Effects of postgastric 13C-acetate processing on measurement of gastric emptying: a systematic investigation in health.

Uniform postgastric processing of the gastric emptying (GE) marker 13C-acetate (Ac) is an unverified assumption behind its widespread application to measure GE. This study assessed the postgastric processing of Ac administered by intraduodenal (i.d.) infusion simulating different physiological conditions. 13CO2 in breath was assessed in three groups of six volunteers after i.d. administration of A: Different caloric densities (0.75/1.5/3 kcal min(-1) in a 200 mL meal at constant 1 mg Ac min(-1) simulating a physiological range of nutrient delivery rates; B: different tracer delivery rates (0.5/1.0/2.5 mg Ac min(-1) simulating delayed, normal and increased GE; C1: a 500 mL meal resulting in same marker and caloric delivery compared to protocol A; C2: 50 mL water bolus injections of 12.5/25/50/100 mg Ac and C3 bolus injections of 50 mg Ac in 50/100/200 mL water in randomized order. A: 13CO2 excretion was independent of caloric load (P = 0.59). B: The dynamic of 13CO2 excretion was modulated by tracer elimination which was in turn dependent on the speed of tracer delivery, i.e. with faster deliveries resulting in lower 13CO2 recovery during infusion (P < 0.001). C: Increasing Ac doses resulted in decreased 13CO2 recovery (P < 0.001) over the first hour. 13CO2 recovery kinetics was independent of the volume delivered. This study shows 13C-acetate absorption and metabolism is independent of the volume and caloric delivery of test meals. The 'lag' in estimates of GE derived from 13CO2 breath tests is due to a postgastric, dose-dependent delay to 13CO2 elimination. This can be corrected for in analytical derivations of GE parameters based on 13C-acetate breath test measurements.

Effects of clonidine and sumatriptan on postprandial gastric volume response, antral contraction waves and emptying: an MRI study.

Gastric emptying (GE) may be driven by tonic contraction of the stomach ('pressure pump') or antral contraction waves (ACW) ('peristaltic pump'). The mechanism underlying GE was studied by contrasting the effects of clonidine (alpha(2)-adrenergic agonist) and sumatriptan (5-HT(1) agonist) on gastric function. Magnetic resonance imaging provided non-invasive assessment of gastric volume responses, ACW and GE in nine healthy volunteers. Investigations were performed in the right decubitus position after ingestion of 500 mL of 10% glucose (200 kcal) under placebo [0.9% NaCl intravenous (IV) and subcutaneous (SC)], clonidine [0.01 mg min(-1) IV, max 0.1 mg (placebo SC)] or sumatriptan [6 mg SC (placebo IV)]. Total gastric volume (TGV) and gastric content volume (GCV) were assessed every 5 min for 90 min, interspersed with dynamic scan sequences to measure ACW activity. During gastric filling, TGV increased with GCV indicating that meal volume dictates initial relaxation. Gastric contents volume continued to increase over the early postprandial period due to gastric secretion surpassing initial gastric emptying. Clonidine diminished this early increase in GCV, reduced gastric relaxation, decreased ACW frequency compared with placebo. Gastric emptying (GE) rate increased. Sumatriptan had no effect on initial GCV, but prolonged gastric relaxation and disrupted ACW activity. Gastric emptying was delayed. There was a negative correlation between gastric relaxation and GE rate (r(2 )=49%, P < 0.001), whereas the association between ACW frequency and GE rate was inconsistent and weak (r2=15%, P = 0.05). These findings support the hypothesis that nutrient liquid emptying is primarily driven by the 'pressure pump' mechanism.

Characterization of gastric volume responses and liquid emptying in functional dyspepsia and health by MRI or barostat and simultaneous C-acetate breath test.

