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Intensive Care Medicine
Published in: Intensive Care Medicine 12/2017

01-12-2017 | Review

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)

Authors: Djillali Annane, Stephen M. Pastores, Wiebke Arlt, Robert A. Balk, Albertus Beishuizen, Josef Briegel, Joseph Carcillo, Mirjam Christ-Crain, Mark S. Cooper, Paul E. Marik, Gianfranco Umberto Meduri, Keith M. Olsen, Bram Rochwerg, Sophia C. Rodgers, James A. Russell, Greet Van den Berghe

Published in: Intensive Care Medicine | Issue 12/2017

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Abstract

Objective

To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI).

Participants

A multispecialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM).

Data sources

Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews.

Results

Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity.

Conclusions

Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI.
Literature
1.
Marik PE, Pastores SM, Annane D, American College of Critical Care Medicine et al (2008) 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(6):1937–1949CrossRefPubMed
2.
Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, Charmandari E (2015) Stress, the stress system and the role of glucocorticoids. NeuroImmunoModulation 22(1–2):6–19CrossRefPubMed
3.
Meduri GU, Annane D, Chrousos GP, Marik PE, Sinclair SE (2009) Activation and regulation of systemic inflammation in ARDS: rationale for prolonged glucocorticoid therapy. Chest 136(6):1631–1643CrossRefPubMed
4.
Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP (2005) Cytokine dysregulation, inflammation and well-being. NeuroImmunoModulation 12(5):255–269CrossRefPubMed
5.
Suffredini AF, Fantuzzi G, Badolato R, Oppenheim JJ, O’Grady NP (1999) New insights into the biology of the acute phase response. J Clin Immunol 19(4):203–214CrossRefPubMed
6.
Friedman R, Hughes AL (2002) Molecular evolution of the NF-kappaB signaling system. Immunogenetics 53(10–11):964–974PubMed
7.
Meduri GU, Muthiah MP, Carratu P, Eltorky M, Chrousos GP (2005) Nuclear factor-kappa B- and glucocorticoid receptor alpha-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(6):321–338CrossRefPubMed
8.
Lee SR, Kim HK, Song IS et al (2013) Glucocorticoids and their receptors: insights into specific roles in mitochondria. Prog Biophys Mol Biol 112(1–2):44–54CrossRefPubMed
9.
Galon J, Franchimont D, Hiroi N et al (2002) Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 16(1):61–71CrossRefPubMed
10.
Li-Tempel T, Larra MF, Sandt E et al (2016) The cardiovascular and hypothalamus-pituitary-adrenal axis response to stress is controlled by glucocorticoid receptor sequence variants and promoter methylation. Clin Epigenet 8:12CrossRef
11.
Midzak A, Papadopoulos V (2016) Adrenal mitochondria and steroidogenesis: from individual proteins to functional protein assemblies. Front Endocrinol 7:1–14CrossRef
12.
Esteban NV, Loughlin T, Yergey AL, Zawadzki JK, Booth JD, Winterer JC, Loriaux DL (1991) Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab 72(1):39–45CrossRefPubMed
13.
Vassiliadi DA, Dimopoulou I, Tzanela M et al (2014) Longitudinal assessment of adrenal function in the early and prolonged phases of critical illness in septic patients: relations to cytokine levels and outcome. J Clin Endocrinol Metab 99(12):4471–4480CrossRefPubMed
14.
15.
Boonen E, Meersseman P, Vervenne H et al (2014) Reduced nocturnal ACTH-driven cortisol secretion during critical illness. Am J Physiol Endocrinol Metab 306(8):E883–E892CrossRefPubMedPubMedCentral
16.
Nenke MA, Rankin W, Chapman MJ et al (2015) Depletion of high-affinity corticosteroid-binding globulin corresponds to illness severity in sepsis and septic shock; clinical implications. Clin Endocrinol (Oxf) 82(6):801–807CrossRef
17.
Beishuizen A, Thijs LG, Vermes I et al (2001) Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med 27:1584–1591CrossRefPubMed
18.
