Richard H. Holloway

Transient lower esophageal sphincter relaxation

RAVINDER K. MITTAL,* RICHARD H. HOLLOWAY,* ROBERTO PENAGINI, § L. ASHLEY BLACKSHAW, t and JOHN DENT* *Department of Internal Medicine, University of Virginia, Charlottesville, Virginia; *Gastrointestinal Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia; and §Cattedra di Gastroenterologia, Istituto di Scienze Mediche, University of Milan, IRCCS Ospedale Maggiore, Milan, Italy

Control of transient lower oesophageal sphincter relaxations and reflux by the GABA B agonist baclofen in patients with gastro-oesophageal reflux disease

Background and aims: Transient lower oesophageal sphincter relaxations (TLOSRs) are the major cause of gastro-oesophageal reflux in normal subjects and in most patients with reflux disease. The gamma aminobutyric acid (GABA) receptor type B agonist, baclofen, is a potent inhibitor of TLOSRs in normal subjects. The aim of this study was to investigate the effect of baclofen on TLOSRs and postprandial gastro-oesophageal reflux in patients with reflux disease. Methods: In 20 patients with reflux disease, oesophageal motility and pH were measured, with patients in the sitting position, for three hours after a 3000 kJ mixed nutrient meal. On separate days at least one week apart, 40 mg oral baclofen or placebo was given 90 minutes before the meal. Results: Baclofen reduced the rate of TLOSRs by 40% from 15 (13.8–18.3) to 9 (5.8–13.3) per three hours (p<0.0002) and increased basal lower oesophageal sphincter pressure. Baclofen also significantly reduced the rate of reflux episodes by 43% from 7.0 (4.0–12.0) to 4.0 (1.5–9) per three hours (median (interquartile range); p<0.02). However, baclofen had no effect on oesophageal acid exposure (baclofen 4.9% (1.7–12.4) v placebo 5.0% (2.7–15.5)). Conclusions: In patients with reflux disease, the GABAB agonist baclofen significantly inhibits gastro-oesophageal reflux episodes by inhibition of TLOSRs. These findings suggest that GABAB agonists may be useful as therapeutic agents for the management of reflux disease.

Control of transient lower esophageal sphincter relaxations and reflux by the GABAB agonist baclofen in normal subjects

BACKGROUND & AIMS Transient lower esophageal sphincter (LES) relaxations are the major mechanism of gastroesophageal reflux in normal subjects and in most patients with reflux disease. gamma-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter within the central nervous system which is present in regions of the brainstem that are believed to mediate transient LES relaxations. The aim of this study was to investigate the effect of a GABA(B) agonist baclofen on postprandial gastroesophageal reflux and transient LES relaxations. METHODS In 20 healthy volunteers, esophageal motility and pH were measured, with the subjects in the sitting position, for 3 hours after a 3000-kJ mixed nutrient meal. On separate days at least 1 week apart, 40 mg oral baclofen or placebo was given 90 minutes before the meal. RESULTS Baclofen significantly reduced the rate of reflux episodes by more than 60% from 1.0 (0.3-2.7) to 0.3 (0-1.0) per hour (median [interquartile range]). Baclofen also reduced the rate of transient LES relaxations from 5.7 (4.9-7.8) to 2.2 (1.3-3.8) per hour and increased basal LES pressure from 8.7 +/- 1.4 to 10.8 +/- 0.8 mm Hg. CONCLUSIONS In normal human subjects, the GABA(B) agonist baclofen significantly inhibits gastroesophageal reflux by inhibition of transient LES relaxations. These findings suggest that GABA(B) agonists may be useful as therapeutic agents for the management of reflux in patients with gastroesophageal reflux disease.

Mechanisms of gastroesophageal reflux in ambulant healthy human subjects

BACKGROUND/AIMS Investigation of the motor events underlying gastroesophageal reflux has largely been confined to resting, recumbent subjects. The motor events associated with reflux during physical activity remain unknown. The aim of this study was to investigate the patterns of lower esophageal sphincter (LES) function underlying reflux in healthy subjects and the effect of exercise and physical activity on reflux mechanisms. METHODS LES pressure was recorded with a perfused sleeve sensor in 10 healthy subjects; intraluminal transducers recorded pressure in the stomach, esophagus, and pharynx, and pH was recorded 5 cm above the LES. Signals were stored in a portable data-logger. Recordings were made for 24 hours, including moderate physical activity, periods of rest and sleep, standardized meals, and standardized exercise. RESULTS Most reflux episodes (81 of 123; 66%) occurred in the 3 hours after food intake; only 2 episodes occurred during exercise. LES pressure was < or = 3 cm H2O in 79% of reflux episodes. Transient LES relaxation was the mechanism of reflux in 82% of episodes, irrespective of activity or body position, whereas swallow-related LES relaxations accounted for 13% and persistently absent LES pressure accounted for 1%. Straining occurred in only 20% of episodes. CONCLUSIONS In ambulant healthy subjects, accurate continuous recording of LES function is possible, reflux usually occurs during transient LES relaxations, and straining is not a major factor in the induction of reflux.

