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Final slides today 5 feb 13
1. Role of Gut Injury in Severe
Acute Pancreatitis
2. Point to be Focus on
• Pancreas
• Acute Pancreatitis
• Pathogenesis of disease
• Clinical Outcome
• Inflammatory Process
• Gut normal Physiology
• Gut Barrier defect
• Gut pancreatic access
• Gut model
• Bacterial translocation
• Method of detection
• Summary
3. Overview of Pancreas
The pancreatic gland contains three major types of cells
• The duct cells make up about 10% of the pancreas and
secrete solutions rich in bicarbonate
• The acinar cells comprise over 80% of the pancreas and
they synthesize and secrete pancreatic enzymes
• The islet cells make up about 10% of the pancreas and form
the endocrine portion of the pancreas and they secrete the
hormones, insulin, glucagon, somatostatin, and pancreatic
polypeptide
5. Pancreatitis
• Pancreatitis is an inflammatory process in which
pancreatic enzymes auto digest the gland
• The gland can sometimes heal without any impairment
of function or any morphologic changes. This process is
known as acute pancreatitis i.e.
• It is an irreversible inflammatory disease, contributing to
the functional and morphologic loss of the gland, the
pathological change referred to as chronic pancreatitis
i.e.
6. Acute Pancreatitis
• Acute inflammatory process involving the pancreas
• Usually painful and self-limited
• Inflammatory disorder
Acute pancreatitis
Mild Acute pancreatitis Severe Acute pancreatitis
Recover within 1 week Leads sepsis induce MODS
7. Acute Pancreatitis: Pathogenesis
Premature
enzyme activation
Alcohol toxicity Microcirculation
disturbance
Autodigestion of pancreatic tissue
Release of
enzymes into
the circulation
Activation
of white
blood cells
Local
vascular
insufficiency
Local
complications
Distant
organ failure
9. Acute Pancreatitis: Pathogenesis
• Initiation factor in Earlier period
• Abnormally activation of pancreatic enzyme
• Alcohol toxicity
• Pancreatic Microcirculation Disorder
• Aggravating factors in later period
• Infection: pancreatic abscess
• Intestinal bacteria translocation
• Cytokine and systemic inflammation reaction
syndrome
• Free radicals
10. Acute Pancreatitis : Clinical Outcome
Severe (Necrotizing)
Mild Organ failure
No Organ failure
80-85%
15-20%
Mortality 1%
Infected
necrosis
Sterile
necrosis
Mortality 5% Mortality 25-70%
11. Biphasic course of AP
Within 1 week SIRS >1 week Infection-Sepsis
Severe SIRS
Bacterial Translocation
Pro-inflammatory cytokines
Severe suppression
of Immune response
Infection /Late MOF
Anti-inflammatory cytokines
Early MOF
13. SIRS: Systemic Inflammatory
Response Syndrome
• A response of the immune system to inflammation
(pancreatitis, ischemia, burns, multiple trauma, shock, and
organ injury)
Opal SM et al. Crit Care Med. 2000;28:S81-2.
14. Infection: Part of a Bigger Picture
Infection is a process in which bacteria, viruses,
fungi or other organisms enter the body, attach to
cells, and multiply.
Opal SM et al. Crit Care Med. 2000;28:S81-2.
15. Definition of Sepsis
Sepsis can now be more accurately defined as a
systemic inflammatory response syndrome (SIRS)
resulting from infection.
Infection + SIRS = Sepsis
Adapted from: Bone RC et al. Chest. 1992;101:1644-55.
16. Sepsis: A Complex Disease
Others
SIRS
Infection Sepsis
Traum
a
Burn
Pancr
eatitis
Opal SM et al. Crit Care Med. 2000;28:S81-2.
17. Multiple Organ Dysfunction Syndrome
Multiple System Organ Failure is when more than one
organ of the body stops working normally. After the onset
of sepsis where intervention is needed to sustain life.
Core Curriculum for Critical Care Nursing, 2006
18. Diagnosis of SIRS
• SIRS: A clinical response arising from a nonspecific insult
manifested by
³2 of the following:
– Temperature
³38°C or £36°C
– HR ³90 beats/min
– Respirations ³20/min
– WBC count ³12,000/mL or £4,000/mL or >10% immature
neutrophils
May be caused by bacterial translocation
19. Diagnosis of Sepsis
• Bacterial infections are the most common cause of
sepsis, but sepsis can also be caused by fungal,
parasitic, or viral infections
• The infection can originate from anywhere in the body.
Infection leads Inflammation may result in organ
damage.
20. Role of Gut
• Sepsis
• Accounts for > 80% of deaths
• Causative microorganism
• Mostly gram negative bacteria (gut origin)
• Mechanism
• Translocation of the bacteria across the gut wall
via barrier defect, imbalance of intestinal flora and
imbalance of immune system
22. GI Tract: Normal Pathophysiology
• GI tract protect body from exposure of foreign Ag,
– Barrier, to prevent the passage of harmful
intra-luminal entities
» Stomach have acidic pH
» Small bowel have alkali Ph
» Mucus production throughout GI
– Small Intestine act as a selective filter( allow
the translocation of essential nutrients and
electrolytes)
23. Component of Gut
• The extrinsic barrier consisting i.e. mucus, bicarbonate, hormones,
cytokines prostaglandins
• The intrinsic barrier is composed of the epithelial cells lining i.e.
