The gastrointestinal tract as a barrier in sepsis - British Medical Bulletin

The gastrointestinal tract as a barrier in sepsis

Brian J Rowlands*, Chee Voon Soong+ and Keith R Gardiner**Section of Surgery, Queen's Medical Centre, University Hospital, Nottingham, UK and^Department of Surgery, Queen's University of Belfast, Belfast, UK

The gastrointestinal tract is an organ of digestion and absorption which ismetabolically active and has specific nutrient requirements. In health, it has anadditional function as a major barrier, protecting the body from harmfulintraluminal pathogens and large antigenic molecules. In disease states, such assepsis when the mucosal barrier is compromised, micro-organisms and their toxicproducts gain access to the portal and systemic circulations producing deleteriouseffects. Under these circumstances, systemic inflammatory response syndrome(SIRS) and multiple organ dysfunction syndrome (MODS) develop leading todeterioration and death of the patient in the intensive care unit. Therapeuticstrategies for such patients in the intensive care unit aim to support generalimmune function and maintain the structure and function of the gastrointestinaltract. For these therapies to be successful, the underlying septic or necrotic focusmust be ablated using appropriate surgical or other invasive techniques.

Correspondence to:Prof. Brian J Rowlands,

Section of Surgery,Queen's Medical Centre.

University Hospital.Nottingham NG7 2UH, UK

Sepsis, systemic inflammatory response syndrome (SIRS) and multipleorgan dysfunction syndrome (MODS) complicate the investigation andmanagement of several surgical diseases1. These include major trauma,obstructive jaundice, inflammatory bowel disease, acute pancreatitis, intra-abdominal sepsis and major vascular surgery. These clinical conditions andtheir septic complications are characterised by a state of 'hyper-metabolism', which leads to a rapid consumption of endogenous stores ofprotein and energy, immunological dysfunction and deterioration of organfunction2. These changes which affect the liver, kidney, gastrointestinaltract, heart and lungs are orchestrated by a series of neuroendocrine eventsand the release of cytokines, activators and mediators. The 'gut-liver axis'appears to have a central role in these responses.

In recent years, the gastrointestinal tract has assumed more importancein the management of the septic patient in the intensive care unit.Previously, the gastrointestinal tract was regarded as an organ thatcontributed little to the pathophysiology of sepsis but it is now recognisedthat the small intestine and colon make important contributions to themaintenance of hypermetabolism in sepsis, SIRS and MODS3. This is dueto changes in gastrointestinal structure and function that promote lossof intestinal barrier function and associated changes in hepatic Kupffer

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Gut barrier in sepsis

cell function. When taken in conjunction with abnormal colonisation byluminal micro-organisms, bacterial translocation and absorption of toxinsdue to increased intestinal permeability, there is a constant trigger to thewidespread activation of pro-inflammatory cells and the release of othermediators of the metabolic response to sepsis. This produces profoundsystemic changes in metabolic homeostasis and immunological dys-function. These problems appear to be enhanced by malnutrition4.

Pathophysiology of sepsis

Sepsis and related conditions present a gradation of severity of illness.Minimal derangement of normal physiology and rapid restoration ofmetabolic homeostasis with therapy is at one end of the spectrum. At theother extreme, is massive disruption of normal organ function, whichleads to progressive deterioration and death despite treatment. Central toour understanding of these events is an appreciation that initially there isa localised response to injury. If the local host defence mechanisms areinadequate or overwhelmed, this may lead subsequently to systemicmanifestations. Localised infections due to bacteria, viruses, fungi andparasites stimulate the release of various mediators, e.g. cytokines,prostaglandins, thromboxanes, platelet activating factors and thecomplement system. These mediators help to combat infection byactivating neutrophils with consequent degranulation and release ofoxygen radicals, which increase local blood flow and vascularpermeability allowing the influx of phagocytic cells. They also activatewhite blood cells and induce chemotaxis. If the severity of the infection issufficient that these mediators spill over into the systemic circulation, aseptic cascade is initiated which leads to septic shock, SIRS, and MODS5.Superoxide radicals now damage host cells. Endotoxin, tumour necrosisfactor, the interleukins, transforming growth factor beta and prosta-glandin E2 all contribute to the initiation and maintenance of this cascade,which may be beneficial or detrimental, depending on the clinical setting.

