Midazolam vs Ketamine as Second Line in Status Epilepticus

🧭 REBEL Rundown

📌 Key Points

  • 🧠 Ketamine for Seizure Control: After two midazolam doses, ketamine increased seizure cessation rates significantly in the prehospital setting.
  • 🧪 Not Yet Standard of Care: Ketamine remains investigational—it wasn’t directly compared to traditional second-line antiepileptics
  • 📉 No Increase in Harm: Ketamine use was not associated with higher rates of intubation or cardiac arrest, supporting its safety in this context.
  • 🚑 EMS-Friendly & Practical: Ketamine is already familiar practical option to EMS providers and was effective when administered via IV or IO.
  • ⚠️ Study Limitations Limit Change: This retrospective, non-randomized design and variable midazolam dosing mean caution is warranted before changing protocols.

📝 Introduction

  • Status epilepticus is traditionally defined as a seizure lasting ≥5 minutes or recurrent seizures without return to baseline in between. It is a neurologic emergency associated with increased morbidity and mortality the longer it persists. Some complications include cardiac arrhythmias, respiratory failure, aspiration pneumonia, and recurrent status epilepticus. The established treatment paradigm includes first line treatment with benzodiazepines (midazolam IM, lorazepam IV, diazepam IV). Second line treatments include antiepileptics (fosphenytoin, levetiracetam, valproate). Third line treatments include anesthetic agents (propofol, ketamine, midazolam infusions).
     
  • The investigation of ketamine as an adjunct treatment for status epilepticus is innovative within the prehospital setting. Ketamine’s unique pharmacologic properties, including its NMDA receptor antagonism and favorable hemodynamic profile, make it particularly well-suited for managing refractory seizures. Additionally, ketamine’s existing availability and familiarity among EMS providers enhance the study’s practical relevance and potential for rapid clinical implementation.

🧾 Paper

Zitek T, Scheppke KA, Antevy P, et al. Midazolam and Ketamine for Convulsive Status Epilepticus in the Out-of-Hospital Setting. Annals of emergency medicine. 2024;85(4):S0196-0644(24)011958. PMID: 39674935

⚙️ What They Did

In adult emergency department patients with suspected infection and hypoperfusion, does early administration of 400 mL of 20% albumin, compared with standard care without albumin , improve systolic blood pressure at 24 hours ?

  • This study employed a retrospective cohort design before and after implementation of a protocol to compare outcomes in out-of-hospital patients with convulsive status epilepticus treated by a single EMS system in Florida between August 1, 2015, and August 5, 2024. 
  • All patients in this before and after study got 2 doses of midazolam. In the after cohort, if 2 doses of midazolam failed, they could get ketamine. In short, there is no comparator for that group. 
  • The ketamine protocol was officially implemented in June 2017, though limited off-protocol use began earlier. 
  • Data were extracted from two EMS electronic medical record systems using automated abstraction, which was validated through manual review of 10% of charts. 
  • Patients were excluded if they were transported by air, received dextrose, had undocumented seizure cessation, or were repeat encounters.

Inclusion Criteria:

  • Patients with convulsive status epilepticus
  • Treated in the prehospital setting by a large EMS system in Florida.
  • Received either: two doses of midazolam, or at least one dose of midazolam followed by ketamine.
  • Encounter occurred between August 1st, 2015, and August 5th, 2024.

Exclusion Criteria:

  • Air transport patients (not managed solely by the EMS system under study).
  • Patients who received dextrose (to exclude seizures secondary to hypoglycemia).
  • Cases without documentation of seizure cessation status before hospital arrival.
  • Repeat encounters involving the same patient (only the first encounter was included in the analysis).
  • Those who received a different dose of ketamine than the protocol

Intervention:

  • The intervention evaluated was the prehospital administration of ketamine as a second line agent following initial treatment with midazolam for convulsive status epilepticus.
    • All patients included initially received midazolam, administered either intramuscularly, intravenously, or intranasally, consistent with EMS protocols for status epilepticus.
  • If seizures persisted after the second dose of midazolam, paramedics could administer ketamine as the next agent after the new protocol was adopted.
  • The ketamine was administered at a dose of 100mg IV, based on EMS protocol, and only via the IV route.

Comparator:

  • There was no true control group in the traditional sense, as this was a before and after retrospective cohort study, not a randomized trial. The comparator group consisted of patients treated prior to June 2017 under the older EMS protocol, which recommended two doses of midazolam alone for ongoing convulsive seizures. These patients received no ketamine. In contrast, patients treated after June 2017 fell under a revised protocol, which added ketamine as a third-line agent following two doses of midazolam.
  • Thus, the comparison reflects differences between two time-based treatment protocols, rather than a contemporaneous control group.

Primary Outcome:

  • Cessation of seizure activity prior to emergency department arrival, as documented by prehospital providers.

Secondary Outcomes:

  • Requirement for endotracheal intubation in the prehospital or ED setting.
  • Occurrence of cardiac arrest during prehospital care or in the ED.

