Novel insights in the HPA-axis during critical illness

Critical illness represents a major challenge for the human body, implicating that an adequate stress response is indispensable for survival. Therefore, for a long time, activation of the hypothalamic pituitary adrenal axis was assumed to be increased to respond to this stressful situation. Recent novel insights, however, provided evidence that the HPA-axis is regulated differently during critical illness. Cortisol metabolism was shown to be reduced which contributed to hypercortisolism in an energy efficient way without increasing cortisol production dramatically. Yet, the concomitant low ACTH levels, explained by negative feedback inhibition, could lead to an understimulation of the adrenal gland and affect adrenal structure and function, given the crucial role of ACTH for adrenal gland maintenance. This side-effect could negatively affect outcome predominantly in the prolonged phase of critical illness and could explain the increased incidence of adrenal failure in these patients. Altogether, novel findings represent a paradigm shift in our current understanding of HPA-axis regulation during critical illness and redirect future research perspectives with an urgent need to well-designed clinical trials to further explore HPA-axis functioning during critical illness.