Plasma angiopoietin-2 in clinical acute lung injury: prognostic and pathogenetic significance

Carolyn S Calfee, Diana Gallagher, Jason Abbott, B Taylor Thompson, Michael A Matthay, NHLBI ARDS Network, G R Bernard, D A Schoenfeld, B T Thompson, N Ringwood, C Oldmixon, F Molay, A Korpak, R Morse, D Hayden, M Ancukiewicz, A Minihan, J G N Garcia, R Balk, S Emerson, M Shasby, W Sibbald, R Spragg, G Corbie-Smith, J Kelley, K Leeper, A S Slutsky, B Turnbull, C Vreim, P Parsons, L Hudson, K Steinberg, M Neff, R Maier, K Sims, C Cooper, T Berry-Bell, G Carter, L Andersson, G B Toews, R H Bartlett, C Watts, R Hyzy, D Arnoldi, R Dechert, M Purple, H Silverman, C Shanholtz, A Moore, L Heinrich, W Corral, R Brower, D Thompson, H Fessler, S Murray, A Sculley, H P Wiedemann, A C Arroliga, J Komara, T Isabella, M Ferrari, J Kern, R Hejal, D Haney, A F Connors, E Abraham, R McIntyre, F Piedalue, C Welsh, I Douglas, R Wolkin, T Bost, B Sagel, A Hawkes, N MacIntyre, J Govert, W Fulkerson, L Mallatrat, L Brown, S Everett, E VanDyne, N Knudsen, M Gentile, P Rock, S Carson, C Schuler, L Baker, V Salo, A P Wheeler, G Bernard, T Rice, S Bozeman, T Welch, P Lanken, J Christie, B Fuchs, B Finkel, S Kaplan, V Gracias, C W Hanson, P Reilly, M B Shapiro, R Burke, E O'Connor, D Wolfe, J Gottlieb, P Park, D M Dillon, A Girod, J Furlong, A Morris, C Grissom, L Weaver, J Orme, T Clemmer, R Davis, J Gleed, S Pies, T Graydon, S Anderson, K Bennion, P Skinner, C Lawton, J d'Hulst, D Hanselman, K Sundar, T Hill, K Ludwig, D Nielson, M A Matthay, M Eisner, B Daniel, O Garcia, J Luce, R Kallet, M Peterson, J Lanford, K Guntupalli, V Bandi, C Pope, J Steingrub, M Tidswell, L Kozikowski, B deBoisblanc, J Hunt, C Glynn, P Lauto, G Meyaski, C Romaine, S Brierre, C LeBlanc, K Reed, D Taylor, C Thompson, F Simeone, M Johnston, M Wright, G Schmidt, J Hall, S Hemmann, B Gehlbach, Vinayak, W Schweickert, J Dematte D'Amico, H Donnelly, A Anzueto, J McCarthy, S Kucera, J Peters, T Houlihan, R Steward, D Vines, J Truwit, A F Connors, M Marshall, W Matsumura, R Brett, M Donahoe, P Linden, J Puyana, L Lucht, A Verno, R D Hite, P Morris, A Howard, A Nesser, S Perez, P Wright, C Carter-Cole, J McLean, J Russell, L Lazowski, K Foley, D Chittock, L Grandolfo, M Murray, Carolyn S Calfee, Diana Gallagher, Jason Abbott, B Taylor Thompson, Michael A Matthay, NHLBI ARDS Network, G R Bernard, D A Schoenfeld, B T Thompson, N Ringwood, C Oldmixon, F Molay, A Korpak, R Morse, D Hayden, M Ancukiewicz, A Minihan, J G N Garcia, R Balk, S Emerson, M Shasby, W Sibbald, R Spragg, G Corbie-Smith, J Kelley, K Leeper, A S Slutsky, B Turnbull, C Vreim, P Parsons, L Hudson, K Steinberg, M Neff, R Maier, K Sims, C Cooper, T Berry-Bell, G Carter, L Andersson, G B Toews, R H Bartlett, C Watts, R Hyzy, D Arnoldi, R Dechert, M Purple, H Silverman, C Shanholtz, A Moore, L Heinrich, W Corral, R Brower, D Thompson, H Fessler, S Murray, A Sculley, H P Wiedemann, A C Arroliga, J Komara, T Isabella, M Ferrari, J Kern, R Hejal, D Haney, A F Connors, E Abraham, R McIntyre, F Piedalue, C Welsh, I Douglas, R Wolkin, T Bost, B Sagel, A Hawkes, N MacIntyre, J Govert, W Fulkerson, L Mallatrat, L Brown, S Everett, E VanDyne, N Knudsen, M Gentile, P Rock, S Carson, C Schuler, L Baker, V Salo, A P Wheeler, G Bernard, T Rice, S Bozeman, T Welch, P Lanken, J Christie, B Fuchs, B Finkel, S Kaplan, V Gracias, C W Hanson, P Reilly, M B Shapiro, R Burke, E O'Connor, D Wolfe, J Gottlieb, P Park, D M Dillon, A Girod, J Furlong, A Morris, C Grissom, L Weaver, J Orme, T Clemmer, R Davis, J Gleed, S Pies, T Graydon, S Anderson, K Bennion, P Skinner, C Lawton, J d'Hulst, D Hanselman, K Sundar, T Hill, K Ludwig, D Nielson, M A Matthay, M Eisner, B Daniel, O Garcia, J Luce, R Kallet, M Peterson, J Lanford, K Guntupalli, V Bandi, C Pope, J Steingrub, M Tidswell, L Kozikowski, B deBoisblanc, J Hunt, C Glynn, P Lauto, G Meyaski, C Romaine, S Brierre, C LeBlanc, K Reed, D Taylor, C Thompson, F Simeone, M Johnston, M Wright, G Schmidt, J Hall, S Hemmann, B Gehlbach, Vinayak, W Schweickert, J Dematte D'Amico, H Donnelly, A Anzueto, J McCarthy, S Kucera, J Peters, T Houlihan, R Steward, D Vines, J Truwit, A F Connors, M Marshall, W Matsumura, R Brett, M Donahoe, P Linden, J Puyana, L Lucht, A Verno, R D Hite, P Morris, A Howard, A Nesser, S Perez, P Wright, C Carter-Cole, J McLean, J Russell, L Lazowski, K Foley, D Chittock, L Grandolfo, M Murray

