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Randomized Clinical Trial of Activated Protein C for the Treatment of Acute Lung Injury

¹ Division of Nephrology and Critical Care Medicine, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, California; ² Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California; ³ Cardiovascular Research Institute, UCSF, San Francisco, California; ⁴ Division of Pulmonary and Critical Care Medicine, Baystate Medical Center, Springfield, Massachusetts; ⁵ Pulmonary and Critical Care Section, Yale University, New Haven, Connecticut; ⁶ Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, California; ⁷ Division of Pulmonary and Critical Care Medicine, UCSF Fresno, Fresno, California; ⁸ Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon; ⁹ Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and ¹⁰ Division of Occupational Medicine, Department of Medicine, and ¹¹ Departments of Anesthesia and Medicine and the Cardiovascular Research Institute, UCSF, San Francisco, California

Correspondence and requests for reprints should be addressed to Kathleen D. Liu, M.D., Ph.D., M.C.R., Division of Nephrology and Critical Care Medicine, Department of Medicine, Box 0532, University of California, San Francisco, San Francisco, CA 94143-0532. E-mail: kathleen.liu{at}ucsf.edu

Rationale: Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days.

Objectives: To test the efficacy of activated protein C (APC) as a therapy for patients with ALI.

Methods: Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 µg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days.

Measurements and Main Results: APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25–75% interquartile range]: 19 [0–24] vs. 19 [14–22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups.

Conclusions: APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.

Clinical trial registered with www.clinicaltrials.gov (NCT 00112164).

Key Words: acute respiratory distress syndrome • acute lung injury • activated protein C • ventilator-free days • mortality

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject There are no pharmacologic therapies that have been proven to be effective for the treatment of acute lung injury (ALI) and acute respiratory distress syndrome. It is unknown whether activated protein C would benefit patients with ALI. What This Study Adds to the Field We tested activated protein C as a treatment for ALI. Although plasma protein C levels increased and pulmonary dead space fraction decreased, there was no benefit with regard to ventilator-free days (primary study endpoint), mortality, or lung injury score.

 

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