Clinical investigations of gastro-oesophageal reflux: Part 1

Most people have at some time experienced the symptoms of heartburn associated with gastro-oesophageal reflux. Fortunately, these symptoms are usually short-lived and require no treatment, but in some patients severe and prolonged reflux of gastric juice into the mouth can cause dental erosion. This paper, the first in a two-part series, describes the aetiology of gastro-oesophageal reflux and associated problems that may be encountered.     

Effects of oral rabeprazole on oesophageal and gastric pH in patients with gastro-oesophageal reflux disease

BACKGROUND: This study examined the dose-response effects of the new proton-pump inhibitor rabeprazole on oesophageal and gastric pH in patients with gastro-oesophageal reflux disease. METHODS: This study had a single-centre, double-blind, randomized, two-way crossover design. Twenty patients were treated for two 7-day periods separated by a 7-10-day washout period. Patients were randomly assigned to receive either 20 mg of rabeprazole once daily during the first treatment period and 40 mg once daily during the second treatment period, or 40 mg during the first treatment period and 20 mg during the second treatment period. The primary efficacy variable was oesophageal acid exposure determined by 24-hour ambulatory pH monitoring. Acid-reflux time was defined as the percentage of time over 24 h that oesophageal pH was < 4. A dosage was considered effective if reflux time was reduced to < 6%, a number which has been our internal laboratory reference. RESULTS: Both rabeprazole 20 mg and 40 mg, given once daily, normalized reflux time, with decreases of 79% and 92% in acid exposure by day 7. Both dosages also decreased the mean total number of reflux episodes and the number of episodes lasting > 5 min, with no significant differences between dosages for any reflux parameter. Mean gastric pH increased with 20 mg from 1.86 at baseline to 3.71 on day 1 and 4.17 on day 7. Rabeprazole 40 mg once daily increased gastric pH from 2.01 to 4.37 on day 1, and to 4.65 on day 7. Safety analyses revealed no significant acute side-effects for either dosage. CONCLUSIONS: Pathological oesophageal acid exposure was normalized with both 20 mg and 40 mg dosages of rabeprazole, and the effects of these two doses did not differ. Rabeprazole was well-tolerated in this short-term study.     

Long-term results of the Angelchik prosthesis for gastro-oesophageal reflux

INTRODUCTION: Between 1982 and 1989, 46 patients had insertion of an Angelchik prosthesis for gastro-oesophageal reflux. Eleven patients (24 per cent) subsequently had the prosthesis removed, all but one for intractable dysphagia. METHODS: Thirty-six of the original patients were followed by questionnaire, and 32 of these had a barium marshmallow swallow investigation. RESULTS: A high proportion of patients (20 of 26) with a prosthesis in situ had symptoms of dysphagia. On objective evaluation by marshmallow swallow, the transit time was significantly slower than that of an age-matched control group (P < 0.01), but showed no significant deterioration with time compared with previous postinsertion studies. CONCLUSION: The Angelchik prosthesis causes long-term dysphagia in a high proportion of patients, severe enough in one-quarter to necessitate its removal. Its continued use cannot, therefore, be recommended.     

Abnormal gastro-oesophageal reflux in Chinese with atypical chest pain

Although atypical chest pain has been well described in the Western population, its frequency in Chinese is unknown. Over a period of 42 months, we studied 521 Chinese patients with chest pain and identified 108 patients (20.7%) whose pain was not related to cardiac causes, as determined by exercise ECG or cardiac catheterization. Using 24 h ambulatory pH monitoring and baseline oesophageal manometry, 28.7, 19.4 and 5.6% of these patients were found to have abnormal reflux parameters, abnormal manometric findings or both, respectively. There were significantly more patients complaining of chest pain during the study in the gastro-oesophageal reflux disease (GERD) group than in the non-GERD group (16/31 vs 20/77; P < 0.001). The lower oesophageal sphincter pressure was lower in those with abnormal reflex parameters than in those with normal reflux parameters (12.7 +/- 5.4 vs 17.8 +/- 5.8 mmHg; P < 0.05). There was no significant difference in symptoms, such as heartburn (54.8 vs 42.9%), regurgitation (38.7 vs 35.1%) and dysphagia (19.4 vs 24.7%), among the two groups. Non-specific changes were the most frequent baseline motility pattern. In conclusion, atypical chest pain and gastro-oesophageal reflux disease are not uncommon in Chinese and this deserves special emphasis as the continuation of anti-anginal drugs may aggravate their condition.     

Is gastro-oesophageal reflux a factor in exercise-induced asthma?

