title: 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).
  
  
  RESULTS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00675714; and NCT00673309.
authors.affiliation: Shriners Hospitals for Children, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Jeschke
authors.forename: Felicia N
authors.initials: FN
authors.lastname: Williams
authors.forename: Celeste C
authors.initials: CC
authors.lastname: Finnerty
authors.forename: Noe A
authors.initials: NA
authors.lastname: Rodriguez
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Kulp
authors.forename: Arny
authors.initials: A
authors.lastname: Ferrando
authors.forename: William B
authors.initials: WB
authors.lastname: Norbury
authors.forename: Oscar E
authors.initials: OE
authors.lastname: Suman
authors.forename: Robert
authors.initials: R
authors.lastname: Kraft
authors.forename: Ludwik K
authors.initials: LK
authors.lastname: Branski
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Al-mousawi
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000627:therapeutic use; D000209:Acute-Phase Proteins / Q000378:metabolism; D000935:Antifungal Agents / Q000627:therapeutic use; D001823:Body Composition / Q000187:drug effects; D002056:Burns / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism; D002648:Child; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D008660:Metabolism / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D011446:Prospective Studies
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000209:Acute-Phase Proteins; D000935:Antifungal Agents; D016207:Cytokines; D009124:Muscle Proteins; D007654:Ketoconazole; D006854:Hydrocortisone