Fructose-1,6-bisphosphate and MK-801 by aortic arch flush for cerebral preservation during exsanguination cardiac arrest of 20 min in dogs. An exploratory study

Abstract

In our exsanguination cardiac arrest (CA) outcome model in dogs we are systematically exploring suspended animation (SA), i.e. preservation of brain and heart immediately after the onset of CA to enable transport and resuscitative surgery during CA, followed by delayed resuscitation. We have shown in dogs that inducing moderate cerebral hypothermia with an aortic arch flush of 500 ml normal saline solution at 4°C, at start of CA 20 min no-flow, leads to normal functional outcome. We hypothesized that, using the same model, but with the saline flush at 24°C inducing minimal cerebral hypothermia (which would be more readily available in the field), adding either fructose-1,6-bisphosphate (FBP, a more efficient energy substrate) or MK-801 (an N-methyl- d-aspartate (NMDA) receptor blocker) would also achieve normal functional outcome. Dogs (range 19–30 kg) were exsanguinated over 5 min to CA of 20 min no-flow, and resuscitated by closed-chest cardiopulmonary bypass (CPB). They received assisted circulation to 2 h, mild systemic hypothermia (34°C) post-CA to 12 h, controlled ventilation to 20 h, and intensive care to 72 h. At CA 2 min, the dogs received an aortic arch flush of 500 ml saline at 24°C by a balloon-tipped catheter, inserted through the femoral artery (control group, n=6). In the FBP group ( n=5), FBP (total 1440 or 4090 mg/kg) was given by flush and with reperfusion. In the MK-801 group ( n=5), MK-801 (2, 4, or 8 mg/kg) was given by flush and with reperfusion. Outcome was assessed in terms of overall performance categories (OPC 1, normal; 2, moderate disability; 3, severe disability; 4, coma; 5, brain death or death), neurologic deficit scores (NDS 0–10%, normal; 100%, brain death), and brain histologic damage scores (HDS, total HDS 0, no damage; >100, extensive damage; 1064, maximal damage). In the control group, one dog achieved OPC 2, one OPC 3, and four OPC 4; in the FBP group, two dogs achieved OPC 3, and three OPC 4; in the MK-801 group, two dogs achieved OPC 3, and three OPC 4 ( P=1.0). Median NDS were 62% (range 8–67) in the control group; 55% (range 34–66) in the FBP group; and 50% (range 26–59) in the MK-801 group ( P=0.2). Median total HDS were 130 (range 56–140) in the control group; 96 (range 64–104) in the FBP group; and 80 (range 34–122) in the MK-801 group ( P=0.2). There was no difference in regional HDS between groups. We conclude that neither FBP nor MK-801 by aortic arch flush at the start of CA, plus an additional i.v. infusion of the same drug during reperfusion, can provide cerebral preservation during CA 20 min no-flow. Other drugs and drug-combinations should be tested with this model in search for a breakthrough effect.