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

<div><p>Background</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>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.</p></div

Multivariate Analysis of Biomarker Association with Shock.

<p>OR = Odds Ratio per doubling; CI = Confidence Interval; APACHE III = Acute Physiology and Chronic Health Evaluation III.</p><p>^<i>a</i> Logistic regression adjusted for age, gender, presence of infection, admitting service (medical vs. surgical), source of admission (outside hospital vs. emergency room), body mass index, smoking status, diabetes mellitus, chronic renal insufficiency, and cirrhosis</p><p>^<i>b</i> Adjusted for Log₂(IL-6) concentration and covariates in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141251#t004fn002" target="_blank">^a</a>.</p><p>^<i>c</i> Adjusted for Log₂(sTNFR-1) concentration and covariates in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141251#t004fn003" target="_blank">^b</a>.</p><p>^<i>d</i> For the number of tests in this table, a Bonferroni p<0.05 is equivalent to p<2.08x10^-3</p><p>Multivariate Analysis of Biomarker Association with Shock.</p

Subject Characteristics.

<p>SD = Standard Deviation; APACHE III = Acute Physiology and Chronic Health Evaluation III; BMI = Body Mass Index</p><p>Subject Characteristics.</p

Comparison of Plasma Biomarkers and 28 day mortality.

<p>IQR = Interquartile Range; IL-6 = Interleukin-6; IL-8 = Interleukin-8; G-CSF = Granulocyte colony stimulating factor; sTNFR-1 = Soluble Tumor Necrosis Factor Receptor-1; Ang-1 = Angiopoietin-1; Ang-2 = Angiopoietin-2; sVCAM-1 = Soluble Vascular Adhesion Molecule-1.</p><p>^<i>a</i> P value for Mann-Whitney U Test</p><p>Comparison of Plasma Biomarkers and 28 day mortality.</p

Multivariate Analysis of Biomarker Association with 28 Day Mortality.

<p>OR = Odds Ratio per doubling; CI = Confidence Interval; APACHE III = Acute Physiology and Chronic Health Evaluation III.</p><p>^<i>a</i> Logistic regression adjusted for age, gender, presence of infection, admitting service (medical vs. surgical), source of admission (outside hospital vs. emergency room), body mass index, smoking status, diabetes mellitus, chronic renal insufficiency, and cirrhosis</p><p>^<i>b</i> Adjusted for APACHE III and covariates in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141251#t003fn002" target="_blank">^a</a>.</p><p>^<i>c</i> Adjusted for Log₂(IL-6) concentration and covariates in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141251#t003fn002" target="_blank">^a</a>.</p><p>^<i>d</i> Adjusted for Log₂(sTNFR-1) concentration and covariates in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141251#t003fn002" target="_blank">^a</a>.</p><p>^e For the number of tests in this table, a Bonferroni p<0.05 is equivalent to p<1.56x10^-3</p><p>Multivariate Analysis of Biomarker Association with 28 Day Mortality.</p

Multivariate Analysis of Biomarker Association with Day 3 SOFA Score.

<p>SOFA = sequential organ failure assessment, β = Beta coefficient for increase in SOFA score with each doubling of biomarker concentration; CI = confidence interval.</p><p>^<i>a</i> Linear regression adjusted for age, gender, presence of infection, admitting service (medical vs. surgical), source of admission (outside hospital vs. emergency room), body mass index, smoking status, diabetes mellitus, chronic renal insufficiency, and cirrhosis</p><p>^<i>b</i> Adjusted for Log₂(IL-6) concentration and covariates in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141251#t005fn002" target="_blank">^a</a>.</p><p>^<i>c</i> Adjusted for Log₂(sTNFR-1) concentration and covariates in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141251#t005fn002" target="_blank">^a</a>.</p><p>^e For the number of tests in this table, a Bonferroni p<0.05 is equivalent to p<1.56x10^-3</p><p>Multivariate Analysis of Biomarker Association with Day 3 SOFA Score.</p