The document discusses the metabolic response to injury, including key concepts like homeostasis and the graded nature of injury response. It describes the "ebb and flow" model where the initial ebb phase conserves energy and the hypermetabolic flow phase mobilizes resources for repair. Major mediators that drive the catabolic response are increased metabolism, altered protein metabolism in muscles and liver, and insulin resistance. Factors like ongoing hemorrhage, hypothermia, edema, underperfusion, starvation, and immobility can compound this response. The goal is to control these avoidable factors to benefit patient recovery.

1. METABOLIC
RESPONSE TO INJURY
NUR IZZATUL NAJWA SHARUPUDDIN
036

2. LEARNING OBJECTIVE
• At the end of this seminar student should know about
– Concept of homeostasis
– Mediators of metabolic response to injury
– The ‘EBB and FLOW model’
– Changes in body composition following injury
– Avoidable factors that compound the response to injury
– Concept behind enhanced recovery after surgery.

3. BASIC CONCEPTS OF HOMEOSTASIS
• 18th and 19th century
– The stability of “milieu interieur” is the primary condition for freedom and independence of
existence (Claude Bernard)
• Eg: body system act to maintain internal constancy
– The coordinated physiological process which maintains most of the steady states of the organism.
(Walter Cannon)
– There is a circumstance attending accidental injury which does not belong to the disease, namely
that the injury done, has in all cases a tendency to produce both the deposition and means of
cure (John Hunter)
• This concept only pertained to normal physiological and mild/moderate injury. This is also
known as ‘classical homeostasis’

4. • Modern era
– Such concepts do not account for disease evolution following
major injury/sepsis or the injured patient who would have die but
for artificial organ support.
– Only with medical / surgical resolution of the primary abnormality
is a return to classical homeostasis possible.

5. BASIC CONCEPTS
 HOMEOSTASIS IS THE FOUNDATION OF NORMAL PHYSIOLOGY
 ‘STRESS-FREE’ PERIOPERATIVE CARE HELPS TO RESTORE
HOMEOSTASIS FOLLOWING ELECTIVE SURGERY
 RESUSCITATION, SURGICAL INTERVENTION AND CRITICAL
CARE CAN RETURN THE SEVERELY INJURED PATIENT TO A
SITUATION IN WHICH HOMEOSTATIS BECOMES POSSIBLE ONCE
AGAIN

6. THE GRADED NATURE OF THE INJURY RESPONSE
‘ THE MORE SEVERE THE INJURY, THE
GREATER THE RESPONSE’
• The concept applies to
– Physiological changes
– Metabolic changes
– Immunological changes
• (macrophages, neutrophil, dendritic cells)
• Following surgery,
– there may be rise in temperature, heart
rate, respiratory rate energy expenditure
and leukocytosis

7. • Following major trauma/sepsis
– Systemic inflammatory syndrome (SIRS),
hypermetabolism, marked catabolism
and even multiple organ dysfunction
(MODS)
• Following major injury
– Proinflammatory state into
compensatory inflammatory syndrome
(CARS)

8. Systemic Inflammatory Response Syndrome (SIRS)
• SIRS is defined as :
 Fever > 38◦c (100.4 F) or < 36 ◦c (96.8F)
 Heart rate > 90 beats per minute
 Respiratory rate >20 breaths per minute or arterial CO2 tension
(PaCO2) of < 32 mmHg
 Abnormal white blood cell count(>12,000/microliter or <4000/
microliter or >10% immature [band] forms)

9. Multiple Organ Dysfunction Syndrome (MODS)
• Clinical syndrome characterised by the development of
progressive and potentially reversible physiologic dysfunction
in 2 or more organs that is induced by a variety of acute insults
including sepsis

10. Mediators of metabolic response to injury
• The classical neuroendocrine pathways of the
stress response.
– Hypothalamus-release corticotophin factor (CRF)
– Increases Adrenocorticotrophic hormone (ACTH)
from anterior pituitary and growth hormone
– Increases adrenaline and cortisol
• Stimulate glucagon
• Altered insulin release and sensitivity
– Reduces insulin like growth factor-1(IGF-1),
peripheral thyroid hormone, gonadal function –
reduce anabolic effect

11. • Innate immune system(principally
macrophage) interacts with the adaptive
immune system (T cells,B cells) in co
generating the metabolic response to
injury.
– First 24 hour, pro inflammatory cytokine
release IL-1, tumour necrosis factor alpha, IL-
6, IL-8,
• act directly on hypothalamus and produce pyrexia
• Act on skeletal muscle and produce proteolysis
• Induce acute phase protein in liver
• Peripheral insulin resistance
• Nitric oxide release via inducible nitric oxide
synthethase (iNOS)
• Endothelin-1 cause excessive vasoconstriction (eg.
Renal hypoperfusion/impairment)

