title: Biomarkers of endothelial cell activation in early sepsis.
abstract: OBJECTIVE
  The objective of this study was to investigate the association of endothelial-related markers with organ dysfunction and in-hospital mortality to validate our earlier findings in a multicenter study. We hypothesize that (i) endothelial biomarkers will be associated with organ dysfunction and mortality in sepsis and that (ii) soluble fms-like tyrosine kinase 1 (sFlt-1) holds promise as a novel prognostic marker in sepsis.
  
  
  METHODS
  This was a prospective, multicenter, observational study of a convenience sample of emergency department (ED) patients with a suspected infection presenting to one of four urban, academic medical center EDs between January 2009 and January 2010. We collected plasma while the patients were in the ED and subsequently assayed endothelial-related biomarkers, namely, sFlt-1, soluble E-selectin, soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and plasminogen activator inhibitor 1 (PAI-1). Outcomes were organ dysfunction and in-hospital mortality.
  
  
  RESULTS
  We enrolled a total of 166 patients: 63 with sepsis (38%), 61 with severe sepsis (37%), and 42 with septic shock (25%). All endothelial biomarkers were significantly associated with sepsis severity, P < 0.002. We found a significant intercorrelation between all biomarkers, strongest between sFlt-1 and PAI-1 (r = 0.61, P < 0.001) and PAI-1 and soluble E-selectin and soluble intercellular adhesion molecule 1 (r = 0.49, P < 0.001). Among the endothelial biomarkers, sFlt-1 had the strongest association with Sequential Organ Failure Assessment score (r = 0.58, P < 0.001). Soluble fms-like tyrosine kinase 1 and PAI-1 had the highest area under the operating receiver characteristic curve for mortality of 0.87.
  
  
  CONCLUSIONS
  This multicenter validation study confirms that markers of endothelial activation are associated with sepsis severity, organ dysfunction, and mortality in sepsis. This supports the hypothesis that the endothelium plays a central role in the pathophysiology of sepsis and may serve as a more accurate prediction tool and a target for therapies aimed at ameliorating endothelial cell dysfunction. In addition, sFLT-1 holds promise as a novel sepsis severity biomarker.
authors.affiliation: Department of Emergency Medicine and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. sskibste@bidmc.harvard.edu
authors.forename: Simon
authors.initials: S
authors.lastname: Skibsted
authors.forename: Alan E
authors.initials: AE
authors.lastname: Jones
authors.forename: Michael A
authors.initials: MA
authors.lastname: Puskarich
authors.forename: Ryan
authors.initials: R
authors.lastname: Arnold
authors.forename: Robert
authors.initials: R
authors.lastname: Sherwin
authors.forename: Stephen
authors.initials: S
authors.lastname: Trzeciak
authors.forename: Philipp
authors.initials: P
authors.lastname: Schuetz
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
authors.forename: Nathan I
authors.initials: NI
authors.lastname: Shapiro
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D019040:E-Selectin / Q000097:blood; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011446:Prospective Studies; D018805:Sepsis / Q000097:blood* / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood
chemical_list: D015415:Biomarkers; D019040:E-Selectin; D017395:Plasminogen Activator Inhibitor 1; D018799:Intercellular Adhesion Molecule-1; D040281:Vascular Endothelial Growth Factor Receptor-1