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SIGNIFICANCE OF GIT IN CRITICALLY ILL

SIGNIFICANCE OF GIT IN CRITICALLY ILL. Prof. Mehdi Hasan Mumtaz. ANATOMY & HISTORY OF GUT. FUNCTIONS. Barrier Transport Endocrine. Barrier Transport Endocrine. BARRIER. Permeability & Permeation Transcellular Paracellular. PORES. Large Small (6.5nm) (0.4-0.7nm)

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SIGNIFICANCE OF GIT IN CRITICALLY ILL

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  1. SIGNIFICANCE OF GIT IN CRITICALLY ILL Prof. Mehdi Hasan Mumtaz

  2. ANATOMY & HISTORY OF GUT

  3. FUNCTIONS Barrier Transport Endocrine Barrier Transport Endocrine

  4. BARRIER Permeability & Permeation Transcellular Paracellular

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

  6. PERMEATION PATHWAYS Paracellular Transcellular (energy dependent) (small pores) 85% 15%

  7. 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

  8. FACTORS MODULATING FUCTION OF ZO • I/C Camp Concentration. • I/C Ca+ Concentration. • Activation State Of Protein Kinase. What is Cytoskeleton?

  9. TRANSLOCATION DEFINITION

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

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

  12. 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. FACTORS

  13. MECHANISM M. Cells. Transcellular. Ulcerations.

  14. ALTERED PERMEABILITY MECHANISM

  15. NON-OCCLUSIVE HYPOPERFUSION • Hypovolaemia. • Cardiogenic. • Septic shock.

  16. 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 HYPOPERFUSION

  17. ROS Role of Allopurinal

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

  19. ENDOTOXINS • Ischaemia. • Direct injury. • metabolic demand of GUT. • Alteration of micro-circulation.

  20. MEASUREMENT OF GUT PERMEABILITY • Isotope tests. • PEG tests. • Dual sacharide tests. • Lactulose/Rhamnose. • Lactulose/Mannitol.

  21. NON MUCOSAL FACTORS • Gastric emptying. • Intestinal transit. • Dilution by secretion. • Surface area available. • Altered renal clearance.

  22. 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.

  23. IMMUNONUTRTION(Nutritional Paharmacology) Why Name Immunonutrition? • Lipids  -3,  -6 • Aminoacids • Arginine • Glutamine • Ribonucleic acid • Vitamins, E,C and A

  24. 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.

  25. -3 Immunostimulatory Protect against gut origin sepsis. Reduce incidence of allograft rejection -6 Immunodepressive LIPIDS

  26. VITAMINS, E,C,A • Control lipid peroxidation. • Regulate RO intermediates (macrophages).

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

  28. ARGININE • Produce NO. • Resistance. • T-cell immunity. • Wound healing. • Cancer growth. • Protein content. • Lymphocyte nitrogen & allogenic response. • No effect on translocation.

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

  30. NUCLEOTIDES •  Resistance. •  Immune response.

  31. EFFECT OF CRITICAL ILLNESS ON GIT • Starvation & Bowel rest. • Metabolic stress. • Entral/Parenteral nutrition. • Sepsis. • Shock.

  32. 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. STARVATION

  33. GIT IMMUNOLOGIC DEFENCE • IgA. • Lymphocyte macrophages & neutrophils. • Lymph nodes. • Kupffer cells in liver.

  34. 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

  35. PRESENCE OF LUMINAL NUTRIENTS NECESSARY FOR NORMAL GUT GROWTH & FUNCTION

  36. 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

  37. 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.

  38. 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

  39. TEN vs TPN Criticism  Scrutiny TEN = Recommended. TPN = Strong indication. Partial TEN

  40. 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.

  41. Mucosal Hypoxia Villous counter current exchanging O2 Supply. Perfusion. Mitochondrial oxidation  Anaerobic Metabolism  Less ATP  Cytoskeleton Integrity  Permeability EFFECT OF SEPSIS(LPS Induced Hyperpermeability) RO Metabolits  G-3P   ATP + Mitochondrial Phosphorylation  Permeability Altered Utilization of Substrates Activity of glutamin   ATP from glutamin  Cytoskeleton + ZO  Permeability

  42. EFFECTS OF SHOCK Effect of Ischaemia Central Control Local Humoral Substances (Renin-Angiotensin)

  43. THE CONTINUUM OF INTESTINAL ISCHAEMIC INJURY Normal Mucosa Capillar Permeability Mucosal Permeability  Superficial Mucosal Injury Transmucosal Injury Transmural Injury

  44. 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

  45. THERAPEUTIC APPROACH • Intraluminal therapeutic approach. • Maintenance of Gut Wall. • Intravasal therapeutic measures.

  46. INTRALUMINAL THERAPEUTIC APPROACH • Peristaltic movement. • Fibre application. • Bacterial adherence. • Bacterial elimination. • SDD. • LPS Neutralization. • Bile acids. • Lactoferin. • Lactulose.

  47. MAINTENANCE OF GUT WALL • Splanchnic perfusion. • Fluid support. • TXA2 receptor blocker • Angiotensin blocker. • Xanthin oxidase blockade. • NO – donors. • Metabolic support. • Growth factors support.

  48. INTRAVASAL THERAPEUTIC MEASURES • Bacterial killing. • LPS neutralization. • LPS – antibodies. • BPI (Bactericidal permeability increasing protein). • Inflammatory mediaters.

  49. 4.2 4.3 Systemic Circulation TNF Gut Wall Therapeutic Targets LPS Bact/LPS LIVER Kupffer Cells Thoracic Duct Portal vein 2 Intraluminal 3 THERAPEUTIC APPROACH

  50. 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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