SIGNIFICANCE OF GIT IN CRITICALLY ILL

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SIGNIFICANCE OF GIT IN CRITICALLY ILL

• Prof. Mehdi Hasan Mumtaz

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• ANATOMY
• HISTORY OF GUT

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FUNCTIONS

• Barrier
• Transport
• Endocrine

Barrier Transport Endocrine
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BARRIER

• Permeability Permeation
• Transcellular Paracellular

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PORES

• Large Small
• (6.5nm) (0.4-0.7nm)
• Surface area of
• - 2 million cm2.
• - Single tennis court.

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PERMEATION PATHWAYS

• Paracellular Transcellular
• (energy dependent) (small pores)

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TIGHT JUNCTIONSZona Occludence)

• ZO
• Kisses Pores

• Permeability depends
• Hydrodynamic radius
• Electrical charge.
• Functional status of ZO

• Barrier function regulation
• Number of kisses/cell.
• Channels open or closed.
• Membrane pump

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FACTORS MODULATING FUCTION OF ZO

• I/C Camp Concentration.
• I/C Ca Concentration.
• Activation State Of Protein Kinase.
• What is Cytoskeleton?

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TRANSLOCATION

• DEFINITION

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CAUSES

• Non Occlusive Intestinal Gangrene.
• Neutropenia.
• Colon Cancer.
• Penumatosis Intestinals.
• Necrtising Enterocolitis.
• Ionizing Radiation.
• Cytotoxic Drugs.

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CAUSES

• Cytokine Release Syndrome.
• Crohns Disease.
• Ulcerative Colitis.
• Haemorrhagic Shock.
• Severe Trauma
• Burn Injury.
• Leukaemia.

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FACTORS

• ?luminal microbial density.
• Damage to eipthelium.
• Irradiation.
• Cytotoxic drugs.
• Irritants.
• Cytomegatovirus.
• Mucosal disease.
• Bowel manipulation.
• Obstruction.
• Free O2 radicals.

• Diminished blood flow.
• Haemorrhagic shock.
• Burn.
• Inflammtory agent.
• Endotoxins.
• M. occlusion.
• Hypoxia.
• Fever.
• Immunosuppressant.
• Corticosteroids in high dosage.
• Blood transfusion.

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MECHANISM

• M. Cells.
• Transcellular.
• Ulcerations.

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ALTERED PERMEABILITY MECHANISM
Hypoperfusion (non-occlusive mesenteric hypoperfusion) ROS ? Role of Alopurinol Corrosive Factors Endotoxins
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NON-OCCLUSIVE HYPOPERFUSION

• Hypovolaemia.
• Cardiogenic.
• Septic shock.

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HYPOPERFUSION

• ?Renin Angiotensin Axis
• ?
• Intense Vasoconstriction
• (Splanchnic)
• ?
• Hypoxic Injury Degree
• - Duration
• ?
• ?Permeability
• Large Molecules Small Molecules
• ?
• Subepithelial Oedema

• Shedding Off Epithelium Top
• ?
• Full Mucosal Necrosis
• ?
• Disruption Of Submucosa
• ?
• Disruption Of Muscular
• Propria
• ?
• Transmural Necrosis

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ROS

• Role of Allopurinal

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CORROSIVE FACTORS

• Hydrochloric acid.
• Bile salts.
• Bacteria.
• Bacterial toxins.
• Proteases.
• Digestive enzymes.

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ENDOTOXINS

• Ischaemia.
• Direct injury.
• ?metabolic demand of GUT.
• Alteration of micro-circulation.

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MEASUREMENT OF GUT PERMEABILITY

• Isotope tests.
• PEG tests.
• Dual sacharide tests.
• Lactulose/Rhamnose.
• Lactulose/Mannitol.

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NON MUCOSAL FACTORS

• Gastric emptying.
• Intestinal transit.
• Dilution by secretion.
• Surface area available.
• Altered renal clearance.

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TECHNIQUE FOR MEASUREMENT OF GUT PERMEABILITY
USING LACTULOSE L-RHAMNOSE.

