Symptomatic Reflux Episodes Research Articles

Determinants of reflux perception in patients with non-erosive reflux disease who have reflux-related symptoms on potassium-competitive acid blocker therapy.

This study investigated potential determinants of reflux perception in patients with non-erosive reflux disease (NERD) who had reflux-related symptoms on potassium-competitive acid blocker (P-CAB) therapy. This study included 23 patients with reflux-related symptoms despite P-CAB therapy. Esophageal impedance-pH monitoring was performed on P-CAB and the following potential determinants of reflux perception were investigated: reflux nadir pH value; change in pH (baseline-nadir); bolus clearance time; reflux extent; proportions of acid, weakly acidic, and weakly alkaline reflux episodes; and proportions of liquid and mixed reflux episodes. Overall, ≥ 90% of all and symptomatic reflux episodes were weakly acidic reflux and 63% of symptomatic reflux episodes were reflux episodes with pH ≥ 5. There were no significant differences regarding potential determinants between symptomatic and asymptomatic reflux episodes. However, the proportion of symptomatic reflux episodes was significantly greater with pH < 5 (13.8%) than with pH ≥ 5 (9.5%) (P = 0.0431). In reflux episodes with pH < 5, the proportion of symptomatic reflux episodes was significantly greater in proximal sites (20.6%) than in distal sites (10.6%) (P = 0.0178). Conversely, in reflux episodes with pH ≥ 5, there was no significant difference regarding reflux perception according to reflux extent (proximal: 9.6% vs. distal: 9.0%, P = 0.9337). In patients with P-CAB-resistant NERD, reflux symptoms were mainly caused by reflux episodes with pH ≥ 5 on P-CAB therapy. The proportions of symptomatic reflux episodes among reflux sites differed according to reflux pH value; thus, the mechanisms of reflux perception may differ according to reflux pH value.

Banded Versus Nonbanded Sleeve Gastrectomy: A Randomized Controlled Trial With 3 Years of Follow-up.

The aim of this study was to compare silicone-banded sleeve gastrectomy (BSG) to nonbanded sleeve gastrectomy (SG) regarding weight loss, obesity-related comorbidities, and complications. As a primary bariatric procedure, SG leads to excellent weight loss, yet weight regain is a relevant issue in mid- to long-term follow-up. Retrospective analyses suggest that banding a sleeve using a silicone ring may decrease weight regain and improve weight loss. The banded versus nonbanded sleeve gastrectomy single-center, randomized controlled trial was conducted from January 2015 to August 2019. The primary endpoint was defined as excess weight loss 3 years after surgery. Secondary endpoints included the surgery's impact on obesity-related comorbidities, quality of life, and complications. The study was registered under DRKS00007729. Among 94 patients randomized, 97% completed 3-year follow-up. Mean initial body mass index was 50.9 kg/m [95% confidence interval (CI), 49.6-52.2]. Mean adjusted excess weight loss 3 years after SG amounted to 62.3% (95% CI, 56.2-68.5) and 73.9% ( 95% CI, 67.8-80.0) after BSG (difference 11.6%, P = 0.0073). Remission of type 2 diabetes occurred in 66.7% (4/6) after SG and in 91.0% (10/11) following BSG (P = 0.21). Three years after surgery, ring implantation correlated with decreased frequency of symptomatic reflux episodes (P = 0.01) but increased frequency of regurgitation (P = 0.03). The rate of major complications was not different between the study groups (BSG, n = 3; SG, n = 2; P = 0.63). Quality of life was better following BSG (P = 0.001). BSG provided better weight loss than nonbanded SG 3 years after surgery. Regurgitation was the main clinically relevant negative effect after BSG.

Characteristics of symptomatic reflux episodes in Japanese proton pump inhibitor-refractory non-erosive reflux disease patients.

To clarify the pathogenesis of gastroesophageal reflux disease symptoms in non-erosive reflux disease (NERD) patients. Thirty-five NERD patients with persistent symptoms, despite taking rabeprazole 10 mg twice daily for at least 8 wk, were included in this study. All patients underwent 24 h combined impedance - pH on rabeprazole. The symptom index (SI) was considered to be positive if ≥ 50%, and proximal reflux episodes were determined when reflux reached 15 cm above the proximal margin of the lower esophageal sphincter. In 14 (40%) SI-positive patients, with liquid weakly acid reflux, the occurrence rate of reflux symptoms was significantly more frequent in proximal reflux episodes (46.7%) than in distal ones (5.7%) (P < 0.001). With liquid acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes (38.5%) and distal ones (20.5%) (NS). With mixed liquid-gas weakly acid reflux, the occurrence rate of reflux symptoms in proximal reflux episodes was significantly more frequent (31.0%) than in distal reflux ones (3.3%) (P < 0.001). With mixed liquid-gas acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes (29.4%) and distal ones (14.3%) (NS). The proximal extent of weakly acidic liquid and mixed liquid-gas reflux is a major factor associated with reflux perception in SI-positive patients on proton pump inhibitor therapy.

