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


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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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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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 (2021).

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  • HPA
  • Cortisol
  • Corticotropin
  • ACTH
  • Pro-opiomelanocortin
  • POMC
  • Adrenal failure
  • Critical-illness-induced corticosteroid insufficiency
  • Cosyntropin test