Abstract
Background:
Integrated relaxation pressure (IRP) calculation depends on the selection of a single gastric reference sensor. Variable gastric pressure readings due to sensor selection can lead to diagnostic uncertainty. This study aimed to examine the effect of gastric reference sensor selection on IRP measurement and diagnosis.
Methods:
We identified high-resolution manometry (HRM) conducted between January and November 2017 with at least 6 intragastric reference sensors. IRP measurements and Chicago Classification 3.0 (CCv3) diagnoses were obtained for each of 6 gastric reference sensors. Studies were categorized as “stable” (no change in diagnosis) or “variable” (change in diagnosis with gastric reference selection). Variable diagnoses were further divided into “variable normal/dysmotility” (≥1 normal IRP measurement and ≥1 CCv3 diagnosis), or “variable dysmotility” (≥1 CCv3 diagnosis, only elevated IRP measurements). Bland-Altman plots were used to compare IRP measurements within HRM studies.
Key Results:
The analysis included 100 HRM studies, among which 18% had variable normal/dysmotility, and 10% had variable dysmotility. The average IRP difference between reference sensors was 6.7 mmHg for variable normal/dysmotility and 5.9 mmHg for variable dysmotility. The average difference between the proximal-most and distal-most sensors was −1.52 mmHg (lower limit of agreement −10.03 mmHg, upper limit of agreement 7.00 mmHg).
Conclusions & Inferences:
IRP values can vary greatly depending on the reference sensor used, leading to inconsistent diagnoses in 28% of HRM studies. Choosing the correct gastric reference sensor is crucial for accurate test results and avoiding misdiagnosis. Standardization of reference sensor selection or supportive testing for uncertain results should be considered.
Keywords: manometry, esophagus, achalasia, esophagogastric junction
Graphical Abstract
INTRODUCTION
High-resolution esophageal manometry (HRM) is a diagnostic test that permits the comprehensive evaluation of esophageal motor function by generating topographic pressure plots. A crucial measurement of HRM is the integrated relaxation pressure (IRP), which reflects the adequacy of esophagogastric junction (EGJ) relaxation during deglutition. Impaired IRP is among the most common and important esophageal motility abnormalities.1 It is a cornerstone of the Chicago Classification, a schema for the diagnosis of esophageal motility disorders using HRM.2 An abnormally elevated IRP defines disorders of EGJ outflow, which include achalasia, its subtypes, and esophagogastric junction outflow tract obstruction (EGJOO). As such, the importance of IRP accuracy and its intrinsic link to the integrity of the Chicago Classification cannot be overstated.
By convention, the IRP is derived by obtaining the mean minimum EGJ pressure over 4 seconds (contiguous or noncontiguous) of lower esophageal sphincter (LES) relaxation within the 10-second window of a swallow referenced to the intragastric pressure.3 Accurate IRP measurements rely on the selection of an intragastric reference pressure, which can vary depending on the chosen sensor. Given that the Chicago Classification hinges on IRP measurement, the selected reference sensor may alter a patient’s manometric diagnosis. Although HRM protocols often suggest choosing a gastric sensor 2–3 cm below the LES, such selection remains subjective.
In our clinical experience, we have observed significant variations in gastric pressure readings depending on the location and selection of the gastric sensor. This may cause diagnostic confusion, particularly when it comes to evaluating achalasia and EGJOO. In this study, we aimed to evaluate how the selection of the gastric reference sensor affects the calculation of the IRP and in turn, the final diagnosis using the Chicago Classification.
MATERIALS AND METHODS
This study was a retrospective cross-sectional analysis of all HRM studies performed at a tertiary academic medical center between January 2017 and November 2017. The inclusion criteria required at least 6 gastric sensors in the HRM study. If there were more than 6 sensors, the 6 closest to the LES were used for IRP measurements. The sensors were labeled GM1 to GM6, with GM1 being the most proximal and GM6 the most distal. Patients with a significant hiatal hernia detected on HRM were excluded from the study. Since this was a proof of principle study, an a priori decision was made to review HRM studies performed beginning in November 2017 and then to review all studies prior until 100 appropriate studies meeting inclusion criteria were identified.