Birds are difficult to sex. Nestlings rarely show sex-linked morphology and we estimate that adult females appear identical to males in over 50% of the world's bird species. This problem can hinder both evolutionary studies and human-assisted breeding of birds. DNA-based sex identification provides a solution. We describe a test based on two conserved CHD (chromo-helicase-DNA-binding) genes that are located on the avian sex chromosomes of all birds, with the possible exception of the ratites (ostriches, etc.; Struthioniformes). The CHD-W gene is located on the W chromosome; therefore it is unique to females. The other gene, CHD-Z, is found on the Z chromosome and therefore occurs in both sexes (female, ZW; male, ZZ). The test employs PCR with a single set of primers. It amplifies homologous sections of both genes and incorporates introns whose lengths usually differ. When examined on a gel there is a single CHD-Z band in males but females have a second, distinctive CHD-W band.     

Comparison of simultaneous esophageal pH monitoring and scintigraphy in infants with gastroesophageal reflux

1. Analysis of the Soret spectra of hemoglobins A, S and F has been used to determine the extent of heme exposure and release from these hemoglobins in the presence of several solvent perturbants. 2. Oxyhemoglobin S unfolding in the presence of either urea or propyl urea resulted in greater heme exposure and release than either oxyhemoglobins A or F. 3. Methemoglobin formation resulted in lower denaturation midpoints for each hemoglobin compared to the reduced oxyhemoglobin state; methemoglobin F had the lowest denaturation midpoint under isothermal denaturing conditions. 4. Rate of heme exposure was greater for oxyhemoglobin S than oxyhemoglobin A in the presence of 200 microM the anionic detergent sodium dodecyl sulfate. 5. Evidence for increased levels of heme release in hemoglobin S may be related to the greater tendency of sickled red cell membranes to undergo lipid oxidation.     

Is functional dyspepsia largely explained by gastro-oesophageal reflux disease?

Functional dyspepsia is a chronic disorder of unknown aetiology. The lack of endoscopic abnormalities in patients with this disorder has led many physicians to believe that gastro-oesophageal reflux disease may be responsible for most symptoms. Our group has addressed this issue, by pathophysiological studies in a large cohort of Dundee patients with persistent dyspeptic symptoms. Peptic ulcer and gallstones were excluded in all patients by appropriate tests. Ambulatory pH monitoring showed oesophageal acid reflux that lay above the conventional diagnostic threshold in approximately 20% of patients. This subset was diagnosed as having gastro-oesophageal reflux disease. In the remainder, moderate or severe reflux-like symptoms were reported by approximately 44% patients, who were categorized as reflux-like functional dyspepsia. Reflux symptoms were mild or absent in 36% patients, who were categorized as non-reflux-like dyspepsia. While oesophageal pH profiles lay within the conventional normal range in both of these functional dyspepsia subgroups, patients with reflux-like functional dyspepsia had significantly greater acid exposure values, including total oesophageal acid exposure time, percentage time at a pH of less than 4.0, DeMeester scores and pain reflux event correlation. Hence patients with reflux-like functional dyspepsia have oesophageal acid exposure that lies below the diagnostic threshold for gastro-oesophageal reflux disease but exceeds that of patients with non-reflux dyspepsia. The high pain/reflux event correlation in reflux-like functional dyspepsia suggests that subthreshold oesophageal acid exposure may be associated with troublesome reflux symptoms.     

Holding the baby: head downwards positioning for physiotherapy does not cause gastro-oesophageal reflux

The head-downwards tipped position for physiotherapy has been claimed to exacerbate gastro-oesophageal reflux (GOR) in infants with cystic fibrosis (CF). This was investigated using lower oesophageal pH monitoring during physiotherapy. Twenty-one infants (age range 1-27 months) with respiratory disorders (CF=11), undergoing lower oesophageal pH monitoring were recruited. Subjects received two physiotherapy episodes in random order, A/B or B/A, 12 h apart. A began the gravity-assisted positioning head downward tip for: right lower lobe, middle lobe, left lower lobe and lingula; then supine with no tip for anterior segments of the upper lobes followed by apical segments of upper lobes in a sitting position. B was in the reverse order. Intermittent chest clapping was carried out for 4 min in each position by a physiotherapist blinded to the pH data. During episode A, the median change in pH from baseline was -0.32 (range -2.07 to +1.0) in non-CF subjects (NS) and -0.52 (range -2.7 to +0.52) in CF subjects (p<0.02). During episode B, the median change in non-CF subjects was -0.1 (NS; range - 1.7 to -0.15) and in CF subjects was -0.05 (NS; range -0.67 to +0.5). There was no order effect for positioning. In the CF subjects the sitting position was twice as likely to have the lowest pH measurement during physiotherapy than the other positions (p<0.04). In conclusion, the head-downward tipped positioning for physiotherapy treatment neither induces nor aggravates gastro-oesophageal reflux. There is no justification for routinely changing the way in which infant physiotherapy is carried out.     

