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.
Liu
Kathleen D
KD
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
Levitt
Joseph
J
Zhuo
Hanjing
H
Kallet
Richard H
RH
Brady
Sandra
S
Steingrub
Jay
J
Tidswell
Mark
M
Siegel
Mark D
MD
Soto
Graciela
G
Peterson
Michael W
MW
Chesnutt
Mark S
MS
Phillips
Charles
C
Weinacker
Ann
A
Thompson
B Taylor
BT
Eisner
Mark D
MD
Matthay
Michael A
MA
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