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Prophylactic antibiotics cannot reduce infected pancreatic necrosis and mortality in acute necrotizing pancreatitis: evidence from a meta-analysis of randomized controlled trials |
Bai Y, Gao J, Zou D W, Li Z S |
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CRD summary The review concluded that prophylactic antibiotics could not reduce either infected pancreatic necrosis or mortality in participants with acute necrotising pancreatitis. The review was generally well conducted and the authors' conclusions seem appropriate. Given the limited number of participants in the included studies and some methodological flaws in the review process, the reliability of the conclusions is unclear. Authors' objectives To assess the efficacy of prophylactic antibiotics to prevent infected pancreatic necrosis and reduce mortality in participants with acute necrotising pancreatitis (ANP). Searching MEDLINE, EMBASE, Cochrane Controlled Trials Register, The Cochrane Library and the Science Citation Index (updated to May 2007) were searched to locate relevant studies. Reference lists of retrieved articles and major conference abstracts were also searched. Study selection To be eligible for inclusion in the review, studies needed to be randomised controlled trials (RCTs) that compared the effects of prophylactic antibiotics versus placebo or no treatment on infected pancreatic necrosis and mortality in participants with severe acute pancreatitis with computed tomography (CT) proven necrosis.
In the included studies, antibiotic prophylaxis included intravenous imipenem (in two doses, 0.5 g or 1 g given intravenously eight hourly), cefuroxime, ofloxacin and metronidazole, ciprofloxacin and metronidazole or meropenem. No other details of the characteristics of the participants, the type of control used (no treatment or placebo) and the means of measuring infection were provided.
The authors stated neither how the papers were selected for review nor how many reviewers performed the selection. Assessment of study quality Studies were categorised as having a low risk of bias if they demonstrated adequate generation of allocation sequence, adequate allocation concealment and blinding. Studies with a high risk of bias had one or more of these criteria classified as inadequate or unclear.
Two reviewers independently assessed study quality with disagreements resolved by discussion. Data extraction Data were extracted on occurrence of infected pancreatic necrosis and mortality and were used to calculate a risk ratio (RR) and corresponding 95% confidence interval (CI).
Two authors independently extracted data using a specially developed form, but they did not state how discrepancies were resolved. Methods of synthesis The pooled risk ratios and 95% CIs were calculated using both fixed- and random-effects models in a meta-analysis. Subgroup analyses were specified a priori to explore clinical heterogeneity in terms of single or multi-centre setting, single or double blinding, beta-lactam or quinolone-based antibiotic and risk of bias to identify potential differences in treatment within the included studies. Statistical heterogeneity was assessed with the Χ2 test and the I2 quantity. Publication bias was assessed by examining funnel plots of effect size against sample size. Results of the review Seven RCTs (n=467, range 26 to 100) were included in the review. Five studies were classified as having a high risk of bias and two were classified as having a low risk of bias. Four studies had single blinding, two had double blinding and one study had no blinding. There was no evidence of statistical heterogeneity for either of the two assessed outcomes. Funnel plots were displayed.
There was no evidence that prophylaxis with antibiotics reduced either the rate of infected pancreatic necrosis (RR 0.81, 95% CI: 0.54, 1.22, p=0.32) or mortality (RR 0.7, 95% CI: 0.42, 1.17, p=0.17). In the subgroup analyses, there were no statistically significant differences for any of the multiple comparisons except for single-centered trials (RR 0.3, 95% CI 0.1, 0.95, p=0.04) and single-blinded trials (RR 0.4, 95% CI 0.16, 0.96, p=0.04) that assessed mortality. The results were not significantly altered by use of either a fixed- or random-effects model. Authors' conclusions Prophylactic antibiotics were not associated with a reduction in the rate of infected pancreatic necrosis or mortality in participants with acute necrotising pancreatitis. CRD commentary The review had clearly stated inclusion criteria with respect to study design, participants, treatments and outcomes. The authors searched a variety of sources for relevant studies. It was not clear whether any attempts were made to minimise language and publication biases. Funnel plots were displayed, but the authors did not appear to use any tests to determine whether publication bias was present so this cannot be excluded. Methods were used to minimise bias and reviewer error in the quality assessment of included studies and data extraction, but the process of study selection was unclear. Attempts were made to explore clinical and statistical heterogeneity and the results of this were used to interpret the findings. The statistical analysis methods used in the meta-analysis were appropriate.
The confidence intervals for the summary effect estimates were wide and the small overall number of participants in the overall analyses (and particularly the subgroup analyses) suggested that the review may have been underpowered to identify real effects of antibiotic prophylaxis and determine whether the prophylaxis is useful in particular subgroups of participants. In addition, it was not possible to conclusively rule out the chance that studies could have been missed and errors made in study selection. Most of the included studies had a high risk of bias. The review was generally well conducted and the authors' conclusions reflect the evidence presented, but the reliability of the conclusions is unclear because of the limitations of the included studies. Implications of the review for practice and research Practice: The authors stated that routine prophylactic antibiotics may not be useful for all patients with acute necrotising pancreatitis.
Research: The authors stated that further RCTs should target only individuals with CT-verified pancreatic necrosis. The sample size should be sufficient to detect a significant difference. Large scale, high quality, placebo-controlled double blind trials should also include more details; the infected necrosis and mortality rates in different age and aetiology groups and the timing of initiation of antibiotics should be recorded. Focus in future RCTs should also be placed on participants with a high risk for infected pancreatic necrosis. Bibliographic details Bai Y, Gao J, Zou D W, Li Z S. Prophylactic antibiotics cannot reduce infected pancreatic necrosis and mortality in acute necrotizing pancreatitis: evidence from a meta-analysis of randomized controlled trials. American Journal of Gastroenterology 2008; 103(1): 104-110 Other publications of related interest (1) Villatoro E, Bassi C, Larvin M. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database of Systematic Reviews 2006; (4):CD002941.
(2) Heinrich S, Schafer M, Rousson V, Clavien PA. Evidence-based treatment of acute pancreatitis: a look at established paradigms. Annals of Surgery 2006;243:154-168.
(3) Sharma VK, Howden CW. Prophylactic antibiotic administration reduces sepsis and mortality in acute necrotizing pancreatitis: a meta-analysis. Pancreas 2001;22:28-31.
(4) Golub R, Siddiqi F, Pohl D. Role of antibiotics in acute pancreatitis: a meta-analysis. Journal of Gastrointestinal Surgery 1998;2:496-503.
(5) Mazaki T, Ishii Y, Takayama T. Meta-analysis of prophylactic antibiotic use in acute necrotizing pancreatitis. British Journal of Surgery 2006;93:674-684. Indexing Status Subject indexing assigned by NLM MeSH Anti-Bacterial Agents /therapeutic use; Antibiotic Prophylaxis /methods; Bacterial Infections /complications /prevention & Disease Progression; Humans; Pancreatitis, Acute Necrotizing /complications /mortality /pathology; Randomized Controlled Trials as Topic; Severity of Illness Index; Survival Rate /trends; Treatment Outcome; control AccessionNumber 12008000262 Date bibliographic record published 03/11/2008 Date abstract record published 29/07/2009 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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