Elevated intrabolus pressure identifies obstructive processes when integrated relaxation pressure is normal on esophageal high-resolution manometry

Integrated relaxation pressure (IRP) above the upper limit of normal defines esophageal outflow obstruction using high-resolution manometry. In patients with normal IRP, elevated intrabolus pressure (IBP) can be a surrogate marker for a structural restrictive or obstructive process at the esophagogastric junction (EGJ). This has the potential to augment the clinical value of esophageal HRM by raising suspicion for a structural EGJ process when IBP is elevated.

Abstract

Elevated integrated relaxation pressure (IRP) on esophageal high-resolution manometry (HRM) identifies obstructive processes at the esophagogastric junction (EGJ). Our aim was to determine whether intrabolus pressure (IBP) can identify structural EGJ processes when IRP is normal. In this observational cohort study, adult patients with dysphagia and undergoing HRM were evaluated for endoscopic evidence of structural EGJ processes (strictures, rings, hiatus hernia) in the setting of normal IRP. HRM metrics [IRP, distal contractile integral (DCI), distal latency (DL), IBP, and EGJ contractile integral (EGJ-CI)] were compared among 74 patients with structural EGJ findings (62.8 ± 1.6 yr, 67.6% women), 27 patients with normal EGD (52.9 ± 3.2 yr, 70.3% women), and 21 healthy controls (27.6 ± 0.6 yr, 52.4% women). Findings were validated in 85 consecutive symptomatic patients to address clinical utility. In the primary cohort, mean IBP (18.4 ± 0.9 mmHg) was higher with structural EGJ findings compared with dysphagia with normal EGD (13.5 ± 1.1 mmHg, P = 0.002) and healthy controls (10.9 ± 0.9 mmHg, P < 0.001). However, mean IRP, DCI, DL, and EGJ-CI were similar across groups (P > 0.05 for each comparison). During multiple rapid swallows, IBP remained higher in the structural findings group compared with controls (P = 0.02). Similar analysis of the prospective validation cohort confirmed IBP elevation in structural EGJ processes, but correlation with dysphagia could not be demonstrated. We conclude that elevated IBP predicts the presence of structural EGJ processes even when IRP is normal, but correlation with dysphagia is suboptimal.

NEW & NOTEWORTHY Integrated relaxation pressure (IRP) above the upper limit of normal defines esophageal outflow obstruction using high-resolution manometry. In patients with normal IRP, elevated intrabolus pressure (IBP) can be a surrogate marker for a structural restrictive or obstructive process at the esophagogastric junction (EGJ). This has the potential to augment the clinical value of esophageal HRM by raising suspicion for a structural EGJ process when IBP is elevated.

the first high-fidelity, water-based conventional esophageal manometry systems were developed in the mid-1970s, but pressure recording sites were limited along the esophagus, and measurements were often cumbersome and inconsistent (5). With modern solid-state catheters containing up to 36 pressure sensors reliably measuring pressure data, high-resolution manometry (HRM) provides accurate, sensitive, and reproducible measurements of esophageal pressure phenomena (4, 5). HRM data is displayed in a three-dimensional topographic “Clouse plot” of time, distance, and pressure representation as a color scale. Peristalsis is visualized as a chain of contracting segments and relaxing sphincters, assessed using measurements of smooth muscle contraction vigor [distal contractile integral (DCI)], peristaltic timing [distal latency (DL)], and nadir residual pressures at the esophagogastric junction during swallows [integrated relaxation pressure (IRP)] using software tools (2, 5, 6).

The IRP, defined as the lowest mean esophagogastric junction (EGJ) pressure over four contiguous or noncontiguous seconds of relaxation, evaluates deglutitive EGJ function (2). Median IRP above the upper limit of normal identifies obstructive pathophysiology at the EGJ (9). Elevated IRP can lead to compartmentalization of intrabolus pressure (IBP) antecedent to the contractile front and upstream of the obstruction (7, 12). IBP elevation can also result from increases in bolus size or when esophageal or lower esophageal sphincter (LES) distensibility is impaired (1, 12). In most settings, the IBP needs to overcome the EGJ residual pressure for the bolus to cross the EGJ (7). Therefore, an elevated IBP can potentially indicate restriction in transit across the EGJ even when a conventional measure of esophageal outflow obstruction, i.e., IRP, is within the limits of normal (7).

