Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus in Adults Admitted to Intensive Care Units: Protocol for a Double-Blind, Multicenter Randomized Controlled Trial

Abstract

Background: Generalized convulsive status epilepticus (GCSE) is a frequent medical emergency. GCSE treatment focuses on the administration of benzodiazepines followed by a second-line antiepileptic drug (AED). Despite this stepwise strategy, GCSE is not controlled in one-quarter of patients and is associated with protracted hospitalization, high mortality, and long-term disability. Valproic acid (VPA) is an AED with good tolerability and neuroprotective properties.

Objective: This study aims to demonstrate that administration of VPA as an adjuvant for first- and second-line treatment in GCSE can improve outcomes.

Methods: A multicenter, double-blind, randomized controlled trial was conducted, comparing VPA with a placebo in adults admitted to intensive care units (ICUs) for GCSE in France. GCSE was diagnosed by specifically trained ICU physicians according to standard criteria. All patients received standard of care, including a benzodiazepine and a second-line AED (not VPA), at the discretion of the treating medical team. In the intervention arm, VPA was administered intravenously at a loading dose of 30 mg/kg over 15 minutes, followed by a continuous infusion of 1 mg/kg/hour over the next 12 hours. In the placebo group, an identical intravenous administration of 0.9% saline was used. The primary outcome was the proportion of patients discharged alive from the hospital by day 15. Secondary outcomes were frequency of refractory and super refractory GCSE, ICU-related morbidity, adverse events related to VPA, and cognitive dysfunction at 3 months. Statistical analyses will be performed according to the intent-to-treat principle.

Results: The first patient was randomized on February 18, 2013, and the last patient was randomized on July 7, 2018. Of 248 planned patients, 98.7% (245/248) were enrolled across 20 ICUs. At present, data management is still ongoing, and all parties involved in the trial remain blinded.

Conclusions: The Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus (VALSE) trial will evaluate whether the use of VPA as an adjuvant for first- and second-line treatment in GCSE improves outcomes.

Trial registration: ClinicalTrials.gov NCT01791868; https://ichgcp.net/clinical-trials-registry/NCT01791868.

International registered report identifier (irrid): DERR1-10.2196/22511.

Keywords: generalized convulsive status epilepticus; intensive care unit; seizure; valproic acid.

Conflict of interest statement

Conflicts of Interest: None declared.

©Tarek Sharshar, Omar Ben Hadj Salem, Raphaël Porcher, Lamiae Grimaldi-Bensouda, Nicholas Heming, Bernard Clair, Eric Azabou, Aurélien Mazeraud, Benjamin Rohaut, Hervé Outin. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 24.02.2021.

Figures

Figure 1

Study design. AED: antiepileptic drug; EEG: electroencephalogram; GCS: Glasgow Coma Scale; ICU: intensive care unit; IV: intravenous. *Guidelines from the French Intensive Care Society [11].