SIGNIFICANCE OF GIT IN SIGNIFICANCE OF GIT IN CRITICALLY ILLCRITICALLY ILL

Prof. Mehdi Hasan MumtazProf. 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)

Surface area of:

- 2 million cm2.

- Single tennis court.

PERMEATION PATHWAYS

Paracellular Transcellular

(energy dependent) (small pores)

15% 85%

TIGHT JUNCTIONSZona Occludence)

ZO

Kisses + Pores

Permeability depends:

1. Hydrodynamic radius

2. Electrical charge.

3. Functional status of ZO

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. luminal microbial density.2. Damage to eipthelium.

– Irradiation.– Cytotoxic drugs.– Irritants.– Cytomegatovirus.– Mucosal disease.– Bowel manipulation.– Obstruction.– Free O2 radicals.

3. Diminished blood flow.– Haemorrhagic shock.– Burn.– Inflammtory agent.– Endotoxins.– M. occlusion.– Hypoxia.– Fever.

4. 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.

1. 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 L-

rhamnose 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 enterally7. %recovery lactulose to %recovery L-rhamnose ratio

calculated. Normal range 0-0.08.

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).

ARGININE1. Production and secretion.

– Pitintary GH.– Protaction.– IGF-1.– Glucagon.– Somatostatin.– Pancreatic polypeptide.– Nor-epinephrin.

2. Pre-cursor of growth factors.– Putrescine.– Spermine.– Spermidine.

ARGININE

3. Produce NO.

4. Resistance.

5. T-cell immunity.

6. Wound healing.

7. Cancer growth.

8. Protein content.

9. Lymphocyte nitrogen & allogenic response.

10. 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

Pancreatic & biliary secretions

Autonomic CNS

enterohormones

Dilatation & mesenteric blood flow

Intestinal cell proliferation & differentiation

Endocrine effects

paracrine effects

METABOLIC STRESSStarvation+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 ILLNESSHypermetabolism

+

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 HypoxiaVillous counter current

exchangingO2 Supply.Perfusion.

Mitochondrial oxidation

Anaerobic Metabolism

Less ATP

Cytoskeleton Integrity

Permeability

RO Metabolits

G-3P

ATP+

MitochondrialPhosphorylation

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

TNFLPS

LIVER

Kupffer Cells

Systemic Circulation

4.34.2

Thoracic Duct

Portal vein

Intraluminal Bact/LPS2

Gut Wall

3

Therapeutic Targets

NEW & FUTURE THERAPIES

Metabolic intestinal fuels.– Glutamine.– Shot-chain fatty acids (SCFA).

Intestinal growth factors. Immunomodulation.

– Arginine. -3 fatty acids.

Antioxidants.

SELECTIVE DECONTAMINATION OF DIGESTIVE

TRACT