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
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
EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis
Angeli, P., Bernardi, M., Villanueva, C., Francoz, C., Mookerjee, R. P., Trebicka, J., Krag, A. A., Laleman, W., & Ginès, P. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.03.024 · Cited by 3,033
“Serum-free cortisol levels <50 nmol/L at baseline, or <86 nmol/L (9 μg/dl) after adrenocorticotrophic hormone suggest the presence of RAI in critically ill patients [450].”
BackgroundThe diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline.
Nieman, L. K., Biller, B. M. K., Findling, J. W., Newell-Price, J., Savage, M. O., Stewart, P. M., & Montori, V. M. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0125 · Cited by 2,718
“are associated with decreased serum cortisol values (39, 46).”
BackgroundHydrocortisone Therapy for Patients with Septic Shock
Sprung, C. L., Annane, D., Keh, D., Moreno, R. P., Singer, M., Freivogel, K., Weiss, Y., Benbenishty, J., Kalenka, A., Forst, H., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa071366 · Cited by 2,179
Bornstein, S. R., Allolio, B., Arlt, W., Barthel, A., Don-Wauchope, A., Hammer, G. D., Husebye, E. S., Merke, D. P., Murad, M. H., Stratakis, C. A., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-1710 · Cited by 1,769
“period (51) or who require intensive care (52) may have”
BackgroundAnnane, D., Bellissant, É., & Cavaillon, J. (2005) · The Lancet · doi:10.1016/s0140-6736(04)17667-8 · Cited by 1,262
Russell, J. A. (2006) · New England Journal of Medicine · doi:10.1056/nejmra043632 · Cited by 1,054
Marik, P. E., Pastores, S. M., Annane, D., Meduri, G. U., Sprung, C. L., Arlt, W., Keh, D., Briegel, J., Beishuizen, A., Dimopoulou, I., et al. (2008) · Critical Care Medicine · doi:10.1097/ccm.0b013e31817603ba · Cited by 912
Davis, A. L., Carcillo, J. A., Aneja, R. K., Deymann, A. J., Lin, J. C., Nguyen, T. C., Okhuysen‐Cawley, R., Relvas, M. S., Rozenfeld, R. A., Skippen, P. W., et al. (2017) · Critical Care Medicine · doi:10.1097/ccm.0000000000002425 · Cited by 689
“The role of free cortisol in the diagnosis of adrenal insufficiency determination has not been sufficiently elucidated (303, 304).”
BackgroundCortisol and post-traumatic stress disorder in adults: Systematic review and meta-analysis
Meewisse, M.-L., Reitsma, J. B., De Vries, G.-J., Gersons, B. P. R., & Olff, M. (2007) · British Journal of Psychiatry · doi:10.1192/bjp.bp.106.024877 · Cited by 661
Technical and clinical aspects of cortisol as a biochemical marker of chronic stress
Lee, D. Y., Kim, E., & Choi, M. H. (2015) · BMB Reports · doi:10.5483/bmbrep.2015.48.4.275 · Cited by 484
Measuring cortisol in human psychobiological studies
Levine, A., Zagoory‐Sharon, O., Feldman, R., Lewis, J. G., & Weller, A. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.08.025 · Cited by 503
Sleep Deprivation in Critical Illness
Kamdar, B. B., Needham, D. M., & Collop, N. A. (2011) · Journal of Intensive Care Medicine · doi:10.1177/0885066610394322 · Cited by 477
Measuring cortisol in serum, urine and saliva—Are our assays good enough?
El-Farhan, N., Rees, D. A., & Evans, C. (2017) · Annals of Clinical Biochemistry: International Journal of Laboratory Medicine · doi:10.1177/0004563216687335 · Cited by 395
“The low protein concentrations typical of these patients affect the serum total cortisol response to Synacthen stimulation, resulting in a diagnosis of adrenal insufficiency in up to 40% of patients with no HPA axis disease.(135) Assay differences are accentuated, with one study showing concordance between the results…”
ResultAnnane, D., Pastores, S. M., Rochwerg, B. N., Arlt, W., BALK, R. A., Beishuizen, A., Briegel, J., Carcillo, J. A., Christ‐Crain, M., Cooper, M. S., et al. (2017) · Intensive Care Medicine · doi:10.1007/s00134-017-4919-5 · Cited by 380
“A prospective study of 112 critically ill adults with treatment-insensitive hypotension, published after the 2008 recommendations, found a good correlation between serum concentrations of free and total cortisol before and after 250 μg ACTH stimulation testing [15].”
