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Abstract

Introduction: Our previous work suggests that markers of endothelial cell activation/dysfunction are associated with organ dysfunction and mortality in patients with sepsis. Hypothesis: The objective of this study is to investigate the association between endothelial markers with organ dysfunction (assessed by SOFA-score) and in-hospital mortality to validate our earlier findings in a multicenter study. We hypothesize that endothelial biomarkers, particularly sfLT-1 hold promise as novel prognostic markers in sepsis. Methods: This was a prospective, multicenter, observational study of a convenience sample consisting of three cohorts of adult patients at four university emergency departments: 1) a septic shock cohort (SBP<90mmHg after fluid challenge), 2) a sepsis without shock cohort, and 3) ED patients without infection. We collected plasma at enrollment, and then assayed biomarkers of endothelial activation, namely, soluble vascular endothelial growth factor R1 (sFLT-1), sE-Selectin, soluble intercellular adhesion molecule (sICAM-1), soluble vascular cell adhesion molecule (sVCAM-1), plasminogen activator inhibitor-1 (tPAI-1) and the inflammatory cytokine IL-6. Outcomes were organ dysfunction (measured as Sequential Organ Failure Assessment (SOFA) score at 24 hours) and in-hospital mortality. Results: We enrolled a total of 203 patients. The overall mean age was 63 (± 16) years, of whom 60% were males. There was a relationship between nearly all target biomarkers and organ dysfunction at 24 hours (sVEGF-R1 r=0.59, sVCAM-1 r=0.42, sE-Selectin r=0.37, PAI-1 r=0.32 p <0.0001 for each; and sICAM-1 r=0.16 and P <0.028). Among the endothelial biomarkers, sVEGF-R1 had the strongest association with SOFA score at 24 hours. sFLT-1 and TPAI-1 had the highest area under the receiver operator characteristic curves for mortality of 0.89 (95% CI 0.81-0.98) and 0.90 (0.82-0.97) respectively. For comparison IL-6 had an AUC of 0.82 (0.72-0.91). Conclusions: This multicenter validation study confirms that markers of endothelial cell activation are associated with organ dysfunction and mortality in sepsis.