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.     

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.     

Reflux monitoring in children

Recently, multichannel intraluminal impedance (MII) monitoring was added to the repertoire of tests to evaluate the (patho)physiology of gastroesophageal reflux (GER) in children. Its advantage above the sole monitoring of the esophageal pH lies in the ability of the detection of both acid and nonacid GER and to discern between liquid and gas GER. Currently, combined 24 h pH‐MII monitoring is recommended for evaluation of gastro‐esophageal reflux disease (GERD) and its relation to symptoms in infants and children, despite the lack of reference values in these age groups. There is new evidence in the current issue of this Journal supporting the role of pH‐MII monitoring for the evaluation of children presenting with gastrointestinal symptoms suggestive of GERD and the prediction of the presence of reflux esophagitis. However, several issues should be taken into account when performing pH‐MII clinically.     

Characteristics of gastro‐esophageal reflux episodes in Barrett’s esophagus,erosive esophagitis and healthy volunteers

Background Gastro‐esophageal reflux is considered a major culprit in the pathogenesis of Barrett’s esophagus (BE). Still, there is controversy on the role of weakly acidic and weakly alkaline reflux in BE. To compare characteristics of reflux episodes patients with BE, erosive esophagitis (EE), and healthy volunteers (HV). Methods One hundred consecutive patients with BE (75 short‐segment BE, 25 long‐segment BE), 50 with EE and 48 HV underwent multichannel intraluminal impedance‐pH off‐therapy. We quantified esophageal acid exposure, characteristics, and proximal extension of reflux episodes. Key Results Total and acid reflux episodes gradually increased from HV [28 (17.5–43) and 18 (8–31)] to EE [73.5 (54–96) and 52 (39–68)], short‐segment BE (SSBE) [83 (73.2–131) and 65 (43.3–95)] and long‐segment BE (LSBE) [105 (102–187) and 77 (75–107)]. Weakly acidic reflux episodes were significantly higher (P < 0.05) in LSBE [36 (27.5–50.5)] and SSBE [34 (18.5–41)] compared to EE [21.5 (15–37)] and HV [19 (14–25)]. No differences in terms of proportion of acid, weakly acidic and weakly alkaline reflux were found [HV (49%–49%–2%) vs EE (68%–32%–1%) vs SSBE (65%–34%–1%) vs LSBE (69%–30%–1%); P = ns]. In LSBE, a higher percentage of reflux episodes (P < 0.05) reached the proximal esophagus (59%) compared with SSBE (43%). Conclusions & Inferences Barrett esophagus patients have more severe reflux as shown by the number of acid and weakly acidic reflux episodes, re‐reflux episodes and proximal migration. Given that PPI change only the pH of the refluxate, the role of weakly acidic reflux in Barrett’s patients on acid suppressive therapy warrants further investigation.     

Increasing body weight enhances prevalence and proximal extent of reflux in GERD patients ‘on’ and ‘off’ PPI therapy

Background Increased body weight is associated with higher intragastric pressure. Proximal extent of reflux is a determinant of symptoms in patients with gastro‐esophageal reflux disease (GERD). We aimed to investigate the association between body mass index (BMI) and abdominal circumference on the incidence and proximal extent of reflux. Methods A total of 95 patients [37 men, age 51(16–82) years] with typical and/or atypical GERD symptoms underwent 24 h impedance‐pH monitoring. Forty‐nine patients were studied ‘off’ and 46 ‘on’ proton pump inhibitors (PPI) treatment. Reflux was classified as acid (pH < 4) or weakly acidic (pH 4–7). Proximal extent was defined as the number of reflux events reaching ≥15 cm above the lower esophageal sphincter. Body mass index and abdominal circumference (cm) were assessed. Key Results In patients ‘off’ PPI, there was a correlation between BMI and esophageal acid exposure (ρ = 0.53, P < 0.001), volume exposure (ρ = 0.48, P < 0.001), total number of reflux events (ρ = 0.47, P < 0.001) and number of acid reflux events (ρ = 0.49, P < 0.001). In patients ‘on’ PPI there was a correlation between BMI and esophageal acid exposure (ρ = 0.32, P = 0.03), volume exposure (ρ = 0.46, P < 0.01) and total number of reflux events (ρ = 0.33, P = 0.03). Similar correlations were found between abdominal circumference and reflux. A correlation between BMI and proximal extent of reflux was present in patients ‘off’ PPI (ρ = 0.32, P = 0.03). In patients ‘on’ PPI, we found a correlation between abdominal circumference and proximal extent (ρ = 0.31, P = 0.03). Conclusions & Inferences Body mass index and abdominal circumference may contribute to GER and its proximal extent, in patients ‘on and ‘off’ PPI. Further studies investigating the role of weight reduction in the control of GERD symptoms are warranted.     

