Postprandial High Resolution Impedance Manometry Identifies Mechanisms of Non-Response to Proton Pump Inhibitors

Abstract

Background & Aims

Recognition of rumination and supragastric belching is often delayed as symptoms may be mistakenly attributed to gastroesophageal reflux disease (GERD). However, distinct from GERD, rumination and supragastric belching are more responsive to behavioral interventions than to acid-suppressive and anti-reflux therapies. Postprandial high-resolution impedance manometry (PP-HRIM) is an efficient method to identify rumination and belches. We investigated the distribution of postprandial profiles determined by PP-HRIM, and identified patient features associated with postprandial profiles among patients with non-response to proton pump inhibitors (PPIs).

Methods

We performed a retrospective analysis of PP-HRIM studies performed on 94 adults (mean age, 50.6 yrs; 62% female) evaluated for PPI non-responsiveness at an esophageal referral center, from January 2010 through May 2016. Following a standard esophageal manometry protocol, patients ingested a solid refluxogenic test meal (identified by patients as one that induces symptoms) with postprandial monitoring up to 90 min (median 50 min). Patients were assigned to 1 of 4 postprandial profiles: normal; reflux only (>6 transient lower esophageal sphincter relaxations (TLESRs)/hour); supragastric belch (>2 supragastric belches/hour), with or without TLESR; or rumination (≥1 rumination episode/hour) with or without TLESR and supragastric belching. The primary outcome was postprandial profile.

Results

Of the study participants, 24% had a normal post-prandial profile, 14% had a reflux only profile, 42% had a supragastric belch profile, and 20% had a rumination profile. In multinomial regression analysis, the rumination group most frequently presented with regurgitation, the supragastric belch and rumination groups were younger in age, and the reflux-only group had a lower esophagogastric junction contractile integral. The number of weakly acidic reflux events measured by impedance-pH monitoring in patients receiving PPI therapy was significantly associated with frequency of rumination episodes and supragastric belches.

Conclusion

In a retrospective analysis of 94 non-responders to PPI therapy evaluated by PP-HRIM, we detected an abnormal post-prandial pattern in 76% of cases: 42% of these were characterized as supragastric belching, 20% as rumination, and 14% as reflux only. Age, esophagogastric junction contractility, impedance-pH profiles, and symptom presentation differed significantly among groups. PP-HRIM can be used in the clinic to evaluate mechanisms of PPI non-response.

INTRODUCTION

Up to 40% of patients with suspected gastroesophageal reflux disease (GERD) do not respond to proton pump inhibitor (PPI) therapy¹. This population of PPI non-responders (PPINRs) represents a large health care burden, and strategies to effectively characterize and manage this heterogeneous group are critically needed. Prior studies report that approximately one-third of patients referred for PPI non-response suffer from functional gastroduodenal disorders, including rumination syndrome and belching disorders ^{2, 3}. Since symptoms associated with rumination and supragastric belching overlap with GERD, diagnosis and appropriate treatment is often delayed⁴. Furthermore, rumination and supragastric belching are more responsive to behavioral interventions rather than acid-suppressive and anti-reflux strategies utilized for refractory GERD ^{2, 5, 6}. Thus, timely detection and management of these behavioral conditions are essential.

High resolution impedance manometry (HRIM) concurrently assesses directionality of liquid and gas movement in the esophageal body and changes in cavity and sphincter pressures⁷. Additional postprandial HRIM (PP-HRIM) monitoring facilitates assessment of manometric responses to aversive digestive stimuli within a short time frame of less than 60 minutes. In recent years groups have defined objective HRIM criteria for transient lower esophageal sphincter relaxations (TLESRs), rumination syndrome, and supragastric belching^{7, 8}. While research highlights PP-HRIM as an efficient and accurate diagnostic tool, the clinical applicability of PP-HRIM in identifying mechanisms of PPI non-response is unknown. Thus, the aims of this study were to investigate the distribution of postprandial profiles determined by PP-HRIM, and to identify patient features associated with postprandial profiles among a PPINR population.

Methods

Study Design & Subjects

This retrospective analysis examines all PP-HRIM studies performed on patients older than 18 years of age referred to a single tertiary care center for the evaluation of PPI non-response from January 2010 to May 2016. This protocol was approved by the Northwestern University Institutional Review Board.

