G. S. Hebbard

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.

Motor function of the proximal stomach and visceral perception in gastro-oesophageal reflux disease

Background—The abnormally high postprandial rate of transient lower oesophageal sphincter relaxations seen in patients with reflux disease may be related to altered proximal gastric motor function. Heightened visceral sensitivity may also contribute to reporting of symptoms in these patients. Aims—To assess motor function of the proximal stomach and visceral perception in reflux disease with a barostat. Methods—Fasting and postprandial proximal gastric motility, sensation, and symptoms were measured in nine patients with reflux disease and nine healthy subjects. Gastric emptying of solids and liquids was assessed in six of the patients on a different day (and compared to historical controls). Results—Minimal distending pressure and gastric compliance were similar in the two groups, whereas the patients experienced fullness at lower pressures (p<0.05) and discomfort at lower balloon volumes (p<0.005) during isobaric and isovolumetric distensions respectively. Maximal gastric relaxation induced by the meal was similar in the two groups. Late after the meal, however, proximal gastric tone was lower (p<0.01) and the score for fullness higher (p<0.01) in the reflux patients, in whom the retention of both solids and liquids in the proximal stomach was greater (p<0.05). Conclusions—Reflux disease is associated with delayed recovery of proximal gastric tone after a meal and increased visceral sensitivity. The former may contribute to the increased prevalence of reflux during transient lower oesophageal sphincter relaxations and the delay in emptying from the proximal stomach, whereas both may contribute to symptom reporting.

Hyperglycaemia affects proximal gastric motor and sensory function in normal subjects

Objective: Hyperglycaemia delays gastric emptying in normal subjects and patients with diabetes mellitus by uncertain mechanisms and may affect the perception of somatic sensations. The effects of hyperglycaemia on the motor function of the proximal stomach and the perception of gastric distension were evaluated in normal subjects. Design: Paired studies were performed in randomized order in 10 healthy volunteers on separate days during euglycaemia and hyperglycaemia (blood glucose ≈ 15mmol/l). Methods: With a barostat and a balloon positioned in the proximal stomach, fasting subjects underwent a stepwise gastric distension. Each 2mmHg step was maintained at a constant pressure for 2min. The volume of the barostat balloon was measured and perception of the sensations of fullness, desire to belch, nausea, abdominal discomfort and hunger was scored at each step. Results: Hyperglycaemia was associated with an increase in proximal gastric compliance (P<0.01) evident from 2mmHg above basal intragastric pressure. Perception scores for the sensations of nausea and desire to belch were greater during hyperglycaemia than euglycaemia (P<0.05) in relation to both pressure at each step and volume. Hyperglycaemia did not affect perception of the sensations of abdominal discomfort, fullness or hunger. Conclusions: Hyperglycaemia increases proximal gastric compliance, reflecting a reduction in gastric tone. This may contribute to the previously observed delay in gastric emptying associated with hyperglycaemia. Hyperglycaemia appears to increase the perception of some of the sensations induced by gastric distension.

Quantification of distal antral contractile motility in healthy human stomach with magnetic resonance imaging.

To quantify healthy postprandial: 1) propagation, periodicity, geometry, and percentage occlusion by distal antral contraction waves (ACWs); and 2) changes in ACW activity in relationship to gastric emptying (GE).

Physiology of the oesophageal transition zone in the presence of chronic bolus retention: studies using concurrent high resolution manometry and digital fluoroscopy.

Abstract  Distinct contraction waves (CWs) exist above and below the transition zone (TZ) between the striated and smooth muscle oesophagus. We hypothesize that bolus transport is impaired in patients with abnormal spatio‐temporal coordination and/or contractile pressure in the TZ. Concurrent high resolution manometry and digital fluoroscopy were performed in healthy subjects and patients with reflux oesophagitis; a condition associated with ineffective oesophageal contractility and clearance. A detailed analysis of space–time variations in bolus movement, intra‐bolus and intra‐luminal pressure was performed on 17 normal studies and nine studies in oesophagitis patients with impaired bolus transit using an interactive computer based system. Compared with normal controls, oesophagitis patients had greater spatial separation between the upper and lower CW tails [median 5.2 cm (range 4.4–5.6) vs 3.1 cm (2.2–3.7)], the average relative pressure within the TZ region (TZ strength) was lower [30.8 mmHg (28.3–36.5) vs 45.8 mmHg (36.1–55.7), P < 0.001], and the risk of bolus retention was higher (90%vs 12%; P < 0.01). The presence of bolus retention was associated with a wider spatial separation of the upper and lower CWs (>3 cm, the upper limit of normal; P < 0.002), independent of the presence of oesophagitis. We conclude that bolus retention in the TZ is associated with excessively wide spatial separation between the upper and lower CWs and lower TZ muscle squeeze. These findings provide a physio‐mechanical basis for the occurrence of bolus retention at the level of the aortic arch, and may underlie impaired clearance with reflux oesophagitis.

