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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
The APACHE III Prognostic System
Knaus, W. A., Wagner, D. P., Draper, E. A., Zimmerman, J. E., Bergner, M., BASTOS, P. G., Sirio, C., Murphy, D. J., Lotring, T., Damiano, A., et al. (1991) · CHEST Journal · doi:10.1378/chest.100.6.1619 · Cited by 3,539
Annane, D. (2002) · JAMA · doi:10.1001/jama.288.7.862 · Cited by 3,075
The APACHE III Prognostic System
Teres, D., & Lemeshow, S. A. (1992) · CHEST Journal · doi:10.1378/chest.102.6.1919b · Cited by 2,896
The Hypothalamic–Pituitary–Adrenal Axis and Immune-Mediated Inflammation
Chrousos, G. P. (1995) · New England Journal of Medicine · doi:10.1056/nejm199505183322008 · Cited by 2,579
DUNN, J. F., NISULA, B. C., & RODBARD, D. (1981) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-53-1-58 · Cited by 1,238
Corticosteroid insufficiency in acutely ill patients
Cooper, M. S., & Stewart, P. M. (2003) · New England Journal of Medicine · doi:10.1056/nejmra020529 · Cited by 1,033
Annane, D. (2000) · JAMA · doi:10.1001/jama.283.8.1038 · Cited by 1,000
Oelkers, W. (1996) · New England Journal of Medicine · doi:10.1056/nejm199610173351607 · Cited by 737
Biologic Effects of Transdermal Estradiol
Chetkowski, R. J., Meldrum, D. R., Steingold, K. A., Randle, D., Lu, J. K., Eggena, P., Hershman, J. M., Alkjaersig, N. K., Fletcher, A. P., & Judd, H. L. (1986) · New England Journal of Medicine · doi:10.1056/nejm198606193142505 · Cited by 482
Corticosteroid Therapy in Severe Illness
Lamberts, S. W. J., Bruining, H. A., & de Jong, F. H. (1997) · New England Journal of Medicine · doi:10.1056/nejm199710303371807 · Cited by 477
Flagged first, then by citations
1 of the 40 references couldn’t be matched to a known paper.
Research works printed but not linked: 4
- 10.1210/jc.79.4.923 · DOI · Paper page
- Ekins RP. Free hormone in blood. In: Albertini P, Ekins RP, eds. Monoclonal antibodies and developments in immunoassays. Amsterdam: Elsevier, 1982:73-90.
- 10.1210/jc.80.6.1799 · DOI
- 10.1210/jc.84.8.2834 · DOI
Cited by
Sorted by citations
Items 101–200 of 724
Principles and pitfalls of free hormone measurements
Faix, J. D. (2013) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2013.06.007 · Cited by 81
Pitfalls in the diagnosis and management of Cushing's syndrome
Bansal, V., Asmar, N. E., Selman, W. R., & Arafah, B. M. (2015) · Neurosurgical FOCUS · doi:10.3171/2014.11.focus14704 · Cited by 81
Self-citationSuri, D., Moran, J., Hibbard, J. U., Kasza, K., & Weiss, R. E. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1049 · Cited by 80
Hypopituitarism is uncommon after aneurysmal subarachnoid haemorrhage
Klose, M., Brennum, J., Poulsgaard, L., Kosteljanetz, M., Wagner, A., & Feldt‐Rasmussen, U. (2010) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2010.03791.x · Cited by 81
Cortisol Response to Critical Illness: Effect of Intensive Insulin Therapy
Vanhorebeek, I., Peeters, R. P., Perre, S. V., Jans, I., Wouters, P. J., Skogstrand, K., Hansen, T. K., Bouillon, R., & den Berghe, G. V. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-2089 · Cited by 80
Högler, W., Baumann, U., & Kelly, D. A. (2011) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0b013e31823e9412 · Cited by 79
“3 nmol/L in times of critical illness (46).”
