Development and Validation of Temperature Trajectory-Based Phenotypes in Pediatric Sepsis: A Multicenter Retrospective Cohort Study, 2012–2018

OBJECTIVES: Sepsis is a heterogeneous syndrome resulting from a complex interaction between the infectious agent and the host response. In adults with sepsis, longitudinal temperature measurements have been used to identify phenotypes with distinct clinical characteristics, immune profiles, and outcomes. Our objective was to develop and validate temperature trajectory-based phenotypes in critically ill children with sepsis. We hypothesized that the temperature trajectory-based phenotypes would be independently associated with clinical outcomes. DESIGN: Retrospective observational cohort study. SETTING: A total of 13 PICUs in the United States from January 1, 2012, to January 1, 2018. PATIENTS: Children (age 0-18 y) with community-acquired sepsis meeting Phoenix sepsis criteria admitted to a PICU directly or via an emergency department, who survived to 24 hours and had greater than or equal to 4 temperature measurements in the first 24 hours of admission were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 11,566 patients met all criteria for study inclusion. A total of 2327 patients (20%) developed the primary outcome of persistent multiple organ dysfunction syndrome (MODS) assessed at day 7 of admission. We used group-based trajectory modeling to identify temperature trajectory-based phenotypes. Three groups were identified: "hyperthermic" (35%), "normothermic" (59%), and "hypothermic" (6%), which were reproducible and had similar outcomes on a validation set. The "hypothermic" trajectory-based phenotype group had the highest odds of persistent MODS odds ratio (OR), 5 (95% CI, 4-6), and ICU mortality OR, 11 (95% CI, 9-15). In an exploratory analysis, hypothermia (< 35°C) at the time of PICU admission was also associated with persistent MODS and ICU mortality. The association between "hypothermic" trajectory-based phenotype and poor outcome remained after adjusting for hypothermia at admission, severity of illness, age, and technology dependence. CONCLUSIONS: We developed and validated temperature trajectory-based phenotypes of pediatric sepsis in a large multicenter cohort. The "hypothermic" trajectory-based phenotype was independently associated with worse clinical outcomes.