Hormonal Stress Response

Hormonal Stress Response

• The surgical response to stress is characterized by activation of the SNS and several endocrinologic processes.
• Afferent neuronal fibers conveying nociceptive information project to the cerebral cortex and hypothalamus, thereby eliciting sympathetic activation and the release of hypothalamic hormones.¹ This is followed by downstream hormonal secretion from other organs, including, but not limited to, the anterior and posterior pituitary, adrenal cortex and medulla, and pancreas.¹
• These hormonal shifts optimize cardiac output, shunt blood to vital “fight or flight” organs and musculature, and increase fluid retention to maintain cardiovascular stability.¹
• The hormonal stress response also promotes catabolism and the mobilization of fuel sources through gluconeogenesis, glycogenolysis, peripheral insulin resistance, and lipolysis.¹

Pathways in the Hormonal Stress Response

Sympathoadrenal Pathway¹

• Preganglionic sympathetic neurons from the lateral horns of the T5-T8 spinal cord segments form the greater splanchnic nerve, which innervates the adrenal medulla.
• Sympathetic activation of the adrenal medulla causes the release of the catecholamines epinephrine and norepinephrine.
• Slower, systemic, and hormone-based, modulating the entire sympathetic response.

Sympathetic Neurogenic Pathway¹

• Sympathetic activation leads to the release of norepinephrine from postganglionic adrenergic neurons, which act directly onto α1-adrenergic receptors of vascular smooth muscle.
• Fast, targeted, and neurotransmitter-based – one of the primary determinants of vascular tone, providing moment-to-moment blood pressure control.

Hypothalamic-Pituitary-Adrenal (HPA) Axis²

• The hypothalamus releases corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GHRH), among other hormones.
• CRH and GHRH activate the anterior pituitary to release adrenocorticotropic hormone (ACTH) and growth hormone (GH), respectively.
• ACTH stimulates the adrenal cortex to release both glucocorticoids (cortisol) and mineralocorticoids (aldosterone).

Catecholamines Involved in the Hormonal Stress Response

Norepinephrine³

• Primary function: Acts mainly as a neurotransmitter, via the sympathetic neurogenic pathway, and as a secondary role as a circulating catecholamine.
• Sites of synthesis: Produced in sympathetic postganglionic neurons, chromaffin cells of the adrenal medulla, and noradrenergic neurons in the central nervous system.
• Receptor affinity: Strong affinity to α1, α2, and β1 receptors, with minimal β2 affinity.
• Stronger affinity to α1 compared to epinephrine.
• Physiologic effects: potent vasoconstriction, increased heart rate, and increased contractility.

Epinephrine³

• Primary function: Acts as a circulatory hormone.
• Sites of synthesis: Produced primarily in the chromaffin cells of the adrenal medulla through the conversion of norepinephrine by the enzyme phenylethanolamine N-methyltransferase.
• Receptor affinity: Strong affinity to β1, β2, and α1, and moderate affinity to α2
  • Exhibits dose-dependent receptor activation:
    • Low dose: β2 > α1
    • Higher doses: α1 > β2
• Physiologic effects: Results in increased heart rate and contractility, vasodilation at lower doses, vasoconstriction at higher doses, bronchodilation, and promotion of catabolism.

α1 Adrenergic Receptors³

• Located in the peripheral vasculature, including renal, splanchnic, mesenteric, and cutaneous vascular beds.
• Causes vasoconstriction, leading to an increase in systemic vascular resistance (SVR) and mean arterial pressure
• Results in decreased blood flow to “rest and digest organs” and redirects it to vital organs, including the heart, brain, and skeletal muscle.

α2 Adrenergic Receptors³

• Located in pancreatic β-cells and cells of the gastrointestinal tract.
• Leads to decreased insulin secretion and slowed gastric motility.
• Inhibits norepinephrine release via a negative feedback mechanism.

β1 Adrenergic Receptors³

• Located in the SA node, AV node, myocardium, and juxtaglomerular cells of the kidneys.
• Increases heart rate, cardiac conduction velocity, and contractility.
• Stimulates renin release from the kidneys.

β2 Adrenergic Receptors³

• Located in bronchial smooth muscle, vascular smooth muscle of skeletal muscle beds, uterine smooth muscle, and the liver.
• Causes bronchodilation and skeletal muscle vasodilation, improving oxygen delivery to musculature.
• Promotes glycogenolysis and gluconeogenesis in the liver

β3 Adrenergic Receptors³

• Located primarily in adipose tissue
• Stimulates lipolysis, mobilizing free fatty acids for energy production

Hormones Involved in the Hormonal Stress Response That Increase Blood Glucose

Cortisol^1,4

• A steroidal glucocorticoid hormone secreted from the zona fasciculata of the adrenal cortex in response to ACTH from the anterior pituitary
• Promotes gluconeogenesis, protein catabolism, and lipolysis, leading to increased blood glucose levels
• Enhances the effects of catecholamines by upregulation of α1 adrenergic receptors.
  • Patients on chronic steroids have suppression of the HPA-axis and have a cortisol deficiency.
  • This is the etiology of vasopressor-resistant hypotension seen in patients on chronic steroids, and the physiology behind the need for stress dose steroids in these patients.
• Inhibits proinflammatory cytokines, including IL-1, IL-2, IL-6, TNF-α, and interferon-γ.
• Suppresses immune cell activation.

