Patients with severe agitation are frequently encountered in the emergency department (ED) setting. The first steps in the management of agitation are de-escalation and calming techniques, situational modifications, and, if needed, oral medications. Unfortunately, these techniques may be insufficient. Emergency departments can be crowded and chaotic, further exacerbating mental health issues. Intoxication with drugs and/or alcohol can inhibit comprehension. As a result, patients with severe agitation may require sedating medication for the safety of the patient and treating clinicians.

When this happens—what medication(s) do you reach for? Is it haloperidol and lorazepam (known as “5 and 2”)? A “B52” (the prior combination plus diphenhydramine)? Monotherapy with olanzapine, droperidol, haloperidol, ketamine, or midazolam? The ideal medications work very quickly, does not require additional dosing or rescue medications, and does not overly sedate a patient or cause respiratory depression.

Choices in the ED

The choice of sedating or calming medication is often an inherited or local practice, rather than rooted in evidence. We reach for what we are comfortable with, which is usually what we learned during training. Additionally, the evidence is complex—studies compare various combinations of medications, different doses, and different routes (intravenous [IV] versus intramuscular [IM]). A new clinical policy from the American College of Emergency Physicians (ACEP) seeks to distill the often indirect evidence and guide clinicians in choosing the best parenteral agents for patients with severe agitation.¹ The winners: droperidol/midazolam and ketamine.

The clinical policy gives a Level B recommendation, which carries a moderate level of scientific certainty, to the use of a combination of droperidol and midazolam (or another atypical antipsychotic plus midazolam) for “more rapid and efficacious treatment of severe agitation.” This is a critical point. Rapid and efficacious. Many agents can sedate patients sufficiently to proceed with medical evaluation and treatment safely. However, we should only use these medications when other options have failed and the need is critical. Under these circumstances, rapidity is critical for the safety of the patient, the treating team, and other nearby patients.

Speed Matters

The combination of droperidol and midazolam appears to result in rapid sedation, requires fewer additional medications, and has a favorable safety profile in agitated ED patients. Though once maligned due to a black box warning, droperidol has an extensive safety record.² A randomized study found that droperidol (5 mg IV) plus midazolam (5 mg IV) resulted in a higher proportion of patients adequately sedated at 10 minutes compared with droperidol (10 mg IV) or olanzapine (10 mg IV) alone.³ In a similar vein, another randomized study found that a combination of droperidol 5 mg IV with midazolam or olanzapine 5 mg IV and midazolam resulted in quicker time to adequate sedation than intravenous midazolam alone. Both droperidol and olanzapine probably work slightly more quickly than haloperidol.³

The key and perhaps ovelooked ingredient in the recommended combination is midazolam. This point becomes apparent when juxtaposing another Level B recommendation in the clinical policy that states, “For efficacious treatment of severe agitation in the emergency department, use the above agents as described or haloperidol alone or in combination with lorazepam.” Notably this recommendation is for efficacious, not efficacious and more rapid. Midazolam works quickly. A 2018 study by Klein et al., found that more patients were adequately sedated at 15 minutes with 5 mg of intramuscular midazolam compared with haloperidol 5 mg, haloperidol 10 mg, and ziprasidone 20 mg. Midazolam also outperformed olanzapine 10 mg, but this did not reach statistical significance.⁴ The onset of action of lorazepam is longer, which is less ideal when attempting to achieve safety. The data on midazolam is mixed, likely due to differences in patient population and dosing; however, benzodiazepine monotherapy appears to have a less favorable profile, necessitating rescue medications.

Ketamine, at a dose of 3 to 5 mg/kg intramuscularly, achieves sedation in two–10 minutes. Few, if any medications, reliably achieve effective sedation this quickly following a single dose. The trade-off, however, is the potential for adverse effects including respiratory depression and laryngospasm. An ED study found that ketamine 5mg/kg IM resulted in sedation in about 6 minutes, almost nine minutes quicker than haloperidol 5 mg plus midazolam 5 mg IM.⁵ The policy provides a Level C recommendation (consensus) for the use of ketamine in critical circumstances stating, “In situations where safety of the patient, bystanders, or staff is a concern, consider ketamine to rapidly treat severe agitation in the ED.”

The “5 and 2” combination of haloperidol and lorazepam was the sedation regime I was trained to use and works fine. However, I’ve traded in this combination for medications that are likely to work more quickly and retain an excellent safety profile: droperidol 5mg/midazolam 5 mg IM or ketamine when there is a substantial safety risk. Unfortunately, we still have minimal data to support recommendations for older adults, the prehospital setting, and pediatric patients.

Disclaimer: Although Dr. Westafer is a member of the ACEP Clinical Policy Committee, the views in this article do not represent the views of ACEP or the ACEP Clinical Policy Committee.

Dr. Westafer (@Lwestafer) is an attending physician and research fellow at Baystate Medical Center, clinical instructor at the University of Massachusetts Medical School in Worcester, and co-host of FOAMcast.

References

1. Thiessen ME, Godwin SA, Hatten BW, et al. Clinical policy: Critical issues in the evaluation and management of adult out-of-hospital or emergency department patients presenting with severe agitation. ACEP website. Published October 6, 2023. Accessed November 30, 2023.
2. ACEP Policy statement: Use of droperidol in the emergency department. ACEP website. Published January, 2021. Accessed November 30, 2023.
3. Taylor DM, Yap CYL, Knott JC, et al. Midazolam-droperidol, droperidol, or olanzapine for acute agitation: a randomized clinical trial. Ann Emerg Med. 2017;69(3).
4. Klein LR, Driver BE, Miner JR, et al. Intramuscular midazolam, olanzapine, ziprasidone, or haloperidol for treating acute agitation in the emergency department. Ann Emerg Med. 2018;72(4).
5. Barbic D, Andolfatto G, Grunau B, et al. Rapid agitation control with ketamine in the emergency department: a blinded, randomized controlled trial. Ann Emerg Med. 2021;78(6):788-795.