Manometric features of eosinophilic esophagitis in esophageal pressure topography

Background Although most of the patients with eosinophilic esophagitis (EoE) have mucosal and structural changes that could potentially explain their symptoms, it is unclear whether EoE is associated with abnormal esophageal motor function. The aims of this study were to evaluate the esophageal pressure topography (EPT) findings in EoE and to compare them with controls and patients with gastro‐esophageal disease (GERD). Methods Esophageal pressure topography studies in 48 EoE patients, 48 GERD patients, and 50 controls were compared. The esophageal contractile pattern was described for ten 5‐mL swallows for each subject and each swallow was secondarily characterized based on the bolus pressurization pattern: absent, pan‐esophageal pressurization, or compartmentalized distal pressurization. Key Results Thirty‐seven percent of EoE patients were classified as having abnormal esophageal motility. The most frequent diagnoses were of weak peristalsis and frequent failed peristalsis. Although motility disorders were more frequent in EoE patients than in controls, the prevalence and type were similar to those observed in GERD patients (P = 0.61, chi‐square test). Pan‐esophageal pressurization was present in 17% of EoE and 2% of GERD patients while compartmentalized pressurization was present in 19% of EoE and 10% of GERD patients. These patterns were not seen in control subjects. Conclusions & Inferences The prevalence of abnormal esophageal motility in EoE was approximately 37% and was similar in frequency and type to motor patterns observed in GERD. Eosinophilic esophagitis patients were more likely to have abnormal bolus pressurization patterns during swallowing and we hypothesize that this may be a manifestation of reduced esophageal compliance.     

Effects of mosapride on esophageal secondary peristalsis in humans

Background Secondary peristalsis is important for the clearance of refluxate or retained food bolus from the esophagus. Mosapride is a prokinetic agent that enhances GI motility by stimulating 5‐hydroxytrypatamine₄ (5‐HT₄) receptors, but its effects on secondary peristalsis are yet unclear in humans. We aimed to investigate the effect of a 5‐HT₄ agonist mosapride on esophageal distension‐induced secondary peristalsis in normal subjects. Methods After a baseline recording esophageal motility, secondary peristalsis was generated by slow and rapid mid‐esophageal injections of air in 15 healthy subjects. Two separate sessions with 40 mg oral mosapride or placebo were randomly performed to test their effects on esophageal secondary peristalsis. Key Results Mosapride decreased the threshold volume for triggering secondary peristalsis during rapid air distension (4.5 ± 0.3 vs 5.3 ± 0.4 mL; P = 0.04) but not slow air distension (14.3 ± 1.2 vs 13.3 ± 1.3 mL; P = 0.41). Secondary peristalsis was triggered more frequently in response to rapid air distension after application of mosapride [100% (90–100%) vs 90% (80–100%); P = 0.02]. Mosapride significantly increased pressure wave amplitudes of secondary peristalsis during slow (135.4 ± 13.8 vs 105.0 ± 12.9 mmHg; P = 0.001) and rapid air distensions (124.0 ± 11.6 vs 95.9 ± 14.0 mmHg; P = 0.002). Conclusions & Inferences Mosapride enhances sensitivity to distension‐induced secondary peristalsis and facilitates secondary peristaltic contractility. These data provide an evidence for modulation of esophageal secondary peristalsis by the 5‐HT₄ agonist mosapride, as well support for its clinical utility.     

High‐resolution esophageal pressure topography is superior to conventional sleeve manometry for the detection of transient lower esophageal sphincter relaxations associated with a reflux event

Background Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro‐esophageal reflux and are detected during manometric studies using well defined criteria. Recently, high‐resolution esophageal pressure topography (HREPT) has been introduced and is now considered as the new standard to study esophageal and lower esophageal sphincter (LES) function. In this study we performed a head‐to‐head comparison between HREPT and conventional sleeve manometry for the detection of TLESRs. Methods A setup with two synchronized MMS‐solar systems was used. A solid state HREPT catheter, a water‐perfused sleeve catheter, and a multi intraluminal impedance pH (MII‐pH) catheter were introduced in 10 healthy volunteers (M6F4, age 19–56). Subjects were studied 0.5 h before and 3 h after ingestion of a standardized meal. Tracings were blinded and analyzed by the three authors according to the TLESR criteria. Key Results In the HREPT mode 156 TLESRs were scored, vs 143 during sleeve manometry (P = 0.10). Hundred and twenty‐three TLESRs were scored by both techniques. Of all TLESRs (177), 138 were associated with reflux (78%). High‐resolution esophageal pressure topography detected significantly more TLESRs associated with a reflux event (132 vs 119, P = 0.015) resulting in a sensitivity for detection of TLESRs with reflux of 96% compared to 86% respectively. Analysis of the discordant TLESRs associated with reflux showed that TLESRs were missed by sleeve manometry due to low basal LES pressure (N = 5), unstable pharyngeal signal (N = 4), and residual sleeve pressure >2 mmHg (N = 10). Conclusions & Inferences The HREPT is superior to sleeve manometry for the detection of TLESRs associated with reflux. However, rigid HREPT criteria are awaited.     

