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Levels of Evidence for the Pharmacologic Effectiveness of Prolonged Methylprednisolone Treatment in Unresolving ARDS*

G. Umberto Meduri, MD, FCCP
Author and Funding Information

*From the Memphis Lung Research Program, Baptist Memorial Hospitals; Veterans Affairs Medical Center; and the Department of Medicine, College of Medicine, University of Tennessee, Memphis, TN. Supported by the Baptist Memorial Health Care Foundation and by the University of Tennessee, Memphis, Clinical Research Center.

Correspondence to: G. Umberto Meduri, MD, FCCP, Professor of Medicine, University of Tennessee-Memphis, Division of Pulmonary and Critical Care Medicine, 956 Court Ave, Room H316, Memphis, TN 38163; e-mail: umeduri@utmem1.utmem.edu



Chest. 1999;116(suppl_1):116S-118S. doi:10.1378/chest.116.suppl_1.116S
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Extract

ARDS is a life-threatening disease of multifactorial etiology caused by a direct or indirect insult to the pulmonary lobules. We have tested a therapeutic intervention on a previously defined model of ARDS,1 in which the three fundamental elements of a disease process2—pathogenesis, structural alterations, and functional consequences—were described during the course of the disease. In this single “hit” model, degree and duration of the host defense response (HDR) determine the adaptive vs maladaptive evolution of the reparative process and final outcome. We have reported previously that patients with unresolving ARDS have biological and morphologic evidence of intense, protracted, and dysregulated pulmonary inflammatory and fibrotic activity. Over time, these patients have persistent and exaggerated elevation in plasma and BAL tumor necrosis factor-α, interleukins (IL)-1β, IL-6, IL-8,34 migration inhibitor factor,5 soluble intercellular adhesion molecule-1 (unpublished data, Thomas L. Petty Aspen Lung Conference, 41st Annual Meeting, Aspen, CO, June 3–6, 1998) and procollagen aminoterminal propeptide type I (PINP), and type III (PIIINP) levels.5 During the first week of ARDS, cytokine levels declined in all survivors, while levels remained persistently elevated in all nonsurvivors. Histologic findings of open lung biopsy specimens provided morphologic evidence of persistent activation of the HDR, including (1) new injury to the endothelial and epithelial surfaces of previously spared pulmonary lobules with associated intravascular coagulation and extravascular fibrin deposition and (2) progressive fibroproliferative obliteration of the previously involved lobules, with transformation of the initially fibrinous exudate into myxoid connective tissue matrix and eventually into dense acellular fibrous tissue.6


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