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
13.
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
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