Diagnosis of supra‐esophageal gastric reflux: correlation of oropharyngeal pH with esophageal impedance monitoring for gastro‐esophageal reflux

Background Oropharyngeal (OP) pH monitoring has been developed as a new way to diagnose supra‐esophageal gastric reflux (SEGR), but has not been well validated. Our aim was to determine the correlation between OP pH and gastro‐esophageal reflux (GER) events detected by multichannel intraluminal impedance‐pH (MII‐pH). Methods Fifteen patients (11 males, median age 10.8 years) with suspected GER were prospectively evaluated with ambulatory 24‐h OP pH monitoring (positioned at the level of the uvula) and concomitant esophageal MII‐pH monitoring. Potential OP events were identified by the conventional pH threshold of <4 and by the following alternative criteria: (i) relative pH drop >10% from 15‐min baseline and (ii) absolute pH drop below thresholds of <5.5, 5.0, and 4.5. The 2‐min window preceding each OP event was analyzed for correlation with an episode of GER detected by MII‐pH. Key Results A total of 926 GER events were detected by MII‐pH. Application of alternative pH criteria increased the identification of potential OP pH events; however, a higher proportion of OP events had no temporal correlation with GER (45–81%), compared with the conventional definition of pH < 4 (40%). A total of 306 full‐column acid reflux episodes were detected by MII‐pH, of which 10 (3.3%) were also identified by OP pH monitoring. Conclusions & Inferences Use of extended pH criteria increased the detection of potential SEGR events, but the majority of decreases in OP pH were not temporally correlated with GER. Oropharyngeal pH monitoring without concurrent esophageal measurements may overestimate the presence of SEGR in children.     

Poor effectiveness of proton pump inhibitors in non‐erosive reflux disease: the truth in the end!

Despite acid secretion being normal in the majority of patients with gastro‐esophageal reflux disease (GERD) or Barrett’s esophagus, acid inhibition represents the mainstay of treatment for both these conditions, with the aim of reducing the aggressive nature of the refluxate toward the esophageal mucosa. Proton pump inhibitors (PPIs) represent, therefore, the first choice medical treatment for GERD, in that they are able to provide an 80–85% healing rate for esophageal lesions, a 56–76% symptom relief and also reduce the incidence of complications, such as strictures as well as dysplasia and adenocarcinoma in Barrett’s esophagus. According to a widely quoted systematic review, compared to patients with erosive esophagitis, patients with non‐erosive reflux disease (i.e., NERD) display a reduced symptom relief with PPIs, with about 20% reduction of therapeutic gain. In this issue of NeuroGastroenterology & Motility, Weijenborg et al. address for the first time the PPI efficacy in subpopulations of patients with NERD. The study shows clearly that, when the diagnosis is accurately made by including a functional test, NERD patients respond to PPI therapy in a similar way to those with erosive disease. Although not as frequent as previously suggested, however, PPI‐refractory heartburn does exist. Some 20% (range: 15–27%) of correctly diagnosed and appropriately treated patients do not respond to PPI treatment at standard doses. Although the pathophysiology underlying PPI failure in GERD is complex and likely multifactorial, acid (be it the sole component of refluxate or not) still remains a major causative factor. A better and more predictable form of acid suppression should therefore be pursued.     

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.     

Effect of low‐proof alcoholic beverages on duodenogastro‐esophageal reflux in health and GERD

