Stress and Critical Illness: The Integrated Immune/Hypothalamic-Pituitary-Adrenal Axis Response

Critical illness leads to a coordinated reaction that is categorized as the stress response; activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system leads to metabolic and cardiovascular changes that are generally directed toward maintenance of homeostasis. The HPA axis and the sympathetic nervous system are linked via reciprocally activating brainstem pathways. The immune system acts via cytokines, which are hormones, to activate the HPA axis. Glucocorticoid secretion suppresses immune activity, thus completing an immune-HPA feedback loop. Restraint of immune activity may be a major function of glucocorticoids during stress, thus averting the potential for immune-mediated damage to healthy tissues. Cortisol also acts to produce adaptive metabolic, cardiovascular, and cognitive changes. Activation of the stress system is also associated with inhibition of thyroid, gonadal, and growth axes through neuroendocrine and peripheral mechanisms; such effects can be seen as directed toward conservation of energy. There is growing evidence that hyperfunction and hypofunction of the integrated stress system may lead to a variety of previously unexplained disorders. Recently, a more detailed understanding of the stress system combined with astute clinical observation of critically ill patients has led to promising new avenues for therapeutic investigation.