Background: Hypothermia has been shown to improve survival and neurological outcomes for ventricular fibrillation (VF) cardiac arrest. The electrophysiological mechanisms of hypothermia are not well-Understood, nor are the effects of beginning cooling during the resuscitation. Methods and results: We hypothesized that inducing hypothermia prior to the onset of VF would slow the deleterious changes seen in the ECG during VF and that inducing hypothermia at the start of resuscitation would increase the rates of ROSC and short-term survival in a porcine model of prolonged VF. We randomly assigned 42 domestic swine (27.2 +/- 2.3 kg) to either pretreatment with hypothermia before induction of VF (PRE), normothermic resuscitation (NORM) or intra-resuscitation hypothermia (IRH). During anesthesia, animals were instrumented via femoral cutdown. Lead 11 ECG was recorded continuously. PRE animals were cooled before the induction of VF, with a rapid infusion of 4 degrees normal saline (30 mL/kg). VF was induced electrically, left untreated for 8 min, then mechanical CPR began. During CPR the NORM animals got 30 mL/kg body-temperature saline and the IRH animals got 30 mL/kg 4 degrees saline. In all groups first rescue shocks were delivered after 13 min of VF. We calculated the VF scaling exponent (ScE) for the entire 8 min period (compared using GEE). ROSC and survival were compared with Fisher's exact test. Mean temperature in degrees C at the onset of VF was PRE = 34.7 degrees (+/-0.8), NORM = 37.8 (+/-0.9), and IRH = 37.9 (+/-0.9). The ScE values over time were significantly lower after 8 min in the PRE group (p = 0.02). ROSC: PRE = 10/14 (71%), NORM = 6/14 (43%) and IRH = 12/14 (86%): p for IRH vs. NORM = 0.02. Survival: PRE = 9/14 (64%), NORM = 5/14 (36%), IRH 8/14 (57%). Conclusion: Hypothermia slowed the decay of the ECG wavefrom during prolonged VF. IRH improved ROSC but not short-term survival compared to NORM. It is possible to rapidly induce mild hypothermia during CPR using an IV infusion of ice-cold saline. (C) 2008 Elsevier Ireland Ltd. All rights reserved.