Patterns of gas and liquid reflux during transient lower oesophageal sphincter relaxation: a study using intraluminal electrical impedance

Background Belching has been proposed as a major mechanism underlying acid gastro-oesophageal reflux in normal subjects. However, the presence of oesophageal gas has not been measured directly but only inferred from manometry. Aims To investigate, using intraluminal electrical impedance, the patterns of gas and liquid reflux during transient lower oesophageal sphincter (LOS) relaxations, the main mechanism of acid reflux in normal subjects. Methods Impedance changes associated with the passage of gas were studied in vitro, and in vivo in cats. Oesophageal manometry, pH, and intraluminal electrical impedance measurements were performed in 11 normal subjects after a meal. Results Gas reflux caused a sudden increase in impedance that propagated rapidly to the proximal oesophagus whereas liquid reflux induced a retrogressively propagated fall in impedance. Impedance showed gas or liquid reflux during most (102/141) transient LOS relaxations. When acid reflux occurred, impedance showed evidence of intraoesophageal retrograde flow of liquid in the majority (78%) of events. Evidence of gas retroflow was found in almost half (47%) of acid reflux episodes. When present together, however, liquid preceded gas on 44% of occasions. Overall, gas reflux occurred as the initial event in only 25% of acid reflux episodes. Conclusions These findings suggest that in upright normal subjects, although belching can precipitate acid reflux, most acid reflux occurs as a primary event.

Composition of the postprandial refluxate in patients with gastroesophageal reflux disease

OBJECTIVE:It is not known whether the characteristics of the postprandial refluxate in patients with gastroesophageal reflux disease (GERD) differ from those observed in normal subjects. The aim of this study was to characterize the postprandial refluxate in adult patients with GERD using combined intraluminal electrical impedance and pH measurements.METHODS:Postprandial gastroesophageal reflux was assessed in 16 patients with GERD and 15 controls. pH and intraluminal electrical impedance were used to identify acid and nonacid reflux of liquid, mixed (liquid + gas) or gas.RESULTS:Transient lower esophageal sphincter relaxations (TLESRs) and reflux of gastric contents were equally frequent in both groups. However, patients with GERD had more acid reflux [8 (4.7–10.5)/h vs 3.5 (2.6–6)/h, p < 0.05], and normal subjects had more nonacid reflux [5 (4.3–6.7)/h vs 3 (1–3.5)/h, p < 0.05]. Gas reflux was less frequent in GERD than in controls (51% vs 68%; p < 0.05). Pure liquid reflux, however, was more frequent (40% vs 26%, p < 0.05) and twice as likely to be acid in GERD. During TLESRs, liquid acid reflux was more frequent in GERD than in controls.CONCLUSIONS:TLESRs and reflux of gastric contents are similarly frequent in patients with GERD and controls. However, patients with GERD have more acid reflux and less nonacid reflux. Differences in the air–liquid composition of the refluxate may contribute to the higher rate of acid reflux observed in these patients.

Provocation of transient lower esophageal sphincter relaxations by meals in patients with symptomatic gastroesophageal reflux

The effect of a meal on the rate of transient lower esophageal sphinter (LES) relaxations and patterns of gastroesophageal reflux was investigated in 49 patients referred for evaluation of gastroesophageal reflux. Esophageal motility and pH were recorded concurrently before and after a standard meal. In the patients with symptomatic reflux, the meal induced a four-to sevenfold increase in the gastroesophageal reflux through two mechanisms: a four-to fivefold increase in the rate of transient LES relaxations and an increase in the proportion of transient LES relaxations accompanied by reflux from 47% to 68^. Overall the rate of reflux episodes that occurred by mechanisms other than transient LES relaxation did not increase significantly. An exception to these findings were those in six patients with chronically absent basal LES pressure in whom transient LES relaxations could not be scored. In these patients, reflux increased postprandially through mechanisms other than transient LES relaxation. These findings confirm the pivotal importance of transient LES relaxations in the pathogenesis of gastroesophageal reflux.