• Stop nasogastric feed/nil by mouth for 6 h prior
  to the study.
• Empty bladder urinary collecting system.
• Isotonic solution containing 5g oflactulose and
  1g of L-rhamnose administred via the nasogastric
  tube.
• All urine collected over 5h. Total volume noted
  and a 20 ml sample frozen for future analysis.
• Concentration of sugrs in urine quantified.
• recovery of each sugar calculated
• Sugar concentration x urine volume
• Recovery ---------------------------------------
  --------------- x 100
• Amount of sugar given enterally
• recovery lactulose to recovery L-rhamnose ratio
  calculated. Normal range 0-0.08.

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IMMUNONUTRTION(Nutritional Paharmacology)

• Why Name Immunonutrition?
• Lipids ? -3, ? -6
• Aminoacids
• Arginine
• Glutamine
• Ribonucleic acid
• Vitamins, E,C and A

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LIPIDS

• ?Production of free radicals.
• ?Inflammatory response.
• ?Ulcer formation.
• ?Hypersensitivity response.
• Altered renal vascular flow.
• ?Uterine contraction.
• ?Incidence of atherosclerosis.
• ?Incidence of heart attacks.
• ? Bleeding tendency.
• ?Haemorrhagic strokes.

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LIPIDS

• ?-3
• Immunostimulatory
• Protect against gut origin sepsis.
• Reduce incidence of allograft rejection

• ?-6
• Immunodepressive

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VITAMINS, E,C,A

• Control lipid peroxidation.
• Regulate RO intermediates (macrophages).

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ARGININE

• ?Production and secretion.
• Pitintary GH.
• Protaction.
• IGF-1.
• Glucagon.
• Somatostatin.
• Pancreatic polypeptide.
• Nor-epinephrin.
• Pre-cursor of growth factors.
• Putrescine.
• Spermine.
• Spermidine.

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ARGININE

1. Produce NO.
2. ?Resistance.
3. ?T-cell immunity.
4. ?Wound healing.
5. Cancer growth.
6. ?Protein content.
7. Lymphocyte nitrogen allogenic response.
8. No effect on translocation.

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GLUTANINE

• Barrier function.
• T-cell function.
• Neutrophil function.
• Kills translocated bacteria.
• Hospital stay.

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NUCLEOTIDES

• ? Resistance.
• ? Immune response.

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EFFECT OF CRITICAL ILLNESS ON GIT

• Starvation Bowel rest.
• Metabolic stress.
• Entral/Parenteral nutrition.
• Sepsis.
• Shock.

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STARVATION

• Structural
• ?
• Mucosal Atrophy
• ?
• ?Villous height.
• ?Mucosal thickness.
• ?Crypt dipth.
• ?Mucosal height.
• ?ONA, RNA
• ?Protein contents.

• Functional
• ?
• ?Activity of disaccharidasis.
• ?Transport.
• Glutamin
• Arginine
• ?Immunity.
• ?IgA secretion.

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GIT IMMUNOLOGIC DEFENCE

• IgA.
• Lymphocyte macrophages neutrophils.
• Lymph nodes.
• Kupffer cells in liver.

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BOWEL REST

• ?G.I. Mass.
• ?Small bowel mucosal weight.
• ?DNA content.
• ?Protein content.
• ?Villous height.
• ?Enzyme activity.
• Even if nitrogen balance is maintained on TPN

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• PRESENCE OF LUMINAL NUTRIENTS NECESSARY FOR
  NORMAL GUT GROWTH FUNCTION

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ENTERAL NUTRIENTS MEDIATE MUCOSAL TROPHISM
ENTERAL FEEDING
Autonomic CNS
Blood vessels
Direct provision of energy mechanical
epithelial contact
enterohormones
Pancreatic biliary secretions
paracrine effects
Endocrine effects
Dilatation ?mesenteric blood flow
Intestinal cell proliferation differentiation
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METABOLIC STRESS

• StarvationBowel RestCritical Illness, Shock,
  Hypovolaemia
• ?Mesenteric blood flow.
• Hypoxia.
• ?Production of intestinal mucous.
• Mucosal acidosis.
• ? Mucosal permeability.
• Epithelial necrosis.
• O2 free radicals.
• Antibiotic.
• Microflora.
• Colonization.
• ?Gastric acid ?? colonization.
• Mucosal immunologic impairment.
• ?
• Passage of intraduminal microbes toxins
  intocirculation.