The diagnostic implication of an elevated IBP in nonachalasic settings where IRP is normal has not been systematically evaluated. The aim of this study was to determine whether compartmentalization of IBP in the setting of a normal IRP in no-achalasic disorders has clinical and management implications. A secondary aim was to assess whether elevated IBP can be used as a surrogate marker for structural EGJ processes when IRP is normal. A primary cohort of dysphagic patients with normal IRP was first evaluated to determine the value of IBP measurements with and without structural EGJ processes. Findings were then validated within a consecutive cohort of symptomatic patients with normal IRP referred for esophageal HRM.

METHODS

Primary cohort.

All adult (>18 yr of age) patients with esophageal-type dysphagia referred to one author (CPG) for evaluation over an 8-yr period (2006–2014) were eligible for this study. For inclusion, patients had to be studied at a minimum with esophageal HRM and esophagogastroduodenoscopy (EGD), with both performed at the motility and endoscopy centers at the Division of Gastroenterology, Washington University, St. Louis, MO. Exclusion criteria consisted of elevated IRP from any etiology, major motor disorders, prior foregut surgery, and incomplete or inadequate HRM studies. EGD reports and electronic medical records were scrutinized by an author not involved in clinical management (F. Quader) for evidence of structural processes at the EGJ (esophageal strictures, webs, rings, hiatus hernia). Comparison groups consisted of patients referred for dysphagia undergoing HRM studies, but without evidence of structural processes on EGD, as well as healthy controls. This study protocol, including review of HRM studies, EGD reports, and electronic medical records, was approved by the Human Research Protection Office (Institutional Review Board) at the Washington University School of Medicine.

Subjects.

For inclusion, all patients had to have presented for further evaluation of esophageal type dysphagia, with initial negative evaluation by the referring physician, with no esophageal mucosal or motor diagnosis. Patients for inclusion were identified from interrogation of all upper endoscopic examinations performed by one gastroenterologist (C. P. Gayawali) between the years of 2006 and 2014 on a single database that stored images and reports. Evaluation criteria included indication for endoscopy, gross findings on visual inspection of the esophagus, and biopsies, if any. An endoscopy was considered normal if no obstruction was recorded on the endoscopic report or present on images within the endoscopy report. Abnormal endoscopy consisted of structural processes, including strictures, webs, and hiatus hernia. Hiatus hernias were further subdivided based on EGJ images and documentation on the EGD report (no hiatus hernia, axial hiatus hernia, paraesophageal hiatus hernia, or combined axial/paraesophageal hiatus hernia). Studies were excluded if there was evidence of achalasia, prior foregut or esophageal surgery. The database created from EGD records was cross-referenced with the institution’s HRM database to identify patients who had also been evaluated with esophageal HRM in the context of undiagnosed dysphagia, with no evidence of esophageal outflow obstruction or major motor disorders.

Symptoms.

All patients were asked to complete a symptom survey before esophageal HRM for a description of dysphagia and secondary symptoms. These were recorded on five-point Likert scales generated a priori for esophageal testing at our center, assessing symptom frequency from 0 (no symptoms) to 4 (multiple daily episodes) and symptom severity from 0 (no symptoms) to 4 (very severe symptoms) as used in previous publications (11, 19, 22) and validated for use in evaluating esophageal symptoms (20). Symptom intensity was then calculated as the product of the frequency and severity of the dominant symptom being evaluated [dominant symptom intensity (DSI)] for a final score ranging from 0 to 16. Finally, patients rated their global symptom severity (GSS) over the previous 2 wk on a 100-mm visual analog scale (11, 19, 22).

Follow-up was based the final clinical encounter available in the electronic medical record (EMR). EMR interrogation determined whether dysphagia persisted, was resolved, or recurred and whether recurrence led to a repeat of endoscopic evaluation. Patients were considered lost to follow up if only one clinical encounter was documented in the EMR. The number of EGDs and endoscopic dilations performed were also extracted from the EMR.

Prospective validation cohort.

A prospective validation cohort was identified with two goals: 1) assess the reliability of findings from the primary cohort and 2) assess the significance of endoscopic findings in relation to dysphagia. This cohort consisted of consecutive patients presenting for esophageal HRM over a 1-yr period (2014–2015). Inclusion criteria were similar to the primary cohort described above. For the validation cohort, patients with elevated IRP were used for comparison purposes and characterized further. Other exclusions were similar to the primary cohort.

Validation cohort symptom analysis.

