title: Elevated Plasma Angiopoietin-2 Levels Are Associated With Fluid Overload, Organ Dysfunction, and Mortality in Human Septic Shock.
abstract: OBJECTIVE
  Angiopoietins modulate endothelial permeability via endothelial cell junctions. Angiopoietin-2 blocks the angiopoietin-1/Tie-2 interaction that stabilizes these junctions, and elevated plasma angiopoietin-2 levels are associated with vascular leakage. We hypothesized that plasma angiopoietin-1 and angiopoietin-2 levels are associated with indirect markers of increased vascular permeability, organ dysfunction, mortality, and plasma proinflammatory cytokine levels in human septic shock.
  
  
  METHODS
  Multicenter observational cohort study derived from a randomized controlled trial (Vasopressin and Septic Shock Trial of vasopressin versus norepinephrine in septic shock).
  
  
  METHODS
  ICUs of hospitals in Canada, Australia, and the United States.
  
  
  METHODS
  Three hundred forty-one patients in the randomized, controlled Vasopressin and Septic Shock Trial trial of vasopressin versus norepinephrine in septic shock.
  
  
  METHODS
  None.
  
  
  RESULTS
  We measured plasma levels of angiopoietin-1 and angiopoietin-2 at study baseline and determined their association with percent fluid overload and acute organ dysfunction and generated a receiver operating characteristic curve for plasma angiopoietin-2 levels versus acute kidney injury. We also determined the association of angiopoietin-1 and angiopoietin-2 levels with hemodynamics, mortality, and plasma cytokine levels. Plasma angiopoietin-2 levels were directly associated with percent fluid overload at baseline (rs = 0.18; p = 0.0008) and at 6 hours (rs = 0.13; p = 0.023), but not at 24 hours (rs = 0.041; p = 0.46). Plasma angiopoietin-2 levels were associated with the development of hepatic (p < 0.0001) and coagulation (p < 0.0001) dysfunction and acute kidney injury (p < 0.0001). Receiver operating characteristic curve had an area under the curve of 0.73 for acute kidney injury. angiopoietin-2 levels were also inversely associated with days alive (r = -0.24; p = 0.010) and positively associated with increased 7-day (log-rank trend chi-square = 5.9; p = 0.015) and 28-day (log-rank chi square = 4.9; p = 0.027) mortality. A threshold of angiopoietin-2 levels above the first quartile (> 5,807 pg/mL) was observed to be associated with increased mortality risk, which aligns with prior studies. Plasma angiopoietin-2 levels were positively associated with plasma cytokine levels, including tumor necrosis factor-α and interleukin-6 at baseline (rs = 0.39; p < 0.0001 and rs = 0.51; p < 0.0001) and at 24 hours (rs = 0.29; p < 0.0001 and rs = 0.41; p < 0.0001).
  
  
  CONCLUSIONS
  Increased plasma angiopoietin-2 levels are associated with increased fluid overload, hepatic and coagulation dysfunction, acute kidney injury, mortality, and plasma cytokines in human septic shock. angiopoietin-2 activation may increase vascular leakage leading to increased fluid requirements, organ dysfunction, and death from septic shock.
authors.affiliation: 1Centre for Heart Lung Innovation, St. Paul's Hospital and University of British Columbia, Vancouver, BC, Canada. 2Division of Critical Care Medicine, St. Paul's Hospital and University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jane
authors.initials: J
authors.lastname: Fisher
authors.forename: James J
authors.initials: JJ
authors.lastname: Douglas
authors.forename: Adam
authors.initials: A
authors.lastname: Linder
authors.forename: John H
authors.initials: JH
authors.lastname: Boyd
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
mesh_terms: D058186:Acute Kidney Injury / Q000453:epidemiology*; D042702:Angiopoietin-2 / Q000097:blood*; D001315:Australia / Q000453:epidemiology; D015415:Biomarkers / Q000097:blood; D001778:Blood Coagulation Disorders / Q000453:epidemiology*; D002170:Canada / Q000453:epidemiology; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008107:Liver Diseases / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D012772:Shock, Septic / Q000401:mortality*; D014481:United States / Q000453:epidemiology; D014883:Water-Electrolyte Imbalance / Q000453:epidemiology*
chemical_list: D042702:Angiopoietin-2; D015415:Biomarkers; D016207:Cytokines; D005938:Glucocorticoids; D019344:Lactic Acid