S. Yauw1, M. Arron1, R. Lomme1, P. Van Den Broek2, R. Greupink2, A. Bhatt3, M. Redinbo3, H. Van Goor1 1Radboudumc,Department Of Surgery,Nijmegen, GELDERLAND, Netherlands 2Radboudumc,Department Of Pharmacology And Toxicology,Nijmegen, GELDERLAND, Netherlands 3University Of North Carolina At Chapel Hill,Department Of Biochemistry And Microbiology,Chapel Hill, NORTH CAROLINA, USA
Introduction:
Use of diclofenac in colorectal surgery has been associated with increased rates of anastomotic leakage. Previous experiments suggest drug metabolites in bile play a role in this process. Cleavage of the diclofenac-acyl-glucuronide metabolite by bacterial glucuronidase in the gut releases a harmful aglycone, which causes small intestinal mucosal damage in mice. Administration of a beta-glucuronidase inhibitor (Inh1) prevents this. It was studied if inhibition of glucuronidase prevents the development of diclofenac-induced anastomotic leakage in rats.
Methods:
In one hundred and eight male Wistar rats an anastomosis of the ileum was constructed. Animals were allocated to six groups, three with diclofenac and three without diclofenac. For the diclofenac groups, group Dic received diclofenac only and the groups Dic-Inh1-low and Dic-Inh1-high received diclofenac and beta-glucuronidase inhibitor in either a low (800ug/kg/d) or high dose (4000ug/kg/d) orally. For the non-diclofenac groups, animals received either low dose beta-glucuronidase inhibitor (group Inh1-low), vehicle (methylcellulose; group Veh) or no solution (group Neg). All solutions were given from the day of surgery until sacrifice on day three. Plasma levels of diclofenac were determined to rule out a systemic effect. Outcomes were anastomotic leakage, leak severity score, bursting pressure and breaking strength.
Results:
Anastomotic leak rates were 67% in group Dic, 33% in group Dic-Inh1-low (p=0.094) and 50% in group Dic-Inh1-high (p=0.500). Leak severity was reduced in group Dic-Inh1-low (p=0.029), but not in the high dose group (p=0.293). In non-diclofenac cohort rates were 0% in group Neg, 17% in group Inh1-low (0.230), 17% in group Veh (p=0.227). Bursting pressure and breaking strength were not significantly different. Plasma levels of diclofenac were not changed by Inh-1.
Conclusion:
Beta-glucuronidase inhibitor reduces anastomotic leakage when given in low doses, suggesting a toxic effect of diclofenac metabolite on anastomotic healing. The absent effect in the high dose might be due to an intrinsic toxicity of the inhibitor or clumping of the substance. These findings improve our understanding of the pathogenesis of anastomotic leakage.