(898) Inverse U-Shaped Association Between Serum Angiopoietin-2 and MODS Risk in Pediatric Septic Shock

Introduction: Pediatric sepsis is associated with significant morbidity and mortality with limited therapies available to use beyond antibiotics and intensive organ support. Global endothelial activation is a key hallmark of sepsis. Angiopoietin-2, a key endothelial molecule, acts as a context dependent competitive antagonist of the Tie-2 receptor, promoting endothelial permeability in synergy with inflammatory cytokines. Angpt-2 has been previously implicated as causal gene in the critical illness pathobiology. We hypothesized that the association between serum Angpt-2 and multiple organ dysfunction risk may exist along a spectrum with potential for either benefit or harm, depending of its concentration.

Methods: Secondary analyses of a prospective observational cohort of pediatric septic shock. The primary outcome of interest was complicated course defined as death by day 7 or persistence of 2 or more organ dysfunctions on day 7 after enrollment. Secondary outcomes included persistent cardiovascular, respiratory, and kidney dysfunctions on day 7 after enrollment. Serum Angpt-2 and Tie-2 concentrations were measured using Luminex Multiplex Assays in biobanked serum collected on day . Multi-variable logistic regression analyses to test the independent association between Angpt-2 concentrations and Angpt-2/Tie-2 ratios with outcomes of interest. Polynomial regression to measure non-linear associations between biomarkers and outcomes of interest.

Results: A total 835 patients with biomarker data were included in this study. The median age of the cohort was 5 years (IQR: 1.6-9.4). Upon adjusting for age and illness severity (PRISM-III score), both Angpt-2 concentration and Angpt-2/Tie ratio (p < 0.0001) were independently associated with risk of complicated course. Polynomial regression analyses revealed an inverse U-shaped association between biomarkers tested and risk of primary and secondary outcomes (p values < 0.0001) with highest risk of outcomes of interest noted between Angpt-2 concentrations of 40-70 ng/ml and Angpt-2/Tie-2 ratio of 5-20.

Conclusions: Serum Angpt-2 and Anpgt-2/Tie-2 ratios have an inverse U-Shaped association with risk of organ dysfunctions. Future therapeutic trials considering Angpt-2 blockade in septic shock must consider dose titration to balance risk/benefit those critically ill.