John K. Marshall

Consensus Recommendations for Managing Patients with Nonvariceal Upper Gastrointestinal Bleeding

Upper gastrointestinal (GI) bleeding represents a substantial clinical and economic burden. It has a prevalence of approximately 170 cases per 100 000 adults per year (1), at an estimated total cost of

Systematic Review of the Risk of Enteric Infection in Patients Taking Acid Suppression

750 million in U.S. dollars (2). Peptic ulcer disease accounts for 50% to 70% of cases of acute nonvariceal upper GI bleeding (3, 4). Despite recent advances in therapy, mortality rates have remained essentially unchanged at 6% to 8% (1, 2, 5). This could be explained by the fact that patients are older and have more concurrent illnesses; it may also be due to underuse of endoscopic hemostatic techniques. The Canadian Registry in Upper Gastrointestinal Bleeding and Endoscopy (RUGBE) initiative and international data have demonstrated wide variations in the utilization and timing of different diagnostic and therapeutic technologies, as well as disparate management approaches (4-10). In this context, it is surprising that, except for the recent British Society of Gastroenterology guidelines (9), the last widely disseminated consensus conference and publication of practice guidelines occurred more than 10 years ago (11, 12). Since publication of the British Society of Gastroenterology guidelines, new data have become available and are strengthened by a series of evidence-based systematic reviews and meta-analyses performed for this consensus (13, 14). The current guidelines are a consensus paper with multisociety representation. Methods The recommendation statements were developed according to generally accepted standards (15, 16). A 7-step approach addressing most of 37 pertinent criteria of validity was followed (16-20). The process of guideline development is described in the Figure. Figure. The adopted process of guideline development . Determination of Need for Guidelines The need for clinical practice guidelines on the management of patients with nonvariceal upper GI bleeding was identified by an initial review of the existing literature, current recommendations, and the timing of previously published guidelines. Recommendations are directed primarily to the management of nonvariceal bleeding largely due to peptic ulcers. Membership of the Consensus Group An organizing committee selected a multidisciplinary group of 25 voting participants for their expertise in the management of patients with acute nonvariceal upper GI bleeding, evidence-based medicine, and continuing medical education. The group included Canadian and international gastroenterologists, endoscopists, surgeons, family physicians, emergency medicine physicians, pharmacologists, epidemiologists (with methodologic and health economic expertise), and a hospital pharmacist. The attendees represented 11 national societies (Appendix). A representative from the Canadian Association of General Surgeons reviewed the consensus guidelines a posteriori. Nonvoting observers included representatives from government (Health Canada), the pharmaceutical industry, and distributors and manufacturers of endoscopic equipment (Appendix). Determination of Clinically Relevant Issues The issues were determined according to perceived clinical importance, likelihood of being resolved with the existing knowledge base, applicability to current practice, and perceived need for change (16). The RUGBE data were critical to this process (4). The conference organizer and a small working group generated a list of topics and circulated it electronically in advance (21, 22). For each topic, a statement was proposed to the consensus conference participants for discussion, revision, and voting. Nature and Extent of Background Preparation Literature review methods for relevant articles included MEDLINE searches and manual searches of bibliographies of key articles published in English between 1966 and June 2002. Search terms included upper GI bleeding, non-variceal, guidelines, meta-analysis, naso-gastric tube, risk stratification, re-bleeding, mortality, surgery, endoscopy, second-look, clot, stigmata, injection, thermal coaptive, laser, hemostatic clips, proton pump inhibitor, histamine-receptor antagonist, somatostatin, and octreotide. We referred to past reviews, meta-analyses, and published consensus conferences to summarize data up to 1992. New systematic reviews were conducted on data from the past 10 years on the prevalence and natural history of nonvariceal GI bleeding, risk stratification, and various management strategies. Economic considerations were recognized, but the country-specific nature of most cost data limited the review. Data were formally reviewed, including previous consensus opinions (for recommendations 1, 2, 3, and 18), narrative reviews (for recommendations 4, 11, 12, 13, 14, and 19), systematic reviews (for recommendations 5.1, 5.2, 6, and 20), and meta-analyses (for recommendations 7, 8, 9, 10, 15, 16, and 17). Data available only in abstract form were