that these technologies are used for patients who meet the appropriate clinical requirements is also an important related topic. In the US, reimbursement for medical services by telemedicine has gradually expanded from coverage of services provided in rural settings to a broader program (Medicare Access and CHIP Reauthorization Act).Training and development projects have been created in Brazil, along with a continuing medical education with special attention to the SAMU/UPA care model, developed by the Ministry of Health and private hospitals.Regarding the payment for telemedicine and telehealth services in Brazil, as already mentioned, it should be considered that the main source of funds has been the public sector:- public communications from national (such as the National Council for Scientific and Technological Development -CNPq -and the Financier of Studies and Projects -FINEP) and regional research and innovation funding agencies (state research supporting foundations); - agreements or direct transfer of funds to universities and health departments, within the scope of the program Telessaúde Brasil, then Telessaúde Brasil Redes; - service providing agreements between public administrators and telehealth centers at university centers; 232 - projects within hospitals receiving tax waiving by the PRO-ADI SUS program from the Ministry of Health.Many of these investments occurred at an early stage of technological development in the country, and only some of the fostered nuclei became active, sustainable services.There is a clear need for inclusion of telehealth procedures in the list of procedures paid by the SUS in order to regulate and encourage their routine use in the health system. Supplementary health, in turn, lacks formal mechanisms of payment and reimbursement for telehealth activities, so telemedicine actions in this sector have been focused on optimizing care and reducing costs, and are often associated with specific conditions like stroke.Of note, the Ministry of Health Secretariat of Science, Technology, and Strategic Inputs, through Ordinance 26, of August 2, 2017, made public the decision to incorporate remote monitoring technology for the evaluation of patients with cardiac implantable electronic devices (CIEDs) within the scope of the SUS. This is an unprecedented incorporation of remote monitoring technology as a result of industry demand. The requester assessed the budgetary impact of the technology over 5 years, considering only direct expenses with the purchase of the remote monitoring device and the provision of conventional monitoring in a base case. A second scenario analyzed a model of dynamic transition state to account for opportunity costs of both technologies, exploring the advantages and disadvantages of each strategy. With the decision, the technology should have been included in the SUS within 180 days from the publication of the incorporation order by the Secretary of Science, Technology, and Strategic Inputs, but to date, the Clinical Protocol and Therapeutic Guidelines making this technology available in the SUS have still not been published.Unfortunately, there are still several gaps in the process of recognizing medical services in telemedicine for the purpose of reimbursement. The example above is the only one deliberated for public health. The process of coding hierarchical classifications or other payment modalities for the various telemedicine services has not yet been properly structured. A more complete and structured set of codes would also provide more accurate data to address the scarcity of systematic economic evaluation of the benefits of telemedicine in both pay-per-service and value-based models.Bridging this gap is essential to guiding public and private health care providers and technology buyers and investors on decisions about investment returns in this field. ## Telemedicine in supplementary health In 1988, Brazil opted for the establishment of a universal health care system free and fully accessible, pursuant to art. 196 of the Federal Constitution. However, health care is available to private initiative, as established in the Magna Carta (Paragraph 1 of Art. 199) pertaining to the scope of participation of the private initiative: "Private institutions may participate in a complementary way in the SUS, according to its guidelines, by means of a contract of public law or agreement, with preference given to philanthropic and nonprofit entities."Supplementary health assists over 47 million beneficiaries in Brazil and is governed by its own legislation, regulated by the National Health Agency. This is a health care system with its own characteristics and regulatory framework guided by specific legislation (Law No. 9.656/1998). The benefits gained from the remarkable development of ICT also apply to supplementary health. However, it should be noted that, due to particularities of laws governing the sector, health care plan operators are required to offer a myriad of procedures included in the List of Procedures and Events in Health of the National Health Agency.Also worthy of note is the fact that when one buys a health care plan, priority is given to access to physicians and therapies that supplement the list of policies offered by the SUS. Most of the supplementary health beneficiaries live in large centers, with over 35 million beneficiaries in the Southeast and South (6,912,748) regions and more than 18 million in capital cities. An analysis of the intersection of demographic data of supplementary health beneficiaries and Brazilian physicians, including cardiologists, shows that the proportion of physicians per inhabitant (beneficiaries of supplementary health) in these regions is different from the one observed in public health, where truly remote areas receive no coverage. It is imperative to consider that the in-person relationship between physician and patient is the rule in supplementary health, which does not hinder the possibility of making telemedicine resources available.Accordingly, the various services provided by telemedicine are fully applicable to supplementary health. However, the provision of face-to-face consultations with experts rather than their "tele" versions is a legal demand. ICT resources should not be offered to replace face-to-face interaction but should be an option to improve care also in the context of supplementary health. Increased efficiency in health care requires quality improvements and costs savings.The integration of telemedicine into outpatient clinics and hospitals, including supplementary health, can help achieve both goals.Medical care is, without question, one of the most (if not the most) complex sectors in the economy. Considerable financial investment and years of persistence are required to build an effective telemedicine system. The widespread adoption of this type of practice also requires behavioral adaptations by many physicians, organizations, and patients.The industry in this area still requires better regulation. Telemedicine can be an affordable alternative to meet the health needs of vulnerable populations with multiple comorbidities requiring frequent care.Improving patient engagement, telemedicine can provide an effective platform for patients to engage in their own decisions.For example, the US Veterans Health Administration introduced a national telemedicine program named Care Coordination/Home Telehealth. This model allows patients to manage their own conditions,and some important studies have reported that the shared-decision model has reduced hospitalization rates.Unequal access to health, even in supplementary health, is persistent in Brazil and requires major investments to improve the organization of health care systems. Even when health care services and evidence-based guidelines are available for common and relevant conditions like hypertension and diabetes, the implementation gap is vast, and best practices are not absorbed by health care professionals, or recommended measures are not followed by patients and their relatives. The science of implementation has proved to be as important as data analysis in recent decades for the recognition of bottlenecks preventing full use of preventive and therapeutic measures to ensure benefits for patients who can live longer and better by taking advantage of all available knowledge,reducing costs and increasing the efficiency of private health care systems. Direct physician-patient teleconsultation, not yet regulated in Brazil, is the most frequently used model. A US report showed that telecardiology was useful for evaluating both new and recent postoperative referrals, with the potential benefit of knowledge transfer to local primary care. In Canada, teleconsultation has been useful for the evaluation of new patients with syncope and supraventricular tachycardia.In the United Kingdom, a wide range of inpatient and outpatient telecardiology services is available at district hospitals using various technologies.This approach has improved access, was cost neutral, and increased patient satisfaction. The authors emphasized that it complemented but did not replace regular consultations. The demand for home care using web-based applications directed to consumers, including tablet and smartphone applications, is growing exponentially.Many health care providers worldwide are adopting this technology as a way to provide low-cost care for common problems that could result in a visit to the emergency department.Most of these applications rely solely on video and audio connections with additional software for scheduling, billing, sharing of still images, and documentation. Also, some peripherals, such as smartphone-compatible heart rate sensing devices,are available for purchase at decreasing prices. Limited financial availability for the acquisition and maintenance of telemedicine equipment and infrastructure remains a barrier to the widespread deployment of telemedicine.This is particularly true for many health care providers or small systems that may lack the required resources and often have conflicting demands for available funds. Other costs associated with telemedicine programs include salary, administrative support and supplies, software and application development and upgrade costs, training programs, and initiatives to promote the program to patients.With increased mobile connectivity, smartphones, and video compression, the costs to implement simple telemedicine interactions have decreased. Currently, none of the procedures used in telemedicine are included in the Supplementary Health List of Procedures and Events in Health, i.e., a regulatory vacuum current places telemedicine in a field of conjecture and frustrated expectations dissociated from the interest of the regulated sector. There is also no concrete scientific evidence available to support the formal use of this technology.Telemedicine is a disruptive innovation with the potential to change health, and its influence is likely to increase rapidly. Guided by what is best for patients, telemedicine, if properly applied, will help usher in a new age for health care that will be built by patients and physicians, identifying new ways of care, increasing quality and rationalizing costs also in supplementary care. ## Economic evaluation and budgetary Impact of the Incorporation of Telemedicine in Cardiology in Brazil ## Concepts of economic evaluation in telemedicine The implementation of telemedicine services seeks to provide accessible and quality health care at a low cost.Since the 1990s, as technological communication capabilities advanced, telemedicine services became more prevalent.The emergence of new telemedicine-related capabilities and their integration into care systems offers opportunities to enhance value-based clinical care, promote health, and prevent diseases.The values associated with the adoption of telemedicine services include the collaboration with the agile accessibility of patients to highly complex centers,along with a reduction in mortalityand frequency of hospitalizations.In cardiology, recent publications portray telemedicine and teleconsultation services as effective in the management of patients with chronic heart failure, 260,261 preparation of ECG reports, guidance of patients through mobile applications,and cardiac rehabilitation,among others. From reported experiences, telemedicine is universally seen as offering interesting benefits for improving accessibility and quality of health.However, scientific and financial investments required to introduce these technologies into the health care system are high,which potentiates the importance of accurate studies on economic analysis to guide decisions upon implementation of telemedicine services.Economic analysis is one of the pillars of health care assessment that aims to support and guide decision making. For a new technology to be applied to a process, it must replace existing alternatives with equal or better results. That is, it must be effective. In addition, the results thus obtained should be less expensive than the alternatives or present reasonable values related to benefits, i.e., it must be cost effective. However, the economic evaluation of telemedicine strategies has some specificities: constant change of technology, lack of an adequate study design to manage undersized samples, inadequacy of conventional economic assessment techniques, and health outcome assessment problems not directly related to health.As a consequence, different types of cost analysis have gained an important role in the evaluation of telemedicine services. # Applied economic methods Different approaches have been used to assess the economic impact of telemedicine services with varying levels of acceptability. Basically, five methods are available for calculation of cost effectiveness between conventional and telemedicine interventions: cost-minimization analysis, costbenefit analysis, cost-effectiveness analysis, and cost-utility analysis. Additionally, return on investment has been used in telemedicine projects.Cost-minimization analyses assume that both alternatives (conventional and telemedicine) are equally effective in health outcomes but differ in cost. A cost-minimization analysis considers changes but keeps health outcomes unaltered. For example, telecardiology for ECG reports assumes the same result but with different costs. Consequently, managers have to consider only differences in costs when deciding which alternative is less expensive.Cost-benefit analysis recognizes that different projects are equally effective, but results and costs change. Changes in health costs and outcomes are considered simultaneously and attribute a monetary or numerical value not only to costs but also to health outcomes in order to express the nondimensional cost/benefit ratio. However, the idea of attributing monetary values to health outcomes, such as years of life, is not always acceptable to health decision makers. Cost-effectiveness analysis appears as a solution when costs and results are considered simultaneously, without attributing monetary values to results. Each outcome is defined according to its specific unit so that the final indices demonstrate a relationship between economic and health outcomes. Therefore, the final decision depends on the relationship that the decision maker considers best. This ratio (incremental cost-effectiveness ratio, ICER) represents the cost for each additional result unit.Cost-utility analyses consider individuals' quality of life and the time of life that they will obtain as a result of an intervention. This is a particular case of cost effectiveness in which results are measured in terms of full-life lived years, usually expressed in quality-adjusted life-years (QALYs) or disability-adjusted life-years (DALY). The WHO recommends a value for DALY equivalent to three times the gross domestic product per capita. Return on investment is a nondimensional relationship between the monetary value invested and the monetary gain resulting from these investments, and measures the efficiency of the investment. ## Literature review A systematic literature review of cost-benefit review studies on the adoption of telemedicine services was conducted by the Federal University of Minas Gerais (UFMG) in 2016, gathering publications from 2000 to 2016.Considering the keywords employed in the study, a search was performed on the PubMed database with the inclusion criterion being only studies related to cardiology. Other reviews manually searched in databases and/or journals of the area were also added. Thus, the search included literature review articles on the assessment of the incorporation of telemedicine in cardiology from 2000 to April 2019. Variables related to the economic analysis method, purpose of telemedicine in cardiology, clinical effectiveness, and cost reduction were extracted from the studies. For effectiveness, the impact on the reduction of mortality and hospitalizations, improvement of medication management, and anticipation of diagnosis were evaluated. From the search and application of exclusion criteria, 35 articles were fully analyzed by two researchers (A.E. and B.Z.) for the collection of variables. .1 presents the flowchart of the selection of the articles. The number of studies focusing on telemedicine, especially the monitoring of chronic diseases, has increased over the last decade. Of the 35 studies identified, 19 were published after 2015..1 summarizes the characteristics of the articles. Among the studies, 26 evaluated the telemedicine telemonitoring service mHealth as primary intervention versus usual face-to-face treatment. According to the authors, the ease of use of mobile phones, through the use of applications for remote monitoring and quick communication with patients, was the most common.The most common outcomes in the evaluated studies were a reduction in mortality rate (54% of the reviews) and in the number of hospital readmissions (57% of the reviews), with at least one of these outcomes appearing in 26 studies. Other expected results were reduced hospitalization, early diagnosis, and better medication adherence. On the other hand, economic evaluations were less frequent. Only 16 reviews found conclusive results with cost analyses, of which 13 concluded that telemedicine provided savings to the paying source by reducing costs. Eight reviews included the economic evaluation of incorporating telemedicine in cardiology, with cost effectiveness being the most frequent evaluation (seven studies), while cost minimization was included in a single study. One study suggested that the few existing economic assessments have Briefly, studies on heart failure telemonitoring have shown that support strategies (video conferencing or telephone) are cost effective, meaning, they have a potential for financial return. Studies evaluating monitoring by cardiac devices showed an incremental cost-effective ratio of US$ 13,979 per QALYs. In a meta-analysis, device telemonitoring was related to a 44% reduction in hospital visits, with no effect on mortality, but a 15-50% reduction in direct health costs.The economic results of noninvasive telemonitoring are even more heterogeneous. Some clinical trials have shown neutral results, while one showed a significant reduction in heart failure readmissions and a direct total cost reduction of € 3,546 per patient for 6 months of follow-up.In a Dutch clinical trial, the TEHAF trial, the likelihood of costeffectiveness for remote monitoring was 48% (€ 50,000/ QALY threshold), probably due to differences between institutions. One of the most detailed studies was developed for the UK health system perspective using a Markov model comparing usual treatment, telephone support, or remote telemonitoring for patients with heart failure after hospital discharge. Assuming monthly costs of £ 27 for standard care, £ 179 for telephone support, and £ 175 for telemonitoring during business hours, the most cost-effective strategy was telemonitoring, with values below £ 20,000 per QALY. The telephone support strategy was very unfavorable, with an ICER of £ 228,035/QALY compared with telemonitoring.Variables evaluating effectiveness repeat across the studies, notably the reduction in mortality and in hospitalization frequency. However, accurate cost collection methods, definition of which cost variables should be collected, and the application of economic models still lack standard recommendations in the literature. More than 70% of the studies did not consider at least one category: health care costs, patient and family expenses, or lost productivity. Many failed to include salaries and benefits, training time, amortized capital investments, data and follow-up operations, and overhead costs. Moreover, an important constraint in these economic analyses has been the great heterogeneity of technology (intervention) and even the control group (alternatives). Technologies supporting telemedicine services advance at an impressive pace and range from complex structures and large investments less than 10 years ago to cost-effective solutions based on cell phones and mobile devices.These are distinct services requiring a high initial investment, but most data point to a return on investment over time due to the volume of patients who then do not require the use of the traditional health care system.Economic assessment methods must, therefore, track the service over time, including the outcomes of patients receiving care or monitored by the telemedicine services. Given the diversity of the benefits gained, the applied cost methodology -dedicated data reflecting conditions of the local health care system -must be evaluated for a proper understanding of the cost effectiveness of these technologies. ## Economic evaluations of telemedicine in brazil These new technologies are being gradually introduced in the routine of hospitals, clinics, and offices in the private and public sectors in Brazil. The first of these technologies to be applied was the transmission of ECG data for remotely reporting. In 1994, the company Telecardio started using this technology, transmitting the tests by telephone, and in 1995, the Instituto do Coração (InCor) created a service called ECG-FAX. Later, in 2005, a telecardiology system or Minas Telecardio project was implemented at UFMG's Clinics Hospital.In 2007, the Ministry of Health, aiming to develop actions to support primary care teams through permanent education and virtual technologies, created the Telessaúde Brasil program, later renamed Telessaúde Brasil Redes. Nine Brazilian Telehealth Centers (Núcleos de Telessaúde no were initially established, offering teleconsulting (consultation between professionals) and telediagnosis (ECG) in the public sector. Currently, several companies offer remote reporting of ambulatory BP monitoring (ABPM), Holter, and remote echocardiography and imaging analysis. AI is currently used in teleconsulting and is at an advanced stage in the preparation of diagnostic test reports. Telemonitoring of patients with heart failure is also ongoing in Brazil. The routine use of these technologies in Brazil is an indirect indication of their effectiveness, and the continuing operation of companies in this sector is an indirect measure of costeffectiveness, although there are few formal studies on this subject in Brazil. At least two initiatives for the application of new technologies in cardiology in Brazil focused on these costeffectiveness studies: 1) the telemedicine service and remote patient monitoring of InCor at the University of São Paulo Medical School and 2) the telediagnosis and teleconsultation system of the Minas Gerais Teleasssistance Network (RTMG) of the Clinics Hospital at UFMG. In addition to the results from telecardiology services, an analysis of savings estimates for the state of Rio Grande do Sul through the TelessaúdeRS project, which offers 20 clinical specialty teleconsultation services, was conducted and are presented in this chapter as a third approach to an economic evaluation of telemedicine in Brazil. ## Incor-fmusp telemedicine and patient monitoring service Stevens et al. evaluated the economic burden and impact on patients' disability of four main heart conditions -heart failure, AMI, AFib, and hypertension -in 2015 in Brazil.Specifically for hypertension, the authors assessed the cost effectiveness of conventional care versus telemedicine and structured telephone support over a 30-year time horizon after 2015. A summary of the results found in the study is shown in.2. Both technologies were considered cost effective by the authors, assuming the standard defined by the WHO of an intervention being considered cost effective when having a cost per life-year between one and three times the gross domestic product per capita per QALY. However, the Brazilian health authorities have not yet defined the country's ICER. Thus, safe inferences cannot be made on whether the procedures applied in telemedicine within the SUS would be cost effective or not within these scenarios. According to Brazilian law, products, medications, or procedures included in SUS' protocols must be evaluated for safety, efficacy, effectiveness, and cost effectiveness. Therefore, an effective reference is still needed to validate the economic assessment in question.Telecare activities include teleconsultation and telediagnosis. Teleconsultations are mostly asynchronous through regulatory calls in medicine, nursing, dentistry, physiotherapy, pharmacy, psychology, nutrition, and speech therapy. Telediagnosis consists of the analysis and reports of ECGs, ABPM, Holter, and retinography, along with synchronous cardiology teleconsultations to support critical clinical cases. The service is registered in the CRM of the State of Minas Gerais. ## Telediagnosis and teleconsultation The RTMG activity was initiated with the research project Minas Telecardio in 2006, implementing a telecardiology service with ECG reports and teleconsultation in 82 municipalities in Minas Gerais. The RTMG activities expanded over time and currently connects 814 municipalities with more than 1,000 telehealth units in Minas Gerais. Within the ONTD project of the Ministry of Health, it began to offer nationwide telecardiology services on September 2017, and currently serves 90 municipalities in the states of Acre, Bahia, Ceará, Mato Grosso and Roraima. This expansion was partly the result of studies proving the cost effectiveness of the system for the main RTMG funders (Ministry of Health and Minas Gerais State Department of Health). Using the results of the Minas Telecardio Project, Andrade et al.compared the cost-benefit ratio of remote ECG reporting, considering the hypothesis of economic benefit in performing ECGs in the telecardiology project compared with the referral of the patient to perform ECG examination at another location.The study was conducted between June 2006 and November 2008 in 82 municipalities in rural areas of the state of Minas Gerais. Each municipality received a microcomputer with a digital electrocardiograph machine and had the possibility of forwarding the ECG recordings and establishing communication with the cardiology department at university hospitals of the RTMG. The costs of the project were divided into two categories: related to the implementation and related to the maintenance of the telecardiology system. The cost of moving patients was assessed, including the cost of transportation (using city-provided resources), the cost of food during their absence from home, and the cost of a missed working day (both paid by the patient). The cost-benefit without inclusion (perspective of the public health service) and with inclusion (perspective of the society) of the patients' costs were evaluated. For the face-to-face scenario, the cost of ECG and cost of the consultation were added (R$ 5.15 and R$ 10.00, respectively, based on the SUS' reference table). The sources of data for the analysis were mainly the National Household Sample Survey (Pesquisa Nacional de Amostra de Domicílios, PNAD), SIA-SUS Ambulatory Information System, and CNES. Considering the cost of implementation and maintenance of the project of R$ 1,818,282.87 and the number of examinations performed in the 30-month period (62,865 examinations from August 2006 to December 2008), the unit cost of each remote report was R$ 28.92. A summary of the results is shown in.3. A sensitivity analysis showed that the results are sensitive to patient travel costs, particularly related to the driver's salary and number of patients per vehicle. Given the small difference between scenarios 1 and 2, it can be concluded that, in some situations, telecardiology may not be more economical from the point of view of public health service. At that time, the system had a relatively low output and, since the activities have a high fixed cost, resulted in a high cost for the remote report. With the expansion of the system to other municipalities, the cost of the activities reduced, increasing the cost effectiveness of the system. In 2007, the Ministry of Health, with resources from PAHO, engaged the CTS HC/UFMG in the project "Analysis of the Financial Management of Telehealth Services Applied to Primary Care." In the project, the analysis of the economic sustainability of the application of telehealth in primary care was based on a comparison of costs between two scenarios: I. Face-to-face care: when the patient is treated in primary care and requires to be subsequently referred to secondary level care; II. Remote care: when the primary care physician receives remote support through a telehealth service, and this support avoids the referral of the patient. The results refer to 20 municipalities participating in the National Telehealth Project with reliable data, located in the North/Northeast regions and Jequitinhonha Valley in Minas Gerais, considered one of the poorest regions of the state. The main results of the project are shown in table This project presented more realistic results compared with the previous one, as it collected information about the cost of patient referral directly in the municipalities. However, it maintained the sample of the participating municipalities concentrated in the same region of the state, the Jequitinhonha Valley, which has a low human development index (HDI). In 2009, the Minas Telecardio Expansion project expanded the service to higher HDI regions for a final sample of 66 other municipalities. The results were similar to those of the previous project and are shown in table 5.5.Recently, a study (pending publication) was conducted to assess the cost effectiveness of the ONTD. The ONTD is a project of the Ministry of Health to offer telecardiology services (ECG reports and teleconsultations) to all Brazilian states, for which the CTS HC/UFMG was chosen as Specialist Center, that is, the service provider. State Telehealth Centers receive funding from the Ministry of Health to train and implement care in municipalities of their state, previously agreed with the State Health Departments, which may forward 24/7 their test requests and teleconsultations to the Expert Center. The requests may be elective or urgent. The report is available on a platform, and, when necessary, local physicians can ask questions as part of teleconsultation. An alert system informs physicians and nurses about critically emergent situations. The effectiveness of the system has been proven by performance indicators (time to submit tests, waiting time for analysis of urgent/elective reports, time to the first analysis of the report, number of tests requested by the municipality, etc.), and user satisfaction. The results proved the effectiveness of the system by replacing alternatives previously available to obtain the test/report (referral of the patient, periodic visits of the cardiologist to the municipality, and outsourcing of tests to private companies/clinics). In terms of these alternatives, the cost of the test by the ONTD is about five times lower, demonstrating cost effectiveness. ## Analysis of the economic impact of the telessaúders teleconsulting service An economic analysis of the TelessaúdeRS service was performed to evaluate the financial results of the service generated to the state. Teleconsultations are offered for various specialties, in addition to the contribution to the regulation of waiting lists for the state of Rio Grande do Sul. Teleconsultations in endocrinology, gastroenterology, proctology, rheumatology, and urology were selected as samples. The cost per teleconsultation (R$ 110.29) was evaluated considering data from 8 months of service and included costs of the physical structure of the service (rent, energy, depreciation, server capacity, among others) and payment of professionals. As a premise, all teleconsultations and regulations that resulted in the cancellation of the face-to-face consultation would represent, for the state, savings in patient transportation to Porto Alegre (which is variable according to the municipality of origin) and payment of face-to-face consultation to the municipality (R$ 100.00). Estimated savings were calculated as the difference between the cost of performing canceled teleconsultations and the cost of face-to-face care. The analysis identified that over 21 months (October 2016 to June 2018), the state saved R$ 2,287,121.78, of which 47% were related to consultations and 53% to transportation services. For teleconsultation, the service was found to be attractive up to the amount of payment per consultation of R$ 38.95, considering the average cost of transportation. The municipalities with the greatest distances from Porto Alegre had higher savings, except for four municipalities neighboring Porto Alegre, which had a higher number of avoided teleconsultations than the others' average. Of note, a comparison of these results with those of other states and services should consider that the services of Telessaúde are provided by scholars and "CLT" professionals (employees following the Brazilian Labor Laws); therefore, Telessaúde can operate at a lower cost per teleconsultation. The operation of a similar service including only "CLT" employees would increase the cost per each teleconsultation and require additional economic analysis. The WHO considers cost effective those interventions with ICER between 1 and 3 times the gross domestic product per capita per life-year, unless adjusted for QALY. ## Recommendations The Brazilian Society of Cardiology, due to the growing interest in the use of telemedicine for the expansion of health care, particularly in the area of cardiology, prepared this guideline to inform the medical category and society in general on the scientific and technological basis of telemedicine applications considering the current scenario. Even though there is growing enthusiasm for the democratization of information and communication technologies, it is important to point out that barriers to implementation persist across the country and must be addressed. The most significant ones are: - update of laws and regulations applicable by the health authorities and CFM; - provision of minimum telecommunications infrastructure in health care facilities, especially in remote areas; - cost of technology; - need for qualification and training of human resources; - incorporation of technologies in the SUS' public policy list and in the List of Procedures and Events in Health of the National Health Agency. By bringing to light the discussion about telemedicine applications, in addition to its media repercussion, we seek to provide scientific and technical support for the elaboration of health care policies consistent with the use of this technology. In this sense, we must formally incorporate, after due evaluation by the CONITEC, the various possibilities available today linked to the respective clinical protocols and therapeutic guidelines (PCDT). Also, in the context of supplementary health, it is necessary to include in the List of Procedures and Events in Health of the National Health Agency those with scientific recognition and authorized for current use in the country. As discussed in this guideline, with rare exceptions, there is no provision in the Brazilian Hierarchical Classification of Medical Procedures (which is a condition for inclusion in the NHA coverage list) for common procedures in telemedicine. Generic coding is used, with descriptions that are broad in nature and allow for likelihood use, such as code 2.01.01.20-1 (clinical and electronic evaluation of a patient with a cardiac pacemaker or resynchronization defibrillator or defibrillator). However, the reimbursement of this service will depend on the health care provider's sole decision. This fact limits the applicability of telemedicine in the field of supplementary health, with the related consequences. In 2015, the Brazilian Society of Cardiology, through the Telecardiology Guideline for the Care of Patients with Acute Coronary Syndrome and other Heart Diseases,made recommendations on this topic. However, the current version of the broader guideline addresses new applications for telecardiology, especially those already incorporated into the health care system. It still deals with future perspectives, such as the use of telerobotics and AI. The authors, focusing on current scientific evidence and cost effectiveness, have updated the recommendations to guide public and private health care providers on judicious use of telemedicine applications in Brazil.	None	http://www.scielo.br/pdf/abc/v113n5/0066-782X-abc-113-05-1006.pdf	Apresentacao Em boa hora, decidiu a Sociedade Brasileira de Cardiologia (SBC) fazer uma diretriz em telemedicina aplicada a cardiologia, tambem designada telecardiologia. A Organizacao Pan-americana de Saude (OPAS) e a Organizacao Mundial de Saude (OMS) definem Telemedicina como “a prestacao de servicos de saude remotos na promocao, prevencao, diagnostico, tratamento e reabilitacao pelos profissionais de saude que utilizam as tecnologias de informacao e comunicacao, que lhes permitem trocar dados, com o objetivo de facilitar o acesso e a oportunidade na [...]
c985142d8374c3733e3b67a19cf75fd123dc6d7a	pubmed	Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of the management of high-risk population	Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of the management of high-risk population ## Correspondence to # Introduction In the past two decades, stroke has been a big healthcare burden in China. From the results of 2013 national survey, the age-adjusted stroke incidence and mortality rates were 246.8/100 000 and 114.8/100 000 person-years, respectively. Stroke prevalence was 1114.8/100 000. Based on this calculation, there are >11 million stroke survivors, >2.4 million new strokes and >1.1 million people dying of stroke every year in China. The disability-adjusted loss of life-years was 2010.0/100 000 person-years. In addition, there are approximately 270 million patients with hypertension, 110 million with diabetes mellitus and 160 million with dyslipidaemia and the number of people with these risk factors of stroke continues to rise in China.The best treatment of stroke is prevention. Many studies showed that primary prevention is the key to reduce stroke incidence and mortality. The aim of this guideline is to recommend the appropriate prevention strategies for population at high risk for stroke. This executive summary offers a simplified version of the comprehensive recommendations that have been published, but with an update since the publication of the original version. The recommendations and levels of evidence are in line with the American Heart Association (AHA) guidelines for the primary prevention of stroke. ## Controlling the risk factors of stroke genetic factors Recommendations ► Inquiring a family history can help identify individuals at increased risk of stroke (class IIa; level of evidence A). ► For patients with rare genetic causes of stroke (such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, COL4A1-related intracerebral haemorrhage, autosomal-dominant polycystic kidney disease, Ehlers-Danlos type IV), referral for genetic counselling may be considered (Class IIb; level of evidence C). In general population routine genetic screening for the prevention of a first stroke is not recommended (class III; level of evidence C). ► For patients with ≥2 first-degree relatives with SAH or intracranial aneurysms, non-invasive screening such as CT Angiography (CTA) or MR Angiography (MRA) of brain for detecting any unruptured intracranial aneurysm (UIA) may be reasonable (class IIb; level of evidence C). ► For patients with autosomal-dominant polycystic kidney disease, ≥1 relatives with autosomal-dominant polycystic kidney disease and subarachnoid hemorrhage (SAH) or ≥1 relatives with autosomal-dominant polycystic kidney disease and intracranial aneurysms, non-invasive screening such as CTA or MRA of brain for detecting any UIAs may be considered (class IIb; level of evidence C). ► For patients with (cervical) fibromuscular dysplasia, non-invasive screening such as CTA or MRA brain for detecting any UIAs may be considered (class IIb; level of evidence C). DSA can be conducted if needed. It is reasonable to consider a first follow-up at 6-12 months after initial discovery of UIA, and follow-up every 1-2 years (class IIa; level of evidence C). ► Treatment includes surgical clipping and endovascular treatment. Treatment selection is related to multiple factors including aneurysm location, size and morphology; documented growth of aneurysms during the follow-up; the age of the patient; history of aSAH; family history of cerebral aneurysm; the presence of multiple aneurysms or the presence of concurrent pathology such as an arteriovenous malformation or other cerebrovascular or inherited pathology (class I; level of evidence C). The management of patients with UIAs (figure 5). ## Modifiable risk factors ## Cigarette smoking Recommendations ► Smoking cessation ought to involve both smokers and the whole society, by adopting comprehensive tobacco control measures including psychological counselling, nicotine replacement, smoking cessation medications, and intervention in the community (class I; level of evidence A). ► Non-smokers should avoid passive smoking (class I; level of evidence B). ► Publicity and education should continue to be strengthened to raise public awareness of the harm of active and passive smoking. Local government should legislate against smoking in public places as soon as possible, such as smoking bans in offices, meeting rooms, airplanes or trains, to reduce the harm of smoking (class IIa; level of evidence B). ## Alcohol consumption Recommendations ► Drinkers should reduce or eliminate alcohol consumption (class I; level of evidence A). ► Drinking only in moderation should be recommended among individuals who choose to consume alcohol. Moderate alcohol consumption of ≤25 g/day for men and half for women is reasonable (class IIb; level of evidence B). ## Obesity and body fat distribution ## Open access ## Diet and nutrition Recommendations ► Daily diet should be diverse to make the intake of energy and nutrition more reasonable; a balanced diet including whole grains, legumes, tubers, fruits, vegetables, dairy product and a low intake of total fat and saturated fat is recommended (class I; level of evidence A). ► Reducing the intake of salt and increasing the intake of potassium are recommended to reduce the risk of stroke by lowing BP. A salt intake of ≤6 g/day is recommended (class I; level of evidence A). ► Encouraging more intake of fruits, vegetables and certain dairy product, and reducing the intake of saturated fat and trans fatty acids (class I; level of evidence A). The total fat intake per day should be less than 30% of total calories and trans fatty acids of less than 2 g; fresh vegetables intake of 400-500 g; fruits intake of 200-400 g; moderate consumption of fish, poultry, eggs and lean meat, with an average total intake of 120-200 g; various dairy product, with an intake equivalent to 300 g of liquid milk; vegetable oil intake of <25 g; added sugar (or free sugar, ie, the monosaccharide added in food, such as rock candy, refined cane sugar, etc) intake of <50 g/day, preferably <25 g/day. ## Physical inactivity Recommendations ► Appropriate physical activities are recommended to reduce the risk of stroke (class I; level of evidence B). In elderly and high-risk people, individualised exercise programme should be planned, after conducting a safer maximal exercise tolerating test. ► Healthy adults should perform at least moderate-tovigorous-intensity aerobic physical activity (such as brisk walking, jogging, cycling or other aerobics) for at least 40 min per day for 3-4 days per week (class I; level of evidence B). ► Standing up and moving limbs around for a few minutes after an hour of sitting still is recommended for people who are sedentary in their daily work, including those who have already had enough regular exercise weekly is recommended (class I; level of evidence C). ## Evidence insufficient or potential modifiable risk factors Metabolic syndrome Recommendations ► Metabolic syndrome is a clinical condition in which multiple metabolic abnormalities occur in the human body, including central obesity (abdominal obesity), dyslipidaemia, hypertension and elevated fasting blood glucose. Metabolic syndrome is increasingly common. Interventions of every single risk factor of the metabolic syndrome are recommended, including lifestyle measures and pharmacotherapy (ie, medications for BP lowering, lipid-lowering, glycaemic control, etc). Detailed interventions refer to relevant sections on 'hypertension', 'abnormal glucose metabolism', 'dyslipidaemia' of this guideline. ## Sleep-disordered breathing Recommendations ► Screening for patients with sleep apnoea requires a detailed history. The screening methods include structured questionnaires such as the Epworth Sleepiness Scale, Berlin Questionnaire, physical examination. And polysomnography may be considered depending on the patients' condition (class IIb; level of evidence C). ► The effectiveness of treatment for sleep apnoea in stroke prevention is still not well established (class IIb; level of evidence C). ## Migraine Recommendations ► For women and geriatric patients with migraine with aura, smoking cessation is recommended (class I; level of evidence B). ► For women with active migraine with aura, withdrawal of oral contraceptives (OCs), especially those containing oestrogen, should be considered (class IIa; level of evidence B). ► Treatments to reduce migraine frequency (especially for migraines with specific aura symptoms) might be able to reduce the risk of stroke (class IIa; level of evidence B). ► For patients with migraine, the clinical benefit of closing PFO for the prevention of stroke is unproven (class III; level of evidence B). ## Hyperhomocysteinaemia Recommendations ► Hyperhomocysteinaemia is a risk factor of stroke (level of evidence A). For patients with hyperhomocysteinaemia, the use of folic acid or folic acid in combination with cobalamin (B12) and pyridoxine (B6) might be effective in the prevention of stroke (class IIa; level of evidence B). ## Elevated lp(a) ## Hypercoagulability Recommendations ► For patients with inherited hypercoagulable states, the effectiveness of genetic screening for the prevention of stroke is not well established (class IIb; level of evidence C). ► The effectiveness of treatments for the primary prevention of stroke in asymptomatic patients with a Open access glomerular filtration rate <30 mL/min/1.73 m 2 ), aspirin is not recommended anymore. ► Aspirin is not recommended for preventing a first ever stroke in low-risk individuals whose 10 year risk is less than 10% (class III; level of evidence A). ► Aspirin is not recommended for preventing a firstever stroke in people over 70 years old (class III; level of evidence B). ## Assessing the risk of first stroke recommendations The use of a risk assessment tool is reasonable and can help identify individuals who could benefit from therapeutic interventions. For high-risk individuals, treatment decisions should be individualised according to the overall risk profile of the patient (class IIa; level of evidence B . Contributors WW, YW, YJ, and ZL designed the protocol and framework. WW, BJ, XR, DS and HS drafted the sections of unmodifiable risk factors, cigarette smoking, alcohol consumption, obesity and body fat distribution, diet and nutrition, and physical inactivity. XX drafted the section of hypertension. QJ drafted the section of diabetes and prediabetes. HZ and YY drafted the sections of dyslipidaemia and elevated Lp(a). SL and XY drafted the sections of atrial fibrillation and other heart diseases. HQ, LZ and YumX drafted the section of asymptomatic extracranial or intracranial stenosis. YC and YJ drafted the section of unruptured intracranial aneurysms. PW and TW drafted the sections of metabolic syndrome and infection and inflammation. HQ and MZ drafted the sections of sleep-disordered breathing and antiplatelet agents and aspirin. LG drafted the section of migraine. WL drafted the section of hyperhomocysteinaemia. HZ and SH drafted the sections of hypercoagulability, drug abuse, oral contraceptives and postmenopausal hormone therapy. YL, YG and YuyX drafted the section of assessing the risk of first stroke. WW, YW, HZ, HQ, BJ and SH discussed and updated the final version. SH and LG did the translation for the supplement material. Funding This research received specific funding from Chinese Stroke Association Guidelines Writing Committee. Competing interests None declared. Patient consent for publication Not required. Provenance and peer review Commissioned; externally peer reviewed. Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http:// creativecommons. org/ licenses/ by-nc/ 4. 0/.	None	https://svn.bmj.com/content/svnbmj/5/3/270.full.pdf	Aim Cerebrovascular disease is the leading cause of death and disability in China, causing a huge burden among patients and their families. Hence, stroke prevention is critical, especially in the high-risk population. Here, we present the evidence-based guideline suitable for the Chinese population. Methods Literature search of PubMed and Cochrane library (from January 1964 to June 2019) was done. After thorough discussion among the writing group members, recommendations were listed and summarised. This guideline was reviewed and discussed by the fellow writing committees of the Chinese Stroke Association’s Stroke. Results This evidence-based guideline was written in three parts: controlling the risk factors of stroke, utilisation of antiplatelet agents and assessing the risks of first-ever stroke. All recommendations were listed along with the recommending classes and levels of evidence. Conclusions This guideline provides recommendations for primary prevention of cerebrovascular disease among high-risk population in China. Controlling related risk factors, appropriately using antiplatelet agents, assessing the risk of developing first-ever stroke should help reduce the rate of cerebrovascular disease in China.
