Early midazolam exposure and short-term risk of acute exacerbation of COPD in critically ill patients: a target trial emulation using the MIMIC-IV database.

Background: Sedation is frequently required in the intensive care unit (ICU), but benzodiazepines may worsen respiratory outcomes in patients with chronic obstructive pulmonary disease (COPD). Objective: To evaluate whether early midazolam exposure after ICU admission is associated with the short-term risk of acute exacerbation of COPD (AECOPD) among critically ill COPD patients. Methods: Using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, we emulated a target trial and applied a clone-censor-weight (CCW) approach to address immortal time bias and informative censoring. Exposure was midazolam administration within a grace period after ICU admission (primary: 24 h; sensitivity: 12 and 36 h). The primary outcome was AECOPD, defined as initiation of systemic corticosteroids or antibiotics between 24 h and 7 days after ICU admission. Outcomes were compared using inverse probability of censoring weights (IPCW). Results: Among 3,416 ICU stays, 233 (6.8%) received midazolam within 24 h. After IPCW weighting, AECOPD incidence was 29.8% in the midazolam group versus 23.5% in controls (risk difference +6.3%, 95% CI -2.7% to +15.8%; odds ratio 1.38, 95% CI 0.86-2.12; Conclusion: In the primary 24 h analysis, early midazolam exposure was associated with a numerically higher short-term AECOPD risk. These observational findings cannot establish causality, and the present study did not demonstrate a statistically significant causal effect; nevertheless, in view of existing ICU sedation evidence, continued caution in the use of midazolam in critically ill COPD patients appears prudent.