Abstract

Background: Angiopoietin-2 is a proinflammatory mediator of endothelial injury in animal models, and increased plasma angiopoietin-2 levels are associated with poor outcomes in patients with sepsis-associated acute lung injury. Whether angiopoietin-2 levels are modified by treatment strategies in patients with acute lung injury is unknown.

Objectives: To determine whether plasma angiopoietin-2 levels are associated with clinical outcomes and affected by fluid management strategy in a broad cohort of patients with acute lung injury.

Design, setting, and participants: Plasma levels of angiopoietin-2 and von Willebrand factor (a traditional marker of endothelial injury) were measured in 931 subjects with acute lung injury enrolled in a randomized trial of fluid liberal vs. fluid conservative management.

Measurements and main results: The presence of infection (sepsis or pneumonia) as the primary acute lung injury risk factor significantly modified the relationship between baseline angiopoietin-2 levels and mortality (p = .01 for interaction). In noninfection-related acute lung injury, higher baseline angiopoietin-2 levels were strongly associated with increased mortality (odds ratio, 2.43 per 1-log increase in angiopoietin-2; 95% confidence interval, 1.57-3.75; p < .001). In infection-related acute lung injury, baseline angiopoietin-2 levels were similarly elevated in survivors and nonsurvivors; however, patients whose plasma angiopoietin-2 levels increased from day 0 to day 3 had more than double the odds of death compared with patients whose angiopoietin-2 levels declined over the same period of time (odds ratio, 2.29; 95% confidence interval, 1.54-3.43; p < .001). Fluid-conservative therapy led to a 15% greater decline in angiopoietin-2 levels from day 0 to day 3 (95% confidence interval, 4.6-24.8%; p = .006) compared with fluid-liberal therapy in patients with infection-related acute lung injury. In contrast, plasma levels of von Willebrand factor were significantly associated with mortality in both infection-related and noninfection-related acute lung injury and were not affected by fluid therapy.

Conclusions: Unlike von Willebrand factor, plasma angiopoietin-2 has differential prognostic value for mortality depending on the presence or absence of infection as an acute lung injury risk factor. Fluid conservative therapy preferentially lowers plasma angiopoietin-2 levels over time and thus may be beneficial in part by decreasing endothelial inflammation.

