Caspase Inhibition Enhances Ischemic Tolerance of Fasciocutaneous Flaps

Abstract

To demonstrate the significance of apoptosis in ischemia-reperfusion injury in revascularized fasciocutaneous flaps and test the hypothesis that pharmacologic inhibition of caspases prolongs the allowable primary ischemia time of these flaps. Animal study using the epigastric flap in adult male Sprague-Dawley rats. Fifty-nine rats were treated with the caspase inhibitor (Q-VD-OPH) reconstituted in dimethylsulfoxide (DMSO) (n = 20, 8 mg/kg:0.8 mL/kg), DMSO alone (n = 19, 0.8 mL/kg), or saline (n = 20, 0.8 mL/kg). Treatment was given as a single intraperitoneal injection 30 minutes before starting primary ischemia. Epigastric flaps were subjected to increasing ischemia times followed by reperfusion. The flaps were harvested and analyzed 7 days later, and viability was assessed. Probit statistical analysis was used to determine the critical ischemia time. This was defined as the time point when 50% of the flaps in each group were expected to survive. The calculated critical ischemia times were 8.92 hours (95% confidence interval 7.19-10.47 h) for the saline group, 16.35 hours (95% confidence interval 11.82-19.89 h) for the DMSO group, and 21.73 hours (95% confidence interval 19.39-25.37 h) for the DMSO with Q-VD-OPH group. These differences were significantly different from each other. Pretreatment of fasciocutaneous flaps with a free radical scavenger alone or in combination with a caspase inhibitor significantly increases the flap's tolerance of primary ischemia. The added benefit of the caspase inhibitor suggests that apoptosis plays an important role in ischemia-reperfusion injury in soft tissue flaps.