Abstract
Critical illnesses are characterized by increased systemic cortisol availability, which is a vital part of the stress response. Relative adrenal failure (later termed critical-illness-related corticosteroid insufficiency (CIRCI)) is a condition in which the systemic availability of cortisol is assumed to be insufficiently high to face the stress of the illness and is most typically thought to occur in the acute phase of septic shock. Researchers suggested that CIRCI could be diagnosed by a suppressed incremental cortisol response to an injection of adrenocorticotropic hormone, irrespective of the baseline plasma cortisol. This concept triggered several randomized clinical trials on the impact of large stress doses of hydrocortisone to treat CIRCI, which gave conflicting results. Recent novel insights into the response of the hypothalamic–pituitary–adrenal axis to acute and prolonged critical illnesses challenge the concept of CIRCI, as currently defined, as well as the current practice guidelines for diagnosis and treatment. In this Review, these novel insights are integrated within a novel conceptual framework that can be used to re-appreciate adrenocortical function and dysfunction in the context of critical illness. This framework opens new avenues for further research and for preventive and/or therapeutic innovations.
Key points
-
The amount of cortisol that is produced by patients during critical illness is not much higher, if at all, than that produced when healthy.
-
Increased systemic cortisol availability during critical illness is largely driven by decreased cortisol-binding proteins in the circulation, by the reduced binding affinity of these proteins and by suppressed cortisol breakdown.
-
Circulating free cortisol that is elevated via such peripheral mechanisms may partially explain why adrenocorticotropic hormone (ACTH) levels are low in patients with critical illness, owing to feedback inhibition.
-
Low ACTH levels that are present for an extended period of time may negatively affect adrenocortical integrity and function.
-
An ACTH stimulation test is invalid for assessing adrenocortical integrity and function in critically ill patients, as the test results are confounded by the increased cortisol distribution volume.
-
Doses of hydrocortisone currently advised for treating critically ill patients do not take the substantially increased half-life of cortisol into account, are thus likely too high and may further increase central adrenocortical suppression via feedback inhibition.
-
Future research should focus on patients who are critically ill for an extended period, on patients who may be at risk of developing central hypoadrenalism and on novel strategies to prevent and treat this complication.
Similar content being viewed by others
References
Bernard, C. Leçons sur les Phénomènes de la Vie Communs aux Annimaux et aux Végétaux (J.-B. Baillière, Paris, 1878).
Selye, H. A syndrome produced by diverse nocuous agents. Nature 138, 32 (1936).
Guillemin, R. & Rosenberg, B. Humoral hypothalamic control of anterior pituitary: a study with combined tissue cultures. Endocrinology 57, 599–607 (1955).
Guillemin, R. Hypothalamic hormones a.k.a. hypothalamic releasing factors. J. Endocrinol. 184, 11–28 (2005).
Melby, J. C. & Spink, W. W. Comparative studies on adrenal cortical function and cortisol metabolism in healthy adults and in patients with shock due to infection. J. Clin. Invest. 37, 1791–1798 (1958).
Vermes, I. & Beishuizen, A. The hypothalamic-pituitary-adrenal response to critical illness. Best Pract. Res. Clin. Endocrinol. Metab. 15, 495–511 (2001).
Boonen, E. et al. Reduced cortisol metabolism during critical illness. N. Engl. J. Med. 368, 1477–1488 (2013). This landmark study documents the contribution of decreased cortisol metabolism to the increase in plasma cortisol levels observed during critical illness.
Boonen, E. et al. Reduced nocturnal ACTH-driven cortisol secretion during critical illness. Am. J. Physiol. Endocrinol. Metab. 306, E883–E892 (2014). In this study, nocturnal ACTH and cortisol secretory profiles are deconvolved from plasma concentration time series in critically ill patients and matched healthy volunteers, revealing suppressed rather than increased ACTH-driven cortisol secretion during critical illness.