21615e015a3ad6b7424ec4d290912bb9e68acd72	pubmed	2018 consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary	2018 consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary Cancer of unknown primary (CUP) is defined as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They differ from other primary tumours in their biological features and how they spread, which means that they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, CUP can account for 2-9% of all cancer patients, mostly 60-75 years old. This article reviews the main clinical, pathological, and molecular studies conducted to analyse and determine the origin of CUP.The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed. # Introduction Cancer of unknown primary (CUP) is defined as a heterogeneous group of tumours that present initially with metastasis, and in which a properly standardised diagnostic work-up cannot identify the original site of the malignancy [bib_ref] Cancer of unknown primary (CUP), Pavlidis [/bib_ref] [bib_ref] Cancer of unknown primary site, Pavlidis [/bib_ref]. In the last few years, various consensus statements and international clinical guidelines have tried to define more clearly what diagnostic work-up should be performed before a case is regarded as CUP. The US National Cancer Institute (NCI), the National Comprehensive Cancer Network (NCCN), and the European Society of Medical Oncology (ESMO) have published minimum recommendations on this subject, with a reminder that any cancer presenting with metastasis must undergo the initial testing before being regarded as CUP [bib_ref] Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment..., Fizazi [/bib_ref]. CUP can be considered a separate entity, because its biological properties set it apart from other known primary tumours. In addition, it generally has atypical patterns of spread and clinical behaviour, which are inconsistent with the supposed site of origin. There are two hypotheses regarding CUP biology: the first suggests that the neoplasm might arise from a stem cell, without first producing a premalignant lesion or a primary tumour; the second maintains that it represents rapid progression of metastasis from a very early primary tumour [bib_ref] Parallel progression of primary tumours and metastases, Klein [/bib_ref]. Chromosomal instability was recently suggested as a plausible explanation, or even a prognostic factor for more aggressive presentation and chemoresistance of CUP [bib_ref] Cancers of unknown primary origin (CUP) are characterized by chromosomal instability (CIN)..., Vikesa [/bib_ref]. It has been shown that, generally, CUP is not associated with specific mutations in oncogenes or suppressor genes. Instead, it is characterised by angiogenesis activation (50-89%), oncogene over-expression (10-30%), a greater presence of hypoxia-related proteins and epithelial-mesenchymal transition markers , and the activation of intracellular signals such as AKT or MAPK (20-35%) [bib_ref] Cancer of unknown primary patients with midline nodal distribution: midway between poor..., Pentheroudakis [/bib_ref]. Depending on the definition used and how exhaustive the diagnostic procedures are, CUP can account for 2% to 9% of all cancer patients [bib_ref] Cancer of unknown primary (CUP), Pavlidis [/bib_ref]. Accordingly, the incidence of CUP may change as new diagnostic technologies are implemented. In purely numerical terms, CUP is currently the eighth most frequent cancer diagnosis [bib_ref] Cancer of unknown primary (CUP), Pavlidis [/bib_ref]. Its incidence is highest in patients aged 60-75 years [bib_ref] Descriptive epidemiology of cancer of unknown primary site in Scotland, Brewster [/bib_ref] [bib_ref] Epidemiology of unknown primary tumours, Levi [/bib_ref]. The most common underlying occult primary tumours are basically of lung and biliopancreatic origin, as observed in the pooled analysis of over 800 patients in 12 autopsy series [bib_ref] Switching benchmarks in cancer of unknown primary: from autopsy to microarray, Pentheroudakis [/bib_ref]. ## Basic clinical work-up The initial clinical assessment of patients diagnosed with CUP should not be exhaustive. Instead, it should aim to determine the extent of the disease, and to identify tumour subtypes in which a specific therapy may have a positive impact on patient progress and prognosis. The basic clinical investigations that should be done include history-taking and physical examination, basic laboratory tests, and computed tomography (CT) of the chest, abdomen, and pelvis. A full medical history and physical examination should include genitourinary and rectal examination, as well as examining the breasts and pelvic region in women, and the prostate in men. Special attention should be paid to the previous diseases, biopsies or lesions removed, spontaneously regressing lesions, previous imaging tests, and family cancer history. The laboratory tests recommended are a full blood count with differential white cell count, measurement of electrolytes, creatinine and calcium, liver function tests, and basic urinalysis [bib_ref] Clinical guideline SEOM: cancer of unknown primary site, Collado Martín [/bib_ref]. Serum tumour markers should not be tested routinely. Elevations in these markers are not highly sensitive or specific, and testing for them during CUP diagnosis has not been shown to be cost-effective. In men, however, tests for prostate-specific antigen (PSA), serum chorionic gonadotropin (β-hCG), and alpha-fetoprotein (AFP) are recommended, to rule out treatable extragonadal germ cell tumours or prostate cancer eligible for endocrine therapy. In the case of adenocarcinomas with peritoneal involvement in women, a CA 125 test should be done [bib_ref] Cancer of unknown primary site, Pavlidis [/bib_ref] [bib_ref] Carcinoma of unknown primary (CUP), Pavlidis [/bib_ref]. As far as the initial radiological tests are concerned, patients should have a contrast-enhanced CT scan of the chest, abdomen, and pelvis. If there are cervical lymphadenopathies, this should be accompanied by a CT scan of the neck. Positron emission tomography (PET) can be useful in certain clinical presentations, for both diagnosis and staging [bib_ref] Localised disease in cancer of unknown primary (CUP): the value of positron..., Rades [/bib_ref]. It has 87% sensitivity and 71% specificity [bib_ref] Meta-analysis of the performance of 18F-FDG PET in primary tumor detection in..., Delgado-Bolton [/bib_ref]. One of the limitations of PET is its moderate precision regarding anatomical sites or functional abnormalities, because of low tracer uptake by some tumour tissues. In these cases, it is more helpful to combine PET with CT. A meta-analysis and systematic review of combined PET/CT in patients diagnosed with CUP found that primary tumours were detected in 37% of patients, with 84% sensitivity and identical 84% specificity [bib_ref] Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and..., Kwee [/bib_ref]. This primary tumour detection rate is higher in the case of specific metastatic scenarios, such as cervical lymphadenopathies, and sensitivity is higher too [bib_ref] 18F-fluorodeoxyglucose positron emission tomography-computed tomography as a diagnostic tool in patients with..., Zhu [/bib_ref]. However, in the only prospective study done, PET/CT proved no superior to CT [bib_ref] A prospective comparison of 18F-FDG PET/CT and CT as diagnostic tools to..., Moller [/bib_ref]. PET is, therefore, not recommended as the initial test. Its use should be confined to specific clinical presentations (single metastases and cervical lymphadenopathies), and when local or regional therapy is being considered. In women, it is helpful to perform mammography, and/ or magnetic resonance imaging of the breasts if the mammography result is equivocal [bib_ref] Carcinoma of unknown primary (CUP), Pavlidis [/bib_ref]. On the other hand, endoscopy should not be routinely employed, because it rarely detects the primary tumour in asymptomatic patients, and false positives can cause confusion [bib_ref] A mini review on cancer of unknown primary site: a clinical puzzle..., Pavlidis [/bib_ref]. The choice of other diagnostic procedures should be based on interpretation of the histological sample obtained by biopsy. ## Pathological diagnosis ## Optimising the sample Obtaining a sample of enough tissue is essential for diagnosing and investigating CUP, both for tumour typing and for conducting additional molecular studies. The sample should be obtained using a procedure that provides as much tissue as possible but is not highly invasive for the patient [bib_ref] Optimizing tissue sampling for the diagnosis, subtyping, and molecular analysis of lung..., Ofiara [/bib_ref]. Although the minimum number of cells needed for histological and molecular investigations is not well established, samples containing at least 400 cells are recommended [bib_ref] Enabling a genetically informed approach to cancer medicine: a retrospective evaluation of..., Johnson [/bib_ref]. Some studies show that cytology specimens can be 1 3 diagnostically useful [bib_ref] Cytology-based gene mutation tests to predict response to antiepidermal growth factor receptor..., Malapelle [/bib_ref] [bib_ref] Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung..., Rekhtman [/bib_ref]. To enable all the necessary tests to be done, however, solid tissue samples obtained by core-needle biopsy (CNB), incisional biopsy, or surgical resection are preferable. On the other hand, it is essential to optimise the material obtained. The available material should be divided between multiple paraffin blocks, to conserve as much tissue as possible. Diagnostic immunohistochemical tests should be confined to reasonable panels, according to the available clinical and radiological evidence, to prevent unnecessary staining. In cases likely to require molecular techniques, it is advisable to prepare a few blank slides when serial sections are cut for routine immunostaining. ## Basic histopathology study and classification by morphological/histopathological subtype After the initial clinical assessment, the sample is examined using histopathological techniques, which may require a basic immunohistochemical (IHC) panel. Preliminary classification then becomes possible [bib_ref] Cancer of unknown primary site, Pavlidis [/bib_ref] [bib_ref] ESMO Guidelines Working Group. Cancers of unknown primary site: ESMO Clinical Practice..., Fizazi [/bib_ref] [bib_ref] Carcinomas of an unknown primary origin -diagnosis and treatment, Massard [/bib_ref] : ## Initial classification The most common initial classifications are: - Carcinoma/neuroendocrine tumour: -adenocarcinoma (60%); -poorly differentiated carcinoma, including poorly differentiated adenocarcinoma (20%); -squamous cell (epidermoid) and/or transitional cell carcinoma (5-10%); -neuroendocrine tumour (5%); -undifferentiated carcinoma; - lymphoma; - extragonadal germ cell tumour; - melanoma; - sarcoma. In this first classification, it should be remembered that CUP may be due to tumours of atypical site, morphology, and immunophenotype. The most common metastases at that site have to be ruled out. Tumours that have effective specific therapies must also be appropriately excluded, such as germ cell tumours, neuroendocrine tumours, lymphoma, and hormone-dependent tumours (prostate in men and breast in women). Moreover, IHC markers may have limited specificity and sensitivity in this first classification. ## General histopathological patterns The general histopathological patterns are as follows: - Epithelial/epithelioid: carcinoma, "epithelioid" sarcoma, and melanoma; - Spindle cell: sarcoma, sarcomatoid carcinoma, and melanoma; - Small cell: lymphoma, sarcoma, neuroendocrine tumour, primitive neuroectodermal tumour (PNET), and melanoma; - Pleomorphic: all. ## Second classification: most likely primary tumour In poorly differentiated carcinomas and adenocarcinomas, immunohistochemistry is essential. In squamous cell carcinomas, morphology and immunohistochemistry are relatively non-specific, although there are subtypes associated with human papillomavirus that have greater specificity. In some cases, relevant differences may exist between primary tumours and their metastases. For example, compared with primary tumours, melanoma metastases show greater cytokeratin (CK) AE1/AE3 staining (22%) and less HMB45 staining (65%). The marker S100 may be expressed in adenocarcinomas of the lung, breast, endometrium, and kidney (up to 80%), and other sites to a lesser extent [bib_ref] S-100 protein expression by primary and metastatic adenocarcinomas, Herrera [/bib_ref]. Certain epithelioid or spindle cell sarcomas can be confused with carcinomas or melanomas. Many sarcomas have specific molecular alterations that can be demonstrated by immunohistochemistry or fluorescence in situ hybridisation (FISH) [bib_ref] Novel uses of immunohistochemistry in the diagnosis and classification of soft tissue..., Hornick [/bib_ref]. Molecular diagnostics are particularly recommended for sarcomas of atypical morphology or site. ## Prognostic classification of cup The prognosis is favourable in 15-20% of CUP cases [bib_ref] ESMO Guidelines Working Group. Cancers of unknown primary site: ESMO Clinical Practice..., Fizazi [/bib_ref] [bib_ref] Carcinomas of an unknown primary origin -diagnosis and treatment, Massard [/bib_ref]. These tumours are more chemosensitive and overall survival is better. This category includes poorly differentiated midline carcinomas, peritoneal papillary adenocarcinomas in women, metastatic adenocarcinoma involving the axillary lymph nodes only, metastatic squamous cell carcinoma in the cervical lymph nodes, single-node metastases, poorly differentiated neuroendocrine carcinoma, resectable tumours, and germ cell tumours. In contrast, other cases of CUP have a poor prognosis. These include adenocarcinomas with liver metastases, non-papillary malignant ascites, and multiple brain, bone, or lung metastases. ## Specific histopathology study ## Advisable minimum ihc panel The initial IHC panel should be based on the patient's clinical details (age, sex, disease history, site, etc.) and morphological examination of the mass. For a general approach to CUP, the basic IHC panel should mainly consist of epithelial 1 3 cell markers (CK AE1/AE3, CK Cam 5.2, EMA), S100, vimentin, and leucocyte common antigen (LCA or CD45) [fig_ref] Figure 1: Advisable minimum IHC panel [/fig_ref]. If epithelial origin of the lesion is confirmed (CK+ , S100−, vimentin ± and LCA−), a combination of CK7 and CK20 will give a first indication of the organ in which the tumour is most likely to have originated [bib_ref] Application of Immunohistochemistry in undifferentiated neoplasms: a practical approach, Kandukuri [/bib_ref]. In general, although carcinomas express CK and mesenchymal tumours express vimentin, the exceptions to that rule must be remembered. For example, poorly differentiated carcinomas can show an unpredictable CK expression pattern, or CK expression may be lost completely (as in cases involving the kidney or adrenal gland), whereas some carcinomas co-express vimentin and CK (typically those found in the endometrium, thyroid, and kidney, among others). On the other hand, some types of sarcoma, such as epithelioid or synovial sarcomas, leiomyosarcomas or malignant peripheral nerve sheath tumours, can co-express vimentin and CK. This also occurs in polyphenotypic tumours/blastomas, such as Ewing sarcoma/PNET, desmoplastic small round cell tumour, or medulloblastoma. Staining positive for CD45 and negative for CK suggests a lesion of haematological origin, although some haematolymphoid tumours (granulocytic sarcoma, myelomas, Hodgkin's lymphoma, or anaplastic lymphomas) may have very little or no CD45 expression and test positive for S100 or EMA. S100 is highly specific for lesions of melanocytic or neural origin and may be expressed in a nuclear and cytoplasmic pattern. Vimentin is an intermediate filament characteristic of mesenchymal cells. It is found in almost all sarcomas, melanomas, and a good proportion of lymphomas. It tends to play a supportive role together with other markers. The detection of tumours with neuroendocrine differentiation and tumours of germ cell origin deserves special mention. For neuroendocrine tumours, the panel should include synaptophysin, chromogranin A, and CD56. For germ cell tumours, a specific panel should be considered, such as PLAP, alpha-fetoprotein, or OCT 3/4. When the tumour's microscopic features show it to be clearly epithelial, some of the markers in this profile can be omitted. In that case, the initial panel can be restricted to CK7 and CK20, and testing completed with the extended panel. ## Optional extended ihc panel First, the following points should be considered. Tumour types with widely differing phenotypic profiles arise in each organ. Therefore, this article refers to the most common and most clinically relevant in each case. Phenotypic profiles of tumours of the same origin and histological type vary from one case to another, according to their degree of differentiation, and as they progress. This article, therefore, always refers to expression patterns in general, on the understanding that each particular case may display atypical, aberrant, or exceptional phenotypes. As markers can be identified in tumours of different histological types arising in different organs, and practically no absolutely specific markers exist, it is advisable to test for several markers simultaneously to reach a conclusive diagnosis. Once a first approximation has been obtained using an initial panel [fig_ref] Figure 1: Advisable minimum IHC panel [/fig_ref] , combined with clinical details (age, gender, past medical and family history, lesion site, biochemistry, imaging, etc.) and the tumour's histological pattern, thereby confirming that it is a carcinoma and that other tumour types (melanomas, lymphomas, germ line malignancies, etc.) can reasonably be ruled out, specific expression patterns should be studied [fig_ref] Table 1: Main phenotypic profiles of the most common tumoursUnderlining indicates markers recommended for... [/fig_ref]. ## Molecular diagnostics Thanks to advances in immunohistochemistry, the proportion of CUP cases in which the origin cannot be identified has fallen to 15-20%. This is the patient group most reliant on the use of molecular platforms. Molecular techniques offer information for possible specific therapy. Strategies fall into two categories: platforms for identifying the organ harbouring the primary tumour; and next-generation sequencing to characterise the tumour's mutation profile. ## Platforms for identifying the organ harbouring the primary tumour Various molecular platforms exist for evaluating gene expression, microRNA profile or epigenetic pattern in CUP [bib_ref] Cancer of unknown primary origin in the genomic era: elucidating the dark..., Economopoulou [/bib_ref] [bib_ref] A quantitative reverse transcriptase-polymerase chain reaction assay to identify metastatic carcinoma tissue..., Talantov [/bib_ref] [bib_ref] Prospective gene signature study using microRNA to identify the tissue of origin..., Varadhachary [/bib_ref] [bib_ref] Interlaboratory performance of a microarray-based gene expression test to determine tissue of..., Dumur [/bib_ref] [bib_ref] A multicenter study directly comparing the diagnostic accuracy of gene expression profiling..., Handorf [/bib_ref] [bib_ref] Gene expression microarray-based assay to determine tumor site of origin in a..., Azueta [/bib_ref] [bib_ref] Multisite validation study to determine performance characteristics of a 92-gene molecular cancer..., Kerr [/bib_ref] [bib_ref] Performance and clinical evaluation of the 92-gene real-time PCR assay for tumor..., Erlander [/bib_ref] [bib_ref] Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis, Morán [/bib_ref]. Once a tumour's molecular profile has been obtained, it is compared against database results from a range of sites and histological types. The molecular profile of the tumour being tested is assessed for similarity to these patterns, and the diagnosis provided suggests one or more sites, each with its estimated probability (similarity score). [fig_ref] Table 2: Main molecular diagnostics platforms for cancer of unknown primary [/fig_ref] lists the main features of these platforms. The choice of one platform over another depends on several factors, such as availability in different countries. Strategies of more recent introduction tend to be more informative, because they analyse a larger number of possible sites. In general, these platforms correlate well with immunohistochemistry, and reduce the number of CUP cases in which the primary cannot be identified. The main difficulties involved in using them are: (1) detecting unusual tumours (3) to date, these platforms are not funded by the national health system. The results of these molecular techniques are highly dependent on the quantity, quality, and percentage of tumour cells. Strategies, therefore, need to be established for obtaining optimal material and preserving it after immunohistochemical testing has taken place. There are a few prospective studies to support the usefulness of these platforms. In a study involving 194 patients, Hainsworth et al. showed that survival was better when the platform predicted tumour types clinically associated with a better response [bib_ref] Molecular gene expression profiling to predict the tissue of origin and direct..., Hainsworth [/bib_ref]. In general, molecular platforms are regarded as complementary to immunohistochemistry, and useful when a reasonable number of immunohistochemical stains have failed to predict tumour origin, especially in poorly differentiated tumours [bib_ref] A multicenter study directly comparing the diagnostic accuracy of gene expression profiling..., Handorf [/bib_ref]. ## Next-generation sequencing to characterise the tumour's mutation profile Sequencing with gene panels enables mutations associated with responses to specific drugs (actionable mutations) to be identified. This strategy has been tested in several studies. Gatalica et al. evaluated 1806 CUP cases by immunohistochemistry (23 markers), sequencing (47 genes) and in situ hybridisation (7 genes) [bib_ref] Comprehensive tumor profiling identifies numerous biomarkers of drug response in cancers of..., Gatalica [/bib_ref]. They found actionable alterations in 96% of cases. In another study, Ross et al. studied formalin-fixed, paraffin-embedded specimens from 200 patients with CUP, 125 of whom had adenocarcinomas [bib_ref] Comprehensive genomic profiling of carcinoma of unknown primary site: New routes to..., Ross [/bib_ref]. These authors examined 236 genes and the introns of 19 genes often altered in cancer. At least one actionable mutation was identified in 96% of cases. Tothill et al. used panels representing 701 genes and identified actionable mutations in 12 out of 16 cases [bib_ref] Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown..., Tothill [/bib_ref]. The main objection to using massively parallel sequencing in CUP arises from the belief that the potential drug response conferred by a given mutation depends on the type of tumour in which the mutation is found. That is, the context of histological type and tumour site can affect the response to the drug [bib_ref] Using somatic mutations to guide treatment decisions: Context matters, Horlings [/bib_ref]. That assumption is based on studies such as the SHIVA study, which showed that molecularly targeted off-label drug use failed to improve patients' disease-free survival [bib_ref] Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for..., Tourneau [/bib_ref]. Accordingly, sequencing techniques are complementary to platforms for predicting the primary cancer site. ## Targeted clinical work-up and prognosis The median survival of patients with CUP is approximately 9-10 months, similar to that seen in metastatic lung cancer [bib_ref] Sitespecific survival rates for cancer of unknown primary according to location of..., Hemminki [/bib_ref]. A gradual increase has been detected in CUP survival, probably because of improved therapy for malignancies of known origin and better management of metastatic disease, as well as optimisation of diagnostic resources in general [bib_ref] Time trends in survival from cancer of unknown primary: small steps forward, Riihimaki [/bib_ref]. Nevertheless, patients who present with metastasis of a known tumour have better survival than patients whose primary tumour is unknown [bib_ref] Comparison of survival of patients with metastases from known versus unknown primaries:..., Riihimaki [/bib_ref]. Successfully identifying tumour origin improves the patient's prognosis, probably because it enables better treatment selection and adjustment [bib_ref] Molecular profiling diagnosis in unknown primary cancer: accuracy and ability to complement..., Greco [/bib_ref]. That was demonstrated in patients whose CUP molecular profiling results proved consistent with colorectal cancer, and who were treated accordingly (median survival 27 months and 50% response to specific therapy, similar to figures obtained in colon cancer) [bib_ref] A retrospective study of treatment outcomes in patients with carcinoma of unknown..., Hainsworth [/bib_ref]. Therefore, the factor most likely to improve the prognosis of a patient with CUP is actually not having CUP any more. That is why the algorithm for diagnosing and managing CUP looks for "greatest similarity" to known tumours, in terms of IHC, clinical features, and/or molecular findings. In the absence of a definitive diagnosis, the clinical workup should aim to identify tumours that can be treated according to consensus guidelines because of similarity to known primary tumours [bib_ref] Cancer of unknown primary site, Pavlidis [/bib_ref] [bib_ref] Carcinomas of an unknown primary origin -diagnosis and treatment, Massard [/bib_ref] [bib_ref] Optimal therapeutic management of patients with distinct clinicopathological cancer of unknown primary..., Pavlidis [/bib_ref]. Patients with "favourable" CUP have a better prognosis. These cases should be treated with locoregional or systemic therapies, because the survival achieved will be longer and/or similar to their known homologues [bib_ref] Longterm survivors among patients with cancer of unknown primary, Pavlidis [/bib_ref]. Unfortunately, these patients only account for 22-23% of cases [bib_ref] Review of primary unknown cancer: cases referred to the National Cancer Center..., Matsubara [/bib_ref]. The remainder are categorised in the "unfavourable" CUP group, and their prospects depend on various prognostic factors. Their median survival ranges from 3 to 10 months. Clinical, laboratory, and histological prognostic factors have been documented. Poor clinical prognostic factors of particular note are: presenting with multiple metastases (especially at more than 3 sites); and liver, bone, or adrenal metastases [bib_ref] Carcinoma of unknown primary: retrospective study of 437 patients treated at Salah..., Fehri [/bib_ref] [bib_ref] Survival in cancer of unknown primary site: population-based analysis by site and..., Hemminki [/bib_ref]. Single sites confer a better prognosis, as do lymph node metastases with no visceral involvement [bib_ref] Sitespecific survival rates for cancer of unknown primary according to location of..., Hemminki [/bib_ref]. If only lymph nodes are affected, patients with just the cervical, axillary, and/or inguinal lymph nodes involved have a better prognosis than those with lymph node metastases in pelvic or abdominal locations. Other factors that worsen the prognosis are impaired performance status and previous weight loss [bib_ref] Evaluation of prognosis for carcinoma of unknown origin in elderly patients, Lu [/bib_ref] [bib_ref] Cancer of unknown primary in adolescents and young adults: clinicopathological features, prognostic..., Raghav [/bib_ref]. As far as laboratory tests are concerned, common poor prognostic factors are mainly increased lactate dehydrogenase (LDH) and hypoalbuminemia, probably related to weight loss [bib_ref] Evaluation of prognosis for carcinoma of unknown origin in elderly patients, Lu [/bib_ref] [bib_ref] Cancer of unknown primary in adolescents and young adults: clinicopathological features, prognostic..., Raghav [/bib_ref]. In terms of haematological findings, leucocytosis and anaemia also constitute independent poor prognostic factors [bib_ref] Unfavorable cancers of unknown primaries: presentation and prognostic factors. A population-based 8-year..., Randen [/bib_ref]. It is possible that the "inflammation-based" Glasgow Prognostic Score, calculated from the neutrophil/lymphocyte ratio (NLR), may predict with more certainty how a particular case will behave [bib_ref] Inflammation as a validated prognostic determinant in carcinoma of unknown primary site, Mohamed [/bib_ref]. Among histological factors, adenocarcinomas and undifferentiated tumours have a worse prognosis (3.5% 3-year survival) than squamous cell carcinomas (41.6% 3-year survival) [bib_ref] Identification and survival outcomes of a cohort of patients with cancer of..., Kim [/bib_ref]. Petrakis et al. described a prognostic algorithm based on factors that, in their series, independently affected patient survival (Ioannina Score for CUP Outpatient Oncologic Prognostication, I-SCOOP). Those factors were: leucocytosis, CUP subset (visceral disease), and performance status [bib_ref] Prognostication in cancer of unknown primary (CUP): development of a prognostic algorithm..., Petrakis [/bib_ref]. Using advanced statistical methods, they constructed an algorithm that gave a 5-tier point score. This enabled patients to be categorised into three risk levels: low, intermediate, and high. Other algorithms have been published by various authors, but no consensus has ever been reached, probably because of the heterogeneous nature of the cases included in each series. ## Treating cancer of unknown primary Treatment strategies for CUP are quite challenging, because these malignancies represent an extremely heterogeneous group of metastatic tumours with, in general, a dismal prognosis. Nevertheless, some subsets of CUP patients, who may harbour chemosensitive and potentially curable tumours, have a favourable risk (about 20%) [bib_ref] Carcinomas of an unknown primary origin -diagnosis and treatment, Massard [/bib_ref]. Favourable-risk CUP can be identified on the basis of clinical and pathological features, so every effort should be made to identify such cases. To establish a rational approach to treatment in this scenario, two main groups can be identified: a) CUP in which Favourable cancers of unknown primary and specific therapy AFP alpha-fetoprotein, CK cytokeratin, CT chemotherapy, ER oestrogen receptors, hCG human chorionic gonadotropin, IHC immunohistochemistry, LND lymph node dissection, M1 metastasis, MRI magnetic resonance imaging, PET positron emission tomography, PR progesterone receptors, PSA prostate-specific antigen, RT radiotherapy a Breast cancer: females with adenocarcinoma and axillary lymphadenopathy should be treated as if they had stage II breast cancer b Ovarian cancer: females with peritoneal carcinomatosis should be treated as if they had stage III ovarian cancer, especially in the case of raised CA 12.5, known adenocarcinoma histology, and if gastrointestinal origin has been ruled out c Prostate cancer: males with blastic bone metastases and raised serum prostate-specific antigen should be treated as if they had metastatic prostate cancer d Colorectal cancer: patients whose clinical and pathological features are consistent with a primary colorectal tumour should be treated using the same protocols as for metastatic colorectal cancer, especially in the case of known adenocarcinoma histology and CK20+/CK7-or CDX2+ immunohistochemical staining e Tumours of the head and neck, and anogenital tumours: in patients with squamous cell carcinoma involving the cervical or inguinal lymph nodes only, locoregional approaches based on chemotherapy/radiotherapy strategies are warranted f Extragonadal germ cell tumours: young males with poorly differentiated mediastinal or retroperitoneal tumours should be treated as if they had extragonadal germ cell tumours the primary site of tumour origin is strongly suspected from the clinical and pathological features; and b) tumours for which no suspicion can be formulated regarding the origin of the primary tumour [bib_ref] Cancer of unknown primary site, Pavlidis [/bib_ref] [fig_ref] Figure 2: Summary of proposed management of cancer of unknown primary [/fig_ref]. In the first case, the treatment plan should be based on the same standard strategies established for tumours thought to be primaries [bib_ref] Cancer of unknown primary site, Pavlidis [/bib_ref] [bib_ref] Treatment for patients with unknown primary cancer and favorable prognostic factors, Hainsworth [/bib_ref]. As well as the subsets mentioned above, other cases of CUP inviting no suspicions as to primary origin may show a favourable prognosis. That is true of the following patient subsets: (a) Poorly differentiated malignancies: up to 60% of these cases are accounted for by lymphomas, which can be suspected on detection of widespread involvement of lymph node territories and organs, such as the liver, and especially the spleen. In these cases, it can be useful to conduct appropriate analysis, including a PET scan and repeated biopsies, if feasible, to guide the use of specific therapies [bib_ref] Treatment for patients with unknown primary cancer and favorable prognostic factors, Hainsworth [/bib_ref]. (b) Involvement of a single site: locoregional strategies, including surgery, is highly advisable. The use of PET is strongly recommended in this situation, provided not only that limited locoregional CUP is suspected, but also that treatment with curative intent is feasible [bib_ref] Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment..., Fizazi [/bib_ref]. (c) Low/intermediate/high-grade neuroendocrine tumours: these tumours represent a heterogeneous group of malignancies. Well-differentiated neuroendocrine tumours (low and intermediate grades) share similar approaches to diagnosis and treatment. Clinical syn-dromes may be displayed due to production of hormones or vasoactive substances. Low-grade tumours are often slow-growing, so managing them like welldifferentiated neuroendocrine tumours of the gastrointestinal tract is recommended. At advanced stages, the preferred approach is simple observation (asymptomatic patients) or symptomatic treatment with somatostatin analogues (octreotide). Intensive platinum-based chemotherapy seems unhelpful in this context [bib_ref] Neuroendocrine carcinoma of unknown primary site, Spigel [/bib_ref] ; however, sunitinib or everolimus therapy may be considered when a functioning pancreatic neuroendocrine tumour is suspected [bib_ref] Sunitinib malate for the treatment of pancreatic neuroendocrine tumors, Raymond [/bib_ref] [bib_ref] Everolimus for advanced pancreatic neuroendocrine tumors, Yao [/bib_ref]. On the other hand, poorly differentiated neuroendocrine tumours are always high-grade tumours (grade 3), with aggressive clinical behaviour and a poor prognosis. These tumours require rapid evaluation and therapy. They typically respond to chemotherapy, so they are treated like disseminated small cell lung cancer. The treatment of choice is chemotherapy cycles of cisplatin and etoposide. This provides overall response rates in the 70-80% range. Other more intensive regimens show a similar response rate but have greater toxicity [bib_ref] Neuroendocrine carcinoma of unknown primary site, Spigel [/bib_ref]. Although more consistent evidence is needed, retrospective studies have revealed that favourable-risk CUP patients show clinical behaviour and responses resembling those seen in patients with metastatic tumours of known primary origin [bib_ref] Carcinomas of an unknown primary site: a curable disease, Levy [/bib_ref]. The great majority of CUP patients are categorised in the poor-risk subset. Unfortunately, these patients share a rather dismal prognosis, with median overall survival of 8-12 months from diagnosis [bib_ref] Development and validation of a prognostic model to predict the length of..., Culine [/bib_ref]. Chemotherapy combinations studied in this context show no evidence of superiority using any regimen [bib_ref] Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site:..., Golfinopoulos [/bib_ref]. Most of the combinations tested have been based on platinum salts (cisplatin, carboplatin, and oxaliplatin) with other drugs (taxanes, gemcitabine, etoposide, irinotecan, etc.) [bib_ref] Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown..., Culine [/bib_ref] [bib_ref] Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: results..., Gross-Goupil [/bib_ref]. However, very modest outcomes have been documented with this approach. It provides symptom relief at best, with no clear overall impact on survival confirmed. Because of its high toxicity and relatively low efficacy in CUP, chemotherapy should always be used judiciously, once other potentially more effective options have been reasonably ruled out [fig_ref] Figure 2: Summary of proposed management of cancer of unknown primary [/fig_ref]. In the era of personalised medicine, efforts have also been made to confirm whether there may be a role for targeted therapies in CUP management. The modern gene expression profile assays on the market can identify the origin of CUP tissues in up to 80% of cases [bib_ref] Prospective gene signature study using microRNA to identify the tissue of origin..., Varadhachary [/bib_ref]. One method for elucidating the origin of a tissue is to select a therapy of proven effectiveness in a class of tumours, and/or to use that information to implement personalised therapies in each patient. This has not yet been tested in clinical trials, but a Phase III prospective trial is being conducted (GEFCAPI04, clinicaltrials.gov NCT01540058). As well as determining tissue origin based on tumour tissue samples, another promising strategy involves liquid biopsies that detect circulating tumour DNA in patients with CUP. In a recent study of 442 CUP patients, liquid biopsy detected a genomic alteration in 65.6% of cases. The most common mutations were in TP53, KRAS, and PIK3CA [bib_ref] Utility of genomic analysis in circulating tumor DNA from patients with carcinoma..., Kato [/bib_ref]. EGFR abnormalities, ERBB2 alterations, and BRAF V600E mutations were found in 5.9, 3.6, and 1.6% of cases, respectively. Changes in a mismatch repair (MMR) gene were also detected in 1.6% of cases, making immune checkpoint inhibitor therapy an option. A trial is currently in progress using pembrolizumab in patients with rare tumours, including CUP (clinicaltrials.gov NCT02721732). As well as MMR mutations, other promising biomarkers that may help with immunotherapy, such as tumour mutational burden, are being tested intensively and may play an important role in CUP treatment strategies [bib_ref] Tumor mutational burden as an independent predictor of response to immunotherapy in..., Goodman [/bib_ref]. # Conclusions Because of the biological features of CUP, the way in which it spreads, and its aggressive, chemoresistant nature in some cases, it is very important to diagnose it promptly and accurately. Attempts should be made to determine its extent and identify the tumour subtype to which it belongs, to enable use of a specific therapy that has a positive impact on the patient. However, identifying the origin of these tumours is not easy, especially because the same organ can give rise to different tumour types, and tumours with the same origin can vary in phenotypic profile from case to case. Moreover, the literature evidence is sometimes confusing or contradictory, because the diagnostic methods used are not always the same, and results may be interpreted in different ways. It is, therefore, important to have standardised protocols for diagnosis and interpretation of the results. On the other hand, it is important to obtain a good biopsy, ensuring adequate numbers of tumour cells, and to plan tissue use to obtain as much information as possible. The algorithm proposed by the Spanish Society of Pathology (SEAP) is shown in [fig_ref] Figure 3: SEAP diagnostic algorithm [/fig_ref]. The recommendation is to use a basic IHC panel based on the tumour's clinical and microscopic features, and a specific advanced IHC panel. A limited number of techniques should be performed with both panels, so that a suitable amount of tissue is preserved for using a molecular platform, if thought necessary. Molecular diagnostics and gene expression platforms are considered helpful when used to complement IHC testing, because the results which they provide can be compared against many databases, allowing more accurate diagnosis and specification of tumour origin. Sample material should be obtained by imaging or surgical techniques, preferably in the form of a core-needle, incisional or excisional biopsy. In the pathology department, optimal use of the material should be ensured. This may mean separating fragments into different paraffin blocks to save material for future use, if necessary. Tests should then be done using a basic immunohistochemical panel, according to morphology, and an advanced immunohistochemical panel, based on information obtained from the basic panel, clinical features, and microscopy findings. The recommended number of stains is approximately 7. The aim is to preserve material for possible use of a molecular platform [fig] Figure 1: Advisable minimum IHC panel. IHC immunohistochemistry [/fig] [fig] Figure 2: Summary of proposed management of cancer of unknown primary [/fig] [fig] Figure 3: SEAP diagnostic algorithm. [/fig] [table] Table 1: Main phenotypic profiles of the most common tumoursUnderlining indicates markers recommended for their greater specificity and usefulness [/table] [table] Table 2: Main molecular diagnostics platforms for cancer of unknown primary [/table]	None	https://link.springer.com/content/pdf/10.1007/s12094-018-1899-z.pdf	None
