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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:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes 
  4. The patients were analyzed in the groups to which they were randomized. Yes 
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Unsure 
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes
  12. 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, providing clearer understanding of a treatment’s true clinical benefit.

Importantly, they also did not report whether the child returned to baseline. This may falsely increase the perceived efficacy of the ketamine and midazolam versus the midazolam alone groups.

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. Its absence in this trial limits both the internal validity of the findings and their generalizability to centers where EEG is routinely used in the management of status epilepticus. In future trials assessing emergent seizure therapies, the inclusion of EEG monitoring (whether continuous or post-intervention) would substantially improve the rigor of outcome assessment and provide a clearer understanding of a treatment’s true clinical benefit.

Duration of Seizures

The median duration of seizure activity to hospital arrival was 34 minutes. Almost 60% of those included had seizure activity lasting more than 30 minutes before hospital presentation. One of the inclusion criteria for this study was that none of these patients had received any anti-seizure medication prior.

This is a long time to be seizing before any intervention. We mentioned before that we want to treat seizures as early as possible. Table 3 demonstrates that while there was a difference between seizure cessation between the groups based on duration of seizure before presentation, this difference was much more pronounced in the group that had longer seizure duration.

 

The median time of seizure duration was about 30 minutes. Yet serum pH’s were normal. This doesn’t add up. 30 minutes of convulsive status should cause profound mixed metabolic and respiratory acidosis. A typical patient like this in the United States has a pH of about 7.0 to 7.1 and a PCO2 >60

Is it worth adding medication like ketamine to first-line seizure treatment, or is it better to focus on quicker administration of a benzodiazepine instead?

Route of Seizure Medication

One aspect that can improve the time of administration of seizure medication is the route of administration. All of these study medications were administered IV. They excluded patients in whom they could not get IV access within 5 minutes. Midazolam can be given via other routes, including intramuscular, intranasal, and buccal. Ketamine can also be given intramuscular or intranasal. It would be interesting to evaluate these possible routes of administration as well in circumstances where IV access may be difficult or delayed.

Generalizability

Another notable limitation of the Ket-Mid trial is its setting in a single academic center in Egypt, which raises questions about the external validity of the findings to other healthcare systems, particularly those in higher resourced countries. Differences in healthcare infrastructure, emergency medical services, medication availability, and timing of treatment initiation can all influence outcomes in status epilepticus. For example, delays in presentation or access to care, common in some low- and middle-income settings, may result in a patient population with longer seizure durations before treatment, which could affect responsiveness to first-line therapies.

Additionally, variations in the prevalence of underlying etiologies such as febrile seizures, CNS infections, or untreated epilepsy may limit generalizability. While the biological mechanism of ketamine and midazolam would be expected to operate similarly across populations, clinical decision-making, protocols for seizure management, and available resources differ widely. Caution is warranted in applying these findings without considering these contextual differences. External validation in diverse healthcare settings, ideally through multicenter trials, would strengthen the applicability of the results to broader populations.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusion. We look forward to larger, multicenter studies investigating the use of ketamine as an adjunct treatment in pediatric status epilepticus.

SGEM Bottom Line: Give benzodiazepines as early as possible in the treatment of seizures. If the seizures remain refractory, consider a load of another anti-epileptic drug or ketamine.

Case Resolution: After the patient is safely transported out of the ED and admitted, you sit and talk with the medical student. You review the typical treatment recommendations for pediatric refractory status epilepticus and discuss the emerging evidence for the use of ketamine.

Clinical Application: This paper is interesting and opens the path for larger multicenter studies. The use of ketamine in the first-line treatment of pediatric seizures remains to be determined. This study included many patients who had prolonged seizures (>30 minutes). We would recommend efforts focusing on prioritizing earlier administration of a benzodiazepine rather than adding ketamine in the first-line treatment of seizures.

What Do I Tell the Student? When treating pediatric seizures, it is important to try and identify any underlying causes, such as electrolyte abnormalities and correct those. Typically, we treat seizures with a benzodiazepine. If that doesn’t work, we give another dose. If that still doesn’t work, we give a load of antiepileptic medication. We must monitor their airway closely as these patients may develop respiratory depression. There is growing interest in the use of ketamine, but the optimal timing of administration has not yet been determined.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References

  1. Kapur J, Elm J, Chamberlain JM, et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med. 2019;381(22):2103-2113.
  2. Chiriboga N, Spentzas T, Abu-Sawwa R. A systematic review and meta-analysis of ketamine in pediatric status epilepticus. Epilepsia. 2024;65(8):2200-2212.
  3. Adhikari A, Yadav SK, Nepal G, et al. Use of ketamine in super refractory status epilepticus: a systematic review. Neurol Res Pract. 2024;6(1):33.