Development and Validation of 72-Hour Fluid Balance Trajectory Subphenotypes and Prognosis in Sepsis: A Multicenter Cohort Study

Background Fluid management in sepsis is controversial, and while persistent positive fluid balance is linked to adverse outcomes, the prognostic value of the temporal patterns (trajectories) of cumulative fluid balance (CFB) during the first 72 hours after sepsis diagnosis remains unclear. This study aimed to identify distinct subphenotypes based on 72-hour CFB trajectories in adult sepsis patients and evaluate their independent association with 28-day mortality. Methods This multicenter retrospective cohort study utilized three large-scale critical care databases (MIMIC-IV, MIMIC-III-CareVue, and eICU). We included adult patients meeting Sepsis-3 criteria with an ICU stay of over 72 hours. Group-Based Trajectory Modeling (GBTM) identified five distinct 72-hour CFB (mL/kg) subphenotypes in the MIMIC-IV development cohort (n = 16,069). Trajectories were validated in the MIMIC-III (n = 2,162) and eICU (n = 13,805) cohorts. We used Kaplan-Meier analysis and multivariable Cox proportional hazards models, including Inverse Probability of Treatment Weighting (IPTW), to assess the association with 28-day mortality, adjusting for baseline confounders. Results GBTM identified five reproducible CFB subphenotypes, notably a "Persistent Negative Balance" (Class 1), a "High, Rapid Decline" (Class 4), and a "Persistently High Balance" (Class 5). Class 5 patients exhibited the highest illness severity (e.g., highest SOFA scores). Kaplan-Meier analysis showed significant differences in 28-day survival (P < 0.001), with Class 1 and Class 4 having the best survival and Class 5 the worst. In the MIMIC-IV cohort, compared to the highest-risk Class 5 (reference) after full multivariable adjustment, all other trajectories were associated with significantly lower 28-day mortality: Class 1 (HR: 0.50, 95% CI: 0.44–0.56) and Class 4 (HR: 0.51, 95% CI: 0.46–0.57). These protective findings were consistent across all validation cohorts. Conclusion Sepsis patients exhibit five distinct, reproducible CFB trajectories strongly associated with 28-day mortality, independent of baseline severity. The finding that the "High, Rapid Decline" (Class 4) trajectory shares an excellent prognosis with the "Persistent Negative" (Class 1) trajectory challenges static fluid assessments. The ability to predict the high-risk Class 5 phenotype early using machine learning (AUC ≈ 0.81) provides a tangible pathway toward individualized fluid stewardship.