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Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome

The ARDS Clinical Trials Network;; National Heart, Lung, and Blood Institute;; National Institutes of Health

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Objective: To determine whether the administration of lisofylline (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) would decrease mortality in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS).

Design: A prospective, randomized, double-blind, placebo-controlled, multicenter study.

Setting: Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network.

Patients: A total of 235 patients who met eligibility criteria were enrolled in the study (116 into the lisofylline group, 119 into the placebo group).

Interventions: Patients were randomized to receive either lisofylline or placebo. The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs. The intravenous solution of study drug was administered over 10 mins every 6 hrs. Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing.

Measurements and Main Results: The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis. The patient groups had similar characteristics at enrollment. No significant safety concerns were associated with lisofylline therapy. There was no significant difference between groups in the number of patients who had died at 28 days (31.9% lisofylline vs. 24.7% placebo, p = .215). There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures, ventilator-free days, infection-related deaths, or development of serious infection during the 28-day study period. The median number of organ failure–free days for the five nonpulmonary organ failures examined (cardiovascular, central nervous system, coagulation, hepatic, and renal) was not different between the lisofylline and placebo groups. Although lisofylline has been reported to decrease circulating free fatty acid levels, we did not find any such treatment effect compared with placebo.

Conclusions: In this study, there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS.

Network Participants: Cleveland Clinic Foundation—Herbert P. Wiedemann, MD*†, Alejandro C. Arroliga, MD†, John Komara, BA, RRT; Denver VA Medical Center—Carolyn Welsh, MD†; Duke University Medical Center—William J. Fulkerson Jr, MD*†, Neil MacIntyre, MD†, Lee Mallatratt, RN, Mark Sebastian, MD†, Robert Sladen, MD†, Carroll Wilcox, RN; Johns Hopkins University—Roy G. Brower, MD†, David Thompson, MS, RN; LDS Hospital—Alan H. Morris, MD*†, Terry Clemmer, MD†, Robin Davis, RRT, James Orme Jr, MD†; McKay-Dee Hospital—Charles B. Lawton, MD†, Janice d'Hulst, RRT; MetroHealth Medical Center—Carolyn Smith, RN; Thomas Jefferson University Hospital—Jonathan Gottlieb, MD†, Aimee Girod, RN; University of California, San Francisco—Michael A. Matthay, MD*†, Brian Daniel, RCP, RRT, Richard Kallet, MS, RRT, John M. Luce, MD†, Michael A. Gryzner, MD, PhD; University of Colorado Health Sciences Center—Edward Abraham, MD*†, Fran Piedalue, RRT, Dawn Kalous, RN, Christine Walberg, RN, John Lockrem, MD†, Robert McIntyre, MD†, Polly Parsons, MD†, Chris Stevens, RN; University of Maryland—Henry J. Silverman, MD*†, Wanda Corral, BSN, RN; University of Michigan—Galen B. Toews, MD*†, Deborah Arnoldi, MHSA, Robert H. Bartlett, MD†, Ron Dechert, RRT, Charles Watts, MD†; University of Pennsylvania—Paul N. Lanken, MD*†, Harry Anderson III, MD†, Barbara Finkel, MSN, RN, C. William Hanson, MD†; University of Washington/Harborview Medical Center—Leonard D. Hudson, MD*†, Claudette Lee, BS, RN, Ronald V. Maier, MD†, Kenneth P. Steinberg, MD†; Vanderbilt University—Arthur P. Wheeler, MD*†, Gordon Bernard, MD*†, Chair, Libby Stone, RN. Clinical Coordinating Center: Massachusetts General Hospital, Harvard Medical School—David A. Schoenfeld, PhD*†, B. Taylor Thompson, MD†, Marek Ancukiewicz, PhD, Douglas Hayden, MA, Francine Molay, MSW, Nancy Ringwood, BSN, RN, Gail Wenzlow, MSW, MPH. *Steering Committee: Gordon R. Bernard, MD, Chair, principal investigator from each center, as indicated by an asterisk above. National Heart, Lung, and Blood Institute Staff: Dorothy B. Gail, PhD†, Carol H. Bosken, MD†, Andrea Harabin, MD†, Pamela Randall, Myron Waclawiw, PhD. CTI: Carolyn Paradise, MD†, Steven Dahlberg, MA†. Data and Safety Monitoring Board: Roger G. Spragg, MD, Chair, James M. Boyett, PhD, Jason Kelley, MD, Kenneth Leeper, MD, Marion Gray Secundy, PhD, Arthur S. Slutsky, MD. Protocol Review Committee: Thomas M. Hyers, MD, Chair, Scott S. Emerson, MD, PhD, Joe G.N. Garcia, MD, Susan K Pingleton, MD, Michael D. Shasby, MD, William J. Sibbald, MD. Writing Committee: Edward Abraham, MD, Chair, Polly Parsons, MD, Michael Matthay, MD, Kenneth P. Steinberg, MD. †ARDS Network Investigator responsible for the content of this manuscript.

Supported, in part, by National Institutes of Health/National Heart, Lung, and Blood Institute ARDS Contract (NO1-HR 46054-64) and CTI.

Address requests for reprints to: Edward Abraham, MD, Division of Pulmonary Sciences and Critical Care Medicine, Box C272, University of Colorado Health Sciences Center, 4200 E. Ninth Avenue, Denver, CO 80262. E-mail: edward.abraham@uchsc.edu

© 2002 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins