Surgery chapters
Metabolic response to injury
How the body reacts to surgery, trauma and sepsis: the ebb and flow phases, the hormones and cytokines that drive them, muscle wasting, the acute phase response and how modern perioperative care limits the damage.
- Injury triggers a neuroendocrine (cortisol, catecholamines, glucagon, ADH, aldosterone) and cytokine (IL-1, IL-6, TNFα) response.
- Cuthbertson's ebb phase (first 24–48 h, low metabolism, shock) is followed by the flow phase (hypermetabolic and catabolic, then anabolic).
- Result: hyperglycaemia with insulin resistance, negative nitrogen balance, salt and water retention; ERAS measures reduce the response.
On this page
Overview
Any injury (an operation, trauma, burns or sepsis) sets off a coordinated stress response. Its purpose is survival without medical help: keep the circulation full, supply fuel to vital organs and the wound, and fight infection. The cost is catabolism: muscle and fat are broken down, glucose rises and salt and water are held back.
The size of the response is graded: the bigger the injury, the bigger the rise in metabolic rate and nitrogen loss. Complications such as infection keep it going. Modern perioperative care (minimal access surgery, good analgesia, short fasting, early feeding and mobilisation) aims to blunt the parts that do harm.
Mediators of the response
Neuroendocrine pathway
Pain and other afferent signals from the injured area travel via the spinal cord to the hypothalamus.
- Hypothalamus → CRF → anterior pituitary ACTH → adrenal cortisol.
- Sympathetic activation → adrenaline (and noradrenaline) and glucagon release.
- Cortisol, glucagon and catecholamines are the counter-regulatory (catabolic) hormones; infusing them together reproduces much of the injury response.
- Growth hormone and prolactin rise, but IGF-1 is low; GH is lipolytic and opposes insulin.
- Peripheral thyroid hormone is inactivated (low T3) and gonadal function is suppressed.
- Insulin levels may rise, but tissues become resistant to it.
Volume-conserving hormones
| Hormone | Trigger | Effect |
|---|---|---|
| ADH (vasopressin) | Baroreceptors (carotid, aortic arch), atrial volume receptors, pain | Water retention by the kidney |
| Aldosterone | Renin–angiotensin system (low renal perfusion), ACTH | Na+ (and water) reabsorption; K+ lost in urine |
| Catecholamines | Sympathetic drive | Tachycardia, vasoconstriction, glycogen breakdown, lipolysis |
The net effect of ADH and aldosterone is the normal oliguria after surgery with retention of sodium and water. Giving large volumes of saline worsens this and causes tissue and gut-wall oedema (slow gastric emptying, delayed eating, longer stay).
Cytokines and inflammation
- IL-1, TNFα, IL-6 and IL-8 are released by macrophages within the first 24 hours.
- They act on the hypothalamus to cause fever, act on muscle to cause proteolysis, contribute to insulin resistance and drive the liver to make acute phase proteins.
- This is the systemic inflammatory response (SIRS). It is soon followed by a rise in cytokine antagonists (IL-1Ra, soluble TNF receptor). If prolonged it may swing into a counter-inflammatory response syndrome with immunosuppression.
- Other mediators: nitric oxide, prostaglandins, complement.
Cortisol is immunosuppressive at high doses, yet after injury it works together with IL-6 to boost hepatic acute phase protein production.
The ebb and flow model (Cuthbertson)
| Feature | Ebb phase | Flow phase |
|---|---|---|
| Timing | From injury, about 24–48 hours | Follows resuscitation; catabolic part about 3–10 days, then anabolic phase for weeks |
| Metabolic rate | Reduced | Increased (hypermetabolism) |
| Cardiac output | Low | High |
| Temperature | Hypothermia | Fever |
| Other | Hypovolaemia, lactic acidosis | Tissue oedema, leukocytosis, raised O2 use, gluconeogenesis, weight and nitrogen loss |
| Main hormones | Catecholamines, cortisol, aldosterone | Catecholamines, cortisol, glucagon, insulin (with resistance), cytokines |
| Purpose | Conserve volume and energy | Mobilise stores for repair, then rebuild tissue |
Good resuscitation shortens the ebb phase but does not abolish it. The flow phase corresponds to SIRS.
Ebb = ebbing tide: everything goes down (metabolism, output, temperature). Flow = flowing: everything goes up (metabolism, output, temperature, catabolism).
Key metabolic changes in the flow phase
The body re-routes resources away from muscle, fat and skin towards the liver, immune system and wound.
Hypermetabolism
Most injured patients burn about 15–25% more energy than predicted at rest. Bed rest, ventilation and temperature control in intensive care partly offset this; very large burns are the exception with much higher needs.
Skeletal muscle wasting
- Muscle protein breakdown rises and synthesis falls.
- Main mechanism: the ATP-dependent ubiquitin–proteasome pathway (lysosomal cathepsins and calcium–calpain help).
- Loss also affects respiratory muscle (hypoventilation, chest infection) and gut muscle (poor motility); cardiac muscle is largely spared.
- In severe sepsis urinary nitrogen loss can reach 14–20 g per day, roughly 500 g of muscle a day.
- Feeding cannot fully stop this loss while the stress response continues. Over-feeding (hyperalimentation) is itself a stress; aim to reduce rather than fully replace losses.
Nitrogen and lean tissue
- 1 g nitrogen is contained in 6.25 g protein, which sits in about 36 g wet lean tissue.
- A normal adult eats 70–100 g protein a day and passes about 14 g nitrogen.
- In simple starvation the body adapts and nitrogen loss falls. After major injury or sepsis this adaptation fails ("autocannibalism").