Boonen, E. & Van den Berghe, G. Mechanisms in endocrinology: new concepts to further unravel adrenal insufficiency during critical illness. Eur. J. Endocrinol. 175, R1–R9 (2016).
Peeters, B. et al. Drug-induced HPA axis alterations during acute critical illness: a multivariable association study. Clin. Endocrinol. (Oxf.) 86, 26–36 (2017). This study identifies iatrogenically suppressed cortisol by drugs frequently used in the ICU.
Peeters, B. et al. Adrenocortical function during prolonged critical illness and beyond: a prospective observational study. Intensive Care Med. 44, 1720–1729 (2018). This study is the first to document adrenocortical function during the prolonged phase of critical illness and the first week of recovery, identifying a possible central suppression of adrenocortical function during an ICU stay. This study also shows that the ACTH stimulation test is invalid for assessing adrenocortical integrity and function in the context of critical illness.
Peeters, B. et al. ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study. Intensive Care Med. 44, 2048–2058 (2018). This study shows that with increasing duration of critical illness, the ACTH responses to CRH become suppressed, which is compatible with feedback inhibition exerted by cortisol that is elevated through peripheral rather than central drivers.
Annane, D. et al. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a multispecialty task force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Crit. Care Med. 45, 2089–2098 (2017).
Annane, D. et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. 43, 1751–1763 (2017). This paper presents updated guidelines for the diagnosis and management of CIRCI.
McIntosh, T. K. et al. Circadian rhythm of cortisol is altered in postsurgical patients. J. Clin. Endocrinol. Metab. 53, 117–122 (1981).
Mohler, J. L., Michael, K. A., Freedman, A. M., Griffen, W. O. Jr & McRoberts, J. W. The serum and urinary cortisol response to operative trauma. Surg. Gynecol. Obstet. 161, 445–449 (1985).
Widmer, I. E. et al. Cortisol response in relation to the severity of stress and illness. J. Clin. Endocrinol. Metab. 90, 4579–4586 (2005).
Rothwell, P. M., Udwadia, Z. F. & Lawler, P. G. Cortisol response to corticotropin and survival in septic shock. Lancet 337, 582–583 (1991).
Dinneen, S., Alzaid, A., Miles, J. & Rizza, R. Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans. J. Clin. Invest. 92, 2283–2290 (1993).
Peckett, A. J., Wright, D. C. & Riddell, M. C. The effects of glucocorticoids on adipose tissue lipid metabolism. Metabolism 60, 1500–1510 (2011).
Yang, S. & Zhang, L. Glucocorticoids and vascular reactivity. Curr. Vasc. Pharmacol. 2, 1–12 (2004).
Walker, B. R. et al. 11 β-hydroxysteroid dehydrogenase in vascular smooth muscle and heart: implications for cardiovascular responses to glucocorticoids. Endocrinology 129, 3305–3312 (1991).
Cain, D. W. & Cidlowski, J. A. Immune regulation by glucocorticoids. Nat. Rev. Immunol. 17, 233–247 (2017).
Cooper, M. S. & Stewart, P. M. Corticosteroid insufficiency in acutely ill patients. N. Engl. J. Med. 348, 727–734 (2003).
Rothwell, P. M. & Lawler, P. G. Prediction of outcome in intensive care patients using endocrine parameters. Crit. Care Med. 23, 78–83 (1995).
Marana, E. et al. Neuroendocrine stress response in laparoscopic surgery for benign ovarian cyst. Can. J. Anaesth. 51, 943–944 (2004).
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).
Gibbison, B. et al. Dynamic pituitary-adrenal interactions in response to cardiac surgery. Crit. Care Med. 43, 791–800 (2015).
Cooper, C. E. & Nelson, D. H. Acth levels in plasma in preoperative and surgically stressed patients. J. Clin. Invest. 41, 1599–1605 (1962).
Chrousos, G. P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332, 1351–1362 (1995).
