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.