- Once 30–40% of body protein is lost, survival is unlikely.
Urinary nitrogen loss = 15 g/day
Protein broken down = 15 × 6.25 = 93.75 g (about 94 g)
Wet lean tissue lost = 15 × 36 = 540 g per day
Hepatic acute phase response
| Positive reactants (rise) | Negative reactants (fall) |
|---|---|
| CRP, fibrinogen, other acute phase proteins | Albumin (and other export proteins) |
IL-6 is the main signal for acute phase protein synthesis. Albumin falls mainly because it leaks out of capillaries (increased permeability), not mainly because the liver makes less. So albumin is a poor marker of nutrition in the acutely ill.
Insulin resistance and hyperglycaemia
- Glucose production rises (glycogenolysis, gluconeogenesis) while uptake falls in muscle and fat.
- Degree is proportional to the injury; after upper abdominal surgery it can last about 2 weeks.
- The patient behaves like a type 2 diabetic; managed with intravenous insulin infusion when needed.
- Preoperative carbohydrate drinks reduce postoperative insulin resistance.
Fat and fuel
- Lipolysis increases; fat is the main energy store used.
- Fatty acids become ketones, but after injury ketosis is less marked than in simple starvation because insulin is high.
Body composition
A 70 kg man has about 13 kg fat and 57 kg lean mass (12 kg protein, 42 kg water, 3 kg mineral). After resuscitation of severe sepsis or trauma, extracellular water may expand by 6–10 litres in 24 hours, so weight goes up even though fat and muscle are being lost.
A critically ill patient who gains weight in the first days is not well nourished; the gain is oedema fluid while lean tissue falls.
Starvation compared with injury
| Feature | Simple starvation | After injury/sepsis |
|---|---|---|
| Insulin | Low | High but resisted |
| Metabolic rate | Falls | Rises |
| Ketosis | Marked (brain switches to ketones) | Blunted |
| Nitrogen loss | Falls with adaptation | Stays high |
| Fuel for the brain | Glycogen first day, then gluconeogenesis, later ketones | Glucose from gluconeogenesis |
The brain needs about 100 g glucose a day. Two litres of 4% dextrose/0.18% saline gives about 80 g glucose a day and spares some protein.
Avoidable factors that make the response worse
- Continuing haemorrhage and tissue underperfusion
- Hypothermia (shivering raises demand; also impairs clotting)
- Tissue oedema from excess fluid
- Starvation, including long preoperative fasting
- Immobility (inactive muscle does not respond to feeding)
- Pain, anxiety, infection and dehydration
Reducing the stress response: enhanced recovery (ERAS)
| Measure | Why it helps |
|---|---|
| Minimal access (laparoscopic) surgery | Smaller tissue injury |
| Blocking pain signals: epidural or spinal analgesia, wound catheters | Reduces cortisol rise and insulin resistance (epidural mainly for open surgery) |
| Short fasting: clear fluids up to 2 hours before anaesthesia, carbohydrate drink | Less insulin resistance, thirst and anxiety |
| Avoid excess saline | Less oedema and ileus |
| Early oral feeding | Limits catabolism |
| Early mobilisation | Prevents muscle wasting |
| Normothermia, opioid-sparing analgesia | Less stress and faster gut recovery |
β-blockers and statins have been associated with better long-term survival after major surgery, possibly by damping the innate immune response.
ERAS in four words: "Less cut, less pain, less fasting, more moving."
Expect: features of the ebb versus flow phase and their timing; which hormones rise after injury (cortisol, catecholamines, glucagon, GH, ADH, aldosterone) and their effects (hyperglycaemia, insulin resistance, oliguria, sodium and water retention); IL-6 and the acute phase response with CRP up and albumin down; negative nitrogen balance and the ubiquitin–proteasome pathway; why weight rises early in sepsis; factors that worsen the response; and the components of enhanced recovery programmes.
Quick revision
- Stress response = neuroendocrine (cortisol, catecholamines, glucagon, ADH, aldosterone) + cytokines (IL-1, IL-6, TNFα).
- Ebb (24–48 h): low metabolism, low output, cold, lactic acidosis.
- Flow: hypermetabolic and catabolic (3–10 days), then anabolic (weeks).
- Hyperglycaemia with insulin resistance; behaves like type 2 diabetes.
- Negative nitrogen balance; ubiquitin–proteasome muscle breakdown; heart spared.
- IL-6 → CRP and fibrinogen up; albumin down (capillary leak).
- Postoperative oliguria from ADH and aldosterone; urine K+ loss, Na+ retained.
- Early weight gain = extracellular fluid, not nutrition.
- ERAS: laparoscopy, regional analgesia, 2-hour clear fluids, carbohydrate loading, early feeding and mobilisation.
Written by The House Job from standard references (Bailey & Love's Short Practice of Surgery, 27th edition).
FAQ
What is the difference between the ebb and flow phases?
The ebb phase is the first day or two of shock-like low metabolism; the flow phase that follows is hypermetabolic and catabolic, then later anabolic as tissues are rebuilt.
Why is urine output low on the first day after surgery?
ADH and aldosterone released in the stress response make the kidney retain water and sodium, so a modest fall in urine output is expected.
Which cytokine is most linked to the acute phase response?
IL-6, which drives the liver to make CRP and fibrinogen.
Can nutrition stop muscle loss after major injury?
Not completely; while the stress response continues, feeding only slows the loss, and over-feeding adds further metabolic stress.
Why are clear fluids allowed up to 2 hours before surgery?
Shorter fasting with a carbohydrate drink reduces thirst, anxiety and postoperative insulin resistance without raising aspiration risk.