cd4049edfc893deb6b1cf2bc372eb09d087d5aaf	pubmed	Aids to management of headache disorders in primary care (2nd edition)	Aids to management of headache disorders in primary care (2nd edition) The Aids to Management are a product of the Global Campaign against Headache, a worldwide programme of action conducted in official relations with the World Health Organization. Developed in partnership with the European Headache Federation, they update the first edition published 11 years ago. The common headache disorders (migraine, tension-type headache and medication-overuse headache) are major causes of ill health. They should be managed in primary care, firstly because their management is generally not difficult, and secondly because they are so common. These Aids to Management, with the European principles of management of headache disorders in primary care as the core of their content, combine educational materials with practical management aids. They are supplemented by translation protocols, to ensure that translations are unchanged in meaning from the English-language originals. The Aids to Management may be individually downloaded and, as is the case for all products of the Global Campaign against Headache, are available without restriction for non-commercial use. ## Preface Medical management of headache disorders does not, for the vast majority of people affected by them, require specialist skills or investigations. It can and should be based in primary care . Nonetheless, non-specialists throughout Europe may have received limited training in the diagnosis and treatment of headache . This publication combines educational materials with practical management aids. It is a product of the Global Campaign against Headache, a worldwide programme of action for the benefit of people with headache conducted by the UK-registered non-governmental organization Lifting The Burden (LTB) in official relations with the World Health Organization. Aids to management of headache disorders in primary care (2nd edition) updates the first edition, published 11 years ago. The content has been put together by a writing group of experts convened by LTB in collaboration with the European Headache Federation (EHF). It has undergone review by a wider consultation group of headache experts, including representatives of the member national societies of EHF, primary-care physicians from eight countries of Europe, and lay advocates from member organisations of the European Headache Alliance. While the focus is Europe, these aids may be useful to a much wider population. The European principles of management of headache disorders in primary care, laid out in 14 sections, are the core of the content. Each section is stand-alone and may be separately down-loaded (Management of migraine is in four separate parts), in order to act as a practical management aid as well as an educational resource. There is a set of additional practical management aids. An abbreviated version of the International Classification of Headache Disorders, 3rd edition, provides diagnostic criteria for the relatively few headache disorders relevant to primary care. A headache diary further assists diagnosis and a headache calendar supports follow-up. A measure of headache impact, the HALT-90 Index, can be employed in pre-treatment assessment of illness severity. Its derivative, the HALT-30 Index, may be more useful in follow-up, along with the HURT questionnaire, an outcome measure designed to guide follow-up. Any of seven information leaflets may be offered to patients to improve their understanding of their headache disorders and their management. Each of these may also be separately down-loaded. LTB and EHF offer these aids for use without restriction for non-commercial purposes, as is the case for all products of the Global Campaign against Headache. We hope for benefits for both physicians and patients. For the former, the aids have been designed expressly to assist primary-care physicians in delivering appropriate care more efficiently and more cost-effectively for a group of disorders that, collectively, are very common and very disabling. For the latter, there should be better outcomes for the many people with headache who need medical treatment. The materials will need translating into many languages. Among the supplementary materials are translation protocols developed by LTB to ensure that translations as far as possible are unchanged in meaning from the English-language originals. 2 European principles of management of headache disorders in primary care # Introduction Headache disorders are the second-highest cause of disability in Europe. Three of these disorders (migraine, tension-type headache and medication-overuse headache are important in primary care because they are common and responsible for almost all burden attributed to headache. Management of these belongs largely in primary care . A fourth headache disorder, cluster headache, is also important because, although not common, it is extremely painful. It is treatable in specialist care, but is very often misdiagnosed, and consequently not referred, over many years. Also requiring specialist management and therefore important to recognise are trigeminal neuralgia and persistent idiopathic facial pain. The management of migraine, TTH and MOH is in most cases not difficult. The purpose of these principles is to help primary-care physicians correctly diagnose these few disorders, manage them well when they can, recognise warnings of serious headache disorders and refer for specialist care whenever necessary. ## Development process ## Stakeholder involvement These principles were developed by Lifting The Burden (LTB) in collaboration with the European Headache Federation (EHF) as a product of the Global Campaign against Headache. ## The principles To facilitate use in routine practice, these principles are designed as and additionally set out in 14 stand-alone management aids (see below). For this reason, there is deliberate repetition of some content between them. They are likely to be most useful if read through at least once in their entirety, then used for reference. The principles are in three parts: Guides to diagnosis (some elements of these will need to be assimilated into routine practice, whereas others can serve as check lists and aide-mémoires). Headache as a presenting complaint (Additional file 1) Typical features of the headache disorders relevant to primary care (Additional file 2) Diagnosis of headache disorders (Additional fileGuides to management (these are information sources to be referred to once the diagnosis has been made; they include guidance on information to patients (Additional file 5)). General aspects of headache management (Additional file 4) Advice to patients (Additional file 5) Management of migraine (Additional files 6, 7, 8 and 9) a) Acute or symptomatic management of episodic migraine (Additional file 7) b) Prophylactic management of episodic migraine (Additional file 8) c) Management of chronic migraine (Additional file 9) Management of tension-type headache (Additional file 10) Management of cluster headache (Additional file 11) Management of medication-overuse headache (Additional file 12) Management of trigeminal neuralgia and persistent idiopathic facial pain (Additional file [bib_ref] The Global Campaign, World Health Organization and Lifting The Burden: collaboration in..., Steiner [/bib_ref] criteria for headache disorders in primary care: The International Classification of Headache Disorders, 3rd edition (ICHD-3)abbreviated form (also, Additional file 15)). ▪ Primary headache disorders include migraine, tension-type headache (TTH) and cluster headache, all of which are important in primary care . ▪ Secondary headache disorders have another causative disorder underlying them; therefore, the headache occurs in close temporal relation to the other disorder, and/or worsens or improves in parallel with worsening or improvement of that disorder. These associations are keys to their diagnosis. Secondary headache disorders include medication-overuse headache (MOH), also important in primary care . ▪ Painful cranial neuropathies and other facial pains include two disorders, trigeminal neuralgia and persistent idiopathic facial pain, that need to be recognised in primary care. A patient may have more than one of these disorders concomitantly. ## Which headaches should be managed where? Four headache disorders are of particular importance in primary care . All have a neurobiological basis. They are variably painful and disabling, but all may cause lost productivity and impair quality of life. Collectively they are the second highest cause of disability worldwide, and therefore very costly. ▪ Migraine, TTH and MOH can and should, almost always, be managed well in primary care. ▪ Specific advice on each of these is given below (also, Additional files . ▪ The exception is chronic migraine. This uncommon type should be recognised in primary care, but it is difficult to treat and likely to require specialist management. ▪ Specific advice on this is given below (also, Additional file 9). ▪ Cluster headache should be diagnosed in primary care because it is easily recognisable, but referred for specialist management. ▪ Specific advice on this is given below (also, Additional file 11). ▪ Among painful cranial neuropathies and other facial pains are trigeminal neuralgia and persistent idiopathic facial pain. These should be recognised when present, but require specialist management. ▪ Specific advice on each of these is also given below (also, Additional file 13). ▪ Any headache not responding satisfactorily to management in primary care should also be referred for specialist management. ▪ Of the large number of other secondary headache disorders, some are serious. Overall these account for <1% of patients presenting with headache, but they must be recognised. ▪ Advice on these is provided under 2.4.3 Diagnosis of headache disorders (also, Additional file 3). More general advice on indications for referral to specialist management is set out under 2.6.1 Headache management in primary care: When to refer (also, Additional file 14). ## Typical features of the headache disorders relevant to primary care This guide can be separately downloaded (Additional file 2). The distinguishing features of the important primary headache disorders are summarised in [fig_ref] Table 2: Summary of features distinguishing the important primary headache disorders [/fig_ref]. ## Migraine Migraine is typically a moderate-to-severe headache accompanied by nausea, vomiting and sensitivity to light and/or noise. It is more prevalent among women than among men. Migraine is usually episodic, occurring in attacks lasting hours to a few days. The two principal types are migraine without aura and the less common migraine with aura. One patient may have both types. There is also an uncommon chronic type. The headache disorders of particular importance in primary care - Usually episodic, occurring in 15-25% of the general population, in women more than men in a ratio of up to 3:1; - A chronic type is recognised, with headache occurring on more days than not Tension-type headache - Usually episodic, affecting most people from time to time but, in at least 10%, recurring frequently; - In up to 3% of adults and some children it is chronic, occurring on more days than not Cluster headache - Extremely intense and frequently recurring but short-lasting headache attacks, affecting up to 3 in 1000 men and up to 1 in 2000 women ## Medication-overuse headache - A secondary headache, but occurring only as a complication of a pre-existing headache disorder, usually migraine or tension-type headache, present on most days (≥15 days/month) and affecting 1-2% of adults, women more than men, and about 0.5% of children and adolescents Migraine without aura Adults with this disorder describe: ▪ recurrent episodic moderate or severe headaches which, typically but not always: ▪ are unilateral and/or pulsating; ▪ last (when untreated) from 4 h to 3 days; ▪ are associated with: ▪ nausea and/or vomiting; ▪ photophobia, phonophobia and sometimes osmophobia; ▪ are aggravated by routine physical activity, and disabling; ▪ and during which they limit their activity and prefer dark and quiet; ▪ freedom from these symptoms between attacks. In children: ▪ attacks may be shorter-lasting; ▪ headache is more often bilateral and less often pulsating; ▪ gastrointestinal disturbance is often more prominent. ## Migraine with aura This type affects about one third of people with migraine, although only a minority of these experience aura symptoms with every attack. It is characterised by: ▪ aura preceding or less commonly accompanying headache and consisting of one or more neurological symptoms (see [fig_ref] Table 3: Symptoms of aura [/fig_ref] ▪ headache that is similar to migraine without aura, or may be rather featureless. Typical aura without headache may occur in patients with a past history of migraine with aura. ## Chronic migraine This highly disabling migraine type develops, in a small minority of patients, from episodic migraine. Over time, attacks become more frequent, with loss of clear periodicity. Simultaneously, the specific characteristics of migraine become less pronounced. Chronic migraine is not simply more frequent migraine. It is essentially characterised by: ▪ headache occurring on ≥15 days/month for at least 3 months which: ▪ on ≥8 days/month meets diagnostic criteria for migraine (or responds to migraine-specific drug treatment); and often complicated by: ▪ depression and/or anxiety; ▪ low back and/or neck pain; ▪ medication overuse. Transformation of episodic migraine to a chronic headache disorder is very often causally associated with medication overuse: ▪ the correct diagnosis is then medication-overuse headache (MOH); ▪ chronic migraine and MOH are not mutually exclusive but, when medication is being overused, it may be that only MOH and not chronic migraine is present. ## Tension-type headache (tth) This disorder is typically a mild-to-moderate headache of highly variable frequency and duration, without associated symptoms or the specific features of migraine. It tends to be more common in women than in men. It has three types. Infrequent episodic TTH, occurring less than once a month, is not medically important. The others are frequent episodic TTH and chronic TTH. Frequent episodic tension-type headache ▪ occurs in attack-like episodes on 1-14 days/month, each lasting hours to a few days; ▪ can be unilateral but is more often generalised; ▪ is typically described as pressure or tightness like a vice or tight band around the head, often spreading to the neck; ▪ lacks the associated symptom complex of migraine. Chronic tension-type headache This type has features similar to those of frequent episodic TTH but: ▪ occurs by definition on ≥15 days/month for >3 months, and may be daily and unremitting; ▪ may be associated with mild nausea. ## Cluster headache This disorder is characterised by frequently recurring, localised, short-lasting but extremely severe headache accompanied by a set of very recognisable autonomic symptoms. It affects men three times as commonly as women. It should never be missed. It demands accelerated specialist referral, investigation and treatment. Cluster headache occurs in attacks, which very typically: ▪ are characterised by headache of excruciating intensity, which is ▪ strictly unilateral and localised around the eye or over the temple; ▪ accompanied by highly characteristic and strictly ipsilateral autonomic features, including any or all of: ▪ red and watering eye; ▪ running or blocked nostril; ▪ ptosis; ▪ associated with marked agitation (the patient, unable to stay in bed, paces the room, even going outdoors); ▪ occur once or more daily, very often at night (causing awakening); ▪ last 15-180 min (commonly 30-60). Cluster headache has two subtypes, episodic and (less common) chronic. ## Episodic cluster headache ▪ occurs in bouts (clusters) of recurring attacks, typically once or twice a year, which: ▪ are of 6-12 weeks' duration (but may be longer); ▪ then remit until the next cluster, at least 3 months later. Chronic cluster headache ▪ persists, still as recurring attacks but without remissions, or with remissions of <3 months; ▪ may develop from and/or revert to episodic cluster headache. ## Medication-overuse headache (moh) This is one of the syndromes characterised by headache occurring on ≥15 days/month. It is often daily, but variable in site, intensity and character. It greatly impairs quality of life. It is more common in women. Medication-overuse headache: ▪ occurs daily or near-daily (by definition on ≥15 days/month); ▪ is presentand often at its worstearly in the morning; ▪ is causally associated with regular use, over >3 months, of: ▪ non-opioid analgesics on ≥15 days/month, and/or ▪ opioids, ergots or triptans, or any combination of these, on ≥10 days/month. MOH is an aggravation of a prior headache (usually migraine or tension-type headache) by chronic overuse of medication taken to treat headache or other pain. A history can usually be elicited of increasingly frequent and difficult-to-treat headache episodes, with increasing medication use, over months to many years. All acute headache medications may have this effect. Frequency, regularity and duration of intake are important determinants of risk. MOH tends to worsen initially when attempts are made to reduce consumption of the overused medication(s), but in most cases improves within 2 months after overuse is stopped. 2.4.2.5 Important causes of facial pain Many causes of facial pain may bring patients to GPs. Two in particular, although not common, require recognition. ## Trigeminal neuralgia (tn) This disorder presents as recurrent, unilateral, brief but severe, electric-shock-like pains in the distribution of the trigeminal nerve, abrupt in onset and termination and often triggered by innocuous stimuli. ▪ Trigeminal neuralgia (TN) affects women twice as commonly as men, and mostly those above 50 years of age (but may occur in younger people). It has no other known risk factors. ▪ It is often associated with neurovascular compression of the trigeminal nerve close to its point of entry to the brainstem (classical trigeminal neuralgia). ▪ TN is one of the most painful disorders, demanding accelerated specialist referral, investigation and treatment. ▪ MRI of the brain (including brainstem) is essential. ▪ This may demonstrate neurovascular compression, but is required in any case to exclude secondary causes that give rise to pains indistinguishable from classical TN. These occur more often in younger people. ## Classical trigeminal neuralgia: ▪ occurs in bouts of repeated, stabbing or electricshock-like pains in the distribution of one or more divisions of the trigeminal nerve (usually the 2nd and/ or 3rd), which are: ▪ excruciating; ▪ of sudden onset; ▪ highly characteristically triggered by sensory stimuli to the affected side of the face (touching, washing, applying make-up) or by talking, eating, chewing, drinking or smoking; ▪ short-lasting (from less than a second up to 2 min); ▪ strictly unilateral, and not switching side between bouts; ▪ often serial, with up to hundreds of pain paroxysms during 1 day; ▪ may also feature a constant aching pain between attacks, in the affected area, of moderate intensity. Bouts may remit completely for months or years in an unpredictable pattern. Otherwise, treatment may require surgical decompression. ## Secondary trigeminal neuralgia ▪ has characteristics similar to classical trigeminal neuralgia, but is secondary to another disorder (usually cerebellopontine angle tumour, AV-malformation or multiple sclerosis). ## Persistent idiopathic facial pain (pifp) Previously termed "atypical facial pain", this disorder presents as variable but persistent, poorly localized facial and/or oral pain. It is more common in women. Persistent idiopathic facial pain (PIFP): ▪ is dull, aching or nagging; ▪ recurs daily for >2 h and persists over >3 months; ▪ is unassociated with neurological deficit; ▪ is aggravated by stress. PIFP is associated with high levels of psychiatric comorbidity and psychosocial disability, and difficult to manage. It usually requires specialist referral. However: ▪ patients are often referred for exclusion of sinus and dental problems, then returned untreated to primary care; ▪ referral to a specialist clinic with a pain management programme is preferable. Temporomandibular disorder (TMD) is in the differential diagnosis of PIFP. This is itself a very complex problem: ▪ the pain associated with TMD is usually most prominent in the pre-auricular areas of the face, masseter muscles and/or temporal regions; ▪ there is significant overlap between TMD and tension-type headache and jaw, dental and bite disorders. ## Diagnosis of headache disorders This guide can be separately downloaded (Additional file 3). The universally accepted basis for the diagnosis of any headache is the International Classification of Headache Disorders, an abbreviated version of which is included in these aids (3.2 Diagnostic criteria for headache disorders in primary care: The International Classification of Headache Disorders, 3rd edition (ICHD-3)abbreviated form (also, Additional file 15)). In all health-care settings, diagnostic practice should employ ICHD terminology. 1 2.4.3.1 Differential diagnosis of the headache disorders relevant to primary care Diagnosis of episodic migraine or episodic tension-type headache requires multiple attacks; neither diagnosis should be made after a first attack without exclusion of other disorders. ▪ Each of the primary headaches is in the differential diagnosis of each of the others. ▪ Medication-overuse headache is in the differential diagnosis of chronic migraine or chronic tension-type headache. ▪ The distinguishing features of these are described above (2.4.2 Typical features of the headache disorders relevant to primary care) (also in Additional file 2). ▪ Otherwise, the differential diagnosis potentially includes a small number of serious secondary headaches that are important to recognise (see Warning features in the history or on examination, below). ## Taking a diagnostic history The history is all-important in the diagnosis of the primary headache disorders and of medication-overuse headache. There are no useful diagnostic tests. [fig_ref] Table 4: Diagnostic questions to ask in the history How many different headaches types... [/fig_ref] indicates diagnostic questions to elicit any that may be present of the features described above (2.4.2 Typical features of the headache disorders relevant to primary care) (also in Additional file 2). ## Diagnostic diary A diary kept over a few weeks can be a very helpful diagnostic aid, clarifying the pattern and frequency of headaches and associated symptoms as well as medication use or overuse. An example is included here, among the management aids (3.3.2 Diary and calendar for use in primary care (also, Additional files 16)). ## Warning features in the history The history should also elicit any warning features of a serious secondary headache disorder: ▪ any new headache, or a significant change in headache characteristics, should provoke a new diagnostic enquiry; ▪ very frequent headache should always lead to detailed enquiry into medication use, since overuse is a likely cause; ▪ in addition, there are a number of specific warning features ("red flags") that may be elicited [fig_ref] Table 5: Specific warning features [/fig_ref]. ## Physical examination of headache patients Migraine, tension-type headache, cluster headache and medication-overuse headache are diagnosed solely on history. Signs are present in cluster headache patients when seen during attacks (red and/or watering eye, running or blocked nostril and/or ptosis ipsilateral to the pain). ▪ Blood pressure measurement in all cases is good practice. ▪ Physical examination is mandatory when the history is suggestive of secondary headache, and then may elicit warning signs. Investigation of headache patients ▪ Routine blood tests as a screen for general health may be worthwhile in primary care. ▪ Special investigations, including neuroimaging, are not indicated unless the history or examination suggests headache may be secondary to another condition. ## Diagnostic caveats The following tend to be greatly overdiagnosed: ▪ cervicogenic headache (headache caused by a disorder of the cervical spine and its component bony, disc and/or soft tissue elements, usually but not invariably accompanied by neck pain); ▪ headache attributed to arterial hypertension (chronic arterial hypertension below 180/110 mmHg does not appear to cause headache); ▪ headache attributed to refractive error (rare in adults, although some evidence exists for it in children); ▪ headache attributed to "sinusitis" (a misdiagnosis commonly applied to migraine); ▪ trigeminal neuralgia (recurrent unilateral brief electric shock-like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve and triggered by innocuous stimuli); ▪ occipital neuralgia (paroxysmal shooting or stabbing pain in the posterior part of the scalp, in the distributions of greater, lesser and/or third occipital nerves). ## Guides to management 2.5.1 general aspects of headache management This guide can be separately downloaded (Additional file 4). The purpose of these principles of management is to provide guidance, while demonstrating that headache management in most cases is not difficult. The following are generally important for all headache disorders managed in primary care. 2.5.1.1 Educating and reassuring patients Many people with recurrent headache wrongly fear underlying disease, so education and appropriate reassurance should never be omitted. Good treatment of patients with any headache disorder therefore begins with explanations of their disorder and the purpose and means of management. ▪ Explanation is a crucial element of preventative management in patients with migraine or frequent episodic tension-type headache, who are at particular risk of escalating medication consumption. Advice on further information that may be requested by patients is provided below under 2.5.2 Advice to patients (also, Additional file 5). A series of patient information leaflets included here, in Section 4, provide basic explanations of migraine (also, Additional file 21), tension-type headache (also, Additional file 22), cluster headache (also, Additional file 23), medication-overuse headache (also, Additional file 24), trigeminal neuralgia (also, Additional file 26) and persistent idiopathic facial pain (also, Additional file 27), and their management. 2.5.1.2 Acknowledging and assessing impact Assessment of impact at start of treatment establishes need and priority for treatment and measures the baseline for later evaluation of treatment. In addition to symptom-burden, impact of recurrent headache particularly includes disability. The HALT-90 Index developed by Lifting The Burden is an easy-to-use instrument for assessing burden in terms of lost productive time. It is included here, among the management aids (3.4.2 The Headache-Attributed Lost Time (HALT) Indices (also, Additional file 18)). In addition, recurrent disabling headache: ▪ may lead to lifestyle compromise, either in response to attacks or in a bid to avoid them (in this way, episodic headache can have continuous impact); ▪ has impact not only on the person with it but also on other people (family, work colleagues and employer). ## Realistic aims of management Primary headache disorders cannot be cured, but in most cases can be effectively managed. This means controlled by reductions in attack frequency and severity to minimise impact. ## Causes and triggers Many patients seek help in identifying triggers, but the importance of these should not be over-emphasised. ▪ Correctly identified triggers offer the possibility of avoidance (perhaps by life-style change) as a sometimes major contribution to management. ▪ When triggers are relevant to individual patients, they are usually self-evident. ▪ Triggers may be less readily identified when they are cumulative in their effect, jointly lowering the threshold above which attacks are initiated. ▪ Even when they are correctly identified, triggers are not always avoidable. 2.5.1.5 Follow-up Every patient to whom treatment is offered, or whose treatment is changed, requires follow-up in order to ensure that optimum treatment has been established. ); ▪ a headache calendar (see below). ▪ Persistent management failure is an indication for specialist referral. ## Diaries and calendars The principal distinction between these is in the amount of information collected. An example of each is provided here, among the management aids (see 3.3 Headache diary and calendar to aid diagnosis and follow-up in primary care (also, Additional file 16 and 17)). Diaries capture more descriptive features of symptoms (headache intensity and character, associated symptoms), perhaps using free text. ▪ Diaries, used particularly as an aid to diagnosis, are useful for: ▪ recording symptoms and temporal patterns that contribute to correct diagnosis; ▪ recording acute medication use or overuse prior to diagnosis; ▪ reporting lost productive time as part of pretreatment assessment. Calendars essentially note the temporal occurrence of headache episodes and related events such as menstruation and medication intake. ▪ revealing associations with the menstrual cycle and possibly other triggers; ▪ monitoring acute medication use or overuse during follow-up; ▪ encouraging adherence to prophylactic medication; ▪ recording treatment effect on headache frequency, and charting outcomes. ## Advice to patients This guide can be separately downloaded (Additional file 5). Patients with headache disorders commonly request information. Many find or have found misleading information on the internet. In addition to the advice below, a series of patient information leaflets developed by Lifting The Burden are provided here, in Section 4 and in the Additional files (see below). ▪ Feverfew preparations on sale everywhere are highly variable in content and their toxicity is not well understood. ▪ Butterbur has some efficacy in migraine, but preparations on sale are variable in content and not all are free of liver toxins. ▪ Nutraceuticals are mostly not recommended. The following have some evidence for efficacy in migraine, and may be tried where preparations of pharmaceutical quality are available: ▪ coenzyme Q10 (CoQ10) (100 mg three times daily); ▪ magnesium (as citrate, starting at 100 mg three times daily to avoid diarrhoea, and increasing to 200 mg three times daily); ▪ riboflavin (200 mg twice daily). ▪ Homoeopathy is of unproven value. There is no arguable case for over-the-counter sales of homoeopathic remedies. ▪ Reflexology has no scientific basis. ▪ Cold packs or menthol gel applied to the head and/ or neck are found by some people to relieve pain or discomfort while being harmless and inexpensive. ▪ Dental treatment, including splints and bite-raising appliances, is of unproven value in treating headache and should be discouraged for this purpose. ▪ Spectacles should be professionally prescribed and worn when needed, but refractive errors are rarely a cause of troublesome headache. ▪ For the same reason, accommodation training, sometimes offered by optometrists, is not an accepted treatment for headache or likely to be beneficial. ▪ Surgical procedures. No surgical procedures produce benefit in migraine or tension-type headache. Hysterectomy has no place in migraine management. ## Advice on hormonal contraception and hrt With one important exception, migraine is not a contraindication to hormonal contraception or hormone replacement therapy (HRT). ▪ Migraine with aura and the ethinylestradiol component of combined hormonal contraceptives (CHCs) are independent risk factors for stroke in young women. ▪ Every woman seeking hormonal contraception in primary care should be screened for migraine with aura and, if positive, offered progestogen-only contraception or non-hormonal alternatives. ▪ Otherwise, headache is often a side-effect of CHCs (pills, patches or vaginal rings), and many women report onset or aggravation of migraine after starting them. ▪ Such symptoms usually resolve with continued use; if not, alternatives to CHCs should be offered. ▪ Other women, particularly those with menstruallyrelated migraine (without aura), report improvement, especially when CHCs are taken continuously without a week's break. The following advice on hormonal contraception may be given to patients with migraine: ▪ CHCs increase risk of stroke in young women with migraine with aura, who should therefore use alternatives; ▪ a change from migraine without aura to migraine with aura after starting CHCs is a clear signal to stop immediately; ▪ progestogen-only contraception is acceptable with any type or subtype of migraine. The following advice on hormone replacement therapy (HRT) may be given to patients with migraine: ▪ HRT is not contraindicated in migraine with or without aura; ▪ decisions about commencing or continuing HRT should be made according to generally applicable criteria. ## Management of migraine This guide can be separately downloaded (Additional file 6). Migraine is typically a moderate-to-severe headache accompanied by nausea, vomiting and sensitivity to light and/or noise. It is commonly disabling. It is usually episodic, but there is an uncommon chronic form. ## Principles of management ▪ Good treatment of migraine begins with education of patients, explaining their disorder and the purpose and means of management. ▪ Impact of migraine should be assessed prior to planning treatment: ▪ the HALT-90 Index, assessing burden in terms of lost productive time, is included here, among the management aids (see 3.4.2 The Headache-Attributed Lost Time (HALT) Indices (also, Additional file 18)). ▪ Triggers and predisposing factors should not be overemphasised but should nonetheless be considered early in management (with life-style modification when called for). ▪ Almost all patients with migraine will require drug therapy for acute attacks, but not necessarily prescription drugs (see 2.5.4 Acute or symptomatic management of episodic migraine (also, Additional file 7)). ▪ Any patient who is not well controlled with acute therapy alone and whose quality of life is impaired by migraine, whether adult or child, should be offered prophylaxis in addition (see 2.5.5 Prophylactic management of episodic migraine (also, Additional file 8)). ▪ Every patient to whom treatment is offered, or whose treatment is changed, requires follow-up to ensure that optimum treatment has been established. ## Education of patients a patient information leaflet on migraine and its management, developed by Lifting The Burden, is provided here in Section 4 (also, Additional file 21). Key points of information are: ▪ migraine is a common disorder which, while it may be disabling, is benign; ▪ it is often familial, and probably genetically inherited; ▪ it cannot be cured but can be successfully treated; ▪ trigger or predisposing factors are common in migraine, and should be identified and avoided or modified when possible, but not all can be; ▪ a headache calendar helps good management by recording over time: ▪ the symptoms and pattern of attacks (eg, menstrual relationship); ▪ medication use (thus identifying overuse); ▪ regular activity (eg, sport or exercise 2-3 times per week) may reduce intensity and frequency of migraine attacks. Hormonal contraception and HRT Many women report onset or aggravation of migraine after starting combined hormonal contraceptives (CHCs). Others, particularly those with menstrually-related migraine, report improvement, especially when CHCs are taken continuously without a week's break. The following advice on hormonal contraception may be given: ▪ migraine with aura and the ethinylestradiol component of CHCs are independent risk factors for stroke in women, especially in those under 50 years; ▪ alternatives to CHCs are therefore very strongly recommended for women with migraine with aura; ▪ a change from migraine without aura to migraine with aura after starting CHCs is a clear signal to stop immediately; ▪ progestogen-only contraception is acceptable with any type or subtype of migraine. The following advice on hormone replacement therapy (HRT) may be given: ▪ HRT is not contraindicated in migraine with or without aura; ▪ decisions about commencing or continuing HRT should be made according to generally applicable criteria. A patient information leaflet on female hormones and headache, developed by Lifting The Burden, is provided here in Section 4 (also, Additional file 25). ## Follow-up ▪ Use of a calendar is recommended to encourage adherence with prophylactic medication and record treatment effect. An example of a simple calendar is included here among the management aids (see 3.3 Headache diary and calendar to aid diagnosis and follow-up in primary care (also, Additional file 17)). ). ▪ Persistent management failure is an indication for specialist referral. ## Acute or symptomatic management of episodic migraine This guide can be separately downloaded (Additional file 7). 2.5.4.1 General principles ▪ All adults with episodic migraine should have access to acute medication. ▪ Children with short-lasting attacks may respond well to bed-rest without medical treatment. ▪ In adults and children, regular use of acute medication at high frequency (on >2 days/week) risks the development of medication-overuse headache. ▪ Many patients seek help in identifying triggers (see below). The importance of trigger factors in migraine is nonetheless often overemphasised. ## Trigger and predisposing factors ▪ Correctly identified triggers offer the possibility of avoidance (perhaps by life-style change) as a sometimes major contribution to management. ▪ When triggers are relevant to individual patients, they are usually self-evident. ▪ Cyclical hormonal fluctuations may be an obvious factor in menstruating women. ▪ Irregular lifestyle, poor sleep pattern and "stress" are important predisposing factors in anybody with migraine. Missing meals is a potent trigger factor. ▪ Triggers may be less readily identified when they are cumulative in their effect, jointly lowering the threshold above which attacks are initiated. ▪ Even when they are correctly identified, triggers are not always avoidable. ▪ Contrary to popular belief, there is no "migraine diet". The only dietary triggers with good evidential support are certain alcoholic drinks (especially red wine). ## Drug intervention All patients should climb a treatment ladder (stepped management), usually treating three attacks at each step before proceeding to the next. This strategy, when followed correctly, reliably achieves the most effective and cost-effective individualised care. Step one: symptomatic therapy ▪ non-opioid analgesic ▪ plus, when needed, an antiemetic. Recommended drugs and doses are shown in [fig_ref] Table 7: Recommended drugs and doses for acute migraine therapy, step one [/fig_ref]. ## Drugs to avoid ▪ Opioids (including codeine and dihydrocodeine) are ineffective for migraine, associated with multiple adverse effects, potentially addictive and commonly implicated in medication-overuse headache; ▪ Barbiturates have no place in the treatment of migraine. ## Principles of step one ▪ Use soluble analgesics (or mouth-dispersible formulations with water) when available. ▪ Take early in the attack. ▪ Use adequate dosage (see [fig_ref] Table 7: Recommended drugs and doses for acute migraine therapy, step one [/fig_ref] : in most cases, adequate doses require more than a single tablet). ▪ A prokinetic antiemetic counters gastric stasis, an early feature of migraine, which impairs bioavailability of oral medication. ▪ Rectal formulations (where available) may be preferable in the presence of vomiting. ▪ Proceed to step two after three attacks without success (local guidelines may recommend trying more than one analgesic in step one before proceeding to step two). Step two: specific therapy ▪ Where available, and unless contraindicated, specific therapy [fig_ref] Table 8: Specific anti-migraine drugs, formulations and doses for step two [/fig_ref] should be offered to all patients failing step one. ▪ Availability of drugs varies from country to country. ## Drugs to avoid ▪ Ergotamine is a poor substitute for triptans: it has very low and unpredictable bioavailability, which impairs its efficacy, and poor tolerability. It is no longer recommended for routine use. ## Principles of step two ▪ Triptans are more effective when taken while headache is still mild (but not during aura) (this instruction should be given only to patients who can reliably distinguish migraine from tension-type headache). ▪ The initial dose of all oral triptans (except eletriptan in some cases) is one tablet. ▪ A second dose for non-response is not recommended by most triptan manufacturers but, taken not less than 2 h after the first, may nonetheless be effective in some cases. ▪ Triptans should not be used regularly on ≥10 days/ month to avoid the risk of medication-overuse headache. ▪ Triptans differ slightly, but there are large and unpredictable individual variations in responses to them: ▪ one may work where another has not; ▪ patients are best served if they can try several, in different formulations, and choose between them. ▪ When nausea is present, domperidone 10 mg may be added. ▪ When vomiting is present, zolmitriptan nasal spray (absorbed through the nasal mucosa) or sumatriptan subcutaneous injection may be preferred. ▪ Efficacy of sumatriptan may be increased by combination with naproxen 500-1000 mg (there are no data on combinations of other triptans and NSAIDs). ▪ When all other triptans are ineffective, sumatriptan by subcutaneous injection 6 mg should be considered. ## Treatment of relapse ▪ A repeat dose of a triptan is usually effective. ▪ A further relapse may occur: ▪ in a minority of patients, this happens repeatedly, a major management problem with high risk of developing medication-overuse headache; ▪ a different triptan should be tried in future attacks; ▪ concomitant use of a triptan and naproxen may reduce susceptibility to relapse. ## Contraindications and special precautions in step two ▪ Triptans should not be taken during aura of migraine with aura, but at the onset of headache. ▪ All triptans should be avoided by people with: ▪ uncontrolled hypertension (one reason for measuring blood pressure); ▪ coronary heart disease, cerebrovascular disease or peripheral vascular disease; ▪ multiple risk factors for coronary or cerebrovascular disease; ▪ In the elderly, all of these are more common, and triptans should therefore be used with greater caution. ▪ In pregnancy: limited safety data are available only for sumatriptan, which should be used with caution and only under specialist supervision. ▪ In addition, there are specific precautions attached to some triptans (see pharmacopoeia). Step two for children and adolescents ▪ Failure of step one in children is an indication for specialist referral. ▪ No specific anti-migraine drug has been shown to have efficacy in children (under 12 years old). ▪ For adolescents (12-17 years), the following have efficacy and are approved: ▪ sumatriptan nasal spray 10 mg; ▪ zolmitriptan nasal spray 2.5 mg and/or 5 mg (in some countries). ## Follow-up Every patient to whom treatment is offered, or whose treatment is changed, requires follow-up to ensure that optimum treatment has been established. ▪ Use of a calendar is recommended to monitor acute medication use or overuse. An example of a simple calendar is included here among the management aids (see 3.3 Headache diary and calendar to aid diagnosis and follow-up in primary care (also, Additional file 17)). ). ▪ Failure of acute therapy may be an indication for prophylaxis (see below). ## Prophylactic management of episodic migraine This guide can be separately downloaded (Additional file 8). 2.5.5.1 General principle Any patient with migraine who is not well controlled with acute therapy alone, whether adult or child, should be offered prophylaxis in addition to acute medication. ## Indications for prophylaxis Prophylactic therapy should be added when migraine impairs quality of life, and ▪ attacks cause disability on two or more days per month, and ▪ acute therapy has been optimised but does not prevent this, or is poorly tolerated, or ▪ there is a risk of over-frequent use of acute therapy, even when it is effective; and ▪ the patient is willing to take daily medication. Frequent absences from school because of migraine are an additional indication for prophylaxis in children (who should be referred for specialist assessment). ## Principles of prophylaxis ▪ A calendar should be kept by every patient on prophylaxis to assess efficacy and promote adherence. An example of a simple calendar is included here among the management aids (see 3.3 Headache diary and calendar to aid diagnosis and follow-up in primary care (also, Additional file 17)). ▪ Poor adherence is a major factor impairing efficacy of migraine prophylactics; once-daily dosing is associated with better adherence. ▪ The dose of any drug should start low in the suggested range and be increased in the absence of troublesome side-effects. ▪ Drugs that appear ineffective should not be discontinued too soon; 2-3 months may be the minimum to achieve and observe efficacy. ▪ Failure of one drug does not predict failure of others in a different class. ▪ Tapered withdrawal may be considered after 6 months of good control, and should be considered no later than after 1 year. ▪ Children requiring prophylactic medication should be referred for specialist assessment. ## Effective drugs for prophylaxis A range of drugs have proven efficacy [fig_ref] Table 9: Migraine prophylactic drugs with evidence of efficacy in adults [/fig_ref] , all with contraindications and side-effects (refer to pharmacopoeia). ▪ Availability and regulatory approval vary from country to country, and many are not specifically licensed for migraine prophylaxis. Use of drugs offlicence rests on individual clinical responsibility. ▪ Across the range, expected benefit is no greater than 50% fewer attacks in 50% of users after 3 months of treatment (with individual benefit varying between zero and [rarely] 100%). ▪ Once daily dosing (as opposed to more frequent) is associated with better adherence, an important determinant of efficacy. ## Other treatments patients may ask about ▪ onabotulinum toxin a (botox) . This is not effective in episodic migraine and is not recommended for this condition. ▪ Surgical procedures. There is no evidence to support any surgical procedure as a treatment for episodic migraine. ▪ In particular, migraine is not improved by closure of patent foramen ovale (PFO). This procedure should not be undertaken for migraine prophylaxis: it carries a small but relevant risk of serious adverse events including stroke, pericardial tamponade, atrial fibrillation and death. ▪ Acupuncture has differing forms, and is highly dependent on the skill of the therapist. There is limited evidence that acupuncture can be effective in reducing intensity and frequency of migraine attacks, but large clinical trials have failed to distinguish between acupuncture and sham procedures. Benefits experienced by some patients may be attributable to placebo effect. ▪ Devices. Many are on the market, some very costly and promoted with insupportable claims of efficacy. "Testimonials" can be attributed to placebo effect and should be disregarded. The only clear recommendation possible is that successful trial usage should precede any expensive purchase. ▪ A range of transcutaneous electrical nerve stimulators (TENS) and noninvasive neuromodulating devices for peripheral vagal nerve, supraorbital nerve and single-pulse transcranial magnetic stimulation are available, with evidence of efficacy in some people. ▪ Herbals are not recommended. Evidence of both efficacy and safety in prolonged use is poor. They may interfere with other medications. ▪ Feverfew preparations are highly variable in content, and not all of pharmaceutical quality. Their toxicity is not well understood. ▪ Butterbur has some efficacy and is approved for use in some countries, but preparations on sale are variable in content and not all of pharmaceutical quality (not guaranteed to be free of liver toxins). ▪ Nutraceuticals are mostly not recommended. The following have some evidence for efficacy, and may be tried where preparations of pharmaceutical quality are available: ▪ coenzyme Q10 (CoQ10) (100 mg three times daily); ▪ magnesium (as citrate, starting at 100 mg three times daily to avoid diarrhoea, and increasing to 200 mg three times daily); ▪ riboflavin (200 mg twice daily). ▪ Homoeopathy is of unproven value. There is no arguable case for over-the-counter sales of homoeopathic remedies. ## Prophylaxis in pregnancy ▪ This is better avoided, and rarely required since migraine often remits during pregnancy. ▪ Sodium valproate is absolutely contraindicated; topiramate and candesartan are contraindicated. ▪ Propranolol and amitriptyline have best evidence of safety, but specialist guidance is recommended. ▪ Riboflavin (vitamin B2), 200 mg twice daily, may be tried, but may not show efficacy for 3 months. 2.5.5.7 Follow-up Every patient to whom prophylactic treatment is offered, or whose treatment is changed, requires follow-up to ensure that optimum treatment has been established. ▪ Use of a calendar is recommended to encourage adherence with prophylactic medication and record treatment effect. An example of a simple calendar is included here among the management aids (see Headache diary and calendar to aid diagnosis and follow-up in primary care (also, Additional file 17)). ▪ The use of outcome measures is recommended to guide follow-up. The following are included here among the management aids: ▪ the HURT questionnaire was developed expressly for primary care (see 3. 