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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