All HRM studies were performed according to the standardized Chicago Classification 3.0 (CCv3) protocol, which was the most recent version at the time of data collection.4 A 36-sensor ManoScan esophageal HRM catheter (Medtronic, Minnesota, USA) was placed through the nares into the esophagus. After confirming catheter positioning, patients rested for 5 minutes to acclimate to the catheter. Testing consisted of 10 supine swallows with 5 mL of water per swallow, followed by 1 multiple rapid swallow sequence and then 5 upright swallows. Considering that upright swallows were not standard practice during the study period and the potential variation in the protocol for obtaining upright swallows, only IRP measurements obtained during supine swallows were included in the study.
Normal IRP was defined as a median pressure across 10 supine swallows ≤ 15 mmHg. Measurements were obtained using the ManoView ESO analysis software (Medtronic, Minnesota, USA) and 6 separate gastric sensors (GM1 – GM6) as intragastric references. Intragastric sensors were identified by their location below the LES. The LES was identified by the ManoView ESO software as the point of maximum resting pressure. Differences in IRP measurements were compared with each reference and their association with CCv3 diagnosis. Demographics and HRM indications were obtained from the patient’s medical record.
Data were analyzed in December 2017. Patients were categorized based on the consistency of their esophageal motility and CCv3 diagnosis across the 6 IRP measurements. Patients with only normal motility, or the same dysmotility, for all IRP measurements, were classified as “stable diagnosis”, while those with differing dysmotility were classified as “variable diagnosis”. Patients with a stable diagnosis were further subcategorized as “stable normal motility” (normal motility for all IRP measurements) or “stable dysmotility” (the same CCv3 diagnosis for all IRP measurements). Patients with a variable diagnosis were subdivided into either “variable normal/dysmotility” (at least one normal IRP measurement and 1 CCv3 diagnosis), or “variable dysmotility” (dysmotility across all 6 IRP measurements, but with varying CCv3 diagnoses). Mann-Whitney U test was used to compare IRP measurements between stable and variable diagnoses. Kruskal-Wallis test was used to compare IRP measurements between stable normal, stable dysmotility, variable normal/dysmotility, and variable dysmotility groups. Dunn’s multiple comparison test was used to identify which values varied significantly between groups. Within-patient comparisons of IRP measurements were performed using intra-class correlation coefficients and visualized with Bland-Altman plots. Statistical significance was defined as a p-value <0.05 and all tests were two-sided.
RESULTS
A total of 100 HRM studies were analyzed during the study period. Included patients had a median age of 54 and 73% were female (Table 1). Among 97 patients who reported their race, 81.4% were White, 16.5% Hispanic, 1% Asian, and 1% Black. The median body mass index (BMI) was 26.3 kg/m2. Indications for manometry included dysphagia (50%), gastroesophageal reflux (40%), post-lung transplant (5%), noncardiac chest pain (4%), and nausea (1%). No correlation was seen between gastric pressure heterogeneity and recorded demographic features, including BMI.
Table 1.
Demographics, characteristics, and manometry indication of study participants.
| Cohort characteristics (n=100) | |
|---|---|
|
| |
| Age, years, median (IQR) | 54.0 (39.9, 64.8) |
|
| |
| Female sex, n (%) | 73 (73.0%) |
|
| |
| Race, n (%) (n=97) | |
| White | 79 (81.4%) |
| Hispanic | 16 (16.5%) |
| Asian | 1 (1.0%) |
| Black | 1 (1.0%) |
|
| |
| Body mass index, kg/m2, median (IQR) | 26.3 (23.0, 29.0) |
|
| |
| Manometry indication, n (%) | |
| Dysphagia | 50 (50.0%) |
| Heartburn/reflux | 40 (40.0%) |
| Post-lung transplant | 5 (5.0%) |
| Chest pain | 4 (4.0%) |
| Nausea | 1 (1.0%) |
Changing the gastric baselines for IRP measurements altered the diagnosis in 28% of studies (Table 2). Among the study participants, 43% had stable normal motility, 29% had stable dysmotility, 18% had variable normal/dysmotility, and 10% had variable dysmotility. All instances of variable normal/dysmotility were related to EGJOO versus normal motility (18 patients) (Figure 1). Among occurrences of variable dysmotility, diagnoses included EGJOO + jackhammer esophagus versus jackhammer esophagus alone (3 patients), absent contractility versus achalasia type I (3 patients), distal esophageal spasm (DES) versus achalasia type III (2 patients), EGJOO + DES versus DES alone (1 patient), and jackhammer esophagus + DES versus EGJOO + DES + jackhammer esophagus (1 patient).
