Comprehensive Physiology Wiley Online Library

Adrenocortical Stress Response during the Course of Critical Illness

Full Article on Wiley Online Library



ABSTRACT

Critically ill patients have elevated plasma cortisol concentrations, in proportion to illness severity. This was traditionally attributed exclusively to a central activation of the hypothalamus‐pituitary axis. However, low rather than high plasma ACTH concentrations have been reported in critically ill patients, with loss of diurnal ACTH and cortisol rhythm. Low ACTH together with high cortisol is referred to as “ACTH‐cortisol dissociation.” Although cortisol production is somewhat increased with inflammation, a reduced cortisol breakdown explains to a larger extent the hypercortisolism during critical illness. Inflammation‐driven decrease in cortisol binding proteins further increase the active free cortisol fraction. Several drugs administered to ICU patients suppress plasma cortisol in a dose‐dependent manner.

Sustained low circulating ACTH might contribute to adrenal atrophy and dysfunction in the prolonged phase of critical illness. In the acute phase of sepsis or septic shock, a condition referred to as “relative adrenal insufficiency” has been suggested to ensue from glucocorticoid resistance and insufficiently elevated circulating cortisol to overcome such resistance, with pathological changes possibly occurring at every level of the HPA axis. However, it remains highly controversial whether tissue‐specific glucocorticoid resistance is adaptive or maladaptive, how to diagnose “relative” adrenal insufficiency, and how it should be treated. Large RCTs, investigating the effect of 200 mg/d hydrocortisone treatment for sepsis or septic shock have shown conflicting, mainly negative, results. Not taking into account the reduced cortisol breakdown, which increases the risk of overdosing hydrocortisone, might have played a role. Further research on diagnostic, therapeutic and dosing aspects is urgently warranted. Compr Physiol 8:283‐298, 2018.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Shown are the biphasic neuroendocrine responses of the anterior pituitary hormones and their peripheral hormones to acute and chronic critical illness. In the acute phase of illness the growth hormone (GH) and thyrotrophin (TSH) secretory activity is amplified (red), and adrenocorticotropic hormone (ACTH) secretory activity is increased in some cases. Plasma concentrations of their anabolic peripheral hormones (insulin‐like growth factor‐I, triiodothyronine) are decreased (green), but cortisol levels are elevated (yellow). In prolonged critical illness, secretion of GH, TSH, and ACTH is consistently suppressed, with a further decrease of their peripheral hormones. Plasma cortisol levels remain high, but in some cases low plasma cortisol levels appear in the chronic phase of critical illness. (Figure was reproduced from Van den Berghe (), with permission from The Journal of Clinical Endocrinology and Metabolism.)
Figure 2. Figure 2. Mean values and standard errors for plasma ACTH (Panel A), total cortisol (Panel B), and free cortisol (Panel C) in ICU patients from admission onward until day 3 of ICU stay. The blue shaded area represents the interquartile range of morning values in healthy control subjects. *P ≤ 0.05, **P < 0.001, for the comparison with controls. §P ≤ 0.05, §§P < 0.01, §§§P < 0.0001, for the comparison of paired values of the consecutive days with the admission sample. For each day, the number of patients still in ICU is displayed below the figure. ICU denotes intensive care unit, adm denotes admission. (Figure was reproduced from Peeters (), with permission from Clinical Endocrinology.)
Figure 3. Figure 3. Cortisol metabolism in humans. Cortisol and cortisone are mainly broken down via A‐ring reductases, 5α‐reductase and 5β‐reductase, in the liver to generate 5α‐ and 5β‐tetrahydrocortisol. In the kidney, cortisol is metabolized by 11β‐hydroxysteroid dehydrogenase (11β‐HSD) type 2, generating cortisone, which can further be broken down to tetra‐hydrocortisone (THE) by 5β‐reductase. 11β‐HSD type 1 can reconvert cortisone to cortisol.
Figure 4. Figure 4. Adrenocorticotropic hormone (ACTH) binds to its receptor, the melanocortin 2 receptor (MC2R), on the membrane of the adrenocortical cells, which increases cyclic AMP (cAMP) and stimulates protein kinase A (PKA). PKA causes the release of cholesterol from the lipid droplets into the cytoplasm and de novo production from acetyl coenzyme A (acetyl CoA). ACTH increases the expression of the steroidogenic acute regulatory protein (STAR) to transport cholesterol from the cytoplasm to the inner membrane of the mitochondria where steroidogenesis takes place. Cholesterol is converted into different steroid hormones. The long‐term impact of ACTH involves increased transcription of genes important for cholesterol uptake [scavenger‐receptor class B, member 1 (SCARB1), LDL receptor (LDLR)] and cholesterol synthesis [3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR)], and for steroidogenesis (STAR and CYP11A1). ACTH has a direct stimulatory effect on the expression of its own receptor (MC2R). Blue lines represent ACTH effects. (Figure was reproduced from Boonen (), with permission from The Lancet Diabetes & Endocrinology.)
Figure 5. Figure 5. mRNA expression of ACTH‐regulated proteins in adrenal glands, harvested from individuals dying suddenly out of hospital (control subjects), from patients dying after short critical illness and from patients after prolonged critical illness. The mRNA data are expressed, normalized to RNA18S as a fold difference from the mean of the controls. Boxes represent medians and interquartile ranges and whiskers represent firstquartile‐1.5*IQR and thirdquartile+1.5*IQR. (Figure was reproduced from Boonen (), with permission from The Journal of Clinical Endocrinology and Metabolism.)
Figure 6. Figure 6. Overview of the regulation of hypercortisolism during critical illness. ↑, elevated plasma concentrations; ↓, decreased plasma concentrations; ?, no univocal data available; +, stimulates; −, inhibits; PVN, paraventricular nucleus; ACTH, adrenocorticotropic hormone; CBG, corticosteroid‐binding globulin.


Figure 1. Shown are the biphasic neuroendocrine responses of the anterior pituitary hormones and their peripheral hormones to acute and chronic critical illness. In the acute phase of illness the growth hormone (GH) and thyrotrophin (TSH) secretory activity is amplified (red), and adrenocorticotropic hormone (ACTH) secretory activity is increased in some cases. Plasma concentrations of their anabolic peripheral hormones (insulin‐like growth factor‐I, triiodothyronine) are decreased (green), but cortisol levels are elevated (yellow). In prolonged critical illness, secretion of GH, TSH, and ACTH is consistently suppressed, with a further decrease of their peripheral hormones. Plasma cortisol levels remain high, but in some cases low plasma cortisol levels appear in the chronic phase of critical illness. (Figure was reproduced from Van den Berghe (), with permission from The Journal of Clinical Endocrinology and Metabolism.)


Figure 2. Mean values and standard errors for plasma ACTH (Panel A), total cortisol (Panel B), and free cortisol (Panel C) in ICU patients from admission onward until day 3 of ICU stay. The blue shaded area represents the interquartile range of morning values in healthy control subjects. *P ≤ 0.05, **P < 0.001, for the comparison with controls. §P ≤ 0.05, §§P < 0.01, §§§P < 0.0001, for the comparison of paired values of the consecutive days with the admission sample. For each day, the number of patients still in ICU is displayed below the figure. ICU denotes intensive care unit, adm denotes admission. (Figure was reproduced from Peeters (), with permission from Clinical Endocrinology.)