Vermes, I., Beishuizen, A., Hampsink, R. M. & Haanen, C. Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone. J. Clin. Endocrinol. Metab. 80, 1238–1242 (1995).
Bornstein, S. R. et al. The role of toll-like receptors in the immune-adrenal crosstalk. Ann. NY Acad. Sci. 1088, 307–318 (2006).
Kanczkowski, W. et al. Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation. Proc. Natl Acad. Sci. USA 110, 14801–14806 (2013).
Drucker, D. & Shandling, M. Variable adrenocortical function in acute medical illness. Crit. Care Med. 13, 477–479 (1985).
Roth-Isigkeit, A. K. & Schmucker, P. Postoperative dissociation of blood levels of cortisol and adrenocorticotropin after coronary artery bypass grafting surgery. Steroids 62, 695–699 (1997).
Veldhuis, J. D., Keenan, D. M. & Pincus, S. M. Motivations and methods for analyzing pulsatile hormone secretion. Endocr. Rev. 29, 823–864 (2008).
Henley, D., Lightman, S. & Carrell, R. Cortisol and CBG — getting cortisol to the right place at the right time. Pharmacol. Ther. 166, 128–135 (2016).
Pemberton, P. A., Stein, P. E., Pepys, M. B., Potter, J. M. & Carrell, R. W. Hormone binding globulins undergo serpin conformational change in inflammation. Nature 336, 257–258 (1988).
Coolens, J. L., 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).
Faix, J. D. Principles and pitfalls of free hormone measurements. Best Pract. Res. Clin. Endocrinol. Metab. 27, 631–645 (2013).
Vanhorebeek, I. et al. Cortisol response to critical illness: effect of intensive insulin therapy. J. Clin. Endocrinol. Metab. 91, 3803–3813 (2006).
Redelmeier, D. A. New thinking about postoperative hypoalbuminemia: a hypothesis of occult protein-losing enteropathy. Open Med. 3, e215–e219 (2009).
Vincent, J. L. et al. Albumin administration in the acutely ill: what is new and where next? Crit. Care 18, 231 (2014).
Moshage, H. J., Janssen, J. A., Franssen, J. H., Hafkenscheid, J. C. & Yap, S. H. Study of the molecular mechanism of decreased liver synthesis of albumin in inflammation. J. Clin. Invest. 79, 1635–1641 (1987).
Barle, H. et al. Synthesis rates of total liver protein and albumin are both increased in patients with an acute inflammatory response. Clin. Sci. 110, 93–99 (2006).
Nenke, M. A. et al. Depletion of high-affinity corticosteroid-binding globulin corresponds to illness severity in sepsis and septic shock; clinical implications. Clin. Endocrinol. (Oxf.) 82, 801–807 (2015).
Emptoz-Bonneton, A., Crave, J. C., LeJeune, H., Brebant, C. & Pugeat, M. Corticosteroid-binding globulin synthesis regulation by cytokines and glucocorticoids in human hepatoblastoma-derived (HepG2) cells. J. Clin. Endocrinol. Metab. 82, 3758–3762 (1997).
Jenniskens, M. et al. The hepatic glucocorticoid receptor is crucial for cortisol homeostasis and sepsis survival in humans and male mice. Endocrinology 159, 2790–2802 (2018). This study proposes the hepatic glucocorticoid receptor as a new central player in controlling cortisol availability, inflammation and survival from sepsis-induced critical illness.
Hamrahian, A. H., Oseni, T. S. & Arafah, B. M. Measurements of serum free cortisol in critically ill patients. N. Engl. J. Med. 350, 1629–1638 (2004).
Chan, W. L., Carrell, R. W., Zhou, A. & Read, R. J. How changes in affinity of corticosteroid-binding globulin modulate free cortisol concentration. J. Clin. Endocrinol. Metab. 98, 3315–3322 (2013).
Tomlinson, J. W. & Stewart, P. M. Cortisol metabolism and the role of 11β-hydroxysteroid dehydrogenase. Best Pract. Res. Clin. Endocrinol. Metab. 15, 61–78 (2001).
