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.