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Reflux characteristics triggering post‐reflux swallow‐induced peristaltic wave (PSPW) in patients with GERD symptoms

Abstract Background Esophageal chemical clearance has been evaluated with the post‐reflux swallow‐induced peristaltic wave (PSPW) index. The factors triggering PSPW in Gastro‐esophageal reflux disease (GERD) have not yet been investigated. This multicenter study was aimed at evaluating the characteristics of reflux episodes associated with PSPW occurrence in patients with typical GERD symptoms. Methods Impedance‐pH tracings from patients with typical reflux symptoms were analyzed. Sixteen healthy subjects were included for comparison. Multivariate analysis was performed to determine predictors of PSPW events. Key results Impedance‐pH tracings from 60 patients and 16 healthy subjects were evaluated. A total of 3454 refluxes were recorded. In patients, comparing reflux episodes followed with those not followed by a PSPW, significantly higher proportions of acid (79% vs. 74%, p: 0.02), mixed (47% vs. 32%, p: 0.0001) and proximal refluxes (34% vs. 20%, p: 0.0001) were observed. A multivariate analysis, acid (OR: 1.3, 95% CI: 1.05–1.6), mixed (OR: 2, 95% CI: 1.6–2.3), and proximal (OR: 2.1, 95% CI: 1.7–2.5) refluxes were independently associated with PSPWs. Reflux episodes followed by a PSPW were characterized by a significantly higher bolus clearing time [(mean ± SD) 41 s ± 6 s vs. 30 s ± 5 s, p < 0.05] whereas nadir pH value of reflux events preceding PSPWs was tangentially but not significantly lower [(mean ± SD) 2.61 ± 1.22 vs. 2.74 ± 1.26, p: 0.057]. Conclusions and inferences Acid, mixed and proximal refluxes, and their duration are key factors in eliciting PSPWs. PSPW represents a response to reflux directly related to the potential harmfulness of reflux contents.


| INTRODUC TI ON
Gastro-esophageal reflux disease (GERD) represents one of the most common gastrointestinal disorders, with an increasing worldwide prevalence. [1][2][3] GERD is a complex disease and is characterized by various symptom profiles as well as complex pathogenesis.
Esophageal clearance of refluxate represents, among all, a key factor in preventing the development of reflux disease and disease progression. 4,5 The clearance of reflux episodes is usually mediated by primary and secondary peristalsis, the latter elicited by local activation of mechanoreceptors removing the bulk of refluxate-volume clearance-and the former triggered by a vagal esophago-salivary reflex inducing salivary swallow and increasing esophageal pH-chemical clearance-. [6][7][8] Nevertheless, volume and chemical clearance do not always restore the esophageal pH preceding the reflux event.
Recently, the esophageal chemical clearance mechanism has been demonstrated with the post-reflux swallow-induced peristaltic wave (PSPW), that is, the impedance drops propagating from the proximal to the distal esophagus and occurring within 30 s after a reflux event and triggered by the esophago-salivary reflex. 9 Dividing the number of PSPWs by the number of reflux events a new multichannel intra-luminal impedance-pH (MII-pH) variable, namely the PSPW index, has been obtained. 9 It has been shown that patients with GERD present lower PSPW index values as compared to controls, being this variable also a potential diagnostic tool when other MII-pH parameters are inconclusive. 10 Moreover, PSPW index appears to be a promising variable in predicting response to acid-suppressive therapy, 11 as suggested by current international guidelines. [12][13][14] Very recently, it has been shown that PSPWs are associated with significantly higher pH increments in GERD patients responding to proton pump inhibitor (PPI) therapy compared to non-responders, thus confirming the defense role of the esophagosalivary reflex against reflux. 15 Nowadays, it is still not completely understood why, in GERD patients, less than half of reflux episodes are followed by PSPW events. Recently, two studies were aimed at evaluating the potential factors triggering PSPWs. Zhang et al 16 have shown, in a large cohort of asymptomatic subjects, that reflux episodes followed by PSPWs were more frequently mixed, with a higher proximal extent, occurring while awake and associated with a shorter chemical clearance time. Furthermore, it has been shown in a small group of GERD patients that PSPWs were elicited more frequently by reflux episodes with a higher proximal extent whilst the role of the acid component of refluxate seemed not to be less important. 17 Finally, it has recently been shown that patients with reflux symptoms and evidence of esophageal hypomotility as detected at high-resolution manometry (HRM) are characterized by significantly lower PSPW index values than patients with normal esophageal motility. 18 In order to better elucidate the relationship between reflux properties and PSPW occurrence, we evaluated the characteristics of reflux episodes associated with PSPW occurrence in a large group of patients with typical GERD symptoms.

