REVIEW OF: Cole JB et al, Ann Emerg Med 2024;84:658–667

STUDY TYPE: Retrospective cohort study

If you’ve ever managed a severely agitated patient in the emergency department (ED) or inpatient unit, you know it’s critical to bring the situation under control quickly and safely. Injectable olanzapine is often a go-to medication for calming patients, thanks to its rapid action and reliability. But what happens when olanzapine alone isn’t enough? You might consider adding a benzodiazepine like lorazepam to intensify sedation, but the FDA warning against combining injectable (IM or IV) olanzapine with benzodiazepines may give you pause. Based on early post-marketing safety data, the warning cites risks of excessive sedation and cardiorespiratory depression. In contrast, the American College of Emergency Physicians (ACEP) 2023 clinical policy recommends combining an atypical antipsychotic with a benzodiazepine, such as midazolam, for more rapid and effective sedation in severe agitation (Thiessen MEW et al, Ann Emerg Med 2024;83(1):e1–e30). This tension between the FDA’s warning and ACEP’s recommendation leaves us in a quandary.

This study sought to provide clarity by examining the safety of combining injectable (IM or IV) olanzapine with injectable benzodiazepines, focusing on outcomes like intubation and other respiratory complications. Researchers reviewed nearly 700 ED cases of severe agitation treated between 2017 and 2019. Patients received either 2 doses of parenteral olanzapine (n=549) or a combination of olanzapine and a benzodiazepine like midazolam, lorazepam, or diazepam (n=144), all administered within 60 minutes. The primary outcome was tracheal intubation rates, and secondary outcomes were hypoxemia (oxygen saturation < 90%) and hypotension (systolic blood pressure < 90 mmHg). Patients who received other sedatives or more than two medication doses were excluded to avoid confounding. About 80% of cases of agitation were substance related, and 70% of treatments were delivered IM.

No significant difference was found in intubation rates between the groups: 3.8% with olanzapine alone vs 3.5% with the combination. Hypoxemia occurred in 2% and 3%, respectively, and hypotension rates were identical in both groups (9%). These results held steady even when the dosing window was expanded to 120 minutes during sensitivity analyses, which reinforces the study’s robustness.

CARLAT TAKE
You can breathe a little easier (no pun intended) knowing that combining injectable olanzapine with benzodiazepines doesn’t appear to raise the risk of serious respiratory outcomes like intubation. That said, you should still proceed with caution, especially in intoxicated patients or those with baseline respiratory compromise.