Figure 3. Cortisol metabolism in humans. Cortisol and cortisone are mainly broken down via A‐ring reductases, 5α‐reductase and 5β‐reductase, in the liver to generate 5α‐ and 5β‐tetrahydrocortisol. In the kidney, cortisol is metabolized by 11β‐hydroxysteroid dehydrogenase (11β‐HSD) type 2, generating cortisone, which can further be broken down to tetra‐hydrocortisone (THE) by 5β‐reductase. 11β‐HSD type 1 can reconvert cortisone to cortisol.


Figure 4. Adrenocorticotropic hormone (ACTH) binds to its receptor, the melanocortin 2 receptor (MC2R), on the membrane of the adrenocortical cells, which increases cyclic AMP (cAMP) and stimulates protein kinase A (PKA). PKA causes the release of cholesterol from the lipid droplets into the cytoplasm and de novo production from acetyl coenzyme A (acetyl CoA). ACTH increases the expression of the steroidogenic acute regulatory protein (STAR) to transport cholesterol from the cytoplasm to the inner membrane of the mitochondria where steroidogenesis takes place. Cholesterol is converted into different steroid hormones. The long‐term impact of ACTH involves increased transcription of genes important for cholesterol uptake [scavenger‐receptor class B, member 1 (SCARB1), LDL receptor (LDLR)] and cholesterol synthesis [3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR)], and for steroidogenesis (STAR and CYP11A1). ACTH has a direct stimulatory effect on the expression of its own receptor (MC2R). Blue lines represent ACTH effects. (Figure was reproduced from Boonen (), with permission from The Lancet Diabetes & Endocrinology.)


Figure 5. mRNA expression of ACTH‐regulated proteins in adrenal glands, harvested from individuals dying suddenly out of hospital (control subjects), from patients dying after short critical illness and from patients after prolonged critical illness. The mRNA data are expressed, normalized to RNA18S as a fold difference from the mean of the controls. Boxes represent medians and interquartile ranges and whiskers represent firstquartile‐1.5*IQR and thirdquartile+1.5*IQR. (Figure was reproduced from Boonen (), with permission from The Journal of Clinical Endocrinology and Metabolism.)