| Patients
Ambulatory 24-h MII-pH tracings from consecutive adult patients (age > 18 years), assessed at six centers in Italy, were retrospectively evaluated. Inclusion criteria were the presence of dominant esophageal symptoms (heartburn, regurgitation, and non-cardiac chest pain) 19 unresponsive to acid-suppressive therapy or responsive but requiring reflux testing to confirm the need for long-term PPI therapy or to document pathologic reflux prior to anti-reflux surgery. A validated structured questionnaire, administered and in the presence of a senior investigator and based on a four-grade Likert-type scale, was used in each center to evaluate esophageal, dyspeptic and extra-esophageal reflux symptoms, (0 = none; 1 = mild/occasional; 2 = moderate/frequent; 3 = severe/constant). 20

Key points
• It has been shown that PSPWs are associated with remarkable increments of esophageal pH, higher in PPIresponsive than in PPI refractory GERD, revealing the occurrence of esophago-salivary reflex, and its clinical relevance as a neural-mediated defense mechanism against reflux.
• In the present study, we show that PSPWs are more frequently elicited by acid, mixed, and proximal refluxes as well as by prolonged reflux events.
• The present findings indicate that eliciting of PSPWs is directly related to the aggressive characteristics of refluxate.
The study was carried out in accordance with the Declaration of Helsinki and was approved by institutional review boards. Signed informed consent was obtained from all individuals before undergoing clinical investigations.

| 24-h MII-pH monitoring
Multichannel intra-luminal impedance-pH was recorded using a 2.3 mm diameter polyvinyl catheter assembly containing a series of impedance electrodes, each 4 mm in axial length, spaced at 2 cm intervals, and a distal antimony pH electrode (Sandhill Scientific Inc.).
The pH electrodes were calibrated using pH 4.0 and pH 7.0 buffer solutions before MII-pH monitoring. Following esophageal manometry, the catheter was passed through the anesthetized nostril, and positioned with the pH electrode 5 cm above the LES, and impedance electrodes at 3, 5, 7, 9, 15, and 17 cm proximal to the LES. MII-pH was always preceded by HRM for accurate location of the LES and exclusion of major motility disorders according to guidelines. 23 Event markers, corroborated with paper diaries, were used to record symptoms, meal times, and supine periods. Tracings were manually assessed with the aid of commercial software. Liquid and liquid-gas reflux events were distinguished into acid (nadir pH < 4.0), weakly acidic (nadir pH between 4.0 and 7.0), and weakly alkaline (nadir pH not below 7.0); meal times were excluded. Acid exposure time (AET) was defined as pathological if the time pH < 4 exceeded 6% of the total recording time. 12 Reflux-symptom association was assessed using symptom index (SI) and symptom association probability (SAP) for all reflux episodes using previously described methodology. 24,25 Bolus clearing time (BCT), that is, time-frame between reflux entry and exit, was calculated at 5 cm above LES. 26 PSPWs were defined as antigrade 50% drops in impedance, originating in the proximal esophagus and reaching the distal lumen within 30 s after reflux events. The PSPW index was calculated by dividing the number of PSPWs by the number of reflux events. 9,27 A reflux episode was defined as preceded by another reflux if the latter occurred in the preceding 5-min time-window frame. Refluxes followed by symptom recording and subsequently followed or not by a PSPW event, within a 30 s time window, were measured. Moreover, reflux episodes followed by a PSPW event and subsequently followed by a symptom (within a 2 min time window) were also measured.

| Statistical analysis
Data are presented as means and standard deviation (SD) unless otherwise indicated. Comparisons between groups were assessed using the Fisher's exact test and the Mann-Whitney U test when appropriate. Multivariate regression models were generated to evaluate the association between each reflux characteristic and PSPW events.
Significance was achieved when the p value was <0.05. Statistical analysis was performed using SPSS version 16.0 software (SPSS Inc.).

