title: Elevated plasma-free cortisol concentrations and ratios are associated with increased mortality even in the presence of statin therapy in patients with severe sepsis.
abstract: BACKGROUND
  Dissociation between plasma-free cortisol and total cortisol profiles exists in critical illness. Data on plasma-free cortisol are based on either calculated values or immunoassay-based measurements. Both have significant limitations. Statins have been advocated as a therapy in sepsis. Whether they impact on plasma cortisol through inhibition of cholesterol synthesis is unclear.
  
  
  OBJECTIVE
  In patients enrolled into a randomized trial of statins in sepsis (n = 250), we examined the association of mass spectrometry measured plasma-free cortisol, plasma-free cortisol/plasma total cortisol ratios, and outcome and the impact of concomitant statin therapy on cortisol profiles in 80 steroid naïve patients.
  
  
  METHODS
  Two hundred twenty serial measurements of plasma-free cortisol, plasma total cortisol, and interleukin-6 were collected from 80 patients (43 placebo and 37 statins). Data from 10 volunteers were used as controls.
  
  
  RESULTS
  Data are presented as median and interquartile range. Compared with controls, in severe sepsis, baseline plasma total cortisol was elevated two-fold (463 nmol/L [284-742 nmol/L] vs 245 nmol/L [200-299 nmol/L], p < 0.001), plasma-free cortisol 20-fold (75 nmol/L [20-151 nmol/L] vs 5 nmol/L [5-7 nmol/L], p < 0.001), and plasma-free cortisol/plasma total cortisol ratio six-fold (0.15 vs 0.02, p = 0.058). Baseline interleukin-6 was elevated at 121 pg/mL (65-611 pg/mL). In severe sepsis, there were no differences in plasma total cortisol (p = 0.66), plasma-free cortisol (p = 0.77), and interleukin-6 (p = 0.29) between statins and placebo groups. Plasma-free cortisol, plasma total cortisol, and plasma-free cortisol/plasma total cortisol were positively correlated with interleukin-6 (p = 0.0001, p < 0.0004, and p < 0.001, respectively) and day 90 mortality (p = 0.03, p = 0.03, and p = 0.058, respectively). Elevated plasma-free cortisol/plasma total cortisol ratios were associated with increased length of stay (p = 0.04). Baseline plasma-free cortisol, plasma total cortisol, and plasma-free cortisol/plasma total cortisol ratios were higher in nonsurvivors as compared with survivors (174 nmol/L [77-329 nmol/L] vs 57 nmol/L [17-122 nmol/L], p = 0.016; 890 nmol/L [333-1,430 nmol/L] vs 408 nmol/L [269-681 nmol/L], p = 0.035; and 0.19 [0.13-0.29] vs 0.14 [0.07-0.20]; p = 0.054, respectively).
  
  
  CONCLUSIONS
  In severe sepsis, plasma-free cortisol increase is 10-fold greater than that of plasma total cortisol. Both are similarly associated with inflammatory response and mortality. Elevated plasma-free cortisol/plasma total cortisol ratios were associated with increased length of stay. Statin therapy does not influence the plasma cortisol profiles in patients with severe sepsis.
authors.affiliation: 1Department of Intensive Care, Princess Alexandra and Wesley Hospitals, University of Queensland, Queensland, Australia. 2Department of Intensive Care, Princess Alexandra Hospital, Queensland, Australia. 3Department of Intensive Care, Princess Alexandra Hospital, University of Queensland, Queensland, Australia. 4Department of Intensive Care, Royal Brisbane Hospital, University of Queensland, Queensland, Australia. 5School of Population Health, University of Queensland, Queensland, Australia. 6Australian and New Zealand Intensive Care Research Centre, Melbourne, Victoria, Australia.
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Venkatesh
authors.forename: Lee
authors.initials: L
authors.lastname: Imeson
authors.forename: Peter
authors.initials: P
authors.lastname: Kruger
authors.forename: Jeremy
authors.initials: J
authors.lastname: Cohen
authors.forename: Mark
authors.initials: M
authors.lastname: Jones
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
mesh_terms: D018806:APACHE; D000368:Aged; D016638:Critical Illness / Q000628:therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000097:blood; D007902:Length of Stay; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D006854:Hydrocortisone