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Probiotics: Did we go wrong, and if so, where?
Clinical Nutrition (2008) 27, 173e178
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http://intl.elsevierhealth.com/journals/clnu
INVITED EDITORIAL
Probiotics: Did we go wrong, and if so, where? Introduction There is substantial evidence that the flora of the gut plays an important role in health and disease of the intestine. Important functions include fermentation of non-digestible fiber and subsequent absorption of the products of fermentation, contributing to the preservation of energy and nonenergy components of the food ingested. Some bacterial strains have specific trophic effects on the intestinal mucosa and on its immune function. A balanced flora protects the host against potentially pathogenetic bacteria. The composition of the intestinal microflora varies and is not stable in composition and may have deleterious effects on gut-associated diseases like irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), diverticulitis, colon cancer, pouchitis, etc. The indigenous flora may play a role in the genesis of multiple organ dysfunction syndrome (MODS). Some evidence suggests that modifying the composition of the microflora may have beneficial effects on these diseases. Acute necrotizing pancreatitis is one of the most difficult diseases to treat in surgery. In the Netherlands the disease is caused in more than 80% of cases by gallstone disease or by alcohol abuse and starts as a severe non-infectious inflammatory process in the pancreas. By definition the inflammatory process leads to necrosis of parts of the pancreas and often also of peripancreatic fatty tissue. As long as this necrosis remains sterile MODS does not develop or does not rapidly progress. This allows to follow a ‘‘wait and see’’ approach which has major advantages. First it allows the necrosis to mature and to demarcate so that in case of surgery debridement/removal of the necrotic tissue is more complete and is not accompanied by major bleeding. Secondly, it increases the likelihood that the necrotic tissues can be effectively dealt with by the body itself. When the necrosis gets infected (gangrene), MODS generally develops necessitating surgical removal of the infected necrosis, essential for survival but fraught with significant morbidity and mortality, still ranging between 10 and 30% in the best of hands. Infection of necrosis is thought to arise from bacterial translocation due to an
inflammatory process in the intestine leading to increased permeability of the mucosal barrier. Severe localized inflammatory processes of any origin also induce a systemic inflammatory response, which affects the intestine as well as other organs. Increased permeability constitutes an integral part of this inflammatory process. However, it has also been suggested that in necrotizing pancreatitis bacterial overgrowth in the intestine may contribute to mucosal inflammation and increased translocation of pathogens, in turn leading to infected necrosis. In view of the deleterious effects of infected necrosis, prophylactic antibiotics and selective gut decontamination have been widely used. Unfortunately, randomized clinical trials and meta-analyses have not demonstrated a significant benefit. On the basis of the assumption that bacterial overgrowth with potentially pathogenetic bacterial strains promotes infection of (peri)pancreatic necrosis (see above), probiotics have been hypothesized to have beneficial effects by reduction of small bowel overgrowth, which in turn diminishes mucosal inflammation and permeability and translocation. Thus far, beneficial effects have been demonstrated in elective surgery. Probiotics also appeared to have a beneficial effect in one small study in patients with non-biliary pancreatitis. The studies were underpowered, however, and did not adhere to the intention to treat principle. In critically ill adult and pediatric patients increases in infectious complications were noted in the probiotics groups (see Refs. [1,2]). In view of the facts that the issue is not settled and that mortality of acute necrotizing pancreatitis is still substantial, a large nation wide multicentre study was started in the Netherlands and admirably completed. All academic medical centers and seven major teaching hospitals participated in the study.
Results: PRObiotics in PAncreatitis TRIAl (PROPATRIA) in the Netherlands1,2 Only patients with severe acute pancreatitis defined as APACHE Score 8, Imrie/modified Glasgow score 3,
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174 C-reactive protein >150 mg/L were included. Patients were randomized to receive a total daily dose of 1010 probiotics (Lactobacillus adidophilus, Lactobacillus casei, Lactobacillus salivarius, Lactococcus lactis, Bifidobacterium bifidum, Bifidobacterium lactis, and cornstarch and maltodextins) in two daily dosages. All patients received a fiber containing formula (Nutrison Multifibre, containing 1.5 g/100 ml of soypolysaccharides, Arabic gum, resistant starch, inulin, a-cellulose, oligofructose) continuously up to 125 kJ/kg. Patients (298) with predicted severe acute pancreatitis were randomized to treatment, 153 received probiotics and 145 placebo. Ultimately 152 and 144, respectively, were analyzed. The amount of enteral formula received was not mentioned in the manuscript. The median intake of probiotics or placebo was 100%. The differences in primary composite endpoints (infectious complications: infected necrosis, bacteraemia, pneumonia, urosepsis, infected ascites) between the probiotics and the placebo group did not reach significance. Mortality amounted to 24 (16%) in the group receiving probiotics and 9 (6%) in the group receiving placebo (p Z 0.01). In patients in which necrotizing pancreatitis was diagnosed 19 (41%) of 46 patients in the probiotics group died, and 5 (15%) of 34 in the placebo group (p Z 0.01). In the probiotics group in 9 patients an ischaemic bowel was diagnosed at operation or at autopsy, 8 of which died, whereas no ischemic bowel was noticed in the placebo group (p Z 0.004). The authors mention that these results were unexpected and at variance with smaller studies mentioned earlier, and therefore scrutinized the results and methodology for other explanations than a deleterious effect of probiotics. Randomisation was found to be successful, there were no differences in treatment effects in the subgroup analyses, dosages were similar as in earlier studies, the six probiotic strains were carefully chosen on the basis of their capacity to inhibit growth of gut-derived pathogens and to modulate immune responses in vitro. They were tested in healthy volunteers and in three small clinical studies in patients with low disease severity. No untoward side effects were noted. The authors therefore conclude that probiotics should not be administered routinely to patients with predicted severe acute pancreatitis. They conclude in addition that probiotics can no longer be considered to be harmless adjuncts to enteral nutrition in critically ill patients.
How strong are the data and do we need more studies and a meta-analysis to substantiate the results? In view of the size of the study, the post-study exclusion of confounding factors, the careful selection of bacterial strains3 and the highly significant results, the results should be taken seriously and should influence our views on the use of probiotics in critically ill patients. Many reports in the Lancet and the NEJM, the most frequently quoted newspapers in clinical medicine, are published because they furnish alternative views, results of new treatments, new pathogenetic findings which subsequently are the starting point of studies to support the leading study and subsequently to allow meta-analyses to furnish evidence-based
Invited Editorial answers. The question therefore is whether the PROPATRIA study should be repeated to settle the issue whether probiotics have a beneficial or deleterious effect in the treatment of patients with severe acute pancreatitis or in patients that are critically ill. The answer in my mind is negative, and the reason for it is that what is presently known about the pathophysiology of severe (intestinal) illness is supported by the negative outcome of the study. The question may also be raised whether the differences in outcome should be exclusively ascribed to the patients dying from ischemic bowel. Sixteen patients died in the probiotic group from other causes than an ischemic bowel, compared with 9 patients in the placebo group. This difference roughly corresponds with the higher number of patients developing multiple organ failure in the probiotic group. Although these differences are not significant it cannot be excluded that probiotics have aggravated or induced necrotizing pancreatitis and multiple organ failure, hypothetically via bowel ischemia not leading to necrosis. In theory it cannot be excluded that other probiotic strains might have less deleterious effects. I agree with the authors that at present it is not advisable to take the risk to study the effects of other probiotics in critically ill patients.
