Dose optimization of early high-dose valproic acid for neuroprotection in a swine cardiac arrest model

Aim: High-dose valproic acid (VPA) improves the survival and neurologic outcomes after asphyxial cardiac arrest (CA) in rats. We characterized the pharmacokinetics, pharmacodynamics, and safety of high-dose VPA in a swine CA model to advance clinical translation. Methods: After 8 min of untreated ventricular fibrillation CA, 20 male Yorkshire swine were resuscitated until return of spontaneous circulation (ROSC). They were block randomized to receive placebo, 75 mg/kg, 150 mg/kg, or 300 mg/kg VPA as 90-min intravenous infusion (n = 5/group) beginning at ROSC. Animals were monitored for 2 additional hours then euthanized. Experimental operators were blinded to treatments. Results: The mean(SD) total CA duration was 14.8(1.2) minutes. 300 mg/kg VPA animals required more adrenaline to maintain mean arterial pressure >= 80 mmHg and had worse lactic acidosis. There was a strong linear correlation between plasma free VPA C-max and brain total VPA (r(2) = 0.9494; p < 0.0001). VPA induced dosedependent increases in pan- and site-specific histone H3 and H4 acetylation in the brain. Plasma free VPA C-max is a better predictor than peripheral blood mononuclear cell histone acetylation for brain H3 and H4 acetylation (r(2) = 0.7189 for H3K27ac, r(2) = 0.7189 for pan-H3ac, and r(2) = 0.7554 for pan-H4ac; p < 0.0001). Conclusions: Up to 150 mg/kg VPA can be safely tolerated as 90-min intravenous infusion in a swine CA model. High-dose VPA induced dose-dependent increases in brain histone H3 and H4 acetylation, which can be predicted by plasma free VPA C-max as the pharmacodynamics biomarker for VPA target engagement after CA.