Skip to main content

Advertisement

SpringerLink
Log in

Risk of anastomotic leakage with use of NSAIDs after gastrointestinal surgery

  • Review
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

Analgesic regimes to avoid opioid-related adverse effects have been recommended in gastrointestinal surgery. Non-steroidal anti-inflammatory drugs (NSAIDs) are an important component of opioid sparing regimes in that these drugs indirectly reduce pain by inhibiting inflammation. Although beneficial for most surgical patients, animal studies and recent clinical studies suggest a harmful effect on new intestinal anastomoses by increasing the rate of leakage. NSAIDs may indirectly disturb anastomotic healing by inhibiting inflammation as an integrated part of the wound healing process in an early, critical phase after surgery.

Methods

A literature review based on a structured search in PubMed of clinical and experimental studies investigating the effects of NSAIDs on anastomotic healing and leakage rates after intestinal surgery, as well as proposed mechanisms and effects studied in animal models.

Results

Three recent observational cohort studies (accumulated n = 882) indicate an increased rate of anastomotic leakages (15–21%) associated with cyclooxygenase-2 (COX-2) selective NSAIDs after intestinal surgery compared to the leakage rates in controls or historical cohorts (1–4%). Three prospective studies on related topics contain relevant data on NSAIDs and are compared to these studies. Several experimental animal studies support an increased risk for anastomotic leakage with the use of NSAIDs.

Conclusion

The reported effects of NSAIDs on anastomotic healing suggest an increased risk for leakage. A better understanding of the complex interactions of NSAID-induced inhibition on anastomotic healing is a prerequisite for the safe use of NSAIDs. Until more data are available, a careful use of NSAIDs may be warranted in gastrointestinal anastomotic surgery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Pineda CE, Shelton AA, Hernandez-Boussard T et al (2008) Mechanical bowel preparation in intestinal surgery: a meta-analysis and review of the literature. J Gastrointest Surg 12:2037–2044

    Article  PubMed  Google Scholar 

  2. Shikata S, Yamagishi H, Taji Y et al (2006) Single- versus two-layer intestinal anastomosis: a meta-analysis of randomized controlled trials. BMC Surg 6:2–9

    Article  PubMed  Google Scholar 

  3. Pickleman J, Watson W, Cunningham J et al (1999) The failed gastrointestinal anastomosis: an inevitable catastrophe? J Am Coll Surg 188:473–482

    Article  PubMed  CAS  Google Scholar 

  4. Golub R, Golub RW, Cantu R et al (1997) A multivariate analysis of factors contributing to leakage of intestinal anastomoses. J Am Coll Surg 184:364–372

    PubMed  CAS  Google Scholar 

  5. Iancu C, Mocan LC, Todea-Iancu D et al (2008) Host-related predictive factors for anastomotic leakage following large bowel resections for colorectal cancer. J Gastrointestin Liver Dis 17:299–303

    PubMed  Google Scholar 

  6. Nandakumar G, Stein SL, Michelassi F (2009) Anastomoses of the lower gastrointestinal tract. Nat Rev Gastroenterol Hepatol 6:709–716

    Article  PubMed  Google Scholar 

  7. Sørensen LT, Jørgensen T, Kireby LT et al (1999) Smoking and alcohol abuse are major risk factors for anastomotic leakage in colorectal surgery. Br J Surg 86:927–931

    Article  PubMed  Google Scholar 

  8. Scharfenberg M, Raue W, Junghans T et al (2007) “Fast-track” rehabilitation after colonic surgery in elderly patients — is it feasible? Int J Colorectal Dis 22:1469–1474

    Article  PubMed  CAS  Google Scholar 

  9. 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 144:961–969

    Article  PubMed  Google Scholar 

  10. Hendry PO, Hausel J, Nygren J et al (2009) Determinants of outcome after colorectal resection within an enhanced recovery programme. Br J Surg 96:197–205

    Article  PubMed  CAS  Google Scholar 

  11. Kehlet H (2005) Postoperative opioid sparing to hasten recovery. Anesthesiology 102:1083–1085

    Article  PubMed  Google Scholar 

  12. Taylor S, Voytovich AE, Kozol RA (2003) Has the pendulum swung too far in postoperative pain control? Am J Surg 186:472–475

