The immunoneuroendocrine axis in critical illness: beneficial adaptation or neuroendocrine exhaustion?

Over the last years, endocrinology has been incorporated in critical care medicine, and acknowledgment of the complex neuro-endocrine adaption of critical illness has led to new insights and major breakthroughs in clarifying pathophysiological mechanisms and the targeting of therapeutic strategies. This review focuses on the important role of the hypothalamic-pituitary-adrenal (HPA) axis during critical illness and the occurrence of neuroendocrine failure.The distinction between acute (activated anterior pituitary function and inactivated peripheral anabolic pathways) and prolonged (reduced neuroendocrine stimulation) critical illness as different neuroendocrine paradigms has brought a new approach to the critically ill patient. The HPA adaptation in the prolonged phase is characterized by hypercortisolism induced by non-ACTH driven pathways as ACTH levels are low. In spite of the high-normal (total) cortisol levels, HPA insufficiency appears to be quite common. On the other hand, there is a marked depletion of corticosteroid-binding globulin (CBG) in the acute phase of critical illness, resulting in increased free and biologically active cortisol. There is a persistent marked depletion of dehydroeplandrosterone sulfate, possibly indicating adrenal exhaustion, while macrophage inhibitory factor is upregulated in sepsis, affecting and contraregulating the biological effects of glucocorticoids.The endocrine system is highly interrelated with the immune and neural systems, the neuroimmunoendocrine axis is subject to clear biphasic changes in the acute and chronic phases of critical illness, most likely reflecting a beneficial adaptation. These neuroendocrine dynamics should be considered when assessing the neuroendocrine system, in particular the HPA axis.