Papers

Background: Patients with chronic obstructive pulmonary disease (COPD) complicated by pulmonary hypertension (PH) represent a high-risk population with limited evidence regarding early ICU fluid management. We investigated whether persistent positive fluid balance during the first 48 hours after ICU admission was associated with in-hospital mortality. Methods: We performed a retrospective multicenter cohort study using MIMIC-IV as the discovery cohort and eICU as the external validation cohort. Adult ICU patients with diagnosis-coded COPD complicated by PH were included. The main exposure was persistent positive fluid balance, defined as positive net fluid balance on both day 1 and day 2 after ICU admission. The primary outcome was in- hospital mortality. Multivariable logistic regression with multiple imputation was used as the primary analysis. Propensity score overlap weighting, stabilized inverse probability of treatment weighting (IPTW), complete-case analysis, nonlinear spline analysis, and clinically relevant subgroup analyses were performed. Results: The analysis included 1,891 ICU stays (1,493 from MIMIC-IV and 398 from eICU), with 348 in- hospital deaths. Persistent positive 48-hour fluid balance occurred in 484 patients (25.6%). Crude mortality was higher in the persistent positive group than in the non-persistent positive group (30.0% vs 14.4%). In the main multiply imputed multivariable model, persistent positive fluid balance was associated with higher in-hospital mortality in MIMIC-IV (OR 1.45, 95% CI 1.01-2.07; P=0.043) and in eICU (OR 1.88, 95% CI 1.06-3.32; P=0.030), with a fixed-effect pooled OR of 1.56 (95% CI 1.15-2.11; P=0.004). The association remained robust after overlap weighting, stabilized IPTW, and complete- case analysis. Subgroup analyses showed directionally consistent associations across all examined strata. Conclusions: Among ICU patients with diagnosis-coded COPD complicated by PH, persistent positive fluid balance during the first 48 hours was independently associated with higher in-hospital mortality and externally validated in eICU. Persistent early positive fluid balance may represent a high-risk dynamic fluid phenotype rather than a causal treatment effect. Keywords: COPD; pulmonary hypertension; fluid balance; intensive care unit; MIMIC-IV; eICU; mortality; multiple imputation