Probiotic Prophylaxis in Predicted Severe Acute Pancreatitis: Commentary from F1000

Jan De Waele; Ingvar Bjarnason; Bruce Bistrian

Disclosures

Faculty of 1000 

Besselink MG, van Santvoort HC, Buskens E, Boermeester MA, van Goor H, Timmerman HM, Nieuwenhuijs VB, Bollen TL, van Ramshorst B, Witteman BJ, Rosman C, Ploeg RJ, Brink MA, Schaapherder AF, Dejong CH, Wahab PJ, van Laarhoven CJ, van der Harst E, van Eijck CH, Cuesta MA, Akkermans LM, Gooszen HG, Dutch Acute Pancreatitis Study Group
Lancet 2008 Feb 23 371(9613):651-9

Changes Clinical Practice: Probiotics should not be given to critically ill patients, especially those with predicted severe acute pancreatitis.

It has been suggested that probiotics could reduce the incidence of infectious complications in patients with severe acute pancreatitis. This well-designed RCT showed an increased mortality in patients who received probiotics as prophylactic therapy to reduce infections, and, hence, probiotics should not be considered in patients with predicted severe acute pancreatitis. Infectious complications are an important source of morbidity and mortality in patients with acute pancreatitis, with infected pancreatic necrosis as the most feared complication. Recently, two RCTs showed no benefit of prophylactic antibiotics, a practice which was widespread based on small, non-controlled studies. As the gastrointestinal (GI) tract is considered to be the source of superinfection in pancreatic necrosis in a setting of increased permeability, manipulation of the GI flora is an attractive target for intervention. To address this issue, Besselink et al. conducted a well-designed prospective study of patients with predicted severe acute pancreatitis (APACHE2 score of eight or higher; Imrie score of three or more; C-reactive protein of 150mg/L or higher), who received a multispecies preparation of probiotics or placebo within 72h after the start of symptoms, combined with early enteral (nasojejenual) nutrition. This was a double-blinded study which enrolled 298 patients; both groups were comparable at baseline. The primary endpoint was any infectious complication, which was not different in the two groups. Mortality, however, was significantly higher in the intervention group, which was solely caused by fatal bowel ischemia in eight patients in the intervention group, whereas none of the patients in the control group developed bowel ischemia. Because of the observed high rate of fatal bowel ischemia, probiotics should not be used in critically ill patients until proven beneficial in large, well-designed clinical studies. Probiotics were associated with increased mortality in this study, and, although no hard data are available, autopsy data in this study suggest that a locally increased metabolism in the proximal jejunum, attributable to probiotics in a setting of already impaired microcirculation, may lead to irreversible damage. Probiotics should not be used in critically ill patients until proven beneficial in large, well-designed clinical studies.

Changes Clinical Practice: Probiotics that contain live bacteria should not be used in patients with acute pancreatitis and only used with great care in patients with a severely compromised small bowel function, characterised by increased intestinal permability.

Probiotic enthusiasts will be surprised to see that probiotics administered to patients with severe acute pancreatitis increased mortality and did not reduce infectious complications. The authors carried out an exceptionally robust double-blind, placebo-controlled trial involving almost 300 patients with predicted severe pancreatitis with a view to reduce 'intestinally' derived systemic infections. Half of the patients received a probiotic via a tube positioned in the jejunum and the other half received placebo. Not only were there no reductions in infections but also there was a significant increase in mortality (16% versus 10%) in the treated group. The cause of mortality in the treatment group (which was not seen in the placebo group) was intestinal 'ischemia'. The authors, therefore, do not recommend probiotic prophylaxis in these patients. For those of us who have been involved in research on the pathogenesis of enteropathies, these findings do not come as a surprise and are almost predictable. Hence, there are over 30 enteropathies that all seem to share a common final pathogenic pathway (Bjarnason et al., Scand J Gastroenterol 2004, 39:807-815). NSAID-induced enteropathy is the prototype for these disorders. NSAIDs cause mucosal ischemia and damage the surface epithelium. Both effects result in increased mucosal permeability. The consequences of this permeability increase is that luminal bacteria gain access to the mucosa and set up an inflammatory reaction. The intensity of the inflammation is dependent on the magnitude of the permeability change and the amount of luminal bacteria. In patients with severe pancreatitis, there is an increase in intestinal permeability, probably caused by ischaemia as a result of reduced blood flow (Ammori, Pancreas 2003, 26:122-129). However, many of the patients in the trial were also alcoholics, were critically ill and/or had other infections. All of these situations are associated with increased intestinal permeability and the effects are most likely additive. The teams then delivered the probiotic to the site of increased intestinal permeability, and it is highly likely that these bacteria gained access to the mucosa and this aggravated the ischemia and caused the intestinal inflammation that led to the death of the patients. In my view, the fundamental misconception in the probiotic field is the concept of 'friendly' or 'good' intestinal bacteria. Yes, some probiotics can displace pathogenic intestinal bacteria, but these 'friendly' bacteria may kill patients if they gain access to the peritoneum or the circulation. Intestinal bacteria are in the gut because we supply them with nutrients and a hospitable environment and their main feast will come when you die. We gain little or nothing from their presence. Indeed germ-free animals do not develop intestinal inflammatory disease and we seem to spend a lot of energy in maintaining an immune system in order for us to live with them.

Changes Clinical Practice: Use of probiotics should be avoided in critically ill patients diagnosed with severe acute pancreatitis, at least directly into the jejunum.

This study raises profound concerns about the use of probiotics in the critically ill, and also elicits concern about feeding boluses of other nutrients that might selectively increase local circulatory demand as well. Early nutritional support of critically ill patients has generally been acknowledged to improve morbidity and often mortality but this generally requires nasojejunal feeding (enteral route). In a large randomized, double blind trial (registration number: ISRCTN38327949) of probiotic prophylaxis in patients with severe acute pancreatitis, a signficant increase in mortality was produced by the administration of probiotics, provided as a mixture of non-pathogenic bacteria, compared to a placebo in conjunction with early nasojejunal feeding in both groups. Although organ failure was more common in the probiotic group and organ failure appeared to underlie the increased mortality rate, bowel ischemia was limited to the probiotic group. Bowel ischemia, which usually led to mortality and was responsible for the major difference in mortality rates, was only seen in the probiotic group.

Faculty of 1000 Medicine Evaluations, Dissents and Author responses for: [Besselink MG et al. Probiotic prophylaxis in predicted severe acute pancreatitis. Lancet 2008 Feb 23 371(9613):651-9]. 2007 Mar 3. http://www.f1000medicine.com/article/id/1102213/evaluation

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