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

Calfee, Carolyn S. MD, MAS; Gallagher, Diana MD, MMSc; Abbott, Jason BS; Thompson, B. Taylor MD; Matthay, Michael A. MD

doi: 10.1097/CCM.0b013e3182451c87
Clinical Investigations

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.

From the Department of Medicine (CSC, MAM), Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA; Cardiovascular Research Institute (CSC, JA, MAM), San Francisco, CA; Department of Anesthesia (CSC, MAM), University of California San Francisco, San Francisco, CA; Department of Medicine (DG), Division of Pulmonary, Critical Care and Sleep, Beth Israel Deaconess Medical Center Boston, MA; Department of Medicine (BTT), Pulmonary and Critical Care Medicine Unit, Massachusetts General Hospital, Boston, MA; Biostatistics Unit (BTT), Massachusetts General Hospital, Boston, MA.

*See also p. 1966.

Supported, in part, by contracts (NO1-HR 46046-64 and NO1-HR-16146-54) with the National Heart, Lung, and Blood Institute (NHLBI). Dr. Calfee was supported by HL090833, by the Flight Attendant Medical Research Institute, and by KL2RR024130 from the NCRR, a component of the NIH. Dr. Matthay was supported by HL 51856.

Drs. Calfee and Gallagher contributed equally to this work.

Dr. Calfee consulted for GlaxoSmithKline and Ikaria. D. Gallagher has worked at Merck Research Labs in December 2010 (after all the work on the manuscript was complete). The remaining authors have not disclosed any potential conflicts of interest.

The following persons and institutions participated in the FACTT trial:

Steering Committee Chair: G.R. Bernard; Clinical Coordinating Center: D.A. Schoenfeld, B.T. Thompson, N. Ringwood, C. Oldmixon, F. Molay, A. Korpak, R. Morse, D. Hayden, M. Ancukiewicz, A. Minihan; Protocol-Review Committee—J.G.N. Garcia, R. Balk, S. Emerson, M. Shasby, W.Sibbald; Data Safety and Monitoring Board: R. Spragg, G. Corbie-Smith, J. Kelley, K. Leeper, A.S. Slutsky, B. Turnbull, C. Vreim; ARDS Clinical Trials Network Consultant: P. Parsons; Clinical Centers are as follows: University of Washington, Harborview: L. Hudson, K. Steinberg, M. Neff, R. Maier, K. Sims, C. Cooper, T. Berry-Bell, G. Carter, L. Andersson; University of Michigan: G.B. Toews, R.H. Bartlett, C. Watts, R. Hyzy, D. Arnoldi, R. Dechert, M. Purple; University of Maryland: H. Silverman, C. Shanholtz, A. Moore, L. Heinrich, W. Corral; Johns Hopkins University: R. Brower, D. Thompson, H. Fessler, S. Murray, A. Sculley; Cleveland Clinic Foundation: H.P. Wiedemann, A.C. Arroliga, J. Komara, T. Isabella, M. Ferrari; University Hospitals of Cleveland: J. Kern, R. Hejal, D. Haney; MetroHealth Medical Center: A.F. Connors; University of Colorado Health Sciences Center: E. Abraham, R. McIntyre, F. Piedalue; Denver Veterans Affairs Medical Center: C. Welsh; Denver Health Medical Center: I. Douglas, R. Wolkin; St. Anthony Hospital: T. Bost, B. Sagel, A. Hawkes; Duke University: N. MacIntyre, J. Govert, W. Fulkerson, L. Mallatrat, L. Brown, S. Everett, E. VanDyne, N. Knudsen, M. Gentile; University of North Carolina: P. Rock, S. Carson, C. Schuler, L. Baker, V. Salo; Vanderbilt Universit: A.P. Wheeler, G. Bernard, T. Rice, S. Bozeman, T. Welch; University of Pennsylvania: 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; Jefferson Medical College: J. Gottlieb, P. Park, D.M. Dillon, A. Girod, J. Furlong; LDS Hospital: A. Morris, C. Grissom, L. Weaver, J. Orme, T. Clemmer, R. Davis, J. Gleed, S. Pies, T. Graydon, S. Anderson, K. Bennion, P. Skinner; McKay-Dee Hospital: C. Lawton, J. d’Hulst, D. Hanselman; Utah Valley Regional Medical Center: K. Sundar, T. Hill, K. Ludwig, D. Nielson; University of California, San Francisco: M.A. Matthay, M. Eisner, B. Daniel, O. Garcia; San Francisco General: J. Luce, R. Kallet; University of California, San Francisco, Fresno: M. Peterson, J. Lanford; Baylor College of Medicine: K. Guntupalli, V. Bandi, C. Pope; Baystate Medical Center: J. Steingrub, M. Tidswell, L. Kozikowski; Louisiana State University Health Sciences Center: B. deBoisblanc, J. Hunt, C. Glynn, P. Lauto, G. Meyaski, C. Romaine; Louisiana State University Earl K. Long Center: S. Brierre, C. LeBlanc, K. Reed; Alton-Ochsner Clinic Foundation: D. Taylor, C. Thompson; Tulane University Medical Center: F. Simeone, M. Johnston, M. Wright; University of Chicago: G. Schmidt, J. Hall, S. Hemmann, B. Gehlbach, Vinayak, W. Schweickert; Northwestern University: J. Dematte D’Amico, H. Donnelly; University of Texas Health Sciences Center: A. Anzueto, J. McCarthy, S. Kucera, J. Peters, T. Houlihan, R. Steward, D. Vines; University of Virginia: J. Truwit, A.F. Connors, M. Marshall, W. Matsumura, R. Brett; University of Pittsburgh: M. Donahoe, P. Linden, J. Puyana, L. Lucht, A. Verno; Wake Forest University: R.D. Hite, P. Morris, A. Howard, A. Nesser, S. Perez; Moses Cone Memorial Hospital: P. Wright, C. Carter-Cole, J. McLean; St. Paul’s Hospital, Vancouver: J. Russell, L. Lazowski, K. Foley; Vancouver General Hospital: D. Chittock, L. Grandolfo; Mayo Foundation: M. Murray.

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© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins