title: Glucocorticoid Sensitivity Is Highly Variable in Critically Ill Patients With Septic Shock and Is Associated With Disease Severity.
abstract: OBJECTIVE
  To measure tissue glucocorticoid sensitivity in patients with septic shock and determine its relationship to standard measurements of adrenal function and of outcome.
  
  
  METHODS
  Prospective observational trial.
  
  
  METHODS
  Teaching hospital ICU.
  
  
  METHODS
  Forty-one patients and 20 controls were studied.
  
  
  METHODS
  Glucocorticoid sensitivity was measured by in vitro suppression of cytokine production from lipopolysaccharide-stimulated leukocytes.
  
  
  RESULTS
  There was no significant difference between the groups in the relative suppression of cytokine production, although there was a greater range and variance in the patient data. Patients in the lowest quartile of glucocorticoid sensitivity had higher Acute Physiology and Chronic Health Evaluation II scores (25 [24-28] vs 20 [14-23]; p = 0.02) and a trend toward higher mortality (30% vs 0%; p = 0.2) compared to those in the highest. The mRNA expression of the β variant of the glucocorticoid receptor and the 11-β hydroxysteroid dehydrogenase 2 isozyme were significantly higher in patients compared to controls (8.6-fold, p = 0.002 and 10.1-fold, p = 0.0002, respectively). Changes in mRNA expression of these genes did not correlate with measurements of glucocorticoid sensitivity.
  
  
  CONCLUSIONS
  Patients with septic shock and controls do not differ in their median glucocorticoid sensitivity. However, patients exhibited a greater variability in glucocorticoid responsiveness and had evidence of association between increased sickness sensitivity and reduced glucocorticoid sensitivity. Sensitivity to glucocorticoids did not appear to be mediated by changes in the expression of the β variant of the glucocorticoid receptor or the 11-β hydroxysteroid dehydrogenase 2 isozyme.
authors.affiliation: 1Burns Trauma and Critical Care Research Centre, University of Queensland, Royal Brisbane Hospital, Brisbane, QL, Australia. 2Pathology Queensland Department of Chemical Pathology, University of Queensland, Brisbane, QL, Australia. 3Department of Chemical Pathology, Pathology Queensland, Queensland Health, Brisbane, QL, Australia. 4The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QL, Australia. 5Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QL, Australia. 6Department of Intensive Care, Princess Alexandra and Wesley Hospitals, University of Queensland, Brisbane, QL, Australia.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Cohen
authors.forename: Carel J
authors.initials: CJ
authors.lastname: Pretorius
authors.forename: Jacobus P J
authors.initials: JP
authors.lastname: Ungerer
authors.forename: John
authors.initials: J
authors.lastname: Cardinal
authors.forename: Antje
authors.initials: A
authors.lastname: Blumenthal
authors.forename: Jeff
authors.initials: J
authors.lastname: Presneill
authors.forename: Marcela
authors.initials: M
authors.lastname: Gatica-Andrades
authors.forename: Paul
authors.initials: P
authors.lastname: Jarrett
authors.forename: Melissa
authors.initials: M
authors.lastname: Lassig-Smith
authors.forename: Janine
authors.initials: J
authors.lastname: Stuart
authors.forename: Rachel
authors.initials: R
authors.lastname: Dunlop
authors.forename: Therese
authors.initials: T
authors.lastname: Starr
authors.forename: Bala
authors.initials: B
authors.lastname: Venkatesh
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics; D018806:APACHE; D000311:Adrenal Glands / Q000503:physiopathology; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D015850:Interleukin-6; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; C121943:glucocorticoid receptor beta; D016753:Interleukin-10; D003907:Dexamethasone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006854:Hydrocortisone