Corticosteroid Biology in Critical Illness: Modulatory Mechanisms and Clinical Implications

  • M. Williams
  • D. K. Menon
Conference paper


In recent years there has been renewed interest in the use of steroids in sepsis and septic shock, focusing on lower doses and longer courses with the aim of supplementing a presumed under-activity of the hypothalamic-pituitary-adrenal (HPA) axis due to relative adrenal insufficiency or target tissue glucocorticoid resistance. An international task force of the American College of Critical Care Medicine recently published guidelines for the diagnosis and treatment of what they termed “critical illness-related corticosteroid insufficiency” [1]. This paper makes important recommendations regarding steroid therapy in sepsis and acute respiratory distress syndrome (ARDS). The authors also suggested biochemical definitions of relative adrenal insufficiency. A rational approach would be to use such definitions to make decisions regarding corticosteroid supplementation in critical illness. However, the authors concluded that the available literature provides no evidence to use such biochemical parameters as a basis for treating patients with supplemental steroids. This discordance, in large part, may arise from the fact that classical concepts of the HPA axis ignore many important nuances of glucocorticoid production, bioavailability and cellular action. The purpose of this chapter is to explore these nuances with particular focus on cellular and regional mechanisms of regulation of corticosteroid action, with specific reference to the context of critical illness.


Septic Shock Glucocorticoid Receptor Critical Illness Mineralocorticoid Receptor Relative Adrenal Insufficiency 
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  1. 1.
    Marik PE, Pastores SM, Annane D, et al (2008) Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 36: 1937–1949CrossRefPubMedGoogle Scholar
  2. 2.
    Bornstein SR, Engeland WC, Ehrhart-Bornstein M, Herman JP (2008) Dissociation of ACTH and glucocorticoids. Trends Endocrinol Metab 19: 175–180CrossRefPubMedGoogle Scholar
  3. 3.
    Perrot D, Bonneton A, Dechaud H, Motin J, Pugeat M (1993) Hypercortisolism in septic shock is not suppressible by dexamethasone infusion. Crit Care Med 21: 396–401CrossRefPubMedGoogle Scholar
  4. 4.
    Pemberton PA, Stein PE, Pepys MB, Potter JM, Carrell RW (1988) Hormone binding globulins undergo serpin conformational change in inflammation. Nature 336: 257–258CrossRefPubMedGoogle Scholar
  5. 5.
    Owen CA, Campbell MA, Sannes PL, Boukedes SS, Campbell EJ (1995) Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases. J Cell Biol 131: 775–789CrossRefPubMedGoogle Scholar
  6. 6.
    Hammond GL, Smith CL, Underhill CM, Nguyen VT (1990) Interaction between corticosteroid binding globulin and activated leukocytes in vitro. Biochem Biophys Res Commun 172: 172–177CrossRefPubMedGoogle Scholar
  7. 7.
    Jirasakuldech B, Schussler GC, Yap MG, Drew H, Josephson A, Michl J (2000) A characteristic serpin cleavage product of thyroxine-binding globulin appears in sepsis sera. J Clin Endocrinol Metab 85: 3996–3999CrossRefPubMedGoogle Scholar
  8. 8.
    Vogeser M, Briegel J (2007) Effect of temperature on protein binding of cortisol. Clin Biochem 40: 724–727CrossRefPubMedGoogle Scholar
  9. 9.
    Beishuizen A, Thijs LG, Vermes I (2001) Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med 27: 1584–1591CrossRefPubMedGoogle Scholar
  10. 10.
    Cole TJ, Harris HJ, Hoong I, et al (1999) The glucocorticoid receptor is essential for maintaining basal and dexamethasone-induced repression of the murine corticosteroid-binding globulin gene. Mol Cell Endocrinol 154: 29–36CrossRefPubMedGoogle Scholar
  11. 11.
    Marti O, Martin M, Gavalda A, et al (1997) Inhibition of corticosteroid-binding globulin caused by a severe stressor is apparently mediated by the adrenal but not by glucocorticoid receptors. Endocrine 6: 159–164CrossRefPubMedGoogle Scholar
  12. 12.