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CRITICAL ILLNESS

• Hypermetabolism
• Hypercatabolism
• Nutritional support

Enteral (TEN) To Neutralise Disadvantages of
bowel rest

• Parenteral (TPN)
• Frequently utilized
• Stomach atony.
• Risk of aspiration.
• Venous access.
• Despite - Expensive
• - Catheter sepsis
• -Translocation

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TEN vs TPN

• Criticism ????? Scrutiny
• TEN Recommended.
• TPN Strong indication.
• Partial TEN

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TPN IMMUNE SYSTEM

• I/V lipids
• ?RES function.
• ?Bacterial clearance.
• Lipid formulation ?-6 FA.
• Promote synthesis of Pro-inflammatory bioactive
  lipids.
• ?Secretion of IgA.
• ?Bacterial translocation.
• ?GUT neuro-endocrine stimulation dependent on gut
  nutrient.
• Glutamine important for cellular immunity.

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EFFECT OF SEPSIS(LPS Induced Hyperpermeability)

• Mucosal Hypoxia
• ?Villous counter current exchanging
• ?O2 Supply.
• ?Perfusion.
• Mitochondrial oxidation
• ?
• Anaerobic Metabolism
• ?
• Less ATP
• ?
• Cytoskeleton Integrity
• ?
• ?Permeability

RO Metabolits ? G-3P ? ? ATP ?Mitochondrial Phos
phorylation ? ?Permeability
Altered Utilization of Substrates ?Activity of
glutamin ? ? ATP from glutamin ? ?Cytoskeleton
ZO ? ?Permeability
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EFFECTS OF SHOCK

• Effect of Ischaemia
• Central Control Local Humoral Substances
• (Renin-Angiotensin)

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THE CONTINUUM OF INTESTINAL ISCHAEMIC INJURY

• Normal Mucosa
• Capillar Permeability?
• Mucosal Permeability ?
• Superficial Mucosal Injury
• Transmucosal Injury
• Transmural Injury

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MECHANISM OF INTESTINAL MUCOSAL INJURY

• Ischaemic Injury
• ?O2 delivery.
• Reduced intestinal (mucosal) blood flow.
• ?Short circuiting of O2 in the villus
  countercurrent exchange.
• ?Needs of O2.
• Reperfusion injury

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THERAPEUTIC APPROACH

• Intraluminal therapeutic approach.
• Maintenance of Gut Wall.
• Intravasal therapeutic measures.

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INTRALUMINAL THERAPEUTIC APPROACH

• ?Peristaltic movement.
• Fibre application.
• ?Bacterial adherence.
• ?Bacterial elimination.
• SDD.
• ?LPS Neutralization.
• Bile acids.
• Lactoferin.
• Lactulose.

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MAINTENANCE OF GUT WALL

• Splanchnic perfusion.
• Fluid support.
• TXA2 receptor blocker
• Angiotensin blocker.
• Xanthin oxidase blockade.
• NO donors.
• Metabolic support.
• Growth factors support.

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INTRAVASAL THERAPEUTIC MEASURES

• Bacterial killing.
• LPS neutralization.
• LPS antibodies.
• BPI (Bactericidal permeability increasing
  protein).
• Inflammatory mediaters.

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THERAPEUTIC APPROACH
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NEW FUTURE THERAPIES

• Metabolic intestinal fuels.
• Glutamine.
• Shot-chain fatty acids (SCFA).
• Intestinal growth factors.
• Immunomodulation.
• Arginine.
• ?-3 fatty acids.
• Antioxidants.

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• SELECTIVE DECONTAMINATION OF DIGESTIVE TRACT