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Adrenal function/dysfunction in critically ill patients: a concise narrative review of recent novel insights

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Abstract

The “fight or flight” response to critical illness relies on increased cortisol availability, traditionally attributed to several-fold-increased cortisol production via hypothalamus–pituitary–adrenal-axis activation. Recent studies provided evidence against this concept with clinical implications. First, high cortisol availability during critical illness is driven by suppressed cortisol binding and reduced cortisol breakdown rather than increased cortisol production. This implies reduction of hydrocortisone doses when prescribed in ICU. Second, plasma ACTH is low, explained by feedback inhibition by peripherally driven high free cortisol and/or other central glucocorticoid-receptor ligands. Third, ICU patients have elevated plasma concentrations of the ACTH-precursor hormone, pro-opiomelanocortin, because of impaired pituitary processing into ACTH, and pro-opiomelanocortin could drive some adrenocortical cortisol production in face of low ACTH. Fourth, in prolonged critically ill patients, endogenously suppressed ACTH, aggravated by exogenous corticosteroids, associates with poor outcome. In long-stay ICU patients, central adrenal insufficiency may occur due to lack of trophic ACTH signaling. Finally, the Cosyntropin test is not suitable to assess adrenocortical reserve in ICU patients as the test is confounded by increased cortisol distribution volume. These insights necessitate further research focusing on the need, if any, of treating ICU patients with corticosteroids, and timing thereof, outside indications for pharmacological anti-inflammatory drugs.

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References

  1. Téblick A, Peeters B, Langouche L, Van den Berghe G. Adrenal function and dysfunction in critically ill patients. Nat Rev Endocrinol. 2019;15:417–27.

    Article  Google Scholar 

  2. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383:2152–67.

    Article  CAS  Google Scholar 

  3. Betterle C, Morlin L. Autoimmune Addison’s disease. Endocr Dev. 2011;20:161–72.

    Article  CAS  Google Scholar 

  4. Annane D, Sébille V, Troché G, Raphaël JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA. 2000;283:1038–45.

    Article  CAS  Google Scholar 

  5. Annane D, Sébille V, Charpentier C, Bollaert P-E, François B, Korach J-M, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaud Ph, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862–71.

    Article  CAS  Google Scholar 

  6. Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Meduri GU, Olsen KM, Rodgers S, Russell JA, Van den Berghe G. 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. 2017;43:1751–63.

    Article  Google Scholar 

  7. Boonen E, Vervenne H, Meersseman Ph, Andrew R, Mortier L, Declercq PE, Vanwijngaerden Y-M, Spriet I, Wouters PJ, Vander Perre S, Langouche L, Vanhorebeek I, Walker BR, Van den Berghe G. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013;368:1477–88.

    Article  CAS  Google Scholar 

  8. Boonen E, Meersseman Ph, Vervenne H, Meyfroidt G, Guïza F, Wouters PJ, Veldhuis JD, Van den Berghe G. Reduced nocturnal ACTH-driven cortisol secretion during critical illness. Am J Physiol Endocrinol Metab. 2014;306:E883–92.

    Article  CAS  Google Scholar 

  9. Peeters B, Güiza F, Boonen E, Meersseman Ph, Langouche L, Van den Berghe G. Drug-induced HPA axis alterations during acute critical illness: a multivariable association study. Clin Endocrinol (Oxf). 2017;86:26–36.

    Article  CAS  Google Scholar 

  10. Peeters B, Meersseman Ph, Vander Perre S, Wouters PJ, Vanmarcke D, Debaveye Y, Billen J, Vermeersch P, Langouche L, Van den Berghe G. Adrenocortical function during prolonged critical illness and beyond: a prospective observational study. Intensive Care Med. 2018;44:1720–9.

    Article  CAS  Google Scholar 

  11. 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 (Oxf). 2015;82:801–7.

    Article  CAS  Google Scholar 

  12. Jenniskens M, Weckx R, Dufour T, Vander Perre S, Pauwels L, Derde S, Téblick A, Güiza F, Van den Berghe G, Langouche L. The hepatic glucocorticoid receptor is crucial for cortisol homeostasis and sepsis survival in humans and male mice. Endocrinology. 2018;159:2790–802.

