The effect of ketoconazole on post-burn inflammation, hypermetabolism and clinical outcomes

Abstract

Background: Hypercortisolemia has been suggested as a primary hormonal mediator of whole-body catabolism following severe burn injury. Ketoconazole, an anti-fungal agent, inhibits cortisol synthesis. We, therefore, studied the effect of ketoconazole on post-burn cortisol levels and the hyper-catabolic response in a prospective randomized trial (block randomization 2:1).

Methodology/principal findings: Fifty-five severely burned pediatric patients with >30% total body surface area (TBSA) burns were enrolled in this trial. Patients were randomized to receive standard care plus either placebo (controls, n = 38) or ketoconazole (n = 23). Demographics, clinical data, serum hormone levels, serum cytokine expression profiles, organ function, hypermetabolism measures, muscle protein synthesis, incidence of wound infection sepsis, and body composition were obtained throughout the acute hospital course. Statistical analysis was performed using Fisher's exact test, Student's t-test, and parametric and non-parametric two-way repeated measures analysis of variance where applicable. Patients were similar in demographics, age, and TBSA burned. Ketoconazole effectively blocked cortisol production, as indicated by normalization of the 8-fold elevation in urine cortisol levels [F(1, 376) = 85.34, p<.001] with the initiation of treatment. However, there were no significant differences in the inflammatory response, acute-phase proteins, body composition, muscle protein breakdown or synthesis, or organ function between groups.

Conclusions: Both groups were markedly hypermetabolic and catabolic throughout the acute hospital stay. Normalization of hypercortisolemia with ketoconazole therapy had no effect on whole-body catabolism or the post-burn inflammatory or hypermetabolic response, suggesting that hypercortisolemia does not play a central role in the post-burn hypermetabolic catabolic response.

Trial registration: ClinicalTrials.gov NCT00675714; and NCT00673309.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Consort Diagram.

Figure 2. Ketoconazole administration reduces urinary cortisol levels.

Data are presented as mean ± SEM. *Significant difference for control vs. ketoconazole at corresponding time point, p<.05. There were no significant differences between control and ketoconazole-treated patients before ketoconazole treatment. Ketoconazole therapy was initiated by the first week post burn. Urinary cortisol approached normal values in ketoconazole-treated patients and was significantly decreased during therapy.

Figure 3. Nor-epinephrine levels are not altered by ketoconazole administration.

Data are presented as mean ± SEM. Norepinephrine was significantly elevated post-burn compared to normal values (p<0.05).

Figure 4. Ketoconazole administration does not alter hypermetabolism or catabolism.

Data are presented as mean ± SEM. A, Resting energy expenditure was significantly higher in control and ketoconazole-treated patients than in non-burned volunteers. There were no significant differences between control and ketoconazole-treated patients. B, Changes in net protein balance induced by burn injury, or more specifically changes in muscle protein synthesis and breakdown, were measured by stable isotope studies using d5-phenyalanine infusion. Black bars indicate week one post burn and white bars week three post burn. There were no significant differences between groups. Both groups were catabolic during the study period. C, There was severe whole-body catabolism post burn. There were no significant differences between groups.