2.5.5.8 When prophylaxis fails ▪ Failure may be due to subtherapeutic dosage (itself perhaps due to non-adherence) or insufficient duration of treatment. ▪ The following actions are recommended: ▪ review the diagnosis; ▪ review adherence; ▪ review other medication, especially for overuse. ▪ When prophylaxis still fails to have clear benefit, discontinue it. ▪ When all options fail, specialist referral is indicated. ## Management of chronic migraine This guide can be separately downloaded (Additional file 9). Chronic migraine develops in a small minority of people with episodic migraine. It is one of the syndromes characterised by headache on ≥15 days/month, but is not simply migraine that is more frequent: it is often complicated by medication overuse, depression, anxiety and low back and/or neck pain. Chronic migraine should be: ▪ suspected in any patient: ▪ with a history of migraine ▪ who reports (or records in a diary) headache on ≥15 days/month; ▪ diagnosed, in the absence of medication overuse, in patients with: ▪ headache on ≥15 days/month over the last 3 months, which ▪ on ≥8 days/month: ▪ fulfilled the diagnostic criteria for migraine, or ▪ responded to migraine-specific drug treatment. The presence of medication overuse in such patients complicates the diagnosis: ▪ medication-overuse headache (MOH) is another syndrome characterised by headache on ≥15 days/month; ▪ chronic migraine and MOH are not mutually exclusive but, even when the conditions above are met, only MOH and not chronic migraine may be present when medication is being overused; ▪ medication overuse, whether or not occurring with chronic migraine, must always be recognised and managed as a separate medical problem. Medication-overuse, and MOH, can often be successfully managed in primary care (see 2.5.9 Management of medication-overuse headache (also, Additional file 12)), but patients with chronic migraine should be referred for specialist care. 2.5.6.1 Principles of management Chronic migraine is difficult to treat. Management in specialist care includes: ▪ education of patients about chronicity and its causes and risk factors; ▪ recognition and management of medication overuse, when present; ▪ management of any comorbidities; ▪ use of preventative drugs [fig_ref] Table 10: Drugs used by specialists in chronic migraine prophylaxis Topiramate, 50 mg or... [/fig_ref] ; ▪ follow up, with both medical and psychological care. 2.5.6.2 Preventative drugs Those used in specialist care, with evidence of efficacy, are shown in [fig_ref] Table 10: Drugs used by specialists in chronic migraine prophylaxis Topiramate, 50 mg or... [/fig_ref]. ## Management of tension-type headache (tth) This guide can be separately downloaded (Additional file 10). Tension-type headache (TTH) is typically a mild-tomoderate headache of highly variable frequency and duration, without associated symptoms or the specific features of migraine. Two types of TTH are medically important: ▪ frequent episodic TTH, with headache attacks on 1-14 days/month on average; ▪ chronic TTH, one of the syndromes characterised by headache occurring on ≥15 days/month, either with highly-frequent attacks or, occasionally, continuous and unremitting. 2.5.7.1 General principles ▪ Good treatment of patients with troublesome TTH (of either type) begins with their education, explaining their disorder and the purpose and means of management. ▪ Impact of TTH should be assessed prior to planning treatment: ▪ the HALT-90 Index, assessing burden in terms of lost productive time, is included here, among the management aids (see 3.4.2 The Headache-Attributed Lost Time (HALT) Indices (also, Additional file 18)). ▪ Infrequent headaches (on ≤2 days/week) are managed with over-the counter (OTC) analgesics. ▪ When headache is more frequent: ▪ advice on lifestyle may be helpful, possibly accompanied by psychological intervention such as cognitive behavioural therapy; ▪ analgesics (even OTC) should be used with care because of the risk of medication-overuse headache; ▪ prophylaxis may be indicated. ## Education of patients a patient information leaflet on tth and its management, developed by lifting The Burden, is provided here in Section 4 (also, Additional file 22). ## Key points of information are: ▪ TTH is a very common disorder but, while it may be disabling and troublesome when headaches are frequent, it is benign; ▪ episodic TTH can be successfully treated, usually with OTC analgesics; ▪ over-frequent use of medications, even OTC, will make headaches worse; ▪ chronic TTH cannot be regularly treated with analgesics and usually requires other long-term continuous medication and/or non-pharmacological interventions; ▪ a headache calendar helps good management by recording over time the symptoms and pattern of attacks and medication use; ▪ predisposing factors sometimes include stress and/ or poor head and neck posture; ▪ regular activity (eg, sport or exercise 2-3 times per week) may help frequent TTH. 2.5.7.3 Acute intervention Symptomatic treatment with OTC analgesics [fig_ref] Table 11: Analgesics for episodic tension-type headache [/fig_ref] is appropriate for episodic TTH occurring on ≤2 days/week. ## Drugs to avoid ▪ Opioids (including codeine and dihydrocodeine) are ineffective for headache, associated with multiple adverse effects, potentially addictive and commonly implicated in medication-overuse headache. ▪ Barbiturates have no place in the treatment of TTH. ▪ Metamizol has limited evidence for efficacy and is associated with agranulocytosis. ▪ Triptans are specific for migraine, and ineffective in TTH. ## Principles of acute intervention ▪ Episodic TTH occurring on ≤2 days/week can usually be successfully treated with OTC analgesics alone; ▪ As the frequency of headaches increases, so does the risk of medication overuse: ▪ episodic TTH on >2 days/week is a clear indication for prophylaxis (see below) in place of, rather than in addition to, acute intervention; ▪ acute treatments are unlikely to be effective in chronic TTH and put the patient at clear risk of medication-overuse headache. ## Prophylaxis Principles of prophylaxis ▪ A calendar should be kept to assess efficacy and promote adherence. An example of a simple calendar is included here among the management aids (see Headache diary and calendar to aid diagnosis and follow-up in primary care (also, Additional file 17)). ▪ Patients receiving medication more often used as an antidepressant should be advised of this, and why; otherwise, they may default when they find out. ▪ Prophylaxis that appears ineffective should not be discontinued too soon; 2-3 months may be the minimum to achieve and observe efficacy. ▪ Tapered withdrawal may be considered after 6 months of good control, but prolonged treatment is sometimes indicated. Effective drugs A narrow range of drugs have efficacy [fig_ref] Table 2: Summary of features distinguishing the important primary headache disorders [/fig_ref] , although none is specifically licensed for TTH prophylaxis. Use of drugs off-licence rests on individual clinical responsibility. ## Drugs to avoid ▪ Onabotulinum toxin A is ineffective in TTH. ## Non-pharmacological prophylaxis ▪ There is limited evidence that acupuncture is effective in reducing intensity and frequency of TTH episodes. While some patients experience benefit, this may be due to placebo effect. Acupuncture has differing forms, and is highly dependent on the skill of the therapist. ▪ There is well-documented evidence of efficacy of various forms of biofeedback. They are highly dependent on the skill of the therapist. 2.5.7.5 Follow-up Every patient to whom treatment is offered, or whose treatment is changed, requires follow-up to ensure that optimum treatment has been established. ). ## When prophylaxis fails ▪ Failure may be due to subtherapeutic dosage (itself perhaps due to non-adherence) or insufficient duration of treatment. ▪ The following actions are recommended: ▪ review the diagnosis; ▪ review adherence; ▪ review other medication, especially for overuse; ▪ When prophylaxis still fails to have clear benefit, discontinue it. ▪ When all options fail, specialist referral is indicated. ## Pain management ▪ Despite best efforts, chronic TTH is often refractory to medical treatment or may become so. ▪ Patients in this situation require referral into a pain management programme with emphasis on psychological approaches. ## Management of cluster headache This guide can be separately downloaded (Additional file 11). Cluster headache, a type of trigeminal autonomic cephalalgia, is characterised by frequently recurring, localised, short-lasting but extremely severe headache, which is accompanied by a set of highly characteristic autonomic symptoms. ▪ Cluster headache is easily recognisable (see 2.4.2 Typical features of the headache disorders relevant to primary care (also, Additional file 2)). ▪ It should never be missed. It has two subtypes: ▪ episodic cluster headache, with attacks occurring in bouts (clusters) that last for a few or many weeks and then remit for ≥3 months; ▪ chronic cluster headache, less common, but persisting without remissions, or with remissions of <3 months. 2.5.8.1 General principles ▪ Patients with this disorder suffer very badly if ineffectively treated: ▪ cluster headache management is, at least initially, better left to specialists who see this disorder frequently; ▪ on first presentation it demands accelerated referral for investigation and treatment; ▪ recognition in primary care is crucial to ensure prompt referral. ▪ The objective of management in both episodic and chronic subtypes is total attack suppression. This is not always achievable. ▪ Both acute medication and prophylaxis have a role in management, but preventative drugs are the mainstay of treatment in most cases. ▪ Once effective treatment has been established, future clusters, or maintenance therapy in the case of chronic cluster headache, may be managed in primary care. 2.5.8.2 Acute therapies There are limited options [fig_ref] Table 3: Symptoms of aura [/fig_ref] , but efficacy may be high. ▪ Availability varies between countries. ▪ Most are not specifically licensed for cluster headache. Use of drugs off-licence rests on individual clinical responsibility. ## Drugs to avoid ▪ Oral triptans are slow in onset of action and are not useful substitutes. ▪ Analgesics, including opioids, have little or no place in treating cluster headache. ## Preventative therapy Specialists employ the following: ▪ transition therapy [fig_ref] Table 4: Diagnostic questions to ask in the history How many different headaches types... [/fig_ref] , used at onset of treatment to achieve more rapid response during dose escalation of any of the preventative drugs; ▪ maintenance prophylaxis [fig_ref] Table 5: Specific warning features [/fig_ref] , balancing efficacy of drugs against their significant toxicity (refer to pharmacopoeia). ▪ Combinations of drugs may be tried, but the potential for toxicity is obviously high. ▪ For episodic cluster headache, maintenance prophylaxis should be discontinued by tapering, usually 2 weeks after full remission. ▪ For chronic cluster headache, maintenance prophylaxis may need to be continued long-term. ## Principles of preventative therapy Other treatment options ▪ Neuromodulation, non-invasive or invasive, is occasionally used by specialists. ## Follow-up Every patient with active cluster headache requires frequent follow-up both to ensure that optimum acute and preventative treatments are maintained and to monitor for treatment toxicity. ▪ Patients with episodic cluster headache in remission should be advised to return promptly at the onset of the next cluster episode. 2.5.8.5 Information for patients A patient information leaflet on cluster headache and its management, developed by Lifting The Burden, is provided here in Section 4 (also, Additional file 23). ## Management of medication-overuse headache (moh) This guide can be separately downloaded (Additional file 12). Medication-overuse headache (MOH) is one of the syndromes characterised by headache occurring on ≥15 days/month. It is often daily, but variable in site, intensity and character. It greatly impairs quality of life. MOH is an aggravation of a prior headache disorder (usually migraine, but sometimes tension-type headache) caused by chronic overuse of medication taken to treat it. ## General principles ▪ Prevention, through education, is preferable to cure. ▪ Once MOH has developed, early intervention has better chance of success. ▪ The necessary management of established MOH is to stop overuse of the suspected medication(s). ▪ Patient education, that medication taken to relieve headache is in fact its cause, is the essential first step: ▪ success in management depends crucially on patients' understanding that their medication taken to relieve their headache is in fact its cause. ▪ Management is usually possible in primary care. ▪ The long-term prognosis is usually very good. Most cases revert to episodic headache, although the outcome depends on: ▪ the type of headache from which MOH developed; ▪ the class of medication overused (opioids causing greatest difficulty); ▪ the duration of overuse; ▪ comorbidities (psychiatric, or other causes of chronic pain). 2.5.9.2 Education of patients A patient information leaflet on medication-overuse headache and its management, developed by Lifting The Burden, is provided here in Section 4 (also, Additional file 24). Key points of information are: ▪ The "treatment" a patient is taking for headache is actually the cause of it. ▪ Effective treatment requires, in the first instance, stopping use of the suspected medication(s) (withdrawal): ▪ there is no other option; ▪ many patients recover from this alone. ▪ Initial worsening of symptoms for 1-2 weeks during and after withdrawal must be expected. ▪ The outcome is usually very good, with reversion in most cases, within 2 months, to the antecedent episodic headache disorder. 2.5.9.3 Objectives There are four separate objectives in the complete management of MOH, and all are important: ▪ stop the overused medication; ▪ recovery from MOH (which should follow); ▪ review and reassess the underlying headache disorder (usually migraine or tension-type headache); ▪ prevent relapse, while allowing acceptable use of medications. In addition, comorbidities may require management. 2.5.9.4 Principles of withdrawal ▪ Worsening headache for 1-2 weeks is almost inevitable: ▪ accordingly, withdrawal should be planned to avoid unnecessary lifestyle disruption; ▪ 1-2 weeks' sick leave may be needed; ▪ admission to hospital during withdrawal is rarely necessary unless: ▪ overused medication(s) include opioids; ▪ for management of comorbidities. ▪ Withdrawal may be undertaken in any of three ways, the choice being made by the patient: ▪ abruptly: ▪ there is evidence that this is the most successful approach; ▪ by tapering over a period of 2-4 weeks: ▪ withdrawal symptoms are likely to be less intense but more prolonged; ▪ by replacing the overused medication(s) with naproxen 500 mg twice daily for 3-4 weeks and no longer: ▪ the purpose is to break the behavioural "have headachetake medication" link; ▪ many patients become headache-free on this medication; ▪ naproxen must be stopped after this period (never continued). ▪ Headache usually shows signs of improvement 1-2 weeks after stopping overused medication(s). ▪ Recovery continues slowly for up to 2 months. ▪ Prophylaxis against the antecedent headache (most often migraine) may be introduced on its return, or commenced in parallel with the withdrawal process. 2.5.9.5 Follow-up Every patient stopping medication overuse requires follow-up in order to provide support and observe outcome. ▪ First review is advised after 2-3 weeks to ensure withdrawal has been successfully achieved. ▪ Use of a calendar during withdrawal is strongly recommended to record symptoms and medication use, and to record changing headache pattern. An example of a simple calendar is included here among the management aids (see 3.3 Headache diary and calendar to aid diagnosis and follow-up in primary care (also, Additional file 17)). ▪ Most patients revert to their antecedent headache (usually migraine or tension-type headache) within 2 months; this will need review and appropriate management. ▪ The relapse rate is high within the first year: further follow-up is important to avoid it, and many patients require extended support. ## Re-introducing withdrawn medication ▪ Previously overused medications should be reassessed: ▪ alternatives should be used whenever possible; ▪ if still needed, they may be cautiously reintroduced after 2 months. ▪ Frequency of use should be on no more than 10 days/month: ▪ use on more than 6 days/month raises the risk of recidivism; ▪ patients should avoid treating headaches on more than 3 days in a row. ## Management of trigeminal neuralgia and persistent idiopathic facial pain This guide can be separately downloaded (Additional file 13). Management of these uncommon but troublesome disorders is better left to specialists. ▪ Recognition in primary care is crucial to ensure prompt referral. ## Trigeminal neuralgia (tn) This disorder presents as recurrent, unilateral, brief but severe, electric-shock-like pains in the distribution of the trigeminal nerve, abrupt in onset and termination and often triggered by innocuous stimuli. It is not common, affecting 1-2 in every 1000 people. Women are twice as likely to be affected as men. ▪ TN is extremely painful, and untreated is physically, psychologically and socially debilitating: ▪ patients may avoid the triggers of eating and drinking, seriously impairing food and fluid intake. ▪ TN therefore demands accelerated specialist referral for investigation and treatment. ▪ Good treatment begins with education of patients, explaining their disorder and the purpose and means of management. ▪ The objective in management, by medical or surgical means, is abatement of attacks and pain freedom. This is not always achievable. ▪ MRI is mandatory since classical TN and secondary TN (due usually to cerebellopontine angle tumour, AV-malformation or multiple sclerosis) may be indistinguishable by symptom presentation. ▪ First-line treatment is prophylactic (antiepileptic) medication. ▪ Acute therapies (opioids or other analgesics) have no place in management since attacks are very short-lasting. ▪ Severe exacerbations with anorexia and dehydration, due to pain triggered by eating or drinking, may require hospital admission for intravenous hydration and medication. ## Principles of management Education of patients A patient information leaflet on trigeminal neuralgia is provided here in Section 4 (also, Additional file 26). Key points of information are: ▪ TN produces very characteristic, very severe, electricshock-like pains: ▪ along a nerve on one side of the face, usually in the cheek or jaw; ▪ repetitively, in short-lasting bouts (up to 2 min), which: ▪ occur daily for weeks or months but sometimes remit spontaneously; ▪ usually start without warning, but can be provoked by light touch, wind, cold air, eating, drinking, brushing the teeth or speaking. ▪ The cause of TN is often not known: ▪ some people have a blood vessel in close contact with and compressing the affected nerve: an MRI brain scan is required to show this; ▪ however, there are other unknown causes. ▪ Specialist referral is therefore necessary. ▪ There are a number of treatments for TN, which often work well: ▪ these are preventative medications, to be taken daily; ▪ painkillers do not help; ▪ occasionally, surgery is required, but as a last resort; ▪ TN does not require dental treatment. ## Preventative medications A narrow range of antiepileptic drugs are effective, and used by specialists. Maximum dosages may be necessary to achieve pain relief, and balancing efficacy against toxicity is difficult. ## Principles of drug prophylaxis ▪ Dosages should be up-titrated slowly until pain relief is achieved or side effects become unacceptable. ▪ Patients established on medication may be taught to titrate up and down, according to symptom severity. ▪ Combinations may cause fewer side-effects because lower doses may be required of each drug. ▪ Treatment may be slowly tapered after complete freedom from pain, and discontinued in the absence of relapse. Other treatment options in medically refractory patients ▪ Neurosurgical treatments are relevant when medical treatment with maximum tolerated doses achieve insufficient efficacy, but: ▪ microvascular decompression (appropriate when neurovascular compression, not merely contact, has been demonstrated) carries a small risk of severe complications such as cranial nerve palsy or stroke; ▪ gamma-knife and/or percutaneous procedures (balloon compression, glycerol injection, thermocoagulation or pulsed radiofrequency treatment) targeting the trigeminal ganglion are less invasive but probably less efficacious. ## Follow-up While every patient with TN requires specialist initial management, long-term follow-up once stable is appropriate in primary care. ▪ Patients should be educated on: ▪ how to taper medication cautiously once pain freedom is achieved; ▪ how to reintroduce medication by careful uptitration if/when pain returns. 2.5.10.2 Persistent idiopathic facial pain (PIFP) Previously termed "atypical facial pain", this disorder presents as dull, aching or nagging, poorly localized facial and/ or oral pain, which recurs daily for >2 h over >3 months. Only rarely are there electric-shock-like pain attacks as in trigeminal neuralgia. PIFP is rare, mostly affecting younger women, but it can start at any age. Principles of management ▪ PIFP is painful, and can be physically, psychologically and socially debilitating. ▪ It is often difficult to manage, often has comorbidities, and usually requires specialist referral in the first instance. ▪ Good treatment begins with education of patients, explaining their disorder and the purpose and means of management. ▪ Freedom from pain is difficult to achieve: the objectives in management, by medical, physical and/or psychological therapies, are reduction of pain intensity and developing patients' coping mechanisms. ▪ Treatment is prophylactic: acute therapies (opioids or other analgesics) have no place in management of PIFP. Education of patients A patient information leaflet on persistent idiopathic facial pain is provided here in Section 4 (also, Additional file 27). Key points of information are: ▪ PIFP is most often a constant, dull, nagging or aching pain in the cheek and lower jaw. Rarely there are electric-shock-like pains also. ▪ There are no specific triggers. ▪ The causes are unknown. ▪ There are no tests to confirm the diagnosis. ▪ Preventative medications, taken every day, are the best treatments for most people with PIFP: ▪ these medications are more commonly used as antidepressants, but are very useful against chronic pain disorders even in people who are not depressed; ▪ painkillers are unhelpful and, if taken too often, are likely to make things worse. ## Preventative medications Drugs with some efficacy are shown in [fig_ref] Table 7: Recommended drugs and doses for acute migraine therapy, step one [/fig_ref]. Maximum dosages may be necessary. ▪ Use of drugs off-licence rests on individual clinical responsibility. Principles of prophylaxis ▪ Patients receiving medication more often used as an antidepressant should be advised of this, and why; otherwise, they may default on finding out. ▪ Dosages should be up-titrated slowly until pain relief is achieved or side effects become unacceptable. ▪ Combinations may cause fewer side-effects because lower doses may be required of each drug. ## Follow-up While every patient with PIFP requires specialist initial management, long-term follow-up once stable is appropriate in primary care. 2.6 Guides to referral 2.6.1 Headache management in primary care: when to refer This guide can be separately downloaded (Additional file [bib_ref] on behalf of the European Headache Federation and Lifting The Burden: the..., Steiner [/bib_ref]. Most headache disorders presenting to primary care are migraine, tension-type headache or medication-overuse headache. These, usually, can be and are best managed in primary care. 2.6.1.1 Reasons for specialist referral ▪ Diagnostic uncertainty after due enquiry. ▪ Diagnosis of any of the following, which are best managed by specialists: ▪ migraine with aura including motor weakness; ▪ chronic migraine; ▪ cluster headache; ▪ trigeminal neuralgia; ▪ persistent idiopathic facial pain. ▪ Suspicion of serious secondary headache, or of serious pathology where investigation may be necessary and is not available in primary care: ▪ progressively worsening headache over weeks or longer; ▪ headache brought on by coughing, exercise or sexual activity; ▪ headache associated with any of the following: ▪ postural change indicative of high or low intracranial pressure; ▪ unexplained fever; ▪ stiffness of the neck; ▪ unexplained focal neurological symptoms or signs or with epileptic seizures; ▪ disorder of consciousness or memory, or change in personality; ▪ weight-loss or poor general condition; ▪ new headache: ▪ in any patient that is thunderclap in nature (intense headache with abrupt or "explosive" onset); ▪ that is daily and persistent from onset in a patient without a prior history of headache; ▪ in a patient older than 50 years; ▪ in a patient with a history of cancer; ▪ in a patient with a history of immunodeficiency (including HIV infection); ▪ in a patient with a history of polymyalgia rheumatica; ▪ in a patient with a family history of glaucoma; ▪ unusual migraine aura, especially: ▪ prolonged aura (duration >1 h); ▪ aura featuring brainstem symptoms and/or motor weakness; ▪ new aura without headache in a patient older than 50 years and in the absence of a prior history of migraine. ▪ Persistent management failure. ▪ Comorbid disorders requiring specialist management. ## Instruments and other materials to aid diagnosis and management of headache disorders in primary care # Introduction Headache disorders are common, and the second-highest cause of disability in Europe. Migraine, tension-type headache (TTH) and medication-overuse headache (MOH) are particularly important because they are common and responsible for almost all burden attributed to headache [bib_ref] The global burden of headache: a documentation of headache prevalence and disability..., Stovner [/bib_ref]. Management of these belongs largely in primary care [1], partly because of the numbers involved but also because it is usually not difficult, requiring neither specialist skills nor investigations. Yet, throughout Europe and elsewhere, health-care providers in primary care may have received limited training in the diagnosis and treatment of headache [1]. The instruments and other materials collated here are developed, mostly by Lifting The Burden, specifically to aid primary-care physicians in both diagnosis and management. They should be used in conjunction with European principles of management of headache disorders in primary care (see Section 2, and Additional files 1, 2, 3, 4, 5, . The following are included here: While intended for use in primary care, these instruments and materials may also be useful in specialist practice. Additionally, in Section 4 are Additional files 21, 22, 23, 24, 25, 26 and 27 Patient information leaflets to aid headache management in primary care (2nd edition). ## Diagnostic criteria for headache disorders in primary care: the international classification of headache disorders, 3rd edition (ichd-3)abbreviated form This aid can be separately downloaded (Additional file 15). # Introduction Headache disorders are common, and the second highest cause of disability worldwide (after low back pain). The International Classification of Headache Disorders, 3rd edition (ICHD-3), published by the International Headache Society, is the authoritative catalogue of headache disorders. It describes over 200 distinct headache types, subtypes or subforms, and incorporates explicit diagnostic criteria for each one. Only a small number of these disorders are important in primary care. The purpose of this diagnostic aid, an adaptation of ICHD-3 specifically for primary care, is to help primary-care physicians recognise and correctly diagnose these. It sets out the diagnostic criteria for the three primary headache disorders (with seven types or subtypes), nine secondary headaches and two facial pains that are most likely to be seen in primary care or are important because they are symptomatic of another serious underlying disorder. ## How the system works this diagnostic aid should be used as a reference. The classification distinguishes between primary headaches, which have no other underlying causative disorder, and secondary headaches, which are attributed to some other disorder. Onset in close temporal relation to another disorder known to cause headache is therefore a diagnostic criterion for all secondary headaches. The third section of the classification covers painful cranial neuropathies and other facial pain. All diagnoses are numbered according to their position within the classification hierarchy. In this abbreviated version, numbers are not consecutive because many headaches are not included. Diagnoses are made by applying the criteria set out in the classification. A diagnosis is confirmed only when all criteria for that disorder are fulfilled. However, symptoms may have been modified by treatment, and this possibility should be considered in deciding whether criteria are met. One patient may simultaneously have two or more headache disorders. Each should be separately diagnosed because each may require separate management. The presence of more than one headache disorder can cause confusion, especially when a patient fails to distinguish between them. When this is suspected, it is recommended that he or she prospectively fills out a diagnostic headache diary, for a month or longer, recording the important characteristics of each headache episode. Diaries not only improve diagnostic accuracy but also allow precise judgment of medication consumption. A diary is included here among the management aids (see 3.3 Headache diary and calendar to aid diagnosis and follow-up in primary care (also, Additional file 16)). ## Definitions of common terms ## Attack of headache (or pain): Headache (or pain) that builds up, remains at a certain level for minutes to 72 h, then wanes until it is gone completely. Attributed to: This term in ICHD-3 describes the relationship between a secondary headache and the disorder believed to cause it. It requires fulfilment of criteria establishing an accepted level of evidence of causation. Close temporal relation: This term is used to describe the relation between an organic disorder and a secondary headache attributed to it. Duration of attack: Time from onset until termination of an attack of headache (or pain) meeting criteria for a particular headache type or subtype. When the patient falls asleep during an attack and wakes up relieved, duration is until time of awakening. When an attack of migraine is successfully relieved by medication but symptoms recur within 48 h, these may represent a relapse of the same attack or a new attack (see Frequency of attacks). Facial pain: Pain below the orbitomeatal line, above the neck and anterior to the pinnae. Fortification spectrum: Angulated, arcuate and gradually enlarging visual disturbance typical of migrainous aura. Frequency of attacks: The rate of occurrence of attacks of headache (or pain) per time period (commonly 1 month). Successful relief of a migraine attack with medication may be followed by relapse within 48 h. The IHS Guidelines for Controlled Trials of Drugs in Migraine, 3rd edition, recommend as a practical solution, especially in differentiating attacks recorded as diary entries over the previous month, to count as distinct attacks only those that are separated by at least 48 h headache-free. Headache: Pain located in the head, above the orbitomeatal line and/or nuchal ridge. Headache days: Number of days during an observed period of time (commonly 1 month) affected by headache for any part or the whole of the day. Intensity of pain: Level of pain, usually scored on a four-point numerical rating scale (0-3) equivalent to no, mild, moderate and severe pain, or on a visual analogue scale (commonly 10 cm). It may also be scored on a verbal rating scale expressed in terms of its functional consequence: 0, no pain; 1, mild pain, does not interfere with usual activities; 2, moderate pain, inhibits but does not wholly prevent usual activities; 3, severe pain, prevents all activities. New headache: Any type, subtype or subform of headache from which the patient was not previously suffering. Persistent: This term, used in the context of certain secondary headaches, describes headache, initially acute and caused by another disorder, that fails to remit within a specified time interval (usually 3 months) after that disorder has resolved. Phonophobia: Hypersensitivity to sound, even at normal levels, usually causing avoidance. Photophobia: Hypersensitivity to light, even at normal levels, usually causing avoidance. Pressing/tightening: Pain of a constant quality, often compared to a tight band around the head. Primary headache (disorder): Headache, or a headache disorder, not caused by or attributed to another disorder. It is distinguished from secondary headache disorder. Pulsating: Characterized by rhythmic intensifications in time with the heart beat; throbbing. Scintillation: Visual hallucinations that are bright and fluctuate in intensity, often at approximately 8-10 Hz. They are typical of migraine aura. Scotoma: Loss of part(s) of the visual field of one or both eyes. Scotoma may be absolute (no vision) or relative (obscured or reduced vision). In migraine, scotomata are homonymous. Secondary headache (disorder): Headache, or a headache disorder, caused by another underlying disorder. In ICHD-3, secondary headaches are attributed to the causative disorder. Secondary headaches are distinguished from primary headaches. A secondary headache may have the characteristics of a primary headache but still fulfil criteria for causation by another disorder. ## Primary headaches ## Migraine Migraine is a common disabling primary headache disorder. In the Global Burden of Disease Survey 2010 (GBD 2010), it was ranked as the third most prevalent disorder in the world. In GBD 2015, it was ranked third-highest cause of disability worldwide in both males and females under the age of 50 years. Migraine has two major types. 1.1 Migraine without aura is a clinical syndrome characterized by headache with specific features and associated symptoms. 1.2 Migraine with aura is primarily characterized by the transient focal neurological symptoms that usually precede but sometimes accompany the headache. Some patients, with either type, also experience a prodromal phase, occurring hours or days before the headache, and/or a postdromal phase following headache resolution. Common prodromal symptoms include fatigue, elated or depressed mood, unusual hunger and cravings for certain foods; postdromal include fatigue, elated or depressed mood and cognitive difficulties. When a patient fulfils criteria for both these types of migraine, both should be diagnosed. A third type, 1.3 Chronic migraine, is much less common but very highly disabling. ## Migraine without aura ## Description: A recurrent headache disorder manifesting in attacks lasting 4-72 h. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity and association with nausea and/or photophobia and phonophobia. ## Diagnostic criteria: A. At least five attacks fulfilling criteria B-D B. Headache attacks lasting 4-72 h (when untreated) 1 C. Headache has at least two of the following four characteristics: 1. unilateral location 2. pulsating quality 3. moderate or severe pain intensity D. aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) E. During headache at least one of the following: 1. nausea and/or vomiting 2. photophobia and phonophobia F. Not better accounted for by another ICHD-3 diagnosis. Note: 1. In children and adolescents (aged under 18 years), attacks may last 2-72 h. ## Migraine with aura Description: Recurrent attacks, lasting minutes, of unilateral fully-reversible visual, sensory or other central nervous system symptoms that usually develop gradually and are usually followed by headache and associated migraine symptoms. ## Diagnostic criteria: A. At least two attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms: 1. visual 2. sensory 3. speech and/or language 4. motor, brainstem and/or retinal 1 C. At least three of the following six characteristics: 1. at least one aura symptom spreads gradually over ≥5 min 2. two or more aura symptoms occur in succession 3. each individual aura symptom lasts 5-60 min 4. at least one aura symptom is unilateral 2 5. at least one aura symptom is positive6. the aura is accompanied, or followed within 60 min, by headache 4 D. Not better accounted for by another ICHD-3 diagnosis. ## Notes: 1. Motor, brainstem and retinal symptoms are atypical, occurring in specific subtypes of migraine with aura, and should lead to referral. 2. Aphasia is regarded as a unilateral symptom. 3. Scintillations and pins and needles are positive symptoms of aura. 4. Typical aura without headache is a recognised subtype but, in the absence of headache, the diagnosis of aura and its distinction from mimics that may signal serious disease (eg, transient ischaemic attack) becomes more difficult and often requires investigation. ## Chronic migraine Description: Headache occurring on 15 or more days/month for more than 3 months, which, on at least 8 days/month, has the features of migraine headache. ## Diagnostic criteria: A. Headache (migraine-like or tension-type-like 1 ) on ≥15 days/month for >3 months, and fulfilling criteria B and C B. Occurring in a patient who has had at least five attacks fulfilling criteria B-D for 1.1 Migraine without aura and/or criteria B and C for 1.2 Migraine with aura C. On ≥8 days/month for >3 months, fulfilling any of the following 2 : 1. criteria C and D for 1.1 Migraine without aura 2. criteria B and C for 1.2 Migraine with aura 3. believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative D. Not better accounted for by another ICHD-3 diagnosis 3, 4 . ## Notes: 1. It is impossible to distinguish the individual episodes of headache in patients with such frequent or continuous headaches. In this situation, attacks with and those without aura are both counted in diagnosing 1.3 Chronic migraine, as are both migraine-like and tension-type-like headaches. 2. Characterization of frequently recurring headache generally requires a headache diary to record information on pain and associated symptoms dayby-day for at least 1 month. 3. Because tension-type-like headache is within the diagnostic criteria for 1.3 Chronic migraine, this diagnosis excludes the diagnosis of 2. Tension-type headache or its types. 4. The most common cause of symptoms suggestive of chronic migraine is medication overuse, as defined under 8.2 Medication-overuse headache. Around 50% of patients apparently with 1.3 Chronic migraine revert to an episodic migraine type after drug withdrawal; such patients are in a sense wrongly diagnosed as 1.3 Chronic migraine. Equally, many patients apparently overusing medication do not improve after drug withdrawal; the diagnosis of 8.2 Medication-overuse headache may be inappropriate for these. Therefore, patients meeting criteria for 1.3 Chronic migraine and for 8.2 Medication-overuse headache should be coded for both. After drug withdrawal, migraine will either revert to an episodic type or remain chronic, and should be re-diagnosed accordingly; either diagnosis may be rescinded. ## Tension-type headache This is the most common headache. In the Global Burden of Disease Survey 2010 (GBD 2010), it was ranked as the second most prevalent disorder in the world (behind dental caries). Two types are important. ## Frequent episodic tension-type headache Description: Frequent episodes of headache, typically bilateral, pressing or tightening in quality and of mild to moderate intensity, lasting minutes to days. The pain lacks the specific characteristics of migraine: it does not worsen with routine physical activity and is not associated with nausea, although either photophobia or phonophobia may be present. ## Diagnostic criteria: A. At least 10 episodes of headache occurring on 1-14 days/month on average for >3 months (≥12 and <180 days/year) and fulfilling criteria B-D B. Lasting from 30 min to 7 days C. At least two of the following four characteristics: 1. bilateral location 2. pressing or tightening (non-pulsating) quality 3. mild or moderate intensity 4. not aggravated by routine physical activity such as walking or climbing stairs D. Both of the following: 1. no nausea or vomiting 2. no more than one of photophobia or phonophobia E. Not better accounted for by another ICHD-3 diagnosis 1 . Note: 1. 2.2 Frequent tension-type headache often coexists with 1.1 Migraine without aura, in which case both diagnoses should be given. A diagnostic headache diary may be required to separate them. ## Chronic tension-type headache ## Description: A disorder evolving from frequent episodic tension-type headache, with daily or very frequent episodes of headache, typically bilateral, pressing or tightening in quality and of mild to moderate intensity, lasting hours to days, or unremitting. The pain does not worsen with routine physical activity, but may be associated with mild nausea, photophobia or phonophobia. ## Diagnostic criteria: A. Headache occurring on ≥15 days/month on average for >3 months (≥180 days/year), fulfilling criteria B-D B. Lasting hours to days, or unremitting C. At least two of the following four characteristics: 1. bilateral location 2. pressing or tightening (non-pulsating) quality 3. mild or moderate intensity 4. not aggravated by routine physical activity such as walking or climbing stairs D. Both of the following: 1. no more than one of photophobia, phonophobia or mild nausea 2. neither moderate or severe nausea nor vomiting E. Not better accounted for by another ICHD-3 diagnosis 1, 2 . Notes: ## Trigeminal autonomic cephalalgias This group of uncommon disorders shares the clinical features of short-duration headache and prominent cranial parasympathetic autonomic features. Only one, with a prevalence of one per 1000 in males and lower in females, is expected to be seen and diagnosed in primary care. The others are even rarer and, if seen, may be mistaken for it. All should be referred for specialist management in the first instance. ## Cluster headache ## Description: Attacks of severe, strictly unilateral pain which is orbital, supraorbital, temporal or in any combination of these sites, lasting 15-180 min and occurring from once every other day to eight times a day. The pain is associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis, ptosis and/or eyelid oedema, and/or with restlessness or agitation. ## Diagnostic criteria: A. At least five attacks fulfilling criteria B-D B. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15-180 min (when untreated) C. Either or both of the following: 1. at least one of the following symptoms or signs, ipsilateral to the headache: a) conjunctival injection and/or lacrimation b) nasal congestion and/or rhinorrhoea c) eyelid oedema d) forehead and facial sweating e) miosis and/or ptosis 2. a sense of restlessness or agitation Two subtypes are important. ## Episodic cluster headache Description: Cluster headache attacks occurring in periods lasting from 7 days to 1 year, separated by pain-free periods lasting at least 3 months. ## Diagnostic criteria: A. Attacks fulfilling criteria for 3.1 Cluster headache and occurring in bouts (cluster periods) B. At least two cluster periods lasting from 7 days to 1 year (when untreated) and separated by pain-free remission periods of ≥3 months. ## Chronic cluster headache Description: Cluster headache attacks occurring for 1 year or longer without remission, or with remission periods lasting less than 3 months. ## Diagnostic criteria: A. Attacks fulfilling criteria for 3.1 Cluster headache, and criterion B below B. Occurring without a remission period, or with remissions lasting <3 months, for at least 1 year. ## Secondary headaches Secondary headache disorders have another causative disorder underlying them; therefore, the headache occurs in close temporal relation to the other disorder, and/or worsens or improves in parallel with worsening or improvement of that disorder. These associations are keys to their diagnosis. ## General diagnostic criteria for secondary headaches: A. Any headache fulfilling criterion C B. Another disorder scientifically documented to be able to cause headache has been diagnosed 1, 2 C. Evidence of causation demonstrated by at least two of the following: 1. headache has developed in temporal relation to the onset of the presumed causative disorder 2. either or both of the following: a) headache has significantly worsened in parallel with worsening of the presumed causative disorder b) headache has significantly improved in parallel with improvement of the presumed causative disorder 3. headache has characteristics typical for the causative disorder 4. other evidence exists of causation D. Not better accounted for by another ICHD-3 diagnosis. Notes: 1. The diagnostic criteria for secondary headache disorders do not set out criteria for diagnosing the underlying disorder. 2. This criterion may require tests or procedures that cannot be undertaken in primary care. In such cases, the diagnosis cannot be confirmed in primary care. The crucial role of primary care is to recognise the possibility of the diagnosis. The secondary headaches described below are those that are common or otherwise important (must not be missed) in primary care. ## Headache attributed to trauma or injury to the head and/or neck ## Persistent headache attributed to traumatic injury to the head Persistent post-traumatic headache is often part of the post-traumatic syndrome, which includes symptoms such as equilibrium disturbance, poor concentration, decreased work ability, irritability, depressive mood and sleep disturbances. ## Description: Headache of more than 3 months' duration caused by traumatic injury to the head. ## Diagnostic criteria: A. Any headache fulfilling criteria C and D B. Traumatic injury to the head has occurred C. Headache is reported to have developed within 7 days after one of the following: 1. the injury to the head 2. regaining of consciousness following the injury to the head 3. discontinuation of medication(s) impairing ability to sense or report headache following the injury to the head D. Headache persists for >3 months after its onset E. Not better accounted for by another ICHD-3 diagnosis 1 . Note: 1. When headache following head injury becomes persistent, the possibility of 8.2 Medication-overuse headache needs to be considered. 