Tomlinson JW, Moore J, Cooper MS et al (2001) Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines. Endocrinology 142:1982–1989CrossRefPubMed
19.
Cai TQ, Wong B, Mundt SS et al (2001) Induction of 11beta-hydroxysteroid dehydrogenase type 1 but not -2 in human aortic smooth muscle cells by inflammatory stimuli. J Steroid Biochem Mol Biol 77:117–122CrossRefPubMed
20.
Hapgood JP, Avenant C, Moliki JM (2016) Glucocorticoid-independent modulation of GR activity: implications for immunotherapy. Pharmacol Ther 165:93–113CrossRefPubMedPubMedCentral
21.
Charmandari E, Nicolaides NC, Chrousos GP (2014) Adrenal insufficiency. Lancet 383(9935):2152–2167CrossRefPubMed
22.
23.
Goodwin JE, Feng Y, Velazquez H, Sessa WC (2013) Endothelial glucocorticoid receptor is required for protection against sepsis. Proc Natl Acad Sci USA 110(1):306–311CrossRefPubMed
24.
25.
Peeters RP, Hagendorf A, Vanhorebeek I et al (2009) Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clin Endocrinol (Oxf) 71(1):145–153CrossRef
26.
Oakley RH, Cidlowski JA (2013) The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 132(5):1033–1044CrossRefPubMedPubMedCentral
27.
Boonen E, Bornstein SR, Van den Berghe G (2015) New insights into the controversy of adrenal function during critical illness. Lancet Diabetes Endocrinol. 3(10):805–815CrossRefPubMed
28.
Le Tulzo Y, Pangault C, Amiot L et al (2004) Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock. Am J Respir Crit Care Med 169(10):1144–1151CrossRefPubMed
29.
Keh D, Boehnke T, Weber-Cartens S et al (2003) Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med 167:512–520CrossRefPubMed
30.
Arnalich F, Garcia-Palomero E, López J et al (2000) Predictive value of nuclear factor kappa B activity and plasma cytokine levels in patients with sepsis. Infect Immun 68(4):1942–1945CrossRefPubMedPubMedCentral
31.
Lee YL, Chen W, Chen LY, Chen CH, Lin YC, Liang SJ, Shih CM (2010) Systemic and bronchoalveolar cytokines as predictors of in-hospital mortality in severe community-acquired pneumonia. J Crit Care 25(1):176.e7–176.e13CrossRef
32.
Gomez HG, Gonzalez SM, Londoño JM et al (2014) Immunological characterization of compensatory anti-inflammatory response syndrome in patients with severe sepsis: a longitudinal study. Crit Care Med 42(4):771–780CrossRefPubMed
33.
Fernandez-Botran R, Uriarte SM, Arnold FW et al (2014) Contrasting inflammatory responses in severe and non-severe community-acquired pneumonia. Inflammation. 37(4):1158–1166CrossRefPubMed
34.
Kellum JA, Kong L, Fink MP et al (2007) GenIMS Investigators. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 167(15):1655–1663CrossRefPubMedPubMedCentral
35.
Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, Umberger R, Leeper K (1995) Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 107(4):1062–1073CrossRefPubMed
36.
Meduri GU, Kohler G, Headley S, Tolley E, Stentz F, Postlethwaite A (1995) Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest 108(5):1303–1314CrossRefPubMed
37.
38.
Aisiku IP, Yamal JM, Doshi P et al (2016) Plasma cytokines IL-6, IL-8, and IL-10 are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury. Crit Care 20:288CrossRefPubMedPubMedCentral
39.
Yende S, D’Angelo G, Kellum JA, GenIMS Investigators et al (2008) Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med 177(11):1242–1247CrossRefPubMedPubMedCentral
40.
41.
Besedovsky H, del Rey A, Sorkin E, Dinarello CA (1986) Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233(4764):652–654CrossRefPubMed
42.
Kanczkowski W, Sue M, Zacharowski K, Reincke M, Bornstein SR (2015) The role of adrenal gland microenvironment in the HPA axis function and dysfunction during sepsis. Mol Cell Endocrinol 408:241–248CrossRefPubMed
43.
Darling G, Goldstein DS, Stull R, Gorschboth CM, Norton JA (1989) Tumor necrosis factor: immune endocrine interaction. Surgery 106(6):1155–1160PubMed
44.
Mikhaylova IV, Kuulasmaa T, Jääskeläinen J, Voutilainen R (2007) Tumor necrosis factor-alpha regulates steroidogenesis, apoptosis, and cell viability in the human adrenocortical cell line NCI-H295R. Endocrinology 148(1):386–392CrossRefPubMed