Pathophysiology of intestinal function in critical illness Three factors may be responsible for the apparent discrepant effects of probiotics in patients with acute pancreatitis, when compared with their effects in IBS, IBD, pouchitis, cancer, constipation and in experimental animals.4,5 First of all patients were critically ill which has profound effects on the uptake of food. Secondly, critical illness has major influences on colonization of the gut, and thirdly jejunal feeding itself is increasingly associated with acute bowel ischemia. Although it is likely that the pathophysiology of these three elements overlap and integrate they will be discussed separately.
Critical illness Focal inflammatory/infectious processes induce a systemic inflammatory response regardless of their anatomical location. In severe cases this leads to varying degrees of MODS including dysfunction of the gut.6,7 In critical illness the three components determining the successful digestion and absorption of food are compromised. Experimentally motility has been found to be disturbed not only in the stomach but migrating motor complexes are pathologic across the entire intestinal tract in endotoxin treated dogs.8,9 Gastro-intestinal motility is severely disturbed when peritonitis lymph is infused in the jugular vein of rats and mRNA gene expression of TNF-a is increased.10 Isotopic studies in pigs have indirectly shown that secretion of enzymes is compromised in critical illness.11 Similarly absorption is compromised in peritonitis models.12,13 T-cell activation by TNF-a or anti-CD3 antibody has been shown to cause diarrhea and malabsorption of sodium and co-transported or exchanged glucose, amino acids and electrolytes, and to lead to secretion of fluid into the gut lumen in experimental animals.14,15 Increased fluid secretion into the gut lumen is
Invited Editorial not directly mediated by TNF-a but may result from increased smooth muscle tone in the submucosa driving fluid from capillaries with increased permeability through the intercellular tight junctions back into the gut lumen.14 These experimental findings elucidate the findings in patients. The more ill the patient is, the less successful enteral nutrition will be.16 Unfortunately no single accurate predictor exists for gut failure. It is well known that in the presence of systemic inflammatory response syndrome (SIRS) and MODS the capacity of the intestine to extract oxygen and substrate from the already reduced mesenteric blood flow is reduced.17,18 In addition enteral nutrition significantly increases oxygen and substrate demand, which may lead to mesenteric ischemia.19 In clinical practice the clinical findings of distended bowel, sparse high pitched bowel sounds, paradoxical foul smelling diarrhea, or even worse, total constipation in patients with SIRS and MODS should be carefully monitored and should urge the medical and nursing staff to diminish or discontinue enteral nutrition.
The gut microflora in health and disease The numbers of microorganisms in healthy individuals are high in the oral cavity (predominantly anaerobes) and low in the stomach and in the duodenum and jejunum (0e103/ ml or g predominantly aerobes). More distally bacterial counts gradually increase in the small bowel to 102e107 in the ileum and 1010e1012/g or ml in the colon while the number of anaerobes increases from the stomach to the colon. After a meal bacterial counts increase in the stomach, duodenum and proximal jejunum to approximately 105 but after a few hours decrease to their post-absorptive low levels. The composition of this flora varies more from individual to individual than it does in individuals studied over time. Under healthy conditions the normal indigenous or ‘‘autochthonous’’ flora is so far advanced that no immune response is elicited by this flora. Transient colonization by pathogenic strains requires perturbation of the resident flora, e.g. by antibiotics, antacids, stomach resections or influences of severe illness. Even when substantial numbers of bacteria are ingested increases in bacterial counts are relatively short-lived (hours) because the proximal gut contains several effective mechanisms to clear bacteria. Intestinal motility is an important mechanism to limit proliferation of organisms in the small bowel.20 Gastric acid production acts as a defense mechanism against exogenous pathogenic microorganisms as well as suppresses colonization of the proximal small bowel by both the oropharyngeal organisms and the fecal flora. In the presence of hypochlorhydria the concentration of organisms in the stomach and small bowel increases.20,21 Although it is not certain that primary bile acids inhibit bacterial growth in vivo, bacterial hydroxylation of primary to secondary bile acids may cause diarrhea due to the inflammatory effects of secondary bile acids on colonic mucosa. sIgA is produced by liver and proximal intestine and plays an important role in intestinal immunity. The interactions between sIgA and bacteria are complex however, because some bacterial strains produce proteases that inactivate sIgA. Another defense mechanism consists of an extensive immune system in the gut, called gut-associated lymphoid tissue (GALT). It is of interest that Peyer’s patches
175 develop only when germfree animals are exposed to bacteria and are most abundant in the ileum where bacterial counts reach levels just 10e100 times lower than in the colon, but 105e108 higher than in the proximal jejunum. Most, if not all, of these mechanisms are disturbed in critical illness. Motility is decreased leading to severe bowel distension.20 The issue is still not fully settled whether bacterial translocation or severe cytokine induced inflammatory activity in the intestinal wall plays a role in promoting the progression of MODS.22 However, it is a well known surgical finding that acute and complete obstruction of the small bowel may within 24 h lead to bacterial peritonitis due to bacterial translocation without overt macroscopic rupture. This is supported by the finding that only in acute small bowel obstruction bacteria can be cultured from mesenteric lymph nodes in patients significantly more often (40%) than all other patients undergoing surgery in which mesenteric lymph nodes yield on average only in 10% positive cultures.23 The conclusion is that aperistaltic and dilated small bowel is prone to translocate. Almost all severely ill patients that are artificially ventilated develop after a week a diminished gastric acidity even when no antacids, H2 receptor blockers or proton pump inhitors are given.24 The secretion of mucus sIgA and bile acids is diminished in critical illness.25 In clinical practice bile secretion is often diminished leading to intrahepatic cholestasis and diminished secretion of sIgA into the gut lumen. The more ill the patient, the more deficient the mechanisms are that can effectively deal with ingested bacteria, including probiotics. In most disease states where probiotics were not harmful or showed benefit, inflammatory activity was mild, with no or very low accompanying systemic inflammatory activity (IBD, IBS, cancer, pouchitis, etc). In these situations one may assume that defense mechanisms are appropriate to deal with a potential overload of probiotic bacteria, allowing to achieve a beneficial effect more distally in the intestine. The probiotics administered shortly after admission in the PROPATRIA study must have reached far higher counts in the jejunum than normal early after onset of acute pancreatitis. This must have caused mesenteric ischemia in the patients developing a necrotic bowel. One may speculate whether in the other patients receiving probiotics that died from multiple organ failure, mesenteric ischemia, not leading to necrosis, has played a pathogenetic role. I agree with the authors that the exact mechanism cannot be deducted with certainty from the results of the study. Nevertheless it seems unlikely that the, in absolute quantities, low amounts of probiotic bacteria have led to such an increase in oxygen and substrate demand that this precipated ischemia and necrosis. Their second explanation seems more likely, i.e. that the quantity of bacteria given is unusually high for the jejunum and has further aggravated mucosal inflammation, already present due to the systemic inflammatory activity induced by severe acute pancreatitis. This in turn increases the demand of substrate and oxygen in a patient, in which supply is already marginal. It should be emphasized that this severe inflammatory and ischemic process in the intestine has led to infectious complications with ‘‘normal’’ non-probiotic bacteria present in the gut. Many factors influence the virulence of these normally non-pathogenic bacterial strains. Virulence factors
176 may be enhanced by existing stress (inflammation, surgery) but the local effects of high probiotic counts in the proximal intestine on virulence factors in the autochthonous flora are unknown.26,27 On the other hand it has been shown that different probiotic Lactobacillus strains with similar pathogen exclusion properties have distinctive, different effects on intestinal barrier integrity loss following hemorrhagic shock.28 An important finding in the PROPATRIA study is that a major part of the excess mortality in the probiotics group occurred within 14 days and that organ failure in the patients developing bowel necrosis occurred with one exception after 1 or 2 days as if there was an instantaneous effect of the regimen. Both the probiotic and the placebo group received prebiotics. The role of prebiotics is uncertain. The fact that in the placebo group, only receiving prebiotics, no bowel necrosis was diagnosed and that mortality was low (15% in the group with necrotizing pancreatitis) suggests that mortality in patients using prebiotics is low. The results do not allow concluding that prebiotics are beneficial. At present we can only conclude that a combination of pro- and prebiotics yield deleterious results whereas it is unclear what would have happened if probiotics would have been given alone. There is reason for some theoretical and ‘‘collateral’’ concern with regard to the use of symbiotics (combinations of pro- and probiotics) in critical illness. Not only is a bacterial load given to a patient with low colonization resistance but also a culture medium allowing bacteria to proliferate, to produce gas, etc. Probiotics have been given with and without prebiotics (inulin) to patients with IBS and beneficial probiotic effects were noted in both groups, but the group receiving inulin in addition to probiotics suffered significantly more of bloating, flatulence, bowel cramps and abdominal distension.29 Such symptoms are quite common also in healthy people or individuals overeating fiber and in travelers ingesting prophylactic prebiotics.30 These largely mechanical problems of gas formation and bowel distension may also occur in ill patients in which peristalsis is diminished and bowel distension is a prominent feature. The ultimate proof that probiotics all by themselves cause bowel necrosis would be furnished in a study in which one arm receives exclusively probiotics and a non-fiber containing formula, and the other arm placebo and the formula. Support for such a study comes from observations that the probiotic effect does not require the presence of large amounts of prebiotics .31 Nevertheless at present there is too much and too little knowledge to embark upon such a study.