Table 2.
Categorization of manometric diagnosis stability across gastric marker positions.
| Diagnosis across gastric markers | n (%) |
|---|---|
|
| |
| Stable diagnosis at all positions | 72 (72.0%) |
| Normal motility | 43 (43.0%) |
| Same dysmotility diagnosis | 29 (29.0%) |
|
| |
| Variable diagnosis across positions | 28 (28.0%) |
| Normal motility and dysmotility | 18 (18.0%) |
| Different dysmotility diagnoses | 10 (10.0%) |
Figure 1.
Manometric diagnosis for each study per gastric sensor used as the reference for IRP measurement. DES, distal esophageal spasm; EGJOO, esophagogastric junction outflow obstruction; IEM, ineffective esophageal motility
For studies with stable normal motility, the median IRPmin was 4.4 mmHg and IRPmax was 9.3 mmHg (4.1 mmHg change across gastric sensors) (Table 3). For stable dysmotility, the median IRPmin was 6.8 mmHg and IRPmax was 12.3 mmHg (5.5 mmHg change). For variable normal/dysmotility, the median IRPmin was 10.3 mmHg and IRPmax was 17.9 mmHg (6.7 mmHg change). For variable dysmotility, the median IRPmin was 10.5 mmHg and IRPmax was 17.7 mmHg (5.9 mmHg change). The p-value across groups for both IRPmin and IRPmax was <0.0001. The p-value across groups for the change in IRP was 0.0013. The range of IRPs derived from each study by changing the gastric baseline is visualized in Figure 2.
Table 3.
Median IRP values and interquartile ranges for different categories of manometric diagnosis stability.
| IRP, mmHg, median (IQR) | Stable normal motility (n=43) | Stable dysmotility diagnosis (n=29) | Variable normal and dysmotility (n=18) | Variable dysmotility diagnosis (n=10) | p-value* |
|---|---|---|---|---|---|
| IRPmin | 4.4 (3.0, 6.6) | 6.8 (4.7, 17.0) | 10.3 (6.7, 13.0) | 10.5 (8.9, 13.4) | <0.0001 ƚ |
| IRPmax | 9.3 (7.7, 11.7) | 12.3 (8.1, 23.0) | 17.9 (16.0, 19.6) | 17.7 (15.7, 19.0) | <0.0001 ƚ |
| Δ IRP | 4.1 (3.0, 5.8) | 5.5 (3.4, 6.1) | 6.7 (5.3, 11.2) | 5.9 (5.2, 7.7) | 0.0013 ƚ |
Kruskal-Wallis test (across-group comparison)
Dunn’s test post-hoc 2 group comparisons with statistical significance:
IRPmin: stable normal motility vs all other groups (p<0.001)
IRPmax: stable normal motility vs all other groups (p<0.001), stable dysmotility vs normal and dysmotility (p=0.013)
Δ IRP: stable normal motility vs normal and dysmotility (p=0.002), stable dysmotility vs normal and dysmotility (p=0.020)
Figure 2.
Range of IRPs calculated by using different gastric sensors as the intragastric reference.
Agreement between IRP measurements for each gastric reference was quantified by the mean bias, or difference, between measurements (Table 4). The bias grew with increasing distance between sensors. The greatest bias was observed between GM1 and GM6 (−1.52 mmHg), which had a lower limit of agreement of −10.03 mmHg and an upper limit of agreement of 7.00 mmHg. A negative bias indicated that on average, using GM1 as the gastric reference produced a lower IRP than GM6. Comparisons of IRP measurements between GM1 and GM6 are represented by a Bland-Altman plot in Figure 3.
Table 4.
