British Journal of Surgery

The Beyond TME Collaborative ; Ali, S Mohammed; Antoniou, Anthony; Beynon, John; Bhangu, Aneel; Bose, Pradeep; Boyle, Kirsten; Branagan, Graham; Brown, Gina; Burling, David; Chang, George J; Clark, Susan K; Colquhoun, Patrick; Crane, Christopher H; Darzi, Ara; Das, Prajnan; de Wilt, Johannes H W; Delaney, Conor P; Desai, Anant; Davies, Mark; Dietz, David; Dozois, Eric J; Duff, Michael; Dziki, Adam; Fitzgerald, J Edward; Frizelle, Frank A; George, Bruce; George, Mark L; Georgiou, Panagiotis; Glynne-Jones, Rob; Goldin, Robert D; Gupta, Arun; Harji, Deena; Harris, Dean A; Hawkins, Maria; Heriot, Alexander G; Holm, Torbjörn; Hompes, Roel; Jeys, Lee; Jenkins, John T; Kiran, Ravi P; Koh, Cherry E; Laurberg, Soren; Law, Wai L; Liberman, A Sender; Marshall, Michele; McArthur, David R; Mirnezami, Alex H; Moran, Brendan; Mortenson, Neil; Myers, Eddie; Nicholls, R John; O'Connell, P Ronan; O'Dwyer, Sarah T; Oliver, Alex; Pallan, Arvind; Patel, Prashant; Patel, Uday B; Radley, Simon; Ramsey, Kelvin W D; Rasmussen, Peter C; Richard, Carole; Rutten, Harm J T; Sagar, Peter; Sebag-Montefiore, David; Solomon, Michael J; Stocchi, Luca; Swallow, Carol J; Tait, Diana; Tan, Emile; Tekkis, Paris P; van As, Nicholas; Vuong, Te; Wiggers, Theo; Wilson, Malcolm; Winter, Desmond; Woodhouse, Christopher