    Article  PubMed  Google Scholar 

  13. Marret E, Kurdi O, Zufferey P et al (2005) Effects of non-steroidal anti-inflammatory drugs on patient-controlled analgesia morphine side effects: meta-analysis of randomized controlled trials. Anesthesiology 102:1249–1260

    Article  PubMed  CAS  Google Scholar 

  14. Beck A, Krischak G, Sorg T et al (2003) Influence of diclofenac (group of non-steroidal anti-inflammatory drugs) on fracture healing. Arch Orthop Trauma Surg 123:327–332

    Article  PubMed  CAS  Google Scholar 

  15. Boursinos LA, Karachalios T, Poultsides L et al (2009) Do steroids, conventional non-steroidal anti-inflammatory drugs and selective cox-2 inhibitors adversely affect fracture healing? J Muskuloskelet Neuronal Interact 9:44–52

    CAS  Google Scholar 

  16. Dodwell ER, Latorre JG, Parisini E et al (2010) NSAID Exposure and Risk of Non-union: A Meta-Analysis of Case-Control and Cohort Studies. Calcif Tissue Int 87:193–202

    Article  PubMed  CAS  Google Scholar 

  17. Levi S, Goodlad RA, Lee CY et al (1990) Inhibitory effect of non-steroidal anti-inflammatory drugs on mucosal cell proliferation associated with gastric ulcer healing. Lancet 336:840–843

    Article  PubMed  CAS  Google Scholar 

  18. Ukawa H, Yamakuni H, Kato S et al (1998) Effects of cyclooxygenase-2 selective and nitric oxide-releasing non-steroidal anti-inflammatory drugs on mucosal ulcerogenic and healing responses of the stomach. Dig Dis Sci 43:2003–2011

    Article  PubMed  CAS  Google Scholar 

  19. Sánchez-Fidalgo S, Martín-Lacave I, Illanes M et al (2004) Angiogenesis, cell proliferation and apoptosis in gastric ulcer healing. Effect of a selective cox-2 inhibitor. Eur J Pharmacol 505:187–194

    Article  PubMed  Google Scholar 

  20. Ofman JJ, MacLean CH, Straus WL et al (2002) A meta-analysis of severe upper gastrointestinal complications of non-steroidal anti-inflammatory drugs. J Rheumatol 29:804–812

    PubMed  CAS  Google Scholar 

  21. McGettigan P, Henry D (2006) Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and non-selective inhibitors of cyclooxygenase 2. JAMA 296:1633–1644

    Article  PubMed  CAS  Google Scholar 

  22. Rainsford KD (2007) Anti-inflammatory drugs in the 21st century. Subcell Biochem 42:3–27

    Article  PubMed  CAS  Google Scholar 

  23. Warner TD, Mitchell JA (2004) Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 18:790–804

    Article  PubMed  CAS  Google Scholar 

  24. Fitzgerald GA (2004) Coxibs and cardiovascular disease. N Engl J Med 351:1709–1711

    Article  PubMed  CAS  Google Scholar 

  25. Zimmerman KC, Sarbia M, Schrör K et al (1998) Constitutively cyclooxygenase-2 expression in healthy human and rabbit gastric mucosa. Mol Pharmacol 54:536–540

    Google Scholar 

  26. Rosenberg J, Harvald T (2007) Severe complications with diclofenac after colonic resection. Dis Colon Rectum 50:685

    Article  PubMed  Google Scholar 

  27. Klein M, Andersen LP, Harvald T et al (2009) Increased risk of anastomotic leakage with diclofenac treatment after laparoscopic colorectal surgery. Dig Surg 26:27–30

    Article  PubMed  CAS  Google Scholar 

  28. 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 96:650–654

    Article  PubMed  CAS  Google Scholar 

  29. 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 21:2212–2219

    Article  PubMed  CAS  Google Scholar 

  30. 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 clinical trial of celecoxib or diclofenac vs. placebo. Aliment Pharmacol Ther 30:987–998

    Article  PubMed  CAS  Google Scholar 

  31. Vonkemann HE, Fernandes RW, van der Palen J et al (2007) Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to non-steroidal anti-inflammatory drugs: a nested case-control study. Nat Clin Pract Rheumatol 3:694–695

