Journal Article

The Effect of Ketoconazole on Post-Burn Inflammation, Hypermetabolism and Clinical Outcomes

Kraft, Robert, Herndon, David N., Jeschke, Marc G., Kulp, Gabriela A., Ferrando, Arny, Branski, Ludwik K., Finnerty, Celeste C., Norbury, William B., Suman, Oscar E., Williams, Felicia N., Rodriguez, Noe A., Al-mousawi, Ahmed M.

2012

Overview

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). 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. 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. ClinicalTrials.gov NCT00675714; and NCT00673309.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 14-alpha Demethylase Inhibitors - therapeutic use / Acute phase proteins / Acute phase substances / Acute-Phase Proteins - metabolism / Antiandrogens / Antifungal agents / Antifungal Agents - therapeutic use / Body composition / Body composition (biology) / Body Composition - drug effects / Burns / Burns - complications / Burns - drug therapy / Burns - metabolism / Catabolism / Child / Child health / Clinical outcomes / Cytokines / Cytokines - metabolism / Demographics / Demography / Female / Fungicides / Gender / Glucocorticoids / Hormones / Humans / Hydrocortisone / Hydrocortisone - biosynthesis / Inflammation / Inflammation - drug therapy / Inflammation - etiology / Inflammation - metabolism / Inflammatory response / Ketoconazole / Ketoconazole - therapeutic use / Liver / Male / Medicine / Metabolism / Metabolism - drug effects / Muscle Proteins - metabolism / Muscles / Patient outcomes / Patients / Pediatrics / Physiological aspects / Prospective Studies / Protein biosynthesis / Protein composition / Protein synthesis / Proteins / Randomization / Respiratory distress syndrome / Sepsis / Statistical analysis / Surface area / Surgery / Ultrasonic imaging / Urine / Variance analysis / Wound infection