Endocrine Abstracts

Critical illness represents a major challenge for the human body where an adequate stress response is indispensable for survival. Concomitantly high cortisol levels are observed and for a long time, an increased activation of the hypothalamic-pituitary-adrenal axis (HPA) was assumed to explain this hypercortisolism. Furthermore, insufficient activation of the HPA-axis during critical illness was described and referred to as ‘relative adrenal insufficiency’ or ‘critical illness-related corticosteroid insufficiency’ (CIRCI). These terms comprise insufficient adrenal cortisol production to match the level of stress due to a malfunctioning of the HPA-axis or a cortisol resistance of the peripheral tissues. Suggested diagnostic criteria were based on a landmark study by Annane et al. who identified a cortisol incremental response of <9 μg/dl after ACTH-injection and a baseline cortisol level >34 μg/dl as discriminative for increased risk of death. However, other investigators have not been able to replicate this. Furthermore, it remains debated whether CIRCI should be treated with exogenous glucocorticoids and with which doses. Indeed, randomized controlled studies generated conflicting results. The important lack of knowledge on the pathophysiology of CIRCI currently retains further improvement of diagnosis and treatment of CIRCI.

Recent novel insights have shown that cortisol metabolism was reduced which contributed to hypercortisolism, with limited increased cortisol production. The concomitant low ACTH levels, explained by negative feedback, could lead to an understimulation of the adrenal gland and negatively affect adrenal structure and function, given the crucial role of ACTH for adrenal gland maintenance. Predominantly in the prolonged phase of critical illness this could influence outcome and explain the increased incidence of adrenal failure in these patients.

These findings represented a paradigm shift in our current understanding of HPA-axis regulation during critical illness and will redirect future research, underlining the urgent need for well-designed clinical trials.