A study of proximal esophageal baseline impedance in identifying and predicting laryngopharyngeal reflux

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A study of proximal esophageal baseline impedance in identifying and predicting laryngopharyngeal reflux

distal reflux proton pump

Songfeng Chen1; Mengya Liang2; Mengyu Zhang1;

Niandi Tan1; Yuqing Lin1; Peixian Cao1; Yinglian Xiao1

1 Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University

2 Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University

Abstract

Background and aim: Laryngopharyngeal reflux (LPR) is caused by the reflux of gastric contents beyond the esophagus into the larynx and pharynx. However, upper esophageal sphincter (UES) motility and proximal esophagus reflux parameters are poorly studied. This study aims to explore the characteristics of UES motility and reflux parameter among LPR patients.

Methods: Patients with laryngopharyngeal symptoms only (L), patients with laryngopharyngeal symptoms and typical esophageal symptoms (L + E), patients with typical esophageal symptoms only (E), and healthy controls (H) were retrospectively included. Physiological profiles were studied and compared among groups using both high-resolution manometry and pH-impedance monitoring, including UES basal pressure, residual pressure, relaxation duration time, recovery time, the time to nadir pressure, UES length, proximal contractile integral, and proximal mean nocturnal baseline impedance (MNBI). Patients' symptom outcomes were also analyzed.

Results: A total of 242 patients were included. Proximal MNBI was significantly lower in patients with both laryngopharyngeal and esophageal symptoms (17 cm above low esophageal sphincter [LES]: L vs L + E vs E vs H = 3689.7 vs 2500.0 vs 3073.0 vs 3996.0; 15 cm above LES: L vs L + E vs E vs H = 3155.9 vs 2553.4 vs 3198.9 vs 2985.2; P < 0.001). Patients responded to proton pump inhibitor treatment also had lower proximal MNBI than those who did not (17 cm above LES: 1834.0 vs 3500.0; 15 cm above LES: 1946.5 vs 3432.6; P < 0.001).

Conclusion: Decreased proximal MNBI can not only identify LPR patients but also predict patients' symptom outcomes.

Keywords: Baseline impedance; Laryngopharyngeal reflux; Manometry; pH-impedance monitoring

Introduction

Recent systematic review on epidemiological studies of gastroesophageal reflux disease (GERD) shows that the prevalence of GERD is up to 18.1%-27.8% in North America, 8.8%-25.9% in Europe, 2.5%-7.8% in East Asia1. Both esophageal and extraesophageal symptoms could be presented in GERD patients. Among all the extraesophageal symptoms, laryngopharyngeal reflux (LPR) is the most common one which is characterized by hoarseness, cough, sore or burning throat, globus, and throat clearing. In general population, it was found that the prevalence of LPR was 18.8 % in Greece2 and 5% in China3.

The difficulty of LPR in the clinical practice lies in the diagnosis. Questionnaires, including Reflux Symptoms Index (RSI) and Reflux Finding Score (RFS) are not exclusive to LPR4,5. PPI was not as effective in LPR patients as those with typical esophageal symptoms6. Ambulatory reflux monitoring has been recognized as gold standard for GERD with esophageal symptoms, while the criteria for pathologic reflux around UES area is controversial7,8. Salvia pepsin and trypsin detection is yet to be mature for the lack of established optimal timing and location for sampling, as well as threshold values9. Thus there was unmet need for the diagnosis of LPR.

Recent efforts in the field of LPR has been devoted to figure out some parameters which is beneficial to LPR diagnosis and associated with therapeutic outcome. Highresolution manometry (HRM) and multichannel impedance-pH monitoring (MII-pH) provide detailed information on esophageal motility as well as reflux parameters. Endeavor to find the motility and reflux metrics in the distal esophagus correlated with laryngopharyngeal symptoms has failed. However, these metrics in UES proximal esophagus has not been fully investigated.

This study hypothesized that the impairment of upper esophageal sphincter (UES) motility might aggravate the reflux of gastric contents beyond esophagus into larynx and pharynx, and prolonged reflux stimulation might be detected by proximal reflux parameters. Therefore, the purpose of this study was to explore the characteristics of LPR patients in UES motility and proximal reflux parameters, meanwhile try to find out potential parameters which can predict patients' symptom outcomes.

