A DOUBLE-BLIND, PROSPECTIVE, RANDOMIZED TRIAL OF KETOCONAZOLE, A THROMBOXANE SYNTHETASE INHIBITOR, IN THE PROPHYLAXIS OF THE ADULT-RESPIRATORY-DISTRESS-SYNDROME
Mh. Yu et G. Tomasa, A DOUBLE-BLIND, PROSPECTIVE, RANDOMIZED TRIAL OF KETOCONAZOLE, A THROMBOXANE SYNTHETASE INHIBITOR, IN THE PROPHYLAXIS OF THE ADULT-RESPIRATORY-DISTRESS-SYNDROME, Critical care medicine, 21(11), 1993, pp. 1635-1642
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.