| RE SULTS
Multichannel intra-luminal impedance-pH tracings from 60 patients and 16 controls were evaluated. Demographics and MII-pH characteristics of patients and controls included in the study are reported in Table 1. In patients, the majority of cases were characterized by a pathological AET or a positive SAP and/or SI. Twelve patients (20%) were non-responders to previous PPI treatments; of these, 10 were characterized by a pathological AET and the remaining 2 by a positive SAP and/or SI. All controls displayed normal AET.
A total of 3096 reflux episodes were detected in GERD patients.
The mean reflux number for each patient was 51.6 (SD: 29). Overall  preceded by a previous reflux episode, in the 5-min time window, were comparable between the two groups. In controls, among reflux episodes followed by a PSPW event, a significantly higher proportion of mixed and proximal refluxes was observed when compared with the reflux episodes not followed by a PSPW ( Table 3).
In patients, reflux episodes followed by a PSPW were characterized by a significantly higher BCT at 5 cm above the LES compared with refluxes not followed by a PSPW (Figure 1). were followed by a PSPW event within 30 s whilst the remaining 166 refluxes (80%) were not (p < 0.0001). Thirty-two reflux episodes followed by a PSPW event were followed by symptom recording within a 2 min time window.
According to multivariate analysis, mixed liquid-gas and reflux reaching the proximal esophagus were characterized by a significantly higher probability to be associated to a PSPW event in controls whilst, in patients, acid, mixed liquid-gas and reflux reaching the proximal esophagus were characterized by a significantly higher probability to be associated to a PSPW event ( Table 4). were characterized by a significantly higher probability to be associated with a PSPW event ( Table 5). In patients with pathologic AET value and in those with both physiologic AET value and negative SAP and/or SI, mixed liquid-gas and proximal reflux episodes were characterized by a significantly higher probability to be associated with a PSPW ( Table 5).

| DISCUSS ION
To our knowledge, this is the first study evaluating the potential intra-esophageal factors associated with PSPW events, an important The majority of our patients were responders to previous PPI tri- In controls, among reflux episodes followed by a PSPW event, a significantly higher proportion of mixed liquid-gas and proximal refluxes was observed when compared with those not followed by a PSPW whilst in patients, among reflux episodes followed by a PSPW event, a significantly higher proportion of acid, mixed liquid-gas and proximal refluxes was observed when compared with those not followed by a PSPW. Proportion of refluxes preceded by a previous reflux episode, in the 5-min time window, were comparable between the two groups in both controls and patients. In controls, multivariate analysis showed that mixed liquid-gas and refluxes reaching the proximal esophagus were independently characterized by a significantly higher probability to be associated to a PSPW event. When patients were considered all together, multivariate analysis confirmed that acid, mixed liquid-gas and refluxes reaching the proximal esophagus were independently characterized by a significantly higher probability to be associated with a PSPW event. In patients with a pathological AET, mixed liquid-gas, and refluxes reaching the proximal esophagus were characterized by a significantly higher probability to be associated with a PSPW event, while in patients with positive SAP/SI and normal AET acid refluxes were also characterized by a significantly higher probability to be associated with a PSPW event.
Our results further corroborate most of the currently available data on this topic. Zhang et al 16 have recently demonstrated, in healthy subjects, that reflux episodes with high proximal extent and containing gas play a relevant role in eliciting PSPWs, similarly to results obtained in our controls. In agreement with the study by Xu et al, 17 carried out in patients with reflux symptoms, our results show that refluxes reaching 15 cm above LES are strongly associated with PSPW occurrence.
Several mechanisms might explain the findings reported herewith in healthy subjects and patients. It is conceivable that acid reflux, as well as reflux with higher proximal extent or containing gas, may stimulate afferent nerves, through activation of esophageal chemoreceptors and mechanoreceptors, and, in turn, eliciting the esophago-salivary reflex as revealed by a PSPW event. It has been demonstrated that the proximal esophagus is characterized by a more superficial innervation compared to the distal esophagus. It is conceivable, therefore, that the proximal esophagus is more sensitive to intra-luminal stimuli, and thereby predisposed to trigger reflexes when stimulated. 28,29 Moreover, it is also known that refluxes reaching the proximal esophagus and containing gas are more likely to be perceived in GERD patients. 30,31 We speculate that the acidic component of refluxate might contrib- Refluxes preceded by a reflux episode (5 min  As far as we know, this is the first multicenter study aimed at evaluating the potential factors involved in the elicitation of PSPW events in a large cohort of patients with GERD symptoms and in a group of controls. Some limitations could temper the strengths of our investigation. In particular, the retrospective patients evaluation and data analysis, although data collection was prospectively carried out for the whole study population. Moreover, MII-pH tracings were evaluated separately in each center involved in the study, although a satisfactory agreement between the same investigators has been achieved in previously published studies based on MII-pH tracings analysis. 15,41 Future outcome studies are needed to confirm the balance between aggressive factors and defense response in GERD.
In summary, our results demonstrate the relevance of acid and volume burden, mixed liquid-gas, proximal refluxes in eliciting PSPWs. Our findings corroborate the usefulness of performing MII-pH in the difficult management of patients with GERD symptoms and lead to the conclusion that PSPW, a key factor of epithelial protection, is correlated to reflux characteristics.