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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