The assessment of gastric accommodation and emptying by different methodologies provides inconsistent results. We aimed to compare magnetic resonance imaging (MRI), barostat and 13C-acetate breath test (BT) for the assessment of gastric volume responses and emptying in healthy controls (HC) and patients with functional dyspepsia (FD). Eight HC and eight FD patients underwent: (i) continuous BT with simultaneous MRI in the upright position after ingestion of isocaloric, 300 kcal, 200 and 800 mL meals, both labelled with 100 mg of (13)C-acetate; and (ii) BT with gastric barostat after ingestion of the 200 mL meal. MRI measured total gastric volume and gastric content volume (GCV) at baseline, after filling and during emptying. Meal emptying half-times (T(1/2)) for MRI and BT were calculated (mean +/- SD). We found: (i) Initial GCV was lower in FD than in HC (762 +/- 22 vs 810 +/- 52 mL, P < 0.04) after the 800 mL meal but not the 200 mL meal. T(1/2)(MRI) was shorter for the 800 mL than the 200 mL meal (P < 0.001), but similar in HC and FD (200 mL: HC 117 +/- 30 min vs FD 138 +/- 42 min, ns; 800 mL: HC 71 +/- 16 min vs FD 78 +/- 27 min, ns). In contrast, T(1/2)(BT) was similar between meals and groups (200 mL: HC 111 +/- 11 min vs FD 116 +/- 19 min; 800 mL: HC 114 +/- 14 min vs FD: 113 +/- 17 min). (ii) Barostat measurements showed similar postprandial volume increases between groups. We conclude that direct measurements by MRI provide a sensitive, non-invasive assessment of gastric accommodation and emptying after a meal. In contrast to MRI, BT did not detect faster emptying of high-volume compared to low-volume liquid nutrient meals in HC or FD.

Clinical trial: the effects of adding ranitidine at night to twice daily omeprazole therapy on nocturnal acid breakthrough and acid reflux in patients with systemic sclerosis--a randomized controlled, cross-over trial.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is an important problem in systemic sclerosis due to impaired salivation and oesophageal function. AIM: To determine the efficacy of adding ranitidine at bedtime to control nocturnal acid breakthrough (NAB) and GERD in patients with systemic sclerosis already prescribed high-dose omeprazole. METHODS: Patients with systemic sclerosis and GERD symptoms (n = 14) were treated with omeprazole 20 mg b.d. and either placebo or ranitidine 300 mg at bedtime for 6 weeks in a randomized, cross-over, placebo controlled study. At the end of each period a 24 h pH-study with intragastric and oesophageal pH measurement was performed. RESULTS: Pathological acid reflux occurred in eight patients with omeprazole/placebo and in seven with omeprazole/ranitidine (P = ns) with technically adequate oesophageal pH-studies (n = 13). NAB was present in eight patients with omeprazole/placebo and six with omeprazole/ranitidine (P = ns) in whom technically adequate gastric pH-studies were obtained (n = 10). The addition of ranitidine had no consistent effect on patient symptoms or quality of life. CONCLUSION: Many patients with systemic sclerosis experienced NAB and pathological oesophageal acid exposure despite high-dose acid suppression with omeprazole b.d. Adding ranitidine at bedtime did not improve NAB, GERD or quality of life in this population.

Clinical trial: effects of tegaserod on gastric motor and sensory function in patients with functional dyspepsia.

BACKGROUND Tegaserod, a serotonin receptor type-4 partial agonist, stimulates gastrointestinal motility and has been shown to increase gastric volumes before and after a meal in healthy volunteers. Its effect on gastric motor and sensory function in patients with functional dyspepsia is unclear. AIM To evaluate the effects of tegaserod on gastric compliance, accommodation and gastric sensory function in patients with functional dyspepsia and healthy volunteers. METHODS Sixteen patients with functional dyspepsia and 12 healthy volunteers were studied on two occasions, each after a 7-day treatment with either placebo or tegaserod 6 mg b.d. using a double-blind, randomized, crossover design. After each treatment period a gastric barostat study was performed fasting and during intraduodenal lipid infusion. RESULTS Tegaserod increased postprandial gastric compliance in functional dyspepsia patients (P = 0.04). Healthy volunteers showed enhanced postprandial gastric compliance after placebo (P = 0.03). Between-treatment analysis of gastric accommodation revealed a significant increase in intrabag volumes after tegaserod in healthy volunteer (P = 0.04); no difference could be seen in functional dyspepsia patients. Tegaserod had no effect on gastric sensation. CONCLUSIONS Tegaserod enhances postprandial gastric compliance in functional dyspepsia patients and gastric accommodation in healthy volunteers. The improvement of proximal gastric motor function suggests a beneficial role of tegaserod in patients with functional dyspepsia.