Sepsis is not synonymous with overwhelming infection and in manypatients who fit the criteria for SIRS, no micro-organism can bedemonstrated or cultured6. Our understanding of the development oforgan failure and death has expanded greatly since originally described7

and we now recognise three stages in the development of SIRS8. Thebalance between the anti-inflammatory systemic response and the pro-inflammatory systemic response is important for metabolic homeostasis,and the disruption of this equilibrium gives rise to a number of syndromes(Fig. 1). Clinical manifestations of these syndromes are cardiovascularcompromise (shock), suppression of immunity, apoptosis and organdysfunction9-10. The balance of cytokines, their natural antagonists and

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Intensive care medicine

Major Surgery

Acute pancreatitis

Obstructive jaundice

Intra-abdominal sepsis

Inflammatory bowel disease

Ischaemia-reperfusion

Multisystem trauma

Burns

SEPSIS

SIRS

CARS

MODS

Cardiovascular compromise (shock)

„ Suppression of immunity

Apoptosis

Organ dysfunction

Homeostasis

DEATH

Rg. 1 Commonsurgical conditions

that lead to wellrecognised syndromes,

disruption of meta-bolic homeostasis and

death.

SIRS

CARS

MODS

:- systemic inflammatory responsesyndrome

:- compensatory anti-inflammatoryresponse syndrome

:- multiple organ dysfunctionsyndrome

endogenous antibodies to endotoxins is important in determiningoutcome in patients with sepsis syndrome11.

The gastrointestinal tract in health

The gastrointestinal tract is regarded primarily as an organ of digestionand absorption but it is a metabolically active organ that requires specificnutrients. It has a major barrier function, protecting the body fromharmful intraluminal pathogens and large antigenic molecules12. Inaddition, it plays a pivotal role in the metabolism of glutamine13. The gutmucosal barrier comprises both immunological and non-immunologicalprotective components, the former being divided into local and systemiccomponents and the latter comprises mechanical and chemical barriers aswell as intraluminal bacteria (Table 1). The maintenance of normalepithelial cell structure prevents transepithelial migration of particles fromthe gut lumen, and the preservation of tight junctions between the cellsprevents movement through the paracellular channels14. Acid secretion inthe stomach, alkali secretions in the small bowel and mucous productionthroughout the gastrointestinal tract provides additional protection. Thelumen of the gut is colonised by aerobic and anaerobic micro-organisms,

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•fable 1 Components of the gut mucosal barrier

Immunological Non immunological

Local• Gut associated lymphoid tissue (GALT)• Intra-epithelial lymphocytes• Submucosal aggregates• Peyer"s patches• Mesenteric lymph nodes• Secretory IgA

Systemic• Circulatory lymphocytes• Hepatic Kupffer cells

(

Mechanical• Healthy enterocyte• Tight junction

Cell turnoverNormal motility

Bacteriological> Aerobic micro-organisms• Anaerobic micro-organisms

ZhemicalGastric aciditySalivary lysozymeLactoferrinMucous secretionBile salts

and there is a progressive increase in their numbers from the stomach,where gastric acid produces an almost sterile environment, to the colon,which harbours 108 aerobes and 1011 anaerobes. Under normal circum-stances, these micro-organisms remain within the lumen of the bowelwhere they have important functions in metabolic and nutritionalhomeostasis. In disease states, when the mucosal barrier is compromised,these micro-organisms and their toxic products may 'escape' from thelumen and reach the systemic circulation to produce deleterious effects,despite the presence of other defences, e.g. the gut associated lymphoidtissue (GALT), mesenteric lymph nodes and hepatic Kupffer cells (Fig. 2).

The gastrointestinal tract in disease

The demonstration of intestinal atrophy manifest by changes in weight,structure and mucosal content of DNA and protein have been assumedto indicate impaired intestinal barrier function, but this has not beenconfirmed in animal studies of protein malnutrition15. Recent clinicalevidence demonstrates a strong association between compromise of gutbarrier function and malnutrition, which suggests a mechanism thatfacilitates gut-derived infection and sepsis16. Dysfunction of the mucosalbarrier is thought to result from an imbalance of aggressive anddefensive factors on the gastrointestinal mucosa17. Genetic and environ-mental factors may modify the response of the gastrointestinal mucosa


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Hepatic Kupffer cells

Luminal secretions

Fig. 2 Components ofthe 'gut-liver axis' that

provide a barrier toinvasion of the

systemic circulation bybacteria and toxins.