All patients in the validation cohort were asked to complete several additional symptom questionnaires before the HRM study in addition to that utilized for the primary cohort. These consisted of the Short Form 36 (SF-36), Mayo dysphagia questionnaire-30 day (MDQ-30), visceral sensitivity index (VSI), and global symptom severity (GSS). The SF-36 is a self-reported questionnaire widely used as a generic measure of health-related quality of life. Scores are computed as two summary scores, one for the physical component and another for the mental component (23). The MDQ-30 is a 28-question questionnaire that has been validated as a reliable tool in evaluating dysphagia (13). The VSI questionnaire consists of 15 questions in which patients select a score between 1 and 6 that corresponds to the degree of agreement of each question. The VSI has been validated in assessing gastrointestinal-specific anxiety related to functional bowel disorders. Although not validated in esophageal disorders, we attempted to identify anxiety related to dysphagia in these patient populations. The GSS was calculated using the technique described for the primary cohort.

Comparison cohorts.

A cohort of healthy asymptomatic individuals with no medical conditions and on no medications was utilized as normal controls. These individuals underwent esophageal HRM similar to patient cohorts. Furthermore, in the validation cohort, patients with overt esophageal outflow obstruction (IRP >15 mmHg) were identified for comparison purposes. In addition to HRM studies, these patients filled similar questionnaires as the validation cohort.

HRM studies.

HRM studies were performed in a similar fashion in all patient groups and controls. Following an overnight fast, a 36-channel catheter system with high-fidelity circumferential sensors 1 cm apart along the catheter (Given Imaging/Covidien/Medtronic, Duluth, GA) was passed through an anesthetized nasal channel, using previously described methodology (18). The manometry catheter was advanced such that three recording ports had an intragastric location. Patients then were asked to swallow 5 ml of room temperature water spaced at 20- to 30-s intervals for 10 swallows in the supine position. Multiple rapid swallows (MRS) consisted of at least four 2-ml water swallows in rapid succession with less than a 4-s interval between each swallow. Studies were analyzed using dedicated computerized HRM acquisition, display, and analysis systems (ManoView; Given Imaging/Covidien/Medtronic).

HRM studies were analyzed for esophagogastric junction (EGJ) outflow obstruction as well as major and minor motility disorders according to the Chicago Classification version 3.0 (9). Standard manometric software tools utilized included integrated relaxation pressure (IRP), distal contractile integral (DCI), distal latency (DL) for each of the 10 test swallows (9), and MRS sequences when available (22). Intrabolus pressure (IBP) was measured for each swallow 1 cm proximal to the LES during the emptying phase of esophageal peristaltic topography, using software tools embedded in analysis software (12, 21). This metric measures the mean of the maximum pressure within the designated window (starting at upper esophageal sphincter relaxation and ending at the contraction front) over a noncontinuous 3-s width relative to atmospheric pressure. The mean of the IBP measurements across 10 test swallows constituted the mean IBP for each patient. The EGJ contractile integral (EGJ-CI) was included as a metric to evaluate EJG barrier function, using methodology described elsewhere (3). Minor motor disorders were identified according to Chicago Classification version 3.0 as follows: ineffective esophageal motility (IEM): DCI <450 mmHg·cm·s with ≥50% ineffective swallows, fragmented persistalsis (≥50% with ≥5 cm breaks in the 20 mmHg isobaric contour and DCI >450 mmHg·cm·s) (9, 13a). Low LES pressure was defined as a resting end-expiratory LES pressure of <5 mmHg. EGJ morphology was further subdivided based on LES and crural diaphragm (CD) location, with type 1 having complete overlap of the CD and LES, type 2 with a separation of 1–2 cm, and type 3 ≥3 cm; types 2 and 3 constituted hiatus hernia (16). MRS sequences were analyzed for IRP, DCI, and IBP compared with mean values across the 10 test swallows performed as part of the routine HRM protocol.

Data analysis.

Data are reported as means ± SE unless otherwise indicated. Normative values for IBP were determined from analysis of data from normal controls. Comparisons were made between patients with dysphagia and structural processes at the EGJ, those with dysphagia without evidence of structural processes, and normal healthy controls. Continuous and categorical variables were compared using Student’s t-test and χ-squared analysis, respectively. In all instances, a P value of <0.05 was required for statistical significance. All statistics and plots were performed with Microsoft Excel and GraphPad Prism 7 (La Jolla, CA).

RESULTS

Primary cohort.

