Finding the optimal glycemic target in sepsis using a joint longitudinal-survival model on the MIMIC-IV and eICU cohorts

Background A previous single-center observational study (Struja et al., 2026) proposed a glycemic target of 160-190 mg/dL for ICU patients with sepsis, consistent with Surviving Sepsis Campaign guidelines of ≤180 mg/dL. Objective The goal of this study was to replicate the joint longitudinal-survival model analysis of Struja et al. (2026) using MIMIC-IV, and to externally validate the findings using the eICU Database, a multicenter platform spanning 335 hospitals across the United States. Methods We conducted a retrospective cohort study using two independent ICU databases. Joint longitudinal-survival models were fit to estimate associations between time-varying glucose trajectories, organ dysfunction (SOFA score, with SpO₂ as proxy for the respiratory component), and three outcomes of in-hospital mortality, mild hypoglycemia (<80 mg/dL), and severe hypoglycemia (<50 mg/dL). The MIMIC-IV replication cohort comprised 8006 patients meeting Sepsis-3 criteria; the eICU validation cohort consisted of 4866 patients identified by diagnosis-based sepsis criteria. Results Across both databases, higher time-weighted average glucose was consistently associated with greater SOFA burden and worse survival. The SOFA trajectory association parameter was strongly positive in MIMIC-IV (HR 2.187, 95% credible interval 1.991-2.415) and remained significant in eICU (HR 3.019, 95% CI 2.654-3.428), with differences attributable to temporal resolution and multicenter heterogeneity. Invasive mechanical ventilation and renal replacement therapy were associated with reduced mortality in both cohorts. Predicted hazard curves showed mortality risk increasing above 120 mg/dL while hypoglycemia risk decreased monotonically. Conclusions Our findings provide the first multicenter external validation of joint longitudinal-survival models for sepsis-related glycemic control in ICUs, providing directionally consistent multicenter evidence supporting the plausibility of a 160-190 mg/dL therapeutic range that balances survival benefit with hypoglycemic risk.