A Common Reference-Based Indirect Comparison Meta-Analysis of Buccal versus Intranasal Midazolam for Early Status Epilepticus

Intranasal and buccal midazolam have recently emerged as possible alternatives to intravenous or rectal diazepam or intravenous lorazepam in the treatment of early status epilepticus (SE). However, to date no randomized controlled trial (RCT) has directly compared intranasal midazolam with buccal midazolam. The aim of this study was to indirectly compare intranasal midazolam with buccal midazolam in the treatment of early SE using common reference-based indirect comparison meta-analyses. RCTs comparing intranasal or buccal midazolam versus either intravenous or rectal diazepam for early SE were systematically searched. Random-effects Mantel-Haenszel meta-analyses were performed to obtain odds ratios (ORs) for the efficacy and safety of intranasal or buccal midazolam versus either intravenous or rectal diazepam. Adjusted indirect comparisons were then made between intranasal and buccal midazolam using the obtained results. Fifteen studies, with a total of 1662 seizures in 1331 patients (some studies included patients with more than one episode of SE) were included; 1303 patients were younger than 16 years. Indirect comparisons showed no difference between intranasal and buccal midazolam for seizure cessation (OR 0.98, 95 % CI 0.32-3.01, comparator: intravenous diazepam; OR 0.87, 95 % CI 0.46-1.64, comparator: rectal diazepam). For serious adverse effects, we found a large width and asymmetrical distribution of confidence intervals around the obtained OR of 2.81 (95 % CI 0.39-20.12; comparator: rectal diazepam). No data were available for OR using intravenous diazepam as the comparator. Indirect comparisons suggest that intranasal and buccal midazolam share similar efficacy in the treatment of early SE in children. Intranasal midazolam should be used with caution and under clinical monitoring of vital functions. RCTs directly comparing intranasal midazolam with buccal midazolam are required to confirm these findings.