    Article  Google Scholar 

  32. Neuss H, Raue W, Müller 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 24:551–557

    Article  PubMed  Google Scholar 

  33. Mastboom WJ, Hendriks T, van Elteren P et al (1991) The influence of NSAIDs on experimental intestinal anastomoses. Dis Colon Rectum 34:236–243

    Article  PubMed  CAS  Google Scholar 

  34. 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 34:613–617

    Article  PubMed  Google Scholar 

  35. 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 91:1613–1618

    Article  PubMed  CAS  Google Scholar 

  36. 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 93:489–497

    Article  PubMed  Google Scholar 

  37. 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 4:222–227

    Article  PubMed  Google Scholar 

  38. Klein M, Krarup PM, Burcharth J et al (2011) Epub Dec 2010) Effect of diclofenac on cyclooxygenase-2 levels and early breaking strength of experimental colonic anastomoses and skin incisions. Eur Surg Res 46:26–31

    Article  PubMed  CAS  Google Scholar 

  39. Hirasawa N, Ohuchi K, Watanabe M et al (1987) Mechanism of the inhibitory action of cyclooxygenase inhibitors on leukocyte infiltration: involvement of endogenous histamine. Eur J Pharmacol 144:267–275

    Article  PubMed  CAS  Google Scholar 

  40. Menezes GB, Rezende RM, Pereira-Silva PE et al (2008) Differential involvement of cyclooxygenase isoforms in neutrophil migration in vivo and in vitro. Eur J Pharmacol 598:118–122

    Article  PubMed  CAS  Google Scholar 

  41. Ceelen W, El Malt M, Cardon A et al (2001) Influence of preoperative high-dose radiotherapy on postoperative outcome and colonic anastomotic healing: experimental study in the rat. Dis Colon Rectum 44:717–721

    Article  PubMed  CAS  Google Scholar 

  42. Jones MK, Wang H, Peskar BM et al (1999) Inhibition of angiogenesis by non-steroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 5:1418–1423

    Article  PubMed  CAS  Google Scholar 

  43. Midwood KS, Williams LV, Schwarzbauer JE (2004) Tissue repair and the dynamics of the extracellular matrix. Int J Biochem Cell Biol 36:1031–1037

    Article  PubMed  CAS  Google Scholar 

  44. Shen W, Prisk V, Li Y et al (2006) Inhibited skeletal muscle healing in cyclooxygenase-2 gene-deficient mice: the role of PGE2 and PGF2alpha. J Appl Physiol 101:1215–1221

    Article  PubMed  CAS  Google Scholar 

  45. Shigeta J, Takahashi S, Okabe S (1998) Role of cyclooxygenase-2 in the healing of gastric ulcers in rats. J Pharmacol Exp Ther 286:1383–1390

    PubMed  CAS  Google Scholar 

  46. Schmassmann A (1998) Mechanisms of ulcer healing and effects of non-steroidal anti-inflammatory drugs. Am J Med 104:43S–51S

    Article  PubMed  CAS  Google Scholar 

  47. Hatazawa R, Tanigami M, Izumi N et al (2007) Prostaglandin E2 stimulates VEGF expression in primary rat gastric fibroblasts through EP4 receptors. Inflammopharmacology 15:214–217

    Article  PubMed  CAS  Google Scholar 

  48. Gallo O, Franchi A, Magnelli L et al (2001) Cyclooxygenase-2 pathway correlates with VEGF expression in head and neck cancer. Implications for tumor angiogenesis and metastasis. Neoplasia 3:53–61

    Article  PubMed  CAS  Google Scholar 

  49. Bates DO (2010) Vascular endothelial growth factors and vascular permeability. Cardiovasc Res 87:262–271

    Article  PubMed  CAS  Google Scholar 

  50. Senger DR, Galli SJ, Dvorak AM et al (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985

    Article  PubMed  CAS  Google Scholar 

  51. Tomisato W, Tsutsumi S, Rokutan K et al (2001) NSAIDs induce both necrosis and apoptosis in guinea pig gastric mucosal cells in primary culture. Am J Physiol 281:G1092–G1100

    CAS  Google Scholar 

  52. Spehlmann ME, Eckmann L (2009) Nuclear factor-kappa b in intestinal protection and destruction. Curr Opin Gastroenterol 25:92–99

