Homeostasis, the internal milieu of the human body

1. Homeostasis
&
Response to Injury

2. • ‘Homeostasis’ refers to the maintenance of constant internal environment of the
body (homeo = same; stasis= standing)
• The coordinated physiological process which maintains most of the steady states
of the organism; i.e. complex homeostatic responses involving the brain, nerves,
heart, lungs, kidneys and spleen work to maintain body constancy
• We live in a perfectly organized and controlled internal environment, which is
called ‘milieu interieur’

3. • In essence, the concept evolved that the constancy of the ‘milieu intérieur’ allowed for
the independence of organisms, that complex homeostatic responses sought to
maintain this constancy, and that within this range of responses were the elements of
healing and repair.
• But these ideas pertained only to normal physiology and mild/moderate injury
• In the modern era, such concepts do not account for disease evolution following major
injury/sepsis
• Such patients exemplify less of the classical homeostatic control system and more of
the ‘open loop’ system, whereby only with medical/surgical resolution of the primary
abnormality is a return to classical homeostasis possible.

4. • Resuscitation, surgical intervention and critical care can return the severely
injured patient to a situation in which homeostasis becomes possible once again

5. RESPONSE TO INJURY
• The response to injury is graded: the more severe the injury, the greater the
response
• This concept not only applies to physiological/metabolic changes but also to
immunological changes/sequelae

6. • Following surgery of intermediate severity, there may be a transient and modest
rise in temperature, heart rate, respiratory rate, energy expenditure and peripheral
white cell count
• Following major trauma/sepsis, these changes are accentuated, resulting in a
systemic inflammatory response syndrome (SIRS), hypermetabolism, marked
catabolism, shock and even multiple organ dysfunction (MODS).
• The metabolic response is not only graded, but it also evolves with time. In
particular, the immunological

7. Response Components
Physiological Metabolic Clinical Laboratory
• Increased Cardiac
Output
• Hypermetabolism • Fever • Leucocytosis /
Leucopenia
• Increased Ventilation • Accelerated
Gluconeogenesis
• Tachycardia • Hyperglycemia
• Increased Membrane
Transport
• Enhanced Protein
breakdown
• Tachypnea • Elevated CRP / Altered
acute phase reactants
• Weight loss • Increased Fat Oxidation • Presence of wound or
inflammation
• Hepatic / Renal
dysfunction
• Wound Healing • Anorexia

8. MEDIATORS OF THE METABOLIC
RESPONSE TO INJURY
• Neuro-endocrine (Hormonal)
• Metabolic and Cytokine axes

10. Neuro-endocrine response
The Neuro-endocrine response to severe injury/critical illness is biphasic
1. Acute phase
• characterized by an actively secreting pituitary & elevated counter regulatory hormones (cortisol,
glucagon, adrenaline)
• Changes are thought to be beneficial for short-term survival.
2. Chronic phase
• associated with hypothalamic suppression & low serum levels of the respected target organ
hormones.
• Changes contribute to chronic wasting

11. • The constellation of Neuro-endocrine changes following injury acts to
1. Provide essential substrates for survival
2. Postpone anabolism
3. Optimize host defense
• These changes may be helpful in the short term, but may be harmful in the long
term, especially to the severely injured patient who would otherwise not have
survived without medical intervention

12. Physiological response
The natural response to injury includes
1. Immobility
2. Anorexia
3. Catabolism

13. • Metabolic response to injury in humans is divided into “ebb “ and “flow” phases

14. • The ebb phase begins at the time of injury and lasts for approximately 24–48
hours.
• It may be attenuated by proper resuscitation, but not completely abolished.

15. Ebb phase is characterized by
1. Hypovolemia
2. Decreased Basal Metabolic Rate
3. Reduced Cardiac Output
4. Hypothermia
5. Lactic Acidosis
6. Decreased Insulin
7. Hyperglycemia
8. Gluconeogenesis
9. Increased substrate consumption
10. Hepatic Acute phase response
11. Immune activation

16. • The predominant hormones regulating the ebb phase are
1. Catecholamines
2. Cortisol
3. Aldosterone
• The main physiological role of the ebb phase is to conserve both circulating
volume and energy stores for recovery and repair.

17. • Following resuscitation, the ebb phase evolves into a hypermetabolic flow phase,
which corresponds to SIRS.
• This phase involves the mobilization of body energy stores for recovery and
repair, and the subsequent replacement of lost or damaged tissue.

18. It is characterized by
• Tissue oedema (from vasodilatation and increased capillary leakage)
• Increased basal metabolic rate (hypermetabolism)
• Increased cardiac output
• Raised body temperature
• Leukocytosis
• Increased oxygen consumption
• Increased gluconeogenesis

19. • The flow phase may be subdivided into
1. Catabolic phase, lasting approximately 3–10 days
2. Anabolic phase, which may last for weeks
• During the catabolic phase, the increased production of counter-regulatory hormones
and inflammatory cytokines results in significant fat and protein mobilisation, leading
to significant weight loss and increased urinary nitrogen excretion.
• The increased production of insulin at this time is associated with significant insulin
resistance and, therefore, injured patients often exhibit poor glycaemic control.

20. • The combination of pronounced or prolonged catabolism in association with
insulin resistance places patients within this phase at increased risk of
complications.
• Obviously, the development of complications will further aggravate the
neuroendocrine and inflammatory stress responses, thus creating a vicious
catabolic cycle.

