Colin W. Howden

Appropriate Acid Suppression for the Management of Gastro-Oesophageal Reflux Disease

Gastro-oesophageal reflux disease (GORD) results from an abnormally prolonged dwell time of acidic gastric contents in the oesophagus. Although GORD is primarily a motor disorder, the injurious effects of gastric acid are central to the pathogenic process of oesophagitis, and the severity of disease correlates with the degree and duration of oesophageal acid exposure. In the majority of patients with mild disease, oesophageal acid exposure occurs predominantly during post-prandial periods. Conventional doses of H2-receptor antagonists cannot overcome the integrated stimulus to acid secretion resulting from a meal, and are thus relatively ineffective in preventing daytime, post-prandial oesophageal acid exposure. In patients with more severe grades of oesophagitis, there are abnormally high levels of nocturnal acid exposure, with the intra-oesophageal pH being less than 4.0 for 36% of the time, compared with 5% of the time in patients with mild GORD. Control of nocturnal acid secretion thus becomes increasingly important. This may be made worse by relative gastric acid hypersecretion in some patients with severe GORD. The long duration of action and effective inhibition of meal-stimulated acid secretion probably explains the superiority of omeprazole in treating GORD. Preliminary meta-analysis shows that the healing rate of erosive oesophagitis at 8 weeks by antisecretory agents is directly related to the duration of suppression of gastric acid secretion achieved over a 24-hour period (r = 0.87; p less than 0.05).

Guidelines for the Management of Helicobacter pylori Infection

PREAMBLE Guidelines for clinical practice are intended to suggest preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When data are not available that will withstand objective scrutiny, a recommendation may be made based on a consensus of experts. Guidelines are intended to apply to the clinical situation for all physicians without regard to specialty. Guidelines are intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. Given the wide range of choices in any health care problem, the physician should select the course best suited to the individual patient and the clinical situation presented. These guidelines are developed under the auspices of the American College of Gastroenterology and its practice parameters committee. These guidelines are also approved by the governing boards of the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the American Association for the Study of Liver Diseases. Expert opinion is solicited from the outset for the document. Guidelines are reviewed in depth by the committee, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments at a later time. The following guidelines are intended for adults and not for pediatric patients.

The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-analysis

Introduction The risk of oesophageal adenocarcinoma (OAC) in non-dysplastic Barretts oesophagus (BO) may have been overestimated. The objective was to estimate the incidence of OAC in patients with BO without dysplasia. Methods The authors searched MEDLINE and EMBASE from 1966 to 2011 and performed a bibliographic review of previous publications, excluding abstracts, non-peer-reviewed publications and those not published in English, for prospective or retrospective studies of the incidence of OAC in patients with BO. They excluded patients with any degree of dysplasia at baseline and those without documented intestinal metaplasia. Studies were independently reviewed by two individuals. 57 of 3450 studies were included. The authors extracted information on number of patients with BO, length of follow-up, incident cases of OAC, mean age of patients, country of origin, whether prospective or retrospective, mean length of BO segments and mortality from causes other than OAC. Study quality was assessed by the Ottawa Newcastle criteria. Results The 57 included studies comprised 11 434 patients and 58 547 patient-years of follow-up. The pooled annual incidence of OAC was 0.33% (95% CI 0.28% to 0.38%). Among 16 studies that provided appropriate information on mortality, there were 56 incident cases of OAC but 684 deaths from apparently unrelated causes. Among 16 studies that provided information on patients with short-segment BO, the annual incidence of OAC was only 0.19%. Conclusions The incidence of OAC in non-dysplastic BO is around 1 per 300 patients per year. The incidence of OAC in short-segment BO is under 1 per 500 patients per year.

Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs.