Measurement agreement among gastric sensor pairs. Bias represents the mean difference between IRP measurements. GM1 is the most proximal gastric sensor and GM6 is the most distal. Units for all numerical measurements are in millimeters of mercury (mmHg). LOA, limit of agreement.
| Bias (CI) | Lower LOA (CI) | Upper LOA (CI) | |
|---|---|---|---|
| GM1 vs GM2 | −0.39 (−0.88, 0.09) | −5.19 (−6.03, −4.36) | 4.41 (3.58, 5.25) |
| GM1 vs GM3 | −0.23 (−0.94, 0.49) | −7.29 (−8.51, −6.06) | 6.83 (5.60, 8.05) |
| GM1 vs GM4 | −0.57 (−1.24, 0.09) | −7.15 (−8.30, −6.01) | 6.01 (4.87, 7.15) |
| GM1 vs GM5 | −1.34 (−2.28, −0.41) | −10.59 (−12.20, −8.99) | 7.90 (6.30, 9.51) |
| GM1 vs GM6 | −1.52 (−2.38, −0.66) | −10.03 (−11.51, −8.56) | 7.00 (5.52, 8.48) |
| GM2 vs GM3 | 0.16 (−0.43, 0.75) | −5.69 (−6.71, −4.68) | 6.02 (5.00, 7.03) |
| GM2 vs GM4 | −0.18 (−0.82, 0.46) | −6.52 (−7.62, −5.42) | 6.15 (5.05, 7.25) |
| GM2 vs GM5 | −0.95 (−1.83, −0.07) | −9.63 (−11.13, −8.12) | 7.72 (6.21, 9.23) |
| GM2 vs GM6 | −1.13 (−1.93, −0.33) | −9.03 (−10.40, −7.66) | 6.77 (5.40, 8.14) |
| GM3 vs GM4 | −0.34 (−0.83, 0.14) | −5.12 (−5.95, −4.29) | 4.44 (3.61, 5.27) |
| GM3 vs GM5 | −1.11 (−1.80, −0.42) | −7.93 (−9.11, −6.74) | 5.70 (4.52, 6.88) |
| GM3 vs GM6 | −1.29 (−1.99, −0.59) | −8.23 (−9.44, −7.03) | 5.65 (4.45, 6.86) |
| GM4 vs GM5 | −0.77 (−1.40, −0.14) | −7.00 (−8.08, −5.92) | 5.46 (4.37, 6.54) |
| GM4 vs GM6 | −0.95 (−1.70, −0.19) | −8.41 (−9.71, −7.11) | 6.52 (5.22, 7.81) |
| GM5 vs GM6 | −0.18 (−0.79, 0.43) | −6.20 (−7.25, −5.16) | 5.85 (4.80, 6.90) |
Figure 3.
Bland-Altman plot representing the agreement of IRP measurements between IRP calculated using GM1 (most proximal) as the gastric reference, and GM6 (most distal) as the reference. The mean bias is −1.52 mmHg. The lower limit of agreement is −10.03 mmHg. The upper limit of agreement is 7.00 mmHg.
DISCUSSION
In this single-center retrospective cross-sectional study of 100 HRM studies with at least 6 intragastric sensors, over a quarter (28%) had a variable diagnosis contingent on the selected reference sensor and IRP measurement. Among the 28 studies with variable diagnoses, 18 showed either normal motility or EGJOO depending on the selected intragastric reference. The remaining 10 studies exhibited either EGJ outflow disorders or disordered peristalsis conditional on the selected intragastric reference. Our data suggest that the gastric pressure varies significantly and the establishment of a single, true intragastric reference sensor for IRP calculation may not be as straightforward as previously thought.
Accurately ascertaining the IRP during HRM is crucial for the diagnosis of esophageal motility disorders. Both CCv3 and the newer Chicago Classification 4.0 (CCv4) hinge on the IRP value, which differentiates disorders of EGJ outflow from those of peristalsis.2,4 However, elevated IRP measurements are often not reproducible on repeat HRM testing.5,6 This may be in part due to variable IRP measurements dependent on the intragastric sensor selected as the reference pressure. Our results show that by simply moving the gastric baseline, the average IRP can differ by as much as 6.7 mmHg. This heterogeneity challenges the reliability of IRP measurements and their use as the cornerstone of the Chicago Classification diagnostic framework.
