Enhanced Recovery in Colorectal Surgery Good morning chairman, seniors and colleagues. It is my pleasure today to present to you all . One day, a patient came in for elective right hemicolectomy for his Ca Caecum and he asked : when can I be discharged after surgery? As I have important personal matters to deal with. can I be discharged after 4-5days ?” With regards to this question, I have looked into the literature and realized there are several measures, all together named enhanced recovery/ fast track surgery that can shorten the hospital stay without compromising outcomes. And I would like to share my findings on this topic. Joint Hospital Surgical Grand Round 24.10.2015 By Chau Pui Ling, Bonnie

Introduction Concept of fast track surgery since 1990s by Kehlet1 Evidence based and multidisciplinary approach Reduce stress Reduced morbidity Maintain postoperative physiological function Faster recovery Enhanced recovery is first conceptualized in the late 1990s by Kehlet, a Denmark surgeon It is an evidence based and multidisciplinary approach that aimed to reduce stress, maintain postoperative physiological function and enhanced mobilisation, and hereby leading to reduced morbidity, faster recovery and shorter hospital stay. The details of the approach would be elaborated in a later slide. Enhanced mobilisation Shorter hospital stay 1. Wilmore, D. W., & Kehlet, H. (2001). Management of patients in fast track surgery. BMJ: British Medical Journal (International Edition), 322(7284), 473

ERAS ERAS(Enhanced recovery after surgery) society first established ERAS protocol in colorectal surgery in 2005 Latest version published in 2013- colonic and rectal surgery2,3 More and more types of surgeries now included in ERAS- gastrectomy, radical cystectomy and pancreaticoduodenectomy The ERAS society was founded by a group of european surgeons and they first establish ERAS protocol in colorectal surgery in 2005. With reviews and updates by the panel from time to time, the latest version was published in 2013 and a separate protocol was set up for rectal surgery in addition to colonic surgery. The protocol was also extended to cover other surgeries and now included gastrectomy, radial cystectomy and pancreaticoduodenectomy. 2. Gustafsson, U., Scott, M., Schwenk, W., Demartines, N., Roulin, D., Francis, N., & ... Ljungqvist, O. (2013). Guidelines for Perioperative Care in Elective Colonic Surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations. World Journal Of Surgery, 37(2), 259-284. doi:10.1007/s00268-012-1772-0 3. Nygren, J., Thacker, J., Carli, F., Fearon, K., Norderval, S., Lobo, D., & ... Ramirez, J. (2012). Guidelines for perioperative care in elective rectal/pelvic surgery: Enhanced Recovery After Surgery (ERAS^®) Society recommendations. Clinical Nutrition, 31(6), 801-816. doi:10.1016/j.clnu.2012.08.012

Content Look into the ERAS pathway in colorectal surgery in elective setting Selected individual components- a) Preoperative: i) Bowel Preparation ii) Preoperative Fasting and Carbohydrate Loading b) Intraoperative: i) Laparoscopic and Modification of Surgical Access ii) Perioperative Analgesia ERAS pathway as a whole Conclusion and take home message For interest of time, I would focus on the implementation of ERAS pathway in elective colorectal surgery. The previously mentioned selected components would be elaborated further. Then I would provide an overview of the ERAS pathway as a whole in terms on efficacy and compliance

Postoperative Preoperative Intraoperative The ERAS protocol in colonic and rectal surgery comprised of 20 components which can be broadly divided into preoperative, intraoperative and postoperative factors as listed in this diagram. Previous studies have demonstrated the confounding effect of postoperative recovery on ERAS components compliance and therefore in this presentation I will focus on selected components including bowel preparation, preoperative carbohydrate loading, epidural analgesia and mode of surgical access which is not included in the diagram. The reason why I have chosen these components is that these have been shown to be either effective in promoting recovery or arguable in terms of their efficacy. Intraoperative Diagram adopted from www.intechopen.com