Bowelmotility

Gut associatedlymphoidtissue

Luminalbacteria

Mesentericblood flow

to pro-inflammatory factors. Increased gastric acid production, colon-isation with Helicobacter pylori, ingestion of non-steroidal anti-inflam-matory analgesics and the use of broad-spectrum antibiotics, predisposethe gastrointestinal mucosa to ulceration. Maintenance of mucosal bloodflow, oxidative fuel supply and a normal intestinal bacterial flora protectagainst barrier dysfunction. Failure of the intestinal mucosal barrier resultsin permeation of microbial and dietary antigens across the intestinal wall.The transmural migration of enteric bacteria or their products(endotoxins) to extra-intestinal sites has been termed translocation, andmay occur by the transcellular or paracellular routes. Enhanced uptake ofmacromolecules and bacteria has been demonstrated where the intestinalmucosa is damaged by inflammation, infection, neoplasia or trauma. Inaddition, systemic endotoxaemia, bacterial translocation, and increasedintestinal permeability to macromolecules have been demonstrated inpatients with rheumatic diseases, haemorrhagic shock, burns, burn sepsis,major trauma, following chemotherapy or radiotherapy, and inexperimental endotoxaemia in the absence of macroscopic intestinaldisease. However, translocations of endotoxin or bacteria have not beenfound commonly in patients after major trauma or burns18.

Factors influencing intestinal mucosal barrier function

Clinical studies strongly suggest that intestinal barrier dysfunction andincreased permeability occur in patients with intestinal inflammation


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and other diseases associated with increased mortality and morbidity19.The significance of this is difficult to determine, but a working hypothesissuggests that translocating micro-organisms and toxins activate a systemicinflammatory cascade and promote organ dysfunction and failure.Factors that predispose to the development of sepsis syndromes arechanges in the luminal micro-environment, perfusion and oxygen defects,ischaemia reperfusion injury, malnutrition,and hepatic dysfunction.

The luminal micro-environment

In the small intestine, peristalsis, mucus secretions rich in IgA, andresident flora help to minimise the growth of pathogenic species. Theperistaltic waves discourage adherence of the organism to the bowel walland prevent colonisation with overgrowth. The higher bacterial counts ofthe colon are a reflection of this decreased motility in comparison to thesmall bowel. The development of paralytic ileus and the formation of ablind loop allow stagnation of intraluminal contents, creating favourableconditions for microbial proliferation. The use of systemic and oralantibiotics cause a reduction in the normal colonisation-resistant residentflora and an increase in number of potentially harmful pathogenic species.

Perfusion and oxygenation defects

The mucosa at the tip of the villi is particularly prone to ischaemia due tothe counter current exchange mechanism of the vessels and occurs whenthere is shunting of blood during low flow states. More subtle mucosaldamage detectable only microscopically may occur following mildischaemia. In transient hypoperfusion or hypoxia, the mucosal injury ismore pronounced during reperfusion when the oxygen supply is re-established. Blood loss and shock have detrimental effects on the immuneand hepatic cells, reducing their capacity to clear bacteria and endotoxin.Blood transfusion can activate polymorphonuclear leucocytes which thensequestrate in various sites and has been imphcated in the development oftransfusion-related renal and pulmonary pathology. Autologous bloodmay have the same effect leading to leucocyte activation and cytokinerelease. The activation and accumulation of neutrophils leads to sludgingof capillaries and reduction of mucosal blood flow.

Complete disruption of the bowel wall, which may occur withperforation or frank infarction, can induce profound hypotension andshock due to massive fluid losses into the bowel wall and peritonealcavity. This may result in the intraluminal contents entering the systemiccirculation either directly or indirectly. If there is minimal contamination

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and haemodynamic disturbance, the initial invasion will be via theportal system with systemic bacteraemia delayed because of hepaticKupffer cell activity. With severe intestinal wall damage, direct massiveperitoneal contamination and profound shock, bacteria and endotoxinenter the systemic circulation directly from the peritoneal cavitybypassing the protective barrier of the 'gut-liver axis'.

