Efficacy of Add-on Ketamine With Second-dose Midazolam for Prehospital Treatment of Epileptic Children With Status Epilepticus

Status epilepticus (SE) is the most prevalent neurological emergency in children. Benzodiazepines (BDZs) remain the first-line anti-seizure medication (ASM) for SE, but about one-third of seizures are not controlled by BDZs. Moreover, second-line ASMs (levetiracetam, valproate, phenytoin) fail to terminate BDZ-refractory SE in 50% of cases. Such prolonged SE is linked with progressive brain damage and an increased risk of epilepsy, irreversible neurodevelopmental sequelae, and mortality. Accordingly, early control of SE is critical for enhancing clinical outcomes.

A possible strategy for rapid control of SE is using early ASM combination. Ketamine seems a promising choice for such a combination. Ketamine acts to antagonize N-methyl-D-aspartate (NMDA) receptors, which become increasingly upregulated and trafficked to the synaptic membrane during ongoing seizure activity. Numerous observational studies have demonstrated that administration of ketamine is associated with termination or attenuation of refractory SE (RSE) and super-refractory SE (SRSE). Furthermore, the recently published Ket-Mid study showed that the ketamine-midazolam combination was more effective than midazolam alone in the initial treatment of pediatric generalized CSE. However, the Ket-Mid study also highlighted a significant delay in hospital arrival and administration of first-line ASM, by a median of 34 minutes, reflecting delayed access to emergency care due to socioeconomic challenges, geographic barriers, and limited prehospital emergency medical services. Such a challenge also applies to resource-limited settings, where treatment delays are more common. Notably, a review by Gaínza-Lein et al. of 15 studies involving 2212 patients with SE reported average times to ASM treatment and hospital arrival of 42.4 and 56 minutes, respectively. Such delay to the administration of ASM is associated with increased resistance to BZDs, longer SE, and increased risk of complications. Accordingly, there is a growing interest in the early use of ASM for prehospital treatment of SE.

Ketamine has been used in prehospital setting for a long time, mainly for sedation and analgesia purposes with a high safety profile. Multiple observational studies have reported the efficacy of ketamine in the pre-hospital emergency treatment of BZD-refractory status epilepticus. However, this was not adequately investigated in clinical trials.

The present study (Prehospital Early Administration of Ketamine for Status Epilepticus in Epileptic Kids, PEAK-SEEK) aims to investigate the efficacy of adding ketamine to second-dose midazolam vs. second-dose midazolam alone as ASM for prehospital treatment of epileptic children with convulsive status epilepticus.