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On the Randomized Trial of Activated Protein C in Acute Lung Injury

We thank Drs. Guérin and Richard for their questions and comments about the article reporting on our randomized clinical trial of activated protein C in acute lung injury (1). With regard to the timing of administration of activated protein C, patients met criteria for acute lung injury 27.8 ± 18.4 hours prior to receiving the study drug. We agree that if activated protein C were efficacious for the treatment of acute lung injury in this population, it should be administered when the lung coagulation pathway is "fully" altered for maximum benefit. Thus, our study focused on a population of patients with early acute lung injury, and indeed there was evidence of abnormal coagulation at the time of initiation of therapy, based on the abnormal protein C and plasminogen-activator inhibitor-1 levels (1). We note that our results are similar to the experimental results of Looney and colleagues (2), where administration of activated protein C to mice with hyperoxia-induced acute lung injury did not prevent lung injury or treat established lung injury.

We agree that there was a trend toward more severe lung injury in the activated protein C (APC)–treated group. We acknowledged in our article (1) that a type II error is always possible in a phase II trial. Nonetheless, based on the low mortality rate of this population with acute lung injury (overall mortality rate of 13.3%), we do not believe that a large, phase III clinical trial, powered to detect a difference in mortality, is feasible or warranted.

As in the ARDS Network clinical trials, the ventilator rate was set to maintain a pH of 7.30 to 7.45 (3). The set respiratory rate was 22 ± 7 breaths per minute in the placebo group and 24 ± 6 breaths per minute in the APC-treated group at baseline (P = 0.34); the Pa_CO2 was 40 ± 9 and 42 ± 11 mm Hg, respectively (P = 0.41). Neither the set respiratory rate nor the Pa_CO2 changed significantly in either the placebo or APC-treated groups over the first 4 days of the study.

Kathleen D. Liu, Hanjing Zhuo and Michael A. Matthay

University of California, San Francisco
San Francisco, California

FOOTNOTES

Conflict of Interest Statement: K.D.L. owned shares in Eli Lilly until 2006. H.Z. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.A.M. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. Liu KD, Levitt J, Zhuo H, Kallet RH, Brady S, Steingrub J, Tidswell M, Siegel MD, Soto G, Peterson MW, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med 2008;178:618–623.[Abstract/Free Full Text]
2. Looney MR, Esmon CT, Matthay MA. The role of coagulation pathways and treatment with activated proteinC in hyperoxic lung injury. Thorax (In Press).
3. Brower RG, Shanholtz CB, Fessler HE, Shade DM, White P Jr, Wiener CM, Teeter JG, Dodd-o JM, Almog Y, Piantadosi S. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 1999;27:s1492–s1498.

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