Assessment of the delta opioid agonist DADLE in a rat model of lethal hemorrhage treated by emergency preservation and resuscitation

Emergency preservation and resuscitation (EPR) is a new approach for resuscitation of exsanguination cardiac arrest (CA) victims. EPR uses a cold aortic flush to induce deep hypothermic preservation during no-flow to buy time for transport and damage control surgery, followed by resuscitation with cardiopulmonary bypass (CPB). We reported previously that 20-60 min EPR in rats was associated with intact outcome, while 75 min EPR resulted in high mortality and neurological impairment in survivors. The delta opioid agonist DADLE ([d-Ala(2),d-Leu(5)]-enkephalin) was shown previously to be protective against ischemia-reperfusion injury in multiple organs, including brain. We hypothesized that DADLE could augment neurological outcome after EPR in rats. After rapid lethal hemorrhage, EPR was initiated by perfusion with ice-cold crystalloid to induce hypothermia (15 °C). After 75 min EPR, resuscitation was attempted with CPB. After randomization, three groups were studied (n = 10 per group): DADLE 0 mg/kg (D0), 4 mg/kg (D4) or 10 mg/kg (D10) added to the flush and during reperfusion. Survival, overall performance category (OPC; 1 = normal, 5 = death), neurological deficit score (NDS; 0-10% normal, 100% = max deficit), and histological damage score (HDS) were assessed in survivors on day 3. In D0 group, 2/10 rats survived, while in D4 and D10 groups, 4/10 and 5/10 rats survived, respectively (p = NS). Survival time (h) was 26.7 ± 28.2 in D0, 36.3 ± 31.9 in D4 and 47.1 ± 30.3 in D10 groups, respectively (p = 0.3). OPC, NDS and HDS were not significantly different between groups. In conclusion, DADLE failed to confer benefit on functional or histological outcome in our model of prolonged rat EPR.