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METABOLIC RESPONSE OF TISSUE TO INJURY
Dr.Prashanth.SJunior Resident
Dept.of General Surgery
Why??
Restore tissue function
Eradicate invading Microorganisms.
Objectives
Homeostasis - Concept Components of Responses Mediators of Responses Phases of Responses & Key elements Factors – Exacerbate & Avoidable
HomeostasisThe 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.
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.
Nature of the injury response
Metabolic response to injury is Graded and evolves with time
Immunological
HormonalCellular response
PHYSIOLOGICAL METABOLIC
Response Components
↑ Cardiac Output↑ Ventilation↑ Membrane Transport
Weight lossWound Healing
HypermetabolismAcclerated Gluconeogenesis
Enhanced Protein breakdown
Increased Fat oxidation
CLINICAL LABORATORY
Response Components
FeverTachycardiaTachypnoeaPresence of wound or Inflammation
Anorexia
Leucocytosis/Leucopenia
HyperglycemiaElevated CRP/Altered acute phase reactants
Hepatic/Renal dysfunction
Mediators of Injury Response
Neuro – Endocrine [ Hormonal ]
Immune System [ Cytokines ]
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.
Purpose - Neuro-endocrine response
Rapidly mobilizes essential substrates for survival
Postpone anabolism
Optimise host defence
Hormone Response to InjuryHypothalamic
regulation1. CRH2. TRH3. GHRH4. LHRH
Anterior Pituitary regulation5. ACTH – cortisol6. TSH – T3/T47. GH8. Gonadotrophins9. Sex hormones10.Insulin-like growth
factor11. Somatostatin12. Prolactin13. Endorphins
Posterior Pituitary regulation1. Vasopressin2. Oxytocin
Autonomic System3. NE / E4. Aldosterone
Renin-angiotensin system
5. Insulin6. Glucagon7. Enkephalins
HORMONES UNDER ANTERIOR PITUITARYREGULATION1. 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
c. 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
1. CRF – ACTH – Cortisol: is an effective immuno-suppressive agent
1. Caused thymic involution2. Depressed cell mediated immune
response3. Cause monocyte & neutrophil
mediated intracellular bacterial killing4. It downregulates proinflammatory
cytokines production (TNF alpha, IL-1, IL-6); and increases the production of anti-inflammatory mediator IL-10.
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.
3. Macrophage Inhibitory Factor: Produced by:
a. Anterior pituitary glandb. 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
5. Thyroid Hormone (T4 / T3): In injury:
a. Low T3b. (-) TSH releasec. 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
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
2. Aldosterone (Mineralocorticoid): Released by adrenal zona glomerulosa Release is caused by:
1. Angiotensin II2. Hyperkalemia3. Aldosterone stimulating factor (ASF) in
pituitary4. 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
3. Renin – Angiotensin: Renin in Juxtaglomerular apparatus is released
by:a. ACTH, Glucagon, prostagladin, K+, Mg++, and
Ca++b. Baroreceptor – respond to decrease blood
pressurec. Macula densa detects changes in chloride
concentration.
Action of angiotensin II:d. Vasoconstrictore. (+) aldosteronef. (+) ADHg. (+) Eh. Increase heart rate and contractility
4. Glucagon: alpha islet cell catabolic role elevated release after injury
5. Insulin: its release in injury is inhibited by
a. Catecholamineb. Glucagonc. Somatostatind. Beta endorphinse. IL-1
Hormones Under Posterior Pituitary Regulation:
1. Vasopressin / ADH / Arginine Vasopressin (AVP):
Causes a. reabsorption of H2O in DCTb. Vasoconstriction peripherallyc. 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. PAIN2. Beta adrenergic3. Angiotensin II4. Opiods5. Elevated glucose
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
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 }
Phases – Physiological response[ David Cuthbertson – 1930 ]
Injury
EBB FLOW RECOVERY
SHOCKCATABOLISM
ANABO LISM
Hours
Days Weeks
BREAKING DOWN ENERGY STORES
BUILDING UP USED ENERGY
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
Metabolic response
Sequence of events
surgical problem infection
operation
bleeding tissue traumabacterial contamination
necrotic debris
local inflammatory response
wound healing
recovery
hypermetabolism
muscle wastingimmunosuppressionorgan failure
mortality
*
*mortality
food deprivation
wound pain
infection
immobility
Ebb phase
Flow phase
Anabolic phase
*acute stress
Key catabolic elements of flow phase
Hypermetabolism Alterations in skeletal muscle protein Alterations in Liver protein Insulin resistance
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
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.
3.Hepatic acute phase response
Cytokines – IL- 6 ↑ Synthesis of Positive
acute phase proteins : Fibrinogen & CRP
Negative acute reactants : Albumin decreases
Not Compensated
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.
Strategy to attenuate metabolic response to surgeryDuring ebb phase
•Prompt fluid and blood replacement to maintain blood pressure•Adequate oxygen supply and ventilation•Cardiovascular support by inotropes•Antibiotics
During flow phaseNutritional supportWarm room temperatureMobilizationHemodialysisTimely intervention for complication
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.
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
Factors influencing the Extent and Duration of the Metabolic ResponsePain and Fear Surgical Factors:
Type of surgeryRegionDurationPreoperative support
Extent of the trauma and degree of resuscitation
Post traumatic complications:HemorrhageHypoxia Sepsis and FeverRe-operation
Pre-existing nutritional statusAge and sexAnaesthetic considerations
Avoidable factors that compound the response to injury
Continuing haemorrhage Hypothermia Tissue oedema Tissue underperfusion Starvation Immobility
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.
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.
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.
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.
Approach to prevent unnecessary aspects of stress response
Minimal access techniques
Minimal periods of Starvation Epidural analgesia
Early mobilisation
Thank you
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.
2. All of the following hormones regulate the ebb phase except –
A Glucagon
B Cortisol
C Aldosterone
D Catecholamines
3.Which one of the following will not exacerbate the metabolic response to surgical injury ?
A Hypothermia
B Hypertension
C Starvation
D Immobilisation
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.
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