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