SIGNIFICANCE OF GIT IN CRITICALLY ILL Prof Mehdi

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. 5 nm) Surface area of: - 2 million cm 2. - Single tennis court. Small (0. 4 -0. 7 nm)

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

TRANSLOCATION DEFINITION

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

CAUSES q q q q 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 O 2 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 q Hypovolaemia. q Cardiogenic. q 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 q q q Hydrochloric acid. Bile salts. Bacterial toxins. Proteases. Digestive enzymes.

ENDOTOXINS q q Ischaemia. Direct injury. metabolic demand of GUT. Alteration of micro-circulation.

MEASUREMENT OF GUT PERMEABILITY q q q Isotope tests. PEG tests. Dual sacharide tests. – Lactulose/Rhamnose. – Lactulose/Mannitol.

NON MUCOSAL FACTORS q q q 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 5 g oflactulose and 1 g of Lrhamnose administred via the nasogastric tube. 4. All urine collected over 5 h. 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? q q Lipids -3, -6 Aminoacids – Arginine – Glutamine q q Ribonucleic acid Vitamins, E, C and A

LIPIDS q q q q q 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 q Immunostimulatory – Protect against gut origin sepsis. – Reduce incidence of allograft rejection -6 q Immunodepressive

VITAMINS, E, C, A q Control lipid peroxidation. q 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. – 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 q q q Barrier function. T-cell function. Neutrophil function. Kills translocated bacteria. Hospital stay.

NUCLEOTIDES q Resistance. q Immune response.

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

STARVATION Structural Mucosal Atrophy q q q Villous height. Mucosal thickness. Crypt dipth. Mucosal height. ONA, RNA Protein contents. Functional q q Activity of disaccharidasis. Transport. – Glutamin – Arginine q q Immunity. Ig. A secretion.

GIT IMMUNOLOGIC DEFENCE q q Ig. A. Lymphocyte macrophages & neutrophils. Lymph nodes. Kupffer cells in liver.

BOWEL REST q q q 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 q q q q Mesenteric blood flow. Hypoxia. Production of intestinal mucous. Mucosal acidosis. Mucosal permeability. Epithelial necrosis. O 2 free radicals. Antibiotic. – – q 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 q I/V lipids – RES function. – Bacterial clearance. q Lipid formulation -6 FA. – Promote synthesis of Pro-inflammatory bioactive lipids. q q Secretion of Ig. A. 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 O 2 Supply. Perfusion. Mitochondrial oxidation Anaerobic Metabolism Less ATP Cytoskeleton Integrity Permeability RO Metabolits G-3 P 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 Transmural Injury

MECHANISM OF INTESTINAL MUCOSAL INJURY Ischaemic Injury q O 2 delivery. – Reduced intestinal (mucosal) blood flow. – Short circuiting of O 2 in the villus countercurrent exchange. q Needs of O 2. Reperfusion injury

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

INTRALUMINAL THERAPEUTIC APPROACH q Peristaltic movement. – Fibre application. q q Bacterial adherence. Bacterial elimination. – SDD. q LPS Neutralization. – Bile acids. – Lactoferin. – Lactulose.

MAINTENANCE OF GUT WALL q Splanchnic perfusion. – Fluid support. – TXA 2 receptor blocker – Angiotensin blocker. q q Xanthin oxidase blockade. NO – donors. Metabolic support. Growth factors support.

INTRAVASAL THERAPEUTIC MEASURES q q Bacterial killing. LPS neutralization. – LPS – antibodies. q q 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 Bact/LPS 2 3 Gut Wall

NEW & FUTURE THERAPIES q Metabolic intestinal fuels. – Glutamine. – Shot-chain fatty acids (SCFA). q q Intestinal growth factors. Immunomodulation. – Arginine. – -3 fatty acids. q Antioxidants.

SELECTIVE DECONTAMINATI ON OF DIGESTIVE TRACT