Ratio of angiopoietin-2 to angiopoietin-1 as a predictor of mortality in acute lung injury patients

Abstract

Objective: To test the hypothesis that the concentration of angiopoietin-2 relative to angiopoietin-1 may be a useful biological marker of mortality in acute lung injury patients. We also tested the association of concentration of angiopoietin-2 relative to angiopoietin-1 with physiologic and biological markers of activated endothelium.

Design: Prospective, observational cohort study.

Setting: Intensive care units in a tertiary care university hospital and a university-affiliated city hospital.

Patients: Fifty-six mechanically ventilated patients with acute lung injury.

Interventions: Baseline plasma samples and pulmonary dead-space fraction measurements were collected within 48 hrs of acute lung injury diagnosis.

Measurements and main results: Plasma levels of angiopoietin-1 and angiopoietin-2 and of biomarkers of endothelial activation were measured by enzyme-linked immunosorbent assay. Baseline concentration of angiopoietin-2 relative to angiopoietin-1 was significantly higher in patients who died (median, 58 [interquartile range, 17-117] vs. 14 [interquartile range, 6-35]; p = .01). In a multivariable analysis stratified by dead-space fraction, concentration of angiopoietin-2 relative to angiopoietin-1 was an independent predictor of death, with an adjusted odds ratio of 4.3 (95% confidence interval, 1.3-13.5; p = .01) in those with an elevated pulmonary dead-space fraction (p = .03 for interaction between pulmonary dead-space fraction and concentration of angiopoietin-2 relative to angiopoietin-1). Moderate to weak correlation was found with biological markers of endothelial activation.

Conclusions: The ratio of concentration of angiopoietin-2 relative to angiopoietin-1 may be a prognostic biomarker of endothelial activation in acute lung injury patients and, along with pulmonary dead-space fraction, may be useful for risk stratification of acute lung injury patients, particularly in identifying subgroups for future research and therapeutic trials.

Figure 1

Baseline plasma Ang-1 (a), Ang-2 (b), and Ang-2/Ang-1 (c) comparing survivors (n=37) with non-survivors (n=19). Ang-2/Ang-1 was significantly higher in non-survivors as tested by Mann-Whitney rank sum (p= 0.01). The horizontal line represents the median, box encompasses the 25^th through 75^th percentiles, and whiskers encompass the 10^th through 90^th percentiles.

Figure 2

Observed mortality according to tertile of baseline plasma Ang-2/Ang-1 (n=56). Test for trend across tertiles, p=0.004.

Figure 3

Box plots of baseline plasma Ang-2/Ang-1 ratio by survival status stratified by level of pulmonary dead space fraction (n=53). Baseline Ang-2/Ang-1 was associated with in-hospital mortality only in the high pulmonary dead space fraction group. Comparisons were made with the Mann-Whitney rank sum test. The horizontal line represents the median, box encompasses the 25^th through 75^th percentiles, and whiskers encompass the 10^th through 90^th percentiles.