BackgroundSkeletal muscle wasting and contractile performance in septic rats
Minnaard, R., Drost, M. R., Wagenmakers, A. J. M., van Kranenburg, G., Kuipers, H., & Hesselink, M. K. C. (2004) · Muscle & Nerve · doi:10.1002/mus.20268 · Cited by 76
de Jong, M. F. C., Beishuizen, A., Spijkstra, J. J., & Groeneveld, A. B. J. (2007) · Critical Care Medicine · doi:10.1097/01.ccm.0000275387.51629.ed · Cited by 74
“Cortisol/albumin ratios were calculated as an indicator of free cortisol (24).”
MethodInfluentialGuerrero, J., Gatica, H. A., Rodríguez, M., Estay, R., & Goecke, I. A. (2013) · Critical Care · doi:10.1186/cc12774 · Cited by 71
“This selection method and its role as a prognostic factor has also been challenged [20-25].”
MethodCorticosteroid-binding globulin: The clinical significance of altered levels and heritable mutations
Gagliardi, L., Ho, J. T., & Torpy, D. J. (2010) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.07.015 · Cited by 88
Free Cortisol in Sepsis and Septic Shock
Bendel, S., Karlsson, S., Pettilä, V., Loisa, P., Varpula, M., & Ruokonen, E. (2008) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e318172fdba · Cited by 70
“The cut-off values for free cortisol were based on previous studies.(7,13,14) A concentration of free cortisol 22 nmol/L and total cortisol 275 nmol/L was considered to be absolute adrenal insufficiency.”
MethodMeasurement of Serum Free Cortisol Shows Discordant Responsivity to Stress and Dynamic Evaluation
Christ‐Crain, M., Jutla, S., Suter‐Widmer, I., Couppis, O., König, C., Pargger, H., Puder, J. J., Edwards, R., Müller-Stich, B. P., & Grossman, A. B. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2361 · Cited by 68
Adrenal Insufficiency in Adults: A Review
Vaidya, A., Findling, J., & Bancos, I. (2025) · JAMA · doi:10.1001/jama.2025.5485 · Cited by 75
Thévenot, T., Borot, S., Rémy-Martin, A., Sapin, R., Cervoni, J., Richou, C., Vanlemmens, C., Cléau, D., Muel, E., Minello, A., et al. (2011) · Liver international (Print) · doi:10.1111/j.1478-3231.2010.02431.x · Cited by 75
“4 nmol/L were considered to have subnormal response as recently reported (8).”
BackgroundMethodThe Neuroendocrine Effects of Traumatic Brain Injury
Rothman, M. S., Arciniegas, D. B., Filley, C. M., & Wierman, M. E. (2007) · Journal of Neuropsychiatry · doi:10.1176/jnp.2007.19.4.363 · Cited by 68
A Blueprint for a Sepsis Protocol
Shapiro, N. I., Howell, M. D., & Talmor, D. S. (2005) · Academic Emergency Medicine · doi:10.1111/j.1553-2712.2005.tb01957.x · Cited by 68
The diagnosis and investigation of adrenal insufficiency in adults
Wallace, I., Cunningham, S., & Lindsay, J. (2009) · Annals of Clinical Biochemistry · doi:10.1258/acb.2009.009101 · Cited by 43
Ahmed, A. S., Schmidt, C., & Brunner, T. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01438 · Cited by 72
Continuous free cortisol profiles-circadian rhythms in healthy men
Bhake, R. C., Kluckner, V, Stassen, H., Russell, G. M., Leendertz, J., Stevens, K., Linthorst, A. C. E., & Lightman, S. L. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2019-00449 · Cited by 64
Salivary Cortisol Can Replace Free Serum Cortisol Measurements in Patients With Septic Shock
Estrada-Y-Martin, R. M., & Orlander, P. R. (2011) · CHEST Journal · doi:10.1378/chest.11-0448 · Cited by 66
Magnotti, M., & Shimshi, M. (2008) · Endocrine Practice · doi:10.4158/ep.14.2.233 · Cited by 62
Bae, Y. J., & Kratzsch, J. (2015) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2015.09.001 · Cited by 67
Corticosteroids in Septic Shock
Finfer, S. R. (2008) · New England Journal of Medicine · doi:10.1056/nejme0708098 · Cited by 62
Adrenal insufficiency in the critically ill neonate and child
Langer, M., Modi, B. P., & Agus, M. S. D. (2006) · Current Opinion in Pediatrics · doi:10.1097/01.mop.0000236397.79580.85 · Cited by 61
Zhang, Q., Dong, G., Zhao, X., Wang, M., & Li, C.-S. (2014) · Intensive Care Medicine · doi:10.1007/s00134-014-3468-4 · Cited by 62
“Non-survivors may have higher [27] or lower [28] baseline cortisol concentrations than survivors.”
