SAT-857 - Immuno-Metabolic Endotypes of Sepsis: Trajectory Analysis of Chimeric Biomarkers Reveals "Metabolic Inertia" as A Driver of Progression to Critical Illness

B:
We hypothesized that sepsis mortality is driven not by admission values, but by the failure to mobilize adaptive metabolic responses within 72 hrs. Latent Class Analysis (LCA) identified comorbidity-driven endotypes and evaluated whether dynamic biomarker trajectories revealed endotype-specific “Treatable Traits.”

M:
We conducted a retrospective analysis of patients who underwent ICU admission for ≥72h censored at 28d, between January 2020 and November 2025. Applied LCA to 38 discrete domains of the Elixhauser Comorbidity Index to divide the cohort into distinct phenotypic clusters. To capture host adaptive capacity, we calculated dynamic trajectories of synergistic ratio biomarkers (e.g. Albumin/Globulin, Lactate/Glucose) as percent delta between ICU days 1–2 and 1–3. Unlike prior static modeling approaches, we deployed a Boosted Tree predictive model to rank impact of these trajectories on hospital mortality or hospice discharge, calculating percent variance explained for each cluster. Partition Analysis and logistic regression were used to characterize percent change in biomarker trajectories associated with PCI across endotypes.

R:
LCA identified three distinct immuno-metabolic endotypes. Metabolic Renal Exhaustion (36%) oldest cohort (median age 77 y) with high burdens of renal failure and diabetes. Mortality was driven by “Metabolic Chaos,” characterized by extreme outliers in the Lactate/Glucose trajectory, consistent with mitochondrial uncoupling and glycemic deregulation, Immuno-Resilient (33%). Youngest cohort (median age 68 y) with highest survival (76%). Mortality risk was largely independent of metabolic trajectories, suggesting robust physiological reserve. Hepato-Coagulopathic PICS (31%) liver disease and coagulopathy, with highest combined mortality/hospice risk (59%). Mortality was driven by “Metabolic Inertia” in the Albumin/Globulin ratio. Visual analysis revealed a distinct PCI rescue slope among patients who overcame inertia (Delta >10%). A positive trajectory in the Albumin/Globulin ratio was significantly associated with survival, whereas stagnation (Delta ~0%) or catabolic decline was lethal.

D:
Sepsis PCI is functionally distinct across comorbidity phenotypes. We identified a state of Metabolic Inertia (Delta~0%) in PCI, particularly in the high-risk Hepato-Coagulopathic endotype (Cluster 3). In this group, the Albumin/Globulin trajectory represents a definitive “Treatable Trait” where survival depends on breaking the catabolic spiral by improving the ratio. In contrast, Cluster 1 mortality is driven by metabolic instability, notably Lactate/Glucose chaos. These findings suggest that precision resuscitation in sepsis must move beyond hemodynamic normalization toward endotype-specific immuno-metabolic targeting—aiming to induce plasticity in Cluster 3 while stabilizing mitochondrial flux in Cluster 1.

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