Abstract Background Status epilepticus (SE) is a life-threatening pediatric emergency requiring rapid anticonvulsants. While midazolam and diazepam are standard benzodiazepines, their comparative efficacy across various administration routes remains debated. We synthesized high-quality evidence to guide clinical protocols. Methods We searched PubMed, Scopus, Web of Science, and Cochrane for randomized controlled trials comparing buccal, intramuscular, and intravenous formulations. We evaluated treatment outcomes including therapeutic success (seizure cessation), recurrence, and drug-related side effects. We employed meta-analysis, trial sequential analysis (TSA), and GRADE to ensure the robustness of the evidence. Results Nine RCT studies ( n = 1135 children) were included. Midazolam demonstrated superior therapeutic success (RR = 1.13, 95% CI 1.03–1.25, p = 0.01), with TSA confirming conclusive benefit for the buccal route (RR = 1.30, p = 0.002). Midazolam significantly reduced treatment failure (RR = 0.74, 95% CI 0.57–0.95, p = 0.02) and seizure recurrence (RR = 0.51, p = 0.04). Time-to-cessation was shorter with non-intravenous routes (MD = −2.39 min, p = 0.01). Safety profiles regarding respiratory depression were comparable between groups. Conclusion Midazolam is the preferred first-line anticonvulsant for pediatric status epilepticus. It offers superior therapeutic success, lower failure rates, and reduced recurrence, particularly via buccal and intramuscular routes. Given comparable safety, this evidence strongly supports updating emergency medical services guidelines to prioritize non-intravenous midazolam. Impact Midazolam demonstrates superior efficacy over diazepam, particularly via buccal and intramuscular routes. It addresses critical prehospital delays by bypassing the high failure rates associated with pediatric vascular access. Intramuscular administration matches intravenous efficacy while enabling immediate intervention without specialized equipment. Additionally, buccal and nasal formulations represent the most cost-effective non-intravenous rescue options available. Guidelines must prioritize these practical routes for EMS settings, necessitating policy updates to remove insurance barriers.
Kertam et al. (Sat,) studied this question.