Kinetics of transient hiatus hernia during transient lower esophageal sphincter relaxations and swallows in healthy subjects

Background Proximal displacement of the gastro‐esophageal junction (GEJ) is present in hiatus hernia but also occurs transiently during transient lower esophageal sphincter relaxations (TLESRs) and swallows. Using a novel magnetic‐based technique we have performed detailed examination of the GEJ movement during TLESRs and swallows in healthy subjects. Methods In 12 subjects, a magnet was endoscopically clipped to the GEJ and combined assembly of Hall‐Effect locator probe and 36 channel high‐resolution manometer passed nasally. After a test meal the subjects were studied for 90 min. Key Results The median amplitude of proximal movement of GEJ during TLESRs was 4.3 cm (1.6–8.8 cm) and this was substantially greater than during swallowing at 1.2 cm (0.4–2.7 cm), P = 0.002. With both TLESRs and swallows proximal GEJ movement coincided with lower esophageal sphincter (LES) relaxation and return to its original position occurred 4 s after return of LES tone. Kinetic modeling of the movement of the GEJ during TLESRs indicated two return phases with the initial return phase having the greater velocity (0.9 cm s^?1) and being strongly correlated with amplitude of proximal movement (r = 0.8, P < 0.001). Conclusions & Inferences The marked proximal GEJ migration during TLESRs represents very severe herniation of the GEJ. The rapid initial return of the GEJ following TLESRs when the crural diaphragm is relaxed and its correlation with amplitude suggest it is due to elastic recoil of the phreno‐esophageal ligament. The marked stretching of the phreno‐esophageal ligament during TLESRs may contribute to its weakening and development of established hiatus hernia.     

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.     

The lower esophageal sphincter

The lower esophageal sphincters (LES) together with the crural diaphragm are the major antireflux barriers protecting the esophagus from reflux of gastric content. However, reflux of gastric contents into the esophagus is a normal phenomenon in healthy individuals occurring primarily during episodes of transient lower esophageal sphincter relaxation (TLESR), defined as LES relaxation in the absence of a swallow. Transient lower esophageal sphincter relaxation is also the dominant mechanism of pathologic reflux in gastroesophageal reflux disorder (GERD) patients. Frequency of TLESR does not differ significantly between healthy individuals and those with GERD, but TLESRs are more likely to be associated with acid reflux in GERD patients. Understanding the mechanisms responsible for elicitation of a TLESR, using recently introduced novel technology is an area of intense interest. Pharmacologic and non‐pharmacologic manipulation of receptors involved in the control of TLESR has recently emerged as a potential target for GERD therapy.     

Ambulatory high-resolution manometry, lower esophageal sphincter lift and transient lower esophageal sphincter relaxation

Background Lower esophageal sphincter (LES) lift seen on high‐resolution manometry (HRM) is a possible surrogate marker of the longitudinal muscle contraction of the esophagus. Recent studies suggest that longitudinal muscle contraction of the esophagus induces LES relaxation. Aim Our goal was to determine: (i) the feasibility of prolonged ambulatory HRM and (ii) to detect LES lift with LES relaxation using ambulatory HRM color isobaric contour plots. Methods In vitro validation studies were performed to determine the accuracy of HRM technique in detecting axial movement of the LES. Eight healthy normal volunteers were studied using a custom designed HRM catheter and a 16 channel data recorder, in the ambulatory setting of subject’s home environment. Color HRM plots were analyzed to determine the LES lift during swallow‐induced LES relaxation as well as during complete and incomplete transient LES relaxations (TLESR). Key Results Satisfactory recordings were obtained for 16 h in all subjects. LES lift was small (2 mm) in association with swallow‐induced LES relaxation. LES lift could not be measured during complete TLESR as the LES is not identified on the HRM color isobaric contour plot once it is fully relaxed. On the other hand, LES lift, mean 8.4 ± 0.6 mm, range: 4–18 mm was seen with incomplete TLESRs (n = 80). Conclusions & Inferences Our study demonstrates the feasibility of prolonged ambulatory HRM recordings. Similar to a complete TLESR, longitudinal muscle contraction of the distal esophagus occurs during incomplete TLESRs, which can be detected by the HRM. Using prolonged ambulatory HRM, future studies may investigate the temporal correlation between abnormal longitudinal muscle contraction and esophageal symptoms.     

