Diphenhydramine Is Not Associated with Poor Outcomes Among Hospitalized People with Sickle Cell Disease

Abstract Objectives Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease occurring during hospitalization for vaso-occlusive episodes (VOE). Prior studies have suggested an association between intravenous (IV) diphenhydramine and ACS. We evaluated whether IV diphenhydramine use is associated with new-onset ACS after adjusting for inpatient opioid exposure. Methods This retrospective cohort study included adults hospitalized for VOE at three Bronx, NY hospitals (January 2020– January 2024). The primary endpoint was new-onset ACS defined as negative initial chest X-ray followed by subsequent radiographic consolidation and clinical symptoms. Secondary endpoints included ICU transfer and hospital length of stay (LOS). Multivariable logistic regression evaluated associations between diphenhydramine and outcomes, adjusting for daily oral morphine milliequivalents (MME). IV diphenhydramine exposure was categorized as none, 1–50 mg/day, or > 50 mg/day. Results Of 477 patients, 207 patients (43%) received IV diphenhydramine and 47 patients (10%) developed ACS. Compared to no exposure, neither 1–50 mg/day (aOR 0.81, 95% CI 0.39–1.68, p = 0.57) nor >50 mg/day (aOR 0.52, 95% CI 0.18–1.49, p = 0.22) was associated with ACS. No significant associations were found for ICU transfer or LOS. Conversely, higher MME/day was significantly associated with both ACS (OR 1.03, p < 0.01) and increased LOS (OR 1.05, p < 0.01). Conclusion IV diphenhydramine was not associated with ACS, ICU transfer, or LOS. The correlation between higher opioid requirements and ACS suggests that opioid dose may serve as a marker for disease severity or contribute to respiratory outcomes.