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Original Research: CRITICAL CARE MEDICINE |

Prognostic and Pathogenetic Value of Combining Clinical and Biochemical Indices in Patients With Acute Lung Injury

Lorraine B. Ware, MD, FCCP; Tatsuki Koyama, PhD; D. Dean Billheimer, PhD; William Wu, PhD; Gordon R. Bernard, MD, FCCP; B. Taylor Thompson, MD; Roy G. Brower, MD; Theodore J. Standiford, MD; Thomas R. Martin, MD; Michael A. Matthay, MD, FCCP; the NHLBI ARDS Clinical Trials Network*; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction
Author and Funding Information

From the Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine (Drs Ware and Bernard), and the Department of Biostatistics (Drs Koyama and Wu), Vanderbilt University School of Medicine, Nashville, TN; the Department of Agricultural and Biosystems Engineering, and Arizona Statistics Consulting Laboratory (Dr Billheimer), University of Arizona, Tucson, AZ; Pulmonary and Critical Care Medicine (Dr Thompson), Massachusetts General Hospital, Boston, MA; Pulmonary and Critical Care Medicine (Dr Brower), Johns Hopkins Hospital, Baltimore, MD; Pulmonary and Critical Care Medicine (Dr Standiford), University of Michigan, Ann Arbor, MI; Pulmonary and Critical Care Medicine (Dr Martin), University of Washington and Medical Service, VA Puget Sound Healthcare System, Seattle, WA; and the Cardiovascular Research Institute and Departments of Medicine and Anesthesia (Dr Matthay), University of California, San Francisco, CA.

Correspondence to: Lorraine B. Ware, MD, FCCP, Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, T1218 MCN, 1161 21st Ave S, Nashville, TN 37232-2650; e-mail: lorraine.ware@vanderbilt.edu

A complete list of study participants is located in the Appendix.


Funding/Support: This study was supported by the National Institutes of Health [Grants HL81332, HR46059, HL74005, HL73996, HL74024, HL73994].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;137(2):288-296. doi:10.1378/chest.09-1484
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Background:  No single clinical or biologic marker reliably predicts clinical outcomes in acute lung injury (ALI)/ARDS. We hypothesized that a combination of biologic and clinical markers would be superior to either biomarkers or clinical factors alone in predicting ALI/ARDS mortality and would provide insight into the pathogenesis of clinical ALI/ARDS.

Methods:  Eight biologic markers that reflect endothelial and epithelial injury, inflammation, and coagulation (von Willebrand factor antigen, surfactant protein D [SP-D]), tumor necrosis factor receptor-1, interleukin [IL]-6, IL-8, intercellular adhesion molecule-1, protein C, plasminogen activator inhibitor-1) were measured in baseline plasma from 549 patients in the ARDSNet trial of low vs high positive end-expiratory pressure. Mortality was modeled with multivariable logistic regression. Predictors were selected using backward elimination. Comparisons between candidate models were based on the receiver operating characteristics (ROC) and tests of integrated discrimination improvement.

Results:  Clinical predictors (Acute Physiology And Chronic Health Evaluation III [APACHE III], organ failures, age, underlying cause, alveolar-arterial oxygen gradient, plateau pressure) predicted mortality with an area under the ROC curve (AUC) of 0.82; a combination of eight biomarkers and the clinical predictors had an AUC of 0.85. The best performing biomarkers were the neutrophil chemotactic factor, IL-8, and SP-D, a product of alveolar type 2 cells, supporting the concept that acute inflammation and alveolar epithelial injury are important pathogenetic pathways in human ALI/ARDS.

Conclusions:  A combination of biomarkers and clinical predictors is superior to clinical predictors or biomarkers alone for predicting mortality in ALI/ARDS and may be useful for stratifying patients in clinical trials. From a pathogenesis perspective, the degree of acute inflammation and alveolar epithelial injury are highly associated with the outcome of human ALI/ARDS.

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