Based on insights obtained during the past decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical axis in response to critical illness is in need of revision. After a brief central hypothalamus-pituitary-adrenocortical axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol-binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11βHSD1, glucocorticoid receptor-α (GRα), and FK506 binding protein 5 (FKBP51) that appear to titrate increased GRα action in vital organs and tissues while reducing GRα action in neutrophils, possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of pro-opiomelanocortin into ACTH, thereby reducing ACTH-driven cortisol secretion, whereas ongoing central activation results in increased circulating pro-opiomelanocortin. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require intensive care for weeks or longer may develop a form of central adrenal insufficiency. The new findings supersede earlier concepts such as "relative," as opposed to "absolute," adrenal insufficiency and generalized systemic glucocorticoid resistance in the critically ill. The findings also question the scientific basis for broad implementation of stress dose hydrocortisone treatment of patients suffering from acute septic shock solely based on assumption of cortisol insufficiency.

中文翻译：

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下丘脑-垂体-肾上腺皮质对危重疾病的反应：一个需要修订的概念。

根据过去十年获得的见解，激活下丘脑-垂体-肾上腺皮质轴以应对危重疾病的经典概念需要修订。在短暂的中枢下丘脑-垂体-肾上腺皮质轴激活后，全身皮质醇可用​​性增加和应对危重疾病的作用的重要维持主要是由外周适应驱动的，而不是由持续的中枢激活数倍增加的皮质醇产生和分泌驱动的。除了已知的皮质醇结合蛋白减少导致游离皮质醇增加外，这些外周反应还包括肝脏和肾脏中皮质醇代谢受到抑制、皮质醇半衰期延长以及 11βHSD1、糖皮质激素受体-α (GRα) 和 FK506 表达的局部改变结合蛋白 5 (FKBP51) 似乎可以滴定重要器官和组织中 GRα 作用的增加，同时减少中性粒细胞中 GRα 的作用，可能防止全身皮质醇可用​​性增加的免疫抑制脱靶效应。外周增加的皮质醇在垂体水平上产生负反馈抑制，损害阿片黑皮质素原转化为 ACTH 的过程，从而减少 ACTH 驱动的皮质醇分泌，而持续的中枢激活导致循环阿片黑皮质素原增加。这些改变似乎是适应性的，并且在短期内对宿主有利。然而，因此，需要重症监护数周或更长时间的长期危重患者可能会出现某种形式的中枢肾上腺功能不全。新的发现取代了早期的概念，例如“相对”而不是“绝对”、肾上腺功能不全和危重病患者普遍的全身性糖皮质激素抵抗。研究结果还质疑仅基于皮质醇不足的假设而对患有急性感染性休克的患者广泛实施应激剂量氢化可的松治疗的科学依据。