Interaction between fluconazole and midazolam in intensive care patients

Background: Midazolam is used for sedation of intensive care unit (ICU) pat ients and it is extensively metabolised by CYP3A4 enzymes. The antimycotic fluconazole is often used in these patients as well and has been shown to i nhibit CYP3A4-mediated drug metabolism. Methods: In a study of the effect of fluconazole on midazolam in the ICU, t en mechanically ventilated patients (age 29 to 61 years, 8 male) sedated wi th a stable midazolam infusion were enrolled after a decision to start fluc onazole treatment. Fluconazole was infused for 30 min at intervals of 24 h, with an initial dose of 400 mg and following doses of 200 mg. The midazola m infusion rate remained unchanged during the study period of 48 h. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and alpha-hydroxymidaz olam conjugate were determined at baseline, and at 6, 12, 18, 24, 36, and a t 48 h thereafter. Results: Concentrations of midazolam were significantly increased (range 0 to 4-fold, P<0.05) after start of fluconazole treatment. These increases we re most marked in patients with renal failure. During the study period, the ratio of alpha-hydroxymidazolam to midazolam decreased progressively (P<0. 05). Conclusion: In ICU patients receiving fluconazole, reduction of midazolam i nfusion rate should be considered if the degree of sedation is found to be increasing.