Midazolam infusions for therapeutic management of pediatric refractory status epilepticus: a systematic review

Taneille Johnson ^1* Ammar AlZadjali ² Dawoud Al Nasseri ³ Jessie Cunningham ⁴ Kazuhiro Shoya ⁵ Cecil D Hahn ^6,7,8 John Basmaji ⁹ Nicole McKinnon ^10,7*

• ¹ Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
• ² Department of Pediatrics, Sohar Hospital, Ministry of Health (Oman), Sohar, Oman
• ³ Department of Pediatrics, Ibri Hospital, Ministry of Health (Oman), Ibri, Oman
• ⁴ Health Sciences Library, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
• ⁵ Department of Critical Care Medicine, Sakakibara Heart Institute, Tokyo, Tokyo, Japan
• ⁶ Division of Neurology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
• ⁷ Program in Neurosciences and Mental Health, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
• ⁸ Department of Paediatrics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
• ⁹ Division of Critical Care, London Health Sciences Centre, London, Ontario, Canada
• ¹⁰ Department of Paediatrics and Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

We aim to determine the optimal dosing of midazolam continuous intravenous infusions for treatment of pediatric refractory status epilepticus (RSE).We searched Medline ALL, Embase, Embase Classic, Cochrane CENTRAL, and Web of Science in March 2023 and February 2024.Randomized and non-randomized studies of pediatric patients who received continuous midazolam for the treatment of RSE were eligible. Two authors independently undertook screening, full text review, and data extraction. All methods followed PRISMA Reporting Guidelines. A narrative data synthesis was performed due to data heterogeneity. Nineteen studies (448 patients) proved eligible; 3 studies were RCTs while 16 were nonrandomized studies. All had concerns with risk of bias. Overall, midazolam aborted seizures in 363/448 (81%) participants with mean effective doses of 1.7-13.0 mcg/kg/min (0.17-0.78 mg/kg/hr). The 85/448 (19%) who did not have seizure cessation received maximum doses of 1.7-32.0 mcg/kg/min (0.17-1.92 mg/kg/hr) prior to transitioning to another agent. Only 4 studies specified that boluses were given with each titration. Twelve studies reported that seizure cessation occurred at a mean of 1.4-546.0 minutes (range 0-720 minutes) after midazolam initiation. Effective midazolam doses for 8 of these studies clustered at 2.0-5.0 mcg/kg/min (0.12-0.30 mg/kg/hr) with seizure cessation occurring between 10.0-70.0 minutes in 204/221 (92%) participants. Treatment associated adverse events included intubation in 42/221 (19%) and hypotension requiring fluids or no intervention in 18/221 (8%). Studies did not separate those intubations occurring per study protocol or prior to midazolam infusion initiation, or hypotension that was related to coadministration of phenytoin or phenobarbital. Data supporting midazolam continuous infusion dosing are limited and heterogenous. Our data suggests a potential therapeutic window at rates of 2.0-5.0 mcg/kg/min (0.12-0.30 mg/kg/hr), with limited adverse risks. Earlier seizure cessation may occur by targeting this therapeutic window by starting with higher doses than the typically used 1 mcg/kg/min (0.06 mg/kg/hr) and or rapid dose escalation into it.