World Journal of Surgery

, Volume 38, Issue 9, pp 2247–2257 | Cite as

Postoperative Nonsteroidal Anti-inflammatory Drugs and Risk of Anastomotic Leak: Meta-analysis of Clinical and Experimental Studies

  • Aneel Bhangu
  • Prashant Singh
  • J. Edward F. Fitzgerald
  • Alistair Slesser
  • Paris Tekkis
Article

Abstract

Background

Enhanced recovery programs following colorectal resection recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as part of multimodal analgesia. The present study aimed to assess whether postoperative NSAID use increased the risk of anastomotic leak.

Methods

A systematic review of published literature was performed for studies comparing anastomotic leak following NSAID administration versus control. Meta-analysis was conducted for studies in human patients and experimental animal models. The primary endpoint was anastomotic leak.

Results

The final analysis included 8 studies in humans and 12 experimental animal studies. Use of NSAIDs was significantly associated with anastomotic leak in humans (8 studies, 4,464 patients, odds ratio [OR] 2.14; p < 0.001). This effect was seen with nonselective NSAIDs (6 studies, 3,074 patients, OR 2.37; p < 0.001), but not with selective NSAIDs (4 studies, 1,223 patients, OR 2.32; p = 0.170). There was strong evidence of selection bias from all clinical studies, with additional inconsistent definitions and outcomes assessment. From experimental animal models, anastomotic leak was more likely with NSAID use (ten studies, 575 animals, OR 9.51; p < 0.001). Bursting pressures at day 7 were significantly lower in NSAID versus controls (7 studies, 168 animals, weighted mean difference −35.7 mmHg; p < 0.001).

Conclusions

Emerging data strongly suggest that postoperative NSAIDs are linked to anastomotic leak, although most studies are flawed and may be describing pre-existing selection bias. However, when combined with experimental data, these increasing concerns suggest caution is needed when prescribing NSAIDs to patients with pre-existing risk factors for leak, until more definitive evidence emerges.

Supplementary material

268_2014_2531_MOESM1_ESM.doc (68 kb)
Supplementary material 1 (DOC 68 kb)

