S. Yauw1, R. Lomme1, P. Van Den Broek2, R. Greupink2, F. Russel2, H. Van Goor1 1Radboudumc,Department Of Surgery,Nijmegen, GELDERLAND, Netherlands 2Radboudumc,Department Of Pharmacology And Toxicology,Nijmegen, GELDERLAND, Netherlands
Introduction:
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with anastomotic leakage in humans and animals, but underlying mechanisms are unknown. Some studies suggest an increase of bile toxicity by specific NSAIDs, causing small intestinal damage. In this experiment we determined the relevance of biliary diclofenac excretion in anastomotic leakage.
Methods:
Randomized controlled blinded experiment assessing anastomotic leakage, leak severity and anastomotic strength in 138 male Wistar rats, using bile duct and duodenal catheterization techniques and 72 rats as bile donors. It was studied if administration of ‘diclofenac bile’ induces leakage in control rats and, in turn, if diversion or replacement of bile reduces leakage in diclofenac (oral or intramuscular) treated rats. Diclofenac biliary metabolites and plasma levels were determined with HLPC and LCMS.
Results:
Leak rate was 28% after administration of ‘diclofenac bile’ compared to 6% (p=0.089) after control bile. Following oral diclofenac administration 76% leaked compared to 47% (p=0.127) when bile was replaced with control bile. After intramuscular administration 67% leaked and 50% if the rat’s own bile was diverted and returned, compared to 25% (p=0.060) when bile was drained or 20% (p=0.117) when replaced with control bile, respectively. Grading according to an Anastomotic Complication Score revealed signs of leakage were significantly more severe in ‘diclofenac bile’ groups; (p=0.006 versus control bile in control groups; p=0.016 versus control bile in oral diclofenac groups; p=0.025 versus bile drainage in intramuscular diclofenac groups; p=0.283 versus control bile in intramuscular diclofenac groups. Anastomotic strength results grossly supported macroscopic findings. Bile analysis showed diclofenac metabolite levels peak within two hours after administration, with diclofenac-acyl-glucuronide and unchanged diclofenac as main metabolites. Plasma levels of diclofenac did not change following exchange of ‘diclofenac bile’ by ‘control bile‘, or vice versa, and could not explain the different leak rates.
Conclusion:
Altered bile composition aggravates ileal anastomotic leakage in rats treated with diclofenac, which may result from biliary excretion of diclofenac metabolites. This is a newly identified pathway in the pathophysiology of anastomotic leakage and its exact mechanism and clinical relevance should be clarified by further research.