Published ahead of print on June 19, 2008, doi:10.1164/rccm.200803-419OC
Am. J. Respir. Crit. Care Med., Volume 178, Number 6, September 2008, 618-623
A more recent version of this article appeared on September 15, 2008
Submitted on March 14, 2008
Accepted on June 19, 2008
Randomized Clinical Trial of Activated Protein C for the Treatment of Acute Lung Injury
Kathleen D Liu1*, Joseph Levitt2, Hanjing Zhuo3, Richard H Kallet3, Sandra Brady3, Jay Steingrub4, Mark Tidswell4, Mark D Siegel5, Graciela Soto6, Michael W Peterson7, Mark S Chesnutt8, Charles Phillips8, Ann Weinacker2, B. Taylor Thompson9, Mark D Eisner10, and Michael A Matthay11
1 Division of Nephrology and Critical Care Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA,
2 Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA, USA,
3 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA,
4 Division of Pulmonary and Critical Care Medicine, Baystate Medical Center, Springfield, MA, USA,
5 Pulmonary and Critical Care Section, Yale University, New Haven, CT, USA,
6 Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, CA, USA,
7 Division of Pulmonary and Critical Care Medicine, UCSF Fresno, Fresno, CA, USA,
8 Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR, USA,
9 Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA,
10 Division of Occupational Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA,
11 Departments of Anesthesia and Medicine and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA
* To whom correspondence should be addressed. E-mail: kathleen.liu{at}ucsf.edu.
Rationale: Microvascular injury, inflammation and coagulation play critical roles in the pathogenesis of acute lung injury. Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator free days.
Objective: To test the efficacy of activated protein C as a therapy for patients with acute lung injury.
Methods: Eligible subjects were critically ill patients who met the American/European consensus criteria for acute lung injury. Patients with severe sepsis and an APACHE II
score  25 were excluded. Participants were randomized to receive activated protein C (24 mcg/kg/hour for 96 hours) or placebo in a double-blind fashion within 72 hours of the onset of acute lung injury. The primary endpoint was ventilator free days.
Measurements and Main Results: Activated protein C 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 activated protein C (n=37) in the number of ventilator free days (median [25,75%] interquartile range): 19 [0,24] days versus 19 [14,22] respectively, p = 0.78, or in 60-day mortality (5/38 versus 5/37 respectively, p=1.0). There were no differences in the number of bleeding events between the two groups.
Conclusions: Activated protein C did not improve outcomes from acute lung injury. The results of this trial do not support a large clinical trial of activated protein C for acute lung injury in the absence of severe sepsis and high disease severity.
Clinical Trials Registry Information: ID#NCT00112164 registered at www.clinicaltrials.gov
Key words: Acute respiratory distress syndrome, acute lung injury, activated protein C, respiratory failure, ventilator free days
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