Stress response to surgery

Clinical relevance for anaesthetists

Stress response is a coordinated neuroendocrine + inflammatory response to tissue injury, pain, hypovolaemia, hypothermia and anxiety; magnitude relates to severity/duration of surgery and complications (e.g. sepsis).
Aims (adaptive): maintain perfusion, mobilise substrate (glucose, FFA), support immune response and wound healing.
Costs (maladaptive/excess): hyperglycaemia, insulin resistance, catabolism, immunosuppression, ileus, sodium/water retention, hypercoagulability → ↑ infection, poor wound healing, MI/stroke/VTE risk.
Anaesthetic techniques can attenuate components: regional/neuraxial blockade, adequate analgesia, normothermia, euvolaemia, minimally invasive surgery, ERAS principles.

Time course (typical)

Immediate (seconds–minutes): sympathetic activation (catecholamines) + early cytokine signalling; haemodynamic and metabolic shift to glucose availability.
Early (hours): HPA axis (ACTH → cortisol), ADH, RAAS, glucagon; insulin secretion may be normal/↑ but insulin resistance develops.
Late (days): sustained catabolism (proteolysis, lipolysis), negative nitrogen balance; inflammatory/acute phase response; resolution depends on control of pain, infection, complications and nutrition.

Triggers and afferent pathways

Afferent input from nociceptors and mechanoreceptors at surgical site via spinal cord to hypothalamus/brainstem; augmented by hypovolaemia, hypoxia, hypercarbia, hypothermia, anxiety.
Cytokine signalling from injured tissue/immune cells (e.g. IL‑6, IL‑1β, TNF‑α) drives acute phase response and contributes to endocrine changes.

Key neuroendocrine axes and hormones

Sympathoadrenal system: ↑ noradrenaline (sympathetic nerve terminals) and ↑ adrenaline (adrenal medulla).
- Effects: ↑ HR/contractility, vasoconstriction (α1), bronchodilation (β2), glycogenolysis, lipolysis; ↓ insulin secretion (α2) and ↑ glucagon (β).
HPA axis: ↑ CRH → ↑ ACTH → ↑ cortisol (peaks within hours; duration relates to surgical magnitude).
- Cortisol: permissive for catecholamines; ↑ gluconeogenesis, proteolysis, lipolysis; causes insulin resistance; anti-inflammatory/immunomodulatory effects; contributes to muscle wasting and hyperglycaemia.
ADH (vasopressin): ↑ due to pain, nausea, hypovolaemia, positive pressure ventilation.
- Effects: V2 water reabsorption → water retention/hyponatraemia risk; V1 vasoconstriction at higher levels.
RAAS: ↑ renin → ↑ angiotensin II → ↑ aldosterone (also stimulated by SNS and hypovolaemia).
- Effects: vasoconstriction, sodium retention, potassium loss; supports BP but contributes to fluid overload/edema.
Pancreatic hormones: ↑ glucagon; insulin secretion variable but peripheral insulin resistance dominates.
- Mechanisms of insulin resistance: cortisol/catecholamines, inflammatory cytokines, reduced GLUT4 translocation in muscle/adipose, hepatic glucose output ↑.
Growth hormone (GH): ↑ (especially early), but with GH resistance → reduced anabolic effect; contributes to lipolysis and insulin resistance.
Thyroid axis: often low T3 syndrome (↓ T3, normal/low T4, normal/low TSH) in major illness/surgery—adaptive reduction in metabolic rate.

Inflammatory and acute phase response

Tissue injury activates innate immunity: macrophages/monocytes release IL‑6 (key driver), IL‑1, TNF‑α; complement and coagulation pathways activated.
Hepatic acute phase proteins: ↑ CRP, fibrinogen, haptoglobin; ↓ albumin/transferrin (negative acute phase proteins).
Endothelial effects: increased permeability + leukocyte trafficking; contributes to oedema and organ dysfunction in severe systemic inflammation.