45.
Jäättelä M, Carpén O, Stenman UH, Saksela E (1990) Regulation of ACTH-induced steroidogenesis in human fetal adrenals by rTNF-alpha. Mol Cell Endocrinol 68(2–3):R31–R36CrossRefPubMed
46.
Jäättelä M, Ilvesmäki V, Voutilainen R, Stenman UH, Saksela E (1991) Tumor necrosis factor as a potent inhibitor of adrenocorticotropin-induced cortisol production and steroidogenic P450 enzyme gene expression in cultured human fetal adrenal cells. Endocrinology 128(1):623–629CrossRefPubMed
47.
Engström L, Rosen K, Angel A et al (2008) Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland. Endocrinology 149:1436–1450CrossRefPubMed
48.
Bornstein SR, Zacharowski P, Schumann RR et al (2004) Impaired adrenal stress response in Toll-like receptor 2-deficient mice. Proc Natl Acad Sci USA 101(47):16695–16700CrossRefPubMedPubMedCentral
49.
Kanczkowski W, Alexaki VI, Tran N et al (2013) Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation. Proc Natl Acad Sci USA 110:14801–14806CrossRefPubMedPubMedCentral
50.
Jung B, Nougaret S, Chanques G et al (2011) The absence of adrenal gland enlargement during septic shock predicts mortality: a computed tomography study of 239 patients. Anesthesiology 115:334–343CrossRefPubMed
51.
52.
Sharshar T, Annane D, de la Grandmaison GL, Brouland JP, Hopkinson NS, Francoise G (2004) The neuropathology of septic shock. Brain Pathol 14(1):21–33CrossRefPubMed
53.
Mélik Parsadaniantz S, Levin N, Lenoir V, Roberts JL, Kerdelhué B (1994) Human interleukin 1 beta: corticotropin releasing factor and ACTH release and gene expression in the male rat: in vivo and in vitro studies. J Neurosci Res 37(6):675–682CrossRefPubMed
54.
Parsadaniantz SM, Batsché E, Gegout-Pottie P, Terlain B, Gillet P, Netter P, Kerdelhué B (1997) Effects of continuous infusion of interleukin 1 beta on corticotropin-releasing hormone (CRH), CRH receptors, proopiomelanocortin gene expression and secretion of corticotropin, beta-endorphin and corticosterone. Neuroendocrinology 65(1):53–63CrossRefPubMed
55.
Wong ML, Rettori V, al-Shekhlee A et al (1996) Inducible nitric oxide synthase gene expression in the brain during systemic inflammation. Nat Med 2(5):581–584CrossRefPubMed
56.
Sharshar T, Gray F, Lorin de la Grandmaison G et al (2003) Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 362(9398):1799–1805CrossRefPubMed
57.
58.
McCann SM, Kimura M, Karanth S, Yu WH, Mastronardi CA, Rettori V (2000) The mechanism of action of cytokines to control the release of hypothalamic and pituitary hormones in infection. Ann NY Acad Sci 917:4–18 (review) CrossRefPubMed
59.
Boonen E, Langouche L, Janssens T et al (2014) Impact of duration of critical illness on the adrenal glands of human intensive care patients. J Clin Endocrinol Metab 99:1569–1582CrossRefPubMed
60.
61.
Vuong C, Van Uum SH, O’Dell LE, Lutfy K, Friedman TC (2010) The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev 31(1):98–132CrossRefPubMed
62.
Henzen C, Suter A, Lerch E, Urbinelli R, Schorno XH, Briner VA (2000) Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. Lancet 355(9203):542–545CrossRefPubMed
63.
Cortés-Puch I, Hicks CW, Sun J et al (2014) Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia. Am J Physiol Endocrinol Metab 307(11):E994–E1008CrossRefPubMedPubMedCentral
64.
Annane D, Maxime V, Ibrahim F, Alvarez JC, Abe E, Boudou P (2006) Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med 174:1319–1326CrossRefPubMed
65.
Vermes I, Beishuizen A, Hampsink RM, Haanen C (1995) Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metab 80(4):1238–1242PubMed
66.
Polito A, Lorin de la Grandmaison G, Mansart A et al (2010) Human and experimental septic shock are characterized by depletion of lipid droplets in the adrenals. Intensive Care Med 36(11):1852–1858CrossRefPubMed
67.
Buss NA, Gavins FN, Cover PO, Terron A, Buckingham JC (2015) Targeting the annexin 1-formyl peptide receptor 2/ALX pathway affords protection against bacterial LPS-induced pathologic changes in the murine adrenal cortex. FASEB J 29(7):2930–2942CrossRefPubMed
68.
Wang N, Weng W, Breslow JL, Tall AR (1996) Scavenger receptor BI (SR-BI) is up-regulated in adrenal gland in apolipoprotein A-I and hepatic lipase knock-out mice as a response to depletion of cholesterol stores. In vivo evidence that SR-BI is a functional high density lipoprotein receptor under feedback control. J Biol Chem 271(35):21001–21004CrossRefPubMed
69.
Cai L, Ji A, de Beer FC, Tannock LR, van der Westhuyzen DR (2008) SR-BI protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance. J Clin Investig 118(1):364–375CrossRefPubMed
70.
Gilibert S, Galle-Treger L, Moreau M et al (2014) Adrenocortical scavenger receptor class B type I deficiency exacerbates endotoxic shock and precipitates sepsis-induced mortality in mice. J Immunol 193(2):817–826CrossRefPubMed
71.
Bruder EA, Ball IM, Ridi S, Pickett W, Hohl C (2015) Single induction dose of etomidate versus other induction agents for endotracheal intubation in critically ill patients. Cochrane Database Syst Rev 1:CD010225PubMed
72.
Daniell HW (2008) Opioid contribution to decreased cortisol levels in critical care patients. Arch Surg 143(12):1147–1148CrossRefPubMed
73.
Thomson I, Fraser R, Kenyon CJ (1995) Regulation of adrenocortical steroidogenesis by benzodiazepines. J Steroid Biochem Mol Biol 53:75–79CrossRefPubMed
74.
Tominaga T, Fukata J, Naito Y et al (1990) Effects of corticostatin-I on rat adrenal cells in vitro. J Endocrinol 125(2):287–292CrossRefPubMed
75.
Dendoncker K, Libert C (2017) Glucocorticoid resistance as a major drive in sepsis pathology. Cytokine Growth Factor Rev 35:85–96CrossRefPubMed
76.
77.
Bergquist M, Nurkkala M, Rylander C et al (2013) Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis. J Infect 67:574–583CrossRefPubMed
78.
Bergquist M, Lindholm C, Strinnholm M et al (2015) Impairment of neutrophilic glucocorticoid receptor function in patients treated with steroids for septic shock. Intensive Care Med Exp 3:23CrossRefPubMedCentral
79.
Vardas K, Ilia S, Sertedaki A et al (2017) 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(1):10CrossRefPubMedPubMedCentral
80.
Guerrero J, Gatica HA, Rodriguez M, Estay R, Goecke IA (2013) 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(3):R107CrossRefPubMedPubMedCentral
81.
Meduri GU, Tolley EA, Chrousos GP, Stentz F (2002) Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids. Am J Respir Crit Care Med 165(7):983–991CrossRefPubMed
82.
van den Akker EL, Koper JW, Joosten K, de Jong FH, Hazelzet JA, Lamberts SW, Hokken-Koelega AC (2009) Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis. Intensive Care Med 35(7):1247–1254CrossRefPubMedPubMedCentral
83.
Ledderose C, Möhnle P, Limbeck E et al (2012) Corticosteroid resistance in sepsis is influenced by microRNA-124—induced downregulation of glucocorticoid receptor-α. Crit Care Med 40(10):2745–2753CrossRefPubMed
84.
Kamiyama K, Matsuda N, Yamamoto S et al (2008) Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone. Am J Physiol Lung Cell Mol Physiol 295(6):L998–L1006CrossRefPubMed
85.
Cohen J, Pretorius CJ, Ungerer JP (2016) Glucocorticoid sensitivity is highly variable in critically ill patients with septic shock and is associated with disease severity. Crit Care Med 44(6):1034–1041CrossRefPubMed
Metadata
Title
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)
Authors
Djillali Annane
Stephen M. Pastores
Wiebke Arlt
Robert A. Balk
Albertus Beishuizen
Josef Briegel
Joseph Carcillo
Mirjam Christ-Crain
Mark S. Cooper
Paul E. Marik
Gianfranco Umberto Meduri
Keith M. Olsen
Bram Rochwerg
Sophia C. Rodgers
James A. Russell
Greet Van den Berghe
Publication date
01-12-2017
Publisher
Springer Berlin Heidelberg
Published in
Intensive Care Medicine / Issue 12/2017
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-017-4914-x

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