Intramuscular Versus Buccal Midazolam for Pediatric Seizures: A Randomized Double-Blinded Trial

The optimal pharmacologic treatment for early convulsive status epilepticus is unclear.

Population-based epidemiological studies on epilepsy are available mainly from the UK and the Nordic, Baltic and western Mediterranean countries. No studies were identified from large areas of Europe, especially from the former eastern Europe (except the Baltic countries) and the eastern Mediterranean countries. Based on the prevalence of epilepsy in different studies and accounting for incomplete case identification the estimated number of children and adolescents in Europe with active epilepsy is 0.9 million (prevalence 4.5-5.0 per 1000), 1.9 million in ages 20-64 years (prevalence six per 1000) and 0.6 million in ages 65 years and older (prevalence seven per 1000). Approximately 20-30% of the epilepsy population have more than one seizure per month. Based on the age-specific incidence rates in European studies, the estimated number of new cases per year amongst European children and adolescents is 130,000 (incidence rate 70 per 100,000), 96,000 in adults 20-64 years (incidence rate 30 per 100,000) and 85,000 in the elderly 65 years and older (incidence 100 per 100,000). The proportion of both new and established cases with epilepsy in the young, adults and elderly in individual countries may differ substantially from total European distribution because of differences in age structure.

Early termination of prolonged seizures with intravenous administration of benzodiazepines improves outcomes. For faster and more reliable administration, paramedics increasingly use an intramuscular route. This double-blind, randomized, noninferiority trial compared the efficacy of intramuscular midazolam with that of intravenous lorazepam for children and adults in status epilepticus treated by paramedics. Subjects whose convulsions had persisted for more than 5 minutes and who were still convulsing after paramedics arrived were given the study medication by either intramuscular autoinjector or intravenous infusion. The primary outcome was absence of seizures at the time of arrival in the emergency department without the need for rescue therapy. Secondary outcomes included endotracheal intubation, recurrent seizures, and timing of treatment relative to the cessation of convulsive seizures. This trial tested the hypothesis that intramuscular midazolam was noninferior to intravenous lorazepam by a margin of 10 percentage points. At the time of arrival in the emergency department, seizures were absent without rescue therapy in 329 of 448 subjects (73.4%) in the intramuscular-midazolam group and in 282 of 445 (63.4%) in the intravenous-lorazepam group (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to 16.1; P<0.001 for both noninferiority and superiority). The two treatment groups were similar with respect to need for endotracheal intubation (14.1% of subjects with intramuscular midazolam and 14.4% with intravenous lorazepam) and recurrence of seizures (11.4% and 10.6%, respectively). Among subjects whose seizures ceased before arrival in the emergency department, the median times to active treatment were 1.2 minutes in the intramuscular-midazolam group and 4.8 minutes in the intravenous-lorazepam group, with corresponding median times from active treatment to cessation of convulsions of 3.3 minutes and 1.6 minutes. Adverse-event rates were similar in the two groups. For subjects in status epilepticus, intramuscular midazolam is at least as safe and effective as intravenous lorazepam for prehospital seizure cessation. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, ClinicalTrials.gov NCT00809146.).