Ischaemia-reperfusion injury

The causes of intestinal ischaemia are diverse and may represent part of ageneralised hypoperfusion insult or decreased blood flow confined to partof the splanchnic circulation. In sepsis, intestinal ischaemia may developas a result of poor extraction and utilisation of nutrients by the intestinedespite normal oxygen content and delivery20. Selective splanchnic flow-dependent tissue hypoxia may develop in sepsis whereby oxygen deliveryfails to meet demands and blood is shunted away from the mucosa. Areduction in blood flow to a segment of intestine may occur due toobstruction or strangulation of the bowel, or due to atherosclerosis andthromboembolic disease of the splanchnic vessels.

The ischaemic injury sustained and changes observed are dependent onthe duration and severity of the ischaemia and whether these changes arereversible. Three patterns of intestinal ischaemia are apparent. These arecomplete vascular occlusion, compensated partial ischaemia and partialischaemia followed by reperfusion. In complete vascular occlusion rapidprogression to transmural infarction ensues. In compensated partialischaemia, the injury may be so mild that no morphological or physio-logical change can be detected or there is a slight alteration in vascularpermeability. An increase in intestinal capillary permeability is usuallyfound with 1 h partial regional ischaemia but may occur after only 20min. If significant partial ischaemia is reversed, the injury sustained by thebowel may be exacerbated by reperfusion21. A decrease of intestinalarterial pressure to 25-35 mmHg for 3 h may lead to a loss of villousheight and a reduction in mucosal thickness. This mucosal damage isenhanced if the ischaemic episode is followed by 1 h of reperfusion. Thisreperfusion injury is more severe than that produced by 4 h of ischaemiaalone.

When ischaemia is relieved by reperfusion or resuscitation, oxygen-derived free radicals (ODFR) are generated by the xanthine oxidasepathway and cause direct injury to the lipid membranes of cells andhyaluronic acid of their basement membrane22. Xanthine dehydrogenaseoccurs naturally and is found in abundance in the intestine. Thedehydrogenase form catalyses the conversion of xanthine and water touric acid with the reduction of the nicotinamide adenine dinucleotide


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molecule. During ischaemia, the xanthine dehydrogenase is convertedrapidly by a calcium dependent proteolytic enzyme to xanthine oxidasewhich generates uric acid and superoxide anion from hypoxanthine andoxygen. The accumulation of hypoxanthine during ischaemia favours thegeneration of ODER in response to the improvement in oxygenationduring reperfusion. Evidence for the role of ODER in producing injury issupported by the reduction in villous and crypt epithelial cell necrosis byallopurinol (a xanthine oxidase inhibitor) and superoxide dismutase (afree radical scavenger) following reperfusion of ischaemic bowel.

The production of ODER together with calcium will activate the plasmamembrane phospholipase A which releases arachidonic acid andactivates the complement cascade23. Arachidonic acid is then converted toa leucotriene (LT) or thromboxane (TX) depending on whether it followsthe lipo-oxygenase or cyclo-oxygenase pathways. Some of thesearachidonic acid metabolites especially LTB4 and TXA^ and breakdownproducts of complement, e.g. C5a are potent chemo-attractants andchemoactivators which can stimulate neutrophils and up-regulateadhesion molecules on the endothelial membrane. A consequence of thisis the margination and adhesion of neutrophils along the wall of thevessel. This leads to the release of more ODER and other proteolyticenzymes which will cause further damage to the epithelium. Sludging andplugging of the capillaries may then occur giving rise to the 'no re-flow'phenomenon which will compound the ischaemic insult24. The role playedby neutrophils in reperfusion injury is supported by the prevention ofischaemia induced intestinal mucosa injury by pretreatment of animalswith monoclonal antibody against neutrophil adhesion molecules25.Neutropenia and inhibition of neutrophil adherence attenuates theincrease in microvascular permeability26. The initial injury is related to thedirect toxicity of ODFR, independent of neutrophil activation, but laterdamage is dependent on neutrophil activation.

Ischaemia reperfusion injury is not confined to the bowel, and otherremote organs and systems may sustain damage as a result of reduction inblood flow followed by revascularisation and successful resuscitation. Theimpairment sustained by remote organs is dependent on the mass ofrevascularised ischaemic tissue. The production of ODFR and then-byproducts is initially confined to the ischaemic region but subsequentlyspillage into the systemic circulation occurs. An increase in pulmonarypermeability and hepatocellular injury have been observed whenischaemic intestine is reperfused27. These injuries to the lungs and liver areassociated with sequestration of neutrophils but neutropenic animals areprotected. A plasma chemo-activator and chemo-attractant producedfollowing reperfusion of an ischaemic organ can stimulate ODFRproduction by activating neutrophils and increasing microvascularpermeability28.


