Address for Correspondence A. Bogte, M.D., Department of Gastroenterology, University Medical Center, Utrecht, PO Box 85500, 3308 GA Utrecht, The Netherlands. Tel: +31 88 755 55 55; fax: +31 88 755 55 33; e-mail: firstname.lastname@example.org
Background Esophageal high-resolution manometry (HRM) is a novel method for esophageal function testing that has prompted the development of new parameters for quantitative analysis of esophageal function. Until now, the reproducibility of these parameters has not been investigated.
Methods Twenty healthy volunteers underwent HRM on two separate days. Standard HRM parameters were measured. In addition, in conventional (virtual) line tracings, lower esophageal sphincter (LES) resting pressure, relaxation pressure, and relative relaxation pressure were measured. Firstly, for each variable, the mean percentage of covariation (100 × SD/mean: %COV) was derived as a measure of inter- and intra-individual variation. Secondly, Kendall’s coefficients of concordance (W values) were calculated. Thirdly, Bland–Altman plots were used to express concordance graphically.
Key Results Statistically significant concordance values were found for upper esophageal sphincter (UES) pressure (W = 0.90, P = 0.02), transition zone length (W = 0.92, P = 0.01), LES length (W = 0.81, P = 0.04), LES pressure (W = 0.75, P = 0.05), LES relaxation pressure (W = 0.75, P = 0.03), relative LES relaxation pressure (W = 0.78, P = 0.05), gastric pressure (W = 0.81, P = 0.04), and contraction amplitude 5 cm above the LES (W = 0.86, P = 0.03). In conventional setting, only LES resting pressure (W = 0.835, P = 0.03) proved significant. In HRM tracings, concordance values for contraction wave parameters, and in conventional line tracings, LES relaxation pressure and relative relaxation pressure did not reach levels of statistical significance.
Conclusions & Inferences Esophageal HRM yields reproducible results. Parameters that represent anatomic structures show better reproducibility than contraction wave parameters. The reproducibility of LES resting and relaxation pressure assessed with HRM is better than with conventional manometry and further supports the clinical use of HRM.
The main function of the esophagus is transport of food from the mouth to the stomach. Abnormal bolus transport can lead to symptoms such as dysphagia. The efficacy of bolus transport is dependent on several factors; the physical properties of the swallowed material, the biomechanics of the esophagus, the subject’s body position, and structural limitations posed by adjacent thoracic structures.1 The sheer complexity of this process and the inadequacy to collect data that do justice to this complexity lead to the inability to properly identify the cause of dysphagia in many patients.
In the clinical evaluation of patients suffering from dysphagia, manometry has been used to quantitatively study the esophageal motility. With manometry, pressure patterns that drive bolus transport are measured and the technique aims to find the underlying cause of dysphagia.2 Until recently, this has been done with conventional manometry, using a catheter that contains four to eight pressure sensors at 5-cm intervals in the esophagus and stomach and sometimes includes a sleeve sensor at the level of the esophagogastric junction (EGJ).
High-resolution manometry (HRM) might provide new answers as it has several advantages over conventional manometry. Firstly, the manometric high-resolution catheter contains more pressure-recording channels (e.g., 36) which are more closely spaced (e.g., at 1-cm intervals) and therefore, provides a higher spatial resolution. This allows the detection of motor abnormalities that are limited to a short segment of the esophagus. Secondly, where conventional manometry required accurate positioning of the catheter necessitating multiple pull-troughs, HRM catheters span the entire esophagus making positioning not critical. HRM is thus not only easier for the investigator, but is also more patient-friendly.
The result of this new technique is registration of pressure data from closely spaced recording channels and this leads to an almost continuous recording of motor activity over the entire length of the esophagus. The large data sets obtained with HRM can be analyzed and presented, either as conventional manometric line plots, or as spatiotemporal plots (i.e., contour or color plots) (see Fig. 1). It is felt that the spatiotemporal plots facilitate interpretation of esophageal pressure measurements as they provide a more intuitive representation of esophageal motor action.
HRM has already shown its value for scientific research. For example, with HRM the existence of a pressure trough at the transition from striated to smooth muscle in the esophagus has been recognized and might reflect a change in neural sensory afferent innervation and efferent motor control.3–6 This finding has added to our understanding of esophageal motor dysfunction in patients with dysphagia. Furthermore, new paradigms have been developed that aid in determining whether bolus clearance has occurred.7 The ability to have normal bolus transit during swallowing is reduced to a mechanical relationship between driving pressure, intrabolus pressure (IBP), and outflow resistance at the lower esophageal sphincter (LES).
Newly developed parameters serve to uniformly express manometric findings made with HRM. Information on reproducibility of these new parameters is, however, not available. Therefore, our aim was to assess reproducibility of esophageal HRM by measurement of the esophageal motility in healthy subjects and also to compare this with reproducibility of conventional manometry.