BackgroundCritical Illness–induced Corticosteroid Insufficiency: What It Is Not and What It Could Be
Téblick, A., Gunst, J., & den Berghe, G. V. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac201 · Cited by 64
Clinical and Technical Aspects in Free Cortisol Measurement
Choi, M.-H. (2022) · Endocrinology and Metabolism · doi:10.3803/enm.2022.1549 · Cited by 53
“Acute decreases in CBG levels [15] and hypoproteinemia [19] have been observed in sepsis and acute illness, while patients had subnormal total cortisol levels in their sera even though their adrenal function was normal.”
BackgroundCohen, J., Pretorius, C. J., Ungerer, J. P. J., Cardinal, J., Blumenthal, A., Presneill, J., Gatica-Andrades, M., Jarrett, P., Lassig-Smith, M., Stuart, J., et al. (2016) · Critical Care Medicine · doi:10.1097/ccm.0000000000001633 · Cited by 58
Hosoya, S., Johnson, S. C., Iwama, G. K., Gamperl, A. K., & Afonso, L. O. B. (2006) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2006.09.003 · Cited by 59
“In mammals, exposure to acute stressors has been shown to increase the percentage of free cortisol by 2% (Fleshner et al., 1995; Hamrahian et al., 2004).”
BackgroundAdrenal Response in Severe Community-Acquired Pneumonia
Salluh, J. I., Bozza, F. A., Soares, M., Verdeal, J. C. R., Castro-Faria-Neto, H. C., Silva, J. R. L. E., & Bozza, P. T. (2008) · CHEST Journal · doi:10.1378/chest.08-1382 · Cited by 59
Anthrax lethal factor represses glucocorticoid and progesterone receptor activity
Webster, J. I., Tonelli, L. H., Moayeri, M., Simons, S. S., Leppla, S. H., & STERNBERG, E. M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1036973100 · Cited by 60
“Indeed, prolonged treatment of septic shock with high doses of glucocorticoids has been shown to be detrimental to health, and increased cortisol levels have been shown in critically ill patients (Vermes and Beishuizen, 2001; Thompson, 2003; Hamrahian et al., 2004).”
BackgroundHoen, S., Mazoit, J., Asehnoune, K., Brailly‐Tabard, S., Benhamou, D., Moine, P., & Edouard, A. R. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000189743.55352.0e · Cited by 57
“roid binding globulin assessment is a limitation in this study because this protein has a high affinity for binding cortisol and its decrease in stressed patients may interfere with the study of adrenal function (30).”
BackgroundInfluentialManagement of severe sepsis and septic shock
Sessler, C., Perry, J. C., & Varney, K. L. (2004) · Current Opinion in Critical Care · doi:10.1097/01.ccx.0000139363.76068.7b · Cited by 32
The Dynamic Neuroendocrine Response to Critical Illness
Langouche, L., & den Berghe, G. V. (2006) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2006.09.007 · Cited by 54
The Endocrine System during Sepsis
Brierre, S., deBoisblanc, B. P., & Kumari, R. (2004) · The American Journal of the Medical Sciences · doi:10.1097/00000441-200410000-00007 · Cited by 52
Sleep in the Intensive Care Unit Setting
Patel, M., Chipman, J., Carlin, B. W., & Shade, D. A. (2008) · Critical Care Nursing Quarterly · doi:10.1097/01.cnq.0000336816.89300.41 · Cited by 53
Evidence of altered cortisol metabolism in critically ill patients: a prospective study
Venkatesh, B., Cohen, J., Hickman, I., Nisbet, J. C., Thomas, P., Ward, G., Hall, J., & Prins, J. (2007) · Intensive Care Medicine · doi:10.1007/s00134-007-0727-7 · Cited by 48
Al-Aridi, R., Abdelmannan, D. K., & Arafah, B. M. (2010) · Endocrine Practice · doi:10.4158/ep10262.ra · Cited by 52
Self-citationManco, M., Fernández‐Real, J. M., Mora, M. E. V., Déchaud, H., Nanni, G., Tondolo, V., Calvani, M., Castagneto, M., PUGEAT, M. M., & Mingrone, G. (2007) · Diabetes Care · doi:10.2337/dc06-1353 · Cited by 51
“Moreover, FCI is significantly associated with several features of insulin resistance syndrome (15).”
BackgroundDiagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient
Asare, K. (2007) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.27.11.1512 · Cited by 50
“1 μg/dl after the ACTH stimulation test for identifying patients at risk for adrenal insufficiency.(19) This study has been criticized because, although 18 of the 66 patients had sepsis, none had septic shock or multiple organ failure, a rather significant oversight.”
BackgroundMethodInfluentialNovel corticosteroid-binding globulin variant that lacks steroid binding activity.
Perogamvros, I., Underhill, C., Henley, D., Hadfield, K., Newman, W., Ray, D., Lightman, S., Hammond, G., & Trainer, P. (2010) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2010-0746 · Cited by 51
Applied Physiology in Intensive Care Medicine 1
Pinsky, M. R., Antonelli, M. M., Hedenstierna, G., & Brochard, L. J. (2012) · Springer eBooks · doi:10.1007/978-3-642-28270-6 · Cited by 50
Zimmerman, J. J. (2007) · Pediatric Critical Care Medicine · doi:10.1097/01.pcc.0000288710.11834.e6 · Cited by 49
“(71) pointed out that quantification of total vs.”
BackgroundManagement of adrenal insufficiency in different clinical settings
Hahner, S., & Allolio, B. (2005) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.6.14.2407 · Cited by 49
“These data suggest that the total circulating cortisol level may be a poor indicator of glucocorticoid activity at the cellular level [69].”
BackgroundDorin, R., Pai, H. K., Ho, J., Lewis, J., Torpy, D., Urban, F. K., & Qualls, C. (2009) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2008.09.115 · Cited by 64
“The cubic solution also predicts that under conditions of normal CBG and albumin concentrations, free cortisol represents between 4 and 15% of total cortisol across the physiological range of total cortisol concentrations, in agreement with previous reports of measured free and total cortisol in healthy controls [1,18…”
BackgroundMethodResultInfluentialPituitary-adrenal function in dogs with acute critical illness.
Martin, L., Groman, R., Fletcher, D., Behrend, E., Kemppainen, R., Moser, V., & Hickey, K. C. (2008) · Journal of the American Veterinary Medical Association · doi:10.2460/javma.233.1.87 · Cited by 45
Fede, G., Spadaro, L., Tomaselli, T., Privitera, G., Scicali, R., Vasianopoulou, P., Thalassinos, E., Martin, N., Thomas, M., Purrello, F., et al. (2013) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2013.08.028 · Cited by 51
Beishuizen, A., & THIJS, L. G. (2004) · Current Opinion in Critical Care · doi:10.1097/01.ccx.0000142748.40422.c8 · Cited by 48
Serum Free Cortisol Fraction in Healthy and Septic Neonatal Foals
Hart, K. A., Barton, M. H., Ferguson, D. C., Berghaus, R. D., Slovis, N. M., Heusner, G. L., & Hurley, D. J. (2011) · Journal of Veterinary Internal Medicine · doi:10.1111/j.1939-1676.2010.0667.x · Cited by 48
Triantos, C. K., Marzigie, M., Fede, G., Michalaki, M. A., Giannakopoulou, D., Thomopoulos, K., Garcovich, M., Kalafateli, M., Chronis, A., Kyriazopoulou, V. E., et al. (2011) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2011.03.033 · Cited by 48
Bendel, S., Koivisto, T., Ruokonen, E., Rinne, J. K., Romppanen, J., Vauhkonen, I., Kiviniemi, V. V., & Uusaro, A. V. (2008) · Critical Care · doi:10.1186/cc7084 · Cited by 48
“It has also been suggested that serum albumin may affect testing of adrenal function in critically ill patients [12].”
