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Metabolic Response to Injury - Chapter 1, Bailey & Love's Short Practice of Surgery (28th Edition)

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1. INTRODUCTION - What Is the Metabolic Response to Injury?

• Hormonal (neuroendocrine)
• Inflammatory (cytokines)
• Neural circuits

• Altered body metabolism
• Changes in wound healing and immunity
• Specific organ dysfunction

Exam point: If uncontrolled, this response leads to sepsis → MODS (multiple organ dysfunction syndrome). MODS carries ~25% mortality even in modern trauma systems.

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2. HOMEOSTASIS AND THE TWO PHASES

Exam point: The catabolic phase is also called the "ebb" phase and the anabolic flow phase corresponds to SIRS (systemic inflammatory response syndrome).

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3. MAGNITUDE OF THE INJURY RESPONSE

• Minor elective surgery: transient modest rise in temperature, HR, RR, WBC, energy expenditure
• Major trauma/burns/sepsis: SIRS, hypermetabolism, marked catabolism, shock, MODS

Exam point: Genetic variability also determines response intensity - some patients respond much more dramatically than others to similar injuries.

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4. MEDIATORS OF THE METABOLIC RESPONSE

A. Tissue Damage and Inflammation (DAMPs Pathway)

1. Tissue injury releases DAMPs (damage-associated molecular patterns), also called alarmins
   • Examples: heat shock proteins, HMGB1 (high mobility group protein B1), S100 proteins, nucleic acid fragments
2. DAMPs activate PRRs (pattern recognition receptors):
   • Toll-like receptors (TLRs)
   • NOD-like receptors (NLRs)
   • Found on: macrophages, neutrophils, dendritic cells
3. PRR activation triggers formation of inflammasomes (complex intracellular proteins)
4. Inflammasomes activate caspases → activate key cytokines:
   • IL-1, IL-6, TNF-alpha, IL-8, interferons, chemokines
5. Result: sterile systemic inflammatory cascade → local inflammation → SIRS

• Leaky capillaries (oedema)
• Coagulopathy
• Local ischaemia → more DAMPs (self-perpetuating cycle)

• Sepsis
• Haemorrhage
• Massive transfusion
• Acidosis
• Surgery itself
• Crush syndrome
• Ischaemia-reperfusion injury

Exam point: The "redundancy" of DAMPs (ability to activate multiple receptors/pathways) is why therapeutic blockade of inflammation has been so difficult clinically.

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B. Neuroendocrine Response to Injury

Tissue injury/pain
       ↓
Afferent nociceptive neurones
       ↓
Spinal cord → Thalamus → Hypothalamus
       ↓
CRF (corticotropin-releasing factor) released
       ↓
ACTH from anterior pituitary
       ↓
Adrenal cortex → CORTISOL (within hours)

Hypothalamus also activates:
→ Sympathetic nervous system → ADRENALINE (epinephrine)
→ Pancreas → GLUCAGON

• Glucocorticoids (cortisol)
• Glucagon
• Catecholamines (adrenaline)

High-yield exam fact: IV infusion of these three hormones reproduces many aspects of the metabolic response to injury.

• Growth hormone (GH) ↑ - but paradoxically with low IGF-1; GH has direct lipolytic, insulin-antagonising and pro-inflammatory properties
• Prolactin ↑
• Peripheral thyroid hormones inactivated
• Gonadal function suppressed

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C. Cytokines and Their Actions

Exam point: IL-6 is the primary driver of the hepatic acute-phase protein response.

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D. Agonists and Antagonists: An Uncertain Balance

• IL-10, IL-4, TGF-beta (anti-inflammatory)
• Glucocorticoids also have anti-inflammatory effects

Exam point: CARS (Compensatory Anti-inflammatory Response Syndrome) can lead to immune suppression if the anti-inflammatory arm is too dominant, predisposing to secondary infections.

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5. METABOLIC CHANGES AFTER SURGERY AND TRAUMA

Catabolic Phase (0-48 hours)

• Hypovolaemia, ↓ BMR, ↓ cardiac output, hypothermia, lactic acidosis
• Dominant hormones: catecholamines, cortisol, aldosterone
• Insulin levels fall or do not rise appropriately → hyperglycaemia

Flow Phase (after resuscitation - corresponds to SIRS)

• Tissue oedema (vasodilatation + ↑ capillary permeability)
• Hypermetabolism (↑ BMR)
• ↑ Cardiac output
• Raised body temperature
• Leukocytosis
• ↑ Oxygen consumption
• ↑ Gluconeogenesis

• Provide essential substrates for survival via tissue breakdown
• Postpone anabolism
• Optimise host defence

Exam point: These changes are helpful short-term but harmful long-term, especially in the critically ill.