Methods

Study subjects

Patients who received HRM and MII-pH in our hospital in 2016-2019 and had chief complaints of hoarseness, dysphonia, sore or burning throat, excessive throat clearing, chronic cough, globus, dysphagia, apnea for more than 3 months were included. We also included healthy controls and patients with heartburn and (or) regurgitation. Participants mentioned above were then divided into four groups according to their symptoms: (1) patients with laryngopharyngeal symptoms only (L); (2) patients with laryngopharyngeal symptoms and typical esophageal symptoms (L+E); (3) patients with typical esophageal symptoms only (E); (4) healthy controls (H). Exclusion criteria included: (1) laryngopharyngeal or gastroesophageal surgery or tumor history; (2) diagnosed as achalasia by HRM; (3) discontinued proton pump inhibitors (PPI) less than 7 days or prokinetic drugs and antacids less than 3 days; (4) the reflux monitoring time lasted less than 16 hours.

High-resolution manometry

The procedure was conducted as previous reported and included a 30-second basal pressure recording period and ten 5-mL liquid swallows in the supine position10,11.

Analysis of HRM parameters was performed by two certificated investigators with the help of Manoview analysis software (Medtronic Inc. Minnesota). UES basal pressure was calculated during basal pressure recording period. Residual pressure, relaxation duration time, recovery time and the time to nadir pressure were calculated during swallow period. UES boundary and transitional zone (which distinguishes proximal and distal esophagus) were defined using 30 mmHg isobaric contour tool. Proximal contractile integral (PCI) was adopted to assess the function of the skeletal muscle and was defined as the product of length, time, and contractile amplitude above a threshold of 20 mmHg12. Other metrics including integrated relaxation pressure (IRP) and motor diagnosis were measured as described in Chicago Classification 3.0.

Multichannel impedance-pH monitoring

The procedure was conducted as previous reported11. Patients were encouraged to follow their normal routines, and record their symptoms, meals, postures during monitoring.

Analysis was performed manually by two investigators with the Bioview Analysis Software (Bioview Analysis; Sandhill Scientific Inc, Highland Ranch, CO, USA). Meal periods were excluded first. Abnormal distal reflux was defined as a pH < 4 at 5cm above LES ? 4.2% (or ?6 as described in Lyon consensus13) of the total time. The MNBI of the most distal impedance channel, as well as 15 cm and 17 cm above LES channel were calculated during the night time recumbent period. Three 10-minute time periods (around 1.00 am, 2.00 am, and 3.00 am) were selected, excluding refluxes, swallows, and pH drops, and the mean of the three measurements was calculated to obtain the MNBI14. Post reflux swallow induced peristaltic wave (PSPW) is a swallow that occurs following the end of a reflux episode within 30 seconds. PSPW index is calculated as the number of PSPW divided by the number of total reflux15. Other parameters were also collected including: (1) acid exposure time (AET), (2) reflux episode, (3) proximal reflux episode, (4) gas reflux episode and (5) symptom association probability (SAP, positive if ?95%).

Proton pump inhibitors treatment

Patients who received the standard PPI dose twice daily for more than 3 months were analyzed, and treatment were considered as effective when patients reported global symptom score improvement ? 50% in the last week of treatment compared with baseline symptom score.

Statistical analysis

Categorical variables were presented in the form of percentage and compared by chi-square tests. Normally distributed continuous variables were presented as mean ± SD and compared by one-way ANOVA. For quantative data that were not normally distributed, median (95% confidence interval) and Kruskal-Wallis tests were used. Pairwise comparison was conducted after statistical significant difference was observed among four sample groups. The significance level (p-value) was set at 0.05.

Results

A total of 242 patients (median age 41, 50.0% male) were included, including 59 patients with laryngopharyngeal symptoms only (group L), 114 patients with both laryngopharyngeal symptoms and typical esophageal symptoms (group L+ E), 44 patients with typical esophageal symptoms only (group E) and 25 healthy controls (group H). All types of patients were significantly older than healthy volunteers (L vs. L+E vs. E vs. H = 44 .0 (33.0, 56.0) vs. 45.0 (35.8, 55.0) vs. 45.0 (32.3, 59.8) vs. 25.0 (24.0, 26.0); P < 0.001). No significant differences have been found in gender, Body Mass Index (BMI) and laryngoscope results. The GERD Q scores of patients with typical esophageal symptoms were higher than that of patients with both laryngopharyngeal and esophageal symptoms, followed by that of patients with laryngopharyngeal symptoms only (L vs. L+E vs. E = 6.0 (6.0, 6.0) vs.7.0 (6.0, 9.0 ) vs. 9.0 (8.0,11.0); P < 0.001). As for endoscopy findings, patients with typical esophageal symptoms had significantly higher ratio of reflux esophagitis than other patients (L vs. L+E vs. E = 1.7% vs. 5.6% vs. 29.5%).