Postprandial High-Resolution Impedance Manometry Protocol

Patients with persistent typical or atypical symptoms despite double dose PPI therapy who underwent a PP-HRIM study were included. All PP-HRIM studies were ordered by an esophagologist, predominantly for cases with a pre-test suspicion of a functional gastrointestinal disorder. All PP-HRIM studies followed a standardized HRIM protocol using a 36-channel solid-state catheter (Manoscan 360; Medtronic, Minneapolis, MN). First, patients were placed in the supine position and measurements were taken during a baseline phase followed by 10 swallows of 5-ml water. Next, patients were switched to a seated position, and measurements were taken during a baseline phase followed by 10 swallows of 5-ml water, and 200-ml water taken by rapid repeated swallows. Finally, patients ingested a solid refluxogenic test meal (the meal was self-identified by the patient as a meal that is typically symptom inducing) with postprandial monitoring up to 90 minutes. Studies were excluded if the manometry study did not include a minimum of seven technically adequate high quality wet swallows in the supine position or if the duration of postprandial monitoring was less than 20 minutes.

Each PP-HRIM study was independently reviewed by three members of the study team (RY, MT, JEP) using ManoView 3.0 to determine a motility diagnosis per Chicago Classification v3.0⁹ and a postprandial diagnosis. Data from concurrent 24-hour pH-impedance monitoring performed on PPI therapy was collected when available.

Definitions & Groups

The following evidence based criteria was used to define manometric episodes: TLESR – lower esophageal sphincter (LES) relaxation in the absence of a swallow within 4s and 2s after the onset of LES relaxation associated with crural diaphragm inhibition and duration of LES relaxation lasting more than 10 seconds⁸; rumination – rise in intragastric pressure of at least 30 mmHg above baseline associated with a retrograde pressure gradient and return of gastric contents without retching proximal to the upper esophageal sphincter (UES) up to 10s after strain event⁷; supragastric belching –UES relaxation with aboral flow of air followed by rapid expulsion of air in the setting of either esophagogastric junction (EGJ) contraction and/or negative intra-thoracic pressure⁷ (Figure 1).

Figure 1.

Post-prandial events on high-resolution impedance manometry. A) Example of a transient lower esophageal sphincter with inhibition of the crural diaphragm and LES relaxation lasting for > 10 seconds, associated with a reflux episode (retrograde movement of gastric contents proximal to the LES). B) Example of a rumination episode with (1) rise in intragastric pressure > 30mmHg above baseline followed by (2) retrograde flow of gastric contents to the UES, with (3) increased esophageal pressure, and (4) UES relaxation. C) Example of a supragastric belch with (1) EGJ contraction, (2) negative intra-thoracic pressure, (3) UES relaxation, and (4) aboral flow of air as demonstrated by rise in impedance, and (5) retrograde movement and expulsion of air. Figure used with permission from the Esophageal Center at Northwestern’s Digestive Health Center.

Normative thresholds for the frequency of postprandial TLESR, rumination, and supragastric belches are not defined. Thus, in order to delineate thresholds for abnormal in this study, we examined data from a sub-group of our patients with no prior history of foregut surgery, no major esophageal motility disorder, an AET < 2.0% and less than 20 reflux events on impedance-pH testing, and no hiatal hernia as a representation of “normal” physiology and anatomy. We derived cut-offs from the 75^th percentile data among this cohort to determine the abnormal frequency (number of episodes/hour) of TLESR, rumination episodes, and supragastric belches.

Outcomes

The primary outcome was postprandial diagnostic profile. PP-HRIM studies were a priori separated into four profiles: normal, reflux only, supragastric belch, or rumination. Normal group: normal frequency of TLESR episodes and an absence of abnormal rumination and/or supragastric belching. Reflux only: abnormal frequency of TLESR episodes in absence of abnormal rumination and/or supragastric belching. Supragastric belch: an abnormal frequency of supragastric belch episodes +/− abnormal frequency of TLESR episodes. Rumination: an abnormal frequency of rumination episodes +/− abnormal frequency of supragastric belch, +/− abnormal frequency of TLESR episodes.

Data Analysis

A complete case analysis was performed without a predetermined sample size; missing data was not imputed. The a priori goal for primary analysis was to identify independent predictors of postprandial diagnostic profile. As such, a univariate analysis examined differences in baseline clinical variables, physiologic data, and questionnaire scores between postprandial diagnostic profiles. One-way analysis of variance assessed variability among independent continuous variables and Chi Square examined differences in independent categorical variables. Covariates significant at P < 0.20 level were included in a multinomial logistic regression. P values < 0.05 in the regression model were considered statistically significant.

