The document discusses the metabolic response of tissues to injury. It has three main phases - ebb, flow, and recovery. The ebb phase conserves energy reserves through catabolism. The flow phase mobilizes energy stores through increased metabolism and catabolism. The recovery phase restores lost tissues through anabolism. Key elements of the flow phase include hypermetabolism, muscle wasting, insulin resistance, and acute phase responses. Factors like pain, infection, and complications can exacerbate the metabolic response, while avoiding issues like hemorrhage, hypothermia, and starvation can help minimize the response.

1. METABOLIC RESPONSE
OF TISSUE TO INJURY
Dr.Prashanth.S
Junior Resident
Dept.of General Surgery

2. Why??
 Restore tissue function
 Eradicate invading Microorganisms.

3. Objectives
 Homeostasis - Concept
 Components of Responses
 Mediators of Responses
 Phases of Responses & Key elements
 Factors – Exacerbate & Avoidable

4. Homeostasis
The co-ordinated 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.
‘The stability of the “milieu intérieur” is the
primary condition for freedom and independence of
existence i.e. body systems act to maintain internal
constancy.

5. Basic Concepts in Homeostasis
 Homeostasis is the foundation of normal
physiology.
 Stress-free peri-operative care helps to restore
homeostasis following elective surgery.
 Resuscitation, surgical intervention & critical care
can return the severely injured patient to a
situation in which homeostasis becomes possible
once again.

6. Nature of the injury response
Metabolic response to injury is Graded and
evolves with time
Immunological
Hormonal
Cellular
response

7. PHYSIOLOGICAL METABOLIC
Response Components
↑ Cardiac Output
↑ Ventilation
↑ Membrane
Transport
Weight loss
Wound Healing
Hypermetabolism
Acclerated
Gluconeogenesis
Enhanced Protein
breakdown
Increased Fat oxidation

8. CLINICAL LABORATORY
Response Components
Fever
Tachycardia
Tachypnoea
Presence of wound or
Inflammation
Anorexia
Leucocytosis/Leucopenia
Hyperglycemia
Elevated CRP/Altered
acute phase reactants
Hepatic/Renal
dysfunction

9. Mediators of Injury Response
 Neuro – Endocrine [ Hormonal ]
 Immune System [ Cytokines ]

10. Neuro-endocrine response to
injury/critical illness
Biphasic :
Acute phase - An actively secreting pituitary &
elevated counter regulatory hormones (cortisol,
glucagon, adrenaline).Changes are thought to be
beneficial for short-term survival.
Chronic phase - Hypothalamic suppression & low
serum levels of the respective target organ
hormones. Changes contribute chronic wasting.

11. Purpose - Neuro-endocrine
response
 Rapidly mobilizes essential substrates for survival
 Postpone anabolism
 Optimise host defence

13. Hormone Response to Injury
Hypothalamic regulation
1. CRH
2. TRH
3. GHRH
4. LHRH
Anterior Pituitary regulation
1. ACTH – cortisol
2. TSH – T3/T4
3. GH
4. Gonadotrophins
5. Sex hormones
6. Insulin-like growth factor
7. Somatostatin
8. Prolactin
9. Endorphins
Posterior Pituitary
regulation
1. Vasopressin
2. Oxytocin
Autonomic System
1. NE / E
2. Aldosterone
Renin-angiotensin
system
1. Insulin
2. Glucagon
3. Enkephalins

14. HORMONES UNDER ANTERIOR PITUITARY
REGULATION
1. CRF – ACTH – Cortisol:
a. (+) CRF – pain, fear, anxiety, angiotensin II, serotonin,
acetylcholine & interleukin 1/6
b. ACTH – circardian signals is lost in injury
pain, anxiety, vasopressin, angiotensin II, E,
NE, oxytocins & proinflammatory cytokines
b. Cortisol - elevated in any types of injury, longest in burn
pts. (4wks). Actions in injury:
1. potentiates the action of glucagon & E causing hyperglycemia.
2. favors gluconeogenesis; insulin resistance in muscles & adipose
tissue.
3. induces protein degradation in the skeletal muscle & releases
lactate for hepatic gluconeogenesis
4. potentiates release of FA, triglycerides & glycerol from adipose
tissue for energy source

15. 1. CRF – ACTH – Cortisol: is an effective immuno-
suppressive agent
1. Caused thymic involution
2. Depressed cell mediated immune response
3. Cause monocyte & neutrophil mediated
intracellular bacterial killing
4. It downregulates proinflammatory cytokines
production (TNF alpha, IL-1, IL-6); and
increases the production of anti-inflammatory
mediator IL-10.