Relevance of ineffective oesophageal motility during oesophageal acid clearance

Background: Oesophageal clearance of acid reflux consists of an initial volume clearance followed by neutralisation of the acidified mucosa by swallowed saliva (chemical clearance). Ineffective oesophageal motility (IOM), a frequent finding in patients with gastro-oesophageal reflux disease (GORD), has been claimed to underlie prolonged acid clearance by affecting oesophageal emptying and saliva transport. Intraluminal impedance allows non-radiological monitoring of movement of oesophageal liquids. Aims: To evaluate the relevance of IOM during oesophageal volume and chemical clearance using combined pH impedance measurements. Subjects: Impedance was validated with fluoroscopy to study volume clearance in three healthy subjects. Acid clearance tests were performed in 10 healthy subjects in the upright and supine positions, before and after oesophageal peristaltic disruption with sildenafil 50 mg. Methods: After instillation of an acid bolus, simultaneous manometry, pH, and impedance were used to study oesophageal motility, chemical clearance, and volume clearance, respectively. Results: Impedance allowed assessment of volume clearance accurately, showing a strong correlation with fluoroscopy (r2=0.89). Sildenafil provoked a graded impairment in oesophageal motility in healthy subjects without affecting saliva secretion. In the upright position, volume clearance was slightly prolonged only with severe IOM (>80% abnormal peristaltic sequences). In the supine position, severe IOM significantly prolonged chemical and volume clearance. Moderate IOM (30–80% abnormal peristalsis) had no effect. With normal peristalsis and moderate IOM, clearance times were similar in the upright and supine positions. Severe IOM however had a greater impact on clearance in the supine than in the upright position. Conclusion: Ineffective oesophageal motility has little effect on oesophageal clearance during upright acid reflux. With supine reflux, only severe IOM is associated with prolonged oesophageal clearance.

Involvement of nitric oxide in human transient lower esophageal sphincter relaxations and esophageal primary peristalsis.

BACKGROUND & AIMS Nitric oxide (NO) is well accepted as an inhibitory neurotransmitter in the gastrointestinal tract; however, its role in the triggering of transient lower esophageal sphincter relaxations (TLESRs) in humans remains to be determined. Therefore, the effect of NG-monomethyl-L-arginine (L-NMMA), a specific NO synthase blocker, on gastric distention-induced TLESRs was investigated. METHODS Esophageal manometry was performed using a perfused sleeve assembly. The effect of L-NMMA was evaluated on water swallow-evoked primary peristalsis (n = 8; single-blind, placebo-controlled) and on the rate of TLESRs during gastric distention (n = 8; double-blind, placebo-controlled). RESULTS L-NMMA increased the amplitude of peristaltic pressure waves in the distal esophagus and increased peristaltic velocity in the proximal esophagus. In contrast, L-NMMA had no effect on basal lower esophageal sphincter pressure, nadir pressure, duration, and area under the curve of lower esophageal sphincter relaxation. L-NMMA significantly inhibited the increase in TLESRs during gastric distention. L-NMMA also increased the intraballoon pressure during distention. CONCLUSIONS NO is one of the neurotransmitters involved in the reflex arc mediating the triggering of TLESRs. NO is involved in the timing of human esophageal peristalsis and may exert a tonic inhibition on the proximal stomach.

Hypofractionated Versus Conventionally Fractionated Radiotherapy for Prostate Carcinoma: Final Results of Phase III Randomized Trial

PURPOSE To evaluate the long-term efficacy and toxicity of a hypofractionated (55 Gy in 20 fractions within 4 weeks) vs. a conventionally fractionated (64 Gy in 32 fractions within 6.5 weeks) dose schedule for radiotherapy (RT) for localized carcinoma of the prostate. METHODS AND MATERIALS A total of 217 patients were randomized to either the hypofractionated (n=108) or the conventional (n=109) dose schedule. Most patients (n=156) underwent RT planning and RT using a two-dimensional computed tomography method. Efficacy using the clinical, radiologic, and prostate-specific antigen data in each patient was evaluated before RT and at predetermined intervals after RT until death. Gastrointestinal and genitourinary toxicity using the modified Late Effect in Normal Tissue-Subjective Objective Management Analytic (LENT-SOMA) scales was also evaluated before and at intervals after RT to 60 months. RESULTS The whole group has now been followed for a median of 90 months (range, 3-138). Of the 217 patients, 85 developed biochemical relapse (nadir prostate-specific antigen level+2 μg/L), 36 in the hypofractionated and 49 in the conventional group. The biochemical relapse-free, but not overall, survival at 90 months was significantly better with the hypofractionated (53%) than with the conventional (34%) schedule. Gastrointestinal and genitourinary toxicity persisted 60 months after RT and did not differ between the two dose schedules. Multivariate analyses revealed that the conventional schedule was of independent prognostic significance, not only for biochemical failure, but also for an increased risk of worse genitourinary symptoms at 4 years. CONCLUSIONS A therapeutic advantage of the hypofractionated compared with the conventional dose schedule for RT of prostate cancer was evident at 90 months in the present study.