title: Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis.
abstract: BACKGROUND
  Prompt treatment of status epilepticus (SE) is associated with better outcomes. Rectal diazepam (DZP) and nonintravenous (non-IV) midazolam (MDZ) are often used in the treatment of early SE instead of intravenous applications. The aim of this review was to determine if nonintravenous MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE seizures in children and adults.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and MEDLINE for randomized controlled trials comparing non-IV MDZ with DZP (by any route) in patients (all ages) with early SE defined either as seizures lasting >5 min or as seizures at arrival in the emergency department. The following outcomes were assessed: clinical seizure cessation within 15 min of drug administration, serious adverse effects, time interval to drug administration, and time from arrival in the emergency department to seizure cessation. Outcomes were assessed using a random-effects Mantel-Haenszel meta-analysis to calculate risk ratio (RR), odds ratio (OR) and mean difference with 95% confidence intervals (95% CIs).
  
  
  RESULTS
  Nineteen studies with 1933 seizures in 1602 patients (some trials included patients with more than one seizure) were included. One thousand five hundred seventy-three patients were younger than 16 years. For seizure cessation, non-IV MDZ was as effective as DZP (any route) (1933 seizures; RR: 1.03; 95% CIs: 0.98 to 1.08). No difference in adverse effects was found between non-IM MDZ and DZP by any route (1933 seizures; RR: 0.87; 95% CIs: 0.50 to 1.50). Time interval between arrival and seizure cessation was significantly shorter with non-IV MDZ by any route than with DZP by any route (338 seizures; mean difference: -3.67 min; 95% CIs: -5.98 to -1.36); a similar result was found for time from arrival to drug administration (348 seizures; mean difference: -3.56 min; 95% CIs: -5.00 to -2.11). A minimal difference was found for time interval from drug administration to clinical seizure cessation, which was shorter for DZP by any route than for non-IV MDZ by any route (812 seizures; mean difference: 0.56 min; 95% CIs: 0.15 to 0.98 min). Not all studies reported information on time intervals. Comparison by each way of administration failed to find a significant difference in terms of clinical seizure cessation and occurrence of adverse effects. The only exception was the comparison between buccal MDZ and rectal DZP, where MDZ was more effective than rectal DZP in terminating SE but only when results were expressed as OR (769 seizures; OR: 1.78; 95% CIs: 1.11 to 2.85; RR: 1.15; 95% CIs: 0.85 to 1.54). Only one study was entirely conducted in an adult population (21 patients, aged 31 to 69 years), showing no difference in efficacy or time to seizure cessation after drug administration between intranasal MDZ and rectal DZP.
  
  
  CONCLUSIONS
  Non-IV MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE in children and probably also in adults. Times from arrival in the emergency department to drug administration and to seizure cessation are shorter with non-IV MDZ than with intravenous or rectal DZP, but this does not necessarily result in higher seizure control. An exception may be the buccal MDZ, which, besides being socially more acceptable and easier to administer, might also have a higher efficacy than rectal DZP in seizure control. This article is part of a Special Issue entitled Status Epilepticus.
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Italy; Department of Neurology, Franz Tappeiner Hospital, Merano, Italy. Electronic address: dr.francescobrigo@gmail.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brigo
authors.affiliation: Department of Neurology, Franz Tappeiner Hospital, Merano, Italy; Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Nardone
authors.affiliation: Department of Neurology, Franz Tappeiner Hospital, Merano, Italy.
authors.forename: Frediano
authors.initials: F
authors.lastname: Tezzon
authors.affiliation: Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria; Centre for Cognitive Neuroscience, Salzburg, Austria; Department of Public Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall.i.T., Austria.
authors.forename: Eugen
authors.initials: E
authors.lastname: Trinka
mesh_terms: D061605:Administration, Intravenous; D000285:Administration, Rectal; D000927:Anticonvulsants / Q000008:administration & dosage / Q000627:therapeutic use*; D003975:Diazepam / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D008874:Midazolam / Q000008:administration & dosage / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013226:Status Epilepticus / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D003975:Diazepam; D008874:Midazolam
keywords: Diazepam; Meta-analysis; Midazolam; Seizures; Status epilepticus