Ibuprofen inhibition of postsurgical adhesion formation: A time and dose response biochemical evaluation in rabbits

Abstract

Recently, a reduction in postoperative adhesion formation in rabbits which received high-dose ibuprofen (280 mg/kg/day) treatment in the perioperative interval was reported. Because these results could have resulted from a nonspecific effect of ibuprofen, the effects of ibuprofen on peritoneal injury in a time and dose response fashion was evaluated. Seventy rabbits were assigned to seven groups. All rabbits received a dose of ibuprofen 1 hr prior to surgery. The time of the second dose was either 8 or 12 hr after the surgical procedure; 8 hr for groups A, C, and E; 12 hr for groups B, D, and F (A, B: 70 mg/ kg; C, D: 35 mg/kg; E, F: 17.5 mg/kg, respectively). Thereafter, rabbits received further dosing every 6 hr to complete a total 10-dose regimen. Group G served as a nontreatment control. Surgical injury was induced by either abrasion or ischemia of the right uterine horn. Immediately after closing the incision, 10 μCi of 14C-labeled glucosamine and 10 μCi of 14C-labeled proline were injected into each rabbit. All rabbits underwent a second laparotomy on the fifth postoperative day for evaluation of adhesion formation. Uterine tissue adjacent to the site of uterine healing was excised for determination of glycosaminoglycan and collagen concentration. In the nontreatment control group G, 5 of the 10 rabbits had severe grade 2 adhesions at the time of second laparotomy, 3 had grade 1 filmy adhesions, and 2 had no adhesions. This is in marked contrast ( P < 0.025) to the group that received ibuprofen at 70 mg/kg/day with the first postoperative dose 8 hr after surgery (group A). In this group, no rabbits had severe grade 2 adhesions, 3 rabbits had filmy grade 1 adhesions, and 7 rabbits were free of pelvic adhesions. A gradual tendency towards more adhesions and more severe adhesions was apparent in groups B-F as the dose of ibuprofen was decreased and the time of first postoperative injection was prolonged. The recovery of 14C-labeled glucosamine from the glycosaminoglycan extraction demonstrated a positive correlation between the cpm recovered and the severity of adhesions formed. Groups A and B had, overall, the lowest ratios of glucosamine (1.47 ± 0.08 and 1.56 ± 0.09, respectively) which were statistically different from the nontreatment control group G (1.76 ± 0.11, P < 0.05). There was also a positive correlation between the formation of severe adhesions and the ratio of 14C-labeled proline recovered by collagen extraction. Those rabbits which did not develop adhesions had an average collagen ratio of 1.48 ± 0.03; those with grade 1, filmy adhesions, 1.68 ± 0.04; those with grade 2 adhesions, 1.89 ± 0.04 ( P < 0.05 for all treatment vs control groups). Rabbits undergoing either abrasion or devascularization procedures of their uterine horn manifested a significant reduction in peritoneal adhesion formation with perioperative ibuprofen treatment. Further, a positive correlation existed between the formation of glycosaminoglycans and collagen in the site of uterine healing and the subsequent formation of adhesions.