1. Dose optimization of early high-dose valproic acid for neuroprotection in a swine cardiac arrest model
- Author
-
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, and Robert W. Neumar
- Subjects
Cardiac arrest ,Swine model ,Valproic acid ,Histone acetylation ,Pharmacokinetic ,Pharmacodynamics biomarker ,Specialties of internal medicine ,RC581-951 - 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 Cmax and brain total VPA (r2 = 0.9494; p
- Published
- 2020
- Full Text
- View/download PDF