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