Biomarkers of Endothelial Activation Are Associated with Poor Outcome in Critical Illness.
BACKGROUND
Endothelial activation plays a role in organ dysfunction in the systemic inflammatory response syndrome (SIRS). Angiopoietin-1 (Ang-1) promotes vascular quiescence while angiopoietin-2 (Ang-2) mediates microvascular leak. Circulating levels of Ang-1 and Ang-2 in patients with SIRS could provide insight on risks for organ dysfunction and death distinct from inflammatory proteins. In this study, we determined if biomarkers of endothelial activation and inflammation exhibit independent associations with poor outcomes in SIRS.


METHODS
We studied 943 critically ill patients with SIRS admitted to an Intensive Care Unit (ICU) of an academic medical center. We measured plasma levels of endothelial markers (Ang-1, Ang-2, soluble vascular cell adhesion molecule-1 (sVCAM-1)) and inflammatory markers (interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte-colony stimulating factor (G-CSF), soluble tumor necrosis factor receptor-1 (sTNFR-1)) within 24 hours of enrollment. We tested for associations between each marker and 28 day mortality, shock, and day 3 sequential organ failure assessment (SOFA) score. For 28 day mortality, we performed sensitivity analysis for those subjects with sepsis and those with sterile inflammation. We used multivariate models to adjust for clinical covariates and determine if associations identified with endothelial activation markers were independent of those observed with inflammatory markers.


RESULTS
Higher levels of all biomarkers were associated with increased 28 day mortality except levels of Ang-1 which were associated with lower mortality. After adjustment for comorbidities and sTNFR-1 concentration, a doubling of Ang-1 concentration was associated with lower 28 day mortality (Odds ratio (OR) = 0.81; p<0.01), shock (OR = 0.82; p<0.001), and SOFA score (β = -0.50; p<0.001), while Ang-2 concentration was associated with increased mortality (OR = 1.55; p<0.001), shock (OR = 1.51; p<0.001), and SOFA score (β = +0.63; p<0.001). sVCAM-1 was not independently associated with SIRS outcomes.


CONCLUSIONS
In critically ill patients with SIRS, early measurements of Ang-1 and Ang-2 are associated with death and organ dysfunction independently of simultaneously-measured markers of inflammation.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, United States of America.
Carmen
C
Mikacenic
Department of Medicine, Division of Infectious Diseases, University of Washington, Seattle, Washington, United States of America.
William O
WO
Hahn
Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
Brenda L
BL
Price
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, United States of America.
Susanna
S
Harju-Baker
Kidney Research Institute, University of Washington, Seattle, Washington, United States of America.
Ronit
R
Katz
Department of Medicine, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital and the Tropical Disease Unit, University of Toronto, Toronto, Ontario, Canada.
Kevin C
KC
Kain
Kidney Research Institute, University of Washington, Seattle, Washington, United States of America.
Jonathan
J
Himmelfarb
Department of Medicine, Division of Infectious Diseases, University of Washington, Seattle, Washington, United States of America.
W Conrad
WC
Liles
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, United States of America.
Mark M
MM
Wurfel
D015415:Biomarkers / Q000378:metabolism*; D015331:Cohort Studies; D016638:Critical Illness / Q000401:mortality*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000401:mortality*; D063305:Organ Dysfunction Scores; D011379:Prognosis; D015996:Survival Rate; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*
D015415:Biomarkers