Effects of effortful swallow on esophageal function in healthy adults

Background Treatment for esophageal dysmotility is currently limited to primarily pharmacologic intervention, which has questionable utility and frequently associated negative side effects. A potential behavioral intervention for esophageal dysmotility is the effortful oropharyngeal swallow. A previous pilot study using water perfusion manometry found an increase in distal esophageal amplitudes during effortful vs non‐effortful swallowing. The current study sought to duplicate the previous study with improvements in methodology. Methods The effects of swallow condition (effortful vs non‐effortful), sensor site, and gender on esophageal amplitude, duration, velocity, and bolus clearance were examined for 18 adults (nine males and nine females, mean age = 29.9 years) via combined solid‐state manometry and intraluminal impedance. Key Results The effortful swallow condition yielded significantly higher esophageal amplitudes across all sensor locations (P < 0.05). Further, the effortful swallowing decreased the risk of incomplete bolus clearance when compared with non‐effortful swallowing (OR: 0.51; 95% CI: 0.30–0.86). Conclusions & Inferences With improved manometric instrumentation, larger participant numbers, and methodology that controlled for potential confounding factors, this study confirms and advances the results of the previous pilot study: Volitional manipulation of the oropharyngeal phase of swallowing using the effortful swallow indeed affects esophageal physiology. Thus, the effortful swallow offers a behavioral manipulation of the esophageal phase of swallowing, and future studies will determine its clinical potential for treating esophageal dysmotility in patient populations.     

Fragmented esophageal smooth muscle contraction segments on high resolution manometry: a marker of esophageal hypomotility

Background Esophageal peristalsis consists of a chain of contracting striated and smooth muscle segments on high resolution manometry (HRM). We compared smooth muscle contraction segments in symptomatic subjects with reflux disease to healthy controls. Methods High resolution manometry Clouse plots were analyzed in 110 subjects with reflux disease (50 ± 1.4 years, 51.5% women) and 15 controls (27 ± 2.1 years, 60.0% women). Using the 30 mmHg isobaric contour tool, sequences were designated fragmented if either smooth muscle contraction segment was absent or if the two smooth muscle segments were separated by a pressure trough, and failed if both smooth muscle contraction segments were absent. The discriminative value of contraction segment analysis was assessed. Key Results A total of 1115 swallows were analyzed (reflux group: 965, controls: 150). Reflux subjects had lower peak and averaged contraction amplitudes compared with controls (P < 0.0001 for all comparisons). Fragmented sequences followed 18.4% wet swallows in the reflux group, compared with 7.5% in controls (P < 0.0001), and were seen more frequently than failed sequences (7.9% and 2.5%, respectively). Using a threshold of 30% in individual subjects, a composite of failed and/or fragmented sequences was effective in segregating reflux subjects from control subjects (P = 0.04). Conclusions & Inferences Evaluation of smooth muscle contraction segments adds value to HRM analysis. Specifically, fragmented smooth muscle contraction segments may be a marker of esophageal hypomotility.     

