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

Cindy H Hsu; Mohamad H Tiba; Brendan M McCracken; Carmen I Colmenero; Zachary Pickell; Danielle C Leander; Anne M Weitzel; Sarita Raghunayakula; Jinhui Liao; Tulasi Jinka; Brandon C Cummings; Manjunath P Pai; Hasan B Alam; Kevin R Ward; Thomas H Sanderson; Robert W Neumar

doi:10.1016/j.resplu.2020.100007

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

Resusc Plus. 2020 Jun 1:1-2:100007. doi: 10.1016/j.resplu.2020.100007. eCollection 2020 Mar-Jun.

Authors

Cindy H Hsu^{1

2

3}, Mohamad H Tiba^{1

2}, Brendan M McCracken^{1

2}, Carmen I Colmenero^{1

2}, Zachary Pickell^{1

4}, Danielle C Leander^{1

2}, Anne M Weitzel^{1

2}, Sarita Raghunayakula¹, Jinhui Liao¹, Tulasi Jinka^{1

2}, Brandon C Cummings^{1

2}, Manjunath P Pai⁵, Hasan B Alam^{2

3}, Kevin R Ward^{1

2

6}, Thomas H Sanderson^{1

2

7}, Robert W Neumar^{1

2}

Affiliations

¹ Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
² Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA.
³ Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴ College of Literature Science and the Arts, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵ Department of Clinical Pharmacy, College of Pharmacy, University of Michigan Medical School, Ann Arbor, MI, USA.
⁶ Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI, USA.
⁷ Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.

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.

Keywords: Cardiac arrest; Histone acetylation; Pharmacodynamics biomarker; Pharmacokinetic; Swine model; Valproic acid.

Abstract

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