A DOUBLE-BLIND, PROSPECTIVE, RANDOMIZED TRIAL OF KETOCONAZOLE, A THROMBOXANE SYNTHETASE INHIBITOR, IN THE PROPHYLAXIS OF THE ADULT-RESPIRATORY-DISTRESS-SYNDROME

Objective: To determine if ketoconazole, a thromboxane A2 synthetase i nhibitor, given within the first 24 hrs after diagnosis and arrival in the intensive care unit (ICU) would decrease the frequency of adult r espiratory distress syndrome in the septic patient population. Design: Prospective, randomized, double-blind, placeo-controlled study. Setti ng. Twelve-bed, surgical ICU in a university-affiliated hospital. Pati ents: Fifty-four consecutive patients admitted to the surgical ICU wit h the diagnosis of sepsis composed the study sample. Sepsis was define d as including two or more of the following signs in a patient with a systolic blood pressure of <80 mm Hg or a systemic vascular resistance of <800 dyne.sec/cm5: a) temperature greater-than-or-equal-to 39-degr ees-C or less-than-or-equal-to 35-degrees-C; b) white blood cell count of >12,000 leukocytes, or less-than-or-equal-to 4000 leukocytes/muL, or greater-than-or-equal-to 20% immature cells; c) positive blood cult ure; d) known or strongly suspected source of infection from which a k nown pathogen was cultured. Interventions: Patients were randomized to receive either ketoconazole (400 mg) or placebo in a double-blind fas hion as early as possible and in <24 hrs after surgical ICU admission or after the diagnosis of sepsis was established. Measurements and Mai n Results: Adult respiratory distress syndrome (ARDS) was diagnosed if the following criteria were met: a) intrapulmonary shunt of >20% or a PaO2/FIO2 ratio of <150 requiring ventilatory support for >48 hrs; b) pulmonary artery occlusion pressure of <18 mm Hg and no clinical sign s of heart failure; and c) diffuse infiltrates on chest radiograph. Tr eatment resulted in significant (p = .002) reduction in the frequency of ARDS compared with the placebo group, 64% vs. 15% in the ketoconazo le treated group. The mortality rate was also reduced from 39% in the placebo group to 15% in the ketoconazole group (p = .05). A statistica lly significant reduction in ventilator and ICU days was not achieved. Conclusions: Ketoconazole (400 mg through the gastrointestinal tract) given early in the septic course may prevent ARDS and decrease the mo rtality rate in high-risk, septic patients.