    Article  CAS  Google Scholar 

  13. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med. 2004;350:1629–38.

    Article  CAS  Google Scholar 

  14. Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004;25:831–66.

    Article  CAS  Google Scholar 

  15. Nixon M, Upreti R, Andrew R. 5alpha-Reduced glucocorticoids: a story of natural selection. J Endocrinol. 2012;212:111–27.

    Article  CAS  Google Scholar 

  16. Peeters B, Meersseman Ph, Vander Perre S, Wouters PJ, Debaveye Y, Langouche L, Van den Berghe G. 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. 2018;44:2048–58.

    Article  CAS  Google Scholar 

  17. Téblick A, Vander Perre S, Pauwels L, Derde S, Van Oudenhove T, Langouche L, Van den Berghe G. The role of pro-opiomelanocortin in the ACTH-cortisol dissociation of sepsis. Crit Care. 2021;25:65–79.

    Article  Google Scholar 

  18. Jacobs A, Derese I, Vander Perre S, Wouters PJ, Verbruggen S, Billen J, Vermeersch P, Guerra GG, Joosten K, Vanhorebeek I, Van den Berghe G. Dynamics and prognostic value of the hypothalamus-pituitary-adrenal axis responses to pediatric critical illness and association with corticosteroid treatment: a prospective observational study. Intensive Care Med. 2020;46:70–81.

    Article  CAS  Google Scholar 

  19. Boonen E, Langouche L, Janssens T, Meersseman Ph, Vervenne H, De Samblanx E, Pironet Z, Van Dyck 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 Metab. 2014;99:4214–22.

    Article  CAS  Google Scholar 

  20. Lamberts SW, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J Med. 1997;337:1285–92.

    Article  CAS  Google Scholar 

  21. Verstraete S, Verbruggen SC, Hordijk JA, Vanhorebeek I, Dulfer K, Güiza F, van Puffelen E, Jacobs A, Leys S, Durt A, Van Cleemput H, Eveleens RD, Garcia Guerra G, Wouters PJ, Joosten KF, Van den Berghe G. Long-term developmental effects of withholding parenteral nutrition for 1 week in the pediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomized controlled trial. Lancet Respir Med. 2019;7:141–53.

    Article  Google Scholar 

  22. Hermans G, Van Aerde N, Meersseman P, Van Mechelen H, Debaveye Y, Wilmer A, Gunst J, Casaer MP, Dubois J, Wouters P, Gosselink R, Van den Berghe G. Five-year mortality and morbidity impact of prolonged versus brief ICU stay: a propensity score matched cohort study. Thorax. 2019;74:1037–45.

    Article  Google Scholar 

  23. Van Aerde N, Meersseman P, Debaveye Y, Wilmer A, Gunst J, Casaer MP, Wauters J, Wouters PJ, Gosselink R, Van den Berghe G, Hermans G. Five-year outcome of muscle weakness at intensive care unit discharge: a secondary analysis of a propensity score matched cohort study. Thorax. 2021;76:561–7.

    Article  Google Scholar 

  24. Güiza F, Vanhorebeek I, Verstraete S, Verlinden I, Derese I, Ingels C, Dulfer K, Verbruggen SC, Garcia Guerra G, Joosten KF, Wouters PJ, Van den Berghe G. Effect of early parenteral nutrition during pediatric critical illness on DNA methylation as a potential mediator of impaired neurocognitive development: a pre-planned secondary analysis of the PEPaNIC international, randomized controlled trial. Lancet Respir Med. 2020;8:288–303.

    Article  Google Scholar 

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Funding

This work was supported by the European Respiratory Society (ERS Gold Medal in ARDS), the Research Foundation Flanders (FWO) grant G091918N, the European Research Council Advanced Grant (AdvG-2017-785806) from European Union’s Horizon 2020 research and innovation program, and the Methusalem program of the Flemish Government (METH/14/06 via the KU Leuven).

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  1. Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, 3000, Leuven, Belgium

    Greet Van den Berghe

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  1. Greet Van den Berghe
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Correspondence to Greet Van den Berghe.

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Van den Berghe, G. Adrenal function/dysfunction in critically ill patients: a concise narrative review of recent novel insights. J Anesth 35, 903–910 (2021). https://doi.org/10.1007/s00540-021-02977-x

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