Ziverel for PPI-refractory reflux symptoms: efficacy and mechanisms of action in humans.

OBJECTIVES: It is thought that esophageal hypersensitivity in combination with an impaired mucosal barrier function contributes to PPI-resistant reflux symptoms. Ziverel, a bioadhesive agent that coats the esophageal wall, was shown to have a positive effect on reflux symptoms. However, the mechanisms of action are unclear. We aimed to assess the effect of Ziverel on esophageal sensitivity to acid and mucosal barrier function. METHODS: We performed a double-blind randomized placebo-controlled crossover trial in PPI-refractory patients with reflux symptoms. Patients were assigned (1:1) to 14 days of Ziverel followed by 14 days of placebo or opposite treatment order. The effect was evaluated using acid perfusion tests, an upper endoscopy with electrical tissue impedance spectroscopy (ETIS) and esophageal biopsies. The primary outcome was the esophageal sensitivity based on perfusion sensitivity score. Secondary outcomes included mucosal barrier function and reflux symptoms and correlations between the different outcomes. RESULTS: Perfusion sensitivity score was not significantly different during treatment with Ziverel (106 (73-115)) and placebo (102 (67-110)) (p = 0.508) along with total RDQ score (2.6 (1.9-3.3) vs 2.8 (1.6-3.5) p = 0.456). ETIS showed comparable values during treatment with Ziverel (13514 (8846-19734)Ω·m) and placebo (13217 (9127-24942)Ω·m (p = 0.650)). Comparing Ziverel and placebo no difference was seen in transepithelial electrical resistance (TEER) 203 (163-267) Ω.cm2 vs 205 (176-240) Ω.cm2 (p = 0.445) and fluorescein flux 775 (17-6964) nmol/cm2/h vs 187 (4-12209) nmol/cm2/h (p = 0.638). CONCLUSION: Ziverel did not show a benefit on acid sensitivity, reflux symptoms or esophageal mucosal integrity compared to placebo in PPI-refractory patients with reflux symptoms.Trial registration: Netherlands Trial Register number: NL7670.

The Effect of STW5 (Iberogast) on Reflux Symptoms in Patients With Concurrent Dyspeptic Symptoms: A Double-blind Randomized Placebo-controlled Crossover Trial.

Background/Aims: It has been suggested that STW5 (Iberogast) reduces heartburn symptoms in patients with functional dyspepsia, but underlying mechanisms of action are unclear. The aim of this study is to investigate whether STW5 affects esophageal sensitivity or esophageal motility, thereby reducing occurrence and perception of reflux events. Methods: We performed a double-blind, randomized, placebo-controlled, crossover trial in patients with functional dyspepsia (Rome IV) and reflux symptoms. After 4 weeks of treatment with either placebo or STW5, patients were studied with an esophageal acid perfusion test and ambulatory 24-hour pH-impedance monitoring. Results: A total of 18 patients (7 men, median age 54, range [19-76]), were included in the study. Although we found no statistical difference in our primary outcome the total Reflux Disease Questionnaire score 2.33 (0.25-4.33) vs 2.67 (1.17-4.00), P = 0.347, "gastroesophageal reflux disease" and "regurgitation" subscale scores were lower after STW5 treatment compared to placebo (P = 0.049 and P = 0.007). There was no statistical difference in number of reflux events, acid exposure time and acid sensitivity scores between STW5 and placebo. In a subgroup analysis of patients with pH-metry confirmed gastroesophageal reflux disease, treatment with STW5 significantly reduced the total number of acidic reflux events (P = 0.028). Moreover, in patients with reflux esophagitis, the median lag time to acid perception increased after STW5 treatment (P = 0.042). Conclusions: We found some indications pointing towards a beneficial effect of STW5 on reflux symptoms in dyspeptic patients, with reduction of esophageal hypersensitivity as a potential underlying mechanism. Our findings will have to be confirmed in larger studies.

Accuracy of Anorectal Manometry to Detect the Rectoanal Inhibitory Reflex in Children: Awake Versus Under General Anesthesia.

