We measured cortisol levels in banked plasma specimens from critically ill surgical patients who participated in a randomized, double-blind, placebo-controlled trial of fluconazole for the prevention of candidiasis. In this population of critically ill patients, those randomized to fluconazole did not have significantly lower cortisol levels than those randomized to placebo, nor did they have significantly increased odds of adrenal dysfunction. To our knowledge, this is the largest study to date evaluating the impact of fluconazole on cortisol levels in critically ill patients.
Like its predecessor ketoconazole, fluconazole inhibits the fungal cytochrome P450 enzyme 14α-demethylase in the ergosterol biosynthetic pathway. Ketoconazole is a potent inhibitor in vitro and in vivo of mammalian cytochrome P450 enzymes, including 11β-hydroxylase, which converts 11-deoxycortisol to cortisol (26
). The effects of ketoconazole on steroid synthesis may occur after a single dose (33
The effects of fluconazole on steroid biosynthesis and metabolism have not been as well studied. Investigators examined the effects of ketoconazole and fluconazole on rat adrenal cells and found that the concentration of ketoconazole achieving 50% inhibition of corticosterone synthesis was 0.9 μM; 50% inhibition was not achieved with fluconazole concentrations as high as 100 μM (10
). To our knowledge, only a single study of the adrenal effects of fluconazole in critically ill patients has been published previously (29
). In this study, fluconazole had no effect on adrenocorticotropin (ACTH)-stimulated cortisol levels in 19 critically ill surgical patients (29
). The first case report that we are aware of describing a possible association between fluconazole and adrenal dysfunction was published in 1990 (16
); recently, two additional reports have appeared in the literature (1
Diagnostic guidelines for adrenal dysfunction in critically ill patients remain a subject of debate (4
). The normal response to the stress of surgery or severe illness is a marked initial increase in ACTH and basal cortisol levels. Because of this, it has been postulated that for critically ill patients, levels that are within the accepted normal range for healthy, non-critically ill individuals may be inappropriately low (20
). Investigators have used random cortisol levels as well as high-dose (250 μg) and low-dose (1 μg) ACTH stimulation testing (28
) to diagnose adrenal dysfunction in critically ill patients. We were not able to perform ACTH stimulation testing, nor were we able to confirm a laboratory diagnosis of adrenal dysfunction with a clinical response to a trial of corticosteroid therapy. The use of ACTH stimulation testing to diagnose adrenal dysfunction in critically ill patients is controversial (7
). Because critical illness itself may result in maximal adrenal stimulation, such testing may reveal little about the sufficiency of the adrenal response (28
Approximately 45% of patients in our study had adrenal dysfunction, which we defined as an MPCL of less than 15 μg/dl. A recent publication has supported the use of this threshold value (7
). The prevalence in our study was similar to that reported by Rydvall and colleagues, who measured morning plasma cortisol levels in 55 general ICU patients (36
). They found that 36% of patients had plasma cortisol levels of <14.5 μg/dl and 47% had levels of <18.1 μg/dl (36
). By contrast, Barquist and Kirton studied surgical ICU patients with vasopressor-dependent hypotension and an unexplained systemic inflammatory response syndrome, 2 weeks of vasopressor dependency, or ≥2 failed attempts at weaning from mechanical ventilation (3
). They defined adrenal dysfunction as a baseline cortisol level of <15 μg/dl or a 30-min post-ACTH stimulation level of ≤25 μg/dl if the baseline level was between 15 and 20 μg/dl (3
). Less than 1% of all patients met this definition. Among patients hospitalized in the ICU for more than 14 days 6% had adrenal dysfunction, and among patients hospitalized for more than 14 days and over age 55, 11% had adrenal dysfunction (3
Unlike the findings of Barquist and Kirton (3
), neither age nor ICU length of stay was significantly associated with adrenal dysfunction in our study. In fact, none of the demographic or clinical variables included in our multivariate regression analyses were significantly associated with adrenal dysfunction. Mortality was also not significantly different in patients with adrenal dysfunction, compared to those without adrenal dysfunction, although this study had insufficient power to detect differences as small as those observed. Additional studies are needed to determine factors that identify critically ill patients at highest risk for adrenal dysfunction.
This study was not large enough to detect small differences in cortisol levels between patients randomized to fluconazole and those randomized to placebo. We cannot exclude the possibility that fluconazole may cause low-level adrenal suppression, or even clinically significant adrenal dysfunction in individual patients. However, based on our multiple analyses, the results of this study suggest that fluconazole prophylaxis does not contribute to widespread adrenal dysfunction in critically ill surgical patients who are not receiving daily steroid therapy. To minimize the confounding effects of exogenous steroid administration, we excluded those samples drawn less than 2 days after steroid administration. We did not have cortisol data available from patients after ICU discharge and fluconazole discontinuation to explore the impact of fluconazole discontinuation on the metabolism of exogenous steroids and adrenal function. A case report has described a liver transplant patient on prednisone therapy who developed Addisonian crisis after fluconazole was discontinued (42
), presumably due to increased prednisone metabolism following the reversal of P450 enzyme suppression by fluconazole (42
). Itraconazole, another triazole, has been shown to decrease the clearance of methylprednisolone and prolong methylprednisolone's inhibition of adrenal steroid synthesis (21
), although it does not itself appear to cause adrenal dysfunction (32
). Fluconazole (and newer triazoles) may exert the same effects, given its similar structure and mechanism of action. Further studies are needed to determine the effect of fluconazole and the new triazoles on the pharmacokinetics of exogenously administered steroid compounds and whether critically ill patients receiving both triazole antifungal and steroid therapy are at increased risk for adrenal dysfunction after the triazole is discontinued.
In conclusion, randomization to fluconazole was not associated with significantly lower cortisol levels than randomization to placebo. Fluconazole prophylaxis in this group of critically ill surgical patients was not associated with significant adrenal dysfunction.