Tomlinson, J. W. et al. 11β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr. Rev. 25, 831–866 (2004).
Nixon, M., Upreti, R. & Andrew, R. 5α-reduced glucocorticoids: a story of natural selection. J. Endocrinol. 212, 111–127 (2012).
Langlois, V. S., Zhang, D., Cooke, G. M. & Trudeau, V. L. Evolution of steroid-5α-reductases and comparison of their function with 5β-reductase. Gen. Comp. Endocrinol. 166, 489–497 (2010).
Wang, H., Chen, J., Hollister, K., Sowers, L. C. & Forman, B. M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol. Cell 3, 543–553 (1999).
Maruyama, T. et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun. 298, 714–719 (2002).
Zhu, C., Fuchs, C. D., Halilbasic, E. & Trauner, M. Bile acids in regulation of inflammation and immunity: friend or foe? Clin. Exp. Rheumatol. 34, 25–31 (2016).
Russell, D. W. The enzymes, regulation, and genetics of bile acid synthesis. Annu. Rev. Biochem. 72, 137–174 (2003).
McNeilly, A. D. et al. Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice. J. Hepatol. 52, 705–711 (2010).
Ackermann, D. et al. Inhibition of 11β-hydroxysteroid dehydrogenase by bile acids in rats with cirrhosis. Hepatology 30, 623–629 (1999).
Jenniskens, M., Langouche, L., Vanwijngaerden, Y. M., Mesotten, D. & Van den Berghe, G. Cholestatic liver (dys)function during sepsis and other critical illnesses. Intensive Care Med. 42, 16–27 (2016).
Rose, A. J. et al. Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor. Cell Metab. 14, 123–130 (2011).
Rosales, R. et al. FXR-dependent and -independent interaction of glucocorticoids with the regulatory pathways involved in the control of bile acid handling by the liver. Biochem. Pharmacol. 85, 829–838 (2013).
Kino, T. & Chrousos, G. P. Glucocorticoid and mineralocorticoid receptors and associated diseases. Essays Biochem. 40, 137–155 (2004).
Jaaskelainen, T., Makkonen, H. & Palvimo, J. J. Steroid up-regulation of FKBP51 and its role in hormone signaling. Curr. Opin. Pharmacol. 11, 326–331 (2011).
Pratt, W. B. & Toft, D. O. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18, 306–360 (1997).
Picard, D., Salser, S. J. & Yamamoto, K. R. A movable and regulable inactivation function within the steroid binding domain of the glucocorticoid receptor. Cell 54, 1073–1080 (1988).
Lu, N. Z. & Cidlowski, J. A. Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol. 16, 301–307 (2006).
Luisi, B. F. et al. Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature 352, 497–505 (1991).
Ratman, D. et al. How glucocorticoid receptors modulate the activity of other transcription factors: a scope beyond tethering. Mol. Cell Endocrinol. 380, 41–54 (2013).
Diamond, M. I., Miner, J. N., Yoshinaga, S. K. & Yamamoto, K. R. Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science 249, 1266–1272 (1990).
Boldizsar, F. et al. Emerging pathways of non-genomic glucocorticoid (GC) signalling in T cells. Immunobiology 215, 521–526 (2010).
Guerrero, J., Gatica, H. A., Rodriguez, M., Estay, R. & Goecke, I. A. 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).
Abraham, M. N., Jimenez, D. M., Fernandes, T. D. & Deutschman, C. S. Cecal ligation and puncture alters glucocorticoid receptor expression. Crit. Care Med. 46, e797–e804 (2018).
van den Akker, E. L. et al. Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis. Intensive Care Med. 35, 1247–1254 (2009).
Vardas, K. et al. Increased glucocorticoid receptor expression in sepsis is related to heat shock proteins, cytokines, and cortisol and is associated with increased mortality. Intensive Care Med. Exp. 5, 10 (2017).
