Endothelial Permeability and Hemostasis in Septic Shock: Results From the ProCESS Trial

Abstract

We studied patients from the Protocolized Care in Early Septic Shock (ProCESS) trial to determine the effects of alternative resuscitation strategies on circulating markers of endothelial cell permeability and hemostasis and the association between biomarkers and mortality. This was a prospective study of biomarkers of endothelial cell permeability (vascular endothelial growth factor [VEGF], soluble fms-like tyrosine kinase 1 [sFLT-1], angiopoietin 2[Ang-2]) and biomarkers of hemostasis (von Willebrand factor [vWF], thrombomodulin [TM], tissue plasminogen activator [tPA] in 605 of the 1,341 ProCESS participants in a derivation cohort and 305 participants in a validation cohort. Analyses assessed (1) the impact ofvarying resuscitation strategies on biomarker profiles and (2) the association of endothelial biomarkers with 60-day in-hospital mortality. The study was conducted in 31 US EDs in adultpatients with septic shock. Patients were randomly assigned to one of three resuscitation strategies. Blood samples were collected at enrollment, at 6 h, and at 24 h. There were 116 (19.2%) and 52 (17.0%) deaths in the derivation and validation cohorts, respectively. There was no significant association between treatment strategy and any biomarker levels. Permeability (Ang-2 and sFLT-1) and hemostasis (vWF, TM, tPA) biomarkers were higher and VEGF levels were lower in nonsurvivors (P< .05 for all). At baseline, sFLT-1 had the highest point estimate for mortality discrimination (derivation area under the curve [AUC], 0.74; validation, 0.70), similar to lactate (AUC, 0.74) and Sequential Organ Failure Assessment score (AUC, 0.73). In an analysis including all time points and adjusted for age, presence of cancer, and Charlson comorbidity score, the adjusted AUC for sFLT-1 was 0.80. We found no relationship between different resuscitation strategies and biomarker profiles in sepsis, but we did find that elevated levels of endothelial cell biomarkers of permeability and hemostasis were associated with increased mortality. ClinicalTrials.gov; No.: NCT00510835 and NCT00793442; URL: www.clinicaltrials.gov.