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.

背景
内皮激活在全身炎症反应综合征（systemic inflammatory response syndrome, SIRS）患者的器官功能障碍发生过程中发挥了关键作用。血管生成素-1（Angiopoietin-1, Ang-1）可维持血管稳态，而血管生成素-2（Angiopoietin-2, Ang-2）则介导微血管渗漏。SIRS患者外周血中Ang-1与Ang-2的循环水平，能够提供区别于炎症蛋白的器官功能障碍与死亡风险相关信息。本研究旨在明确：SIRS患者的内皮激活与炎症生物标志物，是否与不良临床结局存在独立相关性。

方法
本研究纳入了某学术型医学中心重症监护室（Intensive Care Unit, ICU）收治的943例确诊SIRS的重症患者。在患者入组后24小时内，我们检测了其血浆中的内皮细胞标志物（Ang-1、Ang-2、可溶性血管细胞黏附分子-1（soluble vascular cell adhesion molecule-1, sVCAM-1））与炎症标志物（白细胞介素-6（interleukin-6, IL-6）、白细胞介素-8（interleukin-8, IL-8）、粒细胞集落刺激因子（granulocyte-colony stimulating factor, G-CSF）、可溶性肿瘤坏死因子受体-1（soluble tumor necrosis factor receptor-1, sTNFR-1））水平。我们分析了各项标志物与28天死亡率、休克发生情况及第3天序贯器官衰竭评分（Sequential Organ Failure Assessment, SOFA）之间的相关性。针对28天死亡率这一结局，我们对合并脓毒症患者与无菌性炎症患者分别进行了敏感性分析。本研究采用多变量模型校正临床混杂因素，以明确内皮激活标志物与结局的相关性是否独立于炎症标志物所观察到的关联。

结果
除Ang-1水平升高与28天死亡率降低相关外，其余所有生物标志物水平升高均与28天死亡率升高相关。在校合并症与sTNFR-1浓度后，Ang-1浓度每升高一倍，其28天死亡率（比值比（Odds ratio, OR）=0.81；p<0.01）、休克发生风险（OR=0.82；p<0.001）及SOFA评分（β=-0.50；p<0.001）均显著降低；而Ang-2浓度每升高一倍，则与死亡率升高（OR=1.55；p<0.001）、休克发生风险升高（OR=1.51；p<0.001）及SOFA评分升高（β=+0.63；p<0.001）相关。sVCAM-1与SIRS患者的临床结局无独立相关性。

结论
在确诊SIRS的重症患者中，早期检测的Ang-1与Ang-2水平与死亡及器官功能障碍存在独立相关性，且该相关性不受同期检测的炎症标志物影响。