BackgroundMethodControversies in Corticosteroid use for Sepsis
Long, B., & Koyfman, A. (2017) · Journal of Emergency Medicine · doi:10.1016/j.jemermed.2017.05.024 · Cited by 53
Preclinical challenges in steroid analysis of human samples
Ceglarek, U., Werner, M., Kortz, L., Körner, A., Kieß, W., Thiery, J., & Kratzsch, J. (2010) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2010.03.039 · Cited by 47
Cortisol as a marker of stress
Козлов, А. И., & Kozlova, M. (2014) · Human Physiology · doi:10.1134/s0362119714020091 · Cited by 47
The Hypothalamic-Pituitary-Adrenal Axis in Critical Illness
Johnson, K. L., & Renn, C. (2006) · AACN Clinical Issues Advanced Practice in Acute & Critical Care · doi:10.1097/00044067-200601000-00006 · Cited by 46
Psychophysiological responses to pain identify reproducible human clusters
Farmer, A. D., Coen, S. J., Kano, M., Paine, P., Shwahdi, M., Jafari, J., Kishor, J., Worthen, S. F., Rossiter, H. E., Kumari, V., et al. (2013) · Pain · doi:10.1016/j.pain.2013.05.016 · Cited by 48
“The serum total cortisol, of which 90% to 95% is inactive and bound to cortisol-binding protein, with the remainder being active, is a validated measure of stress response in healthy subjects [8,24].”
BackgroundJenniskens, M., Weckx, R., Dufour, T., Perre, S. V., Pauwels, L., Derde, S., Téblick, A., Güiza, F., den Berghe, G. V., & Langouche, L. (2018) · Endocrinology · doi:10.1210/en.2018-00344 · Cited by 48
Salluh, J. I., Righy, C., Soares, M., Bozza, F. A., Silva, J. R. L. E., Tura, B. R., Bozza, P. T., & García‐Vidal, C. (2010) · Journal of Critical Care · doi:10.1016/j.jcrc.2010.03.004 · Cited by 47
Farwell, A. P. (2008) · Endocrine Practice · doi:10.4158/ep.14.9.1180 · Cited by 45
Nonthyroidal Illness Syndrome and Euthyroid Sick Syndrome in Intensive Care Patients
GOLOMBEK, S. G. (2008) · Seminars in Perinatology · doi:10.1053/j.semperi.2008.09.010 · Cited by 45
Evaluation and Management of Adrenal Insufficiency in Critically ill Patients: Disease State Review
Hamrahian, A. H., & Fleseriu, M. (2017) · Endocrine Practice · doi:10.4158/ep161720.ra · Cited by 43
Self-citationThe Hypothalamic-Pituitary-Adrenal Axis in Critical Illness
Schüetz, P., & Müller-Stich, B. P. (2006) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2006.09.013 · Cited by 45
Measurement of tissue cortisol levels in patients with severe burns: a preliminary investigation
Cohen, J., Deans, R., Dalley, A., Lipman, J., Roberts, M., & Venkatesh, B. (2009) · Critical Care · doi:10.1186/cc8184 · Cited by 41
Cohen, J., Lassig‐Smith, M., Deans, R., Pretorius, C. J., Ungerer, J. P. J., Tan, T. C. H., Jones, M., & Venkatesh, B. (2011) · Shock · doi:10.1097/shk.0b013e318239b809 · Cited by 43
“Measurement techniques that do not distinguish between the bound and free fractions may therefore be unreliable in estimating adrenal activity in circumstances where plasma corticosteroid-binding protein levels are abnormal, as is the case in critical illness (4).”
