Valproic acid as adjuvant treatment for convulsive status epilepticus: a randomised clinical trial
Tarek Sharshar,
Raphaël Porcher,
Pierre Asfar,
Lamiae Grimaldi,
Julien Jabot,
Laurent Argaud,
Christine Lebert,
Pierre-Edouard Bollaert,
Marie Line Harlay,
Patrick Chillet,
Eric Maury,
Francois Santoli,
Pascal Blanc,
Romain Sonneville,
Dinh Chuyen Vu,
Benjamin Rohaut,
Aurelien Mazeraud,
Jean-Claude Alvarez,
Vincent Navarro,
Bernard Clair,
Hervé Outin,
the Valse investigators and for the Groupe d’Explorations Neurologiques en Reanimation (GENER)
Affiliations
Tarek Sharshar
Neuro-Intensive Care Medicine, Anaesthesiology and ICU Department, GHU-Psychiatry and Neurosciences, Pole Neuro, Sainte-Anne Hospital, Institute of Psychiatry and Neurosciences of Paris, INSERM U1266, Université Paris Cité
Raphaël Porcher
Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS)
Pierre Asfar
Department of Medical Intensive Care, University Hospital
Lamiae Grimaldi
Clinical Research Unit, Assistance Publique - Hôpitaux de Paris University Paris-Saclay. Faculty of medicine, University of Versailles Saint-Quentin en Yvelines. Inserm U1018 Team Anti-infective evasion and pharmacoepidemiology
Julien Jabot
Medical-Surgical Intensive Care Unit, CHU Felix-Guyon
Laurent Argaud
Service de Médecine Intensive-Réanimation, Hospices Civils de Lyon, Hôpital Edouard Herriot
Christine Lebert
Médecine Intensive Réanimation, Centre Hospitalier Départemental de Vendée
Pierre-Edouard Bollaert
CHRU-Nancy, Service de Médecine Intensive Réanimation, Université de Lorraine
Marie Line Harlay
Médecine Intensive Réanimation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg
Patrick Chillet
Service de Médecine Intensive - Réanimation, Centre hospitalier Léon Bourgeois
Eric Maury
Service de Médecine Intensive et Réanimation Hôpital Saint-Antoine, Paris-Sorbonne Université
Francois Santoli
Médecine Intensive—Réanimation, Centre Hospitalier Robert Ballanger
Pascal Blanc
Réanimation Médico Chirurgicale, Centre Hospitalier René Dubos
Romain Sonneville
Université de Paris Cité, INSERM UMR1137
Dinh Chuyen Vu
General Intensive Care Unit, Sud-Essonne Hospital
Benjamin Rohaut
Department of Neurology, Neuro-ICU & Brain institute - ICM, Pitié-Salpêtrière Hospital APHP, Sorbonne Université
Aurelien Mazeraud
Anaesthesiology and ICU Department, GHU-Psychiatry and Neurosciences, Pole Neuro, Sainte-Anne Hospital, Perception and Memory Unit, Neurosciences Department, Institut Pasteur, Université Paris Cité
Jean-Claude Alvarez
Department of Pharmacology and Toxicology, Inserm U-1173, Raymond Poincare Hospital, AP-HP, Versailles Saint-Quentin-en-Yvelines University, Paris-Saclay University
Vincent Navarro
AP-HP, Epilepsy Unit, Pitié-Salpêtrière Hospital, Sorbonne Université, and Paris Brain Institute
Bernard Clair
General Intensive Care Unit, APHP, Raymond Poincaré Hospital, University of Versailles Saint-Quentin en Yvelines
Hervé Outin
Intensive Care Unit Centre Hospitalier Intercommunal
the Valse investigators and for the Groupe d’Explorations Neurologiques en Reanimation (GENER)
Abstract 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%) versus placebo, 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 registration No. NCT01791868 (ClinicalTrials.gov registry), registered: 15 February 2012.
