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.     

Increased TRPV1 gene expression in esophageal mucosa of patients with non‐erosive and erosive reflux disease

Background Transient receptor potential channel vanilloid subfamily member‐1 (TRPV1) may play a role in esophageal perception. TRPV1 mRNA and protein expression were examined in the esophageal mucosa of non‐erosive reflux disease (NERD) and erosive esophagitis (EE) patients and correlated to esophageal acid exposure. Methods Seventeen NERD patients, eight EE patients and 10 healthy subjects underwent endoscopy after a 3‐week washout from proton pump inhibitors or H2 antagonists. Biopsies, obtained from the distal esophagus, were used for conventional histology, for Western blot analysis and/or quantitative real‐time polymerase chain reaction (qPCR). Overall 13 NERD patients, four EE patients and five controls underwent ambulatory pH‐testing. Key Results TRPV1 expression was increased in all NERD and EE patients, as measured by Western blot analysis (0.65 ± 0.07 and 0.8 ± 0.05 VS 0.34 ± 0.04 in controls; P < 0.01) and by qPCR (1.98 ± 0.21 and 2.52 ± 0.46 VS 1.00 ± 0.06; P < 0.01). Neutrophilic infiltration, in the mucosa, was detected only in EE patients. Conclusions & Inferences Non‐erosive reflux disease and EE patients presented increased TRPV1 receptors mRNA and protein, although no correlation with acid exposure was demonstrated. Increased TRPV1 in the esophageal mucosa may contribute to symptoms both in NERD and EE patients and possibly account for peripheral mechanisms responsible for esophageal hypersensitivity in NERD patients.     

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.     

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.     

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.     

Cardiovascular compression of the esophagus and spread of gastro‐esophageal reflux

Background Factors that determine the spread of gastro‐esophageal reflux (GER) along the length of the esophagus are not known. We investigated if cardiovascular (CV) compressions on the esophagus may determine the spread of refluxate into the proximal esophagus. Methods High‐resolution manometry (HRM) and multi‐channel intra‐luminal impedance recording (MIIR) were performed simultaneously in 10 normal subjects in the recumbent and upright positions. Pulsatile pressure increases on the esophagus (marker of CV compression) were identified on the HRM. Spread of refluxate into the esophagus was determined by the MIIR. Key Results Cardiovascular compression zones were observed in the esophagus in 9 out of 10 subjects in recumbent position. Forty percent of GER episodes were limited to the distal esophagus in the recumbent position and CV compression pressure was greater than distal esophageal pressure at the time of GER in all such cases. On the other hand, distal esophageal pressure was greater than CV compression pressure when the refluxate extended into the proximal esophagus. In the upright position, CV compression was less frequent than recumbent position and only 12% of GER episodes were limited to the distal esophagus. Conclusions & Inferences Cardiovascular compression of the esophagus is frequently observed in normal healthy subject and restricts the spread of refluxate into the proximal esophagus.