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

Resuscitation Plus (Mar 2020)

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

Affiliations

Cindy H. Hsu: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Corresponding author. Department of Emergency Medicine, Department of Surgery, Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, NCRC B026-309N, 2800 Plymouth Road, Ann Arbor, MI, 48109-2800, USA.
Mohamad H. Tiba: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA
Brendan M. McCracken: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA
Carmen I. Colmenero: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA
Zachary Pickell: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; College of Literature Science and the Arts, University of Michigan Medical School, Ann Arbor, MI, USA
Danielle C. Leander: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA
Anne M. Weitzel: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA
Sarita Raghunayakula: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Jinhui Liao: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Tulasi Jinka: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA
Brandon C. Cummings: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA
Manjunath P. Pai: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan Medical School, Ann Arbor, MI, USA
Hasan B. Alam: Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
Kevin R. Ward: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI, USA
Thomas H. Sanderson: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
Robert W. Neumar: Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA

Journal volume & issue: Vol. 1
p. 100007

Abstract

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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 Cmax 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 Cmax 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 Cmax as the pharmacodynamics biomarker for VPA target engagement after CA.

Published in Resuscitation Plus

ISSN: 2666-5204 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine
Website: https://www.journals.elsevier.com/resuscitation-plus

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