OBJECTIVES: Our objective was to investigate if there is a difference in the detection of the rectoanal inhibitory reflex (RAIR) when an anorectal manometry (ARM) is performed awake or under general anesthesia. METHODS: A retrospective review of ARM studies was performed to identify children who had undergone ARMs both while awake and under general anesthesia. We compared ARM outcomes including the detection of the RAIR and anal canal resting pressure. RESULTS: Thirty-four children had received ARMs both while awake and under general anesthesia (53% female, median age at first ARM 7.5 years [range 3-18 years]). In 9 of 34 (26%) children the RAIR was solely identified during ARM under general anesthesia and not during ARM while awake. In 6 of 9 (66%) this was unrelated to the balloon volumes used during balloon inflations. In 4 of 34 (12%) children, assessment of the RAIR was inconclusive during ARM under general anesthesia due to too low, or loss of anal canal pressure. In 2 of those children, ARMs while awake showed presence of a RAIR. Anal canal resting pressures were higher during ARM while awake versus ARM under general anesthesia (median 70 [interquartile range, IQR 59-85] vs 46 mmHg [IQR 36-65] respectively, P < 0.001). CONCLUSIONS: General anesthesia may affect the detection of a RAIR in 2 ways. On the one hand, it may facilitate better visualization in children in whom a RAIR could not be visualized while awake. On the other hand, it may cause a loss of anal canal pressure resulting in an inconclusive test result.

The inability to belch syndrome: A study using concurrent high-resolution manometry and impedance monitoring.

INTRODUCTION: Although inability to belch has previously been linked to dysfunction of the upper esophageal sphincter (UES), its underlying pathogenesis remains unclear. Our aim was to study mechanisms underlying inability to belch and the effect of UES botulinum toxin (botox) injections in these patients. METHODS: We prospectively enrolled consecutive patients with symptoms of inability to belch. Patients underwent stationary high-resolution impedance manometry (HRIM) with belch provocation and ambulatory 24-h pH-impedance monitoring before and 3 months after UES botox injection. RESULTS: Eight patients (four males, age 18-37 years) were included. Complete and normal UES relaxation occurred in response to deglutition in all patients. A median number of 33(15-64) gastroesophageal gas reflux episodes were observed. Despite the subsequent increase in esophageal pressure (from -4.0 [-7.7-4.2] to 8 [3.3-16.1] mmHg; p < 0.012), none of the gastroesophageal gas reflux events resulted in UES relaxation. Periods of continuous high impedance levels, indicating air entrapment (median air presence time 10.5% [0-43]), were observed during 24-h impedance monitoring. UES botox reduced UES basal pressure (from 95.7[41.2-154.0] to 29.2 [16.7-45.6] mmHg; p < 0.02) and restored belching capacity in all patients. As a result, esophageal air presence time decreased from 10.5% (0-43.4) to 0.7% (0.1-18.6; p < 0.02) and esophageal symptoms improved in all patients (VAS 6.0 [1.0-7.9] to 1.0 [0.0-2.5]; p < 0.012). CONCLUSION: The results of this study underpin the existence of a syndrome characterized by an inability to belch and support the hypothesis that ineffective UES relaxation, with subsequent esophageal air entrapment, may lead to esophageal symptoms.

Clinical Experience With Performing Esophageal Function Testing in Children.

OBJECTIVES: Pediatric high-resolution manometry (HRM) and 24-hour pH-impedance with/without ambulatory manometry (pH-MII+/-mano) tests are generally performed using adult-derived protocols. We aimed to assess the feasibility of these protocols in children, the occurrence of patient-related imperfections and their influence on test interpretability. METHODS: Esophageal function tests performed between 2015 and 2018 were retrospectively analyzed. All tests were subcategorized into uninterpretable or interpretable tests (regardless of occurrence of patient-related imperfections). For HRM, the following patient-related imperfections were scored: patient-related artefacts, multiple swallowing and/or inability to establish baseline characteristics. For pH-MII(+/-mano), incorrect symptom registration and/or premature catheter removal were scored. Results were compared between age-groups (0-3, 4-12, and >12 years). RESULTS: In total 106 HRM, 60 pH-MII, and 23 pH-MII-mano could be fully analyzed. Of these, 94.8% HRM, 91.9% pH-MII, and 95.7% pH-MII-mano were interpretable. Overall, HRM contained imperfections in 78.3% overall and in 8/8 (100%) in the youngest age group, 36/42 (85.7%) in 4 to 12 years and in 37/56 (66.1%) in children above 12 years; P = 0.011. These imperfections led to uninterpretable results in 4 HRM (3.8%), of which 3 were in the youngest age group (3/8, 37.5%). Imperfections were found in 10% of pH-MII and 17.4% of pH-MII-mano. These led to uninterpretable results in 5.0% and 4.3%, respectively. No age-effect was found. CONCLUSIONS: Esophageal function tests in children are interpretable in more than 90% overall. In children under the age of 4 years, all patients had imperfect HRM and 3/8 tests were uninterpretable. HRM in older children and pH-MII+/-mano were interpretable in the vast majority.

