Intramuscular midazolam versus intravenous clonazepam for prehospital treatment of generalized tonic-clonic seizures: A randomized double-blind non-inferiority trial.
Seizure · 2026-08-10 · Randomised trial
Abstract
BACKGROUND: Seizures are a common neurological emergency associated with significant morbidity and mortality. In the prehospital setting, intravenous (IV) benzodiazepines are commonly used as first-line therapy; however, establishing IV access may delay treatment in actively convulsing patients. Intramuscular (IM) midazolam provides a rapid alternative, but comparative evidence with IV clonazepam remains limited. AIM: To evaluate whether IM midazolam is non-inferior to IV clonazepam for the prehospital treatment of generalized tonic-clonic seizures. METHODS: We conducted a prospective, randomized, double-blind, non-inferiority trial over 27 months (January 2023-March 2025) in a physician-staffed prehospital emergency medical service (SAMU 01, Tunis). Patients aged ≥14 years with witnessed tonic-clonic seizures lasting ≥5 min were randomized to receive either IV clonazepam 1 mg with IM placebo or IM midazolam 10 mg with IV placebo. The non-inferiority margin was set at 15%. The co-primary efficacy endpoints were treatment success (seizure cessation within 5 min without recurrence) and time from administration of the active study treatment to complete seizure cessation. Secondary outcomes included time from protocol initiation to seizure cessation, time from protocol initiation to administration of the active study treatment, time required to obtain intravenous access, failure to establish intravenous access within 3 min, treatment-related adverse events, endotracheal intubation, ICU admission, and 48-hour mortality. Analyses were performed according to both the intention-to-treat and per-protocol principles. RESULTS: Sixty-four patients were included (32 per group). Baseline characteristics were comparable. Treatment success was 75% with IM midazolam versus 62.5% with IV clonazepam (risk difference, +12.5 percentage points; 95% CI, -10.0 to +33.4), confirming non-inferiority because the lower confidence limit remained above the prespecified margin of -15 percentage points.The time from administration of the active study treatment to complete seizure cessation was significantly shorter in the IM midazolam group (1:42 ± 1:40 min vs 3:13 ± 1:41 min; p < 0.001). No significant differences were observed in adverse events or 48-hour outcomes, including endotracheal intubation (6%vs 9%; p = 0.74). CONCLUSION: IM midazolam was non-inferior to IV clonazepam with respect to treatment success and was associated with a shorter time to seizure cessation while maintaining a comparable safety profile.
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Tags
Other benzodiazepines & Z-drugs · Endotracheal intubation · Intravenous access · Midazolam · Prehospital physicians · Sedatives & anxiolytics · Time intervals
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