Over the study period, 74 patients (62.8 ± 1.6 yr, 67.7% women) fulfilled study criteria for esophageal-type dysphagia with structural EGJ findings and underwent HRM (Fig. 1). The most frequent finding on endoscopy was a hiatus hernia (66.2%), with the remainder of the patients having esophageal strictures, webs, or rings (Table 1). Comparison groups consisted of 27 consecutive patients (52.9 ± 3.2 yr, 70.3% women) from the same database, with a normal EGD in the setting of esophageal dysphagia and esophageal HRM, and 21 health, asymptomatic controls (27.6 ± 0.60 yr, 52.4% women). During endoscopy, 45 patients in the structural EGJ findings group underwent esophageal biopsy compared with 16 in the normal endoscopy group; common biopsy findings included esophagitis (20 vs. 19% respectively, P = 0.86) and intestinal metaplasia (14 vs. 4%, P < 0.01; Table 1).

Fig. 1.

Flow chart describing primary and validation cohort and normal controls. Achalasia was included as a comparison group with elevated integrated relaxation pressure (IRP) and intrabolus pressure (IBP) in the validation cohort. EGD, esophagogastroduodenoscopy.

Table 1.

Clinical and HRM characteristics of study cohorts

	Primary Cohort		Validation Cohort
	Structural EGJ findings	No structural abnormalities	Structural EGJ findings	No structural abnormalities	Normal Controls
n	74	27	36	30	21
Mean age	62.8 ± 1.6	52.9 ± 3.2	60.2 ± 2.8	49.8 ± 2.6	27.6 ± 0.6
Sex (%women)	67.6	70.3	58.3	76.6	52.4
EGJ morphology
Type 1	25		22
Type 2	34		5
Type 3	15		8
HRM metrics
IBP, mmHg	18.4 ± 0.85*	13.5 ± 1.12	15.37 ± 0.93*	12.11 ± 0.73	10.9 ± 0.90
IRP, mmHg	5.82 ± 0.56	5.46 ± 0.64	4.70 ± 0.58**	5.39 ± 0.54	7.12 ± 0.92
DCI, mmHg·cm·s	1,943 ± 176	1,641 ± 306	1,409 ± 135*	2,014 ± 248	1,712 ± 286
DL, s	7.61 ± 0.25	7.78 ± 0.85	7.30 ± 0.34**	7.45 ± 0.23**	8.85 ± 0.42
EGJ-CI, mmHg/cm	38.1 ± 3.31	37.8 ± 4.58	40.7 ± 3.78	50.7 ± 4.75	46.2 ± 7.59

Values are means ± SE. HRM, high-resolution manometry; EGJ, esophagogastric junction; IBP, intrabolus pressure; IRP, integrated relaxation pressure; DCI, distal contractile integra; DL, distal latency; EGJ-CI, EGJ contractile integral.

^*P ≤ 0.004 when compared with no structural abnormalities and normal controls.

^**P ≤ 0.04 when compared with normal controls.

Symptom burden.

Symptom data was available for 56 subjects with structural EGJ findings and 27 patients with normal endoscopy. Symptom burden was similar in both groups (DSI: 9.0 ± 0.77 vs. 8.0 ± 1.4, respectively, P = 0.48; GSS: 63.4 ± 3.7 vs. 56.5 ± 6.0, respectively, P = 0.30). There was no difference in DSI or GSS between strictures and hiatus hernia in subgroup analysis (P ≥ 0.2 for each comparison).

HRM metrics: wet swallows.

Significantly higher mean IBP values were recorded with structural EGJ findings (18.4 ± 0.9 mmHg) compared with dysphagia without structural EGJ findings (13.5 ± 1.1 mmHg, P < 0.01) and normal controls (10.9 ± 0.90 mmHg, P < 0.01; Fig. 2). In contrast, IBP values were similar between dysphagic patients without structural EGJ findings and normal controls (Table 1). Taking the 95th percentile value in normal controls (17.8 mmHg), 48% with structural EGJ findings had higher values compared with 24% with normal EGJ on endoscopy (P = 0.02; Fig. 3). Conventional HRM metrics, including mean IRP, DCI, DL; and EGJ-CI; were similar across groups (P > 0.05 for each comparison; Table 1). Low sphincter pressures at the LES (EGJ end-expiratory pressure <5 mmHg) were noted in 26% of the structural EGJ findings group compared with 3% in dysphagia patients with a normal EGD. Ineffective esophageal motility was seen more often with normal endoscopy compared with the structural EGJ findings group (19 vs. 4%, P = 0.04).

