title: 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 of varying 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 adult patients 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.
authors.affiliation: Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hou
authors.affiliation: Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Filbin
authors.affiliation: Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL; Department of Emergency Medicine, University of Alabama, Birmingham, AL.
authors.forename: Henry
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of General Medicine, Department of Medicine, Boston, MA.
authors.forename: Long
authors.initials: L
authors.lastname: Ngo
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: David T
authors.initials: DT
authors.lastname: Huang
authors.affiliation: Division of Molecular Medicine, Department of Medicine and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA.
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
authors.affiliation: Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Yealy
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
authors.affiliation: Department of Emergency Medicine and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA. Electronic address: nshapiro@bidmc.harvard.edu.
authors.forename: Nathan I
authors.initials: NI
authors.lastname: Shapiro
mesh_terms: D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006487:Hemostasis; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D010539:Permeability; D012151:Resuscitation / Q000379:methods*; D012772:Shock, Septic / Q000097:blood / Q000401:mortality / Q000628:therapy; D013223:Statistics as Topic; D018180:Thrombomodulin / Q000097:blood; D010959:Tissue Plasminogen Activator / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D042702:Angiopoietin-2; D015415:Biomarkers; D018180:Thrombomodulin; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D010959:Tissue Plasminogen Activator
keywords: biomarkers; endothelium; hemostasis; permeability; sepsis