SGEM#482: Seize the Day with Ketamine and Midazolam for Pediatric Status Epilepticus

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 epilepticus? 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 Population: Children 6 months to 16 years presenting with generalized convulsive status epilepticus without prior treatment with antiseizure medications (ASMs) for the current episode. This was defined as clinically detectable generalized tonic-clonic convulsions that persist or recur without regaining consciousness in between for longer than 5 minutes. Exclusions: Previous treatment with ASM, traumatic brain injury (TBI), conditions associated with increased intracranial pressure, hypertension, glaucoma, hyperthyroidism, pheochromocytoma, end-stage kidney or liver disease, cardiac disease, history of alcohol intake, hypoglycemia, hyperglycemia, inborn errors of metabolism, known allergy or contraindication to study drugs, known or suspected psychiatric disorder, failure to get IV access in first 5 minutes of stabilization, cessation of seizures within the first 5 minutes, and failure to obtain informed consent. Intervention: IV ketamine (2 mg/kg) plus IV midazolam (0.2 mg/kg) Comparison: IV placebo plus IV midazolam Outcome: Primary: Cessation of clinical seizures at 5 minutes post-drug administration Secondary: Need for repeat midazolam during the first 15 minutes of study timeframe, seizure cessation at 15, 35, and 55 minutes, seizure control, adverse events (hypotension, hypertension, arrhythmia, emergence phenomenon, rash), need for intubation, and mortality. Type of Study: Randomized, two-group, parallel, 1:1 superiority, double-masked, placebo-controlled trial Authors’ Conclusions: “Ketamine-midazolam combination may be more effective than midazolam alone for the initial treatment of pediatric GCSE, but this should be confirmed in future research.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. Yes  The patients were analyzed in the groups to which they were randomized. Yes  The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes All groups were treated equally except for the intervention. Unsure  Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. Yes Financial conflicts of interest. No financial conflicts of interest Results: They included 144 children. Half were assigned to the ketamine and midazolam group, and the other half were assigned to the placebo and midazolam group. The most common causes of generalized convulsive status epilepticus include febrile seizures and known epilepsy. Eleven percent had a CNS infection, and four percent had other or unknown etiologies. Key Results: The combination of ketamine and midazolam was superior to midazolam alone in treating children with generalized convulsive status epilepticus. Primary Outcome:  In the combined ketamine and midazolam group, 76.4% of patients had cessation of seizure activity compared to 20.8% of the patients who only received midazolam. Risk Ratio (RR) 3.7 (95% CI: 2.3 to 5.9, p< 0.001) Secondary Outcomes:   The ketamine and midazolam group also had higher percentages of seizure cessation at 15, 35, and 55 minutes. The ketamine and midazolam group had lower percentages of requiring repeat midazolam (23.6% vs 79.3%) or endotracheal intubation (4.2% vs 20.8%). Selection Bias The authors screened 251 patients for eligibility. They excluded around 40% because they didn't meet the inclusion criteria. There was a long list of exclusion criteria. While some of the conditions they excluded could be determined quickly, there are others listed, such as conditions associated with increased intracranial pressure, hyperthyroidism, pheochromocytoma, inborn errors of metabolism, and known or suspected psychiatric disorders that need some time to work up. We’re not sure how they were able to make determinations of all of those potential medical problems before enrollment. This may lead to a selection bias. Primary Outcome Their primary outcome was the cessation of clinical seizure activity, but what about subclinical seizures? One of the challenges in the ED of treating seizures is that we can give medications that stop the clinical seizure activity we can see. Afterwards, when the patient has stopped clinically seizing but is sleepy and has not returned to baseline, we have to try and figure out if they are still not back and baseline because they are post-ictal, sedated from all of the seizure medications, or subclinically seizing. Fortunately, subclinical status is less common in children. It is possible they missed subclinical seizures in this trial, which are important to recognize and treat. From an evidence-based medicine perspective, valid outcome measures are those that are objective, reliably assessed, and aligned with patient-important endpoints. EEG serves as a critical tool to meet these standards in the context of seizure management. Unfortunately, its absence in this trial limits the internal validity and the generalizability to other centers where EEG is routinely used in managing status epilepticus. Future and ongoing studies of status epilepticus in the United States will require placement of a rapid EEG to obviate this ascertainment bias and improves the rigor of the outcome assessment,