Relationship between baseline impedance levels and esophageal mucosal integrity in children with erosive and non-erosive reflux disease

Background Baseline impedance measurement has been reported to be related to esophageal acid exposure and hypothesized to be a marker of microscopic changes of the esophageal mucosa. Aims of the study were to establish whether any relationship existed between the magnitude of intercellular space diameter (ISD) of esophageal mucosa and baseline impedance levels in children with gastro‐esophageal reflux disease (GERD), and to compare baseline impedance levels between children with non erosive (NERD) and erosive (ERD) reflux disease. Methods Fifteen children (median age: 11.2 years) with NERD, and 11 with ERD (median age: 9.6 years) were prospectively studied. All patients underwent upper endoscopy. Biopsies were taken 2–3 cm above the Z‐line, and ISD was measured using transmission electron microscopy. All patients underwent impedance pH‐monitoring, and baseline impedance levels were assessed in the most distal impedance channel. Key Results Mean (±SD) ISD did not differ between NERD (1.0 ± 0.3 μm) and ERD (1.1 ± 0.3 μm, ns). Considering all patients together, no correlation was found between distal baseline impedance and ISD (r: ?0.15; ns). Conversely, negative correlations were found between distal baseline impedance and acid exposure time (r: ?0.76; P < 0.001), long‐lasting reflux episodes (r: ?0.78; P < 0.001), acid reflux episodes (r: ?0.62; P < 0.001), and acid clearance time (r: ?0.79; P < 0.001). Distal baseline impedance was significantly lower in ERD [1455 (947–2338) Ω] than in NERD children [3065 (2253–3771) Ω; P < 0.01]. Conclusions & Inferences In children with GERD baseline impedance levels are not useful in predicting reflux‐induced ultrastructural changes in the esophageal mucosa, despite their ability to discriminate between NERD and ERD.     

Slow esophageal propagation velocity: association with dysphagia for solids

Background Spastic disorders of the esophagus, associated with rapid esophageal propagation velocity, are classically associated with dysphagia and/or chest pain. The aim of this study was to characterize patients with slow esophageal propagation velocity (SPV) on high‐resolution esophageal manometry (HRM). Methods A review of patients undergoing HRM was conducted during 1‐year study period. Patients with achalasia, aperistalsis, and diffuse esophageal spasm were excluded. Patients with contractile front velocity (CFV) ≤2.3 cm s^?1 were defined as having SPV, whereas normal propagation velocity (NPV) was defined as ≥2.6 cm s^?1. A composite isobaric contour of all swallows for each patient was generated to determine composite distal contraction latency (cDL). Key Results A total of 650 HRMs were reviewed and 552 met inclusion criteria. 173 patients had SPV and 339 had NPV. There was a greater female predominance in the SPV group compared with NPV (75.7%vs 66.4%, P = 0.03). Patients in the SPV group reported more dysphagia for solids (66.3%vs 53.3%; P = 0.004) and nausea (68.6%vs 59.0%; P = 0.04) than NPV group. Dysphagia for solids was the only symptom significantly associated with SPV group (OR = 2.21, CI = 1.21–4.02; P = .01). There was a negative correlation between CFV and cDL, r = ?0.494, P < 0.001. Conclusions & Inferences Patients with SPV have a higher prevalence of dysphagia for solids and nausea when compared with NPV. Dysphagia for solids was the only symptom significantly associated with SPV group. Thus, abnormal esophageal propagation velocity (both slow and rapid) is associated with dysphagia.     

Control of esophageal distension‐induced secondary peristalsis by the GABAB agonist baclofen in humans

Background Secondary peristalsis is important for the clearance of retained food bolus or refluxate from the esophagus. The effects of the gamma aminobutyric acid receptor type B (GABA_B) agonist on secondary peristalsis remain unclear in humans. We aimed to investigate the effect of a GABA_B agonist baclofen on esophageal secondary peristalsis. Methods After a baseline recording of esophageal motility, secondary peristalsis was generated by slow and rapid mid‐esophageal injections of air in 15 healthy subjects. Two separate sessions with 40 mg oral baclofen or placebo were randomly performed to test their effects on secondary peristalsis. Key Results Baclofen increased the threshold volume for triggering secondary peristalsis during slow air distension (P = 0.003) and rapid air distension (P = 0.002). Baclofen reduced the rate of secondary peristalsis by rapid air distension from 90% to 30% (P = 0.0002). Baclofen increased basal lower esophageal sphincter pressure (P = 0.03). Baclofen did not affect any of peristaltic parameters during primary or secondary peristalsis. Conclusions & Inferences This study provides an evidence for inhibitory modulation of esophageal secondary peristalsis by the GABA_B agonist baclofen. Activation of secondary peristalsis is probably modulated by GABA_B receptors; however, baclofen does not lead to any motility change in secondary peristalsis.     