Acid reflux episodes sensitize the esophagus to perception of weakly acidic and mixed reflux in non‐erosive reflux disease patients

Non-erosive reflux disease (NERD) patients are more sensitive than erosive esophagitis patients to weakly acidic reflux and to the presence of gas in the refluxate. Intra-esophageal acid perfusion sensitizes esophageal receptors to mechanical and chemical stimuli. To establish whether acid sensitization plays a role in the perception of weakly acidic and mixed reflux episodes, 29 NERD patients, responders and 14 non-responders to proton pump inhibitors (PPIs), underwent pH-impedance monitoring. Non-responders repeated the study while on PPIs. To assess the effect of acid exposure on symptom perception, the time period with pH below 4 was measured in 15- and 30-minute time-windows preceding the onset of each reflux episode. Considering weakly acidic and mixed refluxes, both in responder and non-responder patients (off PPIs), the symptomatic refluxes were preceded by a significantly higher cumulative acid exposure than the asymptomatic refluxes. In all patients, following acid reflux, the percentage of symptomatic weakly acidic reflux episodes was significantly higher than that of asymptomatic refluxes. Non-responder patients, off-treatment, were characterized by a lower proportion of weakly acidic reflux and mixed reflux episodes. In the non-responder patients on PPI, only mixed and weakly symptomatic reflux episodes were preceded by a higher cumulative acid exposure. In NERD patients, spontaneous acid reflux enhances subsequent reflux perception, regardless of acidity or liquid/mixed composition of episodes; in non-responder patients on PPIs, only the perception of mixed and weakly acidic reflux episodes seems to be mediated by a preceding acid exposure.

Increased frequency and enhanced perception of reflux in non-erosive reflux disease patients non-responders to proton pump inhibitors

BackgroundThe unsatisfactory response to medical treatment in non-erosive patients is becoming a real challenge for gastroenterologists. Non-responder patients, evaluated under treatment, present symptoms which are related to non-acidic, mixed and proximal reflux episodes. MethodsTo elucidate the reflux pattern and mechanisms related to persistence of symptoms despite treatment, oesophageal pH-impedance was performed in 55 non-erosive responder and 24 non-responder patients, studied off therapy. Ten responder and 10 non-responder patients underwent a repeated study during proton pump inhibitor treatment. ResultsNon-responders were characterised by a higher overall number and larger proportion of symptomatic reflux episodes. Non-responders were also characterised by an enhanced sensitivity to acidic, mixed and proximal refluxes. Weakly acidic reflux accounted for 29% of symptomatic refluxes in non-responders and 34% in responders. Proportions of acidic and weakly acidic reflux episodes were comparable both in responders and non-responders when analysed off and on treatment. ConclusionsAn increased overall number of reflux episodes and enhanced sensitivity to reflux are strongly associated with treatment failure. Treatment strategies aimed at decreasing transient lower oesophageal sphincter relaxations, pain modulators or anti-reflux surgery should be considered in non-responders in whom a significant relationship between symptoms and reflux has been confirmed.

Characteristics of Symptomatic Reflux Episodes in Patients with Non-Erosive Reflux Disease Who Have a Positive Symptom Index on Proton Pump Inhibitor Therapy

Background and Aim: The reason that some reflux episodes evoke symptoms is poorly understood, therefore the aim of this study is to assess the determinants of reflux perception in patients with non-erosive reflux disease (NERD) on proton pump inhibitor (PPI) therapy. Methods: Ten NERD patients with persistent symptoms, despite double-dose PPI therapy, were included in this study. All patients had a positive symptom index (SI), which was determined by ambulatory 24-hour combined impedance-pH monitoring. Reflux episodes were identified and classified as acid, weakly acidic or weakly alkaline reflux and were considered symptomatic if patients recorded a symptom within 5 min after a reflux episode. Results: A total of 954 liquid reflux episodes were detected, including 135 (14.2%) acid, 782 (82.0%) weakly acidic, and 37 (3.9%) weakly alkaline. Overall, 59 (6.2%) reflux episodes were symptomatic and the majority (88.1%) of symptomatic reflux episodes were weakly acidic reflux. When reflux episodes were confined to the distal esophagus, there were very few reflux symptoms. Proximal reflux is significantly more likely to be associated with reflux symptoms, irrespective of the acidity of the refluxate or the duration of proximal reflux episodes. Conclusions: In NERD patients who have a positive SI on double-dose PPI therapy, the high proximal extent of refluxate is a major factor associated with reflux perception.

