Renli Wang, Xujun Hu, Zhaojun Xu, Rongjun Liu
Early plasma cortisol independently predicts sepsis in-hospital mortality with a distinct nonlinear threshold effect. Although its single-biomarker predictive power is limited, cortisol substantially enhances the risk-stratification capacity of established severity scores, supporting its clinical application as an adjunctive prognostic biomarker.
BACKGROUND: Clinical heterogeneity complicates early accurate prognosis for sepsis. Cortisol is robustly elevated by hypothalamic-pituitary-adrenal (HPA) axis activation during septic stress, yet large multicenter data clarifying its independent association with in-hospital mortality are scarce. This study investigated the prognostic value of early plasma cortisol and its incremental predictive value over classic critical illness severity scores.
METHODS: We retrospectively enrolled 2,364 adult patients meeting Sepsis-3.0 criteria from MIMIC-IV and eICU-CRD databases, with cortisol tested within 24 h after intensive care unit (ICU) admission. Individuals with pituitary/adrenal dysfunction or prior corticosteroid administration before cortisol measurement were excluded. The primary endpoint was all-cause in-hospital mortality. Multivariable Cox regression, restricted cubic splines and threshold models were adopted to characterize cortisol-mortality relationships; receiver operating characteristic (ROC) curves, integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were calculated to evaluate predictive performance.
RESULTS: After full adjustment for confounders, each 1 µg/dL rise in cortisol independently increased mortality risk (HR = 1.004, 95 %CI 1.001-1.006, P = 0.007). A nonlinear threshold of 43.8 µg/dL was detected: below this cutoff, mortality risk rose 1.7 % per µg/dL (HR = 1.017, P < 0.001), whereas no significant correlation existed above the threshold (HR = 0.999, P = 0.696). Cortisol alone showed moderate discrimination (AUC = 0.668). When added to Sequential Organ Failure Assessment (SOFA) score, Acute Physiology Score III (APSIII), or Oxford Acute Severity of Illness Score (OASIS), it significantly improved discrimination (IDI 1.73 %-2.17 %) and risk reclassification (NRI 36.6 %-39.8 %).
CONCLUSION: Early plasma cortisol independently predicts sepsis in-hospital mortality with a distinct nonlinear threshold effect. Although its single-biomarker predictive power is limited, cortisol substantially enhances the risk-stratification capacity of established severity scores, supporting its clinical application as an adjunctive prognostic biomarker.