Figure 6. Overview of the regulation of hypercortisolism during critical illness. ↑, elevated plasma concentrations; ↓, decreased plasma concentrations; ?, no univocal data available; +, stimulates; −, inhibits; PVN, paraventricular nucleus; ACTH, adrenocorticotropic hormone; CBG, corticosteroid‐binding globulin.
References
 1. Abs R , Verhelst J , Maeyaert J , Van Buyten JP , Opsomer F , Adriaensen H , Verlooy J , Van Havenbergh T , Smet M , Van Acker K . Endocrine consequences of long‐term intrathecal administration of opioids. J Clin Endocrinol Metabol 85: 2215‐2222, 2000.
 2. Aitkenhead AR , Pepperman ML , Willatts SM , Coates PD , Park GR , Bodenham AR , Collins CH , Smith MB , Ledingham IM , Wallace PG . Comparison of propofol and midazolam for sedation in critically ill patients. Lancet 2: 704‐709, 1989.
 3. Albrecht U. Timing to perfection: The biology of central and peripheral circadian clocks. Neuron 74: 246‐260, 2012.
 4. Ali M , Allen HR , Vedeckis WV , Lang CH . Depletion of rat liver glucocorticoid receptor hormone‐binding and its mRNA in sepsis. Life Sci 48: 603‐611, 1991.
 5. Aloisi AM , Aurilio C , Bachiocco V , Biasi G , Fiorenzani P , Pace MC , Paci V , Pari G , Passavanti G , Ravaioli L , Sindaco G , Vellucci R , Ceccarelli I . Endocrine consequences of opioid therapy. Psychoneuroendocrinology 34(Suppl 1): S162‐168, 2009.
 6. Annane D , Bellissant E , Bollaert PE , Briegel J , Confalonieri M , De Gaudio R, Keh D , Kupfer Y , Oppert M , Meduri GU . Corticosteroids in the treatment of severe sepsis and septic shock in adults: A systematic review. JAMA 301: 2362‐2375, 2009.
 7. Annane D , Maxime V , Ibrahim F , Alvarez JC , Abe E , Boudou P . Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med 174: 1319‐1326, 2006.
 8. Annane D , Sebille V , Charpentier C , Bollaert PE , Francois B , Korach JM , Capellier G , Cohen Y , Azoulay E , Troche G , Chaumet‐Riffaud P , Bellissant E . Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288: 862‐871, 2002.
 9. Annane D , Sebille V , Troche G , Raphael JC , Gajdos P , Bellissant E . A 3‐level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283: 1038‐1045, 2000.
 10. Arafah BM , Nishiyama FJ , Tlaygeh H , Hejal R . 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 Metabol 92: 2965‐2971, 2007.
 11. Axelrod J , Reisine TD . Stress hormones: Their interaction and regulation. Science 224: 452‐459, 1984.
 12. Balbao VM , Costa MM , Castro M , Carlotti AP . Evaluation of adrenal function in critically ill children. Clin Endocrinol 81: 559‐565, 2014.
 13. Bartanusz V , Corneille MG , Sordo S , Gildea M , Michalek JE , Nair PV , Stewart RM , Jezova D . Diurnal salivary cortisol measurement in the neurosurgical‐surgical intensive care unit in critically ill acute trauma patients. J Clin Neurosci 21: 2150‐2154, 2014.
 14. Beishuizen A , Thijs LG , Vermes I . Patterns of corticosteroid‐binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med 27: 1584‐1591, 2001.
 15. Bergquist M , Nurkkala M , Rylander C , Kristiansson E , Hedenstierna G , Lindholm C . Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis. J Infect 67: 574‐583, 2013.
 16. Bertini R , Bianchi M , Ghezzi P . Adrenalectomy sensitizes mice to the lethal effects of interleukin 1 and tumor necrosis factor. J Exp Med 167: 1708‐1712, 1988.
 17. Boonen E , Bornstein SR , Van den Berghe G . New insights into the controversy of adrenal function during critical illness. Lancet Diabetes Endocrinol 3: 805‐815, 2015.
 18. Boonen E , Langouche L , Janssens T , Meersseman P , Vervenne H , De Samblanx E , Pironet Z , Van Dijck L , Vander Perre S , Derese I , Van den Berghe G . Impact of duration of critical illness on the adrenal glands of human intensive care patients. J Clin Endocrinol Metabol 99: 4214‐4222, 2014.
 19. Boonen E , Meersseman P , Vervenne H , Meyfroidt G , Guiza F , Wouters PJ , Veldhuis JD , Van den Berghe G . Reduced nocturnal ACTH‐driven cortisol secretion during critical illness. Am J Physiol Endocrinol Metab 306: E883‐E892, 2014.
 20. Boonen E , Vervenne H , Meersseman P , Andrew R , Mortier L , Declercq PE , Vanwijngaerden YM , Spriet I , Wouters PJ , Vander PS , Langouche L , Vanhorebeek I , Walker BR , Van den Berghe G . Reduced cortisol metabolism during critical illness. N Engl J Med 368: 1477‐1488, 2013.
 21. Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med 360: 2328‐2339, 2009.
 22. Bornstein SR , Ehrhart‐Bornstein M , Scherbaum WA , Pfeiffer EF , Holst JJ . Effects of splanchnic nerve stimulation on the adrenal cortex may be mediated by chromaffin cells in a paracrine manner. Endocrinology 127: 900‐906, 1990.
 23. Bornstein SR , Engeland WC , Ehrhart‐Bornstein M , Herman JP . Dissociation of ACTH and glucocorticoids. Trends Endocrinol Metab 19: 175‐180, 2008.
 24. Bornstein SR , Zacharowski P , Schumann RR , Barthel A , Tran N , Papewalis C , Rettori V , McCann SM , Schulze‐Osthoff K , Scherbaum WA , Tarnow J , Zacharowski K . Impaired adrenal stress response in Toll‐like receptor 2‐deficient mice. Proc Natl Acad Sci U S A 101: 16695‐16700, 2004.
 25. Brorsson C , Dahlqvist P , Nilsson L , Thunberg J , Sylvan A , Naredi S . Adrenal response after trauma is affected by time after trauma and sedative/analgesic drugs. Injury 45: 1149‐1155, 2014.
 26. Bruder EA , Ball IM , Ridi S , Pickett W , Hohl C . Single induction dose of etomidate versus other induction agents for endotracheal intubation in critically ill patients. Cochrane Database Syst Rev 1: CD010225, 2015.
 27. Buijs RM , Wortel J , Van Heerikhuize JJ , Feenstra MG , Ter Horst GJ , Romijn HJ , Kalsbeek A . Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci 11: 1535‐1544, 1999.
 28. Carroll BJ , Cassidy F , Naftolowitz D , Tatham NE , Wilson WH , Iranmanesh A , Liu PY , Veldhuis JD . Pathophysiology of hypercortisolism in depression. Acta Psychiatr Scand Suppl 115: 90‐103, 2007.
 29. Chapman K , Holmes M , Seckl J . 11beta‐hydroxysteroid dehydrogenases: Intracellular gate‐keepers of tissue glucocorticoid action. Physiol Rev 93: 1139‐1206, 2013.
 30. Charmandari E , Nicolaides NC , Chrousos GP . Adrenal insufficiency. Lancet 383: 2152‐2167, 2014.
 31. Chernow B , Alexander HR , Smallridge RC , Thompson WR , Cook D , Beardsley D , Fink MP , Lake CR , Fletcher JR . Hormonal responses to graded surgical stress. Arch Intern Med 147: 1273‐1278, 1987.
 32. Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol 5: 374‐381, 2009.
 33. Coll AP , Challis BG , Yeo GS , Snell K , Piper SJ , Halsall D , Thresher RR , O'Rahilly S . The effects of proopiomelanocortin deficiency on murine adrenal development and responsiveness to adrenocorticotropin. Endocrinology 145: 4721‐4727, 2004.
 34. Coolens JL , Van Baelen H , Heyns W . Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid‐binding globulin. J Steroid Biochem 26: 197‐202, 1987.
 35. Cooper MS , Stewart PM . Corticosteroid insufficiency in acutely ill patients. N Engl J Med 348: 727‐734, 2003.
 36. Cornil A , Copinschi G , Leclercq R , Franckson JR . Cortisol secretion during acute bacterial infections in man. Acta Endocrinol 58: 1‐5, 1968.
 37. Cornil A , Glinoer D , Leclerco R , Copinschi G . Adrenocortical and somatotrophic secretions in acute and chronic respiratory insufficiency. Am Rev Respir Dis 112: 77‐81, 1975.
 38. Dalegrave D , Silva RL , Becker M , Gehrke LV , Friedman G . Relative adrenal insufficiency as a predictor of disease severity and mortality in severe septic shock. Rev Bras Ter Intensiva 24: 362‐368, 2012.