Proximal gastric compliance and perception of distension in type 1 diabetes mellitus: effects of hyperglycemia

OBJECTIVES:Upper GI symptoms and disordered gastric motor function occur frequently in patients with type 1 diabetes mellitus and may be influenced by the blood glucose concentration. The aims of this study were to evaluate proximal gastric compliance and perception of gastric distension during euglycemia and hyperglycemia in unselected patients with type 1 diabetes.METHODS:Ten randomly selected patients with type 1 diabetes were studied. On a single day, isovolumetric and isobaric distensions of the proximal stomach were performed during both euglycemia (blood glucose, 6 mmol/L) and hyperglycemia (15 mmol/L), in randomized order. Sensations of fullness, nausea, and bloating were scored using visual analog scales during each step. Results were compared with those obtained in 10 healthy subjects studied during euglycemia.RESULTS:During euglycemia, perceptions of fullness (p < 0.01), nausea (p < 0.01), and bloating (p < 0.05) were greater during gastric distension in patients with diabetes when compared with healthy controls. In the patients, hyperglycemia increased gastric compliance (p < 0.05) when compared to euglycemia.CONCLUSIONS:In unselected patients with type 1 diabetes 1) the perception of gastric distension during euglycemia is increased compared with healthy controls, and 2) hyperglycemia increases proximal gastric compliance.

A novel portable perfused manometric system for recording of small intestinal motility

The development of solid‐state catheters with miniature pressure transducers and portable dataloggers with a large memory capacity has allowed recording of gastrointestinal motility in ambulant subjects. Developments in silicone rubber extrusion technology made it possible to build a perfused mano‐metric system, using a perfused manometric assembly requiring a low volume of perfusate. In the present study the feasibility of recording and automated analysis of small intestinal motility using a perfused multiple lumen manometric system was evaluated in seven healthy volunteers. Pressures were recorded from 12 sideholes arranged in four clusters spaced at 10‐cm intervals from the catheter tip. Each channel was perfused at 0.15 mL min−1 with degassed water by a portable, low‐compliance, perfusion pump. The 12 sidehole recording channels were connected to external transducers mounted on a belt. Pressure data were stored in two dataloggers. Motility was recorded in the sitting (30 min), and supine (30 min) position, during walking (30 min) and postprandially (90 min). Using purpose‐built software baseline variations were corrected for and manometric variables (number of pressure waves, mean amplitude and motility index) calculated. Bench testing of the manometric assembly showed a median baseline pressure offset of 4.2 kPa (range 3.7–10.1) and upon occlusion a rise rate of 27.8 kPa sec−1 (range 19.7–30.8). Changes in body position affected baseline pressures so that compared to the supine position changes in baseline pressure varied between 1.5 ± 0.7 kPa and 1.9 ± 0.6 kPa during sitting (P < 0.02), and between 1.7 ± 0.7 kPa and 1.5 ± 0.9 kPa during walking (P < 0.03). Manometric recordings obtained during the fasting period showed an increase in small intestinal motor activity during walking. In the postprandial period no differences in motility variables were observed within one cluster and in time. Recording of small intestinal motility with a multiple‐channel silicone rubber manometric assembly with a portable perfusion system is a feasible technique which is relatively inexpensive. Computer‐assisted data processing allows for adequate elimination of artefacts and automated numerical analysis.

Effects of nitroglycerin on liquid gastric emptying and antropyloroduodenal motility.