BackgroundResultInfluentialMolenaar, N., Groeneveld, A. B. J., Dijstelbloem, H. M., de Jong, M. F. C., Girbes, A. R. J., Heijboer, A. C., & Beishuizen, A. (2011) · Intensive Care Medicine · doi:10.1007/s00134-011-2342-x · Cited by 45
“to increases in cortisol upon ACTH [4, 6].”
BackgroundMethodResultInfluentialThe hypothalamic–pituitary–adrenal axis in critical illness
Venkataraman, S. T., Munoz, R. A., Cândido, C., & Witchel, S. F. (2007) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-007-9058-9 · Cited by 45
“Free cortisol concentrations are often elevated among critically ill patients and likely provide a more reliable indicator of cortisol secretion [100].”
BackgroundStewart, P. M., & Krone, N. P. (2011) · Elsevier eBooks · doi:10.1016/b978-1-4377-0324-5.00015-8 · Cited by 45
Continuous Free Cortisol Profiles in Healthy Men
Bhake, R. C., Russell, G. M., Kershaw, Y. M., Stevens, K. N., Zaccardi, F., Warburton, V. E. C., Linthorst, A. C. E., & Lightman, S. L. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgz002 · Cited by 44
Masharani, U. B., Shiboski, S. C., Eisner, M. D., Katz, P., Janson, S. L., Granger, D. A., & Blanc, P. D. (2005) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2005.03.003 · Cited by 43
“The importance of this point is underlined by the recent report that in an ICU setting, measurements of serum free cortisol was helpful in preventing the unnecessary use of glucocorticoid therapy (Hamrahian et al., 2004).”
BackgroundDimopoulou, I., & Tsagarakis, S. (2005) · Intensive Care Medicine · doi:10.1007/s00134-005-2689-y · Cited by 42
“Thus in severe illness free cortisol may be a better indicator of adrenal function [42].”
BackgroundAdrenal function in patients with community-acquired pneumonia
Gotoh, S., Nishimura, N., Takahashi, O., Shiratsuka, H., Horinouchi, H., Ono, H., Uchiyama, N., & Chohnabayashi, N. (2008) · European Respiratory Journal · doi:10.1183/09031936.00135607 · Cited by 41
“Serum free cortisol is reported to be a more precise marker of adrenal function in patients with hypoproteinaemia, especially in patients whose serum albumin is f2.5 g?dL-1 [ 7 ].”
BackgroundJung, B., Nougaret, S., Chanques, G., Mercier, G., Cisse, M., Aufort, S., Gallix, B., Annane, D., & Jaber, S. (2011) · Anesthesiology · doi:10.1097/aln.0b013e318225cfd7 · Cited by 42
“nosis of critical illness-related corticosteroid insufficiency, which remains challenging.(11,12,15,32) In practice, patients with adrenal gland volume less than 10 cm(3) had higher risk”
BackgroundDaniels, G. H. (2011) · Elsevier eBooks · doi:10.1016/b978-1-4377-0324-5.00002-x · Cited by 41
Genere, N., Kaur, R. J., Athimulam, S., Thomas, M. A., Nippoldt, T. B., Norman, M. V., Singh, R. J., Grebe, S. K. G., & Bancos, I. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab724 · Cited by 41
Ray, J. A., Kushnir, M. M., Rockwood, A. L., & Meikle, A. W. (2011) · Clinica Chimica Acta · doi:10.1016/j.cca.2011.03.016 · Cited by 42
Cortisol levels in patients with severe community-acquired pneumonia
Salluh, J. I., Verdeal, J. C. R., Mello, G. W., Araújo, L. V., Martins, G. A. R., Santino, M. D. S., & Soares, M. (2006) · Intensive Care Medicine · doi:10.1007/s00134-005-0046-9 · Cited by 41
“proteins are related to free cortisol concentrations during critical illness [18].”
BackgroundHypopituitarism after traumatic brain injury
Fernandez-Rodriguez, E., Bernabeu, I., Castro, A. I., & Casanueva, F. F. (2015) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2014.10.012 · Cited by 40
“Conversely, cortisol, prolactin, and vasopressin are stress hormones that are increased in acute phases of severe disease.(51,52) Low or low-normal baseline free cortisol can still be proposed as a potential early marker for the development of chronic corticotropin deficiency in head trauma patients.”