Jejunal feeding Acute intestinal necrosis in the presence of patent vasculature to the gastro-intestinal tract (non-occlusive mesenteric ischaemia; NOMI) has been described since more than two millennia (Galen, 160 AD) and has been related to bacterial overgrowth, achlorhydria, malnutrition, old age, alcoholism, critical illness and several other debilitating conditions. Bacterial strains cultured in these patients are largely similar as the strains cultured in the PROPATRIA trial. These cases are rare and evolution is often dramatic, which promotes recollection of these cases and most gastro-
Invited Editorial intestinal surgeons will remember one or two cases in their career. Necrosis of the small bowel in association with severe acute pancreatitis is rare, and is not mentioned in original articles or textbooks with the exception of the reference listed in the Lancet article.32 These patients were treated in a tertiary referral hospital in Japan, and all patients with NOMI were referred from other hospitals so that the number and percentage mentioned in their population are not representative for the prevalence of NOMI in severe acute pancreatitis. The patients did not receive jejunal feeding, but the authors did not remember how and with what they were actually fed (personal communication). In recent years an increasing number of reports has been published of one or more cases, in which patients receiving jejunal feeding develop acute intestinal necrosis generally close to the exit of the jejunal tube, but sometimes affecting the whole bowel.33e35 The incidence of bowel necrosis varies from 0.14 to 3.5% in patients with jejunal feeding and mortality approximates 60%.36 Patients surviving are either operated very quickly after the first signs of abdominal distension, hypotension and MODS occur. Another group has no full thickness ischemia, and may survive when nutritional support is immediately discontinued and appropriate antibiotics given. Some of these patients have ‘‘pneumatosis intestinalis’’, i.e. gas bubbles in the wall of the intestine or even in the portal vein visible on CT scan or on plain X-ray films of the abdomen.37 In most of these reports no signs of occlusive vascular disease were present or detected and it is speculated that bacterial overgrowth and intestinal wall ischemia may play a role. Most reported patients were critically ill but also cases have been reported in which patients electively operated for malignancies of the proximal gut developed intestinal necrosis. Individual cases sometimes are very instructive. In one patient the infusion of water caused necrosis.38 In another patient undergoing a cystectomy with formation of an ileal conduit (Bricker’s procedure) the complete bowel became necrotic with the exception of the ileal conduit. This suggests that intestinal necrosis results from a local effect of the nutritional regimen on the small bowel itself and that this specifically occurs in patients that are critically ill or undergo major surgery. The fact that this specifically occurs when nutrition is administered in the small bowel may be explained by the fact that the normal predigestion of food in the oral cavity, stomach and duodenum has not taken place because the proximal part of the gastro-intestinal tract is bypassed, including the acidic environment of the stomach. It is likely that the compromised small bowel has even less adaptive ability than normal. It cannot adequately create an isoosmotic partially digested nutritional brew and the energy required to do this (active ion-pumping) may not be met by the already compromised circulation due to surgery or illness. Probiotics in the quantities given far exceed the counts that are reached in less ill patients that take these bacterial strains orally. In relatively healthy patients by the time probiotics will reach the jejunum their counts may be estimated to range between 103 and 105/g or ml. The probiotic boluses, given in the study will achieve locally far higher counts, despite being small in total
Invited Editorial quantity. This may in conjunction with a severely diminished colonization resistance lead to a necrotizing inflammation and subsequently permeation and pathogenicity of normal gut flora. Assuming that the observation that jejunal infusion of water, causing necrosis, is valid, it appears that the pathogenesis of necrosis is multifactorial. A common denominator is a stressful insult (osmotic stress in the case of water) imposed upon an already compromised intestine which leads to further deterioration of the integrity of the bowel wall, and to progressing infection and MODS.
Conclusion In view of the high quality of the Lancet study we must conclude that jejunal feeding of probiotics in conjunction with a fiber containing formula is very likely to have deleterious effects on intestinal perfusion, leading to aggravation of MODS and necrosis of particularly the proximal small bowel. When only fiber containing formula is administered no bowel necrosis was noted. It cannot be concluded with certainty that bowel ischemia would also have occurred when exclusively probiotics would have been administered without prebiotics. The deleterious effects of probiotics were found in patients with acute severe pancreatitis, whereas volunteers or patients that are only mildly ill, do tolerate probiotics well, although in combination with prebiotics flatulence may become severe. The study was performed in pancreatitis patients, but it is likely that similar complications might have occurred in patients that are critically ill for other reasons. In the past two decades bowel necrosis has been linked to jejunal feeding. Jejunal feeding, bypassing the normal predigestive function of the proximal gut and the normal barrier functions of stomach and duodenum is very likely to have aggravated the deleterious effects of the administration of probiotic bacteria. Another contributing factor is the fact that in severe illness the normal defense mechanisms of the gut are decreased, leading to a severely diminished colonization resistance. In view of these considerations at present probiotics should not be used in critically ill patients. The growing list of reports of acute bowel necrosis in jejunal feeding should alert the medical community that jejunal feeding is not a harmless procedure. Great care should be taken to monitor critically ill patients and patients that have undergone major surgery, very carefully, and to discontinue enteral nutrition as soon as clinical signs of intolerance appear (bowel distention, sparse high pitched or absent bowel sounds, foul smelling diarrhea or constipation). At present the pendulum is swinging back and anecdotal studies report a high success rate of gastric feeding in patients with severe acute pancreatitis.39 The dogma that small bowel function can be completely normal whereas gastric emptying and colonic transit are severely disturbed, may be challenged. Maybe we should take gastric retention more seriously and not try to be smarter than the ailing organism. It is reassuring, however, that in the PROPATRIA study in the group, receiving a fiber containing formula and placebo, no bowel ischemia was detected and a very acceptable mortality was achieved. It may be advisable
177 to go back to the laboratory to study interactions between a combination of prebiotics and probiotics and indigenous flora, between probiotics alone and indigenous flora in the proximal intestine, as well as to study the molecular and cell biological effects of individual probiotic strains on intestinal integrity before embarking on new clinical studies.
