This Article Full Text Full Text (PDF) All Versions of this Article: 91/10/3725    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arafah, B. M. Search for Related Content PubMed PubMed Citation Articles by Arafah, B. M. Related Collections Adrenal and Hypertension Neuroendocrinology and Pituitary

Hypothalamic Pituitary Adrenal Function during Critical Illness: Limitations of Current Assessment Methods

Division of Clinical and Molecular Endocrinology, Case Western Reserve University and University Hospitals/Case Medical Center, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: Baha M. Arafah, M.D., Division of Clinical and Molecular Endocrinology, University Hospitals/Case Medical Center, 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: baha.arafah{at}case.edu.

Context: Activation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of several important responses to stressful events and critical illnesses. Despite a large volume of published data, several controversies continue to be debated, such as the definition of normal adrenal response, the concept of relative adrenal insufficiency, and the use of glucocorticoids in the setting of critical illness.

Objectives: The primary objective was to review some of the modulating factors and limitations of currently used methods of assessing HPA function during critical illness and provide alternative approaches in that setting.

Design: This was a critical review of relevant data from the literature with inclusion of previously published as well as unpublished observations by the author. Data on HPA function during three different forms of critical illnesses were reviewed: experimental endotoxemia in healthy volunteers, the response to major surgical procedures in patients with normal HPA, and the spontaneous acute to subacute critical illnesses observed in patients treated in intensive care units.

Setting: The study was conducted at an academic medical center.

Patients/Participants: Participants were critically ill subjects.

Intervention: There was no intervention.

Main Outcome Measure: The main measure was to provide data on the superiority of measuring serum free cortisol during critical illness as contrasted to those of total cortisol measurements.

Results: Serum free cortisol measurement is the most reliable method to assess adrenal function in critically ill, hypoproteinemic patients. A random serum free cortisol is expected to be 1.8 µg/dl or more in most critically ill patients, irrespective of their serum binding proteins. Because the free cortisol assay is not currently available for routine clinical use, alternative approaches to estimate serum free cortisol can be used. These include calculated free cortisol (Coolens’ method) and determining the free cortisol index (ratio of serum cortisol to transcortin concentrations). Preliminary data suggest that salivary cortisol measurements might be another alternative approach to estimating the free cortisol in the circulation. When serum binding proteins (albumin, transcortin) are near normal, measurements of total serum cortisol continue to provide reliable assessment of adrenal function in critically ill patients, in whom a random serum total cortisol would be expected to be 15 µg/dl or more in most patients. In hypoproteinemic critically ill subjects, a random serum total cortisol level is expected to be 9.5 µg/dl or more in most patients. Data on Cosyntropin-stimulated serum total and free cortisol levels should be interpreted with the understanding that the responses in critically ill subjects are higher than those of healthy ambulatory volunteers. The Cosyntropin-induced increment in serum total cortisol should not be used as a criterion for defining adrenal function, especially in critically ill patients.

Conclusions: The routine use of glucocorticoids during critical illness is not justified except in patients in whom adrenal insufficiency was properly diagnosed or others who are hypotensive, septic, and unresponsive to standard therapy. When glucocorticoids are used, hydrocortisone should be the drug of choice and should be given at the lowest dose and for the shortest duration possible. The hydrocortisone dose (50 mg every 6 h) that is mistakenly labeled as low-dose hydrocortisone leads to excessive elevation in serum cortisol to values severalfold greater than those achieved in patients with documented normal adrenal function. The latter data should call into question the current practice of using such doses of hydrocortisone even in the adrenally insufficient subjects.

This article has been cited by other articles:

				M. R. Daley, N. Seam, R. Luboshitzky, G. Qupti, P.-E. Bollaert, P. E. Marik, S. M. Pastores, B. P. Kavanagh, S. Manoach, C. L. Sprung, et al. Corticosteroids for Septic Shock N. Engl. J. Med., May 8, 2008; 358(19): 2068 - 2071. [Full Text] [PDF]

				R. F. A. de Lind van Wijngaarden, B. J. Otten, D. A. M. Festen, K. F. M. Joosten, F. H. de Jong, F. C. G. J. Sweep, and A. C. S. Hokken-Koelega High Prevalence of Central Adrenal Insufficiency in Patients with Prader-Willi Syndrome J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1649 - 1654. [Abstract] [Full Text] [PDF]

				C. L. Sprung, D. Annane, D. Keh, R. Moreno, M. Singer, K. Freivogel, Y. G. Weiss, J. Benbenishty, A. Kalenka, H. Forst, et al. Hydrocortisone Therapy for Patients with Septic Shock N. Engl. J. Med., January 10, 2008; 358(2): 111 - 124. [Abstract] [Full Text] [PDF]

				M. S. Cooper and P. M. Stewart Adrenal Insufficiency in Critical Illness J Intensive Care Med, November 1, 2007; 22(6): 348 - 362. [Abstract] [PDF]

				M. Christ-Crain, D. Stolz, S. Jutla, O. Couppis, C. Muller, R. Bingisser, P. Schuetz, M. Tamm, R. Edwards, B. Muller, et al. Free and Total Cortisol Levels as Predictors of Severity and Outcome in Community-acquired Pneumonia Am. J. Respir. Crit. Care Med., November 1, 2007; 176(9): 913 - 920. [Abstract] [Full Text] [PDF]

				M. T. Bailey, H. Engler, N. D. Powell, D. A. Padgett, and J. F. Sheridan Repeated social defeat increases the bactericidal activity of splenic macrophages through a Toll-like receptor-dependent pathway Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1180 - R1190. [Abstract] [Full Text] [PDF]

				Z. Thomas and G. L Fraser An Update on the Diagnosis of Adrenal Insufficiency and the Use of Corticotherapy in Critical Illness Ann. Pharmacother., September 1, 2007; 41(9): 1456 - 1465. [Abstract] [Full Text] [PDF]

				B. M. Arafah, F. J. Nishiyama, H. Tlaygeh, and R. Hejal Measurement of Salivary Cortisol Concentration in the Assessment of Adrenal Function in Critically Ill Subjects: A Surrogate Marker of the Circulating Free Cortisol J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2965 - 2971. [Abstract] [Full Text] [PDF]

				M. Christ-Crain, S. Jutla, I. Widmer, O. Couppis, C. Konig, H. Pargger, J. Puder, R. Edwards, B. Muller, and A. B. Grossman Measurement of Serum Free Cortisol Shows Discordant Responsivity to Stress and Dynamic Evaluation J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1729 - 1735. [Abstract] [Full Text] [PDF]