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An increase in plasma concentration of tumour necrosis factor (TNF)has been found with intestinal ischaemia with further increases of 5-10-fold following reperfusion. Increased portal vein endotoxin concent-rations precede systemically detectable TNF, suggesting that its releasemay be due to hepatic stimulation by gut-derived endotoxin. TNF is apotent pyrogen and intravenous administration can cause tachycardia,hypotension and death. It activates neutrophils and enhances theirphagocytic ability. Remote organ injury may be abrogated by induction ofneutropenia and by the use of anti-oxidants such as superoxide dismutaseand catalase. Attenuation of the increased microvascular permeability inthe lungs is found by pretreating animals with anti-TNF antibody prior tobowel ischaemia reperfusion injury. Administration of anti-TNF does notprevent neutrophil sequestration in the lungs. Pretreatment withinterleukin-1 receptor antagonist can reduce the injury and myeloper-oxidase activity as a measure of neutrophil infiltration in both lungs andliver following ischaemia reperfusion of the bowel.

Malnutrition

The nutritional status of the patient has been shown to be important indetermining the outcome of patients following trauma and surgicaldisease. Patients may present with pre-existing malnutrition due to theinability to swallow, malabsorption, poverty, self-neglect and prolongedstarvation following surgery and in the intensive care unit. In patientsrecovering from abdominal surgery enteral feeding improves musclefunction and reduces morbidity and mortality. Malnutrition and totalparenteral nutrition have been shown to cause atrophy of theenterocytes and colonocytes. Although total parenteral nutrition (TPN)may improve outcome in those with intestinal failure and in the severelymalnourished it may lead to atrophy of the intestinal mucosa and areduction in IgA antibody production. This is because the enterocytesand colonocytes are better supported by enteral intraluminal infusion ofnutrients. Patients who develop sepsis, SIRS and MODS very rapidlydevelop severe nutritional depletion due to an increase in their rate ofmetabolism and consumption of their endogenous stores of protein andenergy, especially if no attempt is made to support their nutritionalstatus using parenteral or enteral feeding protocols.

Hepatic dysfunction

Hyperbilirubinaemia is a common accompaniment to sepsis. It usuallyrepresents a direct toxic effect on liver parenchymal cells causing

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inflammation in the portal triads and intrahepatic cholestasis. It may beexacerbated by hypovolaemia, the use of intravenous nutrition, drugs andexcessive haemolysis. The combination of fever, rigors and obstructivejaundice should always be investigated quickly as ascending biliary sepsiscan lead to rapid deterioration of the patient with onset of SIRS andMODS, especially acute renal failure. Extrahepatic biliary obstruction dueto stone or stricture may cause ascending cholangitis. Acute acalculouscholecystitis may lead to gall bladder necrosis and biliary peritonitis.Unrecognised and untreated, these conditions have a high mortality sothey should be investigated and treated urgently using surgical,endoscopic and radiological techniques. In the absence of extrahepaticpathology which is treatable, sepsis and hyperbilirubinaemia usuallyindicate severe parenchymal liver disease and/or intrahepatic cholestasiswhich carries a bad prognosis.

Treatment of intestinal mucosai barrier dysfunction

Support of the gut mucosai barrier includes adequate mucosai perfusion,optimal oxygen delivery, prevention of gastrointestinal haemorrhageand maintenance of luminal micro-ecology. These general measurestogether with more specific measures support enterocyte and colonocytestructure and function.

Fluid resuscitation

Hypotension should be reversed with the appropriate intravenous fluids.Initial management should be with crystalloids and depending onresponse, colloids may be given. Synthetic colloids increase the circulatingvolume by a greater degree per volume infused than crystalloids but carrythe risk of anaphylaxis and coagulopathy. It may be necessary tosupplement volume replacement with blood and fresh frozen plasma. Insome cases, hypotension is resistant to fluid alone, possibly due to thegeneration of inflammatory mediators, e.g. TNF and myocardialdepressant factor. Inotropic support with dopamine may be required.Dopamine at low doses (3-5 ug/kg/min) increases renal blood flow via itsdopaminergic receptors but the effect on splanchnic perfusion remainscontroversial29. It may reduce mucosai perfusion and accelerate the onsetof intestinal ischaemia in haemorrhagic shock and in patients withcongestive cardiac failure. Higher doses produce vasoconstriction by ct-adrenergic stimulation off-setting the vasodilatory effect. If dopamine isinadequate noradrenaline or dobutamine should be considered. However,inotropes are no substitute for adequate fluid replacement therapy.