Fig. 2.

Comparison of mean intrabolus pressures (IBP) within the primary and validation cohorts compared with normal controls during wet swallows and during multiple rapid swallows (MRS). Patients with structural esophagogastric junction (EGJ) findings had the highest IBP during both wet swallows and MRS in both cohorts when compared with normal EGD and controls (P ≤ 0.02 for each comparison). IBP values were similar to wet swallows between patients with normal EGD and normal controls (P ≥ 0.1 for each comparison); with MRS, IBP values were similar in the primary cohort but higher in the validation cohort (P = 0.02).

Fig. 3.

Proportions of patients with elevated IBP (>95th percentile of normal) and patients with dysphagia between the primary and validation cohorts. More patients with structural EGJ findings had elevated IBP compared with patients with normal EGD. All patients in the primary cohort had dysphagia by definition. No statistically significant associations could be found between dysphagia, elevated IBP, and structural obstruction in the validation cohort.

In subgroup analysis, no significant differences in IBP were observed between patients with strictures and rings (19.7 ± 1.6 mmHg) and those with hiatus hernias (17.1 ± 1.0 mmHg, P = 0.14). When compared with the normal controls, 51% with strictures or rings and 44% with hiatus hernia had values above the 95th percentile of normal (P < 0.01). Within patients with hiatus hernia, type 3 EGJ morphology resulted in a higher IBP compared with type 2 (22.3 ± 0.93 mmHg vs. 17.7 ± 2.2 mmH.g respectively, P = 0.03). Mean IBP was numerically higher with paraesophageal hernia compared with axial hiatus hernia (23.4 ± 5.7 vs. 17.7 ± 2.2 mmHg, respectively, P = 0.08). Conventional HRM metrics and proportions with minor motor disorders were not different between groups. Upon inspection of the Clouse plots, elevated IBP could be identified as compartmentalization of intrabolus pressure preceding the contraction sequences and proximal to the EGJ (Fig. 4), which was visually distinctive from patients with normal IBP.

Fig. 4.

Examples of Clouse plots in a normal volunteer and in patients with a stricture and a hiatus hernia. An elevated IBP could be visually identified as compartmentalization of intrabolus pressure preceding the contraction sequence and proximal to the EGJ in patients with structural EGJ findings but not in normal controls.

HRM metrics: MRS.

MRS sequences were available for analysis in 59 patients with structural EGJ findings, 24 patients with normal endoscopy, and all 21 controls. As with wet swallows, IRP values during MRS were similar between the two dysphagia groups, whereas IBP was significantly higher in the partial obstruction group (19.2 ± 1.1 mmHg) compared with controls (14.7 ± 1.3, P = 0.02; Fig. 2). In subgroup analysis, no significant difference in IBP analysis was seen between strictures (18.3 ± 2.2 mmHg) and hiatus hernia (21.4 ± 1.2 mmHg, P = 0.18). Thirty-five percent in the structural EGJ findings group had IBP above the 95th percentile of normal (P < 0.01), ompared with 19% of the normal endoscopy group with dysphagia (Fig. 3).

Follow-up and outcome.

Follow-up information was available in 71 patients (52 patients with structural EGJ findings, 19 patients with normal EGD), with a mean follow-up of 30 ± 3.3 mo; 31 patients were only seen once. All 27 patients with the finding of a stricture or web on endoscopy underwent endoscopic dilation, with 21 (77.8%) reporting resolution of symptoms postdilation. In the dysphagia with normal endoscopy group, four of 19 patients (21.1%) underwent empiric dilation, with three patients reporting resolution in dysphagia (75.0%, P = 0.9 when compared with patients with strictures/webs). Of the 15 patients that were not dilated, 73% had resolution in symptoms without therapeutic intervention, whereas 27% did not. IBP values were similar between patients with symptom relief vs. those with persisting symptoms, regardless of whether dilation was performed (P > 0.7 for each comparison). Among patients with a hiatus hernia on endoscopy, 17 of 25 (68.0%) underwent surgical repair, with 16 of 17 (94.1%) reporting relief of dysphagia. When repair was not performed, three of eight patients (37.5%) spontaneously improved, whereas the remaining 62.5% did not (P < 0.01, comparing dysphagia resolution with surgical repair vs. observation). Those that underwent surgical repair had a numerically higher mean IBP when compared with those who did not (19.8 ± 1.7 vs. 16.23 ± 5.9 mmHg, P = 0.44); however, IBP was similar between groups with symptom relief and those with persisting symptoms, regardless of surgical intervention (P > 0.1 for each comparison).

