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The “Forgotten Organ”GUT-DERIVED SEPSIS AND ITS PATHOPHYSIOLOGY: WHAT DO WE KNOW SO FAR?NG ZEE YONG – NUMED, 16/02/2015 – 27/03/2015
What has been forgotten?GUT
1. Up to 50% of patients in ICU who were septic had no obvious infection but a “hidden” infection in the abdomen. [1]
2. Gut failure in critically-ill patients is often occult and difficult to classify by degree.
3. Absence of a consensus definition of GI failure
Gut failure left untreated, increasing risk of gut-derived sepsis.
History 1949, Schweinburg et al found live enteric bacteria in the
peritoneal washings of dogs after haemorrhagic shock [2]
1954, Fine et al proved intestinal bacteria crossed mucosal wall after major trauma and shock [3]
1977, Polk et al found that intra-abdominal infection can lead to remote organ failure [4]
1979, the phenomenon of bacteria crosses intestinal wall was termed as “Bacterial Translocation” by Berg and Garlington. [5]
Bacterial TranslocationThe process whereby viable bacteria or other antigenic
macromolecules (eg. lipopolysaccharide and peptidoglycan) which
normally reside within the GI lumen, spread through the
intestinal mucosa barrier into to extra-intestinal sites, (such
as the mesenteric lymph node complex (MLN), liver, spleen, kidney,
and bloodstream), where they may either cause infection or
activate the immune system leading to organ damage and failure
Sepsis, SIRS, ARDS, MODS
Overview
Critical illness
Visceral hypoperfusion
Gut mucosal ischaemia and barrier disrupted
Increased mucosa permeability
Intestinal bacteria and endotoxins enter systemic circulation
Secretion of chemokines/cytokines
Sepsis, SIRS, ARDS, MODS
(Bacterial Translocation)
(Pro-inflammatory response)
Three hit model Critical illness
Loss gut barrier integrity Ischaemia-reperfusion injury
Visceral hypoperfusion
Intestinal bacteria and endotoxins enter systemic circulation
Secretion of chemokines/cytokines
Sepsis, SIRS, ARDS, MODS
1st hit
2nd hit
3rd hit
Release of inflammatory mediators from gut-associated lymphoid tissues
Inflammatory response augmented
“Gut-lymph” Theory Bacteria
translocationImmune cells and mesenteric lymph nodes trap translocation bacteriaSurviving bacteria, cell wall fragments, pro-inflammatory mediators travels along mesenteric lymphatics
Cisterna chyli
Thoracic duct
Left subclavian vein
Pulmonary circulation
Systemic circulation MODS
Acute lung injury or ARDS
Pancreatic enzymes are released into the gut
Stimulates ischaemic gut to release in vivo activators
Endothelial cells and leukocytes in the circulation are activated
Production of oxygen free radicals
Initiation of adhesion cascade
Accumulation of leukocytes in distant
organs
Cytotoxicity, cell apoptosis, organ dysfunction
In 2000, Schmid-Schonbein et al proposed…
*Identification of specific pancreatic enzymes constituting activators is still under research
In 2000, Jackson et al proposed…
Release of lipopolysaccharide (LPS) / endotoxins
LPS is taken up by liver from blood
Stimulates Kupffer cells production of TNF-a
Secretion of TNF-a into bile and delivery to duodenum
Intestinal damage and disruption of gut mucosal integrity
Systemic inflammatory response syndrome
In 2005, Luyer et al proposed… Dietary fat is administered
Stimulates cholecystokinin (CCK) release by duodenum
CCK binds to CCK-2 receptors of the afferent vagal nerve
Stimulates vagal nerve to secrete acetylcholine
Acetylcholine binds to inflammatory cells
Pro-inflammatory cytokine secretion is suppressed
*The protective effect of dietary fat on intestinal permeability is abolished by vagotomy
Further damage to gut is prevented
Cholinergic anti-inflammatory pathway
Summary Gut plays an important roles in the development of sepsis and
multi-organ dysfunction syndrome.
Gut failure is often occult and missed due to • lack of awareness and more focus is given to other organ systems • Absence of consensus definition
Since the first discovery of bacterial translocation in 1949, we are still researching the cause/causes of gut-derived sepsis.
Gut-derived sepsis is not independently caused by bacterial translocation, it is a multi-factorial condition.
Reference1. Fry DE, Pearlstein L, Fulton RL, Polk HC Jr. Multiple system organ failure. The role of uncontrolled infection.
Arch Surg 1980;115:136-140.2. Schweinburg FB, Frank HA, Frank ED, Heimberg F, Fine J. Transmural migration of intestinal bacteria during
peritoneal irrigation in uremic dogs. Proc Soc Exp Biol Med 1949;71:150-153.3. Fine J. The bacterial factor in traumatic shock. Springfield, IL: Charles C. Thomas Publisher, 19544. Polk HC, Shields CL. Remote organ failure: a valid sign of occult intra-abdominal infection. Surgery
1977;81:310-313.5. Berg RD, Garlington AW. Translocation of certain indigenous bacteria from the gastrointestinal tract to the
mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun 1979;23:403-411.6. Deitch EA Bacterial translocation or lymphatic drainage of toxic products from the gut: what is important
in human beings? Surgery 2002;131:241-244.7. Deitch EA. Gut-origin sepsis: evolution of a concept.
Surgeon 2012;10:350-356.8. Mitsuoka H, Kistler EB, Schmid-Schonbein GW. Generation of in vivo activating factors in the ischemic
intestine by pancreatic enzymes. Proc Natl Acad Sci U S A 2000;97:1772-1777.9. Jackson GD, Dai Y, Sewell WA. Bile mediates intestinal pathology in endotoxemia in rats. Infect Immun
2000;68:4714-4719.10. Luyer MD, Greve JW, Hadfoune M, Jacobs JA, Dejong CH, Buurman WA. Nutritional stimulation of
cholecystokinin receptors inhibits inflammation via the vagus nerve. J Exp Med 2005;202:1023-1029
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