Conflict of interest statement

The remaining authors have not disclosed any potential conflicts of interest.

Figures

Figure 1
Figure 1
Median plasma angiopoietin-2 (A) and von Willebrand factor (vWF) antigen (B) levels stratified by clinical risk factor for acute lung injury. Plasma angiopoietin-2 levels differed significantly based on risk factor for acute lung injury (p = .0001); clinical risk groups that differed significantly after correction for multiple comparisons were sepsis, trauma, and other. Plasma vWF levels also differed significantly based on risk factor for acute lung injury (p = .0001); clinical risk groups that differed significantly after correction for multiple comparisons were sepsis, trauma, and aspiration. Box plots depict median and interquartile range.
Figure 2
Figure 2
Median and interquartile ranges of plasma angiopoietin-2 (Ang-2) levels stratified by the presence of infection-related acute lung injury in survivors and nonsurvivors.

References

    1. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–1349.
    1. Ochoa CD, Wu S, Stevens T. New developments in lung endothelial heterogeneity: Von Willebrand factor, P-selectin, and the Weibel-Palade body. Semin Thromb Hemost. 2010;36:301–308.
    1. Romani de Wit T, Rondaij MG, Hordijk PL, et al. Real-time imaging of the dynamics and secretory behavior of Weibel-Palade bodies. Arterioscler Thromb Vasc Biol. 2003;23:755–761.
    1. Rubin DB, Wiener-Kronish JP, Murray JF, et al. Elevated von Willebrand factor antigen is an early plasma predictor of acute lung injury in nonpulmonary sepsis syndrome. J Clin Invest. 1990;86:474–480.
    1. Flori HR, Ware LB, Milet M, et al. Early elevation of plasma von Willebrand factor antigen in pediatric acute lung injury is associated with an increased risk of death and prolonged mechanical ventilation. Pediatr Crit Care Med. 2007;8:96–101.
    1. Parikh SM, Mammoto T, Schultz A, et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med. 2006;3:e46.
    1. Roviezzo F, Tsigkos S, Kotanidou A, et al. Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage. J Pharmacol Exp Ther. 2005;314:738–744.
    1. Orfanos SE, Mavrommati I, Korovesi I, et al. Pulmonary endothelium in acute lung injury: From basic science to the critically ill. Intensive Care Med. 2004;30:1702–1714.
    1. Ricciuto DR, Dos Santos CC, Hawkes M, et al. Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med. 2011;39:702–710.
    1. Gallagher DC, Parikh SM, Balonov K, et al. Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome. Shock. 2008;29:656–661.
    1. Meyer NJ, Li M, Feng R, et al. ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio. Am J Respir Crit Care Med. 2011;183:1344–1353.
    1. Bhandari V, Choo-Wing R, Lee CG, et al. Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat Med. 2006;12:1286–1293.
    1. Wiedemann HP, Wheeler AP, et al. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354:2564–2575.
    1. Wheeler AP, Bernard GR, et al. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med. 2006;354:2213–2224.
    1. Kuebler WM, Ying X, Singh B, et al. Pressure is proinflammatory in lung venular capillaries. J Clin Invest. 1999;104:495–502.
    1. Knaus WA, Wagner DP, Draper EA, et al. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest. 1991;100:1619–1636.
    1. Eisner MD, Thompson T, Hudson LD, et al. Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;164:231–236.
    1. Vittinghoff E, Glidden D, Shiboski SC, et al. Regression Methods in Biostatistics: Linear, Logistic, Survival, and Repeated Measures Models. NewYork: Springer Science+Business Media; 2005.
    1. van der Heijden M, Pickkers P, van Nieuw Amerongen GP, et al. Circulating angiopoietin-2 levels in the course of septic shock: relation with fluid balance, pulmonary dysfunction and mortality. Intensive Care Med. 2009;35:1567–1574.
    1. van der Heijden M, van Nieuw Amerongen GP, Koolwijk P, et al. Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients. Thorax. 2008;63:903–909.
    1. Ong T, McClintock DE, Kallet RH, et al. Ratio of angiopoietin-2 to angiopoietin-1 as a predictor of mortality in acute lung injury patients. Crit Care Med. 2010;38:1845–1851.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다