Journal Article

Integrated PERSEVERE and endothelial biomarker risk model predicts death and persistent MODS in pediatric septic shock: a secondary analysis of a prospective observational study

Weiss, Scott L., Haileselassie, Bereketeab, Lutfi, Riad, Bigham, Michael T., Alder, Matthew N., Allen, Geoffrey L., Baines, Torrey, Wong, Hector R., Thomas, Neal J., Lindsell, Christopher J., Schwarz, Adam J., Jain, Parag N., Grunwell, Jocelyn R., Fitzgerald, Julie C., Cvijanovich, Natalie Z., Quasney, Michael, Atreya, Mihir R., Nowak, Jeffrey

2022

Overview

Background Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock. Methods We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter. Results Among 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91–0.95) with a summary AUROC of 0.80 (0.76–0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables—ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1—contributed to the models’ predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively. Conclusions The newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics. Graphical abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Biological markers / Biomarkers / Care and treatment / Cell adhesion & migration / Chemokines / Clinical trials / Critical care / Critical Care Medicine / Cytokines / Diagnosis / Emergency Medicine / Endothelial dysfunction / Gene expression / Health risk assessment / Intensive / Intensive care / Ligands / Medical prognosis / Medicine / Medicine & Public Health / Methods / Mortality / Multiple organ dysfunction syndrome / Multiple organ failure / Observational studies / Pediatrics / Precision medicine / Risk factors / Sepsis / Septic shock / Services / The future of Intensive Care Medicine / Variables / Variance analysis