16. 2. Growth Hormone:
 (+) GH is GHRF (-) GH is somatostatin
 Stimulatory:
 Hypoglycemia, decrease ECV, decrease plasma FA & a.a.,
exercise, STRESS and sleep.
 Thyroxine, vasopressin, MSH, testosterone, estrogen and
alpha adrenergic stimulation.
 INSULIN like GROWTH FACTOR-1
(Somatomedin C; IGF-1)
1. The liver is the predominant source of IGF-1.
2. Promotes a.a. incorporation & cellular
proliferation and attenuates proteolysis in
skeletal muscle & liver.
3. In injury: the effects of IGF-1 is inhibited by
proinflammatory cytokines (TNF, IL-1 and IL-6).
Resulting to (-) nitrogen balance.

17. 3. Macrophage Inhibitory Factor:
 Produced by:
a. Anterior pituitary gland
b. T lymphocytes, macrophages at the site of inflammation.
 Actions:
a. A glucocorticoid antagonist (suppresses the
immunosuppresive effects of cortisol).
b. It is a proinflammatory mediator that potentiates gm (-)
& (+) septic shock.
4. Endogenous Opiods:
 Endorphins, enkephalins
 Elevated after injury & surgery
 Endorphins ----> attenuate pain perceptions / hypotension
Enkephalins ----> decrease peristalsis and secretion of GIT

18. 5. Thyroid Hormone (T4 / T3):
 In injury:
a. Low T3
b. (-) TSH release
c. Conversion of T4 – T3 in the target organs are
impaired due to cortisol. T4 is converted to an inactive
T3 called rT3
6. Gonadotrophins (LHRH/GnRH) & (FSH/LH):
 Injury, stress or severe illness ----> (-) GRH ----> (-) LH
and (-) FSH ---> decrease estrogen and androgen
secretions.
 Causes menstrual irregularities and decrease libido.
7. Prolactin:
 Produced by anterior pituitary and T lymphocytes
 Elevated level after injury in adults not seen in children
 Causes amenorrhea

19. HORMONES OF AUTONOMIC SYSTEM:
1. Catecholamines (E / NE):
Causes hypermetabolic state following severe injury
 3 – 4fold increase of E & NE in the plasma for 24 – 48 hrs.
 Causes:
a. Promotes glycogenolysis, gluconeogenesis, lipolysis and
ketogenesis.
b. Decreased insulin release & increase glucagon
secretion.
c. Peripherally, it increases lipolysis in adipose tissue and
induces insulin resistance in skeletal muscle
d. It inhibit the release of aldosterone.
e. Immune function: -- enhances neutrophilia and
lymphocytosis

20. 2. Aldosterone (Mineralocorticoid):
 Released by adrenal zona glomerulosa
 Release is caused by:
1. Angiotensin II
2. Hyperkalemia
3. Aldosterone stimulating factor (ASF) in
pituitary
4. ACTH (is the most potent stimulant).
 Major function is to maintain intravascular
volume by conserving Na & eliminating
potassium and H+ in the early distal convoluted
tubules of nephron

21. 3. Renin – Angiotensin:
 Renin in Juxtaglomerular apparatus is released by:
a. ACTH, Glucagon, prostagladin, K+, Mg++, and
Ca++
b. Baroreceptor – respond to decrease blood pressure
c. Macula densa detects changes in chloride
concentration.
Action of angiotensin II:
a. Vasoconstrictor
b. (+) aldosterone
c. (+) ADH
d. (+) E
e. Increase heart rate and contractility