Peeters, B., Langouche, L. & Van den Berghe, G. Adrenocortical stress response during the course of critical illness. Compr. Physiol. 8, 283–298 (2017).
McMillin, M. et al. Suppression of the HPA axis during cholestasis can be attributed to hypothalamic bile acid signaling. Mol. Endocrinol. 29, 1720–1730 (2015).
Miura, T. et al. Functional modulation of the glucocorticoid receptor and suppression of NF-kappaB-dependent transcription by ursodeoxycholic acid. J. Biol. Chem. 276, 47371–47378 (2001).
Polito, A. et al. Changes in CRH and ACTH synthesis during experimental and human septic shock. PLOS ONE 6, e25905 (2011).
Annane, D. The role of ACTH and corticosteroids for sepsis and septic shock: an update. Front. Endocrinol. (Lausanne) 7, 70 (2016).
Charmandari, E., Nicolaides, N. C. & Chrousos, G. P. Adrenal insufficiency. Lancet 383, 2152–2167 (2014).
Betterle, C. & Morlin, L. Autoimmune Addison’s disease. Endocr. Dev. 20, 161–172 (2011).
Laureti, S. et al. Levels of adrenocortical autoantibodies correlate with the degree of adrenal dysfunction in subjects with preclinical Addison’s disease. J. Clin. Endocrinol. Metab. 83, 3507–3511 (1998).
Tomlinson, J. W. et al. Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 357, 425–431 (2001).
Erichsen, M. M. et al. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J. Clin. Endocrinol. Metab. 94, 4882–4890 (2009).
McDonough, A. K., Curtis, J. R. & Saag, K. G. The epidemiology of glucocorticoid-associated adverse events. Curr. Opin. Rheumatol. 20, 131–137 (2008).
Jurney, T. H. et al. Spectrum of serum cortisol response to ACTH in ICU patients. Correlation with degree of illness and mortality. Chest 92, 292–295 (1987).
Washburn, R. G. & Bennett, J. E. Reversal of adrenal glucocorticoid dysfunction in a patient with disseminated histoplasmosis. Ann. Intern. Med. 110, 86–87 (1989).
Bhatia, E., Jain, S. K., Gupta, R. K. & Pandey, R. Tuberculous Addison’s disease: lack of normalization of adrenocortical function after anti-tuberculous chemotherapy. Clin. Endocrinol. (Oxf.) 48, 355–359 (1998).
Waterhouse, R. A case of suprarenal apoplexy. Lancet 177, 577–578 (1911).
Friderichsen, C. Nebennierenapoplexie bei kleinen kindern [German]. Jahrb Kinderheilk. 87, 109–125 (1918).
Krahulik, D., Zapletalova, J., Frysak, Z. & Vaverka, M. Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults. J. Neurosurg. 113, 581–584 (2010).
Agha, A. et al. Anterior pituitary dysfunction in survivors of traumatic brain injury. J. Clin. Endocrinol. Metab. 89, 4929–4936 (2004).
Tanriverdi, F. et al. Prospective investigation of pituitary functions in patients with acute infectious meningitis: is acute meningitis induced pituitary dysfunction associated with autoimmunity? Pituitary 15, 579–588 (2012).
Giese, J. L. & Stanley, T. H. Etomidate: a new intravenous anesthetic induction agent. Pharmacotherapy 3, 251–258 (1983).
Watt, I. & Ledingham, I. M. Mortality amongst multiple trauma patients admitted to an intensive therapy unit. Anaesthesia 39, 973–981 (1984).
Wagner, R. L., White, P. F., Kan, P. B., Rosenthal, M. H. & Feldman, D. Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N. Engl. J. Med. 310, 1415–1421 (1984).
Loose, D. S., Kan, P. B., Hirst, M. A., Marcus, R. A. & Feldman, D. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J. Clin. Invest. 71, 1495–1499 (1983).