doi: 10.1002/bjs.9192_1pmid: 23901427

Consensus abstract Background The management of primary rectal cancer beyond total mesorectal excision planes (PRC-bTME) and recurrent rectal cancer (RRC) is challenging. There is global variation in standards and no guidelines exist. To achieve cure most patients require extended, multivisceral, exenterative surgery, beyond conventional total mesorectal excision planes. The aim of the Beyond TME Group was to achieve consensus on the definitions and principles of management, and to identify areas of research priority. Methods Delphi methodology was used to achieve consensus. The Group consisted of invited experts from surgery, radiology, oncology and pathology. The process included two international dedicated discussion conferences, formal feedback, three rounds of editing and two rounds of anonymized web-based voting. Consensus was achieved with more than 80 per cent agreement; less than 80 per cent agreement indicated low consensus. During conferences held in September 2011 and March 2012, open discussion took place on areas in which there is a low level of consensus. Results The final consensus document included 51 voted statements, making recommendations on ten key areas of PRC-bTME and RRC. Consensus agreement was achieved on the recommendations of 49 statements, with 34 achieving consensus in over 95 per cent. The lowest level of consensus obtained was 76 per cent. There was clear identification of the need for referral to a specialist multidisciplinary team for diagnosis, assessment and further management. Conclusion The consensus process has provided guidance for the management of patients with PRC-bTME or RRC, taking into account global variations in surgical techniques and technology. It has further identified areas of research priority. Executive summary The executive summary supports the need for standardization of care and a collaborative, cross-discipline consensus statement. Burden of disease: There are 14 000 new rectal cancers per year in the UK, 40 000 in the USA and under half a million new cases per year globally. Of these, 5–10 per cent have invaded adjacent organs at presentation and 10 per cent recur following primary surgery. Complexity of surgery: Major, exenterative, multivisceral resections require specialist multiprofessional care. The surgical procedures are time-consuming (up to 12 h) and are associated with prolonged length of hospital stay (between 10 and 30 days). Long-term 5-year survival rates vary between 30 and 50 per cent. Adverse event rates have been reported in up to 50 per cent of patients. Superspecialist training of surgeons within a multidisciplinary team is required. Inappropriate worldwide variation in practice: There is a wide range of practice from non-specialist and specialist centres, with unequal access to care across global settings. These include differing referral selection criteria, where patients are often denied potentially curative treatment. When surgery is offered, the outcome is neither captured by the national databases nor audited locally. Standardization of definitions: Definitions for the rectum, for primary rectal cancer beyond conventional total mesorectal excision planes, and for recurrent rectal cancer have been defined heterogeneously in the literature and between different institutions, leading to a clear requirement for standardization of the exact definition of these terms. The need for policy: Delay in diagnosis is common and inequalities exist in referral patterns based on geography, with no clear clinical guidelines. No current guidelines exist for these patients, despite the significant burden, cost of surgery, morbidity and national variations in care. Resource impact: The cost-effectiveness of the complex assessments and interventions requires further research. The quality of life and morbidity from non-operative management are unknown. There is a need for specialist training of the multidisciplinary team, which will improve standardization of assessment and management. Consensus statement: The Beyond TME Group comprised representatives from specialist centres in the UK and Ireland, Continental Europe, USA, Canada, Australia, New Zealand and China, who offer treatment for advanced pelvic cancer. The Group has developed a consensus statement that provides guidance for the management of patients with primary rectal cancer beyond total mesorectal excision planes and recurrent rectal cancer, taking into account national and global variations. It has further identified and agreed areas of research priority and training at a national and international level. Introduction Primary rectal cancer beyond total mesorectal excision planes (PRC-bTME) and locally recurrent rectal cancer (RRC) require exenterative-type surgical resection beyond conventional total mesorectal excision (TME) planes. All aspects of their assessment and management are complex, and often require different approaches to conventional rectal cancer treatment. To date, however, no clear guidelines on the management strategy for these patients have been proposed. As a result, there is worldwide variation in standards of care. The objectives of the present collaborative and consensus statement are to provide a clear framework for the assessment and management of these complex patients, and to provide a basis for optimal clinical practice. Additionally, the collaborative aims to foster and advance training and education and high-quality research through international multidisciplinary collaboration, tackling key areas of unmet clinical and research need in advanced primary and recurrent cancers of the rectum. The recommendations are guidelines and not intended to prescribe the treatment plan for an individual patient. Methods This consensus statement was developed using Delphi methodology, incorporating consecutive rounds of anonymous voting, feedback and open discussion at two dedicated international meetings1. A full description of methodology and information used to form and vote on each statement is provided in Appendix 1. Statements are presented as recommendations of care. Levels of voting agreement (presented in parentheses after each statement) and final editing were performed as follows: At least 80 per cent agreement: consensus achieved, with minor editing by the executive committee. Less than 80 per cent agreement: low consensus. Low-consensus statements after the final round were still included in the consensus statement after minor editing by the executive team. The studies were categorized by level of evidence according to the SIGN grading system, developed by the Scottish Intercollegiate Guidelines Network2. The level of evidence in the SIGN grading system ranges from 1++, which includes high-quality meta-analysis, systematic reviews of randomized clinical trials (RCTs) or RCTs with a low risk of bias, to 4, which is in effect expert opinion (Appendix 2). Definitions Definitions for the rectum, PRC-bTME and RRC have been defined heterogeneously in the literature and between different institutions, leading to a clear requirement to standardize the exact definition of these terms. Consensus recommendation The rectum is defined by anatomical criteria demonstrated on magnetic resonance imaging (MRI) as being the portion of the large bowel below the sacral promontory that is surrounded by a definable mesorectum posteriorly. 2+ C (88 per cent). PRC-bTME is that predicted by MRI to require an extended surgical resection beyond the TME plane to achieve a pathological R0 resection. 2+ C (95 per cent). Locally RRC includes recurrence, progression or development of new sites of rectal tumour within the pelvis after previous resectional surgery for rectal cancer. 3 D (95 per cent). Diagnosis The standard of diagnosis for PRC-bTME is tissue biopsy confirmation, typically via a rigid or flexible endoscope. The location of the tumour should be recorded using the anal verge as the landmark. Early imaging to determine the chances of an R0 oncological margin should be established. Tissue biopsy is not always possible and some extraluminal recurrences may prove negative to biopsy or unsafe to sample owing to their anatomical location. The combination of symptoms, with or without a rising carcinoembryonic antigen (CEA) level, with or without positive serial radiological findings (anatomical and functional imaging using MRI and fluorodeoxyglucose (FDG)-positron emission tomography (PET)–computed tomography (CT)) may be sufficient for diagnosis and to thus guide further treatment. MRI and FDG-PET–CT appearances may be ambiguous3, and therefore assessment and decision-making in a multidisciplinary team (MDT) is mandatory when confirmative pathology is lacking. Consensus recommendation The ideal diagnosis of PRC-bTME and RRC is tissue biopsy, although this is not always possible. 2+ C (97 per cent). Where tissue biopsy is not possible or is negative, serial enlargement of a lesion accompanied by either positive PET–CT or rising CEA level and specialist MDT opinion suggestive of malignancy can be accepted for diagnosis. 2– D (100 per cent). Role of the multidisciplinary team The MDT should adopt a standardized approach to patient management, and identify areas for future research and development to improve outcome. This approach will also facilitate audit of activity and outcome. Radiological, oncological and pathological expertise is needed in addition to surgical expertise. Clear referral pathways to regional MDTs dealing with a reasonable volume of these patients should be established. Recurrences require expertise in diagnosis, preoperative therapy (especially if irradiated previously), pathological examination and postoperative management. Patients with recurrent cancer should be referred to a centre that routinely offers assessment and surgery for recurrence. Consensus recommendation The subspecialized MDT requires surgical, oncological, radiological and pathological expertise in pelvic exenteration with a proven record justifying the surgery, including audited histopathological outcomes. 4 D (86 per cent). Patients with a PRC-bTME should be considered for referral to a subspecialized MDT when surgery beyond TME planes is required. 4 D (93 per cent). Patients with RRC should be considered for referral to a subspecialized multidisciplinary team. 4 D (100 per cent). Classification Validation of a single system that should carry prognostic significance as well as anatomical information to guide surgeons would be useful for unit-to-unit communication. There is a lack of suitable classification systems for PRC-bTME, although those used for RRC are likely to be transferrable, once validated. Several classification systems for recurrent disease exist (Appendix 3). In addition to assisting with decision-making regarding resectability, classification adds information about prognosis4. Central recurrences have been shown to be associated with improved survival compared with posterior or lateral recurrences5,6. Consensus recommendation There is a need for consensus validation of a standardized MRI-based classification system derived from the anatomical compartments and interfaces within the pelvis. 2++ C (98 per cent). Imaging and staging The anatomical relationships and assessment of invasion into adjacent organs are of vital importance. A standardized approach to reporting of imaging, particularly MRI, at all stages of management for patients with PRC-bTME and RRC is recommended. Further consensus on reporting of postradiotherapy MRI in terms of post-treatment tumour category (ymrT) and tumour regression grading (mrTRG) is required7. Primary rectal cancer beyond total mesorectal excision planes All participants agreed that MRI was the imaging technique of choice for the pelvis. Predicted R0 resection by MRI includes removal of the mesorectal fascia and en bloc excision of involved structures. Endorectal ultrasonography (ERUS) has been reported to have high sensitivity and specificity for staging primary T4 disease, and may aid targeted biopsy8. However, low consensus was achieved regarding its role, primarily owing to concerns about its inability to add further information above that imparted by MRI, and a preference for some participants for examination under anaesthesia. It is recommended in selected patients when local expertise is available. Recurrent rectal cancer All participants agreed that MRI was the imaging technique of choice for the pelvis. Predicted R0 resection by MRI may involve residual parts of mesorectum, but is more likely to involve assessment of extra-anatomical R0 planes. Radiological detection of locally recurrent disease can be challenging9. A soft tissue mass may persist in the pelvis for 24 months or more following surgery in the absence of recurrence, and this appearance is enhanced by previous radiotherapy or pelvic sepsis due to postoperative anastomotic leakage10,11. Recurrence may be suspected by changes detected over serial scans, and CT-guided biopsy of accessible suspicious areas may be possible12. Both CT and high-resolution MRI can have difficulty distinguishing postoperative scar tissue from recurrent malignant tissue. In some circumstances, PET–CT may improve accuracy in differentiating between scar tissue and metabolically active recurrent disease, but is not 100 per cent specific. Distant disease CT is likely to be the best modality for imaging the lung fields. MRI is helpful in further characterization of suspect liver lesions identified by CT. Bone scans and brain imaging are required where symptoms indicate need. PET–CT may help detect additional occult extrapelvic disease and exclude patients from futile attempts at curative disease resection, although false-positives and -negatives occur13,14. Some units use it routinely owing to its ability to change management15. Restaging following neoadjuvant therapy None of the available imaging modalities (ERUS, MRI, CT) can reliably predict complete pathological remission, which occurs at a rate of up to 15 per cent for primary clinical (c) T3/T4 cancers. It is not yet clear whether surgical planning is best based around the initial MRI or the scan carried out after neoadjuvant treatment, and further research is needed to assess the reliability of this latter scan. Consensus recommendation Preoperative elective staging aims to determine pelvic resectability and the presence of metastatic disease, and should be carried out in all patients being considered for surgery. 2+ C (98 per cent). The optimum modality for imaging the pelvis in patients with PRC-bTME is high-resolution MRI. 2++ B (100 per cent). The optimum modality for imaging the pelvis in patients with suspected or confirmed RRC is high-resolution MRI. 2– C (100 per cent). ERUS may be applied selectively to assess tumour extension adjacent to the rectum, when high-resolution ultrasonography may provide additional or complementary information to MRI. 3 C (76 per cent). Examination under anaesthesia of the pelvis should be applied selectively where it may aid the decision regarding resectability. 3 D (86 per cent). Extrapelvic staging should include contrast-enhanced multidetector CT of the thorax, abdomen and pelvis. 2+ C (100 per cent). Further research into the added value and cost-effectiveness of [18F]FDG-PET–CT for staging is required before a recommendation on its routine use can be made. 3 D (80 per cent). The time to restaging after neoadjuvant therapy should be between 6 and 8 weeks. 3 D (85 per cent). More research is needed to establish the optimum time to restaging and surgery following neoadjuvant therapy. 3 D (98 per cent). Pelvic imaging should have been performed within 6 weeks of the planned date of surgery. 4 D (93 per cent). Diffusion weighted MRI and PET–CT may increase the accuracy of assessing tumour response to neoadjuvant therapy, although more research is required to prove this. 2– D (98 per cent). Role of radiotherapy and chemotherapy Primary rectal cancer: radiotherapy doses and techniques Preoperative chemoradiotherapy (CRT) has gained acceptance as standard treatment for clinically more advanced rectal cancer16–18. In initially non-resectable disease, CRT has been demonstrated to improve resectability and disease-free survival19. The role of CRT includes sterilization of peripherally located disease, including mesorectal breach, and to induce maximal tumour shrinkage to facilitate an R0 resection. For long-course preoperative CRT the standard dose administered in randomized trials has been 45–50·4 Gy. A small-volume external beam boost up to a total dose of 55·8 Gy can be administered (but is not considered mandatory), particularly if concerns regarding anal function are irrelevant because of the intention to perform abdominoperineal excision of the rectum. Intensity-modulated radiotherapy Intensity-modulated radiotherapy (IMRT) allows relative sparing of normal surrounding structures by shaping radiation doses to the target structure. IMRT could be used for dose escalation to all (or part of) the primary tumour in patients with borderline resectable tumours, in an attempt to improve resectability and reduce the risk of a positive resection margin. However, the evidence for IMRT is currently limited and there are associated risks of toxicity20,21. High-dose-rate brachytherapy High-dose-rate brachytherapy (HDR-BT) has been used both as a boost alongside external chemoradiation and as short-term palliation for advanced symptomatic tumours particularly in the very elderly and frail22. In patients with previous pelvic radiation therapy, HDR-BT is an elegant option to downstage tumours and facilitate R0 resection. Intraoperative radiotherapy Although there are no randomized trials evaluating the added benefit of intraoperative radiotherapy (IORT) in addition to external beam radiotherapy, excellent prospective and long-term data incorporating IORT-containing regimens are compelling23,24. The benefits of IORT as a means of delivering higher doses and improving local control have been reported by small retrospective series owing to the limited access of IORT equipment worldwide. Recurrent rectal cancer: radiotherapy and reirradiation When local recurrence occurs where radiotherapy has not previously been administered, radiotherapy or CRT can sterilize microscopic disease within the pelvic cavity and facilitate resectability. Radiotherapy or CRT can also produce good palliation of symptoms, but long-term local control is seldom achieved. The duration of effective palliation is usually short, with further progression of symptoms within 3–6 months after irradiation25. Further reirradiation for locally recurrent cancer remains a controversial issue26,27. Some single-centre experience suggests that this practice may be safe in the short term, although long-term evidence is sparse26. Hyperfractionated (twice daily) reirradiation appears to be well tolerated and may enhance local control28,29. Endorectal HDR-BT is a simple but potentially effective treatment option, especially when the recurrence is central. No centre has access to all of these modalities, and so the specialist MDT, via national referral pathways, should develop the ability to cross-refer where appropriate. Chemotherapy There is a high risk of metastatic disease in PRC-bTME and a potentially higher risk in RRC. Intensification of chemotherapy regimens is emerging as a potential strategy to address this problem. For advanced unresectable tumours, 5-fluorouracil (5-FU)-based chemoradiation has a statistically significant effect on resectability and disease-free survival19,30. Additional cytotoxic drugs The additional integration of oxaliplatin and irinotecan to 5-FU-based chemotherapy has been explored within a CRT schedule in numerous phase II studies in order to increase tumour shrinkage before surgery and potentially mirror the success of oxaliplatin in dealing with distant micrometastases in the adjuvant setting for colonic cancer31,32. Molecularly targeted agents, such as cetuximab, panitumumab and bevacizumab, have also been integrated into standard chemotherapy regimens in colorectal cancer. They appear to improve response rates and extend progression-free and overall survival, again with varying success. Preliminary results of CRT trials with cetuximab have provided disappointing results33; further studies are needed to evaluate the role of incorporating these newer biologically active targeted agents into CRT schedules34. Consensus recommendation Most patients with PRC-bTME and all with RRC should receive neoadjuvant chemoradiation unless contraindicated if they are pelvic radiotherapy-naïve. 2+ C (100 per cent). The risks and benefits of reirradiation in patients who have already undergone pelvic radiotherapy require further assessment in a trial setting. 3 D (96 per cent). Brachytherapy, IORT and stereotactic body radiotherapy may have benefits but require further assessment. 3 D (98 per cent). Surgical approaches By definition, an exenterative procedure entails a pelvic dissection beyond the fascia propria and the mesorectal envelope. It often involves the removal of some or all of the pelvic organs including the bladder, prostate, seminal vesicles, urethra, vagina, uterus, part of the sacrum, and/or the lateral pelvic vasculature35. Preoperative assessment Optimizing patients before multivisceral resection is vital to minimize perioperative morbidity and requires a multispecialist approach36,37. Formal cardiopulmonary testing is an objective assessment to assess fitness and identify areas for potential improvement, with input of cardiologists and respiratory physicians as needed38. General preoperative surgical principles include perioperative stoma counselling/marking, discretionary ureteric stenting to clearly identify the ureteric course, the availability of haemostatic agents during pelvic dissection, and intensive postoperative monitoring. A team approach is important in achieving this, which may include specialists in colorectal, plastic, urology, gynaecological, vascular and orthopaedic surgery, and radiation oncology. Contraindications to resectability The contraindications to resectability remain controversial and are subject to evolving surgical technique. Encasement of external or common iliac vessels as a relative contraindication achieved low consensus as some experts considered it as an absolute contraindication. Clear regional and national referral pathways should exist to allow all patients equal access to appropriate centres with necessary expertise. Sacrectomy R0 abdominosacral resection for PRC-bTME and RRC prolongs survival, has an acceptable postoperative morbidity profile and is associated with acceptable quality of life (QoL). Survival is likely to be worse with R1/2 resections39–41. Although involvement of S1 or S2 was considered a contraindication to surgery, there may be a role for resection with appropriate surgical expertise in highly selected patients42. Pelvic side-wall disease Lateral pelvic side-wall disease, especially when involving the ureters and/or iliac vessels, is associated with a reduced chance of achieving R0 resection43,44. Strategies to improve the curative resection rate include targeted radiotherapy and en bloc removal of iliac vessels followed by reconstruction, embolization with dissection of internal iliac vessels and bony resections as part of partial pelvic resections. Anterior compartment/urogenital disease R0 resection is usually possible only with removal of adjacent organs. When the vagina is involved without the bladder, posterior exenteration can be performed (removal of the rectum, anus, total hysterectomy, bilateral salpingo-oopherectomy and vaginectomy with or without preservation of the anterior vaginal wall in appropriate patients). Partial cystectomy may be carried out when the bladder is involved, although involvement of the trigone typically necessitates total cystectomy with ileal conduit urinary diversion. Central recurrence Isolated central recurrences are associated with the best prognosis of all pelvic recurrences45. Abdominoperineal excision can be performed, or a restorative anterior resection if the tumour is sufficiently high, although planes are often distorted and dissection is outside of the conventional TME plane46,47. Bladder reconstruction The role of bladder reconstruction (rather than cystectomy and ileal conduit) is also unresolved. If the urethra and its sphincters can be preserved, an intestinal neobladder can be formed. However, the risk of fistulation is very high, especially if a low rectal anastomosis is performed at the same time48. An alternative to a reconstruction is to make a continent catheterizable reservoir within the upper abdomen. The urological results are good, with up to 98 per cent continence. However, reconstruction adds about 2 h to an already lengthy procedure. It was not surprising, therefore, to find that attendees at the consensus meeting and the published literature confirmed that, although the techniques are available, few urological reconstructions are actually performed. Distant metastases The full range of options in dealing with metastatic disease is beyond the scope of this consensus document. The sequence of systemic therapy, local resection, resection of distant metastases and pelvic radiotherapy is subject to individualization. Unresectable local disease and palliative resection There may be a role for surgery aiming at high-quality palliation in both RRC and PRC-bTME for superselected patients. Where palliation is the goal of treatment, surgery needs to be considered very carefully, with an expectation of minimal risk of complication for the patient, and hence may be relatively conservative in extent. Aims include reduction of pain, decreased anal discharge and reduction of clinical sepsis, and these operations are likely to be most appropriate in younger patients. Perineal reconstruction Any attempt to reconstruct the perineal defect with plastic surgery techniques should be performed by surgeons who are experienced in the use of rotational or free-flap transfers in order to achieve the best possible results. Techniques used for wound reconstruction include the myocutaneous oblique or vertical rectus abdominis muscle flap, gracilis muscle flap, gluteal rotation flap, inferior gluteal artery perforator flap, free flap or biological graft with omentoplasty49,50 Each has its advantages and disadvantages, and because there are no comparative studies each centre has adopted its preferred technique(s). Reconstruction is often performed in a heavily irradiated field, which may increase the complication rate. Future comparative studies should consider evaluation of the optimal method of perineal reconstruction, and include short- and long-term outcomes as well as QoL. Consensus recommendation Individualized resection for patients with PRC-bTME or RRC often involves surgical planes outside of the mesorectal fascia using a range of exenterative-type procedures. 2++ B (97 per cent). Referral pathways to access superspecialist surgical services should be provided for specialist MDTs. 3 D (100 per cent). Outcomes for patients undergoing pelvic exenteration for PRC-bTME or RRC should be reported separately. 2++ B (97 per cent). A prospective register of operated cases will allow collaborative multicentre reporting of oncological and QoL outcomes. 4 D (98 per cent). The anaesthetist should be involved in preoperative planning and decisions on the need for cardiorespiratory fitness assessments and perioperative care. 3 D (98 per cent). Absolute contraindications to resectability include (2– C): poor performance status/medically unfit patients (for example severe cardiopulmonary impairment) (97 per cent) bilateral sciatic nerve involvement (98 per cent) circumferential bone involvement (94 per cent). Relative contraindications to resectability (benefit unclear) include (2– C): extension of tumour through the sciatic notch (92 per cent) encasement of external iliac vessels – requiring en bloc resection and/or reconstruction of external iliac vessels (78 per cent). high sacral involvement – resection above the S2/3 junction can be performed with suitable surgical expertise and equipment in superspecialist centres (96 per cent). irresectable distant metastases (91 per cent). predicted R2 resection – should be offered only in rare circumstances with MDT agreement, where the indications should be justifiable and the outcomes recorded in an auditable manner (97 per cent). Superspecialist surgical techniques (such as high sacrectomy – S2 and above) should be offered only by surgical units with suitable multidisciplinary expertise. 3 D (98 per cent). A conventional ileal conduit is appropriate for most patients undergoing exenteration, although there is a range of bladder reconstruction options. 3 D (100 per cent). Pathology and prognostic markers Guidelines published by the Royal College of Pathologists in the UK (http://www.rcpath.org/index.asp?pageID=1153) and by the College of American Pathologists guidelines in the USA51 have gained widespread acceptance as the minimum standard for reporting colorectal cancer. Further guidance for the assessment of multivisceral and extended resection specimens is required. Primary rectal cancer beyond total mesorectal excision planes R0 resection is probably the most important factor in predicting prognosis37. Multivisceral resection is likely and so orientation should be clearly marked to aid the pathologist37,52. Most patients will have received neoadjuvant radiotherapy, and so the minimum recommended harvest of 12 lymph nodes may not be applicable53,54. Tumour regression after preoperative treatment should be recorded, as it is likely to provide prognostic information55. A minimum international data set with a common language adapted for use in PRC-bTME would be useful. Recurrent rectal cancer R0 resection of RRC is likely to be the most important factor in predicting prognosis56. R1 resection rates remain problematic, particularly when sacrectomy is required. Some experts argued that obtaining pathology blocks from previous resection specimens was unnecessary and may cause delay, leading to low consensus on this issue. There is no validation of distance to the resection margin as applied to primary cancer57. Anatomical confinements and altered resection planes may mean that these distances can be reduced. A 2-mm or even a 3-mm circumferential margin may not, therefore, be a ‘safe’ circumferential resection margin in the context of local failure and RRC58. Consensus recommendation Accurate pathological reporting of resection margins and other prognostic pathological features is important for informing outcomes and assessing resection quality. 2++ C (100 per cent). Close collaboration between the surgeon, radiologist and pathologist is of particular importance to ensure that the margins most likely to be involved are sampled adequately. 4 D (100 per cent). International guidelines should be developed to guide specimen dissection and reporting to ensure uniformly high standards. 2++ B (100 per cent). Preoperative biopsies should be obtained from referring centres and reviewed by the MDT's specialist pathologist for confirmation of diagnosis. 4 D (81 per cent). Previous resection specimens may be obtained from referring centres and reviewed by the MDT's specialist pathologist for confirmation of diagnosis if doubt exists. 4 D (80 per cent). The prognostic significance of R0 and R1 resection margin distances requires validation for RRC resections. 2++ C (93 per cent). Follow-up Currently, wide variation in practice exists with a low evidence base for both PRC-bTME and RRC. Not all experts agreed that MRI surveillance of the pelvis was appropriate; some argued that it should be in the first year, whereas others argued that it was a waste of resources. Consensus recommendation The optimum follow-up regimens for patients with PRC-bTME and RRC require further development. 3 D (98 per cent). Follow-up regimens following exenteration should include a minimum of annual MRI of the pelvis to detect recurrence. 4 D (83 per cent). A minimum of annual screening for distant metastases with CT of the thorax, abdomen and pelvis is recommended. 2++ C (88 per cent). PET–CT has a role in differentiating pelvic scar tissue from suspected new malignant change, but it is not uniformly reliable. 2+ D (100 per cent). CEA levels can be checked regularly as a rising CEA concentration may indicate recurrence. 2+ D (98 per cent). Quality of life QoL after pelvic exenteration remains understudied. Impairment of sexual, bowel and urinary function is likely, although for variable lengths of time59,60. Retrospective studies have found a difference in QoL following curative versus non-curative resection, suggesting that non-curative resection should be avoided44,60. However, palliative exenteration in carefully selected symptomatic patients may be beneficial, although the role of this approach and its impact on QoL remains unclear59. Research effort should be directed towards collection of QoL data for these patients using a prospectively created database, to include outcomes after curative resection and planned non-curative resection, and QoL among patients managed non-operatively. Validation of current QoL measures for use in the setting of exenterative surgery for PRC-bTME and RRC, or development of new tools, is needed61. Consensus recommendation Prospective assessment of QoL is needed for patients considered for exenterative surgery, to include patients who undergo curative resection, non-curative surgery (R2 resection) and best medical therapy without surgery. 2+ D (100 per cent). Outcome measures for QoL should include (but not be limited to): mobility, bowel function, urinary function, sexual function and postoperative pain. 2+ D (98 per cent). Summary This consensus statement contains a framework for providing cancer care for patients with advanced rectal cancer. PRC-bTME and RRC require significantly different staging and classification, neoadjuvant strategies that perhaps differ from the present standard used for T3 tumours, and surgical interventions distinct from those used to treat ‘simple’ primary cancer. Recurrent cancer presents even further challenges in diagnosis and management, especially in the light of previous irradiation. The inherent variation (and thus adaptability) within these guidelines was due to differences in local resources and expertise. Thus, by including a global multidisciplinary expert group and by suggesting technological enhancement where available, the worldwide generalizability is high. This also provides an example of the framework required for development and delivery of advanced cancer care of all types, with the need for high-quality, unified and global development. The statement has also identified the research priorities that should be addressed in the next decade. Suggested clinical algorithms, related to diagnosis, assessment of resectability, role of chemoradiotherapy, management of non-curable disease and surgical options for curable disease, are shown in Appendix 4. Funding A. Bhangu was supported for this work by a grant from the Imperial College Cancer Research UK centre. The Pelican Foundation, Royal Marsden Hospital and industry grants provided support for conference facilities. Collaborators Author affiliations are shown at the end of Appendix 3. Executive Committee A. Bhangu (UK), J. Beynon (UK), G. Brown (UK), G. Chang (USA), P. Das (USA), A. Desai (UK), F. Frizelle (New Zealand), R. Glynne-Jones (UK), R. Goldin (UK), M. A. Hawkins (UK), A. Heriot (Australia), S. Laurberg (Denmark), A. Mirnezami (UK), B. Moran (UK), R. J. Nicholls (UK), P. Sagar (UK), P. Tekkis (UK), T. Vuong (Canada) and M. Wilson (UK). Scientific Committee S. M. Ali (UK), A. Antoniou (UK), P. Bose (UK), K. Boyle (UK), G. Branagan (UK), D. Burling (UK), S. K. Clark (UK), P. Colquhoun (Canada), C. H. Crane (USA), A. Darzi (UK), M. Davies (UK), C. P. Delaney (USA), D. Dietz (USA), E. J. Dozois (USA), M. Duff (UK), A. Dziki (Poland), J. Faria (Canada), J. E. Fitzgerald (UK), P. Georgiou (UK), B. George (UK), M. L. George (UK), A. Gupta (UK), R. Guy (UK), D. P. Harji (UK), D. A. Harris (UK), D. Herzig (USA), T. Holm (Sweden), R. Hompes (UK), L. Jeys (UK), J. T. Jenkins (UK), R. P. Kiran (USA), C. E. Koh (Australia), W. L. Law (Hong Kong), A. S. Liberman (Canada), M. Marshall (UK), D. R. McArthur (UK), N. Mortensen (UK), E. Myers (Ireland), P. R. O'Connell (Ireland), S. T. O'Dwyer (UK), A. Oliver (UK), A. Pallan (UK), P. Patel (UK), U. B. Patel (UK), S. Radley (UK), K. W. D. Ramsey (UK), P. C. Rasmussen (Denmark), C. Richard (Canada), H. J. T. Rutten (The Netherlands), D. Sebag-Montefiore (UK), M. J. Solomon (Australia), L. Stocchi (USA), C. J. Swallow (Canada), D. M. Tait (UK), E. Tan (UK), N. Van As (UK), T. Wiggers (The Netherlands), J. H. W. de Wilt (The Netherlands), D. C. Winter (Ireland) and C. Woodhouse (UK). Contributions All collaborating authors were part of the Delphi consensus process. The Executive Committee co-wrote, edited and approved the final manuscript. All collaborators were given the opportunity to edit the manuscript and all approved the final version. A. Bhangu had access to all voting results, communications and draft statements during the process. Disclosure The authors declare no conflict of interest. 1 Methodology This consensus statement was developed using Delphi methodology, incorporating consecutive rounds of anonymous voting, feedback and open discussion1. Anonymous voting ensured that no external pressure was exerted during decision-making. Circulation of feedback from previous rounds prevented strong opinion makers dominating the direction of the statement. Experts were identified from a systematic search of published literature and recommendations of other experts. An expert was defined as a physician who contributed to a multidisciplinary team managing patients with advanced or recurrent rectal cancer. During the first stage, a panel of experts drafted a long list of key elements regarding treatment and research priorities. This meeting was a dedicated discussion forum for invited participants, held on 9 September 2011. Subsequently, a long draft of the consensus statement was circulated for editing to all participants. Key single-sentence statements were drawn from this document, which were circulated for anonymous online voting to all members. Voting commenced on 8 January 2012, and remained open for a period of 6 weeks. Voting options were to agree, to disagree or to abstain. Abstaining votes were intended for non-experts and did not count towards the overall percentage agreement (in accordance with instructions to participants). Statements with at least 80 per cent agreement were considered to have reached consensus. Statements with less than 80 per cent agreement were deemed to have achieved low consensus and were forwarded for discussion at the second consensus meeting. This second dedicated meeting was held on 23rd March 2012 and was open to all invited participants. Statements with low consensus and those requiring further editing were discussed openly. Following this meeting, minutes of the discussions and proposed amendments were circulated to all members for feedback. A final round of electronic voting was circulated for all statements, from 22 April and open for 6 weeks, with options to agree, disagree or abstain as before. Levels of voting agreement (presented in parentheses after each statement) and final editing were performed as follows: At least 80 per cent: consensus achieved, with minor editing by the executive committee. Less than 80 per cent: low consensus. Low-consensus statements after the final round were still included in the final document after minor editing by the executive team. A final short version of the consensus statement was circulated for editing by all participants. Statements are presented as recommendations of care. Quality of evidence The studies were categorized as level of evidence according to the SIGN grading system, developed by the Scottish Intercollegiate Guidelines Network2. The level of evidence in the SIGN grading system ranges from 1++, which includes high-quality meta-analysis, systematic reviews of randomized clinical trials (RCTs) or RCTs with a low risk of bias, to 4, expert opinion. 2 Levels of evidence Levels of evidence2 ++High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias +Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias −Meta-analyses, systematic reviews, or RCTs with a high risk of bias ++ High-quality systematic reviews of case–control or cohort studies; high-quality case–control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal +Well conducted case–control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal −Case–control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal Non-analytical studies, such as case reports and case series Expert opinion Grades of recommendation At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+ A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++ Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+ 3 Supporting evidence Aims and scope Aims Target audience and scope Definitions Role of the multidisciplinary team Diagnosis Classification Imaging Staging local disease Staging distant disease Restaging following neoadjuvant therapy Role of radiotherapy and chemotherapy Methods of dose escalation of radiotherapy Intensity-modulated radiotherapy High-dose-rate brachytherapy Intraoperative radiotherapy Recurrent rectal cancer – radiotherapy and reirradiation Chemotherapy Additional cytotoxic drugs Positioning chemotherapy Neoadjuvant or induction chemotherapy Surgical approaches Preoperative assessment Contraindications to resectability Resectable pelvic disease R0 versus R1 versus R2 resection Sacrectomy Pelvic side-wall disease (including vessels) Anterior compartment/urogenital disease Central recurrence Distant metastases and synchronous resections Unresectable local disease Reconstruction of the pelvic outlet Pathology and prognostic factors Follow-up Quality of life Research methods Collaborators Introduction Primary rectal cancer beyond total mesorectal excision planes (PRC-bTME) and locally recurrent rectal cancer (RRC) (that requiring exenterative-type surgical resection, beyond conventional total mesorectal excision (TME) planes) are challenging and life-threatening clinical problems. There is increasing recognition that aggressive multimodality approaches incorporating contemporary neoadjuvant therapies with radical surgery offer options for potential cure and long-term survival. This complex strategy is optimal and cost-effective in carefully selected patients and represents a new standard of care. Target audience and scope It is not intended that this document should be construed as a legal standard of conduct; such standards can be determined only on the basis of all clinical data available for each individual situation. Additionally, the recommendations in the present document are subject to change as patterns of care evolve, and with advances in scientific knowledge and technology. Discussion of the options with the patient should take place in light of the diagnostic and therapeutic modalities accessible with potential for referral to a specialist team where appropriate. The contained recommendations are guidelines and not intended to prescribe the treatment plan for an individual patient and should not be considered inclusive of all acceptable approaches and methods, or exclusive of others. However, it is advised that significant departures from these guidelines be documented in the patient's case records at the time the relevant decision is taken. Definitions Tumours requiring extended resection include: those beyond the magnetic resonance imaging (MRI)-predicted circumferential resection margin (CRM); those invading the sphincter with or without involvement of the levator complex; and those with abnormal side-wall lymph nodes deemed by appropriate imaging and multidisciplinary team (MDT) assessment to contain cancer. Primary rectal cancer beyond total mesorectal excision planes ‘Locally advanced rectal cancer’ has been defined heterogeneously in the literature and between institutions, leading to a clear requirement to standardize the exact definition of this term. This variability reflects several factors including: the application of different editions of the tumour node metastasis (TNM) classification by different international coloproctology societies; differing methods of preoperative imaging for staging of rectal cancer (ultrasonography, computed tomography (CT), MRI); different criteria for what constitutes locally advanced disease; and varying anatomical definitions of the rectum itself62–65. At times, this term has been applied to tumours with a greater risk of local recurrence that may benefit from neoadjuvant therapy, including those in patients with a threatened but not involved CRM. Such tumours may benefit from neoadjuvant therapy in the hope of achieving a downsizing to clear the threatened margin. Examples of different uses of the term ‘locally advanced disease’ in recent studies include the German rectal cancer trial (any T N+, or T3/T4), the MERCURY study (T3c, T3d or T4), the EXPERT study (T1–4 N2; low T3; T4; threatened CRM); the Berlin rectal cancer trial (ultrasound defined (u) T2 N+; any T3, T4 excluded)18,55,66. In this consensus document, ‘primary rectal cancer beyond total mesorectal excision planes (PRC-bTME)’ includes tumours that are predicted by MRI to require an extended surgical resection beyond the TME plane to achieve a pathological R0 resection. Pragmatically, tumours with abnormal side-wall lymph nodes deemed by appropriate imaging and MDT assessment to contain cancer are also placed in this category, as an extended resection may be required. T4a upper rectal tumours (involving the visceral peritoneum but not invading into adjacent structures or viscera) would be excluded from this category as they would not necessitate an extended resection (but are at high risk of local recurrence via intracoelomic seeding and also widespread abdominal recurrence). The term ‘high-risk rectal cancer’ is used to define tumours generally recommended for neoadjuvant therapy to reduce the risk of recurrence, but not requiring an extended surgical resection. This subgroup would include tumours with a potentially threatened CRM such as T3c/d mid and upper rectal tumours, and any T3 tumour in the lower third of the rectum, or any T N1 or 2 disease. The term ‘low-risk rectal cancer’ is used to define earlier stages. Consequently, it can be seen that the key risk in the high-risk locally advanced group is of local recurrence (especially following residual disease), intra-abdominal disease and metastatic disease. Variable application of tumour node metastasis classification The TNM classification system has undergone several revisions in recent years. The fifth edition of TNM was released in 1997 and is applied in slightly modified form within the UK67. The seventh and most recent edition, released in 2010, is widely applied in North America and Australasia68. For locally advanced disease, in particular, this has generated some difficulty as the definitions of pathological (p) T4a and pT4b tumours have been reversed in the latest edition. For the purposes of this consensus statement, the following definitions have been applied for T4 disease: pT4a – tumours invading the visceral peritoneum pT4b – tumours invading adjacent structures or organs. Defining the rectum Key point The rectum is defined by anatomical criteria demonstrated on MRI as being the portion of the large bowel below the sacral promontory that is surrounded by a definable mesorectum posteriorly. 2+ D (88 per cent). Variability is introduced by having non-standardized definitions of what constitutes the rectum, which has been represented as 12, 15 or 16 cm from the anal verge in high-quality multicentre trials18,62–63,67,69. Further variation is introduced by subdividing the rectum into lower, middle and upper thirds. Radiation trials have used length of the rectum as a definition. Recent research suggests that the rectum is more variable and longer than these trials would have appreciated. The mean distance from the anal verge to the anterior peritoneal reflection was 11.9 cm in men and 10 cm in women. The measurements were 18.8 cm (men) and 19.1 cm (women) to the origin of the sigmoid mesentery, and 20.3 cm (men) and 18.8 cm (women) to the confluence of the taenia coli70. In the modern era, high-resolution MRI-based measurements are used to define tumour height more frequently than the traditionally used rigid sigmoidoscope. It is likely that there is anatomical variation between individual patients; collation between clinical and MRI assessment is likely to lead to the most accurate assessment. Recurrent rectal cancer Pelvic recurrence includes anastomotic and tumour bed recurrences, as well as recurrence within lymphatics such as residual mesorectal nodes and pelvic side-wall lymph nodes45,71. Para-aortic disease, by definition beyond the definition of the rectum, is considered as distant disease. Also included is inguinal node recurrence and disease manifesting along drain tracts and surgical scars (abdominal or perineal). The time frame for recurrence is typically within the first 2 years after resection of the primary tumour. However, with improved chemoradiotherapy (CRT) regimens and adjuvant therapies, recurrence may occur as late as 10 years following primary surgery35,45,72. Role of the multidisciplinary team Surgery for both PRC-bTME and RRC is likely to involve multivisceral resection and consideration for additional adjuvant treatments. As these can have a major impact on physical appearance, physical functioning (bowel, urinary and sexual) and emotional health, management will necessitate clinical and psychosocial support in addition to the chance for cure. Patients requiring exenterative surgery for PRC-bTME should be referred to centres that routinely diagnose, assess and manage such cases. There may be regional variation in the rates of referral for exenterative surgery of PRC-bTME owing to differences in services offered geographically. Diagnosis Recurrent rectal cancer Approximately half of patients with RRC have an isolated, potentially curable recurrence73. Highly selected patients with RRC and synchronous metastatic disease may sometimes be appropriately offered combined resection. Recurrences are either symptomatic or asymptomatic74,75. Patients with advanced pelvic recurrences presenting with symptoms, especially pain, have a worse survival as these tumours are often associated with neurovascular invasion and clear resection margins may not be achievable76. Clinical examination to detect recurrence should include digital examination, which may determine luminal or extraluminal recurrence and give an indication of relative fixation. Digital examination of the vagina can also indicate fixity not indicated by imaging. However, fixation does not necessarily prove malignancy and can also indicate postradiation fibrous tissue or a desmoplastic reaction. Proctoscopy (following restorative surgery) is used to identify luminal recurrence. Examination under anaesthesia (EUA)/vaginoscopy and cystoscopy are also used selectively to identify recurrences, and assess adjacent organ invasion and tumour fixity. The ‘gold standard’ for diagnosis of RRC is tissue biopsy confirmation by endoscopic or radiologically guided methods. A clinical diagnosis based on developing signs and symptoms, with or without tissue biopsy, may be an alternative in the face of a negative image-guided biopsy. However, if a patient is to be subjected to major complex exenterative surgery, firm evidence of recurrence should always be sought where possible. Multidisciplinary assessment and decision-making is mandatory. Ongoing pelvic infection or late anastomotic leakage may simulate recurrence. MRI may not be able to distinguish scar tissue from recurrence. Fluorodeoxyglucose (FDG)-positron emission tomography (PET)–CT may provide a metabolic approach to identifying such tumours, although false-negative results can occur in small deposits or in mucinous tumours. An increase in serum carcinoembryonic antigen (CEA) level may assist in reaching a diagnosis, although a spuriously high or low result can be misleading77. Classification Various pelvic classifications have been proposed to assess tumour resectability. In addition to assisting with decision-making regarding resectability, classification adds information about prognosis4. Central recurrences have been shown to have improved results over posterior or lateral recurrences5,6. The Mayo Clinic classified local recurrence according to site and points of tumour fixation78, whereas Yamada and colleagues79 described local recurrence by the pattern of pelvic fixation into localized, sacral or lateral. The Memorial Sloan-Kettering group has categorized local recurrence based on the anatomical site of invasion by the tumour43. In a recent prospective study by the Royal Marsden Hospital that examined the relationship between site of recurrence and survival after resection, a new classification is described based on the extent of tumour invasion in each of seven intrapelvic compartments, as seen on preoperative pelvic MRI. These correspond to the fascial boundaries and planes of dissection between the pelvic organs, and are described as central (C), posterior (P), inferior (I), anterior above (AA) and below (AB) the peritoneal reflection, lateral (L) and peritoneal reflection (PR)6 (Table 1). Table 1 Classification systems in use for locally recurrent rectal cancer Study group . Classification . Definitions . . Outcomes . Mayo Clinic78 Symptoms S0 Asymptomatic Pain-free patients had better survival S1 Symptomatic without pain S2 Symptomatic with pain Degree and site of fixation F0 No fixation More points of fixation resulted in more complications and worse survival F1 Fixation to 1 point F2 Fixation to 2 points F3 Fixation to > 2 points Yamada79 Pattern of pelvic fixation Localized Invasion to the adjacent pelvic organs or tissue 5-year survival 38% Sacral invasive Invasion to lower sacrum (S3, S4, S5), coccyx, periosteum 5-year survival 10% Lateral invasive Invasion to sciatic nerve, greater sciatic foramen, lateral pelvic wall, upper sacrum (S1, S2) 5-year survival 0% Wanebo Five stages TR1 Limited invasion of the muscularis TR2 Full-thickness penetration of the muscularis propria TR3 Anastomotic recurrences with full-thickness penetration beyond the bowel wall and into the perirectal soft tissue TR4 Invasion into adjacent organs without fixation TR5 Invasion of the bony ligamentous pelvic including sacrum, pelvic/side walls, or sacrotuberous/ischial ligaments Memorial Sloan-Kettering43 Anatomical region involved Axial Anastomotic, mesorectal, perirectal soft tissue, Axial-only recurrence has 90% likelihood of R0; lateral recurrence associated with 36% likelihood of R0 Anterior perineum (APER) Posterior Genitourinary tract Lateral Sacrum and presacral fascia Soft tissues of the pelvic side wall and the lateral bony pelvis Leeds Anatomical region involved Central Tumour confined to pelvic organs or connective tissue without contact with or invasion into bone Sacral Tumour present in the presacral space and abuts on to or invades into sacrum Side wall Tumour involving the structures on lateral pelvic side wall, including greater sciatic foramen and sciatic nerve through to piriformis and gluteal region Composite Sacral and side-wall recurrence combined Royal Marsden Hospital6 MRI; planes of dissection C Rectum or neorectum, intraluminal recurrence, perirectal fat or mesorectum, extraluminal recurrence MRI diagnosis of tumour invasion within the lateral, posterior or in more than two compartments associated with reduced disease-free survival PR AA PR Rectovesical pouch or rectouterine pouch of Douglas AB PR Ureters and iliac vessels above the peritoneal reflection, sigmoid colon, small bowel and lateral side-wall fascia Genitourinary system L Ureters, external and internal iliac vessels, lateral pelvic lymph nodes, sciatic nerve, sciatic notch, S1 and S2 nerve roots, piriformis or obturator internus muscle P Coccyx, presacral fascia, retrosacral space, sacrum up to the upper level of S1 I Levator ani muscles, external sphincter complex, perineal scar (APER), ischioanal fossa Study group . Classification . Definitions . . Outcomes . Mayo Clinic78 Symptoms S0 Asymptomatic Pain-free patients had better survival S1 Symptomatic without pain S2 Symptomatic with pain Degree and site of fixation F0 No fixation More points of fixation resulted in more complications and worse survival F1 Fixation to 1 point F2 Fixation to 2 points F3 Fixation to > 2 points Yamada79 Pattern of pelvic fixation Localized Invasion to the adjacent pelvic organs or tissue 5-year survival 38% Sacral invasive Invasion to lower sacrum (S3, S4, S5), coccyx, periosteum 5-year survival 10% Lateral invasive Invasion to sciatic nerve, greater sciatic foramen, lateral pelvic wall, upper sacrum (S1, S2) 5-year survival 0% Wanebo Five stages TR1 Limited invasion of the muscularis TR2 Full-thickness penetration of the muscularis propria TR3 Anastomotic recurrences with full-thickness penetration beyond the bowel wall and into the perirectal soft tissue TR4 Invasion into adjacent organs without fixation TR5 Invasion of the bony ligamentous pelvic including sacrum, pelvic/side walls, or sacrotuberous/ischial ligaments Memorial Sloan-Kettering43 Anatomical region involved Axial Anastomotic, mesorectal, perirectal soft tissue, Axial-only recurrence has 90% likelihood of R0; lateral recurrence associated with 36% likelihood of R0 Anterior perineum (APER) Posterior Genitourinary tract Lateral Sacrum and presacral fascia Soft tissues of the pelvic side wall and the lateral bony pelvis Leeds Anatomical region involved Central Tumour confined to pelvic organs or connective tissue without contact with or invasion into bone Sacral Tumour present in the presacral space and abuts on to or invades into sacrum Side wall Tumour involving the structures on lateral pelvic side wall, including greater sciatic foramen and sciatic nerve through to piriformis and gluteal region Composite Sacral and side-wall recurrence combined Royal Marsden Hospital6 MRI; planes of dissection C Rectum or neorectum, intraluminal recurrence, perirectal fat or mesorectum, extraluminal recurrence MRI diagnosis of tumour invasion within the lateral, posterior or in more than two compartments associated with reduced disease-free survival PR AA PR Rectovesical pouch or rectouterine pouch of Douglas AB PR Ureters and iliac vessels above the peritoneal reflection, sigmoid colon, small bowel and lateral side-wall fascia Genitourinary system L Ureters, external and internal iliac vessels, lateral pelvic lymph nodes, sciatic nerve, sciatic notch, S1 and S2 nerve roots, piriformis or obturator internus muscle P Coccyx, presacral fascia, retrosacral space, sacrum up to the upper level of S1 I Levator ani muscles, external sphincter complex, perineal scar (APER), ischioanal fossa APER, abdominoperineal resection; MRI, magnetic resonance imaging; C, central; PR, peritoneal reflection; AA, anterior above; AB, anterior below; L, lateral; P, posterior; I, inferior. Open in new tab Table 1 Classification systems in use for locally recurrent rectal cancer Study group . Classification . Definitions . . Outcomes . Mayo Clinic78 Symptoms S0 Asymptomatic Pain-free patients had better survival S1 Symptomatic without pain S2 Symptomatic with pain Degree and site of fixation F0 No fixation More points of fixation resulted in more complications and worse survival F1 Fixation to 1 point F2 Fixation to 2 points F3 Fixation to > 2 points Yamada79 Pattern of pelvic fixation Localized Invasion to the adjacent pelvic organs or tissue 5-year survival 38% Sacral invasive Invasion to lower sacrum (S3, S4, S5), coccyx, periosteum 5-year survival 10% Lateral invasive Invasion to sciatic nerve, greater sciatic foramen, lateral pelvic wall, upper sacrum (S1, S2) 5-year survival 0% Wanebo Five stages TR1 Limited invasion of the muscularis TR2 Full-thickness penetration of the muscularis propria TR3 Anastomotic recurrences with full-thickness penetration beyond the bowel wall and into the perirectal soft tissue TR4 Invasion into adjacent organs without fixation TR5 Invasion of the bony ligamentous pelvic including sacrum, pelvic/side walls, or sacrotuberous/ischial ligaments Memorial Sloan-Kettering43 Anatomical region involved Axial Anastomotic, mesorectal, perirectal soft tissue, Axial-only recurrence has 90% likelihood of R0; lateral recurrence associated with 36% likelihood of R0 Anterior perineum (APER) Posterior Genitourinary tract Lateral Sacrum and presacral fascia Soft tissues of the pelvic side wall and the lateral bony pelvis Leeds Anatomical region involved Central Tumour confined to pelvic organs or connective tissue without contact with or invasion into bone Sacral Tumour present in the presacral space and abuts on to or invades into sacrum Side wall Tumour involving the structures on lateral pelvic side wall, including greater sciatic foramen and sciatic nerve through to piriformis and gluteal region Composite Sacral and side-wall recurrence combined Royal Marsden Hospital6 MRI; planes of dissection C Rectum or neorectum, intraluminal recurrence, perirectal fat or mesorectum, extraluminal recurrence MRI diagnosis of tumour invasion within the lateral, posterior or in more than two compartments associated with reduced disease-free survival PR AA PR Rectovesical pouch or rectouterine pouch of Douglas AB PR Ureters and iliac vessels above the peritoneal reflection, sigmoid colon, small bowel and lateral side-wall fascia Genitourinary system L Ureters, external and internal iliac vessels, lateral pelvic lymph nodes, sciatic nerve, sciatic notch, S1 and S2 nerve roots, piriformis or obturator internus muscle P Coccyx, presacral fascia, retrosacral space, sacrum up to the upper level of S1 I Levator ani muscles, external sphincter complex, perineal scar (APER), ischioanal fossa Study group . Classification . Definitions . . Outcomes . Mayo Clinic78 Symptoms S0 Asymptomatic Pain-free patients had better survival S1 Symptomatic without pain S2 Symptomatic with pain Degree and site of fixation F0 No fixation More points of fixation resulted in more complications and worse survival F1 Fixation to 1 point F2 Fixation to 2 points F3 Fixation to > 2 points Yamada79 Pattern of pelvic fixation Localized Invasion to the adjacent pelvic organs or tissue 5-year survival 38% Sacral invasive Invasion to lower sacrum (S3, S4, S5), coccyx, periosteum 5-year survival 10% Lateral invasive Invasion to sciatic nerve, greater sciatic foramen, lateral pelvic wall, upper sacrum (S1, S2) 5-year survival 0% Wanebo Five stages TR1 Limited invasion of the muscularis TR2 Full-thickness penetration of the muscularis propria TR3 Anastomotic recurrences with full-thickness penetration beyond the bowel wall and into the perirectal soft tissue TR4 Invasion into adjacent organs without fixation TR5 Invasion of the bony ligamentous pelvic including sacrum, pelvic/side walls, or sacrotuberous/ischial ligaments Memorial Sloan-Kettering43 Anatomical region involved Axial Anastomotic, mesorectal, perirectal soft tissue, Axial-only recurrence has 90% likelihood of R0; lateral recurrence associated with 36% likelihood of R0 Anterior perineum (APER) Posterior Genitourinary tract Lateral Sacrum and presacral fascia Soft tissues of the pelvic side wall and the lateral bony pelvis Leeds Anatomical region involved Central Tumour confined to pelvic organs or connective tissue without contact with or invasion into bone Sacral Tumour present in the presacral space and abuts on to or invades into sacrum Side wall Tumour involving the structures on lateral pelvic side wall, including greater sciatic foramen and sciatic nerve through to piriformis and gluteal region Composite Sacral and side-wall recurrence combined Royal Marsden Hospital6 MRI; planes of dissection C Rectum or neorectum, intraluminal recurrence, perirectal fat