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SIGNIFICANCE OF GIT IN CRITICALLY ILL Prof. Mehdi Hasan Mumtaz ANATOMY & HISTORY OF GUT FUNCTIONS Barrier Transport Endocrine BARRIER Permeability & Permeation Transcellular Paracellular PORES Large (6.5nm) Surface area of: - 2 million cm2. - Single tennis court. Small (0.4-0.7nm) PERMEATION PATHWAYS 15% Paracellular (energy dependent) 85% Transcellular (small pores) TIGHT JUNCTIONS Zona Occludence) ZO Permeability depends: 1. Hydrodynamic radius 2. Electrical charge. 3. Functional status of ZO Kisses + Pores Barrier function regulation: 1. Number of kisses/cell. 2. Channels open or closed. 3. Membrane pump FACTORS MODULATING FUCTION OF ZO I/C Camp Concentration. I/C Ca+ Concentration. Activation State Of Protein Kinase. What is Cytoskeleton? TRANSLOCATION DEFINITION CAUSES Non Occlusive Intestinal Gangrene. Neutropenia. Colon Cancer. Penumatosis Intestinals. Necrtising Enterocolitis. Ionizing Radiation. Cytotoxic Drugs. CAUSES Cytokine Release Syndrome. Crohns Disease. Ulcerative Colitis. Haemorrhagic Shock. Severe Trauma Burn Injury. Leukaemia. FACTORS 1. 2. luminal microbial density. Damage to eipthelium. – Irradiation. – Cytotoxic drugs. – Irritants. – Cytomegatovirus. – Mucosal disease. – Bowel manipulation. – Obstruction. – Free O2 radicals. 3. 4. Diminished blood flow. – Haemorrhagic shock. – Burn. – Inflammtory agent. – Endotoxins. – M. occlusion. – Hypoxia. – Fever. Immunosuppressant. – Corticosteroids in high dosage. – Blood transfusion. MECHANISM M. Cells. Transcellular. Ulcerations. ALTERED PERMEABILITY MECHANISM Hypoperfusion (non-occlusive mesenteric hypoperfusion) ROS Role of Alopurinol Corrosive Factors Endotoxins NON-OCCLUSIVE HYPOPERFUSION Hypovolaemia. Cardiogenic. Septic shock. 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 ROS Role of Allopurinal CORROSIVE FACTORS Hydrochloric acid. Bile salts. Bacteria. Bacterial toxins. Proteases. Digestive enzymes. ENDOTOXINS Ischaemia. Direct injury. metabolic demand of GUT. Alteration of micro-circulation. MEASUREMENT OF GUT PERMEABILITY Isotope tests. PEG tests. Dual sacharide tests. – Lactulose/Rhamnose. – Lactulose/Mannitol. NON MUCOSAL FACTORS Gastric emptying. Intestinal transit. Dilution by secretion. Surface area available. Altered renal clearance. TECHNIQUE FOR MEASUREMENT OF GUT PERMEABILITY USING LACTULOSE & L-RHAMNOSE. Stop nasogastric feed/nil by mouth for 6 h prior to the study. 2. Empty bladder & urinary collecting system. 3. Isotonic solution containing 5g oflactulose and 1g of Lrhamnose administred via the nasogastric tube. 4. All urine collected over 5h. Total volume noted and a 20 ml sample frozen for future analysis. 5. Concentration of sugrs in urine quantified. 6. %recovery of each sugar calculated: Sugar concentration x urine volume %Recovery =------------------------------------------------------ x 100 Amount of sugar given enterally 7. %recovery lactulose to %recovery L-rhamnose ratio calculated. Normal range 0-0.08. 1. IMMUNONUTRTION (Nutritional Paharmacology) Why Name Immunonutrition? Lipids -3, -6 Aminoacids – Arginine – Glutamine Ribonucleic acid Vitamins, E,C and A 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. LIPIDS -3 Immunostimulatory – Protect against gut origin sepsis. – Reduce incidence of allograft rejection -6 Immunodepressive VITAMINS, E,C,A Control lipid peroxidation. Regulate RO intermediates (macrophages). ARGININE 1. Production and secretion. – – – – – – – 2. Pitintary GH. Protaction. IGF-1. Glucagon. Somatostatin. Pancreatic polypeptide. Nor-epinephrin. Pre-cursor of growth factors. – Putrescine. – Spermine. – Spermidine. ARGININE 3. 4. 5. 6. 7. 8. 9. 10. Produce NO. Resistance. T-cell immunity. Wound healing. Cancer growth. Protein content. Lymphocyte nitrogen & allogenic response. No effect on translocation. GLUTANINE Barrier function. T-cell function. Neutrophil function. Kills translocated bacteria. Hospital stay. NUCLEOTIDES Resistance. Immune response. EFFECT OF CRITICAL ILLNESS ON GIT Starvation & Bowel rest. Metabolic stress. Entral/Parenteral nutrition. Sepsis. Shock. 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. GIT IMMUNOLOGIC DEFENCE IgA. Lymphocyte macrophages & neutrophils. Lymph nodes. Kupffer cells in liver. 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 PRESENCE OF LUMINAL NUTRIENTS NECESSARY FOR NORMAL GUT GROWTH & FUNCTION ENTERAL NUTRIENTS MEDIATE MUCOSAL TROPHISM ENTERAL FEEDING Direct provision of energy & mechanical epithelial contact Blood vessels Autonomic CNS enterohormones Pancreatic & biliary secretions Endocrine effects Dilatation & mesenteric blood flow Intestinal cell proliferation & differentiation paracrine effects METABOLIC STRESS Starvation+Bowel Rest+Critical 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. 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 TEN vs TPN Criticism Scrutiny TEN = Recommended. TPN = Strong indication. Partial TEN 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. 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 Phosphorylation Permeability Altered Utilization of Substrates Activity of glutamin ATP from glutamin Cytoskeleton + ZO Permeability EFFECTS OF SHOCK Effect of Ischaemia Central Control Local Humoral Substances (Renin-Angiotensin) THE CONTINUUM OF INTESTINAL ISCHAEMIC INJURY Normal Mucosa Capillar Permeability Mucosal Permeability Superficial Mucosal Injury Transmucosal Injury Transmural Injury 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 THERAPEUTIC APPROACH Intraluminal therapeutic approach. Maintenance of Gut Wall. Intravasal therapeutic measures. INTRALUMINAL THERAPEUTIC APPROACH Peristaltic movement. – Fibre application. Bacterial adherence. Bacterial elimination. – SDD. LPS Neutralization. – Bile acids. – Lactoferin. – Lactulose. MAINTENANCE OF GUT WALL Splanchnic perfusion. – Fluid support. – TXA2 receptor blocker – Angiotensin blocker. Xanthin oxidase blockade. NO – donors. Metabolic support. Growth factors support. INTRAVASAL THERAPEUTIC MEASURES Bacterial killing. LPS neutralization. – LPS – antibodies. BPI (Bactericidal permeability increasing protein). Inflammatory mediaters. THERAPEUTIC APPROACH 4.2 LPS LIVER 4.3 TNF Systemic Circulation Thoracic Duct Kupffer Cells Therapeutic Targets Portal vein Intraluminal 2 Bact/LPS 3 Gut Wall NEW & FUTURE THERAPIES Metabolic intestinal fuels. – Glutamine. – Shot-chain fatty acids (SCFA). Intestinal growth factors. Immunomodulation. – Arginine. – -3 fatty acids. Antioxidants. SELECTIVE DECONTAMINATI ON OF DIGESTIVE TRACT