As demonstrated in Figure 1, the most common diagnostic change with variable IRP measurements was between EGJOO and normal motility. The inter-rater agreement for the HRM diagnosis of EGJOO, as measured by kappa, is 0.45 (95% CI 0.41–0.49), indicating suboptimal diagnostic agreement.7 Variable IRP measurements may partly contribute to this diagnostic ambiguity. Challenges differentiating EGJOO from normal motility are well described and addressed in CCv4 as well as the accompanying technical review on EGJOO.8 Our results underscore this ambiguity and substantiate the CCv4 recommendation that adjunct measurements, such as elevated intrabolus pressure, and provocative maneuvers, such as a rapid drink challenge, be employed for the diagnosis of EGJOO.9–11
The bias, or mean difference, between IRP measurements increased with incrementally greater distances between gastric sensors. IRP measurements obtained using proximal sensors as the gastric reference tended to have lower pressures, with higher pressures obtained using distal sensors. Thus, using distal intragastric sensors as the reference pressure is more likely to result in an abnormally elevated IRP and possibly a CCv4 diagnosis suggestive of abnormal EGJ outflow. The reason why distal intragastric sensors yield higher IRP measurements is unclear. However, a hypothesis is that gastric sling fibers near the angle of His may exert myotonic pressure on the distal sensors.12,13 Further study is necessary to determine whether this is the case.
The clinical implication of variable IRP measurements and diagnoses is troubling. Patients may be misdiagnosed and subjected to unnecessary treatments or additional testing. A potential solution requiring further study includes calculating a median IRP derived from all intragastric sensors or selecting the most representative reference two to three sensors distal to the LES. It is important to note that the intragastric sensor provides an imperfect reference range and clinical significance of the findings should be considered on a case-by-case basis. For example, if a patient’s diagnosis is not “stable”, the use of supportive testing with endoluminal functional lumen imaging planimetry (FLIP) or timed barium esophagram may be indicated, as is already recommended for EGJOO per CCv4.14–17 Another solution could be to designate a standard intragastric reference sensor, defined as a certain distance from the LES (e.g. 2–3 cm), or using a composite of the available intragastric pressure data in the formulation of the IRP. If so, this should be explicitly stated within the protocol of the next Chicago Classification.
A study limitation was using CCv3 guidelines to interpret HRM results, which was the most recent version of the Chicago Classification at the time of data collection. CCv4 introduced an updated HRM protocol, which included upright swallows, multiple rapid swallows, and rapid drink challenge. Additionally, jackhammer esophagus was modified to hypercontractile esophagus and the diagnosis of EGJOO was updated to include intrabolus measurements and the use of supportive testing. However, the ascertainment and normal range of IRP has not changed. Both CCv3 and CCv4 rely on the IRP measurement for differentiation between disorders of EGJ outflow and those of peristalsis. Therefore, our results apply to HRM tests interpreted using CCv4. Another study limitation includes the lack of healthy controls or controlling for medication use contributing to result variability. Certain medications, particularly opioids, have been shown to elevate the IRP.18,19 Future studies should focus on collecting comorbidity and medication data at the time of the HRM study, to control for potential confounders. A final limitation would be the small sample size, as only 100 patients were selected for this proof of principle study, but given the strength of our findings, such numbers seem appropriate.
Our study is the first to evaluate changes in IRP arising from the arbitrary selection of intragastric reference pressures. We have shown that values can differ substantially based on reference sensor selection, which results in a variable diagnosis for over one-quarter of HRM studies. For some individuals, the choice of intragastric reference sensor can be the difference between a “normal” test or a diagnosis of EGJOO, which reinforces the need for adjunct testing as described in CCv4. Our findings, however, are more concerning for those patients whose diagnoses teeter between achalasia (type I) and absent contractility, where obviously management implications are significant since they involve invasive endoscopic or surgical options. A corollary of this finding would be the suggestion that patients with absent contractility undergo additional testing to interrogate the EGJ in situations where dysphagia is prominent. Future studies should focus on methods for standardizing the reference sensor to allow for durable, reproducible, and more reliable IRP measurements. Changes in diagnostic accuracy with the addition of other manometric measurements, such as esophageal pressurization, should also be considered.
Practitioner Points.
Integrated relaxation pressure (IRP) calculation is considered the gold standard of lower esophageal sphincter relaxation assessment but depends on the selection of a single gastric reference sensor. Selection is arbitrary and may result in variable IRP measurements and diagnoses.
Varying gastric reference sensor selection alters the diagnosis in greater than one quarter of esophageal manometry studies.
Reference sensor selection should be standardized for consistent and reproducible IRP measurements.
Footnotes
Disclosures: no conflicts of interest to disclose
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