6. Headache attributed to cranial and/or cervical vascular disorder ## Acute headache attributed to non-traumatic subarachnoid haemorrhage Non-traumatic subarachnoid haemorrhage (SAH) is one of the most common causes of persistent, intense and incapacitating headache of abrupt onset (thunderclap headache). It is a serious condition, and delayed diagnosis often has a catastrophic outcome: mortality is 40-50%, with 10-20% of patients dying before arriving at hospital; 50% of survivors are left disabled. ## Description: Headache caused by non-traumatic SAH, typically severe and sudden in onset, peaking in seconds (thunderclap headache) or minutes. It can be the sole symptom of non-traumatic SAH. ## Diagnostic criteria: A. Any new headache fulfilling criteria C and D B. SAH in the absence of head trauma has been diagnosed C. Evidence of causation demonstrated by at least two of the following: 1. headache has developed in close temporal relation to other symptoms and/or clinical signs of SAH, or has led to the diagnosis of SAH 2. headache has significantly improved in parallel with stabilization or improvement of other symptoms or clinical or radiological signs of SAH 3. headache has sudden or thunderclap onset D. Either of the following: 1. headache has resolved within 3 months 2. headache has not yet resolved but 3 months have not yet passed E. Not better accounted for by another ICHD-3 diagnosis. ## Headache attributed to giant cell arteritis Giant cell arteritis (GCA) is conspicuously associated with headache, but its characteristics are variable. GCA must be recognized: any persisting headache with recent onset in a patient over 60 years of age should suggest it. Recent repeated attacks of amaurosis fugax associated with headache are very suggestive of GCA. Blindness is a major risk, but preventable by immediate steroid treatment. The time interval between visual loss in one eye and in the other is usually less than 1 week. ## Description: Headache, with variable features, caused by and symptomatic of GCA. Headache may be the sole symptom of GCA, a disease most conspicuously associated with headache. ## Diagnostic criteria: A. Any new headache fulfilling criterion C B. GCA has been diagnosed C. Evidence of causation demonstrated by at least two of the following: 1. headache has developed in close temporal relation to other symptoms and/or clinical or biological signs of onset of GCA, or has led to the diagnosis of GCA 2. either or both of the following: a) headache has significantly worsened in parallel with worsening of GCA b) headache has significantly improved or resolved within 3 days of high-dose steroid treatment 3. headache is associated with scalp tenderness and/or jaw claudication D. Not better accounted for by another ICHD-3 diagnosis. ## Headache attributed to non-vascular intracranial disorder ## Headache attributed to low cerebrospinal fluid pressure Description: Headache caused by low cerebrospinal fluid (CSF) pressure, usually orthostatic and accompanied by neck pain, tinnitus, changes in hearing, photophophia and/or nausea. It remits after normalization of CSF pressure. Three subtypes are distinguished by aetiology: following-recent dural puncture, attributed to persistent CSF leakage (CSF fistula) or spontaneous. Diagnostic criteria: A. Any headache 1 fulfilling criterion C B. Either or both of the following: 1. low CSF pressure (<60 mm CSF) 2. evidence of CSF leakage on imaging C. Headache has developed in temporal relation to the low CSF pressure or CSF leakage, or led to its discovery D. Not better accounted for by another ICHD-3 diagnosis. Note: 1. 7.2 Headache attributed to low cerebrospinal fluid pressure is usually but not invariably orthostatic. Headache that significantly worsens soon after sitting upright or standing and/or improves after lying horizontally is likely to be caused by low CSF pressure, but this cannot be relied upon as a diagnostic criterion. ## Headache attributed to intracranial neoplasm Headache is a common symptom of intracranial tumours, more so in young patients (including children), but it rarely remains the only symptom: neurological deficits and seizures are common. ## Description: Headache caused by one or more space-occupying intracranial tumours. ## Diagnostic criteria: A. Any headache 1 fulfilling criterion C B. A space-occupying intracranial neoplasm has been demonstrated C. Evidence of causation demonstrated by at least two of the following: 1. headache has developed in temporal relation to development of the neoplasm, or led to its discovery 2. either or both of the following: a) headache has significantly worsened in parallel with worsening of the neoplasm b) headache has significantly improved in temporal relation to successful treatment of the neoplasm 3. headache has at least one of the following four characteristics: a) progressive b) worse in the morning and/or when lying down c) aggravated by Valsalva-like manoeuvres d) accompanied by nausea and/or vomiting D. Not better accounted for by another ICHD-3 diagnosis. Note: 1. There are no pathognomonic features of 7.4.1 Headache attributed to intracranial neoplasm, although progression or deterioration is a key feature. The other suggestive symptoms (severe, worse in the morning and associated with nausea and vomiting) are not a classical triad; they are more likely in the context of intracranial hypertension and with posterior fossa tumours. Nevertheless, a history indicating raised intracranial pressure should first suggest intracranial neoplasm. ## Headache attributed to a substance or its withdrawal ## Carbon monoxide-induced headache Carbon monoxide intoxication is particularly associated with headache, which, at low levels of exposure, may be the only symptom. Usually resulting from open fires or faulty gas boilers in the home, it is not rare in some countries, and likely to present to primary care. ## Description: Headache caused by exposure to carbon monoxide (CO), resolving spontaneously within 72 h after its elimination. Dependent on carboxyhaemoglobin level, headache ranges from mild without other symptoms, through moderate and pulsating with irritability, to severe with nausea, vomiting, blurred vision and, ultimately, impaired consciousness. ## Diagnostic criteria: A. Bilateral headache fulfilling criterion C B. Exposure to CO has occurred C. Evidence of causation demonstrated by all of the following: 1. headache has developed within 12 h of exposure to CO 2. headache intensity varies with the severity of CO intoxication 3. headache has resolved within 72 h of elimination of CO D. Not better accounted for by another ICHD-3 diagnosis. This disorder occurs in patients chronically overusing medication to treat a prior headache disorder, usually 1. Migraine or 2. Tension-type headache; both the prior headache and 8.2 Medication-overuse headache (MOH) should be diagnosed. ## Medication-overuse headache Correct diagnosis of MOH is important because patients will not improve without withdrawal of the offending medication. On the other hand, most patients with MOH improve after withdrawal, as does their responsiveness to preventative treatment. ## Description: Headache occurring on 15 or more days/month in a patient with a pre-existing primary headache and developing as a consequence of regular overuse of acute or symptomatic headache medication for more than 3 months. It usually, but not invariably, resolves after the overuse is stopped. ## Diagnostic criteria: A. Headache occurring on ≥15 days/month in a patient with a pre-existing headache disorder B. Regular overuse for >3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache 1, 2 C. Not better accounted for by another ICHD-3 diagnosis. ## Notes: 1. Drugs may be ergotamine, one or more triptans, non-opioid analgesics including paracetamol (acetaminophen), acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, combination analgesics (typically containing simple analgesics plus opioids, butalbital and/or caffeine) or any combination of these. 2. Overuse is defined as intake on ≥15 days/month for non-opioid analgesics alone and in all other cases as intake on ≥10 days/month. ## Headache attributed to infection ## Headache attributed to bacterial meningitis or meningoencephalitis Headache is the commonest and may be the first symptom of these infections, which should be suspected whenever headache is associated with fever, altered mental state, focal neurological deficits or generalized seizures. ## Description: Headache of variable duration caused by bacterial meningitis or meningoencephalitis. It may develop with mild flu-like symptoms and is typically acute and associated with neck stiffness, nausea, fever and changes in mental state and/or other neurological symptoms and/or signs. In most cases, headache resolves with resolution of the infection. Rarely it persists (as the subform 9.1.1.3 Persistent headache attributed to past bacterial meningitis or meningoencephalitis) for more than 3 months after resolution of the infection. ## Diagnostic criteria: A. Headache of any duration fulfilling criterion C B. Bacterial meningitis or meningoencephalitis has been diagnosed C. Evidence of causation demonstrated by at least two of the following: 1. headache has developed in temporal relation to the onset of the bacterial meningitis or meningoencephalitis 2. headache has significantly worsened in parallel with worsening of the bacterial meningitis or meningoencephalitis 3. headache has significantly improved in parallel with improvement in the bacterial meningitis or meningoencephalitis 4. headache is either or both of the following: a) holocranial b) located in the nuchal area and associated with neck stiffness D. Not better accounted for by another ICHD-3 diagnosis. 11. Headache or facial pain attributed to disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cervical structure 11.3.1 Headache attributed to acute angle-closure glaucoma Acute angle-closure glaucoma generally causes eye and/or periorbital pain, visual acuity loss (blurring), conjunctival injection and oedema, nausea and vomiting. As intraocular pressure rises, so does the risk of permanent visual loss. Early diagnosis is essential. ## Description: Headache, usually unilateral, caused by acute angle-closure glaucoma and associated with other symptoms and clinical signs of this disorder (eye and/or periorbital pain, visual acuity loss [blurring], conjunctival injection and oedema, nausea and vomiting). ## Diagnostic criteria: A. Any headache fulfilling criterion C B. Acute angle-closure glaucoma has been diagnosed, with proof of increased intraocular pressure C. Evidence of causation demonstrated by at least two of the following: 1. headache has developed in temporal relation to the onset of the glaucoma 2. headache has significantly worsened in parallel with progression of the glaucoma 3. headache has significantly improved or resolved in parallel with improvement in or resolution of the glaucoma 4. pain location includes the affected eye D. Not better accounted for by another ICHD-3 diagnosis. ## Painful cranial neuropathies and other facial pain 13. Painful lesions of the cranial nerves and other facial pain ## Trigeminal neuralgia The diagnosis of 13.1.1 Trigeminal neuralgia must be established clinically. Investigations are designed to identify cause. ## Description: A disorder characterized by recurrent unilateral brief electric shock-like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve and triggered by innocuous stimuli. It may develop without apparent cause or be a result of another disorder. Additionally, there may be concomitant continuous pain of moderate intensity within the distribution(s) of the affected nerve division(s). ## Diagnostic criteria: A. Recurrent paroxysms of unilateral facial pain in the distribution(s) of one or more divisions of the trigeminal nerve, with no radiation beyond, and fulfilling criteria B and C B. Pain has all of the following characteristics: 1. lasting from a fraction of a second to 2 min 1 2. severe intensity 2 3. electric shock-like, shooting, stabbing or sharp in quality C. Precipitated by innocuous stimuli within the affected trigeminal distribution 3 D. Not better accounted for by another ICHD-3 diagnosis. ## Notes: 1. Paroxysms may become more prolonged over time. 2. Pain may become more severe over time. 3. Some attacks may be, or appear to be, spontaneous, but there must be a history or finding of pain provoked by innocuous stimuli to meet this criterion. ## Persistent idiopathic facial pain (pifp) Description: Persistent facial and/or oral pain, with varying presentations but recurring daily for more than 2 h/day over more than 3 months, in the absence of clinical neurological deficit. Persistent idiopathic facial pain may be comorbid with other pain conditions such as chronic widespread pain and irritable bowel syndrome. In addition, it presents with high levels of psychiatric comorbidity and psychosocial disability. ## Diagnostic criteria: A. Facial and/or oral pain fulfilling criteria B and C B. Recurring daily for >2 h/day for >3 months C. Pain has both of the following characteristics: 1. poorly localized, and not following the distribution of a peripheral nerve 2. dull, aching or nagging quality D. Clinical neurological examination is normal E. A dental cause has been excluded by appropriate investigations F. Not better accounted for by another ICHD-3 diagnosis. ## Headache diary and calendar to aid diagnosis and follow-up in primary care These aids can be separately downloaded (Additional files 16 and 17). # Introduction Good management of most headache disorders requires monitoring of symptoms over time. Diaries and calendars aid both patients and physicians. The principal distinction between these is in the amount of information collected. Diaries capture more descriptive features of symptoms (headache intensity and character, associated symptoms), perhaps using free text. They are recommended in primary care, for 1-2 months, as aids to diagnosis and in pre-treatment assessment. Specifically, diaries are useful for recording: ▪ symptoms and temporal patterns that contribute to correct diagnosis; ▪ acute medication use (class, dosage and frequency), identifying base-line usage or overuse; Diaries are particularly helpful, and may be essential, in the diagnosis of conditions characterised by headache on ≥15 days per month, including medication-overuse headache. Calendars essentially note the temporal occurrence of headache episodes and related events such as menstruation and medication intake. They are recommended in primary care during follow-up, once the headache is diagnosed. Specifically, calendars are useful for: ▪ revealing associations with the menstrual cycle and, possibly, with other triggers; ▪ monitoring acute medication use or overuse during follow-up; ▪ encouraging adherence to prophylactic medication; ▪ recording treatment effect on headache frequency, and charting outcomes. ## Diary and calendar for use in primary care Many diaries and calendars have been developed, mostly in paper form. An example of each, developed by specialists in headache centres but useful in primary care, is included here (Figs. 1 and 2 (also, Additional files 16 and 17)). ## On-line diaries and smartphone apps There are many of these available, but of varying quality and utility. Some appear to gather data for marketing purposes. On the other hand, some can be useful in establishing the characteristics of individual attacks, response to treatment and associations with potential triggers over time. Some, probably better suited to specialist care, enable data to be shared directly with health-care professionals. ## The headache-attributed lost time (halt) indices: measures of burden for headache management in primary care These aids can be separately downloaded (Additional files 18 and 19). # Introduction Assessment of a headache disorder requires more than diagnosis: there needs to be some measure of impact on the patient's life and lifestyle, both as a prelude to planning best management and to establish the baseline against which to evaluate treatment. The burden attributable to headache disorders has multiple components: there are many ways in which recurrent or persistent headache can damage life. No simple measure can summarise them all in a single index, but the Migraine Disability Assessment (MIDAS) instrument [bib_ref] Validity of the Migraine Disability Assessment (MIDAS) score in comparison to a..., Stewart [/bib_ref] has proved extremely useful. The concept behind MIDAS is estimation of productive time lost through the disabling effect of headache; the result is expressed by a number with intuitively meaningful units (eg, days/month). Despite its name, MIDAS is not truly a measure of disability: unless headache is very severe, people have an element of choice in whether or not to take time out of work or other activities when affected by headache. One person may "work through", another may not. Furthermore, the choice is likely to be influenced by external factors, such as availability of sickness pay. Nevertheless, because productive time is an important casualty of headache, its measurement is highly relevant to burden assessment. ## The headache-attributed lost time (halt) indices The HALT Index was first described in 2007 [bib_ref] The HALT and HART indices, Steiner [/bib_ref] as a direct and close derivative of MIDAS. It was developed by Lifting The Burden to use wording that is more easily translated than the American-English of MIDAS [bib_ref] Validity of the Migraine Disability Assessment (MIDAS) score in comparison to a..., Stewart [/bib_ref]. HALT has five questions similar to the first five questions of MIDAS. Questions 1 and 2 ask about absenteeism due to headache and reduced productivity while at work despite headache (presenteeism). "Work" in this context may be as a paid employee or in self-employment. For children it includes schoolwork. To estimate total lost productive time from work, days wholly lost through absenteeism are added to days of presenteeism with <50% productivity; by way of counterbalance, headache-affected days are ignored in which productivity was nevertheless >50%. Questions 3 and 4 address household work in the same manner. "Household work" refers to the range of chores necessary in daily home living; while the nature of these may to an extent be gender-related, "household work" is not intended only to encompass work that tends, in many cultures, to be left to women (often termed "housework" in English). An instruction is given to avoid double-counting (on a single day, productivity both at work and in the performance of housework may suffer reductions of >50%). Question 5 relates to days on which social occasions are missed because of headache. There are three versions of HALT [bib_ref] The Headache-Attributed Lost Time (HALT) Indices: measures of burden for clinical management..., Steiner [/bib_ref]. Two of these, included here, are useful in headache management while serving different purposes. HALT-90 (also, Additional file 18)) counts days affected by headache during the preceding 3 months (90 days). In the initial assessment of a patient, this best balances two conflicting demands: the need to reflect a patient's illness over a representative period against the problems of recall error when that period is prolonged. During follow-up, the purpose of assessment shifts towards measurement of change attributable to treatment. Measures reflecting shorter periods than 3 months serve this purpose better: HALT-30 accordingly records days affected during the preceding 1 month (30 days). Question 5, however, gives rise to a simple count for which the unit is not whole days, and an error is introduced when this count is added to any of these scores. Furthermore, including question 5 in a summation of responses further invites double counting when a day lost at work is followed by a missed social event during the evening of the same day. Nevertheless, the count of lost social events does reflect additional burden, so question 5 is retained in HALT-90 and included in the total summed score (sum of all five questions), which gives rise to grading, as with MIDAS [bib_ref] Validity of the Migraine Disability Assessment (MIDAS) score in comparison to a..., Stewart [/bib_ref] (see [fig_ref] Table 8: Specific anti-migraine drugs, formulations and doses for step two [/fig_ref]. Grading has value in indicating the level of a patient's personal need and, perhaps, priority for treatment. But for assessment as a prelude to planning management, or for establishing the baseline impact, the individual summed scores are more informative than overall grades. Grading is not used by HALT-30. ## The headache under-response to treatment (hurt) questionnaire: a guide to follow-up in primary care This aid can be separately downloaded (Additional file 20). # Introduction Whenever treatment of a patient is started, or changed, follow-up either ensures that optimum treatment has been established or recognises that it has not. In the latter case, it should then identify any further change(s) to treatment that may be needed. Resources, services and expectations vary greatly between countries and cultures. Even in optimal circumstances, outcomes are rarely perfect. It is not always easy to know whether or not the outcome that has been achieved by an individual patient is the best that the patient can reasonably expect. For the non-specialist, one question that sometimes arises is: "What further effort, in hope of a better outcome, is justified?" A second question, which follows if it is thought that more should be done, may be "What is it that needs changing?" Lifting The Burden developed the HURT questionnaire [bib_ref] The Headache Under-Response to Treatment (HURT) questionnaire, an outcome measure to guide..., Steiner [/bib_ref] as an instrument that would not only assess outcome but also provide answers to these two questions, offering guidance to non-specialists on appropriate actions towards treatment optimisation. ## The headache under-response to treatment (hurt) questionnaire HURT is an 8-item self-administered questionnaire [fig_ref] Figure 5: The [/fig_ref] (also, Additional file 20)): therefore, it is quick and easy to use in primary care. It addresses headache frequency, disability, medication use and effect, patients' perceptions of headache "control" and their understanding of their diagnosis. Responses are either numerated in days over a 1-or 3-month recall-period or selected from Likert options. In either case, responses either fall into an area of "no concern" or are graded into one of three flagged areas indicating increasingly important treatment deficiencies; clinical advice is provided for each of latter. HURT has undergone psychometric validation and clinical testing in various settings and cultures [bib_ref] The Headache Under-Response to Treatment (HURT) questionnaire, an outcome measure to guide..., Steiner [/bib_ref]. 4 Patient information leaflets to aid headache management in primary care (2nd edition) These leaflets can be downloaded from the Additional file (see below). # Introduction Headache management is greatly facilitated when the patient understands his or her headache disorder and the treatment being proposed for it. Adherence is improved and a better outcome is likely. Good treatment of patients with any headache disorder therefore begins with explanations of their disorder and the purpose and means of management. Many people with recurrent headache wrongly fear underlying disease. ▪ Explanation is a crucial element of preventative management in patients with frequent migraine or tension-type headache, who are at particular risk of escalating medication consumption. The general principles of headache management place education and reassurance of patients first. These should never be omitted, but they take time, which is often not available. To assist, Lifting The Burden (LTB) has produced a series of Patient Information Leaflets (PILs). ## Lifting the burden's patient information leaflets The purpose of LTB's PILs is to provide the information and explanations to supplement any advice given directly by health-care providers. One or more may be handed to patients at the time of diagnosis, or later when needed. This purpose requires all content to be: ▪ accurate; ▪ appropriate, comprehensive, informative and helpful; ▪ cross-culturally relevant and understandable. In the original development of these PILs (first edition), LTB accordingly convened a writing and review group, drawn from all world regions, of headache specialists, primary-care physicians and patient representatives and advocates (see Acknowledgements, above). Seven PILs, produced with the help of an expert panel (see Acknowledgements, above), constitute the second edition: ▪ revisions (second editions) of the four leaflets on the important headache disorders in primary care: ▪ migraine (Additional file 21); ▪ tension-type headache (Additional file 22); ▪ cluster headache (Additional file 23); ▪ medication-overuse headache (Additional file 24); ▪ and of the fifth, explaining the relationships between female hormones and headache, which commonly raise questions from patients (Additional file 25); ▪ two new leaflets providing information for people affected by trigeminal neuralgia (Additional file 26) or persistent idiopathic facial pain (Additional file 27). 5 Translation, and the preservation of original meaning, of materials developed to improve headache management # Introduction The Global Campaign against Headache aims to reduce the burden of headache worldwide. It is, by definition and action, a worldwide campaign, pursuing this aim through activities in many countries in a programme intended to improve access to effective and appropriate headache services [bib_ref] Lifting the burden: the global campaign against headache, Steiner [/bib_ref] [bib_ref] Lifting The Burden: the global campaign to reduce the burden of headache..., Steiner [/bib_ref] [bib_ref] The Global Campaign, World Health Organization and Lifting The Burden: collaboration in..., Steiner [/bib_ref]. Foremost among the steps this requires is education about headache: both of health-care professionals and of people affected by headache disorders . The programme also entails the production of a range of written materials, on the one hand to support education and on the other as aids to headache management delivered, in the main, by non-experts in primary care [bib_ref] on behalf of the European Headache Federation and Lifting The Burden: the..., Steiner [/bib_ref]. These materials are invariably developed in English, but they need to be useful in health services in countries, and to people of many cultures, throughout the world. Ready access by people everywhere requires translation into numerous languages. While it is said that 13 languages (Arabic, Bengali, Chinese [Mandarin], Dutch, English, German, French, Hindi/Urdu, Italian, Japanese, Portuguese, Russian and Spanish) can together reach half the world's population, these languages are diverse, and translation is a technical challenge. Documents are produced for the Global Campaign with great care: translations should throw none of this away by failing to preserve their original meaning. The documents are of different typessome technical and some intended for lay users. When written materials are to become a supporting part of health care, the crucial importance of preserving meaning during translation becomes especially evident [bib_ref] Principles of good practice for the translation and cultural adaptation process for..., Wild [/bib_ref] [bib_ref] Translation, adaptation and validation of instruments or scales for use in cross-cultural..., Sousa [/bib_ref] [bib_ref] Translating instruments for cross-cultural studies in headache research, Peters [/bib_ref]. While the apparently simple aim of translation is to produce a translated version that is equivalent to the original version, "equivalence" in this context is not itself a simple concept. There is more than one type of equivalence. Predominant are semantic equivalence (equivalence in the meaning of words [bib_ref] Principles of good practice for the translation and cultural adaptation process for..., Wild [/bib_ref] and conceptual equivalence (important in the case of an instrument required to measure the same theoretical construct in different languages [bib_ref] Translating instruments into other languages: development and testing processes, Hilton [/bib_ref]. A suggested essential requirement of translations is that they are symmetrical, which means that the original and translated versions not only are loyal to meaning but also use language that is equally familiar to the target populations [bib_ref] Translating instruments into other languages: development and testing processes, Hilton [/bib_ref]. The likelihood of achieving all of these is greatly enhanced when translation follows standardised protocols, and is underpinned by explicit quality-control procedures. Without these, there is rather low probability that translated products will carry and impart the same meaning as the originals to users from a wide variety of cultures. Below we briefly describe good translation methodology, the different types of documents produced for the Global Campaign against Headache and the three protocols developed originally by an expert group convened by LTB [bib_ref] Aids for management of common headache disorders in primary care, Peters [/bib_ref]. We explain the purposes behind the protocols, and the importance of following them despite that they may appear somewhat onerous. We also update the protocols below, in a second edition (also, Additional files 28, 29 and 30). These should be used from now on for all Campaign materials, whether related to clinical management, policy or research. # Translation methods The different methods of translation aimed at securing quality include multiple forward translations with reconciliation, committee translation, and forward and back translation with reconciliation. International guidelines have tended to recommend forward and back translation [bib_ref] Principles of good practice for the translation and cultural adaptation process for..., Wild [/bib_ref] [bib_ref] Translation, adaptation and validation of instruments or scales for use in cross-cultural..., Sousa [/bib_ref] , used for example in translating the SF-36 in the International Quality of Life Assessment (IQOLA) project [bib_ref] Translating health status questionnaires and evaluating their quality: the IQOLA project approach, Bullinger [/bib_ref] and the EuroQoL five-dimensional questionnaire (EQ-5D) [bib_ref] From translation to version management: a history and review of methods for..., Rabin [/bib_ref]. Specifically for instruments used in headache management, Peters and Passchier recommended the following steps to achieve high-quality translations [bib_ref] Translating instruments for cross-cultural studies in headache research, Peters [/bib_ref] : 1. written guidance for translators and evaluators; 2. forward and back translation, using at least two forward translators and one back translator; 3. evaluation of translation for quality and equivalence; 4. pilot testing among a sample drawn from the target population (seeking comments on content and comprehensibility); 5. psychometric testing, when appropriate. None of these steps ensures good quality per se, but they contribute collectively to a high level of control of the translation. This increases the likelihood of good translation, and of equivalence between the original and target-language versions. It should be noted that focus on the translation process alone is insufficient: evaluation by representatives of target users is necessary to complete quality assurance. ## Lifting the burden's approach, and three translation protocols The methodological recommendations referred to above were for instruments used in research rather than clinical management. LTB on the other hand creates three different types of document according to purpose [fig_ref] Table 9: Migraine prophylactic drugs with evidence of efficacy in adults [/fig_ref]. In 2007, LTB convened a consensus group, whose members combined expertise in cross-cultural translation and familiarity with the aims and endeavours of LTB, and charged them with developing translation protocols for each document type. The group - Ensure rigour of the translation process and quality of the translated products; - Be suitable and have utility across different countries and cultures; - Include target-user evaluation; - Be pragmatic, recognising that unduly onerous protocols would be rejected and therefore unhelpful. adapted the earlier recommendations accordingly, producing three different protocols to suit the three types. In the process, they stipulated five essential criteria [fig_ref] Table 9: Migraine prophylactic drugs with evidence of efficacy in adults [/fig_ref] [bib_ref] Aids for management of common headache disorders in primary care, Peters [/bib_ref] , to which all three protocols conform. Although there are many similarities between the three protocols, key differences were introduced to make translation less onerous to the extent this was possible without compromising quality. ## Translation protocol for lay documents (2nd edition) This protocol can be separately downloaded (Additional file 28). These guidelines are for the translation of documents ("lay documents") produced for the Global Campaign against Headache as information for lay people, including people with headache, the general public and the lay media. Translations of all lay documents should follow these guidelines to ensure a high quality of translation and to be approved by LTB. ## Procedure Translation should follow five steps. ## Coordination of the translation A translation coordinator, who oversees but does not carry out the translation, is selected according to the following criteria: ▪ bilingual in English and the target language (ideally a native speaker and resident of the country of the target language); ▪ has ability to mediate between different translators and to understand the points of view of lay and professional translators. If the coordinator is not a native speaker, a referee (native speaker) must be nominated. The referee cannot be involved in the translation process, and is called upon to arbitrate should irreconcilable views among translators prevent the production of a consensus-based translation. The tasks of the coordinator include: ▪ selecting the translators, assessor and review panel (and referee when necessary); ▪ organising and overseeing the translation, including meeting with the translators to produce a consensusbased translation; ▪ organising and overseeing the quality assurance of the translation; ▪ producing the report of the translation process. ## Translation into target language Two independent translations into the target language of the original document must be produced. The two translations may be carried out by two individual translators, by two pairs of translators (one translates and the second of the pair reviews the translation) or by two independent panels of translators (with 3-4 members in each panel). If a translator pair or a panel is used, one person should be identified as lead, and be responsible for liaising with the translation coordinator. The two individuals, pairs or panels may not confer with each other until each has produced their translation. Translators are selected according to the following criteria: ▪ native speaker of the target language; ▪ at least one (individual, pair or panel) must be headache or medical expert(s) ▪ (ideally, the other is a professional translator or bilingual person, pair or panel skilled in language/ linguistics, such as a teacher or journalist; if no such translator is available, then a second headache or medical expert [individual, pair or panel] may be used). Translators are instructed to: ▪ keep translations simple, avoiding technical language, so that the documents can be understood by lay people of average reading ability; ▪ make semantic and conceptual translations (rather than literal), so that the meanings of the words and phrases remain as in the original document; ▪ keep a record of any parts that they found difficult to translate. ## Production of a consensus-based translation The coordinator works with the two translators, or the leads of the translation pairs or panels, to reconcile differences between the two translations and produce a consensus-based translation. There are three steps to this process: ▪ the translators each send their translations to the coordinator; ▪ the coordinator makes an initial comparison of the two translations and highlights and records any parts of them that are substantially different; ▪ the coordinator and translators (or leads) meet (or, alternatively, hold a teleconference) to discuss these parts and any other problem areas, agreeing through consensus on one translation. If the translators cannot reach a consensus on any part, the coordinator, if a native speaker, makes the final decision. If the coordinator is not a native speaker, the referee is called upon to make the final decision. ## Quality assessment a) Linguistic review One assessor is selected according to the following criteria: ▪ a lay person (not medically qualified and not a researcher); ▪ a native speaker of the target language (and, ideally, a resident of the relevant country) with good understanding of linguistic factors (such as grammar, readability) but not necessarily bilingual. ## The assessor is instructed: ▪ that the document is to be understood by lay people of average reading ability; ▪ to assess the consensus-based translation for readability, grammatical correctness and cultural suitability; ▪ to keep a record of his/her comments and send these to the coordinator. b) Target audience review A second quality assessment judges suitability for the intended audience. It is carried out by a review panel of six people selected according to the following criteria: ▪ affected by headache disorders; ▪ native speakers of the target language and not necessarily bilingual. Each panel member assesses the consensus-based translation individually, without reference to the others, sending comments to the coordinator. ## C) production of final quality-assured translation Minor changes suggested by the assessor or panel members may be implemented by the coordinator (in consultation if necessary with the referee). When substantial changes are suggested, the coordinator must liaise with the translators, and referee if necessary, in order to agree on an alternative translation. If substantial changes are agreed, the quality of the new translation should be re-assessed by the same processes. ## Report of the translation process The coordinator should produce a report in English on the translation process, documenting the details (qualifications and experience) of the translators, referee, assessors and review panel members. Furthermore, the report will contain: ▪ the original document; ▪ the two first translations, the consensus-based translation, any other intermediate versions and the final translation; ▪ a record of any substantial difficulties encountered during the translation (difficulties may include problematic words or parts of the document that were difficult to translate, points of disagreement and alternatives, or any aspects on which it was difficult to achieve consensus or that were highlighted during the quality assessment of the translation). The report is to be sent to LTB (mail@l-t-b.org), addressed to the Company Secretary. ## Resolving problems Any problems with or queries about this translation process should be addressed to LTB (mail@l-t-b.org). ## Translation protocol for technical documents (2nd edition) This protocol can be separately downloaded (Additional file 29). These guidelines are for the translation of documents ("technical documents") produced for the Global Campaign against Headache and aimed at health-care professionals. Translations of all technical documents should follow these guidelines to ensure a high quality of translation and to be approved by Lifting The Burden. ## Procedure Translation should follow five steps. ## Coordination of the translation A translation coordinator, who oversees but does not carry out the translation, is selected according to the following criteria: ▪ a headache expert; ▪ bilingual in English and the target language (ideally a native speaker and a resident of the country of the target language); ▪ has ability to mediate between different translators and to understand the points of view of lay and professional translators. If the coordinator is not a native speaker, a referee (native speaker) must be nominated. The referee cannot be involved in the translation process, and is called upon to arbitrate should irreconcilable views among translators prevent the production of a consensus-based translation. The tasks of the coordinator include: ▪ selecting the translators and assessors (and referee when necessary); ▪ organising and overseeing the translation, including meeting with the translators to produce a consensusbased translation; ▪ organising and overseeing the quality assurance of the translation; ▪ producing the report of the translation process. ## Translation into target language Two independent translations into the target language of the original document must be produced. The two translations may be carried out by two individual translators, by two pairs of translators (one translates and the second of the pair reviews the translation) or by two independent panels of translators (with 3-4 members in each panel). If a translator pair or a panel is used, one person should be identified as lead, and be responsible for liaising with the translation coordinator. The two individuals, pairs or panels may not confer with each other until each has produced their translation. Translators are selected according to the following criteria: ▪ native speakers of the target language; ▪ at least one (individual, pair or panel) must be headache expert(s) or primary-care physician(s), according to the intended audience of the document; ▪ (ideally, the other is a professional translator or bilingual person, pair or panel skilled in language/linguistics, such as a teacher or journalist; if no such translator is available, then a second headache expert or primary-care physician [individual, pair or panel] may be used). ## Translators are instructed to: ▪ keep translations professional, using technical language; ▪ make semantic and conceptual translations (rather than literal), so that the meanings of the words and phrases remain as in the original document; ▪ avoid invention (adding their own ideas to the text); ▪ keep a record of any parts that they found difficult to translate. ## Production of a consensus-based translation The coordinator works with the two translators, or the leads of the translation pairs or panels, to reconcile differences between the two translations and produce a consensus-based translation. There are three steps to this process: ▪ the translators each send their translations to the coordinator; ▪ the coordinator makes an initial comparison of the two translations and highlights and records any parts of them that are substantially different; ▪ the coordinator and translators (or leads) meet (or, alternatively, hold a teleconference) to discuss these parts and any other problem areas, agreeing through consensus on one translation. If the translators cannot reach a consensus on any part, the coordinator, if a native speaker, makes the final decision. If the coordinator is not a native speaker, the referee is called upon to make the final decision. ## Quality assessment Three assessors are selected according to the following criteria: ▪ either headache experts or primary-care physicians, according to the intended audience of the document; ▪ native speakers of the target language (and, ideally, a resident of the relevant country) with good understanding of linguistic factors (such as grammar, readability) but not necessarily bilingual. ## The assessors are instructed: ▪ that the document is to be utilized by health-care professionals (specified, when appropriate); ▪ to assess the consensus-based translation for readability, grammatical correctness, medical correctness and cultural suitability; ▪ to keep records of their comments and send these to the coordinator. Each assessor reviews the consensus-based translation individually, without reference to the others, sending comments to the coordinator. Minor changes suggested by the assessors may be implemented by the coordinator (in consultation if necessary with the referee). When substantial changes are suggested, the coordinator must liaise with the translators, and referee if necessary, in order to agree on an alternative translation. If substantial changes are agreed, the quality of the new translation should be re-assessed by the same processes. ## Report of the translation process The coordinator should produce a report in English on the translation process, documenting the details (qualifications and experience) of the translators, referee and assessors. Furthermore, the report will contain: ▪ the original document; ▪ the two first translations, the consensus-based translation, any other intermediate versions and the final translation; ▪ a record of any substantial difficulties encountered during the translation (difficulties may include problematic words or parts of the document that were difficult to translate, points of disagreement and alternatives, or any aspects on which it was difficult to achieve consensus or that were highlighted during the quality assessment of the translation). The report is to be sent to LTB (mail@l-t-b.org), addressed to the Company Secretary. ## Resolving problems Any problems with or queries about this translation process should be addressed to LTB (mail@l-t-b.org). ## Translation protocol for hybrid documents (2nd edition) This protocol can be separately downloaded (Additional file 30). These guidelines are for the translation of documents ("hybrid documents") produced for the Global Campaign against Headache and aimed at people with headache, but to be used in support either of clinical practice or of research (such as questionnaires, diaries, survey instruments). Translations of all hybrid documents should follow these guidelines to