Modelling the dynamic interaction of systemic inflammation and the hypothalamic–pituitary–adrenal (HPA) axis during and after cardiac 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 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.

Acute Pancreatitis as an Unusual Culprit of Diabetic Ketoacidosis in a Nondiabetic: A Case-Based Review

“…The primary proposed mechanism of post-pancreatitis DKA likely involves multiple stress-mediated physiologic pathways contributing to a state of acute hyperglycemia [ 21 ]. One proposed hypothesis of stress hyperglycemia involves a neuroendocrine response to a critical illness like acute pancreatitis that results in subsequent activation of the hypothalamic-pituitary-adrenal axis [ 22 ]. Acute changes in adrenocorticotropic hormone levels can increase serum cortisol levels, stimulating hepatic gluconeogenesis and inhibiting the uptake of glucose in peripheral tissues [ 23 ].…”

“…This effect may be compounded by activation of the sympathetic nervous system and presence of pro-inflammatory cytokines which have both been reported in acute pancreatitis [ 24 , 25 ]. The resulting elevation in epinephrine and norepinephrine increases circulating glucose levels through hepatic gluconeogenesis and glycogenolysis [ 22 ]. Pro-inflammatory cytokines, which have a synergistic effect in addition to adrenergic agonists, can produce profound elevation in serum glucose levels through an increase in peripheral insulin resistance [ 26 ].…”

Preoperative depression and anxiety as predictors of postoperative C-reactive protein levels in patients undergoing cardiac surgery: a prospective observational study

“…Alterations in the neuroendocrine and autonomic nervous system might be involved. Both cardiac surgery and acute psychosocial stress activate the innate immune response, with increases in pro-inflammatory cytokines and CRP [36], which is curtailed by cortisol release in a feedback mechanism [37,38]. In patients with CHD, severe anxiety symptoms were associated with a blunted cortisol response to acute psychosocial stress [39], and clinical depression was associated with insufficient glucocorticoid signalling, resulting in increased CRP levels [40].…”

Graves’ disease as a driver of depression: a mechanistic insight

“…The HPA axis is one of the critical physiological systems that regulate systemic inflammatory response and immune response ( 73 ). It secretes three main classes of hormones, which are regulated hierarchically.…”