Incidence, burden, and associated factors of severe potential drug–drug interactions in intensive care unit patients: a real-world retrospective study

Abstract

Severe potential drug-drug interactions (pDDIs) in intensive care unit (ICU) patients remain insufficiently characterized. This study investigated the incidence, patterns, burden, and associated factors of severe pDDIs. This single-center retrospective cohort included ICU admissions from January 2023 through December 2024 for adults aged ≥18 years who received ≥2 eligible systemic medications administered orally or intravenously. Category D and X pDDIs were identified with Lexi-Interact (Lexidrug, UpToDate) using confirmed administration records. Logistic and ordinal logistic regression were performed to evaluate severe-pDDI occurrence (≥1) and admission-level burden (0, 1–2, or ≥3). A total of 1,170 ICU admissions were included, involving 26,627 medication administrations. 64.44% were male and 55.38% received mechanical ventilation support. The most common implicated pharmacological group was alimentary-tract and metabolism agents, while ambroxol and glutathione emerged as the top two individual drugs. Among 1,170 ICU admissions, 1,092 (93.33%) exhibited pDDIs, and 769 (65.73%) experienced at least one category D or X pDDI. The 2,704 severe pDDIs comprised 1,681 (62.17%) category D and 1,023 (37.83%) category X events, yielding 231.1 pDDIs per 100 admissions and 101.6 pDDIs per 1,000 medication administrations. Nervous-system agents predominated; butorphanol [948/5,408 ingredient involvements (17.53%)] and dexmedetomidine [824/5,408 (15.24%)] were most frequently implicated. Butorphanol–dexmedetomidine [335/2,704 events (12.39%)] and noscapine–chlorphenamine [176/2,704 (6.51%)] were the leading category D and X pairs, respectively. Additive pharmacodynamic central nervous system depression predominated. Mechanical ventilation and medication count were the strongest adjusted correlates of severe-pDDI occurrence and burden, while baseline variables (sex, APACHE II score) lost significance after adjusting for ICU process variables. These associations remained materially unchanged after excluding 29 readmission encounters. In an exploratory review of 50 severe-pDDI episodes, 32 (64.0%) had temporally associated clinical signs or events documented and 29 (58.0%) had a documented management action. Category D or X pDDI alerts were frequent, primarily driven by pharmacodynamic additive central nervous system depression from sedative–analgesic combinations. Treatment intensity rather than baseline characteristics was associated with severe-pDDI exposure. Regional ICU-tailored surveillance and pharmacist-integrated medication management may facilitate identification of high-risk combinations, although specific drug pairs require validation across different healthcare settings.