not considered, with the exception of results from 2 meta-analyses by Bardou and colleagues from McGill University (13, 14) and the RUGBE initiative (4), which had been submitted for publication at the time of writing of this manuscript. In addition, for recommendations 7 and 10, data from pivotal abstracts were discussed in detail and were published within 3 months following the conference (23, 24). Consequently, a postconference Delphi process was carried out and results from this final vote were included. More than 875 articles were initially reviewed, and the Delphi process identified 20 issues for discussion. A series of original meta-analyses, including 71 articles and nearly 9000 patients, were performed (13, 14). The key results of specific meta-analyses follow individual statements when appropriate, and full methods and results are available in separate publications (13, 14). Delphi Consensus Process Each statement was graded to indicate the level of evidence available and the strength of the recommendation by using the classification system of the Canadian Task Force on the Periodic Health Examination (Table 1) (25). This scheme was developed to assess therapeutic literature, not literature addressing prognosis (25). Table 1. Categorization of Evidence, Classification of Recommendations, and Voting Schema General Organization A 2-day consensus conference was held in June 2002 under the auspices of the Canadian Association of Gastroenterology. The conference was conducted according to generally accepted standards for the development of clinical practice guidelines (15, 16). At the consensus conference, data were presented and the statements and the grades attributed to evidence were discussed, modified if necessary, and voted on by each participant according to the recognized criteria shown in Table 1 (26). The Canadian Association of Gastroenterology, which administered all aspects of the meeting, secured multipartner funding from industry sponsors. Additional funds were obtained through a peer-review grant received by the Canadian Institutes of Health Research and an internal award from the Research Institute of the McGill University Health Centre. Statements of conflicts of interest were obtained from all voting participants, and additional ethical information was collected (27). Preparation Process and Format of the Report A working group drafted the manuscript, which was then reviewed by all voting conference participants and the nonvoting chair, who approved the final draft. A brief narrative summary regarding the pediatric patient was prepared and can be accessed at www.cag-acg.org/cag_at_glance/positions.htm. An algorithm specifically designed for use in Canada is also under development. Role of the Funding Sources The funding sources had no role in the design, conduct, and reporting of the study or in the decision to submit the results for publication. Recommendation Statements A summary of all of the recommendations is provided in Table 2. Table 2. Summary of Consensus Recommendations for the Management of Patients with Nonvariceal Upper Gastrointestinal Bleeding Initial Management Recommendation 1: Hospitals should develop institution-specific protocols for multidisciplinary management, which should include access to an endoscopist with training in endoscopic hemostasis. Recommendation: C (vote: a, 100%); Evidence: III Previous consensus groups have recommended a multidisciplinary approach with early involvement of a gastroenterologist and surgeon (9, 11, 12, 28). Hospitals with endoscopy services should have a multidisciplinary team in place with a prespecified chain of notification. Not all institutions have immediate access to these specialists, and not all patients require urgent endoscopy; thus, institution-specific protocols should be developed and updated. Endoscopy privileges should be reserved for practitioners who are properly trained according to established credentialing recommendations (29, 30). Recommendation 2: Support staff trained to assist in endoscopy should be available for urgent endoscopy. Recommendation: C (vote: a, 92%; b, 8%); Evidence: III Support staff, including appropriately trained endoscopy assistants, should be available to assist with urgent endoscopies. Any patient identified as high risk for rebleeding ideally should be admitted to a monitored setting for at least the first 24 hours (9). If intensive care beds are unavailable, wards with more intensive monitoring than standard units can be considered. Recommendation 3: Immediate evaluation and appropriate resuscitation are critical to proper management. Recommendation: C (vote: a, 96%; b, 4%); Evidence: III Patients with acute bleeding should be evaluated immediately on presentation. Resuscitation, including stabilization of blood pressure and restoration of intravascular volume (9, 11, 12, 28), should precede further diagnostic and therapeutic measures. Recommendation 4: In selected patients, the placement of a nasogastric tube can be considered because the findings may have prognostic value. Recomme

Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial

CONTEXT:Proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) have become the mainstay of therapy in acid-related upper gastrointestinal disorders. There have been concerns raised about the possible association of PPIs with enteric infections.OBJECTIVE: We conducted a systematic review to evaluate any association between acid suppression and enteric infection. We also assessed differences between types of enteric infections and the type of acid suppression.DATA SOURCES:Electronic searches of MEDLINE (1966–2005), EMBASE (1988–2005), and CINAHL (1982–2005) were undertaken using a combination of subject headings and text words related to PPI therapy, H2RAs, and enteric infections.STUDY SELECTION:All observational studies were eligible, including cross-sectional, case control, and cohort studies that evaluated risk of enteric infection associated with antisecretory therapy. Eligibility assessment was made by two independent researchers.DATA EXTRACTION:Information on study design, patient population, type of acid suppression, type of infection, and outcomes was collected. The odds ratio (OR) of taking acid suppression therapy in cases and controls was calculated and results were synthesized using a random effects model (DerSimonian and Laird, Stats direct version 2.4.4).DATA SYNTHESIS:A total of 12 papers evaluating 2,948 patients with Clostridium difficile were included in the review. There was an increased risk of taking antisecretory therapy in those infected with C. difficile (pooled OR 1.94, 95% CI 1.37–2.75). There was significant heterogeneity between the studies (P = 0.0006) that was not explained by planned subgroup analysis. The association was greater for PPI use (OR 1.96, 95% CI 1.28–3.00) compared with H2RA use (OR 1.40, 95% CI 0.85–2.29). A total of six studies evaluated Salmonella, Campylobacter, and other enteric infections in 11,280 patients. There was an increased risk of taking acid suppression in those with enteric infections (OR 2.55, 95% CI 1.53–4.26). There was significant heterogeneity between the studies (P < 0.0001) that was not explained by subgroup analysis. The association was greater for PPI use (OR 3.33, 95% CI 1.84–6.02) compared with H2RA use (OR 2.03, 95% CI 1.05–3.92).CONCLUSION: There is an association between acid suppression and an increased risk of enteric infection. Further prospective studies on patients taking long-term acid suppression are needed to establish whether this association is causal.

Systematic review and meta-analysis: The incidence and prognosis of post-infectious irritable bowel syndrome.

BACKGROUND & AIMS Ulcerative colitis (UC) is difficult to treat, and standard therapy does not always induce remission. Fecal microbiota transplantation (FMT) is an alternative approach that induced remission in small series of patients with active UC. We investigated its safety and efficacy in a placebo-controlled randomized trial. METHODS We performed a parallel study of patients with active UC without infectious diarrhea. Participants were examined by flexible sigmoidoscopy when the study began and then were randomly assigned to groups that received FMT (50 mL, via enema, from healthy anonymous donors; n = 38) or placebo (50 mL water enema; n = 37) once weekly for 6 weeks. Patients, clinicians, and investigators were blinded to the groups. The primary outcome was remission of UC, defined as a Mayo score ≤2 with an endoscopic Mayo score of 0, at week 7. Patients provided stool samples when the study began and during each week of FMT for microbiome analysis. The trial was stopped early for futility by the Data Monitoring and Safety Committee, but all patients already enrolled in the trial were allowed to complete the study. RESULTS Seventy patients completed the trial (3 dropped out from the placebo group and 2 from the FMT group). Nine patients who received FMT (24%) and 2 who received placebo (5%) were in remission at 7 weeks (a statistically significant difference in risk of 17%; 95% confidence interval, 2%-33%). There was no significant difference in adverse events between groups. Seven of the 9 patients in remission after FMT received fecal material from a single donor. Three of the 4 patients with UC ≤1 year entered remission, compared with 6 of 34 of those with UC >1 year (P = .04, Fishers exact test). Stool from patients receiving FMT had greater microbial diversity, compared with baseline, than that of patients given the placebo (P = .02, Mann-Whitney U test). CONCLUSIONS FMT induces remission in a significantly greater percentage of patients with active UC than placebo, with no difference in adverse events. Fecal donor and time of UC appear to affect outcomes. ClinicalTrials.gov Number: NCT01545908.