BackgroundPredisposing Factors for Adrenal Insufficiency
Bornstein, S. R. (2009) · New England Journal of Medicine · doi:10.1056/nejmra0804635 · Cited by 356
Nguyen, H. B., Rivers, E. P., Abrahamian, F. M., Moran, G. J., Abraham, E. H., Trzeciak, S. W., Huang, D. T., Osborn, T. M., Stevens, D. L., & Talan, D. A. (2006) · Annals of Emergency Medicine · doi:10.1016/j.annemergmed.2006.02.015 · Cited by 359
“Proposed criteria other than the traditional cosyntropin stimulation test include a lower-dose cosyntropin test,(272) a random cortisol level,(273) and measuring serum free cortisol instead of total cortisol.(274) The Annane et al 7 trial has been criticized for a number of reasons, including the enrollment of a limit…”
BackgroundAnnane, D., Pastores, S. M., Rochwerg, B. N., Arlt, W., BALK, R. A., Beishuizen, A., Briegel, J., Carcillo, J. A., Christ‐Crain, M., Cooper, M. S., et al. (2017) · Critical Care Medicine · doi:10.1097/ccm.0000000000002737 · Cited by 348
Arafah, B. M. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0674 · Cited by 331
Self-citationDiagnosis of Adrenal Insufficiency in Severe Sepsis and Septic Shock
Annane, D., Maxime, V., Ibrahim, F., Alvarez, J. C., Abe, E., & Boudou, P. (2006) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200509-1369oc · Cited by 327
“1 #g/dl after cosyntropin stimulation (7).”
BackgroundResultInfluentialOppert, M., Schindler, R., Husung, C., Offermann, K., Gräf, K.-J., Boenisch, O., Barckow, D., Frei, U. A., & Eckardt, K. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000186370.78639.23 · Cited by 326
Fernández, J., Escorsell, À., Zabalza, M., Felipe, V., Navasa, M., Mas, A., Lacy, A. M., Ginès, P., & Arroyo, V. (2006) · Hepatology · doi:10.1002/hep.21352 · Cited by 292
Adrenal insufficiency: still a cause of morbidity and death in childhood
Shulman, D. I., Palmert, M. R., Kemp, S. F., & for the Lawson Wilkins Drug and Therapeutics Committee (2007) · PEDIATRICS · doi:10.1542/peds.2006-1612 · Cited by 282
Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study
Cohan, P., Wang, C., McArthur, D. L., Cook, S. W., Dusick, J. R., Armin, B., Swerdloff, R., Vespa, P., Muizelaar, J. P., Cryer, H. G., et al. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000181735.51183.a7 · Cited by 282
“Therefore, measuring serum total cortisol may not reflect the free or bioavailable cortisol (63).”
BackgroundChrist-Crain, M., Stolz, D., Jutla, S., Couppis, O., Müller, C., Bingisser, R., Schuetz, P., Tamm, M., Edwards, R., Müller, B., et al. (2007) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200702-307oc · Cited by 134
“The free cortisol, rather than the protein-bound fraction, is responsible for the physiologic function ( 11 ).”
BackgroundInfluentialFast, M. D., Hosoya, S., Johnson, S. C., & Afonso, L. O. B. (2007) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2007.10.009 · Cited by 285
“Mammals usually show a 2% increase in the percentage of free cortisol after acute stress [34,35].”
BackgroundSeptic Shock and Sepsis: A Comparison of Total and Free Plasma Cortisol Levels
Ho, J. T., Al-Musalhi, H., Chapman, M. J., Quach, T., Thomas, P. D., Bagley, C. J., Lewis, J. G., & Torpy, D. J. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0265 · Cited by 312
Health, A. A. B. C. S., Visser, M., Kritchevsky, S. B., Newman, A. B., Goodpaster, B. H., Tylavsky, F. A., Nevitt, M. C., & Harris, T. B. (2005) · American Journal of Clinical Nutrition · doi:10.1093/ajcn.82.3.531 · Cited by 249
Adrenal function in sepsis: The retrospective Corticus cohort study
Lipiner-Friedman, D., Sprung, C., Laterre, P., Weiss, Y., Goodman, S. V., Vogeser, M., Briegel, J., Keh, D., Singer, M., Moreno, R., et al. (2007) · Critical Care Medicine · doi:10.1097/01.ccm.0000259465.92018.6e · Cited by 218
“These relatively low baseline levels of total cortisol may have resulted from low levels of albumin and cortisol binding globulin (11), levels of which were not available in this retrospective study.”