Metabolic consequences

Carbohydrate: ↑ hepatic glycogenolysis and gluconeogenesis; hyperglycaemia common even in non-diabetics; reduced peripheral uptake due to insulin resistance.
- Clinical impacts: osmotic diuresis, dehydration, impaired neutrophil function, ↑ infection risk; association with worse outcomes (especially cardiac/ICU).
Protein: ↑ proteolysis (skeletal muscle) → amino acids for gluconeogenesis and acute phase proteins → negative nitrogen balance and weakness.
Fat: ↑ lipolysis → ↑ free fatty acids and ketone production (more prominent with fasting/diabetes/sepsis).
Electrolytes/fluids: sodium and water retention (ADH/aldosterone) with potential dilutional hyponatraemia; potassium tends to fall with aldosterone but may rise with tissue injury/acidosis/renal failure.
Thermogenesis: catecholamines/cytokines increase metabolic rate; hypothermia itself is a stressor and worsens coagulopathy and infection risk.

Cardiovascular, respiratory and renal effects

Cardiovascular: ↑ HR, ↑ SVR, ↑ myocardial O2 demand; risk of demand ischaemia in coronary disease; hypercoagulability increases thrombotic risk.
Respiratory: pain and splinting reduce FRC and promote atelectasis; catecholamines cause bronchodilation but overall pulmonary complications depend on analgesia, ventilation strategy and mobilisation.
Renal: RAAS/ADH reduce urine output; perioperative oliguria may be physiological but must exclude hypovolaemia/obstruction/AKI.

How anaesthesia and perioperative care modify the stress response

General anaesthesia: reduces awareness/anxiety and some afferent input, but does not fully block neuroendocrine response to surgical incision unless analgesia/neuraxial blockade is effective.
Neuraxial (spinal/epidural): blocks afferent nociceptive transmission and sympathetic efferents → marked attenuation of catecholamine/cortisol responses (especially for lower abdominal/lower limb surgery).
Peripheral nerve blocks and multimodal analgesia: reduce pain-driven sympathetic/HPA activation; opioid-sparing can reduce ileus and improve mobilisation.
Minimally invasive surgery: smaller cytokine surge and endocrine response vs open surgery (less tissue trauma).
Normothermia, euvolaemia, oxygenation, and PONV control reduce ADH/catecholamine drive; ERAS elements (carbohydrate loading, early feeding) reduce insulin resistance and catabolism.
Glycaemic management: avoid severe hyperglycaemia; overly tight control risks hypoglycaemia—targets depend on setting (ward vs ICU) and local policy.

Special situations

Diabetes: stress response → marked hyperglycaemia/ketogenesis risk; insulin requirements often increase; monitor ketones if unwell or type 1/insulin-deficient.
Chronic steroids/adrenal insufficiency: inability to mount cortisol response → risk of refractory hypotension; consider perioperative steroid supplementation according to procedure severity and baseline therapy.
Sepsis/major trauma: exaggerated inflammatory response with vasodilation, capillary leak and metabolic derangement; endocrine patterns may include relative adrenal insufficiency and profound insulin resistance.

Define the stress response to surgery and outline its components.

A coordinated response to surgical injury mediated by neural, endocrine and immune pathways.

Components: sympathetic nervous system, HPA axis, ADH/RAAS, metabolic hormone changes (insulin/glucagon/GH), and inflammatory cytokine/acute phase response.
Purpose: maintain perfusion and provide metabolic substrate; downside is hyperglycaemia, catabolism, immunosuppression and hypercoagulability.

Describe the hormonal changes seen during and after major surgery.

Expect rises in catabolic and salt/water-retaining hormones with insulin resistance.

↑ catecholamines (NA/A): haemodynamic stimulation, glycogenolysis, lipolysis; ↓ insulin secretion (α2) and ↑ glucagon.
↑ ACTH/cortisol: gluconeogenesis, proteolysis, lipolysis; permissive for catecholamines; insulin resistance.
↑ ADH and ↑ RAAS (renin/Ang II/aldosterone): water and sodium retention, vasoconstriction.
↑ glucagon; insulin may be normal/↑ but ineffective due to resistance; ↑ GH with GH resistance; possible low T3 syndrome in major illness.

