Association of early chloride-bicarbonate joint phenotypes with in-hospital mortality among intensive care unit patients with sepsis: a dual-database study.

BACKGROUND: Associations of chloride and bicarbonate abnormalities with sepsis outcomes have been studied separately, but whether a prespecified paired classification provides reproducible and interpretable risk characterization remains uncertain.

METHODS: We included adults with sepsis in MIMIC-IV v3.1 and eICU v2.0. Chloride (<98, 98-107, >107 mmol/L) and bicarbonate (<22, 22-26, >26 mmol/L) defined a 3 × 3 phenotype. In-hospital mortality was analyzed using multivariable logistic regression and predictive mean matching multiple imputation. Robustness was assessed through analyses of temporal ordering, threshold selection, cross-database heterogeneity, external transportability, and first-day changes in chloride and bicarbonate.

RESULTS: The cohorts included 25,842 MIMIC-IV stays and 37,045 eICU stays, with mortality rates of 16.31% and 15.50%, respectively. In complete-case Model 3b, the phenotype was globally associated with mortality in both cohorts; the low-low contrast was individually significant in eICU but not MIMIC-IV. The low-low association was supported in multiple-imputation analyses (MIMIC-IV OR 1.276, 95% CI 1.066-1.527; eICU OR 1.507, 95% CI 1.277-1.779) and in strict pre-exposure analyses (OR 1.700 and 1.787, respectively). Formal 4-df categorical interaction tests were not significant (P = 0.095 and P = 0.109). MIMIC-IV-derived data-driven cut points did not significantly outperform the clinical 3 × 3 phenotype in eICU (CART vs. clinical ΔAUROC 0.0009, 95% CI -0.0010 to 0.0029). In the main MIMIC-IV-to-eICU validation, adding the clinical phenotype left discrimination essentially unchanged (ΔAUROC 0.0010, 95% CI -0.0013 to 0.0031), although the Brier score improved modestly (ΔBrier -0.0011, 95% CI -0.0016 to -0.0006); NRI and IDI did not support improved discrimination or reclassification. Incident and persistent low-low states were both associated with higher subsequent mortality in 24 h landmark analyses in both cohorts.

CONCLUSIONS: Prespecified chloride-bicarbonate phenotypes were associated with mortality in both databases, and persistence or incident development of the low-low state during the first ICU day was associated with higher subsequent mortality. The 3 × 3 framework should therefore be interpreted primarily as a transparent, direction-preserving approach to descriptive risk characterization within a broader clinical assessment, rather than as a stand-alone prediction instrument, therapeutic threshold, or treatment guide.