R. H. Hunt

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).

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.

The relationship between the control of pH and healing and symptom relief in gastro-oesophageal reflux disease

Gastro‐oesophageal reflux disease (GERD) is generally considered to be the result of a motility disorder which permits the abnormal and prolonged exposure of the lumen of the oesophagus to the acidic gastric contents.

Can severity of symptoms be used as an outcome measure in trials of non-ulcer dyspepsia and helicobacter pylori associated gastritis?☆

Most trials of non-ulcer dyspepsia (NUD) and Helicobacter pylori associated gastritis (HPAG) have not used validated methods of measuring symptoms. Three attributes are necessary for use of symptom severity scoring systems as outcome measures in clinical trials: reproducibility, responsiveness to change and validity compared to corroborating measures. The objective of this study was to establish that selected gastrointestinal symptoms recorded as a series of 5-point Likert Scales meet the 3 criteria for use as outcome measures in clinical trials. Patients with NUD (Helicobacter pylori-negative) and HPAG were studied. A preliminary assessment of 24 patients was used to select the 8 most frequently occurring and most severe symptoms. These symptoms were then scored in a further 55 patients to assess their utility as outcome measures. Observations were made at 3 time points, enrollment (T1), after 1 week with no intervention (T2) and after 4 weeks of therapy for either disease (T3). The study took place in a university hospital outpatient gastroenterology service. Symptom scores were reproducible before treatment (symptom scores at T1 and T2 were correlated), responsive (symptom scores changed after treatment between T2 and T3) and valid (symptom score changes corresponded to changes in general health status). Scoring of gastrointestinal symptom severity using 5-point Likert Scales satisfies the 3 criteria for use as outcome measures in clinical trials of NUD and HPAG.

Single nocturnal dose of an H2 receptor antagonist for the treatment of duodenal ulcer.

Twenty four hour intragastric acidity and nocturnal acid output have been measured over five separate 24 hour periods in each of 12 patients with duodenal ulcer receiving either placebo, cimetidine 400 mg bd, cimetidine 300 mg nocte, ranitidine 150 mg bd, or ranitidine 300 mg nocte. In these doses ranitidine was significantly more effective at decreasing intragastric acidity and nocturnal acid output than cimetidine. There was no significant difference between twice daily ranitidine and night time ranitidine or between twice daily cimetidine and night time cimetidine in the reduction of intragastric acidity. Nocturnal acid output was controlled significantly better with ranitidine at night, twice daily dosage of ranitidine, and cimetidine at night, than by the twice daily dosage of cimetidine. It is suggested that a single nocturnal dose of cimetidine or ranitidine should be evaluated in a clinical trial.

Canadian Helicobacter Study Group Consensus Conference on the Approach to Helicobacter Pylori Infection in Children and Adolescents

Gastric infection with Helicobacter pylori is common in both children and adults, but children are considerably less susceptible to peptic ulcers and other pathological sequelae. As a result, the risk to benefit ratio of diagnostic studies and therapeutic regimens for H pylori in adults are likely different from those in pediatric populations. These guidelines for the management of pediatric H pylori infection, developed by the Canadian Helicobacter Study Group, are designed to identify when the diagnosis and treatment of H pylori may improve patient care. Given the low prevalence of this infection in Canada, it is important to recognize that indiscriminate testing and treatment programs in children are not recommended, and indeed may threaten the optimal care of children. Diagnostic tests should be employed judiciously and be reserved for children who are most likely to derive measurable benefit, such as those likely to have peptic ulcer disease. At this time a test and treat strategy in children cannot be considered prudent, evidence based or cost effective. It is appropriate to limit diagnosis and treatment to children and adolescents in whom H pylori has been identified during endoscopic investigation.

ANGIODYSPLASIA OF THE COLON: Experience of 26 Cases

26 patients referred for colonoscopy with unexplained anaemia or blood loss per rectum were found to have angiodysplasia located in the caecum and/or ascending colon. All patients had undergone previous extensive investigation. After endoscopic photography of the lesions coagulation and biopsy were carried out in 23 patients. In 3 patients the extent of the lesion demanded surgical management, and right hemicolectomy was carried out without prior coagulation biopsy, 3 other patients underwent surgery at a later date-2 for further bleeding and 1 for complications of coagulation biopsy. Colonoscopy with photography and coagulation biopsy proved a safe and effective approach to the management of angiodysplasia in the majority of patients. It provided successful treatment and confirmation of the diagnosis without resort to major surgery, which in elderly patients is associated with high morbidity and mortality.

The relationship between suppression of acidity and gastric ulcer healing rates.

We have investigated the relationship between the suppression of acidity by antisecretory drugs for the treatment of benign gastric ulcer and their corresponding ulcer‐healing rates. For a variety of antisecretory drug regimens, there was a significant correlation between suppression of 24‐h intragastric acidity and ulcer healing rates after 2, 4 and 8 weeks of treatment. There was a lesser degree of correlation between healing and suppression of nocturnal acidity and the association between suppression of acidity and gastric‐ulcer healing rates was less marked than that previously described for duodenal ulcer.

Secretion of intravenously administered antibiotics in gastric juice: implications for management of Helicobacter pylori.

AIMS: To study whether differences in eradication rates of antibiotics may be explained by differences in secretion of antibiotics in gastric juice. METHODS: A single intravenous dose of either ampicillin 500 mg, erythromycin 500 mg, or metronidazole 500 mg was administered to four healthy Helicobacter pylori negative volunteers on different days. Antibiotic concentrations were measured in gastric juice before and every 10 minutes after administration of the drug for two hours and after one hour in serum. RESULTS: No ampicillin was detected in gastric juice. Erythromycin concentrations in gastric juice showed considerable individual variation and reached maximum concentrations of 2.2-4.8 mcg/ml between 30 and 80 minutes after dosing. Metronidazole concentrations in gastric juice showed much less individual variation and maximum concentrations of 5-6 mcg/ml were reached within 30 minutes and remained high during the study period. CONCLUSION: Metronidazole and erythromycin are secreted across the gastric mucosa, but ampicillin is not.

Review article: should NSAID/low-dose aspirin takers be tested routinely for H. pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing.

Helicobacter pylori infection and the use of nonsteroidal anti‐inflammatory drugs (NSAIDs) can each result in gastric or duodenal ulcer(s) and ulcer complications. Together, H. pylori infection and NSAIDs account for approximately 90% of peptic ulcer disease. In 2003, the results of studies suggest, and guidelines recommend, the careful selection of anti‐inflammatory drugs – NSAIDs or selective COX‐2 inhibitors (coxibs) based upon patients gastrointestinal history and use of aspirin therapy. Testing for, and cure of, H. pylori infection is recommended in patients prior to the initiation of NSAID therapy and in those who are currently receiving NSAIDs and have a history of dyspepsia, peptic ulcer or ulcer complications. For patients who present with peptic ulcer bleeding but require NSAIDs long‐term, H. pylori eradication therapy should be considered, followed by continuous proton pump inhibitor prophylaxis to prevent re‐bleeding, regardless of which kind of NSAID (nonselective NSAID /coxib) is being prescribed. Routine testing for, and eradication of, H. pylori infection has not been recommended for current takers of NSAIDs with no or low risk of complications. The management of patients taking low‐dose aspirin is complex, but eradication of H. pylori infection alone in those with a past history of bleeding does not guarantee complete protection and therefore a proton pump inhibitor should also be given. The success of eradication therapy should always be confirmed, because of the risk of ulcer recurrence and bleeding in H. pylori‐infected patients who require anti‐inflammatory treatments.