Valproic acid as adjuvant treatment in generalized convulsive status epilepticus for adults admitted to the ICU on (VALSE): randomized double blind clinical trial (Preprint)

BACKGROUND Generalized convulsive status epilepticus (GCSE) is a frequent medical emergency. Treatment focuses on administration of benzodiazepines followed by a second line antiepileptic drug (AED). Despite this stepwise strategy, GCSE is not controlled in a quarter of patients and is associated with protracted hospitalization, high-mortality and long-term disability. OBJECTIVE We aimed to show that the administration of valproic acid (VPA) may be suited as a complement of the first and second-line treatment, because of antiepileptic efficacy, neuroprotective properties and good tolerability. METHODS We conducted a multicenter, double-blind, randomized controlled trial comparing VPA to placebo in adults admitted to intensive care units (ICU) for GCSE in France. All patients received standard of care including a benzodiazepine and a second-line AED (except VPA) at the discretion of the treating medical team. In the intervention arm, VPA was administered intravenously as a loading dose of 30mg/kg over 15 minutes followed by a continuous infusion of 1 mg/kg/h over the next 12 hours. In the placebo group, an identical IV administration of 0.9 % saline was used. The primary outcome was the proportion of patients discharged alive from 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. Ethics Committee of Saint-Germain-en-Laye, France, initial approval received on May 14 2012. Results will be disseminated via peer-reviewed publication and presentation at international conferences. RESULTS The first patient was randomized on February 18, 2013 and the last patient on July 7, 2018. 245 (99%) out of 248 planned patients were enrolled across 20 ICUs. At present, data management is still ongoing, and all parties involved in the trial remain blinded.Research CONCLUSIONS This is the first multicentre randomized double-blind controlled trial that assesses whether Valproic Acid can be useful as an adjuvant therapy to recommended first and second line anti-epileptic drugs for improving the outcome of GCSE. CLINICALTRIAL NCT01791868 (registered on May 2012).