• L Nelson Sanchez-Pinto, Tellen D Bennett, Emily K Stroup, Yuan Luo, Mihir Atreya, Juliane Bubeck Wardenburg, Grace Chong, Alon Geva, FaustinoE Vincent SEVSDepartment of Pediatrics, Yale School of Medicine, New Haven, CT., Reid W Farris, Mark W Hall, Colin Rogerson, Sareen S Shah, Scott L Weiss, and Robinder G Khemani.
• Department of Pediatrics, Northwestern University Feinberg School of Medicine and Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
• Pediatr Crit Care Me. 2023 Oct 1; 24 (10): 795806795-806.

ObjectivesUntangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to analyze the organ dysfunction trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify reproducible and clinically relevant sepsis phenotypes and determine if they are associated with heterogeneity of treatment effect (HTE) to common therapies.DesignMulticenter observational cohort study.SettingThirteen PICUs in the United States.PatientsPatients admitted with suspected infections to the PICU between 2012 and 2018.InterventionsNone.Measurements And Main ResultsWe used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-based phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. Overall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS with an in-hospital mortality of 10.1%. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia, encephalopathy, and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score-matched analysis, patients with persistent hypoxemia, encephalopathy, and shock phenotype appeared to have HTE and benefit from adjuvant therapy with hydrocortisone and albumin. When compared with other high-risk clinical syndromes, the persistent hypoxemia, encephalopathy, and shock phenotype only overlapped with 50%-60% of patients with septic shock, moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tier of organ dysfunction burden, suggesting that it represents a nonsynonymous clinical phenotype of sepsis-associated MODS.ConclusionsWe derived and validated the persistent hypoxemia, encephalopathy, and shock phenotype, which is highly reproducible, clinically relevant, and associated with HTE to common adjuvant therapies in children with sepsis.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

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