G.H. Koek

Effect of the GABA B agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors

Background and aims: A subset of patients with gastro-oesophageal reflux disease (GORD) with refractory symptoms during therapy with proton pump inhibitors (PPIs), have persistent non-acid duodeno-gastro-oesophageal reflux (duodenal reflux). The aim of the present study was to investigate the effect of the GABAB receptor agonist baclofen, which was shown to inhibit the occurrence of transient lower oesophageal sphincter relaxations (TLOSRs) in patients with persistent non-acid duodenal reflux during PPI therapy. Methods: Patients were eligible for the study if they had persistent reflux symptoms, normal pH monitoring, and pathological Bilitec monitoring during PPI treatment. Upper gastrointestinal endoscopy and reflux symptom score were performed at the beginning of the study. Baclofen 5 mg three times daily was associated with treatment, and was increased by 5 mg every fourth day until a maintenance dose of 20 mg three times daily was reached. A reflux symptom questionnaire, ambulatory pH monitoring, and Bilitec monitoring were repeated four days later while PPI and baclofen were continued. All data are given as mean (SEM) or median (interquartile range) and were compared using the Student’s t test or the Mann-Whitney U test. Results: Sixteen patients (11 women, mean age 46 (3) years) with persistent heartburn or regurgitation for at least three months, in spite of PPI therapy, were included in the study. Erosive oesophagitis was present in seven patients (five with grade 1, two with grade 2). Under PPI therapy alone, all patients had normal acid exposure (0.3 (0.05; 2.2)% of the time) but pathological duodenal reflux exposure (13.8 (11.8; 15.5)% of the time). After addition of baclofen 20 mg three times daily, acid exposure was similar (0.4 (0.15; 2.3)% of the time; NS) but duodenal reflux had significantly decreased (6.1 (0.8; 10.3)% of the time; p<0.05). The number of duodenal reflux episodes and the number of longlasting duodenal reflux episodes (>5 minutes) was decreased, respectively, from 23 (14.5; 34) to 12 (5; 21) (p = 0.06) and from 5 (3; 8) to 2 (0.5;4.5) (p<0.05). The cumulative severity score for 14 reflux symptoms decreased from 10.3 (1.7) to 5.8 (1.3) (p<0.01). Four patients reported mild side effects of nausea or drowsiness. Conclusions: The GABAB receptor agonist baclofen improves duodenal reflux and associated reflux symptoms that persist during PPI therapy.

The role of acid and duodenal gastroesophageal reflux in symptomatic GERD.

Abstract OBJECTIVE: Mixed reflux of acid and duodenal contents frequently occurs in patients with gastroesophageal reflux disease (GERD). The aim of this study was to establish the contribution of acid and duodenal gastroesophageal reflux (DGER) to symptoms in patients with presumed GERD. METHODS: A total of 72 patients (37 women), mean age 45 yr (±2 yr), underwent 24-h ambulatory pH and Bilitec monitoring. Patients pressed a marker button when experiencing typical symptoms. For each symptom episode, minimal pH and maximal bilirubin optical density in a 2- or 4-min interval were calculated. For each patient, the symptom index (SI) and symptom-association probability for acid and for bile reflux were determined. RESULTS: A total of 544 symptom episodes were identified. Using a 2-min interval, 28% were associated with acid reflux, 9% with DGER, and 12% with mixed reflux. No significant difference was found when a 4-min interval was used. A positive SI for acid reflux was present in 21% of the patients and for DGER in 14%. All patients with a positive SI for DGER had also a positive SI for acid reflux. A positive symptom-association probability for acid reflux was present in 22% of the patients, for DGER in 7% of the patients, and for mixed reflux in 10% of the patients. CONCLUSIONS: Symptom episodes in patients with presumed GERD are more related to acid reflux than to DGER. DGER does not play a major role in producing typical esophageal symptoms.

