Centre for Systems Modelling and Quantitative Biomedicine (SMQB), University of Birmingham, Edgbaston B15 2TT, UK.
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol BS1 3NY, UK.
J R Soc Interface. 2022 Apr;19(189):20210925. doi: 10.1098/rsif.2021.0925. Epub 2022 Apr 27.
Major surgery and critical illness produce a potentially life-threatening systemic inflammatory response. The hypothalamic-pituitary-adrenal (HPA) axis is one of the key physiological systems that counterbalances this systemic inflammation through changes in adrenocorticotrophic hormone (ACTH) and cortisol. These hormones normally exhibit highly correlated ultradian pulsatility with an amplitude modulated by circadian processes. However, these dynamics are disrupted by major surgery and critical illness. In this work, we characterize the inflammatory, ACTH and cortisol responses of patients undergoing cardiac surgery and show that the HPA axis response can be classified into one of three phenotypes: single-pulse, two-pulse and multiple-pulse dynamics. We develop a mathematical model of cortisol secretion and metabolism that predicts the physiological mechanisms responsible for these different phenotypes. We show that the effects of inflammatory mediators are important only in the single-pulse pattern in which normal pulsatility is lost-suggesting that this phenotype could be indicative of the greatest inflammatory response. Investigating whether and how these phenotypes are correlated with clinical outcomes will be critical to patient prognosis and designing interventions to improve recovery.
重大手术和重症疾病会引发潜在危及生命的全身炎症反应。下丘脑-垂体-肾上腺 (HPA) 轴是平衡全身炎症的关键生理系统之一，通过改变促肾上腺皮质激素 (ACTH) 和皮质醇来实现平衡。这些激素通常表现出高度相关的超短周期脉冲性，其振幅受昼夜节律过程调节。然而，这种动力学会被重大手术和重症疾病破坏。在这项工作中，我们描述了接受心脏手术的患者的炎症、ACTH 和皮质醇反应，并表明 HPA 轴反应可以分为三种表型之一：单脉冲、双脉冲和多脉冲动力学。我们开发了皮质醇分泌和代谢的数学模型，预测了导致这些不同表型的生理机制。我们表明，炎症介质的作用仅在失去正常脉冲性的单脉冲模式中很重要——这表明这种表型可能表明炎症反应最大。研究这些表型是否以及如何与临床结果相关将对患者预后和设计改善恢复的干预措施至关重要。