Since the postprandial diagnostic profiles were not based on standardized definitions or normative thresholds, we additionally examined the association between baseline variables and frequency of post-prandial events independent of classification by postprandial diagnostic profile. In this sensitivity analysis we performed multivariable linear regression modeling and included all variables (baseline clinical variables, physiologic data, and questionnaire scores) in the multivariable regression model. P values < 0.05 in the regression model were considered statistically significant.

Since patients that are status post foregut surgery or those with an EGJ outflow obstruction represent a unique mechanistic profile, we performed a post-hoc sub-analysis excluding this group of patients. One-way analysis of variance assessed variability among independent continuous variables and Chi Square examined differences in independent categorical variables.

All analyses were conducted using STATA 14.2 (StataCorp 2015, College Station, TX).

Results

Baseline Data

Overall, 99 PP-HRIM studies met protocol criteria. Among these, five studies uncovered a new diagnosis of achalasia and were excluded from the analysis. Of the 94 remaining studies, patients were a mean age of 45.5 ± 15.6 years and 58 (62%) were female. The most common indications for PP-HRIM included symptoms of regurgitation (54%), heartburn (26%), and dysphagia (25%). The majority of patients had normal esophageal motility (40%) or a minor motility disorder of ineffective esophageal motility or fragmented peristalsis (44%) (Table 1).

Table 1.

Baseline Clinical Data

Baseline data	N=94
Age (years)	45.5 ± 15.6
Female gender	58 (62%)
Body mass index (kg/m2) (n=88)	27.0 ± 7.5
Prior foregut surgery	13 (14%)
GerdQ Score (n=54)	10 ± 2.8
pH Impedance on PPI Data
Subjects with a 24h pH-impedance study ON PPI available	30 (32%)
Acid exposure on 24h pH-impedance ON PPI (n=30)	5.7 ± 6.9
Acidic reflux events	6 (IQR 1–31)
Weakly acidic reflux events	24 (IQR 9–38)
Study Indication
Regurgitation	50 (54%)
Heartburn	24 (26%)
Dysphagia	23 (25%)
Belching	14 (15%)
Chest pain	13 (14%)
Cough	10 (11%)
Laryngeal symptoms	10 (11%)
Manometric Findings
Median IRP (mmHg)	9.3 ± 6.9
EGJ-CI (mmHg-s-cm)	52.5 ± 32.9
EGJ Morphology Type I	70 (75%)
EGJ Morphology Type II	20 (22%)
EGJ Morphology Type III	3 (3%)
Normal Esophageal Motility	37 (40%)
EGJ Outflow Obstruction	12 (13%)
Absent Contractility	2 (2%)
Hypercontractile Esophagus	1 (1%)
Distal Esophageal Spasm	1 (1%)
Minor Motility Disorder (Ineffective esophageal motility or fragmented peristalsis)	41 (44%)
Post Prandial Testing
TLESR episodes per 60 minutes	4.7 (IQR 2.4–6.7)
Rumination episodes per 60 minutes	0 (IQR 0-0)
Supragastric belch episodes per 60 minutes	2.0 (IQR 0–7.6)
Post-prandial monitoring, minutes	50 (32.5–60)

Esophagogastric Junction (EGJ), Transient lower esophageal sphincter relaxation (TLESR); Proton pump inhibitor (PPI)

Postprandial Findings

The median duration of postprandial monitoring was 50 minutes (IQR 32.5–60 minutes). When averaged over 60 minutes of postprandial analysis there was a median of 4.7 (IQR 2.4–6.7) TLESR episodes, 0 (IQR 0-0) rumination episodes, and 2.0 (IQR 0.0–7.6) supragastric belches.

Derivation of Postprandial Thresholds and Profiles

Thirty-two patients had no prior history of foregut surgery, absence of a major esophageal motility disorder, an AET < 2.0%, less than 20 reflux events on impedance-pH monitoring, and did not have a hiatal hernia. Table 2 displays the frequencies of events for this ‘normal’ group. Based on this data we defined the threshold for abnormal frequencies (episodes/hour) as TLESR > 6, rumination > 0, and supragastric belch > 2. According to these thresholds, subjects were grouped as follows: 23 (24%) normal, 13 (14%) reflux only, 39 (42%) supragastric belch, and 19 (20%) rumination. Among the supragastric belch group 14 of 39 also had an abnormal frequency of TLESRs and among the rumination group, 2 of 19 had an abnormal frequency of TLESRs. In total, 42 (45%) had a functional disorder (supragastric belch and/or rumination) in absence of abnormal TLESR frequency.

