Efficacy and Safety of Intravenous Valproate for Status Epilepticus: A Systematic Review

Abstract

IntroductionThe effectiveness of valproate (VPA) in the treatment of focal and generalized epilepsies is well established. The drug has a wide spectrum of action, good tolerability, and has been available as an injectable formulation since 1993. Despite the lack of class A evidence, it has been used extensively in various forms of status epilepticus (SE).AimOur aim was to present a systematic review of data from randomized and non-randomized controlled trials to evaluate the efficacy and safety of intravenous VPA for the treatment of SE.MethodsData sources included MEDLINE, back tracing of references in pertinent studies, and contact with the manufacturer of VPA (Sanofi-Aventis).ResultsOverall, the search strategy yielded 433 results (425 MEDLINE, seven congress abstracts, one unpublished study); after excluding duplicate publications and case reports, 30 studies were identified (the earliest was published in 1993, the most recent in 2012); ten were controlled (six randomized controlled trials, four non-randomized controlled studies), and 20 uncontrolled trials (eight prospective observational studies, 12 retrospective case series). The cumulative literature describes the experiences of 860 patients with various forms of SE treated with intravenous VPA. The overall response rate to abrogate SE was 70.9 % (601/848; 95 % confidence interval [CI] 67.8–73.9). Response rates to intravenous VPA were better in children than in adults and did not differ between the SE types. The most commonly reported effective doses were between 15 and 45 mg/kg in bolus (6 mg/kg/min) followed by 1–3 mg/kg/h infusion. Safety studies of intravenous VPA administration in patients with SE showed a low incidence of adverse events overall (<10 %), mainly dizziness, thrombocytopenia, and mild hypotension, which was independent of infusion rates. Of note, good cardiovascular and respiratory tolerability was observed in these studies, even at high doses and fast infusion rates (up to 30 mg/kg at 10 mg/kg/min), despite multiple morbidities or other antiepileptic drugs. The most serious concern relates to the possibility of acute encephalopathy, sometimes related to hepatic abnormalities or hyperammonemia.ConclusionsThe published experience is consistent with VPA being a safe and effective therapeutic option for patients with established SE who have previously failed conventional first-line treatment with benzodiazepines, but high-quality randomized controlled trials are needed to inform clinicians on its comparative effectiveness in SE.

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

“…We prefer valproate sodium (25-40 mg/kg i.v.) [147][148][149] or fosphenytoin (18-20 phenytoin equivalents/kg i.v.) [150], which are among the best studied antiepileptic therapies in SE.…”

Review and update of the Hong Kong Epilepsy Guideline on status epilepticus

“…24,25 The exact mechanism of anticonvulsant effect has not been fully established. It may involve potentiation of GABAergic functions, N-methyl-D-aspartate (NMDA) inhibition, reduction of γ-hydroxybutyrate release, and blockade of voltagedependent sodium currents.…”

“…It is a broad-spectrum AED that can be used effectively in virtually all types of seizure, and safely in patients whose seizure type is poorly characterised. 25 The mean efficacy of VPA has been reported to be 70% to 76% in more than 800 patients with SE. 23,25 The response rate was better in children than in adults and did not differ between the SE types.…”

“…25 The mean efficacy of VPA has been reported to be 70% to 76% in more than 800 patients with SE. 23,25 The response rate was better in children than in adults and did not differ between the SE types. The effective loading doses vary across different studies.…”

Management and Early Treatment of Status Epilepticus in Adults and Children

“…An efficacy of 70.9% was reported in a large number of studies, including six randomized controls. The most frequently recommended effective dosage is 15-45 mg/kg bolus (6-10 mg/kg/min), followed by 1-3 mg/kg/h infusion therapy (16). High infusion rates, such as 40 mg/kg/min, have also been reported in patients in the ICU.…”