Background Alcoholic beverages are known to increase acidic gastro‐esophageal reflux (GER) and the risk of esophagitis. Moreover, duodenogastro‐esophageal reflux (DGER), containing bile acids, was shown to harmfully alter the esophageal mucosa, alone and synergistically with HCl and pepsin. However, studies directly addressing potential effects of different low proof alcoholic beverages on DGER in health and disease are missing. Methods Bilitec readings for beer and white, rose, and red wine were obtained in vitro from pure and from mixtures with bile. One‐hour DGER monitoring and pH‐metry were performed in 12 healthy subjects and nine reflux patients with DGER after ingestion of a standardized liquid meal together with 300 mL of water, white wine, and in the volunteers, beer and rose wine. Key Results Bilitec measurement was found to be feasible in the presence of beer, white wine, and using a threshold of 0.25, rose wine. However, the presence of red wine resulted in extinction values above this threshold. The consumption of all investigated alcoholic beverages, especially of white wine, triggered increased acidic GER, both in healthy participants and patients with reflux disease. In contrast, no relevant DGER was found after intake of alcoholic beverages. Conclusions & Inferences Fiber‐optic bilirubin monitoring can be used for DGER monitoring in combination with alcoholic beverages, except with red wine. Low‐proof alcoholic beverages are a strong trigger of GER, but not of DGER, both in healthy subjects and patients with reflux disease.     

Esophageal impedance baselines in infants before and after placebo and proton pump inhibitor therapy

Background Esophageal impedance monitoring records changes in conductivity. During esophageal rest, impedance baseline values may represent mucosal integrity. The aim of this study was to assess the influence of acid suppression on impedance baselines in a placebo‐controlled setting. Methods Impedance recordings from 40 infants (0–6 months) enrolled in randomized placebo‐controlled trials of proton pump inhibitor (PPI) were retrospectively analyzed. Infants underwent 24 h pH‐impedance monitoring prior to and after 2 weeks of double blind therapy with placebo or a PPI. Typical clinical signs of gastro‐esophageal reflux (GER) were recorded and I‐GERQ‐R questionnaire was completed. Key Results Median (IQR) impedance baseline increased on PPI treatment (from 1217 (826–1514) to 1903 (1560–2194) Ω, P < 0.001) but not with placebo (from 1445 (1033–1791) to 1650 (1292–1983) Ω, P = 0.13). Baselines before treatment inversely correlate with the number of GER, acid GER, weakly acid GER, acid exposure, and symptoms. The change in baseline on treatment inversely correlates with acid exposure and acid GER. Patients with initial low baselines have no improved symptomatic response to treatment. Conclusions & Inferences Impedance baselines are influenced by GER and increase significantly more with PPI therapy than with placebo. Clinical impact of this observation remains undefined as targeting therapy at infants with low baselines does not improve symptomatic response to treatment.     

Mechanism of gastroesophageal reflux in patients with obstructive sleep apnea syndrome

Background It has been reported that the prevalence of gastroesophageal reflux (GER) disease is high in patients with obstructive sleep apnea (OSA). End‐inspiratory intra‐esophageal pressure decreases progressively during OSA, which has been thought to facilitate GER in OSA patients. The aim of our study was to clarify the mechanisms of GER during sleep (sleep‐GER) in OSA patients. Methods Eight OSA patients with reflux esophagitis (RE), nine OSA patients without RE, and eight healthy controls were studied. Polysomnography with concurrent esophageal manometry and pH recording were performed. Key Results Significantly more sleep‐GER occurred in OSA patients with RE than without RE or in controls (P < 0.05). The severity of OSA did not differ between OSA patients with RE and without RE. Sleep‐GER was mainly caused by transient lower esophageal sphincter relaxation (TLESR), but not by negative intra‐esophageal pressure during OSA. During OSA gastroesophageal junction pressure progressively increased synchronous to intra‐esophageal pressure decrease. OSA patients had significantly more TLESR events during sleep related to preceding arousals and shallow sleep, but the number of TLESR events was not related to RE. Conclusions & Inferences In OSA patients, sleep‐GER was mainly caused by TLESR, but not by negative intra‐esophageal pressure due to OSA.     

Patients with refractory reflux symptoms: What do they have and how should they be managed?

With the widespread use of proton pump inhibitors (PPIs), the frontier of treating reflux disease has shifted from refractory esophagitis to PPI‐refractory symptoms. However, symptoms are inherently less specific than mucosal disease and, as noted by Herregods et al. in their contribution appearing in this issue of Neurogastroenterology and Motility, patients with refractory gastroesophageal reflux disease (GERD) symptoms often do not have GERD. This review discusses potential etiologies for PPI‐refractory symptoms. Three major concepts are explored: subendoscopic esophagitis, weakly acidic reflux events, and alternative explanations for persistent symptoms. With respect to subendoscopic esophagitis and unsuppressed reflux, ample evidence exists that these are present in PPI‐refractory patients. The problem is that these findings are also often present in substantial numbers of individuals with a satisfactory response to PPI therapy. Hence, the emphasis shifts to determinants of symptom perception. The major conclusion of the review is that psychogenic factors such as hyperalgesia, allodynia, hypervigilance, and heightened anxiety are the most plausible explanations as the dominant determinants of PPI‐refractory 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.     

