Midazolam Shows Suboptimal Efficacy as First-Line Therapy for Prehospital Seizures

Itai Shavit, MD

Data from a recent published retrospective analysis of adolescents and children presenting with seizures showed that midazolam is not an effective first-line therapy in prehospital settings, indicated by the nearly 40% of patients who required rescue therapy.

Published in JAMA Network, the study featured 1172 children with a mean age of 5.7 years for whom a mobile intensive care unit was dispatched for an active seizure. Of this cohort, 39.16% (n = 459) required rescue therapy, with nearly half (48.46%; n = 220) using the intranasal route. Senior investigator Itai Shavit, MD, Appointed Director, Division of Pediatrics, Hadassah Medical Center, Israel, and colleagues concluded that these results may not be generalizable to populations where home rescue treatment for seizures is common.

Data from January 2017 to December 2019 was gathered using the database of the INEMS system, which includes a log of dispatched calls, vehicles, paramedics’ records, and the diagnosis and treatment of all patients treated by paramedics. Administration of rescue therapy, the primary outcome, was defined as an additional dose of midazolam following the first midazolam administration during the prehospital encounter.

In total, 713 had seizure activity terminated on first dose, 306 on second dose, and 113 on third dose of midazolam. Furthermore, 40 patients needed 4 or more doses of midazolam to terminate seizure activity, including 2 patients who received 6 doses. Across all patients, 31 were treated with bag-mask ventilation, and 5 underwent endotracheal intubation. In terms of administration route, 31.93% (n = 144) used the intravenous route, 48.46% used the intranasal route, and 35.58% (n = 95) used the intramuscular route.

Shavit et al wrote, "A possible explanation for the inferior performance of midazolam in the prehospital setting could be the long period from the onset of seizures to the time of starting therapy. Another important finding is the substantial number of patients who needed respiratory support among those who received rescue therapy."

In univariable analysis, age, glucose level, route of administration, and chronic disease were significant for inclusion in the multivariable model. In multivariable analysis, only the route of administration was a significant independent factor associated with rescue therapy. Initial treatment by the intranasal and intramuscular routes had an adjusted OR for rescue therapy of 1.65 (95% CI, 1.13-2.42) and 0.97 (95% CI, 0.62-1.53), respectively, compared with the intravenous route.

Previous adult studies have reported similar observations, including a cross-sectional analysis published in 2020. The study, which featured 2494 patients with status epilepticus treated by an emergency medical services, examined the use of benzodiazepines like midazolam and the association between low dose use, breakthrough seizures, and respiratory support. In total, there were 1,537 patients given midazolam at any dose, yielding an administration rate of 62%. Rescue therapy with a second midazolam dose was required in 18% (n = 282) of patients, and higher doses were associated with lower odds of rescue therapy (OR, 0.8; 95% CI, 0.7-0.9). After adjustment, higher doses of midazolam were associated with decreased need for respiratory support (OR, 0.9; 95% CI, 0.8-1.0).

REFERENCES
1. Shavit D, Strugo R, Siman-Tov M, et al. Assessment of first-line therapy with midazolam for prehospital seizures in children. JAMA Netw Open. 2023;6(4):236990. doi:10.1001/jamanetworkopen.2023.6990.
2. Guterman EL, Sanford JK, Betjemann JP, et al. Prehospital midazolam use and outcomes among patients with out-of-hospital status epilepticus. Neurology. 2020;95(24):e3203-e3212. doi:10.1212/WNL.0000000000010913