Abstract
BackgroundDiclofenac increases the risk of anastomotic leakage, but the underlying mechanism is unknown. As diclofenac is excreted largely as biliary metabolites, the aim of this study was to determine the effect of these metabolites on intestinal anastomoses.MethodsThis was a randomized controlled blinded experiment using 210 male Wistar rats to assess the effect of ‘diclofenac bile’ on the anastomotic complication score, leak rate and anastomotic strength following oral and parenteral administration of diclofenac. Bile duct and duodenal catheterization techniques were used for diversion and replacement of bile, and biliary diclofenac metabolites were determined.ResultsReplacement of control bile with diclofenac bile resulted in higher anastomotic complication scores (P = 0·006) and leakage in five of 18 animals, compared with one of 18 controls (P = 0·089). In turn, following oral diclofenac administration, replacement of diclofenac bile with control bile reduced anastomotic complications (P = 0·016). The leak rate was seven of 15 versus 13 of 17 without replacement (P = 0·127). After intramuscular administration of diclofenac, the reduction in anastomotic complications was not significant when bile was replaced with control bile (P = 0·283), but it was significant when bile was drained without replacement (P = 0·025). Diclofenac metabolites in bile peaked within 2 h after administration. Administration of diclofenac bile resulted in nearly undetectable plasma levels of diclofenac (mean(s.d.) 0·01(0·01) μg/ml) after 120 min. Following oral diclofenac, bile replacement with control bile did not affect the plasma concentration of diclofenac (0·12(0·08) μg/ml versus 0·10(0·05) μg/ml with diclofenac bile; P = 0·869).ConclusionAltered bile composition as a result of diclofenac administration increases the ileal anastomotic complication rate in rats.
Highlights
Anastomotic leakage is the leading cause of morbidity and mortality after intestinal surgery, with leak rates varying from 3 to 14 per cent[1]
Non-steroidal anti-inflammatory drugs (NSAIDs) have been related to increased leak rates in both animal and retrospective human studies[2,3,4]. This is worrisome because NSAIDs are recommended as postoperative analgesics in current guidelines[5]
Further research is required to delineate the role of NSAIDs in clinical anastomotic leakage[4,7]
Summary
Anastomotic leakage is the leading cause of morbidity and mortality after intestinal surgery, with leak rates varying from 3 to 14 per cent[1]. Non-steroidal anti-inflammatory drugs (NSAIDs) have been related to increased leak rates in both animal and retrospective human studies[2,3,4]. This is worrisome because NSAIDs are recommended as postoperative analgesics in current guidelines[5]. An alternative explanation could be direct toxicity of intraluminal factors resulting from NSAID treatment (such as drug metabolites and bile products). Following oral diclofenac administration, replacement of diclofenac bile with control bile reduced anastomotic complications (P = 0⋅016). Conclusion: Altered bile composition as a result of diclofenac administration increases the ileal anastomotic complication rate in rats
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