General Ondansetron Exposure and ICU Outcomes: A Comprehensive Analysis of 85,229 Critically Ill Adults Using the Medical Information Mart for Intensive Care IV (MIMIC-IV).

Introduction Nausea and vomiting are frequent in critically ill patients and complicate airway safety, medication delivery, and nutrition. Ondansetron is widely used for symptom control, yet its effect on survival in the intensive care unit (ICU) is unclear. Methods We conducted a retrospective cohort study using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Adult ICU admissions from 2008-2019 were stratified by receipt of ondansetron. The primary outcome was in-hospital mortality; secondary outcomes included ICU length of stay (LOS) and a pragmatic readmission proxy. Analyses included Welch's t-tests, chi-square tests, multivariable logistic regression, prespecified subgroup analyses, and 1:1 propensity score-matching. Results Among 85,229 ICU admissions, 40,205 received ondansetron and 45,024 did not. Mortality was lower with ondansetron than without (9.1% vs 12.9%, p < 0.001). After adjustment, ondansetron was associated with lower odds of death (OR: 0.72, 95% CI: 0.69-0.75). In a 1:1 propensity-matched cohort of 31,221 patients per group, mortality remained lower with ondansetron (11.3% vs 14.6%; OR: 0.74, 95% CI: 0.71-0.78). Ondansetron did not shorten ICU LOS. Conclusions Ondansetron exposure during ICU admission was independently associated with reduced in-hospital mortality. These findings suggest a potential survival benefit of a commonly used, well-tolerated antiemetic and support further prospective evaluation of ondansetron as an adjunctive therapy in critical care.