5.1 Endocrine Physiology and the Neuroendocrine Stress Response

5.1 Endocrine Physiology and the Neuroendocrine Stress Response

Why Endocrine Physiology Matters

Surgery and critical illness activate a coordinated hormonal response. Anaesthetists must understand normal endocrine control to recognise adrenal insufficiency, manage perioperative hyperglycaemia, interpret hyponatraemia and understand how anaesthetic techniques modify the stress response. These topics appear in both papers of EDAIC Part I.

The Hypothalamic-Pituitary Axes

The hypothalamus controls the anterior pituitary through releasing hormones carried in the hypophyseal portal veins, and the posterior pituitary through neurons whose axons end in the gland.

The posterior pituitary releases antidiuretic hormone (ADH, vasopressin) and oxytocin, both made in the supraoptic and paraventricular nuclei. Most axes are regulated by negative feedback: cortisol suppresses CRH and ACTH, and thyroid hormones suppress TRH and TSH.

Thyroid Physiology

The thyroid traps iodide, which is oxidised and attached to tyrosine residues on thyroglobulin by thyroid peroxidase, forming mono- and diiodotyrosine that couple to make thyroxine (T4) and triiodothyronine (T3).

• The gland secretes mainly T4; about 80% of circulating T3 comes from peripheral deiodination of T4.
• T3 is about three to five times more potent than T4 and has a shorter half-life (about 1 day versus about 7 days for T4).
• Over 99% of both hormones are protein-bound, mainly to thyroxine-binding globulin; only the free fraction is active.
• Thyroid hormones act on nuclear receptors to increase basal metabolic rate, oxygen consumption, heat production, and the number and sensitivity of beta-adrenergic receptors.
• In critical illness, peripheral conversion falls, producing a low T3 with normal or low TSH (sick euthyroid syndrome), which does not normally need treatment.

Adrenal Physiology

Adrenal Cortex

Cortisol raises blood glucose (gluconeogenesis, insulin resistance), promotes protein breakdown, has anti-inflammatory effects and is permissive for the vascular response to catecholamines. Normal production is about 10-20 mg/day, with a morning peak. After major surgery it rises to about 75-150 mg/day for 24-72 hours.

Aldosterone acts on the distal nephron to reabsorb sodium and secrete potassium and hydrogen ions.

Adrenal Medulla

The adrenal medulla is a modified sympathetic ganglion. Preganglionic sympathetic fibres release acetylcholine onto chromaffin cells, which secrete mainly adrenaline (about 80%) and noradrenaline. Cortisol from the cortex, delivered through the intra-adrenal portal circulation, induces phenylethanolamine N-methyltransferase, the enzyme that converts noradrenaline to adrenaline.

Glucose Regulation

Insulin secretion is triggered when glucose enters the beta cell through GLUT2, is metabolised, raises ATP, closes ATP-sensitive potassium channels and depolarises the cell, opening calcium channels that trigger insulin release. Sulphonylureas act by closing the same channels. Beta-2 adrenergic stimulation increases insulin release, while alpha-2 stimulation inhibits it.

Water and Sodium Balance

Antidiuretic Hormone

ADH is released when plasma osmolality rises by about 1-2% (osmoreceptors in the hypothalamus) or when circulating volume falls by about 10% or more (baroreceptors). Nausea, pain, surgery, opioids and positive-pressure ventilation also stimulate release.

• V2 receptors in the collecting duct increase cyclic AMP and insert aquaporin-2 water channels, concentrating the urine.
• V1 receptors on vascular smooth muscle cause vasoconstriction through phospholipase C.
• Non-osmotic ADH release after surgery contributes to postoperative hyponatraemia, especially when hypotonic fluids are given.

The Renin-Angiotensin-Aldosterone System

Renin is released from juxtaglomerular cells in response to reduced renal perfusion pressure, reduced sodium delivery to the macula densa, and beta-1 sympathetic stimulation. Renin converts angiotensinogen to angiotensin I, which angiotensin-converting enzyme (mainly in the lung) converts to angiotensin II. Angiotensin II causes vasoconstriction, aldosterone release, thirst, ADH release and efferent arteriolar constriction that supports glomerular filtration.

Natriuretic peptides (atrial and B-type) are released in response to atrial and ventricular stretch and oppose this system by promoting sodium excretion and vasodilation.

The Surgical Stress Response

SURGICAL INJURY
  |-- Afferent nociceptive and autonomic signals --> hypothalamus
  |-- Cytokines (IL-6 peaks at about 24 h) from injured tissue
  v
SYMPATHETIC ACTIVATION       PITUITARY                   OTHER
Adrenaline, noradrenaline    ACTH --> cortisol           Glucagon raised
                             ADH raised                  Insulin relatively low
                             Growth hormone raised       Renin-aldosterone raised
                             TSH, LH, FSH unchanged or low
  v
EFFECTS: hyperglycaemia, protein catabolism (negative nitrogen balance),
lipolysis, sodium and water retention, potassium loss, tachycardia, hypertension

The response is proportional to the extent of tissue injury. Its main consequences are hyperglycaemia (from glucagon, cortisol, catecholamines and insulin resistance), catabolism with loss of muscle protein, and salt and water retention with low urine output in the first 24-48 hours.

Modifying the Stress Response

• Regional anaesthesia: Epidural or spinal blockade covering T4-L1 blocks afferent signals and largely prevents the cortisol, catecholamine and glucose rise during lower abdominal and pelvic surgery; the effect is weaker for upper abdominal and thoracic surgery.
• High-dose opioids suppress the hypothalamic response during surgery but not afterwards.
• Etomidate blocks 11-beta-hydroxylase and suppresses cortisol synthesis for up to 24 hours after a single dose.
• Minimally invasive surgery reduces the cytokine response.
• Enhanced Recovery After Surgery elements such as carbohydrate loading reduce postoperative insulin resistance.