Failure to respond to physiologic challenge characterizes esophageal motility in erosive gastro‐esophageal reflux disease

Background Non‐specific esophageal dysmotility with impaired clearance is often present in patients with gastro‐esophageal reflux disease (GERD), especially those with erosive disease; however the physio‐mechanic basis of esophageal dysfunction is not well defined. Methods Retrospective assessment of patients with erosive reflux disease (ERD; n = 20) and endoscopy negative reflux disease (ENRD; n = 20) with pathologic acid exposure on pH studies (>4.2% time/24 h) and also healthy controls (n = 20) studied by high resolution manometry. Esophageal motility in response to liquid and solid bolus swallows and multiple water swallows (MWS) was analyzed. Peristaltic dysfunction was defined as failed peristalsis, spasm, weak or poorly coordinated esophageal contraction (>3 cm break in 30 mmHg isocontour). Key Results Peristaltic dysfunction was present in 33% of water swallows in controls, 56% ENRD and 76% ERD respectively (P < 0.023 vs controls, P = 0.185 vs ENRD). The proportion of effective peristaltic contractions improved with solid compared to liquid bolus in controls (18%vs 33%, P = 0.082) and ENRD (22%vs 54%, P = 0.046) but not ERD (62%vs 76%, P = 0.438). Similarly, MWS was followed by effective peristalsis in 83% of controls and 70% ENRD but only 30% ERD patients (P < 0.017 vs controls and P < 0.031 vs ENRD). The association between acid exposure and dysmotility was closer for solid than liquid swallows (r = 0.52 vs 0.27). Conclusions & Inferences Peristaltic dysfunction is common in GERD. ERD patients are characterized by a failure to respond to the physiologic challenge of solid bolus and MWS that is likely also to impair clearance following reflux events and increase exposure to gastric refluxate.     

Reproducibility of esophageal high‐resolution manometry

Background Esophageal high‐resolution manometry (HRM) is a novel method for esophageal function testing that has prompted the development of new parameters for quantitative analysis of esophageal function. Until now, the reproducibility of these parameters has not been investigated. Methods Twenty healthy volunteers underwent HRM on two separate days. Standard HRM parameters were measured. In addition, in conventional (virtual) line tracings, lower esophageal sphincter (LES) resting pressure, relaxation pressure, and relative relaxation pressure were measured. Firstly, for each variable, the mean percentage of covariation (100 × SD/mean: %COV) was derived as a measure of inter‐ and intra‐individual variation. Secondly, Kendall’s coefficients of concordance (W values) were calculated. Thirdly, Bland–Altman plots were used to express concordance graphically. Key Results Statistically significant concordance values were found for upper esophageal sphincter (UES) pressure (W = 0.90, P = 0.02), transition zone length (W = 0.92, P = 0.01), LES length (W = 0.81, P = 0.04), LES pressure (W = 0.75, P = 0.05), LES relaxation pressure (W = 0.75, P = 0.03), relative LES relaxation pressure (W = 0.78, P = 0.05), gastric pressure (W = 0.81, P = 0.04), and contraction amplitude 5 cm above the LES (W = 0.86, P = 0.03). In conventional setting, only LES resting pressure (W = 0.835, P = 0.03) proved significant. In HRM tracings, concordance values for contraction wave parameters, and in conventional line tracings, LES relaxation pressure and relative relaxation pressure did not reach levels of statistical significance. Conclusions & Inferences Esophageal HRM yields reproducible results. Parameters that represent anatomic structures show better reproducibility than contraction wave parameters. The reproducibility of LES resting and relaxation pressure assessed with HRM is better than with conventional manometry and further supports the clinical use of HRM.     

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.     

Localization of mGluR5, GABAB, GABAA, and cannabinoid receptors on the vago-vagal reflex pathway responsible for transient lower esophageal sphincter relaxation in humans: an immunohistochemical study

Background Transient lower esophageal sphincter relaxations (TLESRs) are the predominant mechanisms underlying gastro‐esophageal reflux. TLESRs are mediated by a vago‐vagal reflex, which can be blocked by interaction with metabotropic Glutamate Receptor 5 (mGluR5), γ‐aminobutyric acid type B (GABA_B), γ‐aminobutyric acid type A (GABA_A), and cannabinoid (CB) receptors. However, the distribution of these receptors in the neural pathway underlying the triggering of TLESRs has not been evaluated in humans. Methods Using immunohistochemistry, we investigated the distribution of mGluR5, GABA_A, GABA_B, CB1, and CB2 receptors in the human nodose ganglion, the brain stem, and the myenteric plexus of the esophagus. Key Results MGluR5, GABA_B, CB1, and CB2 receptors are abundantly expressed in neurons of the myenteric plexus of the LES, nodose ganglion cell bodies and nerve fibers, the dorsal motor nucleus, and nucleus of the solitary tract in the brain stem. GABA_A receptors are expressed in the same regions except in the nodose ganglion and myenteric plexus of the LES. Conclusions & Inferences Human mGluR5, GABA_A,B, and CB_1,2 receptors are abundantly expressed along the vago‐vagal neural pathway and involved in the triggering of TLESRs. These findings are not only in line with the central side effects observed during treatment with reflux inhibitors such as GABA_B receptor agonists and mGluR5 antagonists, but also suggest that peripherally acting compounds may be effective.     

