Abstract

BackgroundNearly one in three unconscious cardiac arrest survivors experience post-anoxic status epilepticus (PASE). Historically, PASE has been deemed untreatable resulting in its exclusion from status epilepticus clinical trials. However, emerging reports of survivors achieving functional independence following early and aggressive treatment of PASE challenged this widespread therapeutic nihilism. In the absence of proven therapies specific to PASE, standard of care treatment leans on general management strategies for status epilepticus. Vigabatrin—an approved therapy for refractory focal-onset seizures in adults—inhibits the enzyme responsible for GABA catabolism, increases brain GABA levels and may act synergistically with anesthetic agents to abort seizures. Our central hypothesis is that early inhibition of GABA breakdown is possible in the post-cardiac arrest period and may be an effective adjunctive treatment in PASE.MethodsThis is a phase IIa, single-center, open-label, pilot clinical trial with blinded outcome assessment, of a single dose of vigabatrin in 12 consecutive PASE subjects. Subjects will receive a single loading dose of 4500 mg of vigabatrin (or dose adjusted in moderate and severe renal impairment) via enteric tube within 48 h of PASE onset. Vigabatrin levels will be monitored at 0- (baseline), 0.5-, 1-, 2-, 3-, 6-, 12-, 24-, 48-, 72- and 168-h (7 days) post-vigabatrin. Serum biomarkers of neuronal injury will be measured at 0-, 24-, 48-, 72- and 96-h post-vigabatrin. The primary feasibility endpoint is the proportion of enrolled subjects among identified eligible subjects receiving vigabatrin within 48 h of PASE onset. The primary pharmacokinetic endpoint is the measured vigabatrin level at 3 h post-administration. Descriptive statistics with rates and proportions will be obtained regarding feasibility outcomes, along with the noncompartmental method for pharmacokinetic analyses. The area under the vigabatrin concentration-time curve in plasma from zero to the time of the last quantifiable concentration (AUC0-tlqc) will be calculated to estimate dose-linear pharmacokinetics.PerspectiveVigabatrin demonstrates high potential for synergism with current standard of care therapies. Demonstration of the feasibility of vigabatrin administration and preliminary safety in PASE will pave the way for future efficacy and safety trials of this pharmacotherapeutic.Trial Registration NCT04772547.

Highlights

  • Cardiac arrest claims millions of lives annually across the globe

  • Aim The aim of this study is to demonstrate the feasibility of administering a single enteral loading dose of vigabatrin within 48 h of post-anoxic status epilepticus (PASE) onset in unconscious cardiac arrest survivors and characterize its absorption, regardless of location of cardiac arrest and type of non-perfusing rhythm

  • PASE is defined according to American Clinical Neurophysiology Society criteria for electrographic status epilepticus: any pattern displaying definite evolution or epileptiform discharges averaging > 2.5Hz lasting ≥ 10 continuous minutes or comprising ≥ 20% of any 60-minute period of recording [15]

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Summary

Methods

Study design A phase IIa, single-center, open-label pilot clinical trial with blinded outcome assessment, of early administration of a single 4500 mg (or dose adjusted in moderate and severe renal impairment) dose of vigabatrin in 12 consecutive PASE subjects. Those with non-traumatic cardiac arrest will be eligible if the decision to initiate and maintain care aimed at preservation of life in the early post-cardiac arrest period and treat unequivocal electrographic status epilepticus has been made. Blinding This will be an open label study. Long-term monitoring with continuous EEG will be initiated as soon as possible following ROSC and maintained for at least 72 h for all unconscious cardiac arrest survivors or 24 h post-discontinuation of anesthetics in those who develop post-anoxic status epilepticus per institutional practice. Non-traumatic cardiac arrest of any rhythm, etiology and location of occurrence

Introduction
Findings
PASE onset preceding initiation of EEG monitoring
Full Text
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