    Vogeser M, Briegel J, Zachoval R (2002) Dialyzable free cortisol after stimulation with Synacthen. Clin Biochem 35: 539–543CrossRefPubMedGoogle Scholar
  13. 13.
    Moisey R, Wright D, Aye M, Murphy E, Peacey SR (2006) Interpretation of the short Synacthen test in the presence of low cortisol-binding globulin: two case reports. Ann Clin Biochem 43: 416–419CrossRefPubMedGoogle Scholar
  14. 14.
    Davidson JS, Bolland MJ, Croxson MS, Chiu W, Lewis JG (2006) A case of low cortisol-binding globulin: use of plasma free cortisol in interpretation of hypothalamic-pituitary-adrenal axis tests. Ann Clin Biochem 43: 237–239CrossRefPubMedGoogle Scholar
  15. 15.
    Torpy DJ, Bachmann AW, Grice JE, et al (2001) Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J Clin Endocrinol Metab 86: 3692–3700CrossRefPubMedGoogle Scholar
  16. 16.
    Hamrahian AH, Oseni TS, Arafah BM (2004) Measurements of serum free cortisol in critically ill patients. N Engl J Med 350: 1629–1638CrossRefPubMedGoogle Scholar
  17. 17.
    Ho JT, Al-Musalhi H, Chapman MJ, et al (2006) Septic shock and sepsis: a comparison of total and free plasma cortisol levels. J Clin Endocrinol Metab 91: 105–114CrossRefPubMedGoogle Scholar
  18. 18.
    Dubey A, Boujoukos AJ (2005) Free cortisol levels should not be used to determine adrenal responsiveness. Crit Care 9: E2CrossRefGoogle Scholar
  19. 19.
    Coolens JL, Van Baelen H, Heyns W (1987) Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin. J Steroid Biochem 26: 197–202CrossRefPubMedGoogle Scholar
  20. 20.
    Odermatt A, Atanasov AG, Balazs Z, et al (2006) Why is 11beta-hydroxysteroid dehydrogenase type 1 facing the endoplasmic reticulum lumen? Physiological relevance of the membrane topology of 11beta-HSD1. Mol Cell Endocrinol 248: 15–23CrossRefPubMedGoogle Scholar
  21. 21.
    Prigent H, Maxime V, Annane D (2004) Science review: mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids. Crit Care 8: 243–252CrossRefPubMedGoogle Scholar
  22. 22.
    Druce LA, Thorpe CM, Wilton A (2008) Mineralocorticoid effects due to cortisol inactivation overload explain the beneficial use of hydrocortisone in septic shock. Med Hypotheses 70: 56–60CrossRefPubMedGoogle Scholar
  23. 23.
    Annane D, Sebille V, Charpentier C, et al (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288: 862–871CrossRefPubMedGoogle Scholar
  24. 24.
    Scheinman RI, Gualberto A, Jewell CM, Cidlowski JA, Baldwin ASJr (1995) Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors. Mol Cell Biol 15: 943–953PubMedGoogle Scholar
  25. 25.
    Meduri GU (1999) New rationale for glucocorticoid treatment in septic shock. J Chemother 11: 541–550PubMedGoogle Scholar
  26. 26.
    Kino T, Chrousos GP (2003) Tumor necrosis factor alpha receptor-and Fas-associated FLASH inhibit transcriptional activity of the glucocorticoid receptor by binding to and interfering with its interaction with p160 type nuclear receptor coactivators. J Biol Chem 278: 3023–3029CrossRefPubMedGoogle Scholar
  27. 27.
    Meduri GU, Muthiah MP, Carratu P, Eltorky M, Chrousos GP (2005) Nuclear factor-kappaBand glucocorticoid receptor alpha-mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome. Evidence for inflammation-induced target tissue resistance to glucocorticoids. Neuroimmunomodulation 12: 321–338CrossRefPubMedGoogle Scholar
  28. 28.