The effects of intraduodenal nutrient infusion on serum CCK,LES pressure,and gastroesophageal reflux

Background Fats cause reflux symptoms in many patients and cholecystokinin (CCK) may play a role. This study was designed to evaluate the effects of intraduodenal nutrient infusion on serum CCK levels, lower esophageal sphincter (LES) pressure, and gastroesophageal reflux (GER). Methods Twenty‐four asymptomatic volunteers were studied. A Dent sleeve catheter assessed LES function while an impedance‐pH catheter measured reflux events. Participants were randomized to fat (F), carbohydrate (C) or protein (P) infusion. Serum CCK and LES pressures were measured at baseline and after nutrient infusion. Key Results Baseline LES pressures and CCK levels were similar in all three groups. A significant linear decrease was found in LES pressure during F, but not C or P, infusion (P = 0.004). A significant interaction effect was noted between the infusion groups and CCK levels (P = 0.002). A significant linear increase was noted in CCK levels during F but not during C or P infusion (P = 0.02). A significant inverse correlation was found between CCK levels and LES pressure (ρ = ?0.43; P = 0.04). Esophageal acid exposure was significantly increased in the F infusion group (median; interquartile range: 1.10%; 0.25–4.7%) compared to both the C (0.03%; 0.00–0.39%) and P infusion (0.03%; 0.00–0.39%) groups (P = 0.04). Conclusions & Inferences Intraduodenal F infusion was associated with an increase in CCK levels, while P and C were not. LES pressure decreased significantly after fat infusion and reflux events were more frequent. Fat‐induced CCK release is another mechanism that contributes to GER.     

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.     

Measurement of acid exposure of proximal esophagus: a better tool for diagnosing non‐erosive reflux disease

Background The sensitivity of 24‐h pH monitoring is poor in non‐erosive reflux disease (NERD). In NERD patients, the proximal extent of acid reflux is one of the main determinants of reflux perception. The present study was aimed to compare the diagnostic accuracy of acid exposure time (AET), at 5 cm above the lower esophageal sphincter, with those at 10 cm and at 3 cm below the upper esophageal sphincter as well as the reproducibility of these parameters. Methods A total of 93 consecutive NERD patients, with typical symptoms responsive to proton pump inhibitor treatment, and 40 controls underwent esophageal manometry and multi‐channel 24‐h pH‐test; 13 patients underwent the same study on two occasions. Symptom association probability (SAP) values were evaluated at each esophageal level. Key Results The ROC curve indicates that the area under the curve was 0.79 at distal (SE = 0.039), 0.87 (SE = 0.032) at proximal (P = 0.029 vs distal), and 0.85 (SE = 0.033) at very proximal esophagus (P = 0.148). AET showed a reproducibility of 61% (Kappa 0.22) at distal esophagus, 77% (Kappa 0.45) at proximal and 53% (Kappa 0.05) at very proximal esophagus. The percentage of patients with a positive SAP was not significantly different when assessed at the distal compared with the proximal esophagus. Conclusions & Inferences In NERD patients, the diagnostic yield of the pH test is significantly improved by the assessment of AET at the proximal esophagus. As this variable seems to be less affected by the day to day variability, it could be considered a reliable and useful diagnostic tool in NERD patients.     

High‐resolution manometric characteristics help differentiate types of distal esophageal obstruction in patients with peristalsis

Background High‐resolution manometry (HRM) can identify obstructive motor features at the esophagogastric junction and abnormalities in esophageal bolus transit. We sought to determine if HRM patterns can differentiate functional from organic mechanical lower esophageal sphincter (LES) obstruction. Methods Segmental characteristics of peristalsis were examined using HRM in symptomatic subjects with elevated postdeglutitive residual pressure gradients across the LES (≥5 mmHg). Sixteen consecutive patients with non‐achalasic mechanical fixed obstruction were compared with 13 patients with elevated pressure gradients yet no mechanical obstruction and 14 asymptomatic controls. Pressure volumes were determined in mmHg cm s for peristaltic segments defined on HRM Clouse plots using an on‐screen pressure volume measurement tool. Key Results Residual pressure gradients were similarly elevated in both patient groups. A visually conspicuous and distinctive shift in the proportionate pressure strengths of the second and third peristaltic segments was apparent across groups. Whereas the ratios of peak pressures and pressure volumes between second and third segments approached 1 in controls (0.92, 0.98), pressures shifted to the second segment in mechanical obstruction (peak pressure ratio: 1.2 ± 0.4; pressure volume ratio: 1.8 ± 0.9) and to the third segment in functional obstruction (peak ratio: 0.7 ± 0.2; volume ratio: 0.5 ± 0.2; P < 0.02 for any comparison of either group with controls). A threshold volume ratio of 1.0 correctly segregated 93% of obstruction (P < 0.0001); visual pattern inspection was equally effective. Conclusions & Inferences When elevated residual pressure gradients are present in non‐achalasic patients, topographic characteristics of peristalsis can differentiate fixed mechanical obstruction from functional obstruction.     