 39. de Jong MF , Molenaar N , Beishuizen A , Groeneveld AB . Diminished adrenal sensitivity to endogenous and exogenous adrenocorticotropic hormone in critical illness: A prospective cohort study. Crit Care 19: 1, 2015.
 40. de Kloet ER , Karst H , Joels M . Corticosteroid hormones in the central stress response: Quick‐and‐slow. Front Neuroendocrinol 29: 268‐272, 2008.
 41. Debaveye Y , J V, G. VdB. Endocrine emergencies. In: Tubaro M , Danchin N , Filippatos G , Goldstein P , Vranckx P , and Zahger D , editors. The ESC Textbook of Intensive and Acute Cardiac Care. New York: Oxford University Press, 2011, pp. 709‐717.
 42. Dennesen P , van der Ven A , Vlasveld M , Lokker L , Ramsay G , Kessels A , van den Keijbus P , van Nieuw Amerongen A , Veerman E . Inadequate salivary flow and poor oral mucosal status in intubated intensive care unit patients. Crit Care Med 31: 781‐786, 2003.
 43. Desmet SJ , De Bosscher K . Glucocorticoid receptors: Finding the middle ground. J Clin Invest 127: 1136‐1145, 2017.
 44. Deutschman CS , Raj NR , McGuire EO , Kelz MB . Orexinergic activity modulates altered vital signs and pituitary hormone secretion in experimental sepsis. Crit Care Med 41: e368‐e375, 2013.
 45. Dickstein G , Shechner C , Nicholson WE , Rosner I , Shen‐Orr Z , Adawi F , Lahav M . Adrenocorticotropin stimulation test: Effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metabol 72: 773‐778, 1991.
 46. Dimopoulou I , Tzanela M , Vassiliadi D , Mavrou I , Kopterides P , Orfanos S , Kotanidou A , Kontogiannopoulou S , Vasdekis S , Tsangaris I , Armaganidis A , Macheras A , Ilias I , Kostopanagiotou G , Tsagarakis S . Pituitary‐adrenal responses following major abdominal surgery. Hormones (Athens) 7: 237‐242, 2008.
 47. Dispersyn G , Sage D , Challet E , Pain L , Touitou Y . Plasma corticosterone in rats is specifically increased at recovery from propofol anesthesia without concomitant rise of plasma ACTH. Chronobiol Int 26: 697‐708, 2009.
 48. Droste SK , Chandramohan Y , Hill LE , Linthorst AC , Reul JM . Voluntary exercise impacts on the rat hypothalamic‐pituitary‐adrenocortical axis mainly at the adrenal level. Neuroendocrinology 86: 26‐37, 2007.
 49. Droste SK , Schweizer MC , Ulbricht S , Reul JM . Long‐term voluntary exercise and the mouse hypothalamic‐pituitary‐adrenocortical axis: Impact of concurrent treatment with the antidepressant drug tianeptine. J Neuroendocrinol 18: 915‐925, 2006.
 50. Ehrhart‐Bornstein M , Hinson JP , Bornstein SR , Scherbaum WA , Vinson GP . Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. EndocrRev 19: 101‐143, 1998.
 51. Elbuken G , Karaca Z , Tanriverdi F , Unluhizarci K , Sungur M , Doganay M , Kelestimur F . Comparison of total, salivary and calculated free cortisol levels in patients with severe sepsis. J Intensive Care 4: 3, 2016.
 52. Estrada YMR , Orlander PR . Salivary cortisol can replace free serum cortisol measurements in patients with septic shock. Chest 140: 1216‐1222, 2011.
 53. Ferreira JG , Cruz CD , Neves D , Pignatelli D . Increased extracellular signal regulated kinases phosphorylation in the adrenal gland in response to chronic ACTH treatment. J Endocrinol 192: 647‐658, 2007.
 54. Festti J , Grion CM , Festti L , Mazzuco TL , Lima‐Valassi HP , Brito VN , Barbosa DS , Carrilho AJ . Adrenocorticotropic hormone but not high‐density lipoprotein cholesterol or salivary cortisol was a predictor of adrenal insufficiency in patients with septic shock. Shock 42: 16‐21, 2014.
 55. Fiebeler A , Muller DN , Shagdarsuren E , Luft FC . Aldosterone, mineralocorticoid receptors, and vascular inflammation. Curr Opin Nephrol Hypertens 16: 134‐142, 2007.
 56. Garaulet M , Madrid JA . Chronobiological aspects of nutrition, metabolic syndrome and obesity. Adv Drug Deliv Rev 62: 967‐978, 2010.
 57. Gemsenjager E , Staub JJ , Girard J . Pituitary thyroid recovery following surgery in TRH‐unresponsive patients with uni‐ and multinodular goiter. Horm Res 8: 139‐147, 1977.
 58. Gianoulakis C , Dai X , Thavundayil J , Brown T . Levels and circadian rhythmicity of plasma ACTH, cortisol, and beta‐endorphin as a function of family history of alcoholism. Psychopharmacology 181: 437‐444, 2005.
 59. Gibbison B , Spiga F , Walker JJ , Russell GM , Stevenson K , Kershaw Y , Zhao Z , Henley D , Angelini GD , Lightman SL . Dynamic pituitary‐adrenal interactions in response to cardiac surgery. Crit Care Med 43: 791‐800, 2015.
 60. Girotti M , Weinberg MS , Spencer RL . Diurnal expression of functional and clock‐related genes throughout the rat HPA axis: System‐wide shifts in response to a restricted feeding schedule. Am J Physiol Endocrinol Metab 296: E888‐E897, 2009.
 61. Gomez MT , Magiakou MA , Mastorakos G , Chrousos GP . The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic‐pituitary‐adrenal axis in patients with Cushing syndrome. J Clin Endocrinol Metabol 77: 173‐177, 1993.
 62. Gross KL , Lu NZ , Cidlowski JA . Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol Cell Endocrinol 300: 7‐16, 2009.
 63. Guerrero J , Gatica HA , Rodriguez M , Estay R , Goecke IA . Septic serum induces glucocorticoid resistance and modifies the expression of glucocorticoid isoforms receptors: A prospective cohort study and in vitro experimental assay. Crit Care 17: R107, 2013.
 64. Gunnala V , Guo R , Minutti C , Durazo‐Arvizu R , Laporte C , Mathews H , Kliethermis S , Bhatia R . Measurement of salivary cortisol level for the diagnosis of critical illness‐related corticosteroid insufficiency in children. Pediatr Crit Care Med 16: e101‐e106, 2015.
 65. Hagg E , Asplund K , Lithner F . Value of basal plasma cortisol assays in the assessment of pituitary‐adrenal insufficiency. Clin Endocrinol 26: 221‐226, 1987.
 66. Hamrahian AH , Fleseriu M , Committee AAS . Evaluation and management of adrenal insufficiency in critically ill patients’ disease state review. Endocr Pract 23: 716‐725, 2017.
 67. Hamrahian AH , Oseni TS , Arafah BM . Measurements of serum free cortisol in critically ill patients. N Engl J Med 350: 1629‐1638, 2004.
 68. Hastings M , O'Neill JS , Maywood ES . Circadian clocks: Regulators of endocrine and metabolic rhythms. J Endocrinol 195: 187‐198, 2007.
 69. Henley DE , Lightman SL . New insights into corticosteroid‐binding globulin and glucocorticoid delivery. Neuroscience 180: 1‐8, 2011.
 70. Hermans G , De Jonghe B , Bruyninckx F , Van den Berghe G . Clinical review: Critical illness polyneuropathy and myopathy. Crit Care 12: 238, 2008.
 71. Hermans G , Wilmer A , Meersseman W , Milants I , Wouters PJ , Bobbaers H , Bruyninckx F , Van den Berghe G . Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit. Am J Respir Crit Care Med 175: 480‐489, 2007.
 72. Hildreth AN , Mejia VA , Maxwell RA , Smith PW , Dart BW , Barker DE . Adrenal suppression following a single dose of etomidate for rapid sequence induction: A prospective randomized study. J Trauma 65: 573‐579, 2008.
 73. Hinson JP , Vinson GP , Kapas S , Teja R . The role of endothelin in the control of adrenocortical function: stimulation of endothelin release by ACTH and the effects of endothelin‐1 and endothelin‐3 on steroidogenesis in rat and human adrenocortical cells. J Endocrinol 128: 275‐280, 1991.
 74. Ho JT , Al‐Musalhi H , Chapman MJ , Quach T , Thomas PD , Bagley CJ , Lewis JG , Torpy DJ . Septic shock and sepsis: A comparison of total and free plasma cortisol levels. J Clin Endocrinol Metabol 91: 105‐114, 2006.
