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Measurements of Serum Free Cortisol in Critically Ill Patients
Open accessAbstract
BACKGROUND: Because more than 90 percent of circulating cortisol in human serum is protein-bound, changes in the binding proteins can alter measured serum total cortisol concentrations without influencing free concentrations of this hormone. We investigated the effect of decreased amounts of cortisol-binding proteins on serum total and free cortisol concentrations during critical illness, when glucocorticoid secretion is maximally stimulated. METHODS: Base-line serum total cortisol, cosyntropin-stimulated serum total cortisol, aldosterone, and free cortisol concentrations were measured in 66 critically ill patients and 33 healthy volunteers in groups that were similar with regard to sex and age. Of the 66 patients, 36 had hypoproteinemia (albumin concentration, 2.5 g per deciliter or less), and 30 had near-normal serum albumin concentrations (above 2.5 g per deciliter). RESULTS: Base-line and cosyntropin-stimulated serum total cortisol concentrations were lower in the patients with hypoproteinemia than in those with near-normal serum albumin concentrations (P<0.001). However, the mean (+/-SD) base-line serum free cortisol concentrations were similar in the two groups of patients (5.1+/-4.1 and 5.2+/-3.5 microg per deciliter [140.7+/-113.1 and 143.5+/-96.6 nmol per liter]) and were several times higher than the values in controls (0.6+/-0.3 microg per deciliter [16.6+/-8.3 nmol per liter], P<0.001 for both comparisons). Cosyntropin-stimulated serum total cortisol concentrations were subnormal (18.5 microg per deciliter [510.4 nmol per liter] or less) in 14 of the patients, all of whom had hypoproteinemia. In all 66 patients, including these 14 who had hypoproteinemia, the base-line and cosyntropin-stimulated serum free cortisol concentrations were high-normal or elevated. CONCLUSIONS: During critical illness, glucocorticoid secretion markedly increases, but the increase is not discernible when only the serum total cortisol concentration is measured. In this study, nearly 40 percent of critically ill patients with hypoproteinemia had subnormal serum total cortisol concentrations, even though their adrenal function was normal. Measuring serum free cortisol concentrations in critically ill patients with hypoproteinemia may help prevent the unnecessary use of glucocorticoid therapy.
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“Patients with diseases such as nephrotic syndrome (43) and liver disease (50) as well as those who are in the immediate postoperative period (51) or who require intensive care (52) may have lower CBG and albumin and hence, lower cortisol measurements.”
From Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [52]
In the citing paper
“By contrast, serum cortisol concentrations can be decreased in patients with low albumin and cortisol binding globulin, as in hypoalbuminemic states (such as advanced cirrhosis, nephrotic syndrome, and malnutrition), and prolonged critical illness (92, 93).”
From European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency (2024) · cites this paper as [92]
In the citing paper
“For instance, activation and reserve capacity of the hypothalamic–pituitary–adrenal (HPA) axis in critically ill patients undergoing surgery was found to correlate better with serum free than total cortisol concentrations. The use of serum total cortisol alone could lead to a misdiagnosis of HPA axis insufficiency in up to 23% of these patients [241, 242].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [241]
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“It has been known for some time that because the majority of cortisol in the blood is protein-bound, total cortisol may correlate poorly with free cortisol (the physiologically active form) in critically ill patients in which hypoproteinemia is common (12).”
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Zhao, Y., Jiang, S., & Zhao, X. (2013) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0b013e31829bb239 · Cited by 1
Are We Correctly Diagnosing Adrenal Insufficiency or Are We Just Spitting into the Wind?*
Nelson, L. P., & Markovitz, B. P. (2015) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0000000000000388 · Cited by 1
“Consistently the total cortisol levels have increased by a lesser amount with either stress or corticotropin stimulation testing than the free levels, suggesting that the diagnosis of adrenal insufficiency is being erroneously made when only total cortisol is measured (3, 10, 11).”
BackgroundReine, P. A. (2012) · NORA - Norwegian Open Research Archives · Cited by 1
Endokrine Störungen bei kritisch Kranken
Brünnler, T., & Wrede, C. E. (2005) · Intensivmedizin und Notfallmedizin · doi:10.1007/s00390-005-0599-4 · Cited by 1
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Rosenquist, K. J., & Kaiser, U. B. (2013) · Wiley eBooks · doi:10.1002/9781118559406.ch12 · Cited by 1
Glucocorticoids in the treatment of acute respiratory distress syndrome
Roche‐Campo, F., Aguirre-Bermeo, H., & Mancebo, J. (2011) · Réanimation · doi:10.1007/s13546-011-0316-1 · Cited by 1
“The remaining 10%—the biologically active form—circulate freely [27].”
BackgroundSepsis von den Glukokortikoiden bis zum intensiven Insulin: enttäuschte Hoffnungen?
Bosshard, A., & Regli, B. (2009) · Swiss Medical Forum ‒ Schweizerisches Medizin-Forum · doi:10.4414/smf.2009.06754
Relative adrenocorticoid insufficiency exists and should be treated
Webb, S. A. R. (2006) · Critical Care and Resuscitation · doi:10.1016/s1441-2772(23)02075-6
Muscle wasting: the role of the ubiquitin-proteasome pathway in muscle atrophy and remodelling
Minnaard, R. (2006) · Research Publications (Maastricht University) · doi:10.26481/dis.20060921rm
Oznaczanie hormonów steroidowych w materiale biologicznym
Kotłowska, A., Szulfer, J., & Kamysz, W. (2010) · LAB Laboratoria, Aparatura, Badania
ACTH Stimulation Test for Adrenal Insufficiency with Total Cortisol Levels
Ergin, A. B., Hamrahian, A. H., Kennedy, A. L., & Gupta, M. K. (2015) · Springer eBooks · doi:10.1007/978-3-319-13048-4_1
Self-citationRole of human β-defensins in human burn wounds
Syed, M. (2009) · OpenGrey (Institut de l'Information Scientifique et Technique) · doi:10.34737/90zx8
Endocrine Problems and Cardiovascular Critical Care
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Metadata
- Authors
- Hamrahian, A. H., Oseni, T. S., & Arafah, B. M.
- Affiliations
- University Hospitals of Cleveland (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2004-04-15
- Volume
- 350
- Issue
- 16
- Pages
- 1629-1638
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2125017989
- Cited by
- 726
- References
- 40
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 13 · 2023: 11 · 2022: 17 · 2021: 18 · 2020: 17 · 2019: 22 · 2018: 14 · 2017: 28 · 2016: 28 · 2015: 37 · 2014: 41 · 2013: 26 · 2012: 34
- FWCI
- 40.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Center for Research Resources (M01RR000080)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Health Professions › Medical Laboratory Technology › Clinical Laboratory Practices and Quality Control
- Keywords
- free cortisol, cortisol-binding protein, hypoproteinemia, critically ill patients, ACTH stimulation test, glucocorticoid secretion, adrenal function, serum albumin, hypercortisolism, adrenal insufficiency, aldosterone, critically ill children, critically ill adults, critically ill neonates, critically ill infants
- MeSH terms
- Adrenal Insufficiency, Adrenocorticotropic Hormone, Aged, Aldosterone, Cosyntropin, Humans, Hydrocortisone, Hypoproteinemia, Middle Aged, Pituitary-Adrenal System, Regression Analysis, Critical Illness, APACHE, Hypoalbuminemia
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