Table 2.

Frequency of post-prandial episodes by percentile among 32 patients with impedance-pH monitoring with an acid exposure time <2.0 and less than 20 reflux events, and lack of hiatal hernia.

Number of episodes/Hour	Percentile
	5th	25th	50th	75th	95th
TLESR	0	2.1	3.7	6.7	10.2
Rumination	0	0	0	0	8.6
Supragastric belches	0	0	0	3.5	38.3

Primary Analysis – Characteristics by Postprandial Profile

The primary unadjusted analysis is presented in Table 3. Variables significant at the p <0.20 level (age, EGJ-CI, regurgitation, dysphagia, chest pain, and belching) were included in a multinomial logistic regression. The normal group (54.7 ± 14.1 years) was significantly older in age compared to the supragastric belch (43.7 ± 13.8; OR 1.07 (95% CI 1.01 to 1.13), p=0.02) and rumination (36.6 ± 13.4; OR 1.08 (95% CI 1.02 to 1.14), p=0.01) groups. The reflux only group had a significantly lower EGJ contractile integral (31.0 ± 20.2 mmHg-cm) compared to the normal (59.6 ± 41.2 mmHg-cm; OR 0.96 (95% CI 0.92 to 1.00), p=0.02) and supragastric belch (60.7 ± 31.7 mmHg-cm; OR 0.96 (95% CI 0.92 to 1.00), p=0.01) groups. Patients with rumination were 19.7 times more likely to present with regurgitation compared to supragastric belchers (84% vs 45%, OR 19.7 (95% CI 17.4 to 22.0), p=0.01) and 11.6 times more likely to present with regurgitation compared to the reflux only group (84% vs 23%, OR 11.6 (95% CI 9.7 to 13.5), p=0.01). The normal group was 6.7 times more likely to present with dysphagia compared to the supragastric belchers (OR 6.7 (95% CI 5.0 to 8.4), p=0.03).

Table 3.

Predictors of Post-Prandial High Resolution Impedance Manometry Pattern

	Normal, (n=23)	TLESR Only, (n=13)	Supragastric Belch (± TLESR), (n=39)	Rumination (± Supragastric belch; ±TLESR), (n=19)	P-value
Age (years)	54.7 ± 14.1	46.9 ± 18.8	43.7 ± 13.8	36.6 ± 13.4	<0.01
			Adjusted OR 1.07 (95% CI 1.01–1.13)‡	Adjusted OR 1.08 (95% CI 1.02–1.14)‡
Female gender	16 (70%)	7 (54%)	22 (56%)	13 (68%)	0.62
Prior foregut surgery	3 (13%)	3 (23%)	6 (15%)	1 (5%)	0.53
Body mass index (kg/m2)	28.9 ± 9.2	25.2 ± 5.5	26.7 ± 7.2	26.0 ± 6.5	0.47
GerdQ Score	9.3 ± 2.4	9.8 ± 2.4	10.2 ± 3.2	11.3 ± 1.7	0.61
Hiatal hernia > 3cm	7 (32%)	2 (15%)	8 (21%)	6 (33%)	0.52
EGJ Contractile Integral (mmHg-cm)	59.6 ± 41.2	31.0 ± 20.2	60.7 ± 31.7	45.7 ± 25.7	0.02
		Adjusted OR 0.96 (95% CI 0.92–1.00)‡$
EGJ Outflow Obstruction on Manometry	5 (22%)	2 (15%)	4 (11%)	1 (6%)	0.40
Symptoms
Regurgitation	14 (61%)	3 (23%)	17 (45%)	16 (84%)	<0.01
				Adjusted OR 19.7 (95%CI 17.4 to 22.0)$; Adjusted OR 11.6 (95% CI 9.7 to 13.5)†
Heartburn	4 (17%)	5 (38%)	10 (26%)	5 (26%)	0.58
Dysphagia	10 (43%)	3 (23%)	7 (18%)	3 (16%)	0.10
	Adjusted OR 6.7 (95% CI 5.0 to 8.4)$
Chest pain	3 (13%)	5 (38%)	5 (13%)	0 (0%)¥	0.02
Belching	0 (0%)	3 (23%)	3 (8%)	1 (5%)	0.09
Cough	4 (17%)	0 (0%)	5 (13%)	1 (5%)	0.33
Extraesophageal symptoms alone	1 (4%)	2 (15%)	6 (15%)	1 (5%)	0.43
Post-prandial findings
Duration of post-prandial monitoring	52.6 ± 18.8	52.4 ± 18.4	48.4 ± 19.0	36.3 ± 16.3‡	0.03
Frequency of TLESR episodes per 60 minutes	3.7 ± 1.9	8.9 ± 4.6	4.8 ± 3.1	3.0 ± 2.4	<0.01
Frequency of rumination episodes per 60 minutes	0 ± 0	0.1 ± 0.2	0 ± 0	23.1 ± 26.3	<0.01
Frequency of supragastric belch episodes per 60 minutes	0.3 ± 0.6	0.4 ± 0.5	19.6 ± 32.7	6.6 ± 12.2	<0.01
24h pH impedance on PPI therapy
Acid exposure time	6.4 ± 6.6	4.3 ± 1.5	5.2 ± 7.7	8.1 ± 6.8	0.90
Acidic reflux events	11.1 ± 14.8	24.0 ± 26.9	14.8 ± 20.0	26.0 ± 23.9	0.64
Weakly acidic reflux events	28.9 ± 24.2	16.5 ± 16.3	32.3 ± 33.1	87.7 ± 125.9	0.24