References

  1. 1.
    Allison AS, Bloor C, Faux W et al (2010) The angiographic anatomy of the small arteries and their collaterals in colorectal resections: some insights into anastomotic perfusion. Ann Surg 251:1092–1097PubMedCrossRefGoogle Scholar
  2. 2.
    Baron JA, Sandler RS, Bresalier RS et al (2006) A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 131:1674–1682PubMedCrossRefGoogle Scholar
  3. 3.
    Benjamin B, Hazut O, Shaashua L et al (2010) Effect of beta blocker combined with COX-2 inhibitor on colonic anastomosis in rats. Int J Colorectal Dis 25:1459–1464PubMedCrossRefGoogle Scholar
  4. 4.
    Boccola MA, Buettner PG, Rozen WM et al (2011) Risk factors and outcomes for anastomotic leakage in colorectal surgery: a single-institution analysis of 1576 patients. World J Surg 35:186–195. doi:10.1007/s00268-010-0831-7 PubMedCrossRefGoogle Scholar
  5. 5.
    Bruce J, Krukowski ZH, Al-Khairy G et al (2001) Systematic review of the definition and measurement of anastomotic leak after gastrointestinal surgery. Br J Surg 88:1157–1168PubMedCrossRefGoogle Scholar
  6. 6.
    Burton TP, Mittal A, Soop M (2013) Nonsteroidal anti-inflammatory drugs and anastomotic dehiscence in bowel surgery: systematic review and meta-analysis of randomized, controlled trials. Dis Colon Rectum 56:126–134PubMedCrossRefGoogle Scholar
  7. 7.
    Cahill RA, Sheehan KM, Scanlon RW et al (2004) Effects of a selective cyclo-oxygenase 2 inhibitor on colonic anastomotic and skin wound integrity. Br J Surg 91:1613–1618PubMedCrossRefGoogle Scholar
  8. 8.
    Chen JY, Wu GJ, Mok MS et al (2005) Effect of adding ketorolac to intravenous morphine patient-controlled analgesia on bowel function in colorectal surgery patients—a prospective, randomized, double-blind study. Acta Anaesthesiol Scand 49:546–551PubMedCrossRefGoogle Scholar
  9. 9.
    Chen JY, Ko TL, Wen YR et al (2009) Opioid-sparing effects of ketorolac and its correlation with the recovery of postoperative bowel function in colorectal surgery patients: a prospective randomized double-blinded study. Clin J Pain 25:485–489PubMedCrossRefGoogle Scholar
  10. 10.
    Coghill AE, Newcomb PA, Campbell PT et al (2011) Prediagnostic non-steroidal anti-inflammatory drug use and survival after diagnosis of colorectal cancer. Gut 60:491–498PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    de Hingh IH, van Goor H, de Man BM et al (2006) Selective cyclo-oxygenase 2 inhibition affects ileal but not colonic anastomotic healing in the early postoperative period. Br J Surg 93:489–497PubMedCrossRefGoogle Scholar
  12. 12.
    de Sousa JB, Soares EG, Aprilli F (1991) Effects of diclofenac sodium on intestinal anastomotic healing. Experimental study on the small intestine of rabbits. Dis Colon Rectum 34:613–617PubMedCrossRefGoogle Scholar
  13. 13.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188PubMedCrossRefGoogle Scholar
  14. 14.
    Esen E, Sucullu I, Sinan H et al (2008) The effects of non-steroid anti-inflammatory drugs on healing of colonic anastomosis in rats. Eastern J Med 13:13–18Google Scholar
  15. 15.
    Final Report on Carcinogens Background Document for Formaldehyde (2010) Rep Carcinog Backgr Doc (10-5981):i–512Google Scholar
  16. 16.
    Gorissen KJ, Benning D, Berghmans T et al (2012) Risk of anastomotic leakage with non-steroidal anti-inflammatory drugs in colorectal surgery. Br J Surg 99:721–727PubMedCrossRefGoogle Scholar
  17. 17.
    Gustafsson UO, Scott MJ, Schwenk W et al (2013) Guidelines for perioperative care in elective colonic surgery: enhanced recovery after surgery (ERAS) society recommendations. World J Surg 37:259–284. doi:10.1007/s00268-012-1772-0 PubMedCrossRefGoogle Scholar
  18. 18.
    Holte K, Andersen J, Jakobsen DH et al (2009) Cyclo-oxygenase 2 inhibitors and the risk of anastomotic leakage after fast-track colonic surgery. Br J Surg 96:650–654PubMedCrossRefGoogle Scholar
  19. 19.
    Inan A, Koca C, Sen M (2006) Effects of diclofenac sodium on bursting pressures of anastomoses and hydroxyproline contents of perianastomotic tissues in a laboratory study. Int J Surg 4:222–227PubMedCrossRefGoogle Scholar
  20. 20.
    Kearney PM, Baigent C, Godwin J et al (2006) Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 332(7553):1302–1308PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Klein M, Krarup PM, Burcharth J et al (2011) Effect of diclofenac on cyclooxygenase-2 levels and early breaking strength of experimental colonic anastomoses and skin incisions. Eur Surg Res 46:26–31PubMedCrossRefGoogle Scholar
  22. 22.
    Klein M, Gogenur I, Rosenberg J (2012) Postoperative use of non-steroidal anti-inflammatory drugs in patients with anastomotic leakage requiring reoperation after colorectal resection: cohort study based on prospective data. BMJ 345:e6166PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Klein M, Krarup PM, Kongsbak MB et al (2012) Effect of postoperative diclofenac on anastomotic healing, skin wounds and subcutaneous collagen accumulation: a randomized, blinded, placebo-controlled, experimental study. Eur Surg Res 48:73–78PubMedCrossRefGoogle Scholar
