Valproic acid as adjuvant treatment for convulsive status epilepticus: a randomised clinical trial
Authors: Sharshar Tarek , Porcher Raphaël , Asfar Pierre , Grimaldi Lamiae , Jabot Julien , Argaud Laurent , Lebert Christine , Bollaert Pierre-Edouard , Harlay Marie Line , Chillet Patrick , Maury Eric , Santoli Francois , Blanc Pascal , Sonneville Romain , Vu Dinh Chuyen , Rohaut Benjamin , Mazeraud Aurelien , Alvarez Jean-Claude , Navarro Vincent , Clair Bernard , Outin Hervé ,   the Valse investigators and for the Groupe d’Explorations Neurologiques en Reanimation (GENER), Argaud Laurent , Azabou Eric , Beloncle François , Ben-Hadj Omar , Blanc Pascal , Bollaert Pierre-Edouard , Bolgert Francis , Bouadma Lila , Chillet Patrick , Clair Bernard , Corne Philippe , Clere-Jehl Raphaël , Cour Martin , Crespel Arielle , Déiler Véronique , Dellamonica Jean , Demeret Sophie , Harley Marie-Line , Henry-Lagarrigue Matthieu , Jabot Julien , Heming Nicholas , Hernu Romain , Kouatchet Achille , Lebert Christine , Lerolle Nicolas , Maury Eric , Letrou Sophie , Mazeraud Aurélien , Mercat Alain , Mortaza Satar , Mourvillier Bruno , Outin Hervé , Paugham-Burtz Catherine , Pierrot Marc , Provent Marion , Rohaut Benjamin , De La Salle Sylvie , Santoli François , Schenk Maleka , Siami Shidasp , Souday Vincent , Sharshar Tarek , Sonneville Romain , Timsit Jean-François , Thuong Marie , Weiss Nicolas 
Published: January 2023

Background

Generalised convulsive status epilepticus (GCSE) is a medical emergency. Guidelines recommend a stepwise strategy of benzodiazepines followed by a second-line anti-seizure medicine (ASM). However, GCSE is uncontrolled in 20–40% patients and is associated with protracted hospitalisation, disability, and mortality. The objective was to determine whether valproic acid (VPA) as complementary treatment to the stepwise strategy improves the outcomes of patients with de novo established GCSE.

Methods

This was a multicentre, double-blind, randomised controlled trial in 244 adults admitted to intensive care units for GCSE in 16 French hospitals between 2013 and 2018. Patients received standard care of benzodiazepine and a second-line ASM (except VPA). Intervention patients received a 30 mg/kg VPA loading dose, then a 1 mg/kg/h 12 h infusion, whilst the placebo group received an identical intravenous administration of 0.9% saline as a bolus and continuous infusion. Primary outcome was proportion of patients discharged from hospital by day 15. The secondary outcomes were seizure control, adverse events, and cognition at day 90.

Results

A total of 126 (52%) and 118 (48%) patients were included in the VPA and placebo groups. 224 (93%) and 227 (93%) received a first-line and a second-line ASM before VPA or placebo infusion. There was no between-group difference for patients hospital-discharged at day 15 [VPA, 77 (61%)versusplacebo, 72 (61%), adjusted relative risk 1.04; 95% confidence interval (0.89–1.19);p = 0.58]. There were no between-group differences for secondary outcomes.

Conclusions

VPA added to the recommended strategy for adult GCSE is well tolerated but did not increase the proportion of patients hospital-discharged by day 15.

Trial registrationNo. NCT01791868 (ClinicalTrials.gov registry), registered: 15 February 2012.