ensure a high quality of translation and to be approved by Lifting The Burden. ## Procedure Translation should follow six steps. ## Coordination of the translation A translation coordinator, who oversees but does not carry out the translation, is selected according to the following criteria: ▪ has technical knowledge (ie, understands the concepts underlying the questions or instrument being translated); ▪ bilingual in English and the target language (ideally a native speaker and a resident of the country of the target language); ▪ has ability to mediate between different translators and to understand the points of view of lay and professional translators. If the coordinator is not a native speaker, a referee (native speaker) must be nominated. The referee cannot be involved in the translation process, and is called upon to arbitrate should irreconcilable views among translators prevent the production of a consensus-based translation. The tasks of the coordinator include: ▪ selecting the forward-and back-translators, assessor and review panel (and referee when necessary); ▪ liaising when necessary with the document author; ▪ organising and overseeing the forward-and backtranslations, including meeting with the translators first to produce a consensus-based forward-translation and again (when necessary) to resolve discrepancies discovered during back-translation; ▪ organising and overseeing the quality assurance of the translation; ▪ producing the report of the translation process. ## Translation into target language Two independent forward-translations into the target language of the original document must be produced. The two translations may be carried out by two individual translators, by two pairs of translators (one translates and the second of the pair reviews the translation) or by two independent panels of translators (with 3-4 members in each panel). If a translator pair or a panel is used, one person should be identified as lead, and be responsible for liaising with the translation coordinator. The two individuals, pairs or panels may not confer with each other until each has produced their translation. Translators are selected according to the following criteria: ▪ native speaker of the target language; ▪ at least one (individual, pair or panel) must be headache or medical expert(s); ▪ (ideally, the other is a professional translator or bilingual person, pair or panel skilled in language/ linguistics, such as a teacher or journalist; if no such translator is available, then a second headache or medical expert [individual, pair or panel] may be used). Translators are provided by the coordinator with an explanation of the purpose and concepts underlying the ▪ keep translations simple, avoiding technical language, so that the documents can be understood by lay people of average reading ability; ▪ make semantic and conceptual translations (rather than literal), so that the meanings of the words and phrases remain as in the original document; ▪ keep a record of any parts that they found difficult to translate. ## Production of a consensus-based translation The coordinator works with the two translators, or the leads of the translation pairs or panels, to reconcile differences between the two translations and produce a consensus-based translation. There are three steps to this process: ▪ the translators each send their translations to the coordinator; ▪ the coordinator makes an initial comparison of the two translations and highlights and records any parts of them that are substantially different; ▪ the coordinator and translators (or leads) meet (or, alternatively, hold a teleconference) to discuss these parts and any other problem areas, agreeing through consensus on one forward translation. If the translators cannot reach a consensus on any part, the coordinator, if a native speaker, makes the final decision. If the coordinator is not a native speaker, the referee is called upon to make the final decision. ## Back-translation One back-translation of the consensus-based forward translation is carried out by one translator selected according to the following criteria: ▪ a native speaker of English; ▪ either a headache or medical expert, or a professional or bilingual lay translator skilled in language/linguistic issues. The back-translation is sent to the coordinator to forward to the original author with a request to compare the original and back-translated versions and assess their conceptual equivalence. If the author believes conceptual equivalence is not maintained, he or she should be asked to explain the reasons to the coordinator. Following this conceptual comparison, minor amendments may be implemented by the coordinator (in consultation with the referee when appropriate). When substantial discrepancies have been highlighted, the coordinator calls a second meeting (or teleconference) with the forward-translators and back-translator to locate their causes and eliminate them by making changes either to the consensus-based forward-translation or to the back-translation as appropriate. This process produces the back-checked consensusbased translation. ## Quality assessment a) Linguistic review One assessor is selected according to the following criteria: ▪ a lay person (not medically qualified and not a researcher); ▪ a native speaker of the target language (and, ideally, a resident of the relevant country) with good understanding of linguistic factors (such as grammar, readability) but not necessarily bilingual. ## The assessor is instructed: ▪ that the document is to be understood by lay people of average reading ability; ▪ to assess the back-checked consensus-based translation for readability, grammatical correctness and cultural suitability; ▪ to keep a record of his/her comments and send these to the coordinator. b) Target audience review A second quality assessment judges suitability for the intended audience. A review panel of six people are selected according to the following criteria: ▪ affected by headache disorders; ▪ native speakers of the target language and not necessarily bilingual. Each panel member assesses the back-checked consensus-based translation individually, without reference to the others, sending comments to the coordinator. c) Production of final quality-assured translation Minor changes suggested by the assessor or panel members may be implemented by the coordinator (in consultation if necessary with the referee). When substantial changes are suggested, the coordinator must liaise with the forward-translators, and referee if necessary, to agree on an alternative translation. If substantial changes are agreed, the back-translation process should be repeated and, subsequently, the quality of the new translation should be re-assessed. ## Report of the translation process The coordinator should produce a report in English on the translation process, documenting the details (qualifications and experience) of the translators, referee, assessors and review panel members. Furthermore, the report will contain: ▪ the original document; ▪ the two forward-translations, the consensus-based translation, the back-translation, the back-checked consensus-based translation, any other intermediate versions and the final translation; ▪ a record of any substantial difficulties encountered during the translation (difficulties may include problematic words or parts of the document that were difficult to translate, points of disagreement and alternatives, or any aspects on which it was difficult to achieve consensus or that were highlighted during the quality assessment of the translation). The report is to be sent to LTB (mail@l-t-b.org), addressed to the Company Secretary. ## Resolving problems Any problems with or queries about this translation process should be addressed to LTB (mail@l-t-b.org). ## Commonalities between the three translation protocols All protocols aim for semantic and conceptual equivalence: literal translations often produce wording that is not acceptable, is unnatural or has wrong meaning in the target language. Lay and hybrid translation protocols avoid technical jargon, while recognising that medical terminology must nonetheless be accurate. All protocols prescribe two independent forward translations with reconciliation to produce a consensus version. Even when a translator appears to have all the requisite skills, a single translation is unreliable: a non-expert in the field may misunderstand, while experts tend to "invent"introducing their own ideas to "improve" the original. Multiple forward translations are a guard against biased translation and misinterpretations, while helping to highlight areas that are difficult to translate or have not been translated well. All protocols rely on a coordinator, and specify the necessary skills of the translators. The coordinator, bilingual but a native speaker of the target language, selects the translators and organises and oversees (but does not carry out) the translations. Ideally the coordinator should live in the country of the target language in order to be wholly familiar with its culture, but this raises some issues: what, for example, is the native country for Spanish? The obvious answer is neither a complete answer nor necessarily correct: cultural (and to some extent linguistic) differences between Spain and Spanish-speaking countries in Latin America are not negligible. These issues may influence the selection of coordinator and, probably more importantly, of the translators. For Global Campaign translations, support in these selections can be given by LTB. The forward translations are both best made by translators who are translating into their native language [bib_ref] Principles of good practice for the translation and cultural adaptation process for..., Wild [/bib_ref]. But, further, they must speak this target language correctly and with linguistic competence, which is not always the case for native speakers and cannot be assumed. The forward translators should also have an understanding of the culture in which the target language is used, and again, ideally, should therefore be living in the country of the target language. Although emphasis in good translating is often put on linguistic skills, translators also need some knowledge and understanding of the topic area or content of the material [bib_ref] Translation and cross-cultural adaptation of outcome measurements for schizophrenia. EPSILON Study 2...., Knudsen [/bib_ref]. This might, according to the nature of what is being translated, be from the perspective of health-care professional or person with headache, but all three LTB protocols require that at least one forward translator is a headache or medical expert. The coordinator decides whether individual or panel translations are more suitable for the culture and language. Individual translations require fewer translators but, where skilled and otherwise qualified individual translators are not available, a group of translators meeting together as a panel can contribute a wider range of competencies to the translation process. A panel translation is considered to be one translation: the two forward translations should be generated independently. From the two forward translations, one consensus version is produced in a reconciliation process involving direct collaboration between the coordinator and the translators. This step resolves discrepancies between the two forward translations [bib_ref] A comprehensive method for the translation and cross-cultural validation of health status..., Eremenco [/bib_ref] and allowsin fact, requirescomparison of the translated version with the original. The coordinator's role here is to negotiate agreement between the translators, having the final say when the two translators cannot agree. All protocols require quality evaluation, conducted with representatives of the respective target audiences (either people with headache or health-care professionals). These, too, should be native speakers of the target language, but not necessarily bilingual (in English). This additional process ensures that translations make sense, have meaning and are otherwise acceptable to the target audience. Specifically it allows translations to be amended, when necessary, to be more "user-friendly". Finally, all protocols require a full report of these processes, including all translated versions (intermediate and final) and listings of any encountered translation difficulties. This report is sent to LTB. Reporting back in this way to LTB helps to ensure that the translation procedures have been followed, and also that there are not several translations into one target language. It also allows LTB to make already translated documents widely available. ## Differences between the three translation protocols Important differences between the three protocols adapt the recommended procedures according to the type of document being translated. They make translation less onerous whenever this is possible without compromising quality. First, the criteria for coordinators differ. For hybrid translations, the coordinator must have technical knowledgeie, the ability to understand the concepts underlying the instrument to be translated. Hybrid documents are often questionnaires, and accurate translation of items requires capture of the conceptual rather than the literal meaning. In contrast, the coordinator for technical translations must be a headache expert, since the target audience for these is medical and health professionals. A headache expert is more likely to know the correct terminology for this target audience, which is of importance when coordinating the production of a consensus version of the translation. Second, the protocol for hybrid documents requires back translation as an additional step. These documents may be used for research purposes and cross-cultural comparisons, and this further process increases the likelihood of conceptual equivalence, whereas the approach to lay and technical documents is more pragmatic (ie, two forward translations only). This decision reflected the view that more emphasis should rest on quality evaluation by the more-clearly defined target audiences for both lay and technical documents. Consequently, a third difference lies in how translation quality is evaluated. For hybrid and lay documents, evaluation includes a linguistic review in addition to testing by the target audience. This is conducted by a person with a good understanding of language, who need not be a person with headache or a health-care professional. This process is important to exclude jargon, and to make hybrid and lay documents understandable at least to those of average reading ability. ## Updates to the protocols The three protocols were originally published in 2007 [bib_ref] Aids for management of common headache disorders in primary care, Peters [/bib_ref]. In this second edition, the changes are minor: there are new support details, but no material changes have been necessary in the methods prescribed in each. Further updates will be made when circumstances require them. Meanwhile, these second-edition protocols should be used from now on for all Campaign materials, whether related to clinical management, policy or research. ## Resources for translation of lifting the burden documents These three protocols serve several purposes, including standardisation of translations for Global Campaign materials. They set out clear steps for the coordinator, translators and evaluators. Their success in achieving their purpose will depend on their being carefully followed. Those proposing to undertake translation into any language of any Global Campaign product should do so in consultation with LTB. It may be that an accepted translation already exists. By this token, all translations completed in accordance with the appropriate protocol, along with the translation report, should be lodged with LTB (addressed to the Company Secretary [mail@l-t-b.org]). Any problems or queries may be addressed to LTB (mail@l-t-b.org). The Global Campaign depends heavily on volunteers in all its endeavours. Clearly, the main resourcerequirement in translating is for volunteers able to coordinate, perform or evaluate the translation. Hybrid translations call for a minimum of 11 people, lay translations a minimum of 10 people, and technical documents a minimum of five. More are required if panels are used to produce any of the translations. Although these may seem large numbers of people, other translation protocols (eg, EuroQol [bib_ref] From translation to version management: a history and review of methods for..., Rabin [/bib_ref] , ISOQOL [bib_ref] Translating health status questionnaires and evaluating their quality: the IQOLA project approach, Bullinger [/bib_ref] impose similar or greater demands. The IQOLA project used six translators, a national principal investigator (equivalent to our coordinator) and pilot testing with up to 50 respondents [bib_ref] Translating health status questionnaires and evaluating their quality: the IQOLA project approach, Bullinger [/bib_ref]. The recommendations of the ISPOR Task Force for Translation and Cultural Adaptation call for 9-12 people [bib_ref] Principles of good practice for the translation and cultural adaptation process for..., Wild [/bib_ref]. While the translation protocol for hybrid documents is more elaborate because of the additional back translation, and requires more translators, these documents, usually questionnaires, tend to be relatively short. Hence, back translation is not too onerous. Longer lay and technical documents can, of course, often be divided into small sections to reduce the burden of translation on any one translator. ## Endnotes Radojicic (Serbia), U Reuter (Germany), Elena Ruiz de la Torre (Spain), D Szok (Hungary), M Togha (Iran), A Van Dycke (Belgium), J Versijpt (Belgium), MM Wysocka-Bąkowska (Poland), J Zidverc-Trajkovic (Serbia). Translation, and the preservation of original meaning, of materials developed to improve headache management We are very grateful to JM Bertolote (Switzerland/Brazil), C Houchin (UK) and T Kandoura (UK), members of the original expert consensus group, which developed the translation protocols in their original versions. # Funding European Headache Federation (EHF) provided funding for meetings of the writing group for the European principles of management of headache disorders in primary care (Section 2). Lifting The Burden (LTB), International Headache Society and EHF supported the development and collation of the Instruments and other materials to aid diagnosis and management of headache disorders in primary care (Section 3). No financial support was received for development of Patient information leaflets to aid headache management in primary care (2nd edition) (Section 4). LTB covered the expenses of the expert consensus meeting in 2007 for Translation, and the preservation of original meaning, of materials developed to improve headache management (Section 5); otherwise there was no funding for the development of these protocols. No other financial support was received for the preparation of this manuscript. Availability of data and materials All these materials are freely available to clinicians and others who may find them useful for non-commercial purposes. # Authors' contributions European principles of management of headache disorders in primary care As members of the writing group, TJS, RJ, ZK, ML, EAM, VO, KP and PM contributed equally to the development of these principles. TJS drafted this section of the manuscript; all authors critically reviewed and approved its final version. Instruments and other materials to aid diagnosis and management of headache disorders in primary care All these members of the writing group contributed to the collation of these instruments. JO is chairman and TJS is secretary of the Classification Committee of the International Headache Society, which developed the International Classification of Headache Disorders, 3rd edition (ICHD-3). These authors contributed equally to making the abbreviated version herein. RJ was primarily responsible for developing the headache diary and EAM for the headache calendar. TJS led development of the HALT Indices and HURT questionnaire. EAM and RJ were lead writers of the information leaflets, reviewed and approved by all members of the writing group. TJS drafted the encompassing text, which all authors reviewed and approved. Translation, and the preservation of original meaning, of materials developed to improve headache management TJS and MP contributed equally to the translation protocols and accompanying text. Ethics approval and consent to participate Not applicable. ## Consent for publication Not applicable. Competing interests TJS, ML, EAM, JO and MP declare no conflicts of interest. RJ has received honoraria as a speaker and/or conducted clinical trials for Allergan, ATI, Electrocore and Pfizer. ZK has received honoraria as a speaker and/or consultant from Allergan, Bayer, Ely-Lilly, Novartis and TEVA. VO has received honoraria as a speaker and/or consultant from Allergan, Pfizer and Takeda and has conducted clinical trials for Amgen. KP has received honoraria as a speaker and/or consultant, and/or received research support, from Allergan, Amgen/Novartis, Autonomic Technologies Inc., Ely-Lilly and Teva. PM is or has been an Advisory Board member for Allergan, AMGEN, Novartis and TEVA and a Speakers' Bureau member for ACRAF and Elythrapharma, and has received royalties from Springer and travel support from the European Medicines Agency and SpringerNature. [fig] ▪: The use of outcome measures is recommended to evaluate treatment and guide follow-up. The following are included here, among the management aids: the HURT questionnaire, developed by Lifting The Burden expressly to guide management in primary care (see 3.5.2 The Headache Under-Response to Treatment (HURT) questionnaire (also, Additional file 20)); the HALT-30 Index, to record lost productive time in the preceding month (see 3.4.2 The Headache-Attributed Lost Time (HALT) Indices (also, Additional file 19) [/fig] [fig] 5. 2: The Headache Under-Response to Treatment (HURT) questionnaire (also, Additional file 20)); ▪ the HALT-30 Index records lost productive time during the preceding month (see 3.4.2 The Headache-Attributed Lost Time (HALT) Indices (also, Additional file 19)) [/fig] [fig] First: : • reduce efficacy of oral contraceptives; • may induce hyponatraemia (especially oxcarbazepine): regular monitoring is advised; • Mmay induce osteoporosis in long-term treatment: prophylaxis against this is advised Second-line (either as monotherapy or as add-on medication): • Gabapentin 600-3600 mg daily • Pregabalin 150-600 mg daily • Lamotrigine 200-1000 mg daily (very slow up-titration necessary) [/fig] [fig] •: Intolerance is reduced by starting at a low dose (10 mg) and incrementing by 10-25 mg every 1-2 weeks; Nortriptyline has fewer anticholinergic side-effects but less good evidence of efficacy Second line (either as monotherapy or as add-on medication): Gabapentin 600-3600 mg daily Pregabalin 150-600 mg daily Steiner et al. [/fig] [fig] Figure 3, Figure 4: The The Halt-30 Index [/fig] [fig] Figure 5: The [/fig] [table] Table 2: Summary of features distinguishing the important primary headache disorders (NB: two or more of these disorders may occur concomitantly) [/table] [table] Table 3: Symptoms of aura (developing gradually over ≥5 min and usually resolving within 60 min) [/table] [table] Table 4: Diagnostic questions to ask in the history How many different headaches types does the patient have? A separate history is needed for each. [/table] [table] Table 5: Specific warning features ("red flags") in the history New headache in a patient with a history of cancer or immunodeficiency (including HIV infection) Likely to be secondary headache New headache in a patient with a history of polymyalgia rheumatica Temporal (giant cell) arteritis New headache in a patient with a family history of glaucoma Glaucoma [/table] [table] Table 7: Recommended drugs and doses for acute migraine therapy, step one [/table] [table] Table 8: Specific anti-migraine drugs, formulations and doses for step two (listed alphabetically) [/table] [table] Table 9: Migraine prophylactic drugs with evidence of efficacy in adults (drugs are listed in a suggested order of use; within classes [beta blockers and CGRP monoclonal antibodies], they are listed alphabetically) [/table] [table] Table 10: Drugs used by specialists in chronic migraine prophylaxis Topiramate, 50 mg or more twice daily Onabotulinum toxin A, 155-195 units by multisite injection• not licensed for chronic migraine in some countries, or • not reimbursed, and/or • regulators require prior failure of two or more of the drugs used in prophylaxis of episodic migraine [/table] [table] Table 11: Analgesics for episodic tension-type headache [/table] [table] Table 12: Prophylactic drugs with some evidence of efficacy in frequent episodic or chronic tension-type headache ▪ Use of a calendar is recommended to monitor acute medication use or overuse, or to encourage adherence to prophylactic medication, and to record treatment effect. An example of a simple calendar is included here among the management aids (see 3.3 Headache diary and calendar to aid diagnosis and follow-up in primary care (also, Additional file 17)). ▪ The use of outcome measures is recommended to guide follow-up. The following are included here among the management aids: [/table] [table] Table 14: Transition therapies used in cluster headache by specialists [/table] [table] Table 13: Acute therapies used in cluster headache by specialists [/table] [table] Table 15: Drugs used by specialists in maintenance prophylaxis of cluster headache [/table] [table] Table 16: Drugs used by specialists in trigeminal neuralgia prophylaxis [/table] [table] Table 19: The three types of document produced for the Global Campaign, the expert consensus group and their five essential criteria [/table]	None	https://thejournalofheadacheandpain.biomedcentral.com/track/pdf/10.1186/s10194-018-0899-2	None
e9b74b649543bdfdf50b429a2c6f2588aa16ed56	pubmed	Clinical practice guidelines for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons	Clinical practice guidelines for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons The American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) are dedicated to ensuring high-quality innovative patient care for surgical patients by advancing the science, prevention, and management of disorders and diseases of the colon, rectum, and anus as well as minimally invasive surgery. The ASCRS and SAGES society members involved in the creation of these guidelines were chosen because they have demonstrated expertise in the specialty of colon and rectal surgery and enhanced recovery. This consensus document was created to lead international efforts in defining quality care for conditions related to the colon, rectum, and anus and develop clinical practice guidelines based on the best available evidence. While not proscriptive, these guidelines provide information on which decisions can be made and do not dictate a specific form of treatment. These guidelines are intended for the use of all practitioners, healthcare workers, and patients who desire information about the management of the conditions addressed by the topics covered in these guidelines. These guidelines should not be deemed inclusive of all proper methods of care nor exclusive of methods of care reasonably directed toward obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all the circumstances presented by the individual patient. This clinical practice guideline represents a collaborative effort are designed to improve patient outcomes . Outcomes of interest include alleviating nausea and pain, achieving early return of bowel function, and decreasing rates of wound infection and length of hospital stay . Although numerous perioperative protocols exist, this clinical practice guideline will evaluate the evidence in support of individual measures to improve patient outcomes after elective colon and rectal resections. Implementation of ERPs in colorectal surgery has been shown to reduce morbidity rates and decrease length of stay without increasing readmission rates . A 2011 Cochrane review found that ERPs were associated with reduced overall complication rates and length of stay when compared to conventional perioperative patient management . Subsequent studies have shown that ERPs are associated with reduced healthcare costs, improved patient satisfaction, lower rates of complications, and reduced mortality [2, 10, 15-20]. ERPs are also associated with improved outcomes regardless of whether patients undergo laparoscopic or open surgery . In addition, multiple studies have shown that ERPs are safe and efficacious in elderly patient populations . Studies also support that ERPs should not be implemented and maintained dogmatically, but rather require ongoing compliance evaluation and continual quality improvement . Greater adherence to ERPs is associated with decreased complications and shorter length of stay (LOS) . There are many different preoperative, intraoperative, and postoperative components of a typical ERP and it is difficult to identify which are most beneficial within the "bundle" of simultaneously implemented measures. This clinical practice guideline will evaluate the evidence pertaining to different components of ERPs for colorectal surgery. While ostomy surgery, deep vein thrombosis (DVT) prevention, bowel preparation, and frailty are discussed in this CPG, a detailed review of these topics is beyond the scope of this Clinical Practice Guideline; these topics are addressed in depth in other ASCRS Clinical Practice Guidelines . # Methodology The original clinical practice guidelines for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic surgeons were published in 2017 . The present guideline was constructed using the 2017 guidelines as a platform. Compared with 2017, this guideline has 3 new recommendations and 5 statements with updated levels of evidence. All other statements have been reviewed and updated with current evidence [fig_ref] Table 1: What is New in the 2022 ASCRS Enhanced Recovery After Colon and... [/fig_ref]. A systematic search was conducted under the guidance of a librarian. The details of specific search strategies including search terms, inclusion criteria, exclusion criteria, and total number of studies identified, and tables of evidence for each statement are available in the digital supplemental materials. In brief, a systematic search from January 1, 2016 to May 1, 2022 was conducted using the Cochrane Library, EMBASE, and the MEDLINE databases utilizing a variety of key word combinations. A supplemental search was conducted using related articles and bibliographies of previously identified articles. Directed searches of the embedded references from the primary articles were also performed in certain circumstances. Prospective, randomized controlled trials (RCTs) and meta-analyses were given preference. A total of 7,712 abstracts were identified; 6,962 articles were excluded and a total of 750 full-text articles were evaluated. Of those, 547 were excluded, and along with 212 articles from the 2017 guidelines, a total of 415 articles were included in the final document [fig_ref] Figure 1: PRISMA literature search flow sheet [/fig_ref]. The final grade of recommendation was performed using the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system [fig_ref] Table 2: The GRADE system-grading recommendations GRADE Grades of Recommendation, Assessment, Development, and Evaluation,... [/fig_ref]. When agreement was incomplete regarding the evidence base or treatment guideline, consensus from the committee chair, vice chair, and 2 assigned reviewers determined the outcome. Members of the ASCRS Clinical Practice Guidelines Committee worked together with members of the SAGES Colorectal Committee from inception to publication. Recommendations formulated by the subcommittee were reviewed by the entire Clinical Practice Guidelines Committee of ASCRS and the Colorectal Committee of SAGES. The submission was approved by both the ASCRS and SAGES executive council and then peer reviewed by the Diseases of the Colon & Rectum and Surgical Endoscopy. In general, each ASCRS Clinical Practice Guideline (including joint guidelines) is updated every 5 years. No funding was received for preparing this guideline and the authors have declared no competing interests related this material. This guideline conforms to the Appraisal of Guidelines for Research and Evaluation (AGREE) checklist. ## Preoperative interventions ## Preadmission counseling A preoperative discussion regarding clinical milestones and discharge criteria should typically be performed prior to surgery. Grade of recommendation: strong recommendation based on low-quality evidence, 1C Preadmission counseling regarding milestones and discharge criteria are a well-established cornerstone of ERPs . Single-center case series, prospective cohort studies, systematic reviews, and RCTs have reported the benefits of using an ERP that includes preoperative education describing milestones and discharge criteria. [2, 51-72]. Furthermore, compliance with an ERP that includes preoperative patient education is associated with decreased length of stay and decreased complication rates . Despite the benefit, in-person preoperative counseling can be resource intensive, which may limit its widespread use; prescripted phone calls may provide sufficient counseling while saving resources . ## Patients undergoing ileostomy creation should receive stoma teaching and counseling regarding how to avoid dehydration. grade of recommendation: strong recommendation based on moderate-quality evidence, 1b The creation of an ostomy is an independent risk factor for prolonged length of stay after colorectal surgery . Several single-center and multicenter studies as well as a systematic review have shown that structured patient stoma education significantly improves quality of life, facilitates psychosocial adjustment, and reduces hospital length of stay and hospital costs . Ostomy education can also impact readmission rates [80, 95-97]. As dehydration is the most common cause of readmission following ileostomy creation , counseling patients regarding dehydration avoidance is an important element of ERP . In a prospective study of 42 patients versus 168 historical controls, implementation of an ileostomy pathway in which patients were directly engaged in ostomy management, discharged with supplies for measuring input/output, and set up with visiting nurse services reduced the readmission rate for dehydration from 15.5 to 0% (p = 0.02) . Others have reported similar reductions in readmission rates for dehydration when utilizing an ERP focused on ostomy education [100-102]. Gonella et al. in a retrospective study of 296 patients showed that the hospital readmission rate within 30-day postdischarge for dehydration dropped from 9 to 3.9% after protocol application . ## Preadmission nutrition and bowel preparation Clear liquids may be continued up to 2 h prior to general anesthesia. Grade of recommendation: strong recommendation based on high-quality evidence, 1A Drinking clear fluids up to 2 h before induction of anesthesia, according to data from multiple RCTs, is safe and improves patients' sense of well-being . The same RCTs have also reported that ingesting clear liquids within ## Preadmission orders Standardized order sets should be utilized in enhanced recovery pathways. Grade of recommendation: weak recommendation based on low-quality evidence, 2C Comprehensive, multifaceted enhanced recovery protocols are complex and require a multidisciplinary collaboration between stakeholders including nursing teams, A meta-analysis evaluating SSI prevention bundles including 17,557 patients reported risk reductions of 40% in the overall SSI rate, 44% in the superficial infection rate, and 34% in the deep/organ space infection rate. This analysis also reported that utilization of sterile wound closure trays, mechanical bowel preparation with oral antibiotics, and glove changes before fascial closure were considered most important to implement . Another meta-analysis of 20,701 patients found that while there was significant heterogeneity in SSI reduction bundle component elements and compliance rates (ranging from 19 to 90% in the included studies), the OR of SSI was 0.56 with a bundle compared to without . Higher rates of compliance with specific bundle elements within SSI prevention bundles have repeatedly been associated with significantly lower SSI rates [159, 160]. ## Perioperative interventions ## Surgical site infection (ssi) ## Pain control A multimodal, opioid-sparing, pain management plan should be implemented before the induction of anesthesia. ## Grade of recommendation: strong recommendation based on moderate-quality evidence, 1b Multiple studies have demonstrated that minimizing opioids after colorectal surgery is associated with earlier return of bowel function and shorter length of stay [2, 31, 172]. One of the simplest techniques to limit opioid use is to schedule non-narcotic alternatives, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), rather than administering them on an as-needed basis [173-178]. There have been ongoing concerns about the postoperative safety profile of NSAIDs in this setting. However, a 2007 Cochrane review concluded that NSAIDs can cause a clinically unimportant transient reduction in renal function in the early postoperative period and should therefore not be withheld from adults with normal preoperative renal function . In addition, experimental and observational clinical studies have shown that NSAIDs may increase the risk of anastomotic leak and subsequent research has demonstrated that this potential effect on anastomotic leak appears to be molecule and class specific [184]; diclofenac has been associated with the highest risk of leak in this setting. In a retrospective cohort study of 856 patients undergoing elective colorectal surgery, the risk of anastomotic leak was 11.8% versus 6.0% (p = 0.01) in patients receiving diclofenac, but there was no differences in leak rates related to other nonsteroidals . Additionally, two meta-analyses have demonstrated an overall increased risk of anastomotic leak with NSAIDs but no increase in the risk of anastomotic leak with the use of selective NSAIDs (such as cyclooxygenase 2 inhibitors) . In these studies nonselective NSAID diclofenac use was associated with an increased leak rate (OR 2.79 [1.96, 3.96], p < 0.001 and pooled OR 2.02, 95% CI 1.62-2.50, p < 0.001), while ketorolac and selective NSAIDS were not associated with anastomotic leak. In addition, a large multicenter cohort study in Europe showed no differences in anastomotic leak rate with nonselective NSAIDs . Perioperative gabapentinoids, ketamine, lidocaine, magnesium, and α2-agonists have also been administered to improve analgesia and reduce opioid consumption and postoperative hyperalgesia. The role of gabapentinoids is controversial as two large database studies reported that gabapentinoid use after colorectal or orthopedic surgery was associated with increased postoperative pulmonary complications and no reduction in postoperative opioid consumption . A meta-analysis evaluating the perioperative use of gabapentinoids also reported no clinically significant analgesic effect from gabapentinoid use and stated that the routine use of these medications cannot be recommended . Meanwhile, a perioperative low-dose ketamine infusion can be especially useful in patients with chronic pain . However, psychotropic adverse effects, dizziness, and sedation may impair immediate recovery, particularly in elderly patients . Magnesium either as a bolus or infusion is also associated with a decrease in postoperative opioid consumption and can be a useful adjunct . Analgesic blocks and wound infiltration have shown benefit in opioid reduction among patients undergoing open and laparoscopic colorectal surgery . There are an increasing number of block options, including but not limited to transversus abdominis plane (TAP), quadratus lumborum (QL), erector spinae, and rectus sheath blocks. Two meta-analyses of TAP blocks demonstrated decreased length of stay compared with systemic opioid use in laparoscopic colorectal surgery . A recent systematic review and meta-analysis demonstrated that laparoscopicguided TAP block is safe and effective for pain management in minimally invasive surgery and seems to be as effective as US-guided TAP blocks with respect to early pain control and reducing postoperative opioid use . Data remain controversial regarding the purported extended duration of benefit with long-acting local anesthetics such as liposomal bupivacaine in reducing postoperative opioid consumption . Another option, spinal analgesia with intrathecal morphine administration, can be utilized in the perioperative setting. Studies and meta-analyses have shown that intrathecal morphine is more effective than intravenous opioids in laparoscopic surgery and is associated with lower pain scores . The concern about delayed respiratory depression related to this analgesia has not been substantiated and guidelines for postoperative monitoring have been published . . However, epidurals have no analgesic benefit over multimodal analgesia and abdominal wall blocks in laparoscopic surgery. In addition, evidence shows that the analgesic benefits provided by TEA do not translate into faster recovery in either laparoscopic or open colorectal surgery . In fact, TEA may actually delay hospital discharge after laparoscopic surgery [208] due to the higher incidence of hypotension and urinary tract infections that necessitate additional postoperative care . ## Perioperative nausea and vomiting Pre-emptive, multimodal anti-emetic prophylaxis reduces perioperative nausea and vomiting. Grade of recommendation: strong recommendation based on high-quality evidence, 1A Several validated scoring systems have been developed to identify patients at higher risk for PONV . Risk factors for developing PONV include female sex, history of PONV and/or motion sickness, nonsmoking status, young age, laparoscopic surgery, use of volatile anesthesia, prolonged operative time, and opioid analgesia. Strategies to reduce the risk of PONV include using regional anesthesia or propofol-based total intravenous anesthesia (TIVA), avoiding volatile anesthetics, and minimizing perioperative opioids by employing multimodal analgesia [207, 217-220]. Although TIVA has been associated with reduced PONV and significantly better patient satisfaction compared to volatile anesthetics, its high cost has precluded widespread adoption . One guideline updated in 2020 supports preoperative risk assessment in all patients undergoing anesthesia and recommends subsequent tailored multimodal therapy to prevent and treat PONV [220]. Combining risk assessment with a specific recommendation for anti-emetic intervention has been associated with significant reduction in PONV in randomized and non-randomized trials . Given the low cost and minimal risk associated with anti-emetics, the liberal use of a multimodal anti-emetic protocol for all patients (regardless of risk) has been advocated . ERPs, which include multimodal PONV prophylaxis, are associated with reduced rates of PONV and readmission in colorectal surgery . Multiple prospective and observational studies demonstrate that combination therapy using two or more anti-emetics for preventing PONV is superior over a single agent . A description of all the available prophylactic agents is beyond the scope of this CPG. However, a common intervention for patients determined to be high risk for PONV that has been studied in randomized controlled fashion is the administration of dexamethasone and ondansetron (or other 5-hydroxytryptamine 3 (5-HT 3 ) antagonist) . A meta-analysis of 9 RCTs, including 1,089 patients, demonstrated that dexamethasone combined with other anti-emetics provided significantly better PONV prophylaxis than single anti-emetics and decreased the need for rescue therapy . In addition, several meta-analyses found that dexamethasone did not increase postoperative infections or significantly impact glycemic control . ## Fluid management Fluid administration should be tailored to avoid excessive fluid administration and volume overload or undue fluid restriction and hypovolemia. Grade of recommendation: strong recommendation based on high-quality evidence, 1A Both intravenous fluid overload and hypovolemia can significantly impair organ function, increase postoperative morbidity, and prolong hospital stay . Intraoperative infusion regimens based on definitions such as liberal, restrictive, or supplemental should typically be avoided because of the variability in the volumes of fluid infused among different studies using these qualifiers . However, more recently within ERP literature the term "restrictive fluid management" has gained popularity and the amount of fluid recommended with restrictive fluid management has gradually decreased. The term "zero-balance" fluid management was introduced to describe a restrictive fluid regimen aiming to avoid postoperative fluid retention (as indicated by weight gain) . However, while a zerobalance approach might improve postoperative GI function, it is associated with a slightly increased risk of acute kidney injury (8.6% versus 5.0% in an RCT of 3000 patients undergoing major abdominal surgery) . Based on these considerations, the overall goal of fluid management should typically be a positive fluid balance at the end of surgery of ~ 1 L. This should be sufficient to avoid hypovolemia and AKI, while limiting substantial postoperative weight gain (> 2.5 kg/days) which is associated with increased morbidity and prolonged hospital stay . ## Balanced chloride-restricted crystalloid solutions should be used for maintenance infusions and fluid boluses in patients undergoing colorectal surgery. there is no benefit to the routine use of colloid solutions for fluid boluses. grade of recommendation: strong recommendation based on moderate-quality evidence, 1b Results from studies conducted in healthy volunteers and from meta-analyses of small RCTs indicate that balanced chloride-restricted crystalloid solutions should be preferred to normal saline to decrease the risk of hyperchloremic metabolic