Intra-arrest cooling with delayed reperfusion yields higher survival than earlier normothermic resuscitation in a mouse model of cardiac arrest

Abstract

Background: Therapeutic hypothermia (TH) represents an important method to attenuate post-resuscitation injury after cardiac arrest. Laboratory investigations have suggested that induction of hypothermia before return of spontaneous circulation (ROSC) may confer the greatest benefit. We hypothesized that a short delay in resuscitation to induce hypothermia before ROSC, even at the expense of more prolonged ischemia, may yield both physiological and survival advantages.

Methods: Cardiac arrest was induced in C57BL/6 mice using intravenous potassium chloride; resuscitation was attempted with CPR and fluid administration. Animals were randomized into three groups (n=15 each): a normothermic control group, in which 8 min of arrest at 37 degrees C was followed by resuscitation; an early intra-arrest hypothermia group, in which 6.5 min of 37 degrees C arrest were followed by 90s of cooling, with resuscitation attempted at 30 degrees C (8 min total ischemia); and a delayed intra-arrest hypothermia group, with 90s cooling begun after 8 min of 37 degrees C ischemia, so that animals underwent resuscitation at 9.5 min.

Results: Animals treated with TH demonstrated improved hemodynamic variables and survival compared to normothermic controls. This was the case even when comparing the delayed intra-arrest hypothermia group with prolonged ischemia time against normothermic controls with shorter ischemia time (7-day survival, 4/15 vs. 0/15, p<0.001).

Conclusions: Short resuscitation delays to allow establishment of hypothermia before ROSC appear beneficial to both cardiac function and survival. This finding supports the concept that post-resuscitation injury processes begin immediately after ROSC, and that intra-arrest cooling may serve as a useful therapeutic approach to improve survival.

Figure 1

Schematic of experimental protocol. Thick horizontal lines show duration of arrest for each group, dark grey box represent CPR interval, and light grey area represents interval of therapeutic hypothermia. A, normothermic control group with 8 min arrest duration, approximately 3–4 min of CPR and 2 hrs of monitored recovery at 37°C. B, early intra-arrest (EIH) cooling group with 8 min arrest duration and 3–4 min CPR interval. In addition, cooling is initiated at 6.5 min of arrest such that resuscitation occurs at 30°C. After one hour, animals are rewarmed and monitored for 1 hour at 37°C. C, delayed intra-arrest (DIH) cooling group, with 9.5 min arrest duration and 3–4 min CPR interval. Cooling is initiated at 8 min of arrest such that resuscitation occurs at 30°C. After one hr, animals are rewarmed and monitored for an additional hr at 37°C.

Figure 2

Representative left ventricular pressure-volume (P-V) loops measured at baseline, 30, 60 and 120 min post-ROSC from (A) control, (B) early intra-arrest hypothermia (EIH) and (C) delayed intra-arrest hypothermia (DIH) experimental groups.

Figure 3

Cardiac physiological measurements, taken at baseline 10 min before cardiac arrest, and then at 10 min intervals during protocol including (A) peak left ventricular pressures (LVP_max); (B) dP/dt_max, a measure of contractility; (C) cardiac output, and (D) the isovolumic relaxation time constant, tau. Statistically significant differences between both hypothermia groups and controls (*) and between EIH and DIH groups (¥) are denoted for p < 0.05.

Figure 4

Survival after cardiac arrest. Kaplan-Meier survival plot of normothermic control group and the two experimental groups are shown. Statistically significant differences between both hypothermia groups and controls (*) and between EIH and DIH groups (¥) are denoted at 6, 24 and 72 hrs and at 7 days.

Figure 5

Neurological function scores after resuscitation. Each circle represents an individual animal scored at a specific time after resuscitation. A, 6 hrs after ROSC. B, 24 hrs after ROSC. C, 72 hrs after ROSC. The neurological scoring system has been detailed previously. Open circles represent early intra-arrest hypothermia (EIH) animals; grey circles represent delayed intra-arrest hypothermia (DIH) animals; black circles represent normothermic controls.