Optimal timing of hypothermia in relation to myocardial reperfusion

Abstract

Two previous clinical trials investigating hypothermia as an adjunct therapy for myocardial infarction have failed. Recently a pilot study has demonstrated a significant reduction in infarct size. The aims of this study were to elucidate the effects of hypothermia on reperfusion injury and to investigate the optimal hypothermia protocol for a future clinical trial. Pigs (40-50kg) were anesthetized and a normal pig temperature of 38°C was established utilizing an endovascular temperature modulating catheter. The pigs were randomized to a combination hypothermia group (1,000ml of 4°C saline solution and endovascular cooling, n=8), or to normothermic controls (n=8). A PCI balloon was then inflated in the LAD for 40min (control) or 45min with hypothermia induced during the last 5min. Furthermore, hypothermia induced by cold saline alone (n=8), and prolonged combination hypothermia during reperfusion (n=7) were also examined. Infarct size and area at risk were determined ex vivo after 4h of reperfusion using gadolinium-enhanced MRI and Tc-99-tetrofosmin SPECT, respectively. All pigs in the combination hypothermia group were cooled to <35°C within 5min. Combination hypothermia reduced IS/AAR by 18% compared with normothermic controls despite 5min longer ischemic time (61±5 vs. 74±4%, p=0.03). Cold saline did not reduce IS/AAR. Prolonging hypothermia treatment after onset of reperfusion by an additional 45min over that used in a previous paper did not confer any additional benefit. The cardioprotective effects of hypothermia treatment are due to an attenuation of myocardial injury during both ischemia and reperfusion. The results suggest that a hypothermia protocol using a cold saline infusion and endovascular cooling enables hypothermia to be induced in a clinical setting without delaying reperfusion therapy.