The effects of the nitric oxide donor nitroglycerin on gastric emptying and antropyloroduodenal motility were evaluated in nine healthy male subjects (ages 19-36 yr). Antropyloroduodenal pressures were recorded with a manometric assembly that had nine side holes spanning the antrum and proximal duodenum and a pyloric sleeve sensor; gastric emptying was quantified scintigraphically. In each subject, the emptying of 300 ml of 25% glucose labeled with 99mTc was assessed on two separate days during intravenous infusion of either nitroglycerin (5 micrograms/min in 5% dextrose) or 5% dextrose (control). Studies were performed with the subject in the supine position; blood pressure and heart rate were monitored. Nitroglycerin had no significant effect on blood pressure or heart rate. Nitroglycerin slowed gastric emptying (P < 0.02), and this was associated with greater retention of the drink in the proximal stomach (P < 0.05). In both nitroglycerin and control studies, ingestion of the drink was associated with an increase in the number of isolated pyloric pressure waves (P < 0.05) and antral pressure wave sequences (P < 0.05). Nitroglycerin reduced the number of isolated pyloric pressure waves (P < 0.05), basal pyloric pressure (P < 0.05), and the number of antral pressure wave sequences (P < 0. 05), but not the total number of antral pressure waves. The rate of gastric emptying and the number of isolated pyloric pressure waves were inversely related during control (P = 0.03) and nitroglycerin (P < 0.05) infusions. We conclude that in normal subjects, 1) gastric emptying of 300 ml of 25% glucose is inversely related to the frequency of phasic pyloric pressure waves, and 2) nitroglycerin in a dose of 5 micrograms/min inhibits pyloric motility, alters the organization but not the number of antral pressure waves, and slows gastric emptying and intragastric distribution of 25% glucose.The effects of the nitric oxide donor nitroglycerin on gastric emptying and antropyloroduodenal motility were evaluated in nine healthy male subjects (ages 19-36 yr). Antropyloroduodenal pressures were recorded with a manometric assembly that had nine side holes spanning the antrum and proximal duodenum and a pyloric sleeve sensor; gastric emptying was quantified scintigraphically. In each subject, the emptying of 300 ml of 25% glucose labeled with99mTc was assessed on two separate days during intravenous infusion of either nitroglycerin (5 μg/min in 5% dextrose) or 5% dextrose (control). Studies were performed with the subject in the supine position; blood pressure and heart rate were monitored. Nitroglycerin had no significant effect on blood pressure or heart rate. Nitroglycerin slowed gastric emptying ( P < 0.02), and this was associated with greater retention of the drink in the proximal stomach ( P < 0.05). In both nitroglycerin and control studies, ingestion of the drink was associated with an increase in the number of isolated pyloric pressure waves ( P < 0.05) and antral pressure wave sequences ( P < 0.05). Nitroglycerin reduced the number of isolated pyloric pressure waves ( P < 0.05), basal pyloric pressure ( P < 0.05), and the number of antral pressure wave sequences ( P < 0.05), but not the total number of antral pressure waves. The rate of gastric emptying and the number of isolated pyloric pressure waves were inversely related during control ( P = 0.03) and nitroglycerin ( P < 0.05) infusions. We conclude that in normal subjects, 1) gastric emptying of 300 ml of 25% glucose is inversely related to the frequency of phasic pyloric pressure waves, and 2) nitroglycerin in a dose of 5 μg/min inhibits pyloric motility, alters the organization but not the number of antral pressure waves, and slows gastric emptying and intragastric distribution of 25% glucose.

Effects of duodenal distension on antropyloroduodenal pressures and perception are modified by hyperglycemia