BackgroundSalivary cortisone is a potential biomarker for serum free cortisol
Perogamvros, I., Keevil, B. G., Ray, D. W., & Trainer, P. J. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-1215 · Cited by 222
“As a result, there is concern that such patients are overdiagnosed with hypoadrenalism on the basis of total serum cortisol measurement (6, 7).”
BackgroundEtomidate is associated with mortality and adrenal insufficiency in sepsis
Chan, C. M., Mitchell, A. L., & Shorr, A. F. (2012) · Critical Care Medicine · doi:10.1097/ccm.0b013e31825fec26 · Cited by 216
“Furthermore, although all studies used the same criteria to describe relative AI, this definition has never been proven to truly represent a clinically significant loss in adrenal function (26).”
BackgroundHydrocortisone Therapy for Patients With Multiple Trauma
Roquilly, A. (2011) · JAMA · doi:10.1001/jama.2011.360 · Cited by 218
“Injury severity score, median (IQR) 29 (22-35) 27 (22-38) 30 (22-36) 30 (22-38) 27 (22-34)”
The hepatoadrenal syndrome: A common yet unrecognized clinical condition*
Marik, P. E., Gayowski, T., & Starzl, T. E. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000164541.12106.57 · Cited by 212
Low-dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial
Arabi, Y. M., Aljumah, A. A., Dabbagh, O. C., Tamim, H., Rishu, A. H., Al‐Abdulkareem, A., Knawy, B. A., Hajeer, A. H., Tamimi, W., & Cherfan, A. J. (2010) · Canadian Medical Association Journal · doi:10.1503/cmaj.090707 · Cited by 211
“The use of free rather than total serum cortisol levels has been suggested for the diagnosis of relative adrenal insufficiency because of dissociation between the levels of the total and the physiologically active free cortisol.(36) However, recent guidelines have not recommended the routine use of free cortisol measu…”
BackgroundInsights into Severe Sepsis in Older Patients: From Epidemiology to Evidence-Based Management
Girard, T. D., Opal, S. M., & Ely, E. W. (2005) · Clinical Infectious Diseases · doi:10.1086/427876 · Cited by 202
“be abnormally low at the same time that the free cortisol level is normal [45].”
BackgroundHildreth, A. N., Mejia, V. A., Maxwell, R. A., Smith, P. W., Dart, B. W., & Barker, D. E. (2008) · Journal of Trauma: Injury, Infection & Critical Care · doi:10.1097/ta.0b013e31818255e8 · Cited by 197
Jackson, W. L. (2005) · CHEST Journal · doi:10.1378/chest.127.3.1031 · Cited by 196
The cortisol stress response induced by surgery: A systematic review and meta‐analysis
Prete, A., Yan, Q., Al‐Tarrah, K., Akturk, H. K., Prokop, L. J., Alahdab, F., Foster, M. A., Lord, J. M., Karavitaki, N., Wass, J. A., et al. (2018) · Clinical Endocrinology · doi:10.1111/cen.13820 · Cited by 192
Cortisol Response in Relation to the Severity of Stress and Illness
Widmer, I. E., Puder, J. J., König, C., Pargger, H., Zerkowski, H. R., Girard, J., & Müller, B. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0354 · Cited by 225
Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin
Lewis, J. G., Bagley, C. J., Elder, P. A., Bachmann, A. W., & Torpy, D. J. (2005) · Clinica Chimica Acta · doi:10.1016/j.cccn.2005.03.044 · Cited by 214
De Groot, L. J. (2006) · Critical Care Clinics · doi:10.1016/j.ccc.2005.10.001 · Cited by 188
The Diagnosis and Management of Central Hypoadrenalism
Grossman, A. B. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0982 · Cited by 187
“acthen test (SST), where ACTH [1-24] [Cosyntropin (Cor-”
Backgroundden Brinker, M., Joosten, K. F. M., Liem, O., de Jong, F. H., Hop, W. C. J., Hazelzet, J. A., van Dijk, M., & Hokken‐Koelega, A. C. S. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1107 · Cited by 183
“This is in contrast to studies in critically ill adults reporting decreased serum CBG and albumin levels with concomitantly elevated free cortisol fractions especially during the acute phase of critical illness (9, 10, 12).”