22. Key catabolic elements of flow phase
• Hypermetabolism
• Alterations in skeletal muscle protein
• Alterations in Liver protein
• Insulin resistance

23. Hypermetabolism
• Majority of trauma patients demonstrate energy expenditure approximately 15 -
25% above predicted healthy resting values
• Factors which increases this metabolism are
• Central thermo-dysregulation
• Increased sympathetic activity
• Increased protein turnover
• Wound circulation abnormalities etc

24. • Hyper metabolism following injury is
1. Mainly caused by an acceleration of futile metabolic cycles
2. Limited in modern practice on account of elements of routine critical care.

25. Skeletal muscle wasting
• Provides amino acids for protein synthesis in central organ/tissues
• Is mediated at a molecular level mainly by activation of the ubiquitin-protease
pathway
• Can result in immobility & contribute to hypostatic pneumonia & death if prolonged
and excessive

26. Hepatic acute phase response
• The Hepatic acute phase response represents a reprioritization of body protein
metabolism towards the liver & is characterized by:
1. Positive reactants (CRP) : plasma concentration increases
2. Negative reactants (albumin) : plasma concentration decreases

27. Insulin resistance
• The degree of insulin resistance is directly proportional to magnitude of the
injurious process.
• Following routine upper abdominal surgery, insulin resistance may persist for
approx. 2 weeks
• Postop patients with insulin resistance behave in a similar manner to individuals
with type 2 diabetes
• The mainstay of treatment is IV insulin
• Intensive insulin infusions are better over conservative approach

28. CHANGES IN BODY COMPOSITION
FOLLOWING INJURY

29. • Main labile energy reserve in the body is fat
• Main labile protein reserve in the body is skeletal muscle
• While fat mass can be reduced without major detriment to function, loss of protein
mass results not only in skeletal muscle wasting, but also depletion of visceral
protein mass

30. • With lean issue, each 1 g of nitrogen is contained within 6.25 g of protein, which is
contained in approximately 36 g of wet weight tissue.
• Thus the loss of 1 g of nitrogen in urine is equivalent to the breakdown of 36 g of
wet weight lean tissue.
• Protein turnover in the whole body is of the order of 150-200 g per day.

31. • A normal human ingests 70-100 g of protein per day, which is metabolized and
excreted in urine as ammonia and urea(14 g N/day)
• During total starvation, urinary loss of nitrogen is rapidly attenuated by a series of
adaptive changes
• Loss of body weight follows a similar course, thus accounting for the survival of
hunger strikers for a period of 50-60 days

32. • Following major injury, and particularly in the presence of ongoing septic
complications , this adaptive change fails to occur, and there is a state of auto
cannibalism , resulting in continuing urinary nitrogen losses of 10-20 g/day(500 g
lean tissue/day)
• As with total starvation, once loss of body protein mass has reached 30-40 % of
the total, survival is unlikely

33. In critically ill patients with
resuscitation,
• <24 hrs – Body weight increases due to extracellular water expansion by 6-10
litres.
• This can be overcome by careful intra operative management of fluid balance
• 1-10 days – Total body protein will diminish by 15% and body weight will reach
negative balance as the expansion of extra cellular space resolves
• This can be overcome by blocking Neuro endocrine response with epidural analgesia and early
enteral feeds

35. Avoidable factors that compound the
response to injury
1. Continuing haemorrhage
2. Hypothermia
3. Tissue edema
4. Tissue under perfusion
5. Starvation
6. Immobility

36. • Volume loss: Careful limitation of intra operative administration of colloids and
crystalloids so that there is no net weight gain
• Hypothermia : RCT have shown that normothermia by an upper body forced air
heating cover reduces wound infection, cardiac complications and bleeding and
transfusion requirements
• Tissue edema :
• During systemic inflammation, fluid, plasma proteins, leucocytes, macrophages and
electrolytes leave the vascular space and accumulate in the tissues.
• This can diminish the alveolar diffusion of oxygen and may lead to reduced renal function

37. Systemic inflammation and tissue under
perfusion
• The vascular endothelium controls vasomotor tone and micro vascular flow and
regulates trafficking of nutrients and biologically active molecules.
• Administration of activated protein C to critically ill patients has been shown to
reduce organ failure and death and is thought to act, in part, via preservation of
the micro circulation in vital organs
• Maintaining the normoglycemia with insulin infusion during critical illness has
been proposed to protect the endothelium, probably in part, via inhibition of
excessive iNOS- induced NO release , and thereby contribute to the prevention of
organ failure and death

38. Starvation
• During starvation, the body is faced with an obligate need to generate glucose to
sustain cerebral energy metabolism(100g of glucose per day)
• This is achieved in the first 24 hours by mobilizing glycogen stores and thereafter
by hepatic gluconeogenesis from amino acids, glycerol and lactate.
• The energy metabolism of other tissues is sustained by mobilizing fat from
adipose tissue
• Such fat metabolization is mainly dependent on a fall in circulating insulin levels.

39. • Eventually , accelerated loss of lean tissue is reduced as a result of the liver
converting free fatty acids into ketone bodies, which can serve as a substitute for
glucose for cerebral energy metabolism.
• Provision of 2 liters of IV 5% D as iv fluids for surgical patients who are fasted
provides 100g of glucose per day and has a significant protein sparing effect.
• Modern guidelines on fasting prior to anesthesia allow intake of clear fluids upto 2
hours before surgery.
• Administration of carbohydrate drink at this time reduces perioperative anxiety
and thirst and decreases post operative insulin resistance

40. • Immobility : Has been recognized as a potent stimulus for inducing muscle
wasting. Early mobilization is an essential measure to avoid muscle wasting

41. Prospective Approach To Prevent
Unnecessary Aspects Of The Surgical Stress
Response
1. Minimal access techniques
2. Blockade of afferent painful stimuli (epidural anesthesia)
3. Minimal periods of starvation
4. Early mobilization

42. Thank You