Marked hyperglycemia (blood glucose approximately 15 mmol/l) affects gastrointestinal motor function and modulates the perception of gastrointestinal sensations. The aims of this study were to evaluate the effects of mild hyperglycemia on the perception of, and motor responses to, duodenal distension. Paired studies were done in nine healthy volunteers, during euglycemia ( approximately 4 mmol/l) and mild hyperglycemia ( approximately 10 mmol/l), in randomized order, using a crossover design. Antropyloroduodenal pressures were recorded with a manometric, sleeve-side hole assembly, and proximal duodenal distensions were performed with a flaccid bag. Intrabag volumes were increased at 4-ml increments from 12 to 48 ml, each distension lasting for 2.5 min and separated by 10 min. Perception of the distensions and sensations of fullness, nausea, and hunger were evaluated. Perceptions of distension (P < 0.001) and fullness (P < 0.05) were greater and hunger less (P < 0.001) during hyperglycemia compared with euglycemia. Proximal duodenal distension stimulated pyloric tone (P < 0.01), isolated pyloric pressure waves (P < 0.01), and duodenal pressure waves (P < 0.01). Compared with euglycemia, hyperglycemia was associated with increases in pyloric tone (P < 0.001), the frequency (P < 0.05) and amplitude (P < 0.01) of isolated pyloric pressure waves, and the frequency of duodenal pressure waves (P < 0.001) in response to duodenal distension. Duodenal compliance was less (P < 0.05) during hyperglycemia compared with euglycemia, but this did not account for the effects of hyperglycemia on perception. We conclude that both the perception of, and stimulation of pyloric and duodenal pressures by, duodenal distension are increased by mild hyperglycemia. These observations are consistent with the concept that the blood glucose concentration plays a role in the regulation of gastrointestinal motility and sensation.Marked hyperglycemia (blood glucose ∼15 mmol/l) affects gastrointestinal motor function and modulates the perception of gastrointestinal sensations. The aims of this study were to evaluate the effects of mild hyperglycemia on the perception of, and motor responses to, duodenal distension. Paired studies were done in nine healthy volunteers, during euglycemia (∼4 mmol/l) and mild hyperglycemia (∼10 mmol/l), in randomized order, using a crossover design. Antropyloroduodenal pressures were recorded with a manometric, sleeve-side hole assembly, and proximal duodenal distensions were performed with a flaccid bag. Intrabag volumes were increased at 4-ml increments from 12 to 48 ml, each distension lasting for 2.5 min and separated by 10 min. Perception of the distensions and sensations of fullness, nausea, and hunger were evaluated. Perceptions of distension ( P < 0.001) and fullness ( P < 0.05) were greater and hunger less ( P < 0.001) during hyperglycemia compared with euglycemia. Proximal duodenal distension stimulated pyloric tone ( P < 0.01), isolated pyloric pressure waves ( P < 0.01), and duodenal pressure waves ( P< 0.01). Compared with euglycemia, hyperglycemia was associated with increases in pyloric tone ( P < 0.001), the frequency ( P < 0.05) and amplitude ( P < 0.01) of isolated pyloric pressure waves, and the frequency of duodenal pressure waves ( P < 0.001) in response to duodenal distension. Duodenal compliance was less ( P < 0.05) during hyperglycemia compared with euglycemia, but this did not account for the effects of hyperglycemia on perception. We conclude that both the perception of, and stimulation of pyloric and duodenal pressures by, duodenal distension are increased by mild hyperglycemia. These observations are consistent with the concept that the blood glucose concentration plays a role in the regulation of gastrointestinal motility and sensation.

Pharmacokinetic considerations in gastrointestinal motor disorders

SummaryAlthough it has been recognised that alterations in gastrointestinal motility, whether induced by physiological or pathological processes, have significant effects on the pharmacokinetics of orally administered drugs, this subject has received inappropriately little attention. Studies relating to this topic have focused on healthy volunteers and animals and have largely been confined to the effects of single drug doses. There is limited information about the effects of disease on pharmacokinetics under steady-state conditions.Changes in gastrointestinal motility may affect the pharmacokinetics of orally administered drugs by altering the rate of delivery, bioavailability or mucosal absorption of the drug. In general the rate of absorption and time taken to achieve maximal plasma concentrations for well absorbed drugs may be modified by changes in gastrointestinal motility, but overall bioavailability is not usually affected. In these cases the therapeutic and clinical effects of the alteration in pharmacokinetics will, therefore, depend on which parameters are important for the action of the drug. For poorly absorbed drugs both the rate of absorption and bioavailability are likely to be altered by changes in gastrointestinal motility However, the complex effects of food and disease, as well as the properties and formulation of any drug (solubility, ease of dispersion, delayed release formulation) often make the prediction of the magnitude, or even the direction, of any effect difficult to predict. Drugs with direct effects on gastrointestinal motility may influence their own patterns of absorption.In patients with gastrointestinal motility disorders, drugs administered in a controlled release formulation, or those with poor bioavailability, are most likely to have a poorly predictable therapeutic effect. Care should be taken to ensure that the formulation of the drug, its timing of administration in relation to meals and the use of coadministered drugs optimise, or at least ensure consistent absorption.