title: A prospective multicenter cohort study of the association between global tissue hypoxia and coagulation abnormalities during early sepsis resuscitation.
abstract: OBJECTIVE
  Coagulation activation is an integral part of sepsis pathogenesis. Experimental data suggest that endothelial exposure to hypoxia activates coagulation. We aimed to test the hypothesis that the quantity of exposure to global tissue hypoxia is associated with the degree of coagulation activation during early sepsis resuscitation.
  
  
  METHODS
  Prospective, multicenter cohort study.
  
  
  METHODS
  Emergency department and intensive care unit of three academic hospitals.
  
  
  METHODS
  Inclusion criteria were age older than 17, acute infection with two or more signs of systemic inflammation, hypotension despite fluid challenge (or lactate >4 mM), and continuous central venous oxygen saturation (Scvo2) monitoring for quantitative resuscitation. Exclusion criteria were anticoagulant or blood product administration.
  
  
  RESULTS
  We recorded central venous oxygen saturation continuously for 0 to 6 hrs of resuscitation and calculated the area under the curve for central venous oxygen saturation <70%. We defined hypoxia exposure as exceeding the median area under the curve for the entire cohort. At 0, 6, and 24 hrs, we measured conventional coagulation biomarkers plus thrombin-antithrombin complex, plasmin-antiplasmin complex, tissue plasminogen activator, plasminogen activator inhibitor-1, protein C, antithrombin, and endothelial markers (E-selectin, intracellular adhesion molecule-1, thrombomodulin). We compared changes during 0 to 6 hrs and 0 to 24 hrs in biomarkers between hypoxia exposure and nonexposure groups. We enrolled 40 patients (60% requiring vasopressors; 30% mortality). We found that exposure to hypoxia alone was not associated with a significant degree of coagulation activation. However, in secondary analyses we found that exposure to arterial hypotension induced E-selectin and thrombin-antithrombin complex, whereas concomitant exposure to both hypotension and hypoxia was associated with amplification of E-selectin and thrombomodulin, and a reduction in protein C.
  
  
  CONCLUSIONS
  In this sample of patients undergoing quantitative resuscitation for sepsis, we found that exposure to global tissue hypoxia (as quantified by low central venous oxygen saturation) was not associated with major coagulation activation. Further investigation to elucidate the clinical factors that trigger or intensify the procoagulant response to sepsis is warranted.
authors.affiliation: Department of Medicine, Division of Critical Care Medicine, UMDNJ-Robert Wood Johnson Medical School at Camden, Cooper University Hospital, Camden, NJ, USA. trzeciak-stephen@cooperhealth.edu
authors.forename: Stephen
authors.initials: S
authors.lastname: Trzeciak
authors.forename: Alan E
authors.initials: AE
authors.lastname: Jones
authors.forename: Nathan I
authors.initials: NI
authors.lastname: Shapiro
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Pusateri
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Arnold
authors.forename: Michael
authors.initials: M
authors.lastname: Rizzuto
authors.forename: Tanisha
authors.initials: T
authors.lastname: Arora
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parrillo
authors.forename: R Phillip
authors.initials: RP
authors.lastname: Dellinger
mesh_terms: D000046:Academic Medical Centers; D015415:Biomarkers / Q000097:blood; D001778:Blood Coagulation Disorders / Q000097:blood / Q000503:physiopathology*; D001779:Blood Coagulation Factors / Q000032:analysis; D004636:Emergency Service, Hospital; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000503:physiopathology*; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D010100:Oxygen / Q000097:blood; D011446:Prospective Studies; D012151:Resuscitation; D018805:Sepsis / Q000097:blood / Q000503:physiopathology* / Q000628:therapy
chemical_list: D015415:Biomarkers; D001779:Blood Coagulation Factors; D010100:Oxygen