Abstract 3308: Therapeutic Hypothermia Improves Survival and Neurological Outcomes by Akt-mediated Antiapoptotic Protection of the Brain
Background: Neurological dysfunction after cardiopulmonary resuscitation (CPR) accounts for the majority of late morbidities and mortalities. Therapeutic hypothermia has been recommended in patients resuscitated from cardiac arrest; the protective mechanism, however, is not fully understood yet. We therefore investigate the neuroprotective mechanisms underlying therapeutic hypothermia.
Methods: Based on a rat model of asphyxia cardiac arrest (6 min) and CPR, therapeutic hypothermia (32°C) was induced immediately after resuscitation and maintained for 2 h. The rats were then rewarmed to normothermia in another 2 h. The hemodynamics, tissue blood flow of the brain (assessed by OxyFLO probe), and systemic reactive oxygen species (ROS) generation (measured by chemiluminescence method) were compared with those of normothermia control. Bax, Bcl-2 and phosphorylated Akt (Ser 473) of the brain were measured at 4 h post-resuscitation. In a subgroup with minimal invasive procedures, the survival and neurological outcomes were monitored up to 3 days. The brain tissues were sampled on day 3 for TdT-mediated dUTP nick-ends labeling (TUNEL) stain.
Results: The survival was significantly better in the hypothermia group (log-rank P<0.05). The neurological scores were also higher 6 h, 24 h and 3 days post-CPR (all P<0.05). The cerebral blood flow in hypothermia group was neither lower nor higher than that of normothermia. The blood pressure and serial arterial blood gas were not different, either. The systemic blood ROS, however, was significantly lower in hypothermia group since 3 h post-CPR. The Bax/Bcl-2 ratio at 4 h and TUNEL stain of the brain on day 3 were both lower in hypothermia group, suggesting amelioration of apoptotic neuronal death. The phosphorylated Akt at 4 h was higher in hypothermia, suggesting early activation of Akt which triggers downstream antiapoptotic pathways leading to hypothermia protection.
Conclusion: Therapeutic hypothermia improves survival and neurological outcomes by early activation of Akt that leads to antiapoptotic protection. In contrast to other treatment strategies which improve gross physiological indicators, the protection is mediated by triggering of intracellular signaling pathways leading to antiapoptosis.