Prospective validation cohort.

A total of 85 patients were included in the validation cohort: 36 with structural EGJ findings (29 with hiatus hernia, 7 with stricture), 30 with normal endoscopy, and 19 with achalasia. Similar to the primary cohort, mean IBP was higher with structural EGJ findings (15.4 ± 0.93 mmHg) compared with the normal endoscopy group (12.1 ± 0.73 mmHg, P = 0.008) and controls (10.9 ± 0.90 mmHg, P = 0.004). As expected, mean IBP was highest in the achalasia group (35.1 ± 4.48 mmHg) compared with the other three groups (P < 0.001). MRS sequences revealed similar findings, with higher mean IBP (18.9 ± 1.22 mmHg) in the structural EGJ findings compared with normal endoscopy (15.7 ± 1.03 mmHg, P = 0.048) and healthy controls (12.4 ± 0.71 mmHg, P < 0.001). IBP remained high during MRS in achalasia (39.9 ± 4.44 mmHg, P < 0.001 compared with other groups). On subgroup analysis, a greater number of patients with structural EGJ findings (15, 42%) had IBP higher than the 95th percentile value in normal controls compared with those with normal endoscopy group (5, 17%, P = 0.03). All achalasia patients had elevated IBP (P < 0.001 compared with other groups).

Validation cohort symptom analysis.

On symptom evaluation, 63.9% with structural EGJ processes and 50.0% with normal endoscopy reported dysphagia to either solids or liquids as a dominant or secondary symptom (P = 0.26). All patients with strictures reported dysphagia. Symptom burden was highest in achalasia (GSS 69.4 ± 4.8) but was not discriminative of structural EGJ processes (52.8 ± 5.0) or normal endoscopy (62.2 ± 4.7, P = 0.2). Using MDQ data, when IBP was elevated, 53.3% with structural EGJ processes and 20.0% with normal endoscopy had dysphagia (P = 0.19) compared with 88.9% with achalasia (P = 0.03 across groups). The actual IBP value did not correlate with the reporting of dysphagia. Using SF-36, quality of life scores were similarly lower in patients with achalasia (51.74 ± 5.1) and structural EGJ processes (58.52 ± 3.8, P = 0.28), with marginally better scores when endoscopy was normal (63.57 ± 5.0, P = 0.41 compared with the structural obstruction group, P = 0.11 compared with achalasia group). There was no difference in the visceral sensitivity index between the three patient groups or between those with and without dysphagia.

DISCUSSION

In this observational cohort study, we demonstrate that elevated IBP predicts the presence of structural EGJ findings in patients with dysphagia in the absence of esophageal outflow obstruction or major motor disorders on esophageal HRM. This conclusion from our primary focused retrospective cohort was substantiated on our validation cohort of consecutive, prospectively recruited patients. Although elevated IBP is a correlate of structural EGJ findings, this does not necessarily predict the presence of dysphagia. Finally, elevated IBP is easily visualized as low-amplitude pressure compartmentalization in the distal esophagus between the contraction front and the EGJ. Based on our findings, the finding of elevated IBP may warrant careful inspection of the distal esophagus at endoscopy for structural processes and potentially lead to targeted endoscopic dilation of the EGJ or surgical repair of hiatus hernia with clinical symptomatic benefit.

IBP, the pressure within the swallowed bolus, increases with increasing bolus volume and/or in the presence of an obstructive pathology. Maximal IBP correlates with nadir impedance values at each point along the esophageal length on high-resolution impedance manometry (12) and can be tracked concurrent with peak contraction pressures to yield unique bolus flow metrics (14). Tracking of IBP in this fashion, using automated impedance manometry analysis, demonstrates differences between asymptomatic volunteers and patients with dysphagia (14). Furthermore, elevated IBP has been demonstrated with obstructive processes, including hiatus hernia in some settings, suggesting that an elevated IBP can be a surrogate marker for abnormal bolus transit (17). The current study demonstrates the relationship between IBP and structural EGJ processes in dysphagic patients and documents the value of this metric in the setting of a normal IRP. It is well known that structural obstruction and even motor obstruction (i.e., achalasia) can exist with IRP within the upper limit of normal (15). Therefore, surrogate markers for bolus presence such as the IBP can alert the clinician to the potential presence of abnormal bolus transit even when the IRP is normal.