22. 4. Glucagon:
 alpha islet cell
 catabolic role
 elevated release after injury
5. Insulin:
 its release in injury is inhibited by
a. Catecholamine
b. Glucagon
c. Somatostatin
d. Beta endorphins
e. IL-1

23. Hormones Under Posterior Pituitary Regulation:
1. Vasopressin / ADH / Arginine Vasopressin
(AVP):
Causes
a. reabsorption of H2O in DCT
b. Vasoconstriction peripherally
c. Stimulates hepatic glycogenolysis & gluconeogenesis
 Elevated plasma osmolality is its major stimulus:
 Location of osmoreceptors: hypothalamus, portal
circulation
 Its release also happens in 10% loss of ECV stimulating the
baroreceptor in the left atrium
 Other stimulus:
1. PAIN
2. Beta adrenergic
3. Angiotensin II
4. Opiods
5. Elevated glucose

24. 2. Oxytocin:
 Its release caused by sucking the nipple
 Stimulates contraction of mammary gland and
uterus during parturition
 No known function in males
 Role in injury is unknown

26. Proinflammatory
phase
Counter regulatory
phase
Immunological response
 IL-1, IL-6,IL-8, TNF-alpha
 Hypothalamus → pyrexia
 Hepatic acute phase protein
 IL-1 receptor antagonist (IL-1Ra)
and TNFsoluble receptors (TNF-
sR-55 and 75)
 Prevent excessive proinflammatory
activities
 Restore homeostasis
SIRS
MODS
COMP. ANTI-
INFLAMMATORY RESPONSE
SYNDROME { CARS }

27. Phases – Physiological response
[ David Cuthbertson – 1930 ]
Injury
EBB FLOW RECOVERY
SHOCK
CATAB
OLISM
ANABO
LISM
Hours Days Weeks
BREAKING DOWN
ENERGY STORES
BUILDING UP
USED ENERGY

28. Ebb and Flow Phases
Phase Duration Role Physiological Hormones
Ebb 24 - 48
hrs
Conserve - blood
volume & energy
reserves - Repair
↓ BMR, ↓ temp, ↓ CO,
hypovolaemia, lactic
acidosis
Catecholamines,
Cortisol,
aldosterone
Flow
Catabolic 3 – 10
days
Mobilisation of
energy stores –
Recovery & Repair
↑ BMR, ↑ Temp, ↑ O2
consump, ↑ CO
Cytokines + ↑
Insulin,
Glucagon,
Cortisol,
Catechol but
insulin resistance
Anabolic 10 – 60
days
Replacement of lost
tissue
+ve Nitrogen balance Growth
hormone, IGF

29. Metabolic
response
Sequence of events
surgical problem
 infection
operation
bleeding
tissue trauma
bacterial
contamination
necrotic debris
local
inflammatory
response
wound healing
recovery
hypermetabolism
muscle wasting
immunosuppression
organ failure
mortality
*
*
mortality
food deprivation
wound pain
infection
immobility
Ebb
phase
Flow
phase
Anabolic
phase
*acute stress

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

31. 1. Hypermetabolism
 Majority of trauma pts - energy expenditure
approx.15-25% > predicted healthy resting
values.
 Factors which increases this metabolism :
* Central thermodysregulation
* Increased sympathetic activity
* Increased protein turnover,
nutritional support
* Wound circulation abnormalities

32. 2.Skeletal muscle – Metabolism
1. Muscle wasting – result of ↑ muscle protein
degradation + ↓ muscle protein synthesis. (RS &
GIT). Cardiac muscle is spared.
2. Is mediated at a molecular level mainly by
activation of the ubiquitin-protease pathway.
3. Lead - Increased fatigue, reduced functional
ability, ↓QOL & ↑ risk of morbidity & mortality.

33. 3.Hepatic acute phase response
 Cytokines – IL- 6 ↑ Synthesis of Positive
acute phase proteins : Fibrinogen & CRP
 Negative acute reactants : Albumin decreases
 Not Compensated

34. 4.Insulin resistance
 Hyperglycaemia is seen – ↑ glucose production +
↓ glucose uptake – peripheral tissues. ( transient
induction of insulin resistance seen )
 Due to – Cytokines & decreased responsiveness of
insulin- regulated glucose transporter proteins.
The degree of insulin resistance is directly
proportional to magnitude of the injurious process.

