MECHANISMS IN ENDOCRINOLOGY: New concepts to further unravel adrenal insufficiency during critical illness

The concept of 'relative' adrenal insufficiency during critical illness remains a highly debated disease entity. Several studies have addressed how to diagnose or treat this condition but have often yielded conflicting results, which further fuelled the controversy. The main reason for the controversy is the fact that the pathophysiology is not completely understood. Recently, new insights in the pathophysiology of the hypothalamic-pituitary-adrenal axis response to critical illness were generated. It was revealed that high circulating levels of cortisol during critical illness are explained more by reduced cortisol breakdown than by elevated cortisol production. Cortisol production rate during critical illness is less than doubled during the day but lower than in healthy subjects during the night. High plasma cortisol concentrations due to reduced breakdown in turn reduce plasma ACTH concentrations via feedback inhibition, which with time may lead to an understimulation and hereby a dysfunction of the adrenal cortex. This could explain the high incidence of adrenal insufficiency in the prolonged phase of critical illness. These novel insights have created a new framework for the diagnosis and treatment of adrenal failure during critical illness that has redirected future research.