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