FVMany different dosage schedules of antisecretory drugs for the treatment of duodenal ulcer are recommended. The relationship between degree of acid suppression and therapeutic efficacy has not been precisely defined for these drugs. We have examined the association between suppression of intragastric acidity and duodenal ulcer healing rates for a number of therapeutic regimens. For the H2 receptor antagonists alone, the most significant correlation with healing rates was with suppression of intragastric acidity at night (r = 0.926; p = 0.0001). When other classes of drug: high dose antacid, omeprazole and a synthetic prostaglandin (enprostil) were included in the analysis, the closest correlation was with suppression of total 24 hour intragastric acidity (r = 0.911; p less than F0.0001). Stepwise linear regression analysis was used to investigate the relative contributions to healing of suppression of acidity during the day and night. Suppression of nocturnal acidity was found to be the single most important factor in explaining healing rates. No further benefit was obtained with daytime suppression for H2 receptor antagonists; suppression of acidity at night accounted for 86.1% of the observed variation in healing rates among different regimens of H2 receptor antagonists. When all classes of drugs were analysed, inclusion of daytime suppression produced a significant improvement in correlation over nocturnal suppression alone. Drug regimens providing potent suppression of nocturnal acidity produce the highest healing rates in controlled clinical trials. The healing rate for any dose regimen of an antisecretory drug can be predicted from a knowledge of its effect on intragastric acidity. For the H2 receptor antagonists, suppression of nocturnal acidity is the most relevant in this context. Moderate suppression of acidity achieves ulcer healing rates at four to eight weeks which are comparable with those seen with potent suppression at two to four weeks. Increasing degrees of suppression merely accelerate healing.

Proton Pump Inhibitor Therapy for Suspected GERD-Related Chronic Laryngitis: A Meta-Analysis of Randomized Controlled Trials

OBJECTIVE:The role of proton pump inhibitors (PPIs) in suspected GERD-related chronic laryngitis (CL) is controversial. Hence, we performed a meta-analysis of the existing randomized controlled trials (RCTs) to evaluate the efficacy of PPIs in this disorder.METHODS:Data extracted from MEDLINE (1966 to August 2005), Cochrane Controlled Trials Register (1997 to August 2005), EMBASE (1980 to August 2005), ClinicalTrials.gov website, and meetings presentations (1999–2005). Published and unpublished randomized placebo-controlled trials of PPIs in suspected GERD-related CL were selected by consensus. Random effects model was utilized with standard approaches to quality assessment, sensitivity analysis, and an exploration of heterogeneity and publication bias. The primary outcome measure was defined as the proportion of patients with ≥50% reduction in self-reported laryngeal symptoms.RESULTS:Pooled data from 8 studies (N = 344, PPI 195, placebo 149; mean age 51 yr; males 55%; study duration 8–16 wk) were analyzed. No significant quantitative heterogeneity was found among the studies (χ2 = 11.22, P = 0.13). Overall, PPI therapy resulted in a nonsignificant symptom reduction compared to placebo (relative risk 1.28, 95% confidence interval 0.94–1.74). No clinical predictors of PPI response were identified on meta-regression analysis done at study level.CONCLUSIONS:PPI therapy may offer a modest, but nonsignificant, clinical benefit over placebo in suspected GERD-related CL. Validated diagnostic guidelines may facilitate the recognition of those patients most likely to respond favorably to PPI treatment.

Review article: the clinical pharmacology of proton pump inhibitors

Proton pump inhibitors inhibit the gastric H+/K+‐ATPase via covalent binding to cysteine residues of the proton pump. All proton pump inhibitors must undergo acid accumulation in the parietal cell through protonation, followed by activation mediated by a second protonation at the active secretory canaliculus of the parietal cell.

Prophylactic antibiotic administration reduces sepsis and mortality in acute necrotizing pancreatitis : A meta-analysis

Severe acute pancreatitis is frequently complicated by local and systemic infections resulting in substantial morbidity, mortality, and health care costs. Antibiotic prophylaxis may prevent some infections. We searched for randomized, controlled trials comparing antibiotic prophylaxis with no prophylaxis in patients with acute necrotizing pancreatitis (ANP). Only trials that used antibiotics that reach minimum inhibitory concentration (MIC) in necrotic pancreatic tissue were included. We calculated relative risk reduction (RRR), absolute risk reduction (ARR), and number needed to treat (NNT) for individual trials and pooled data. Antibiotic prophylaxis significantly reduced sepsis by 21.1% (NNT = 5) and mortality by 12.3% (NNT = 8) compared with no prophylaxis. There was also a nonsignificant trend toward a decrease in local pancreatic infections (ARR = 12%; NNT = 8). Antibiotic prophylaxis decreases sepsis and mortality in patients with ANP. All patients with ANP should be given prophylaxis with an antibiotic with proven efficacy in necrotic pancreatic tissue.

