The dynamic interaction of systemic inflammation and the hypothalamic-pituitary-adrenal (HPA) axis during and after major surgery

Abstract

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 characterise 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-pulses and multiple-pulses 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.

Misaligned hormonal rhythmicity: Mechanisms of origin and their clinical significance

“…While methods for investigating dynamic responses to perturbations and rhythm misalignment are well known in mathematics, they are relatively new in the context of endocrine research. For example, mathematical modelling of the hypothalamic–pituitary–adrenal (HPA) axis has contributed to our understanding of how systems‐level feedback loops underpin ultradian pulsatility of ACTH and glucocorticoid hormones, 21 how intra‐adrenal feedback loops modulate HPA responses to acute stressors and inflammation, 22 how dynamic disruptions of the HPA axis can propagate to other endocrine systems, 23,24 and its cross‐talk interactions with the inflammatory response 16,25 . While the intensity, duration and frequency of stressors affect the dynamic responses of the HPA axis, hormonal responses are also affected by the timing of perturbations and underlying physiological context.…”

“…14 However, a theoretical framework to understand how rhythm misalignment emerges as a consequence of external disruptors is still lacking. 15 From a dynamical point of view, disruptions in hormonal rhythms can vary in severity and be either transient (i.e., shortlived) 16 or chronic. 17 In many cases, these disruptions can lead to misaligned hormonal rhythmicity, understood as the loss of either the normal physiological frequency, amplitude or phase synchrony between hormonal rhythms (Figure 1).…”

“…For example, mathematical modelling of the hypothalamic-pituitaryadrenal (HPA) axis has contributed to our understanding of how systems-level feedback loops underpin ultradian pulsatility of ACTH and glucocorticoid hormones, 21 how intra-adrenal feedback loops modulate HPA responses to acute stressors and inflammation, 22 how dynamic disruptions of the HPA axis can propagate to other endocrine systems, 23,24 and its cross-talk interactions with the inflammatory response. 16,25 While the intensity, duration and frequency of stressors affect the dynamic responses of the HPA axis, hormonal responses are also affected by the timing of perturbations and underlying physiological context. For example, computationally-derived phaseresponse curves have shown that the magnitude of hormonal responses are critically dependent on the timing of the perturbation.…”