3D‐high resolution manometry of the esophagogastric junction

Background The esophagogastric junction (EGJ) is a complex structure that challenges accurate manometric recording. This study aimed to define EGJ pressure morphology relative to the squamocolumnar junction (SCJ) during respiration with 3D‐high resolution manometry (3D‐HRM). Methods A 7.5‐cm long 3D‐HRM array with 96 independent solid‐state pressure sensors (axial spacing 0.75 cm, radial spacing 45°) was used to record EGJ pressure in 15 normal subjects. Concurrent videofluoroscopy was used to localize the SCJ marked with an endoclip. Ex vivo experiments were done on the effect of bending the probe to match that seen fluoroscopically. Key Results 3D‐high resolution manometry EGJ pressure recordings were dominated by an asymmetric pressure peak superimposed on the lower esophageal sphincter (LES) attributable to the crural diaphragm (CD). Median peak CD pressure at expiration and inspiration (51 and 119 mmHg, respectively) was much greater in 3D‐HRM than evident in HRM with circumferential pressure averaging. Esophagogastric junction length, defined as the zone of circumferential pressure exceeding that of adjacent esophagus or stomach was also substantially shorter (2.4 cm) than evident in conventional HRM. No consistent circumferential EGJ pressure was evident distal to the SCJ in 3D‐HRM recordings and ex vivo experiments suggested that the intra‐gastric pressure peak seen contralateral to the CD related to bending the assembly rather than the sphincter per se. Conclusions & Inferences 3D‐high resolution manometry demonstrated a profoundly asymmetric and vigorous CD component to EGJ pressure superimposed on the LES. Esophagogastric junction length was shorter than evident with conventional HRM and the distal margin of the EGJ sphincteric zone closely correlated with the SCJ.     

Analysis of Spontaneous Gastroesophageal Reflux and Esophageal Acid Clearance in Patients with Reflux Esophagitis

To characterize gastroesophageal reflux episodes and esophageal acid clearance in patients with reflux esophagitis, we obtained 12-hour overnight esophageal pH and manometry recordings in 20 patients with macroscopic reflux esophagitis and in 15 healthy volunteers. Compared to the control subjects, the patients had less pressure in the lower esophageal sphincter (LES) and higher rates of reflux, acid clearance time, and esophageal acid exposure. However, many patients had normal values for one or more of these variables. Transient LES relaxation accounted for 96% of reflux episodes in control subjects and 60% in patients. The remaining 40% of reflux episodes in patients occurred as stress or free reflux. In the control subjects, only one reflux episode occurred during estimated sleep. Of 22 reflux episodes during estimated sleep in patients, most were associated with low basal LES pressure. During esophageal acid clearance, the major esophageal motor event was swallow-induced peristalsis rather than secondary peristalsis. We conclude that esophagitis patients have lower LES pressures, more reflux episodes, impaired esophageal acid clearance, and more esophageal exposure to acid than control subjects. Individual patients, however, exhibit heterogeneous abnormalities with respect to these variables. Transient LES relaxation is the major mechanism of gastroesophageal reflux in both patients and healthy subjects.     

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.     

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.     

Botulinum toxin injection in dysphagia syndromes with preserved esophageal peristalsis and incomplete lower esophageal sphincter relaxation

