24‐Hour Pretreatment with δ Opioid Enhances Survival from Hemorrhagic Shock

Abstract

Delta opioids have been shown to confer ischemic preconditioning and pharmacologic ischemic preconditioning to the myocardium. However, their role in providing extended pharmacologic ischemic preconditioning in hemorrhagic shock has not been explored. The authors examined the effects of 24-hour preinfusions of a selective delta opioid receptor agonist, Deltorphin-Dvariant (Delt-Dvar), on hemodynamic stability and duration of survival in a rat model of severe hemorrhagic shock. Conscious Sprague-Dawley rats with indwelling catheters were hemorrhaged at a rate of 3.18 mL/l00 g over 20 minutes. Twenty-four hours before hemorrhage, the control group (n = 14) was infused with 1.0 mL lactated Ringer's solution, and the Delt-Dvar-treated group (n = 22) was infused with 5.0 mg/kg Delt-Dvar in 1.0 mL lactated Ringer's solution. Rats were continuously monitored for heart rate (HR), mean arterial pressure, and four-hour survival rates. Plasma lactate levels were determined at the beginning of hemorrhage and the end of hemorrhage. At 240 minutes, only one of 14 controls (7.1%) survived, while 16 (72.7%) of the 22 experimental rats survived. No significant differences in heart rate between controls and Delt-Dvar-treated rats were noted. Increases in mean arterial pressure of Delt-Dvar-treated rats at the beginning of hemorrhage and at the end of hemorrhage were found to be significant (p < 0.05). At 240 minutes, heart rate and mean arterial pressure were not different between the single surviving control and the Delt-Dvar group. At the end of hemorrhage, lactate levels in the Delt-Dvar-treated group were 8.5 (+/- 0.5) mmol/L versus 10.8 (+/- 0.6) mmol/L (p < 0.05) in the control group. Twenty-four-hour pretreatment with Delt-Dvar decreases plasma lactate levels and improves hemodynamic stability and survival during hemorrhagic shock. The use of delta-specific opioids may improve survival from hemorrhagic shock and have clinical utility in providing ischemic protection in scenarios of planned ischemia.