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6. MANAGING THE CATABOLIC RESPONSE

• Catabolic (peripheral) tissues: skeletal muscle, adipose tissue, skin
• Anabolic (central) tissues: liver, immune system, wound

A. Hypermetabolism

• Most trauma patients: energy expenditure 15-25% above predicted resting values
• Burns patients can go even higher
• Caused by: central thermodysregulation (cytokine cascade), ↑ sympathetic activity, ↑ protein turnover, wound circulation abnormalities (Cori cycle)

B. Skeletal Muscle Protein Metabolism

• ↑ Protein degradation via the ubiquitin-proteasome pathway (key exam fact)
• ↓ Protein synthesis

• Loss of respiratory muscle → hypoventilation, chest infections
• Loss of gut muscle → ↓ gut motility
• Amino acids (especially glutamine and alanine) exported from muscle to liver (for gluconeogenesis) and wound
• Net catabolism occurs because alanine and glutamine are derived partly from irreversible degradation of branched-chain amino acids

• Provides amino acids for central organs/tissues
• Mediated mainly by ubiquitin-proteasome pathway
• Inevitable to some degree, prolonged by sepsis
• Can cause immobility, poor healing, hypostatic pneumonia, death if excessive

C. Acute-Phase Protein Response (Hepatic)

Exam point: Albumin falls after injury NOT mainly due to reduced synthesis, but due to increased transcapillary escape (3x increase in TER) secondary to microvascular permeability changes. Normal albumin TER is already ~10x the synthesis rate.

D. Insulin Resistance

• Glucose production ↑ (gluconeogenesis)
• Glucose uptake in peripheral tissues ↓
• Mechanism: proinflammatory cytokines + decreased responsiveness of insulin-regulated glucose transporter proteins
• Degree of resistance is proportional to injury magnitude

• After routine upper abdominal surgery: insulin resistance persists ~2 weeks
• With prolonged sepsis: extends further
• Behaves like Type 2 diabetes mellitus
• Management in ICU: IV insulin infusion to maintain blood glucose within limits
• Caution: tight control risks significant hypoglycaemia

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7. CHANGES IN BODY COMPOSITION FOLLOWING INJURY

• Fat: 13 kg
• Fat-free mass (protein + water): ~57 kg

• Fat mass ↓
• Skeletal muscle mass ↓
• Body weight may paradoxically increase due to expansion of extracellular fluid (oedema)

• Catabolism decreases fat mass and skeletal muscle mass
• Body weight may increase paradoxically due to extracellular fluid expansion

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8. AVOIDABLE FACTORS THAT COMPOUND THE RESPONSE

• Baroreceptors (carotid, aortic arch) + volume receptors (left atrium) → CNS → ADH + aldosterone release
• ADH → fluid retention at kidney
• ↓ Pulse pressure → juxtaglomerular apparatus → renin-angiotensin → ↑ aldosterone
• Aldosterone → Na+ reabsorption → water conservation
• Net effect: oliguria after surgery (normal/expected)
• Excess saline resuscitation worsens salt/water retention → peripheral AND visceral oedema → delayed gastric emptying, prolonged hospital stay

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9. ENHANCED RECOVERY AFTER SURGERY (ERAS)

• Minimal access techniques (laparoscopic surgery)
• Blockade of afferent pain stimuli (epidural analgesia, spinal, wound catheters)
  • Note: epidural analgesia is no longer recommended for laparoscopic surgery (patient-controlled analgesia is sufficient)
• Minimal periods of starvation (avoid prolonged preoperative fasting)
• Early mobilisation

• Reductions in length of hospital stay of 30-50%
• Improved outcomes
• Reduced healthcare costs

• Beta-blockers: associated with improved short- and long-term survival after major surgery (by modulating the hyper-adrenergic state)
• Epidural analgesia in open surgery: reduces pain, blocks cortisol stress response, attenuates postoperative insulin resistance
• IV lidocaine infusion (6-12 hr): opioid-sparing, improves gut function
• 'One-shot' spinal diamorphine: opioid-sparing effect

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HIGH-YIELD EXAM SUMMARY

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