References 1. Besselink MG, Timmerman HM, Buskens E, et al. Probiotic prophylaxis in patients with predicted severe acute pancreatitis (PROPATRIA): design and rationale of a doubleblind, placebo-controlled randomised multicenter trial [ISRCTN38327949]. BMC Surg 2004;4:12. 2. Besselink MGH, Van-Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371(9613):651e9. 3. Timmerman HM, Niers LE, Ridwan BU, et al. Design of a multispecies probiotic mixture to prevent infectious complications in critically ill patients. Clin Nutr 2007;26(4):450e9. 4. Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003;361(9356):512e9. 5. Park J, Floch MH. Prebiotics, probiotics, and dietary fiber in gastrointestinal disease. Gastroenterol Clin North Am 2007; 36(1):47e63. 6. Fink MP. Intestinal epithelial hyperpermeability: update on the pathogenesis of gut mucosal barrier dysfunction in critical illness. Curr Opin Crit Care 2003;9(2):143e51. 7. Fink MP, Delude RL. Epithelial barrier dysfunction: a unifying theme to explain the pathogenesis of multiple organ dysfunction at the cellular level. Crit Care Clin 2005;21(2):177e96. 8. Cullen JJ, Caropreso DK, Ephgrave KS. Effect of endotoxin on canine gastrointestinal motility and transit. J Surg Res 1995; 58(1):90e5. 9. Cullen JJ, Caropreso DK, Hemann LL, et al. Pathophysiology of adynamic ileus. Dig Dis Sci 1997;42(4):731e7. 10. Glatzle J, Leutenegger CM, Mueller MH, et al. Mesenteric lymph collected during peritonitis or sepsis potently inhibits gastric motility in rats. J Gastrointest Surg 2004;8(6):645e52. 11. Bruins MJ, Soeters PB, Deutz NE. Endotoxemia affects organ protein metabolism differently during prolonged feeding in pigs. J Nutr 2000;130(12):3003e13. 12. Sodeyama M, Gardiner KR, Regan MC, et al. Sepsis impairs gut amino acid absorption. Am J Surg 1993;165(1):150e4. 13. Gardiner KR, Gardiner RE, Barbul A. Reduced intestinal absorption of arginine during sepsis. Crit Care Med 1995;23(7): 1227e32. 14. Field M. T cell activation alters intestinal structure and function. J Clin Invest; 2006:2580e2. 15. Musch MW, Clarke LL, Mamah D, et al. T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Naþ/Kþ-ATPase. J Clin Invest; 2002:1739e47. 16. Montejo JC. Enteral nutrition-related gastrointestinal complications in critically ill patients: a multicenter study. The nutritional and metabolic working group of the spanish society of intensive care medicine and coronary units. Crit Care Med 1999;27(8):1447e53. 17. WGd Jones, Minei JP, Barber AE, et al. Splanchnic vasoconstriction and bacterial translocation after thermal injury. Am J Physiol 1991;261(4 Pt 2):H1190e6. 18. Kolkman JJ, Mensink PB. Non-occlusive mesenteric ischaemia: a common disorder in gastroenterology and intensive care. Best Pract Res Clin Gastroenterol 2003;17(3):457e73.
178 19. Rokyta Jr R, Matejovic M, Krouzecky A, et al. Enteral nutrition and hepatosplanchnic region in critically ill patients e friends or foes? Physiol Res 2003;52(1):31e7. 20. Husebye E, Skar V, Hoverstad T, et al. Abnormal intestinal motor patterns explain enteric colonization with gram-negative bacilli in late radiation enteropathy. Gastroenterology 1995; 109(4):1078e89. 21. Lovat LB. Age related changes in gut physiology and nutritional status. Gut 1996;38(3):306e9. 22. Soeters PB, Luyer MD, Greve JW, et al. The significance of bowel permeability. Curr Opin Clin Nutr Metab Care 2007; 10(5):632e8. 23. Sedman PC, Macfie J, Sagar P, et al. The prevalence of gut translocation in humans. Gastroenterology 1994;107(3):643e9. 24. Bonten MJ, Gaillard CA, van der Geest S, et al. The role of intragastric acidity and stress ulcus prophylaxis on colonization and infection in mechanically ventilated ICU patients. A stratified, randomized, double-blind study of sucralfate versus antacids. Am J Respir Crit Care Med 1995;152(6 Pt 1):1825e34. 25. Alverdy JC, Aoys E. The effect of dexamethasone and endotoxin administration on biliary IgA and bacterial adherence. J Surg Res 1992;53(5):450e4. 26. Alverdy J, Holbrook C, Rocha F, et al. Gut-derived sepsis occurs when the right pathogen with the right virulence genes meets the right host: evidence for in vivo virulence expression in Pseudomonas aeruginosa. Ann Surg 2000;232(4):480e9. 27. Alverdy JC, Laughlin RS, Wu L. Influence of the critically ill state on hostepathogen interactions within the intestine: gut-derived sepsis redefined. Crit Care Med 2003;31(2):598e607. 28. Luyer MD, Buurman WA, Hadfoune M, et al. Strain-specific effects of probiotics on gut barrier integrity following hemorrhagic shock. Infect Immun 2005;73(6):3686e92. 29. Sairanen U, Piirainen L, Grasten S, et al. The effect of probiotic fermented milk and inulin on the functions and microecology of the intestine. J Dairy Res 2007;74(3):367e73. 30. Cummings JH, Macfarlane GT, Englyst HN. Prebiotic digestion and fermentation. Am J Clin Nutr; 2001:415Se20S.
Invited Editorial 31. Roberfroid M. Prebiotics: the concept revisited. J Nutr; 2007: 830Se7S. 32. Hirota M, Inoue K, Kimura Y, et al. Non-occlusive mesenteric ischemia and its associated intestinal gangrene in acute pancreatitis. Pancreatology 2003;3(4):316e22. 33. Gaddy MC, Max MH, Schwab CW, Kauder D. Small bowel ischemia: a consequence of feeding jejunostomy? South Med J 1986; 79(2):180e2. 34. Schunn CD, Daly JM. Small bowel necrosis associated with postoperative jejunal tube feeding. J Am Coll Surg 1995;180(4): 410e6. 35. Marvin RG, McKinley BA, McQuiggan M, Cocanour CS, Moore FA. Nonocclusive bowel necrosis occurring in critically ill trauma patients receiving enteral nutrition manifests no reliable clinical signs for early detection. Am J Surg 2000; 179(1):7e12. 36. Melis M, Fichera A, Ferguson MK. Bowel necrosis associated with early jejunal tube feeding: a complication of postoperative enteral nutrition. Arch Surg; 2006:701e4. 37. Smith CD, Sarr MG. Clinically significant pneumatosis intestinalis with postoperative enteral feedings by needle catheter jejunostomy: an unusual complication. J Parenter Enteral Nutr 1991;15(3):328e31. 38. Schloerb PR, Wood JG, Casillan AJ, Tawfik O, Udobi K. Bowel necrosis caused by water in jejunal feeding. J Parenter Enteral Nutr 2004;28(1):27e9. 39. Eatock FC, Brombacher GD, Steven A, Imrie CW, McKay CJ, Carter R. Nasogastric feeding in severe acute pancreatitis may be practical and safe. Int J Pancreatol 2000;28(1):23e9.
Peter B. Soetersa Department of Surgery, Academic Hospital Maastricht, The Netherlands E-mail address: [email protected]
28 February 2008
a
Present address: Putstraat 25, 3620 Lanaken, Belgium.