Weber, M. M. et al. Different inhibitory effect of etomidate and ketoconazole on the human adrenal steroid biosynthesis. Clin. Investig. 71, 933–938 (1993).
Brorsson, C. et al. Adrenal response after trauma is affected by time after trauma and sedative/analgesic drugs. Injury 45, 1149–1155 (2014).
Lamberts, S. W., Bruining, H. A. & de Jong, F. H. Corticosteroid therapy in severe illness. N. Engl. J. Med. 337, 1285–1292 (1997).
Baldwin, W. A. & Allo, M. Occult hypoadrenalism in critically ill patients. Arch. Surg. 128, 673–676 (1993).
Salem, M. et al. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann. Surg. 219, 416–425 (1994).
Annane, D. et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283, 1038–1045 (2000). This study is the first to postulate that relative adrenal failure is indicated by a low increment in total plasma cortisol (<9μgdl–1) after a 250μg ACTH stimulation test.
Annane, D. et al. Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve. Br. J. Clin. Pharmacol. 46, 589–597 (1998).
Marik, P. E. et al. 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).
Meduri, G. U., Muthiah, M. P., Carratu, P., Eltorky, M. & Chrousos, G. P. Nuclear factor-κB- and glucocorticoid receptor α- mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome. Evidence for inflammation-induced target tissue resistance to glucocorticoids. Neuroimmunomodulation 12, 321–338 (2005).
Meduri, G. U. & Yates, C. R. Systemic inflammation-associated glucocorticoid resistance and outcome of ARDS. Ann. NY Acad. Sci. 1024, 24–53 (2004).
Bergquist, M. et al. Glucocorticoid receptor function is decreased in neutrophils during endotoxic shock. J. Infect. 69, 113–122 (2014).
Cvijanovich, N. Z. et al. Glucocorticoid receptor polymorphisms and outcomes in pediatric septic shock. Pediatr. Crit. Care Med. 18, 299–303 (2017).
Ledderose, C. et al. Corticosteroid resistance in sepsis is influenced by microRNA-124 — induced downregulation of glucocorticoid receptor-α. Crit. Care Med. 40, 2745–2753 (2012).
Annane, D. et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288, 862–871 (2002). This RCT is the first to document a mortality benefit of glucocorticoid treatment of patients with septic shock.
Annane, D. et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N. Engl. J. Med. 378, 809–818 (2018).
Venkatesh, B. et al. Adjunctive glucocorticoid therapy in patients with septic shock. N. Engl. J. Med. 378, 797–808 (2018). This study is currently the largest RCT to investigate the impact on outcome of glucocorticoid treatment of patients with septic shock and does not find a mortality benefit.
Sprung, C. L. et al. Hydrocortisone therapy for patients with septic shock. N. Engl. J. Med. 358, 111–124 (2008).
Gunst, J. & Van den Berghe, G. Glucocorticoids with or without fludrocortisone in septic shock. N. Engl. J. Med. 379, 894 (2018).
The COIITSS Study Investigators. et al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA 303, 341–348 (2010).
Antcliffe, D. B. et al. Transcriptomic signatures in sepsis and a differential response to steroids: from the VANISH randomized trial. Am. J. Respir. Crit. Care Med. https://doi.org/10.1164/rccm.201807-1419OC (2018).
Wong, H. R. et al. Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am. J. Respir. Crit. Care Med. 191, 309–315 (2015).
Rochwerg, B. et al. Corticosteroids in sepsis: an updated systematic review and meta-analysis. Crit. Care Med. 46, 1411–1420 (2018).
Lamontagne, F. et al. Corticosteroid therapy for sepsis: a clinical practice guideline. BMJ 362, k3284 (2018).
Gomez, M. T., Magiakou, M. A., Mastorakos, G. & Chrousos, G. P. 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. Metab. 77, 173–177 (1993).
Coll, A. P. et al. The effects of proopiomelanocortin deficiency on murine adrenal development and responsiveness to adrenocorticotropin. Endocrinology 145, 4721–4727 (2004).