    Meduri GU, Tolley EA, Chrousos GP, Stentz F (2002) Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory dis-tress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids. Am J Respir Crit Care Med 165: 983–991PubMedGoogle Scholar
  29. 29.
    Nakamori Y, Ogura H, Koh T, et al (2005) The balance between expression of intranuclear NF-kappaB and glucocorticoid receptor in polymorphonuclear leukocytes in SIRS patients. J Trauma 59: 308–314CrossRefPubMedGoogle Scholar
  30. 30.
    Leung DY, Hamid Q, Vottero A, et al (1997) Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med 186: 1567–1574CrossRefPubMedGoogle Scholar
  31. 31.
    van der Laan S, Meijer OC (2008) Pharmacology of glucocorticoids: beyond receptors. Eur J Pharmacol 585: 483–491CrossRefPubMedGoogle Scholar
  32. 32.
    Sousa AR, Lane SJ, Soh C, Lee TH (1999) In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of JUN N-terminal kinase and failure of prednisolone to inhibit JUN N-terminal kinase phosphorylation. J Allergy Clin Immunol 104: 565–574CrossRefPubMedGoogle Scholar
  33. 33.
    Clark AR, Martins JR, Tchen CR (2008) Role of dual specificity phosphatases in biological responses to glucocorticoids. J Biol Chem 283: 25765–25769CrossRefPubMedGoogle Scholar
  34. 34.
    Bertini R, Bianchi M, Ghezzi P (1988) Adrenalectomy sensitizes mice to the lethal effects of interleukin 1 and tumor necrosis factor. J Exp Med 167: 1708–1712CrossRefPubMedGoogle Scholar
  35. 35.
    Reichardt HM, Umland T, Bauer A, Kretz O, Schutz G (2000) Mice with an increased glucocorticoid receptor gene dosage show enhanced resistance to stress and endotoxic shock. Mol Cell Biol 20: 9009–9017CrossRefPubMedGoogle Scholar
  36. 36.
    Hawes AS, Rock CS, Keogh CV, Lowry SF, Calvano SE (1992) In vivo effects of the antiglucocorticoid RU 486 on glucocorticoid and cytokine responses to Escherichia coli endotoxin. Infect Immun 60: 2641–2647PubMedGoogle Scholar
  37. 37.
    Fischer M, Bhatnagar J, Guarner J, et al (2005) Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med 353: 2352–2360CrossRefPubMedGoogle Scholar
  38. 38.
    Miech RP (2005) Pathophysiology of mifepristone-induced septic shock due to Clostridium sordellii. Ann Pharmacother 39: 1483–1488CrossRefPubMedGoogle Scholar
  39. 39.
    Sicard D, Chauvelot-Moachon L (2005) Comment: pathophysiology of mifepristone-induced septic shock due to Clostridium sordellii. Ann Pharmacother 39: 2142–2143PubMedGoogle Scholar
  40. 40.
    Cohen AL, Bhatnagar J, Reagan S, et al (2007) Toxic shock associated with Clostridium sordellii and Clostridium perfringens after medical and spontaneous abortion. Obstet Gynecol 110: 1027–1033PubMedGoogle Scholar
  41. 41.
    Duma D, Silva-Santos JE, Assreuy J (2004) Inhibition of glucocorticoid receptor binding by nitric oxide in endotoxemic rats. Crit Care Med 32: 2304–2310PubMedGoogle Scholar
  42. 42.
    Da J, Chen L, Hedenstierna G (2007) Nitric oxide up-regulates the glucocorticoid receptor and blunts the inflammatory reaction in porcine endotoxin sepsis. Crit Care Med 35: 26–32CrossRefPubMedGoogle Scholar
  43. 43.
    Quan N, Avitsur R, Stark JL, et al (2001) Social stress increases the susceptibility to endotoxic shock. J Neuroimmunol 115: 36–45CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • M. Williams
    • 1
  • D. K. Menon
    • 1
  1. 1.Division of AnesthesiaUniversity of Cambridge Addenbrooke’s HospitalCambridgeUK

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