Intramuscular versus intravenous therapy for prehospital status epilepticus

Abstract

Background: Early termination of prolonged seizures with intravenous administration of benzodiazepines improves outcomes. For faster and more reliable administration, paramedics increasingly use an intramuscular route.

Methods: 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.

Results: 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.

Conclusions: 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.).

Figure 1. Screening, Enrollment, Randomization, and Inclusion in Intention-to-Treat and Per-Protocol Analyses

The number of patients who were assessed and enrolled includes any repeat assessments and enrollments for those who presented to emergency medical services (EMS) with status epilepticus more than once. The number assigned to treatment in the intention-to-treat analysis includes every patient who was enrolled in the study but only the initial enrollment for those enrolled more than once. Randomization was defined as occurring when an autoinjector was applied to the subject. “Misfire” refers to instances when the autoinjector was inadvertently triggered before it could be applied to the subject. “Malfunction” refers to instances when the autoinjector was applied but the drug was not administered because of operator error or mechanical failure. IM denotes intramuscular, and IV intravenous.

Figure 2. Primary Outcome According to Treatment Group

P_IM-P_IV represents the absolute difference in the primary outcome between the proportion of subjects treated with IM midazolam and the proportion treated with IV lorazepam (i.e., the proportion of subjects who did not have seizures on arrival in the emergency department and who did not receive rescue medication). CI denotes confidence interval.

Figure 3. Intervals between Active Treatment and Cessation of Convulsions, Box Opening and Cessation of Convulsions, and Box Opening and Active Treatment

The shorter time to IM drug administration was offset by the faster onset of action after IV drug administration, resulting in similar latency periods until convulsions were terminated. Time to IV administration includes the nominal time (about 20 seconds) needed to administer the drug by means of IM autoinjector. Asterisks indicate means, boxes interquartile ranges, bold vertical lines within boxes medians, I bars 1.5 times the interquartile range, and circles outliers.