Value of Free Cortisol Measurement in Systemic Infection

Abstract

Systemic infection induces an increase in plasma cortisol which accords approximately with illness severity. However, both basal and synthetic ACTH stimulated cortisol levels are not strong predictors of mortality. Moreover, plasma cortisol levels do not readily define those patients who have been clinically observed to respond, with respect to blood pressure elevation, to exogenous hydrocortisone. It is likely that free cortisol, accounting for 6-20% of circulating total (bound plus free) cortisol has most of the life-saving effects on circulation and metabolism in severe sepsis, as corticosteroid-binding globulin bound and albumin-bound cortisol have reduced access to tissues. In addition, sepsis reduces CBG and albumin levels, hence blunting the effect of increasing illness severity on total cortisol. Our recent studies suggest that free cortisol correlates more closely to sepsis severity than total cortisol and that free cortisol levels can be estimated using the plasma CBG and total cortisol, obviating the need for direct free cortisol measurement. Studies directed at determining if free cortisol is a better guide than total cortisol to the need for hydrocortisone supplementation may be of value.

Free cortisol - septic shock - relative adrenal insufficiency (RAI)

References

• 1 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference . Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.  Crit Care Med. 1992;  20 864-874
• 2 Torpy DJ, Chrousos GP. The three-way interactions between the hypothalamic-pituitary-adrenal and gonadal axes and the immune system.  Baillieres Clin Rheumatol. 1996;  10 181-198
• 3 Cardona ML. Waterhouse-Friderichsen syndrome.  Acta Pediatr Esp. 1950;  8 421-429
• 4 Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose.  Ann Intern Med. 2004;  141 47-56
• 5 Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis.  BMJ. 2004;  329 480
• 6 Bollaert PE. Stress doses of glucocorticoids in catecholamine dependency: a new therapy for a new syndrome?.  Intensive Care Med. 2000;  26 3-5
• 7 Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, Stoll C, Peter K. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study.  Crit Care Med. 1999;  27 723-732
• 8 Sam S, Corbridge TC, Mokhlesi B, Comellas AP, Molitch ME. Cortisol levels and mortality in severe sepsis.  Clin Endocrinol (Oxf). 2004;  60 29-35
• 9 Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.  JAMA. 2002;  288 862-871
• 10 Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock.  Lancet. 1991;  337 582-583
• 11 Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin.  JAMA. 2000;  283 1038-1045
• 12 Annane D, Bellissant E, Sebille V, Lesieur O, Mathieu B, Raphael JC, Gajdos P. Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve.  Br J Clin Pharmacol. 1998;  46 589-597
• 13 Emptoz-Bonneton A, Crave JC, Lejeune H, Brebant C, Pugeat M. Corticosteroid-binding globulin synthesis regulation by cytokines and glucocorticoids in human hepatoblastoma-derived (HepG2) cells.  J Clin Endocrinol Metab. 1997;  82 3758-3762
• 14 Hammond GL, Smith CL, Paterson NA, Sibbald WJ. A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils.  J Clin Endocrinol Metab. 1990;  71 34-39
• 15 Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients.  N Engl J Med. 2004;  350 1629-1638
• 16 Beishuizen A, Thijs LG. Relative adrenal failure in intensive care: an identifiable problem requiring treatment?.  Best Pract Res Clin Endocrinol Metab. 2001;  15 513-531
• 17 Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem.  Chest. 2002;  122 1784-1796
• 18 Coolens JL, Van BH, Heyns W. Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin.  J Steroid Biochem. 1987;  26 197-202
• 19 Ho JT, Al-Musalhi H, Chapman MJ, Quach T, Thomas PD, Bagley CJ, Lewis JG, Torpy DJ. Septic shock and sepsis: a comparison of total and free plasma cortisol levels.  J Clin Endocrinol Metab. 2006;  91 105-114
• 20 Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H. Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study.  Am J Respir Crit Care Med. 2003;  167 512-520
• 21 Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della PR, Giorgio C, Blasi F, Umberger R, Meduri GU. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study.  Am J Respir Crit Care Med. 2005;  171 242-248

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