Hypothalamus-pituitary-adrenocortical responses to critical illness: new insights with clinical implications

Critical illness profoundly affects the hypothalamus-pituitary-adrenocortical (HPA) axis. In the acute phase of sepsis and other critical conditions, systemic cortisol levels rise markedly, yet circulating ACTH is low. Peripheral adaptations - reduced cortisol metabolism, decreased cortisol-binding proteins, and tissue-specific modulation of glucocorticoid receptor signaling - rather than sustained central HPA axis activation generate compartmentalized increased cortisol actions. As illness persists beyond one week, patients transition into prolonged critical illness characterized by a central HPA suppression, impaired adrenocortical structure and function, together increasing the risk for ICU-acquired adrenal insufficiency beyond 4 weeks. Although glucocorticoids, in stress doses, remain widely used for shock reversal, they exacerbate this HPA suppression and aggravate acute and long-term complications of critical illness. A better mechanistic understanding is essential to guide targeted and adequately dosed therapies.