Ketoconazole for the prevention of ARDS: review of the literature and novel hypothesis

Introduction

Ketoconazole has been shown in several clinical trials to reduce the risk of developing ARDS in populations at risk. Despite the clinical trials, its use remains limited.

Methods

Literature review and synthesis.

Results

Two small randomized controlled trials found that Ketoconazole prevents the development of ARDS in mixed and septic surgical ICU populations [1, 2]. A third study examined the effect of a guideline implementation for the use of Ketoconazole to prevent ARDS and found that postguideline implementation rates of ARDS were significantly lower than both historical rates and rates in another hospital that did not implement the guideline [3]. A historical case control study of Ketoconazole for prevention of ARDS post-esophagectomy also found a significant reduction [4]. The ARDSNet trial examined the use of Ketoconazole in a prospective design and found no difference in ARDS rates [5]. However, the majority (77%) of patients enrolled in the trial had established ARDS (defined by PaO₂/FiO₂ ratio < 200). Ketoconazole has been shown to reduce a number of mediators involved in the development of acute lung injury and may therefore prevent ARDS if given prior to the onset of severe ALI. The mechanism may involve modulation of the cytochrome p450 enzyme system. Various cytochrome p450 isozymes have been shown to be involved in the inflammatory response that underlies acute lung injury.

Discussion

The ARDSNet trial has had a negative impact on the use of Ketoconazole for prevention of ARDS despite the stated objective of the trial to examine the role of Ketoconazole in treatment of early ARDS rather than prevention of ARDS. The use of Ketoconazole has been further hampered by the lack of a plausible biological mechanism.

Conclusions

An adequately powered randomized controlled trial is needed to assess the role of Ketoconazole in preventing ARDS.