Sympathetic nervous system response 

The paraventricular nucleus (PVN) is a group of neurones in the hypothalamus play a central role..

. The PVN can detect physiological changes, such as hypotension and inflammation.

It acts to relay afferent impulses originating at the site of surgical tissue damage via the limbic system, particularly the amygdala and brainstem nuclei.

Paraventricular nucleus fibres project directly to the posterior pituitary and also control various anterior pituitary functions.

Adrenaline (epinephrine) is secreted directly from the adrenal medulla in response to hypothalamic activation by the sympathetic nervous system (SNS).

Circulating adrenaline strengthens the sympathetic response and mobilises carbohydrate and fat stores.

Rapid sympathetic responses are mediated neurally.

However, slower sustained sympathetic responses are also seen, and these result from hormonal responses (i.e. circulating adrenaline and noradrenaline [norepinephrine]).3

Hypothalamic activation of the neuroendocrine response.

Heart rate and vascular smooth muscle tone are controlled by the SNS. Sympathetic nervous system activation increases efferent signals to vascular smooth muscle, thereby increasing systemic vascular resistance and arterial blood pressure. Blood flow to active muscles is increased alongside a concurrent reduction in blood flow to organs not prioritised for rapid motor activity, such as the kidneys and gastrointestinal tract. Hepatic and muscle lipolysis and glycogenolysis increase, leading to hyperglycaemia. In addition, cellular metabolic activity and the coagulability of blood increase.

Endocrine system response 

The hypothalamus both directly and indirectly coordinates the complex hormonal stress response (Fig 2). Corticotrophin-releasing hormone (CRH), secreted in response to surgical stress, activates the hypothalamic–pituitary–adrenal (HPA) axis cascade and its metabolic consequences. Corticotrophin-releasing hormone stimulates the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH). Adrenocorticotropic hormone acts on cells in the zona fasciculata of the adrenal cortex to promote glucocorticoid (cortisol) secretion.

Fig 2

Integration of the stress response by the hypothalamus, sympathoadrenal, and sympathorenal responses.

In the normal ‘unstressed’ state, physiological levels of glucocorticoid hormones participate in conventional negative-feedback mechanisms to inhibit ACTH and CRH secretion, predominantly at the level of the anterior pituitary gland, but also at the PVN. Activity of the HPA axis is characterised by a circadian rhythm with superimposed ultradian pulsatile release of glucocorticoids (i.e. there is a recurrent cycle of release repeated throughout a 24 h period). The circadian pattern of cortisol release is controlled by the suprachiasmatic nucleus in the hypothalamus. The HPA axis is a stress-responsive neuroendocrine system that adapts and responds to homeostatic challenges, such as surgery. Immediately after surgery, ultradian pulses in ACTH and cortisol both increase.4 Adrenocorticotropic hormone concentrations return to baseline within 24 h, but plasma concentrations of cortisol remain increased for at least 7 days after major surgery. In minimally invasive surgical procedures, when compared with open surgical techniques, the cortisol 'peak' is delayed, and in severe critical illness, the circadian variation is flattened in proportion to the degree of circadian disruption.5

Chronic activation of the HPA axis before surgery is associated with HPA axis dysfunction. Increasing age and frailty are associated with a progressive loss of hypothalamic sensitivity, with higher cortisol concentrations and a decrease in its diurnal variation. Negative-feedback mechanisms of the HPA axis are blunted: CRH (and also vasopressin, discussed in more detail later) in the PVN of elderly people is increased despite increased circulating plasma cortisol concentrations. Pre-existing cardiovascular deconditioning leading to decreased physical activity, as a result of conditions, such as heart failure, chemotherapy for cancer, or chronic joint pain, can contribute to perioperative disruption of neuroendocrine function.6 Hypothalamic–pituitary–adrenal axis dysfunction also occurs in a variety of non-cardiac medical conditions, including clinical depression; anxiety and depression are associated with worse perioperative outcomes. Central hypersecretion of CRH, and consequently increased production of glucocorticoids, may contribute to the HPA axis dysregulation that occurs in 80% of patients with depression. This may partly account for the increased incidence of upper respiratory tract infections, disruption in wound healing, and psychosocial stress when these patients undergo surgery.5

Growth hormone (GH) secretion by the anterior pituitary gland increases in response to the magnitude of the surgical stress response (Fig 2). Growth hormone increases hepatic glycogenolysis leading to hyperglycaemia. Growth hormone also causes insulin resistance, although the molecular mechanism is uncertain.

Antidiuretic hormone (ADH) is a peptide hormone that is synthesised in the hypothalamus before being transported via axons to the posterior pituitary gland and released into the circulation (Fig 2). This process occurs in response to hypovolaemia, hypotension, hyperosmolarity, and an increase in angiotensin II concentrations. The primary function of ADH, also termed vasopressin or arginine vasopressin, is to regulate extracellular fluid volume. Antidiuretic hormone release leads to a reduction in renal free-water clearance by an action on the renal collecting ducts. Antidiuretic hormone stimulates the insertion of aquaporins into the walls of the renal collecting system. This favours free-water resorption down its concentration gradient back into the renal medulla and causes a reduction in urine volume with an increase in urine concentration.

Other hormonal changes associated with the stress response include increased prolactin concentrations and reduced testosterone, thyroxine (T4), and triiodothyronine (T3) concentrations. These normalise to preoperative baseline within a few days and are not thought to exert a significant effect on patient-centred functional outcomes.

Metabolic response 

A state of hypermetabolism and hypercatabolism occurs with the mobilisation of readily useable energy sources (Table 1). Hepatic glycogen stores are converted to glucose, skeletal muscle undergoes proteolysis, and fat reserves undergo lipolysis. The body uses these substrates in tissue repair and as an energy source.

The release of adrenaline seen alongside SNS activation results in the stimulation of glucagon and inhibition of insulin release. Secretion of the key anabolic hormone insulin is reduced by the SNS effect on pancreatic α2-adrenergic receptors, and later a decrease in insulin sensitivity occurs in peripheral cells. These hormonal changes lead to hyperglycaemia and the release of fatty acids with relatively unopposed catabolism of muscle tissue.3

Increased sympathetic activity to the kidneys activates the renin–angiotensin–aldosterone system (RAAS). Adrenaline-induced vasoconstriction of the renal afferent arterioles causes reduced renal blood flow, promoting the secretion of renin. Renin initiates conversion of angiotensin I to angiotensin II by angiotensinogen, which in turn stimulates the release of aldosterone from the adrenal cortex. In addition, the posterior pituitary gland secretes ADH in response to both increased sympathetic activity and angiotensin II. Together, the hormones aldosterone and ADH promote the retention of salt and water. These changes play a role in the sustained maintenance of blood volume and increased vascular tone. Fluid retention, oliguria, and accumulation of extracellular fluid are common in the acute postoperative period. This may act as a protective feature to help maintain arterial blood pressure in the setting of acute loss of plasma volume through, for example, haemorrhage. In addition, ADH and angiotensin have a direct vasopressor effect.3

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