Insulin^1,4

• A peptide hormone released from pancreatic β-cells that decreases blood glucose levels via cellular uptake of glucose, glycogenesis, lipogenesis, and protein synthesis.
• Decreased in response to cortisol, GH, and activation of α2 receptors by epinephrine and norepinephrine.
• Insulin suppression increases blood glucose levels.

Glucagon¹

• A peptide hormone released from α-cells of the pancreas that functions to increase blood glucose by hepatic glycogenolysis, gluconeogenesis, lipolysis, and opposing insulin.
• Released in response to β2-mediated activation by epinephrine and low blood glucose levels

Growth Hormone¹

• A peptide hormone released from the anterior pituitary in response to GHRH from the hypothalamus
• Promotes lipolysis, increases hepatic gluconeogenesis, and antagonizes insulin
• Preferentially promotes fat utilization to avoid excessive protein utilization for fuel sources.

Hormones Involved in the Hormonal Stress Response That Increase Water Retention

Aldosterone^1,2

• A steroidal mineralocorticoid hormone that is secreted from the zona glomerulosa of the adrenal cortex in response to both ACTH and angiotensin II.
• Renin is released in response to decreased renal perfusion and via β1 receptor activation by catecholamines.
• Renin increases the conversion of angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme.
• Angiotensin II directly stimulates aldosterone secretion from the adrenal cortex and acts as a potent vasoconstrictor.
• Aldosterone increases sodium reabsorption and potassium excretion in the distal nephron, thereby promoting water retention and increasing intravascular volume.

Antidiuretic Hormone/Vasopressin^1,5

• A peptide hormone released from neuronal activation of the posterior pituitary by the hypothalamus.
• Released physiologically in response to increased osmolarity, hypotension/low volume stimuli, and via angiotensin II.
• It is also released in response to non-osmotic stress signals, as seen during surgical stress.
• Functions by increasing water reabsorption via aquaporin insertion in the collecting ducts

Anesthetic Consideration of the Hormonal Stress Response

• Surgical stimulation, and particularly the intense nociceptive input associated with airway manipulation, triggers sympathetic activation and the hormonal stress response. This response produces the characteristic physiologic changes described above, including tachycardia, increased systemic vascular resistance, elevated blood pressure, and stress-induced hyperglycemia.
• When managing these responses, anesthesiologists must carefully consider a patient’s comorbidities and their ability to tolerate heightened sympathetic tone.
• Excessive tachycardia should be avoided in patients with coronary artery disease, as increased heart rate raises myocardial oxygen demand and may precipitate supply–demand mismatch or ischemia.
• Hyperglycemia should be managed appropriately, as perioperative hyperglycemia is associated with increased morbidity and mortality.6 Similarly, excessive hypertension should be avoided in patients at risk for cerebrovascular events, as acute elevations in blood pressure may increase the likelihood of stroke or neurologic injury.
• Thoughtful modulation of sympathetic responses is therefore essential to ensure hemodynamic stability and prevent end-organ complications in vulnerable patients.
• The following are some commonly used perioperative medications and describe how they modulate the hormonal stress response.

Hypnotic Sedatives¹

• Propofol
  • Suppresses circulating cortisol levels; however, it does not completely block cortisol or aldosterone secretion.
  • Blunts sympathetic outflow, leading to decreased SVR and blood pressure.
• Etomidate
  • Suppresses adrenocortical function by reversible inhibition of 11β-hydroxylase and 17α-hydroxylase.
  • Should not be used in patients with adrenal insufficiency, or in those who are believed to be catecholamine-depleted, as these patients are reliant on cortisol for vascular tone.
  • Has been shown to have increased mortality when used in patients with sepsis in the intensive care unit.

Analgesics¹

• Opioids reduce sympathetic outflow and CRH and GHRH secretion, via decreased nociceptive signaling to the hypothalamus.
• High-dose opioids can completely suppress both ACTH and cortisol secretion if administered before surgical stimulation.

α2-Adrenergic Agonists¹

• Clonidine and dexmedetomidine act as centrally acting α2-adrenoceptor agonists.
• Reduces sympathetic outflow, leading to a predictable bradycardic response and sedation
• α2-adrenergic agonism also modulates the descending pathways involved in spinal nociceptive processing, reducing hypothalamic activation.
• Dexmedetomidine also reduces cortisol and renin concentrations.

Regional/Neuraxial Anesthesia^1,2

• Regional and neuraxial anesthesia can block HPA axis activation in a similar way to opioids. Afferent nociceptive signals are reduced, thereby decreasing hypothalamic activation.
• In neuraxial anesthesia, the efferent sympathetic limb is also blocked, thereby reducing sympathetic tone.
• ACTH, cortisol, epinephrine, and GH secretion are attenuated in the setting of regional and neuraxial anesthesia.