Effect of beta blocker combined with COX-2 inhibitor on colonic anastomosis in rats

Purpose: Pharmacologic modulation of the perioperative physiologic stress response, using the beta-blocker propranolol, combined with the COX-2 inhibitor etodolac, has been shown to reduce metastatic spread and increase survival rates following surgery for primary tumor excision in rodents. Prior to implantation of this pharmacological approach in clinical trials in patients with colon cancer, the safety of this technique has to be evaluated. This study assessed the effects of these drugs on the healing of colonic anastomosis in rats. Methods: Forty-eight F344 rats were divided into two groups, which were given seven daily subcutaneous injections of either vehicle, or propranolol (up to 1.2 mg/kg/day) combined with etodolac (12.5 mg/kg/day), starting the day before surgery. Each animal underwent laparotomy, colotomy of the descending colon, and anastomosis. Anastomotic leak rate and bursting pressure were compared at 1 week after the operation. The harvested anastomosis was histologically assessed for wound healing parameters. Results: Forty-three rats survived the operation and were eligible for analysis at 1 week. No significant difference in survival, anastomotic leakage, or bursting pressure was found between animals that received propranolol and etodolac versus those receiving vehicle (drugs 179 mmHg∈±∈45.4; vehicle 187 mmHg, SD∈±∈35.0, p∈=∈0.54). Histologic assessment of fibrosis, necrosis, cell infiltration, and tissue reaction zone did not differ between the two groups. Conclusions: Perioperative administration of propranolol and etodolac seems safe in colon operations in rats and does not affect anastomotic failure or colon healing.