^†p <0.05 compared to TLESR;

^‡p <0.05 compared to normal;

^$p<0.05 compared to supragastric belch.

Esophagogastric Junction (EGJ), Transient lower esophageal sphincter relaxation (TLESR); Proton pump inhibitor (PPI)

Sensitivity Analysis – Factors Associated with Postprandial Episodes

Table 4 depicts the multivariable regression model including all covariates. Presence of regurgitation was associated with a mean difference of +7.26 rumination episodes/hour (β 7.26 (95% CI 1.32 to 13.20); p=0.02). In addition, each weakly acidic reflux event on pH-impedance monitoring performed on PPI was associated with +0.12 rumination episodes/hour (β 0.12 (95% CI 0.08 to 0.16); p<0.01) and +0.24 supragastric belches/hour (β 0.24 (95% CI 0.08 to 0.40);p<0.01).

Table 4.

Multivariable linear regression examining predictors of post-prandial episodes

	TLESR Episodes		Rumination Episodes		Supragastric Belch Episodes
	β (95% CI)	P- value	β (95% CI)	P- value	β (95% CI)	P- value
Age	−0.01 (−0.05 to 0.03)	0.53	−0.19 (−0.39 to 0.01)	0.07	−0.29 (−0.60 to 0.02)	0.07
Female gender	0.12 (−1.33 to 1.57)	0.87	−1.16 (−7.37 to 5.05)	0.72	−3.55 (−13.27 to 6.17)	0.48
Body mass index	−0.08 (−0.18 to 0.02)	0.11	−0.19 (−0.62 to 0.24)	0.38	−0.30 (−0.99 to 0.39)	0.39
Regurgitation	−0.67 (−2.06 to 0.72)	0.35	7.26 (1.32 to 13.20)	0.02	3.75 (−5.83 to 13.33)	0.45
Heartburn	0.46 (−1.15 to 2.07)	0.58	1.90 (−5.02 to 8.82)	0.59	4.53 (−6.31 to 15.37)	0.42
Dysphagia	−0.47 (−2.10 to 1.16)	0.57	−3.98 (−11.0 to 3.0)	0.27	−4.51 (−15.51 to 6.49)	0.42
Chest pain	1.37 (−0.65 to 3.39)	0.18	−5.43 (−14.11 to 3.25)	0.22	−7.80 (−21.44 to 5.84)	0.27
Belching	1.73 (−0.92 to 4.38)	0.20	−4.61 (−16.08 to 6.86)	0.43	−6.04 (−24.05 to 11.97)	0.51
Cough	0.82 (−1.43 to 3.07)	0.48	−5.18 (−14.96 to 4.60)	0.30	7.78 (−7.61 to 23.17)	0.32
Extraesophageal symptoms	0.49 (−1.78 to 2.76)	0.67	−4.71 (−14.45 to 5.03)	0.35	−2.45 (−17.82 to 12.92)	0.76
GerdQ Score	−0.15 (−0.42 to 0.12)	0.27	0.04 (−0.06 to 0.14)	0.40	3.62 (1.23 to 6.01)	<0.01
Baseline EGJ Pressure	−0.01 (−0.07 to 0.05)	0.70	−0.04 (−0.31 to 0.23)	0.77	−0.34 (−0.75 to 0.07)	0.11
EGJ Contractile Integral	0.00 (−0.02 to 0.02)	0.70	−0.02 (−0.12 to 0.08)	0.78	−0.02 (−0.12 to 0.08)	0.76
Median Integrated Relaxation Pressure	−0.10 (−0.20 to −0.00)	0.06	−0.24 (−0.67 to 0.19)	0.28	−0.49 (−1.18 to 0.20)	0.17
Acid exposure time*	0.05 (−0.17 to 0.27)	0.68	0.16 (−0.21 to 0.53)	0.41	−0.49 (−1.73 to 0.74)	0.44
Number of acidic reflux events*	0.04 (−0.04 to 0.12)	0.39	0.11 (−0.03 to 0.25)	0.11	0.11 (−0.34 to 0.56)	0.63
Number of weakly acidic reflux events*	−0.02 (−0.06 to 0.02)	0.26	0.12 (0.08 to 0.16)	<0.01	0.24 (0.08 to 0.40)	<0.01

