Comparative Efficacy and Safety of Second-Line Antiseizure Drugs for Pediatric Benzodiazepine-Refractory Status Epilepticus: A Systematic Reviewand Network Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Pediatric status epilepticus (SE) is a time-critical emergency in which benzodiazepines are the first-
line therapy. However, approximately 40% of cases persist despite adequate dosing, constituting benzodiazepine-
refractory SE (BRSE) with a substantial mortality risk. Objectives: Given the divergent guideline recommendations
and limited pediatric-specific evidence for second-line antiseizure drugs (ASDs), this study aimed to compare the
efficacy and safety of second-line agents in children with BRSE using randomized controlled trial (RCT) data. Methods:
A PROSPERO-registered systematic review and frequentist network meta-analysis (Preferred Reporting Items for
Systematic reviews and Meta-Analyses/Cochrane-aligned) searched MEDLINE, EMBASE, and CENTRAL through
March 31, 2022, including English-language peer-reviewed RCTs of patients aged 1 month–18 years with BRSE.
The interventions included Fosphenytoin, Levetiracetam, Valproate, Midazolam, Phenobarbital, and Diazepam, with
phenytoin as the common comparator. Results: The primary outcome was seizure cessation within 60 min, and the
secondary outcomes were 24-h seizure freedom/
seizure recurrence and in-hospital mortality due
to adverse events. Thirteen RCTs (n = 2,282;
59.4% male) from emergency and critical care
settings in seven countries were included; the
risk of bias was low in 10 trials, with two high-
risk studies. No ASD demonstrated statistically
significant superiority for seizure control within
60 min; however, fosphenytoin showed the
highest probability of benefit (P-score 0.71)
amid substantial heterogeneity (I2 = 80.2%) and no evidence of publication bias for the primary outcome. For seizure recurrence, no treatment was clearly superior, although
Levetiracetam ranked highest (P-score 0.84) with marked heterogeneity (I2 = 81.97%). Mortality did not differ significantly
between the treatments; midazolam showed a non-significant trend toward a higher risk. Conclusion: Overall, fosphenytoin may
be most favorable for rapid seizure termination and Levetiracetam for reducing recurrence; however, high heterogeneity, limited
direct comparisons, and imprecision preclude the definitive selection of a single optimal second-line ASD, underscoring the need
for large multicenter pediatric RCTs addressing dosing, safety, and longer-term outcomes.