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Item Derivation, Validation, and Clinical Relevance of a Pediatric Sepsis Phenotype With Persistent Hypoxemia, Encephalopathy, and Shock(Wolters Kluwer, 2023) Sanchez-Pinto, L. Nelson; Bennett, Tellen D.; Stroup, Emily K.; Luo, Yuan; Atreya, Mihir; Bubeck Wardenburg, Juliane; Chong, Grace; Geva, Alon; Faustino, E. Vincent S.; Farris, Reid W.; Hall, Mark W.; Rogerson, Colin; Shah, Sareen S.; Weiss, Scott L.; Khemani, Robinder G.; Pediatrics, School of MedicineObjectives: Untangling 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. Design: Multicenter observational cohort study. Setting: Thirteen PICUs in the United States. Patients: Patients admitted with suspected infections to the PICU between 2012 and 2018. Interventions: None. Measurements and main results: We 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. Conclusions: We 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.Item Riboflavin did not provide anti-inflammatory or antioxidant effects in an experimental model of sepsis(Associação Brasileira de Divulgação Científica, 2022-05-27) Vale, A.H.F.; Nascimento, D.C.; Pineros, A.R.; Ferreira, R.G.; Santos, J.D.; Aragon, D.C.; Cunha, F.Q.; Ramalho, F.S.; Alves-Filho, J.C.; Carlotti, A.P.C.P.; Pediatrics, School of MedicineWe aimed to evaluate whether the administration of riboflavin to septic animals reduces inflammation, oxidative stress, organ dysfunction, and mortality. C57BL/6 mice, 6-8 weeks old, were allocated to the study group (polymicrobial sepsis induced by cecal ligation and puncture (CLP) + antibiotic + iv riboflavin), control (CLP + antibiotic + iv saline), or naïve (non-operated controls). Serum concentrations of alanine aminotransferase (ALT), creatine kinase-MB (CK-MB), urea, and creatinine, and markers of inflammation [interleukin (IL)-6, tumor necrosis factor (TNF)-α, keratinocyte-derived chemokine (KC), and macrophage inflammatory protein (MIP)-2)], and oxidative stress (malondialdehyde (MDA) were measured 12 h after the experiment. Animal survival rates were calculated after 7 days. Means between groups were compared using linear regression models adjusted under the Bayesian approach. No significant difference was observed between control and study groups in serum concentrations of IL-6 (95% credible interval) (-0.35 to 0.44), TNF-α (-15.7 to 99.1), KC (-0.13 to 0.05), MIP-2 (-0.84 to 0.06), MDA (-1.25 to 2.53), or ALT (-6.6 to 11.5). Serum concentrations of CK-MB (-145.1 to -30.1), urea (-114.7 to -15.1), and creatinine (-1.14 to -0.01) were higher in the study group. Survival was similar in both groups (P=0.8). Therefore, the use of riboflavin in mice undergoing sepsis induced by CLP did not reduce inflammation, oxidative stress, organ dysfunction, or mortality compared with placebo.Item Shock volume: Patient-specific cumulative hypoperfusion predicts organ dysfunction in a prospective cohort of multiply injured patients(Wolters Kluwer, 2018-07) McKinley, Todd O.; McCarroll, Tyler; Metzger, Cameron; Zarzaur, Ben L.; Savage, Stephanie A.; Bell, Teresa M.; Gaski, Greg E.; Orthopaedic Surgery, IU School of MedicineBACKGROUND: Multiply injured patients are at risk of developing hemorrhagic shock and organ dysfunction. We determined how cumulative hypoperfusion predicted organ dysfunction by integrating serial Shock Index measurements. METHODS: In this study, we calculated shock volume (SHVL) which is a patient-specific index that quantifies cumulative hypoperfusion by integrating abnormally elevated Shock Index (heart rate/systolic blood pressure ≥ 0.9) values acutely after injury. Shock volume was calculated at three hours (3 hr), six hours (6 hr), and twenty-four hours (24 hr) after injury. Organ dysfunction was quantified using Marshall Organ Dysfunction Scores averaged from days 2 through 5 after injury (aMODSD2–D5). Logistic regression was used to determine correspondence of 3hrSHVL, 6hrSHVL, and 24hrSHVL to organ dysfunction. We compared correspondence of SHVL to organ dysfunction with traditional indices of shock including the initial base deficit (BD) and the lowest pH measurement made in the first 24 hr after injury (minimum pH). RESULTS: SHVL at all three time intervals demonstrated higher correspondence to organ dysfunction (R2 = 0.48 to 0.52) compared to initial BD (R2 = 0.32) and minimum pH (R2 = 0.32). Additionally, we compared predictive capabilities of SHVL, initial BD and minimum pH to identify patients at risk of developing high-magnitude organ dysfunction by constructing receiver operator characteristic curves. SHVL at six hours and 24 hours had higher area under the curve compared to initial BD and minimum pH. CONCLUSION: SHVL is a non-invasive metric that can predict anticipated organ dysfunction and identify patients at risk for high-magnitude organ dysfunction after injury. LEVEL OF EVIDENCE: Prognostic study, level III.