35. Strategy to attenuate metabolic
response to surgery
During ebb phase
•Prompt fluid and blood replacement to maintain blood
pressure
•Adequate oxygen supply and ventilation
•Cardiovascular support by inotropes
•Antibiotics
During flow phase
Nutritional support
Warm room temperature
Mobilization
Hemodialysis
Timely intervention for complication

36. Changes in Body composition –
following surgery / critical ill pts.
Catabolism – Decrease in Fat mass & Skeletal
muscle mass.
Body weight – paradoxically Increase because of
expansion of extracellular fluid space.

37. Role of Glutamine and Arginine in
Metabolic Stress
•Glutamine
•Considered “conditionally essential” for critical patients
•Depleted after trauma(It has been hypothesized that this drop
occurs because glutamine is a preferred substrate for cells of
the gastrointestinal cells and white blood cells.)
•Provides fuel for the cells of the immune system and GI tract
•Helps maintain or restore intestinal mucosal integrity.
•Arginine
• Provides substrates to immune system
• Increases nitrogen retention after metabolic stress
• Improves wound healing in animal models
• Stimulates secretion of growth hormone and is a precursor
for polyamines and nitric oxide

38. Factors influencing the Extent and
Duration of the Metabolic Response
Pain and Fear
Surgical Factors:
Type of surgery
Region
Duration
Preoperative support
Extent of the trauma and degree of resuscitation
Post traumatic complications:
Hemorrhage
Hypoxia
Sepsis and Fever
Re-operation
Pre-existing nutritional status
Age and sex
Anaesthetic considerations

39. Avoidable factors that compound
the response to injury
 Continuing haemorrhage
 Hypothermia
 Tissue oedema
 Tissue underperfusion
 Starvation
 Immobility

40. Avoidable Factors
Volume loss : Careful limitation of intra
operative administration of colloids and
crystalloids so that there is no net weight gain.
Hypothermia : maintaining normothermia by
an upper body forced air heating cover ↓
wound infection, cardiac complications and
bleeding and transfusion requirements.

41. Avoidable Factors
Administration of activated protein C - to
critically ill patients has been shown to ↓ organ
failure and death. It 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 and
thereby contribute to the prevention of organ
failure and death.

42. Avoidable Factors
Starvation : During starvation, the body is
faced with an obligate need to generate glucose
to sustain cerebral energy metabolism(100g of
glucose per day).
Provision of at least 2L of IV 5% dextrose for
fasting patients provides glucose as above.

43. Avoidable Factors
Tissue oedema : is mediated by the variety of
mediators involved in the systemic inflammation.
Careful administration of anti-mediators & reduce
fluid overload during resuscitation reduces this
condition.
Immobility : Has been recognized as a potent
stimulus for inducing muscle wasting. Early
mobilization is an essential measure to avoid muscle
wasting.

44. Approach to prevent unnecessary
aspects of stress response
 Minimal access techniques
 Minimal periods of Starvation
 Epidural analgesia
 Early mobilisation

45. Thank you

48. 1.In stress response which one of
the following statements is false?
A Metabolism and nitrogen excretion are
related to the degree of stress.
B In such a situation there are physiological,
metabolic & immunological changes.
C The changes cannot be modified.
D The mediators to the integrated response
are initiated by pituitary.

49. 2. All of the following hormones regulate
the ebb phase except –
A Glucagon
B Cortisol
C Aldosterone
D Catecholamines

50. 3.Which one of the following will not
exacerbate the metabolic response to
surgical injury ?
A Hypothermia
B Hypertension
C Starvation
D Immobilisation

51. 4.Which one of the following statements
are false regarding Optimal peri-operative
care ?
A Volume loss should be promptly treated
by large intravenous (IV) infusions of fluid.
B Hypothermia and pain are to be avoided.
C Starvation needs to be combated.
D Avoid immobility.

52. 5. Which one of the following interleukin
promotes the hepatic acute phase
response in injury ?
A IL - 4
B IL - 5
C IL - 6
D IL - 8