Mild Hypothermia Attenuates Mitochondrial Oxidative Stress by Protecting Respiratory Enzymes and Upregulating MnSOD in a Pig Model of Cardiac Arrest

Mild hypothermia is the only effective treatment confirmed clinically to improve neurological outcomes for comatose patients with cardiac arrest. However, the underlying mechanism is not fully elucidated. In this study, our aim was to determine the effect of mild hypothermia on mitochondrial oxidative stress in the cerebral cortex. We intravascularly induced mild hypothermia (33°C), maintained this temperature for 12 h, and actively rewarmed in the inbred Chinese Wuzhishan minipigs successfully resuscitated after 8 min of untreated ventricular fibrillation. Cerebral samples were collected at 24 and 72 h following return of spontaneous circulation (ROSC). We found that mitochondrial malondialdehyde and protein carbonyl levels were significantly increased in the cerebral cortex in normothermic pigs even at 24 h after ROSC, whereas mild hypothermia attenuated this increase. Moreover, mild hypothermia attenuated the decrease in Complex I and Complex III (i.e., major sites of reactive oxygen species production) activities of the mitochondrial respiratory chain and increased antioxidant enzyme manganese superoxide dismutase (MnSOD) activity. This increase in MnSOD activity was consistent with the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and protein expressions, and with the increase of Nrf2 nuclear translocation in normothermic pigs at 24 and 72 h following ROSC, whereas mild hypothermia enhanced these tendencies. Thus, our findings indicate that mild hypothermia attenuates mitochondrial oxidative stress in the cerebral cortex, which may be associated with reduced impairment of mitochondrial respiratory chain enzymes, and enhancement of MnSOD activity and expression via Nrf2 activation

Xenon: An Emerging Neuroprotectant With Potential Application for Cardiac Arrest Care

Xenon is an inert, highly polarizable noble gas with demonstrated safety and application in general anesthesia for over 50 years. A potent inhibitor of the N-methyl-D-aspartate subtype of glutamate receptors, xenon has a well-documented ameliorating effect on excitotoxic neuronal injury in numerous cellular and animal models of hypoxic-ischemic brain injury. The most important determinant of overall survival and morbidity in out-of-hospital cardiac arrest is the severity of neurological injury. The only approved neuroprotective strategy in this setting is mild therapeutic hypothermia, which has demonstrated significant, albeit modest, improvements in mortality. The combination therapy of therapeutic hypothermia and xenon in porcine models of cardiac arrest has shown a greater improvement in functional outcomes than either intervention alone, thereby prompting the study of combination therapy in randomized clinical trials. The treatment of postarrest patients with xenon and mild hypothermia is safe and demonstrates favorable cardiovascular features, including a reduced heart rate, a reduction in troponin elevations, and a decreased need for vasopressors. Combination therapy is superior in protecting white matter integrity than hypothermia alone, but did not significantly impact neurological outcomes at 6-month follow-up. Despite an abundance of preclinical evidence supporting xenon\u27s neuroprotective properties, its translational potential in postcardiac arrest care is indeterminate due to a lack of adequately-powered studies