Biomarkers of Endothelial Activation Are Associated with Poor Outcome in Critical Illness

• Published in: PloS one Vol. 10; no. 10; p. e0141251
• Main Authors: Mikacenic, Carmen, Hahn, William O., Price, Brenda L., Harju-Baker, Susanna, Katz, Ronit, Kain, Kevin C., Himmelfarb, Jonathan, Liles, W. Conrad, Wurfel, Mark M.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.10.2015; Public Library of Science (PLoS)
• Subjects: Activation; Analysis; Angiopoietin; Biological markers; Biomarkers; Biomarkers - metabolism; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Clinical outcomes; Cohort Studies; Colony-stimulating factor; Critical care; Critical Illness - mortality; Cytokines; Endothelium; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Failure analysis; Female; Gene expression; Granulocyte colony-stimulating factor; Health care facilities; Humans; Illnesses; Infections; Infectious diseases; Inflammation; Inflammatory response; Intensive care; Interleukin; Interleukin 6; Interleukin 8; Interleukins; Leukocytes (granulocytic); Male; Medical centers; Medical research; Medical schools; Medicine; Microvasculature; Middle Aged; Mortality; Multiple Organ Failure - mortality; Organ Dysfunction Scores; Patient outcomes; Patients; Plasma levels; Prognosis; Proteins; Sensitivity analysis; Sepsis; Survival Rate; Systemic inflammatory response syndrome; Systemic Inflammatory Response Syndrome - metabolism; Systemic Inflammatory Response Syndrome - mortality; Systemic Inflammatory Response Syndrome - pathology; Trauma; Vascular cell adhesion molecule 1; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0141251

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. 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. 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. 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.