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After a brief central hypothalamus-pituitary-adrenocortical axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol-binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11\u03b2HSD1, glucocorticoid receptor-\u03b1 (GR\u03b1), and FK506 binding protein 5 (FKBP51) that appear to titrate increased GR\u03b1 action in vital organs and tissues while reducing GR\u03b1 action in neutrophils, possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of pro-opiomelanocortin into ACTH, thereby reducing ACTH-driven cortisol secretion, whereas ongoing central activation results in increased circulating pro-opiomelanocortin. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require intensive care for weeks or longer may develop a form of central adrenal insufficiency. The new findings supersede earlier concepts such as \u201crelative,\u201d as opposed to \u201cabsolute,\u201d adrenal insufficiency and generalized systemic glucocorticoid resistance in the critically ill. The findings also question the scientific basis for broad implementation of stress dose hydrocortisone treatment of patients suffering from acute septic shock solely based on assumption of cortisol insufficiency.<\/jats:p>","DOI":"10.1210\/endrev\/bnad021","type":"journal-article","created":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T10:03:36Z","timestamp":1688378616000},"page":"1096-1106","source":"Crossref","is-referenced-by-count":37,"title":["The Hypothalamus-pituitary-adrenocortical Response to Critical Illness: A Concept in Need of Revision"],"prefix":"10.1210","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8564-6809","authenticated-orcid":false,"given":"Lies","family":"Langouche","sequence":"first","affiliation":[{"name":"Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven , B-3000 Leuven , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8829-0855","authenticated-orcid":false,"given":"Arno","family":"T\u00e9blick","sequence":"additional","affiliation":[{"name":"Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven , B-3000 Leuven , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2470-6393","authenticated-orcid":false,"given":"Jan","family":"Gunst","sequence":"additional","affiliation":[{"name":"Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven , B-3000 Leuven , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5320-1362","authenticated-orcid":false,"given":"Greet","family":"Van den Berghe","sequence":"additional","affiliation":[{"name":"Clinical Division and Laboratory of 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