Effect of a δ receptor agonist on duration of survival during hemorrhagic shock

Objectives: Selective delta receptor agonists have been shown to stabilize membrane physiologic processes, reduce metabolic rates, and provide protection against ischemic insults through K-ATP channel opening in a variety of organ beds. However, their potential for affecting outcomes in states of generalized ischemia has not been explored. The authors examined the effect of the nonselective delta receptor agonist, DADLE (D-Ala2-Leu5-enkephalin), on hemodynamic stability and duration of survival in an animal model of severe hemorrhagic shock. Methods: Conscious Sprague Dawley rats with indwelling catheters were hemorrhaged at a rate of 3.25 mL/100 grams over 20 minutes after half of the group received 1% DADLE (1 mg/kg IV). Following the hemorrhage, all rats were continuously monitored for heart rate (HR), mean arterial pressure (MAP), and life signs for up to three hours (death defined as apnea, systolic blood pressure < 30 mm Hg without pulsations, and electroencephalographic silence). Survival rates and hemodynamic trends were compared between the control and DADLE-treated groups. Results: In the 14 rats studied (8 DADLE; 6 controls), initial hemorrhage resulted in similar hemodynamic shock (average MAP fall: 118 to 59 vs 119 to 55 mm Hg). Analysis of survival at 3.5 hours revealed statistically significant differences between the control and DADLE groups. While 50% of the DADLE group survived past the three hours, no control animals were still alive at the end of the experimental period. The MAP trended downward and the HR increased for the control group, but all hemodynamic parameters stabilized in the rats treated with DADLE. Conclusions: Most current strategies for treating shock focus on the supply side of resuscitation. The coordinated various actions of DADLE have the potential to work in concert in the intact organism to improve overall survival during severe hemorrhagic shock. In an animal model of severe hemorrhagic shock, there was improvement in hemodynamic stability and a prolonged survival with DADLE treatment. Physiologic manipulation with DADLE appears to be a way to improve survival during shock with possible clinical implications.