ResultHannon, M. J., Crowley, R. K., Behan, L. A., O'Sullivan, E. P., O'Brien, M. M. C., Sherlock, M., Rawluk, D., O'Dwyer, R., Tormey, W., & Thompson, C. J. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1555 · Cited by 184
“Savaridas et al (38) suggested that plasma CBG concentrations fall after TBI; however, a prospective study of TBI patients found that free cortisol rose in parallel with total cortisol as severity of TBI increased (5), and it has been suggested that discrepancies will not emerge between PC and free cortisol unless pat…”
BackgroundMalerba, G., Romano-Girard, F., Cravoisy, A., Dousset, B., Nace, L., L�vy, B., & Bollaert, P.-E. (2005) · Intensive Care Medicine · doi:10.1007/s00134-004-2550-8 · Cited by 179
“recently demonstrated [17] frequent hypoalbuminemia”
Metabolomic Derangements Are Associated with Mortality in Critically Ill Adult Patients
Rogers, A. J., McGeachie, M. J., Baron, R. M., Gazourian, L., Haspel, J. A., Nakahira, K., Fredenburgh, L. E., Hunninghake, G. M., Raby, B. A., Matthay, M. A., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087538 · Cited by 179
“Similarly, cortisol has long been recognized to be elevated in critically ill patients because of hypothalamus-pituitary-adrenal axis stimulation, [25,26] though exact mechanisms for cortisol elevation are”
BackgroundPathophysiology of Delirium in the Intensive Care Unit
Gunther, M. L., Morandi, A., & Ely, E. W. (2008) · Critical Care Clinics · doi:10.1016/j.ccc.2007.10.002 · Cited by 181
Schelling, G., Roozendaal, B., Krauseneck, T., Schmoelz, M., de Quervain, D. J. ‐., & Briegel, J. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1364.005 · Cited by 173
Beuschlein, F., Else, T., Bancos, I., Hahner, S., Hamidi, O., van Hulsteijn, L., Husebye, E. S., Karavitaki, N., Prete, A., Vaidya, A., et al. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae250 · Cited by 172
Rivers, E. (2005) · Canadian Medical Association Journal · doi:10.1503/cmaj.050632 · Cited by 177
Regulation of cortisol bioavailability—effects on hormone measurement and action
Perogamvros, I., Ray, D. W., & Trainer, P. J. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.134 · Cited by 167
Systemic Steroids in Severe Sepsis and Septic Shock
Patel, G. P., & BALK, R. A. (2011) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201011-1897ci · Cited by 154
Glucocorticoid induced adrenal insufficiency
Prete, A., & Bancos, I. (2021) · BMJ · doi:10.1136/bmj.n1380 · Cited by 155
Thyroid function during critical illness
Economidou, F. N., Douka, E., Tzanela, M., Nanas, S., & Kotanidou, A. N. (2011) · HORMONES · doi:10.14310/horm.2002.1301 · Cited by 155
“They are often associated with alterations in other endocrine axes (reductions in serum gonadotropin and sex hormone concentrations and increases in serum adrenocorticotropic hormone and free cortisol levels).(6,7) Thus, the sick euthyroid syndrome should not be viewed as an isolated abnormal event but as part of a ge…”
Adrenal function and dysfunction in critically ill patients
Téblick, A., Peeters, B., Langouche, L., & den Berghe, G. V. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0185-7 · Cited by 158
Adrenal insufficiency: etiology, diagnosis and treatment
Neary, N., & Nieman, L. (2010) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e328338f608 · Cited by 140
Klose, M., Juul, A., Struck, J., Morgenthaler, N. G., Kosteljanetz, M., & Feldt‐Rasmussen, U. (2007) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2007.02931.x · Cited by 142
Endocrine aspects of acute and prolonged critical illness
Vanhorebeek, I., Langouche, L., & Van den Berghe, G. (2006) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0071 · Cited by 141
“resulting in proportionally much higher increases in the free hormone”
Acevedo, J., Fernández, J., Prado, V., Silva, A., Castro, M., Pavesi, M., Roca, D., Jiménez, W., Ginès, P., & Arroyo, V. (2013) · Hepatology · doi:10.1002/hep.26535 · Cited by 141
Salivary cortisol and cortisone in the clinical setting
Blair, J., Adaway, J., Keevil, B., & Ross, R. (2017) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000328 · Cited by 138
Adrenocortical dysfunction in liver disease: A systematic review
Fede, G., Spadaro, L., Tomaselli, T., Privitera, G., Germani, G., Tsochatzis, E. A., Thomas, M., Bouloux, P.-M. G., Burroughs, A. K., & Purrello, F. (2012) · Hepatology · doi:10.1002/hep.25573 · Cited by 134
“Low levels of CBG and overestimation of AI by total cortisol measurement have been demonstrated in noncirrhotic critically ill patients, especially if serum albumin level is <25 g/L.(32,33) CBG was found to be significantly decreased in 47 cirrhotics, compared to 50 healthy controls (mean, 567 versus 859 nmol/L; P < 0.”