Perception of dysphagia: lack of correlation with objective measurements of esophageal function

Background The mechanism underlying increased perception of food bolus passage in the absence of esophageal mechanical obstruction has not been completely elucidated. A correlation between the intensity of the symptom and the severity of esophageal dysfunction, either motility (manometry) or bolus transit (impedance) has not been clearly demonstrated. The aim of this study was to analyze the correlation between objective esophageal function assessment (with manometry and impedance) and perception of bolus passage in healthy volunteers (HV) with normal and pharmacologically‐induced esophageal hypocontractility, and in patients with gastro‐esophageal reflux disease (GERD) with and without ineffective esophageal motility (IEM). Methods Combined manometry‐impedance was performed in 10 HV, 19 GERD patients without IEM and nine patients with IEM. Additionally, nine HV were studied after 50 mg sildenafil, which induced esophageal peristaltic failure. Perception of each 5 mL viscous swallow was evaluated using a 5‐point scale. Manometry identified hypocontractility (contractions lower than 30 mmHg) and impedance identified incomplete bolus clearance. Key Results In HV and in GERD patients with and without IEM, there was no association between either manometry or impedance and perception on per swallow analysis (OR: 0.842 and OR: 2.017, respectively), as well as on per subject analysis (P = 0.44 and P = 0.16, respectively). Lack of correlation was also found in HV with esophageal hypocontractility induced by sildenafil. Conclusions & Inferences There is no agreement between objective measurements of esophageal function and subjective perception of bolus passage. These results suggest that increased bolus passage perception in patients without mechanical obstruction might be due to esophageal hypersensitivity.     

Short-term electrical stimulation of the lower esophageal sphincter increases sphincter pressure in patients with gastroesophageal reflux disease

Background Electrical stimulation (ES) of the lower esophageal sphincter (LES) increases resting LES pressure (LESP) in animal models. Our aims were to evaluate the safety of such stimulation in humans, and test the hypothesis that ES increases resting LESP in patients with gastroesophageal reflux disease (GERD). Methods A total of 10 subjects (nine female patients, mean age 52.6 years), with symptoms of GERD responsive to PPIs, low resting LES pressure, and abnormal 24‐h intraesophageal pH test were enrolled. Those with hiatal hernia >2 cm and/or esophagitis >Los Angeles Grade B were excluded. Bipolar stitch electrodes were placed longitudinally in the LES during an elective laparoscopic cholecystectomy, secured by a clip and exteriorized through the abdominal wall. Following recovery, an external pulse generator delivered two types of stimulation for periods of 30 min: (i) low energy stimulation; pulse width of 200 μs, frequency of 20 Hz and current of 5–15 mA (current was increased up to 15 mA if LESP was less than 15 mmHg), and (ii) high energy stimulation; pulse width of 375 ms, frequency of 6 cpm, and current 5 mA. Resting LESP, amplitude of esophageal contractions and residual LESP in response to swallows were assessed before and after stimulation. Symptoms of chest pain, abdominal pain, and dysphagia were recorded before, during, and after stimulation and 7‐days after stimulation. Continuous cardiac monitoring was performed during and after stimulation. Key Results All patients were successfully implanted nine subjects received high frequency, low energy, and four subjects received low frequency, high energy stimulation. Both types of stimulation significantly increased resting LESP: from 8.6 mmHg (95% CI 4.1–13.1) to 16.6 mmHg (95% CI 10.8–19.2), P < 0.001 with low energy stimulation and from 9.2 mmHg (95% CI 2.0–16.3) to 16.5 mmHg (95% CI 2.7–30.1), P = 0.03 with high energy stimulation. Neither type of stimulation affected the amplitude of esophageal peristalsis or residual LESP. No subject complained of dysphagia. One subject had retrosternal discomfort with stimulation at15 mA that was not experienced with stimulation at 13 mA. There were no adverse events or any cardiac rhythm abnormalities with either type of stimulation. Conclusions & Inferences Short‐term stimulation of the LES in patients with GERD significantly increases resting LESP without affecting esophageal peristalsis or LES relaxation. Electrical stimulation of the LES may offer a novel therapy for patients with GERD.     