acidosis . Large propensity-matched observational studies have reported an association between the use of normal saline and an increased incidence of renal dysfunction, postoperative morbidity, and mortality in surgical patients . A large cluster randomized trial of 15,000 critically ill adults showed similar results, with lower rates of death and renal dysfunction attributed to the use of balanced crystalloids . Based on the evidence from this trial, the current recommendation was upgraded from a 1C in 2017 to a 1B. There is little evidence that colloids offer any benefit over crystalloids for fluid boluses, either during abdominal surgery or postoperatively in intensive care . Meanwhile, there may be some benefit in individual cases, particularly in the setting of blood loss or when rapid resuscitation is needed . Colloids restore circulating volume faster than crystalloids and with a lower fluid volume (although this difference is less than traditionally taught with a ratio of around 1:1.5) . Given that the evidence does not show an outcome benefit with colloids and that colloids are significantly more expensive, their routine use should be discouraged. ## Intraoperative hypotension should be avoided as even short durations of map < 65 are associated with adverse outcomes, in particular myocardial injury and acute kidney injury. grade of recommendation: strong recommendation based on moderate-quality evidence, 1b In a recent retrospective analysis of 4282 patients undergoing noncardiac surgery, intraoperative hypotension defined as MAP < 65 mmHg occurred in 71% of patients . Approximately one-third of these hypotensive events occurred before the surgical incision. There is increasing evidence from large retrospective database reviews showing that even a short duration of hypotension is associated with myocardial injury and acute kidney injury [293-295] and that the severity of injury is associated with both the duration and degree of hypotension [294, 296]. One major prospective interventional trial showed a significant reduction in complications (38% versus 51%, p = 0.02) with individualized blood pressure management (n = 147) compared with standard pressure management (n = 245) . In this study, patients in the intervention group had their fluid status optimized and then had a vasopressor infused to maintain their SBP within 10% of their resting blood pressure. In patients with an epidural block, crystalloid or colloid preloading does not typically prevent hypotension induced by the neuraxial blockade because total blood volume is unchanged after neuraxial blockade [bib_ref] Epidural anesthesia, hypotension, and changes in intravascular volume, Holte [/bib_ref] ; in these circumstances, a low dose of vasopressors, not intravenous fluids, restores colonic perfusion in normovolemic hypotensive patients [bib_ref] Effect of thoracic epidural anaesthesia on colonic blood flow, Gould [/bib_ref]. ## In high-risk patients and in patients undergoing colorectal surgery with anticipated significant intravascular losses, the use of goal-directed hemodynamic therapy is recommended. grade of recommendation: strong recommendation based on moderate-quality evidence, 1b Objective measures of hypovolemia such as cardiac output, stroke volume, oxygen delivery, oxygen extraction, and mixed venous oxygen saturation and dynamic indices of fluid responsiveness (e.g., pulse pressure variation or stroke volume variation) can help physicians decide whether to administer intravenous fluids for purposes of resuscitation. Several meta-analyses of RCTs have shown that goaldirected fluid therapy (GDFT) reduces postoperative morbidity and length of hospital stay, especially in high-risk patients undergoing major surgery [bib_ref] A systematic review and meta-analysis on the use of preemptive hemodynamic intervention..., Hamilton [/bib_ref] [bib_ref] Perioperative increase in global blood flow to explicit defined goals and outcomes..., Grocott [/bib_ref] [bib_ref] The effects of goal-directed fluid therapy based on dynamic parameters on post-surgical..., Benes [/bib_ref]. High-risk patients have been variably defined as patients with a history of severe cardiorespiratory illness (e.g., acute myocardial infarction, chronic obstructive pulmonary disease, stroke), a prolonged planned surgery (> 8 h), age > 70 years with limited physiologic reserve, respiratory failure, and aortic vascular disease. However, it must be acknowledged that advancements in perioperative and surgical care seem to have offset the previously demonstrated benefits of GDFT, especially in low-moderate-risk patients [bib_ref] Goal-directed fluid therapy versus conventional fluid therapy in colorectal surgery: a meta..., Xu [/bib_ref]. The largest multicenter RCT studying these issues, included 734 highrisk patients undergoing major abdominal surgery (45% colorectal surgery and the majority in the context of an ERP) and showed a decrease in complications and mortality in patients treated with GDFT though this difference did not meet statistical significance (relative risk = 0.84 [95% CI 0.71-1.01], p = 0.07) [bib_ref] Effect of a perioperative, cardiac outputguided hemodynamic therapy algorithm on outcomes following..., Pearse [/bib_ref]. Recent studies have focused on goal-directed hemodynamic therapy, rather than goal-directed fluid therapy and showed an improvement in outcomes even in low-moderaterisk patients [bib_ref] Effect of goal-directed haemodynamic therapy on postoperative complications in lowmoderate risk surgical..., Calvo-Vecino [/bib_ref]. These treatment algorithms first optimize stroke volume with fluid boluses and then, if hypotension persists, add a vasopressor to maintain MBP > 65 mmHg. This management reflects the increasing evidence that perioperative hypotension is associated with harm and should be avoided [294, 296, 297]. ## In the absence of surgical complications or hemodynamic instability, intravenous fluids should be routinely discontinued in the early postoperative period. grade of recommendation: strong recommendation based on moderate-quality evidence, 1b A few small, heterogeneous randomized controlled trials support discontinuation of intravenous fluids in the early postoperative period [279, [bib_ref] A meta-analysis of randomised controlled trials of intravenous fluid therapy in major..., Varadhan [/bib_ref] [bib_ref] A randomised comparison of two postoperative fluid regimens, Cook [/bib_ref]. Traditional surgical practice recommends maintaining a minimal urine output target of 0.5 mL/kg/h in the postoperative period. However, a small prospective study of 40 low-risk patients undergoing a variety of elective colorectal resections randomized subjects to a minimum urine output target of 0.2 mL/kg/h or 0.5 mL/kg/h in the perioperative period, using intravenous fluid administration to achieve targets [bib_ref] Low versus standard urine output targets in patients undergoing major abdominal surgery:..., Puckett [/bib_ref]. In this study, there were no differences in postoperative serum creatinine or other markers of acute renal tubular damage. Another RCT of patients undergoing elective colorectal surgery with an ERP evaluated the use of diuretics to achieve a euvolemic state in diuretically naïve patients and found no difference in postoperative length of stay or complications [bib_ref] Early diuresis after colon and rectal surgery does not reduce length of..., Danelich [/bib_ref]. ## Surgical approach A minimally invasive surgical approach should be employed when the expertise is available and when appropriate. Grade of recommendation: strong recommendation based on high-quality evidence, 1A. High-quality evidence from RCTs and large database studies supports the use of laparoscopy in colorectal surgery. Two separate multicenter RCTs of patients with colon cancer, the ALCCaS trial from Australia and the COLOR trial from the Netherlands, showed laparoscopy to be superior to open resection regarding short-term outcomes (e.g., return of bowel function, blood loss, postoperative pain, and hospital length of stay) [bib_ref] Short-term outcomes of the Australasian randomized clinical study comparing laparoscopic and conventional..., Hewett [/bib_ref] [bib_ref] COlon cancer Laparoscopic or Open Resection Study Group (COLOR) et al (2005)..., Veldkamp [/bib_ref]. Several other RCTs have reported improved perioperative morbidity, including total morbidity, wound morbidity, and non-surgical morbidity, following laparoscopic compared to open colonic resection [bib_ref] Randomized clinical trial of laparoscopic versus open left colonic resection, Braga [/bib_ref] [bib_ref] Laparoscopic versus open colorectal surgery: a randomized trial on short-term outcome, Braga [/bib_ref] [bib_ref] Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a..., Lacy [/bib_ref] [bib_ref] Japan Clinical Oncology Group Colorectal Cancer Study Group et al (2014) Short-term..., Yamamoto [/bib_ref]. Other RCTs showed that patients undergoing laparoscopy have decreased time to pulmonary recovery, reduced use of narcotics, and improved short-term quality of life [bib_ref] A prospective, randomized trial comparing laparoscopic versus conventional techniques in colorectal cancer..., Milsom [/bib_ref] [bib_ref] Prospective randomized study of laparoscopic versus open colonic resection for adenocarcinoma, Stage [/bib_ref] [bib_ref] Clinical Outcomes of Surgical Therapy (COST) Study Group (2002) Short-term quality-of-life outcomes..., Weeks [/bib_ref]. These results are consistent with large, database studies that relied on data from the National Surgical Quality Improvement Program and the National Inpatient Sample which support the use of laparoscopy [bib_ref] Laparoscopy within a fast-track program enhances the short-term results after elective surgery..., Feroci [/bib_ref] [bib_ref] Laparoscopy decreases anastomotic leak rate in sigmoid colectomy for diverticulitis, Levack [/bib_ref] [bib_ref] A national comparison of laparoscopic vs. open colectomy using the National Surgical..., Senagore [/bib_ref] [bib_ref] Cost analysis of laparoscopic versus open colectomy in patients with colon cancer:..., Vaid [/bib_ref]. High-quality Cochrane reviews have evaluated short-and long-term outcomes as well and support the laparoscopic approach in colorectal surgery [bib_ref] Short term benefits for laparoscopic colorectal resection, Schwenk [/bib_ref] [bib_ref] Long-term results of laparoscopic colorectal cancer resection, Kuhry [/bib_ref] [bib_ref] Laparoscopic versus open total mesorectal excision for rectal cancer, Vennix [/bib_ref]. The use of robotics in colorectal surgery has increased exponentially over the last decade [bib_ref] Perioperative outcomes and trends in the use of robotic colectomy for medicare..., Sheetz [/bib_ref] and multiple studies have demonstrated the feasibility and safety of robotic colorectal surgery [bib_ref] Perioperative outcomes and trends in the use of robotic colectomy for medicare..., Sheetz [/bib_ref] [bib_ref] Robotic versus laparoscopic right colectomy: an updated systematic review and meta-analysis, Solaini [/bib_ref] [bib_ref] Robot-assisted laparoscopic surgery versus conventional laparoscopic surgery in randomized controlled trials: a..., Roh [/bib_ref] [bib_ref] Effects of laparoscopic vs robotic-assisted mesorectal excision for rectal cancer: an update..., Huang [/bib_ref] [bib_ref] Robotic versus conventional laparoscopic technique for the treatment of left-sided colonic diverticular..., Giuliani [/bib_ref]. However, the benefits of the robotic approach over standard laparoscopy with regard to short-and long-term surgical outcomes have yet to be fully elucidated. Meta-analyses of RCTs suggest lower conversion rates with a robotic approach [bib_ref] Perioperative outcomes and trends in the use of robotic colectomy for medicare..., Sheetz [/bib_ref] [bib_ref] Robot-assisted laparoscopic surgery versus conventional laparoscopic surgery in randomized controlled trials: a..., Roh [/bib_ref] [bib_ref] Effects of laparoscopic vs robotic-assisted mesorectal excision for rectal cancer: an update..., Huang [/bib_ref] [bib_ref] Robotic versus conventional laparoscopic technique for the treatment of left-sided colonic diverticular..., Giuliani [/bib_ref] ; however, operative times and costs are consistently higher with robotic surgery compared to laparoscopy, while complication rates are similar between the two approaches [bib_ref] Robotic versus laparoscopic right colectomy: an updated systematic review and meta-analysis, Solaini [/bib_ref] [bib_ref] Effects of laparoscopic vs robotic-assisted mesorectal excision for rectal cancer: an update..., Huang [/bib_ref]. Notably, many of the included studies in these meta-analyses and 1 3 systematic reviews were of moderate to poor methodological quality. Combining minimally invasive surgery with an ERP is associated with optimal outcomes, as demonstrated in the 4-arm LAFA trial which randomized 427 patients to open versus laparoscopic surgery with an ERP versus a traditional care pathway. In this study, patients undergoing laparoscopic surgery within an ERP had the shortest LOS and morbidity compared to either laparoscopy within a traditional care pathway or open surgery [bib_ref] Laparoscopy in combination with fast track multimodal management is the best perioperative..., Vlug [/bib_ref]. As such, a minimally invasive approach is recommended when appropriate to optimize postoperative recovery within an ERP. The routine use of nasogastric tubes and intra-abdominal drains for colorectal surgery should be avoided. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B Small RCTs evaluating elective colorectal surgery have failed to demonstrate an impact from the routine use of nasogastric tube decompression on nausea, vomiting, time to return of bowel function or length of stay [bib_ref] Gastrointestinal decompression after excision and anastomosis of lower digestive tract, Lei [/bib_ref] [bib_ref] Early oral feeding after colorectal resection: a randomized controlled study, Feo [/bib_ref] [bib_ref] Nasogastric decompression following elective colorectal surgery: a prospective randomized study, Petrelli [/bib_ref]. Alternatively, the routine use of nasogastric tube decompression delays the tolerance of oral intake by an average of two days and has been associated with significantly higher risk of associated complications, notably pharyngolaryngitis [bib_ref] Gastrointestinal decompression after excision and anastomosis of lower digestive tract, Lei [/bib_ref] [bib_ref] Fast Track" nasogastric decompression of rectal cancer surgery, Li [/bib_ref] [bib_ref] Is early postoperative feeding feasible in elective colon and rectal surgery?, Ortiz [/bib_ref]. Similarly, there is no benefit to the routine use of intraabdominal drains in colorectal surgery. RCTs show no significant differences in mortality, leak, or a composite of postoperative complications in patients who had drains placed [51, [bib_ref] A prospective randomised study of drains in infra-peritoneal rectal anastomoses, Brown [/bib_ref] [bib_ref] Is prophylactic pelvic drainage useful after elective rectal or anal anastomosis? A..., Merad [/bib_ref] [bib_ref] Randomized trial of drainage of colorectal anastomosis, Sagar [/bib_ref]. The lack of benefit from operative drains has been demonstrated across a variety of colorectal anastomoses as well as low pelvic anastomoses specifically [bib_ref] A prospective randomised study of drains in infra-peritoneal rectal anastomoses, Brown [/bib_ref] [bib_ref] Is prophylactic pelvic drainage useful after elective rectal or anal anastomosis? A..., Merad [/bib_ref] [bib_ref] Is a drain necessary after anterior resection of the rectum? A systematic..., Cavaliere [/bib_ref] [bib_ref] A meta-analysis of randomized controlled trials on the use of suction drains..., Guerra [/bib_ref] [bib_ref] Pelvic drain after laparoscopic low anterior resection for rectal cancer in patients..., Matsuda [/bib_ref] [bib_ref] Prophylactic intra-abdominal drainage following colorectal anastomoses. A systematic review and meta-analysis of..., Podda [/bib_ref] [bib_ref] To drain or not to drain in colorectal anastomosis: a meta-analysis, Zhang [/bib_ref] [bib_ref] French Research Group of Rectal Cancer Surgery (GRECCAR) et al (2017) To..., Denost [/bib_ref]. Meanwhile, a review of the US Rectal Cancer Consortium data found a nonstatistically significant association between drains and higher leak rates but there was no difference in the rate of intervention for leak between patients with and without drains [bib_ref] Revisiting the value of drains after low anterior resection for rectal cancer:..., Lee [/bib_ref]. Notably, this was a retrospective review and drain placement was left to the discretion of the operating surgeons; drain use was likely a surrogate for patients with a higher risk for leak due to other factors. Contrary to these studies, a retrospective analysis of the Dutch TME data suggested that intra-abdominal drains in the presence of a diverting stoma may be associated with lower rates of surgical intervention in patients with anastomotic failure [bib_ref] Dutch Colorectal Cancer Group et al (2005) Risk factors for anastomotic failure..., Peeters [/bib_ref]. ## Postoperative interventions ## Patient mobilization Early and progressive patient mobilization are associated with shorter length of stay. Grade of recommendation: strong recommendation based on low-quality evidence, 1C Complications of prolonged immobility include skeletal muscle loss and weakness, atelectasis, insulin resistance, thromboembolic disease, and decreased exercise capacity [bib_ref] Consequences of bed rest, Brower [/bib_ref] [bib_ref] An overview of the issues: physiological effects of bed rest and restricted..., Convertino [/bib_ref]. It is estimated that muscle mass decreases by 1.5-2% for every day of bedrest [bib_ref] Skeletal muscle unweighting: spaceflight and ground-based models, Adams [/bib_ref]. However, the deconditioning associated with bedrest can be minimized or avoided by engaging in physical activity. Definitions of early mobilization within a colorectal ERP vary significantly, from any mobilization at all within 24 h of operation to 8 h of activity per day by the second postoperative day [bib_ref] Fast-track colorectal surgery: protocol adherence influences postoperative outcomes, Feroci [/bib_ref]. Compliance with mobilization targets within ERPs varies significantly between centers, but early ambulation has been associated with faster recovery and fewer complications after colorectal surgery [35, [bib_ref] Variation in care for surgical patients with colorectal cancer: protocol adherence in..., Van Zelm [/bib_ref] [bib_ref] Impact of adherence to care pathway interventions on recovery following bowel resection..., Pecorelli [/bib_ref] [bib_ref] Do we really need the full compliance with ERAS protocol in laparoscopic..., Pisarska [/bib_ref]. In a prospective cohort study of 100 patients, individuals who had a higher step count on the first postoperative day after major abdominal or thoracic surgery were more likely to have a shorter length of stay [bib_ref] Association of wearable activity monitors with assessment of daily ambulation and length..., Daskivich [/bib_ref]. There are limited data about interventions that specifically increase mobilization with regard to their effects on postoperative outcomes. A randomized trial compared facilitated supervised mobilization (n = 49) on postoperative days 0 to 3 versus conventional care (n = 50) after colorectal surgery within the construct of an ERP. [bib_ref] Ensuring early mobilization within an enhanced recovery program for colorectal surgery: a..., Fiore [/bib_ref]. In this study, step counts were higher in the intervention group but there were no differences between the two groups in functional recovery, length of stay, complications, or return of gastrointestinal function. A subgroup analysis of this trial also did not find any differences in pulmonary function or postoperative pulmonary complications between the two arms [bib_ref] Impact of facilitation of early mobilization on postoperative pulmonary outcomes after colorectal..., Balvardi [/bib_ref]. These data suggest that additional resources to increase mobilization are not associated with improved outcomes within an established colorectal ERP. However, importantly, no studies have reported harm associated with early mobilization, even after perineal reconstruction following abdominoperineal resection [bib_ref] Early ambulation after colorectal oncologic resection with perineal reconstruction is safe and..., Calotta [/bib_ref]. ## Ileus prevention ## Patients should be offered a regular diet within 24 h after elective colorectal surgery. grade of recommendation: strong recommendation based on moderate-quality evidence, 1b A 2019 Cochrane systematic review and meta-analysis evaluated 17 RCTs that compared early feeding (i.e., within 24 h of surgery) versus "later commencement" after lower gastrointestinal surgery [bib_ref] Early enteral nutrition within 24 hours of lower gastrointestinal surgery versus later..., Herbert [/bib_ref]. In this review, early feeding was associated with a two-day decrease in length of hospital stay (weighted mean difference 1.95, 95% CI 0.91-2.99). However, perioperative management strategies varied significantly within the included trials and the mean length of stay in the control group ranged from 6 to 24 days. Furthermore, the risk of complications such as anastomotic leak, wound infection, pneumonia, and mortality were not affected by early feeding. Even symptoms of nausea and vomiting were not significantly higher in the early feeding group in this review. Early enteral feeding is associated with faster return of gastrointestinal function and with shorter time to flatus and first bowel movement [bib_ref] The effect of diets delivered into the gastrointestinal tract on gut motility..., Hogan [/bib_ref]. While there is heterogeneity between trials, the overall body of evidence supports the benefits of early feeding. Sham feeding (i.e., chewing gum for ≥ 10 min 3-4 times daily) after colorectal surgery is safe, results in small improvements in GI recovery, and may be associated with a reduction in length of hospital stay. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B Sham feeding such as gum chewing has been hypothesized to hasten recovery of gastrointestinal function through increased saliva production and vagal cholinergic stimulation that increases bowel peristalsis [bib_ref] The use of chewing gum for preventing postoperative ileus, Meyer [/bib_ref]. Eighteen RCTs have evaluated chewing gum after colorectal surgery [bib_ref] Effect of gum chewing on ameliorating ileus following colorectal surgery: a meta-analysis..., Liu [/bib_ref]. The majority of these trials used sugar-free gum chewed for at least 5-10 min 3 times daily. However, the majority of these trials were not performed in the context of an ERP were of low quality and had a high risk of bias. A meta-analysis of all 18 randomized trials reported that chewing gum was associated with shorter time to first flatus (weighted mean difference (WMD) − 8.81 h, 95% CI − 13.45 to − 4.17), shorter time to first bowel movement (WMD − 16.43 h, 95% CI − 22.68 to − 10.19), and a reduction in length of stay (WMD − 0.89 days, 95% CI − 1.72 to − 0.07) [bib_ref] Effect of gum chewing on ameliorating ileus following colorectal surgery: a meta-analysis..., Liu [/bib_ref]. The pooled outcome of "postoperative ileus" was also lower in the chewing gum arm (RR 0.41, 95% CI 0.23-0.73). Other outcomes, including complications, readmission, and reoperations, were not significantly different between the two groups. Subgroup analysis of laparoscopic and open approaches maintained these significant associations. However, subgroup analysis of trials performed within the context of an ERP reported that chewing gum was no longer associated with significant decreases in the time to flatus and length of stay. In another systematic review and meta-analysis that only included ten randomized trials that were deemed "high quality," [bib_ref] The impact of sham feeding with chewing gum on postoperative ileus following..., Roslan [/bib_ref] the use of chewing gum was associated with a lower incidence of postoperative ileus (RR 0.55, 95% CI 0.39-0.79) and faster time to first flatus (WMD − 0.31 days, 95% CI − 0.36 to − 0.26) and bowel movement (WMD − 0.47, 95% CI − 0.60 to − 0.34), but no difference in length of stay. However, the trials included in this meta-analysis suffered from many of the same limitations pertaining to heterogeneity and variable perioperative management strategies that were present in the prior studies. Nonetheless, the overall body of literature suggests that chewing gum may only have a small effect on gastrointestinal recovery without a clear effect on length of stay but is safe and not costly. There are even some data to support the use of coffee to facilitate gastrointestinal recovery after colorectal surgery [bib_ref] Effect of coffee on the length of postoperative ileus after elective laparoscopic..., Dulskas [/bib_ref] [bib_ref] Randomized clinical trial on the effect of coffee on postoperative ileus following..., Müller [/bib_ref] [bib_ref] The effects of drinking coffee while recovering from colon and rectal resection..., Piric [/bib_ref]. Caffeine and coffee may stimulate the lower gastrointestinal tract and can potentially reduce postoperative ileus. A meta-analysis of 7 randomized trials including 606 patients reported that drinking coffee decreased the time to first bowel movement and toleration of oral intake, but did not reduce time to flatus, overall complications, or length of stay [bib_ref] Coffee to go? The effect of coffee on resolution of ileus following..., Cornwall [/bib_ref]. ## Alvimopan is recommended to hasten recovery after open colorectal surgery. grade of recommendation: strong recommendation based on moderate-quality evidence, 1b Alvimopan, an oral peripheral acting mu-opioid antagonist that minimizes the effect of opioids on postoperative gastrointestinal function, was first approved by the US Food and Drug Administration in 2008. A systematic review of all relevant studies published up to May 2020 identified 31 studies that investigated the effect of alvimopan on gastrointestinal function in colorectal surgery, of which 23 demonstrated a positive effect and 8 reported no effect [bib_ref] The association of alvimopan treatment with postoperative outcomes after abdominal surgery: a..., Alhashemi [/bib_ref]. Of the 6 randomized trials, 4 were positive and 2 showed no effect related to the medication. Most of the available data supporting alvimopan in the setting of colorectal surgery is limited to open surgery. Several RCTs and pooled post hoc analyses reported accelerated time to recovery of gastrointestinal function with alvimopan 6-mg and 12-mg doses compared to placebo and a significantly shorter hospital length of stay in the alvimopan 12-mg group compared with placebo for patients undergoing open surgery [bib_ref] Alvimopan Postoperative Ileus Study Group et al (2004) Alvimopan, a novel, peripherally..., Wolff [/bib_ref] [bib_ref] Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative..., Viscusi [/bib_ref] [bib_ref] Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist,..., Delaney [/bib_ref] [bib_ref] Postoperative ileus-related morbidity profile in patients treated with alvimopan after bowel resection, Wolff [/bib_ref] [bib_ref] A randomized, placebo-controlled phase 3 trial (Study SB-767905/013) of alvimopan for opioid-induced..., Irving [/bib_ref] [bib_ref] Postoperative upper and lower gastrointestinal recovery and gastrointestinal morbidity in patients undergoing..., Delaney [/bib_ref] [bib_ref] Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase..., Delaney [/bib_ref] [bib_ref] Economic analysis of alvimopan in North American Phase III efficacy trials, Bell [/bib_ref] [bib_ref] Alvimopan for the management of postoperative ileus after bowel resection: characterization of..., Ludwig [/bib_ref] [bib_ref] Alvimopan accelerates gastrointestinal recovery after bowel resection regardless of age, gender, race,..., Senagore [/bib_ref]. A Cochrane review of nine studies affirmed that alvimopan was better than placebo in reversing opioid-induced increased gastrointestinal transit time and constipation and that alvimopan was safe and efficacious in decreasing postoperative ileus, but the studies were limited to open surgery patients without an ERP in place [bib_ref] Mu-opioid antagonists for opioid-induced bowel dysfunction, Mcnicol [/bib_ref]. There have been no randomized trials evaluating alvimopan after laparoscopic surgery [bib_ref] A meta-analysis of the effectiveness of the opioid receptor antagonist alvimopan in..., Vaughan-Shaw [/bib_ref] [bib_ref] Efficacy and safety of mu-opioid antagonists in the treatment of opioidinduced bowel..., Mcnicol [/bib_ref] [bib_ref] Meta-analysis: alvimopan vs placebo in the treatment of post-operative ileus, Tan [/bib_ref]. Most of the non-randomized studies have shown modest benefits in favor of alvimopan for laparoscopic resection albeit within traditional care pathways [bib_ref] Evaluation of clinical outcomes with alvimopan in clinical practice: a national matched-cohort..., Delaney [/bib_ref] [bib_ref] Alvimopan reduces length of stay and costs in patients undergoing segmental colonic..., Simorov [/bib_ref] [bib_ref] Evaluation of healthcare use and clinical outcomes of alvimopan in patients undergoing..., Steele [/bib_ref]. Given the low quality of the available evidence, it may be difficult to justify the use and cost of alvimopan in laparoscopic surgery in the setting of an ERP. ## Urinary catheters Urinary catheters should typically be removed within 24 h of elective colonic or upper rectal resection irrespective of thoracic epidural analgesia use. Grade of recommendation: strong recommendation, based on moderate-quality evidence, 1B Urinary catheterization is routinely used in abdominal and pelvic colorectal surgery for intraoperative bladder decompression and monitoring urinary output. Assessing whether or not to remove catheters early should consider the risk of postoperative urinary retention requiring subsequent catheter reinsertion as well as the risk of urinary tract infection (UTI) related to prolonged use of a catheter. Postoperative urinary retention is associated with decreased functional recovery (e.g., less mobility, more postoperative pain) and longer length of stay [bib_ref] Postoperative urinary retention in colorectal surgery within an enhanced recovery pathway, Grass [/bib_ref]. UTIs are also associated with increased morbidity, longer length of stay, and mortality [bib_ref] Urinary tract infection after surgery for colorectal malignancy: risk factors and complications, Sheka [/bib_ref]. However, longer duration of catheter use is associated with higher rates of UTI and in-and-out (i.e., straight catheterization) catheterization in the setting of postoperative urinary retention is not associated with an increased risk of UTI [bib_ref] members of the iERAS Group et al (2017) Compliance with urinary catheter..., Okrainec [/bib_ref] [bib_ref] Outcomes after early versus delayed urinary bladder catheter removal after proctectomy for..., Hung [/bib_ref]. Overall, the evidence suggests that early urinary catheter removal within 24 h of surgery is safe. In a large multicenter study of 2927 surgery patients (1897 colonic procedures), early catheter removal was associated with a higher incidence of catheter reinsertion compared to later removal (4.9% versus 1.9%, p < 0.001) but a lower rate of UTIs (0.8% versus 4.1%, p = 0.003) [bib_ref] members of the iERAS Group et al (2017) Compliance with urinary catheter..., Okrainec [/bib_ref]. Length of stay in this study was also shorter in the early catheter removal group by 1 day and other studies have reported similar results [bib_ref] Early removal of urinary drainage in patients receiving epidural analgesia after colorectal..., Schreiber [/bib_ref] [bib_ref] Postoperative urinary retention after laparoscopic colorectal resection with early catheter removal: a..., Eriksen [/bib_ref]. There are increasing data suggesting that catheters can be removed even earlier (e.g., within 6 h after surgery) or avoided altogether [bib_ref] Impact of avoiding postoperative urinary catheters on outcomes following colorectal resection in..., Roberts [/bib_ref] [bib_ref] Early urinary catheter removal in patients undergoing colorectal surgery with an enhanced..., Van Backer [/bib_ref] [bib_ref] Laparoscopic colonic resection without urinary drainage: is it "feasible, Alyami [/bib_ref]. In the context of thoracic epidural analgesia, randomized controlled trials have investigated early urinary catheter removal compared with removal at the time of epidural discontinuation and found lower UTI rates after early catheter removal and no differences in re-catherization rates [bib_ref] Less urinary tract infection by earlier removal of bladder catheter in surgical..., Zaouter [/bib_ref] [bib_ref] Indwelling urinary catheter use in the postoperative period: analysis of the national..., Wald [/bib_ref]. In an RCT of 215 patients undergoing abdominal or thoracic surgery with a thoracic epidural that randomized patients to early catheter removal on POD 1 or following epidural removal, the incidence of recatheterization was similar between groups but the incidence of UTI was much lower in the early removal group (2% versus 24%, p = 0.004). [bib_ref] Indwelling urinary catheter use in the postoperative period: analysis of the national..., Wald [/bib_ref]. Urinary catheters should typically be removed within 24-48 h after mid/lower rectal resection. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B Retracting on the bladder and dissecting in close proximity to the lateral pelvic nerves during proctectomy may increase the risk of postoperative urinary retention. There have been 4 randomized controlled trials comparing outcomes between early and late catheter removal specifically in the setting of proctectomy [bib_ref] Early urinary catheter removal following pelvic colorectal surgery: a prospective, randomized, noninferiority..., Patel [/bib_ref] [bib_ref] Optimal duration of urinary drainage after rectal resection: a randomized controlled trial, Benoist [/bib_ref] [bib_ref] Urinary bladder catheter drainage following pelvic surgery-is it necessary for that long?, Zmora [/bib_ref] [bib_ref] Early post-operative removal of urethral catheter in patients undergoing colorectal surgery with..., Coyle [/bib_ref]. A meta-analysis of these 4 trials examined the non-inferiority of early removal (before postoperative day 2) versus late (postoperative day 2 and after) catheter removal and concluded that the data were insufficient to conclude non-inferiority of early catheter removal after proctectomy in terms of the development of postoperative urinary retention [bib_ref] Early urinary catheter removal after rectal surgery: systematic review and meta-analysis, Castelo [/bib_ref]. However, this meta-analysis showed that early catheter removal decreased the risk of UTI (9.7% versus 21.1%; absolute risk difference − 11%, 95% CI − 17, − 4). Another systematic review and meta-analysis compared POD1 catheter removal versus POD3 or POD5 removal and found lower UTI rates of in the earlier removal groups [bib_ref] Optimal timing of urinary catheter removal following pelvic colorectal surgery: a systematic..., Lee [/bib_ref]. There may be some subgroups of patients that were not included in the clinical trials such as pelvic exenteration patients or patients with a difficult hand-sewn coloanal anastomosis, and management of these patients is up to the best clinical judgment of the surgeon balancing the risk of urinary tract infection vs. urinary retention. ## Discharge criteria Hospital discharge prior to return of bowel function may be offered for selected patients. Grade of recommendation: weak recommendation based on moderate-quality evidence, 2B Traditional discharge criteria following colorectal surgery include demonstrating return of bowel function along with tolerance of oral intake, adequate pain control with oral analgesia, and the ability to mobilize in the absence of complications [bib_ref] Criteria to determine readiness for hospital discharge following colorectal surgery: an international..., Fiore [/bib_ref]. Many patients meet these criteria by the first or second postoperative day [57, 58, 62]. However, there are increasing reports of same-day discharge which hinges on the feasibility of discharging patients prior to return of bowel function. The concept of the "ambulatory" or "outpatient" colectomy was first introduced over a decade ago and was initially reported in small case series [62, [bib_ref] 23-hour-stay laparoscopic colectomy, Levy [/bib_ref] [bib_ref] Outpatient colectomy within an enhanced recovery program, Gignoux [/bib_ref]. In these early reports, low-risk patients undergoing colorectal resection were successfully discharged home after an observation period of 24 h without undue complications . An RCT of patients undergoing minimally invasive colorectal resection for cancer randomized 30 patients to discharge on postoperative day 1 regardless of bowel function with telemedicine follow-up on postoperative day 2 versus standard postoperative care with discharge after return of bowel function (RecoverMI trial) [bib_ref] Randomized clinical trial of accelerated enhanced recovery after minimally invasive colorectal cancer..., Bednarski [/bib_ref]. In this study, the median LOS was 28.3 h in the study arm and 51.5 h in the control arm (p = 0.041) and there were no differences in adverse events or quality of life as measured by EQ-5D-5L™ between the 2 groups. Exclusion criteria included patient-reported history of severe postoperative nausea/vomiting. Patients with a serum creatinine above 1.5 ng/ml, measured within 30 days of surgery, or a history of congestive heart failure, defined as ejection fraction of 40% or less, or of more than 40% with systemic signs of heart failure were also excluded. Finally and patients requiring conversion to open surgery or in whom an ostomy was necessary at completion of the study were removed from the study and not randomized. Other retrospective cohort studies have reported that same-day discharge after colorectal surgery was associated with low rates of readmission [bib_ref] Short-term outcomes of ambulatory colectomy for 157 consecutive patients, Gignoux [/bib_ref]. The largest of these retrospective cohort studies included 157 consecutive patients undergoing laparoscopic right, transverse, total, or left colectomy (left colectomy accounted for the majority of cases) [bib_ref] Short-term outcomes of ambulatory colectomy for 157 consecutive patients, Gignoux [/bib_ref]. In this study, same-day discharge was possible in 93% of patients with an associated readmission rate of 6% [bib_ref] Is same-day and next-day discharge after laparoscopic colectomy reasonable in select patients?, Mckenna [/bib_ref]. These studies demonstrate that same-day discharge is feasible within an ERP in selected patients with acceptable complication rates [bib_ref] Is same-day and next-day discharge after laparoscopic colectomy reasonable in select patients?, Mckenna [/bib_ref]. Success of these initiatives depends on patients having adequate support at home, close outpatient surveillance, and the ability to tolerate clear liquids in the postoperative recovery unit . This is an area with limited but evolving evidence. Recommendations could change as more evidence becomes available. Acknowledgements We thank Elaine Attridge, MLS, Quality and Performance Improvement Librarian in the Claude Moore Health Sciences Library at the University of Virginia for her invaluable expertise and guidance. Funding The funding bodies (ASCRS and SAGES) did not influence the content of this work and no other specific funding was received from other entities. Disclosure I. Paquette have no financial disclosure. ## Open access this article is licensed under a creative commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons licence. You do not have permission under this licence to share adapted material derived from this article or parts of it. 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-nc-nd/4. 0/. ## References [fig] Figure 1: PRISMA literature search flow sheet. PRISMA preferred reporting items for systematic reviews and meta-analysis [/fig] [fig] 1: Kang CY, Chaudhry OO, Halabi WJ et al (2012) Outcomes of laparoscopic colorectal surgery: data from the Nationwide Inpatient Sample 2009. Am J Surg 204:952-957 2. 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Honarmand A, Safavi M, Chegeni M, Hirmanpour A, Nazem M, Sarizdi SH (2016) Prophylactic antiemetic effects of Midazolam, Ondansetron, and their combination after middle ear surgery. J Res Pharm Pract 5:16-21 242. Honarmand A, Safavi M, Khalili G, Mohammadnejad F (2012) Prophylactic administration of haloperidol plus midazolam reduces postoperative nausea and vomiting better than using each drug alone in patients undergoing middle ear surgery. Saudi J Anaesth 6:145-151 243. Imeh A, Olaniyi O, Simeon O, Omotola O (2014) Dexamethasone versus a combination of dexamethasone and ondansetron as prophylactic antiemetic in patients receiving intrathecal morphine for caesarean section. Afr Health Sci 14:453-459 244. Joo J, Park YG, Baek J, Moon YE (2015) Haloperidol dose combined with dexamethasone for PONV prophylaxis in high-risk patients undergoing gynecological laparoscopic surgery: a prospective, randomized, double-blind, dose-response and placebocontrolled study. 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Kiran A, Panchaksharimath P, Sharvani R (2013) Comparison of the efficacy of ondansetron versus ondansetron and dexamethasone in the prevention/ reduction of post-operative nausea & vomiting after elective surgeries under general anaesthesia. J Chem Pharm Res 5:1126-1130 249. Kranke P, Bergese SD, Minkowitz HS et al (2018) Amisulpride prevents postoperative nausea and vomiting in patients at high risk: a randomized, double-blind, placebo-controlled trial. Anesthesiology 128:placebo controlled study evaluating preventive role of ondansetron, dexamethasone and ondansetron plus dexamethasone for postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic cholecystectomy. J Int Med Sci Acad 26:217-218 251. Lee MJ, Lee KC, Kim HY, Lee WS, Seo WJ, Lee C (2015) Comparison of ramosetron plus dexamethasone with ramosetron alone on postoperative nausea, vomiting, shivering and pain after thyroid surgery. Korean J Pain 28:39-44 252. Lee SJ, Lee SM, Kim SI et al (2012) The effect of aprepitant for the prevention of postoperative nausea and vomiting in patients undergoing gynecologic surgery with intravenous patient controlled analgesia using fentanyl: aprepitant plus ramosetron vs ramosetron alone. Korean J Anesthesiol 63:221-226 253. Lim CS, Ko YK, Kim YH et al (2013) Efficacy of the oral neurokinin-1 receptor antagonist aprepitant administered with ondansetron for the prevention of postoperative nausea and vomiting. Korean J Anesthesiol 64:212-217 254. Mansour E (2013) Postoperative nausea and vomiting prophylaxis: the efficacy of a novel antiemetic drug (palonosetron) combined with dexamethasone. Egypt J Anaesth 29:117-123 255. Matsota P, Angelidi M, Pandazi A, Tzirogiannis KN, Panoutsopoulos GI, Kostopanagiotou G (2015) Ondansetron-droperidol comhyubination vs. ondansetron or droperidol monotherapy in the prevention of postoperative nausea and vomiting. Arch Med Sci 11:362-370 256. 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Park EY, Lee SK, Kang MH et al (2013) Comparison of ramosetron with combined ramosetron and midazolam for preventing postoperative nausea and vomiting in patients at high risk following laparoscopic gynaecological surgery. J Int Med Res 41:654-663 260. Vallejo MC, Phelps AL, Ibinson JW et al (2012) Aprepitant plus ondansetron compared with ondansetron alone in reducing postoperative nausea and vomiting in ambulatory patients undergoing plastic surgery. Plast Reconstr Surg 129:519-526 261. Wang PK, Tsay PJ, Huang CC et al (2012) Comparison of dexamethasone with ondansetron or haloperidol for prevention of patient-controlled analgesia-related postoperative nausea and vomiting: a randomized clinical trial. World J Surg 36:775-781 262. Yu Q, Gao L, Gu MH et al (2013) Antiemetic effects of combined methylprednisolone and tropisetron in mastectomy. Miner Anestesiol 79:130-136 263. Ryoo SH, Yoo JH, Kim MG, Lee KH, Kim SI (2015) The effect of combination treatment using palonosetron and dexamethasone for the prevention of postoperative nausea and vomiting versus dexamethasone alone in women receiving intravenous patientcontrolled analgesia. Korean J Anesthesiol 68:267-273 264. Som A, Bhattacharjee S, Maitra S, Arora MK, Baidya DK (2016) Combination of 5-HT3 antagonist and dexamethasone is superior to 5-HT3 antagonist alone for PONV prophylaxis tropisetron in the prevention of postoperative nausea and vomiting after total thyroidectomy. Saudi J Anaesth 7:68-74 267. Kovac AL (2013) Update on the management of postoperative nausea and vomiting. Drugs 73:1525-1547 268. Sirajuddin M, Naqvi S, Murtaza G, Abbas N (2014) Metoclopramide alone and metoclopramide with dimenhydrinate for prophylaxis of post operative nausea & vomiting in patients admitted in day care for breast surgery \| M. Sirajuddin \| Request PDF. Med Channel 20:39-42 269. White PF, O'Hara JF, Roberson CR, Wender RH, Candiotti KA, POST-OP Study Group (2008) The impact of current antiemetic practices on patient outcomes: a prospective study on high-risk patients. Anesth Analg 107:452-458 270. McKenzie R, Tantisira B, Karambelkar DJ, Riley TJ, Abdelhady H (1994) Comparison of ondansetron with ondansetron plus dexamethasone in the prevention of postoperative nausea and vomiting. Anesth Analg 79:961-964 271. Si XY, Wu LP, Li XD, Li B, Zhou YM (2015) Dexamethasone combined with other antiemetics for prophylaxis after laparoscopic cholecystectomy. Asian J Surg Asian Surg Assoc 38:21-27 272. Toner AJ, Ganeshanathan V, Chan MT, Ho KM, Corcoran TB (2017) Safety of perioperative glucocorticoids in elective noncardiac surgery: a systematic review and meta-analysis. Anesthesiology 126:234-248 273. Polderman JA, Farhang-Razi V, Van Dieren S et al (2018) Adverse side effects of dexamethasone in surgical patients. Cochrane Database Syst Rev 8:CD011940 274. Thacker JKM, Mountford WK, Ernst FR, Krukas MR, Mythen MMG (2016) Perioperative fluid utilization variability and association with outcomes: considerations for enhanced recovery efforts in sample US surgical populations. Ann Surg 263:502-510 275. Miller TE, Mythen M, Shaw AD et al (2021) Association between perioperative fluid management and patient outcomes: a multicentre retrospective study. Br J Anaesth 126:720-729 276. Miller TE, Myles PS (2019) Perioperative fluid therapy for major surgery. Anesthesiology 130:825-832 277. Brandstrup B, Svendsen PE, Rasmussen M et al (2012) Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance? Br J Anaesth 109:191-199 278. Myles PS, Bellomo R, Corcoran T, Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Australian and New Zealand Intensive Care Society Clinical Trials Group et al (2018) Restrictive versus liberal fluid therapy for major abdominal surgery. N Engl J Med 378:2263-2274 279. Brandstrup B, Tønnesen H, Beier-Holgersen R, Danish Study Group on Perioperative Fluid Therapy et al (2003) Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg 238:641-648 280. Chowdhury AH, Cox EF, Francis ST, Lobo DN (2012) A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 256:18-24 281. Burdett E, Dushianthan A, Bennett-Guerrero E et al (2012) Perioperative buffered versus non-buffered fluid administration for surgery in adults. Cochrane Database Syst Rev 12MW, Self WH, Wanderer JP, SMART Investigators and the Pragmatic Critical Care Research Group et al (2018) Balanced crystalloids versus saline in critically ill adults. N Engl J Med 378:829-839 285. Kabon B, Sessler DI, Kurz A, Crystalloid-Colloid Study Team (2019) Effect of intraoperative goal-directed balanced crystalloid versus colloid administration on major postoperative morbidity: a randomized trial. Anesthesiology 130:728-744 286. Futier E, Garot M, Godet T, FLASH Trial Group et al (2020) Effect of hydroxyethyl starch vs saline for volume replacement therapy on death or postoperative complications among highrisk patients undergoing major abdominal surgery: the FLASH randomized clinical trial. JAMA 323:225-236 287. Feldheiser A, Pavlova V, Bonomo T et al (2013) Balanced crystalloid compared with balanced colloid solution using a goaldirected haemodynamic algorithm. Br J Anaesth 110:231-240 288. Yates DR, Davies SJ, Milner HE, Wilson RJ (2014) Crystalloid or colloid for goal-directed fluid therapy in colorectal surgery. Br J Anaesth 112:281-289 289. Heming N, Lamothe L, Jaber S et al (2018) Morbidity and mortality of crystalloids compared to colloids in critically ill surgical patients: a subgroup analysis of a randomized trial. Anesthesiology 129:1149-1158 290. Chappell D, Jacob M, Hofmann-Kiefer K, Conzen P, Rehm M (2008) A rational approach to perioperative fluid management. Anesthesiology 109:723-740 291. Roger C, Muller L, Deras P et al (2014) Does the type of fluid affect rapidity of shock reversal in an anaesthetized-piglet model of near-fatal controlled haemorrhage? A randomized study. Br J Anaesth 112:1015-1023 292. Orbegozo Cortés D, Gamarano Barros T, Njimi H, Vincent JL (2015) Crystalloids versus colloids: exploring differences in fluid requirements by systematic review and meta-regression. Anesth Analg 120:389-402 293. Maheshwari K, Turan A, Mao G et al (2018) The association of hypotension during non-cardiac surgery, before and after skin incision, with postoperative acute kidney injury: a retrospective cohort analysis. Anaesthesia 73:1223-1228 294. Salmasi V, Maheshwari K, Yang D et al (2017) Relationship between intraoperative hypotension, defined by either reduction from baseline or absolute thresholds, and acute kidney and myocardial injury after noncardiac surgery: a retrospective cohort analysis. Anesthesiology 126:47-65 295. Abbott TEF, Pearse RM, Archbold RA et al (2018) A prospective international multicentre cohort study of intraoperative heart rate and systolic blood pressure and myocardial injury after noncardiac surgery: results of the VISION study. Anesth Analg 126:1936-1945 296. Maheshwari K, Pu X, Rivas E et al (2021) Association between intraoperative mean arterial pressure and postoperative complications is independent of cardiac index in patients undergoing noncardiac surgery. Br J Anaesth 127:e102-e104 297. Futier E, Lefrant JY, Guinot PG, INPRESS Study Group et al (2017) Effect of individualized vs standard blood pressure management strategies on postoperative organ dysfunction among high-risk patients undergoing major surgery: a randomized clinical trial. JAMA 318:1346-1357 [/fig] [table] Table 2: The GRADE system-grading recommendations GRADE Grades of Recommendation, Assessment, Development, and Evaluation, RCT randomized controlled trial. Adapted from Guyatt G, Gutermen D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest. 2006;129:174-181. Used with permission Grade Description Benefit versus risk and burdens Methodologic quality of supporting evi- [/table]	None	https://link.springer.com/content/pdf/10.1007/s00464-022-09758-x.pdf	None