or mesorectum, extraluminal recurrence MRI diagnosis of tumour invasion within the lateral, posterior or in more than two compartments associated with reduced disease-free survival PR AA PR Rectovesical pouch or rectouterine pouch of Douglas AB PR Ureters and iliac vessels above the peritoneal reflection, sigmoid colon, small bowel and lateral side-wall fascia Genitourinary system L Ureters, external and internal iliac vessels, lateral pelvic lymph nodes, sciatic nerve, sciatic notch, S1 and S2 nerve roots, piriformis or obturator internus muscle P Coccyx, presacral fascia, retrosacral space, sacrum up to the upper level of S1 I Levator ani muscles, external sphincter complex, perineal scar (APER), ischioanal fossa APER, abdominoperineal resection; MRI, magnetic resonance imaging; C, central; PR, peritoneal reflection; AA, anterior above; AB, anterior below; L, lateral; P, posterior; I, inferior. Open in new tab Validation of a single system that should carry prognostic significance as well as anatomical information to guide surgeons would be useful for communication. Imaging and staging There is variation in the locoregional staging of rectal cancer80. As both PRC-bTME and RRC are cancers that breach the conventional mesorectal envelope and require surgery beyond the TME plane, assessment of the potential resection margin is more relevant than differentiation between T3 and T4. The anatomical relationships and assessment of invasion into adjacent organs are important. Pelvic staging and assessment of resectablity Most high-volume centres are now using high-resolution MRI for pelvic staging36–37,80. MRI is superior to pelvic CT for imaging lower rectal tumours, especially in assessing involvement of the sphincter complex and in determining depth of penetration within the mesorectal fascia81. However, MRI can have lower sensitivity when assessing the pelvic side wall and female urogenital organs82,83. It may be improved by combining findings with those of diffusion weighted MRI or PET–CT. Mucinous adenocarcinoma has a poorer FDG uptake and so may not be visualized by PET84. Endorectal ultrasonography (ERUS) has been reported to have high sensitivity and specificity for staging primary T4 disease and is useful for targeted biopsy85. CT of the pelvis and ERUS are sometimes used instead of, or in addition to, MRI in some centres in the UK and North America. ERUS may have an application for determining adjacent organ involvement in certain anatomical compartments, particularly the rectal–prostate interface. ERUS alone provides limited information on anatomical planes and is inadequate to safely assess resectability. Examination under anaesthesia EUA can add to the overall assessment of the patient and tumour, and is commonly used by teams experienced in this type of surgery. Digital rectal examination is the only available means of reliably assessing the level of the tumour in relation to the anorectal junction. The use of diagnostic laparoscopy to stage peritoneal disease before planning major exenteration requires further evidence. Assessment of R0 resection plane Treatment strategy is dependent on achieving an R0 resection. MRI is considered the method of choice for the prediction of a clear, or positive, margin86. For PRC-bTME, this will include the mesorectal fascia as well as en bloc removal of involved structures. For RRC, this may involve residual parts of the mesorectum, but is more likely to involve assessment of extra-anatomical R0 planes. Correlation between histopathological findings in relation to precise prediction of the threatened margin is being addressed by ongoing trials, including the National Institute for Health Research Portfolio Low Rectal Cancer Study (MERCURY 2)87. Nodal disease Identification of nodal disease is still a diagnostic problem for radiologists. For PRC-bTME and RRC, nodal disease in the lateral pelvic side wall is an area of particular concern. MRI and FDG-PET–CT may both help to assess the malignant potential of pelvic side-wall nodes. Mesorectal lymph nodes are likely to be cleared as part of exenterative surgery for PRC-bTME, and extended resections for recurrences are likely to clear residual nodes. Thus assessment of nodal disease is less important than assessment of R0 resection margin. Distant disease High-resolution CT of the thorax, abdomen and pelvis is the ‘gold standard’ for extrapelvic staging. CT is likely to be the best modality for imaging the lung fields. MRI is helpful in further characterization of suspect liver lesions identified by CT. Bone scans and brain imaging are required where symptoms indicate need. PET (PET–CT) may help detect additional occult extrapelvic disease and exclude patients from futile attempts at curative disease resection13. Use of PET or PET–CT in patients with PRC-bTME has led to significant changes in staging and management88. Although useful in investigating circumstances such as increasing CEA level, it can provide false-positive and false-negative results. Some centres use PET–CT routinely in all patients likely to undergo multivisceral resection or with suspicion of recurrence, whereas others use it selectively. Thin-section high-resolution CT of the thorax is more sensitive than PET–CT for detection of lung metastases. CT angiography of the inferior epigastric arteries can be performed concurrently (with additional software) to allow assessment of rectus abdominis vasculature when selected for reconstruction. Standardized radiological reporting A standardized approach to reporting of imaging, particularly MRI, at all stages of management for patients with PRC-bTME and RRC is recommended. Consensus on reporting of postradiotherapy MRI in terms of tumour category (ymrT) and tumour regression grading (mrTRG) is required7. These should be related to a single, universal classification system. This may best be addressed through a workshop approach for radiologists and referral to a MDT where appropriate86. Restaging following preoperative therapies If time elapsed from the last MRI to the proposed date of surgery is longer than 6 weeks, restaging is recommended to ensure an accurate and up-to-date assessment. Role of radiotherapy and chemotherapy Complications of long-course radiotherapy Gastrointestinal toxicities are the most clinically significant side-effects associated with pelvic radiotherapy. The published clinical trials of preoperative radiotherapy have used three- or four-field conformal techniques16,18,89. The reported toxicity rates in these studies are at least grade III acute toxicity in approximately 35–45 per cent of patients undergoing radiotherapy with concomitant fluoropyrimidines. The data regarding late bowel toxicity are less readily available, but long-term complication rates of approximately 10–20 per cent have been reported18,90. Methods of dose escalation of radiotherapy Intensity-modulated radiotherapy Technical advances such as intensity-modulated radiotherapy (IMRT) allow greater precision and can reduce the dose to normal surrounding structures such as small bowel compared with conventional two- or three-dimensional planning. Such precision may allow improved compliance with standard treatments, or hopefully facilitate dose escalation without increasing late morbidity. In a recent comparative analysis from the Mayo Clinic, 29 and 3 per cent of patients receiving IMRT for rectal cancer experienced grade II and grade III acute gastrointestinal toxicity respectively20. Yet there was no difference in late toxicity for any of the four arms in the European Organization for Research and Treatment of Cancer (EORTC) 22921 study. Some 522 patients retained their sphincters and, of these, only 1.4 per cent required surgery for small bowel complications91. To some extent, this low level of late morbidity is acceptable, and so questions the enthusiasm to deliver IMRT more widely in rectal cancer with the aim of reducing small bowel toxicity unless an advantage can be shown for dose escalation. For PRC-bTME, IMRT could be used to treat the inguinal regions in patients with low rectal cancer with involved inguinal nodes, either as definitive treatment or before groin dissection. IMRT could provide a definitive high dose to involved iliac nodes, or lateral pelvic lymph nodes, if surgery for these nodes is not intended. Finally, IMRT could be used for dose escalation to all (or part of) borderline resectable primary tumours, in an attempt to improve resectability and reduce the risk of a positive resection margin. However, the evidence for IMRT is currently limited and there are associated risks of toxicity. The phase II trial of preoperative CRT utilizing IMRT for locally advanced rectal cancer, led by the Radiation Therapy and Oncology Group (RTOG0822), demonstrated the feasibility of inverse planned IMRT in a multicentre setting92. Of the 79 patients accrued, 68 were analysable; 22 per cent had grade III and 1 per cent grade IV toxicity. The pathological complete response rate of 15 per cent (10 of 68) suggests that tumour coverage is not compromised by the use of highly conformal radiotherapy. Early data exploring dose escalation with IMRT to 60 Gy reveals that IMRT appears safe and effective, with 16.6 per cent grade II toxicity and an R0 rate of 90 per cent for T4 (positive CRM) rectal cancer21. IMRT shows promise for safe dose escalation, with possible benefits in terms of local control and reduced toxicity. High-dose-rate brachytherapy Intraluminal high-dose-rate brachytherapy (HDR-BT) has the advantage of high conformality (a rapid fall-off of radiation dose), which allows the delivery of a high dose to the tumour while sparing normal surrounding structures such as the adjacent normal rectal mucosa, bladder and small bowel93. This technique is being used in the preoperative setting and has included a percentage of patients with previous pelvic radiation93. However, there are limited data available evaluating the advantages of HDR-BT with external beam radiotherapy (EBRT) compared with EBRT alone. HDR-BT for advanced or inoperable tumours of the rectum has been used as a boost alongside external CRT to escalate the dose for curative treatment and also in the palliative setting22. Future multicentre trials are planned94. Intraoperative radiotherapy Intraoperative radiotherapy (IORT) is a specialized method of delivering a radiation boost (higher doses) to the tumour bed, where there is concern about tumour margins, without compromising the surrounding organs at risk. IORT is delivered under anaesthetic at the time of surgery using electrons, or HDR-BT to specifically selected high-risk areas for close or positive margins. Prospective and long-term data from international centres of excellence incorporating IORT-containing regimens are compelling. However, the IORT literature includes a large spectrum of tumours as the selection criteria varied from one centre to another, making the definite evidence of benefits difficult to ascertain. The low rate of tumour recurrence in IORT fields, and a convergence of survival curves for R0 and R1/2 resections seen in studies with long-term data, support the concept that IORT may offer an oncological advantage in selected patients. In a historical series from the Mayo Clinic, IORT (plus EBRT) reduced the incidence of local failure (40 versus 93 per cent at 3 years) and improved overall survival (19 versus 7 per cent at 5 years; P < 0.001)23. Others have found a significant survival benefit in patients who received IORT compared with patients who did not (3-year survival rate 43 versus 5 per cent; P < 0.001)95. A recent European multinational study evaluated multimodal treatment of locally advanced rectal cancer in four major treatment centres with particular expertise in IORT. This pooled analysis of 605 patients demonstrated exceptionally good oncological outcomes. Additionally, this study noted that 55 per cent of patients with a positive resection margin who received IORT remained free from local recurrence, supporting the view that residual tumour cells after an R1/2 resection may be destroyed by IORT96. Conversely, Dubois and colleagues97 reported on the unique IORT randomized clinical trial that included 142 patients with T3–4 primary and/or recurrent tumours; comparison of EBRT using 40 Gy alone with the same EBRT plus an IORT boost (an additional 18 Gy) did not confirm any disease-free survival (DFS) benefits from IORT treatment (P = 0.781)97. In this series, the composite population of T3 and T4 tumours possibly contributed to these negative results. The limitations of these analyses are the inclusion of patients treated over a relatively long period, the variety of sites of recurrence, the heterogeneity of EBRT and surgery, and variations in subsequent adjuvant chemotherapy. Hence, the precise contribution and effectiveness of IORT as a local boost is difficult to assess accurately. The logic of additional focused radiotherapy to a margin potentially at high risk of involvement, most commonly a lateral margin, is intuitive but attainment of level 1 evidence is challenging. Randomized trials will prove difficult to design, partly owing to limited multicentre capacity. Another part of the problem is that, even when the MDT has made the preoperative decision to utilize IORT, it is not always felt necessary at the time of surgery. There is extremely limited capability to perform IORT in the UK. Globally, however, there are selected centres in Europe, the USA and Australia that can provide this treatment modality. Recurrent rectal cancer: radiotherapy and reirradiation When local recurrence develops where radiotherapy has not previously been administered, radiotherapy or chemoradiation can sterilize microscopic disease within the pelvic cavity and facilitate resectability. Complete responses are rarely achieved even with high radical doses in the region of 60 Gy98. A recent study has reported on patients with unresectable or locally recurrent rectal cancer treated using three-dimensional planning and prolonged venous infusion of 5-fluorouracil (5-FU) to a dose of 45 Gy. There was no difference between unresectable locally advanced cancers and recurrent cancers as regards outcome99. IORT has also been advocated in these circumstances. Further reirradiation of locally recurrent cancer remains controversial100,101. Single-institution studies and a phase II multi-institutional trial have evaluated the use of hyperfractionated (twice daily) radiotherapy for reirradiation. Hyperfractionated reirradiation appears to be well tolerated and may enhance local control28,29. Endorectal HDR-BT is a very simple but effective treatment option that is presently offered widely in Quebec for this patient group, especially when the recurrence is central. No centre has access to all of these modalities, and so the specialist MDTshould develop the ability to cross-refer, via national referral pathways, where appropriate. Chemotherapy There is a high risk of metastatic disease in PRC-bTME and a potentially higher risk in RRC. Intensification of chemotherapy regimens is emerging as a potential strategy to address this problem in PRC-bTME. The induction or preoperative, concurrent, consolidation (after chemoradiation and before surgery) and postoperative adjuvant chemotherapy settings offer potential improvements in outcome, along with the addition of different cytotoxic agents and the integration of biological agents. 5-FU-based chemoradiation is effective in downstaging rectal cancer, and a pathological complete response is achieved in 10–15 per cent of patients16,89,102–103. Equally, on histopathological grounds, one-third of patients have tumours that are resistant to radiotherapy and 5-FU104–106. There is evidence that 5-FU-based CRT produces improvements in locoregional control compared with radiation alone, but this has not translated into an improvement in DFS or overall survival16. For advanced unresectable tumours, or when preoperative MRI shows a threatened or breached CRM (when even technically optimized surgery is unlikely to achieve a curative resection), 5-FU-based chemoradiation has a statistically significant effect on resectability and DFS19,30. In the more recent Scandinavian study considering all stages, local control was significantly better (82 versus 67 per cent at 5 years; P = 0.03), with a trend towards improved overall survival (66 versus 53 per cent at 5 years; P = 0.09)19. Additional cytotoxic drugs The additional integration of oxaliplatin and irinotecan to 5-FU-based chemotherapy has been explored within a CRT schedule in numerous phase II studies in order to increase tumour shrinkage before surgery, and potentially mirror the success of oxaliplatin in dealing with distant micrometastases in the adjuvant setting for colonic cancer31,32. Radiation oncologists have attempted to increase response of the primary by focusing on the integration of oxaliplatin as a radiosensitizer (but at subsystemic doses) in five phase III trials (ACCORD 12/0405-Prodige 2, STAR-01, National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04, CAO/ARO/AIO-04 and PETACC 6). Chemoradiation with oxaliplatin increased grade III/IV toxicity in all four trials with available data17–18,107–108, but only the German CAO/ARO/AIO-04 trial showed a significantly higher rate of pathological complete response18. These randomized trials in rectal cancer selected patients with easily resectable tumours but, where examined, some schedules appear to have reduced the positive CRM rate17,107. None of these trials has results that are sufficiently mature to show late outcomes in terms of DFS, overall survival or late toxicity. However, the majority of these patients in the above trials were probably node-negative. Based on the results of the QUASAR and MOSAIC studies, patients with stage II disease are unlikely to show a large benefit in terms of DFS, even from 5-FU chemotherapy (particularly if aged over 70 years), and patients would have had minimal benefit from the addition of oxaliplatin. Preliminary results of CRT trials with cetuximab have provided disappointing results33. The use of bevacizumab in chemoradiation has considerable preclinical rationale, and the combination with CRT appears potentially deliverable with acceptable toxicity, although some reports have highlighted excess postoperative wound infections. The strategy to incorporate these agents into CRT in rectal cancer schedules may have emerged before full understanding of their mechanisms of action or the knowledge of the ideal sequence of chemotherapy, biological agents and radiotherapy has been learned34. Positioning chemotherapy Several broad strategies to improve outcome have been investigated in rectal cancer: surgery alone followed by adjuvant chemotherapy/CRT; SCPRT followed by immediate surgery, followed by adjuvant chemotherapy; CRT followed by surgery after 6–8 weeks, followed by adjuvant chemotherapy; SCPRT followed by surgery after 6–8 weeks, followed by adjuvant chemotherapy; induction chemotherapy followed by CRT, followed by surgery after 6–8 weeks, followed by adjuvant chemotherapy109–111; induction chemotherapy followed by SCPRT, followed by immediate surgery, followed by adjuvant chemotherapy; CRT followed by consolidation systemic chemotherapy, followed by surgery, followed by more adjuvant chemotherapy; induction chemotherapy alone followed by surgery, followed by more adjuvant chemotherapy; and integration of biological agents into one of the above. Preoperative or induction chemotherapy Concurrent chemotherapy involves administration of only 5–6 weeks of chemotherapy at a radiosensitizing dose. Three alternative approaches include an induction component of systemically active chemotherapy before radiotherapy or chemoradiation109–111, or adding additional chemotherapy after SCPRT or CRT112–115. Surgical approaches There are many surgical principles for treatment of patients with PRC-bTME and RRC116–118. The approach to both is based around individualized multivisceral resection and exenterative procedures. These include extra-anatomical dissection, resecting affected structures and compartments (for example sacrectomy and side-wall dissections) and reconstruction of perineal defects119. Planes of dissection are often lost in patients with RRC compared with patients with PRC-bTME, particularly after extensive radiotherapy. Regional and national referral pathways may involve referral from a specialist MDT to a superspecialized MDT (such as for consideration of high sacrectomy). Preoperative assessment Optimizing patients before multivisceral resection is vital to minimize perioperative morbidity and requires a multispecialist approach36,37. These clinicians include anaesthetists, respiratory physicians, urologists (for assessment of the need for ureteric stents or nephrostomies), cardiologists and stoma nurses. Formal cardiopulmonary testing is an objective test to assess fitness, and diagnose cardiovascular and lung pathophysiology120. Areas for potential improvement can be identified, including ischaemic heart disease121. A management plan can then be determined for the patient's perioperative care and pathway122. Admission 24 h before surgery into a critical care setting may allow maximal preoperative optimization in special cases. Intraoperative monitoring, such as oesophageal Doppler imaging, in association with other invasive monitoring, provides further information on the physiological status of the patient123. Owing to the major resectional nature of the surgery, routine cross-matching of blood is recommended. Clotting products and platelets should be available at short notice in case of severe bleeding, such as during sacrectomy or pelvic dissection close to the iliac veins. Haemostatic materials can assist in sealing bleeding of raw surfaces. General perioperativesurgical principles include preoperative stoma counselling/marking, discretionary ureteric stenting to clearly identify the ureteric course, the availability of haemostatic agents during pelvic dissection and intensive postoperative monitoring. A multispecialist team approach is important in achieving this, which may include specialists in colorectal, plastic, urology, vascular and orthopaedic surgery, and radiation oncology. Postoperative intensive care (at either level 1 or 2) is mandatory after major exenteration. The major postoperative inflammatory response requires close physiological monitoring to maintain organ perfusion and function. The use of enhanced recovery principles, such as perioperative sip feeding, attention to postoperative analgesia, nausea and vomiting, careful fluid management and proactive nursing pathways, are all applicable to these patients. Prolonged postoperative ileus is common. Consideration should be given to early postoperative parenteral nutrition if the likelihood of prolonged ileus is high. Some patients with end stomas undergoing certain exenterative procedures are likely to be able to feed orally at an early stage. Resectable pelvic disease In patients with postirradiated local recurrence, surgical resection offers the only potential for cure and long-term survival35,118,124. Individualized surgery represents the best strategy to deliver an R0 resection to suitable patients. This involves a range of procedures, depending on the nature of the tumour. Anterior invasion may require prostatectomy with or without cystectomy and urinary reconstruction/diversion; posterior invasion may require sacrectomy; and lateral invasion may require side-wall or iliac vessel dissection. By definition, an exenterative procedure entails a pelvic dissection beyond the fascia propria and the mesorectal envelope. It often involves the removal of pelvic organs, including the bladder, prostate, seminal vesicles, urethra, vagina and uterus, and/or part of the sacrum and/or the lateral pelvic vasculature. Planned resection lines following neoadjuvant CRT may be altered from those identified at the initial staging MRI. It is not yet clear whether surgical planning is best based around the initial MRI or the scan obtained after neoadjuvant treatment, and further research is needed to assess the reliability of this latter scan. However, a clear response on MRI may allow more organ-preserving surgery. R0versus R1versus R2 resection The key to successful long-term survival is the ability to achieve an R0 resection (a clear resection margin)9,56,124–125. This is controversial, however, as tumour at or within 1 mm of the resection margin may not be classed as R0, but as R1 (microscopic residual disease at the margin)57. A 2-mm or even a 3-mm circumferential margin may not, therefore, be a ‘safe’ CRM in the context of local failure and RRC58. Contraindications to resectability Contraindications to resectability are based around the probability of R0 resection, the benefit of R1/2 resections, and the resulting quality of life (QoL) from extended resections. Different centres have different contraindications depending on the surgical expertise available, resulting in varying levels of consensus. In addition, some experts considered relative contraindications to be more appropriately classed as absolute, and vice versa. Sacrectomy The main controversy is the definition of resectability in terms of height of sacrectomy required. The traditional cut-off has been at the S2/3 junction40,126. However, higher sacrectomy, including S1/2 and L5/S1 may be possible42. There are increased risks of bleeding and neurological damage, although prolonged survival is achievable in carefully selected patients36. A wider evidence base is needed, including data on the potential future role of computer-aided sacrectomy127. This supraradical procedure is best carried out by specialized surgeons, and so clear referral pathways to these surgeons are needed to maximize the treatment options open to highly selected individuals. Pelvic side-wall disease In cases of bony involvement or threatened resection margins, intraoperative radiation (either as IORT or HDR-BT) may improve outcomes in those who have non-R0 resections and certain close R0 resections35,128–129. There is no clear evidence of benefit in offering surgery to patients with tumour invasion of the pelvic side wall (sciatic nerve, obturator fossa, piriformis muscle). Anterior compartment/urogenital disease Involvement of the urogenital organs may occur with both PRC-bTME and RRC. Radiotherapy may decrease the extent of spread. In highly selected patients without involvement of the side wall or sacrum, involvement of the prostate may be amenable to bladder-sparing prostatectomy, although morbidity is increased. Bladder reconstruction The role of bladder reconstruction rather than cystectomy and ileal conduit is also unresolved. If the urethra and its sphincters can be preserved, an intestinal neobladder can be formed. However, the risk of fistulation is very high, especially if a low rectal anastomosis is performed at the same time. Over a 4-year period, Koda and colleagues48 carried out such operations in five patients, whereas 38 others had only an ileal conduit; two of five developed fistulas. However, three of the five eventually returned to work, compared with two of the 38. This was taken to justify the risks of the reconstructions. As only 12 per cent of possible patients had the urinary reconstruction, there must have been substantial case selection. An alternative to reconstruction in the pelvis where the tissues are likely to have been irradiated is to make a continent catheterizable reservoir within the upper abdomen. Several techniques are available using varying combinations of large and small bowel with or without the appendix. The urological results are good, with up to 98 per cent continence. However, reconstruction adds about 2 h to an already lengthy procedure. There are additional complications related to the diversion. In a series of total pelvic exenterations for gynaecological malignancy, 40 patients had 26 complications related to the urological reconstruction and 24 had non-pouch-related complications130. It was not surprising, therefore, to find that attendees at the consensus meeting and the published literature confirmed that, although the techniques are available, few urological reconstructions are actually performed. Distant metastases Optimum preoperative staging to determine the extent of local disease and the presence or absence of distant metastases is essential when considering surgery for patients with PRC-bTME and RRC. There is controversy over whether resectable synchronous lung or liver disease is a contraindication to attempted removal of local recurrence. In these circumstances preoperative chemotherapy may be useful in evaluating tumour responsiveness. If local and distant tumour response is achieved, resectional surgery may be considered, although the long-term outcome of such borderline cases is yet to be published in large series. The role of synchronous pelvic and hepatic resection is also questionable and may be reserved only for young, fit patients with PRC-bTME cancer. Unresectable local disease and palliative resection The key objectives of palliative resections act as a guide for whom this type of surgery may be appropriate. Many patients with low-volume metastatic disease will live for a considerable time with modern chemotherapy, and the role of surgery in facilitating this is important. The possible benefits of debulking in the presence of grossly unresectable disease require clarification. R1 resection is likely to worsen QoL outcomes compared with R0 resection, especially following exenteration44. Resection with an R1 margin (microscopic residual disease) may lead to longer survival than resection with an R2 margin. However, an R2 resection may not improve QoL if pain is present before operation. The best methods for palliation, which may include radiotherapy, chemotherapy and/or palliative surgery, require careful selection. The role of isolated pelvic chemoperfusion in a select group of patients with unresectable cancer contained within the pelvis needs further investigation131. More information is needed to assess surgery and chemotherapy compared with long-term CRT in terms of QoL. Audit of current management outcomes is needed to determine the role of radical surgery in providing palliation for patients both with PRC-bTME and RRC. Perineal reconstruction A variety of methods for wound reconstruction, including biological implants and flaps, are available and should be encouraged132,133. Any attempt to reconstruct the perineal defect with plastic surgery techniques should be performed by surgeons who are experienced in the use of rotational or free-flap transfers in order to achieve the best possible results. The perineal defect after exenteration may be significant, particularly after sacrectomy, and reconstruction is advantageous to decrease the time frame for wound healing. Techniques used include the myocutaneous oblique or vertical rectus abdominis muscle flap, gracilis muscle flap, gluteal rotation flap, inferior gluteal artery perforator flap or free flap49–50,134. Each has its advantages and disadvantages and, because there are no comparative studies, each centre has adopted its preferred technique(s). Nevertheless flap procedures significantly add to the duration of the procedure and all carry the risk of longer bed rest, flap-related complications and donor-site morbidity135,136. Biological grafts combined with omentoplasty may also be used for repair of large perineal wounds without the addition of a flap procedure, even in irradiated patients137–139. Future comparative studies should consider evaluation of the optimal method of perineal reconstruction, and include short- and long-term outcomes as well as assessement of QoL. Important complications of flaps include wound breakdown and perineal hernias, which can be both challenging to treat and may impact on QoL. Pathology and prognostic markers Close collaboration between the surgeon, radiologist and pathologist is of particular importance, especially for complicated specimens, to ensure that the pathologist knows which margins are most likely to be involved so that they can be sampled adequately. The pathologist can improve clinical management by working as part of the MDT. The pathologist is important for informing prognosis, and evaluating and auditing quality by accurate reporting of resection margins and other prognostic pathological features. Direct collaborative review of the resected specimen by both the surgeon and pathologist is encouraged. There should be national, or preferably international, guidelines for dissection and reporting to help ensure uniformly high standards by pathologists working in a wide range of clinical settings. Pathological assessment The histopathology report must include: Gross description, including which part of the large bowel has been resected, length of the surgical specimen, whether part of the bowel is extraperitoneal (and, if so, how much), tumour site (and its relationship, if any, to the peritoneal reflection), tumour size (three dimensions), distance from proximal or distal margin, depth of invasion, perforation and other lesions not related to the tumour (adenoma, ulcerative colitis, Crohn's disease). Evidence of previous surgery should be noted. Especially in advanced and recurrent cancer, the presence of other organs and the relationship of these organs to the tumour needs to be assessed and documented. Ideally, these specimens should be received unfixed. This will facilitate examination of the specimen and allow tissue to be taken for tissue banking. Photography of the specimen is extremely valuable, as is discussing the case with the surgeon before cutting it. Microscopic description, including histological type, histological grade, response to preoperative therapy (if relevant), depth of invasion, presence of a pushing or infiltrating margin, presence or absence of a marked lymphocytic infiltrate at the tumour margin, positive lymph nodes, total number of lymph nodes examined, involvement of the apical node or specific groups of lymph nodes identified by the surgeon (for example para-aortic nodes), extracapsular spread of tumour, perineural invasion, vascular invasion (specifying whether there is extramural venous invasion), tumour infiltrating lymphocytes, (postradiotherapy, y) pTNM classification, extension of tumour through the bowel wall and into adjacent structures and, if relevant, involvement of other organs, involvement of proximal, distal and radial margins. For adequate staging, ideally at least 12 nodes must be removed; this is particularly important for stage II tumours to reduce the risk of understaging, although may be more difficult in patients who have received neoadjuvant therapy54,140. A minimal data set adapted for use in PRC-bTME and/or RRC would be valuable. Primary rectal cancer beyond total mesorectal excision planes The most common problems during these multivisceral resections include invasion into adjacent structures, lateral tumour clearance and perirectal invasion. Accurately assessing the resection margin status of the complete en bloc specimen is essential to guiding future therapies. The presence of signet ring cells, perineural or extramural vascular invasion increases the likelihood of local recurrence after salvage surgery. Recurrent rectal cancer R0 resection is likely to be the most important factor in predicting prognosis36,56,141–142. R1 resection rates may be as high as 50 per cent for sacrectomy, which may reduce survival by at least 50 per cent at 5 years40. Obtaining the original resection specimen can confirm the original diagnosis and the original resection margin status if doubt exists, although this is unlikely to be required routinely and should not delay management. Abnormal anatomy is likely to be due to previous resection, and dissection with a member of the surgical team present is recommended. Adverse pathological features, including foci of tumour away from the main recurrent mass, may be present in patients with RRC. Biomarkers With the exception of KRAS mutation, which excludes patients unlikely to respond to treatment with antiepidermal growth factor receptor antibodies, no further prognostic/predictive molecular marker is relevant for routine first-line treatment decisions outwith clinical trials34. A range of biomarkers have been investigated in terms of prognosis. Further studies have concentrated on predicting which tumours will respond to CRT, to improve patient selection. More research into novel biomarkers is needed143. Biomarker correlation with features from high-resolution imaging may improve the predictive responses from CRT. Further profiling may help in determining response to CRT and prognosis115. For patients undergoing surgery both for PRC-bTME and RRC, measurement of CEA levels is likely to be of some prognostic value. For those with RRC, preoperative CEA level has a borderline significant association with DFS (10 per cent at 5 years for patients with level above 10 ng/ml versus 34 per cent for those with lower concentration; P = 0.05)73. Tissue biorepository There is a lack of basic science research into both PRC-bTME and RRC tumour types. A high-quality, prospectively maintained, central tissue biorepository will greatly aid future collaborative translational research. Follow-up regimens Follow-up regimens after rectal cancer surgery aim to detect recurrence at an early stage to allow successful excision. Further aims of follow-up include detecting second primaries, patient reassurance, audit and research. Follow-up after resection depends on stage, type of surgery, perioperative treatment and amenability to resection of recurrent disease. The role of CEA measurement in follow-up after surgery for primary or recurrent disease requires clarification, as a normal CEA level does not rule out recurrence/further recurrence, but a rising concentration may indicate the need for further investigation144. Until further evidence emerges regarding the sensitivity, specificity and cost-effectiveness of [18F]FDG-PET in differentiation between scar tissue and postoperative infection/inflammation from malignant change, its routine use cannot be recommended. However, early results suggest that it is promising in accurate detection of recurrence and/or metastases14. Primary rectal cancer beyond total mesorectal excision planes A meta-analysis of the available randomized trials showed a modest but significant benefit for intensive follow-up regimens145. Although follow-up for non-advanced primary rectal cancer typically includes CT of the thorax, abdomen and pelvis twice in the first 3 years, and CEA measurement every 6 months for 3 years, PRC-bTME may need closer monitoring146. An annual MRI of the pelvis for local recurrence, and CT of the thorax, abdomen and pelvis for distant recurrence, are recommended. However, as approximately 75 per cent of local recurrences are detected in the first 3 years, there is an argument for performing MRI of the pelvis every 6 months in the first 3 years45,147. Recurrent rectal cancer Annual MRI of the pelvis for local recurrence, and CT of the thorax, abdomen and pelvis for distant recurrence, are recommended. A third resection for rerecurrent cancer is uncommon and the benefit of intensive follow-up regimens is questioned. Quality of life Traditionally, assessment of cancer treatment outcomes relied heavily on survival, although more recent interest is being paid to QoL. The survival rate after surgery without curative intent is less than 5 per cent at 5 years, with a median of approximately 12 months148,149. This has to be balanced against the considerable surgical morbidity and mortality, and the need for prolonged rehabilitation in a substantial proportion of patients. Palliative surgery can be effective in carefully selected symptomatic patients, and this benefit needs to be quantified. Risk factors associated with poorer QoL are also not clearly defined, although are likely to include sex, age, bony resection, double stoma and pain following surgery. Some patients with disease amenable to pelvic exenteration may opt not to proceed for personal reasons. Their QoL has been poorly studied and may provide further information necessary in the preoperative counselling of potential surgical candidates. In a recent systematic review of QoL measures used in rectal cancer, the EORTC C30 and/ or CR38 QoL measures were the most widely used (49 per cent), with the remaining 51 per cent comprising a variety of QoL measures. A substantial proportion of studies also used non-validated investigator-designed QoL measures. Collaborators Forename . Surname . Specialty . Hospital . S. Mohammed Ali Surgery The Royal Marsden Hospital, London, UK Anthony Antoniou Surgery St Mark's Hospital, Harrow, UK John Beynon Surgery ABM University Trust, Swansea, UK Aneel Bhangu Surgery The Royal Marsden Hospital, London, UK Pradeep Bose Urology Morriston Hospital, Swansea, UK Kirsten Boyle Surgery University Hospitals of Leicester, UK Graham Branagan Surgery Salisbury NHS Foundation Trust, UK Gina Brown Radiology The Royal Marsden Hospital, London, UK David Burling Radiology St Mark's Hospital, Harrow, UK George J. Chang Surgery University of Texas MD Anderson Cancer Center, Houston, Texas, USA Susan K. Clark Surgery St Mark's Hospital, Harrow, UK Patrick Colquhoun Surgery University of Western Ontario, Ontario, Canada Christopher H. Crane Oncology University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Ara Darzi Surgery Imperial College London, St Mary's Hospital, London, UK Prajnan Das Oncology University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Johannes H. W. de Wilt Surgery Radboud University Nijmegen Medical Centre, Nijmegen The Netherlands Conor P. Delaney Surgery University Hospitals Case Medical Center, Cleveland, Ohio, USA Anant Desai Surgery University Hospital Birmingham, Birmingham, UK Mark Davies Surgery ABM University Trust, Swansea, UK David Dietz Surgery Cleveland Clinic, Cleveland, Ohio, USA Eric J. Dozois Surgery Mayo Clinic, Rochester, Minnesota, USA Michael Duff Surgery Gartnavel General Hospital, Glasgow, UK Adam Dziki Surgery Medical University Lodz, Lodz, Poland J. Edward Fitzgerald Surgery The Royal Marsden Hospital, London, UK Frank A. Frizelle Surgery Christchurch Hospital, Christchurch, New Zealand Bruce George Surgery University Hospitals Oxford, Oxford, UK Mark L. George Surgery St Thomas' Hospital, London, UK Panagiotis Georgiou Surgery Chelsea and Westminster NHS Foundation Trust, London, UK Rob Glynne-Jones Oncology Mount Vernon Centre for Cancer Treatment, Northwood, UK Robert D. Goldin Histopathology Centre for Pathology, Imperial College, London, UK Arun Gupta Radiology St Mark's Hospital, Harrow, UK Deena Harji Surgery St James University Hospital, Leeds, UK Dean A. Harris Surgery ABM University Trust, Swansea, UK Maria Hawkins Oncology Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford UK Alexander G. Heriot Surgery Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Torbjörn Holm Surgery Karolinska University Hospital, Stockholm, Sweden Roel Hompes Surgery University Hospitals Oxford, Oxford UK Lee Jeys Orthopaedic Surgery Royal Orthopaedic Hospital, Birmingham, UK John T. Jenkins Surgery St Mark's Hospital, Harrow, UK Ravi P. Kiran Surgery Cleveland Clinic, Cleveland, Ohio, USA Cherry E. Koh Surgery Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Soren Laurberg Surgery Aarhus University Hospital, Aarhus, Denmark Wai L. Law Surgery The University of Hong Kong, Hong Kong, China A. Sender Liberman Surgery McGill University Health Centre, Montreal, Quebec, Canada Michele Marshall Radiology St Mark's Hospital, Harrow, UK David R. McArthur Surgery Heart of England NHS Foundation Trust, Birmingham, UK. Alex H. Mirnezami Surgery University Hospital Southampton, Southampton UK Brendan Moran Surgery Basingstoke and North Hampshire Foundation Trust, Basingstoke, UK Neil Mortenson Surgery University Hospitals Oxford, Oxford, UK Eddie Myers Surgery Galway University Hospitals, Galway, Ireland R. John Nicholls Surgery St Mark's Hospital and Imperial College, London, UK P. Ronan O'Connell Surgery St Vincent's University Hospital, Dublin, Ireland Sarah T. O'Dwyer Surgery The Christie NHS Foundation Trust, Manchester, UK Alex Oliver Anaesthetist The Royal Marsden Hospital, London, UK Arvind Pallan Radiology Heart of England NHS Foundation Trust, Birmingham, UK Prashant Patel Urology University Hospital Birmingham, Birmingham, UK Uday B. Patel Radiology The Royal Marsden Hospital, London, UK Simon Radley Surgery University Hospital Birmingham, Birmingham, UK Kelvin W. D. Ramsey Plastic Surgery The Royal Marsden NHS Foundation Trust, London, UK Peter C. Rasmussen Surgery Aarhus University Hospital, Aarhus, Denmark Carole Richard Surgery Centre Hospitalier de l'Université de Montréal, Montréal, Canada Harm J. T. Rutten Surgery Catharina Hospital, Eindhoven, The Netherlands Peter Sagar Surgery St James's University Hospital, Leeds, UK David Sebag-Montefiore Oncology Leeds Teaching Hospitals NHS Trust, Leeds, UK Michael J. Solomon Surgery Royal Prince Alfred Hospital and University of Sydney, Sydney, New South Wales, Australia Luca Stocchi Surgery Cleveland Clinic, Cleveland, Ohio, USA Carol J. Swallow Surgery Mount Sinai and Princess Margaret Hospitals, Toronto, Ontario, Canada Diana Tait Oncology The Royal Marsden Hospital, London, UK Emile Tan Surgery The Royal Marsden Hospital, London, UK Paris P. Tekkis Surgery The Royal Marsden Hospital, London, UK Nicholas van As Oncology The Royal Marsden Hospital, London, UK Te Vuong Oncology Jewish General Hospital, McGill University, Montreal, Quebec, Canada Theo Wiggers Surgery University Medical Center Groningen, Groningen, The Netherlands Malcolm Wilson Surgery The Christie NHS Foundation Trust, Manchester, UK Desmond Winter Surgery St Vincent's University Hospital, Dublin, Ireland Christopher Woodhouse Urology The Royal Marsden Hospital, London, UK Forename . Surname . Specialty . Hospital . S. Mohammed Ali Surgery The Royal Marsden Hospital, London, UK Anthony Antoniou Surgery St Mark's Hospital, Harrow, UK John Beynon Surgery ABM University Trust, Swansea, UK Aneel Bhangu Surgery The Royal Marsden Hospital, London, UK Pradeep Bose Urology Morriston Hospital, Swansea, UK Kirsten Boyle Surgery University Hospitals of Leicester, UK Graham Branagan Surgery Salisbury NHS Foundation Trust, UK Gina Brown Radiology The Royal Marsden Hospital, London, UK David Burling Radiology St Mark's Hospital, Harrow, UK George J. Chang Surgery University of Texas MD Anderson Cancer Center, Houston, Texas, USA Susan K. Clark Surgery St Mark's Hospital, Harrow, UK Patrick Colquhoun Surgery University of Western Ontario, Ontario, Canada Christopher H. Crane Oncology University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Ara Darzi Surgery Imperial College London, St Mary's Hospital, London, UK Prajnan Das Oncology University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Johannes H. W. de Wilt Surgery Radboud University Nijmegen Medical Centre, Nijmegen The Netherlands Conor P. Delaney Surgery University Hospitals Case Medical Center, Cleveland, Ohio, USA Anant Desai Surgery University Hospital Birmingham, Birmingham, UK Mark Davies Surgery ABM University Trust, Swansea, UK David Dietz Surgery Cleveland Clinic, Cleveland, Ohio, USA Eric J. Dozois Surgery Mayo Clinic, Rochester, Minnesota, USA Michael Duff Surgery Gartnavel General Hospital, Glasgow, UK Adam Dziki Surgery Medical University Lodz, Lodz, Poland J. Edward Fitzgerald Surgery The Royal Marsden Hospital, London, UK Frank A. Frizelle Surgery Christchurch Hospital, Christchurch, New Zealand Bruce George Surgery University Hospitals Oxford, Oxford, UK Mark L. George Surgery St Thomas' Hospital, London, UK Panagiotis Georgiou Surgery Chelsea and Westminster NHS Foundation Trust, London, UK Rob Glynne-Jones Oncology Mount Vernon Centre for Cancer Treatment, Northwood, UK Robert D. Goldin Histopathology Centre for Pathology, Imperial College, London, UK Arun Gupta Radiology St Mark's Hospital, Harrow, UK Deena Harji Surgery St James University Hospital, Leeds, UK Dean A. Harris Surgery ABM University Trust, Swansea, UK Maria Hawkins Oncology Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford UK Alexander G. Heriot Surgery Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Torbjörn Holm Surgery Karolinska University Hospital, Stockholm, Sweden Roel Hompes Surgery University Hospitals Oxford, Oxford UK Lee Jeys Orthopaedic Surgery Royal Orthopaedic Hospital, Birmingham, UK John T. Jenkins Surgery St Mark's Hospital, Harrow, UK Ravi P. Kiran Surgery Cleveland Clinic, Cleveland, Ohio, USA Cherry E. Koh Surgery Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Soren Laurberg Surgery Aarhus University Hospital, Aarhus, Denmark Wai L. Law Surgery The University of Hong Kong, Hong Kong, China A. Sender Liberman Surgery McGill University Health Centre, Montreal, Quebec, Canada Michele Marshall Radiology St Mark's Hospital, Harrow, UK David R. McArthur Surgery Heart of England NHS Foundation Trust, Birmingham, UK. Alex H. Mirnezami Surgery University Hospital Southampton, Southampton UK Brendan Moran Surgery Basingstoke and North Hampshire Foundation Trust, Basingstoke, UK Neil Mortenson Surgery University Hospitals Oxford, Oxford, UK Eddie Myers Surgery Galway University Hospitals, Galway, Ireland R. John Nicholls Surgery St Mark's Hospital and Imperial College, London, UK P. Ronan O'Connell Surgery St Vincent's University Hospital, Dublin, Ireland Sarah T. O'Dwyer Surgery The Christie NHS Foundation Trust, Manchester, UK Alex Oliver Anaesthetist The Royal Marsden Hospital, London, UK Arvind Pallan Radiology Heart of England NHS Foundation Trust, Birmingham, UK Prashant Patel Urology University Hospital Birmingham, Birmingham, UK Uday B. Patel Radiology The Royal Marsden Hospital, London, UK Simon Radley Surgery University Hospital Birmingham, Birmingham, UK Kelvin W. D. Ramsey Plastic Surgery The Royal Marsden NHS Foundation Trust, London, UK Peter C. Rasmussen Surgery Aarhus University Hospital, Aarhus, Denmark Carole Richard Surgery Centre Hospitalier de l'Université de Montréal, Montréal, Canada Harm J. T. Rutten Surgery Catharina Hospital, Eindhoven, The Netherlands Peter Sagar Surgery St James's University Hospital, Leeds, UK David Sebag-Montefiore Oncology Leeds Teaching Hospitals NHS Trust, Leeds, UK Michael J. Solomon Surgery Royal Prince Alfred Hospital and University of Sydney, Sydney, New South Wales, Australia Luca Stocchi Surgery Cleveland Clinic, Cleveland, Ohio, USA Carol J. Swallow Surgery Mount Sinai and Princess Margaret Hospitals, Toronto, Ontario, Canada Diana Tait Oncology The Royal Marsden Hospital, London, UK Emile Tan Surgery The Royal Marsden Hospital, London, UK Paris P. Tekkis Surgery The Royal Marsden Hospital, London, UK Nicholas van As Oncology The Royal Marsden Hospital, London, UK Te Vuong Oncology Jewish General Hospital, McGill University, Montreal, Quebec, Canada Theo Wiggers Surgery University Medical Center Groningen, Groningen, The Netherlands Malcolm Wilson Surgery The Christie NHS Foundation Trust, Manchester, UK Desmond Winter Surgery St Vincent's University Hospital, Dublin, Ireland Christopher Woodhouse Urology The Royal Marsden Hospital, London, UK Open in new tab Forename . Surname . Specialty . Hospital . S. Mohammed Ali Surgery The Royal Marsden Hospital, London, UK Anthony Antoniou Surgery St Mark's Hospital, Harrow, UK John Beynon Surgery ABM University Trust, Swansea, UK Aneel Bhangu Surgery The Royal Marsden Hospital, London, UK Pradeep Bose Urology Morriston Hospital, Swansea, UK Kirsten Boyle Surgery University Hospitals of Leicester, UK Graham Branagan Surgery Salisbury NHS Foundation Trust, UK Gina Brown Radiology The Royal Marsden Hospital, London, UK David Burling Radiology St Mark's Hospital, Harrow, UK George J. Chang Surgery University of Texas MD Anderson Cancer Center, Houston, Texas, USA Susan K. Clark Surgery St Mark's Hospital, Harrow, UK Patrick Colquhoun Surgery University of Western Ontario, Ontario, Canada Christopher H. Crane Oncology University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Ara Darzi Surgery Imperial College London, St Mary's Hospital, London, UK Prajnan Das Oncology University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Johannes H. W. de Wilt Surgery Radboud University Nijmegen Medical Centre, Nijmegen The Netherlands Conor P. Delaney Surgery University Hospitals Case Medical Center, Cleveland, Ohio, USA Anant Desai Surgery University Hospital Birmingham, Birmingham, UK Mark Davies Surgery ABM University Trust, Swansea, UK David Dietz Surgery Cleveland Clinic, Cleveland, Ohio, USA Eric J. Dozois Surgery Mayo Clinic, Rochester, Minnesota, USA Michael Duff Surgery Gartnavel General Hospital, Glasgow, UK Adam Dziki Surgery Medical University Lodz, Lodz, Poland J. Edward Fitzgerald Surgery The Royal Marsden Hospital, London, UK Frank A. Frizelle Surgery Christchurch Hospital, Christchurch, New Zealand Bruce George Surgery University Hospitals Oxford, Oxford, UK Mark L. George Surgery St Thomas' Hospital, London, UK Panagiotis Georgiou Surgery Chelsea and Westminster NHS Foundation Trust, London, UK Rob Glynne-Jones Oncology Mount Vernon Centre for Cancer Treatment, Northwood, UK Robert D. Goldin Histopathology Centre for Pathology, Imperial College, London, UK Arun Gupta Radiology St Mark's Hospital, Harrow, UK Deena Harji Surgery St James University Hospital, Leeds, UK Dean A. Harris Surgery ABM University Trust, Swansea, UK Maria Hawkins Oncology Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford UK Alexander G. Heriot Surgery Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Torbjörn Holm Surgery Karolinska University Hospital, Stockholm, Sweden Roel Hompes Surgery University Hospitals Oxford, Oxford UK Lee Jeys Orthopaedic Surgery Royal Orthopaedic Hospital, Birmingham, UK John T. Jenkins Surgery St Mark's Hospital, Harrow, UK Ravi P. Kiran Surgery Cleveland Clinic, Cleveland, Ohio, USA Cherry E. Koh Surgery Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Soren Laurberg Surgery Aarhus University Hospital, Aarhus, Denmark Wai L. Law Surgery The University of Hong Kong, Hong Kong, China A. Sender Liberman Surgery McGill University Health Centre, Montreal, Quebec, Canada Michele Marshall Radiology St Mark's Hospital, Harrow, UK David R. McArthur Surgery Heart of England NHS Foundation Trust, Birmingham, UK. Alex H. Mirnezami Surgery University Hospital Southampton, Southampton UK Brendan Moran Surgery Basingstoke and North Hampshire Foundation Trust, Basingstoke, UK Neil Mortenson Surgery University Hospitals Oxford, Oxford, UK Eddie Myers Surgery Galway University Hospitals, Galway, Ireland R. John Nicholls Surgery St Mark's Hospital and Imperial College, London, UK P. Ronan O'Connell Surgery St Vincent's University Hospital, Dublin, Ireland Sarah T. O'Dwyer Surgery The Christie NHS Foundation Trust, Manchester, UK Alex Oliver Anaesthetist The Royal Marsden Hospital, London, UK Arvind Pallan Radiology Heart of England NHS Foundation Trust, Birmingham, UK Prashant Patel Urology University Hospital Birmingham, Birmingham, UK Uday B. Patel Radiology The Royal Marsden Hospital, London, UK Simon Radley Surgery University Hospital Birmingham, Birmingham, UK Kelvin W. D. Ramsey Plastic Surgery The Royal Marsden NHS Foundation Trust, London, UK Peter C. Rasmussen Surgery Aarhus University Hospital, Aarhus, Denmark Carole Richard Surgery Centre Hospitalier de l'Université de Montréal, Montréal, Canada Harm J. T. Rutten Surgery Catharina Hospital, Eindhoven, The Netherlands Peter Sagar Surgery St James's University Hospital, Leeds, UK David Sebag-Montefiore Oncology Leeds Teaching Hospitals NHS Trust, Leeds, UK Michael J. Solomon Surgery Royal Prince Alfred Hospital and University of Sydney, Sydney, New South Wales, Australia Luca Stocchi Surgery Cleveland Clinic, Cleveland, Ohio, USA Carol J. Swallow Surgery Mount Sinai and Princess Margaret Hospitals, Toronto, Ontario, Canada Diana Tait Oncology The Royal Marsden Hospital, London, UK Emile Tan Surgery The Royal Marsden Hospital, London, UK Paris P. Tekkis Surgery The Royal Marsden Hospital, London, UK Nicholas van As Oncology The Royal Marsden Hospital, London, UK Te Vuong Oncology Jewish General Hospital, McGill University, Montreal, Quebec, Canada Theo Wiggers Surgery University Medical Center Groningen, Groningen, The Netherlands Malcolm Wilson Surgery The Christie NHS Foundation Trust, Manchester, UK Desmond Winter Surgery St Vincent's University Hospital, Dublin, Ireland Christopher Woodhouse Urology The Royal Marsden Hospital, London, UK Forename . Surname . Specialty . Hospital . S. Mohammed Ali Surgery The Royal Marsden Hospital, London, UK Anthony Antoniou Surgery St Mark's Hospital, Harrow, UK John Beynon Surgery ABM University Trust, Swansea, UK Aneel Bhangu Surgery The Royal Marsden Hospital, London, UK Pradeep Bose Urology Morriston Hospital, Swansea, UK Kirsten Boyle Surgery University Hospitals of Leicester, UK Graham Branagan Surgery Salisbury NHS Foundation Trust, UK Gina Brown Radiology The Royal Marsden Hospital, London, UK David Burling Radiology St Mark's Hospital, Harrow, UK George J. Chang Surgery University of Texas MD Anderson Cancer Center, Houston, Texas, USA Susan K. Clark Surgery St Mark's Hospital, Harrow, UK Patrick Colquhoun Surgery University of Western Ontario, Ontario, Canada Christopher H. Crane Oncology University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Ara Darzi Surgery Imperial College London, St Mary's Hospital, London, UK Prajnan Das Oncology University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Johannes H. W. de Wilt Surgery Radboud University Nijmegen Medical Centre, Nijmegen The Netherlands Conor P. Delaney Surgery University Hospitals Case Medical Center, Cleveland, Ohio, USA Anant Desai Surgery University Hospital Birmingham, Birmingham, UK Mark Davies Surgery ABM University Trust, Swansea, UK David Dietz Surgery Cleveland Clinic, Cleveland, Ohio, USA Eric J. Dozois Surgery Mayo Clinic, Rochester, Minnesota, USA Michael Duff Surgery Gartnavel General Hospital, Glasgow, UK Adam Dziki Surgery Medical University Lodz, Lodz, Poland J. Edward Fitzgerald Surgery The Royal Marsden Hospital, London, UK Frank A. Frizelle Surgery Christchurch Hospital, Christchurch, New Zealand Bruce George Surgery University Hospitals Oxford, Oxford, UK Mark L. George Surgery St Thomas' Hospital, London, UK Panagiotis Georgiou Surgery Chelsea and Westminster NHS Foundation Trust, London, UK Rob Glynne-Jones Oncology Mount Vernon Centre for Cancer Treatment, Northwood, UK Robert D. Goldin Histopathology Centre for Pathology, Imperial College, London, UK Arun Gupta Radiology St Mark's Hospital, Harrow, UK Deena Harji Surgery St James University Hospital, Leeds, UK Dean A. Harris Surgery ABM University Trust, Swansea, UK Maria Hawkins Oncology Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford UK Alexander G. Heriot Surgery Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Torbjörn Holm Surgery Karolinska University Hospital, Stockholm, Sweden Roel Hompes Surgery University Hospitals Oxford, Oxford UK Lee Jeys Orthopaedic Surgery Royal Orthopaedic Hospital, Birmingham, UK John T. Jenkins Surgery St Mark's Hospital, Harrow, UK Ravi P. Kiran Surgery Cleveland Clinic, Cleveland, Ohio, USA Cherry E. Koh Surgery Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Soren Laurberg Surgery Aarhus University Hospital, Aarhus, Denmark Wai L. Law Surgery The University of Hong Kong, Hong Kong, China A. Sender Liberman Surgery McGill University Health Centre, Montreal, Quebec, Canada Michele Marshall Radiology St Mark's Hospital, Harrow, UK David R. McArthur Surgery Heart of England NHS Foundation Trust, Birmingham, UK. Alex H. Mirnezami Surgery University Hospital Southampton, Southampton UK Brendan Moran Surgery Basingstoke and North Hampshire Foundation Trust, Basingstoke, UK Neil Mortenson Surgery University Hospitals Oxford, Oxford, UK Eddie Myers Surgery Galway University Hospitals, Galway, Ireland R. John Nicholls Surgery St Mark's Hospital and Imperial College, London, UK P. Ronan O'Connell Surgery St Vincent's University Hospital, Dublin, Ireland Sarah T. O'Dwyer Surgery The Christie NHS Foundation Trust, Manchester, UK Alex Oliver Anaesthetist The Royal Marsden Hospital, London, UK Arvind Pallan Radiology Heart of England NHS Foundation Trust, Birmingham, UK Prashant Patel Urology University Hospital Birmingham, Birmingham, UK Uday B. Patel Radiology The Royal Marsden Hospital, London, UK Simon Radley Surgery University Hospital Birmingham, Birmingham, UK Kelvin W. D. Ramsey Plastic Surgery The Royal Marsden NHS Foundation Trust, London, UK Peter C. Rasmussen Surgery Aarhus University Hospital, Aarhus, Denmark Carole Richard Surgery Centre Hospitalier de l'Université de Montréal, Montréal, Canada Harm J. T. Rutten Surgery Catharina Hospital, Eindhoven, The Netherlands Peter Sagar Surgery St James's University Hospital, Leeds, UK David Sebag-Montefiore Oncology Leeds Teaching Hospitals NHS Trust, Leeds, UK Michael J. Solomon Surgery Royal Prince Alfred Hospital and University of Sydney, Sydney, New South Wales, Australia Luca Stocchi Surgery Cleveland Clinic, Cleveland, Ohio, USA Carol J. Swallow Surgery Mount Sinai and Princess Margaret Hospitals, Toronto, Ontario, Canada Diana Tait Oncology The Royal Marsden Hospital, London, UK Emile Tan Surgery The Royal Marsden Hospital, London, UK Paris P. Tekkis Surgery The Royal Marsden Hospital, London, UK Nicholas van As Oncology The Royal Marsden Hospital, London, UK Te Vuong Oncology Jewish General Hospital, McGill University, Montreal, Quebec, Canada Theo Wiggers Surgery University Medical Center Groningen, Groningen, The Netherlands Malcolm Wilson Surgery The Christie NHS Foundation Trust, Manchester, UK Desmond Winter Surgery St Vincent's University Hospital, Dublin, Ireland Christopher Woodhouse Urology The Royal Marsden Hospital, London, UK Open in new tab 4 Suggested clinical algorithms Fig. 1 Open in new tabDownload slide Algorithm to diagnose and assess resectability of primary rectal cancer beyond total mesorectal excision planes (PRC-bTME). Boxes in red represent areas of particular controversy. CEA, carcinoembryonic antigen; EUA, examination under anaesthesia; MRI, magnetic resonance imaging; CT, computed tomography; TAP, thorax, abdomen and pelvis; FDG; fluorodeoxyglucose; PET, positron emission tomography; sMDT, specialist multidisciplinary team Fig. 2 Open in new tabDownload slide Algorithm to diagnose and assess resectability of recurrent rectal cancer (RRC). Boxes in red represent areas of particular controversy. CEA, carcinoembryonic antigen; EUA, examination under anaesthesia; MRI, magnetic resonance imaging; CT, computed tomography; TAP, thorax, abdomen and pelvis; FDG, fluorodeoxyglucose; PET, positron emission tomography; sMDT, specialist multidisciplinary team; CEA, carcinoembryonic antigen Fig. 3 Open in new tabDownload slide Role of chemoradiotherapy for primary rectal cancer beyond total mesorectal excision planes (PRC-bTME). Boxes in red represent areas of controversy. IMRT, intensity-modulated radiotherapy Fig. 4 Open in new tabDownload slide Role of chemoradiotherapy in recurrent rectal cancer (RRC). Boxes in red represent areas of controversy. IMRT, intensity-modulated radiotherapy Fig. 5 Open in new tabDownload slide Management of non-curable disease. Red boxes indicate areas of controversy Fig. 6 Open in new tabDownload slide Management options for resectable pelvic disease References 1 Rowe G , Wright G. The Delphi technique as a forecasting tool: issues and analysis . Int J Forecast 1999 ; 4 : 353 – 375 . Google Scholar OpenURL Placeholder Text WorldCat 2 Harbour R , Miller J. A new system for grading recommendations in evidence based guidelines . BMJ 2001 ; 323 : 334 – 336 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Kau T , Reinprecht P, Eicher W, Lind P, Starlinger M, Hausegger KA. FDG PET/CT in the detection of recurrent rectal cancer . Int Surg 2009 ; 94 : 315 – 324 . 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Published by John Wiley & Sons Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd

