The DOI matches its Crossref record; 39 of the 40 references it cites were found in a registry or an index.
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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Jenkins, I. A. (2007) · Journal of Hospital Medicine · doi:10.1002/jhm.162
(2009) · CRC Press eBooks · doi:10.1201/9781420079364.ch7
Klose, M., & Feldt‐Rasmussen, U. (2020) · Springer eBooks · doi:10.1007/978-3-030-39383-0_53
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Omelchuk, N. N. (2023) · Radiation and Risk Bulletin of the National Radiation and Epidemiological Registry · doi:10.21870/0131-3878-2023-32-2-78-87
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“On the other hand, the reduction of CBG levels in critical illness or rare cases of CBG deficiency may favour the suspicion of adrenal insufficiency [6–9].”
BackgroundInterpretation of Neonatal Adrenal Function Results and Adrenal Function Results in Critical Illness
Akyürek, N., Eklioğlu, B. S., & Binay, Ç. (2024) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2024.2024-6-1-s
Single-cell transcriptomics yield insights into the stress-immune interplay and inform disease riskPreprint
Benavides, S., Kosyk, O., Carpenter, L., Georgiou, C., Miller, B. C., Stanley, N., & Zannas, A. S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.05.658150
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Maschmeier, M., & Heinzow, H. S. (2025) · Springer eBooks · doi:10.1007/978-3-662-70167-6_23
Adrenocortical insufficiency in critical illness
Cohen, J., & Venkatesh, B. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-11611-7.00071-2
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Anomalies endocriniennes en réanimation
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Yadav, V., Nayak, R., & Yadav, J. (2026) · doi:10.2196/preprints.96048
The Endocrine Axis and Critical Illness
Kim, S. S., & Saillant, N. N. (2026) · Springer eBooks · doi:10.1007/978-3-032-22660-0_33
Gupta, K., Arora, R. K., Sadhasivam, S., Mirza, A. A., & Mittal, R. (2026) · Indian Journal of Neurosurgery · doi:10.1055/s-0046-1829038
Endocrine Disorders in Older Adults
Austin, H., & Treitl, D. (2026) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2026.08.013
Aghababaeian, A., Azimi, S. A., Nikzad, M. B., Abbasian, S., & Sardar, M. A. (2026) · Asian Journal of Sports Medicine · doi:10.5812/asjsm-163205
Cortisol Dynamics at High Temporal Resolution For Wearable Biosensor Research
Ferdoushi, M., Billings, T., Cai, W., & Khan, Y. (2026) · Advanced Sensor Research · doi:10.1002/adsr.70212
“For example, Hamrahian et al. found that nearly 40% of critically ill patients with hypoproteinemia had apparently subnormal total serum cortisol despite having normal adrenal function [ 111 ].”
Jia, Z., Zhao, X., Liu, X., & 李小丽 (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1962609
“…no cortisol, corticotropin, receptor, or related mechanistic threshold has been validated to identify individual corticosteroid responders (Guerrero et al., 2013; Vardas et al., 2017; Teblick et al., 2022; Annane et al., 2017; Hamrahian et al., 2004; Boonen et al., 2013; Venkatesh et al., 2007).”
Osterbur, K. (2012) · MOspace Institutional Repository (University of Missouri) · doi:10.32469/10355/15969
The Adrenal Glands in Critical Illness and Injury
Menon, K. (2014) · Springer eBooks · doi:10.1007/978-1-4471-6416-6_10
“It is not clear whether the increment in total cortisol level post ACTH stimulation is affected by the serum protein level or not although one study suggested that it is [ 62 ].”
Background
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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