Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients

Abstract

Rationale: Current clinical prediction scores for acute lung injury (ALI) have limited positive predictive value. No studies have evaluated predictive plasma biomarkers in a broad population of critically ill patients or as an adjunct to clinical prediction scores.

Objectives: To determine whether plasma angiopoietin-2 (Ang-2), von Willebrand factor (vWF), interleukin-8 (IL-8), and/or receptor for advanced glycation end products (sRAGE) predict ALI in critically ill patients.

Methods: Plasma samples were drawn from critically ill patients (n = 230) identified in the emergency department. Patients who had ALI at baseline or in the subsequent 6 hours were excluded, and the remaining patients were followed for development of ALI.

Measurements and main results: Nineteen patients developed ALI at least 6 hours after the sample draw. Higher levels of Ang-2 and IL-8 were significantly associated with increased development of ALI (P = 0.0008, 0.004, respectively). The association between Ang-2 and subsequent development of ALI was robust to adjustment for sepsis and vasopressor use. Ang-2 and the Lung Injury Prediction Score each independently discriminated well between those who developed ALI and those who did not (area under the receiver operating characteristic curve, 0.74 for each), and using the two together improved the area under the curve to 0.84 (vs. 0.74, P = 0.05). In contrast, plasma levels of sRAGE and vWF were not predictive of ALI.

Conclusions: Plasma biomarkers such as Ang-2 can improve clinical prediction scores and identify patients at high risk for ALI. In addition, the early rise of Ang-2 emphasizes the importance of endothelial injury in the early pathogenesis of ALI.

Figure 1.

Plasma biomarker levels by newly developed acute lung injury (ALI). Patients who went on to develop ALI at least 6 hours after the sample draw (n = 19) had statistically significant increased levels of angiopoietin (Ang)-2 (A), Ang-2/Ang-1 ratio (B), and IL-8 (C) compared with those who did not develop ALI (n = 148). Receptor for advanced glycation end products (sRAGE) (D) and von Willebrand factor (vWF) (E) levels were equivalent between the two groups.

Figure 2.

Receiver operating characteristic (ROC) curves. Angiopoietin-2 (Ang-2) (area under receiver operating curve [AUROC], 0.74; 95% CI, 0.62–0.84) and the Lung Injury Prediction Score (LIPS) (AUROC, 0.74; 95% CI, 0.65–0.84) each show good discrimination between those who will develop acute lung injury and those who will not, but the combination of both LIPS and Ang-2 is superior to either alone (AUROC, 0.84; P = 0.05 for test of equality of AUROC compared with LIPS alone).