Junctions and channels
• Paracellular pathway (junction)
• Transcellular pathway (channel)
Paracellular pathway regulated by 4 specific junction
• Tight Junction
• Adherens junction
• Desmosomes
• Gap junction
24. TJs Regulate Intestinal Permeability
• Permeability is a process where molecules are allowed to
pass through the epithelial lining by non mediated diffusion
• Barrier properties of the intestinal epithelium are regulated by
TJs. It is generally believed that disease related, increase in
IP is caused by defects in TJ structure
No disease Disease
Normal TJ
regulate normal IP
Disrupted TJ
leads to increase IP
25. Function of Gut Depends Upon
• Normal intestinal flora (Ecological Barrier)
• Mucosal Epithelia (Mechanical barrier)
• Secreting IgA and immune cell ( Immune barrier)
26. Translocation of gram-ve
bacteria via Para-cellular or
trans-cellular
Endotoxemia
·Excess of Inflammatory mediators
·oxidative stress
·Neutrophils transmigration
circulate to multiple organ infection
Sepsis leads SIRS
&MODS
Ischemia-Reperfusion
Defected mucosal
barrier
Mucosal GUT
injury
Acute pancreatitis
Gut Pancreatic Access
•Excess of Inflammatory mediators
•oxidative stress
27. What is Ischemia Reperfusion Injury
• Interruption of blood supply to gut known as Ischemic injury
( during surgery, AP & trauma etc) which damage tissue
• Restoration of blood flow to ischemic tissue leads to
reperfusion injury which exceeds the mucosal damage
28. GUT Hypothesis
Gut
Gut
MOTOR
Gut
STARTER
Intestinal Ischemia reperfusion
Primary state
Neutrophils priming Direct barrier defect
MODS MODS
↑Mortality and morbidity
29. GUT as STARTER
Neutrophils get primed due to mesenteric circulation
Primed neutrophils (inactive) circulate to body until second hit
MODS
Endotoxin
Oxygen free radical
Intestinal Ischemia reperfusion
Priming of neutrophils initiated via PLA2
Release proteases Imbalance of
immune response
Inflammatory
mediators
30. GUT as MOTOR
Ischemia reperfusion injury
Intestinal barrier defect
Luminal content invades
Portal & Lymphatic system
Activates immune cells
Bacterial translocation
MODS
Payers patches
Macrophages of
lamia propria, gut
Mesenteric lymph
nodes
kuppfer cells of
liver
Inflammatory mediators
31. How Intestinal Barrier Get Defected
Malnutrition
Bacterial
overgrowth
Immunodefi
ciency state
Villous
atrophy
Ischemia
Reperfusion
Intestinal
barrier defect
32. Bacterial Translocation Depends on 3 Factors
– Small bowel bacterial overgrowth (SIBO)
– Immunodeficiency state
– Physical damage to intestinal mucosa
• When any of this mechanism separately or in combined
manner leads to sepsis.
33. Route of Bacterial Translocation
Entry of bacteria from the gut lumen into the body through two
routes
•Vascular route (portal vein)
•Lymphatic route (Principal pathway of translocation)
35. Gut Translocation Mediated by Three Hit Model
• Gut insult by Ischemia
• Restoration of blood flow with migration of neutrophils to
intestine
• Loss of integrity of gut barrier function
36. How to Detect Gut Injury
• Ischemia
• SIBO by H2 breath test
• Oxidative stress by ELISA
• Mucosal acidosis (Tonometer)
• Detection of intestinal villous atrophy
• Histological
• Ultrastructurally by Electron microscopy
37. How to Detect Gut Injury
• Intestinal Barrier defect
• Functional
– Intestinal permeability test by dual sugar test using HPLC
• Ultrastructurally
– TJ and other junction of paracellular junction proteins
• localization of barrier’s protein
– expression of barrier’s protein by immuno-histochemistry
• Cellular level
– m RNA of these protein by RT PCR
38. How to Detect Gut Injury
• Sepsis
• Culture (Aerobic & anaerobic culture)
• 16sRNA PCR
• Endotoxaemia
• Endotoxin level
40. AP- Assessment of Severity
14 studies comprising 1478 patients with
acute pancreatitis were meta-analyzed
Patients with OF and no IPN Patients with IPN and no OF
Absolute influence of OF and IPN on mortality is
comparable and thus the presence of either indicates
severe disease
The relative risk of mortality doubles when OF and IPN
are both present and indicates extremely severe
disease.
Gastroenterology, Volume 139;3:2010,813-820
41. Summary
• Association of Gut origin sepsis and MODS in high risk
patient group
• Gut ischemia is an dominating factor in MODS
• Several trials suggested
• Enteral feeding and selective decontamination
improve clinical outcome
43. How Gut injury occur
Ischemia reperfusion injury
Release of OFR due to excess of lipid per-oxidation of cell
membrane via xanthine opathway
OFR initiate migration of activated neutrophils into reperfused
tissue
Accumulation of activated neutrophils leads intestinal injury via 3
ways
↑ Ischemia effect Releasing OFR ↑Inflammatory response
44. Effect of Sepsis
• During septic complication with any of major trauma,
IBD, Pancreatitis and surgery, body comes in hyper-metabolite
state
• This state leads to consumption of stored protein ,
energy, imbalance of immune system and deterioration
of organ i.e. Liver GI, kidney, heart and lung.
• Gut liver axis have major role in these response
45. Role of GI in Pathophysiology of Sepsis
• Gut help in maintaining hyper metabolism state during
Sepsis, SIRS & MODS
• Change in GIT structure &function
• Abnormal colonization of bacteria
• Bacterial translocation
• Absorption of toxins
• They trigger activation of pro-inflammatory cytokines and
release other mediators in metabolic response to sepsis
46. Evidence of gut injury in SAP
• Intestinal atrophy with nutrition depletion
• Intestinal ischemia (mucosal acidosis) can predict death
with overall accuracy 82%
• Increased intestinal permeability correlated with severity
of AP
• Bacterial translocation suggest septic complications
• Endotoxaemia correlates severity of disease suggest
complication and mortality rate