Othman AA, et al. Combined Ketamine and Midazolam Versus Midazolam Alone for Initial Treatment of Pediatric Generalized Convulsive Status Epilepticus (Ket-Mid Study): A Randomized Controlled Trial.
About a third of pediatric GCSE isn't controlled by first-line benzodiazepines. Ket-Mid asks whether ketamine belongs in that first dose, not the third.
Ketamine's current place in most status epilepticus protocols is refractory/super-refractory therapy — reached for after benzodiazepines and a second-line agent (levetiracetam, fosphenytoin, valproate per ESETT) have already failed, often 30–60+ minutes into the seizure. The Ket-Mid investigators' rationale: synaptic GABA-A receptors internalize and NMDA receptors upregulate as seizure duration lengthens, which is exactly why benzodiazepine efficacy falls off the longer a seizure runs. Their hypothesis was that adding an NMDA antagonist (ketamine) from the first dose, rather than waiting for BDZ monotherapy to fail, could pre-empt that receptor shift instead of chasing it.
| Design | Single-center, randomized, double-blind, placebo-controlled superiority trial |
| Population | 144 children, 6 months–16 years, generalized convulsive status epilepticus, no prior ASM given for the current episode |
| Groups | Ket-Mid: IV ketamine 2 mg/kg + IV midazolam 0.2 mg/kg (n=72) · Pla-Mid: placebo + IV midazolam 0.2 mg/kg (n=72) |
| Primary outcome | Clinical seizure cessation at 5 minutes |
| Secondary outcomes | Cessation at 15/35/55 min, need for a second midazolam bolus, 24h seizure control, adverse effects, intubation |
| Etiology | Predominantly febrile seizures and known epilepsy; 11% CNS infection, 4% other/unknown |
| Outcome | Ket-Mid | Pla-Mid | Effect |
|---|---|---|---|
| Seizure cessation at 5 min | 76% | 21% | RR 3.7 (95% CI 2.3–5.9), P<.001 |
| Endotracheal intubation | 4.2% | 20.8% | ≈5× fewer intubations |
Cessation rates favored Ket-Mid at every subsequent checkpoint too (15, 35, and 55 minutes), and the Ket-Mid group required fewer additional midazolam doses to achieve control. The effect was described as most pronounced in patients whose GCSE had already run longer than 30 minutes — consistent with the receptor-kinetics rationale behind the trial.
A single 144-patient trial from one center is strong signal, not a protocol change.
The trial's own authors, and the independent reviews of it (St Emlyn's, SGEM #482), are explicit that this is the first RCT testing this specific combination as first-line therapy, conducted at one hospital in Egypt. There is no confirmatory data yet from a second site, a different healthcare system, or a US/European pediatric ED population. RebelEM's "promising, not practice-changing" line reflects exactly this: strong effect size, narrow evidentiary base.
Worth noting separately: ketamine's evidence base looks different in adults than in children for status epilepticus more broadly. A 2025 REBEL EM review of out-of-hospital ketamine-after-midazolam protocols (Zitek et al., Ann Emerg Med 2024) found the benefit skewed toward adult patients, with a smaller effect in the pediatric subgroup — a useful cross-check when reading a pediatric-specific trial like Ket-Mid in isolation.
The numbers in the source post are accurate and the effect size is genuinely large: 3.7× more 5-minute seizure cessation and roughly a fivefold reduction in intubation with ketamine added to first-line midazolam. But this is one trial, at one center, in one country, and it is the first of its kind — ketamine plus midazolam is a promising signal for pediatric GCSE, not yet an evidence base that should move it ahead of established first- and second-line agents in your own department's protocol without confirmatory multicenter data.