Patients and methods

Results

Discussion

The results of this study indicate that the upper gastrointestinal tract is sterile in a minority of surgical patients. In this series bacterial colonisation occurred most frequently in elderly patients with gastric or small intestinal pathology requiring urgent surgery. Gastric colonisation, and in particular the occurrence of multiple organisms, was associated with a significant increase in septic complications which were of predominantly enteric bacterial origin. Our results also show that gastric colonisation itself predisposes to translocation. Although association does not prove causation, the frequency with which organisms of identical genus were identified in nasogastric aspirates, mesenteric lymph nodes, and subsequently in the postoperative septic focus supports the gut origin of sepsis hypothesis. Figure 1 illustrates the commonality of organisms.

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Figure 1

Commonality of organisms from three culture sites.

The human gastrointestinal tract contains a wide variety of aerobic and anaerobic bacteria. Unique flora reside in each section of the intestine and are prevented from migrating to extraintestinal sites by a single epithelial layer on the mucosa. The upper gut and stomach are usually sterile or sparsely populated with relatively avirulent bacteria.10 These are most commonly Gram positive and aerobic and the most frequently isolated species are streptococci, staphylococci, lactobacilli, and various fungi.15 In the distal ileum Gram negative bacteria outnumber Gram positive organisms. Enterobacteriaceae predominate and anaerobic bacteria are found in substantial numbers.16 ,17

This study confirms that critical illness is often associated with significant proximal gut overgrowth of enteric organisms which may contribute to nosocomial infection.8 ,9 ,18 The similarity in the spectrum of organisms identified in septic foci and those cultured from gastric aspirates is suggestive that the infecting organisms are of gut origin. Marshall et alshowed that over 90% of their ICU patients with infection had at least one episode of infection with an organism that was simultaneously present in the upper gastrointestinal tract.8 In their series colonisation with Candida, Pseudomonas,Staphylococcus epidermidis, andStreptococcus faecalis were the commonest organisms responsible. A study in neonates defined microbial translocation as having occurred if organisms isolated from blood samples were also carried in the throat or rectum.18 They reported six infants with 15 episodes of septicaemia attributable to enteric organisms. In our study E coli, Klebsiella, Candida, and enterococci were most frequently implicated. Our results confirm the preponderance of colonisation by Candida andE coli and also show a similar spectrum of organisms colonising the upper gut as were later identified in septic foci. In addition, our study also shows that the magnitude of colonisation is important. Colonisation with multiple organisms was associated with a significant increase not only in septic complications but also with bacterial translocation. The prognostic value of nasogastric aspirate culture in the management of the critically ill patient merits further investigation.

It is a remarkable testimony to the efficiency of the intestinal barrier that large populations of indigenous bacteria reside in the healthy lower gut without causing harm. This indigenous microflora exerts an important influence in preventing colonisation with exogenous pathogens, so called colonisation resistance.19 Many factors have been implicated in the regulation of the different populations of microflora. These include the creation of “microclimates” whereby facultative bacteria, for example, utilise oxygen, thereby ensuring a suitable environment for obligate anaerobes.16 This has prompted suggestions that obligate anaerobic bacteria may be the principle inhibitors of translocation ofE coli and other potentially pathogenic bacteria.20 ,21 Disruption of the normal flora may predispose to a breakdown in colonisation resistance. This may occur, for example, with antibiotic therapy and there is evidence that substrate utilisation by different organisms will also influence other bacterial concentrations.22 ,23 These factors cannot be implicated in this study as patients were excluded if antibiotics or artificial nutrition had been used in the month prior to admission. It would seem, therefore, that pathological colonisation of the upper gut can occur simply as a consequence of gastrointestinal pathology or serious illness. Bacterial translocation was associated with an increased incidence of septic complications. However, although this difference was not significant we have previously shown that bacterial translocation is associated with a significant increase in septic morbidity in similar patients to those reported here.12The methodology used to establish bacterial translocation almost certainly underestimates the true incidence of this phenomenon. Practical and ethical constraints preclude the sampling of multiple nodes. Despite these logistical difficulties culture of mesenteric lymph nodes provides firm evidence of translocation, whereas the converse is not true. In this series, Gram negative facultative anaerobes, and particularly E coli, were the most common organisms identified in mesenteric lymph nodes. Obligate anaerobes were not identified in this series, but are known to translocate, so absolute intraluminal population density would therefore not seem to have a significant influence on bacterial translocation.12 Previous authors have also reported a low incidence of bacterial translocation by obligate anaerobes.19 ,21 This finding would also suggest that translocation rates cannot be explained by alterations in gut permeability alone.24