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INVITED EDITORIAL
Probiotics: Did we go wrong, and if so, where? Introduction There is substantial evidence that the flora of the gut plays an important role in health and disease of the intestine. Important functions include fermentation of non-digestible fiber and subsequent absorption of the products of fermentation, contributing to the preservation of energy and nonenergy components of the food ingested. Some bacterial strains have specific trophic effects on the intestinal mucosa and on its immune function. A balanced flora protects the host against potentially pathogenetic bacteria. The composition of the intestinal microflora varies and is not stable in composition and may have deleterious effects on gut-associated diseases like irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), diverticulitis, colon cancer, pouchitis, etc. The indigenous flora may play a role in the genesis of multiple organ dysfunction syndrome (MODS). Some evidence suggests that modifying the composition of the microflora may have beneficial effects on these diseases. Acute necrotizing pancreatitis is one of the most difficult diseases to treat in surgery. In the Netherlands the disease is caused in more than 80% of cases by gallstone disease or by alcohol abuse and starts as a severe non-infectious inflammatory process in the pancreas. By definition the inflammatory process leads to necrosis of parts of the pancreas and often also of peripancreatic fatty tissue. As long as this necrosis remains sterile MODS does not develop or does not rapidly progress. This allows to follow a ‘‘wait and see’’ approach which has major advantages. First it allows the necrosis to mature and to demarcate so that in case of surgery debridement/removal of the necrotic tissue is more complete and is not accompanied by major bleeding. Secondly, it increases the likelihood that the necrotic tissues can be effectively dealt with by the body itself. When the necrosis gets infected (gangrene), MODS generally develops necessitating surgical removal of the infected necrosis, essential for survival but fraught with significant morbidity and mortality, still ranging between 10 and 30% in the best of hands. Infection of necrosis is thought to arise from bacterial translocation due to an
inflammatory process in the intestine leading to increased permeability of the mucosal barrier. Severe localized inflammatory processes of any origin also induce a systemic inflammatory response, which affects the intestine as well as other organs. Increased permeability constitutes an integral part of this inflammatory process. However, it has also been suggested that in necrotizing pancreatitis bacterial overgrowth in the intestine may contribute to mucosal inflammation and increased translocation of pathogens, in turn leading to infected necrosis. In view of the deleterious effects of infected necrosis, prophylactic antibiotics and selective gut decontamination have been widely used. Unfortunately, randomized clinical trials and meta-analyses have not demonstrated a significant benefit. On the basis of the assumption that bacterial overgrowth with potentially pathogenetic bacterial strains promotes infection of (peri)pancreatic necrosis (see above), probiotics have been hypothesized to have beneficial effects by reduction of small bowel overgrowth, which in turn diminishes mucosal inflammation and permeability and translocation. Thus far, beneficial effects have been demonstrated in elective surgery. Probiotics also appeared to have a beneficial effect in one small study in patients with non-biliary pancreatitis. The studies were underpowered, however, and did not adhere to the intention to treat principle. In critically ill adult and pediatric patients increases in infectious complications were noted in the probiotics groups (see Refs. [1,2]). In view of the facts that the issue is not settled and that mortality of acute necrotizing pancreatitis is still substantial, a large nation wide multicentre study was started in the Netherlands and admirably completed. All academic medical centers and seven major teaching hospitals participated in the study.
Results: PRObiotics in PAncreatitis TRIAl (PROPATRIA) in the Netherlands1,2 Only patients with severe acute pancreatitis defined as APACHE Score 8, Imrie/modified Glasgow score 3,
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174 C-reactive protein >150 mg/L were included. Patients were randomized to receive a total daily dose of 1010 probiotics (Lactobacillus adidophilus, Lactobacillus casei, Lactobacillus salivarius, Lactococcus lactis, Bifidobacterium bifidum, Bifidobacterium lactis, and cornstarch and maltodextins) in two daily dosages. All patients received a fiber containing formula (Nutrison Multifibre, containing 1.5 g/100 ml of soypolysaccharides, Arabic gum, resistant starch, inulin, a-cellulose, oligofructose) continuously up to 125 kJ/kg. Patients (298) with predicted severe acute pancreatitis were randomized to treatment, 153 received probiotics and 145 placebo. Ultimately 152 and 144, respectively, were analyzed. The amount of enteral formula received was not mentioned in the manuscript. The median intake of probiotics or placebo was 100%. The differences in primary composite endpoints (infectious complications: infected necrosis, bacteraemia, pneumonia, urosepsis, infected ascites) between the probiotics and the placebo group did not reach significance. Mortality amounted to 24 (16%) in the group receiving probiotics and 9 (6%) in the group receiving placebo (p Z 0.01). In patients in which necrotizing pancreatitis was diagnosed 19 (41%) of 46 patients in the probiotics group died, and 5 (15%) of 34 in the placebo group (p Z 0.01). In the probiotics group in 9 patients an ischaemic bowel was diagnosed at operation or at autopsy, 8 of which died, whereas no ischemic bowel was noticed in the placebo group (p Z 0.004). The authors mention that these results were unexpected and at variance with smaller studies mentioned earlier, and therefore scrutinized the results and methodology for other explanations than a deleterious effect of probiotics. Randomisation was found to be successful, there were no differences in treatment effects in the subgroup analyses, dosages were similar as in earlier studies, the six probiotic strains were carefully chosen on the basis of their capacity to inhibit growth of gut-derived pathogens and to modulate immune responses in vitro. They were tested in healthy volunteers and in three small clinical studies in patients with low disease severity. No untoward side effects were noted. The authors therefore conclude that probiotics should not be administered routinely to patients with predicted severe acute pancreatitis. They conclude in addition that probiotics can no longer be considered to be harmless adjuncts to enteral nutrition in critically ill patients.
How strong are the data and do we need more studies and a meta-analysis to substantiate the results? In view of the size of the study, the post-study exclusion of confounding factors, the careful selection of bacterial strains3 and the highly significant results, the results should be taken seriously and should influence our views on the use of probiotics in critically ill patients. Many reports in the Lancet and the NEJM, the most frequently quoted newspapers in clinical medicine, are published because they furnish alternative views, results of new treatments, new pathogenetic findings which subsequently are the starting point of studies to support the leading study and subsequently to allow meta-analyses to furnish evidence-based
Invited Editorial answers. The question therefore is whether the PROPATRIA study should be repeated to settle the issue whether probiotics have a beneficial or deleterious effect in the treatment of patients with severe acute pancreatitis or in patients that are critically ill. The answer in my mind is negative, and the reason for it is that what is presently known about the pathophysiology of severe (intestinal) illness is supported by the negative outcome of the study. The question may also be raised whether the differences in outcome should be exclusively ascribed to the patients dying from ischemic bowel. Sixteen patients died in the probiotic group from other causes than an ischemic bowel, compared with 9 patients in the placebo group. This difference roughly corresponds with the higher number of patients developing multiple organ failure in the probiotic group. Although these differences are not significant it cannot be excluded that probiotics have aggravated or induced necrotizing pancreatitis and multiple organ failure, hypothetically via bowel ischemia not leading to necrosis. In theory it cannot be excluded that other probiotic strains might have less deleterious effects. I agree with the authors that at present it is not advisable to take the risk to study the effects of other probiotics in critically ill patients.
