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

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The Lancet summary of the unexpected deaths reported last month as a result of this trial.

http://www.thelancet.com/journals/lancet/article/PIIS014067360860207X/abstract?isEOP=true

The Lancet Early Online Publication, 14 Febuary 2008

The Lancet DOI:10.1016/S0140-6736(08)60207-X

Articles

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

Marc GH Besselink MD a, Hjalmar C van Santvoort MD a, Buskens MD b c, Marja A Boermeester MD e, Harry van Goor MD f, Harro M Timmerman PhD a, B Nieuwenhuijs MD d, L Bollen MD g, Bert van Ramshorst MD h, Ben JM Witteman MD i, Camiel Rosman MD j, Prof Rutger J Ploeg MD d, Menno A Brink MD k, FM Schaapherder MD l, Cornelis HC Dejong MD m, J Wahab MD n, Cees JHM van Laarhoven MD o, Erwin van der Harst MD p, Casper HJ van Eijck MD q, Prof A Cuesta MD r, Prof Louis MA Akkermans PhD a and Prof Hein G Gooszen MD a , for the Dutch Acute Pancreatitis Study Group

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.

Affiliationsa. Department of Surgery, University Medical Center Utrecht, Utrecht, Netherlandsb. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlandsc. Department of Epidemiology, University Medical Center Groningen, Groningen, Netherlandsd. Department of Surgery, University Medical Center Groningen, Groningen, Netherlandse. Department of Surgery, Academic Medical Center, Amsterdam, Netherlandsf. Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlandsg. Department of Radiology, St Antonius Hospital, Nieuwegein, Netherlandsh. Department of Surgery, St Antonius Hospital, Nieuwegein, Netherlandsi. Department of Gastroenterology, Gelderse Vallei Hospital, Ede, Netherlandsj. Department of Surgery, Canisius Wilhelmina Hospital, Nijmegen, Netherlandsk. Department of Gastroenterology, Meander Medical Center, Amersfoort, Netherlandsl. Department of Surgery, Leiden University Medical Center, Leiden, Netherlandsm. Department of Surgery and NUTRIM, University Hospital Maastricht, Maastricht, Netherlandsn. Department of Gastroenterology, Rijnstate Hospital, Arnhem, Netherlandso. Department of Surgery, St Elisabeth Hospital, Tilburg, Netherlandsp. Department of Surgery, Medical Center Rijnmond Zuid, Rotterdam, Netherlandsq. Department of Surgery, Erasmus Medical Center, Rotterdam, Netherlandsr. Department of Surgery, Vrije Universiteit Medical Center, Amsterdam, Netherlands

Correspondence to: Prof Hein G Gooszen, University Medical Center Utrecht, PO Box 85500, HP G04.228, 3508 GA Utrecht, Netherlands