Ketoconazole in the Prevention of Acute Respiratory Distress Syndrome

Abstract

Objective:

To describe the pharmacology of ketoconazole and examine the use of ketoconazole in critically ill surgical patients to prevent the development of acute respiratory distress syndrome (ARDS).

Data Source:

An English-language literature search from 1985 to 1994 using MEDLINE-identified relevant articles. Search terms were adult, acute respiratory distress syndrome, ketoconazole, thromboxane, and leukotrienes.

Study Selection:

Two randomized, controlled, double-blind studies were identified that examined the use of ketoconazole in critically ill surgical patients. In vitro and animal studies were included to describe the mechanism of ketoconazole on inhibition of leukotriene and thromboxane synthesis.

Data Extraction:

Studies were evaluated for study design, efficacy, and toxicity.

Data Synthesis:

Two randomized, placebo-controlled clinical trials have been conducted in critically ill surgical patients. One study demonstrated a 6% incidence of ARDS in patients receiving ketoconazole 200 mg/d (n = 35) versus 31% on placebo (n = 36) (p < 0.01). Another study demonstrated a 15% incidence of ARDS in patients receiving ketoconazole 400 mg/d (n = 26) versus 64% on placebo (n = 28) (p < 0.002), and showed a statistically significant decrease in mortality in the ketoconazole group (15%) versus placebo (39%) (p < 0.05). There were no reports of serious adverse events, and patients in both treatment and placebo groups were discontinued for increased liver enzyme concentrations.

Conclusions:

Two studies conducted at single sites using prophylactic ketoconazole therapy in dosages of 200–400 mg/d in a small population of critically ill surgical patients at risk for ARDS have demonstrated a significant decrease in the incidence of ARDS. There are no ongoing multicenter trials that would provide the power to measure the true difference between the groups and minimize the selection bias inherent in these studies.