Seizing the Evidence: Should We Consider Ketamine’s Place in Seizure Protocols?

Ketamine was first introduced for human use in 1965 and has been widely utilized as a general anesthetic with an excellent safety profile (Mion 2017, Dorandeu 2013). Ketamine works on several receptors, resulting in various actions such as anesthesia, analgesia, and antidepressant effects. While not widely studied, ketamine has been shown to have antiepileptic properties. In seizures, the excessive release of glutamate leads to the overactivation of N-methyl-D-aspartate (NMDA) receptors, thereby causing neuronal hyperexcitability and seizure-like activity. Ketamine works by regulating neuronal excitability and reducing excessive, synchronized neural activity through non-competitive inhibition of glutamatergic transmission, primarily via NMDA receptor antagonism. More specifically, blocking the NMDA receptor with ketamine decreases neuronal depolarization and excitotoxicity, potentially halting seizure propagation (Tan 2024).

Animal models have shown that NMDA antagonism exerts a synergistic action with benzodiazepines, making it a potentially promising adjunct treatment for status epilepticus as a possible first-line treatment (Naylor 2005). Human data evaluating the role of ketamine in status epilepticus is sparse and primarily evaluates its utility as a rescue medication (Scheppke 2024).

The recent Ket-Mid trial investigated whether adding ketamine to midazolam as first-line therapy improves the rate of seizure cessation in pediatric status epilepticus compared with placebo plus midazolam (Othman 2025). A total of 144 pediatric patients were randomized to receive either ketamine plus midazolam or placebo plus midazolam as initial therapy for status epilepticus. At the 5-minute mark, seizure activity had ceased in 76% of those given ketamine-midazolam compared with 21% in the placebo-midazolam group (RR 3.7; 95% CI, 2.3–5.9). Higher rates of seizure cessation in the ketamine group were maintained at 15, 35, and 55 minutes. This group also required fewer additional doses of midazolam. Endotracheal intubation was performed in 4.2% of patients receiving ketamine-midazolam, compared to 20.8% of those given placebo-midazolam. The investigators concluded that combining ketamine (2 mg/kg) with midazolam (0.2 mg/kg) may offer greater effectiveness than midazolam alone for initial management of pediatric status epilepticus. Of note, intubation rates were lower in the ket-mid group and there were no reported increased harms.

As promising as these results are, the study is limited by several factors that prevent its generalizability. Rates of seizure cessation in the midazolam-only group were lower than rates seen in prior studies (Chamberlain 2024, Kapur 2019). This difference may be related to factors frequently seen in low- and middle-income country settings. This includes delayed presentation with more advanced illness, limited access to prehospital interventions, slower emergency response times, and constraints in patient monitoring and follow-up. In this study, the true therapeutic effect of ketamine may be hidden due to this bias. This limits our ability to interpret whether ketamine has a true therapeutic advantage or is the result of systemic limitations on the control group’s outcomes. Furthermore, the trial was only conducted at a single institution. Future studies like the UVA-KESETT trial may further elucidate the role of ketamine in the treatment of seizures.