BackgroundMinneci, P. C., Deans, K. J., Eichacker, P. Q., & Natanson, C. (2009) · Clinical Microbiology and Infection · doi:10.1111/j.1469-0691.2009.02752.x · Cited by 132
“[43–46].”
Arafah, B. M., Nishiyama, F. J., Tlaygeh, H., & Hejal, R. B. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0181 · Cited by 128
Self-citationPerioperative Steroid Management: Approaches Based on Current Evidence
Liu, M. M., Reidy, A. B., Saatee, S., & Collard, C. D. (2017) · Anesthesiology · doi:10.1097/aln.0000000000001659 · Cited by 126
Asehnoune, K., Séguin, P., Allary, J., Feuillet, F., Lasocki, S., Cook, F., Floch, H. L., Chabanne, R., Geeraerts, T., Roger, C., et al. (2014) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(14)70144-4 · Cited by 129
Novel Therapies for Sepsis: A Review
Deans, K. J., Haley, M., Natanson, C., Eichacker, P. Q., & Minneci, P. C. (2005) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/01.ta.0000158244.69179.94 · Cited by 122
Siraux, V., Backer, D. D., Yalavatti, G., Mélot, C., Gervy, C., Mockel, J., & Vincent, J. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000185641.87051.7c · Cited by 120
“(38) have recently shown that free cortisol levels can be preserved despite decreased total cortisol levels in critically ill patients, due to the decrease in cortisol binding globulin and, especially, albumin levels.”
BackgroundGlucocorticoid therapy in neurologic critical care
Gomes, J. A., Stevens, R. D., Lewin, J. J., Mirski, M. A., & Bhardwaj, A. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000166389.85273.38 · Cited by 118
“There is also an accompanying decrease in the amount of GCbinding globulin and albumin, which in turn leads to increased levels of free cortisol (17, 18).”
BackgroundSalivary Cortisol for Assessment of Hypothalamic-Pituitary-Adrenal Axis Function
Törnhage, C. (2009) · NeuroImmunoModulation · doi:10.1159/000216186 · Cited by 120
Assessment of adrenal function in cirrhotic patients: Salivary cortisol should be preferred
Galbois, A., Rudler, M., Massard, J., Fulla, Y., Bennani, A., Bonnefont‐Rousselot, D., Thibault, V., Reignier, S., Bourrier, A., Poynard, T., et al. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.01.026 · Cited by 118
“Indeed, it has been shown that STC assays overestimate AI prevalence in ICU patients without cirrhosis but who have albuminemia 6 25 g/L [17].”
