Reference:  Othman AA, et al. Combined ketamine and midazolam vs. midazolam alone for initial treatment of pediatric generalized convulsive status epilepticus (Ket-Mid study): A randomized controlled trial. Pediatric Neurology. June 2025

Date: May 27, 2025

Dr. James Chamberlain

Guest Skeptic: Dr. James Chamberlain is a pediatric emergency medicine attending physician at Children’s National Hospital in Washington, DC where he is the Director of Data Analytics and Informatics for the Division of Emergency Medicine. He is also a Professor of Emergency Medicine and Pediatrics at George Washington School of Medicine and Health Sciences. He has led or co-led two large national trials of status epilepticus and is starting a third, the Ketamine adjuvant for Established Status Epilepticus Treatment Trial (KESETT).

Case: A two-year-old boy with a known seizure disorder is brought to the emergency department (ED) by his family for a seizure at home. The episode is described as generalized tonic-clonic activity which self-resolved after about a minute. He was post-ictal afterwards and has not fully returned to baseline. He has not had any recent fevers or illnesses. During your conversation with his parents, he starts seizing again. You administer two doses of a benzodiazepine, but the seizure continues. You give an additional levetiracetam load, which stops the seizure activity, and he is admitted to the hospital for observation. Afterwards, a medical trainee you are working with says to you, “I read that there’s been interest in other medications like ketamine in the treatment of seizures. Do you think there would have been any benefit in giving ketamine earlier?”

Background:

We often see children presenting with seizures in the ED. Currently, the standard of care recommends the use of benzodiazepines such as midazolam as first-line treatment. Midazolam, but not the other benzodiazepines, can be given intravenously, intramuscularly, intranasally, or as a buccal paste. Sometimes this works and stops the seizure activity. Sometimes it does not. Seizures that are refractory to treatment are dangerous and can lead to neuronal injury, long-term deficits, or even death. We want to stop seizure activity as quickly as we can.

The typical management of seizures is to give a benzodiapene. If that does not work, give a second dose. If that still doesn't stop the seizure, then administer another anti-seizure medication like levetiracetam, fosphenytoin, or valproate.

There’s been increasing interest in the use of ketamine for seizures.

There are several factors that make ketamine potentially a very powerful drug for status epilepticus.

Ketamine is an NMDA receptor antagonist and therefore theoretically should break the vicious cycle of status.There have been dozens of animal studies in at least 4 different species demonstrating efficacy as early treatment of status.In some of these studies, ketamine and other NMDA receptor antagonists are neuroprotective.In humans, ketamine is widely used for super refractory status, when all other medications have failed. Estimates are that it is about 70% effective for this indication.We have a long track record of using ketamine safely in the emergency department setting and growing experience in EMS. Ketamine is well tolerated, short-acting, and preserves protective airway reflexes and ventilation. Even very large accidental overdoses have been well tolerated. The one caveat is that we don’t know if all these safety parameters hold in the condition of status epilepticus, but limited case series have not shown safety problems.

Currently, it is not part of conventional therapy for pediatric status epilepticus, but there is thought that it may work synergistically with benzodiazepines in stopping seizures.

Clinical Question: Is ketamine combined with midazolam more effective than midazolam alone in the treatment of pediatric generalized convulsive status...