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

ABSTRACT:

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 (r² = 0.9494; p < 0.0001). VPA induced dose-dependent 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 (r² = 0.7189 for H3K27ac, r² = 0.7189 for pan-H3ac, and r² = 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.

SUBMITTER: Hsu CH

PROVIDER: S-EPMC8244526 | biostudies-literature |

REPOSITORIES: biostudies-literature

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