Sleep-related gastro-oesophageal reflux: provocation with a late evening meal and treatment with acid suppression

BACKGROUND: Two studies were carried out in order to investigate the issue of meal-provoked nocturnal gastrooesophageal reflux. METHODS: In Experiment 1, 20 symptomatic reflux patients underwent both pH and polysomnographic monitoring on two nights. On one night, patients ate a non-provocative meal prior to 19.00 hours, while on the other night patients consumed a late evening meal (21.00 hours). In Experiment 2.17 symptomatic reflux patients were studied using pH and polysomnographic monitoring on two nights subsequent to a late evening provocative meal. On one night, patients received 75 mg of the H2-antagonist ranitidine, while on another night they received a placebo. The data from 12 of the 17 patients studied were used in the analysis. RESULTS: For Experiment 1, no significant differences in the number or duration of reflux events, acid exposure (total %), or polysomnographic measures of per cent of sleep stages between the two nights were observed. The results of the second experiment demonstrated that when given ranitidine, patients experienced significant decrease in acid contact time (total %), and mean duration of reflux events. Subjective reports of discomfort and sleep disturbance were also significantly improved on the drug night. However, significant differences in polysomnographic measures were not observed. CONCLUSIONS: Based on these results, we conclude that in some symptomatic reflux patients a late-night non-provocative meal may not increase the incidence of gastro-oesophageal reflux, and that a low dose of an H2-antagonist is effective in decreasing oesophageal acid contact time following a late evening provocative meal.     

Treating the symptoms of gastro-oesophageal reflux disease: a double-blind comparison of omeprazole and cisapride

BACKGROUND: Few studies have specifically addressed the management of the symptoms of gastro-oesophageal reflux disease, and there are no comparative data in this respect for acid pump inhibitors and prokinetic agents. METHODS: Following endoscopy 424 patients presenting with heartburn as the predominant symptom of gastro-oesophageal reflux disease were randomized to treatment with omeprazole 20 or 10 mg once daily, or cisapride 10 mg four times daily, in a double-blind, double-dummy, parallel group, multicentre study. Symptoms and quality of life were assessed at 4 weeks. Patients still experiencing heartburn continued therapy for a further 4 weeks and the assessments were repeated. RESULTS: At 4 weeks, heartburn was resolved in 65% (95% CI: 57-73%), 56% (48-64%) and 41% (32%-49%) of patients treated, respectively, with omeprazole 20 mg and 10 mg once daily, and cisapride. Both omeprazole doses were significantly more effective than cisapride (P < 0.01). The same order of efficacy was observed regardless of the presence of erosive oesophagitis. Regurgitation and epigastric pain also improved to a greater degree with omeprazole than with cisapride. Quality of life was improved in all treatment groups, and the improvement in the reflux dimension of the Gastrointestinal Symptom Rating Scale (GSRS) score was significantly different between groups (P = 0.002). CONCLUSIONS: Omeprazole 20 or 10 mg once daily is significantly more effective than cisapride in the resolution of heartburn, regardless of the presence of erosive oesophagitis, and this is accompanied by an improvement in patient quality of life.     

Helicobacter pylori in gastro-oesophageal reflux disease: causal agent, independent or protective factor?

Therapeutic monitoring of cyclosporine (CsA) by using area-under-the-concentration-time-curve (AUC) values in renal transplant recipients has been previously demonstrated to predict posttransplant clinical outcome. Two previous studies also reported that limited sampling equations could accurately determine the AUC of CsA using one to six blood concentration determinations in adults. The purpose of this study was to validate the accuracy of these equations in a pediatric population. In 18 pediatric patients who received renal allografts, three limited sampling equations, which used one, four, or five concentration time points, accurately estimated CsA AUC when compared with an actual 7- to 9-point curve. An equation that used a single concentration time point at 5 hours was unbiased and provided the best precision in calculating a 12-hour interval AUC. This equation had a mean absolute percentage error of 5.8% (95% confidence interval, 3.3 to 8.3). Equations using four or five concentration time points were found to provide estimates of AUC for a 24-hour interval AUC, with less than 10% error. These findings suggest that limited sampling models using as few as one to four concentration time points provide accurate estimations of CsA AUC in pediatric patients. The use of these limited sampling models provides the clinical advantage of lower blood sampling requirements and reduced costs associated with the monitoring of cyclosporine.     

