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Elevated Plasma Angiopoietin-2 Levels Are Associated With Fluid Overload, Organ Dysfunction, and Mortality in Human Septic Shock

Fisher, Jane LU ; Douglas, James J; Linder, Adam LU ; Boyd, John H; Walley, Keith R and Russell, James A (2016) In Critical Care Medicine 44(11). p.2018-2027
Abstract

OBJECTIVES: 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.

DESIGN: Multicenter observational cohort study derived from a randomized controlled trial (Vasopressin and Septic Shock Trial of vasopressin versus norepinephrine in septic shock).

SETTING: ICUs of hospitals in Canada, Australia,... (More)

OBJECTIVES: 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.

DESIGN: Multicenter observational cohort study derived from a randomized controlled trial (Vasopressin and Septic Shock Trial of vasopressin versus norepinephrine in septic shock).

SETTING: ICUs of hospitals in Canada, Australia, and the United States.

PATIENTS: Three hundred forty-one patients in the randomized, controlled Vasopressin and Septic Shock Trial trial of vasopressin versus norepinephrine in septic shock.

INTERVENTIONS: None.

MEASUREMENT AND MAIN 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.

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author
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publication status
published
in
Critical Care Medicine
volume
44
issue
11
pages
10 pages
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:84978933370
ISSN
1530-0293
DOI
10.1097/CCM.0000000000001853
language
English
LU publication?
no
id
1a93d087-6ebf-470b-af5d-51ae5b76021f
date added to LUP
2016-10-19 18:32:00
date last changed
2017-09-15 13:20:07
@article{1a93d087-6ebf-470b-af5d-51ae5b76021f,
  abstract     = {<p>OBJECTIVES: 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.</p><p>DESIGN: Multicenter observational cohort study derived from a randomized controlled trial (Vasopressin and Septic Shock Trial of vasopressin versus norepinephrine in septic shock).</p><p>SETTING: ICUs of hospitals in Canada, Australia, and the United States.</p><p>PATIENTS: Three hundred forty-one patients in the randomized, controlled Vasopressin and Septic Shock Trial trial of vasopressin versus norepinephrine in septic shock.</p><p>INTERVENTIONS: None.</p><p>MEASUREMENT AND MAIN 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 &lt; 0.0001) and coagulation (p &lt; 0.0001) dysfunction and acute kidney injury (p &lt; 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 (&gt; 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 &lt; 0.0001 and rs = 0.51; p &lt; 0.0001) and at 24 hours (rs = 0.29; p &lt; 0.0001 and rs = 0.41; p &lt; 0.0001).</p><p>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.</p>},
  author       = {Fisher, Jane and Douglas, James J and Linder, Adam and Boyd, John H and Walley, Keith R and Russell, James A},
  issn         = {1530-0293},
  language     = {eng},
  number       = {11},
  pages        = {2018--2027},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Critical Care Medicine},
  title        = {Elevated Plasma Angiopoietin-2 Levels Are Associated With Fluid Overload, Organ Dysfunction, and Mortality in Human Septic Shock},
  url          = {http://dx.doi.org/10.1097/CCM.0000000000001853},
  volume       = {44},
  year         = {2016},
}