 75. Indyk JA , Candido‐Vitto C , Wolf IM , Venkataraman S , Munoz R , Saladino RA , Witchel SF , Defranco DB . Reduced glucocorticoid receptor protein expression in children with critical illness. Horm Res Paediatr 79: 169‐178, 2013.
 76. Investigators CS , Annane D , Cariou A , Maxime V , Azoulay E , D'Honneur G , Timsit JF , Cohen Y , Wolf M , Fartoukh M , Adrie C , Santre C , Bollaert PE , Mathonet A , Amathieu R , Tabah A , Clec'h C , Mayaux J , Lejeune J , Chevret S . Corticosteroid treatment and intensive insulin therapy for septic shock in adults: A randomized controlled trial. JAMA 303: 341‐348, 2010.
 77. Iwashyna TJ , Hodgson CL , Pilcher D , Bailey M , van Lint A , Chavan S , Bellomo R . Timing of onset and burden of persistent critical illness in Australia and New Zealand: A retrospective, population‐based, observational study. Lancet Respir Med 4: 566‐573, 2016.
 78. Jarek MJ , Legare EJ , McDermott MT , Merenich JA , Kollef MH . Endocrine profiles for outcome prediction from the intensive care unit. Crit Care Med 21: 543‐550, 1993.
 79. Jurney TH , Cockrell JL, Jr. , Lindberg JS , Lamiell JM , Wade CE . Spectrum of serum cortisol response to ACTH in ICU patients. Correlation with degree of illness and mortality. Chest 92: 292‐295, 1987.
 80. Kahn JM , Le T , Angus DC , Cox CE , Hough CL , White DB , Yende S , Carson SS , ProVent Study Group I. The epidemiology of chronic critical illness in the United States* . Crit Care Med 43: 282‐287, 2015.
 81. Kanczkowski W , Alexaki VI , Tran N , Grossklaus S , Zacharowski K , Martinez A , Popovics P , Block NL , Chavakis T , Schally AV , Bornstein SR . Hypothalamo‐pituitary and immune‐dependent adrenal regulation during systemic inflammation. Proc Natl Acad Sci U S A 110: 14801‐14806, 2013.
 82. Karpac J , Czyzewska K , Kern A , Brush RS , Anderson RE , Hochgeschwender U . Failure of adrenal corticosterone production in POMC‐deficient mice results from lack of integrated effects of POMC peptides on multiple factors. Am J Physiol Endocrinol Metab 295: E446‐E455, 2008.
 83. Keh D , Trips E , Marx G , Wirtz SP , Abduljawwad E , Bercker S , Bogatsch H , Briegel J , Engel C , Gerlach H , Goldmann A , Kuhn SO , Huter L , Meier‐Hellmann A , Nierhaus A , Kluge S , Lehmke J , Loeffler M , Oppert M , Resener K , Schadler D , Schuerholz T , Simon P , Weiler N , Weyland A , Reinhart K , Brunkhorst FM , SepNet‐Critical Care Trials G. Effect of hydrocortisone on development of shock among patients with severe sepsis: The HYPRESS Randomized Clinical Trial. JAMA 316: 1775‐1785, 2016.
 84. Keller‐Wood ME , Dallman MF . Corticosteroid inhibition of ACTH secretion. Endocr Rev 5: 1‐24, 1984.
 85. Kleiman A , Hubner S , Rodriguez Parkitna JM , Neumann A , Hofer S , Weigand MA , Bauer M , Schmid W , Schutz G , Libert C , Reichardt HM , Tuckermann JP . Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin‐1 in macrophages. FASEB J 26: 722‐729, 2012.
 86. Kostopanagiotou G , Kalimeris K , Christodoulaki K , Nastos C , Papoutsidakis N , Dima C , Chrelias C , Pandazi A , Mourouzis I , Pantos C . The differential impact of volatile and intravenous anaesthetics on stress response in the swine. Hormones (Athens) 9: 67‐75, 2010.
 87. Krude H , Gruters A . Implications of proopiomelanocortin (POMC) mutations in humans: The POMC deficiency syndrome. Trends Endocrinol Metab 11: 15‐22, 2000.
 88. Krug AW , Vleugels K , Schinner S , Lamounier‐Zepter V , Ziegler CG , Bornstein SR , Ehrhart‐Bornstein M . Human adipocytes induce an ERK1/2 MAP kinases‐mediated upregulation of steroidogenic acute regulatory protein (StAR) and an angiotensin II‐sensitization in human adrenocortical cells. Int J Obes (Lond) 31: 1605‐1616, 2007.
 89. Lebrethon MC , Naville D , Begeot M , Saez JM . Regulation of corticotropin receptor number and messenger RNA in cultured human adrenocortical cells by corticotropin and angiotensin II. J Clin Invest 93: 1828‐1833, 1994.
 90. Ledderose C , Mohnle P , Limbeck E , Schutz S , Weis F , Rink J , Briegel J , Kreth S . Corticosteroid resistance in sepsis is influenced by microRNA‐124–induced downregulation of glucocorticoid receptor‐alpha. Crit Care Med 40: 2745‐2753, 2012.
 91. Lehoux JG , Fleury A , Ducharme L . The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo. Endocrinology 139: 3913‐3922, 1998.
 92. Lehoux JG , Lefebvre A , Belisle S , Bellabarba D . Hormonal regulation of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase mRNA in the rat adrenal gland. J Steroid Biochem 34: 379‐384, 1989.
 93. Lin D , Sugawara T , Strauss JF , 3rd, Clark BJ , Stocco DM , Saenger P , Rogol A , Miller WL . Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267: 1828‐1831, 1995.
 94. Lindgren C , Dahlqvist P , Lindvall P , Nilsson L , Koskinen LO , Naredi S . Cortisol levels are influenced by sedation in the acute phase after subarachnoid haemorrhage. Acta Anaesthesiol Scand 57: 452‐460, 2013.
 95. Liu J , Heikkila P , Meng QH , Kahri AI , Tikkanen MJ , Voutilainen R . Expression of low and high density lipoprotein receptor genes in human adrenals. Eur J Endocrinol 142: 677‐682, 2000.
 96. Livesey JH , Dolamore B . Stability of plasma adrenocorticotrophic hormone (ACTH): Influence of hemolysis, rapid chilling, time, and the addition of a maleimide. Clin Biochem 43: 1478‐1480, 2010.
 97. Loriaux DL , Fleseriu M . Relative adrenal insufficiency. Curr Opin Endocrinol Diabetes Obes 16: 392‐400, 2009.
 98. Loriaux L. Glucocorticoid therapy in the intensive care unit. N Engl J Med 350: 1601‐1602, 2004.
 99. Marana E , Annetta MG , Meo F , Parpaglioni R , Galeone M , Maussier ML , Marana R . Sevoflurane improves the neuroendocrine stress response during laparoscopic pelvic surgery. Can J Anaesth 50: 348‐354, 2003.
 100. Marana E , Colicci S , Meo F , Marana R , Proietti R . Neuroendocrine stress response in gynecological laparoscopy: TIVA with propofol versus sevoflurane anesthesia. J Clin Anesth 22: 250‐255, 2010.
 101. Marcus‐Perlman Y , Tordjman K , Greenman Y , Limor R , Shenkerman G , Osher E , Stern N . Low‐dose ACTH (1 microg) salivary test: A potential alternative to the classical blood test. Clin Endocrinol 64: 215‐218, 2006.
 102. Marik PE. Critical illness‐related corticosteroid insufficiency. Chest 135: 181‐193, 2009.
 103. Marik PE , Pastores SM , Annane D , Meduri GU , Sprung CL , Arlt W , Keh D , Briegel J , Beishuizen A , Dimopoulou I , Tsagarakis S , Singer M , Chrousos GP , Zaloga G , Bokhari F , Vogeser M . Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 36: 1937‐1949, 2008.
 104. Marik PE , Zaloga GP . Adrenal insufficiency in the critically ill: A new look at an old problem. Chest 122: 1784‐1796, 2002.
 105. Marty J , Gauzit R , Lefevre P , Couderc E , Farinotti R , Henzel C , Desmonts JM . Effects of diazepam and midazolam on baroreflex control of heart rate and on sympathetic activity in humans. Anesth Analg 65: 113‐119, 1986.
 106. McIntosh TK , Lothrop DA , Lee A , Jackson BT , Nabseth D , Egdahl RH . Circadian rhythm of cortisol is altered in postsurgical patients. J Clin Endocrinol Metabol 53: 117‐122, 1981.
 107. Meduri GU , Bridges L , Shih MC , Marik PE , Siemieniuk RA , Kocak M . Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: Analysis of individual patients' data from four randomized trials and trial‐level meta‐analysis of the updated literature. Intensive Care Med 42: 829‐840, 2016.
 108. Mohler JL , Michael KA , Freedman AM , Griffen WO, Jr. , McRoberts JW . The serum and urinary cortisol response to operative trauma. Surg Gynecol Obstet 161: 445‐449, 1985.