Effects of lidocaine on esophageal secondary peristalsis in humans

Background Secondary peristalsis is important for the clearance of retained food bolus or refluxate from the esophagus. Lidocaine has been used to evaluate the role of mucosa‐mediating pathways of esophageal reflexes in animal model, but its effects on esophageal secondary peristalsis are yet unclear in humans. We aimed to investigate whether esophageal secondary peristalsis can be affected by intraluminal infusion of lidocaine into the esophagus. Methods After a baseline recording esophageal motility, secondary peristalsis was generated by slow and rapid mid‐esophageal injections of air in 13 healthy subjects. Two separate sessions with saline and lidocaine were randomly performed to test their effects on esophageal secondary peristalsis by mid‐esophageal air distension. Key Results Secondary peristalsis can be induced by slow or rapid air infusion. Secondary peristalsis was triggered less frequently in response to rapid air distension after lidocaine infusion (P = 0.001). After lidocaine infusion, the threshold volume to generate secondary peristalsis was significantly increased during rapid (P = 0.001), but not slow air infusions (P = NS). Infusion of lidocaine or saline did not affect pressure wave amplitude or duration during rapid and slow air infusions (P = NS). Conclusions & Inferences We have demonstrated selectively inhibitory effect of lidocaine on the triggering of esophageal secondary peristalsis during acute gaseous esophageal distension. The data suggest that part of the activation of secondary peristalsis is probably mediated by lidocaine‐sensitive mechanoreceptors; however, the infusion of lidocaine does not lead to any motility change in secondary peristalsis induced by either slow or rapid air infusions.     

Efficacy,tolerability and pharmacokinetics of a modified release formulation of ADX10059, a negative allosteric modulator of metabotropic glutamate receptor 5: an esophageal pH‐impedance study in healthy subjects

Background Animal studies show metabotropic glutamate receptor 5 inhibition reduces transient lower esophageal sphincter relaxations and increases lower esophageal sphincter tone. A preliminary, single‐day study, demonstrated oral ADX10059 reduced 24‐h esophageal acid exposure and clinical symptoms in gastro‐esophageal reflux disease (GERD) patients, but had suboptimal tolerability, ascribable to the compound’s rapid absorption. This study evaluated ADX10059 modified‐release (MR) formulation pharmacokinetics, tolerability, and pharmacodynamics. Methods Randomized, double‐blind placebo‐controlled study. Three groups of eight healthy, male subjects received placebo (n = 2) or ADX10059 (n = 6) 50, 125 or 250 mg b.i.d. for 6 days. Esophageal pH‐impedance was performed on day 1 and day 6 of treatment, for 1‐h fasting and for 4 h post refluxogenic meal. Treatment effect was determined by Kruskall–Wallis test and placebo comparison by Wilcoxon rank sum. Key Results Following placebo, reflux episodes increased from day 1 to day 6. Significant treatment effect was seen for total esophageal acid exposure (P = 0.048) and postprandial number of weakly acidic reflux episodes (P = 0.041). Significant differences from placebo were seen for 125 mg b.i.d.; 250 mg b.i.d. was not more effective than 125 mg b.i.d. Twice daily ADX10059 MR gave satisfactory 24‐h exposure and good tolerability. Conclusions & Inferences ADX10059 decreased reflux episodes in healthy subjects. The MR formulation is suitable for longer‐term treatment to evaluate symptom control in GERD patients.     

Multiple rapid swallow responses segregate achalasia subtypes on high‐resolution manometry

Background Multiple rapid swallows (MRS) inhibit esophageal peristalsis and lower esophageal sphincter (LES) tone; a rebound excitatory response then results in an exaggerated peristaltic sequence. Multiple rapid swallows responses are dependent on intact inhibitory and excitatory neural function and could vary by subtype in achalasia spectrum disorders. Methods Consecutive subjects with incomplete LES relaxation on high‐resolution manometry (HRM) (Sierra Scientific, Los Angeles, CA, USA) in the absence of mechanical obstruction were prospectively identified. Achalasia spectrum disorders were classified and HRM plots reviewed according to Chicago criteria. Esophageal peristaltic performance and LES function were assessed after 10 wet swallows and MRS (five 2 mL water swallows 2–3 s apart). Findings were compared with 18 healthy controls (28.5 ± 0.6 years, 44% women). Key Results A total of 46 subjects (57.1 ± 2.1 years, 52.2% women) met inclusion criteria. There was complete failure of peristalsis with MRS in all subjects with achalasia subtypes 1 and 2. In contrast, 80% of achalasia subtype 3 and incomplete LES relaxation (EGJ outflow obstruction) with preserved esophageal body peristalsis had a contractile response to MRS (P < 0.001 compared with subtypes 1 and 2); controls demonstrated 94.4% peristalsis. Percent decrease in LES residual pressure during MRS (compared to wet swallows) segregated achalasia subtypes; those with aperistalsis (subtypes 1 and 2) had a lesser decline (22.6%) compared to those with retained esophageal body peristalsis (40.5%) and controls (51.3%, P < 0.001 across groups). Conclusions & Inferences Multiple rapid swallow responses segregate achalasia spectrum disorders into two patterns differentiated by presence or absence of esophageal body contraction response to wet swallows. These findings support subtyping of achalasia, with pathophysiologic implications.     