Antibiotic Therapy in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Background  Individual studies suggest that post‐infectious irritable bowel syndrome is common, but symptoms gradually improve.

Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario

The etiology of inflammatory bowel disease (IBD) is unknown but may relate to an unidentified bacterial pathogen or an immunological reaction to gut microbiota. Antibiotics have therefore been proposed as a therapy for Crohns disease (CD) and ulcerative colitis (UC) to induce remission in active disease to prevent relapse. Current data are conflicting and we therefore conducted a systematic review of randomized controlled trials (RCTs) evaluating antibiotics in IBD. Only parallel group RCTs were considered eligible. Studies with adult patients receiving any dose of therapy for at least 7 days and up to 16 weeks for active disease, or at least 6 months of follow-up for preventing relapse in quiescent disease were analyzed. We included any antibiotics alone or in combination using predefined definitions of remission and relapse. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat methodology. The data were summarized using relative risk (RR) and pooled using a random effects model. For active CD, there were 10 RCTs involving 1,160 patients. There was a statistically significant effect of antibiotics being superior to placebo (RR of active CD not in remission=0.85; 95% confidence interval (CI)=0.73–0.99, P=0.03). There was moderate heterogeneity between results (I2=48%) and a diverse number of antibiotics were tested (anti-tuberculosis therapy, macrolides, fluroquinolones, 5-nitroimidazoles, and rifaximin) either alone or in combination. Rifamycin derivatives either alone or in combination with other antibiotics appeared to have a significant effect at inducing remission in active CD. In perianal CD fistula there were three trials evaluating 123 patients using either ciprofloxacin or metronidazole. There was a statistically significant effect in reducing fistula drainage (RR=0.8; 95% CI=0.66–0.98) with no heterogeneity (I2=0%) and an number needed to treat 5 (95% CI=3–20). For quiescent CD, there were 3 RCTs involving 186 patients treated with different antibiotics combinations (all including antimycobacterials) vs. placebo. There was a statistically significant effect in favor of antibiotics vs. placebo (RR of relapse=0.62; 95% CI=0.46–0.84), with no heterogeneity (I2=0%). In active UC, there were 9 RCTs with 662 patients and there was a statistically significant benefit for antibiotics inducing remission (RR of UC not in remission=0.64; 95% CI=0.43–0.96). There was moderate heterogeneity (I2=69%) and antibiotics used were all different single or combination drugs. Antibiotic therapy may induce remission in active CD and UC, although the diverse number of antibiotics tested means the data are difficult to interpret. This systematic review is a mandate for further trials of antibiotic therapy in IBD.

Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults - Update 2004

Background : Post‐infectious irritable bowel syndrome is a common clinical phenomenon of uncertain aetiology.

Genetic Risk Factors for Post-Infectious Irritable Bowel Syndrome Following a Waterborne Outbreak of Gastroenteritis

