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Reference: Muldowney et al. A Comparison of Ketamine to Midazolam for the Management of Acute Behavioral Disturbance in the Out-of-Hospital Setting. Ann Emerg Med. 2025 

Date: April 24, 2025

Guest Skeptic: Dr. Howie Mell received his Medical Doctorate (MD) from the University of Illinois at Chicago, College of Medicine at Rockford. Prior to that, he received a Master of Public Health (MPH) degree emphasizing Environmental and Occupational Health from the University of Illinois at Chicago, School of Public Health, while serving as a firefighter/paramedic in the Chicago suburbs. He completed his residency in emergency medicine at the Mayo Graduate School of Medicine, Rochester, Minnesota. Dr. Mell is board-certified by the American Board of Emergency Medicine in both Emergency Medicine (EM) and Emergency Medical Services (EMS) Medicine. He is a Fellow of the American College of Emergency Physicians (FACEP). Dr. Mell serves as an Ambassador Emergency Physician for Vituity (formerly CEP-America), and he is currently assigned to Schneck Medical Center in Seymour, Indiana (John Cougar Mellencamp’s “Small Town”).

Case: You’re an experienced paramedic working a busy night shift in an urban EMS system. Dispatch sends you to a call for a 35-year-old male found acting erratically in a public park. Upon arrival, you find him disoriented, agitated, and combative. Bystanders report that he has been using methamphetamine and alcohol.

The patient is uncooperative, making verbal de-escalation ineffective. Physical restraint is needed for transport. Your EMS protocol allows for pharmacologic sedation with either midazolam (1 to 5 mg IV/IM, repeat every 2 to 5 minutes as needed) or ketamine (5 mg/kg IM, max 500 mg).

The patient is tachycardic (HR 122 bpm), hypertensive (BP 156/96 mmHg), and has a Glasgow Coma Scale (GCS) score of 12. You need to act quickly for scene safety and the patient’s well-being.

Background: Acutely agitated patients in the pre-hospital setting present a unique challenge for emergency medical services (EMS). Agitation can stem from various underlying conditions, including psychiatric disorders, substance intoxication, metabolic disturbances, traumatic brain injury, or postictal states​. If not managed appropriately, severe agitation can escalate, leading to self-harm, harm to others, or interference with necessary medical care.

Initial management emphasizes verbal de-escalation techniques, which should always be attempted first. However, when these strategies fail, pharmacologic sedation may be necessary to ensure the safety of both the patient and pre-hospital providers. The choice of sedative agent is a critical decision. The paramedic must balance the need for rapid sedation with the risk of adverse effects, including respiratory depression and cardiovascular instability​.

Benzodiazepines, such as midazolam, have historically been used for pre-hospital sedation due to their anxiolytic and muscle-relaxant properties. However, their use is associated with risks such as respiratory depression and paradoxical agitation. In recent years, ketamine has gained popularity due to its rapid onset, potent dissociative properties, and preservation of airway reflexes​. Despite its advantages, ketamine is not without concerns, including the potential for emergence reactions, increased blood pressure, and the need for airway management in some cases.

Current guidelines lack consensus on the optimal pharmacologic approach, leading to significant variation in practice across EMS systems. The ongoing debate surrounding the best sedation strategy highlights the need for robust clinical research to guide evidence-based practice. A newly published study aims to address this knowledge gap by comparing ketamine and midazolam in the out-of-hospital setting, shedding light on their relative efficacy and safety.

Clinical Question: In prehospital patients requiring pharmacologic sedation for acute behavioural disturbance, does ketamine or midazolam result in a lower need for emergent airway support?

Reference: Muldowney et al. A Comparison of Ketamine to Midazolam for the Management of Acute Behavioral Disturbance in the Out-of-Hospital Setting. Ann Emerg Med. 2025

  • Population: Patients with acute behavioural disturbances treated by an urban EMS system between 2017 and 2021​.
    • Exclusion: Patients simultaneously administered both drugs
  • Exposure: Administration of midazolam
  • Comparison: Administration of ketamine
  • Outcome:
    • Primary Outcome: The need for emergent airway support, defined as endotracheal intubation or supraglottic airway insertion​.
    • Secondary Outcomes: ED intubation rates and overall mortality​.
  • Type of Study: Retrospective cohort study

Authors’ Conclusions: “In this cohort study of patients with acute behavioral disturbance, emergent airway support and other outcomes did not differ following out-of-hospital treatment with midazolam or ketamine.”​

Quality Checklist for Observational Study:

  1. Did the study address a clearly focused issue? Yes
  2. Did the authors use an appropriate method? Yes
  3. Was the cohort recruited in an acceptable way? Unsure
  4. Was the exposure accurately measured? Yes
  5. Was the outcome accurately measured? Yes
  6. Were all important confounding factors identified? No
  7. Was follow-up complete enough? Yes
  8. How precise are the results? The confidence intervals suggest uncertainty, indicating a need for a larger study population​.
  9. Do you believe the results? Yes
  10. Can the results be applied to the local population? Yes
  11. Do the results fit with other available evidence? Yes
  12. Who funded the study? This project did not receive any external funding.
  13. Did the authors declare conflicts of interest? All authors report no relevant conflicts of interest.