The added value of quantitative analysis of on-therapy impedance-pH parameters in distinguishing refractory non-erosive reflux disease from functional heartburn

Background By analysis of symptom‐reflux association, endoscopy‐negative refractory heartburn can be related to acid/non‐acid refluxes with impedance‐pH monitoring. Unfortunately, patients frequently do not report symptoms during the test. We aimed to assess the contribution of quantitative analysis of impedance‐pH parameters added to symptom‐reflux association in evaluating patients with endoscopy‐negative heartburn refractory to high‐dose proton pump inhibitor therapy. Methods The symptom association probability (SAP), the symptom index (SI), the esophageal acid exposure time and the number of distal and proximal refluxes were assessed at on‐therapy impedance‐pH monitoring. Relationships with hiatal hernia and manometric findings were also evaluated. Key Results Eighty patients were prospectively studied. Refractory heartburn was more frequently related to reflux by a positive SAP/SI and/or abnormal impedance‐pH parameters (52/80 cases) (65%) than by a positive SAP/SI only (38/80 cases) (47%) (P = 0.038). In patients with refractory non‐erosive reflux disease (NERD) defined by a positive SAP/SI and/or abnormal impedance‐pH parameters, the prevalence of hiatal hernia was significantly higher (56%vs 21%, P = 0.007) and the mean lower esophageal sphincter tone was significantly lower (18.7 vs 25.8 mmHg, P = 0.005) than in those (35%) with reflux‐unrelated, i.e., functional heartburn (FH). On the contrary, no significant difference was observed subdividing patients according to a positive SAP/SI only. Conclusions & Inferences Quantitative analysis of impedance‐pH parameters added to symptom‐reflux association allows a subdivision of refractory‐heartburn patients into refractory NERD and FH which is substantiated by pathophysiological findings and which restricts the diagnosis of FH to one third of cases.     

The effect of baclofen on nocturnal gastroesophageal reflux and measures of sleep quality: a randomized, cross-over trial

Background Baclofen, a GABA_b agonist, has been shown to reduce episodes of gastroesophageal reflux (GER). To determine if baclofen would significantly reduce reflux during sleep, and also improve objective and subjective measures of sleep. Methods Twenty‐one individuals with complaints of nighttime heartburn at least twice a week and a Carlsson GERD score of at least 5 were studied. Patients underwent polysomnography (PSG) and simultaneous esophageal pH monitoring on two occasions separated by approximately 1 week in a cross‐over design. The night of each polysomnographic study, patients consumed a refluxogenic meal. Baclofen (40 mg) or placebo was given in random order 90 min prior to the start of the PSG. Key Results Baclofen significantly reduced the number of reflux events compared with placebo. Upright and recumbent acid contact times were both reduced by baclofen vs placebo, but the differences were not significant. Regarding sleep outcomes, several variables were significantly improved by baclofen. Total sleep time and sleep efficiency increased, and wake after sleep onset decreased in the baclofen condition compared with placebo. Proportion of Stage 1 sleep was also significantly decreased on baclofen. Conclusions & Inferences In addition to reducing the number of reflux events during sleep, baclofen significantly improved several measures of sleep in patients with documented GER and sleep disturbances. Baclofen could therefore be considered as a useful adjunct therapy to proton pump inhibitors (PPIs) in patients with nighttime heartburn and sleep disturbance who continue to have heartburn and/or sleep complaints despite PPI therapy.     

