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Journal of Gastrointestinal Surgery

, Volume 22, Issue 4, pp 587–594 | Cite as

Ketorolac and Other NSAIDs Increase the Risk of Anastomotic Leakage After Surgery for GEJ Cancers: a Cohort Study of 557 Patients

  • Kaare Terp Fjederholt
  • Cecilie Okholm
  • Lars Bo Svendsen
  • Michael Patrick Achiam
  • Jakob Kirkegård
  • Frank Viborg Mortensen
Original Article
  • 381 Downloads

Abstract

Objective

The objective of this study is to investigate the impact of ketorolac and other nonsteroidal anti-inflammatory drugs on anastomotic leakage after surgery for gastro-esophageal-junction cancer.

Summary Background Data

Within the last two decades, the incidence of gastro-esophageal-junction cancer has increased in the western world and surgery is the curative treatment modality of choice. Anastomotic leakage is a feared complication of gastro-esophageal surgery, as it increases recurrence, morbidity, and mortality. Nonsteroidal anti-inflammatory drugs are widely used for postoperative pain relief. Nonsteroidal anti-inflammatory drugs have, however, in colorectal surgery, been shown to increase the risk of anastomotic leakage.

Method

In a historical cohort study, we investigated the impact of nonsteroidal anti-inflammatory drugs on anastomotic leakage in 557 patients undergoing surgery for gastro-esophageal-junction cancer. Data were collected from a prospective maintained database, the Danish National Patient Registry, and patient medical records. Data were analyzed using univariate and multivariate statistical models and were stratified for theoretical confounders.

Results

In univariate analysis, we did not observe any difference in age, gender, tobacco exposure, or comorbidity status between patients experiencing anastomotic leakage and those without. In multivariate analysis, gender, histology, and type of anastomosis proved to affect odds ratios for anastomotic leakage. After adjustment for possible confounders, we found an odds ratio of 6.05 (95% confidence interval 2.71; 13.5) for ketorolac use and of 5.24 (95% confidence interval 1.85; 14.8) for use of other nonsteroidal anti-inflammatory drugs for anastomotic leakage during the first seven postoperative days.

Conclusion

In the present study, we found a strong association between the postoperative use of ketorolac and other nonsteroidal anti-inflammatory drugs and the risk for anastomotic leakage after surgery for gastro-esophageal-junction cancers.

Keywords

Anastomotic leak Epidemiology Esophageal neoplasms Anti-inflammatory agents,  Nonsteroidal 

Notes

Acknowledgements

We are grateful for the funding of this work provided by the Danish Cancer Society and Aage and Johanne Louis-Hansen’s Foundation.

Contributions

Kaare Terp Fjederholt: Study design, manuscript draft, data analysis, and critical revision

Cecilie Okholm: Data collection and critical revision

Lars Bo Svendsen: Study design, data collection, and critical revision

Michael Patrick Achiam: Data collection and critical revision

Jakob Kirkegård: Critical revision

Frank Viborg Mortensen: Study design, manuscript draft, and critical revision

Source of Funding

The Danish Cancer Society and Aage and Johanne Louis-Hansen’s Foundation supported this work.

Compliance with Ethical Standards

Conflicts of Interest

No conflicts of interest declared.