Metaanalysis of randomized controlled trials of endoscopic retrograde cholangiography and endoscopic sphincterotomy for the treatment of acute biliary pancreatitis

Objective:Endoscopic retrograde cholangiography with endoscopic sphincterotomy (ERC+ES) has been advocated for the management of acute biliary pancreatitis. However, it is also viewed as dangerous. Our objective was to review published randomized, controlled trials (RCTs) of ERC+ES in patients with acute biliary pancreatitis and, by metaanalysis, to estimate the overall efficacy and safety of this approach.Methods:We performed a fully recursive literature search for published RCTs of ERC+ES in gallstone-related acute pancreatitis. RCTs were pooled. Individual and overall mortality and complication rates were calculated, together with their 95% confidence intervals (CI), absolute risk reduction (ARR), relative risk reduction (RRR), and numbers needed to treat (NNT) for avoidance of complications or death.Results:Four published RCTs had a numerically lower complication rate, and three had a numerically lower mortality rate, in the treated groups than in controls. After pooling, there were 460 treated patients and 374 controls. Complications occurred in 115 (25.0%) treated patients and 143 (38.2%) controls (z = 4.10; p < 0.001). Twenty-four treated patients (5.2%) and 34 controls (9.1%) died (z = 2.15; p < 0.05). ERC+ES had a 34.6% RRR for complications and a 42.9% RRR for death; ARR for complications and death was 13.2% (95% CI: 6.9–19.5%) and 3.9% (95% CI: 0.35–7.45%), respectively. The NNT for avoidance of complications and death was 7.6 and 25.6, respectively.Conclusions:ERC+ES reduces morbidity and mortality in patients with acute biliary pancreatitis. Treating 26 such patients with ERC+ES is predicted to save one life.

Systematic Review of the Epidemiology of Complicated Peptic Ulcer Disease: Incidence, Recurrence, Risk Factors and Mortality

Background/Aims: The incidence of uncomplicated peptic ulcer has decreased in recent years. It is unclear what the impact of this has been on the epidemiology of peptic ulcer complications. This systematic review aimed to determine the incidence, recurrence and mortality of complicated peptic ulcer and the risk factors associated with these events. Methods: Systematic PubMed searches. Results: Overall, 93 studies were identified. Annual incidence estimates of peptic ulcer hemorrhage and perforation were 19.4–57.0 and 3.8–14 per 100,000 individuals, respectively. The average 7-day recurrence of hemorrhage was 13.9% (95% CI: 8.4–19.4), and the average long-term recurrence of perforation was 12.2% (95% CI: 2.5–21.9). Risk factors for peptic ulcer complications and their recurrence included nonsteroidal anti-inflammatory drug and/or acetylsalicylic acid use, Helicobacter pylori infection and ulcer size ≧1 cm. Proton pump inhibitor use reduced the risk of peptic ulcer hemorrhage. Average 30-day mortality was 8.6% (95% CI: 5.8–11.4) after hemorrhage and 23.5% (95% CI: 15.5–31.0) after perforation. Older age, comorbidity, shock and delayed treatment were associated with increased mortality. Conclusions: Complicated peptic ulcer remains a substantial healthcare problem which places patients at a high risk of recurrent complications and death.

Meta-analysis of randomized, controlled trials of antibiotic prophylaxis before percutaneous endoscopic gastrostomy

OBJECTIVES:We sought to review the published literature on the value of antibiotic prophylaxis for the prevention of wound infection that occurs after percutaneous endoscopic gastrostomy. We also sought by meta-analysis to estimate the efficacy of antibiotic prophylaxis in preventing wound infection.METHODS:We performed a fully recursive literature search for randomized, controlled trials of antibiotic prophylaxis against wound infection occurring after percutaneous endoscopic gastrostomy. Relative and absolute risk reductions and the numbers needed to treat were derived for individual trials and pooled data.RESULTS:We identified seven trials, two of which did not find a statistically significant benefit of antibiotic prophylaxis. After pooling, antibiotic prophylaxis was found to reduce the relative and absolute risk of wound infection by 73% and 17.5%, respectively. The number needed to treat to prevent one wound infection was 5.7 (95% confidence interval = 4.4–8.0).CONCLUSION:A single intravenous dose of a broad-spectrum antibiotic, given approximately 30 min before percutaneous endoscopic gastrostomy is effective in reducing the incidence of peristomal wound infections.