McLaughlin-Rotman Centre for Global Health, McLaughlin Centre for Molecular Medicine, University Health Network, The University of Toronto, Ontario, Canada.
Crit Care Med. 2011 Apr;39(4):702-10. doi: 10.1097/CCM.0b013e318206d285.
To determine the utility of angiopoietin-1 and angiopoietin-2 as potentially novel biomarkers of morbidity and mortality in patients with severe sepsis.
Multicenter longitudinal cohort study.
Three tertiary hospital intensive care units in Hamilton, Ontario, Canada.
A total of 70 patients with severe sepsis were enrolled within 24 hrs of meeting the inclusion criteria for severe sepsis and followed until day 28, hospital discharge, or death.
Clinical data and plasma samples were obtained at intensive care unit admission for all 70 patients and then daily for 1 wk and weekly thereafter for a subset of 43 patients. Levels of angiopoietin-1 and angiopoietin-2 in stored plasma samples were measured and compared with clinical characteristics, including the primary outcomes of 28-day mortality and morbidity measured by the Multiple Organ Dysfunction score.
Lower angiopoietin-1 plasma levels (≤ 5.5 ng/mL) at admission were associated with increased likelihood of death (relative risk 0.49 [95% confidence interval of 0.25-0.98], p = .046). Lower angiopoietin-1 levels remained a significant predictor of 28-day mortality in a multiple logistic regression model (adjusted odds ratio of 0.282 [95% confidence interval of 0.086-0.93], p = .037). Analysis of serial data using linear mixed models confirmed that sepsis survivors had higher levels of angiopoietin-1 (p = .012) and lower daily levels of angiopoietin-2 (p = .022) than nonsurvivors. Furthermore, survivors had higher peak angiopoietin-1 levels (median 13 vs. 10 ng/mL, p = .019) and lower nadir angiopoietin-2 levels (median 2.8 vs. 6.2 ng/mL, p = .013) than nonsurvivors. A score incorporating angiopoietin-1 and angiopoietin-2 and three other markers of endothelial activation discriminated with high accuracy between fatal and nonfatal cases (c-index of 0.80 [95% confidence interval of 0.69-0.90], p < .001). Plasma levels of angiopoietin-2 correlated with clinical markers of organ dysfunction and molecular markers of endothelial cell activation.
Angiopoietin-1 levels at admission and both angiopoietin-1 and angiopoietin-2 levels measured serially correlated with 28-day mortality in severe sepsis. Angiopoietin-2 levels also correlated with organ dysfunction/injury and a validated clinical sepsis score. These results suggest the use of angiopoietins as clinically informative biomarkers of disease severity and patient outcome in severe sepsis.
确定血管生成素-1 和血管生成素-2 是否可作为严重脓毒症患者发病率和死亡率的潜在新型生物标志物。
多中心纵向队列研究。
加拿大安大略省汉密尔顿的 3 家三级医院重症监护病房。
共纳入 70 例严重脓毒症患者，在符合严重脓毒症纳入标准后 24 小时内入组，并随访至第 28 天、出院或死亡。
所有 70 例患者入院时均采集临床数据和血浆样本，然后每日采集 1 周，之后对 43 例患者每周采集 1 次。测量并比较存储的血浆样本中血管生成素-1 和血管生成素-2 的水平，将其与临床特征进行比较，包括采用多器官功能障碍评分（Multiple Organ Dysfunction score）衡量的 28 天死亡率和发病率的主要结局。
入院时较低的血管生成素-1 血浆水平（≤5.5ng/mL）与死亡率增加相关（相对风险 0.49[95%置信区间为 0.25-0.98]，p=0.046）。在多变量逻辑回归模型中，较低的血管生成素-1 水平仍然是 28 天死亡率的显著预测因子（调整后的比值比为 0.282[95%置信区间为 0.086-0.93]，p=0.037）。使用线性混合模型对系列数据进行分析，证实脓毒症幸存者的血管生成素-1 水平较高（p=0.012），且每日血管生成素-2 水平较低（p=0.022）。此外，幸存者的血管生成素-1 峰值水平较高（中位数 13ng/mL 比 10ng/mL，p=0.019），血管生成素-2 最低水平较低（中位数 2.8ng/mL 比 6.2ng/mL，p=0.013）。一项纳入血管生成素-1 和血管生成素-2 以及其他 3 种内皮激活标志物的评分，能够以较高的准确度区分致命性和非致命性病例（c 指数为 0.80[95%置信区间为 0.69-0.90]，p<0.001）。血管生成素-2 水平与器官功能障碍的临床标志物和内皮细胞激活的分子标志物相关。
严重脓毒症患者入院时的血管生成素-1 水平以及连续测量的血管生成素-1 和血管生成素-2 水平均与 28 天死亡率相关。血管生成素-2 水平也与器官功能障碍/损伤和经过验证的临床脓毒症评分相关。这些结果提示，血管生成素可用作严重脓毒症患者疾病严重程度和患者预后的临床信息生物标志物。
