title: Efficacy and safety of intravenous valproate for status epilepticus: a systematic review.
abstract: BACKGROUND
  The 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).
  
  
  OBJECTIVE
  Our 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.
  
  
  METHODS
  Data sources included MEDLINE, back tracing of references in pertinent studies, and contact with the manufacturer of VPA (Sanofi-Aventis).
  
  
  RESULTS
  Overall, the search strategy yielded 433 results (425 MEDLINE, seven congress abstracts, one unpublished study); after excluding duplicate publications and case reports, 30 studies were identified (the earliest was published in 1993, the most recent in 2012); ten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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Neurology, Christian Doppler Klinik, Centre for Cognitive Neuroscience Salzburg, Paracelsus Medical University Salzburg, Ignaz Harrerstrasse 79, 5020, Salzburg, Austria, e.trinka@salk.at.
authors.forename: Eugen
authors.initials: E
authors.lastname: Trinka
authors.forename: Julia
authors.initials: J
authors.lastname: Höfler
authors.forename: Alexander
authors.initials: A
authors.lastname: Zerbs
authors.forename: Francesco
authors.initials: F
authors.lastname: Brigo
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000367:Age Factors; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D006801:Humans; D013226:Status Epilepticus / Q000188:drug therapy*; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid