Adrenal function and dysfunction in critically ill patients

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. In this Review, new insights into the hypothalamic–pituitary–adrenal axis are integrated within a novel conceptual framework that can be used to re-appreciate adrenocortical function and dysfunction in the context of critical illness. 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. Do