Multivariate analysis of the association of acid and duodeno-gastro-oesophageal reflux exposure with the presence of oesophagitis, the severity of oesophagitis and barrett's oesophagus

Background: Exposure to acid and duodeno-gastro-oesophageal reflux (DGOR) both increase with oesophageal lesions in gastro-oesophageal reflux disease (GORD). It is unknown whether DGOR exposure is an independent risk factor for oesophageal lesions. A multivariate analysis was performed on the relationship between oesophageal lesions and demographics and acid and DGOR exposure. Methods: In 422 patients with suspected GORD, upper endoscopy, oesophageal manometry, and pH and DGOR monitoring were performed. Stepwise logistic regression was used to identify factors associated with the presence of oesophagitis, severity of oesophagitis and the presence of Barrett’s oesophagus. ORs and 95% CIs were computed at different cut-offs. Results: 54% of the patients had no oesophagitis, 36% had grade A–B oesophagitis, 3% had grade C–D oesophagitis and 7% had Barrett’s oesophagus. In multivariate analysis, oesophagitis was associated with hiatal hernia (OR 3.621, 95% CI 2.263 to 5.794) and DGOR exposure (OR up to 2.236, 95% CI 1.356–3.685), while a low body mass index (BMI) seemed protective (OR for BMI >first quartile 2.245, 95% CI 1.371 to 3.677). Severity of oesophagitis was only associated with acid exposure (OR up to 5.038, 95% CI 1.452 to 17.480). The presence of Barrett’s oesophagus was associated with male sex (OR 3.621, 95% CI 2.263 to 5.794), DGOR (OR up to 5.017, 95% CI 2.051 to 12.274) and acid exposure (OR up to 3.031, 95% CI 1.216 to 7.556). Conclusions: Several independent factors are associated with oesophageal lesions in GORD. The risk of oesophagitis is associated with hiatal hernia, BMI and DGOR exposure; severity of oesophagitis depends on acid exposure; and Barrett’s oesophagus is associated with male sex and exposure to both acid and DGOR.

Analysis of ambulatory duodenogastroesophageal reflux monitoring.

Some methodological in vitro observations concerning bile reflux monitoring (Bilitec) suggested that Bilitec monitoring is underestimating reflux in an acid environment. Moreover, other studies showed that the area above the cutoff level of bilirubin absorbance would provide an adequate quantitative marker for reflux of duodenal contents. Our aim was to study whether correction for intraesophageal acidity and the area above cutoff during Bilitec monitoring affects the results and the correlation with pH measurement and esophageal lesions. In 84 patients (46 men; mean age 46 ± 2.7 years) evaluated for suspected gastroesophageal reflux disease, we performed ambulatory 24-hr esophageal pH and Bilitec monitoring after an upper gastrointestinal endoscopy. We obtained total area, percent total time, and correction by computer software. The correction factor for bilirubin absorbance was based on literature data for acidified bile (0.06 for pH < 3.6; 0.21 for pH < 2.6). Endoscopy revealed esophagitis grade 1–2 (E1–2) and 3–4 (E3–4) in 23 and 16 patients, respectively. A progressive increase of mixed (acid + bile) reflux occurred with increasing severity of endoscopic lesions (E3–4 vs no esophagitis, P < 0.05). A pathologic Bilitec monitoring result was present in the same 35 patients before and after correction and the correlation between the pH measurement and percent time of bile reflux was not improved by correction for intraesophageal pH (r = 0.386 and r = 0.391; P < 0.05). The total area of bilirubin absorbance above 0.14 (abs × min) was 7.8 ± 2.2 in patients without esophagitis, and 11.7 ± 4.4 and 17.0 ± 4.2 in the E1–2 and E3–4 groups, respectively (E3–4 vs no esophagitis, P < 0.05). The correlation between the Bilitec monitoring and pH measurement regarding percent (r = 0.427, P < 0.01) or area of time below 4 (r = 0.280, P < 0.05) was not improved by considering the area of bilirubin absorbance above the cutoff level. Correction for intraesophageal pH has only a minor effect on the results of ambulatory Bilitec monitoring. Taking into account the surface rather than the percent of time above the cutoff level for bilirubin absorbance does not improve the correlation of Bilitec with acid reflux and with esophageal lesions.

Dietary restrictions during ambulatory monitoring of duodenogastroesophageal reflux.

To avoid food impaction artifacts during ambulatory bile reflux monitoring (Bilitec), some groups have allowed only a liquid diet, while others omitted the meal and postprandial periods from the analysis. Our aim was to study whether Bilitec monitoring requires the use of a liquid diet. In 40 healthy subjects and 211 consecutive patients evaluated for suspected gastroesophageal reflux disease, we performed ambulatory 24-hr esophageal pH and Bilitec monitoring. The subjects were randomized to either solid or liquid meals during the procedure. All patients underwent an upper gastrointestinal endoscopy. In healthy subjects, liquid and solid diets were followed by similar acid exposure of the distal esophagus. During bile reflux monitoring, major meal artifacts occurred in 19% of the patients using solid meals, but in none of the patients using liquid meals. With liquid meals, but not with solid meals, a progressive increase in duodenoesophageal reflux occurred with increasing severity of endoscopic lesions. With liquid meals, but not with solid meals, the prevalence of pathological exposure to duodenoesophageal reflux increased with increasing severity of endoscopic lesions. With liquid meals, the results of pH monitoring and bile reflux monitoring correlated better than with solid meals. Thus, ambulatory Bilitec monitoring requires the use of liquid meals, as the use of solid meals is associated with too many meal artifacts and a poorer correlation with acid reflux and severity of endoscopic lesions.