BACKGROUND Gastroesophageal reflux disease (GERD) is the most prevalent acid-related disorder in Canada and is associated with significant impairment of health-related quality of life. Since the last Canadian Consensus Conference in 1996, GERD management has evolved substantially. OBJECTIVE To develop up-to-date evidence-based recommendations relevant to the needs of Canadian health care providers for the management of the esophageal manifestations of GERD. CONSENSUS PROCESS A multidisciplinary group of 23 voting participants developed recommendation statements using a Delphi approach; after presentation of relevant data at the meeting, the quality of the evidence, strength of recommendation and level of consensus were graded by participants according to accepted principles. OUTCOMES GERD applies to individuals who reflux gastric contents into the esophagus causing symptoms sufficient to reduce quality of life, injury or both; endoscopy-negative reflux disease applies to individuals who have GERD and a normal endoscopy. Uninvestigated heartburn-dominant dyspepsia - characterised by heartburn or acid regurgitation - includes erosive esophagitis or endoscopy-negative reflux disease, and may be treated empirically as GERD without further investigation provided there are no alarm features. Lifestyle modifications are ineffective for frequent or severe GERD symptoms; over-the-counter antacids or histamine H2-receptor antagonists are effective for some patients with mild or infrequent GERD symptoms. Proton pump inhibitors are more effective for healing and symptom relief than histamine H2-receptor antagonists; their efficacy is proportional to their ability to reduce intragastric acidity. Response to initial therapy - a once-daily proton pump inhibitor unless symptoms are mild and infrequent (fewer than three times per week) - should be assessed at four to eight weeks. Maintenance medical therapy should be at the lowest dose and frequency necessary to maintain symptom relief; antireflux surgery is an alternative for a small proportion of selected patients. Routine testing for Helicobacter pylori infection is unnecessary before starting GERD therapy. GERD is associated with Barretts epithelium and esophageal adenocarcinoma but the risk of malignancy is very low. Endoscopic screening for Barretts epithelium may be considered in adults with GERD symptoms for more than 10 years; Barretts epithelium and low-grade dysplasia generally warrant surveillance; endoscopic or surgical management should be considered for confirmed high-grade dysplasia or malignancy. CONCLUSION Prospective studies are needed to investigate clinically relevant risk factors for the development of GERD and its complications; GERD progression, on and off therapy; optimal management strategies for typical GERD symptoms in primary care patients; and optimal management strategies for atypical GERD symptoms, Barretts epithelium and esophageal adenocarcinoma.

Rectal aminosalicylate therapy for distal ulcerative colitis: a meta-analysis

BACKGROUND & AIMS Acute gastroenteritis is the strongest risk factor for irritable bowel syndrome (IBS). In May 2000, >2300 residents of Walkerton, Ontario, developed gastroenteritis from microbial contamination of the municipal water supply; a longitudinal study found that >36.2% of these developed IBS. We used this cohort to study genetic susceptibility to post-infectious (PI)-IBS. METHODS We screened 79 functional variants of genes with products involved in serotoninergic pathways, intestinal epithelial barrier function, and innate immunity and performed fine mapping in regions of interest. We compared data from Walkerton residents who developed gastroenteritis and reported PI-IBS 2 to 3 years after the outbreak (n = 228, cases) with data from residents who developed gastroenteritis but did not develop PI-IBS (n = 581, controls). RESULTS Four variants were associated with PI-IBS, although the association was not significant after correction for the total number of single nucleotide polymorphisms. Two were located in TLR9, which encodes a pattern recognition receptor (rs352139, P545P; P = .0059 and rs5743836, -T1237C; P = .0250; r(2) < 0.14); 1 was in CDH1, which encodes a tight junction protein (rs16260, -C160A; P = .0352); and 1 was in IL6, which encodes a cytokine (rs1800795, -G174C; P = .0420). Denser mapping of these 3 regions revealed 1 novel association in IL6 (rs2069861; P = .0069) and 14 associations that could be accounted for by linkage disequilibrium with the 4 original variants. The TLR9, IL6, and CDH1 variants all persisted as independent risk factors for PI-IBS when controlling for previously identified clinical risk factors. CONCLUSION This is the first descriptive study to assess potential genetic determinants of PI-IBS. Genes that encode proteins involved in epithelial cell barrier function and the innate immune response to enteric bacteria are associated with development of IBS following acute gastroenteritis.

Glucocorticosteroid Therapy in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis

Background: To summarize and quantify the evidence supporting rectal 5‐ or 4‐aminosalicylate (ASA) therapies for disease exacerbation or remission maintenance in distal ulcerative colitis, we performed a meta‐analysis.