[Esophageal dysphagia]. / Osophageale Schluckstörungen.

Dysphagia can be caused by a number of disorders such as benign or malignant obstruction of the esophagus, inflammatory alterations of the mucosa or primary esophageal motility disorders. Endoscopic evaluation is recommended for all patients to exclude malignancy and to establish or confirm a diagnosis. This article provides an overview of the most frequent inflammatory and functional esophageal disorders causing dysphagia. Clinical findings, diagnostic procedures and therapeutic management of primary esophageal motility disorders such as achalasia and diffuse esophageal spasm as well as of GERD and eosinophilic esophagitis are discussed. The diagnosis of achalasia is made by barium swallow with fluoroscopy and by manometry. Therapeutic options for achalasia are pneumatic dilatation of the esophagogastric junction, laparoscopic cardiomyotomy combined with fundoplication and botulinum toxin injection of the lower esophageal sphincter Diffuse esophageal spasm is manometrically characterized by normal peristalsis intermittently interrupted by simultaneous contractions. Potential medical therapies are PPIs for underlying GERD, smooth-muscle relaxants and antidepressant medications. GERD is a multifaceted disease caused by abnormal reflux of gastric contents into the esophagus leading to chronic symptoms or mucosal damage. Therapy includes lifestyle modifications, acid suppressive medications mainly by PPI and laparoscopic fundoplication in selected patients. Eosinophilic esophagitis is a chronic inflammatory disorder of the esophagus diagnosed histologically. The main symptom of eosinophilic esophagitis is dysphagia for solid food with imminent risk of food impaction. Systemic or topical corticosteroids are the therapy of choice.

Intersubject and intrasubject variability of gastric volumes in response to isocaloric liquid meals in functional dyspepsia and health.

Gastric emptying (GE) has a considerable variability, but data on reproducibility of gastric volume measurements are sparse. We aimed to study the reproducibility of postprandial gastric volume responses and GE using magnetic resonance imaging (MRI) in healthy controls (HC) and patients with functional dyspepsia (FD). Eight HC and eight FD patients underwent a MRI study on two occasions. MR images were acquired in seated position before and up to 120 min after liquid meal administration (200 mL, 300 kcal). Fasting (V0), initial postprandial stomach volumes (V1), volume changes (V1 - V0) and meal emptying half-times (T 1/2) were determined. Intersubject and intrasubject coefficients of variation (CV(inter), CV(intra)) and Pearson's correlation coefficients (r) were calculated. T 1/2 on both occasions were (mean +/- SD) 113 +/- 28 and 121 +/- 30 min in HC (ns) and 127 +/- 31 and 128 +/- 37 min in FD (ns), respectively. In HC, CV(inter), CV(intra), r were 31%, 23%, 0.49 for V0; 13%, 7%, 0.68 for V1; 10%, 4%, 0.71 for V1 - V0 and 25%, 7%, 0.90 for T 1/2. In FD these parameters were for V0: 42%, 41%, -0.06; for V1: 18%, 10%, 0.40; for V1 - V0: 20%, 14%, 0.74 and for T 1/2: 26%, 10%, 0.84. The stomach accommodates to a given meal volume, resulting in similar and reproducible postprandial volumes within- and between-subjects. MRI provides reproducible measurements of gastric volume responses in health and disease.

High-resolution manometry predicts the success of oesophageal bolus transport and identifies clinically important abnormalities not detected by conventional manometry.

BACKGROUND AND AIMS: High-resolution manometry (HRM) is a recent development in oesophageal measurement; its value in the clinical setting remains a matter of controversy. (i) We compared the accuracy with which bolus transport could be predicted from conventional manometry and HRM. (ii) The clinical value of HRM was assessed in a series of patients with endoscopy-negative dysphagia in whom conventional investigations had been non-diagnostic. METHOD: (i) Control subjects and patients with endoscopy-negative dysphagia underwent concurrent HRM and video-fluoroscopy. Ninety-five records were reviewed using HRM with spatiotemporal plot and conventional line plots of the pressure data derived from the same recording. (ii) The HRM and notes of patients with endoscopy-negative dysphagia and abnormal bolus transport were analysed to identify additional information provided by the new technique. RESULTS: (i) Receiver operating characteristic analysis demonstrated that HRM predicts the presence of abnormal bolus transport more accurately than conventional manometry. (ii) HRM identified clinically important motor dysfunction not detected by manometry and radiography. These included localized disturbances of peristalsis and abnormal movement of the lower oesophageal sphincter during oesophageal spasm. CONCLUSION: The HRM predicts bolus movement more accurately than conventional manometry and identifies clinically relevant oesophageal dysfunction not detected by other investigations including conventional manometry.