The impact of primary peristalsis,contractile reserve,and secondary peristalsis on esophageal clearance measured by timed barium esophagogram

Background

Primary and secondary peristalsis facilitate esophageal bolus transport; however, their relative impact for bolus clearance remains unclear. We aimed to compare primary peristalsis and contractile reserve on high-resolution manometry (HRM) and secondary peristalsis on functional lumen imaging probe (FLIP) Panometry with emptying on timed barium esophagogram (TBE) and incorporate findings into a comprehensive model of esophageal function.

Methods

Adult patients who completed HRM with multiple rapid swallows (MRS), FLIP, and TBE for esophageal motility evaluation and without abnormal esophagogastric junction outflow/opening or spasm were included. An abnormal TBE was defined as a 1-min column height >5 cm. Primary peristalsis and contractile reserve after MRS were combined into an HRM–MRS model. Secondary peristalsis was combined with primary peristalsis assessment to describe a complementary neuromyogenic model.

Key Results

Of 89 included patients, differences in rates of abnormal TBEs were observed with primary peristalsis classification (normal: 14.3%; ineffective esophageal motility: 20.0%; absent peristalsis: 54.5%; p = 0.009), contractile reserve (present: 12.5%; absent: 29.3%; p = 0.05), and secondary peristalsis (normal: 9.7%; borderline: 17.6%; impaired/disordered: 28.6%; absent contractile response: 50%; p = 0.039). Logistic regression analysis (akaike information criteria, area under the receiver operating curve) demonstrated that the neuromyogenic model (80.8, 0.83) had a stronger relationship predicting abnormal TBE compared to primary peristalsis (81.5, 0.82), contractile reserve (86.8, 0.75), or secondary peristalsis (89.0, 0.78).

Conclusions and Inferences

Primary peristalsis, contractile reserve, and secondary peristalsis were associated with abnormal esophageal retention as measured by TBE. Added benefit was observed when applying comprehensive models to incorporate primary and secondary peristalsis supporting their complementary application.     

Treatment of gastro‐esophageal reflux disease: the new kids to block

Refractory gastro‐esophageal reflux disease (GERD), defined as persistent symptoms despite proton pump inhibitor (PPI) therapy, is an increasingly prevalent condition and is becoming a major challenge for the clinician. Since non‐acidic reflux may be associated with symptoms persisting during PPI treatment, the lower esophageal sphincter (LES), the most important barrier protecting against reflux, has become an important target for the treatment of (refractory) GERD. Preclinical research has identified several receptors that are involved in the control of transient lower esophageal sphincter relaxations (TLESRs), the predominant mechanism of both acid and non‐acidic reflux events, and several drugs have now been tested in humans. The GABA_B agonist baclofen has demonstrated to effectively reduce the rate of TLESRs and the amount of reflux in both GERD patients and healthy volunteers. Nevertheless, the occurrence of central side effects limits its clinical use for the treatment of GERD. Several analogues are being developed to overcome this limitation and have shown promising results. Additionally, metabotropic glutamate receptor 5 (mGluR5) receptor antagonists have shown to reduce both acid and non‐acidic reflux in GERD patients and several molecules are currently being evaluated. Although CB₁ antagonists have been shown to reduce TLESRs, they are also associated with central side effects, limiting their clinical applicability. Despite the identification of several potentially interesting drugs, the main challenge for the future remains the reduction of central side effects. Moreover, future studies will need to demonstrate the efficacy of these treatments in patients with refractory GERD.     