Preoperative Bowel Preparation Cochrane review 20114 20 trials included No statistically significant difference in wound infection (SSI) and anastomotic leakage rates comparing groups of no bowel preparation and those who received mechanical bowel preparation For rectal surgery further evaluation is needed, so as the case of laparoscopic surgery ERAS society recommendation: No routine mechanical bowel preparation; however, further studies are needed for evaluation in rectal surgery with defunctioning ileostomy The need of preoperative bowel preparation has been debated for long and a cochrane review published in 2011, which included 20 trials, demonstrated that there is no statistically significant difference in wound infection and anastomotic leakage rates comparing groups of no bowel preparation and those who received mechanical bowel preparation in colonic surgery However, the review concluded that further evaluation is needed for rectal surgery and laparoscopic surgery as the possible catastrophic effect of anastomotic leakage in rectal surgery and anticipated difficulty in tumour localization during laparoscopic surgery Based on this cochrane review, the ERAS society recommended no routine use of mechanical bowel preparation for colonic surgery and selected bowel preparation for rectal surgery with defunctioning ileostomy 4. Güenaga, K. F. (2011). Mechanical bowel preparation for elective colorectal surgery. Cochrane Database Of Systematic Reviews, (9), doi:10.1002/14651858.CD001544.pub4

Preoperative Bowel Preparation (2) What’s new? Recent retrospective analysis published in Annals of Surgery 8/2015 by American College of Surgeons National Surgical Quality Improvement Program ( ACS NSQIP) 5 Combined bowel preparation with mechanical cleansing and oral antibiotics resulted in significantly lower rates of incidence of incisional surgical site infection, anastomotic leakage and hospital readmission However, there is a recent retrospective analysis of prospectively entered data published in Annals of surgery in august this year by the American college of surgeon national surgical quality improvement program which questioned omitting bowel preparation before surgery and showed that combined bowel preparation with mechanical cleansing and oral antibiotics resulted in significantly lower rates of SSI, anastomotic leak and hospital stay 5. Kiran, R. P., Murray, A. A., Chiuzan, C., Estrada, D., & Forde, K. (2015). Combined Preoperative Mechanical Bowel Preparation With Oral Antibiotics Significantly Reduces Surgical Site Infection, Anastomotic Leak, and Ileus After Colorectal Surgery. Annals Of Surgery, 262(3), 416-425. doi:10.1097/SLA.0000000000001416

Preoperative Bowel Preparation (3) The study included nearly 5000 patients from 121 centers in 2012 with 4 levels of bowel prep status, namely no bowel preparation, mechanical bowel preparation only, oral antibiotics only and combined mechanical and oral antibiotics . Results showed that in the almost 30 per cent of patients who received mechanical bowel preparation and oral antibiotics have significantly lower rates of SSI and anastomotic leak compared to no bowel preparation without prolonging hospital stay. Either administration of mechanical bowel preparation or oral antibiotics alone does not significantly decrease infection complications

Preoperative Bowel Preparation (4) In this table from the paper, you can see that combined oral and mechanical bowel preparation resulted in significantly lower SSI and anastomotic leak compared to no preparation

Preoperative Bowel Preparation (5) The length of hospital stay is also significantly shortened in patients who received combined bowel preparation then no prep The study supports previous results that mechanical bowel prep confers no additional benefits compared to no bowel preparation. However, the combined mechanical oral bowel preparation seemed to have significantly decreased SSI and anastomotic leakage rates. Further randomized studies are needed to prove the benefits.

Postoperative Preoperative Intraoperative Next I m going to talk about preoperative fasting and carbohydrate loading Traditional beliefs that patient should be kept nil by mouth from midnight is abandoned by the ERAS society and they recommended shorter fasting period together with giving carbohydrate loaded drinks shortly before operation Let us look into the evidence behind the guideline Intraoperative Diagram adopted from www.intechopen.com