Dietary protein precipitation properties have effects on gastric emptying in healthy volunteers.

BACKGROUND & AIMS: Strategies that reduce the size of particles in the stomach accelerate gastric emptying. Partial dephosphorylation of casein reduces the size of protein precipitates (curds) in acid conditions and facilitates peptic digestion. We hypothesized that changing the precipitation properties of casein by partial dephosphorylation would accelerate gastric emptying. METHODS: Eight healthy male volunteers entered a prospective, double blind, randomized study with crossover design. Gastric emptying of milk based formula containing either unmodified or dephosphorylated casein was assessed by scintigraphy. Gastric pH measurements were acquired concurrently. RESULTS: A trend to faster gastric emptying was observed for the unmodified preparation, with lower median half time (unmodified 133; dephosphorylated 214 min, P = 0.09) and area under the curve (unmodified 8425 min%; dephosphorylated 9135 min%, P = 0.08). A positive correlation was found between half time for the dephosphorylated preparation and the treatment effect (r2 = 0.81, P < 0.02). Gastric pH was unaffected. CONCLUSIONS: The study hypothesis was rejected; indeed gastric emptying tended to be faster for the unmodified than the dephosphorylated protein. This effect was more pronounced in subjects with slow gastric emptying on the dephosphorylated preparation. Properties other than the size of protein precipitates determine the rate of gastric emptying for milk based formula.

The pathophysiology of faecal spotting in obese subjects during treatment with orlistat.

BACKGROUND: The intermittent loss of oil or liquid faeces ('spotting') is an adverse effect that occurs in obese patients during treatment with the lipase inhibitor orlistat; the pathophysiology is unknown. AIM: To investigate the effects of orlistat on anorectal sensorimotor function and continence. METHODS: Obese subjects susceptible to spotting were identified by an unblind trial of orlistat. Obese spotters (n = 15) and non-spotters (n = 16) completed a randomized, double-blind, cross-over trial of orlistat and placebo. Anorectal function was assessed by rectal barostat and anal manometry, together with a novel stool substitute retention test, a quantitative measurement of faecal continence. RESULTS: Orlistat increased stool volume and raised faecal fat and water. Treatment had no effect on anorectal motor function, but rectal sensation was reduced; on retention testing, the volume retained was increased. Subjects susceptible to spotting had lower rectal compliance, heightened rectal sensitivity and weaker resting sphincter pressure than non-spotters. On retention testing, gross continence was maintained; however, spotters lost small volumes of rectal contents during rectal filling. CONCLUSION: Treatment with orlistat has no direct adverse effects on anorectal function or continence. Spotting occurs during treatment with orlistat when patients with sub-clinical anorectal dysfunction are exposed to increased stool volume and altered stool composition.

Analysis of the meal-dependent intragastric performance of a gastric-retentive tablet assessed by magnetic resonance imaging.

BACKGROUND: Modern medical imaging modalities can trace labelled oral drug dosage forms in the gastrointestinal tract, and thus represent important tools for the evaluation of their in vivo performance. The application of gastric-retentive drug delivery systems to improve bioavailability and to avoid unwanted plasma peak concentrations of orally administered drugs is of special interest in clinical and pharmaceutical research. AIM: To determine the influence of meal composition and timing of tablet administration on the intragastric performance of a gastric-retentive floating tablet using magnetic resonance imaging in the sitting position. METHODS: A tablet formulation was labelled with iron oxide particles as negative magnetic resonance contrast marker to allow the monitoring of the tablet position in the food-filled human stomach. Labelled tablet was administered, together with three different solid meals, to volunteers seated in a 0.5-T open-configuration magnetic resonance system. Volunteers were followed over a 4-h period. RESULTS: Labelled tablet was detectable in all subjects throughout the entire study. The tablet showed persistent good intragastric floating performance independent of meal composition. Unfavourable timing of tablet administration had a minor effect on the intragastric tablet residence time and floating performance. CONCLUSION: Magnetic resonance imaging can reliably monitor and analyse the in vivo performance of labelled gastric-retentive tablets in the human stomach.