12. • Within hours after release of proinflammatory cytokine, endogenous
cytokine antagonist( eg. Interleukine receptor antagonist (IL-1Ra) , TNF
soluble receptors(TNF-sr-55 and 75) enter the circulation to control the
inflammatory response.
• Development of a Th-2 type counterinflammatory response (IL-4,5,9,13
and transforming growth factor beta (TGFB)) if it prolonged in critical
illness it is characterised as compensatory anti-inflammatory syndrome
(CARS) and results in immunosuppression.
• Within inflamed tissue there is specialised proresolving mediators
(SPM) eg. Lipoxins, resolvins, protectins maresins
– Clearance of apoptotic polymorphonuclear cells
– Uptake of microbial particles’
– Reduce proinflammatory cytokine
– Removal of cellular debris

14. THE METABOLIC RESPONSE STRESS RESPONSE TO
SURGERY AND TRAUMA : THE ‘EBB AND FLOW’ MODEL
• 1930, Sir David Cuthbertson divided
metabolic response to injury into
– EBB and Flow phase

15.  Begins at 24-24 hours.
 Characterised by :
• Hypovolemia
• Decreased basal metabolic rate
• Decreased cardiac output
• Hypothermia
• lactic acidosis
 Predominant hormones regulate :
• Catecholamine,cortisol, aldosterone
 Role of ebb phase is to conserve both circulating volume and energy store for recovery
and repair.

16. • Following resuscitation, ebb phase evolves into hypermetabolic phase.
• Role : mobilisation of body energy and subsequent replacement of lost
and damaged tissue
– Characterised by
• Tissue oedema
• Increase BMR,CO,body temperature, oxygen consumption, gluconeogenesis,
• Leukocytosis

17. • Flow phase
– Initial catabolic phase: 3-10 days
– Anabolic phase : weeks
• Initial catabolic phase
– Increase counter regulatory hormone and inflammatory cytokine.
– Cause weight loss, increase urinary nitrogen, insulin resistance.

18. KEY CATABOLIC ELEMENTS OF THE FLOW PHASE OF
THE METABOLIC STRESS RESPONSE
• CONCEPT- body repriotise limited resources
away from peripheral tissue to viscera and
wound
• Characterised by :
– Hypermetabolism
– Alterations in skeletal muscle protein metabolism
– Altered hepatic protein metabolism : the acute
phase protein response
– Insulin resistance

19. 1. Hypermetabolism
• Energy expenditure of trauma patients is 15%-25% more than a healthy resting
value.
• Due to
– increase metabolic rate
– Peripheral energy utilisation
– Central thermodysregulation-(proinflammatory cascade)
– Increase sympathetic activity
– Abnormal wound circulation
– Increased protein turn over
• Counteract the symptom by
– bed rest
– External temperature regulation
– Ventilation

20. 2. Alterations in skeletal muscle protein metabolism
• Muscle protein is continually synthesised and breakdown at the protein turnover
of 1-2% per day. Synthesis = breakdown
• Muscle protein growth during feeding and exercise
• During exercise muscle protein synthesis depress and increases again during
feeding and rest.
• Catabolic phase
– Decrease muscle protein synthesis and increase degradation of
• Peripheral muscle
• Respiratory muscle
• Gut
• Cardiac muscle is spared
– Urinary nitrogen loss can reach up to 14-20g/day = 500g of skeletal muscle
• This is due to impaired ATP-dependent ubiquitin proteasome pathway.

21. 3. Alterations in hepatic protein metabolism : the
acute phase protein response
• The liver and skeletal muscle together account for >50% daily
protein turnover.
• Protein synthesis in liver is divided between
– Renewal of structural protein
– Synthesis of export proteins
• Major export protein is albumin
• transcapillary escape rate (TER) 10x rate of synthesis
• Short term changes is due to capillary permeability
• Albumin TER increases following injury

22. • In inflammatory conditions, blood
mononuclear cells secrete
proinflammatory cytokine.
– Cytokine mainly IL-6 promote hepatic
synthesis of acute phase proteins. Eg.
Fibrinogen and c-reactive protein
– Acute positive phase proteins
response – “double edged sword”
– It provides recovery and repair at the
expense of valuable lean tissue and
energy reserve
• Positive reactant increase
following injury
• Negative reactant fall due to TER
following permeability of vessels