High-resolution manometry

UES basal pressure is higher in all kinds of patients than in healthy controls (table 1). IRP was lower in patients with laryngopharyngeal and concomitant esophageal symptoms than in healthy controls (L+E vs. H= 7.9 (4.0) vs. 10.9 (4.3); P = 0.013). As for esophageal motility classification, patients of all groups had higher ratios of abnormal esophageal motility than healthy controls (L vs. L+E vs. E vs. H= 45.1% vs. 45.0% vs. 43.2% vs. 16.7%; P=0.010). No statistically significant difference was observed in other parameters of UES motility.

Table 1 Motility comparison based on HRM in different groups

Caption. L: patients with laryngopharyngeal symptoms only; L+E: patients with laryngopharyngeal symptoms and typical esophageal symptoms; E: patients with typical esophageal symptoms only; H: healthy controls; UES: upper esophageal sphincter; PCI: proximal contractile integral; HRM: high-resolution manometry.

Multichannel impedance-pH monitoring

For the distal reflux parameters, patients with laryngopharyngeal and concomitant esophageal symptoms had significantly higher AET%, acid clearance time and ratio of pathological reflux (?4.2 or 6) than patients with only laryngopharyngeal symptoms and healthy controls (table 2). As for reflux episodes, patients with laryngopharyngeal and concomitant esophageal symptoms had more acidic reflux and total reflux episodes than healthy controls (table 2). All kinds of patients had higher ratios of SAP positive than healthy controls. PSPW index was lower in patients with laryngopharyngeal and concomitant esophageal symptoms than in patients with only esophageal symptoms (table 2). When comparing distal MNBI, patients with laryngopharyngeal and concomitant esophageal symptoms and patients with only esophageal symptoms both had lower MNBI than other two groups (table 2). To sum up, the distal reflux profiles of patients with laryngopharyngeal and concomitant esophageal symptoms were different from patients with only laryngophartngeal symptoms.

Table 2 Distal reflux parameters comparison between different group

Caption. L: patients with laryngopharyngeal symptoms only; L+E: patients with laryngopharyngeal symptoms and typical esophageal symptoms; E: patients with typical esophageal symptoms only; H: healthy controls; AET: acid exposure time; SAP: symptom association probability; MNBI: mean nocturnal baseline impedance; PSPW: post reflux swallow induced peristaltic wave.

As for proximal reflux parameters, patients with laryngopharyngeal and concomitant esophageal symptoms had significantly more proximal acidic reflux episodes than healthy controls (L+E vs. H = 10.0 (4.0, 9.0) vs. 1.0 (0.0, 8.0); P=0.014). 17 cm and 15 cm above LES MNBI were both lower in patients with laryngopharyngeal and concomitant esophageal symptoms than in other sample groups (17cm above LES: L vs. L+E vs. E vs. H = 3689.7 (2809.3, 4447.3) vs. 2500.0 (1940.0, 3417.0) vs. 3073.0 (2539.0, 3698.3) vs. 3996.0 (3588.5, 5020.9); 15cm above LES: L vs. L+E vs. E vs. H = 3155.9 (766.8) vs. 2553.4 (870.0) vs. 3198.9 (1031.1) vs. 2985.2 (455.9); P<0.001; figure 1a and 1b). Thus, proximal reflux parameters in patients with laryngopharyngeal and concomitant esophageal symptoms were different from that of other groups.

Proton pump inhibitors treatment

Sixty-three patients with laryngopharyngeal symptoms (L+E: 47; L: 16) in total have taken standard dose, twice daily PPI treatment for more than 3 months. Patients with laryngopharyngeal and esophageal symptoms responded better to PPI than those with only laryngopharyngeal symptoms did (59.6% vs. 18.8%; P=0.005). Patients were then divided into PPI responders (n=31) and non-responders (n=32) based on their PPI efficacy. Responders were older (50.0 (41.0, 59.0) vs. 38.0 (31.0, 51.0); P = 0.005), with male occupying higher proportion than non-responders (67.7% vs. 40.6%; P = 0.031). PPI responders were more likely to have typical esophageal symptoms (90.3% vs. 59.4%; P=0.005). However, no significant difference was observed in endoscopy findings and esophageal motility parameters. For distal reflux parameters, PPI responders had higher AET%, mean acid clearance time and proportion of pathological reflux (? 4.2 or 6) (table 3). We further compared novel metrics including PSPW index and MNBI by PPI efficacy to explore whether these novel metrics could be of value in predicting symptom outcome. In our study, PSPW index and distal MNBI was significantly lower in PPI responders (table 3), which indicates esophageal function and distal mucosa integrity was impaired in patients responded to PPI treatment. As for proximal reflux parameters, although no significant difference could be found in proximal reflux episodes, but PPI responders did have lower proximal MNBI than non-responders (17 cm above LES: 1834 (1500.0, 2109.3) vs. 3500.0 (2821.3, 4475.0); 15 cm above LES: 1946.5 (757.0) vs. 3432.6 (925.0); P<0.001; figure 2).