This study confirms that critical illness is associated with proximal gut overgrowth and that this predisposes to septic morbidity. A purely descriptive study such as this cannot establish causation with certainty. It could be argued that gut colonisation is a consequence of infection and a manifestation of microbial dissemination from the initial focus of infection. Indwelling urinary or venous catheters are known to be associated with septic morbidity and the presence of a nasogastric tube may itself predispose to infection by permitting aspiration. In this study sampling of gastric aspirate and mesenteric lymph nodes occurred either on admission or at the time of surgery before indwelling catheters had been present for any prolonged period. Further, in this series, there was a significant increase in the incidence of multiorganism colonisation in elderly patients with acute conditions. These patients must have been immunosuppressed to some extent and it is possible that this is the common factor that predisposes the patient to both gastric colonisation as well as subsequent sepsis.

While accepting these caveats the evidence from this study does lend support to the gut origin of sepsis theory. Firstly, it is improbable that organisms cultured from mesenteric lymph nodes originated from anywhere other than the gut lumen as patients with peritoneal contamination were excluded. Ethical constraints precluded routine sampling of portal venous blood but systemic cultures were routinely obtained and only one was positive. In the absence of persistent bacteraemia we consider it probable that organisms cultured from mesenteric nodes must have arisen from the gut lumen. Secondly, the presence of bacterial translocation was associated with an increase in septic complications (38% versus 30%). Previous studies have confirmed a significant correlation between bacterial translocation and septic morbidity.12 Thirdly, the commonality of organisms identified from nasogastric aspirates, mesenteric lymph nodes, and septic foci supports the hypothesis. The organisms responsible for postoperative infections in this series were all gut pathogens which have been shown to translocate and furthermore, the commonest, the Enterobacteriaceae, were also responsible for postoperative septic complications in 63% (27/43) of cases. Of those patients in whom bacteria were cultured from mesenteric lymph nodes and who also subsequently developed postoperative sepsis, 45% (5/11) grew at least one similar species type at both sites.

Enteric bacteria and particularly the Enterobacteriacae are the most frequently implicated bacteria in the gut origin of sepsis hypothesis and these organisms predominated in our study at all three sites sampled. These associations may have occurred simply because Enterobacteriacae are commonly found in the gut and are frequent pathogens. This, in our view, is unlikely; the commonality of organisms shown between the three separate culture sites is not what would be anticipated if concentrations within the gut were the major factor in the development of subsequent sepsis. Further, no evidence for candidal translocation was found in this study despite its prevalence in both nasogastric aspirates (54%) and postoperative septic foci (11%). Others have reported that Candida in sufficient numbers can migrate across a normal intestinal mucosal barrier and that translocation occurs after bolus ingestion.25 ,26 The absence of candidal translocation in our series suggests that luminal concentration alone is unlikely to be the only predisposing factor to translocation. Virulence factors and local conditions within the lumen of the intestine may well play an as yet undefined role in the processs of translocation. It must also be recognised that translocation is unlikely to account for all septic morbidity. Our failure to show Candida in mesenteric lymph nodes suggests that candidal infestation may well occur by means other than translocation. It is well established, for example, that aspiration of gastric Candida may explain fungal pneumonias.

In conclusion, we recognise that the associations shown in this descriptive study do not prove causation with respect to the gut origin of sepsis hypothesis. However, absolute proof that intestinally derived bacteria translocate and result in sepsis would necessitate precise phage typing of all gastrointestinal flora on a daily basis with concomitant culture of all subsequent septic foci to show commonality and a temporal relation. The practical and ethical difficulties of establishing such a clinical study are obvious. This study supports the gut origin of sepsis hypothesis and suggests a pathological significance to the phenomenon of bacterial translocation. Taken with other reports we consider that bacterial translocation probably occurs in all individuals but is not clinically significant in the presence of a fully functional immune system. Destruction of translocated bacteria in mesenteric lymph nodes is dependent on the immunological competence of the host and individual bacterial virulence factors. In severely immunocompromised individuals, viable translocated bacteria are propagated to extraintestinal sites as potential foci of sepsis. Bacterial translocation seems to be an important early step in the promotion of sepsis in debilitated postoperative patients. Elucidation of the defence mechanisms by which intestinal microflora are confined within the gut lumen will be a significant advance in the understanding of gut derived infection.