💥 Critical Results

  • Ketamine added to midazolam significantly increased the likelihood of convulsion cessation before hospital arrival, both in unadjusted and propensity-matched analyses.
  • Adults benefited more from ketamine than pediatric patients.
  • Ketamine was not associated with an increased risk of cardiac arrest or intubation.
  • IV and IO routes of ketamine were associated with the highest rates of seizure termination.

💪 Strengths

  • The study’s main outcome, seizure cessation, is highly relevant for EMS, reflecting the goal for emergency seizure care. 
  • Propensity score matching helped balance patient differences, making the treatment groups more comparable and reducing bias. 
  • Including children improves the study’s relevance across all ages and fills a gap in pediatric prehospital seizure research.
  • The use of a standardized protocol to check seizure activity every five minutes ensures accurate, consistent outcome tracking.

⚠️ Limitations

  • Being retrospective in nature, the study is susceptible to inherent biases such as incomplete data, lack of randomization, and potential inaccuracies in medical records or EMS documentation.
  • Patients weren’t randomly assigned, introducing potential selection bias.
  • There are unmeasured variables such as comorbid conditions, concurrent medications, and delays to initial treatment were not fully accounted for.
  • Other changes in care over time (before and after the study) may have influenced outcomes but weren’t captured in the dataset or protocol.
  • While propensity matching improves comparability between treatment groups based on observed variables, it cannot adjust for unmeasured factors such as clinician judgment, seizure etiology, precise timing of events, or severity of underlying brain injury.
  • The cessation of seizure activity was not objectively characterized, raising concerns about the reliability and consistency of this outcome measure. The true end of seizure activity may be subjective and difficult to precisely determine in the field.
  • The study reports outcomes primarily focused on field termination of seizures, with no follow-up on in-hospital outcomes, neurologic recovery, or survival, which restricts the understanding of the long-term impact and overall effectiveness of the intervention.
  • The protocol changed after July 2017, with initial data from 2015–2017 involving lower doses of midazolam (2.5 mg or 5 mg) before the dose was doubled. This inconsistency may affect comparability and interpretation of treatment effects across the study period.
  • Many patients may have received subtherapeutic doses of midazolam (standard dose is 0.15mg/kg, but study doses were often much lower). 
  • Midazolam was delivered through different routes which could affect absorption and efficacy.
  • Ketamine was effectively compared to no treatment (as a third dose of medication) rather than to another active medication.
  • The sample size of patients receiving ketamine reduces statistical power.
  • The study was conducted within a single EMS system, which may limit the generalizability of the findings to other geographic regions or EMS protocols with different operational practices.

🗣️ Discussion

  • Ketamine’s broad utility and familiarity in prehospital care is already established for RSI, agitation, and pain. Ketamine may be effective post-midazolam, but until it’s compared head to head with traditional second-line antiepileptics, we cannot draw any conclusions from this study.
  • Prehospital seizure cessation is important but not a surrogate for functional recovery. It may be inconsistently interpreted by different providers, particularly in patients with subtle motor signs, postictal states, or altered mental status.

📘 Author's Conclusion

“In this retrospective study of out-of-hospital patients with active convulsive seizures, patients who received ketamine were more likely to have stopped convulsing prior to hospital arrival than those who received midazolam alone. ““Early identification, trial enrollment, and intervention in ED patients with sepsis are feasible. In this pilot study, concentrated albumin given early in resuscitation did not improve blood pressure at 24 hours.However, albumin was associated with less total fluid and vasopressor requirements up to 72 hours and improved organ dysfunction. A multicenter study is indicated.”

💬 Our Conclusion

While the data suggest a possible advantage with ketamine, it remains an option rather than a clinically established intervention for prehospital status epilepticus. With a 14% difference of cessation in seizures between the only-midazolam group and the ketamine group, I have hesitation in changing guidelines due to limitations of the study

🚨 Clinical Bottom Line

Stick with current benzodiazepine protocols as first-line treatment, as midazolam remains the mainstay of treatment. Ensure adequate initial dosing as underdosing is common and delays seizure control. If considering ketamine, reserve it for true refractory cases after standard benzodiazepines have failed and other second-line options (like levetiracetam or fosphenytoin) are unavailable or delayed.

📚 References

  1. Rezaie, S.
    “The ESETT Trial: 2nd Line Medications in Status Epilepticus – REBEL EM – Emergency Medicine Blog.”     REBEL EM – Emergency Medicine Blog, 23 Dec. 2019
    Full Blog Post Here
  2. Mion G, Villevieille T.
    Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).
    CNS Neurosci Ther. 2013 Jun;19
    PMID: 23575437
  3. Finney JD, et al.
    Prehospital Ketamine Administration in Benzodiazepine Refractory Status Epilepticus: A Case Series Review.
    Prehosp Emerg Care. 2025 Apr 16:
    PMID: 40193549

Post Peer Reviewed By: Mark Ramzy, DO (X: @MRamzyDO), and Anand Swaminathan (X: @EMSwam)

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Cite this article as: Kevin Mishan, DO, "Midazolam vs Ketamine as Second Line in Status Epilepticus", REBEL EM blog, November 10, 2025. Available at: https://rebelem.com/midazolam-vs-ketamine/.
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