Preoperative Fasting and Carbohydrate Loading Meta-analysis published in 20136 21 randomised studies with 1685 patients, including those undergoing major abdominal surgery, laparoscopic cholecystectomy, hernia repair, thyroidectomy and orthopedic surgery. Results showed no overall difference in length of hospital stay between patients receiving preoperative carbohydrate treatment and placebo. However in subgroup analysis including patients who received preoperative carbohydrate treatment prior to major open abdominal surgery, length of stay is significantly reduced by 1 day (p=0.007) No reported aspiration pneumonitis No increase in complications In a metaanalysis published in 2013, including 21 randomised studies with 1700 patients undergoing different typs of operation from major abdominal surgery, lap choles to orthopedic surgery Results showed that there is no overall difference in length of hospital stay between patients receiving preoperative carbyhydrate treatment and placebo. However, in subgroup analysis where only patients undergoing major open abdominal surgery were included, the hospital stay is significantly recduced by 1 day in patients who received carbohydrate treatment There is no reported aspiration pneumonitis and no increase in complications 6. Awad, S., Varadhan, K. K., Ljungqvist, O., & Lobo, D. N. (2013). A meta-analysis of randomised controlled trials on preoperative oral carbohydrate treatment in elective surgery. Clinical Nutrition, 32(1), 34-44. doi:10.1016/j.clnu.2012.10.011

Preoperative Fasting and Carbohydrate Loading (2) This is the table showing a significant reduction in length of stay in patients undergoing major open abdominal surgery who received preoperative carbohydrate treatment.

Preoperative Fasting and Carbohydrate Loading (3) ERAS recommendation: Clear fluids allowed up to 2 hours and solids up to 6 hours prior to induction of anaesthesia. Preoperative carbohydrate treatment should be used routinely Giving fluid containing high concentration of complex carbohydrates can enable patients to undergo surgery in a metabolically fed state Reduced postoperative thirst, hunger and anxiety The ERAS society thus recommended allowing solids up to 6 hours and clear fluids up to 2 hours before induction. A preoperative carbohydrate loaded drink should be given to all patients The theory behind is that complex carbohydrates can enable patients to undergo surgery in a metabolically fed state, reducing postoperative insulin resistance and improved well being after operation

Laparoscopic and Modification of Surgical Access LAFA trial in 2011 LAFA trial is a RCT7 with 9 Dutch hospitals comprising 427 patients from age 40-80, randomized into 4 treatment groups (laparoscopic/fast track, lap/standard, open/ FT, open/standard), only colectomy patients included Results showed Lap/ FT care resulted in significantly faster recovery after colonic surgery than all other combinations in terms of shorter total hospital stay by a median of 1 day. Overall morbidity, complications and mortality did not differ significantly For intraoperative factors, The mode of surgical approach has been discussed with ERAS protocol Some may question that with a fast track protocol, whether the well known benefits of laparoscopy will be overcome by the improved patient recovery, and that a open surgery within an ERAS protocol may produce similar outcome The LAFA trial is an RCT randomising 400sth colectomy patients into 4 treatment groups namely, laparoscopic /fast tract, lap/standard/ open/FT, open /standard 7.Vlug, M. S., Wind, J., Hollmann, M. W., Ubbink, D. T., Cense, H. A., Engel, A. F., & ... Bemelman, W. A. (2011). Laparoscopy in combination with fast track multimodal management is the best perioperative strategy in patients undergoing colonic surgery: a randomized clinical trial (LAFA-study). Annals Of Surgery, 254(6), 868-875. doi:10.1097/SLA.0b013e31821fd1ce

LAFA-Trial This table showed that the total hospital stay is shortened by 1-2days comparing Lap/FT with all the other groups and is statisfically significant

LAFA Trial (2) This table showed that the over complications is not different between all 4 groups In summary , LAFA trial concluded that combined laparoscopy and fast track protocol leads to best perioperative outcomes

Laparoscopy and Modification of Surgical Access (2) ERAS recommendation: Laparoscopic surgery for colonic resections is recommended if expertise is available Reduced postoperative complications, pain and hospital stay without compromising oncological outcomes The ERAS society also supported this and recommended laparoscopic surgery for colonic resections.

Postoperative Preoperative Intraoperative For the last eras elements that im going to talk about is the choice of perioperative analgesia, which may be of greater interests in anaesthetists. Intraoperative Diagram adopted from www.intechopen.com

Perioperative Analgesia ERAS recommendation: In open surgery: Thoracic epidural analgesia with low dose local anaesthetic and opioids should be used In laparoscopic surgery: In alternative to TEA is a carefully administered spinal analgesia with a low dose long acting opioid; opioids should be avoided to prevent PONV and ileus ERAS recommended that thoracic epidural analgesia should be used in open surgery and that in lap surgery, spinal analgesia can be used as an alternative The use of opioids should be minimised or avoided to prevent postoperative nausea and vomittng and ileus.