Oesophageal clearance of acid and bile: a combined radionuclide, pH, and Bilitec study.

Background: Studies combining pH and Bilitec monitoring found a high prevalence of both acid and duodeno-gastro-oesophageal reflux in severe reflux disease. Clearance of refluxed material is a major defence mechanism against reflux. Several studies have been devoted to oesophageal acid clearance but oesophageal clearance of refluxed duodenal contents (DC) has rarely been addressed. Aim: To compare oesophageal acid and DC clearance. Methods: Ten healthy volunteers (five women, mean age 23 (1) years) were studied. Firstly, a balloon tip catheter, positioned in the duodenum under fluoroscopy, was used to aspirate DC after stimulation by a high caloric liquid meal (200 ml, 300 kcal). During the second session, pH and Bilitec probes were positioned 5 cm above the lower oesophageal sphincter and a small infusion catheter was introduced into the proximal oesophagus. The subject was placed supine under a gamma camera. One of two different solutions (DC mixed with 0.2 mCi Tc99m pertechnetate or citric acid (pH 2) mixed with 0.2 mCi Tc99m pertechnetate) was infused into the proximal oesophagus and the subject was instructed to swallow at 20 second intervals. Clearance was assessed using scintigraphy (dynamic acquisition, one frame per second in the anterior view; calculation of time to clear peak counts to background level), pH (time to pH<4) or Bilitec (time absorbance >0.14) monitoring, with or without continuous saliva aspiration. Each condition was studied twice in a randomised design; measurement time was four minutes, interrupted by water flushing, with a two minute rest period. Results are given as mean (SEM) and were compared by Student’s t test and Pearson correlation. Results: Scintigraphic evaluation showed a volume clearance time of 29 (3) seconds for acid and 28 (9) seconds for DC (NS). Saliva aspiration had no significant influence on volume clearance of acid or DC (28 (4) and 30 (13) seconds, respectively; NS). pH monitoring showed an acid clearance time of 217 (15) seconds, which was significantly prolonged to 324 (30) seconds during saliva aspiration (p<0.05). Bilitec monitoring showed a DC clearance time of 131 (27) seconds, which was not significantly prolonged by saliva aspiration (176 (36) seconds; p = 0.08). DC clearance was faster than acid clearance, either without or with saliva aspiration (p<0.055 and p<0.05, respectively). Conclusions: Under experimental conditions, liquid acid and DC solutions have comparable volume clearances. Chemical clearance occurs slightly faster for DC than for acid, and saliva plays a major role in the clearance of acid only.

Mechanisms underlying duodeno-gastric reflux in man

BACKGROUND Recent studies suggest that duodeno-gastro-oesophageal reflux (DGER) contributes to the occurrence of reflux oesophagitis and Barretts oesophagus. The mechanisms underlying duodeno-gastric reflux (DGR), a prerequisite for DGER, are poorly understood. AIMS To study the occurrence of DGR in relation to interdigestive and postprandial gastroduodenal motility. SUBJECTS AND METHODS Ten healthy subjects underwent stationary gastroduodenal manometry with simultaneous duodenal and antral Bilitec recording 4 h before and 5 h after ingestion of a liquid meal. Eight volunteers underwent the same study, with administration of erythromycin postprandially. RESULTS During the interdigestive phase II, all volunteers had short DGR episodes. Postprandially, DGR occurred in all subjects, on average 39 +/- 28 min after the start of the meal, and was cleared from the stomach after 242 +/- 23 min. Induction of increased antral motility and of a premature phase III, by administration of erythromycin, was associated with faster gastric DGR clearance. However, there was no direct temporal relationship between erythromycin-induced gastric phase III and erythromycin-induced DGR clearance. CONCLUSION In healthy subjects, duodenogastric reflux occurs sporadically in the interdigestive state and is a normal phenomenon in the postprandial period. Erythromycin induces faster clearance of DGR from the stomach, which depends on enhanced antral contractile activity rather than premature phase III.