Ketamine vs Droperidol for Emergency Department Agitation and Associated Intubation and Respiratory Failure Risk

Ketamine is increasingly used for severe agitation in the emergency department (ED) due to its rapid onset. While effective for sedation, its comparative safety profile versus traditional agents like droperidol regarding serious adverse outcomes is not well defined. The objective of this study was to compare rates of intubation and respiratory failure in ED patients with acute agitation treated with parenteral ketamine versus droperidol.

Methods: This retrospective cohort study used the TriNetX database, identifying ED encounters (data queried [January, 2026]) with a primary diagnosis of agitation or related conditions. Cohorts were defined by administration of parenteral ketamine (n=29,606) or droperidol (n=55,914). Cohorts were propensity score matched on demographics and comorbidities, yielding 27,372 matched pairs. Primary outcomes were endotracheal intubation, respiratory failure, and non-invasive ventilation. Secondary outcomes included hypoxemia, hypertensive emergency, and shock. Outcome rates were compared between cohorts using tests of proportions, reporting risk differences and 95% confidence intervals (CI).

In the matched cohort, ketamine was associated with significantly higher rates of adverse outcomes. The endotracheal intubation rate was higher with ketamine (5.34%) than with droperidol (2.85%), corresponding to an absolute risk increase of 2.48% (95% CI 2.12% to 2.85%; p<0.0001) and an odds ratio of 1.87 (95% CI 1.71 to 2.05). Respiratory failure occurred more frequently with ketamine (9.12% vs. 5.89%; risk difference 3.24%, 95% CI 2.72% to 3.75%; p<0.0001). Need for non-invasive ventilation was also more common with ketamine (5.48% vs. 2.40%; risk difference 3.09%, 95% CI 2.75% to 3.43%; p<0.0001). Hypoxemia and shock were also significantly more frequent with ketamine ( p<0.0001). Hypertensive emergency did not differ significantly between groups.

In this large propensity-matched analysis, ketamine for ED agitation was associated with significantly higher rates of intubation and respiratory failure compared to droperidol, highlighting important safety considerations. Study limitations include reliance on depersonalized coded data.