References

  1. 1.
    Devesa SS, Blot WJ, Fraumeni JF Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer. 1998;83(10):2049–2053.CrossRefPubMedGoogle Scholar
  2. 2.
    Gregersen LH, Friis S, Olsen JH. [Cancer in esophagus and cardia—incidence trends in Denmark]. Ugeskrift for laeger. 2008;170(17):1460–1464.PubMedGoogle Scholar
  3. 3.
    Gronbaek M, Becker U, Johansen D, Tonnesen H, Jensen G, Sorensen TI. Population based cohort study of the association between alcohol intake and cancer of the upper digestive tract. Bmj. 1998;317(7162):844–847.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lagergren J, Bergstrom R, Lindgren A, Nyren O. The role of tobacco, snuff and alcohol use in the aetiology of cancer of the oesophagus and gastric cardia. Int J Cancer. 2000;85(3):340–346.CrossRefPubMedGoogle Scholar
  5. 5.
    Wu AH, Wan P, Bernstein L. A multiethnic population-based study of smoking, alcohol and body size and risk of adenocarcinomas of the stomach and esophagus (United States). Cancer Causes Control. 2001;12(8):721–732.CrossRefGoogle Scholar
  6. 6.
    Kofoed SC, Brandt B, Breno J, et al. [Long-term survival after curative resection for oesophageal and cardia cancer]. Ugeskrift for laeger. 2010;172(21):1597–1602.PubMedGoogle Scholar
  7. 7.
    Kofoed SC, Calatayud D, Jensen LS, et al. Intrathoracic anastomotic leakage after gastroesophageal cancer resection is associated with increased risk of recurrence. J Thorac Cardiovasc Surg. 2015.Google Scholar
  8. 8.
    Jensen LS, Bendixen A, Kehlet H. Organisation and early outcomes of major upper gastrointestinal cancer surgery in Denmark 1996-2004. Scand J Surg. 2007;96(1):41–45.CrossRefPubMedGoogle Scholar
  9. 9.
    Rentz J, Bull D, Harpole D, et al. Transthoracic versus transhiatal esophagectomy: a prospective study of 945 patients. J Thorac Cardiovasc Surg. 2003;125(5):1114–1120.CrossRefPubMedGoogle Scholar
  10. 10.
    Talsma AK, Lingsma HF, Steyerberg EW, Wijnhoven BP, Van Lanschot JJ. The 30-day versus in-hospital and 90-day mortality after esophagectomy as indicators for quality of care. Ann Surg. 2014;260(2):267–273.CrossRefPubMedGoogle Scholar
  11. 11.
    Urschel JD. Esophagogastrostomy anastomotic leaks complicating esophagectomy: a review. Am J Surg. 1995;169(6):634–640.CrossRefPubMedGoogle Scholar
  12. 12.
    Sinha VR, Kumar RV, Singh G. Ketorolac tromethamine formulations: an overview. Expert opinion on drug delivery. 2009;6(9):961–975.CrossRefPubMedGoogle Scholar
  13. 13.
    Klein M, Gogenur I, Rosenberg J. 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. 2012;345:e6166.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Danish Esophageal Cagcd. Årsrapport 2012. 2012; http://decv.gicancer.dk/Content/Files/Dokumenter/DECV_rapport2012_final.pdf. 2012
  15. 15.
    Frank L. Epidemiology. When an entire country is a cohort. Science. 2000;287(5462):2398–2399.CrossRefPubMedGoogle Scholar
  16. 16.
    Migita K, Takayama T, Matsumoto S, et al. Risk factors for esophagojejunal anastomotic leakage after elective gastrectomy for gastric cancer. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2012;16(9):1659–1665.CrossRefGoogle Scholar
  17. 17.
    Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–383.CrossRefPubMedGoogle Scholar
  18. 18.
    Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scandinavian journal of public health. 2011;39(7 Suppl):30–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Gorissen KJ, Benning D, Berghmans T, et al. Risk of anastomotic leakage with non-steroidal anti-inflammatory drugs in colorectal surgery. Br J Surg. 2012;99(5):721–727.CrossRefPubMedGoogle Scholar
  20. 20.
    Saleh F, Jackson TD, Ambrosini L, et al. Perioperative nonselective non-steroidal anti-inflammatory drugs are not associated with anastomotic leakage after colorectal surgery. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2014;18(8):1398–1404.CrossRefGoogle Scholar
  21. 21.
    Kuper MA, Scholzl N, Traub F, et al. Everolimus Interferes with the Inflammatory Phase of Healing in Experimental Colonic Anastomoses. Journal of Surgical Research. 2011;167(1):158–165.CrossRefPubMedGoogle Scholar
  22. 22.
    Diller R, Stratmann U, Helmschmied T, et al. Microcirculatory dysfunction in endotoxemic bowel anastomosis: the pathogenetic contribution of microcirculatory dysfunction to endotoxemia-induced healing impairment. J Surg Res. 2008;150(1):3–10.CrossRefPubMedGoogle Scholar
  23. 23.
    Kokoska ER, Smith GS, Wolff AB, Deshpande Y, Miller TA. Nonsteroidal anti-inflammatory drugs attenuate epidermal growth factor-induced proliferation independent of prostaglandin synthesis inhibition. J Surg Res. 1999;84(2):186–192.CrossRefPubMedGoogle Scholar
  24. 24.
    Turkyilmaz A, Eroglu A, Aydin Y, Tekinbas C, Muharrem Erol M, Karaoglanoglu N. The management of esophagogastric anastomotic leak after esophagectomy for esophageal carcinoma. Dis Esophagus. 2009;22(2):119–126.CrossRefPubMedGoogle Scholar
  25. 25.
    Van Daele E, Van de Putte D, Ceelen W, Van Nieuwenhove Y, Pattyn P. Risk factors and consequences of anastomotic leakage after Ivor Lewis oesophagectomydagger. Interact Cardiovasc Thorac Surg. 2015.Google Scholar
  26. 26.
    Richards CH, Campbell V, Ho C, Hayes J, Elliott T, Thompson-Fawcett M. Smoking is a major risk factor for anastomotic leak in patients undergoing low anterior resection. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2012;14(5):628–633.CrossRefGoogle Scholar
  27. 27.
    Sorensen LT, Jorgensen T, Kirkeby LT, Skovdal J, Vennits B, Wille-Jorgensen P. Smoking and alcohol abuse are major risk factors for anastomotic leakage in colorectal surgery. Br J Surg. 1999;86(7):927–931.CrossRefPubMedGoogle Scholar
  28. 28.
    Fischer C, Lingsma H, Hardwick R, Cromwell DA, Steyerberg E, Groene O. Risk adjustment models for short-term outcomes after surgical resection for oesophagogastric cancer. Br J Surg. 2016;103(1):105–116.CrossRefPubMedGoogle Scholar
  29. 29.
    Svendsen LB, Jensen LS, Holm J, et al. Differences in the pattern of anastomotic leakage after oesophagectomy in two high-volume centres. Danish medical journal. 2013;60(12):A4733.PubMedGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2017

Authors and Affiliations

  • Kaare Terp Fjederholt
    • 1
  • Cecilie Okholm
    • 2
  • Lars Bo Svendsen
    • 2
  • Michael Patrick Achiam
    • 2
  • Jakob Kirkegård
    • 1
  • Frank Viborg Mortensen
    • 1
  1. 1.Department of Surgery, Section for upper gastrointestinal and hepato-pancreato-biliary surgeryAarhus University HospitalAarhus CDenmark
  2. 2.Department of Surgical Gastroenterology and TransplantationRigshospitaletCopenhagenDenmark

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