Results: 376 patients with acute behavioural disturbances were included in the study. The median age was 35 years, 78% were male, and the most common cause of agitation was substance use (51%).

Key Result: There was no statistical difference between agitated patients who required advanced airway management and were treated with midazolam vs ketamine.

  • Primary Outcome: Advanced airway management was required in 12% of midazolam patients vs. 11% of ketamine patients (difference: 0.5%, 95% CI: -6% to 7%)​. Adjusted odds ratio (aOR) for airway management: 1.02 (95% CI: 0.44 to 2.38), suggesting no significant difference​.
  • Secondary Outcomes:
    • No statistical difference in ED intubation rates (14% vs. 11%)
    • No statistical difference in mortality (2% vs. 1%)​

1) Retrospective Design: A major limitation of the retrospective study design is its reliance on existing records, which can introduce selection bias, information bias, and confounding. Unlike prospective studies, where variables can be controlled and standardized in real time, retrospective studies depend on previously collected data, which may be incomplete, inconsistent, or inaccurately documented. A prospective or randomized design would be stronger.

2) Selection Bias: This type of bias occurs when the study population is not representative of the broader patient population due to systematic differences in how participants are included or excluded. In this retrospective EMS study, selection bias could arise if certain patients with acute agitation were not documented or excluded due to incomplete records, leading to an overrepresentation of cases where sedation outcomes were more favourable or easier to track. 

3) Information Bias. This occurs when inaccuracies in data collection, which can lead to systematic errors in measuring exposures or outcomes. In this retrospective EMS study, information bias could arise from inconsistent documentation of key variables, such as the exact dose and route of sedative administration, the severity of agitation, or the criteria used for initiating airway management. Suppose some EMS providers were more meticulous in documenting adverse events, while others underreported complications like transient hypoxia or delayed sedation onset. In that case, the study might underestimate or overestimate the true risks associated with ketamine or midazolam.

4) Confounders: This is a limitation of observational studies. Confounding variables are factors that are associated with both the intervention (midazolam vs ketamine) and the outcome (need for airway management), potentially distorting the true relationship between them. In this EMS study, patient characteristics such as underlying medical conditions (e.g., COPD, obesity, or intoxication level), severity of agitation, or additional sedative medications administered could have influenced airway management independently of whether ketamine or midazolam was used. If, for example, ketamine was more frequently given to severely agitated patients who were already at higher risk for airway compromise, this could make ketamine appear riskier than it is. Conversely, if midazolam was preferentially used in patients with known respiratory conditions, providers might have been more cautious, leading to fewer airway interventions. Without randomization or robust statistical adjustments, these confounders could obscure true differences between the medications and limit the study’s validity​.

5) Generalizability: The external validity of this study depends on how well its findings apply to other EMS systems, patient populations, and clinical settings. Since the study was conducted in an urban EMS system, its results may not translate directly to rural or suburban settings, where transport times, provider training, and access to advanced airway management differ.

Additionally, variability in EMS protocols, such as differences in sedation dosing, monitoring practices, or local guidelines, could limit the applicability of these findings to regions with different pre-hospital care standards. The patient population also plays a role—if the study included a higher proportion of substance-related agitation, the results may not fully reflect outcomes in psychiatric agitation or postictal states.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.

SGEM Bottom Line: Both midazolam and ketamine seem like reasonable choices in managing agitated patients in the pre-hospital setting, depending on clinical context and provider preference​.

Case Resolution: You administer intramuscular ketamine, and the patient becomes much calmer. His vital signs are stable, maintains spontaneous respirations with no signs of airway compromise and is safely transported to the ED.

Clinical Application: Given the comparable safety profiles, your decision should weigh speed of onset, route of administration, and context (i.e. it all depends).

What Do I Tell the Patient? When we found you, you were very agitated and possibly at risk of hurting yourself or others. For your safety and ours, we had to give you medication to calm you down. We used a sedative that works quickly and is commonly used in emergencies like yours. Thankfully, you didn’t need a breathing tube, and everything went smoothly.

Keener Kontest: Last week’s winner was Dr. Steven Steltz from New Zealand. He knew the first computer that stored a program in its memory was the Manchester Baby, also known as the Small-Scale Experimental Machine (SSEM). It was developed at the University of Manchester in England and ran its first program on June 21, 1948.

Listen to the SGEM podcast for this week’s question. If you know, then send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a shoutout on the next episode.

Other FOAMed on Agitation:

  • SGEM#45: Vitamin H (Haloperidol for Psychosis)
  • SGEM#218: Excited Delirium Syndrome
  • SGEM#328: I Can’t Fight This Med Any Longer – Droperidol for Acute Agitation
  • SGEM Xtra: I’m So Excited – But Don’t Call It Excited Delirium

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