 109. Nenke MA , Rankin W , Chapman MJ , Stevens NE , Diener KR , Hayball JD , Lewis JG , Torpy DJ . Depletion of high‐affinity corticosteroid‐binding globulin corresponds to illness severity in sepsis and septic shock; clinical implications. Clin Endocrinol 82: 801‐807, 2015.
 110. Nguyen PT , Lewis JG , Sneyd J , Lee RS , Torpy DJ , Shorten PR . Development of a formula for estimating plasma free cortisol concentration from a measured total cortisol concentration when elastase‐cleaved and intact corticosteroid binding globulin coexist. J Steroid BiochemMolBiol 141: 16‐25, 2014.
 111. Oster H , Damerow S , Kiessling S , Jakubcakova V , Abraham D , Tian J , Hoffmann MW , Eichele G . The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock. Cell Metab 4: 163‐173, 2006.
 112. Pascoe JE , Williams KL , Mukhopadhyay P , Rice KC , Woods JH , Ko MC . Effects of mu, kappa, and delta opioid receptor agonists on the function of hypothalamic‐pituitary‐adrenal axis in monkeys. Psychoneuroendocrinology 33: 478‐486, 2008.
 113. Pascualy M , Petrie EC , Brodkin K , Peskind ER , Wilkinson CW , Raskind MA . Hypothalamic pituitary adrenocortical and sympathetic nervous system responses to the cold pressor test in Alzheimer's disease. Biol Psychiatry 48: 247‐254, 2000.
 114. Patel GP , Balk RA . Systemic steroids in severe sepsis and septic shock. Am J Respir Crit Care Med 185: 133‐139, 2012.
 115. Peeters B , Guiza F , Boonen E , Meersseman P , Langouche L , Van den Berghe G . Drug‐induced HPA axis alterations during acute critical illness: A multivariable association study. Clin Endocrinol 86: 26‐36, 2017.
 116. Peeters RP , Hagendorf A , Vanhorebeek I , Visser TJ , Klootwijk W , Mesotten D , Wouters PJ , Koper JW , de Jong FH , Feelders RA , Lamberts SW , Van den Berghe G . Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clin Endocrinol (Oxf) 71: 145‐153, 2009.
 117. Perogamvros I , Aarons L , Miller AG , Trainer PJ , Ray DW . Corticosteroid‐binding globulin regulates cortisol pharmacokinetics. Clin Endocrinol 74: 30‐36, 2011.
 118. Perogamvros I , Keevil BG , Ray DW , Trainer PJ . Salivary cortisone is a potential biomarker for serum free cortisol. J Clin Endocrinol Metabol 95: 4951‐4958, 2010.
 119. Plunkett JJ , Reeves JD , Ngo L , Bellows W , Shafer SL , Roach G , Howse J , Herskowitz A , Mangano DT . Urine and plasma catecholamine and cortisol concentrations after myocardial revascularization. Modulation by continuous sedation. Multicenter Study of Perioperative Ischemia (McSPI) Research Group, and the Ischemia Research and Education Foundation (IREF). Anesthesiology 86: 785‐796, 1997.
 120. Polito A , Sonneville R , Guidoux C , Barrett L , Viltart O , Mattot V , Siami S , Lorindl G , Chretien F , Singer M , Gray F , Annane D , Brouland JP , Sharshar T . Changes in CRH and ACTH synthesis during experimental and human septic shock. PLoS One 6: e25905, 2011.
 121. Raff H , Biru N , Reisinger N , Kramer DJ . Dissociation of ACTH and cortisol in septic and non‐septic ICU patients. Endocrine 55: 307‐310, 2017.
 122. Raff H , Brock S , Findling JW . Cosyntropin‐stimulated salivary cortisol in hospitalized patients with hypoproteinemia. Endocrine 34: 68‐74, 2008.
 123. Raff H , Flemma RJ , Findling JW . Fast cortisol‐induced inhibition of the adrenocorticotropin response to surgery in humans. J Clin Endocrinol Metabol 67: 1146‐1148, 1988.
 124. Raff H , Lee JJ , Widmaier EP , Oaks MK , Engeland WC . Basal and adrenocorticotropin‐stimulated corticosterone in the neonatal rat exposed to hypoxia from birth: Modulation by chemical sympathectomy. Endocrinology 145: 79‐86, 2004.
 125. Raff H , Sharma ST , Nieman LK . Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing's syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol 4: 739‐769, 2014.
 126. Rask E , Olsson T , Soderberg S , Andrew R , Livingstone DE , Johnson O , Walker BR . Tissue‐specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metabol 86: 1418‐1421, 2001.
 127. Reichardt HM , Kaestner KH , Tuckermann J , Kretz O , Wessely O , Bock R , Gass P , Schmid W , Herrlich P , Angel P , Schutz G . DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93: 531‐541, 1998.
 128. Rhodes A , Evans LE , Alhazzani W , Levy MM , Antonelli M , Ferrer R , Kumar A , Sevransky JE , Sprung CL , Nunnally ME , Rochwerg B , Rubenfeld GD , Angus DC , Annane D , Beale RJ , Bellinghan GJ , Bernard GR , Chiche JD , Coopersmith C , De Backer DP , French CJ , Fujishima S , Gerlach H , Hidalgo JL , Hollenberg SM , Jones AE , Karnad DR , Kleinpell RM , Koh Y , Lisboa TC , Machado FR , Marini JJ , Marshall JC , Mazuski JE , McIntyre LA , McLean AS , Mehta S , Moreno RP , Myburgh J , Navalesi P , Nishida O , Osborn TM , Perner A , Plunkett CM , Ranieri M , Schorr CA , Seckel MA , Seymour CW , Shieh L , Shukri KA , Simpson SQ , Singer M , Thompson BT , Townsend SR , Van der Poll T , Vincent JL , Wiersinga WJ , Zimmerman JL , Dellinger RP . Surviving sepsis campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 43: 304‐377, 2017.
 129. Rittmaster RS , Cutler GB, Jr. , Sobel DO , Goldstein DS , Koppelman MC , Loriaux DL , Chrousos GP . Morphine inhibits the pituitary‐adrenal response to ovine corticotropin‐releasing hormone in normal subjects. J Clin Endocrinol Metabol 60: 891‐895, 1985.
 130. Roth‐Isigkeit AK , Schmucker P . Postoperative dissociation of blood levels of cortisol and adrenocorticotropin after coronary artery bypass grafting surgery. Steroids 62: 695‐699, 1997.
 131. Rothwell PM , Udwadia ZF , Lawler PG . Cortisol response to corticotropin and survival in septic shock. Lancet 337: 582‐583, 1991.
 132. Rubin RT , Miller TH , Rhodes ME , Czambel RK . Adrenal cortical responses to low‐ and high‐dose ACTH(1‐24) administration in major depressives vs. matched controls. Psychiatry Res 143: 43‐50, 2006.
 133. Russell GM , Henley DE , Leendertz J , Douthwaite JA , Wood SA , Stevens A , Woltersdorf WW , Peeters BW , Ruigt GS , White A , Veldhuis JD , Lightman SL . Rapid glucocorticoid receptor‐mediated inhibition of hypothalamic‐pituitary‐adrenal ultradian activity in healthy males. J Neurosci 30: 6106‐6115, 2010.
 134. Sacre K , Dehoux M , Chauveheid MP , Chauchard M , Lidove O , Roussel R , Papo T . Pituitary‐adrenal function after prolonged glucocorticoid therapy for systemic inflammatory disorders: an observational study. J Clin Endocrinol Metabol 98: 3199‐3205, 2013.
 135. Sage D , Maurel D , Bosler O . Involvement of the suprachiasmatic nucleus in diurnal ACTH and corticosterone responsiveness to stress. Am J Physiol Endocrinol Metab 280: E260‐E269, 2001.
 136. Sapolsky RM , Krey LC , McEwen BS . The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocr Rev 7: 284‐301, 1986.
 137. Selye H. A syndrome produced by diverse nocuous agents. Nature 138: 32, 1936.
 138. Selye H. The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol Metabol 6: 117‐230, 1946.
 139. Shifren JL , Mesiano S , Taylor RN , Ferrara N , Jaffe RB . Corticotropin regulates vascular endothelial growth factor expression in human fetal adrenal cortical cells. J Clin Endocrinol Metabol 83: 1342‐1347, 1998.
 140. Shinoda T , Murakami W , Takamichi Y , Iizuka H , Tanaka M , Kuwasako Y . Effect of remifentanil infusion rate on stress response in orthopedic surgery using a tourniquet application. BMC Anesthesiol 13: 14, 2013.