61cb06ea849f6fdb01f87ebfcd79886b750ceb2b	pubmed	Arthroscopic surgery for degenerative knee arthritis and meniscal tears: a clinical practice guideline	Arthroscopic surgery for degenerative knee arthritis and meniscal tears: a clinical practice guideline ## Population ## The evidence The panel requested two systematic reviews to inform the recommendation. The systematic review on the net benefit of knee arthroscopy compared with non-operative care pools data from 13 randomised trials for benefit outcomes (1668 patients) and an additional 12 observational studies for complications (>1.8 million patients). [bib_ref] Knee arthroscopy versus conservative management in patients with degenerative knee disease: a..., Brignardello-Peterson [/bib_ref] gives an overview of the patients included, the study funding, and patient involvement in the design of the studies. Panel members identified three outcomes-pain, function, and quality of life-as the most important for patients with degenerative knee disease who are considering surgery. Although the included studies reported these patient-important outcomes, it is difficult to know whether changes recorded on an instrument measuring subjective symptoms are important to those with symptoms-for example, a change of three points might have completely different meanings in two different pain scales. Therefore, a second team performed a linked systematic review addressing what level of individual change on a given scale is important to patients, 20 a characteristic called the minimally important difference (MID). [bib_ref] Interpreting treatment effects in randomised trials, Guyatt [/bib_ref] The study identified a range of credible MIDs for each key outcome; this range of MID estimates informed sensitivity analyses for the review on net benefit, informed discussions on the patient values and preferences, and was key to interpreting the magnitude of effect sizes as well as the strength of the recommendation. 20 ## Understanding the recommendations The infographic provides an overview of the benefits and harms of arthroscopy in standard GRADE format. Arthroscopic knee surgery for degenerative knee disease is the most common orthopaedic procedure in countries with available data [bib_ref] Ambulatory surgery in the United States, Cullen [/bib_ref] and on a global scale is performed more than two million times each year [fig_ref] Fig 1 \|: Population adjusted trends in frequency of knee arthroscopy [/fig_ref]. [bib_ref] Arthroscopy for knee osteoarthritis has not decreased after a clinical trial, Adelani [/bib_ref] [bib_ref] Trends in elective knee arthroscopies in a population-based cohort, Bohensky [/bib_ref] [bib_ref] Knee arthroscopy: influence of systems for delivering healthcare on procedure rates, Hamilton [/bib_ref] [bib_ref] Large increase in arthroscopic meniscus surgery in the middle-aged and older population..., Thorlund [/bib_ref] Arthroscopic procedures for degenerative knee disease cost more than $3bn per year in the US alone. [bib_ref] Arthroscopic surgery for knee pain, Järvinen [/bib_ref] A high prevalence of features advocated to respond positively to arthroscopic surgery (such as meniscal tears, mechanical symptoms, and sudden symptom onset) as well as financial incentives may explain why arthroscopic knee surgery continues to be so common despite recom- - Degenerative knee disease is an inclusive term, which many consider synonymous with osteoarthritis. We use the term degenerative knee disease to explicitly include patients with knee pain, particularly if they are >35 years old, with or without: -Imaging evidence of osteoarthritis -Meniscus tears -Locking, clicking, or other mechanical symptoms except persistent objective locked knee -Acute or subacute onset of symptoms - Most people with degenerative arthritis have at least one of these characteristics. The term degenerative knee disease does not include patients having recent debut of their symptoms after a major knee trauma with acute onset of joint swelling (such as haemarthrosis) The panel is confident that the randomised controlled trials included adequate representation from groups commonly cited to derive benefit from arthroscopic knee surgery for degenerative knee disease-notably those with meniscal tears, no or minimal radiographic evidence of osteoarthritis, and those with sudden but non-traumatic symptom onset. Thus the recommendation applies to all or almost all patients with degenerative knee disease. Further, the evidence applies to patients with any severity of mechanical symptoms, with the only possible exception being those who are objectively unable to fully extend their knee (that is, a true locked knee). We did not consider young patients with sports related injuries or patients with major trauma in any age. Trials that enrolled a majority of patients without radiographic osteoarthritis showed similar effect sizes to trials enrolling patients with radiographic evidence of osteoarthritis. Most of these trials exclusively included patients E stimates of baseline risk for effects comes from the control arms of the trials; for complications, comparator risk was assumed to be nil. The panel is confident that arthroscopic knee surgery does not, on average, result in an improvement in long term pain or function. Most patients will experience an important improvement in pain and function without arthroscopy. However, in <15% of participants, arthroscopic surgery resulted in a small or very small improvement in pain or function at three months after surgery-this benefit was not sustained at one year. In addition to the burden of undergoing knee arthroscopy (see practical issues below), there are rare but important harms, although the precision in these estimates is uncertain (low quality of evidence). It is unlikely that new information will change interpretation of the key outcomes of pain, knee function, and ## How the recommendation was created A randomised controlled trial published in The BMJ in June 2016 found that, among patients with a degenerative medial meniscus tear, knee arthroscopy was no better than exercise therapy. [bib_ref] Exercise therapy versus arthroscopic partial meniscectomy for degenerative meniscal tear in middle..., Kise [/bib_ref] This study adds to the body of evidence suggesting that the benefits of arthroscopy may not outweigh the burden and risks. The RapidRecs executive felt that the study, when considered in context of the full body of evidence, might change practice. [bib_ref] Introduction to BMJ Rapid Recommendations, Siemieniuk [/bib_ref] Our international panel including orthopaedic surgeons, a rheumatologist, physiotherapists, a general practitioner, general internists, epidemiologists, methodologists, and people with lived experience of degenerative knee disease (including those who had undergone and those who had not undergone arthroscopy) met to discuss the evidence. No person had financial conflicts of interest; intellectual and professional conflicts were minimised and managed (see appendix 1 on bmj.com). The panel followed the BMJ Rapid Recommendations procedures for creating a trustworthy recommendation and used the GRADE approach to critically appraise the evidence and create recommendations (appendix 2). [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] The panel considered the balance of benefits, harms, and burdens of the procedure, the quality of evidence for each outcome, typical and expected variations in patient values and preferences, and acceptability. Recommendations can be strong or weak, for or against a course of action. ## How patients were involved in the creation of this article Three people with lived experience of osteoarthritis, one of whom had arthroscopic knee surgery, were full panel members. These panel members identified important outcomes and led the discussion on values and preferences. Pain was weighed as higher importance for most patients: for example, the patient panel members felt that a possible small benefit to function without a reduction in pain would be unimportant to almost all patients. Those with lived experience identified key practical issues including concerns with cost and accessibility for both arthroscopy and interventions provided by physiotherapists. The members participated in the teleconferences and email discussions and met all authorship criteria. - To what extent might you use information in this article to alter the conversations you have with patients with degenerative knee disease, or those considering arthroscopic surgery? ing or physical activity is limited during the recovery period. 27 outlines the key practical issues for those considering arthroscopic knee surgery versus nonsurgical management for degenerative knee disease. Degenerative knee disease is a chronic condition in which symptoms fluctuate. On average, pain tends to improve over time after seeing a physician for pain, and delaying knee replacement is encouraged when possible. [bib_ref] The American Academy of Orthopaedic Surgeons evidencebased clinical practice guideline on surgical..., Mcgrory [/bib_ref] Values and preferences Our strong recommendation against arthroscopy reflects a low value on a modest probability (<15%) of small or very small improvement in short term pain and function that does not persist to one year, and a higher value on avoiding the burden, postoperative limitations, and rare serious adverse effects associated with knee arthroscopy. The panel, including the patient participants, felt that with meniscus tears. Meniscus tears are common, usually incidental findings, and unlikely to be the cause of knee pain, aching, or stiffness. 1 Mechanical symptoms were also a prominent feature for most trial participants, and many had sudden or subacute onset of symptoms. [bib_ref] Knee arthroscopic surgery is beneficial to middle-aged patients with meniscal symptoms: a..., Gauffin [/bib_ref] [bib_ref] A randomized trial of arthroscopic surgery for osteoarthritis of the knee, Kirkley [/bib_ref] [bib_ref] Finnish Degenerative Meniscal Lesion Study Group. Mechanical symptoms and arthroscopic partial meniscectomy..., Sihvonen [/bib_ref] [bib_ref] Finnish Degenerative Meniscal Lesion Study (FIDELITY) Group. Arthroscopic partial meniscectomy versus sham..., Sihvonen [/bib_ref] Given that there is evidence of harm and no evidence of important lasting benefit in any subgroup, the panel believes that the burden of proof rests with those who suggest benefit for any other particular subgroup before arthroscopic surgery is routinely performed in any subgroup of patients. ## Practical issues It takes between two and six weeks to recover from arthroscopy, during which time patients may experience pain, swelling, and limited function. almost all patients would share these values. The recommendation is not applicable to patients who do not share these values (that is, those who place a high value on a small, uncertain, and transient reduction in pain and function, and a low value on avoiding the burden and postoperative limitation associated with arthroscopy). ## Costs and resources The panel focused on the patient perspective rather than that of society when formulating the recommendation. However, implementation of this recommendation will almost certainly result in considerable cost savings for health funders. A rigorous economic analysis found that knee arthroscopy for degenerative knee disease is not close to cost effective by traditional standards, even in extreme scenarios that assume a benefit with arthroscopy. [bib_ref] Cost-effectiveness analysis of arthroscopic surgery compared with non-operative management for osteoarthritis of..., Marsh [/bib_ref] The panel made a strong recommendation against arthroscopy, which applies to almost all patients with degenerative knee disease, implying that non-use of knee arthroscopy can be used as a performance measure or tied to health funding. 31 # Future research Key research questions to inform decision makers and future guidelines are: - Randomised trials-Does arthroscopic knee surgery benefit patients who are objectively unable to fully extend their knee or who have persistent, severe, and frequent mechanical symptoms? - Implementation studies-What are the most effective ways to reduce the overuse of arthroscopic surgery for degenerative knee disease? [fig_ref] Table 2 \|: New evidence which has emerged after initial publication There are currently no... [/fig_ref] shows evidence which has emerged since the publication of this article. As new evidence is published, a group will assess the new evidence and make a judgment on to what extent it is expected to alter the recommendation. ## Updates to this article We thank Alison Hoens for critical review of the recommendation and manuscript. We also thank Tahira Devji for expertly leading the systematic review of minimally important differences. Funding: This guideline was not funded. Competing interests: All authors have completed the BMJ Rapid Recommendations interests disclosure form, and a detailed, contextualised description of all disclosures is reported in appendix 1. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions. Transparency: R Siemieniuk affirms that the manuscript is an honest, accurate, and transparent account of the recommendation being reported; that no important aspects of the recommendation have been omitted; and that any discrepancies from the recommendation as planned (and, if relevant, registered) have been explained. [fig] Fig 1 \|: Population adjusted trends in frequency of knee arthroscopy; percent. Arthroscopic knee surgery remains common despite accumulating evidence suggesting little benefit [/fig] [fig] •: Project: how many arthroscopic procedures are scheduled in your organisation for degenerative knee disease? Based on the information you have read in this article or in this package of Rapid Recommendation articles, is there anything which you might alter your practice? [/fig] [fig] Fig 2 \|Fig 3 \|: Characteristics of patients and trials included in systematic review of arthroscopic knee surgery No commercial reuse: See rights and reprints http://www.bmj.Practical issues about use of arthroscopic knee surgery versus non-surgical management for degenerative knee disease [/fig] [table] Table 1 \|: Support from current guidance for arthroscopic surgery in patients with subgroups of degenerative knee disease [/table] [table] 28: Most patients cannot bear full weight on the leg (that is, they may need crutches) in the first week after surgery, and driv-Use this information to gauge how similar your patients' conditions are to those of people studied in the trialsMEAN SYMPTOM DURATION monthsNo trials involved patients in design or conduct 12 of 13 trials were free of industry funding [/table] [table] Table 2 \|: New evidence which has emerged after initial publication There are currently no updates to the article [/table]	None	https://www.bmj.com/content/bmj/357/bmj.j1982.full.pdf	#### What you need to know What is the role of arthroscopic surgery in degenerative knee disease? An expert panel produced these recommendations based on a linked systematic review triggered by a randomised trial published in The BMJ in June 2016, which found that, among patients with a degenerative medial meniscus tear, knee arthroscopy was no better than exercise therapy. The panel make a strong recommendation against arthroscopy for degenerative knee disease. Box 1 shows all of the articles and evidence linked in this Rapid Recommendation package. The infographic provides an overview of the absolute benefits and harms of arthroscopy in standard GRADE format. Table 2 below shows any evidence that has emerged since the publication of this article. #### Box 1: Linked articles in this BMJ Rapid Recommendations cluster
c24dee3ffbdc4aba12295a21f1c4c410e779f734	pubmed	STOPP/START criteria for potentially inappropriate prescribing in older people: version 2	STOPP/START criteria for potentially inappropriate prescribing in older people: version 2 Purpose: screening tool of older people's prescriptions (STOPP) and screening tool to alert to right treatment (START) criteria were first published in 2008. Due to an expanding therapeutics evidence base, updating of the criteria was required. Methods: we reviewed the 2008 STOPP/START criteria to add new evidence-based criteria and remove any obsolete criteria. A thorough literature review was performed to reassess the evidence base of the 2008 criteria and the proposed new criteria. Nineteen experts from 13 European countries reviewed a new draft of STOPP & START criteria including proposed new criteria. These experts were also asked to propose additional criteria they considered important to include in the revised STOPP & START criteria and to highlight any criteria from the 2008 list they considered less important or lacking an evidence base. The revised list of criteria was then validated using the Delphi consensus methodology. Results: the expert panel agreed a final list of 114 criteria after two Delphi validation rounds, i.e. 80 STOPP criteria and 34 START criteria. This represents an overall 31% increase in STOPP/START criteria compared with version 1. Several new STOPP categories were created in version 2, namely antiplatelet/anticoagulant drugs, drugs affecting, or affected by, renal function and drugs that increase anticholinergic burden; new START categories include urogenital system drugs, analgesics and vaccines. Conclusion: STOPP/START version 2 criteria have been expanded and updated for the purpose of minimizing inappropriate prescribing in older people. These criteria are based on an up-to-date literature review and consensus validation among a European panel of experts. # Introduction Adverse drug reactions (ADRs) in older people currently represent a serious and growing public health problem [bib_ref] Quality of drug prescribing in older patients: is there a problem and..., Scott [/bib_ref]. Polypharmacy and inappropriate prescribing (IP) are wellknown risk factors for ADRs, which commonly cause adverse clinical outcomes in older people [bib_ref] The epidemiology of serious adverse drug reactions among the elderly, Atkin [/bib_ref] [bib_ref] Strategies to reduce the risk of iatrogenic illness in complex older adults, Onder [/bib_ref]. IP encompasses potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) [bib_ref] Inappropriate prescribing: criteria, detection and prevention, O'connor [/bib_ref]. STOPP/START criteria for potential IP in older people recognise the dual nature of IP by including a list of PIMs (STOPP criteria) and PPOs (START criteria). Since the first iteration of STOPP/START criteria in 2008 [bib_ref] Screening Tool of Older Person's Prescriptions) and START (Screening Tool to Alert..., Gallagher [/bib_ref] , our research group has shown a number of important properties of STOPP/START criteria, namely: - STOPP criteria medications are significantly associated with adverse drug events (ADEs), unlike Beers 2003 criteria medications [bib_ref] Potentially inappropriate medications defined by STOPP criteria and the risk of adverse..., Hamilton [/bib_ref]. - STOPP/START criteria as an intervention applied at a single time point during hospitalisation for acute illness in older people significantly improve medication appropriateness [bib_ref] Prevention of potentially inappropriate prescribing for elderly patients: a randomized controlled trial..., Gallagher [/bib_ref] , an effect that is maintained 6 months postintervention. - STOPP/START criteria as an intervention applied within 72 h of admission significantly reduce ADRs (with an absolute risk reduction of 9.3%; number needed to treat = 11) and average length of stay by 3 days in older people hospitalised with unselected acute illnesses For these reasons, we contend that STOPP/START criteria have practical clinical value. Although these findings are recent, it has become clear that an updated version of STOPP/START criteria is required due to a changing evidence base underpinning the first version of STOPP/ START, the licensing of important new drugs since 2008 and the recognition of a more extensive list of PIMs than had been included in version 1. In addition, a number of STOPP/START criteria were no longer considered completely accurate or relevant, e.g. the use of calcium channel blockers (of any kind) in patients with chronic constipation (STOPP criterion) and the use of aspirin for primary prevention of cardiovascular disease in patients with diabetes (START criterion). It was also clear that a small number (12 in total) of criteria in STOPP/START version 1 were lacking in clinical importance or prevalence and were therefore of less relevance compared with other criteria in the list. In addition, there were some important criteria that were absent from STOPP/START version 1. Finally, we considered that STOPP/START criteria would be enhanced by seeking the input of a wider ranging panel of experts from across Europe than the panel of Irish and UK experts involved in the validation of version 1; this was to reflect Europe-wide prescribing practices in the general population of older people. The aim of this study was to prepare and validate a new version of STOPP/START criteria so as to reflect more complete and up-to-date sets of PIMs and PPOs that may have serious negative effects on the health and well-being of older people in most clinical settings. # Methods We proposed new criteria to be added to the 2008 list of STOPP/START criteria on the basis of an expanded evidence base since 2008. We evaluated these proposed new criteria in terms of their clinical importance, accuracy and evidence base. If the proposed new criteria met these requirements, we included them in the first draft of the STOPP/ START version 2 criteria for further validation. We recruited a panel of 19 experts from 13 countries in Europe, who had recognised expertise in Geriatric Medicine and pharmacotherapy in older people. We asked each expert to comment on the 2008 STOPP/START criteria, in particular their opinions on their current validity and relevance. We asked the expert panel members to propose additional STOPP and START criteria and ways to improve the structure and content of the existing criteria. We evaluated all new criteria proposed by the expert panel in terms of their clinical importance, accuracy and evidence base. We then undertook a process of establishment of the evidence base to support all proposed criteria, including both the criteria to be retained from STOPP/START version 1 and also the suggested additional criteria. The STOPP/START version 1 criteria were reviewed in terms of the current evidence base to support them. Some of the version 1 criteria were found to lack a firm evidence base, e. g. statin therapy for primary prevention of cardiovascular disease in diabetes mellitus. The authors proposed some new criteria, as did the expert panel members. We then searched PubMed, Embase and Cochrane Library databases for recent published evidence to underpin each version 1 criterion and the proposed new criteria. The key search words relating to each proposed criterion were entered in the three databases and relevant articles identified in the categories: systematic reviews, randomised controlled trials (RCTs) and reviews. In addition, we examined other sources, such as recently published textbooks, the British National Formulary and NICE (http://www.nice. org.uk/) and SIGN (http://www.sign.ac.uk/guidelines/ published/numlist.html, 1 March 2014, date last accessed) treatment guidelines for sources of references. Where we did not find systematic reviews to support a particular criterion, we searched for reviews or RCTs that indicated clearly that the criterion was evidence based and therefore appropriate to include in STOPP/START version 2. Three members of the research team (the principal author and two postgraduate students under the principal author's supervision) read the selected articles to ensure their suitability as support evidence. From the initial list of proposed criteria, we removed criteria that did not have a clear evidence base. The remaining proposed criteria were organised according to physiological systems for further consensus assessment by the expert panel. We then made available all of the relevant reference articles that constituted the support reference bank for the STOPP/START version 2 draft criteria to the members of the expert panel; we provided the latter in an online reference paper repository, using DropBox ® software. The Delphi panel members were offered the abstracts and full publication versions of all of the selected articles relating to each proposed criterion. Each of the selected articles provided an evidence base to support each proposed criterion, and it was left to the discretion/need of each Delphi panel member to assess the evidence presented from the selected articles provided by the literature search. We did not ask the Delphi panel members to read all articles in a systematic manner and to provide a standardised rating of each article offered as evidence to support individual criteria. Rather, the articles were provided as a reference repository to be accessed whenever the expert panel members needed to check the supporting reference papers relating to particular proposed STOPP/ START criteria. As with STOPP/START version 1, topics were chosen for inclusion according to their considered importance within each physiological system, provided they had a sound evidence base, following literature search. When the review of the first draft of version 2 criteria was complete, we sent the draft criteria to each member of the expert panel for review and feedback. We used SurveyMonkey ® software to facilitate an online Delphi validation, an established method of achieving consensus. Using the Delphi validation method, we presented each criterion to the expert panel members in the form of a statement, e.g. Antipsychotics (i.e. other than quetiapine or clozapine) in older patients with Parkinsonism or Lewy Body Disease should be avoided due to the risk of severe extra-pyramidal symptoms. Each expert panel member then chose his/her level of agreement with each statement, ranging from 'strongly agree' to 'strongly disagree'. Panellists were also given a 'don't know' option and had the opportunity to comment on each suggested criterion using free text feedback before moving to the next proposed criterion for evaluation. A Likert scale was used to measure the responses: 0 = don't know; 1 = strongly agree; 2 = agree; 3 = neutral; 4 = disagree; 5 = strongly disagree. The median and interquartile range values were calculated for each response in each iteration of the Delphi process. Criteria with a median value of 1 or 2 and a 75th centile value of not >2 were retained. Criteria with a higher median value were excluded. Following the first validation round, we removed any proposed criteria that did not meet the retention requirements. We then drew up the second draft of the new criteria and proceeded to a second round of Delphi validation, once again using an online method, and inviting free text feedback from panel members on each criterion. As in the first validation round, we excluded those criteria that did not meet the retention requirements detailed previously. We planned to continue this process of repeated Delphi validation rounds until agreement to retain or reject was reached on all proposed criteria before declaring that the validation process was complete. The construction and validation process of STOPP/ START version 2 is summarised as follows: [fig_ref] Table 1: details those criteria rejected during the Delphi consensus validation of STOPP/START version... [/fig_ref] on the basis of a lack of sufficiently robust or consistent evidence in the published literature [bib_ref] A comparison of prescribing criteria when applied to older community-based patients, Sackett [/bib_ref]. [fig_ref] Table 2: Proposed criteria rejected by the expert panel for inclusion in STOPP/START version... [/fig_ref] Version 2 of STOPP/START, with 114 criteria, represents a 31% increase in the total number of criteria included in version 1. This number of criteria may be considered unwieldy by some users, particularly those in busy clinical practice. Development of STOPP/START software applications has opened up the real possibility of applying the criteria in routine clinical practice globally. Undoubtedly, some criteria have greater clinical importance than others, and there may be an argument in favour of hierarchical prioritisation within the overall set of STOPP/ START criteria. However, we considered that such hierarchical prioritisation might introduce unnecessary complexity to using STOPP/START, particularly when the criteria refer to potential rather than absolute medication inappropriateness. Inevitably, there will be comparisons between STOPP/ START version 2 and Beers criteria version 4 published in 2012. Although we have included a new section in STOPP criteria containing three implicit prescribing rules, STOPP/START, like Beers criteria, are essentially explicit criteria for PIMs. However, some important essential differences between STOPP/START and Beers criteria remain, principally the list of PPO's (START criteria) and the avoidance of mention of some Beers criteria drugs that are now absent from most European drug formularies, e.g. guanabenz, reserpine, mesoridazine, estazolam, trimethobenzamide and metaxalone. In STOPP/START criteria, we decided not to indicate the comparative clinical relevance/severity of each criterion, since we considered almost all of the potential instances of IP in STOPP and START lists to be non-trivial, i.e. potentially serious. There are several PIM criteria sets in the published literature [bib_ref] Inappropriate prescribing: criteria, detection and prevention, O'connor [/bib_ref]. However, only five published studies describe the application of PIM criteria as an intervention tool for improving medication appropriateness [bib_ref] Potential adverse drug events in an indigent and homeless geriatric population, Spiker [/bib_ref] [bib_ref] Reduction of inappropriate medications among older nursing-home residents: a nurse-led, pre/postdesign, intervention..., Blozik [/bib_ref] [bib_ref] The beers criteria as an outpatient screening tool for potentially inappropriate medications, Dunn [/bib_ref] [bib_ref] Improving prescribing in the elderly: a study in the long term care..., Gill [/bib_ref]. Three of these five studies describe the use of Beers criteria or variations of Beers criteria [bib_ref] Potential adverse drug events in an indigent and homeless geriatric population, Spiker [/bib_ref] [bib_ref] Reduction of inappropriate medications among older nursing-home residents: a nurse-led, pre/postdesign, intervention..., Blozik [/bib_ref] [bib_ref] The beers criteria as an outpatient screening tool for potentially inappropriate medications, Dunn [/bib_ref] , one study deals with inappropriate prescribing in the elderly tool (IPET) criteria [bib_ref] Improving prescribing in the elderly: a study in the long term care..., Gill [/bib_ref] and one study with STOPP/START criteria [bib_ref] Prevention of potentially inappropriate prescribing for elderly patients: a randomized controlled trial..., Gallagher [/bib_ref]. In our opinion, only those sets of PIM criteria that have tangible clinical benefit when applied as an intervention merit serious attention. Three of these five intervention studies used either Beers criteria or an adaptation of Beers criteria or IPET criteria as both the intervention and the primary outcome measure [bib_ref] Potential adverse drug events in an indigent and homeless geriatric population, Spiker [/bib_ref] [bib_ref] Reduction of inappropriate medications among older nursing-home residents: a nurse-led, pre/postdesign, intervention..., Blozik [/bib_ref] [bib_ref] The beers criteria as an outpatient screening tool for potentially inappropriate medications, Dunn [/bib_ref]. Gill et al. [bib_ref] Improving prescribing in the elderly: a study in the long term care..., Gill [/bib_ref] reported that 37.9% of PIMs identified by IPET were discontinued by the prescribing physician, i.e. the intervention and the outcome measure were essentially the same. Although all five studies report benefit, only the study by Gallagher et al. [bib_ref] Prevention of potentially inappropriate prescribing for elderly patients: a randomized controlled trial..., Gallagher [/bib_ref] described an intervention (STOPP/ START criteria) that was distinct from the outcome measure (Medication Appropriateness Index). All explicit IP criteria essentially aim to improve medication appropriateness and/or avoid potentially serious ADRs and ADEs. IP criteria are clinically relevant if they significantly reduce the rate of ADRs or ADEs when applied prospectively to an unselected population of older patients in a particular clinical setting. STOPP/START criteria meet this essential requirement for clinical relevance on the basis of a highly significant reduction in ADR incidence in older hospitalised patients whose medication has been adjusted according to STOPP/START criteria compared with similar older patients receiving standard pharmaceutical care. The present validation study shows the need to update and revise explicit IP criteria on a regular basis. The total number of STOPP/START criteria has increased by 31% from version 1 to version 2 between 2008 and 2013. Most of the extra criteria do not pertain to new drugs with new indications arriving on the market during that 5-year time interval. Rather, they arise from new trial information, new systematic reviews and expert panel suggestions for additional criteria. Although there are research data to indicate that the first iteration of STOPP/START as an intervention has clinical relevance in the acute hospital setting, it remains to be seen whether STOPP/START version 2 offers further ADR/ ADE prevention benefits to older patients in various clinical settings. A recently funded European Commission Seventh Framework Programme project, called SENATOR [http:// www.senator-project.eu (19 June 2014, date last accessed)], will examine the efficacy of a new pharmacotherapy optimisation software intervention based largely on STOPP/ START criteria. The primary outcome measure of the international multi-centre RCT designed to test SENATOR software's efficacy will be ADR incidence in older people hospitalised with acute illness. ## Key points - PIMs and PPOs are commonly encountered in older people. PIMs and PPOs are closely related to ADEs and ADRs, but they are preventable. - STOPP/START criteria have been shown to be significantly associated with ADEs in acutely ill older people, unlike Beers criteria. - In single-centre RCTs, STOPP/START criteria used as an intervention significantly improve medication appropriateness and reduce the incidence of ADRs in older people in hospital, compared with standard pharmaceutical care. - Since the first publication of STOPP/START criteria in 2008, the therapeutics evidence base as it applies to older people has expanded significantly, indicating the need for updating and revision of STOPP/START criteria. The present study describes this process, resulting in a 31% increase of the number of STOPP/START criteria compared with the 2008 version, i.e. 114 criteria. [fig] Phase 1: Call for review of STOPP/START version 1 criteria and proposal of a new evidence-based criteria/removal of obsolete criteria. Phase 2: Draft 1 of STOPP/START version 2 criteria. Phase 3: Search of PubMed, Embase and Cochrane databases for systematic reviews, reviews and other references to support STOPP/START version 2 criteria. Phase 4: Draft 2 of STOPP/START version 2 criteria, with support literature. Phase 5: Delphi validation Round 1 (19 experts). Phase 6: Draft 3 of STOPP/START version 2 criteria. Phase 7: Delphi validation Round 2 (19 experts). Phase 8: Draft 4 of STOPP/START version 2 criteria (final draft). Results For the first expert panel consultation, there was a list of 138 proposed STOPP/START criteria for evaluation. These included the original 87 STOPP/START version 1 criteria plus 37 possible additional criteria proposed by the Irish STOPP/START criteria group; we also received suggestions for a further 14 criteria from the international expert review panel. Of the 138 proposed criteria, 127 criteria had supporting published evidence sufficient to warrant their inclusion in Round 1 of the Delphi validation which yielded 124 criteria with median Likert scores of 1 or 2. One hundred and seven of these 124 criteria had median Likert scores with 75th centile values of 1 or 2 and were retained as validated criteria. The remaining 17 criteria (7 STOPP and 10 START criteria) formed the basis for Delphi consensus Round 2 which achieved consensus on 7 criteria; a third consensus validation round was not required. The full list of references which supports the new STOPP criteria and START criteria is given in Supplementary data, Appendices 1 and 2 and the final list of new STOPP criteria and the new START criteria is given in Supplementary data, Appendices 3 and 4 available in Age and Ageing online, respectively. Fifteen of the criteria from STOPP/START version 1 were not included in STOPP/START version 2 [/fig] [table] Table 1: details those criteria rejected during the Delphi consensus validation of STOPP/START version 2. STOPP/START version 1 criteria removed from the proposed version 2 because of weak or equivocal supporting evidence The fact that STOPP/START criteria have been successfully applied for both research and practical clinical purposes in several countries in Europe, Asia, Australia, North America and South America indicates that the criteria probably have true global relevance. The relevance of STOPP/ START criteria is further supported by the tangible clinical benefits demonstrated in the studies completed by our group, alluded to in the Introduction. [/table] [table] Table 2: Proposed criteria rejected by the expert panel for inclusion in STOPP/START version 2 using Delphi consensus SSRIs with concurrent bleeding diathesis, prescription of anticoagulants or antiplatelet agents (increased risk of bleeding in general), active peptic ulcer disease or concurrent NSAID prescription (risk of gastrointestinal bleeding) SSRIs in patients with previous history of major non-traumatic bleeding or in combination with drugs that may promote peptic ulceration, e.g. NSAIDs (increased risk of recurrent major bleeding) Aspirin, clopidogrel, dipyridamole, vitamin K antagonists, direct thrombin inhibitors or factor Xa inhibitors with concurrent high bleeding risk, i.e. HAS-BLED score ≥3; HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history, labile INRs, elderly (age > 65 years), drugs that promote bleeding/alcohol) Antidepressants of any kind in patients with recurrent falls Rejected new START criteria Memantine for moderate-severe Alzheimer's disease Dopamine agonist (e.g. ropinirole or pramipexole) for Restless Legs Syndrome once iron deficiency has been excluded Statin therapy in diabetes mellitus, unless the patient is at end of life or more appropriate for palliation Phosphodiesterase type-5 inhibitor with persistent erectile dysfunction SSRI, selective serotonin reuptake inhibitor; NSAID, non-steroidal antiinflammatory drug. While these criteria have a significant supportive evidence, the expert panel did not judge them to be of such high importance as to be considered potentially inappropriate in every case where they are encountered. [/table]	None	https://academic.oup.com/ageing/article-pdf/44/2/213/28880824/afu145.pdf	Abstract Purpose: screening tool of older people's prescriptions (STOPP) and screening tool to alert to right treatment (START) criteria were first published in 2008. Due to an expanding therapeutics evidence base, updating of the criteria was required. Methods: we reviewed the 2008 STOPP/START criteria to add new evidence-based criteria and remove any obsolete criteria. A thorough literature review was performed to reassess the evidence base of the 2008 criteria and the proposed new criteria. Nineteen experts from 13 European countries reviewed a new draft of STOPP & START criteria including proposed new criteria. These experts were also asked to propose additional criteria they considered important to include in the revised STOPP & START criteria and to highlight any criteria from the 2008 list they considered less important or lacking an evidence base. The revised list of criteria was then validated using the Delphi consensus methodology. Results: the expert panel agreed a final list of 114 criteria after two Delphi validation rounds, i.e. 80 STOPP criteria and 34 START criteria. This represents an overall 31% increase in STOPP/START criteria compared with version 1. Several new STOPP categories were created in version 2, namely antiplatelet/anticoagulant drugs, drugs affecting, or affected by, renal function and drugs that increase anticholinergic burden; new START categories include urogenital system drugs, analgesics and vaccines. Conclusion: STOPP/START version 2 criteria have been expanded and updated for the purpose of minimizing inappropriate prescribing in older people. These criteria are based on an up-to-date literature review and consensus validation among a European panel of experts.

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