• Joo Suk Oh, Jinka Tulasi, Ren Xiaodan, William C Stacey, and Robert W Neumar.
• 1Department of Emergency Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 2Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI. 3Michigan Center for Integrative Research in Critical Care (MCIRCC), University of Michigan, Ann Arbor, MI. 4Department of Neurology, University of Michigan Medical School, Ann Arbor, MI.
• Crit. Care Med. 2017 Nov 1; 45 (11): e1149-e1156.

ObjectivesHigh-dose valproic acid in combination with hypothermic-targeted temperature management has been reported to synergistically improve neurologic outcomes after cardiac arrest. This study investigated the potential synergistic mechanisms.DesignProspective, randomized, experimental study.SettingUniversity research institution.SubjectsMale Long Evans rats.InterventionRats resuscitated from asphyxial cardiac arrest were randomized to one of the three groups: normothermic-targeted temperature management (37°C ± 1°C), hypothermic-targeted temperature management (33° ± 1° × 24 hr + placebo infusion), hypothermic-targeted temperature management plus high-dose valproic acid (300 mg/kg IV × 1 initiated 5 min post return of spontaneous circulation and infused over 20 min) (hypothermic-targeted temperature management + valproic acid).Measurements And Main ResultsSeventy-two-hour survival was significantly greater with hypothermic-targeted temperature management + valproic acid, compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p < 0.05). Survival with good neurologic function, neurodegeneration, expression of HSP70, phosphorylation of Akt and Erk1/2 were not significantly different between hypothermic-targeted temperature management and hypothermic-targeted temperature management + valproic acid. The prevalence of seizures during the first 72-hour postcardiac arrest was significantly lower with hypothermic-targeted temperature management + valproic acid compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p = 0.01).ConclusionsHigh-dose valproic acid combined with hypothermic-targeted temperature management prevents postcardiac arrest seizures and improves survival. It remains to be determined if the mechanism of seizure prevention is through the antiepileptic effect of valproic acid or direct neuroprotection. Overall, the combination of high-dose valproic acid and hypothermic-targeted temperature management remains a promising strategy to improve cardiac arrest outcomes.

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