Normative values and inter‐observer agreement for liquid and solid bolus swallows in upright and supine positions as assessed by esophageal high‐resolution manometry

Background High‐resolution manometry (HRM) with spatiotemporal representation of pressure data is a recent advance in esophageal measurement. At present, normal values are available for 5 mL water swallows in the supine position. This study provides reference values for liquid and solid bolus swallows in the upright seated and supine positions. Methods A total of 23 asymptomatic volunteers (11M : 12F, age 20–56) underwent HRM (Manoscan 360; Sierra Scientific Instruments) with 5 mL water and 1 cm³ bread swallows in the upright and supine positions. Normal values for primary parameters associated with effective bolus transport [proximal transition zone length (PTZ, assesses peristaltic coordination], contraction front velocity (CFV), distal contractile index (DCI) and integrated relaxation pressure (IRP)] are presented. For each parameter, median values along with the 5–95th percentile range are reported. Inter‐observer agreement between independent observers is reported using the intra‐class correlation coefficient. Key Results A higher proportion of swallows were peristaltic for liquids than solids in both the upright and supine positions (both P < 0.05). As workload increases with solid bolus and on moving from the upright to the supine position the esophageal contractile response resulted in a shorter PTZ, a slower CFV, and a more vigorous DCI. Also IRP increased during solid bolus transit (all P < 0.01). There was significant agreement between independent observers for HRM parameters. Conclusions & Inferences Normative values for esophageal function for solids as well as liquids and in the ‘physiologic’, upright position will optimize the utility of HRM studies. The high level of inter‐observer agreement indicates that these can be applied as reference values in clinical practice.     

Concomitant irritable bowel syndrome is associated with failure of step‐down on‐demand proton pump inhibitor treatment in patients with gastro‐esophageal reflux disease

Background The predictors for treatment failure of on‐demand proton pump inhibitor (PPI) therapy in gastro‐esophageal reflux disease (GERD) patients are unclear. We studied the efficacy and predictors for treatment failure of step‐down on‐demand PPI therapy in patients with non‐erosive reflux disease (NERD) and those with low grade erosive esophagitis. Methods Consecutive symptomatic GERD patients who had positive esophageal pH studies and complete symptom resolution with initial treatment of esomeprazole were given step‐down on‐demand esomeprazole for 26 weeks. Patients with esophagitis of Los Angeles (LA) grade C or above and recent use of PPI were excluded. Treatment failure was defined as an inadequate relief of reflux symptoms using global symptom assessment. Potential predictors of treatment failure were determined using multivariate analysis. Key Results One hundred and sixty three NERD and 102 esophagitis patients were studied. The 26‐week probability of treatment failure was 36.2% (95% CI: 23.9–46.5%) in NERD group and 20.1% (95% CI: 10.9–28.3%) in esophagitis group, respectively (P = 0.021). Irritable bowel syndrome (adjusted HR: 2.1, 95% CI: 1.5–3.8, P = 0.01), in addition to daily reflux symptom (adjusted hazard ratio: 2.7, 95% CI: 1.9–4.2, P = 0.001) and concomitant dyspepsia (adjusted hazard ratio: 1.7, 95% CI: 1.1–2.8, P = 0.04), were independent predictors for treatment failure. Conclusions & Inferences Compared to patients with esophagitis, NERD patients have higher failure rate of on‐demand PPI therapy. Concomitant irritable bowel syndrome, in addition to daily reflux symptom and dyspepsia, is associated with the failure of on‐demand PPI in these patients.     

Effect of proximal gastric volume on hiatal hernia

Background Spatial separation of the diaphragm and the lower esophageal sphincter (LES) occurs frequently and intermittently in patients with a sliding hiatus hernia and favors gastro‐esophageal reflux. This can be studied with high‐resolution manometry. Although fundic accommodation is associated with a lower basal LES pressure, its effect on esophagogastric junction configuration and hiatal hernia is unknown. Therefore, the aim of this study was to investigate the relationship between proximal gastric volume, the presence of a hiatal hernia profile and acid reflux. Methods Twenty gastro‐esophageal reflux disease (GERD) patients were studied and compared to 20 healthy controls. High‐resolution manometry and pH recording were performed for 1 h before and 2 h following meal ingestion (500 mL per 300 kcal). Volume of the proximal stomach was assessed with three‐dimensional ultrasonography before and every 15 min after meal ingestion. Key Results During fasting, the hernia profile [2 separate high‐pressure zones (HPZs) at manometry] was present for 31.9 ± 4.9 min h^?1 (53.2%) in GERD patients, and 8.7 ± 3.3 min h^?1 (14.5%) in controls (P < 0.001). In GERD patients, the presence of hernia profile decreased during the first postprandial hour to 15.9 ± 4.2 min h^?1, 26.5%, P < 0.01 whilst this phenomenon was not observed in controls. The rate of transition between the two profiles was 5.7 ± 1.1 per hour in GERD patients and 2.5 ± 1.0 per hour in controls (P < 0.001). The pre and postprandial acid reflux rate in GERD patients during the hernia profile (6.4 ± 1.1 per hour and 18.4 ± 4.3 per hour respectively) was significantly higher than during reduced hernia (2.1 ± 0.6 per hour; P < 0.05 and 3.8 ± 0.9 per hour; P < 0.05). A similar difference was found in controls. Furthermore, an inverse correlation was found between fundic volume and the time the hernia profile was present (r = ?0.45; P < 0.05) in GERD patients, but not in controls. Conclusions & Inferences (i) In GERD patients a postprandial increase in proximal gastric volume is accompanied by a decrease in hernia prevalence, which can be explained by a reduction of the intra‐thoracic part of the stomach. (ii) A temporal hernia profile also occurs in healthy subjects. (iii) During the hernia profile, acid reflux is more prevalent, especially after meal ingestion.     