BackgroundRežonja, K., Šoštarič, M., Vidmar, G., & Marš, T. (2014) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000000108 · Cited by 40
Glucocorticoid Therapy in the Intensive Care Unit
LORIAUX, L. D. (2004) · New England Journal of Medicine · doi:10.1056/nejmp048052 · Cited by 40
ACUTE RELATIVE ADRENAL INSUFFICIENCY AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE
Weant, K. A., Sasaki‐Adams, D., Dziedzic, K., & Ewend, M. G. (2008) · Neurosurgery · doi:10.1227/01.neu.0000325728.50939.15 · Cited by 40
“However, serum albumin concentrations were collected and only 1 patient had a concentration of less than 2 g/dL, the level below which the percentage bound is noted to be reduced (20).”
BackgroundChallenges in treatment of patients with non-classic congenital adrenal hyperplasia
Adriaansen, B. P. H., Schröder, M. A. M., Span, P. N., Sweep, F. C. G. J., van Herwaarden, A. E., & der Grinten, H. L. C. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1064024 · Cited by 44
“During physical stress, such as sick days or surgery, ACTH levels increase leading to increased production of cortisol, which is necessary to modulate the immune response and maintain adequate blood pressure (24, 25).”
BackgroundRecent Developments in the Diagnosis and Management of Severe Sepsis
Wheeler, A. P. (2007) · CHEST Journal · doi:10.1378/chest.06-2535 · Cited by 40
Adrenal response in children with septic shock
Casartelli, C. H., Garcia, P. C. R., Branco, R. G., Piva, J. P., Einloft, P. R., & Tasker, R. C. (2007) · Intensive Care Medicine · doi:10.1007/s00134-007-0699-7 · Cited by 39
“cortisol and not free cortisol level, which better reflects the bioavailability and activity of this hormone [17].”
BackgroundKalil, A. C., & Sun, J. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002291 · Cited by 39
“25 subgroup analysis without prospective validation [3] and the poor results of this subgroup in the ADDRESS trial [49,89]; the controversial definitions of adrenal insufficiency [20,90,91], and the just reported Low-Dose Steroid phase III trial with negative results [66]; and the failure of the Intensive Insulin Ther…”
ResultAdrenal response in patients with septic shock of abdominal origin: relationship to survival
Riché, F. C., Boutron, C., Valleur, P. D., Berton, C., Laisné, M.-J. C., Launay, J., Chappuis, P., Peynet, J., Vicaut, É., Payen, D. M., et al. (2007) · Intensive Care Medicine · doi:10.1007/s00134-007-0770-4 · Cited by 39
“unaltered while total cortisol concentration is reduced in hypoprotidemic patients [35].”
BackgroundBowirrat, A., Armaly, Farah, F., Bisharat, Qader, A. E., Jabbour, Hamzi, Haj, & Saba (2012) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s31903 · Cited by 39
“70 It 71–73 High circulating cortisol levels may also be related to the kidneys.”
Huang, W., Kalhorn, T. F., Baillie, M. T., Shen, D. D., & Thummel, K. E. (2007) · Therapeutic Drug Monitoring · doi:10.1097/ftd.0b013e31803d14c0 · Cited by 39
“Moreover, in some patients, rapid changes in plasma protein binding of cortisol may lead to changes in free cortisol concentration, which can be difficult to discern when only total cortisol concentration is measured.(4) Thus, measuring plasma free cortisol concentration in those patients should provide a better evalu…”
BackgroundMethodRelative Adrenal Failure in the ICU: An Identifiable Problem Requiring Treatment
Gonzalez, H., Nardi, O., & Annane, D. (2006) · Critical Care Clinics · doi:10.1016/j.ccc.2005.09.001 · Cited by 37
“Stress also results in a decrease in CBG, leading to an increase in free cortisol blood levels [21,22].”