[Gastrointestinal motility disorders relevant to general practice]. / Praxisrelevante gastrointestinale Motilitätsstörungen.

Gastroesophageal reflux disease, achalasia and esophageal spasms are the most frequent esophageal motility disorders and are associated with dysphagia and non-cardiac chest pain. The diagnosis of achalasia is based on manometric criteria. Pneumatic dilatation, laparoscopic myotomy, and the minimal invasive injection of botulinum toxin are therapeutic options. Long-term-pH-metry is the gold standard to diagnose gastroesophageal reflux disease. Proton pump inhibitors (PPI) are the first-line therapy in reflux disease. Esophageal manometry and pH-metry are essential investigations prior to an antireflux operation. The evaluation of chronic constipation refractory to medical treatment should include anal manometry, and MR-defecography for the diagnosis of anorectal outlet obstruction such as anismus which could be treated successfully by biofeedback therapy.

Pathophysiology of functional dyspepsia.

Functional dyspepsia is a symptom complex characterised by postprandial upper abdominal discomfort or pain, early satiety, nausea, vomiting, abdominal distension, bloating, and anorexia in the absence of organic disease. Gastrointestinal motor abnormalities, altered visceral sensation, and psychosocial factors have all been identified as major pathophysiological mechanisms. This perspective has now replaced the earlier view that the condition was the result of a sole motor or sensory disorder of the stomach. Future therapeutic strategies should be aimed at reducing nociception as well as enhancing the accommodation response.

Non-invasive measurement of gastric accommodation in humans.

Gastric accommodation describes the reduction in gastric tone and increase in compliance that follows ingestion of a meal and involves at least two responses: "receptive relaxation" which allows the stomach to accept a volume load without a significant rise in gastric pressure and "adaptive relaxation" which modulates gastric tone in response to the specific properties of the meal ingested. However, there are considerable technical difficulties in measuring the accommodation process. The current standard barostat studies, and other methods such as conventional and three dimensional ultrasound, or single photon emission computed tomography have significant disadvantages. Preliminary findings from the development and validation of a new magnetic resonance imaging technique that addresses many of the deficiencies of previous methods are presented.

Pressure-geometry relationship in the antroduodenal region in humans.

Understanding of the control mechanisms underlying gastric motor function is still limited. The aim of the present study was to evaluate antral pressure-geometry relationships during gastric emptying slowed by intraduodenal nutrient infusion and enhanced by erythromycin. In seven healthy subjects, antral contractile activity was assessed by combined dynamic magnetic resonance imaging and antroduodenal high-resolution manometry. After intragastric administration of a 20% glucose solution (750 ml), gastric motility and emptying were recorded during intraduodenal nutrient infusion alone and, subsequently, combined with intravenous erythromycin. Before erythromycin, contraction waves were antegrade (propagation speed: 2.7 +/- 1.7 mm/s; lumen occlusion: 47 +/- 14%). Eighty-two percent (51/62) of contraction waves were detected manometrically. Fifty-four percent of contractile events (254/473) were associated with a detectable pressure event. Pressure and the degree of lumen occlusion were only weakly correlated (r(2) = 0.02; P = 0.026). After erythromycin, episodes of strong antroduodenal contractions were observed. In conclusion, antral contractions alone do not reliably predict gastric emptying. Erythromycin induces strong antroduodenal contractions not necessarily associated with fast emptying. Finally, manometry reliably detects ~80% of contraction waves, but conclusions from manometry regarding actual contractile activity must be made with care.

Helicobacter pylori and symptomatic relapse of gastro-oesophageal reflux disease: a randomised controlled trial.