Pathophysiology of intestinal function in critical illness Three factors may be responsible for the apparent discrepant effects of probiotics in patients with acute pancreatitis, when compared with their effects in IBS, IBD, pouchitis, cancer, constipation and in experimental animals.4,5 First of all patients were critically ill which has profound effects on the uptake of food. Secondly, critical illness has major influences on colonization of the gut, and thirdly jejunal feeding itself is increasingly associated with acute bowel ischemia. Although it is likely that the pathophysiology of these three elements overlap and integrate they will be discussed separately.
Critical illness Focal inflammatory/infectious processes induce a systemic inflammatory response regardless of their anatomical location. In severe cases this leads to varying degrees of MODS including dysfunction of the gut.6,7 In critical illness the three components determining the successful digestion and absorption of food are compromised. Experimentally motility has been found to be disturbed not only in the stomach but migrating motor complexes are pathologic across the entire intestinal tract in endotoxin treated dogs.8,9 Gastro-intestinal motility is severely disturbed when peritonitis lymph is infused in the jugular vein of rats and mRNA gene expression of TNF-a is increased.10 Isotopic studies in pigs have indirectly shown that secretion of enzymes is compromised in critical illness.11 Similarly absorption is compromised in peritonitis models.12,13 T-cell activation by TNF-a or anti-CD3 antibody has been shown to cause diarrhea and malabsorption of sodium and co-transported or exchanged glucose, amino acids and electrolytes, and to lead to secretion of fluid into the gut lumen in experimental animals.14,15 Increased fluid secretion into the gut lumen is
Invited Editorial not directly mediated by TNF-a but may result from increased smooth muscle tone in the submucosa driving fluid from capillaries with increased permeability through the intercellular tight junctions back into the gut lumen.14 These experimental findings elucidate the findings in patients. The more ill the patient is, the less successful enteral nutrition will be.16 Unfortunately no single accurate predictor exists for gut failure. It is well known that in the presence of systemic inflammatory response syndrome (SIRS) and MODS the capacity of the intestine to extract oxygen and substrate from the already reduced mesenteric blood flow is reduced.17,18 In addition enteral nutrition significantly increases oxygen and substrate demand, which may lead to mesenteric ischemia.19 In clinical practice the clinical findings of distended bowel, sparse high pitched bowel sounds, paradoxical foul smelling diarrhea, or even worse, total constipation in patients with SIRS and MODS should be carefully monitored and should urge the medical and nursing staff to diminish or discontinue enteral nutrition.
The gut microflora in health and disease The numbers of microorganisms in healthy individuals are high in the oral cavity (predominantly anaerobes) and low in the stomach and in the duodenum and jejunum (0e103/ ml or g predominantly aerobes). More distally bacterial counts gradually increase in the small bowel to 102e107 in the ileum and 1010e1012/g or ml in the colon while the number of anaerobes increases from the stomach to the colon. After a meal bacterial counts increase in the stomach, duodenum and proximal jejunum to approximately 105 but after a few hours decrease to their post-absorptive low levels. The composition of this flora varies more from individual to individual than it does in individuals studied over time. Under healthy conditions the normal indigenous or ‘‘autochthonous’’ flora is so far advanced that no immune response is elicited by this flora. Transient colonization by pathogenic strains requires perturbation of the resident flora, e.g. by antibiotics, antacids, stomach resections or influences of severe illness. Even when substantial numbers of bacteria are ingested increases in bacterial counts are relatively short-lived (hours) because the proximal gut contains several effective mechanisms to clear bacteria. Intestinal motility is an important mechanism to limit proliferation of organisms in the small bowel.20 Gastric acid production acts as a defense mechanism against exogenous pathogenic microorganisms as well as suppresses colonization of the proximal small bowel by both the oropharyngeal organisms and the fecal flora. In the presence of hypochlorhydria the concentration of organisms in the stomach and small bowel increases.20,21 Although it is not certain that primary bile acids inhibit bacterial growth in vivo, bacterial hydroxylation of primary to secondary bile acids may cause diarrhea due to the inflammatory effects of secondary bile acids on colonic mucosa. sIgA is produced by liver and proximal intestine and plays an important role in intestinal immunity. The interactions between sIgA and bacteria are complex however, because some bacterial strains produce proteases that inactivate sIgA. Another defense mechanism consists of an extensive immune system in the gut, called gut-associated lymphoid tissue (GALT). It is of interest that Peyer’s patches
175 develop only when germfree animals are exposed to bacteria and are most abundant in the ileum where bacterial counts reach levels just 10e100 times lower than in the colon, but 105e108 higher than in the proximal jejunum. Most, if not all, of these mechanisms are disturbed in critical illness. Motility is decreased leading to severe bowel distension.20 The issue is still not fully settled whether bacterial translocation or severe cytokine induced inflammatory activity in the intestinal wall plays a role in promoting the progression of MODS.22 However, it is a well known surgical finding that acute and complete obstruction of the small bowel may within 24 h lead to bacterial peritonitis due to bacterial translocation without overt macroscopic rupture. This is supported by the finding that only in acute small bowel obstruction bacteria can be cultured from mesenteric lymph nodes in patients significantly more often (40%) than all other patients undergoing surgery in which mesenteric lymph nodes yield on average only in 10% positive cultures.23 The conclusion is that aperistaltic and dilated small bowel is prone to translocate. Almost all severely ill patients that are artificially ventilated develop after a week a diminished gastric acidity even when no antacids, H2 receptor blockers or proton pump inhitors are given.24 The secretion of mucus sIgA and bile acids is diminished in critical illness.25 In clinical practice bile secretion is often diminished leading to intrahepatic cholestasis and diminished secretion of sIgA into the gut lumen. The more ill the patient, the more deficient the mechanisms are that can effectively deal with ingested bacteria, including probiotics. In most disease states where probiotics were not harmful or showed benefit, inflammatory activity was mild, with no or very low accompanying systemic inflammatory activity (IBD, IBS, cancer, pouchitis, etc). In these situations one may assume that defense mechanisms are appropriate to deal with a potential overload of probiotic bacteria, allowing to achieve a beneficial effect more distally in the intestine. The probiotics administered shortly after admission in the PROPATRIA study must have reached far higher counts in the jejunum than normal early after onset of acute pancreatitis. This must have caused mesenteric ischemia in the patients developing a necrotic bowel. One may speculate whether in the other patients receiving probiotics that died from multiple organ failure, mesenteric ischemia, not leading to necrosis, has played a pathogenetic role. I agree with the authors that the exact mechanism cannot be deducted with certainty from the results of the study. Nevertheless it seems unlikely that the, in absolute quantities, low amounts of probiotic bacteria have led to such an increase in oxygen and substrate demand that this precipated ischemia and necrosis. Their second explanation seems more likely, i.e. that the quantity of bacteria given is unusually high for the jejunum and has further aggravated mucosal inflammation, already present due to the systemic inflammatory activity induced by severe acute pancreatitis. This in turn increases the demand of substrate and oxygen in a patient, in which supply is already marginal. It should be emphasized that this severe inflammatory and ischemic process in the intestine has led to infectious complications with ‘‘normal’’ non-probiotic bacteria present in the gut. Many factors influence the virulence of these normally non-pathogenic bacterial strains. Virulence factors
176 may be enhanced by existing stress (inflammation, surgery) but the local effects of high probiotic counts in the proximal intestine on virulence factors in the autochthonous flora are unknown.26,27 On the other hand it has been shown that different probiotic Lactobacillus strains with similar pathogen exclusion properties have distinctive, different effects on intestinal barrier integrity loss following hemorrhagic shock.28 An important finding in the PROPATRIA study is that a major part of the excess mortality in the probiotics group occurred within 14 days and that organ failure in the patients developing bowel necrosis occurred with one exception after 1 or 2 days as if there was an instantaneous effect of the regimen. Both the probiotic and the placebo group received prebiotics. The role of prebiotics is uncertain. The fact that in the placebo group, only receiving prebiotics, no bowel necrosis was diagnosed and that mortality was low (15% in the group with necrotizing pancreatitis) suggests that mortality in patients using prebiotics is low. The results do not allow concluding that prebiotics are beneficial. At present we can only conclude that a combination of pro- and prebiotics yield deleterious results whereas it is unclear what would have happened if probiotics would have been given alone. There is reason for some theoretical and ‘‘collateral’’ concern with regard to the use of symbiotics (combinations of pro- and probiotics) in critical illness. Not only is a bacterial load given to a patient with low colonization resistance but also a culture medium allowing bacteria to proliferate, to produce gas, etc. Probiotics have been given with and without prebiotics (inulin) to patients with IBS and beneficial probiotic effects were noted in both groups, but the group receiving inulin in addition to probiotics suffered significantly more of bloating, flatulence, bowel cramps and abdominal distension.29 Such symptoms are quite common also in healthy people or individuals overeating fiber and in travelers ingesting prophylactic prebiotics.30 These largely mechanical problems of gas formation and bowel distension may also occur in ill patients in which peristalsis is diminished and bowel distension is a prominent feature. The ultimate proof that probiotics all by themselves cause bowel necrosis would be furnished in a study in which one arm receives exclusively probiotics and a non-fiber containing formula, and the other arm placebo and the formula. Support for such a study comes from observations that the probiotic effect does not require the presence of large amounts of prebiotics .31 Nevertheless at present there is too much and too little knowledge to embark upon such a study.