Increase of weakly acidic gas esophagopharyngeal reflux (EPR) and swallowing‐induced acidic/weakly acidic EPR in patients with chronic cough responding to proton pump inhibitors

Background Gastro‐esophageal reflux disease (GERD)‐related chronic cough (CC) may have multifactorial causes. To clarify the characteristics of esophagopharyngeal reflux (EPR) events in CC patients whose cough was apparently influenced by gastro‐esophageal reflux (GER), we studied patients with CC clearly responding to full‐dose proton pump inhibitor (PPI) therapy (CC patients). Methods Ten CC patients, 10 GERD patients, and 10 healthy controls underwent 24‐h ambulatory pharyngo‐esophageal impedance and pH monitoring. Weakly acidic reflux was defined as a decrease of pH by >1 unit with a nadir pH >4. In six CC patients, monitoring was repeated after 8 weeks of PPI therapy. The number of each EPR event and the symptom association probability (SAP) were calculated. Symptoms were evaluated by a validated GERD symptom questionnaire. Key Results Weakly acidic gas EPR and swallowing‐induced acidic/weakly acidic EPR only occurred in CC patients, and the numbers of such events was significantly higher in the CC group than in the other two groups (P < 0.05, respectively). Symptom association probability analysis revealed a positive association between GER and cough in three CC patients. Proton pump inhibitor therapy abolished swallowing‐induced acidic/weakly acidic EPR, reduced weakly acidic gas EPR, and improved symptoms (all P < 0.05). Conclusions & Inferences Most patients with CC responding to PPI therapy had weakly acidic gas EPR and swallowing‐induced acidic/weakly acidic EPR. A direct effect of acidic mist or liquid refluxing into the pharynx may contribute to chronic cough, while cough may also arise indirectly from reflux via a vago‐vagal reflex in some patients.     

Effects of transcranial direct current stimulation on esophageal motility in patients with gastroesophageal reflux disease

ObjectiveTo evaluate the effects of transcranial direct current stimulation (tDCS) on esophageal peristalsis in patients with gastroesophageal reflux disease (GERD).MethodsPatients with GERD preliminary diagnosis were included in a randomized double-blind sham-controlled study. Esophageal manometry was performed before and during transcranial direct current stimulation (tDCS) of the right precentral cortex. Half of patients were randomly assigned to anodal, half to sham stimulation. Distal waves amplitude and pathological waves percentage were measured, after swallowing water boli, for ten subsequent times. Last, a 24 h pH-bilimetry was done to diagnose non-erosive reflux disease (NERD) or functional heartburn (FH). The values obtained before and during anodal or sham tDCS were compared.ResultsSixty-eight patients were enrolled in the study. Distal waves mean amplitude increased significantly only during anodal tDCS in NERD (p = 0.00002) and FH subgroups (p = 0.008) while percentage of pathological waves strongly decreased only in NERDs (p = 0.002).ConclusionsTranscranial stimulation can influence cortical control of esophageal motility and improve pathological motor pattern in NERD and FH but not in erosive reflux disease (ERD) patients.SignificancePathophysiological processes in GERD are not only due to peripheral damage but to central neural control involvement as well. In ERD patients dysfunctions of the cortico-esophageal circuit seem to be more severe and may affect central nervous system physiology.