Elsevier

The Lancet

Volume 371, Issue 9613, 23–29 February 2008, Pages 651-659
The Lancet

Articles
Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(08)60207-XGet rights and content

Summary

Background

Infectious complications and associated mortality are a major concern in acute pancreatitis. Enteral administration of probiotics could prevent infectious complications, but convincing evidence is scarce. Our aim was to assess the effects of probiotic prophylaxis in patients with predicted severe acute pancreatitis.

Methods

In this multicentre randomised, double-blind, placebo-controlled trial, 298 patients with predicted severe acute pancreatitis (Acute Physiology and Chronic Health Evaluation [APACHE II] score ≥8, Imrie score ≥3, or C-reactive protein >150 mg/L) were randomly assigned within 72 h of onset of symptoms to receive a multispecies probiotic preparation (n=153) or placebo (n=145), administered enterally twice daily for 28 days. The primary endpoint was the composite of infectious complications—ie, infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis, or infected ascites—during admission and 90-day follow-up. Analyses were by intention to treat. This study is registered, number ISRCTN38327949.

Findings

One person in each group was excluded from analyses because of incorrect diagnoses of pancreatitis; thus, 152 individuals in the probiotics group and 144 in the placebo group were analysed. Groups were much the same at baseline in terms of patients' characteristics and disease severity. Infectious complications occurred in 46 (30%) patients in the probiotics group and 41 (28%) of those in the placebo group (relative risk 1·06, 95% CI 0·75–1·51). 24 (16%) patients in the probiotics group died, compared with nine (6%) in the placebo group (relative risk 2·53, 95% CI 1·22–5·25). Nine patients in the probiotics group developed bowel ischaemia (eight with fatal outcome), compared with none in the placebo group (p=0·004).

Interpretation

In patients with predicted severe acute pancreatitis, probiotic prophylaxis with this combination of probiotic strains did not reduce the risk of infectious complications and was associated with an increased risk of mortality. Probiotic prophylaxis should therefore not be administered in this category of patients.

Introduction

The incidence of acute pancreatitis in Europe and the USA is increasing by about 5% per year, mainly owing to an increase in biliary pancreatitis.1, 2, 3 About a fifth of patients will develop necrotising pancreatitis, which is associated with a 10–30% mortality rate, mostly attributed to infectious complications and infection of (peri)pancreatic necrotic tissue in particular.1 These infections are thought to be the sequelae of a cascade of events starting with small-bowel bacterial overgrowth, mucosal barrier failure, and a proinflammatory response leading to bacterial translocation of intestinal bacteria.4, 5, 6 Systemic antibiotic prophylaxis has long been studied as a measure to prevent secondary infection in acute pancreatitis.1 However, two double-blind, placebo-controlled trials7, 8 and two meta-analyses9, 10 have failed to show a beneficial effect, and many clinicians have abandoned this strategy. In the two antibiotic trials, the incidence of extrapancreatic infections (eg, bacteraemia, pneumonia) and pancreatic infection remained high.7, 8 Consequently, there is a clear need for other strategies to prevent infectious complications in patients with acute pancreatitis.

Probiotics, as an adjunct to enteral nutrition, have raised high expectations and are currently gaining worldwide popularity for their presumed health-promoting effects.11, 12 Certain strains of probiotic bacteria might prevent infectious complications by reducing small-bowel bacterial overgrowth, restoring gastrointestinal barrier function, and modulating the immune system.11, 12 A reduction of infectious complications has been reported in several clinical studies with probiotics in patients undergoing elective abdominal operations13, 14 and in patients with acute pancreatitis.15 However, because of their small size and methodological quality, these studies do not justify global implementation of probiotics as a preventive measure in acute pancreatitis. Accordingly, we embarked on a nationwide multicentre randomised, double-blind, placebo-controlled trial—the PRObiotics in PAncreatitis TRIAl (PROPATRIA)—to assess the effects of probiotic prophylaxis in patients with predicted severe acute pancreatitis.

Section snippets

Patients

The design and rationale of the study have been described in detail elsewhere.16 Adult patients admitted with a first episode of acute pancreatitis were enrolled in eight university medical centres and seven major teaching hospitals in the Netherlands. Acute pancreatitis was defined as abdominal pain in combination with serum amylase or lipase concentrations that were raised to at least three times the institutional upper limit of normal. Patients were not enrolled in the study if any of the

Results

732 consecutive patients with a first episode of acute pancreatitis were registered prospectively between March, 2004, and March, 2007 (figure 1). 298 patients were predicted to have a severe disease course (135 patients with APACHE II score ≥8, 204 with Imrie score ≥3, 252 with C-reactive protein >150 mg/L), and were randomly assigned treatment with probiotics or with placebo (figure 1). Two patients—one in each group—were excluded from the final analysis because of an incorrect diagnosis of

Discussion

This randomised, double-blind, placebo-controlled trial in patients with predicted severe acute pancreatitis showed no beneficial effect of probiotic prophylaxis on the occurrence of infectious complications. However, mortality in the probiotics group was about twice as high as in the placebo group. Thus, this combination of probiotics should not be administered routinely in patients with predicted severe acute pancreatitis, and such preparations can no longer be considered to be harmless

References (40)

  • M Hirota et al.

    Non-occlusive mesenteric ischemia and its associated intestinal gangrene in acute pancreatitis

    Pancreatology

    (2003)
  • A Nazli et al.

    Epithelia under metabolic stress perceive commensal bacteria as a threat

    Am J Pathol

    (2004)
  • J Omata et al.

    Intraluminal glutamine administration during ischemia worsens survival after gut ischemia-reperfusion

    J Surg Res

    (2007)
  • Anon

    UK guidelines for the management of acute pancreatitis

    Gut

    (2005)
  • CF Frey et al.

    The incidence and case-fatality rates of acute biliary, alcoholic, and idiopathic pancreatitis in California, 1994–2001

    Pancreas

    (2006)
  • D Yadav et al.

    Trends in the epidemiology of the first attack of acute pancreatitis: a systematic review

    Pancreas

    (2006)
  • EA Deitch

    The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure

    Arch Surg

    (1990)
  • PA Van Leeuwen et al.

    Clinical significance of translocation

    Gut

    (1994)
  • EP Dellinger et al.

    Early antibiotic treatment for severe acute necrotizing pancreatitis: a randomized, double-blind, placebo-controlled study

    Ann Surg

    (2007)
  • T Mazaki et al.

    Meta-analysis of prophylactic antibiotic use in acute necrotizing pancreatitis

    Br J Surg

    (2006)
  • Cited by (0)

    View full text