 141. Siebig S , Meinel A , Rogler G , Klebl E , Wrede CE , Gelbmann C , Froh S , Rockmann F , Bruennler T , Schoelmerich J , Langgartner J . Decreased cytosolic glucocorticoid receptor levels in critically ill patients. Anaesth Intensive Care 38: 133‐140, 2010.
 142. Simpson ER , Waterman MR . Regulation by ACTH of steroid hormone biosynthesis in the adrenal cortex. Can J Biochem Cell Biol 61: 692‐707, 1983.
 143. Skoglund K , Enblad P , Hillered L , Marklund N . The neurological wake‐up test increases stress hormone levels in patients with severe traumatic brain injury. Crit Care Med 40: 216‐222, 2012.
 144. Smith SM , Vale WW . The role of the hypothalamic‐pituitary‐adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 8: 383‐395, 2006.
 145. Son GH , Chung S , Kim K . The adrenal peripheral clock: Glucocorticoid and the circadian timing system. Front Neuroendocrinol 32: 451‐465, 2011.
 146. Soni A , Pepper GM , Wyrwinski PM , Ramirez NE , Simon R , Pina T , Gruenspan H , Vaca CE . Adrenal insufficiency occurring during septic shock: Incidence, outcome, and relationship to peripheral cytokine levels. Am J Med 98: 266‐271, 1995.
 147. Span LF , Hermus AR , Bartelink AK , Hoitsma AJ , Gimbrere JS , Smals AG , Kloppenborg PW . Adrenocortical function: An indicator of severity of disease and survival in chronic critically ill patients. Intensive Care Med 18: 93‐96, 1992.
 148. Sprung CL , Annane D , Keh D , Moreno R , Singer M , Freivogel K , Weiss YG , Benbenishty J , Kalenka A , Forst H , Laterre PF , Reinhart K , Cuthbertson BH , Payen D , Briegel J . Hydrocortisone therapy for patients with septic shock. N Engl J Med 358: 111‐124, 2008.
 149. Stavreva DA , Wiench M , John S , Conway‐Campbell BL , McKenna MA , Pooley JR , Johnson TA , Voss TC , Lightman SL , Hager GL . Ultradian hormone stimulation induces glucocorticoid receptor‐mediated pulses of gene transcription. Nat Cell Biol 11: 1093‐1102, 2009.
 150. Stocco DM , Clark BJ . Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev 17: 221‐244, 1996.
 151. Sun X , Mammen JM , Tian X . Sepsis induces the transcription of the glucocorticoid receptor in skeletal muscle cells. Clin Sci (Lond) 105: 383‐391, 2003.
 152. Tagami T , Matsui H , Horiguchi H , Fushimi K , Yasunaga H . Low‐dose corticosteroid use and mortality in severe community‐acquired pneumonia patients. Eur Respir J 45: 463‐472, 2015.
 153. Taniguchi H , Sasaki T , Fujita H , Takano O , Hayashi T , Cho H , Yoshikawa T , Tsuburaya A . The effect of intraoperative use of high‐dose remifentanil on postoperative insulin resistance and muscle protein catabolism: A randomized controlled study. Int J Med Sci 10: 1099‐1107, 2013.
 154. Taylor T , Dluhy RG , Williams GH . Beta‐endorphin suppresses adrenocorticotropin and cortisol levels in normal human subjects. J Clin Endocrinol Metabol 57: 592‐596, 1983.
 155. Ten S , New M , Maclaren N . Clinical review 130: Addison's disease 2001. J Clin Endocrinol Metabol 86: 2909‐2922, 2001.
 156. Toth IE , Szabo D , Bruckner GG . Lipoproteins, lipid droplets, lysosomes, and adrenocortical steroid hormone synthesis: Morphological studies. Microsc Res Tech 36: 480‐492, 1997.
 157. Uchoa ET , Aguilera G , Herman JP , Fiedler JL , Deak T , de Sousa MB . Novel aspects of glucocorticoid actions. J Neuroendocrinol 26: 557‐572, 2014.
 158. Udelsman R , Norton JA , Jelenich SE , Goldstein DS , Linehan WM , Loriaux DL , Chrousos GP . Responses of the hypothalamic‐pituitary‐adrenal and renin‐angiotensin axes and the sympathetic system during controlled surgical and anesthetic stress. J Clin Endocrinol Metabol 64: 986‐994, 1987.
 159. Van den Berghe G , de Zegher F , Baxter RC , Veldhuis JD , Wouters P , Schetz M , Verwaest C , Van der Vorst E , Lauwers P , Bouillon R , Bowers CY . Neuroendocrinology of prolonged critical illness: Effects of exogenous thyrotropin‐releasing hormone and its combination with growth hormone secretagogues. J Clin Endocrinol Metabol 83: 309‐319, 1998.
 160. Van den Berghe G , de Zegher F , Bouillon R . Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metabol 83: 1827‐1834, 1998.
 161. Van den Berghe G , de Zegher F , Veldhuis JD , Wouters P , Awouters M , Verbruggen W , Schetz M , Verwaest C , Lauwers P , Bouillon R , Bowers CY . The somatotropic axis in critical illness: Effect of continuous growth hormone (GH)‐releasing hormone and GH‐releasing peptide‐2 infusion. J Clin Endocrinol Metabol 82: 590‐599, 1997.
 162. Van den Berghe G , de Zegher F , Veldhuis JD , Wouters P , Gouwy S , Stockman W , Weekers F , Schetz M , Lauwers P , Bouillon R , Bowers CY . Thyrotrophin and prolactin release in prolonged critical illness: Dynamics of spontaneous secretion and effects of growth hormone‐secretagogues. Clin Endocrinol 47: 599‐612, 1997.
 163. Van den Berghe G , Wouters P , Weekers F , Mohan S , Baxter RC , Veldhuis JD , Bowers CY , Bouillon R . Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone‐releasing peptide and thyrotropin‐releasing hormone in patients with protracted critical illness. J Clin Endocrinol Metabol 84: 1311‐1323, 1999.
 164. van der Voort PH , Gerritsen RT , Bakker AJ , Boerma EC , Kuiper MA , de Heide L . HDL‐cholesterol level and cortisol response to synacthen in critically ill patients. Intensive Care Med 29: 2199‐2203, 2003.
 165. Vandevyver S , Dejager L , Libert C . Comprehensive overview of the structure and regulation of the glucocorticoid receptor. Endocr Rev 35: 671‐693, 2014.
 166. Vanhorebeek I , Langouche L , Van den Berghe G . Endocrine aspects of acute and prolonged critical illness. Nat Clin Pract Endocrinol Metab 2: 20‐31, 2006.
 167. Vaughan GM , Becker RA , Allen JP , Goodwin CW, Jr. , Pruitt BA, Jr. , Mason AD, Jr. Cortisol and corticotrophin in burned patients. J Trauma 22: 263‐273, 1982.
 168. Veldhuis JD , Keenan DM , Pincus SM . Motivations and methods for analyzing pulsatile hormone secretion. Endocr Rev 29: 823‐864, 2008.
 169. Vermes I , Beishuizen A , Hampsink RM , Haanen C . Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: Possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metabol 80: 1238‐1242, 1995.
 170. Vierhapper H , Nowotny P , Waldhausl W . Production rates of cortisol in obesity. Obes Res 12: 1421‐1425, 2004.
 171. Vining RF , McGinley RA . The measurement of hormones in saliva: Possibilities and pitfalls. J Steroid Biochem 27: 81‐94, 1987.
 172. Volbeda M , Wetterslev J , Gluud C , Zijlstra JG , van der Horst IC , Keus F . Glucocorticosteroids for sepsis: Systematic review with meta‐analysis and trial sequential analysis. Intensive Care Med 41: 1220‐1234, 2015.
 173. Walker JJ , Terry JR , Lightman SL . Origin of ultradian pulsatility in the hypothalamic‐pituitary‐adrenal axis. Proc Biol Sci 277: 1627‐1633, 2010.
 174. Watanabe K , Kashiwagi K , Kamiyama T , Yamamoto M , Fukunaga M , Inada E , Kamiyama Y . High‐dose remifentanil suppresses stress response associated with pneumoperitoneum during laparoscopic colectomy. J Anesth 28: 334‐340, 2014.
 175. Watt I , Ledingham IM . Mortality amongst multiple trauma patients admitted to an intensive therapy unit. Anaesthesia 39: 973‐981, 1984.
 176. Watts AG. Glucocorticoid regulation of peptide genes in neuroendocrine CRH neurons: A complexity beyond negative feedback. Front Neuroendocrinol 26: 109‐130, 2005.
 177. Widmer IE , Puder JJ , Konig C , Pargger H , Zerkowski HR , Girard J , Muller B . Cortisol response in relation to the severity of stress and illness. J Clin Endocrinol Metabol 90: 4579‐4586, 2005.

