First-Day Glycemic Exposure and 28-Day Mortality in the ICU: A Multicenter Cohort Study.

Importance: Early glycemic exposure in the ICU is common and clinically modifiable, yet bedside assessment often relies on single glucose values rather than exposure-aware metrics. Interpretable, first-day prediction may support individualized glycemic targets and early intervention. Objective: To examine the association between first-day time-weighted average glucose (TWAG) and 28-day mortality, and to evaluate GlucoSurvAI, an interpretable ensemble model for first-day risk stratification. Design Setting and Participants: Retrospective cohort study using electornic health records from 13 U.S. hospitals. Among 18,868 adult ICU encounters, 8,048 patients from 7 U.S. hospitals met inclusion criteria (≥1 glucose value and hospital length of stay ≥24 hours). Exposures: First-day glycemic exposure summarized as TWAG, categorized as <100, 100-139 (reference), 140-179, and ≥180 mg/dL. Prespecified covariates included diabetes/prediabetes, first-day insulin and glucose, corticosteroids, vasopressors, shock, cancer, glucose-monitoring intensity, and clinical site. Main Outcome and Measures: Primary outcome: 28-day all-cause mortality. Associations were estimated with multivariable Cox models (adjusted hazard ratios [aHRs], 95% CIs). GlucoSurvAI performance was assessed using Area Under the Receiver Operating Characteristic (AUROC) and Brier score; SHapley Additive exPlanations (SHAP) provided 28-day interpretability. Results: Of 8,048 patients, most were euglycemic (70-180 mg/dL) on day 1, although hyperglycemic excursions were frequent. Higher TWAG was associated with higher 28-day mortality: 140-179 mg/dL aHR 1.42 (95% CI, 1.25-1.62); ≥180 mg/dL aHR 1.41 (95% CI, 1.17-1.69). TWAG <100 mg/dL showed a nonsignificant trend toward higher survival. GlucoSurvAI achieved AUROC 0.967 (±0.008) with a low Brier score (~0.026). Adjusted SHAP analyses paralleled Cox results, identifying 100-139 mg/dL as the exposure range associated with decreased mortality, with risk increasing ≥140 mg/dL. First-day vasopressors and corticosteroids were also associated with higher mortality; insulin exposure marked higher risk after adjustment. Conclusions and Relevance: During the first ICU day, exposure-aware TWAG assessmentidentified a practical upper boundary near 140 mg/dL associated with higher 28-day mortality. An interpretable ensemble integrating TWAG, treatments, and physiology provided accurate first-day risk estimates, supporting risk-informed, individualized glycemic targets and earlier intervention in high-risk ICU patients.