Perioperative Analgesia (2) RCT on epidural vs patient controlled analgesia for laparoscopic colorectal surgery in ERP- Annals of surgery 4/201510 128 patients from a single center randomised to PCA/ EDA Medical recovery was shorter by median of 1 day in PCA group compared to EDA group (4 days vs 5 days), but did not reach statistical significance Subgroup analysis excluding patients with major complications showed that medical recovery was achieved in significantly shorter time in PCA group compared to EDA group Overall hospital stay similar But recent study has been publish to disagree on the recommendation. A RCT comparing epidural vs PCA for lap colorectal surgery within an enhanced recovery program discovered that medical recovery was shortened by 1 day in PCA group then EDA group, but not reaching statistical significance In subgroup analysis excluding patient with major complications which will prolong the hospital stay The results became significant Overall hospital stay ( where patients may stay after medical recovery achieved due to social reasons) was similar Base on the results, the authors do not recommend epidural in laparoscopic surgery 10. Hübner, M., Blanc, C., Roulin, D., Winiker, M., Gander, S., & Demartines, N. (2015). Randomized clinical trial on epidural versus patient-controlled analgesia for laparoscopic colorectal surgery within an enhanced recovery pathway. Annals Of Surgery, 261(4), 648-653. doi:10.1097/SLA.0000000000000838

Meta-analysis of ERAS Meta-analysis of 16 RCTs published in 12/201311 ERAS reduced overall morbidity rates with decreased non-surgical complications and shortened hospital stay (mean LOS 5.8 days in ERAS vs 8 days in standard group) without increasing readmission rates 16 RCTs, no of items applied ranged from 4 to 13, most frequently applied items included early feeding, no routine nasogastric tubes, early mobilisation, no preoperative fasting and epidural anaesthesia Then I am going to look into the ERAS pathway as a whole and examine the efficacy and compliance issues There is a metaanalysis of ERAS involving 16 RCT published in 2013 Showing that ERAS can reduce overall morbidity rates with decreased non surgical complicas and shortened hospital stay by ~ 2days Readmission rates were not increase The no of ERAS elements applied in the 16 RCT ranged from 4 to 13, and the most commonly adopted items including early feeding, no routine nasogastric tubes, early mobilisation, no preoperative fasting and epidural anaesthesia 11. Greco, M., Capretti, G., Beretta, L., Gemma, M., Pecorelli, N., & Braga, M. (2014). Enhanced recovery program in colorectal surgery: a meta-analysis of randomized controlled trials. World Journal Of Surgery, 38(6), 1531-1541. doi:10.1007/s00268-013-2416-8

Non surgical complications are significantly reduced

Length of hospital stay is also significantly reduced

Impact of Compliance of ERAS Retrospective review of a prospectively entered international database of 1509 colonic and 843 rectal resections between 2008 to 2013 in 6 countries12 As there are so many items in the ERAS protocol, One would certainly question the relative benefit of each component to the program A retrospective review was published by the ERAS compliance group in june this year They looked into 1500 colonic and 800 + rectal resections in 5 years interval across 6 conutries 12. The Impact of Enhanced Recovery Protocol Compliance on Elective Colorectal Cancer Resection: Results From an International Registry. (2015). Annals Of Surgery, 261(6), 1153-1159. doi:10.1097/SLA.0000000000001029

Impact of Compliance of ERAS (2) Results showed that use of laparoscopy, total intravenous anaesthesia, and preoperative carbohydrate drinks are associated with a significant reduction in lOS One interesting point to note is that use of epidural analgesia is associated with an increased LOS , in keeping with the findings of the RCT mentioned earlier on

Compliance and Length of Stay Median LOS OR/95% CI/ P <50% 8 days ( IQR 6-10) - 75-90% OR=0.94/ 95%% CI 0.90-0.98/ P=0.012 >90% 6 days (IQR 4-8) OR= 0.88/ 95% CI 0.82-0.92/ P<0.001 Compliance is also inversely proportional to LOS Increasing compliance >90% has signicifantly shorter LOS in patients with less than 50% compliance