^*Results from impedance-pH monitoring performed on PPI therapy.

Esophagogastric Junction (EGJ).

Sub-analysis Excluding Patients with a History of Foregut Surgery of Outflow Obstruction

Twenty-two of 94 patients had an EGJ outflow obstruction on manometry and/or a history of prior foregut surgery, and were excluded from the sub-analysis. Of the remaining 72, the postprandial profiles were: 15 (21%) Normal, 9 (13%) reflux only, 31 (43%) supragastric belch, and 17 (24%) rumination. The results are displayed in supplemental Table 1. Briefly, compared to the other groups, the normal group was older in age and supragastric belchers had the highest EGJ contractile integral. The rumination group was more likely to present with regurgitation compared to the other groups. In addition, chest pain was less frequently seen among supragastric belchers and ruminators compared to the refluxers.

Discussion

The management of PPI non-responders is a major health care challenge. After failing PPI optimization, patients often undergo various paths including diagnostic testing with endoscopy and reflux testing, referral to tertiary care centers, consideration for anti-reflux interventions, and/or indefinite PPI therapy^{1, 10}. In many cases, these strategies fail to clarify the underlying mechanism of PPI non-response or improve outcomes. This study assessed 94 PP-HRIM studies performed at a tertiary care esophageal referral center in patients referred for PPI non-response in order to examine the diagnostic utility of PP-HRIM. PP-HRIM detected an abnormal postprandial pattern in 76% of patients, with 62% of cases exhibiting a behavioral pattern – 42% with supragastric belching and 20% with rumination. Patients demonstrating behavioral patterns were younger, and those with rumination presented more commonly with regurgitation.

Understanding mechanisms of reflux symptoms is essential, as treatment strategies differ accordingly. For instance, among the 14% of the cohort with reflux only, management options include TLESR inhibition and potentially anti-reflux interventions¹⁰. On the other hand, for the 45% (n=42) with an abnormal frequency of rumination and/or supragastric belching in the absence of increased TLESR episodes, management should focus on behavioral treatment strategies such as diaphragmatic breathing, speech therapy and hypnosis. Importantly, this is a group that may not require long-term PPI therapy or anti-reflux interventions⁴. For the 17% of subjects with reflux and behavioral overlap it would be reasonable to consider a combined approach of TLESR inhibition, optimization of acid-suppression, and behavioral therapy, reserving invasive interventions as a second-line option. Elucidating post-prandial profiles may also have investigative value. For instance, despite optimism for lesogaberan as an effective TLESR inhibitor for PPI non-response, a clinical trial in 2010 examining lesogaberan reported considerable variability in the number of TLESRs among subjects and a small (8%) therapeutic gain. It is possible that patients with functional heartburn, rumination and/or supragastric belching diluted the study group ^{11, 12}. Future studies could benefit from using PP-HRIM to select representative patient populations.