The IRP remains a consistent marker for esophageal outflow obstruction and is the first parameter evaluated within the Chicago classification of motor disorders (9). Even within this paradigm, elevated IBP is used as a surrogate marker for abnormal bolus presence. For instance, panesophageal compartmentalization of IBP defines type 2 achalasia, and compartmentalization of intrabolus pressure is noted between the contraction front and the EGJ in EGJ outflow obstruction (9). Elevated IBP in these settings is due to bolus accumulation within the esophageal lumen with ineffective esophageal emptying, but the obstructive element at the EGJ is profound, leading to elevated IRP. Our results suggest that similar but less profound abnormalities in esophageal emptying can be part of structural processes; this concept has been explored in a limited sense previously (7). Dysphagia presentations with elevated IBP may be clinically relevant, as these findings can lead to structural treatments (e.g., disruption of esophageal rings, targeted balloon or bougie dilation) that can potentially provide symptomatic benefit.

Currently utilized methods assessing of the EGJ barrier do not include an abnormal IBP in designating diagnoses or in recommending further evaluation of the EGJ. Thus, although most IBP elevations occur in the setting of elevated IRP, we demonstrate that pressure compartmentalization in the distal esophagus can occur despite a normal IRP. This compartmentalization is not predicted by any of the other existing HRM metrics (DCI, DL), symptom reporting, or quality-of-life metrics on questionnaires. Therefore, an abnormal IBP in the setting of normal IRP raises suspicion for a structural process and can potentially direct further management. As expected, dysphagia in the setting of strictures and webs responded to dilation in the setting of an elevated IBP, but the magnitude of IBP elevation did not predict symptoms or symptom improvement in this study.

Our study has a few limitations. The primary study cohort consisted of patients meticulously evaluated with repeat dedicated endoscopy and HRM after initial negative evaluation in most instances, which has likely selected out a unique patient population enriched by a tertiary referral practice; therefore, the findings may not necessarily be generalizable to the average gastroenterology practice. However, to mitigate this issue, we utilized a consecutive prospective validation cohort, which affirmed our initial findings. Furthermore, despite careful esophageal inspection, subtle structural lesions may have been missed, and patients with true structural processes could have been placed in the normal endoscopy group. Our data suggested that hiatus hernias were comparable with structural processes such as strictures and rings, but management of these entities is vastly different. Moreover, hiatus hernias can be intermittent, and intermittent hiatus hernia may not have been identified on either HRM or endoscopy. Follow-up periods were variable in the study, and many patients were lost to follow up. Since patients included in our study cohorts were collected before availability of distensibility measurements using the functional lumen imaging probe, we are unable to corroborate IBP measurements to distensibility. Furthermore, since we utilized historical cohorts, details of alternate testing could not be evaluated, interrogated, or corroborated. Despite these limitations, we believe assessment of IBP adds value to HRM interpretation, especially in the setting of otherwise normal HRM parameters in patients with dysphagia.

In conclusion, we demonstrate that elevated IBP is often associated with structural EGJ findings even when IRP is normal, but the finding does not correlate well with transit symptoms. Elevated IBP directs management of transit symptoms with therapy targeted at EGJ findings. Based on these conclusions, further prospective research on the clinical value of IBP elevation is warranted in the future.

GRANTS

This study was partially funded through National Institute of Diabetes and Digestive and Kidney Diseases Grant T32-DK-007130-AP and the Washington University Mentors in Medicine and Clinical Science Research and Training Program (to F. Quader and C. Reddy).

DISCLOSURES

C. P. Gyawali has research funding from Medtronic and has served as a consultant and a speaker for Medtronic. However, this project was not funded by Medtronic, and no conflicts of interest exist. None of the other authors have disclosures. No writing assistance was obtained.

AUTHOR CONTRIBUTIONS

F.Q. and C.R. performed experiments; F.Q., A.P., and C.P.G. analyzed data; F.Q., C.R., A.P., and C.P.G. interpreted results of experiments; F.Q. and C.P.G. prepared figures; F.Q. and C.P.G. drafted manuscript; F.Q., A.P., and C.P.G. edited and revised manuscript; F.Q., C.R., A.P., and C.P.G. approved final version of manuscript; C.P.G. conceived and designed research.