Table3 Distal reflux parameters comparison according to PPI efficacy.

Caption. AET: acid exposure time; SAP: symptom association probability; MNBI: mean nocturnal baseline impedance; PSPW: post reflux swallow induced peristaltic wave.

Discussion

Epidemiological investigations based on symptom questionnaires indicated that more than 5% of total population in China3 and 18.8% in Greece2 were affected by LPR. LPR was estimated to account for 10% of ear, nose, and throat (ENT) outpatients and 50% of patients with voice complaints16. Though many techniques have been used in LPR, none of these techniques is able to predict patients' symptom outcome6,17. This study was designed to focus on UES motility and reflux parameters in the proximal esophagus and try to find some relevant metrics for LPR. In this study, proximal MNBI was found to be significantly lower in patients with both laryngopharyngeal and esophageal symptoms. It is also shown that suspected LPR patients who responded to PPI have significantly lower proximal esophagus MNBI than PPI non-responders.

Previous studies failed to find the distinct motility and reflux characteristics in the distal esophagus of LPR patients. A recent prospective multicenter observational study published by Lien included 40 suspected LPR patients and 66 patients with isolated laryngopharyngeal symptoms18. The PPI-responsiveness and AET% were similar between groups mentioned above. No current established reflux metrics have been validated as a valuable predictor of symptom outcomes of LPR patients. Therefore, it seems inappropriate to use distal parameters to reflect the reflux situation in LPR, calling for urgent need to study parameters in the proximal esophagus.

Studies focusing on UES motility in LPR patients are limited and controversial. A retrospective study which compared suspected LPR patients with typical GERD patients has revealed that LPR was characterized by higher UES residual pressure19. Findings on UES motility were further supported by the efficacy of UES assist device in the patients with laryngeal symptoms20,21. However, another retrospective study which included 22 esophageal symptom patients, 22 extra-esophageal symptom patients and 44 healthy controls have found that both esophageal symptom patients and extra-esophageal symptom patients had lower UES basal pressure and shorter UES length than healthy controls22. Whether UES motility impairment is unique to LPR still remain uncertain. In this study, UES basal pressure was found to be significantly higher in all kinds of patients than in healthy controls, indicating that UES motility impairment was not exclusive to LPR.

Distal MNBI is a promising marker of reflux induced mucosa damage and is strongly related to acid exposure23-25. A prospective study which included 135 persistent GERD symptoms patients also showed that distal MNBI can predict symptomatic improvement of GERD treatment26. However, proximal MNBI showed no relation to acid exposure and treatment outcomes in these studies26. A possible explanation is that these studies only included patients with typical esophageal symptoms, whose reflux might be confined to distal esophagus. As a result, no positive finding was observed in the proximal esophagus. A former study published by Sakin YS retrospectively included suspected LPR patients and nonerosive reflux disease patients. Proximal baseline impedance and proximal-to-distal ratios were found to be lower among patients with pathologic laryngopharyngeal RFS27. However, patients with suspected esophageal motility disorders and esophagitis were all excluded and therapy outcome was not discussed in the study. Despite the prevalence of patients with laryngopharyngeal symptoms, only part of them are real LPR patients, still fewer of them respond to PPI. As such, it is of great clinical significance to identify this particular group of patients. Laryngopharyngeal symptoms of patients with concomitant esophageal symptoms are more likely to be caused by refluxes than those who without. Patients responded to PPI therapy might also be more likely to have acid reflux than those who didn't. Refluxes in these patients might caused proximal esophagus mucosa damage and integrity impairment, which can be revealed by proximal MNBI. As expected, in this study, proximal MNBI was significantly lower in suspected LPR patients and PPI responders.

There are some limitations in this study. Firstly, healthy controls were significantly younger than patients, which might influence the results of esophageal pressure and reflux parameters. Secondly, as a retrospective study, patients' symptom outcomes might be influenced by recall bias. Thirdly, only 63 patients with laryngopharyngeal symptoms (36.4%) received PPI treatment for more than 3 months. Last but not least, as a retrospective study, we did not control patients' diet. Although meal period was excluded while analyzing, potential bias caused by uncontrolled diet might still exist.

In conclusion, this study demonstrated that decreased MNBI in the proximal esophagus can not only identify LPR patients but also predict patients' symptom outcomes. However, further studies are needed to identify the normal limits, the sensitivity and specificity of proximal MNBI in the diagnosis of LPR.

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