In this study, we performed a primary analysis as well as sensitivity and sub-analyses in attempt to identify predictors of postprandial patterns. Overall, EGJ contractility as measured by the EGJ-CI was lowest among refluxers, with the mean EGJ-CI falling below published normative values of 39 mmHg-cm¹³. These results are consistent with prior literature demonstrating lower EGJ-CI among GERD patients^{13, 14}. In contrast, the EGJ-CI was high among supragastric belchers and the normal group, suggesting that dysfunction of the anti-reflux barrier is not a driver of supragastric belching. In addition, the rumination group demonstrated a borderline mean EGJ-CI of 46 mmHg-cm. While EGJ-CI values in rumination have not been previously reported, prior studies do report lower resting EGJ pressures among patients with rumination^{6, 15}. Our data further corroborates the idea that patients with rumination do not have an intact anti-reflux barrier or reflex arc.

The study results also support pre-existing notions regarding the relationship between symptoms and underlying mechanism. For instance, patients with rumination were more likely to present with regurgitation compared to the other groups whereas patients with rumination never presented with chest pain. Although not statistically significant, a greater portion of normal patients presented with dysphagia and also were found to have EGJ outflow obstruction on manometry. TLESR is the primary mechanism of gastric belching, and in this study belching was most commonly encountered among refluxers.

In addition, both rumination episodes and supragastric belches were associated with an elevated number of weakly acidic reflux events. Belches are identifiable on a careful evaluation of combined impedance-pH monitoring as impedance detects direction of flow and discerns liquid from gas ⁵. However, impedance-pH monitoring is limited by an inability to measure pressure and gradient alterations in the esophageal body. As such, rumination episodes may be misinterpreted as reflux events and/or elevated acid exposure on pH-impedance leading to a misdiagnosis of GERD or esophageal hypersensitivity.

These study findings suggest that PP-HRIM should be included in the armamentarium of diagnostic tools to evaluate PPI non-response, particularly when a primary behavioral or overlap profile is suspected. In order for PP-HRIM to be easily adopted and used in the clinical setting, future work is needed to identify the optimal clinical postprandial protocol such as meal type, monitoring period, and role of provocation, the normative thresholds for frequency of events, and the inter-rater diagnostic reliability. In our study, most postprandial profiles were apparent within 20 minutes of monitoring, and the duration of postprandial monitoring was shorter among rumination and supragastric belches supporting the idea that early pattern detection resulted in early study termination. Similar to reflux monitoring, it would be interesting to measure symptom association with postprandial evetns to understand which episodes carry clinical significance. While appropriate diagnosis is paramount, it is even more important that we develop pragmatic strategies to effectively treat these patients. Future studies should examine treatment impacts on patient outcomes, health care utilization and costs.

This study has important strengths and limitations. Generalizability of this study is limited due to referral and selection biases. The data likely overestimates the prevalence of rumination and/or belching disorders in the general gastroenterology setting as the study was performed at a single urban academic esophageal referral center and PP-HRIM studies were performed for a pre-test suspicion of a behavioral disorder. However, the patient mix is diverse and adequately representative of referrals to tertiary care centers for evaluation of ongoing PPI non-response. Since thresholds for postprandial diagnoses are not available, we defined postprandial groups based on our ‘normative’ cohort. In an attempt to address this limitation, we performed a sensitivity analysis examining the number of postprandial episodes linearly. In addition, the postprandial meal content and duration were not standardized. However, patients were given options of refluxogenic meals and we excluded studies with less than 20 minutes of monitoring. Given the retrospective nature of the study, we do not have complete reflux testing data prior to PP-HRIM testing for all patients which limits our ability to discern the presence of underlying GERD based on pH-metry, however, we do include data for the subset of patients for whom we performed pH-MII.

In conclusion, a significant portion of patients with PPI non-response may suffer from rumination or belching disorders and PP-HRIM offers an efficient and sophisticated method to evaluate underlying mechanisms of PPI non-response. Clinicians should consider performing or referring for PP-HRIM studies in PPINRs, particularly when the etiology of non-response is not forthcoming, in the setting of a history or suspicion of behavioral disorders, in younger patients presenting with regurgitation and in patients with elevated weakly acidic reflux events on pH-impedance monitoring.

Abbreviations

EGJ

Esophagogastric junction

GERD

Gastroesophageal reflux disease

HRIM

High resolution impedance manometry

LES

Lower esophageal sphincter

PPI

Proton pump inhibitor

PPINRs

PPI non-responders

PP-HRIM

Postprandial high-resolution impedance manometry

TLESRs

Transient lower esophageal sphincter relaxations

UES

Upper esophageal sphincter