Effect of alginate and alginate-cimetidine combination therapy on stimulated postprandial gastro-oesophageal reflux

This randomized, single-blind cross-over study compared the effectiveness of a conventional alginate reflux barrier formulation (20 mL single dose of Liquid Gaviscon; sodium alginate, sodium bicarbonate, calcium carbonate) with a 20 mL single dose of an alginate-cimetidine combination formulation (Algitec Suspension; sodium alginate, cimetidine) in the suppression of food and acid reflux into the oesophagus after a test meal in 12 healthy volunteers. Subjects were fasted overnight before the study. A pH electrode and gamma detector were accurately positioned 5 cm above the cardia. The volunteers received a 99mTc-labelled meal designed to provoke reflux and then either remained untreated, or 30 min later were given either Algitec Suspension or Liquid Gaviscon. Reflux of both food and acid into the oesophagus was measured for 3 h. There was a seven day wash-out period between each treatment. Food reflux in the control group was 22,878 +/- 14,385 counts x 10(3) and this was significantly suppressed by both Liquid Gaviscon (174 +/- 128 (s.e.) counts x 10(3); P = 0.003); however, although the reduction of food reflux to 3812 +/- 2322 counts x 10(3) observed after Algitec treatment was considerable, this did not reach statistical significance (P > 0.05) due to the large intersubject variation. Liquid Gaviscon was significantly better at reducing food reflux than Algitec (P = 0.001). Gaviscon also significantly reduced acid reflux when compared with the control group (1.08 +/- 0.73 vs 5.87 +/- 3.27% recording time oesophageal pH < 4, respectively) (P = 0.03). The slight reduction in acid reflux after Algitec treatment (3.25 +/- 1.82% recording time oesophageal pH < 4) also did not reach statistical significance. The difference between Algitec and Gaviscon treatment was also not significant.     

One-year prophylactic efficacy and safety of pantoprazole in controlling gastro-oesophageal reflux symptoms in patients with healed reflux oesophagitis

BACKGROUND: Pantoprazole is a benzimidazole derivative which selectively inhibits the proton pump H+. K+-ATPase necessary for the final step in gastric acid secretion. AIM: To investigate the tolerability and the prophylactic effect of pantoprazole 40 mg once daily on relapse in patients whose reflux oesophagitis had been healed. METHODS: The safety of pantoprazole 40 mg once daily was assessed in an open 1-year trial on 222 patients whose reflux oesophagitis had been healed with omeprazole or pantoprazole. Relapse was defined as endoscopically-confirmed reflux oesophagitis (at least Grade I), with endoscopies being performed for patients experiencing 3 consecutive days of disease-specific symptoms. RESULTS: Kaplan-Meier survival analysis at 6 and 12 months gave estimated treatment failure rates of 2% and 6% from confirmed relapses (per-protocol), and of 9% and 30% for a worst-case group (all withdrawals counted as failures). The only population shift in laboratory variables was a doubling of the median serum gastrin level over the first 6 months; thereafter it stabilized. Fifty-four (24%) patients experienced adverse events; 15 of these withdrew. Serious adverse events were reported for 12 patients. CONCLUSIONS: Pantoprazole appears to be highly effective and to have a good safety profile for long-term prophylaxis of reflux oesophagitis.     

Persistent gastroesophageal reflux disease after antireflux surgery in children: I. immediate postoperative evaluation using extended esophageal pH monitoring

PURPOSE: There is a paucity of quantitative and reproducible follow-up data on childhood operations for gastroesophageal reflux disease (GERD). With the development of minimally invasive techniques for antireflux operations in children, there is a need to quantitatively determine immediate outcomes for such operations performed by laparotomy for comparison. METHODS: A retrospective review of 385 children (age range, 1 week to 15 years) who had a primary antireflux operation in a Children's or University Hospital performed by laparotomy between 1983 and 1997, and who also had an extended esophageal pH study performed within the first 12 postoperative weeks, was conducted. The operations performed included Nissen fundoplication (n = 135), Thal fundoplication (n = 195), and Boerema gastropexy (n = 55). An immediate postoperative failure of the operation to control GERD was defined as an abnormal esophageal pH score persisting up to the twelfth postoperative week. RESULTS: Eleven patients (2.9%) were classified as having an immediate postoperative failure of their operation to control GERD. An additional three patients had an abnormal esophageal pH score 2 weeks postoperatively, which subsequently reverted to a normal esophageal pH score by 12 weeks. The immediate postoperative failure rate was 1.5% (2 of 135) for the Nissen fundoplication, 1.5% (3 of 195) for the Thal fundoplication, and 10.9% (6 of 55) for the Boerema gastropexy. A higher failure rate (five patients, 36%) was seen for the first 14 patients who underwent a Boerema gastropexy during the learning curve period for this operation before 1985, and by excluding these patients the failure rate was 2.4% (1 of 41) after 1985. There was no significantly increased probability of immediate postoperative failure in patients with central nervous system disorders, prematurity, repaired esophageal atresia, or gastric emptying abnormalities. Only 5 (36%) of the 14 children with persisting symptoms suggestive of GERD had immediate postoperative failure of their operation. CONCLUSIONS: Extended esophageal pH monitoring during the first 12 postoperative weeks is a helpful tool to assess the immediate outcome of antireflux operations in children because clinical symptoms alone may be unreliable. The immediate failure rate for an antireflux operation performed in children by laparotomy is very low and seems to be unaffected by comorbid factors.