23. 4. Insulin resistance
• Postoperative hyperglcycemia developed as a result of
– Increased glucose production
– Decreased glucose uptake in peripheral tissues
• This is due to the action of
– proinflammatory cytokine
– Decreased responsiveness of insulin-regulated glucose transporter
proteins

24. Changes in body composition following injury
• Average 70 kg male
– Fat – 13 kg
– fat free mass(body lean mass)-57 kg
• Protein 12 kg
– Skeletal muscle 4kg
– Non skeletal muscle 8kg (visceral protein mass)
• Water 42kg
– Intracellular 28 kg
– Extracellular 12kg
• Minerals(bony skeleton) 3kg
• Main labile energy – fat
• Main labile protein – skeletal muscle
– Loss of protein mass lead to muscle wasting,
deplete visceral mass
– 1g nitrogen = 6.25g of protein = 36g of wet
weight tissue

25. • Protein turnover 150-200g/day
• Protein ingest 70-100g/day
• 14g N/day excreted in urine
• Following injury
– State of ‘autocannibalism’
– Urinary nitrogen loss 10-20g N/day =
500g wt weight lean tissue/day
• In critically ill patient
– Body weight increases following
resuscitation with an expansion of 6-
10litres within 24 hours
– Total body protein diminish by 15% in
the next 10 days when extracellular
space resolves

26. Avoidable factors that compound the response to
injury
Any attempt to control or limit these factors is beneficial to the
patient.
• Continuing haemorrhage
• Hypothermia
• Tissue oedema
• Tissue underperfusion
• Starvation
• Immobility

27. 1. Volume loss
• Simple haemorrhage –
– pressor receptors in carotid artery, aortic arch and volume receptors in the wall of left atrium
initiated,
• Pain
• Stimulate antidiuretic hormone (ADH) and aldosterone– fluid retention.
• Decreases pulse pressure – stimulate juxtaglomerular apparatus – activates renin
angiotensin system – aldosterone release
• ACTH release also augment aldosterone
• These causes sodium and water retention (exacerbated following resuscitation)
• promote peripheral and visceral oedema
• Leads to delayed gastric emptying, delayed resumption of food intake, prolonged hospital
stay
• Solution : Careful administration of balanced crystalloid has been proven to reduce post
operative complication and length of hospital stay

28. 2. Hypothermia
• Increased elaboration of cathecolamine and steroids
• Leads to cardiac arrhythmia and increased catabolism
• Solution ; upper body forced air heating cover reduces wound
infections, cardiac complications, bleeding and transfusion
requirement.

29. 3. Tissue oedema
• Inflammation– fluid, plasma protein, leukocytes, macrophages,
electrolytes – leaves vascular space and accumulate in tissues.
• Diminish alveolar diffusion of oxygen
• Reduced renal function
• Solution ; adequate resuscitation to replenish intravascular and
extravascular extracellular volume

30. 4. Systemic inflammation and tissue underperfusion
• Function of vascular endothelium
– Control vasomotor tone
– Microvascular flow
– Regulates trafficking of nutrients
• Following injury, endothelial activation is excessive –
compromised microcirculation and cellular hypoxia
• Solution : insulin infusion can maintain normoglycemia can
inhibit excessive iNOS-induced NO release and administration
of protein c

31. 5. Starvation
• Body needs 100g glucose/day to maintain cerebral energy
metabolism.
• 1st 24 hours, mobilise glycogen and fat stores and hepatic
gluconeogenesis
• Solution –
– 2 litres of IV 4% dextrose/0.18% sodium chloride
– Avoid unnecessary fasting
– Early oral/enteral/parenteral nutrition
– Fasting but allow intake of fluid up to 2 hours before surgery
– Administer carbohydrate drink reduces perioperative anxiety, post
operative insulin resistance and thirst.

32. 6. Immobility
• Avoid unnecessary bed rest and active early mobilisation can
avoid muscle wasting

33. Concepts behind enhanced recovery after surgery
• Minimal access techniques eg; laparoscopic
• Blockade of afferent painful stimuli by analgesia
• Minimal period of fasting
• Early mobilisation
• Avoid excessive IV fluid administration

34. SUMMARY
• At the end of this seminar student should know about
– Concept of homeostasis
– Mediators of metabolic response to injury
– The ‘EBB and FLOW model’
– Changes in body composition following injury
– Avoidable factors that compound the response to injury
– Concept behind enhanced recovery after surgery.

35. Reference
• BAILEY AND LOVE’S SHORT PRACTICE OF SURGERY VOLUME
ONE 25TH EDITION
• https://emedicine.medscape.com/article/168943-overview