Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome - A randomized controlled trial

Context Three clinical studies have suggested that ketoconazole, a syntheti c imidazole with anti-inflammatory activity, may prevent the development of acute respiratory distress syndrome (ARDS) in critically ill patients. How ever, 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 mo rbidity in patients with ALI or ARDS. Design Randomized, double-blind, placebo-controlled trial conducted from Ma rch 1996 to January 1997. Setting Twenty-four hospitals associated with 10 network centers in the Uni ted States, constituting the ARDS Network. Patients A total of 234 patients with ALI or ARDS. Intervention Patients were randomly assigned to receive ketoconazole, 400 m g/d (n=117),or placebo (n=117), initiated within 36 hours of fulfilling stu dy entry criteria and given enterally for up to 21 days. Main Outcome Measures Primary outcome measures were the proportion of patie nts alive with unassisted breathing at hospital discharge and the number of days of unassisted breathing (ventilator-free days) during 28 days of foll ow-up. Secondary outcome measures included the proportion of patients achie ving unassisted breathing for 48 hours or more, the number of organ failure -free days, and changes in plasma interleukin 6 (IL-6) and urinary thrombox ane A(2) metabolites (thromboxane B-2 [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 o f 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 statisticall y significant differences in the n umber of organ failure-free days, pulmon ary physiology, or adverse events between treatment groups. The median seru m ketoconazole level was 1.25 mu g/mL and serum levels greater than 0.5 mu g/mL were detected in 96% of patients assayed. Plasma IL-6, urinary TXB2, a nd 11-dehydro-TXB2 levels were unaffected by ketoconazole. Conclusions In these patients with ALI or ARDS, ketoconazole was safe and b ioavailable but did not reduce mortality or duration of mechanical ventilat ion or improve lung function. These data do not support the use of ketocona zole,for the early treatment of ALI or ARDS.