title: Assessment of the delta opioid agonist DADLE in a rat model of lethal hemorrhage treated by emergency preservation and resuscitation.
abstract: 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 degrees C). After 75 min EPR, resuscitation was attempted with CPB. After randomization, three groups were studied (n=10 per group): DADLE 0mg/kg (D0), 4 mg/kg (D4) or 10mg/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.
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, United States. drabekt@anes.upmc.edu
authors.forename: Tomas
authors.initials: T
authors.lastname: Drabek
authors.forename: Fei
authors.initials: F
authors.lastname: Han
authors.forename: Robert H
authors.initials: RH
authors.lastname: Garman
authors.forename: Jason
authors.initials: J
authors.lastname: Stezoski
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Tisherman
authors.forename: S William
authors.initials: SW
authors.lastname: Stezoski
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Morhard
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
mesh_terms: D000818:Animals; D002315:Cardiopulmonary Bypass; D004195:Disease Models, Animal; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology*; D007036:Hypothermia, Induced; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods*; D012771:Shock, Hemorrhagic / Q000628:therapy*; D018709:Statistics, Nonparametric; D015996:Survival Rate
chemical_list: D016308:Enkephalin, Leucine-2-Alanine