BackgroundLigtenberg, J. J. M., & Zijlstra, J. G. (2004) · Current Opinion in Critical Care · doi:10.1097/01.ccx.0000145100.58940.95 · Cited by 39
Adrenocortical Stress Response during the Course of Critical Illness
Peeters, B., Langouche, L., & den Berghe, G. V. (2017) · Comprehensive physiology · doi:10.1002/cphy.c170022 · Cited by 45
“…critically ill patients reported that hypoproteinemia results in low total plasma cortisol levels with a low total cortisol response to Synacthen, indicating adrenal insufficiency, while free plasma cortisol levels were consistently elevated and several times higher than in healthy volunteers (67).”
The role of neuroendocrine pathways in prognosis after stroke
Husseini, N. E., & Laskowitz, D. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2014.877841 · Cited by 33
Hydrocortisone Supplementation Enhances Hemodynamic Stability in Brain-dead Patients
Nicolas-Robin, A., Barouk, J., Amour, J., Coriat, P., Riou, B., & Langeron, O. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181d4f34d · Cited by 36
“Therefore, measured total plasma cortisol concentration can be misleadingly lower than anticipated, resulting in the incorrect conclusion that adrenal function is impaired.(36) However, these considerations do not change the hemodynamic response incidence and intensity, which was the aim of our study.”
BackgroundAdrenal Insufficiency in Septic Shock
Maxime, V., Lesur, O., & Annane, D. (2009) · Clinics in Chest Medicine · doi:10.1016/j.ccm.2008.10.003 · Cited by 39
“However, clinicians do not routinely measure either free cortisol or CBG.59,81”
BackgroundInfluentialHigh serum levels of free cortisol indicate severity of cirrhosis in hemodynamically stable patients
Thévenot, T., Dorin, R. I., Monnet, É., Qualls, C., Sapin, R., Grandclément, É., Borot, S., Sheppard, F., Weil, D., Degand, T., et al. (2012) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2012.07188.x · Cited by 38
Exaggerated adrenarche and altered cortisol metabolism in Type 1 diabetic children
Remer, T., Maser‐Gluth, C., Boye, K. R., Hartmann, M. F., Heinze, E., & Wudy, S. A. (2006) · Steroids · doi:10.1016/j.steroids.2006.02.005 · Cited by 38
Critical Illness–Related Corticosteroid Insufficiency in Small Animals
Martin, L. G. (2011) · Veterinary Clinics of North America Small Animal Practice · doi:10.1016/j.cvsm.2011.03.021 · Cited by 37
“Based on these findings, the authors concluded that many of these cats had CIRCI.”
BackgroundInfluentialSahebkar, A., Rathouska, J., Simental‐Mendía, L. E., & Nachtigal, P. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.10.013 · Cited by 37
Hyponatraemia and hypernatraemia: Disorders of Water Balance in Neurosurgery
Castle‐Kirszbaum, M., Kyi, M., Wright, C. A., Goldschlager, T., Danks, R. A., & Parkin, W. G. (2021) · Neurosurgical Review · doi:10.1007/s10143-020-01450-9 · Cited by 37
“However, as cortisol is highly protein bound, simultaneous “negative acute-phase” changes in carrier protein concentration may dictate that free cortisol levels are actually normal [47, 68].”
BackgroundEndocrine Perturbation Increases Susceptibility of Mice to Anthrax Lethal Toxin
Moayeri, M., Webster, J. I., Wiggins, J. F., Leppla, S. H., & STERNBERG, E. M. (2005) · Infection and Immunity · doi:10.1128/iai.73.7.4238-4244.2005 · Cited by 37
“Indeed, it has been found with human patients that high doses and prolonged treatment of septic shock with GCs is detrimental to survival, and increased cortisol levels have been found in critically ill patients (13, 21, 43, 50).”
BackgroundEtomidate, Adrenal Function, and Mortality in Critically Ill Patients
Sunshine, J. E., Deem, S. A., Weiss, N. S., Yanez, N. D., Daniel, S., Keech, K., Brown, M., & Treggiari, M. M. (2012) · Respiratory Care · doi:10.4187/respcare.01956 · Cited by 37
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