    Article  PubMed  CAS  Google Scholar 

  53. Patrono C, Patrignani P, Garcia Rodriguez L (2001) Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical read-outs. J Clin Invest 108:7–13

    PubMed  CAS  Google Scholar 

  54. Gan TJ (2010) Diclofenac: an update on its mechanism of action and safety profile. Curr Med Res Opin 26:1715–1731

    Article  PubMed  CAS  Google Scholar 

  55. Stamm C, Burkhalter CE, Pearce W et al (1994) Benign colonic ulcers associated with non-steroidal with non-steroidal anti-inflammatory drug ingestion. Am J Gastroenterol 89:2230–2233

    PubMed  CAS  Google Scholar 

  56. Tomlinson J, Blikslager A (2003) Role of non-steroidal anti-inflammatory drugs in gastrointestinal tract injury and repair. JAVMA 222:946–951

    Article  PubMed  CAS  Google Scholar 

  57. Day JP, Lanas A, Rustagi P et al (1996) Reversible prolonged skin bleeding time in acute gastrointestinal bleeding presumed due to NSAIDs. J Clin Gastroenterol 22:96–103

    Article  PubMed  CAS  Google Scholar 

  58. Crofford LJ, Lipsky PE, Brooks P et al (2000) Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum 43:4–13

    Article  PubMed  CAS  Google Scholar 

  59. Simon LS, Weaver AL, Graham DY et al (1999) Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 282:1921–1928

    Article  PubMed  CAS  Google Scholar 

  60. Polat A, Nayci A, Polat G et al (2002) Dexamethasone down-regulates endothelial expression of intercellular adhesion molecule and impairs the healing of bowel anastomoses. Eur J Surg 168:500–506

    Article  PubMed  CAS  Google Scholar 

  61. Gürleyik G, Gürleyik E, Yilmazcan A et al (2002) Effects of neurotensin on the healing of experimental anastomosis of the colon. Acta Chir Belg 102:33–36

    PubMed  Google Scholar 

  62. Eubanks TR, Greenberg JJ, Dobrin PB et al (1997) The effects of different corticosteroids on the healing colon anastomosis and cecum in a rat model. Am Surg 63:266–269

    PubMed  CAS  Google Scholar 

  63. Aszodi A, Ponsky JL (1984) Effects of corticosteroid on the healing bowel anastomosis. Am Surg 50:546–548

    PubMed  CAS  Google Scholar 

  64. Furst MB, Stromberg BV, Blatchford GJ et al (1994) Colonic anastomoses: bursting strength after corticosteroid treatment. Dis Colon Rectum 37:12–15

    Article  PubMed  CAS  Google Scholar 

  65. Wang JJ, Ho ST, Liu YH et al (1999) Dexamethasone reduces nausea and vomiting after laparoscopic cholecystectomy. Br J Anaesth 83:772–775

    PubMed  CAS  Google Scholar 

  66. Block BM, Liu SS, Rowlingson AJ et al (2003) Efficacy of postoperative epidural analgesia. A meta analysis. JAMA 290:2455–2463

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, University Hospital of North Norway, 9038, Tromsø, Norway

    Christian Fredrik Rushfeldt & Barthold Vonen

  2. Institute of Medical Biology, University of North Norway, Tromsø, Norway

    Baldur Sveinbjørnsson

  3. Childhood Cancer Research Unit, Karolinska University Hospital, Stockholm, Sweden

    Baldur Sveinbjørnsson

  4. Department of Surgery, Stavanger University Hospital, Stavanger, Norway

    Kjetil Søreide

  5. Institute of Surgical Sciences, University of Bergen, Bergen, Norway

    Kjetil Søreide

Authors
  1. Christian Fredrik Rushfeldt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Baldur Sveinbjørnsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kjetil Søreide
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barthold Vonen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christian Fredrik Rushfeldt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rushfeldt, C.F., Sveinbjørnsson, B., Søreide, K. et al. Risk of anastomotic leakage with use of NSAIDs after gastrointestinal surgery. Int J Colorectal Dis 26, 1501–1509 (2011). https://doi.org/10.1007/s00384-011-1285-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-011-1285-6

Keywords

Search

Navigation