Randomized clinical trial of activated protein C for the treatment of acute lung injury.
BACKGROUND
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.


OBJECTIVE
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 microg/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.


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.
Division of Nephrology and Critical Care Medicine, Department of Medicine, Box 0532, University of California, San Francisco, San Francisco, CA 94143-0532, USA. kathleen.liu@ucsf.edu
Kathleen D
KD
Liu
Joseph
J
Levitt
Hanjing
H
Zhuo
Richard H
RH
Kallet
Sandra
S
Brady
Jay
J
Steingrub
Mark
M
Tidswell
Mark D
MD
Siegel
Graciela
G
Soto
Michael W
MW
Peterson
Mark S
MS
Chesnutt
Charles
C
Phillips
Ann
A
Weinacker
B Taylor
BT
Thompson
Mark D
MD
Eisner
Michael A
MA
Matthay
D018806:APACHE; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011486:Protein C / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D012121:Respiration, Artificial; D012126:Respiratory Dead Space; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D017211:Treatment Failure
D000925:Anticoagulants; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D011486:Protein C