 

Teaching Material

B. Peeters, L. Langouche, G. Van den Berghe. Adrenocortical Stress Response during the Course of Critical Illness. Compr Physiol. 8: 2018, 283-298.

Didactic Synopsis

Major Teaching Points:

  • Unlike the hypothalamus-pituitary-adrenal axis response to stress outside the context of intensive care, the stress response to critical illness is hallmarked by low rather than high plasma ACTH in the face of high plasma cortisol.
  • During critical illness, the diurnal rhythm of ACTH and cortisol secretion is absent.
  • A normal or only slightly increased cortisol production and a consistently reduced cortisol breakdown determine the degree of hypercortisolism during critical illness.
  • Sustained suppressed circulating ACTH can contribute to risk of adrenal atrophy specifically in prolonged critically ill patients
  • Drugs often given to critically ill patients such as etomidate, opioids and propofol can suppress plasma cortisol. One should consider omitting these before initiating treatment with hydrocortisone for low plasma cortisol.
  • It remains controversial whether “relative” adrenal insufficiency is a clinical entity ensuing from glucocorticoid resistance with cortisol availability that is insufficiently elevated to overcome such resistance.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Shown are the biphasic neuroendocrine responses of the anterior pituitary hormones and their peripheral hormones to acute and chronic critical illness. In the acute phase of illness the growth hormone (GH) and thyrotrophin (TSH) secretory activity is amplified (red), and adrenocorticotropic hormone (ACTH) secretory activity is increased in some cases. Plasma concentrations of their anabolic peripheral hormones (insulin-like growth factor-I, triiodothyronine) are decreased (green), but cortisol levels are elevated (yellow). In prolonged critical illness, secretion of GH, TSH and ACTH is consistently suppressed, with a further decrease of their peripheral hormones. Plasma cortisol levels remain high, but in some cases low plasma cortisol levels appear in the chronic phase of critical illness. [Figure was reproduced from Van den Berghe (160), with permission from The Journal of Clinical Endocrinology and Metabolism.]

Figure 2. Teaching points: Mean values and standard errors for plasma ACTH (Panel A), total cortisol (Panel B), and free cortisol (Panel C) in ICU patients from admission onward until day 3 of ICU stay. The blue shaded area represents the interquartile range of morning values in healthy control subjects. *P ≤ 0.05, **P < 0.001, for the comparison with controls. §P ≤ 0.05, §§P < 0.01, §§§P < 0.0001, for the comparison of paired values of the consecutive days with the admission sample. For each day, the number of patients still in ICU is displayed below the figure. ICU denotes intensive care unit, adm denotes admission. [Figure was reproduced from Peeters (115), with permission from Clinical Endocrinology.]

Figure 3. Teaching points: Cortisol metabolism in humans. Cortisol and cortisone are mainly broken down via A-ring reductases, 5α-reductase and 5β-reductase, in the liver to generate 5α- and 5β-tetrahydrocortisol. In the kidney, cortisol is metabolized by 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, generating cortisone, which can further be broken down to tetra-hydrocortisone (THE) by 5β-reductase. 11β-HSD type 1 can reconvert cortisone to cortisol.

Figure 4. Teaching points: Adrenocorticotropic hormone (ACTH) binds to its receptor, the melanocortin 2 receptor (MC2R), on the membrane of the adrenocortical cells, which increases cyclic AMP (cAMP) and stimulates protein kinase A (PKA). PKA causes the release of cholesterol from the lipid droplets into the cytoplasm and de novo production from acetyl coenzyme A (acetyl CoA). ACTH increases the expression of the steroidogenic acute regulatory protein (STAR) to transport cholesterol from the cytoplasm to the inner membrane of the mitochondria where steroidogenesis takes place. Cholesterol is converted into different steroid hormones. The long-term impact of ACTH involves increased transcription of genes important for cholesterol uptake [scavenger-receptor class B, member 1 (SCARB1), LDL receptor (LDLR)] and cholesterol synthesis [3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)], and for steroidogenesis (STAR and CYP11A1). ACTH has a direct stimulatory effect on the expression of its own receptor (MC2R). Blue lines represent ACTH effects. [Figure was reproduced from Boonen (17), with permission from The Lancet Diabetes & Endocrinology.]

Figure 5. Teaching points: mRNA expression of ACTH-regulated proteins in adrenal glands, harvested from individuals dying suddenly out of hospital (control subjects), from patients dying after short critical illness and from patients after prolonged critical illness. The mRNA data are expressed, normalized to RNA18S as a fold difference from the mean of the controls. Boxes represent medians and interquartile ranges and whiskers represent firstquartile-1.5*IQR and thirdquartile + 1.5*IQR. [Figure was reproduced from Boonen (18), with permission from The Journal of Clinical Endocrinology and Metabolism.]

Figure 6. Teaching points: Overview of the regulation of hypercortisolism during critical illness. ↑, elevated plasma concentrations; ↓, decreased plasma concentrations; ?, no univocal data available; + , stimulates; -, inhibits; PVN, paraventricular nucleus; ACTH, adrenocorticotropic hormone; CBG, corticosteroid-binding globulin.

 


Related Articles:

Steroidogenesis—Adrenal Cell Signal Transduction
The Multifaceted Mineralocorticoid Receptor
Regulation of the Hypothalamic‐Pituitary‐Adrenocortical Stress Response
Hypothalamic‐Pituitary‐Adrenal Axis—Feedback Control
HPA Axis‐Rhythms

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Bram Peeters, Lies Langouche, Greet Van den Berghe. Adrenocortical Stress Response during the Course of Critical Illness. Compr Physiol 2017, 8: 283-298. doi: 10.1002/cphy.c170022