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Tissue oxygenation

Oxygen delivery and degree of shunting due to ventilation/perfusionmismatch in the lungs can be measured from blood gas analysis and theinspired oxygen concentration. An accurate indication of tissueperfusion can be obtained using a silicone tonometer. The principles ofthe tonometer are based on the assumption that the partial pressure ofcarbon dioxide within the bowel is similar to that of the lumen, and theconcentration of standard bicarbonate within the tissues is similar tothat of arterial blood. The tonometer measures the intramucosal pH ofthe bowel which correlates well with diminished perfusion once oxygendelivery falls below a critical level30. The fall in gastric intramucosal pHfollowing cardiac surgery is associated with a higher incidence ofmorbidity and mortality. Tonometric measurements of gastric pH are anaccepted method of monitoring systemic oxygenation and outcome inICU patients31. Sustained acidosis beyond 2 h is highly predictive ofmortality and major complications in aortic surgery. Intramucosalacidosis may be an early warning of an impending complication andtherapy guided by intramucosal pH measurements may significantlyimprove outcome in critically ill patients32.

Selective digestive decontamination

Gastrointestinal haemorrhage used to be a major problem in septicpatients requiring ICU management, but improvements in overallpatient management have diminished the problem to an extent thatprophylaxis with antacids, H2 receptor antagonists or sucralfate areused sparingly. The use of selective digestive decontamination (SDD) ofthe gastrointestinal tract has its advocates. Meta-analysis of therandomised controlled trials of SDD carried out over 15 years showedthat it was an effective technique for reducing infection relatedmorbidity and mortality in ICU patients33. The data showed that toprevent one respiratory tract infection you would need to treat 5patients and to prevent one death you would need to treat 23 patients.Although SDD continues to be evaluated in specific groups of patientsadmitted to ICU, it has not been universally adopted due to doubtsabout efficacy in a general ICU population and concerns about thedevelopment of multiresistant organisms with widespread usage.

Gut barrier dysfunction improves when the intestinal pool of Gram-negative bacteria/endotoxin is reduced by the administration of non-selective or selective antibiotics, lactulose to promote non-pathogeniclactobacilli, or adsorbents to bind intraluminal endotoxin. Theadministration of anti-inflammatory drugs (steroids), systemically or

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topically, may enhance the healing of mucosal inflammatory lesions.Intravenous injection of taurolidine, a drug with antiseptic, antibiotic andanti-endotoxin activity, significantly reduces systemic endotoxaemia inexperimental colitis whereas systemic broad-spectrum antibiotic (metro-nidazole and cefuroxime) therapy was ineffective34. Administration ofanti-TNF antibody (cTN3) significantly reduced systemic endotoxaemia,plasma IL-6 concentration, acute phase protein response and weight loss.Repair of the intestinal barrier may be hastened by multi-targeted therapyaimed at reducing luminal aggressive factors, reducing the inflammatoryresponse (steroids, nitric oxide synthase inhibition, anticytokines) andselective gut nutrition.

Nutritional support

The use of nutritional support techniques improves outcome of patientswith sepsis and SIRS35. Recently, there have been two major trends in theuse of nutritional support. First there is a major shift from intravenousadministration of nutrients to enteral feedings and second the quantityof nutrients being administered is decreasing and the quality of nutrientmix is improving. In sepsis, a number of studies have demonstrated thatenteral feeding has a major advantage over parenteral nutrition36-37. Thebeneficial effects of nutrition are its support of generalized immunefunction, enhancement of mucosal barrier function, reduction ofbacterial translocation, modification of hepatic Kupffer cell function,cytokine release and acute phase protein production by the liver.Additional benefits of enteral nutrition are the maintenance of thestructural and functional integrity of the gastrointestinal tract bystimulation of 'gut' hormone release, 'gut' motility and mucousproduction and maintenance of luminal milieu of nutrients, micro-organisms and trophic factors that are important for normal digestionand barrier function. The theoretical advantages of enteral nutrition aresometimes undermined by an inability to deliver sufficient nutrients intothe gastrointestinal tract due to prolonged ileus, bloating, abdominaldistention or diarrhoea. The latter may have a small additional benefitin reducing numbers of luminal bacteria and toxins which arepotentially deleterious. If diarrhoea persists, it may lead to dehydrationand electrolyte imbalance.