Jejunal feeding Acute intestinal necrosis in the presence of patent vasculature to the gastro-intestinal tract (non-occlusive mesenteric ischaemia; NOMI) has been described since more than two millennia (Galen, 160 AD) and has been related to bacterial overgrowth, achlorhydria, malnutrition, old age, alcoholism, critical illness and several other debilitating conditions. Bacterial strains cultured in these patients are largely similar as the strains cultured in the PROPATRIA trial. These cases are rare and evolution is often dramatic, which promotes recollection of these cases and most gastro-
Invited Editorial intestinal surgeons will remember one or two cases in their career. Necrosis of the small bowel in association with severe acute pancreatitis is rare, and is not mentioned in original articles or textbooks with the exception of the reference listed in the Lancet article.32 These patients were treated in a tertiary referral hospital in Japan, and all patients with NOMI were referred from other hospitals so that the number and percentage mentioned in their population are not representative for the prevalence of NOMI in severe acute pancreatitis. The patients did not receive jejunal feeding, but the authors did not remember how and with what they were actually fed (personal communication). In recent years an increasing number of reports has been published of one or more cases, in which patients receiving jejunal feeding develop acute intestinal necrosis generally close to the exit of the jejunal tube, but sometimes affecting the whole bowel.33e35 The incidence of bowel necrosis varies from 0.14 to 3.5% in patients with jejunal feeding and mortality approximates 60%.36 Patients surviving are either operated very quickly after the first signs of abdominal distension, hypotension and MODS occur. Another group has no full thickness ischemia, and may survive when nutritional support is immediately discontinued and appropriate antibiotics given. Some of these patients have ‘‘pneumatosis intestinalis’’, i.e. gas bubbles in the wall of the intestine or even in the portal vein visible on CT scan or on plain X-ray films of the abdomen.37 In most of these reports no signs of occlusive vascular disease were present or detected and it is speculated that bacterial overgrowth and intestinal wall ischemia may play a role. Most reported patients were critically ill but also cases have been reported in which patients electively operated for malignancies of the proximal gut developed intestinal necrosis. Individual cases sometimes are very instructive. In one patient the infusion of water caused necrosis.38 In another patient undergoing a cystectomy with formation of an ileal conduit (Bricker’s procedure) the complete bowel became necrotic with the exception of the ileal conduit. This suggests that intestinal necrosis results from a local effect of the nutritional regimen on the small bowel itself and that this specifically occurs in patients that are critically ill or undergo major surgery. The fact that this specifically occurs when nutrition is administered in the small bowel may be explained by the fact that the normal predigestion of food in the oral cavity, stomach and duodenum has not taken place because the proximal part of the gastro-intestinal tract is bypassed, including the acidic environment of the stomach. It is likely that the compromised small bowel has even less adaptive ability than normal. It cannot adequately create an isoosmotic partially digested nutritional brew and the energy required to do this (active ion-pumping) may not be met by the already compromised circulation due to surgery or illness. Probiotics in the quantities given far exceed the counts that are reached in less ill patients that take these bacterial strains orally. In relatively healthy patients by the time probiotics will reach the jejunum their counts may be estimated to range between 103 and 105/g or ml. The probiotic boluses, given in the study will achieve locally far higher counts, despite being small in total
Invited Editorial quantity. This may in conjunction with a severely diminished colonization resistance lead to a necrotizing inflammation and subsequently permeation and pathogenicity of normal gut flora. Assuming that the observation that jejunal infusion of water, causing necrosis, is valid, it appears that the pathogenesis of necrosis is multifactorial. A common denominator is a stressful insult (osmotic stress in the case of water) imposed upon an already compromised intestine which leads to further deterioration of the integrity of the bowel wall, and to progressing infection and MODS.
Conclusion In view of the high quality of the Lancet study we must conclude that jejunal feeding of probiotics in conjunction with a fiber containing formula is very likely to have deleterious effects on intestinal perfusion, leading to aggravation of MODS and necrosis of particularly the proximal small bowel. When only fiber containing formula is administered no bowel necrosis was noted. It cannot be concluded with certainty that bowel ischemia would also have occurred when exclusively probiotics would have been administered without prebiotics. The deleterious effects of probiotics were found in patients with acute severe pancreatitis, whereas volunteers or patients that are only mildly ill, do tolerate probiotics well, although in combination with prebiotics flatulence may become severe. The study was performed in pancreatitis patients, but it is likely that similar complications might have occurred in patients that are critically ill for other reasons. In the past two decades bowel necrosis has been linked to jejunal feeding. Jejunal feeding, bypassing the normal predigestive function of the proximal gut and the normal barrier functions of stomach and duodenum is very likely to have aggravated the deleterious effects of the administration of probiotic bacteria. Another contributing factor is the fact that in severe illness the normal defense mechanisms of the gut are decreased, leading to a severely diminished colonization resistance. In view of these considerations at present probiotics should not be used in critically ill patients. The growing list of reports of acute bowel necrosis in jejunal feeding should alert the medical community that jejunal feeding is not a harmless procedure. Great care should be taken to monitor critically ill patients and patients that have undergone major surgery, very carefully, and to discontinue enteral nutrition as soon as clinical signs of intolerance appear (bowel distention, sparse high pitched or absent bowel sounds, foul smelling diarrhea or constipation). At present the pendulum is swinging back and anecdotal studies report a high success rate of gastric feeding in patients with severe acute pancreatitis.39 The dogma that small bowel function can be completely normal whereas gastric emptying and colonic transit are severely disturbed, may be challenged. Maybe we should take gastric retention more seriously and not try to be smarter than the ailing organism. It is reassuring, however, that in the PROPATRIA study in the group, receiving a fiber containing formula and placebo, no bowel ischemia was detected and a very acceptable mortality was achieved. It may be advisable
177 to go back to the laboratory to study interactions between a combination of prebiotics and probiotics and indigenous flora, between probiotics alone and indigenous flora in the proximal intestine, as well as to study the molecular and cell biological effects of individual probiotic strains on intestinal integrity before embarking on new clinical studies.
