NEWS & VIEWS SURGERY

NSAIDs and risk of anastomotic leaks after colorectal surgery Julie Ann M. Van Koughnett and Steven D. Wexner

NSAIDs provide improved pain control and reduce the use of opioids —both important components of enhanced recovery programs after colorectal surgery. However, the possible association between NSAID use and anastomotic leaks is greatly debated. Anastomotic leak remains an important concern due to the substantial associated morbidity. Van Koughnett, J. A. M. & Wexner, S. D. Nat. Rev. Gastroenterol. Hepatol. 11, 523–524 (2014); published online 29 July 2014; doi:10.1038/nrgastro.2014.130

Two studies published in the Journal of Gastrointestinal Surgery have assessed the effect of NSAIDs on the development of postoperative anastomotic leaks after elective colorectal surgery for IBD or colorectal cancer. Subendran et al.1 used a matched nested case–control design to compare 131 patients with and without leaks over a 10 year period, which is quite a large cohort compared with other studies on the topic and is a strength of the paper.1 Saleh et al.2 included a cohort of 731 patients over a 7 year period and compared groups who had received ketorolac (a nonselective NSAID) or no NSAIDs at all.2 Both the number of patients and number of anastomotic leaks were comparable between the groups. Saleh and colleagues found no increased risk of anastomotic leak in the ketorolac group and found that smoking was the only predictor of leak on multivariate analysis.2 In slight contrast, Subendran and colleagues did find a significant increase in anastomotic leaks in patients who received ketorolac (OR 2.09, CI 1.12–3.89, p 0.02); however, no significant increase in leaks was found in the NSAIDs group overall nor was there any significant association with cumulative NSAID utilization during h­ospital stay.1

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No surgical techniques or adjunctive therapies have been able to eliminate the risk of anastomotic leak

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Anastomotic leak is an important risk of primary anastomoses in colorectal surgery, occurring in about 3–5% of resections.1,2

The treatment of a leak ranges from a course of antibiotics, to percutaneous drainage, or re-operation and takedown of the anasto­ mosis. These treatments add substantial morbidity, cost and additional days in hospital. No surgical techniques or adjunctive therapies have been able to eliminate the risk of anasto­motic leak. As we continue to seek ways to decrease this complication of surgery, we have also come to focus on the patient’s experience, patient-centred care and cost-effective health-care delivery. Enhanc­ed recovery after surgery (ERAS®; ERAS Soci­ ety, Stockholm, Sweden) programs have sought to improve patient recovery after colorectal surgery through a multimodality approach, which includes early ambulation, return to solid diet, alternative medications for pain control and bowel recovery, and early discharge from hospital.3 Connor Delaney and colleagues have published extensively on ‘fast track’ programs with excellent results for both open and laparoscopic colorectal surgery.4 As narcotics slow bowel recovery, a large focus of the medications aspect of any ERAS®program is aimed at reducing the amount of narcotics received. Alternatives include oral and/or intravenous NSAIDs, among other things. A randomized study by Schlachta et al.5 in 2007 found that the addition of ketorolac improved pain control and other metrics such as time to flatus.5 However, although the study number was small, the authors were concerned about a nonsignificant trend toward anastomotic leak in the ketorolac group, prompting a call for further studies.5 Both animal and human studies have yielded conflicting results on the effect of

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NSAIDs on intestinal anastomoses. Klein investigated the subject in clinical and experimental models and found in one study that NSAIDs significantly reduced collagen deposition at colonic anasto­moses in rats, though this did not translate to reduced breaking strength of the anastomosis.6 Another animal study found ileal anastomoses to be more susceptible to leak than colonic anastomoses and that certain NSAIDs could be more detrimental than others.7 Gorissen et al.8 sought to clarify this issue by stratifying patients based on the class of NSAID prescribed and concluded that nonselective NSAIDs conferred a higher risk of leak compared with selective NSAIDs.8 Two meta-analyses found an increased odds ratio of about 2.1 for NSAID use and anastomotic leak, although one of them did not find a statistically significant difference. 9,10 Both meta-analyses suggested that low numbers and potentially biased patient selection might be masking an otherwise significant risk of anastomotic leak with NSAID use. Concern also exists regarding bleeding risk with preoperative and post­operative NSAIDs used in colo­ rectal surgery, though this issue has not been ­specifically examined in the literature. Both papers published in the Journal of Gastrointestinal Surgery have sought to clarify the confusion, but with differing study designs. Saleh and colleagues, using a retrospective design, reported relatively few leaks, but they included patients who received only ketorolac, which is a very relevant design given that many ERAS® programs and surgeons use ketorolac exclusively as their NSAID of choice.2 Although they concluded that ketorolac does not confer increased risk, it should be noted that they did find a dose-dependent increased leak rate with ketorolac use. This fact must be considered; we routinely limit ketorolac usage to 48–72 h post-surgery and specify dose limits for each patient. The study design of Subendran et al.1 showed a trend toward leaks with the use of NSAIDs, but more importantly showed a significant increase in leaks with ketorolac use. However, the increase was not dosedependent. Although neither study recommended stopping ketorolac or other NSAID use after colorectal surgery, both contained concerning findings that must be considered. VOLUME 11  |  SEPTEMBER 2014

NEWS & VIEWS Ideally, a sufficiently powered randomized multicentre trial is needed to definitively clarify the issue. Both Subendran and Saleh and their colleagues are to be commended for their efforts to shed light on this compli­cated issue; how­ever, physicians must continue to use their clinical judgement in selecting patients suitable for NSAID use after sur­ gery, carefully balancing the pain control and opioid-sparing benefits of NSAIDs with the potential risks and m­orbidity of an a­nastomotic leak. Division of General Surgery, Department of Surgery, University Hospital, Western University, 339 Windermere Road, Room C8‑128, London, Ontario N6A 5A5, Canada (J.A.M.V.K.). Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic Florida, 2950 Cleveland Clinic Boulevard, Weston, FL 33331, USA (S.D.W.). Correspondence to: S.D.W. [email protected]

SEPTEMBER 2014  |  VOLUME 11

Competing interests The authors declare no competing interests. 1.

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Subendran, J., Siddiqui, N., Victor, J. C., McLeod, R. S. & Govindarajan, A. NSAID use and anastomotic leaks following elective colorectal surgery: a matched case-control study. J. Gastrointest. Surg. http://dx.doi.org/ 10.1007/s11605‑014‑2563–8. Saleh, F. et al. Perioperative nonselective non‑steroidal anti-inflammatory drugs are not associated with anastomotic leakage after colorectal surgery. J. Gastrointest. Surg. http:// dx.doi.org/ 10.1007/s11605‑014‑2486–4. Gustafsson, U. O. et al. Guidelines for perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS(®)) Society recommendations. World J. Surg. 37, 259–284 (2013). Delaney, C. P. et al. ‘Fast track’ postoperative management protocol for patients with high co‑morbidity undergoing complex abdominal and pelvic colorectal surgery. Br. J. Surg. 88, 1533–1538 (2001). Schlachta, C. M. et al. Optimizing recovery after laparoscopic colon surgery (ORAL-CS): effect of intravenous ketorolac on length of



hospital stay. Surg. Endosc. 21, 2212–2219 (2007). 6. Klein, M. et al. Effect of postoperative diclofenac on anastomotic healing, skin wounds and subcutaneous collagen accumulation: a randomized, blinded, placebo-controlled, experimental study. Eur. Surg. Res. 48, 73–78 (2012). 7. van der Vijver, R. J., van Laarhoven, C. J., Lomme, R. M. & Hendriks, T. Diclofenac causes more leakage than naproxen in anastomoses in the small intestine of the rat. Int. J. Colorectal Dis. 28, 1209–1216 (2013). 8. Gorissen, K. J. et al. Risk of anastomotic leakage with non-steroidal anti-inflammatory drugs in colorectal surgery. Br. J. Surg. 99, 721–727 (2012). 9. Burton, T. P., Mittal, A. & Soop, M. Nonsteroidal anti-inflammatory drugs and anastomotic dehiscence in bowel surgery: systematic review and meta-analysis of randomized, controlled trials. Dis. Colon Rectum 56, 126–134 (2013). 10. Bhangu, A., Singh, P., Fitzgerald, J. E., Slesser, A. & Tekkis, P. Postoperative nonsteroidal antiinflammatory drugs and risk of anastomotic leak: meta-analysis of clinical and experimental studies. World J. Surg. http://dx.doi.org/ 10.1007/s00268‑014‑2531–1.

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Surgery. NSAIDs and risk of anastomotic leaks after colorectal surgery.

NSAIDs provide improved pain control and reduce the use of opioids--both important components of enhanced recovery programs after colorectal surgery. ...
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