Boonen, E. et al. Impact of duration of critical illness on the adrenal glands of human intensive care patients. J. Clin. Endocrinol. Metab. 99, 4214–4222 (2014).
Marik, P. E. The role of glucocorticoids as adjunctive treatment for sepsis in the modern era. Lancet Respir. Med. 6, 793–800 (2018).
Verstraete, S. et al. Long-term developmental effects of withholding parenteral nutrition for 1 week in the paediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomised, controlled trial. Lancet Respir. Med. 7, 141–153 (2018).
Bone, R. C. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101, 1644–1655 (1992).
Vincent, J. L. et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit. Care Med. 26, 1793–1800 (1998).
Singer, M. et al. The Third International Consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315, 801–810 (2016).
Rhodes, A. et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit. Care Med. 45, 486–552 (2017).
Acknowledgements
The authors acknowledge the support of the Research Foundation-Flanders (FWO) (grant G091918N to G.V.d.B.), which was awarded by the Methusalem Program of the Flemish Government (METH/14/06 to G.V.d.B. and L.L. via KU Leuven), and of a European Research Council Advanced Grant [AdvG-2017-785809 to G.V.d.B.], which was awarded from the European Union’s Horizon 2020 research and innovation programme.
Reviewer information
Nature Reviews Endocrinology thanks M. Christ-Crain, I. Dimopoulou and P. Marik for their contribution to the peer review of this work.
Author information
Authors and Affiliations
Contributions
G.V.d.B., A.T., B.P. and L.L. researched data for the article, provided substantial contribution to the discussion of content and reviewed and edited the manuscript before submission. G.V.d.B., A.T. and L.L. wrote the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Critical illness
-
Any trauma or disease leading to life-threatening organ dysfunction that requires mechanical or pharmacological support to prevent imminent death.
- Fluid resuscitation
-
The administration of intravenous fluids during the first hours after onset of sepsis with the aim to stabilize and/or reverse sepsis-induced tissue hypoperfusion and prevent evolution to septic shock.
- Neutrophil elastase
-
A serine protease that is secreted by immune cells, such as activated neutrophils, during inflammation. This enzyme hydrolyses a broad range of proteins, including cortisol-binding globulin (CBG).
- Glucocorticoid resistance
-
A decrease in the cellular response to endogenous or exogenous glucocorticoids.
- Waterhouse–Friderichsen syndrome
-
A life-threatening acute adrenal haemorrhage that leads to adrenal failure, which is caused by severe bacterial infections, most often involving meningococci or streptococci.
- Stress dose
-
The pharmacological dose of glucocorticoids that was, until recently, assumed to be necessary to meet the cortisol demands of patients with critical illnesses.
- Cortisol distribution volume
-
The theoretical volume in which a known amount of cortisol is dissolved to bring about a specific plasma concentration. In healthy individuals, >90% of plasma cortisol is protein-bound, which limits the distribution volume of cortisol.
Rights and permissions
About this article
Cite this article
Téblick, A., Peeters, B., Langouche, L. et al. Adrenal function and dysfunction in critically ill patients. Nat Rev Endocrinol 15, 417–427 (2019). https://doi.org/10.1038/s41574-019-0185-7
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41574-019-0185-7
- Springer Nature Limited
This article is cited by
-
Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness
Clinical Epigenetics (2024)
-
Critical illness-related corticosteroid insufficiency (CIRCI) in paediatric patients: a diagnostic and therapeutic challenge
Italian Journal of Pediatrics (2024)
-
Glucocorticoid treatment increases cholesterol availability during critical illness: effect on adrenal and muscle function
Critical Care (2024)
-
Inflammation-induced adrenal dysfunction
Nature Reviews Endocrinology (2023)
-
Adrenocortical Dysfunctions in Neonatal Septic Shock
Indian Journal of Pediatrics (2022)