BackgroundMethodResultDoes serum 25-hydroxyvitamin D decrease during acute-phase response? A systematic review
Silva, M. C., & Furlanetto, T. W. (2014) · Nutrition Research · doi:10.1016/j.nutres.2014.12.008 · Cited by 117
Beuschlein, F., Else, T., Bancos, I., Hahner, S., Hamidi, O., van Hulsteijn, L. T., Husebye, E. S., Karavitaki, N., Prete, A., Vaidya, A., et al. (2024) · European Journal of Endocrinology · doi:10.1093/ejendo/lvae029 · Cited by 137
Deal, B. J., Mavroudis, C. D., Jacobs, J. P., Gevitz, M., & Backer, C. L. (2008) · Cardiology in the Young · doi:10.1017/s104795110800293x · Cited by 108
Endocrine Responses to Critical Illness: Novel Insights and Therapeutic Implications
Boonen, E., & Van den Berghe, G. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-4115 · Cited by 105
Increased Risk of Adrenal Insufficiency Following Etomidate Exposure in Critically Injured Patients
Cotton, B. A. (2008) · Archives of Surgery · doi:10.1001/archsurg.143.1.62 · Cited by 106
A Prospective Multicenter Study of Adrenal Function in Critically Ill Children
Menon, K., Ward, R., Lawson, M. L., Gaboury, I., Hutchison, J. S., & Hébert, P. C. (2010) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200911-1738oc · Cited by 106
“Stollery Children’s Hospital, Edmonton, AB, Canada (42): A.”
BackgroundInfluentialOn the Neuroendocrinopathy of Critical Illness. Perspectives for Feeding and Novel Treatments
den Berghe, G. V. (2016) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201607-1516ci · Cited by 109
Endocrine failure after traumatic brain injury in adults
Powner, D. J., Boccalandro, C., Alp, M. S., & Vollmer, D. G. (2006) · Neurocritical Care · doi:10.1385/ncc:5:1:61 · Cited by 105
Narinx, N., David, K., Walravens, J., Vermeersch, P., Claessens, F., Fiers, T., Lapauw, B., Antonio, L., & Vanderschueren, D. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04562-1 · Cited by 96
“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].”
BackgroundVenkatesh, B., Mortimer, R. H., Couchman, B. A., & Hall, J. (2005) · Anaesthesia and Intensive Care · doi:10.1177/0310057x0503300208 · Cited by 100
Pawluski, J. L., Rayen, I., Niessen, N., Kristensen, S., van Donkelaar, E. L., Balthazart, J., Steinbusch, H. W. M., & Charlier, T. D. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.06.034 · Cited by 97
McWhinney, B. C., Briscoe, S., Ungerer, J. P. J., & Pretorius, C. J. (2010) · Journal of Chromatography B · doi:10.1016/j.jchromb.2010.08.044 · Cited by 97
Adrenal insufficiency in critical illness
Cooper, M. S., & Stewart, P. M. (2007) · Journal of Intensive Care Medicine · doi:10.1177/0885066607307832 · Cited by 97
“” Another option is to measure free cortisol directly using equilibrium dialysis (a technique in which free but not bound cortisol can diffuse across a membrane and be measured directly) [11] or cortisol in a fluid that contains minimal binding proteins (such as saliva) [81].”
BackgroundThe diagnosis of Cushing’s syndrome
Carroll, T. B., & Findling, J. W. (2010) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-010-9143-3 · Cited by 95
“Estrogen-induced increases in CBG (from oral contraceptives or pregnancy) or decreases caused by critical illness or nephrotic syndrome, also can affect the validity of the DST by increasing or decreasing the total blood cortisol level [19, 20].”
BackgroundTan, T. C. H., Chang, L., Woodward, A. J., McWhinney, B. C., Galligan, J., Macdonald, G. A., Cohen, J., & Venkatesh, B. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.05.020 · Cited by 95
“[27] Higher ranges from 52 nmol/L have also been observed [20] Additionally, a comparison of salivary cortisol levels following ACTH testing in healthy controls and patients with documented adrenal insufficiency suggested a normal lower limit for salivary levels of 23.”
BackgroundResultApplications of Steroid in Clinical Practice: A Review
Shaikh, S., Verma, H., Yadav, N., Jauhari, M., & Bullangowda, J. (2012) · ISRN Anesthesiology · doi:10.5402/2012/985495 · Cited by 93
“[62] showed that, during continuous hydrocortisone infusion (10 mg/hr), plasma total cortisol levels were over 3000 nmol/L, well above the levels reported in patients with septic shock (mean 880 nmol/L) [63].”