Persistent Reflux Symptoms in the Proton Pump Inhibitor Era: The Changing Face of Gastroesophageal Reflux Disease

Given the widespread use of potent acid suppressive therapies and primary caregivers’ increasing comfort with prescribing these medications at high doses, the patient population presenting to gastroenterologists for symptoms of gastroesophageal reflux disease (GERD) has changed. Whereas previous consultation often revolved around the control of erosive disease and other mucosal manifestations of GERD, and terminated with the prescription of proton pump inhibitor (PPI) therapy, gastroenterologists often now only enter the scene after failure of PPI therapy, for symptoms either resistant or only partially responsive to these medications. Because of the high proportion of subjects with esophagitis who are healed with PPI, 1,2 upper endoscopy of such individuals is low yield, 3 with only a small minority demonstrating erosive disease. The care of such patients is challenging. High-quality evidence supporting useful diagnostic testing or alternative effective therapies is largely lacking. However, the number of subjects with GERD symptoms incompletely or nonresponsive to PPI therapies is high, and their utilization of healthcare resources is substantial. The purpose of this mini-review is to examine the definition and epidemiology of esophageal GERD symptoms incompletely responsive to PPI therapy, the potential pathophysiologic mechanisms behind these symptoms, the differential diagnosis and evaluation of such patients, and current and developing therapeutic options.

A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease

Background:In preclinical models, antagonism of metabotropic glutamate receptor 5 (mGluR5) reduces transient lower oesophageal sphincter relaxations (TLOSRs) and increases LOS pressure. This study evaluated the effect of ADX10059, a potent,...

Characteristics of Symptomatic Reflux Episodes on Acid Suppressive Therapy

Persistent symptoms on acid suppressive therapy are due to either acid or nonacid gastroesophageal reflux (GER) episodes or are not related to reflux. To compare physical and chemical characteristics of GER episodes associated with symptoms in patients on acid suppressive therapy. Patients with persistent symptoms on acid suppressive therapy underwent combined impedance-pH monitoring. Reflux episodes were classified as acid if nadir pH was <4.0, and nonacid if it remained at >/=4.0, separated into liquid-only or mixed (liquid-gas), and considered to reach the proximal esophagus if liquid was present 15 cm above the lower esophageal sphincter (LES). Reflux episodes were considered symptomatic if patients recorded a symptom within 5 min after the reflux episode. Risk factors of symptomatic reflux episodes were identified using multivariable generalized estimating equations (GEEs). One hundred twenty patients (85 women, median age 54 yr, range 18-85 yr) recorded 3,547 reflux episodes (84.3% nonacid, 50.6% mixed), of which 468 (13.2%) were symptomatic. Based on multivariable GEE analysis with episode-level symptom status (symptomatic vs nonsymptomatic) as the outcome variable, reflux episode acidity was not significantly associated with symptoms (P= 0.40). Mixed reflux episodes were significantly associated with symptoms relative to liquid-only episodes (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.19-1.87, P= 0.0005), as were reflux episodes reaching the proximal esophagus compared with those reaching the distal esophagus only (OR 1.28, 95% CI 1.06-1.55, P= 0.012). The majority of reflux episodes on acid suppressive therapy are asymptomatic. Reflux episodes extending proximally and having a mixed (liquid-gas) composition are significantly associated with symptoms, irrespective of whether pH is acid (<4) or nonacid (>/=4).

When are reflux episodes symptomatic?

