Context: Three clinical studies have suggested that ketoconazole, a synthetic imidazole with anti-inflammatory activity, may prevent the development of acute respiratory distress syndrome (ARDS) in critically ill patients. However, the use of ketoconazole as treatment for acute lung injury (ALI) and ARDS has not been previously studied.

Objective: To test the efficacy of ketoconazole in reducing mortality and morbidity in patients with ALI or ARDS.

Design: Randomized, double-blind, placebo-controlled trial conducted from March 1996 to January 1997.

Setting: Twenty-four hospitals associated with 10 network centers in the United States, constituting the ARDS Network.

Patients: A total of 234 patients with ALI or ARDS.

Intervention: Patients were randomly assigned to receive ketoconazole, 400 mg/d (n = 117), or placebo (n = 117), initiated within 36 hours of fulfilling study entry criteria and given enterally for up to 21 days.

Main outcome measures: Primary outcome measures were the proportion of patients alive with unassisted breathing at hospital discharge and the number of days of unassisted breathing (ventilator-free days) during 28 days of follow-up. Secondary outcome measures included the proportion of patients achieving unassisted breathing for 48 hours or more, the number of organ failure-free days, and changes in plasma interleukin 6 (IL-6) and urinary thromboxane A2 metabolites (thromboxane B2 [TXB2] and 11-dehydro-TXB2).

Results: In-hospital mortality (SE) was 34.1% (4.3%) for the placebo group and 35.2% (4.3%) for the ketoconazole group (P=.85). The median number of ventilator-free days within 28 days of randomization was 9 in the placebo group and 10 in the ketoconazole group (P=.89). There were no statistically significant differences in the number of organ failure-free days, pulmonary physiology, or adverse events between treatment groups. The median serum ketoconazole level was 1.25 microg/mL and serum levels greater than 0.5 microg/mL were detected in 96% of patients assayed. Plasma IL-6, urinary TXB2, and 11-dehydro-TXB2 levels were unaffected by ketoconazole.

Conclusions: In these patients with ALI or ARDS, ketoconazole was safe and bioavailable but did not reduce mortality or duration of mechanical ventilation or improve lung function. These data do not support the use of ketoconazole for the early treatment of ALI or ARDS.