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 inhibitor, given within the first 24 hrs after diagnosis and arrival in the intensive care unit (ICU) would decrease the frequency of adult respiratory distress syndrome in the septic patient population. Design: Prospective, randomized, double-blind, placeo-controlled study. Setting. Twelve-bed, surgical ICU in a university-affiliated hospital. Patients: Fifty-four consecutive patients admitted to the surgical ICU with the diagnosis of sepsis composed the study sample. Sepsis was defined 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-degrees-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 culture; d) known or strongly suspected source of infection from which a known pathogen was cultured. Interventions: Patients were randomized to receive either ketoconazole (400 mg) or placebo in a double-blind fashion as early as possible and in <24 hrs after surgical ICU admission or after the diagnosis of sepsis was established. Measurements and Main 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 signs of heart failure; and c) diffuse infiltrates on chest radiograph. Treatment resulted in significant (p = .002) reduction in the frequency of ARDS compared with the placebo group, 64% vs. 15% in the ketoconazole treated group. The mortality rate was also reduced from 39% in the placebo group to 15% in the ketoconazole group (p = .05). A statistically 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 mortality rate in high-risk, septic patients.