Microbial Glucuronidase Inhibition Reduces Severity of Diclofenac-Induced Anastomotic Leak in Rats.

BACKGROUND: The non-steroidal anti-inflammatory drug diclofenac has been associated with intestinal anastomotic leakage, although the underlying pathophysiology is unclear. Previous data suggest that reactivation of biliary diclofenac metabolites by microbial ß-glucuronidases in the gut plays a role in harming the intestinal mucosa, and that microbiome-targeted glucuronidase inhibition prevents this damage. Here, the microbial glucuronidase inhibitor Inh1 was examined for its ability to reduce diclofenac-induced anastomotic leakage in rats. METHODS: Ninety male Wistar rats were allocated to five groups. In the two diclofenac groups, group DCF received diclofenac (3 mg/kg per day) and group DCF-Inh1 additionally received 800 mcg/kg per day of glucuronidase inhibitor Inh1 solution orally. In non-diclofenac groups, animals received either Inh1 (800 mcg/kg per day; group Inh1) solution, the vehicle (methylcellulose; group Veh), or no solution (group Ctrl). All solutions were provided from the day of surgery until sacrifice on day three. Plasma concentrations of diclofenac were determined. Outcomes were anastomotic leakage, leak severity, and anastomotic strength. RESULTS: Anastomotic leak rates were 89% in group DCF and 44% in group DCF-Inh1 (p = 0.006). Leak severity was reduced in group DCFic-Inh1 (p = 0.029). In non-diclofenac cohorts, mostly minor leakage signs were observed in 25% in group Ctrl, 39% in group Inh1 (0.477), and 24% in group Veh (p = 1.000). Bursting pressure and breaking strength were not significantly different. Plasma concentrations of diclofenac were not changed by Inh1. CONCLUSION: Microbial glucuronidase inhibitor reduces diclofenac-induced anastomotic leakage severity, which suggests a harmful effect of diclofenac metabolite reactivation in the gut. This finding improves the understanding of the pathogenesis of anastomotic leakage.

Safety and Efficacy of Alginate Adhesion Barrier Gel in Compromised Intestinal Anastomosis.

BACKGROUND: For any anti-adhesive barrier developed for abdominal surgery, the use under conditions in which anastomotic healing is compromised needs to be investigated. The current study evaluates the effect of a new ultrapure alginate gel on early healing of high-risk anastomoses in the ileum and compares this with the gold standard used in clinical practice. MATERIALS AND METHODS: In 75 adult male Wistar rats, a 5 mm ileal segment was resected and continuity was restored by construction of an inverted anastomosis. Rats were divided randomly into a control group and groups receiving either alginate gel or a sodium hyaluronate carboxymethylcellulose (HA/CMC) film around the anastomosis (n = 25 each). Carprofen, given in a daily dose of 1.25 mg/kg, was used to compromise anastomotic healing. At day three, animals were killed and scored for signs of anastomotic leakage and the presence of adhesions. RESULTS: The incidence of adhesion formation was 95% in the HA/CMC film group, which was significantly higher than in the controls (64%, p = 0.010) and the alginate gel group (52%, p = 0.004). The adhesion score was nearly 40% lower in the alginate gel group compared with the HA/CMC film group. The incidence of ileal leakage in the HA/CMC film group (92%) was significantly higher than in the controls (68%, p = 0.016). Leakage rate did not differ between the alginate gel and control groups. There was no significant difference between groups in either incision bursting pressure or incision breaking strength. CONCLUSION: Ultrapure alginate gel does not interfere with repair of ileal anastomoses constructed under conditions in which chances of anastomotic dehiscence are high. The alginate gel performs better than the HA/CMC film.

Diclofenac causes anastomotic leakage in the proximal colon but not in the distal colon of the rat.

BACKGROUND: Nonsteroidal anti-inflammatory drugs have been associated with anastomotic leakage. It was studied if diclofenac affects anastomoses differently depending on the location in the gut. METHODS: Ninety-five rats were randomized to 6 groups with an anastomosis in either ileum (IL), proximal colon (PC), or distal colon (DC). Groups IL+ (n = 10), PC+ (n = 30), and DC+ (n = 10) received diclofenac (3 mg/kg/day) from day 0 until sacrifice on day 3. Group PC- (n = 15) did not receive diclofenac. Groups PC1+ and PC2+ (n = 15 each) were given diclofenac from day 1 to 4 and from day 2 to 5. RESULTS: Leak rates were 10/10 in group IL+, 22/30 in PC+, 1/10 in DC+, and 1/15 in PC-. Delayed administration of diclofenac by 1 or 2 days (6/15, P = .05) resulted in reduced leakage rates. Mechanical strength results corresponded with leak rates. CONCLUSIONS: Diclofenac causes leakage of anastomoses in rat IL and PC, but not in the DC. This suggests a role for the ileal and proximal colonic content in diclofenac-induced leakage.

Serosal abrasion of bowel ends does not enhance anastomotic healing.

BACKGROUND: Anastomotic leakage rates remain unacceptably high, warranting reconsideration of current anastomotic technique. Anastomotic healing may improve by abrading the serosal surface of bowel ends that are invertedly anastomosed, based on the concept that serosal damage evokes inflammatory adherent processes. It is studied if local abrasion leads to stronger anastomoses and reduces leakage. METHODS: Ninety-eight Wistar rats were allocated to six groups. Either a regular anastomosis (RA) or abraded anastomosis (AA) was constructed in the proximal colon. Animals were sacrificed at day 3 (groups RA3 and AA3, n = 2 × 17) or day 5 (groups RA5 and AA5, n = 2 × 17). Groups RA-Dic and AA-Dic (n = 2 × 15) received diclofenac from day 0 until sacrifice on day 3 to impair anastomotic healing. Outcomes were leakage, bursting pressure, breaking strength, adhesions, and histological appearance. RESULTS: Both in abraded (AA3 and AA5) and control (RA3 and RA5) groups without diclofenac, 1 of 17 anastomoses leaked (6%). Leak rate was 9 of 15 (60%) in group AA-Dic and 8 of 15 (53%) in RA-Dic (P = 1.0). The bursting pressure in group RA3 (127 ± 44 mm Hg) was higher (P = 0.006) compared with group AA3 (82 ± 34 mm Hg), breaking strength was comparable (P = 0.331). Mechanical strength was similar between groups RA5 and AA5. Abrasion did not increase mechanical strength in the diclofenac groups. Adhesion formation was not different between groups. Histology showed dense interserosal scar formation in abraded groups, compared with loose connective tissue in control anastomoses. CONCLUSIONS: Abrasion of serosal edges of large bowel ends invertedly anastomosed does not improve anastomotic strength, neither does it reduce leakage in anastomoses compromised by diclofenac.