Background Botulinum toxin injection into the lower esophageal sphincter (LES) treats dysphagia syndromes with preserved peristalsis and incomplete LES relaxation (LESR). We evaluated clinical and esophageal motor characteristics predicting response, and compared duration of efficacy to similarly treated achalasia patients. Methods Thirty‐six subjects (59 ± 2.2 years, 19F/17M) with incomplete LESR on high resolution manometry (HRM) treated with botulinum toxin injection were identified. Individual and composite symptom indices were calculated, and HRM characteristics extracted. Symptom resolution for 6 months was a primary outcome measure, and repeat botulinum toxin injection, dysphagia recurrence or employment of alternate therapeutic approaches were secondary outcome measures. Duration of response was compared using Kaplan‐Meier survival curves to a historical cohort of similarly treated achalasia subjects. Key Results Response lasted a mean of 12.8 ± 2.3 months. Symptom relief for >6 months was seen in 58.3%; short (<6 months) response was associated with younger age, higher chest pain index, and esophageal body spastic features (P ≤ 0.04). On multivariate logistic regression, chest pain, younger age and contraction amplitudes >180 mmHg independently predicted <6 months relief (P < 0.05 for each). On survival analysis, relief with a single injection extended to 1 year in 54.8% and 1.5 years in 49.8%, statistically equivalent to that reported by 42 similarly treated achalasia subjects (59 ± 3.2 years, 24F/18M). Symptom relief was more prolonged compared to achalasia when repeat injections were performed on demand (P = 0.003). Conclusions & Inferences Botulinum toxin injections can provide lasting symptom relief in dysphagia syndromes with incomplete LESR. Prominent perceptive symptoms and non‐specific spastic features may predict shorter relief.     

Mechanisms of gastroesophageal reflux in children with sequelae of birth asphyxia

Patterns of childhood gastroesophageal reflux (GER) have been studied extensively; however, the mechanisms underlying its occurrence in neurologically impaired children (NIC) are poorly understood. Concurrent esophageal manometry and pH monitoring was conducted in 10 un-operated children (7 male; mean age: 59.5 months) with sequelae birth asphyxia and esophagitis. Reflux episodes were scored when esophageal pH decreased to <4 for at least 5s. When the rate of decrease of lower esophageal sphincter (LES) pressure was >1mmHg/s, the decrease of LES pressure was defined as LES relaxation. The time relationship of the pharyngeal manometric swallowing signal to LES relaxation onset was then evaluated in order to distinguish between LES relaxations associated with swallowing (type II or III, associated with one or more swallows, respectively) and those that occurred independently of swallowing (type I). Results: Esophageal manometry and pH monitoring were conducted for a mean duration of 91.5min. Basal LES pressure averaged (+/-SD) 9.2+/-4.8mmHg; in 4 of 10 patients (40%) the LES pressure was largely undetectable, varying between 0 and 2mmHg. Mean LES pressure was inversely correlated with age (r=0.7, P=0.02). The total number of reflux episodes/h averaged 32.1+/-12.1 LES pressure reached 0mmHg in 98% of reflux episodes. Type I LES relaxations were present in 3.15+/-1.1 reflux episodes/h, whereas type II LES relaxation occurred in 2.3+/-2.4 episodes/h. Acid reflux episodes appeared during absent basal LES tone periods, without phasic LES relaxations, in 74%. Conclusions: Absent basal LES tone is the main mechanism of GER in a subgroup of NIC, especially in older children. Transient LES relaxation, the most common known event associated with acid reflux in neurologically normal children, seems to precede a minority of reflux events in NIC.     

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.     

Objective definition and detection of transient lower esophageal sphincter relaxation revisited: is there room for improvement?

Background The advent of drugs that inhibit transient lower esophageal sphincter relaxation (TLESR) necessitates accurate identification and scoring. We assessed the intra‐ and inter‐assessor variability of the existing objective criteria for TLESR, improving them where necessary. Methods Two 3‐h postprandial esophageal manometric and pH recordings were performed in 20 healthy volunteers. Each recording was duplicated. The recordings were analyzed by five experienced observers for TLESRs based on their expert opinion. TLESRs were also analyzed for the presence of the original four criteria as well as inhibition of the crural diaphragm (ID), a prominent after‐contraction (AC), acid reflux and an esophageal common cavity. Key Results The overall inter‐ and intra‐observer agreements for TLESRs scored, according to observer’s expert opinion, were 59% (range 56–67%) and 74% (60–89%), respectively. When TLESRs were restricted to those fulfilling the original criteria, these agreements fell to 46% (40–53%) and 60% (44–67%), respectively. Cleaning the recordings by removal of technically flawed sections improved agreements by 5%. Inclusion of additional criteria (ID and AC) resulted in inter‐ and intra‐observer agreements of 62% (52–70%) and 69% (53–79%), respectively. A consensus analysis performed collectively by three observers and based on the new criteria (original ± ID and AC) resulted in 84% agreement between the paired recordings. Conclusions & Inferences The original criteria for the definition of TLESRs allows for substantial inter‐ and intra‐observer variability, which can be reduced by incorporation of additional objective criteria. However, the highest level of intra‐observer agreement can be achieved by consensus analysis.