References 1. Besselink MG, Timmerman HM, Buskens E, et al. Probiotic prophylaxis in patients with predicted severe acute pancreatitis (PROPATRIA): design and rationale of a doubleblind, placebo-controlled randomised multicenter trial [ISRCTN38327949]. BMC Surg 2004;4:12. 2. Besselink MGH, Van-Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371(9613):651e9. 3. Timmerman HM, Niers LE, Ridwan BU, et al. Design of a multispecies probiotic mixture to prevent infectious complications in critically ill patients. Clin Nutr 2007;26(4):450e9. 4. Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003;361(9356):512e9. 5. Park J, Floch MH. Prebiotics, probiotics, and dietary fiber in gastrointestinal disease. Gastroenterol Clin North Am 2007; 36(1):47e63. 6. Fink MP. Intestinal epithelial hyperpermeability: update on the pathogenesis of gut mucosal barrier dysfunction in critical illness. Curr Opin Crit Care 2003;9(2):143e51. 7. Fink MP, Delude RL. Epithelial barrier dysfunction: a unifying theme to explain the pathogenesis of multiple organ dysfunction at the cellular level. Crit Care Clin 2005;21(2):177e96. 8. Cullen JJ, Caropreso DK, Ephgrave KS. Effect of endotoxin on canine gastrointestinal motility and transit. J Surg Res 1995; 58(1):90e5. 9. Cullen JJ, Caropreso DK, Hemann LL, et al. Pathophysiology of adynamic ileus. Dig Dis Sci 1997;42(4):731e7. 10. Glatzle J, Leutenegger CM, Mueller MH, et al. Mesenteric lymph collected during peritonitis or sepsis potently inhibits gastric motility in rats. J Gastrointest Surg 2004;8(6):645e52. 11. Bruins MJ, Soeters PB, Deutz NE. Endotoxemia affects organ protein metabolism differently during prolonged feeding in pigs. J Nutr 2000;130(12):3003e13. 12. Sodeyama M, Gardiner KR, Regan MC, et al. Sepsis impairs gut amino acid absorption. Am J Surg 1993;165(1):150e4. 13. Gardiner KR, Gardiner RE, Barbul A. Reduced intestinal absorption of arginine during sepsis. Crit Care Med 1995;23(7): 1227e32. 14. Field M. T cell activation alters intestinal structure and function. J Clin Invest; 2006:2580e2. 15. Musch MW, Clarke LL, Mamah D, et al. T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Naþ/Kþ-ATPase. J Clin Invest; 2002:1739e47. 16. Montejo JC. Enteral nutrition-related gastrointestinal complications in critically ill patients: a multicenter study. The nutritional and metabolic working group of the spanish society of intensive care medicine and coronary units. Crit Care Med 1999;27(8):1447e53. 17. WGd Jones, Minei JP, Barber AE, et al. Splanchnic vasoconstriction and bacterial translocation after thermal injury. Am J Physiol 1991;261(4 Pt 2):H1190e6. 18. Kolkman JJ, Mensink PB. Non-occlusive mesenteric ischaemia: a common disorder in gastroenterology and intensive care. Best Pract Res Clin Gastroenterol 2003;17(3):457e73.
178 19. Rokyta Jr R, Matejovic M, Krouzecky A, et al. Enteral nutrition and hepatosplanchnic region in critically ill patients e friends or foes? Physiol Res 2003;52(1):31e7. 20. Husebye E, Skar V, Hoverstad T, et al. Abnormal intestinal motor patterns explain enteric colonization with gram-negative bacilli in late radiation enteropathy. Gastroenterology 1995; 109(4):1078e89. 21. Lovat LB. Age related changes in gut physiology and nutritional status. Gut 1996;38(3):306e9. 22. Soeters PB, Luyer MD, Greve JW, et al. The significance of bowel permeability. Curr Opin Clin Nutr Metab Care 2007; 10(5):632e8. 23. Sedman PC, Macfie J, Sagar P, et al. The prevalence of gut translocation in humans. Gastroenterology 1994;107(3):643e9. 24. Bonten MJ, Gaillard CA, van der Geest S, et al. The role of intragastric acidity and stress ulcus prophylaxis on colonization and infection in mechanically ventilated ICU patients. A stratified, randomized, double-blind study of sucralfate versus antacids. Am J Respir Crit Care Med 1995;152(6 Pt 1):1825e34. 25. Alverdy JC, Aoys E. The effect of dexamethasone and endotoxin administration on biliary IgA and bacterial adherence. J Surg Res 1992;53(5):450e4. 26. Alverdy J, Holbrook C, Rocha F, et al. Gut-derived sepsis occurs when the right pathogen with the right virulence genes meets the right host: evidence for in vivo virulence expression in Pseudomonas aeruginosa. Ann Surg 2000;232(4):480e9. 27. Alverdy JC, Laughlin RS, Wu L. Influence of the critically ill state on hostepathogen interactions within the intestine: gut-derived sepsis redefined. Crit Care Med 2003;31(2):598e607. 28. Luyer MD, Buurman WA, Hadfoune M, et al. Strain-specific effects of probiotics on gut barrier integrity following hemorrhagic shock. Infect Immun 2005;73(6):3686e92. 29. Sairanen U, Piirainen L, Grasten S, et al. The effect of probiotic fermented milk and inulin on the functions and microecology of the intestine. J Dairy Res 2007;74(3):367e73. 30. Cummings JH, Macfarlane GT, Englyst HN. Prebiotic digestion and fermentation. Am J Clin Nutr; 2001:415Se20S.
Invited Editorial 31. Roberfroid M. Prebiotics: the concept revisited. J Nutr; 2007: 830Se7S. 32. Hirota M, Inoue K, Kimura Y, et al. Non-occlusive mesenteric ischemia and its associated intestinal gangrene in acute pancreatitis. Pancreatology 2003;3(4):316e22. 33. Gaddy MC, Max MH, Schwab CW, Kauder D. Small bowel ischemia: a consequence of feeding jejunostomy? South Med J 1986; 79(2):180e2. 34. Schunn CD, Daly JM. Small bowel necrosis associated with postoperative jejunal tube feeding. J Am Coll Surg 1995;180(4): 410e6. 35. Marvin RG, McKinley BA, McQuiggan M, Cocanour CS, Moore FA. Nonocclusive bowel necrosis occurring in critically ill trauma patients receiving enteral nutrition manifests no reliable clinical signs for early detection. Am J Surg 2000; 179(1):7e12. 36. Melis M, Fichera A, Ferguson MK. Bowel necrosis associated with early jejunal tube feeding: a complication of postoperative enteral nutrition. Arch Surg; 2006:701e4. 37. Smith CD, Sarr MG. Clinically significant pneumatosis intestinalis with postoperative enteral feedings by needle catheter jejunostomy: an unusual complication. J Parenter Enteral Nutr 1991;15(3):328e31. 38. Schloerb PR, Wood JG, Casillan AJ, Tawfik O, Udobi K. Bowel necrosis caused by water in jejunal feeding. J Parenter Enteral Nutr 2004;28(1):27e9. 39. Eatock FC, Brombacher GD, Steven A, Imrie CW, McKay CJ, Carter R. Nasogastric feeding in severe acute pancreatitis may be practical and safe. Int J Pancreatol 2000;28(1):23e9.
Peter B. Soetersa Department of Surgery, Academic Hospital Maastricht, The Netherlands E-mail address: [email protected]
28 February 2008
a
Present address: Putstraat 25, 3620 Lanaken, Belgium.