The Role of Symptom Association Analysis in Gastroesophageal Reflux Testing.

Gastroesophageal reflux disease is characterized by the reflux of gastric contents into the esophagus with an estimated worldwide prevalence of 8%-33%. The current paradigm in gastroesophageal reflux disease diagnosis relies on recognition of symptoms and/or the presence of mucosal disease at the time of esophagogastroduodenoscopy. Recognition of symptoms, however, can arise with challenges, particularly when patients complain of less typical symptoms. Since first reported in 1969 by Spencer et al., the application of prolonged intraesophageal pH monitoring to identify pathologic reflux has evolved considerably. Utility of pH monitoring aims to investigate the degree of acid burden and frequency of reflux episode, and the relationship between symptoms and acid reflux events. This relationship is represented by either the Symptom Index, Symptom Sensitivity Index, Symptom Association Probability, or Ghillebert Probability Estimate. This article reviews symptom-association analysis during esophageal reflux testing, covering the literature on current methods of reflux testing, interpretation of symptom association, and practical issues that can arise during symptom analysis.

The role of ambulatory 24-hour esophageal manometry in clinical practice.

High-resolution manometry revolutionized the assessment of esophageal motility disorders and upgraded the classification through the Chicago Classification. A known disadvantage of standard HRM, however, is the inability to record esophageal motility function for an extended time interval; therefore, it represents only a more snapshot view of esophageal motor function. In contrast, ambulatory esophageal manometry measures esophageal motility over a prolonged period and detects motor activity during the entire circadian cycle. Furthermore, ambulatory manometry has the ability to measure temporal correlations between symptoms and motor events. This article aimed to review the clinical implications of ambulatory esophageal manometry for various symptoms, covering literature on the manometry catheter, interpretation of findings, and relevance in clinical practice specific to the evaluation of non-cardiac chest pain, chronic cough, and rumination syndrome.

Prevalence of esophageal motility abnormalities increases with longer disease duration in adult patients with eosinophilic esophagitis.

BACKGROUND: During the natural course of eosinophilic esophagitis (EoE), the risk for esophageal stricture formation increases. It remains unknown whether motility abnormalities in EoE also develop over time. We aimed to determine the relationship between disease duration, clinical characteristics, and manometric pattern of EoE patients. METHODS: We compared esophageal high-resolution manometry (HRM) measurements of 31 adult EoE patients with HRM data from 31 GERD controls and 31 healthy controls. Subsequently, we assessed differences in disease duration and clinical characteristics between EoE patients with normal and those with abnormal esophageal motility. KEY RESULTS: In EoE patients, peristaltic integrity was more frequently failed (12 vs 6%) or weak (27 vs 15%; p < 0.001) compared with healthy controls; however, this pattern was also seen in GERD controls (failed 14%, weak 27%). We found no differences regarding symptoms and signs of EoE between EoE patients with normal (42%) and abnormal motility (58%). However, disease duration was longer in EoE patients with abnormal motility than in those with normal motility (13 (6-18) years vs 4 (1-11) years; p < 0.05). In EoE, but not GERD, disease duration was identified as a risk factor for abnormal motility (OR for each year 1.142; 95% CI 1.004-1.299), and with longer disease duration, the prevalence of abnormal motility increased from 36% (duration 0-5 years) to 83% (duration ≥16 years; p < 0.05). CONCLUSIONS & INFERENCES: Weak and failed peristaltic integrity are more often present in adult EoE patients than in healthy controls. The prevalence of manometric abnormalities in EoE patients increases with longer disease duration.