BackgroundEpidemiological approaches to measure childhood stress
Vanaelst, B., Vriendt, T. D., Huybrechts, I., Rinaldi, S., & Henauw, S. D. (2012) · Paediatric and Perinatal Epidemiology · doi:10.1111/j.1365-3016.2012.01258.x · Cited by 105
The altered adrenal axis and treatment with glucocorticoids during critical illness
Mesotten, D., Vanhorebeek, I., & den Berghe, G. V. (2008) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0921 · Cited by 94
“Also, severely reduced albumin levels have been observed in critically ill patients”
BackgroundPrognostic value of relative adrenal insufficiency after out-of-hospital cardiac arrest
Pène, F., Hyvernat, H., Mallet, V. O., Cariou, A., Carli, P. A., Spaulding, C. M., Dugué, M.-A., & Mira, J. P. (2005) · Intensive Care Medicine · doi:10.1007/s00134-005-2603-7 · Cited by 91
ACTH and cortisol response to critical illness in term and late preterm newborns
Fernandez, E. F., Montman, R., & Watterberg, K. L. (2008) · Journal of Perinatology · doi:10.1038/jp.2008.190 · Cited by 89
Assessment of adrenocortical reserve in stable patients with cirrhosis
Fede, G., Spadaro, L., Tomaselli, T., Privitera, G., Piro, S., Rabuazzo, A. M., Sigalas, A., Xirouchakis, E., O’Beirne, J. P., Garcovich, M., et al. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.06.034 · Cited by 90
“However, there is no established consensus on the diagnostic criteria of adrenal insufficiency using the LDSST and several threshold values of post-stimulation cortisol have been proposed [4,20,32,34,35].”
BackgroundMethodAdrenal-exhaustion syndrome in patients with liver disease
Marik, P. (2006) · Intensive Care Medicine · doi:10.1007/s00134-005-0005-5 · Cited by 91
Lipopolysaccharide: An Endotoxin or an Exogenous Hormone?
Marshall, J. C. (2005) · Clinical Infectious Diseases · doi:10.1086/432000 · Cited by 89
“Similarly, 190% of circulating cortisol is bound to corticosteroid-binding globulin or albumin [43]; acute reductions in the levels of these proteins in trauma or critical illness confounds accurate measurement of cortisol levels and may contribute to altered end-organ responses [44, 45].”
BackgroundThe Neuroendocrine Response to Critical Illness is a Dynamic Process
Vanhorebeek, I., & den Berghe, G. V. (2006) · Critical Care Clinics · doi:10.1016/j.ccc.2005.09.004 · Cited by 88
“Because CBG levels are substantially decreased, in part because of elastaseinduced cleavage [68,69], the proportional increase in free cortisol is much higher than that in total cortisol [70,71].”
BackgroundUpdate on adrenal insufficiency in patients with liver cirrhosis
Trifan, A. V. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i4.445 · Cited by 84
Marshall, J. C. (2006) · Current Infectious Disease Reports · doi:10.1007/s11908-006-0045-1 · Cited by 85
“Finally, the binding of a marker to proteins such as albumin can result in variability in assay results [ 16 ].”
ResultTechnical details influence the diagnostic accuracy of the 1 μg ACTH stimulation test
Wade, M., Baid, S., Calis, K., Raff, H., Sinaii, N., & Nieman, L. (2010) · European Journal of Endocrinology · doi:10.1530/eje-09-0746 · Cited by 83
Multiple measures elucidate glucocorticoid responses to environmental variation in predation threat
Clinchy, M., Zanette, L., Charlier, T. D., Newman, A. E. M., Schmidt, K. L., Boonstra, R., & Soma, K. K. (2011) · Oecologia · doi:10.1007/s00442-011-1915-2 · Cited by 83
“Given the hypothesized importance of free CORT, we calculated the level of free CORT in the plasma of each individual using the free CORT index (FCI), defined as (total CORT 9 100)/CBG, with both total CORT and CBG in molar units (Hamrahian et al. 2004; Davidson et al. 2006).”
MethodEtomidate for emergency anaesthesia; mad, bad and dangerous to know?
Morris, C., & McAllister, C. (2005) · Anaesthesia · doi:10.1111/j.1365-2044.2005.04325.x · Cited by 82
Association between Adrenal Insufficiency and Ventilator Weaning
Huang, C., & Lin, H. (2005) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200504-545oc · Cited by 84
Relative Adrenal Insufficiency in Dogs with Sepsis
Burkitt, J. M., Haskins, S. C., Nelson, R. W., & Kass, P. H. (2007) · Journal of Veterinary Internal Medicine · doi:10.1111/j.1939-1676.2007.tb02953.x · Cited by 83
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