The role of novel substrates in maintaining gut integrity has beenextensively reviewed by considering their metabolism in health anddisease, the effects on the gut mucosa and the experimental and clinicalevidence supporting their use in clinical practice18. Evidence that thesesubstrates improve gut mucosal barrier function and increase survivaldoes not necessarily imply that restored barrier function and improved


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survival are causally linked. The substrates may exert their beneficialeffects by improving nitrogen balance and metabolism or by enhancingimmune function and clearance of translocated bacteria. The strongestcandidates as selective gut nutrients are glutamine for the enterocyte andshort chain fatty acids for the colonocyte. Recent evidence shows thatglutamine supplemented parenteral nutrition improves outcome incritically ill intensive care unit patients and surgical patients38'39. Theresults from studies of enteral supplementation of glutamine aredisappointing40, but a recent study shows encouraging results in severelyinjured patients with a low frequency of pneumonia, sepsis andbacteraemia41. Modest intakes of standard oral diet (0.6 g nitrogen/kgdaily) are sufficient to maintain gut integrity and immune function.Short chain fatty acids and n-3 polyunsaturated have modest beneficialeffect in patients with intestinal inflammation42. Arginine has provenimmunological benefits43. Despite this, oral supplementation witharginine has been shown to be detrimental in experimental colitiscausing increased colonic inflammation44 but beneficial to mucosalbarrier function and survival after experimental ischaemia/reperfusioninjury45. There is growing evidence that the L-arginine-nitric oxidepathway is important in the development of colonic inflammation andthat this may lead to new therapeutic strategies in inflammatory boweldiseases46-47. Arginine supplements for critically ill patients should beused cautiously at present. There is insufficient evidence from clinicalstudies to support the use of orthinine, branched chain amino acid ornucleotide supplementation by themselves. Supplementation of enteraldiets with combinations of novel substrates is beneficial to patients in anumber of different clinical situations where gut barrier function iscompromised by malnutrition and hypermetabolism48'49. The use of diets(containing fibre, fermented oats and lactobacillus) that supportprobiotic bacteria (microbial interference treatment) has been advocatedas an important new development in the support of these patients50'51.

Newer therapies

A number of new therapies have been developed based on threeimportant theories about the sepsis syndrome namely: (i) oxygen debtcauses organ injury; (ii) endotoxin is a critical mediator; and (iii) thehost inflammatory response is harmful52. A number of clinical trialsemploying new therapeutic strategies have failed to show convincingevidence of an improved outcome for patients with sepsis or septic shockand some agents have caused harm9'53. An explanation of thesetherapeutic failures is that our concept of the pathophysiology of sepsisis too simplistic or incorrect and fails to consider the influence of the

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compensatory anti-inflammatory response. More studies of specificdiseases are clearly indicated.

Surgical treatment

None of the aforementioned therapies will be successful if theunderlying source of infection is not controlled. This may be easy if thepatient has an obvious wound infection, an abscess or soft tissueinfection or a necrotic limb. Frequently, the source of the sepsis or SIRSis not apparent and intrathoracic or intra-abdominal sepsis may bedifficult to diagnose. Treatment may require thoracatomy orlaparotomy. Surgical exploration should be carried out after appropriateresuscitation of the patient. The extent of the surgical procedure willdepend on the location and extent of the septic lesion. Adequatedrainage and debridement should be carried out. In abdominal sepsis itmay be necessary to consider the use of stomas, tubes or drains and, incertain circumstances, planned relaparotomy or laparostomy may be atreatment option53. The chances of survival are enhanced by the earlyeradication of the source of sepsis or SIRS. The surgical approach isdictated by the condition of the patient and the experience of thesurgeon. The survival rate for patients requiring laparotomy forabdominal sepsis in an ICU setting is approximately 40% and multipleoperations are associated with diminishing returns and increasingmortality.

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The gastrointestinal tract as a barrier in sepsis - British Medical Bulletin