  24. 24.
    Kube R, Mroczkowski P, Granowski D et al (2010) Anastomotic leakage after colon cancer surgery: a predictor of significant morbidity and hospital mortality, and diminished tumour-free survival. Eur J Surg Oncol 36:120–124PubMedCrossRefGoogle Scholar
  25. 25.
    Lanas A, Baron JA, Sandler RS et al (2007) Peptic ulcer and bleeding events associated with rofecoxib in a 3-year colorectal adenoma chemoprevention trial. Gastroenterology 132:490–497PubMedCrossRefGoogle Scholar
  26. 26.
    Lassen K, Soop M, Nygren J et al (2009) Consensus review of optimal perioperative care in colorectal surgery: enhanced recovery after surgery (ERAS) group recommendations. Arch Surg 144:961–969PubMedCrossRefGoogle Scholar
  27. 27.
    Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127:820–826PubMedCrossRefGoogle Scholar
  28. 28.
    Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Mastboom WJ, Hendriks T, van Elteren P et al (1991) The influence of NSAIDs on experimental intestinal anastomoses. Dis Colon Rectum 34:236–243PubMedCrossRefGoogle Scholar
  30. 30.
    Mirnezami A, Mirnezami R, Chandrakumaran K et al (2011) Increased local recurrence and reduced survival from colorectal cancer following anastomotic leak: systematic review and meta-analysis. Ann Surg 253:890–899PubMedCrossRefGoogle Scholar
  31. 31.
    Neuss H, Raue W, Muller V et al (2009) Effects of cyclooxygenase inhibition on anastomotic healing following large bowel resection in a rabbit model—a randomized, blinded, placebo-controlled trial. Int J Colorectal Dis 24:551–557PubMedCrossRefGoogle Scholar
  32. 32.
    Peeters KC, Tollenaar RA, Marijnen CA et al (2005) Risk factors for anastomotic failure after total mesorectal excision of rectal cancer. Br J Surg 92:211–216PubMedCrossRefGoogle Scholar
  33. 33.
    Rothwell PM, Wilson M, Elwin CE et al (2010) Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376(9754):1741–1750PubMedCrossRefGoogle Scholar
  34. 34.
    Schlachta CM, Burpee SE, Fernandez C et al (2007) Optimizing recovery after laparoscopic colon surgery (ORAL-CS): effect of intravenous ketorolac on length of hospital stay. Surg Endosc 21:2212–2219PubMedCrossRefGoogle Scholar
  35. 35.
    Sim R, Cheong DM, Wong KS et al (2007) Prospective randomized, double-blind, placebo-controlled study of pre- and postoperative administration of a COX-2-specific inhibitor as opioid-sparing analgesia in major colorectal surgery. Colorectal Dis 9:52–60PubMedCrossRefGoogle Scholar
  36. 36.
    Trencheva K, Morrissey KP, Wells M et al (2013) Identifying important predictors for anastomotic leak after colon and rectal resection: prospective study on 616 patients. Ann Surg 257:108–113PubMedCrossRefGoogle Scholar
  37. 37.
    van der Vijver RJ, van Laarhoven CJ, de Man BM et al (2012) Perioperative pain relief by a COX-2 inhibitor affects ileal repair and provides a model for anastomotic leakage in the intestine. Surg Innov 20:113–118PubMedCrossRefGoogle Scholar
  38. 38.
    van der Vijver RJ, van Laarhoven CJ, Lomme RM et al (2013) Diclofenac causes more leakage than naproxen in anastomoses in the small intestine of the rat. Int J Colorectal Dis 28:1209–1216PubMedCrossRefGoogle Scholar
  39. 39.
    Varadhan KK, Neal KR, Dejong CH et al (2010) The enhanced recovery after Surgery (ERAS) pathway for patients undergoing major elective open colorectal surgery: a meta-analysis of randomized controlled trials. Clin Nutr 29:434–440PubMedCrossRefGoogle Scholar
  40. 40.
    Vlug MS, Wind J, Hollmann MW et al (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). Ann Surg 254:868–875PubMedCrossRefGoogle Scholar
  41. 41.
    Wattchow DA, De Fontgalland D, Bampton PA et al (2009) Clinical trial: the impact of cyclooxygenase inhibitors on gastrointestinal recovery after major surgery—a randomized double blind controlled trial of celecoxib or diclofenac vs. placebo. Aliment Pharmacol Ther 30:987–998PubMedCrossRefGoogle Scholar
  42. 42.
    Wells GA, O’Connell D, Peterson J, et al (2000) The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. In: 3rd symposium on systematic reviews: beyond the basics, Oxford, 2000Google Scholar
  43. 43.
    Wind J, Polle SW, Fung Kon Jin PH et al (2006) Systematic review of enhanced recovery programmes in colonic surgery. Br J Surg 93:800–809PubMedCrossRefGoogle Scholar

Copyright information

© Société Internationale de Chirurgie 2014

Authors and Affiliations

  • Aneel Bhangu
    • 1
    • 2
  • Prashant Singh
    • 1
    • 2
  • J. Edward F. Fitzgerald
    • 1
    • 2
  • Alistair Slesser
    • 1
    • 2
  • Paris Tekkis
    • 1
    • 2
  1. 1.Department of Colorectal SurgeryRoyal Marsden HospitalLondonUK
  2. 2.Division of SurgeryImperial CollegeLondonUK

Personalised recommendations