Compliance and Complications Rate OR/95% CI/P <50% 47.8% (120/251 cases) - 75-90% 41.3% (251/614 cases) OR=0.85/ 95%CI 1.40-1.64/ P<0.001 >90% 33.3% (100/300 cases) OR=0.69/ 95%CI 0.50-0.89/ P<0.001 Likewise, Compliance is also inversely proportional to complications raate Patient with >90% compliance had lower complications rate compared to patients with <50% compliance

Conclusion Some of the items have already been adopted in standard care-maintenance of normothermia, antimicrobial prophylaxis However, idea of ERAS in terms of evidence based medicine is fundamental for modern medicine Laparoscopic surgery, preoperative carbohydrate loading are shown to be effective in promoting early recovery Methods of analgesia, bowel preparation may need further studies for evaluation Increasing compliance may lead to improved efficacy

Reference Wilmore, D. W., & Kehlet, H. (2001). Management of patients in fast track surgery. BMJ: British Medical Journal (International Edition), 322(7284), 473 Gustafsson, U., Scott, M., Schwenk, W., Demartines, N., Roulin, D., Francis, N., & ... Ljungqvist, O. (2013). Guidelines for Perioperative Care in Elective Colonic Surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations. World Journal Of Surgery, 37(2), 259-284. doi:10.1007/s00268-012-1772-0 Kiran, R. P., Murray, A. A., Chiuzan, C., Estrada, D., & Forde, K. (2015). Combined Preoperative Mechanical Bowel Preparation With Oral Antibiotics Significantly Reduces Surgical Site Infection, Anastomotic Leak, and Ileus After Colorectal Surgery. Annals Of Surgery, 262(3), 416-425. doi:10.1097/SLA.000000000000141 Güenaga, K. F. (2011). Mechanical bowel preparation for elective colorectal surgery. Cochrane Database Of Systematic Reviews, (9), doi:10.1002/14651858.CD001544.pub Awad, S., Varadhan, K. K., Ljungqvist, O., & Lobo, D. N. (2013). A meta-analysis of randomised controlled trials on preoperative oral carbohydrate treatment in elective surgery. Clinical Nutrition, 32(1), 34-44. doi:10.1016/j.clnu.2012.10.011 Vlug, M. S., Wind, J., Hollmann, M. W., Ubbink, D. T., Cense, H. A., Engel, A. F., & ... Bemelman, W. A. (2011). Laparoscopy in combination with fast track multimodal management is the best perioperative strategy in patients undergoing colonic surgery: a randomized clinical trial (LAFA-study). Annals Of Surgery, 254(6), 868-875. doi:10.1097/SLA.0b013e31821fd1ce Kennedy, R. H., Francis, A., Dutton, S., Love, S., Pearson, S., Blazeby, J. M., & ... Kerr, D. J. (2012). EnROL: a multicentre randomised trial of conventional versus laparoscopic surgery for colorectal cancer within an enhanced recovery programme. BMC Cancer, 12181. doi:10.1186/1471-2407-12-18 Greco, M., Capretti, G., Beretta, L., Gemma, M., Pecorelli, N., & Braga, M. (2014). Enhanced recovery program in colorectal surgery: a meta-analysis of randomized controlled trials. World Journal Of Surgery, 38(6), 1531-1541. doi:10.1007/s00268-013-2416-8 The Impact of Enhanced Recovery Protocol Compliance on Elective Colorectal Cancer Resection: Results From an International Registry. (2015). Annals Of Surgery, 261(6), 1153-1159. doi:10.1097/SLA.0000000000001029 Hübner, M., Blanc, C., Roulin, D., Winiker, M., Gander, S., & Demartines, N. (2015). Randomized clinical trial on epidural versus patient-controlled analgesia for laparoscopic colorectal surgery within an enhanced recovery pathway. Annals Of Surgery, 261(4), 648-653. doi:10.1097/SLA.0000000000000838

Thank you