Careful scrutiny of pH recordings and symptom diaries in patients having 24-hour pH-metry reveals that most reflux episodes are asymptomatic. Although this observation is well known and long recognized, the explanation for why one reflux episode leads to symptoms and others do not is incompletely understood. Forty-four patients with chronic typical gastroesophageal reflux disease (GERD) symptoms referred for ambulatory pH testing were studied. Antisecretory medication was stopped 2 weeks prior to the study. Two meals were taken during the study; one standardized (hamburger, fries, milk-shake) and one at the patient's discretion. A system onset marker noted the type, beginning and end of symptoms (heartburn, regurgitation, chest pain). Age, sex, upright/supine position, nadir pH, time pH < 4, and relationship to meals were compared for symptomatic/asymptomatic reflux episodes. An acid reflux event was defined as a drop in pH < 4 lasting > 5 seconds. The pH catheter detected 1464 reflux episodes. Only 93 (6.3%) were symptomatic. Forty-six of the 93 (49.4%) were associated with heartburn, 38 (40.9%) with regurgitation, and nine (9.7%) with chest pain. Nadir pH was significantly lower in symptomatic episodes. Nearly 50% of symptomatic reflux episodes occurred after meals, especially after non-standardized compared to standardized meal. Symptomatic episodes tended to be longer in duration and to occur in the supine position, while age/sex made no difference. Six percent of the reflux episodes were temporally associated with typical GERD symptoms. This association seems to be influenced by the acidity of the refluxate. Nearly half of the symptomatic reflux episodes occurred after eating.

Endoscopic Injection of Durasphere for the Treatment of GERD - Long Term Human Pilot Study

Background: Endoscopic treatment of gastroesophageal reflux (GERD) remains suboptimal. The ideal endoscopic therapy for GERD should be safe, efficacious, durable, and easy to perform with minimal discomfort. The aim of this study was to demonstrate the feasibility, safety, and antireflux efficacy of submucosal augmentation, at or just below the squamocolumnar junction, with a biocompatible, nonmigratory, nonabsorbable pyrolytic carbon-coated bead suspension (Durasphere®. Methods: Ten GERD patients (mean age 40), with heartburn symptoms responsive to PPI use were enrolled. Clinical assessment included: endoscopy, esophageal manometry, Bravo pH monitoring, heartburn diary, and GERD-HRQL severity scoring at baseline, 3, 6, and 12 months. The procedure was performed in an outpatient endoscopy clinic using conscious sedation. Durasphere® was injected into the submucosal space, using a sclerotherapy catheter in two sets of 1-2 cc four quadrant injections, at and just below the squamocolumnar junction. The mean initial injection volume of Durasphere was 8.6 (4.7-13.9) mls. 3 patients who experienced incomplete symptom relief were reinjected. Outcome measures included PPI use, change in GERD-HRQL symptom scores, change in Bravo pH scores, and adverse events. Results: 12 month data is pending. At 6 months, 80% of patients had reduced their PPI dose by ≥50% compared to baseline, and 70% eliminated PPI use entirely (p < .001). The mean GERD-HRQL symptom score was 26.9 at baseline (off PPI) and 9.1 at follow-up - a 66% reduction (p < .002). Bravo pH results were available on eight patients. The mean percent total time with pH ≤ 4 for these patients was 14.2 at baseline and 9.9 following injection, a 30% reduction (p < .066). Symptomatic reflux episodes improved from an average of 46.7 at baseline to 6.6 episodes at follow-up - a reduction of 86% (p < .011). 3 of 8 patients normalized their DeMeester score. There were no serious adverse events. Transient (<12 hours) mild epigastric discomfort was reported by 60% of the patients but did not require analgesia. There was no dysphagia, and all patients resumed a regular diet within a few hours of the procedure. The technique was rated as “simple” by the endoscopist. Conclusions: Endoscopic injection of Durasphere into the submucosal space, at the GE junction, is a feasible, new method for the treatment of GERD. This preliminary clinical study has shown that Durasphere is technically simple, has excellent short-term efficacy and can be safely performed in an outpatient endoscopy clinic. Further study of this technique, evaluating a larger number of patients in the setting of a 1 year controlled trial is warranted.

Underlying mechanisms of respiratory symptoms with esophageal acid when there is no evidence of airway response

Although a strong association exists between gastroesophageal reflux (GER) and asthma, results of studies designed to maximize the likelihood of identifying that GER worsens pulmonary function in patients with asthma have been negative or inconclusive. Asthma symptoms worsen during symptomatic reflux episodes, and asthma symptom severity correlates with the severity of symptomatic reflux. Various reasons have been proposed to explain these findings. Discomfort associated with GER can cause reflux-associated respiratory symptoms even when pulmonary function is normal. New findings suggest that increases in minute ventilation rather than inhibition of diaphragm activity are responsible for the changes in respiratory sensation during acid perfusion of the esophagus in nonasthmatic subjects. These results may also pertain to asthmatic patients, because increasing minute ventilation can cause dyspnea and bronchospasm in this population. Treating GER, either medically or surgically, may improve asthma symptoms by preventing GER-induced changes in minute ventilation.