PPI therapy is equally effective in well-defined non-erosive reflux disease and in reflux esophagitis: a meta-analysis

Background Symptomatic response to proton pump inhibitor (PPI) therapy in patients with non‐erosive reflux disease (NERD) is often reported as lower than in patients with erosive reflux disease (ERD). However, the definition of NERD differs across clinical trials. This meta‐analysis aims to estimate the rate of symptom relief in response to PPI in NERD patients. Methods MEDLINE (1966–2010), Cochrane Comprehensive Trial Register (1997–2010) and EMBASE (1985–2010) databases were searched and manual searches from studies’ references were performed. Randomized clinical trials were selected that included patients with heartburn, and analyzed the effect of short‐term PPI treatment. The primary outcome of selected studies was defined as complete or partial heartburn relief. Two reviewers independently extracted data and assessed study quality of selected articles. Random effects models and meta‐regression were used to combine and analyze results. Key Results The pooled estimate of complete relief of heartburn after 4 weeks of PPI therapy in patients with ERD was 0.72 (95% CI 0.69–0.74) (32 studies), vs 0.50 (0.43–0.57) (eight studies) in empirically treated patients, 0.49 (0.44–0.55) (12 studies) in patients defined as non‐erosive by negative endoscopy, and 0.73 (0.69–0.77) (two studies) in patients defined as non‐erosive by both negative endoscopy and a positive pH‐test. Conclusions & Inferences In well‐defined NERD patients, the estimated complete symptom response rate after PPI therapy is comparable to the response rate in patients with ERD. The previously reported low response rate in studies with patients classified as NERD is likely the result of inclusion of patients with upper gastrointestinal symptoms that do not have reflux disease.     

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.     

Regional oesophageal sensitivity to acid and weakly acidic reflux in patients with non-erosive reflux disease

Abstract  The mechanisms underlying symptoms in non-erosive reflux disease (NERD) remain to be elucidated. Non-erosive reflux disease patients appear to be more sensitive to intraluminal stimula than erosive patients, the proximal oesophagus being the most sensitive. In order to assess regional oesophageal changes in reflux acidity and sensitivity to reflux, according either to the acidity or the composition of the refluxate, combined multiple pH and multiple pH-impedance (pH-MII) was performed in 16 NERD patients. According to multiple pH-metry, 29% and 12% of reflux events reached the middle and proximal oesophagus respectively, and 35% and 19% according to conventional pH-MII ( P  < 0.05). The per-individual analysis confirmed the difference between the two techniques. According to combined distal and proximal pH-MII, approximately 30% of distal acid reflux became weakly acidic at the proximal oesophagus. In all patients, the frequency of symptomatic refluxes, both acid and weakly acidic, was significantly higher at the proximal, compared with distal oesophagus (25 ± 8% vs 11 ± 2% for acid reflux and 27 ± 8% vs 8 ± 2% for weakly acidic reflux; P  < 0.05). Compared with multiple pH-metry, pH-MII shows a higher sensitivity in the detection of proximal reflux. As approximately 30% of acid reflux becomes weakly acidic along the oesophageal body, to better characterize proximal reflux, in clinical practice, combined proximal pH-impedance monitoring should be used. In NERD patients, the proximal oesophagus seems to be more sensitive to both acid and weakly acidic reflux.     

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.     

The frequency of apneas in very preterm infants is increased after non‐acid gastro‐esophageal reflux

Background To evaluate whether physical and/or chemical features of gastro‐esophageal reflux (GER) influence its relationship with apnea of prematurity (AOP). Methods Fifty‐eight preterm newborns (GA ≤33 weeks) with recurrent apneas were studied by simultaneous polysomnography and combined impedance and pH monitoring, to analyze whether the correlation between GER and AOP varies according to the acidity, duration and height of GERs. Key Results The frequency of apnea (number apnea/min) occurring after‐GER [median (range) 0.07 (0–0.25)] was higher than the one detected in GER‐free period [0.06 (0.04–0.13), P = 0.015], and also than the one detected before‐GER [0 (0–0.8), P = 0.000]. The frequency of apneas detected in the 30’’ after pH‐GER [median (range), 0 min^?1 (0–1.09)] was higher than the frequency detected in the 30’’ before [0 (0–0.91), P = 0.04]; even more, the frequency of apneas detected after non‐acid MII‐GER episodes [0 (0–2)] was significantly higher than the one detected before [0 (0–1), P = 0.000], whereas the frequency of apneas detected before acid MII‐GER episodes [0 (0–0.67)] did not differ from the one detected after [0 (0–2), P = 0.137]. The frequency of pathological apneas detected in the 30’’ after‐GER (0 min^?1, range 0–0.55) was higher than the frequency detected before (0, range 0–0.09; P = 0.001). No difference in mean height or in mean duration was found between GERs correlated and those non‐correlated to apnea. Conclusions & Inferences Non‐acid GER is responsible for a variable amount of AOP detected after‐GER: this novel finding must be taken into consideration when a therapeutic strategy for this common problem is planned.