BACKGROUND: There is little information on the effects of Helicobacter pylori eradication in patients with a primary diagnosis of gastro-oesophageal reflux disease (GORD). Our aim was to investigate the effect of H pylori eradication in this group of patients. METHODS: We did a double-blind, randomised, placebo-controlled study in 70 patients with GORD. We assigned individuals to three groups. All patients received lansoprazole 30 mg twice daily for 10 days, followed by 30 mg once daily for 8 weeks. Patients infected with H pylori received either antibiotics (clarithromycin 500 mg and amoxicillin 1000 mg twice daily) or placebo for the first 10 days. Controls were patients not infected with H pylori. Patients were followed up for 6 months at 2-week intervals for GORD symptoms. At the end of the study we repeated endoscopy and oesophageal and gastric 24 h-pH monitoring. FINDINGS: 58 of 70 patients completed our study. At the end of the study 16 of these patients were H pylori-positive (14 placebo and two eradication failures), 13 were negative because of successful H pylori eradication, and 29 were controls. H pylori-positive patients relapsed earlier (54 days) than did those in whom H pylori was eradicated (100 days) (p=0.046). The H pylori-negative control group relapsed after the longest period (110 days). However, time to relapse was also affected by oesophagitis grade (no oesophagitis 127 days, grade III or IV oesophagitis 18 days). When results were corrected for the affect of oesophagitis grade, H pylori-positive patients relapsed earlier (p=0.086) than H pylori-eradiated patients and controls (p=0.001). INTERPRETATION: H pylori infection positively affects the relapse rate of GORD. Eradication of H pylori could, therefore, help to prolong disease-free interval in patients with GORD.

Effects of alosetron on gastrointestinal transit time and rectal sensation in patients with irritable bowel syndrome.

BACKGROUND: Alosetron, a 5-HT3-receptor antagonist, relieves abdominal pain and improves bowel function in non-constipated, female patients with irritable bowel syndrome. 5-HT3 antagonists delay colonic transit, increase colonic compliance, and increase small intestinal water absorption. AIM: To evaluate the effects of alosetron on gastrointestinal and colonic transit, rectal compliance and rectal sensation in irritable bowel syndrome. METHODS: A double-blind, placebo-controlled, two-dose study of alosetron was performed in 25 non-constipated irritable bowel syndrome patients, with paired studies before and after 4 weeks of treatment with placebo (n=5), 1 mg alosetron (n=10) or 4 mg (n=10) alosetron b.d. Gastrointestinal and colonic transit were measured by scintigraphy. Rectal compliance and sensation were assessed by rectal balloon distention with a barostat. RESULTS: There was a trend (P=0.06) for 1 mg alosetron to increase rectal compliance (median pressure at half maximum volume 11 mmHg after alosetron vs. 15.6 mmHg before alosetron). The 1 mg b.d. alosetron dose non-significantly retarded proximal colonic transit. Alosetron and placebo reduced sensory scores relative to baseline values; none of the changes induced by alosetron was significant relative to placebo. CONCLUSIONS: Alosetron had no significant effect on gastrointestinal transit or rectal sensory and motor mechanisms in non-constipated irritable bowel syndrome patients in this study. Alosetron's effects on colonic sensorimotor function and central sensory mechanisms deserve further evaluation.

Modulation of gastric sensory and motor functions by nitrergic and alpha2-adrenergic agents in humans.

BACKGROUND & AIMS: Disturbed gastric accommodation and sensation contribute to postprandial symptoms in dyspepsia, but the controlling mechanisms are unclear. Nitrergic and alpha2-adrenergic modulation of gastric sensory and motor function were assessed in this study. METHODS: Using a factorial design, we assessed drug effects on gastric sensation during isobaric distentions and fasting and postprandial gastric motor function in 32 healthy volunteers. Each participant received one treatment: placebo; 0.3 or 0.5 microgram. kg-1. min-1 intravenous nitroglycerin; 0.0125, 0.025, or 0.1 mg clonidine orally; or combined nitroglycerin plus clonidine. In 16 other healthy subjects, the effects of clonidine and placebo on gastric emptying of solids were evaluated using the 13C-octanoic acid breath test. RESULTS: Clonidine and nitroglycerin increased gastric compliance, but normal postprandial accommodation was still observed despite the induced relaxation. Clonidine but not nitroglycerin reduced aggregate and pain perception averaged over four distention levels. There were no significant drug interactions. No dose effect of clonidine was observed on gastric emptying. CONCLUSIONS: Clonidine relaxes the stomach and reduces gastric sensation without inhibiting accommodation or emptying. Nitroglycerin relaxes the stomach without altering perception. Studies of the effects of clonidine on these gastric functions and symptoms in disease are warranted.