Galandiuk, S

doi: 10.1002/bjs.9147pmid: 23666801

We are currently in a transition phase of surgery. In both Europe and the USA severe restrictions have been placed on surgical training hours, resulting in a demographic shift in our trainees; never before have so many women been enrolled in surgical training programmes. We are all creatures of emulation, of both good and bad. When surgical training was an apprentice system, with trainees spending long hours and years observing the behaviour of their surgical mentors, they copied both the good and the bad. With the change in training and work style, we as surgical educators are now being asked to teach surgical behaviour. In the USA, this concept of desirable surgical behaviour includes the characteristics of lifelong learning, the poorly defined and overly broad concept of professionalism, and the equally nebulous system-based practice. How can professionalism be taught? Just as a growing child learns right from wrong, the learning of surgical behaviour is a complex process. No matter which healthcare or employment scheme surgeons work under, we must ensure that future surgeons continue to learn correct surgical behaviour. Correct in that they realize the responsibility to be true to themselves, the best that they can be throughout their career, especially as the advocate for their patients, while providing the best care they are capable of giving. Correct surgical behaviour encourages collaboration with healthcare professionals and basic scientists, and ultimately must improve quality of care. Having been asked to write on surgical behaviour I undertook an electronic search, and was dismayed to see terms such as ‘verbal abuse’, ‘domineering’, ‘disruptive’ and ‘egregious’ among the very first hits. For a discipline characterized by teamwork and collaboration, this is a sad indictment regarding others' perception of our specialty. Behaviour used in conjunction with surgery can refer either to a surgeon's behaviour when confronted with a variety of clinical situations in the operating theatre or clinical environment, or it can refer to interpersonal relationships or interactions with fellow healthcare professionals and patients. Finally, it can refer to professional attitudes and lifelong habits of working and learning. Over the past 40 years there has been a gradual change in both the public and institutional perception of the role of a surgeon. In the past, the surgeon was truly the master of the ship, the commander, leader of the team. This evolution in public perception is perhaps best illustrated by changes in the manner in which surgeons are characterized in art. One of the outstanding surgeon portraits of the past century is that of Eakins' Samuel D. Gross (Fig. 1). The surgeon is at the forefront – at the centre of all proceedings in terms of both lighting and composition. Roughly a century later, in a less well known portrait by Joe Wilder, a surgeon artist, Dr Arthur Aufses, is shown operating quietly with the assistance of another, leaving the viewer with a totally different impression, the epitome of the gentleman surgeon (Fig. 2). Dr. Wilder is said to have said, “I teach that the operating room should be seen as a Cathedral in which all occupants must respect the sancity of the space. All attention must be focused on the patient and the operative procedure being accomplished, resulting in successful surgery. Loud talking and jokes are not permitted. A quiet ambience must be pervasive with the same respect that we show in our place of worship.” Fig. 1 Open in new tabDownload slide Thomas Eakins, 1875. The Gross Clinic. Oil on Canvas; 240 cm × 200 cm. Philadelphia Museum of Art and Pennsylvania Academy of Fine Arts, Philadelphia Fig. 2 Open in new tabDownload slide Chief of Surgery, Arthur H. Aufses, Jr., MD: 1988. Artwork by Joe Wilder, MD, FACS, joewildermedicalart.com. (With permission, and courtesy of Madeline Stern Wilder at [email protected]) These two paintings reflect a vast change in attitude towards surgeons. In past generations, the surgeon was considered infallible. The concepts of infallibility and others' willingness blindly to obey all their dictates are no longer true. A case in point was cited recently in the lay press: ‘A neurosurgeon was wrestled to the floor by sheriff's deputies outside the operating room after he threw a fit because he had to wait for instruments to be sterilized’1. Although this generates regretful smiles and nods from many, and the case in point was in fact dismissed, I am certain that readers can imagine surgeons of their acquaintance who could exhibit such behaviour. Disruptive behaviour has been well characterized1. For surgeons, such inappropriate conduct includes the following. Inappropriate language and/or behaviour. Profane or disrespectful language, demeaning behaviour, such as name-calling, sexual comments or innuendo, inappropriate touching, sexual or otherwise, and racial or ethnic jokes. Uncontrolled anger. Outbursts of anger, throwing instruments, charts or other objects. Personal criticism of doctors, nurses or even institutions in front of patients or staff. Criticizing other caregivers in front of patients or other staff, or making comments that undermine a patient's trust in other caregivers or the hospital. Much of the current change in attitudes towards surgical behaviour has come from the safety movement and literature. There are reports of adverse clinical events (death or major complications) being more likely in environments where there is less team behaviour2. A surgeon's attitude must reflect the change in their role. With changes in patient care processes, shorter hospital stays, and the advent of minimally invasive procedures (diagnostic and therapeutic), patients are in hospital for much less time. The surgeon, rather than being totally responsible for a patient's care, must interact with a variety of healthcare providers and administrators, at one timeacting as the patient's advocate and at another time as an economist. The patient's contact with the surgeon will be reduced from what was formerly a variable stay in hospital to what is now often a short inpatient or even totally outpatient experience. Depending on the type and scope of practice, continuity of care in the future will be threatened. Despite the changes that are in store for surgery as a specialty over the next century, we must not lose sight of the fact that the essence of surgical behaviour lies in doing what is best for a patient, no matter the setting, the timing or the type of care delivered. This must always be foremost in everything we do. The past century has seen a great change not only for surgeons but also for BJS. What was formerly the British Journal of Surgery is now also the official journal of four non-UK surgical societies. It is our common interests and behaviour that unite us as surgeons in a progressively shrinking world. Disclosure The authors declare no conflict of interest. References 1 Porto G , Lauve R. Disruptive Clinician Behavior: a Persistent Threat to Patient Safety . http://www.psqh.com/julaug06/disruptive.html [accessed 24 March 2013]. 2 Mazzocco K , Petitti DB, Fong KT, Bonacum D, Brookey J, Graham S et al. Surgical team behaviors and patient outcomes . Am J Surg 2009 ; 197 : 678 – 685 . Google Scholar Crossref Search ADS PubMed WorldCat © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd

Petter-Puchner, A H; Dietz, U A

doi: 10.1002/bjs.9156pmid: 23674082

Around 1989 a patient with an intestinal leak and an open abdomen was in hospital in South America. A young resident, Ulrich Dietz, borrowed a bovine pericardial patch from the cardiac surgeons to protect the intestines from further harm caused by dehydration and cotton dressings. Luckily, the patient survived. At about this time many surgeons tried biological patches to protect contaminated viscera, although the idea was gradually abandoned when knitted synthetic absorbable meshes made of polyglactic acid were introduced. Some years ago, biological implants returned to the scene, mainly in reconstructive and plastic surgery, and were eventually translated to hernia surgery1. They received a warm welcome. The idea of reinforcing the abdominal wall without leaving a permanent foreign body suited the new, minimally invasive concept of surgery. Soon, the mission for ‘biomeshes’ was branded ‘reconstruction rather than repair’ and biological meshes started to be used in reinforcement. It now seems timely to take stock and evaluate outcomes associated with their use. An understanding of the biology of mesh incorporation and remodelling would seem critical. What are the individual inflammatory and epigenetic responses of the receptor to the implanted mesh? Does remodelling mean the gradual substitution of foreign collagen through lysis and new synthesis by receptor–tissue interaction, or is remodelling rather a product of spatial rearrangement of the ‘transplanted’ fibrils? In reality, little is known about these issues, yet we have experienced a process that Nietzsche described as the illusion of truth: ‘where metaphors are enhanced, transposed and embellished rhetorically in such a way that, after some time, they seem firm, canonical and obligatory’2. Surgeons are often innovators and strive to find new solutions to clinical problems. In doing so, pitfalls have to be considered. There is the temptation to be among the first to use a new product, even when this is barely supported by evidence. Failure to apply the principles of sound research and good evidence can not only harm patients but also damage the reputation of an otherwise promising treatment. In addition, when other options have been exhausted, it is tempting to do something rather than nothing. This rationale blinds the surgeon and leads unavoidably to ‘commission bias’. The experimental basis for the use of biologicals is weak. There is no reason to believe that biologicals will elicit less foreign body reaction or immunological response than any synthetic implant3. The opposite, in fact, seems more credible. Biologicals can lead to long-lasting foreign body reactions and marked immunological responses. Some products even contain fragments of donor DNA4. Recent evidence indicates that clearance of bacteria does not occur in biologicals5. The raised levels of collagenases and endotoxin in contaminated wounds lead to a rapid breakdown of non-cross-linked and an alteration of cross-linked biologicals6. The clinical results unfortunately bear out the weaknesses of the scientific foundations supporting this approach. An initial series of clinical studies suggested that it was not only feasible but that the best results could be achieved in challenging repairs. The attempts at early closure of open abdomen with biologicals led to a short revival of operative techniques prone to failure, such as mesh interlay (inlay). As we know today, these efforts were misled and often resulted in recurrences and aggravated wound situations. Shrinkage, bulging, defragmentation and persisting foreign body reactions have not been rare, but rather under-reported complications. Evidence-based indications for biological implants are virtually non-existent. A published high-quality reliable randomized clinical trial does not exist. The results are variable, cannot be described as reproducible and, regardless of methodological quality, all studies have been characterized by slow recruitment of small numbers of patients7. It is evident that biologicals have not improved the quality of hernia surgery as expected. Instead it has become increasingly clear that they are not wonder products and that many problems addressed in early experimental research have materialized with their clinical use. Before condemning them, however, it would seem far more appropriate to conduct further experimental work to understand their behaviour, so that rational clinical studies might follow. Inevitably, commercial influences have had an impact on the introduction of biological meshes. They have undoubtedly awakened high hopes and expectations of sales volume, and one could argue that the creation of a thriving multibillion euro market in hernia and abdominal wall repair in the USA and parts of Europe came as no big surprise. Could it be that, blinded by numbers and driven by shareholders, companies pressed too quickly into this technology? More than 20 years ago, Hans Jonas8 argued that it would be responsible to abstain voluntarily from (quick) progress (and consequently also from sales volume) in order to secure the ethical and experimental knowledge of the new before using it in patients. Patients do not need newer products and innovation alone, but do need safer products and predictable technologies that work in the long run. Ethical responsibilities and threats of litigation should lead industry and surgeons in this direction. Although the spectrum of successful applications of synthetic mesh materials is widening constantly, particularly in the context of infected wounds, the spectrum for biologicals seems to be narrowing constantly9. Despite improvements in technology and the quality of the latest generation of biologicals, the main indication for use seems to be back at square one as a temporary and bridging protection for an infected wound. Further clinical indications are not in sight. Basic research, including biocompatibility, epigenetics and tissue engineering, are all needed. In clinical research, national registries should exist to gain full access to patient histories, complications and follow-up data. One such registry is the EuraHS platform (European Registry of Abdominal Wall Hernias) from the European Hernia Society10. At the present time, a patient should not receive a biological mesh for abdominal wall reinforcement outside a registry or transparent study protocol. Disclosure The authors declare no conflict of interest. References 1 Helton WS , Fisichella PM, Berger R, Horgan S, Espat NJ, Abcarian H. Short-term outcomes with small intestinal submucosa for ventral abdominal hernia . Arch Surg 2005 ; 140 : 549 – 560 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Nietzsche F . On truth and lie in an extra-moral sense. In The Portable Nietzsche , Kaufmann W (ed.). Penguin Books : New York , 1976 ; 42 – 47 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 3 Petter-Puchner AH , Fortelny RH, Silic K, Brand J, Gruber-Blum S, Redl H. Biologic hernia implants in experimental intraperitoneal onlay mesh plasty repair: the impact of proprietary collagen processing methods and fibrin sealant application on tissue integration . Surg Endosc 2011 ; 25 : 3245 – 3252 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Gilbert TW , Freund JM, Badylak SF. Quantification of DNA in biologic scaffold materials . J Surg Res 2009 ; 152 : 135 – 139 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Bellows CF , Wheatley BM, Moroz K, Rosales SC, Morici LA. The effect of bacterial infection on the biomechanical properties of biological mesh in a rat model . PLoS One 2011 ; 6 : e21228 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Kissane NA , Itani KM. A decade of ventral incisional hernia repairs with biologic acellular dermal matrix: what have we learned? Plast Reconstr Surg 2012 ; 130 ( Suppl 2 ): 194S – 202S . Google Scholar Crossref Search ADS PubMed WorldCat 7 Itani KM , Rosen M, Vargo D, Awad SS, Denoto G III, Butler CE; RICH Study Group. Prospective study of single-stage repair of contaminated hernias using a biologic porcine tissue matrix: the RICH Study . Surgery 2012 ; 152 : 498 – 505 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Jonas H . Das Prinzip Verantwortung. Versuch einer Ethik für die technologische Zivilisation . Suhrkamp : Frankfurt am Main , 1988 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 9 Dietz UA , Wichelmann C, Wunder C, Kauczok J, Spor L, Strauß A et al. Early repair of open abdomen with a tailored two-component mesh and conditioning vacuum packing: a safe alternative to the planned giant ventral hernia . Hernia 2012 ; 16 : 451 – 460 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Muysoms F , Campanelli G, Champault GG, DeBeaux AC, Dietz UA, Jeekel J et al. EuraHS: the development of an international online platform for registration and outcome measurement of ventral abdominal wall hernia repair . Hernia 2012 ; 16 : 239 – 250 . Google Scholar Crossref Search ADS PubMed WorldCat © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd

Stansby, G; Berridge, D

doi: 10.1002/bjs.9187pmid: 23754642

Vascular surgeons and radiologists are becoming increasingly involved in difficult decision-making about acute venous thrombolysis, insertion of inferior vena cava (IVC) filters and management of the long-term outcomes of venous thromboembolism (VTE). The National Institute for Health and Clinical Excellence (NICE) in the UK has recently issued guidance (CG144) that includes recommendations for investigative algorithms, the use of IVC filters and strategies aiming to reduce post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT)1. CG144 also focuses on the link between cancer and VTE, and recommends specific investigations for cancer in patients over the age of 40 years who have an unprovoked VTE. IVC filters have been in use for more than 40 years but, disappointingly, they have been the subject of few randomized trials. CG144 recommends offering temporary IVC filters to patients with proximal DVT who cannot have anticoagulation treatment, for example during major surgery, with subsequent filter removal when the patient becomes eligible for anticoagulation treatment1. However, currently many filters are forgotten and left in situ permanently2. It is highlighted that, at the time of insertion, there should be a clear management plan, including the indication for insertion, the intended length of time that the filter is likely to be necessary and the intended point at which the filter should be removed. Use of a registry may improve retrieval rates3. The guidance suggests that IVC filters should be considered only after exploring alternative treatments, such as increasing the target international normalized ratio to 3–4 for long-term high-intensity oral anticoagulant therapy or switching treatment to low molecular weight heparin (LMWH). Other authors have highlighted their increasing use of IVC filters in trauma and bariatric patients, although there is a lack of level I evidence in this area and trials are needed urgently4. Decisions about IVC filters need to be made individually, considering the balance between the risks of bleeding and VTE. A further key recommendation in CG144 is that catheter-directed thrombolytic therapy should be considered for patients with acute symptomatic iliofemoral DVT who have symptoms for fewer than 14 days, good functional status, life expectancy of at least 1 year and a low risk of bleeding. This differs from the recommendation of the 2012 American College of Chest Physicians guideline, which recommends anticoagulants alone over thrombolysis5. The reason for this recommendation from NICE is that early removal of deep vein thrombus has been shown to reduce the rate of subsequent PTS, which develops as a result of either residual venous obstruction or valvular reflux; early clot removal may allow normal valvular function to be retained6. When longer term outcomes are considered, thrombolysis is likely to be cost-effective7. The implications are that many more vascular units need to develop the facilities to offer venous thrombolysis, usually with joint input from vascular surgery and interventional radiology. In practice, relatively few catheter-directed thrombolysis interventions are currently undertaken in the UK, and changes to facilities or local referral arrangements may be required to enable this to happen in line with other aspects of vascular reorganization8. The guideline also recognizes that the evidence available at present, although supportive, has important methodological limitations. The follow-up in most controlled trials was only 6 months. It is important that future randomized studies have at least a 2-year follow-up. It is suggested that the primary outcome measures for future studies should be mortality, major bleeding, VTE recurrence at 3 months, incidence and severity of PTS at 2 years, and quality of life. Finally, the link between cancer and VTE is well known and patients with cancer have a 20 per cent lifetime risk of VTE, which is associated with poor prognosis9,10. Of more than 56 000 VTEs in 2010–2011 in the UK (Hospital Episode Statistics data), 4150 patients had an underlying cancer11. Most importantly, studies have shown that 10–12 per cent of patients who present with an unprovoked VTE are diagnosed with an occult cancer within a few years; approximately 40–60 per cent are at an advanced stage by the time of diagnosis9,12. Despite this, most international guidelines do not currently recommend investigation for cancer in patients presenting with VTE. CG144, however, recommends that all patients diagnosed with an unprovoked DVT or pulmonary embolism should have a physical examination (guided by the patient's full history) and a chest X-ray, basic blood tests and urinalysis1. Further investigations for cancer (abdominopelvic computed tomography, and mammography for women) should be considered in all patients aged over 40 years with a first unprovoked VTE who have no signs or symptoms of cancer after initial investigation. Patients with cancer who develop VTE should be offered LMWH in preference to warfarin, for at least 6 months, and then reassessed. This is based on evidence that there is an important reduction in recurrent VTE with this strategy. Surgeons need to be more proactive in the changing management of VTE. They should play an integral part in the delivery of these key NICE recommendations, which should improve the overall patient experience and outcome. Surgeons also need to drive forward much needed further research in this area. Disclosure The authors declare no conflict of interest. References 1 National Institute for Health and Clinical Excellence (NICE) . Venous Thromboembolic Diseases: the Management of Venous Thromboembolic Diseases and the Role of Thrombophilia Testing (CG144) . NICE : London , 2012 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 2 Uberoi R , Tapping CR, Chalmers N, Allgar V British Society of Interventional Radiology (BSIR) Inferior Vena Cava (IVC) Filter Registry . Cardiovasc Intervent Radiol 2013 ; [Epub ahead of print]. 3 Kalina M , Bartley M, Cipolle M, Tinkoff G, Stevenson S, Fulda G. Improved removal rates for retrievable inferior vena cava filters with the use of a ‘filter registry’ . Am Surg 2012 ; 78 : 94 – 97 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Kidane B , Madani AM, Vogt K, Girotti M, Malthaner RA, Parry NG. The use of prophylactic inferior vena cava filters in trauma patients: a systematic review . Injury 2012 ; 43 : 542 – 547 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Guyatt GH , Akl EA, Crowther M, Gutterman DD, Schuunemann HJ. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines . Chest 2012 ; 141 ( Suppl ): 7S – 47S . Google Scholar Crossref Search ADS PubMed WorldCat 6 Meissner MH , Gloviczki P, Comerota AJ, Dalsing MC, Eklof BG, Gillespie DL et al. Society for Vascular Surgery; American Venous Forum. Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum . J Vasc Surg 2012 ; 55 : 1449 – 1462 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Enden T , Resch S, White C, Wik HS, Klow NE, Sandset PM Cost-effectiveness of additional catheter-directed thrombolysis for deep vein thrombosis . J Thromb Haemost 2013 ; [Epub ahead of print]. Google Scholar OpenURL Placeholder Text WorldCat 8 Saunders JH , Arya PH, Abisi S, Yong YP, MacSweeney S, Braithwaite B et al. Catheter-directed thrombolysis for iliofemoral deep vein thrombosis . Br J Surg 2013 ; 100 : 1025 – 1029 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Sorensen HT , Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism . N Engl J Med 1998 ; 338 : 1169 – 1173 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Sorensen HT , Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism . N Engl J Med 2000 ; 343 : 1846 – 1850 . Google Scholar Crossref Search ADS PubMed WorldCat 11 National Institute for Health and Clinical Excellence (NICE) . Venous thromboembolic diseases and the role of thrombophilia testing . Costing Report. http://nice.org.uk/nicemedia/live/13767/59730.pdf. [accessed 22 May 2013]. 12 Baron JA , Gridley G, Weiderpass E, Nyren O, Linet M. Venous thromboembolism and cancer . Lancet 1998 ; 351 : 1077 – 1080 . Google Scholar Crossref Search ADS PubMed WorldCat © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd

O'Callaghan, J M; Morgan, R D; Knight, S R; Morris, P J

doi: 10.1002/bjs.9169pmid: 23754643

Abstract Background Adequate preservation of renal allografts for transplantation is important for maintaining and improving transplant outcomes. There are two prevalent methods: hypothermic machine perfusion and static cold storage. The preferred method of storage, however, remains controversial. The objective was to review systematically the evidence comparing outcomes from these two modalities. Methods A literature search was performed using MEDLINE, Embase, the Cochrane Library, the Transplant Library and the International Clinical Trials Registry Platform. The final date for searches was 30 November 2012. Studies were assessed for methodological quality. Summary effects were calculated as relative risk (RR) with 95 per cent confidence interval (c.i.). Randomized clinical trials (RCTs) and non-RCTs were included, but evaluated separately. Results from RCTs alone were used for meta-analysis. Results Eighteen studies met the inclusion criteria, including seven RCTs (1475 kidneys) and 11 non-RCTs (728 kidneys). The overall risk of delayed graft function was lower with hypothermic machine perfusion than static cold storage (RR 0·81, 95 per cent c.i. 0·71 to 0·92; P = 0·002). There was no difference in the rate of primary non-function (RR 1·15, 0·46 to 2·90; P = 0·767). There was a faster initial fall in the level of serum creatinine with hypothermic machine perfusion in two RCTs, but not in another. There was no relationship between rates of acute rejection or patient survival and the method of preservation. Conclusion Data from the included studies suggest that hypothermic machine perfusion reduces delayed graft function compared with static cold storage. There was no difference in primary non-function, acute rejection, long-term renal function or patient survival. A difference in renal graft survival is uncertain. Introduction The quality of preservation of renal allografts for transplantation is important for maintaining and improving transplant outcomes. There are two prevailing methods for the hypothermic storage of deceased-donor renal allografts, either by static cold storage on ice or by hypothermic machine perfusion. Static cold storage requires the flushout of blood via the renal artery in situ and/or on the back-Tablewith chilled preservation fluid. The kidney is then stored in a bag of preservation fluid on ice. Hypothermic machine perfusion involves cannulation of the renal artery after flushout, so that cold preservation fluid can be administered in a pulsatile fashion or continuously within a pump system (Fig. 1). Fig. 1 Open in new tabDownload slide Schematic of a hypothermic machine perfusion device. The kidney rests in a bath of preservation solution surrounded by an ice box. The solution is withdrawn from the reservoir and pumped through the renal artery. Temperature, pressure and flow dynamics can be monitored Hypothermic machine perfusion was the preferred method when renal transplant programmes were first developed, particularly for longer periods of preservation and the preservation of kidneys considered to have worse outcomes1. Subsequently, static cold storage became more popular as novel preservation fluids were developed, and equivalent outcomes to those of hypothermic machine perfusion were demonstrated, at greatly reduced immediate costs and with easier management of the stored kidneys2. The preferred method of storage remains controversial in scientific terms owing to differing results of recent randomized clinical trials (RCTs) and the need to establish cost-effectiveness. Two previous systematic reviews have attempted to address this issue. One of these included four studies and was unable to provide a clear recommendation for either modality3. An earlier systematic review, conducted before the publication of two recent good-quality RCTs, concluded that hypothermic machine perfusion can reduce delayed graft function by 20 per cent, but does not improve graft survival4. The increasing use of donor after circulatory death (DCD) organs and expanded criteria donors5 has further increased interest in the preservation and resuscitation of organs6. The aim of this review was to appraise systematically the available evidence comparing hypothermic machine perfusion with static cold storage, and to compare outcomes for these two modalities. Methods This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement7. The review protocol was registered prospectively with the National Institute for Health Research (PROSPERO) system on 18 April 2011 and can be found online (registration number: CRD42011001080)8. Literature search A systematic literature search was performed using Ovid MEDLINE (from 1948), Embase (from 1980), the Cochrane Library, the Transplant Library of RCTs from the Centre for Evidence in Transplantation, and the International Clinical Trials Registry Platform. The final date for literature searches was 30 November 2012. Searches were conducted using medical subject heading (MeSH) and Emtree keywords ‘kidney transplantation, organ preservation, perfusion’ combined with free-text terms for renal transplantation and machine perfusion (Appendix S1, supporting information). No language limits were applied. Inclusion criteria Inclusion criteria specified any prospective, comparative study of static cold storage versus hypothermic machine perfusion of deceased-donor kidneys, from both adult and paediatric donors. First and subsequent transplants were included. Retrospective, multiple organ, animal, non-comparative and/or live donor studies were excluded. Abstracts for inclusion were reviewed by two authors independently and differences agreed by discussion with a third author. Outcomes The primary outcome was the rate of delayed graft function. Where studies reported delayed graft function in more than one way (for example requirement for dialysis or no reduction in serum creatinine level), the method relating to a requirement for dialysis was used for meta-analysis. There is evidence that functional definitions of delayed graft function may be more reliable and objective9,10. However, the definition used was that most commonly employed in RCTs and observational studies. Secondary outcomes were graft survival, primary non-function of the renal graft, renal graft function, acute renal graft rejection and patient survival. Data extraction Demographic, quality and outcome data were extracted independently by two authors. Data were taken from all papers describing the studies. In the case of discrepancies between papers relating to the same study, the most recent full report was used. Any differences in data extraction were settled by discussion and consultation with the senior authors. Quality assessment All studies were assessed for general quality measures including sample size calculation, description of statistical tests and similarity between group demographics. In addition, RCTs were assessed using the Jadad score11, the description of intention-to-treat analysis, allocation concealment and risk of bias using the Cochrane Collaboration risk of bias tool12. The assessment of intention-to-treat analysis followed the approach outlined in the CONSORT statement13 and was centred on the four analysis strategies proposed by the Centre for Evidence in Transplantation14. All first authors were contacted with a standard letter detailing the present assessment and requesting a response. Letters were returned for four RCTs and three non-RCTs. Eleven groups did not reply, three of which had undertaken RCTs. Responses affected the present assessment in three instances where the method of randomization15, donor type16 and blinding methods17 were clarified. No changes were made to the assessment of the other four studies with returned information18–21. Data synthesis The statistical package R22 was used for statistical analysis in combination with the metafor package available for R23. Meta-analysis was conducted using data from RCTs alone. Heterogeneity was analysed using Cochran's Q test, with P < 0·100 indicating significant heterogeneity, and the I2 test, which describes the proportion of variation that is due to heterogeneity beyond chance. In the absence of heterogeneity, studies were combined using a fixed-effects meta-analysis24. If there was heterogeneity, a cause was sought; if none could be established, the results were combined using a random-effects meta-analysis25. Mixed-effects meta-analysis was used to assess for interaction between the study effect and the moderator variables: publication year and cold ischaemia time. Binary outcomes were analysed using the Pearson χ2 test, or Fisher's exact test for samples of fewer than ten. The test of interaction methods of Altman and Bland were used to compare estimates from different subgroups26. P < 0·050 was considered statistically significant. Results Initial literature searches identified 2619 non-duplicated references across all databases. Eighteen studies (7 RCTs and 11 non-RCTs) described in 35 publications met the full inclusion criteria15–21,27–54 (Fig. 2). One study was described in just one abstract, but the outcomes were not presented in a usable fashion and the authors declined to provide more information, so these results are not discussed in this article55. Two ongoing RCTs were identified in trial registries56,57. The principal investigators were contacted and confirmed that these trials are still recruiting in the UK (N. Jamieson and C. Watson, personal communication). Fig. 2 Open in new tabDownload slide PRISMA flow chart showing search strategy with inclusions and exclusions. ICTRP, International Clinical Trials Registry Platform; Transplant Library, library of randomized clinical trials (RCTs) from the Centre for Evidence in Transplantation; HMP, hypothermic machine perfusion; SCS, static cold storage A total of 2203 kidneys were included, 1475 of which were from RCTs and were used in the meta-analysis (Table 1). Recent European studies have been reported in papers with overlapping populations of patients17,34–41. Results from these studies were requested from the Scientific Steering Committee so that meta-analysis could be performed without duplicating patients. The results from these studies in combination are referred to in this manuscript as Moers et al. (2008). Table 1 Details of included randomized and non-randomized studies Study* . Reference . Year* . No. of kidneys . Machine type (perfusate) . SCS fluid . Donor type . Country . RCTs  Halloran et al. 18, 27 1985 181 Waters/Gambro (CPP) Collins DBD/DCD Canada  Mozes et al. 28 1985 187 Waters MOX100 (silica gel fraction) EC DBD USA  Heil et al. 16 1987 54 Waters MOX100 (silica gel fraction) EC DBD USA  Danielewicz et al. 29–32 1996 74 Waters MOX100 (MPS) UW DBD/DCD Poland  Van der Vliet et al. 33 2001 71 Gambro (MPS) UW DCD Eurotransplant  Moers et al. 17, 34–41 2008 818 ORS LifePort® (MPS) UW or HTK DBD/DCD Eurotransplant  Watson et al. 20 2010 90 ORS LifePort® (MPS) UW DCD UK Non-RCTs  Sterling et al. 42 1971 10 Lifemed Belzer LI400 (CPP) Unclear DCD USA  Sheil et al. 19 1975 171 Waters MOX100 (human albumin) Collins or Perfadex® DCD Australia  Marshall et al. 43–45 1977 181 Gambro (CPP) HOC DCD Australia  Toledo-Pereyra et al. 46 1983 20 Waters MOX100 (NR) TPII DBD/DCD USA  Alijani et al. 47 1985 58 Waters MOX100 (PPF) EC DBD/DCD USA  Mendez et al. 48 1987 52 Waters MOX100 (Belzer Plasmanate®) Collins DBD/DCD USA  Tamaki et al. 49 1989 8 Nikkiso LPS-II (CPP) EC DCD Japan  Merion et al. 50 1990 102 Waters MOX100 (silica gel fraction) EC DBD/DCD USA  Matsuno et al. 51–53 1993 46 Nikkiso LPS-II (CPP) UW or EC DCD Japan  Veller et al. 15 1994 36 Waters 1000 (CPP) UW DBD South Africa  Abboud et al. 21, 54 2011 44 ORS LifePort® (MPS) Unclear ECD France Study* . Reference . Year* . No. of kidneys . Machine type (perfusate) . SCS fluid . Donor type . Country . RCTs  Halloran et al. 18, 27 1985 181 Waters/Gambro (CPP) Collins DBD/DCD Canada  Mozes et al. 28 1985 187 Waters MOX100 (silica gel fraction) EC DBD USA  Heil et al. 16 1987 54 Waters MOX100 (silica gel fraction) EC DBD USA  Danielewicz et al. 29–32 1996 74 Waters MOX100 (MPS) UW DBD/DCD Poland  Van der Vliet et al. 33 2001 71 Gambro (MPS) UW DCD Eurotransplant  Moers et al. 17, 34–41 2008 818 ORS LifePort® (MPS) UW or HTK DBD/DCD Eurotransplant  Watson et al. 20 2010 90 ORS LifePort® (MPS) UW DCD UK Non-RCTs  Sterling et al. 42 1971 10 Lifemed Belzer LI400 (CPP) Unclear DCD USA  Sheil et al. 19 1975 171 Waters MOX100 (human albumin) Collins or Perfadex® DCD Australia  Marshall et al. 43–45 1977 181 Gambro (CPP) HOC DCD Australia  Toledo-Pereyra et al. 46 1983 20 Waters MOX100 (NR) TPII DBD/DCD USA  Alijani et al. 47 1985 58 Waters MOX100 (PPF) EC DBD/DCD USA  Mendez et al. 48 1987 52 Waters MOX100 (Belzer Plasmanate®) Collins DBD/DCD USA  Tamaki et al. 49 1989 8 Nikkiso LPS-II (CPP) EC DCD Japan  Merion et al. 50 1990 102 Waters MOX100 (silica gel fraction) EC DBD/DCD USA  Matsuno et al. 51–53 1993 46 Nikkiso LPS-II (CPP) UW or EC DCD Japan  Veller et al. 15 1994 36 Waters 1000 (CPP) UW DBD South Africa  Abboud et al. 21, 54 2011 44 ORS LifePort® (MPS) Unclear ECD France * Author and year of the earliest reference. SCS, static cold storage; RCT, randomized clinical trial; CPP, cryoprecipitated plasma; DBD, donor after brain death; DCD, donor after circulatory death; EC, Euro-Collins solution; UW, University of Wisconsin solution; MPS, Machine Perfusion Solution–Belzer UW®; HTK, histidine–tryptophan–ketoglutarate; HOC, hyperosmolar citrate; TPII, hyperosmolar colloid; NR, not recorded; PPF, plasma protein fraction; ECD, expanded criteria donor. MOX100 (Waters Medical Systems, Rochester Minnesota, USA); Gambro (Gambro, Peterborough, UK); Machine Perfusion Solution–Belzer UW® (Bridge to Life, Columbia, South Carolina, USA); Organ Recovery Systems (ORS; Itasca, Illinois, USA); Perfadex® (XVIVO Perfusion, Göteborg, Sweden); Plasmanate® (Grifols International, Barcelona, Spain); Nikkiso LPS-II (Nikksio, Tokyo, Japan). Open in new tab Table 1 Details of included randomized and non-randomized studies Study* . Reference . Year* . No. of kidneys . Machine type (perfusate) . SCS fluid . Donor type . Country . RCTs  Halloran et al. 18, 27 1985 181 Waters/Gambro (CPP) Collins DBD/DCD Canada  Mozes et al. 28 1985 187 Waters MOX100 (silica gel fraction) EC DBD USA  Heil et al. 16 1987 54 Waters MOX100 (silica gel fraction) EC DBD USA  Danielewicz et al. 29–32 1996 74 Waters MOX100 (MPS) UW DBD/DCD Poland  Van der Vliet et al. 33 2001 71 Gambro (MPS) UW DCD Eurotransplant  Moers et al. 17, 34–41 2008 818 ORS LifePort® (MPS) UW or HTK DBD/DCD Eurotransplant  Watson et al. 20 2010 90 ORS LifePort® (MPS) UW DCD UK Non-RCTs  Sterling et al. 42 1971 10 Lifemed Belzer LI400 (CPP) Unclear DCD USA  Sheil et al. 19 1975 171 Waters MOX100 (human albumin) Collins or Perfadex® DCD Australia  Marshall et al. 43–45 1977 181 Gambro (CPP) HOC DCD Australia  Toledo-Pereyra et al. 46 1983 20 Waters MOX100 (NR) TPII DBD/DCD USA  Alijani et al. 47 1985 58 Waters MOX100 (PPF) EC DBD/DCD USA  Mendez et al. 48 1987 52 Waters MOX100 (Belzer Plasmanate®) Collins DBD/DCD USA  Tamaki et al. 49 1989 8 Nikkiso LPS-II (CPP) EC DCD Japan  Merion et al. 50 1990 102 Waters MOX100 (silica gel fraction) EC DBD/DCD USA  Matsuno et al. 51–53 1993 46 Nikkiso LPS-II (CPP) UW or EC DCD Japan  Veller et al. 15 1994 36 Waters 1000 (CPP) UW DBD South Africa  Abboud et al. 21, 54 2011 44 ORS LifePort® (MPS) Unclear ECD France Study* . Reference . Year* . No. of kidneys . Machine type (perfusate) . SCS fluid . Donor type . Country . RCTs  Halloran et al. 18, 27 1985 181 Waters/Gambro (CPP) Collins DBD/DCD Canada  Mozes et al. 28 1985 187 Waters MOX100 (silica gel fraction) EC DBD USA  Heil et al. 16 1987 54 Waters MOX100 (silica gel fraction) EC DBD USA  Danielewicz et al. 29–32 1996 74 Waters MOX100 (MPS) UW DBD/DCD Poland  Van der Vliet et al. 33 2001 71 Gambro (MPS) UW DCD Eurotransplant  Moers et al. 17, 34–41 2008 818 ORS LifePort® (MPS) UW or HTK DBD/DCD Eurotransplant  Watson et al. 20 2010 90 ORS LifePort® (MPS) UW DCD UK Non-RCTs  Sterling et al. 42 1971 10 Lifemed Belzer LI400 (CPP) Unclear DCD USA  Sheil et al. 19 1975 171 Waters MOX100 (human albumin) Collins or Perfadex® DCD Australia  Marshall et al. 43–45 1977 181 Gambro (CPP) HOC DCD Australia  Toledo-Pereyra et al. 46 1983 20 Waters MOX100 (NR) TPII DBD/DCD USA  Alijani et al. 47 1985 58 Waters MOX100 (PPF) EC DBD/DCD USA  Mendez et al. 48 1987 52 Waters MOX100 (Belzer Plasmanate®) Collins DBD/DCD USA  Tamaki et al. 49 1989 8 Nikkiso LPS-II (CPP) EC DCD Japan  Merion et al. 50 1990 102 Waters MOX100 (silica gel fraction) EC DBD/DCD USA  Matsuno et al. 51–53 1993 46 Nikkiso LPS-II (CPP) UW or EC DCD Japan  Veller et al. 15 1994 36 Waters 1000 (CPP) UW DBD South Africa  Abboud et al. 21, 54 2011 44 ORS LifePort® (MPS) Unclear ECD France * Author and year of the earliest reference. SCS, static cold storage; RCT, randomized clinical trial; CPP, cryoprecipitated plasma; DBD, donor after brain death; DCD, donor after circulatory death; EC, Euro-Collins solution; UW, University of Wisconsin solution; MPS, Machine Perfusion Solution–Belzer UW®; HTK, histidine–tryptophan–ketoglutarate; HOC, hyperosmolar citrate; TPII, hyperosmolar colloid; NR, not recorded; PPF, plasma protein fraction; ECD, expanded criteria donor. MOX100 (Waters Medical Systems, Rochester Minnesota, USA); Gambro (Gambro, Peterborough, UK); Machine Perfusion Solution–Belzer UW® (Bridge to Life, Columbia, South Carolina, USA); Organ Recovery Systems (ORS; Itasca, Illinois, USA); Perfadex® (XVIVO Perfusion, Göteborg, Sweden); Plasmanate® (Grifols International, Barcelona, Spain); Nikkiso LPS-II (Nikksio, Tokyo, Japan). Open in new tab Three of the seven included RCTs described an adequate method of allocation concealment (Table S1, supporting information)17–18,20. One RCT used a strict intention-to-treat analysis20, one used a modified intention-to-treat analysis33, three RCTs used a per-protocol analysis17,28–29 and in two RCTs the analysis strategy was unclear16,18. One RCT reported a prospective sample size calculation17. One RCT reported using sequential analysis to establish the study endpoint20. Twelve studies used, and described, appropriate statistical tests15–18,20–21,28–29,44,48,50–51. Three studies used, but did not describe, statistical tests19,33,47, and three studies did not appear to use any statistical tests42,46,49. Thirteen studies provided demographic information that showed the treatment groups to be similar15,17–18,20–21,28–29,33,44,46–48,50, three studies had demographic differences between the study arms19,42,49 and in two studies it was unclear16,51. Results from randomized trials Delayed graft function Reported rates of delayed graft function varied between the included RCTs (range 28.9–57 per cent) (Table S2, supporting information). Delayed graft function was defined as a requirement for any dialysis in the first week in five trials17–18,20,28–29, as a requirement for dialysis in one16, and was not defined in the remaining RCT33. Meta-analysis showed that the relative risk (RR) of delayed graft function was lower with hypothermic machine perfusion than with static cold storage (fixed-effects analysis: RR 0·81, 95 per cent confidence interval 0·71 to 0·92; P = 0·002) (Fig. 3). There was no significant heterogeneity (I2 = 0 per cent; Cochran's Q = 6·62, P = 0·357). Fig. 3 Open in new tabDownload slide Forest plot showing proportions of kidneys with delayed graft function after hypothermic machine perfusion compared with static cold storage in randomized clinical trials. Squares represent individual study effects, with the size of the box relating to the weight of the study in the meta-analysis. The diamond represents the summary effect from meta-analysis. The summary relative risk was calculated by fixed-effects meta-analysis; a value below 1 favours hypothermic machine perfusion. Horizontal bars and values in parentheses represent 95 per cent confidence intervals. Tests for heterogeneity: I2 = 0 per cent; Cochran's Q = 6·62, P = 0·357 A sensitivity analysis was performed using good-quality RCTs (Jadad score at least 3). Meta-analysis of this subgroup was supportive of the overall analysis (fixed- effects analysis: RR 0·83, 0·70 to 0·98; P = 0·030). There was no significant heterogeneity in this subgroup (I2 = 0 per cent; Cochran's Q = 2·12, P = 0·346). Funnel plot did not show any asymmetry and suggested no missing studies, although the small number of studies included limits this method of assessment (Fig. S1, supporting information). RCTs were grouped by donor type to perform a subgroup analysis for DCD and donor after brain death (DBD) kidneys. One study provided results for each donor type and the appropriate numbers were included in each subgroup analysis17,39–40. Two small RCTs were excluded from the subgroup analysis as they did not report split results by donor type18,29. There was no significant difference in the rate of delayed graft function between hypothermic machine perfusion and static cold storage for DBD kidneys (fixed-effects analysis: RR 0·84, 0·69 to 1·03; P = 0·090) or for DCD kidneys (random-effects analysis: RR 0·80, 0·62 to 1·04, P = 0·094). Heterogeneity was low in both analyses (I2 = 0 per cent, Cochran's Q = 2·20, P = 0·333 and I2 = 40 per cent, Cochran's Q = 3·56, P = 0·169 respectively). When these subgroup summary effects were tested for interaction, there was no evidence to support a different treatment effect in DBD and DCD kidneys (P = 0·762). Mixed-effects meta-analysis showed no significant interaction between the RR of delayed graft function with hypothermic machine perfusion and the year of publication (P = 0·674) or mean cold ischaemia time in the study (P = 0·321). Renal graft survival Graft survival rates varied between included studies (Table S3, supporting information)16–17,20,28,33. Hazard ratios were reported by one study; Moers and colleagues17 found that death-censored graft survival was improved with hypothermic machine perfusion compared with static cold storage (hazard ratio 0·52; P = 0·03). The effect was seen particularly in the subgroup of expanded criteria donor kidneys (92·3 versus 80·2 per cent; hazard ratio 0·35; P = 0·02)41. Improved 1-year graft survival was also shown for DBD but not for DCD kidneys in the same RCT40. Three-year graft survival in this study showed a persisting benefit of hypothermic machine perfusion (91 versus 87 per cent; P = 0·04)35. Three trials found no difference in 12-month graft survival20,28,33. Two of these studies showed the same direction of effect, favouring hypothermic machine perfusion, and one did not; however, each study individually was underpowered. Heil and co-workers16 found a difference in 12-month graft survival (89 versus 74 per cent for hypothermic machine perfusion versus static cold storage; P < 0·05), but with just 27 kidneys per group this statistical analysis cannot be reproduced. Primary non-function of renal graft Reported rates of primary non-function ranged from less than 1 to 14·9 per cent (Table S4, supporting information)17–18,20,28–29. Three RCTs defined primary non-function as lack of allograft function from the time of transplantation17–18,29. One trial defined primary non-function as ‘failure to provide 1-month dialysis free survival, excluding losses attributable to rejection or vascular thrombosis’20, and it was not defined in the other study28. The overall rate of primary non-function was no different between hypothermic machine perfusion and static cold storage groups (random-effects analysis: RR 1·15, 0·46 to 2·90; P = 0·767) (Fig. 4). Heterogeneity was moderate (I2 = 60·5 per cent; Cochran's Q = 8·55, P = 0·073) and may have been due to the low incidence of this outcome and the associated variability in direction of effect. The recent European studies demonstrated a reduction in primary non-function with hypothermic machine perfusion17,39–41. This effect comes largely from the inclusion of results from expanded criteria donor kidneys and the Eurotransplant Senior Programme (kidneys from donors aged at least 65 years are preferentially matched with recipients aged at least 65 years), in which the primary non-function rate was significantly reduced by hypothermic machine perfusion (3 versus 12 per cent, P = 0·04; 3·5 versus 12·9 per cent, P = 0·02)39,41. Fig. 4 Open in new tabDownload slide Forest plot showing proportions of kidneys with primary non-function after hypothermic machine perfusion compared with static cold storage in randomized clinical trials. Squares represent individual study effects, with the size of the box relating to the weight of the study in the meta-analysis. The diamond represents the summary effect from meta-analysis. The summary relative risk was calculated by random-effects meta-analysis; a value below 1 favours hypothermic machine perfusion. Horizontal bars and values in parentheses represent 95 per cent confidence intervals. Tests for heterogeneity: I2 = 60·5 per cent, Cochran's Q = 8·55, P = 0·073 Renal graft function Renal function was reported at variable time points after surgery, so it was not possible to perform a meta-analysis. Two RCTs found a significantly quicker fall in serum creatinine level with hypothermic machine perfusion than static cold storage17,18, but one did not20. At 14 days there was no significant difference in estimated glomerular filtration rate20 or serum creatinine clearance17. One trial reported a significantly lower serum creatinine concentration for kidneys stored by hypothermic machine perfusion compared with static cold storage at both 12 and 24 months29. Three RCTs found no significant difference in renal function at follow-up times up to 12 months17,20,33. Acute renal graft rejection Three RCTs provided rates of biopsy-proven acute rejection17,20,29 and one reported numbers of grafts lost owing to acute rejection18. Immunosuppressive regimens are reported in Table S5 (supporting information). Given the small number of studies reporting this outcome, as well as differences in length of follow-up and immune suppression regimens, meta-analysis was not appropriate. Danielewicz and colleagues29 (median follow-up 22 months) found an increased rejection rate with static cold storage compared with hypothermic machine perfusion (50 versus 34 per cent; P < 0·01). Both Moers and colleagues17 (14 days' follow-up) and Watson et al.20 (12 months' follow-up) found no significant difference in acute rejection rates (14 versus 13 per cent, P = 0·82; 22 versus 9 per cent, P = 0·1). Halloran and Aprile27 found no significant difference in graft loss due to acute rejection (59 versus 71 per cent; P = 0·34)27. Patient survival Three RCTs that reported patient survival at 1 year after transplantation (range 89–97 per cent) found no relationship between the method of preservation and patient survival17,20,28. Two other trials determined patient survival at a median follow-up of 17 months18 and 22 months29, and reported no relationship between preservation method and patient survival. Heterogeneity in the length of follow-up and the number of patients lost to follow-up in some studies prevented meta-analysis. Results from non-randomized trials Delayed graft function was defined less consistently in the non-randomized trials than in the RCTs, and there was also a wider range of rates (20–80 per cent) (Table S6, supporting information). Delayed graft function was defined as a requirement for dialysis in the first week by five studies15,21,44,47,49, as a requirement for dialysis in the first 2 weeks by two studies46,51, and as any requirement for dialysis by one study50. One study defined delayed graft function as a lack of urine output more than 1 litre above normal48 and in two studies it was not defined at all19,42. Two studies found a significant reduction in delayed graft function following hypothermic machine perfusion47,48; the remaining nine did not15,19,21,42,44,46,49–51. Graft survival at 12 months was reported by six studies, and overall it was lower than in the RCTs, at 63 per cent, assuming full follow-up. One study found a significantly better 12-month survival with hypothermic machine perfusion19, but the remaining five studies did not15,21,44,46,48. One study declared that graft survival was equivalent with the two preservation methods at 12 months, but did not provide numbers47. Graft survival was no different between the preservation modalities at 1 month19,50–51 and 3 months21,44 after transplantation. Three studies reported rates of primary non-function (range 2–3·9 per cent) (Table S7, supporting information), with no difference between the two preservation modalities21,50–51. One study provided renal function data on the first 14 days after surgery, and reported a significantly quicker fall in serum creatinine concentration with hypothermic machine perfusion than with static cold storage46. One study provided estimated glomerular filtration rates up to 12 months, showing no difference between the two methods of preservation21. In three studies trends in renal function after transplantation were described as the same, or similar, for both preservation modalities, but no values were provided42,50–51. One study found an increased rate of graft loss owing to acute rejection with static cold storage compared with hypothermic machine perfusion (30 versus 15 per cent; P = 0·03)19, and another reported no significant difference (4 versus 10 per cent; P = 0·44)50. Three studies that reported patient survival found no difference between hypothermic machine perfusion and static cold storage 9 months21 and 12 months44,47 after operation. Discussion This systematic review has examined the evidence for the use of hypothermic machine perfusion in comparison with static cold storage for the preservation of deceased donor kidneys. The RCTs showed a statistically significant reduction in delayed graft function following hypothermic machine perfusion; however, this reduction may be modest. Delayed graft function is an important outcome and may be a surrogate for graft survival owing to its relationship with both early and late graft loss58. The present findings suggest that hypothermic machine perfusion is likely to reduce delayed graft function of kidneys from all donor types: DBD, DCD and expanded criteria donors. The RR reduction for both DBD and DCD subgroups is the same as in the overall meta-analysis, with a trend towards significance in both groups. The fact that these subanalyses are non-significant might be explained by a lack of statistical power, given the much smaller numbers in each. There does not appear to be an effect on short- or longer-term renal function, but this may be confounded by the large number of patients with delayed graft function in the static cold storage group in these studies. The most recent publication from the European multicentre trial has shown an improvement in graft survival related to the reduction in delayed graft function35. The other secondary outcomes (primary non-function, acute rejection and patient survival) were not affected by the preservation method in the present analysis. It is possible that the included studies were not large enough to discern a relationship between the mode of preservation and these outcomes. The study from Watson and colleagues20 stands out by demonstrating no benefit of hypothermic machine perfusion in DCD. It is possible that this result may be related to the short duration of hypothermic machine perfusion in some patients before transplantation in the study group. This effect has been demonstrated in animal studies59. An important consideration in developing new interventions is cost-effectiveness. The most recent cost analysis suggests that investment in hypothermic machine perfusion is cost-effective60. However, this analysis was based on the results of the European machine perfusion trial alone and Dutch costs, which may not be relevant in other countries or healthcare systems60. Registry data from the Collaborative Transplant Study (91 674 transplants) show that hypothermic machine perfusion is associated with reduced graft survival compared with static cold storage6. In this registry analysis, hypothermic machine perfusion was used more commonly for kidneys from older, diabetic, African–American donors, or donors with higher terminal creatinine levels and longer cold ischaemia times61. In contrast, an analysis of the Scientific Registry of Transplant Recipients (98 736 transplants) showed reduced rates of delayed graft function following hypothermic machine perfusion, despite the apparently greater use of machine perfusion for kidneys with risk factors for delayed function61. A more recent analysis of 4923 DCD kidneys in the same database has also shown a lower risk of delayed graft function with hypothermic machine perfusion compared with static cold storage (adjusted odds ratio 0·70)62. The present study has several important limitations. The number of studies included is relatively small, and there is unlikely to be adequate power to identify differences in secondary outcomes such as acute rejection rates and primary non-function. Furthermore, the short follow-up in the majority of studies means that the long-term risk of the modest increase in delayed graft function identified in the static cold storage group is unclear. The definition of delayed graft function varies between studies, although it was the same for five of the seven RCTs. Furthermore, the underlying effect being measured should be the same, and the same definition is used between arms in each individual study. The combination of these studies in meta-analysis is supported by the lack of the heterogeneity, and the consistency between the sensitivity analysis of best-quality studies and the overall analysis. The results seen here may have been confounded by the fact that the three earliest RCTs used Collins or Euro-Collins as the cold storage solution in the static cold storage arm. A recent systematic review has suggested that Euro-Collins is associated with a higher risk of delayed graft function than University of Wisconsin solution63. Therefore, any benefit of hypothermic machine perfusion noted in these earlier studies might have been mitigated if newer, more effective, cold storage solutions had been used. The preferred machine and machine perfusate has also changed over time. This suggests that the relative benefit of hypothermic machine perfusion has been maintained over the range of cold storage fluids available, and this is reinforced by the lack of heterogeneity. Although there have been small animal experiments using University of Wisconsin solution as a pump fluid64,65, Belzer machine perfusion solution (Machine Perfusion Solution–Belzer UW®; Bridge to Life, Columbia, South Carolina, USA) has not been tested as a preservation fluid for static cold storage. If this solution is as effective a preservative in a static system as it is within a pump system, the apparent effect of the pump may be negated. It should be noted that no included study used the same fluid for both hypothermic machine perfusion and static cold storage. These studies were also conducted over a long interval (25 years for RCTs) but, despite this, no interaction between the year of the study and the relative reduction in risk of delayed graft function was found; again, no heterogeneity between studies was identified for this outcome. Acknowledgements The authors are grateful to J. Southard for information regarding the early development of University of Wisconsin and Belzer machine perfusion solutions; and to J. Smits and the Scientific Steering Committee of the Eurotransplant study for data relating to the study extensions. No funding was received for the conduct of the research. Disclosure: P.J.M. chairs a Data and Safety Monitoring Board for Bristol Myers Squibb, and has received lecture fees in the past from Novartis, Roche, Astellas and Genzyme. S.R.K. has received a travel grant from Roche. The authors declare no other conflict of interest. References 1 Belzer FO , Southard JH. The future of kidney preservation . Transplantation 1980 ; 30 : 161 – 165 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Opelz G , Terasaki P. Advantage of cold storage over machine perfusion for preservation of cadaver kidneys . Transplantation 1982 ; 33 : 64 – 68 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Bond M , Pitt M, Akoh J, Moxham T, Hoyle M, Anderson R. 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Google Scholar Crossref Search ADS PubMed WorldCat 51 Matsuno N , Kozaki M, Sakurai E, Uchiyama M, Iwahori T, Kozaki K et al. Effect of combination in situ cooling and machine perfusion preservation on non-heart-beating donor kidney procurement . Transplant Proc 1993 ; 25 : 1516 – 1517 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 52 Matsuno N , Sakurai E, Tamaki I, Uchiyama M, Kozaki K, Kozaki M. The effect of machine perfusion preservation versus cold storage on the function of kidneys from non-heart-beating donors . Transplantation 1994 ; 57 : 293 – 294 . Google Scholar Crossref Search ADS PubMed WorldCat 53 Matsuno N , Sakurai E, Uchiyama M, Kozaki K, Tamaki I, Kozaki M. Use of in situ cooling and machine perfusion preservation for non-heart-beating donors . Transplant Proc 1993 ; 25 : 3095 – 3096 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 54 Abboud I , Antoine C, Serrato T, Lefaucheur C, Pilleboult E, Gaudez F et al. Pulsatile perfusion preservation for expanded-criteria donors kidneys: impact on delayed graft function rate . Transpl Int 2011 ; 24 ( Suppl 2 ): 281 . Google Scholar OpenURL Placeholder Text WorldCat 55 Amaduzzi A , Catena F, Montori G, Ravaioli M, Pinna A. Hypothermic machine perfusion (HMP) versus static cold storage (CS) in kidney allograft preservation. Prospective case–control trial . Transpl Int 2011 ; 24 ( Suppl 2 ): 151 . Google Scholar OpenURL Placeholder Text WorldCat 56 HBDPump . http://www.controlled-trials.com/ISRCTN35082773 [accessed 30 November 2012]. 57 CAD-MP . http://www.controlled-trials.com/ISRCTN50082383 [accessed 30 November 2012]. 58 Perico N , Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation . Lancet 2004 ; 364 : 1814 – 1827 . Google Scholar Crossref Search ADS PubMed WorldCat 59 Hosgood SA , Mohamed IH, Bagul A, Nicholson ML. Hypothermic machine perfusion after static cold storage does not improve the preservation condition in an experimental porcine kidney model . Br J Surg 2011 ; 98 : 943 – 950 . Google Scholar Crossref Search ADS PubMed WorldCat 60 Groen H , Moers C, Smits JM, Treckmann J, Monbaliu D, Rahmel A et al. Cost-effectiveness of hypothermic machine preservation versus static cold storage in renal transplantation . Am J Transpl 2012 ; 12 : 1824 – 1830 . Google Scholar Crossref Search ADS WorldCat 61 Schold JD , Kaplan B, Howard RJ, Reed AI, Foley DP, Meier-Kriesche HU. Are we frozen in time? Analysis of the utilization and efficacy of pulsatile perfusion in renal transplantation . Am J Transpl 2005 ; 5 : 1681 – 1688 . Google Scholar Crossref Search ADS WorldCat 62 Lodhi SA , Lamb KE, Uddin I, Meier-Kriesche HU. Pulsatile pump decreases risk of delayed graft function in kidneys donated after cardiac death . Am J Transpl 2012 ; 12 : 2774 – 2780 . Google Scholar Crossref Search ADS WorldCat 63 O'Callaghan JM , Knight SR, Morgan RD, Morris PJ. Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis . Am J Transpl 2012 ; 12 : 896 – 906 . Google Scholar Crossref Search ADS WorldCat 64 McAnulty JF , Vreugdenhil PK, Southard JH, Belzer FO. Use of UW cold storage solution for machine perfusion of kidneys . Transplant Proc 1990 ; 22 : 458 – 459 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 65 Lindell SL , Compagnon P, Mangino MJ, Southard JH. UW solution for hypothermic machine perfusion of warm ischemic kidneys . Transplantation 2005 ; 79 : 1358 – 1361 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Presented to the International Congress of the Transplantation Society, Berlin, Germany, July 2012; published in abstract form as Transplantation 2012; 94(Suppl): 277 © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd

Rollins, K E; Jackson, D; Coughlin, P A

doi: 10.1002/bjs.9127pmid: 23649310

Abstract Background Critical leg ischaemia (CLI) has been associated with high mortality rates. There is a lack of contemporary data on both short- and long-term mortality rates in patients diagnosed with CLI. Methods This was a systematic literature search for studies prospectively reporting mortality in patients diagnosed with CLI. Meta-analysis and meta-regression models were developed to determine overall mortality rates and specific patient-related factors that were associated with death. Results A total of 50 studies were included in the analysis The estimated probability of all-cause mortality in patients with CLI was 3·7 per cent at 30 days, 17·5 per cent at 1 year, 35·1 per cent at 3 years and 46·2 per cent at 5 years. Men had a statistically significant survival benefit at 30 days and 3 years. The presence of ischaemic heart disease, tissue loss and older age resulted in a higher probability of death at 3 years. Conclusion Early mortality rates in patients diagnosed with CLI have improved slightly compared with previous historical data, but long-term mortality rates are still high. Introduction Critical leg ischaemia (CLI) has a number of definitions that have evolved over time. The TransAtlantic Inter-Society Consensus (TASC) document on the management of peripheral arterial disease II (2007) defines CLI as the presence of chronic ischaemic rest pain, ulcers or gangrene attributable to objectively proven arterial occlusive disease1. Recent estimates suggest that up to 1000 new cases of CLI per million population are diagnosed every year in Europe and North America2. Risk factors for CLI are the same as for any atherosclerotic disease, but the increasing incidence of diabetes mellitus allied to an ageing population means that the incidence of CLI is likely to increase. The natural history of CLI is often quoted as follows: at presentation, vascular reconstruction will be attempted in 50–60 per cent of patients, with approximately 25 per cent having a primary amputation; after 1 year, 20–25 per cent of patients will have died, with only 25 per cent being alive without major amputation and free from symptoms of CLI3. These data are now somewhat historical and there is a lack of robust contemporary mortality data for patients with CLI. The aim of this study was to examine modern studies that report mortality rates in patients diagnosed with CLI and to combine the results using meta-analysis. Methods An electronic search was undertaken using the PubMed database from January 1991 to December 2011. The search used the term ‘critical limb ischaemia’, which was combined with the term ‘mortality’. Abstracts of the citations identified were then scrutinized by two of the authors to determine eligibility for inclusion. Further references were found by review of the bibliographies of selected articles. Studies were included if they were prospective, included only patients with CLI, and reported on at least 100 patients with a minimum of 1 year of follow-up for mortality. Patients undergoing all forms of treatment (reconstruction, amputation, medical (including gene therapy and invasive methods of delivering analgesia) or conservative) were included. The primary outcome of the meta-analysis was all-cause mortality, stratified by follow-up interval: 30 days, 6 months, 1, 2, 3 and 5 years. Data from each study were recorded for patient demographics, co-morbidity (ischaemic heart disease, diabetes, chronic renal failure and dialysis, chronic obstructive pulmonary disease) and treatment strategy (surgery, angioplasty, medical treatment, amputation, conservative treatment). Study-specific definitions were used to determine the presence of a co-morbidity. Where possible, rates of loss to follow-up were determined within each study. Statistical analysis Three types of analysis were employed; all used empirical log odds of death as the outcome, where halves were added to zero death counts at early time points to avoid infinite log odds. The primary analyses used outcomes at six time points (30 days, 6 months, 1, 2, 3 and 5 years) in separate univariable meta-analyses. The outcome data were pooled in univariable random-effects meta-analyses using the standard method of DerSimonian and Laird4 to provide pooled log odds of death and 95 per cent confidence intervals. The pooled log odds and their 95 per cent confidence bounds were then converted to probabilities. The I2 statistics from these meta-analyses were also reported5. A limitation of univariable meta-analyses is that they use only outcome data at the time point of interest and so do not allow outcome data from other time points to inform the corresponding analysis. A secondary multivariable random-effects meta-analysis was therefore done, using DerSimonian and Laird's method6. The within-study correlations between the log odds of death at different time points were calculated from a Taylor series expansion, assuming a multinomial distribution with three groups: patients who died by the first time point, patients who died after this but before the second time point, and patients who survived both time intervals. A difficulty, however, was that only one study provided outcome data at both 6 months and 5 years, which resulted in estimation problems when attempting to fit the six-dimensional meta-analysis. The dimension of the multivariable meta-analysis was therefore reduced to five, and outcome data at 5 years were not used. As in the univariable meta-analyses, the pooled log odds and their 95 per cent confidence bounds were converted to probabilities. Finally, univariable meta-regression was used to determine whether study level co-variables were associated with improved survival, using outcome data at 30 days, 1 and 3 years7. These time intervals were chosen because the studies provided sufficient outcome data. Meta-regressions were performed where at least ten studies provided both the required outcome data and risk factor of interest. Only one risk factor was included in each meta-regression and, as the outcomes were empirical log odds of death, the regression coefficient in the meta-regressions were log odds ratios, which were converted to odds ratios. The co-variables used in these meta-regressions were: average age and the proportion (from 0 to 1) of patients with a particular risk factor. Hence the odds ratio of the meta-regression for age compared studies with patients whose average age differed by 1 year; all other odds ratios compared binary outcomes. Odds ratios greater than 1 indicate that the corresponding risk factor was associated with a higher probability of death. All analyses were performed using Stata®, using the commands metan, mvmeta and metareg (StataCorp LP, College Station, Texas, USA). Results A total of 680 potentially relevant articles were identified (Fig. 1), of which 50 met the inclusion requirements for systematic review, containing a total of 28 517 patients (Table S1, supporting information)8–57. The average (mean or median) age ranged from 67 to 85·5 years, and 18 436 of the patients were men. Fig. 1 Open in new tabDownload slide PRISMA flow diagram showing search results for the study. CLI, critical leg ischaemia Of the 50 studies, 26 reported on open surgical revascularization, 33 on endovascular revascularization, ten on amputation (including one study on minor digital amputations), ten on medical treatment and seven on no treatment (Table S2, supporting information). Data were available with regard to loss to follow-up in 31 of the 50 papers; 19 papers reported no loss, whereas 12 reported an overall loss of 3·2 per cent (139 of 4341 patients) at a median follow-up of 3 years. From the univariable meta-analyses, the estimated probability of all-cause mortality in patients with CLI was 3·7 per cent at 30 days, 14·0 per cent at 6 months, 17·5 per cent at 1 year, 28·4 per cent at 2 years, 35·1 per cent at 3 years and 46·2 per cent at 5 years (Table 1). The I2 statistics are very large suggesting that the survival rates varied a great deal across studies. These findings were corroborated using the multivariable method of DerSimonian and Laird, which produced similar results. The multivariable analysis provides a notably lower estimated probability of death after 2 years, but the confidence interval overlaps the value from the corresponding univariable meta-analysis. Table 1 Pooled probabilities of death for six time points using six univariable and a multivariable random-effects meta-analysis . Univariable analyses . . Multivariable analysis . Pooled probability of death . I2 (%) . Pooled probability of death . 30 days 0·037 (0·030, 0·046) 76 0·040 (0·033, 0·050) 6 months 0·140 (0·096, 0·199) 93 0·138 (0·100, 0·188) 1 year 0·175 (0·150, 0·202) 95 0·173 (0·140, 0·212) 2 years 0·284 (0·209, 0·373) 97 0·218 (0·165, 0·283) 3 years 0·351 (0·272, 0·438) 97 0·341 (0·283, 0·405) 5 years 0·462 (0·329, 0·601) 99 –* . Univariable analyses . . Multivariable analysis . Pooled probability of death . I2 (%) . Pooled probability of death . 30 days 0·037 (0·030, 0·046) 76 0·040 (0·033, 0·050) 6 months 0·140 (0·096, 0·199) 93 0·138 (0·100, 0·188) 1 year 0·175 (0·150, 0·202) 95 0·173 (0·140, 0·212) 2 years 0·284 (0·209, 0·373) 97 0·218 (0·165, 0·283) 3 years 0·351 (0·272, 0·438) 97 0·341 (0·283, 0·405) 5 years 0·462 (0·329, 0·601) 99 –* Values in parentheses are 95 per cent confidence intervals. * Only one study provided outcome data at both 6 months and 5 years, which resulted in estimation problems for the six-dimensional meta-analysis. Open in new tab Table 1 Pooled probabilities of death for six time points using six univariable and a multivariable random-effects meta-analysis . Univariable analyses . . Multivariable analysis . Pooled probability of death . I2 (%) . Pooled probability of death . 30 days 0·037 (0·030, 0·046) 76 0·040 (0·033, 0·050) 6 months 0·140 (0·096, 0·199) 93 0·138 (0·100, 0·188) 1 year 0·175 (0·150, 0·202) 95 0·173 (0·140, 0·212) 2 years 0·284 (0·209, 0·373) 97 0·218 (0·165, 0·283) 3 years 0·351 (0·272, 0·438) 97 0·341 (0·283, 0·405) 5 years 0·462 (0·329, 0·601) 99 –* . Univariable analyses . . Multivariable analysis . Pooled probability of death . I2 (%) . Pooled probability of death . 30 days 0·037 (0·030, 0·046) 76 0·040 (0·033, 0·050) 6 months 0·140 (0·096, 0·199) 93 0·138 (0·100, 0·188) 1 year 0·175 (0·150, 0·202) 95 0·173 (0·140, 0·212) 2 years 0·284 (0·209, 0·373) 97 0·218 (0·165, 0·283) 3 years 0·351 (0·272, 0·438) 97 0·341 (0·283, 0·405) 5 years 0·462 (0·329, 0·601) 99 –* Values in parentheses are 95 per cent confidence intervals. * Only one study provided outcome data at both 6 months and 5 years, which resulted in estimation problems for the six-dimensional meta-analysis. Open in new tab Univariable meta-regression was used to assess whether risk factors of interest had an effect on the observed mortality rates (Table 2). This analysis suggests that men had a survival benefit at 30 days and 3 years, with a non-significant survival benefit at 1 year. The presence of ischaemic heart disease, tissue loss and older age resulted in a significantly higher probability of death at 3 years and higher estimated mortality rates at earlier time points. There is no evidence that diabetes, rest pain or renal failure affects the risk of death. Table 2 Estimated odds ratios for death associated with study-level co-variables from the meta-regressions Risk factor . Odds ratio . 30-day outcome . 1-year outcome . 3-year outcome . Age 1·06 (0·98, 1·15) 1·06 (1·00, 1·12) 1·12 (1·07, 1·18) Proportion men 0·05 (0·00, 0·79) 0·16 (0·02, 1·10) 0·03 (0·00, 0·30) Proportion with rest pain 0·80 (0·20, 3·27) 0·76 (0·26, 2·26) 0·33 (0·04, 2·76) Proportion with IHD, angina 3·22 (0·08, 123·08) 8·36 (0·85, 81·98) 60·29 (1·39, 2621·39) Proportion with diabetes 0·32 (0·06, 1·65) 1·54 (0·25, 9·52) 2·43 (0·31, 18·88) Proportion with tissue loss 2·66 (0·24, 28·87) 3·50 (0·78, 15·72) 27·47 (2·05, 368·13) Proportion with renal failure 0·22 (0·01, 6·31) 14·57 (0·09, 2318·59) –* Risk factor . Odds ratio . 30-day outcome . 1-year outcome . 3-year outcome . Age 1·06 (0·98, 1·15) 1·06 (1·00, 1·12) 1·12 (1·07, 1·18) Proportion men 0·05 (0·00, 0·79) 0·16 (0·02, 1·10) 0·03 (0·00, 0·30) Proportion with rest pain 0·80 (0·20, 3·27) 0·76 (0·26, 2·26) 0·33 (0·04, 2·76) Proportion with IHD, angina 3·22 (0·08, 123·08) 8·36 (0·85, 81·98) 60·29 (1·39, 2621·39) Proportion with diabetes 0·32 (0·06, 1·65) 1·54 (0·25, 9·52) 2·43 (0·31, 18·88) Proportion with tissue loss 2·66 (0·24, 28·87) 3·50 (0·78, 15·72) 27·47 (2·05, 368·13) Proportion with renal failure 0·22 (0·01, 6·31) 14·57 (0·09, 2318·59) –* Values in parentheses are 95 per cent confidence intervals. * One meta-regression did not provide enough data to meet the criterion to fit the model. Odds ratios greater than 1 indicate that the corresponding risk factor is associated with a higher probability of death. IHD, ischaemic heart disease. Open in new tab Table 2 Estimated odds ratios for death associated with study-level co-variables from the meta-regressions Risk factor . Odds ratio . 30-day outcome . 1-year outcome . 3-year outcome . Age 1·06 (0·98, 1·15) 1·06 (1·00, 1·12) 1·12 (1·07, 1·18) Proportion men 0·05 (0·00, 0·79) 0·16 (0·02, 1·10) 0·03 (0·00, 0·30) Proportion with rest pain 0·80 (0·20, 3·27) 0·76 (0·26, 2·26) 0·33 (0·04, 2·76) Proportion with IHD, angina 3·22 (0·08, 123·08) 8·36 (0·85, 81·98) 60·29 (1·39, 2621·39) Proportion with diabetes 0·32 (0·06, 1·65) 1·54 (0·25, 9·52) 2·43 (0·31, 18·88) Proportion with tissue loss 2·66 (0·24, 28·87) 3·50 (0·78, 15·72) 27·47 (2·05, 368·13) Proportion with renal failure 0·22 (0·01, 6·31) 14·57 (0·09, 2318·59) –* Risk factor . Odds ratio . 30-day outcome . 1-year outcome . 3-year outcome . Age 1·06 (0·98, 1·15) 1·06 (1·00, 1·12) 1·12 (1·07, 1·18) Proportion men 0·05 (0·00, 0·79) 0·16 (0·02, 1·10) 0·03 (0·00, 0·30) Proportion with rest pain 0·80 (0·20, 3·27) 0·76 (0·26, 2·26) 0·33 (0·04, 2·76) Proportion with IHD, angina 3·22 (0·08, 123·08) 8·36 (0·85, 81·98) 60·29 (1·39, 2621·39) Proportion with diabetes 0·32 (0·06, 1·65) 1·54 (0·25, 9·52) 2·43 (0·31, 18·88) Proportion with tissue loss 2·66 (0·24, 28·87) 3·50 (0·78, 15·72) 27·47 (2·05, 368·13) Proportion with renal failure 0·22 (0·01, 6·31) 14·57 (0·09, 2318·59) –* Values in parentheses are 95 per cent confidence intervals. * One meta-regression did not provide enough data to meet the criterion to fit the model. Odds ratios greater than 1 indicate that the corresponding risk factor is associated with a higher probability of death. IHD, ischaemic heart disease. Open in new tab Discussion CLI is usually associated with extensive atherosclerosis within the leg arterial tree58, and similar disease in the coronary and cerebrovascular circulation. As a consequence, patients have significant concomitant cardiac and cerebral co-morbidity and mortality3. A number of epidemiological studies have attempted to determine the natural history of patients with CLI. Historical studies reported mortality rates of 20–25 per cent at 1 year3, but it has been suggested that these figures may not reflect present outcomes. Improvements in medical treatment of cardiovascular risk in patients with CLI are likely to have had significant benefit59. Secondary risk factor management is well established among vascular specialists. Reassessment of short-, mid- and longer-term mortality rates in patients with CLI is overdue60. The lack of studies reporting antiplatelet and statin use in recent papers has limited the conclusions that can be drawn about their effects. Similarly, the reporting of smoking status is notoriously inaccurate and as such was not included in the present analysis. The present results suggest that there has been a small reduction (down to 17·5 per cent) in 1-year mortality rates compared with previous data1. Of concern, however, is the continued high long-term mortality rates, with almost half of patients with CLI being dead at 5 years. It was impossible to determine whether the deaths were due to cardiovascular or other diseases, but the mortality rates associated with CLI remain significant, and are in excess of those of a number of common cancers61,62. This study also shows that increasing age and the presence of ischaemic heart disease are predictive of late mortality, suggesting that many deaths are cardiac-related. Male sex seems to be protective in both the short and longer term. This association between female sex and poor outcome has been reported for many cardiovascular diseases, but the cause remains largely unknown63–65, and is an area that needs targeted research. No significant effect on mortality rates was seen from either renal failure or diabetes. This may be due partly to variable definitions of renal failure employed in the papers analysed. Both of these chronic diseases will become more prevalent over the decades and could have increasing effects on mortality66,67. The inclusion criteria here were relatively strict, so that only studies with strong methodology were included; the data are an accurate reflection of available published material. Papers were included only if they reported on more than 100 patients to ensure that studies were sufficiently large to justify the use of normal approximations during meta-analysis. Published results may be biased by coming from hospitals with an interest in CLI and its treatment. It is unlikely that units with poor results will publish them, so mortality rates reported here are probably an underestimate. A further issue that may result in an under-reporting of mortality rates is the dropout effect. Some studies provided details of loss to follow-up, but many did not. Given the poor quality of the available data, the meta-analyses performed handled all studies in the same way regardless of the extent to which follow-up was reported. Thus all loss to follow-up (both known and unknown) was treated as survival. The present results should be regarded as conservative; mortality rates, particularly at later time points, are likely to be higher. All the outcome data used in these analyses were provided numerically; supplementary values from graphs, where these were available, were not used because of the difficulty in ensuring accuracy of data. Definitions of co-morbidities varied between papers, so information was included based on the definitions provided. Given the heterogeneous nature of the populations, exact treatment methods (surgery or angioplasty) were difficult to determine, but there did not appear to be major differences. There was only one significant factor at presentation that affected subsequent mortality rates: tissue loss or no tissue loss. There is little in the literature that compares demographic data and outcomes in CLI with, or without tissue loss. There is a need to examine possible differences in outcomes, as patients with CLI and tissue loss may be a distinct group. Although there appears to have been a slight improvement in short-term mortality rates in patients with CLI, longer-term mortality rates continue to be poor. One cause may be a lack of awareness with regard to cardiovascular risk, which will affect compliance with medication and smoking cessation68. Improvement in patient education is still required as is continued aggressive management of cardiovascular risk factors. Acknowledgements D.J. is employed by the UK Medical Research Council (Unit Programme no. U105260558). Disclosure: The authors declare no conflict of interest. References 1 Norgren L , Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG et al. ; TASC II Working Group. Inter-society consensus for the management of peripheral arterial disease . Int Angiol 2007 ; 26 : 81 – 157 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 2 Norgren L , Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) . J Vasc Surg 2007 ; 45 (Suppl S ): S5 – S6 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Becker F , Robert-Ebadi H, Ricco JB, Setacci C, Cao P, de Donato G et al. Chapter I: Definitions, epidemiology, clinical presentation and prognosis . Eur J Vasc Endovasc Surg 2011 ; 42 ( Suppl 2 ): S4 – S12 . Google Scholar Crossref Search ADS PubMed WorldCat 4 DerSimonian R , Laird N. 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The Beyond TME Collaborative ; Ali, S Mohammed; Antoniou, Anthony; Beynon, John; Bhangu, Aneel; Bose, Pradeep; Boyle, Kirsten; Branagan, Graham; Brown, Gina; Burling, David; Chang, George J; Clark, Susan K; Colquhoun, Patrick; Crane, Christopher H;

Jones, C; Kelliher, L; Dickinson, M; Riga, A; Worthington, T; Scott, M J; Vandrevala, T; Fry, C H; Karanjia, N; Quiney, N

doi: 10.1002/bjs.9165pmid: 23696477

Abstract Background Enhanced recovery programmes (ERPs) have been shown to reduce length of hospital stay (LOS) and complications in colorectal surgery. Whether ERPs have the same benefits in open liver resection surgery is unclear, and randomized clinical trials are lacking. Methods Consecutive patients scheduled for open liver resection were randomized to an ERP group or standard care. Primary endpoints were time until medically fit for discharge (MFD) and LOS. Secondary endpoints were postoperative morbidity, pain scores, readmission rate, mortality, quality of life (QoL) and patient satisfaction. ERP elements included greater preoperative education, preoperative oral carbohydrate loading, postoperative goal-directed fluid therapy, early mobilization and physiotherapy. Both groups received standardized anaesthesia with epidural analgesia. Results The analysis included 46 patients in the ERP group and 45 in the standard care group. Median MFD time was reduced in the ERP group (3 days versus 6 days with standard care; P < 0·001), as was LOS (4 days versus 7 days; P < 0·001). The ERP significantly reduced the rate of medical complications (7 versus 27 per cent; P = 0·020), but not surgical complications (15 versus 11 per cent; P = 0·612), readmissions (4 versus 0 per cent; P = 0·153) or mortality (both 2 per cent; P = 0·987). QoL over 28 days was significantly better in the ERP group (P = 0·002). There was no difference in patient satisfaction. Conclusion ERPs for open liver resection surgery are safe and effective. Patients treated in the ERP recovered faster, were discharged sooner, and had fewer medical-related complications and improved QoL. Registration number: ISRCTN03274575 (http://www.controlled-trials.com). Introduction Liver resection is the preferred treatment for a variety of primary and secondary liver tumours. In the UK, 1600 liver resections are performed every year for colorectal cancer metastases alone1. Liver surgery is associated with a high rate of postoperative morbidity ranging from 15 to 48 per cent2,3. The most recent figures from the UK reflect this, with a mean length of hospital stay (LOS) after liver resection reported as 10 (median 8) days4. There is increasing evidence that major postoperative complications may affect long-term cancer survival5. Enhanced recovery programmes (ERPs) have been shown to reduce morbidity and LOS following colorectal surgery6. It has been suggested that they may have similar benefits for other surgical specialties, including liver surgery. Despite a large volume of research examining ERPs in colorectal surgery, a recent Cochrane review stated that, although such programmes are safe, many of the trials had variable compliance with the elements of enhanced recovery and lacked sufficient outcome parameters to justify implementation of ERPs as a standard of care for colorectal resection7; it concluded that more trials in ERPs were warranted. To date there is limited evidence for the use of ERPs in liver resection surgery. Three cohort studies using retrospective controls8–10 and one pilot study with no control group11 have shown that ERPs are feasible and safe in both open and laparoscopic liver resection surgery. Only one randomized clinical trial (RCT) has been conducted in this area; it examined the use of laxatives within an ERP, but did not compare ERP with standard care12. None of these liver ERP studies measured any markers of quality of life (QoL). Therefore, a comprehensive ERP was designed, based on Enhanced Recovery After Surgery (ERAS®) Society recommendations13, to investigate its effect on short-term recovery and morbidity following open liver resection compared with standard perioperative care in a randomized trial at the Royal Surrey County Hospital. Methods This RCT was conducted between March 2011 and May 2012. The trial was ethically approved by the National Health Service Research Ethics Committee, and monitored by the Trust Research and Development Department. The trial was registered at controlled-trials.com (ISRCTN03274575). Participants and recruitment All adult patients presenting for open liver resection at the Royal Surrey County Hospital were eligible. Patients were excluded if they underwent an entirely laparoscopic operation, needed a second concomitant procedure (for example bile duct repair), were found to be inoperable at the time of surgery, or were unable to consent. Patients were first approached in the outpatient clinic and given a trial information sheet. A second, more comprehensive, discussion took place in the preassessment unit before consent was obtained. Patients were then randomized either to treatment within the ERP or standard care. The randomization sequence of group allocation by means of brown opaque envelopes was generated by an independent statistician from the University of Surrey. Preoperative care Patients randomized to the ERP underwent extra and more detailed explanation of the usual perioperative course than those in the standard care group. They received a checklist and information booklet about the operation and postoperative rehabilitation, giving them daily mobilization and nutritional goals. Patients in the ERP group received one 125-ml bottle of Fortisip Compact® (Nutricia Clinical Care, Trowbridge, UK) three times a day for 3 days before surgery in addition to their normal diet. Patients following the ERP were also instructed to drink 800 ml preOp® (4 cartons; Nutricia Clinical Care) at 21.00 hours on the evening before, and 400 ml at 06.00 hours on the morning of surgery. Patients in the standard care group followed the normal preoperative starvation guidelines of nil by mouth from midnight. All patients in both groups were admitted on the morning of surgery. No preoperative bowel preparation or premedication was given. Perioperative care and anaesthesia Both groups had the same standardized anaesthetic. Anaesthesia was induced with 2–4 mg/kg propofol, 2–3 µg/kg fentanyl and 0·15–0·30 mg/kg cisatracurium. The trachea was intubated and the lungs ventilated mechanically. Anaesthesia was maintained with sevoflurane in oxygen-enriched air, together with intravenous remifentanil (0·05–0·10 µg per kg per min), phenylephrine (0·05–0·20 µg per kg per min to maintain mean arterial blood pressure above 55 mmHg) and glyceryl trinitrate (1–5 mg/h to maintain central venous pressure at 0–2 mmHg). Routine antibiotic prophylaxis was administered. A thoracic epidural (between levels T10 and T6) was placed in all patients for postoperative analgesia. Patients received 10 ml of 0·125 per cent levobupivacaine via the epidural catheter as a bolus at the start of the operation, followed by an infusion of 0·1 per cent levobupivacaine and 2 µg/ml fentanyl that was continued into the postoperative period. Normothermia was achieved during surgery with a forced-air warming blanket. Intermittent pneumatic leg compression devices were applied to all patients. Nausea and vomiting were treated initially with 25 mg intramuscular or intravenous cyclizine, or 4 mg intravenous ondansetron if this failed. Surgical technique All patients had open surgery performed by one of three consultant surgeons. A right subcostal incision with xiphisternal extension was used. All surgical procedures were performed in a similar way, with transection of the liver parenchyma by an ultrasonic dissection technique using the Cavitron Ultrasonic Surgical Aspirator (CUSA®; ValleyLab, Boulder, Colorado, USA). The exact procedure and the need for Pringle manoeuvre was decided by the individual operating surgeon. Routine abdominal drains were avoided and only placed if deemed necessary by the operating surgeon. No perioperative fluids were administered until hepatic resection had been completed and haemostasis obtained. Patients in both groups then received 1000 ml compound sodium lactate (Hartmann's solution; Baxter, Norfolk, UK) for initial intravenous fluid resuscitation; all patients then received a further 500 ml of 6 per cent Volulyte® (Fresenius Kabi, Runcorn, UK), a hydroxyethyl starch. Postoperative care Immediately after the operation all patients were extubated, and transferred to a level 2 high-dependency unit for further observation. Patients in the ERP group received fluid resuscitation and additional monitoring using the LiDCOrapid™ (LiDCO, Cambridge, UK) and goal-directed fluid therapy (GDFT) for 6 h after hepatic resection (Fig. S1, supporting information). This involved 250-ml intravenous boluses of colloid (6 per cent Volulyte®) to maximize stroke volume, in accordance with the protocol. The LiDCOrapid™ is an uncalibrated system that uses a specific algorithm from the pulse power analysis of the arterial waveform to calculate the stroke volume. This is based on the principle that fluctuations in blood pressure about the mean are directly proportional to the stroke volume14. After the 6 h of GDFT, a maintenance fluid infusion of compound sodium lactate was started, at a rate of 1–2 ml per kg per h. Oral intake was encouraged and maintenance fluid was stopped as soon as adequate intake was achieved. Patients in the standard care group received fluid optimization by the admitting intensive care team, using traditional markers of hypovolaemia, such as pulse rate, central venous pressure, urine output, arterial lactate and mixed venous saturations from the central line. Maintenance fluids were then started at 1–2 ml per kg per h and continued until oral intake was satisfactory. All patients were allowed to eat and drink a normal diet. However, patients on the ERP were encouraged to take oral supplements (Fortisip Compact®) immediately on waking. A multidimensional approach to prevent ileus was adopted for those in the ERP group, by avoiding intravenous opioids and excess intravenous fluids, in accordance with the ERAS® Society guidelines13. After surgery patients in the ERP group received physiotherapy twice a day (compared with the standard treatment of once a day), until they were deemed independently mobile. They were encouraged to mobilize as soon as possible. Patients in the standard care group were mobilized by either the bedside nurse or physiotherapist. All patients received deep vein thromboembolism prophylaxis after operation. In the ERP group oral paracetamol (1 g four times daily, reduced in patients with extended right-sided resections) and tramadol hydrochloride (50–100 mg four times daily) were started on the morning after surgery. Patients in the standard care group were given additional oral analgesics only if they requested them. On the morning of the second postoperative day (POD), patients in the ERP group received a bolus dose of 3 mg diamorphine via the epidural catheter before its removal by the bedside nurse. Central venous and urinary catheters were removed within 4 h of the epidural being removed. Abdominal drains were usually removed on day 1 or 2 depending on clinical need. Oral morphine was prescribed for breakthrough analgesia as required. The epidural catheter in the standard care group was managed by an acute pain team and was removed on POD 3 or 4, according to the usual protocol. All catheters and drains were removed as directed by the surgical team. The ERP and standard care are summarized in Table 1. Table 1 Summary of enhanced recovery programme and comparison with standard care . ERP . Standard care . Before surgery Information and education, including mobilization and dietary goals NA Oral nutritional supplements NA Carbohydrate drink NA During surgery Standard anaesthetic protocol and surgical management Standard anaesthetic protocol and surgical management Thoracic epidural for postop. analgesia Thoracic epidural for postop. analgesia All patients extubated and taken to level 2 HDU All patients extubated and taken to level 2 HDU POD 0 Eat and drink normally Eat and drink normally Oral nutritional supplements NA Goal-directed fluid therapy for 6 h to optimize stroke volume Fluid resuscitation to standard markers: CVP, urine output, lactate, mixed venous saturations LiDCOrapid™—250 ml colloid boluses Fluid therapy at discretion of intensive care team Chest physiotherapy NA POD 1 Physiotherapy/mobilization twice daily Physiotherapy once daily Stop i.v. maintenance fluid Fluid therapy at discretion of intensive care team Oral nutritional supplements NA Eat and drink normally Eat and drink normally POD 2 Diamorphine 3 mg via epidural NA Epidural removed in the morning, or stopped and capped off if INR ≥ 1·5 Epidural managed by acute pain team Regular oral analgesics and oral morphine as needed NA Physiotherapy/mobilization twice daily Physiotherapy once daily Urinary catheter removed 4 h after epidural NA Removal of surgical drains (if appropriate) Removal of surgical drains (if appropriate) CVC removed CVC removed at discretion of surgical team Blinded assessment of discharge criteria Blinded assessment of discharge criteria POD 3 (+4) Physiotherapy/mobilization twice daily Epidural managed by acute pain team; usually removed on POD 3 or 4 Home if meets blinded assessment of discharge criteria Urinary catheter removed 12 h after epidural in accordance with current guidelines Blinded assessment of discharge criteria Blinded assessment of discharge criteria . ERP . Standard care . Before surgery Information and education, including mobilization and dietary goals NA Oral nutritional supplements NA Carbohydrate drink NA During surgery Standard anaesthetic protocol and surgical management Standard anaesthetic protocol and surgical management Thoracic epidural for postop. analgesia Thoracic epidural for postop. analgesia All patients extubated and taken to level 2 HDU All patients extubated and taken to level 2 HDU POD 0 Eat and drink normally Eat and drink normally Oral nutritional supplements NA Goal-directed fluid therapy for 6 h to optimize stroke volume Fluid resuscitation to standard markers: CVP, urine output, lactate, mixed venous saturations LiDCOrapid™—250 ml colloid boluses Fluid therapy at discretion of intensive care team Chest physiotherapy NA POD 1 Physiotherapy/mobilization twice daily Physiotherapy once daily Stop i.v. maintenance fluid Fluid therapy at discretion of intensive care team Oral nutritional supplements NA Eat and drink normally Eat and drink normally POD 2 Diamorphine 3 mg via epidural NA Epidural removed in the morning, or stopped and capped off if INR ≥ 1·5 Epidural managed by acute pain team Regular oral analgesics and oral morphine as needed NA Physiotherapy/mobilization twice daily Physiotherapy once daily Urinary catheter removed 4 h after epidural NA Removal of surgical drains (if appropriate) Removal of surgical drains (if appropriate) CVC removed CVC removed at discretion of surgical team Blinded assessment of discharge criteria Blinded assessment of discharge criteria POD 3 (+4) Physiotherapy/mobilization twice daily Epidural managed by acute pain team; usually removed on POD 3 or 4 Home if meets blinded assessment of discharge criteria Urinary catheter removed 12 h after epidural in accordance with current guidelines Blinded assessment of discharge criteria Blinded assessment of discharge criteria ERP, enhanced recovery programme; NA, not applicable; HDU, high-dependency unit; POD, postoperative day; CVP, central venous pressure; i.v., intravenous; INR, international normalized ratio; CVC, central venous catheter. Open in new tab Table 1 Summary of enhanced recovery programme and comparison with standard care . ERP . Standard care . Before surgery Information and education, including mobilization and dietary goals NA Oral nutritional supplements NA Carbohydrate drink NA During surgery Standard anaesthetic protocol and surgical management Standard anaesthetic protocol and surgical management Thoracic epidural for postop. analgesia Thoracic epidural for postop. analgesia All patients extubated and taken to level 2 HDU All patients extubated and taken to level 2 HDU POD 0 Eat and drink normally Eat and drink normally Oral nutritional supplements NA Goal-directed fluid therapy for 6 h to optimize stroke volume Fluid resuscitation to standard markers: CVP, urine output, lactate, mixed venous saturations LiDCOrapid™—250 ml colloid boluses Fluid therapy at discretion of intensive care team Chest physiotherapy NA POD 1 Physiotherapy/mobilization twice daily Physiotherapy once daily Stop i.v. maintenance fluid Fluid therapy at discretion of intensive care team Oral nutritional supplements NA Eat and drink normally Eat and drink normally POD 2 Diamorphine 3 mg via epidural NA Epidural removed in the morning, or stopped and capped off if INR ≥ 1·5 Epidural managed by acute pain team Regular oral analgesics and oral morphine as needed NA Physiotherapy/mobilization twice daily Physiotherapy once daily Urinary catheter removed 4 h after epidural NA Removal of surgical drains (if appropriate) Removal of surgical drains (if appropriate) CVC removed CVC removed at discretion of surgical team Blinded assessment of discharge criteria Blinded assessment of discharge criteria POD 3 (+4) Physiotherapy/mobilization twice daily Epidural managed by acute pain team; usually removed on POD 3 or 4 Home if meets blinded assessment of discharge criteria Urinary catheter removed 12 h after epidural in accordance with current guidelines Blinded assessment of discharge criteria Blinded assessment of discharge criteria . ERP . Standard care . Before surgery Information and education, including mobilization and dietary goals NA Oral nutritional supplements NA Carbohydrate drink NA During surgery Standard anaesthetic protocol and surgical management Standard anaesthetic protocol and surgical management Thoracic epidural for postop. analgesia Thoracic epidural for postop. analgesia All patients extubated and taken to level 2 HDU All patients extubated and taken to level 2 HDU POD 0 Eat and drink normally Eat and drink normally Oral nutritional supplements NA Goal-directed fluid therapy for 6 h to optimize stroke volume Fluid resuscitation to standard markers: CVP, urine output, lactate, mixed venous saturations LiDCOrapid™—250 ml colloid boluses Fluid therapy at discretion of intensive care team Chest physiotherapy NA POD 1 Physiotherapy/mobilization twice daily Physiotherapy once daily Stop i.v. maintenance fluid Fluid therapy at discretion of intensive care team Oral nutritional supplements NA Eat and drink normally Eat and drink normally POD 2 Diamorphine 3 mg via epidural NA Epidural removed in the morning, or stopped and capped off if INR ≥ 1·5 Epidural managed by acute pain team Regular oral analgesics and oral morphine as needed NA Physiotherapy/mobilization twice daily Physiotherapy once daily Urinary catheter removed 4 h after epidural NA Removal of surgical drains (if appropriate) Removal of surgical drains (if appropriate) CVC removed CVC removed at discretion of surgical team Blinded assessment of discharge criteria Blinded assessment of discharge criteria POD 3 (+4) Physiotherapy/mobilization twice daily Epidural managed by acute pain team; usually removed on POD 3 or 4 Home if meets blinded assessment of discharge criteria Urinary catheter removed 12 h after epidural in accordance with current guidelines Blinded assessment of discharge criteria Blinded assessment of discharge criteria ERP, enhanced recovery programme; NA, not applicable; HDU, high-dependency unit; POD, postoperative day; CVP, central venous pressure; i.v., intravenous; INR, international normalized ratio; CVC, central venous catheter. Open in new tab Primary outcome measures LOS was measured from time of surgery to day of discharge. Patients were deemed to be medically fit for discharge when they met certain criteria, as judged daily by an independent assessor who was blinded to the patient group allocation and unaware of the ERP. These criteria were: good pain control with oral analgesia, tolerance of solid food, independently mobile, normal or decreasing serum bilirubin level, and willingness of the patient to be discharged. Secondary outcome measures Pain scores were measured daily using a visual analogue scale (VAS) ranging from 0 to 10. Morbidity was calculated as the percentage of patients with at least one complication after surgery. General complications were defined using the Postoperative Morbidity Survey15. Complications were graded according to the Dindo–Clavien classification16. Mortality was defined as death in hospital or within 30 days after surgery. Other measures included volume of intravenous fluid administered in the first 6 and 24 h after surgery, and time to return of bowel sounds, passage of flatus, tolerance of a full diet, bowel opening and mobilization. Patients completed the validated EQ-5D™ (EuroQol Group, Rotterdam, The Netherlands)17 QoL measure in the preassessment clinic after giving informed consent, and on POD 2, 3, 5, 7, 10, 14 and 28. The measure consists of a descriptive system and a VAS. The descriptive system contains the dimensions mobility, self-care, usual activities, pain/discomfort and anxiety/depression, from which an overall health value index can be calculated (range − 0·59 to + 1·00). With repeated EQ-5D™ measures taken in the postoperative period, differences between groups in health-related QoL were calculated using the area under the curve (AUC) method. The VAS records the patients self-rated health state, on a scale from 0 to 100. A satisfaction questionnaire was filled out by patients at home after discharge, and included questions on pain management, expectations regarding timing of discharge and mobilization. Statistical analysis The sample size calculation was based on the level of variation (mean(s.d.) 9·21(4·95) days) of postoperative LOS determined by retrospective audit of all patients undergoing liver resection at the Royal Surrey County Hospital in the previous 12 months. It was assumed that a clinically significant reduction in LOS would be 3 days. The sample size was calculated with a power of 80 per cent using a two-sided two-sample Student's t test. A minimum of 89 patients was calculated to be required (45 in each group). Continuous data with a normal distribution were statistically tested for group differences using a two-sample Student's t test. Data without a normal distribution were analysed using the Mann–Whitney U test. Fisher's exact test or χ2 test was used for analysis of dichotomous secondary outcome measures. Statistical analyses were performed with SPSS® for Windows® version 19 (IBM, Armonk, New York, USA). Results A total of 104 consecutive patients were enrolled in the trial. Thirteen patients were withdrawn after randomization because of changes to their original oncological staging. They either underwent additional procedures, were inoperable at the time of surgery, or had a laparoscopic resection (Fig. 1). Ninety-one patients completed the study, 45 who received standard care and 46 treated within the ERP. Fig. 1 Open in new tabDownload slide CONSORT diagram for the trial. ERP, enhanced recovery programme Patient characteristics, preoperative risk scores and surgical data are shown in Table 2. Patients in the ERP group had higher Portsmouth modification of the Physiological and Operative Severity Score for the EnUmeration of Mortality and morbidity (P-POSSUM) operative severity scores, reflecting more major resections in this group (P = 0·012). More patients in the ERP presented with colorectal metastases (P = 0·021) and correspondingly more patients had received preoperative neoadjuvant chemotherapy (P = 0·021). Table 2 Patient demographics and operative details . ERP (n = 46) . Standard care (n = 45) . Age (years)* 64 (27–83) 67 (27–84) Sex ratio (M : F) 31 : 15 23 : 22 Body mass index (kg/m2)† 25·6(5·0) 26·9(4·4) ASA fitness grade  I 0 2  II 43 38  III 3 5 Diagnosis Colorectal metastases 35 26  Other metastases 10 10  Benign disease 1 9 Neoadjuvant chemotherapy 36 25 P-POSSUM†  Physiological score 16·4(3·4) 16·8(3·6)  Operative severity score 19·4(3·7) 17·1(4·8) Operation  Major resection (≥ 3 segments) 21 12  Minor resection 25 33 Specimen weight (g)* 373·3 (156·3–780·5) 179·5 (69·6–606·3) Blood loss (ml)* 350 (174–900) 340 (150–645) Need for blood transfusion 7 3 Death 1 1 . ERP (n = 46) . Standard care (n = 45) . Age (years)* 64 (27–83) 67 (27–84) Sex ratio (M : F) 31 : 15 23 : 22 Body mass index (kg/m2)† 25·6(5·0) 26·9(4·4) ASA fitness grade  I 0 2  II 43 38  III 3 5 Diagnosis Colorectal metastases 35 26  Other metastases 10 10  Benign disease 1 9 Neoadjuvant chemotherapy 36 25 P-POSSUM†  Physiological score 16·4(3·4) 16·8(3·6)  Operative severity score 19·4(3·7) 17·1(4·8) Operation  Major resection (≥ 3 segments) 21 12  Minor resection 25 33 Specimen weight (g)* 373·3 (156·3–780·5) 179·5 (69·6–606·3) Blood loss (ml)* 350 (174–900) 340 (150–645) Need for blood transfusion 7 3 Death 1 1 * Values are median (interquartile range) and † mean(s.d.). ERP, enhanced recovery programme; ASA, American Society of Anesthesiologists; P-POSSUM, Portsmouth modification of the Physiological and Operative Severity Score for the EnUmeration of Mortality and morbidity. Open in new tab Table 2 Patient demographics and operative details . ERP (n = 46) . Standard care (n = 45) . Age (years)* 64 (27–83) 67 (27–84) Sex ratio (M : F) 31 : 15 23 : 22 Body mass index (kg/m2)† 25·6(5·0) 26·9(4·4) ASA fitness grade  I 0 2  II 43 38  III 3 5 Diagnosis Colorectal metastases 35 26  Other metastases 10 10  Benign disease 1 9 Neoadjuvant chemotherapy 36 25 P-POSSUM†  Physiological score 16·4(3·4) 16·8(3·6)  Operative severity score 19·4(3·7) 17·1(4·8) Operation  Major resection (≥ 3 segments) 21 12  Minor resection 25 33 Specimen weight (g)* 373·3 (156·3–780·5) 179·5 (69·6–606·3) Blood loss (ml)* 350 (174–900) 340 (150–645) Need for blood transfusion 7 3 Death 1 1 . ERP (n = 46) . Standard care (n = 45) . Age (years)* 64 (27–83) 67 (27–84) Sex ratio (M : F) 31 : 15 23 : 22 Body mass index (kg/m2)† 25·6(5·0) 26·9(4·4) ASA fitness grade  I 0 2  II 43 38  III 3 5 Diagnosis Colorectal metastases 35 26  Other metastases 10 10  Benign disease 1 9 Neoadjuvant chemotherapy 36 25 P-POSSUM†  Physiological score 16·4(3·4) 16·8(3·6)  Operative severity score 19·4(3·7) 17·1(4·8) Operation  Major resection (≥ 3 segments) 21 12  Minor resection 25 33 Specimen weight (g)* 373·3 (156·3–780·5) 179·5 (69·6–606·3) Blood loss (ml)* 350 (174–900) 340 (150–645) Need for blood transfusion 7 3 Death 1 1 * Values are median (interquartile range) and † mean(s.d.). ERP, enhanced recovery programme; ASA, American Society of Anesthesiologists; P-POSSUM, Portsmouth modification of the Physiological and Operative Severity Score for the EnUmeration of Mortality and morbidity. Open in new tab Time to being medically fit for discharge was significantly reduced in the ERP group compared with the standard care group (median (interquartile range) 3 (3–4) versus 6 (6–7) days; P < 0·001) (Fig. 2). Actual LOS (including readmissions) was also significantly reduced in this group (4 (3–5) versus 7 (6–8) days; P < 0·001) (Fig. 2). Fig. 2 Open in new tabDownload slide Comparison of time after surgery until medically fit for discharge and length of hospital stay between patients who were treated according to an enhanced recovery programme (ERP) and those who received standard care. Median (bold line), interquartile range (box) and range not including outliers (error bars) are shown. Outliers (more than 1·5 box lengths) and extreme outliers (more than 3 box lengths) are represented by circles and asterisks respectively. Both, bP < 0·001 (Mann–Whitney U test) Overall morbidity and complication rates tended to be reduced in the ERP group (17 versus 31 per cent) but this did not reach statistical significance (P = 0·126). Liver surgery-specific complication rates were similar in both groups (15 versus 11 per cent; P = 0·612) (Table S1, supporting information). However, significantly fewer patients in the ERP group had any general complication (3 versus 12 patients; P = 0·020) (Table S2, supporting information). The total numbers of general complications were also reduced from 20 in the standard care group to only four in the ERP group (P = 0·009). Two patients in the ERP group were readmitted (both for abdominal collections) compared with none who received standard care, but this was not significant (P = 0·153). There was one death in each group (P = 0·987). Both deaths resulted from postoperative small liver syndrome in patients who had undergone extensive preoperative neoadjuvant chemotherapy. There was only one epidural failure; a patient in the standard care group required conversion to morphine patient-controlled analgesia. Forty-four of 46 patients in the ERP group followed the planned protocol of stopping the epidural infusion on POD 2. Two patients in this group with preoperative chronic pain syndromes kept the epidural in place for longer. Pain scores measured daily showed no difference between the two groups, except on POD 2 when mean(s.d.) pain scores were significantly lower in the ERP group (2·5(1·4) versus 3·3(2·0); P = 0·044) (Fig. S2, supporting information). Total intravenous fluids given in the first 6 and 24 h were similar in the ERP and standard care groups (6 h: median 2750 versus 2550 ml, P = 0·071; 24 h: 4557 versus 4422 ml, P = 0·535). Significantly more colloid was used in the first 6 h after the operation in the ERP group as part of GDFT (median 1500 versus 1000 ml; P < 0·001). Patients in the ERP group resumed oral intake sooner after surgery (median 115 versus 330 min; P < 0·001) and drank more in the first 24 h (1375 versus 810 ml; P < 0·001). All patients were able to tolerate an oral diet by POD 1. However, one patient developed an incarcerated port-site hernia from a previous laparoscopic procedure on POD 5, and was temporarily unable to tolerate an oral diet. Bowel sounds returned sooner (P < 0·001), flatus passed earlier (P = 0·008) and bowels were opened sooner (P = 0·001) in the ERP group (although 19 patients in the ERP group had been discharged home before the bowels were opened, compared with 7 in the standard care group). Almost a third of patients in the ERP group (13 of 46) were independently mobile on the morning of POD 2 and more than three-quarters (37 of 46) by POD 3; in contrast, only four of 45 patients receiving standard care were independently mobile on POD 3 (P < 0·001). There were 19 enhanced recovery elements used in this programme; however, 13 of these also comprised part of the previous standard care. For each of these elements there was a high compliance rate (Table 3). Table 3 Nineteen enhanced recovery elements based on recent Enhanced Recovery After Surgery Society recommendations13 . ERP . Standard care . Element present . No. in EFP group who followed element . Element present . No. in standard care group who followed element . Preop. information, education, counselling + daily goals Yes 46 No 0 Preop. physiological optimization Yes 46 Yes 45 Avoid preop. bowel preparation Yes 46 Yes 45 Preop. fasting + carbohydrate drink up to 2 h before surgery Yes 46 No 0 Avoid anaesthetic premedication Yes 46 Yes 45 Prophylaxis against thromboembolism Yes 46 Yes 45 Antimicrobial prophylaxis Yes 46 Yes 45 Standard anaesthetic protocol Yes 46 Yes 45 PONV—multimodal approach Yes 46 Yes 45 Avoid nasogastric tube Yes 46 Yes 45 Prevent intraop. hypothermia Yes 46 Yes 45 Periop. fluid management—goal-directed fluid therapy Yes 46 No 0 Avoid routine surgical drainage Yes 46 Yes 45 Urinary drainage: 1–2 days only Yes 30 No 0 Prevention of ileus—multimodal approach Yes 46 Yes 44 Postop. analgesia—thoracic epidural (avoid i.v. opiates) Yes 46 Yes 44 Periop. nutritional care (supplements) Yes 46 No 0 Postop. glucose control Yes 46 Yes 45 Early mobilization—intensive physiotherapy (twice daily) Yes 46 No 0 Overall 19 of 19 13 of 19 . ERP . Standard care . Element present . No. in EFP group who followed element . Element present . No. in standard care group who followed element . Preop. information, education, counselling + daily goals Yes 46 No 0 Preop. physiological optimization Yes 46 Yes 45 Avoid preop. bowel preparation Yes 46 Yes 45 Preop. fasting + carbohydrate drink up to 2 h before surgery Yes 46 No 0 Avoid anaesthetic premedication Yes 46 Yes 45 Prophylaxis against thromboembolism Yes 46 Yes 45 Antimicrobial prophylaxis Yes 46 Yes 45 Standard anaesthetic protocol Yes 46 Yes 45 PONV—multimodal approach Yes 46 Yes 45 Avoid nasogastric tube Yes 46 Yes 45 Prevent intraop. hypothermia Yes 46 Yes 45 Periop. fluid management—goal-directed fluid therapy Yes 46 No 0 Avoid routine surgical drainage Yes 46 Yes 45 Urinary drainage: 1–2 days only Yes 30 No 0 Prevention of ileus—multimodal approach Yes 46 Yes 44 Postop. analgesia—thoracic epidural (avoid i.v. opiates) Yes 46 Yes 44 Periop. nutritional care (supplements) Yes 46 No 0 Postop. glucose control Yes 46 Yes 45 Early mobilization—intensive physiotherapy (twice daily) Yes 46 No 0 Overall 19 of 19 13 of 19 ERP, enhanced recovery programme; PONV, postoperative nausea and vomiting; i.v. intravenous. Open in new tab Table 3 Nineteen enhanced recovery elements based on recent Enhanced Recovery After Surgery Society recommendations13 . ERP . Standard care . Element present . No. in EFP group who followed element . Element present . No. in standard care group who followed element . Preop. information, education, counselling + daily goals Yes 46 No 0 Preop. physiological optimization Yes 46 Yes 45 Avoid preop. bowel preparation Yes 46 Yes 45 Preop. fasting + carbohydrate drink up to 2 h before surgery Yes 46 No 0 Avoid anaesthetic premedication Yes 46 Yes 45 Prophylaxis against thromboembolism Yes 46 Yes 45 Antimicrobial prophylaxis Yes 46 Yes 45 Standard anaesthetic protocol Yes 46 Yes 45 PONV—multimodal approach Yes 46 Yes 45 Avoid nasogastric tube Yes 46 Yes 45 Prevent intraop. hypothermia Yes 46 Yes 45 Periop. fluid management—goal-directed fluid therapy Yes 46 No 0 Avoid routine surgical drainage Yes 46 Yes 45 Urinary drainage: 1–2 days only Yes 30 No 0 Prevention of ileus—multimodal approach Yes 46 Yes 44 Postop. analgesia—thoracic epidural (avoid i.v. opiates) Yes 46 Yes 44 Periop. nutritional care (supplements) Yes 46 No 0 Postop. glucose control Yes 46 Yes 45 Early mobilization—intensive physiotherapy (twice daily) Yes 46 No 0 Overall 19 of 19 13 of 19 . ERP . Standard care . Element present . No. in EFP group who followed element . Element present . No. in standard care group who followed element . Preop. information, education, counselling + daily goals Yes 46 No 0 Preop. physiological optimization Yes 46 Yes 45 Avoid preop. bowel preparation Yes 46 Yes 45 Preop. fasting + carbohydrate drink up to 2 h before surgery Yes 46 No 0 Avoid anaesthetic premedication Yes 46 Yes 45 Prophylaxis against thromboembolism Yes 46 Yes 45 Antimicrobial prophylaxis Yes 46 Yes 45 Standard anaesthetic protocol Yes 46 Yes 45 PONV—multimodal approach Yes 46 Yes 45 Avoid nasogastric tube Yes 46 Yes 45 Prevent intraop. hypothermia Yes 46 Yes 45 Periop. fluid management—goal-directed fluid therapy Yes 46 No 0 Avoid routine surgical drainage Yes 46 Yes 45 Urinary drainage: 1–2 days only Yes 30 No 0 Prevention of ileus—multimodal approach Yes 46 Yes 44 Postop. analgesia—thoracic epidural (avoid i.v. opiates) Yes 46 Yes 44 Periop. nutritional care (supplements) Yes 46 No 0 Postop. glucose control Yes 46 Yes 45 Early mobilization—intensive physiotherapy (twice daily) Yes 46 No 0 Overall 19 of 19 13 of 19 ERP, enhanced recovery programme; PONV, postoperative nausea and vomiting; i.v. intravenous. Open in new tab In both groups the QoL measures showed an initial reduction from baseline, as expected after surgery (Fig. 3). There was a significant difference in QoL between the two groups during the 28 days after surgery, as measured by the multidimensional health value index. The median AUC was 37·2 for the ERP group compared with 35·6 for the standard care group (P = 0·002). There was no significant difference in the EQ-VAS scores, reflecting the patient's own health perception. In addition, there was no difference in satisfaction rates between groups. The questionnaire included questions about timing of discharge (P = 0·318), quality of pain control (P = 0·729) and whether patients started mobilizing at the correct time (P = 0·627). Fig. 3 Open in new tabDownload slide Comparison of median EQ-5D™ health value index scores between patients who were treated according to an enhanced recovery programme (ERP) and those who received standard care. Error bars represent 95 per cent confidence intervals Discussion This RCT has demonstrated the efficacy of a specifically designed ERP in reducing both the time until being medically fit for discharge and LOS by 3 days in patients undergoing open liver resection. This is in keeping with previous studies on enhanced recovery in open or laparoscopic liver resection8–10. In the present study a third of patients in the ERP group left hospital on POD 3. Interestingly, LOS in the standard care group was also decreased compared with historical data3. This could be due to changes in culture within the authors' unit, with healthcare professionals becoming more familiar with the principles of enhanced recovery resulting in alterations to standard care. Additionally, there may have been a ‘Hawthorne effect’18, whereby patients altered their behaviour because they were participating in a trial, accompanied by changes in behaviour of the care givers. Although the total amount of intravenous fluids administered in the first 6 and 24 h was similar in both groups, the ratio of fluid given was different, with patients in the ERP group receiving larger volumes of colloid. Oral intake was encouraged in the ERP, facilitating earlier discontinuation of intravenous maintenance fluid. The subsequent reduction in postoperative crystalloid administered to the ERP group may have contributed to the reduction in postoperative ileus19. Gustafsson and colleagues20 compared the impact of different enhanced recovery elements in 953 patients, and found that the risk of postoperative symptoms delaying discharge increased by 16 per cent and the risk of complications by 32 per cent for each additional litre of fluid given during the day of operation. Targeted fluid therapy or GDFT can be used to optimize intravascular volume and therefore tissue perfusion, and may reduce LOS and postoperative complications after abdominal surgery21. This may have been particularly important in the present trial as the patients were relatively hypoperfused during liver resection. In this trial the LiDCOrapid™ was used to monitor cardiac output and guide intravenous fluid therapy. Other trials of ERP have used transoesophageal Doppler monitoring for this purpose22, but this is often poorly tolerated by conscious patients. The LiDCOrapid™ was used because the patients in this study were awake during the period of fluid optimization. Although the LiDCOrapid™ is uncalibrated, stroke volume optimization may still be achieved by monitoring the response to individual fluid challenges23. A notable finding in this trial was that, although epidural catheters were removed earlier in the ERP group (on POD 2), there was no increase in pain scores. This was probably due to early instigation of regular oral analgesia. Early removal of epidural catheters after major surgery may, if tolerated, be useful as early mobilization is a key component of ERPs, and an epidural is an impediment to this. To facilitate early mobilization, patients in the ERP group received physiotherapy sessions twice a day, compared with once in the standard treatment group. In addition, invasive tubes and catheters were removed as early as possible. This resulted in patients in the ERP group becoming independently mobile sooner than those who received standard care. In addition to the reduced LOS, there was a trend towards a reduction in overall morbidity in the ERP group. The overall complication rate of 17 per cent within the ERP compares favourably with rates of 37·7 and 41 per cent in previous studies of enhanced recovery for open liver resection8,9. Complications related to liver surgery (such as persistent bile leak or transient hepatic dysfunction) are unlikely to be affected by an ERP and, in keeping with this, no differences in such complications were noted between groups. However, there was a reduction in general medical morbidity in the ERP group. A recent meta-analysis of six colorectal RCTs found a similar reduction in morbidity in the ERP group6, but this was not confirmed in a more recent RCT24 or previous studies of enhanced recovery in liver surgery8–10. Here, the overall mortality rate for both groups was 2 per cent, similar to reported rates3,25. The relationship between the individual enhanced recovery elements is complex and it is still unclear which are most important. The exact definition of some of the elements is also open to interpretation. Comparison between different trials can be difficult because of the different number of enhanced recovery elements used, but there is also the question of compliance with these elements in the different studies. Even in a recent RCT on enhanced recovery in colonic surgery, compliance was only around 73 per cent in the ERP group compared with 40 per cent in controls24. Outcomes have been shown to improve with higher rates of compliance20, and thus the high compliance in the present trial may have contributed to the improved outcome. Interestingly, as 13 of 19 elements were already included in the standard care pathway, it appears that the six other elements had an effect in reducing postoperative medical complications. Unfortunately the reduction in morbidity cannot be attributed clearly to any one element of the ERP, such as early mobilization, use of nutritional supplements or the use of GDFT. Potentially the benefit comes through combining the elements to produce a series of ‘marginal gains’, and all elements must be delivered for an ERP to be fully effective20. Of the six individual elements that differed between the ERP and standard treatment, carbohydrate loading is one of the more extensively researched. Gustafsson and colleagues20 showed that carbohydrate loading reduced postoperative symptoms that could delay discharge (for example nausea and vomiting) by up to 44 per cent. Insulin resistance and consequent hyperglycaemia is an independent predictor of morbidity and mortality in major surgery26. Carbohydrate loading can reduce insulin resistance by up to 50 per cent27 and so may confer a major advantage. Reducing complications may also influence longer-term outcomes, as complications after major surgery have been shown to reduce survival28,29. A recent editorial has also suggested that enhanced recovery may have a role in improved cancer outcomes5, owing to changes in cell-mediated immunity and because patients may be fit enough for postoperative neoadjuvant chemotherapy more quickly. The present RCT was not double-blinded because of the nature of the intervention, a common difficulty with research in this area. In an attempt to minimize bias, an independent blinded clinician determined whether patients met the predefined fitness for discharge criteria; this has not been done in any other published trials of ERPs. Despite randomization, there were baseline differences between the two groups. A significantly greater proportion of patients in the ERP group had received preoperative neoadjuvant chemotherapy. Chemotherapy has two potential effects on the patient; it can cause liver parenchymal damage, increasing the risk of postoperative liver dysfunction30, and it can reduce cardiovascular fitness and therefore physiological reserve. Patients in the ERP group also had higher P-POSSUM operative severity scores. In spite of these differences, patients in this group were still discharged sooner. This study demonstrated an improvement in short-term QoL in the ERP group. A recent systematic review found that, although there was no evidence that an ERP adversely affected QoL, there was no strong evidence for an improvement either31. There is limited research in this area. Only ten studies were included in this review and many of them used only single-dimensional tools to measure QoL (such as fatigue scores only). This study has demonstrated that an ERP is a safe and effective intervention for patients undergoing open liver resection surgery. A comprehensive ERP with a high level of compliance with the different elements can result in a significant reduction in LOS and fewer postoperative medical complications, together with improved short-term QoL. Acknowledgements The authors thank L. Spring, the hepatobiliary clinical nurse specialist who was instrumental in organizing the patient diary and helped with patient follow-up; D. Clements, who carried out the blinded assessments; P. McCabe, a statistician from the University of Surrey who helped with the statistical analysis; H. Gage who helped design the QoL analysis and with the AUC calculation; and W. J. Fawcett and P. Prabhu who provided anaesthesia for a significant number of trial patients. Disclosure: LiDCOrapid™ smart cards were kindly provided by LiDCO, and Nutricia provided the preOp® carbohydrate drinks; neither had any input into the design of the study, nor the presentation and publication of the results. Thanks also go to GUTS (Guildford Undetected Tumour Screening) and LCSA (Liver Cancer Surgery Appeal) charities who kindly provided grants helping to fund the trial. The authors declare no other conflict of interest. References 1 Garden OJ , Rees M, Poston GJ, Mirza D, Saunders M, Ledermann J et al. Guidelines for resection of colorectal cancer liver metastases . Gut 2006 ; 55 ( Suppl 3 ): iii1 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Benzoni E , Molaro R, Cedolini C, Favero A, Cojutti A, Lorenzin D et al. Liver resection for HCC: analysis of causes and risk factors linked to postoperative complications . Hepatogastroenterology 2007 ; 54 : 186 – 189 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 3 Karanjia ND , Lordan JT, Fawcett WJ, Quiney N, Worthington TR. Survival and recurrence after neo-adjuvant chemotherapy and liver resection for colorectal metastases: a ten year study . Eur J Surg Oncol 2009 ; 35 : 838 – 843 . 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Google Scholar Crossref Search ADS PubMed WorldCat 31 Khan S , Wilson T, Ahmed J, Owais A, MacFie J. Quality of life and patient satisfaction with enhanced recovery protocols . Colorectal Dis 2010 ; 12 : 1175 – 1182 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Presented in part to the 15th World Federation of Societies of Anaesthesiologists World Congress of Anaesthesiologists, Buenos Aires, Argentina, March 2012, and the First International Enhanced Recovery After Surgery Congress, Cannes, France, October 2012; published in abstract form as Br J Anaesth 2012; 108(Suppl 2): ii242–ii243 © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd

Saunders, J H; Arya, P H; Abisi, S; Yong, Y P; MacSweeney, S; Braithwaite, B; Altaf, N

doi: 10.1002/bjs.9158pmid: 23696442

Abstract Background Recent international guidance recommends the use of catheter-directed thrombolysis (CDT) in selected patients with symptomatic iliofemoral deep vein thrombosis (DVT). The aim of this study was to estimate the potential increase in workload as a result of this recommendation. Methods Using the radiology database, a review was performed of all DVTs diagnosed between August 2010 and February 2012 at a large tertiary referral hospital. The National Institute for Health and Clinical Excellence and American College of Chest Physicians guidance was applied retrospectively to this cohort, using case-note review by two independent clinicians to determine which patients would have been suitable for CDT. Results Some 563 patients had DVT confirmed radiologically over the 18-month interval. Fifty-three of the 128 patients with iliofemoral DVT would have been eligible for intervention with CDT, equivalent to 4·4 patients per 100 000 per year. Only eight (15 per cent) of the 53 were actually referred to vascular services for treatment. All eight patients had successful CDT, which involved a stay in critical care for monitoring (median 2 (range 1–3) sessions). Conclusion Vascular units should be prepared for a major increase in the requirement for CDT for iliofemoral DVT. This increase will affect inpatient beds, the interventional radiology suite, critical care and interhospital referrals. Introduction Acute deep vein thrombosis (DVT) of the iliofemoral vein is a significant cause of morbidity. Standard anticoagulation decreases pulmonary embolism and thrombus propagation, but does not treat the occlusion itself. Up to half of all patients with an iliofemoral DVT treated by anticoagulation alone subsequently develop post-thrombotic syndrome (PTS)1–3. PTS is associated with significant morbidity (leg swelling, pain, ulceration), resulting in poor quality of life, and lifelong socioeconomic implications4. Catheter-directed thrombolysis (CDT) aims to remove the obstructing thrombus and restore flow in the iliofemoral veins, thereby reducing the risk and severity of PTS in these patients. A Cochrane review suggested a significant reduction in PTS from 65 to 48 per cent with any thrombolysis5, and more recent systematic review reported PTS with systemic thrombolysis in 57 per cent reduced to 27 per cent with CDT6. The recently published Norwegian CaVenT trial7 provided good-quality evidence to support the American College of Chest Physicians (ACCP) guidelines8 as well as the recent UK National Institute for Health and Clinical Excellence (NICE) guidance9, which recommend a change in practice to the use of CDT in selected patients with symptomatic iliofemoral DVT10. The aim of this study was to assess the potential increase in workload from the implementation of these recommendations, and its effect on service provision. Methods This was a review of all DVTs diagnosed between August 2010 and February 2012 (18 months) at Nottingham University Hospitals NHS Trust (NUH). NUH provides services to a population of 800 000 across Nottinghamshire, with 1663 inpatient beds. The majority of patients referred to NUH with suspected DVT are assessed in the nurse-led DVT clinic, which is supported by physicians in the medical assessment unit. Onward referrals to vascular services are then made according to individual clinical judgement. The hospital radiology computer database was used to identify all patients with a radiologically confirmed leg DVT. Radiology reports were then examined independently by two investigators to determine the extent of the radiological thrombus. For a proximal thrombus to be considered for CDT, the entire deep venous outflow of the leg should be occluded (thrombus occluding both the common femoral and profunda veins, with or without suprainguinal extension into the iliac veins), as this group has the greatest risk of PTS1–3,11–15. The ACCP/NICE guidance was then applied retrospectively to this cohort, using case-note review by the two independent clinicians to determine which patients were potentially suitable for CDT. Any discrepancies were referred to a third clinician for adjudication. The outcomes, patient demographics, mode of presentation and exclusion criteria were all recorded. The ACCP/NICE guidance for inclusion criteria is clear, but not comprehensive, and leaves room for individual judgement around issues such as concomitant cancer. It suggests the following indications for CDT of symptomatic iliofemoral DVT: symptoms for fewer than 14 days, good functional status, life expectancy of 1 year or more, and low risk of bleeding. There is a 5–11 per cent risk of bleeding complications6, so careful patient selection is important to ensure that only patients with a high risk of PTS and a low risk of bleeding complications are offered intervention. To maintain this favourable risk–benefit ratio for CDT intervention, the literature upon which the ACCP/NICE guidance is based was examined, and the inclusion criteria for the three major international randomized clinical trials – CaVenT, CAtheter Versus Anticoagulation (CAVA) and ATTRACT7,16,17– were noted in order to create an evidence-based series of unambiguous selection criteria (Appendix S1, supporting information). These were applied to the cohort of patients, which also helped avoid the risk of interobserver bias. All patients treated with CDT in the series had intervention using a pharmacomechanical thrombectomy (PhMT) technique, by means of the AngioJet® system (Possis, Medical, Minneapolis, Minnesota, USA)18. If thrombus clearance was not achieved in the first session then a slow catheter-directed infusion of tissue plasminogen activator was commenced with concurrent heparinization. This was continued overnight, followed by further venography and repeat PhMT the following day, until thrombus clearance had been achieved. Results A total of 563 patients with a radiologically confirmed DVT were identified over the 18-month interval; 301 had a proximal (above-knee) DVT that could potentially have been referred to vascular services for further assessment (Table 1). Review of the radiological reports showed that 128 DVTs were extensive enough to be suitable for consideration for CDT. Table 1 Anatomical location of the above-knee deep vein thrombosis Proximal extent of thrombus . Deep venous outflow obstruction . No. of patients (n = 301) . Inferior vena cava Yes 3 (1·0) Iliac veins Yes 50 (16·6) Common femoral and profunda vein Yes 75 (24·9) Superficial femoral vein No 114 (37·9) Popliteal vein No 59 (19·6) Proximal extent of thrombus . Deep venous outflow obstruction . No. of patients (n = 301) . Inferior vena cava Yes 3 (1·0) Iliac veins Yes 50 (16·6) Common femoral and profunda vein Yes 75 (24·9) Superficial femoral vein No 114 (37·9) Popliteal vein No 59 (19·6) Values in parentheses are percentages. Open in new tab Table 1 Anatomical location of the above-knee deep vein thrombosis Proximal extent of thrombus . Deep venous outflow obstruction . No. of patients (n = 301) . Inferior vena cava Yes 3 (1·0) Iliac veins Yes 50 (16·6) Common femoral and profunda vein Yes 75 (24·9) Superficial femoral vein No 114 (37·9) Popliteal vein No 59 (19·6) Proximal extent of thrombus . Deep venous outflow obstruction . No. of patients (n = 301) . Inferior vena cava Yes 3 (1·0) Iliac veins Yes 50 (16·6) Common femoral and profunda vein Yes 75 (24·9) Superficial femoral vein No 114 (37·9) Popliteal vein No 59 (19·6) Values in parentheses are percentages. Open in new tab Of this group of 128 patients, 63·3 per cent were diagnosed and managed as an outpatient, 25·0 per cent were diagnosed as an outpatient but required admission for treatment, and 11·7 per cent were already in hospital when diagnosed. Their mean age was 64 (range 16–100) years and 50·8 per cent were men. The thrombus extended above the groin in 41·4 per cent. The suspected cause of thrombosis is outlined in Table 2. Table 2 Suspected cause of deep vein thrombosis . No. of patients (n = 128) . Spontaneous 68 (53·1) Immobility 21 (16·4) Hypercoagulability 5 (3·9) Cancer 21 (16·4) Intravenous drug use 9 (7·0) After surgery 3 (2·3) Pregnancy 1 (0·8) . No. of patients (n = 128) . Spontaneous 68 (53·1) Immobility 21 (16·4) Hypercoagulability 5 (3·9) Cancer 21 (16·4) Intravenous drug use 9 (7·0) After surgery 3 (2·3) Pregnancy 1 (0·8) Values in parentheses are percentages. Open in new tab Table 2 Suspected cause of deep vein thrombosis . No. of patients (n = 128) . Spontaneous 68 (53·1) Immobility 21 (16·4) Hypercoagulability 5 (3·9) Cancer 21 (16·4) Intravenous drug use 9 (7·0) After surgery 3 (2·3) Pregnancy 1 (0·8) . No. of patients (n = 128) . Spontaneous 68 (53·1) Immobility 21 (16·4) Hypercoagulability 5 (3·9) Cancer 21 (16·4) Intravenous drug use 9 (7·0) After surgery 3 (2·3) Pregnancy 1 (0·8) Values in parentheses are percentages. Open in new tab Examination of patient records revealed that, with application of the detailed selection criteria, 53 of the 128 patients would have been eligible for intervention with CDT of their iliofemoral DVT (Fig. 1). The reasons for exclusion are summarized in Table 3. The demographics of the patients considered suitable for intervention were similar to those of patients treated in other studies from the UK19,20 and USA21: mean age was 56 (range 16–80) years and 52 per cent were men. The thrombus extended above the groin in 43 per cent. The majority of the 53 patients (70 per cent) presented as an outpatient, 17 per cent as outpatients who needed admission, and 13 per cent were inpatients. The lower proportion of potential CDT patients in the group ‘outpatients requiring admission’ was due to exclusion of elderly patients who were unable to cope at home but too old for CDT. Fig. 1 Open in new tabDownload slide Patient selection for possible catheter-directed thrombolysis (CDT) for iliofemoral deep vein thrombosis Table 3 Reasons why catheter-directed thrombolysis not indicated . No. of patients (n = 75) . Disseminated malignancy 19 (25) Age > 80 years 32 (43) Intravenous drug use 9 (12) Poor functional status and immobility 7 (9) Chronicity (>14 days) 4 (5) After surgery 1 (1) Pregnancy 1 (1) Renal transplant 1 (1) Large abdominal aortic aneurysm 1 (1) . No. of patients (n = 75) . Disseminated malignancy 19 (25) Age > 80 years 32 (43) Intravenous drug use 9 (12) Poor functional status and immobility 7 (9) Chronicity (>14 days) 4 (5) After surgery 1 (1) Pregnancy 1 (1) Renal transplant 1 (1) Large abdominal aortic aneurysm 1 (1) Values in parentheses are percentages. Open in new tab Table 3 Reasons why catheter-directed thrombolysis not indicated . No. of patients (n = 75) . Disseminated malignancy 19 (25) Age > 80 years 32 (43) Intravenous drug use 9 (12) Poor functional status and immobility 7 (9) Chronicity (>14 days) 4 (5) After surgery 1 (1) Pregnancy 1 (1) Renal transplant 1 (1) Large abdominal aortic aneurysm 1 (1) . No. of patients (n = 75) . Disseminated malignancy 19 (25) Age > 80 years 32 (43) Intravenous drug use 9 (12) Poor functional status and immobility 7 (9) Chronicity (>14 days) 4 (5) After surgery 1 (1) Pregnancy 1 (1) Renal transplant 1 (1) Large abdominal aortic aneurysm 1 (1) Values in parentheses are percentages. Open in new tab These numbers represent 17 potential patients per month with an above-knee DVT who might have been referred to vascular services and an estimated three per month requiring CDT. This is equivalent to 4·4 patients per 100 000 population per year, and an estimated 29 per cent increase in the number of patients admitted to hospital for treatment of iliofemoral DVT. In the 18-month study interval, only eight of the 53 potentially suitable patients were actually referred to vascular services; all eight subsequently underwent CDT. Seven patients needed multiple sessions of PhMT to achieve complete thrombus clearance. Between these sessions thrombolysis was maintained overnight with a slow catheter-directed infusion. Four patients required two sessions and three patients required three sessions of PhMT; patients were all treated and monitored in the critical care unit. Three patients had May–Thurner syndrome and underwent venous stenting to prevent recurrence at the time of the second session of PhMT. Only one patient had a caval filter inserted before CDT, due to thrombus extending into the inferior vena cava. Routine caval filter insertion was not done22–25. There was a single complication from CDT: one episode of non-severe, self-limiting, gastrointestinal bleeding. Discussion Implementation of international guidelines for the management of iliofemoral DVT with CDT could have a significant service impact. This additional cohort of patients will require new pathways for referral and management, and careful planning for increased inpatient care, interventional treatment as well as critical care support. The development of a clear and well publicized strategy is required to ensure a smooth adoption of the new treatment pathway, and also to deal with potential barriers to CDT. Current nurse-led DVT assessment units identify iliofemoral DVT in 7–9 per cent of patients undergoing duplex ultrasound assessment20,21. These outpatient units clearly provide an efficient service for assessment and referral of patients who potentially require intervention. In the present study only eight (15 per cent) of 53 patients with iliofemoral DVT suitable for CDT were actually referred to vascular services. Vascular units should form links with DVT assessment services to support their practice and introduce new referral pathways. Education of medical colleagues is also important to ensure timely referral of hospital inpatients. Where expertise and facilities are not available, referral to larger centres will be required9. The current policy at this institution is for all patients undergoing infusion thrombolysis to be monitored in critical care. The impact of the extra workload might be reduced by centralizing these patients on an experienced specialist vascular ward. Single-session CDT (initial full thrombus clearance without requirement for overnight lysis with critical care support) has been described26–28, particularly with the Trellis® system (Trellis®-8 infusion system; Bacchus Vascular, Santa Clara, California, USA). Although one study demonstrated that caval filters placed before PhMT for iliofemoral DVT had evidence of thrombus in 2 of 7 patients29, concurrent symptomatic pulmonary embolism is rare in those undergoing CDT or PhMT without caval filter placement and reported in fewer than 1 per cent of patients22–24. Pragmatic indications for caval filter insertion include iliofemoral DVT while anticoagulated or proximal thrombus extension into the inferior vena cava. Routine (temporary) filter insertion carries its own potential complications, such as thrombosis, migration and perforation. It also requires a second procedure for filter removal25. Percutaneous mechanical thrombectomy alone does not remove sufficient thrombus, and so is best used in conjunction with CDT to provide PhMT25. PhMT has been used successfully in the treatment of peripheral arterial occlusions and recently a number of studies have reported that it improves the effectiveness of proximal DVT clearance29–31. This study was retrospective and therefore limited by the assumption that the outcomes from CDT are widely reproducible. Ongoing prospective controlled studies will provide more information about cost-effectiveness. The implementation of CDT guidelines for iliofemoral DVT will involve education of other medical disciplines, reorganization and expansion of services, with a significant increase in workload and bed occupancy. It is expected, however, to result in both long-term cost reduction and improved outcomes for patients with iliofemoral DVT. Acknowledgements Lead members of the Department of Vascular and Endovascular Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust: S. N. Chandrasekar, A. O. Oluwole and W. G. Tennant (consultant vascular surgeons), R. O'Neil, S. Travis, G. Ramjas, S. Whittaker and S. Habib (consultant vascular radiologists), and A. Beech (head vascular scientist). Disclosure: The authors declare no conflict of interest. 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J Vasc Interv Radiol 2007 ; 18 : 715 – 724 . Google Scholar Crossref Search ADS PubMed WorldCat 28 O'Sullivan GJ . The role of interventional radiology in the management of deep venous thrombosis: advanced therapy . Cardiovasc Intervent Radiol 2011 ; 34 : 445 – 461 . Google Scholar Crossref Search ADS PubMed WorldCat 29 Bush RL , Lin PH, Bates JT, Mureebe L, Zhou W, Lumsden AB. Pharmacomechanical thrombectomy for treatment of symptomatic lower extremity deep venous thrombosis: safety and feasibility study . J Vasc Surg 2004 ; 40 : 965 – 970 . Google Scholar Crossref Search ADS PubMed WorldCat 30 Lin PH , Zhou W, Dardik A, Mussa F, Kougias P, Hedayati N et al. Catheter-direct thrombolysis versus pharmacomechanical thrombectomy for treatment of symptomatic lower extremity deep venous thrombosis . Am J Surg 2006 ; 192 : 782 – 788 . Google Scholar Crossref Search ADS PubMed WorldCat 31 Martinez Trabal JL , Comerota AJ, LaPorte FB, Kazanjian S, DiSalle R, Sepanski DM. The quantitative benefit of isolated, segmental, pharmacomechanical thrombolysis (ISPMT) for iliofemoral venous thrombosis . J Vasc Surg 2008 ; 48 : 1532 – 1537 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Parikh S , Motarjeme A, McNamara T, Raabe R, Hagspiel K, Benenati JF et al. Ultrasound-accelerated thrombolysis for the treatment of deep vein thrombosis: initial clinical experience . J Vasc Interv Radiol 2008 ; 19 : 521 – 528 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Presented to the Annual Meeting of the Vascular Society of Great Britain and Ireland, Manchester, UK, November 2012; published in abstract form as Br J Surg 2013; 100(Suppl 2): 1 © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd

Musallam, K M; Porter, J B; Sfeir, P M; Tamim, H M; Richards, T; Lotta, L A; Peyvandi, F; Jamali, F R

doi: 10.1002/bjs.9176pmid: 23754644

Abstract Background Preoperative anaemia is associated with adverse postoperative outcomes. Data on raised preoperative haematocrit concentration are limited. This study aimed to evaluate the effect of raised haematocrit on 30-day postoperative mortality and vascular events in patients undergoing major surgery. Methods This was a cohort study using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Thirty-day mortality and vascular events, demographics and perioperative risk factors were obtained for adults undergoing major surgery. The adjusted effect of raised (over 0·50) compared with normal (0·41–0·50, American Medical Association reference range) preoperative haematocrit concentration on postoperative outcomes was assessed. Separate sex-specific analyses were also conducted, using haematocrit concentration thresholds commonly used in the diagnosis and management of apparent or absolute erythrocytosis. Results Some 3961 (2·0 per cent) of 197 469 patients had a raised haematocrit concentration before surgery. After adjustment, the 30-day postoperative mortality rate was higher in patients with raised haematocrit than in those without (odds ratio (OR) 2·23, 95 per cent confidence interval 1·77 to 2·80). Thirty-day rates of deep vein thrombosis (OR 1·95, 1·44 to 2·64) and pulmonary embolism (OR 1·79, 1·17 to 2·73), but not myocardial infarction or stroke, were also higher in patients with a raised haematocrit concentration. The effect on mortality was noted beyond the haematocrit thresholds of 0·48 in women and 0·52 in men; the effect estimates were considerably higher for values exceeding 0·54. Values between 0·41 and 0·45 were not associated with increased mortality risk. Similar observations were noted for venous thrombosis, although with apparent sex differences. Conclusion A raised haematocrit concentration was associated with an increased risk of 30-day mortality and venous thrombosis following major surgery. Introduction Efforts to increase awareness of an abnormal preoperative haematocrit concentration in patients undergoing major surgical procedures are mounting. This is attributed partly to the expanding body of evidence regarding the association between preoperative anaemia and adverse surgical outcomes. Preoperative anaemia is a risk factor for perioperative blood transfusion1. Recent evidence highlights that blood transfusion increases the risk of postoperative morbidity and mortality, even when as little as 1 unit of packed red blood cells (pRBC) has been given2–4. Moreover, even mild preoperative anaemia is associated with increased morbidity and mortality across a wide range of surgical procedures and settings, irrespective of transfusion status, age or sex4–7. Data on the effects of a raised preoperative haematocrit concentration on surgical outcomes are limited. The largest available study by Wu and colleagues6 was restricted to a cohort of elderly, mostly male veterans, and evaluated only mortality and cardiac events, leaving other serious morbidities unexplored. The remaining studies were small or primarily involved patients with polycythaemia vera8–10. Further study of the effects of raised haematocrit concentrations on postoperative outcomes is thus warranted, especially as a multitude of medical conditions can lead to raised haematocrit (Table S1, supporting information)11. The aim here was to establish whether patients presenting with a raised haematocrit concentration before major surgery were less likely to survive, or more likely to have arterial or venous events after operation, than those with normal haematocrit levels, using a large database from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). Methods This was a cohort study using data from the ACS NSQIP database. Details of the ACS NSQIP (http://www.acsnsqip.org) have been described5 and are summarized in Appendix S1 (supporting information). It is a validated outcomes registry designed to provide feedback to participating hospitals on 30-day risk-adjusted surgical mortality and morbidity12,13. The database includes deidentified data on demographics, perioperative variables and 30-day postoperative outcomes for adult patients undergoing major surgery in participating non-veterans' administration hospitals12. Trained surgical clinical reviewers collect patient data on admission from the medical chart, operative log, anaesthesia record, interviews with the attending surgeon and telephone interviews with the patient12. Data quality is ensured by comprehensive training of the nurse reviewers, an inter-rater reliability audit of participating sites, regular conference calls and an annual meeting14. For this study, the available files for the years 2008 (271 368 patients from 211 sites) and 2009 (336 190 patients from 237 sites) were retrieved for all major operations performed at participating ACS NSQIP medical centres. In accordance with the American University of Beirut's guidelines (which follow the US Code of Federal Regulations for the Protection of Human Subjects), institutional review board approval was not needed or sought for the present analysis because data were collected as part of quality assurance. Preoperative haematocrit concentration The study included all patients with a preoperative haematocrit concentration of at least 0·41, which corresponds to the lower limit of the American Medical Association normal reference range for haematocrit concentration (reference range 0·41–0·50)15. The patients were divided into two groups: normal haematocrit concentration (0·41–0·50) and raised haematocrit concentration (more than 0·50). The study cohort was also divided into six groups according to ascending haematocrit concentration values: 0·41 to less than 0·43, 0·43 to less than 0·45, 0·45 to 0·48, more than 0·48 to 0·52, more than 0·52 to 0·54, and more than 0·54. These latter values were selected based on clinically relevant thresholds for the diagnosis and management of various medical conditions leading to apparent or absolute erythrocytosis11. Postoperative outcomes Evaluated outcomes were 30-day postoperative mortality, myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism, defined as follows: any death occurring within 30 days following surgery, regardless of cause, in or out of hospital; an acute myocardial infarction manifested by one of the following: electrocardiographic changes, raised level of troponin greater than three times the upper level of the reference range, or physician diagnosis of myocardial infarction; embolic, thrombotic or haemorrhagic stroke with motor, sensory or cognitive dysfunction persisting for 24 h or more; deep vein thrombosis confirmed by duplex ultrasonography, venography or computed tomography (CT); and pulmonary embolism documented from a ventilation/perfusion (V-Q) scan interpreted as indicating a high probability of pulmonary embolism, or positive spiral CT, pulmonary arteriography or CT angiography. Statistical analysis Descriptive statistics are presented as mean(s.d.) and percentages. The unadjusted and adjusted odds ratios (ORs) and 95 per cent confidence intervals (c.i.) for each outcome were calculated for relevant preoperative haematocrit concentration groups. Models were built using multivariable logistic regression analysis, by adjusting the association between preoperative haematocrit concentration and outcome for potential confounders (all selected confounders entered into the model). Confounders were determined using directed acyclic graphs, and the following variables were considered as potential confounders: demographics (age, sex and race), general health status (American Society of Anesthesiologists (ASA) fitness grade), causes of apparent erythrocytosis (obesity, hypertension, smoking and alcohol use) and causes of secondary absolute erythrocytosis (preoperative pRBC transfusion, cancer, renal failure, and hypoxic disease – chronic obstructive pulmonary disease or congestive heart failure). Model discrimination was assessed using the C statistic. The analysis was also stratified according to surgical specialty, smoking history (an essential confounder) and serum creatinine level (to exclude the potential effect of dehydration). Data were near-complete, with missing values only for body mass index (2·9 per cent) that were replaced by the respective means for similar sex and age groups. All analyses were performed using SAS® software version 9.2 (SAS Institute, Cary, North Carolina, USA). Results Of 526 479 patients who had haematocrit concentration measured before the index operation, 197 469 had a level of at least 0·41 and were included in the present study. Their mean(s.d.) age was 54·7(16·2) years and 60·9 per cent were men. The prevalence of patients with a raised preoperative haematocrit concentration according to the American Medical Association criteria was 2·0 (95 per cent c.i. 1·9 to 2·1) per cent. Some 98·0 (97·9 to 98·1) per cent had normal values. Patients with a raised haematocrit concentration were older and more commonly men. They were also more likely to have a higher ASA fitness grade, and had a higher prevalence of hypertension, renal failure, chronic obstructive pulmonary disease and congestive heart failure. This group included a higher proportion of smokers and alcohol consumers, and they were more likely to have received more than 4 units of pRBC units before surgery (Table 1). Tables S2 and S3 (supporting information) detail the distribution of patients among surgical specialties and the ten most common procedures performed in each specialty. Table 1 Characteristics of 197 469 patients undergoing major surgery . Normal haematocrit . Raised haematocrit . (n = 193 508) . (n = 3961) . Mean(s.d.) age (years) 54·6(16·5) 59·0(14·8) Men (%) 60·4 86·2 Race (%) White 81·5 82·1 Black or African American 6·2 6·1 Other/unknown 12·3 11·7 ASA fitness grade* I or II 60·9 47·6 III 34·9 41·9 IV or V 4·2 10·5 Smoker during previous year (%) 24·4 41·8 Alcohol consumption (%)† 3·5 7·6 Obese (%)‡ 41·5 40·5 Hypertension requiring medication (%) 43·9 49·7 Renal failure (%)§ 0·7 1·2 Chronic obstructive pulmonary disease (%) 4·4 8·6 Dyspnoea (%) None 90·6 87·0 With moderate exertion 8·7 10·6 At rest 0·7 2·4 Congestive heart failure (%) 0·3 0·9 Disseminated cancer (%) 1·1 0·7 Chemotherapy in previous 30 days (%) 0·3 0·2 Preop. transfusion > 4 units pRBC (%) < 0·1 < 0·1 . Normal haematocrit . Raised haematocrit . (n = 193 508) . (n = 3961) . Mean(s.d.) age (years) 54·6(16·5) 59·0(14·8) Men (%) 60·4 86·2 Race (%) White 81·5 82·1 Black or African American 6·2 6·1 Other/unknown 12·3 11·7 ASA fitness grade* I or II 60·9 47·6 III 34·9 41·9 IV or V 4·2 10·5 Smoker during previous year (%) 24·4 41·8 Alcohol consumption (%)† 3·5 7·6 Obese (%)‡ 41·5 40·5 Hypertension requiring medication (%) 43·9 49·7 Renal failure (%)§ 0·7 1·2 Chronic obstructive pulmonary disease (%) 4·4 8·6 Dyspnoea (%) None 90·6 87·0 With moderate exertion 8·7 10·6 At rest 0·7 2·4 Congestive heart failure (%) 0·3 0·9 Disseminated cancer (%) 1·1 0·7 Chemotherapy in previous 30 days (%) 0·3 0·2 Preop. transfusion > 4 units pRBC (%) < 0·1 < 0·1 * American Society of Anesthesiologists (ASA) fitness grade: I, healthy; II, mild systemic disease but no functional limitations; III, severe systemic disease with definite functional limitations; IV, severe systemic disease that is a constant threat to life; V, moribund and unlikely to survive 24 h with, or without operation. † More than two drinks/day in previous 2 weeks. ‡ Body mass index at least 30 kg/m2. § Currently on dialysis. pRBC, packed red blood cell units. Open in new tab Table 1 Characteristics of 197 469 patients undergoing major surgery . Normal haematocrit . Raised haematocrit . (n = 193 508) . (n = 3961) . Mean(s.d.) age (years) 54·6(16·5) 59·0(14·8) Men (%) 60·4 86·2 Race (%) White 81·5 82·1 Black or African American 6·2 6·1 Other/unknown 12·3 11·7 ASA fitness grade* I or II 60·9 47·6 III 34·9 41·9 IV or V 4·2 10·5 Smoker during previous year (%) 24·4 41·8 Alcohol consumption (%)† 3·5 7·6 Obese (%)‡ 41·5 40·5 Hypertension requiring medication (%) 43·9 49·7 Renal failure (%)§ 0·7 1·2 Chronic obstructive pulmonary disease (%) 4·4 8·6 Dyspnoea (%) None 90·6 87·0 With moderate exertion 8·7 10·6 At rest 0·7 2·4 Congestive heart failure (%) 0·3 0·9 Disseminated cancer (%) 1·1 0·7 Chemotherapy in previous 30 days (%) 0·3 0·2 Preop. transfusion > 4 units pRBC (%) < 0·1 < 0·1 . Normal haematocrit . Raised haematocrit . (n = 193 508) . (n = 3961) . Mean(s.d.) age (years) 54·6(16·5) 59·0(14·8) Men (%) 60·4 86·2 Race (%) White 81·5 82·1 Black or African American 6·2 6·1 Other/unknown 12·3 11·7 ASA fitness grade* I or II 60·9 47·6 III 34·9 41·9 IV or V 4·2 10·5 Smoker during previous year (%) 24·4 41·8 Alcohol consumption (%)† 3·5 7·6 Obese (%)‡ 41·5 40·5 Hypertension requiring medication (%) 43·9 49·7 Renal failure (%)§ 0·7 1·2 Chronic obstructive pulmonary disease (%) 4·4 8·6 Dyspnoea (%) None 90·6 87·0 With moderate exertion 8·7 10·6 At rest 0·7 2·4 Congestive heart failure (%) 0·3 0·9 Disseminated cancer (%) 1·1 0·7 Chemotherapy in previous 30 days (%) 0·3 0·2 Preop. transfusion > 4 units pRBC (%) < 0·1 < 0·1 * American Society of Anesthesiologists (ASA) fitness grade: I, healthy; II, mild systemic disease but no functional limitations; III, severe systemic disease with definite functional limitations; IV, severe systemic disease that is a constant threat to life; V, moribund and unlikely to survive 24 h with, or without operation. † More than two drinks/day in previous 2 weeks. ‡ Body mass index at least 30 kg/m2. § Currently on dialysis. pRBC, packed red blood cell units. Open in new tab Patients with a raised preoperative haematocrit concentration had a higher incidence of all the adverse 30-day postoperative outcomes evaluated than patients with a normal level (Fig. 1). However, after adjustment for potential confounders, a raised haematocrit concentration was still associated with increased 30-day mortality (OR 2·23, 95 per cent c.i. 1·77 to 2·80), deep vein thrombosis (OR 1·95, 1·44 to 2·64) and pulmonary embolism (OR 1·79, 1·17 to 2·73), but not myocardial infarction (OR 1·09, 0·65 to 1·84) or stroke (OR 1·13, 0·66 to 1·93). The C statistic for the models ranged between 0·86 and 0·92, indicating good discrimination. Of note, when the association between preoperative haematocrit and 30-day postoperative mortality was adjusted for the rate of postoperative pulmonary embolism, the OR dropped minimally from 2·23 (1·77 to 2·80) to 2·20 (1·75 to 2·77), suggesting that the increased mortality risk was not due to fatal pulmonary embolism. Fig. 1 Open in new tabDownload slide Cumulative incidence of 30-day postoperative outcomes in patients with a raised or normal haematocrit concentration. *P < 0·001, †P = 0·030, ‡P = 0·047 (χ2 test) The association between raised preoperative haematocrit concentration and increased mortality and venous thrombosis was observed across all surgical specialties, with the greatest effects noted in general and vascular surgery (Table S4, supporting information). Moreover, the association was present irrespective of smoking history (Table S5, supporting information) or amount smoked, although with high uncertainty (Table S6, supporting information). The association between raised preoperative haematocrit concentration and increased mortality and venous thrombosis was also independent of age (at least 65 years) and serum creatinine level (below or above 1·2 mg/dl), confirming that the association was not affected by dehydration (Table S7, supporting information). Two sensitivity analyses were done. When considering the timing of preoperative haematocrit measurement, 98·3 per cent of patients had the measurement within 2 months of index surgery, 93·5 per cent within 1 month and 80·8 per cent within 14 days. When the analysis was restricted to each of the three groups, the results remained essentially unchanged. Moreover, as the ACS NSQIP records only preoperative use of more than 4 units of pRBC, an analysis was done that excluded these patients (2 patients with raised and 45 patients with normal haematocrit concentration) and which was also restricted to patients having same-day surgery (who were least likely to have received any pRBC transfusion; 181 177 patients, 91·7 per cent of study population); the results also remained unchanged. The analyses were conducted using the six relevant ascending preoperative haematocrit concentration groups: 0·41 to less than 0·43 (80 860 patients), 0·43 to less than 0·45 (59 147), 0·45 to 0·48 (44 945), more than 0·48 to 0·52 (11 276), more than 0·52 to 0·54 (812) and more than 0·54 (429) (Table 2). An effect on 30-day postoperative mortality was mainly noted beyond the thresholds of 0·48 in women and 0·52 in men (Fig. 2). These are the thresholds used to flag the need for further investigation of erythrocytosis11. Moreover, the effect estimates became considerably higher for both men and women beyond the 0·54 threshold, which is generally used to indicate the need for intervention in many conditions leading to erythrocytosis (Fig. 2)11. Haematocrit levels below the threshold of 0·45 in patients who require intervention11,16 were not associated with increased 30-day mortality. Similar observations were noted for 30-day postoperative deep vein thrombosis, although with greater variation and uncertainty, especially in women; the effects on the risk of pulmonary embolism were apparently restricted to men (Fig. S1, supporting information). The analysis also showed that women with a very high preoperative haematocrit concentration may be at increased risk of myocardial infarction and stroke, although with great uncertainty. Table 2 Odds ratios for 30-day postoperative mortality and vascular events according to ascending preoperative haematocrit concentration . Preoperative haematocrit concentration . 0·41 to < 0·43 (n = 80 860) . 0·43 to < 0·45 (n = 59 147) . 0·45 to 0·48 (n = 44 945) . > 0·48 to 0·52 (n = 11 276) . > 0·52 to 0·54 (n = 812) . > 0·54 (n = 429) . Death* 554 (0·7) 369 (0·6) 318 (0·7) 121 (1·1) 21 (2·6) 31 (7·2) Unadjusted OR† 1·00 (reference) 0·91 (0·80, 1·04) 1·03 (0·90, 1·19) 1·57 (1·29, 1·92) 3·85 (2·48, 5·98) 11·29 (7·76, 16·43) Adjusted OR‡ 1·00 (reference) 0·99 (0·87, 1·14) 1·20 (1·04, 1·39) 1·56 (1·27, 1·93) 2·21 (1·37, 3·57) 5·63 (3·67, 8·63) Myocardial infarction* 189 (0·2) 112 (0·2) 90 (0·2) 35 (0·3) 4 (0·5) 2 (0·5) Unadjusted OR† 1·00 (reference) 0·81 (0·64, 1·02) 0·86 (0·67, 1·10) 1·33 (0·93, 1·91) 2·11 (0·78, 5·70) 2·00 (0·50, 8·08) Adjusted OR† Referent 0·83 (0·65, 1·04) 0·88 (0·68, 1·13) 1·14 (0·79, 1·64) 1·21 (0·44, 3·29) 0·90 (0·22, 3·65) Stroke* 160 (0·2) 128 (0·2) 85 (0·2) 37 (0·3) 4 (0·5) 1 (0·2) Unadjusted OR† 1·00 (reference) 1·09 (0·87, 1·38) 0·96 (0·73, 1·24) 1·66 (1·16, 2·38) 2·50 (0·92, 6·75) 1·18 (0·17, 8·44) Adjusted OR† 1·00 (reference) 1·12 (0·88, 1·41) 0·98 (0·75, 1·28) 1·48 (1·03, 2·13) 1·48 (0·54, 4·04) 0·59 (0·08, 4·21) Deep vein thrombosis* 347 (0·4) 274 (0·5) 227 (0·5) 83 (0·7) 7 (0·9) 9 (2·1) Unadjusted OR† 1·00 (reference) 1·08 (0·92, 1·27) 1·18 (0·99, 1·39) 1·72 (1·34, 2·19) 2·01 (0·95, 4·28) 4·97 (2·55, 9·70) Adjusted OR† 1·00 (reference) 1·09 (0·93, 1·28) 1·19 (1·01, 1·42) 1·61 (1·26, 2·06) 1·48 (0·69, 3·15) 3·13 (1·59, 6·16) Pulmonary embolism* 214 (0·3) 172 (0·3) 137 (0·3) 47 (0·4) 4 (0·5) 1 (0·2) Unadjusted OR† 1·00 (reference) 1·10 (0·90, 1·34) 1·15 (0·93, 1·43) 1·58 (1·15, 2·16) 1·87 (0·69, 5·03) 0·88 (0·12, 6·29) Adjusted OR† 1·00 (reference) 1·12 (0·91, 1·37) 1·20 (0·97, 1·50) 1·59 (1·15, 2·20) 1·61 (0·60, 4·37) 0·67 (0·09, 4·81) . Preoperative haematocrit concentration . 0·41 to < 0·43 (n = 80 860) . 0·43 to < 0·45 (n = 59 147) . 0·45 to 0·48 (n = 44 945) . > 0·48 to 0·52 (n = 11 276) . > 0·52 to 0·54 (n = 812) . > 0·54 (n = 429) . Death* 554 (0·7) 369 (0·6) 318 (0·7) 121 (1·1) 21 (2·6) 31 (7·2) Unadjusted OR† 1·00 (reference) 0·91 (0·80, 1·04) 1·03 (0·90, 1·19) 1·57 (1·29, 1·92) 3·85 (2·48, 5·98) 11·29 (7·76, 16·43) Adjusted OR‡ 1·00 (reference) 0·99 (0·87, 1·14) 1·20 (1·04, 1·39) 1·56 (1·27, 1·93) 2·21 (1·37, 3·57) 5·63 (3·67, 8·63) Myocardial infarction* 189 (0·2) 112 (0·2) 90 (0·2) 35 (0·3) 4 (0·5) 2 (0·5) Unadjusted OR† 1·00 (reference) 0·81 (0·64, 1·02) 0·86 (0·67, 1·10) 1·33 (0·93, 1·91) 2·11 (0·78, 5·70) 2·00 (0·50, 8·08) Adjusted OR† Referent 0·83 (0·65, 1·04) 0·88 (0·68, 1·13) 1·14 (0·79, 1·64) 1·21 (0·44, 3·29) 0·90 (0·22, 3·65) Stroke* 160 (0·2) 128 (0·2) 85 (0·2) 37 (0·3) 4 (0·5) 1 (0·2) Unadjusted OR† 1·00 (reference) 1·09 (0·87, 1·38) 0·96 (0·73, 1·24) 1·66 (1·16, 2·38) 2·50 (0·92, 6·75) 1·18 (0·17, 8·44) Adjusted OR† 1·00 (reference) 1·12 (0·88, 1·41) 0·98 (0·75, 1·28) 1·48 (1·03, 2·13) 1·48 (0·54, 4·04) 0·59 (0·08, 4·21) Deep vein thrombosis* 347 (0·4) 274 (0·5) 227 (0·5) 83 (0·7) 7 (0·9) 9 (2·1) Unadjusted OR† 1·00 (reference) 1·08 (0·92, 1·27) 1·18 (0·99, 1·39) 1·72 (1·34, 2·19) 2·01 (0·95, 4·28) 4·97 (2·55, 9·70) Adjusted OR† 1·00 (reference) 1·09 (0·93, 1·28) 1·19 (1·01, 1·42) 1·61 (1·26, 2·06) 1·48 (0·69, 3·15) 3·13 (1·59, 6·16) Pulmonary embolism* 214 (0·3) 172 (0·3) 137 (0·3) 47 (0·4) 4 (0·5) 1 (0·2) Unadjusted OR† 1·00 (reference) 1·10 (0·90, 1·34) 1·15 (0·93, 1·43) 1·58 (1·15, 2·16) 1·87 (0·69, 5·03) 0·88 (0·12, 6·29) Adjusted OR† 1·00 (reference) 1·12 (0·91, 1·37) 1·20 (0·97, 1·50) 1·59 (1·15, 2·20) 1·61 (0·60, 4·37) 0·67 (0·09, 4·81) Values in parentheses are * percentages and † 95 per cent confidence intervals. Adjusted odds ratio (ORs) were derived from multivariable logistic regression models built by adjusting the association between preoperative haematocrit concentration and outcomes for the following variables: age, sex, race, American Society of Anesthesiologists grade, smoking, alcohol consumption, obesity, hypertension, renal failure, chronic obstructive pulmonary disease, dyspnoea, congestive heart failure, disseminated cancer, chemotherapy in previous 30 days, and preoperative transfusion of more than 4 units of packed red blood cells. Open in new tab Table 2 Odds ratios for 30-day postoperative mortality and vascular events according to ascending preoperative haematocrit concentration . Preoperative haematocrit concentration . 0·41 to < 0·43 (n = 80 860) . 0·43 to < 0·45 (n = 59 147) . 0·45 to 0·48 (n = 44 945) . > 0·48 to 0·52 (n = 11 276) . > 0·52 to 0·54 (n = 812) . > 0·54 (n = 429) . Death* 554 (0·7) 369 (0·6) 318 (0·7) 121 (1·1) 21 (2·6) 31 (7·2) Unadjusted OR† 1·00 (reference) 0·91 (0·80, 1·04) 1·03 (0·90, 1·19) 1·57 (1·29, 1·92) 3·85 (2·48, 5·98) 11·29 (7·76, 16·43) Adjusted OR‡ 1·00 (reference) 0·99 (0·87, 1·14) 1·20 (1·04, 1·39) 1·56 (1·27, 1·93) 2·21 (1·37, 3·57) 5·63 (3·67, 8·63) Myocardial infarction* 189 (0·2) 112 (0·2) 90 (0·2) 35 (0·3) 4 (0·5) 2 (0·5) Unadjusted OR† 1·00 (reference) 0·81 (0·64, 1·02) 0·86 (0·67, 1·10) 1·33 (0·93, 1·91) 2·11 (0·78, 5·70) 2·00 (0·50, 8·08) Adjusted OR† Referent 0·83 (0·65, 1·04) 0·88 (0·68, 1·13) 1·14 (0·79, 1·64) 1·21 (0·44, 3·29) 0·90 (0·22, 3·65) Stroke* 160 (0·2) 128 (0·2) 85 (0·2) 37 (0·3) 4 (0·5) 1 (0·2) Unadjusted OR† 1·00 (reference) 1·09 (0·87, 1·38) 0·96 (0·73, 1·24) 1·66 (1·16, 2·38) 2·50 (0·92, 6·75) 1·18 (0·17, 8·44) Adjusted OR† 1·00 (reference) 1·12 (0·88, 1·41) 0·98 (0·75, 1·28) 1·48 (1·03, 2·13) 1·48 (0·54, 4·04) 0·59 (0·08, 4·21) Deep vein thrombosis* 347 (0·4) 274 (0·5) 227 (0·5) 83 (0·7) 7 (0·9) 9 (2·1) Unadjusted OR† 1·00 (reference) 1·08 (0·92, 1·27) 1·18 (0·99, 1·39) 1·72 (1·34, 2·19) 2·01 (0·95, 4·28) 4·97 (2·55, 9·70) Adjusted OR† 1·00 (reference) 1·09 (0·93, 1·28) 1·19 (1·01, 1·42) 1·61 (1·26, 2·06) 1·48 (0·69, 3·15) 3·13 (1·59, 6·16) Pulmonary embolism* 214 (0·3) 172 (0·3) 137 (0·3) 47 (0·4) 4 (0·5) 1 (0·2) Unadjusted OR† 1·00 (reference) 1·10 (0·90, 1·34) 1·15 (0·93, 1·43) 1·58 (1·15, 2·16) 1·87 (0·69, 5·03) 0·88 (0·12, 6·29) Adjusted OR† 1·00 (reference) 1·12 (0·91, 1·37) 1·20 (0·97, 1·50) 1·59 (1·15, 2·20) 1·61 (0·60, 4·37) 0·67 (0·09, 4·81) . Preoperative haematocrit concentration . 0·41 to < 0·43 (n = 80 860) . 0·43 to < 0·45 (n = 59 147) . 0·45 to 0·48 (n = 44 945) . > 0·48 to 0·52 (n = 11 276) . > 0·52 to 0·54 (n = 812) . > 0·54 (n = 429) . Death* 554 (0·7) 369 (0·6) 318 (0·7) 121 (1·1) 21 (2·6) 31 (7·2) Unadjusted OR† 1·00 (reference) 0·91 (0·80, 1·04) 1·03 (0·90, 1·19) 1·57 (1·29, 1·92) 3·85 (2·48, 5·98) 11·29 (7·76, 16·43) Adjusted OR‡ 1·00 (reference) 0·99 (0·87, 1·14) 1·20 (1·04, 1·39) 1·56 (1·27, 1·93) 2·21 (1·37, 3·57) 5·63 (3·67, 8·63) Myocardial infarction* 189 (0·2) 112 (0·2) 90 (0·2) 35 (0·3) 4 (0·5) 2 (0·5) Unadjusted OR† 1·00 (reference) 0·81 (0·64, 1·02) 0·86 (0·67, 1·10) 1·33 (0·93, 1·91) 2·11 (0·78, 5·70) 2·00 (0·50, 8·08) Adjusted OR† Referent 0·83 (0·65, 1·04) 0·88 (0·68, 1·13) 1·14 (0·79, 1·64) 1·21 (0·44, 3·29) 0·90 (0·22, 3·65) Stroke* 160 (0·2) 128 (0·2) 85 (0·2) 37 (0·3) 4 (0·5) 1 (0·2) Unadjusted OR† 1·00 (reference) 1·09 (0·87, 1·38) 0·96 (0·73, 1·24) 1·66 (1·16, 2·38) 2·50 (0·92, 6·75) 1·18 (0·17, 8·44) Adjusted OR† 1·00 (reference) 1·12 (0·88, 1·41) 0·98 (0·75, 1·28) 1·48 (1·03, 2·13) 1·48 (0·54, 4·04) 0·59 (0·08, 4·21) Deep vein thrombosis* 347 (0·4) 274 (0·5) 227 (0·5) 83 (0·7) 7 (0·9) 9 (2·1) Unadjusted OR† 1·00 (reference) 1·08 (0·92, 1·27) 1·18 (0·99, 1·39) 1·72 (1·34, 2·19) 2·01 (0·95, 4·28) 4·97 (2·55, 9·70) Adjusted OR† 1·00 (reference) 1·09 (0·93, 1·28) 1·19 (1·01, 1·42) 1·61 (1·26, 2·06) 1·48 (0·69, 3·15) 3·13 (1·59, 6·16) Pulmonary embolism* 214 (0·3) 172 (0·3) 137 (0·3) 47 (0·4) 4 (0·5) 1 (0·2) Unadjusted OR† 1·00 (reference) 1·10 (0·90, 1·34) 1·15 (0·93, 1·43) 1·58 (1·15, 2·16) 1·87 (0·69, 5·03) 0·88 (0·12, 6·29) Adjusted OR† 1·00 (reference) 1·12 (0·91, 1·37) 1·20 (0·97, 1·50) 1·59 (1·15, 2·20) 1·61 (0·60, 4·37) 0·67 (0·09, 4·81) Values in parentheses are * percentages and † 95 per cent confidence intervals. Adjusted odds ratio (ORs) were derived from multivariable logistic regression models built by adjusting the association between preoperative haematocrit concentration and outcomes for the following variables: age, sex, race, American Society of Anesthesiologists grade, smoking, alcohol consumption, obesity, hypertension, renal failure, chronic obstructive pulmonary disease, dyspnoea, congestive heart failure, disseminated cancer, chemotherapy in previous 30 days, and preoperative transfusion of more than 4 units of packed red blood cells. Open in new tab Fig. 2 Open in new tabDownload slide Sex-stratified adjusted odds ratios for 30-day postoperative mortality, according to preoperative haematocrit concentration: 0·41 to less than 0·43 (43 866 women, 36 994 men), 0·43 to less than 0·45 (21 859 women, 37 288 men), 0·45 to 0·48 (9703 women, 35 242 men), more than 0·48 to 0·52 (1510 women, 9766 men), more than 0·52 to 0·54 (108 women, 704 men), and more than 0·54 (90 women, 339 men). The multivariable logistic regression model was built as described in Table 3 Discussion Using a large multicentre database, it was demonstrated that patients with a raised preoperative haematocrit concentration are at increased risk of 30-day mortality and venous, but not arterial, complications following major surgery. Risk estimates were established for several haematocrit concentration thresholds that carry diagnostic and treatment implications in patients with apparent or absolute erythrocytosis. Most available studies of raised haematocrit concentration have typically described morbidity and mortality in the long term. Raised haematocrit has been associated with a higher incidence of, and mortality from, cardiovascular disease and venous thrombosis in studies of patients with apparent or absolute erythrocytosis11,17–20. Studies evaluating outcomes in the short term, such as that relevant in the surgical setting, are limited. The largest available study found that raised haematocrit concentration was associated with increased mortality and cardiac events in elderly, mostly male, veterans undergoing major surgery6. The present study confirmed this increased risk, but extended these findings to a large cohort including adult men and women. A similarly increased risk of myocardial infarction (Wu and colleagues6 did not evaluate stroke) was not observed, except in women with very high haematocrit concentrations and with wide confidence intervals. As both studies undertook similar adjustment for potential confounders, this discrepancy may be attributed to the study populations themselves. In contrast to the present findings, Lubarsky and colleagues8 did not find an association between secondary erythrocytosis due to chronic obstructive pulmonary disease and the risk of postoperative thrombotic complications. This may be attributed to a different threshold used to record erythrocytosis (haemoglobin level 160 g/l), or more likely the limited sample size (200) in that study. Erythrocytosis leads to increased blood volume and viscosity, and subsequently increased cardiac afterload, decreased cardiac output and a higher risk of target organ damage6,21–22. Moreover, higher blood viscosity carries thrombogenic potential23–25. These alterations are probably exacerbated by surgery, and explain the increased mortality and venous complications observed here. The lack of effect on arterial events and the discrepancy in the observed outcomes between men and women warrant further investigation. Despite the heterogeneity in reference values for a normal haematocrit concentration, several thresholds have been established to help in the diagnosis and management of patients with apparent or absolute erythrocytosis11. It is generally recommended that patients with a haematocrit concentration above 0·48 (women) and 0·52 (men) undergo further evaluation to identify the underlying cause of erythrocytosis11. These were in fact the thresholds at which an association with adverse postoperative outcomes started to be noted in the present study. It is recommended that patients with apparent or absolute erythrocytosis do not undergo intervention (such as venesection) unless the haematocrit concentration is over 0·54 (more than 0·56 in patients with hypoxic pulmonary disease), the aim being to drop the haematocrit concentration to below 0·45 (less than 0·50 in hypoxic pulmonary disease)11. These are based mainly on observations of adverse outcomes around these thresholds, but are modifiable in the presence of other relevant risk factors11. The present data support the use of these thresholds as the target for interventional trials in the surgical setting, as a considerable rise in postoperative mortality was noted in patients with a preoperative haematocrit concentration above 0·54, whereas no risk was noted in patients with values below 0·45, although other intermediate thresholds with low risk could also be considered. Finally, establishment of risk estimates for haematocrit values in the non-anaemic range could help tailor management of anaemia and avoid overtreatment. This study had limitations. Owing to the nature of the data captured by the ACS NSQIP database, it was not possible to identify the exact underlying cause of raised haematocrit concentrations. Although the adverse effects attributed to raised haematocrit are probably independent of the underlying cause, an analysis directed towards groups with a specific cause of erythrocytosis would have been informative. Although adjustment was made for the potential confounding effects of such underlying causes, omitted variables and residual confounding remain characteristic of observational studies. The ACS NSQIP database does not record the use of venesection, antiaggregant or anticoagulant therapy. Had these measures been applied more commonly in patients with a raised haematocrit level or associated risk factors, the estimates of adverse postoperative outcomes may have been underestimated. In addition, about 6·5 per cent of the preoperative haematocrit concentrations were obtained more than 1 month before surgery and might not have been identical to the value at the time of the index operation. The reported effect of raised haematocrit on postoperative outcomes, however, remained significant, irrespective of the interval between preoperative measurement and operation. The present study confirmed that the relationship between preoperative haematocrit concentration and surgical outcomes is non-linear; patients with a raised haematocrit level had higher rates of mortality and vascular complications, similar to observations in patients with anaemia. It highlights the need for further investigation of the impact of haematocrit reduction on surgical outcomes. Preoperative management of causal factors may also help to reduce haematocrit concentration in time for the operation, without the need for further intervention. The efficacy and safety of preoperative venesection and perioperative thromboprophylaxis in this setting warrant future investigation. Acknowledgements The authors thank A. Soweid, J. J. Hoballah, M. Khalife and S. Zeineldine (American University of Beirut Medical Centre) for their help in collecting data and thoughtful comments on the final manuscript. 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Published by John Wiley & Sons Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd