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Adrenal function and dysfunction in critically ill patients

  • Review Article
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From Nature Reviews Endocrinology

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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.

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Fig. 1: Newly proposed conceptual framework for adrenocortical function and dysfunction during critical illness.
Fig. 2: Time-dependent and dose-dependent changes in plasma concentrations of key components during critical illness.

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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.

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Nature Reviews Endocrinology thanks M. Christ-Crain, I. Dimopoulou and P. Marik for their contribution to the peer review of this work.

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Authors and Affiliations

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

    Arno Téblick, Bram Peeters, Lies Langouche & Greet Van den Berghe

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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.

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Correspondence to Greet Van den Berghe.

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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.

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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

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