Explain why perioperative hyperglycaemia occurs in non-diabetic patients and why it matters.

It is driven by increased glucose production and reduced utilisation.

Mechanisms: catecholamines and glucagon → glycogenolysis; cortisol and cytokines → gluconeogenesis; reduced peripheral uptake due to insulin resistance.
Consequences: impaired neutrophil function, increased infection risk, osmotic diuresis/dehydration; association with worse outcomes (especially cardiac/critical care).
Management principles: monitor glucose, avoid severe hyperglycaemia; avoid overly tight control that risks hypoglycaemia.

What is the acute phase response and which cytokine is most closely associated with it?

A systemic inflammatory response to tissue injury that alters hepatic protein synthesis and immune activity.

Key cytokines: IL‑6 (major driver), IL‑1β, TNF‑α.
Hepatic changes: ↑ CRP, fibrinogen; ↓ albumin/transferrin; contributes to hypercoagulability and altered drug binding (low albumin).

How does neuraxial anaesthesia modify the stress response compared with general anaesthesia alone?

Neuraxial techniques can substantially blunt afferent nociceptive input and sympathetic efferent output.

Epidural/spinal blocks reduce catecholamine and cortisol responses, particularly for lower abdominal and lower limb surgery.
GA alone reduces awareness but does not reliably prevent endocrine responses to incision unless analgesia/blocks are adequate.
Clinical implications: improved pain control, reduced ileus, improved mobilisation; must balance against hypotension and need for vasopressors/fluids.

Outline the effects of ADH and RAAS in the perioperative period and how they relate to oliguria.

Both systems conserve water/sodium and support blood pressure, often causing low urine output.

ADH: V2-mediated water reabsorption → concentrated urine; V1 vasoconstriction at higher levels.
RAAS: Ang II vasoconstriction + aldosterone sodium retention (with potassium loss).
Oliguria: may be physiological in early postoperative period, but assess for hypovolaemia, obstruction, nephrotoxins and AKI; interpret with haemodynamics and trends.

Describe the metabolic changes in protein and fat metabolism after major surgery.

A catabolic state develops to provide substrate for healing and glucose production.

Protein: ↑ muscle proteolysis → amino acids for gluconeogenesis and acute phase proteins → negative nitrogen balance and weakness.
Fat: ↑ lipolysis → ↑ free fatty acids; ketone production may increase with fasting/insulin deficiency/sepsis.

How do surgical magnitude and technique influence the stress response?

Greater tissue injury and complications amplify endocrine and inflammatory responses.

Magnitude correlates with incision size, duration, tissue trauma, blood loss, pain, and postoperative complications (infection/sepsis).
Minimally invasive surgery generally reduces cytokine release and endocrine activation compared with open surgery.

A patient on long-term prednisolone is having major abdominal surgery. What is the concern regarding the stress response and how would it present?

Chronic exogenous steroids can suppress the HPA axis, preventing an adequate cortisol response.

Concern: adrenal insufficiency → hypotension refractory to fluids/vasopressors, hyponatraemia, hyperkalaemia, hypoglycaemia (variable).
Management: assess risk (dose/duration), continue baseline steroids, and provide perioperative supplementation according to local guidance and surgical stress; treat suspected crisis with IV hydrocortisone and supportive care.

List perioperative strategies that reduce the stress response and briefly state the mechanism for each.

Target pain pathways, inflammation, and metabolic derangements.

Regional/neuraxial analgesia: blocks afferent nociception and sympathetic output → ↓ catecholamines/cortisol.
Multimodal analgesia: reduces pain-driven SNS/HPA activation; opioid-sparing improves gut function.
Normothermia: reduces catecholamine surge and coagulopathy/infection risk.
Goal-directed fluids/euvolemia: reduces RAAS/ADH activation and organ hypoperfusion.
ERAS (carbohydrate loading, early feeding/mobilisation): reduces insulin resistance and catabolism; improves functional recovery.