Development and validation of novel sepsis subphenotypes using trajectories of vital signs

Purpose: Sepsis is a heterogeneous syndrome and identification of sub-phenotypes is essential. This study used trajectories of vital signs to develop and validate sub-phenotypes and investigated the interaction of sub-phenotypes with treatment using randomized controlled trial data. Methods: All patients with suspected infection admitted to four academic hospitals in Emory Healthcare between 2014–2017 (training cohort) and 2018–2019 (validation cohort) were included. Group-based trajectory modeling was applied to vital signs from the first 8 h of hospitalization to develop and validate vitals trajectory sub-phenotypes. The associations between sub-phenotypes and outcomes were evaluated in patients with sepsis. The interaction between sub-phenotype and treatment with balanced crystalloids versus saline was tested in a secondary analysis of SMART (Isotonic Solutions and Major Adverse Renal Events Trial). Results: There were 12,473 patients with suspected infection in training and 8256 patients in validation cohorts, and 4 vitals trajectory sub-phenotypes were found. Group A (N = 3483, 28%) were hyperthermic, tachycardic, tachypneic, and hypotensive. Group B (N = 1578, 13%) were hyperthermic, tachycardic, tachypneic (not as pronounced as Group A) and hypertensive. Groups C (N = 4044, 32%) and D (N = 3368, 27%) had lower temperatures, heart rates, and respiratory rates, with Group C normotensive and Group D hypotensive. In the 6,919 patients with sepsis, Groups A and B were younger while Groups C and D were older. Group A had the lowest prevalence of congestive heart failure, hypertension, diabetes mellitus, and chronic kidney disease, while Group B had the highest prevalence. Groups A and D had the highest vasopressor use (p < 0.001 for all analyses above). In logistic regression, 30-day mortality was significantly higher in Groups A and D (p < 0.001 and p = 0.03, respectively). In the SMART trial, sub-phenotype significantly modified treatment effect (p = 0.03). Group D had significantly lower odds of mortality with balanced crystalloids compared to saline (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.23–0.67, p < 0.001). Conclusion: Sepsis sub-phenotypes based on vital sign trajectory were consistent across cohorts, had distinct outcomes, and different responses to treatment with balanced crystalloids versus saline.