Materials and Methods
Twenty healthy volunteers (7 males, 13 females: mean age 25 years, range 19–52 years) underwent two separate recordings of esophageal HRM within an interval of 1–2 weeks. Subjects were devoid of any gastrointestinal symptoms and were not taking any medication. Informed written consent was obtained before the start of the study and the protocol was approved by the Ethics Committee of the University Medical Center, Utrecht.
Esophageal high-resolution manometry
The participants were not allowed to take any medication, smoke, or drink alcoholic beverages the day before and on the day of the measurements. After a 6-h fast, a 36-channel solid-state catheter (Unisensor AG, Attikon, Switzerland) was placed transnasally. The catheter was positioned with its 36 channels straddling the esophagus and its sphincters. The catheter was fixed in place by taping it to the nose. After being placed in supine position, the participants were asked to swallow 5 mL of water and repeat this for a total of 10 times separated by 30-s intervals. The manometry signals were stored in a personal computer using a sample frequency of 8 Hz.
Data were analyzed using dedicated software (Medical Measurement Systems, Enschede, The Netherlands). Previously established criteria were used to characterize esophageal motility using pressure topography parameters, also known as the Chicago Classification. 8,9 Measurement within the color plots of LES relaxation pressure, resting pressure, and length, as well as upper esophageal sphincter (UES) pressures were facilitated by automated analysis software, referenced to gastric pressure and atmospheric pressure, respectively. Hereby, the upper limit of the LES was measured at inspiration, and the lower limit of the LES was measured at expiration. The transition zone was defined as the segment between the demarcation at the end of the proximal esophageal segment and the beginning of the distal esophageal segment in the 30 mmHg isobaric contour. Contraction amplitudes were measured at 5 and 15 cm above the LES. The contractile front velocity (CFV) was defined as the slope of the line connecting the points on the 30 mmHg isobaric contour at the proximal and the distal margin of the distal esophageal segment and was considered normal when <7.5 cm s−1.10 Distal contractile integral (DCI) quantifies the contractile activity in a space-time box by multiplying the length of the smooth muscle esophagus by the duration of propagation of the contractile wave front, and the mean pressure in the entire box excluding pressures below 20 mmHg. The DCI was considered normal when below 5000 mmHg s cm.8 Integrated relaxation pressure (IRP) represents the lowest 1- and 4-s cumulative pressure values for the deglutitive time period through the anatomic zone defining the EGJ and is considered normal below 12 and 15 mmHg, respectively.11 Intrabolus pressure (IBP) was measured between the peristaltic wavefront and the EGJ, and was considered normal when below 15 mmHg.8
In addition, making use of the conventional line tracings, LES resting pressure was measured at end-expiration, referenced to intragastric pressure, and was considered normal if between 5 and 26 mmHg (0.6–3.5 kPa). LES relaxation pressure was defined as the minimum pressure reached during relaxation after a swallow, similar to the technique used in conventional tracing analysis, and was considered normal when below 10 mmHg (<1.4 kPa).12 Relative relaxation pressure was defined as relaxation pressure/resting pressure × 100%.
Evaluation of reproducibility
Standard deviation (SD) and percentage coefficient of variation (100 × SD/mean: %COV) were calculated for all HRM data. The mean %COV of the 20 values of the first measurement and the mean %COV of the 20 values of the second measurement were calculated. An overall mean %COV was derived as a measure of inter-individual variation. Furthermore, the mean %COV of the first and the second measurement in the 20 volunteers was calculated. This value, calculated from the values of the 20 individuals, was used as a measure of intra-individual reproducibility.
As a second measure for reproducibility, Kendall’s coefficients of concordance (W values) were calculated using the mean values for the named variables from individual recordings and tested for significance. An error probability of P ≤ 0.05 was considered statistically significant. Throughout the manuscript, data are presented as mean ± SEM.
Assessment of reproducibility was facilitated by presenting data in Bland–Altman plots. In these plots the difference between the first and the second measurement is plotted against the mean value of the two measurements, making it possible to compare these two values graphically. When the difference between measurements on the first day and the second day is small, data points are scattered closely to the x-axis. Symmetric scattering around the x-axis indicates that there is no trend toward a difference of the measurements of the second day compared to the measurements of the first day and the difference between the two measurements occurs in a random fashion. Separate SD values were calculated for the two measurement days.
In addition, concordances of normal HRM values were calculated between the two measurements. Concordance was expressed as % of patients with either both measurements normal, or both measurements abnormal on day 1 and 2.
As shown in Table 1, for most parameters, the intra-individual %COV was at least 25% smaller than the inter-individual %COV, indicating reproducibility. Kendall’s W values were above 0.5 for almost all parameters. Statistically significant concordance values and lowest intra-individual %COVs were found for UES pressure (W = 0.90, P = 0.02), transition zone length (W = 0.92, P = 0.01), LES length (W = 0.81, P = 0.04), LES pressure (W = 0.75, P = 0.05), LES relaxation pressure (W = 0.75, P = 0.03), LES relative relaxation pressure (W = 0.78, P = 0.05), and gastric pressure (W = 0.81, P = 0.04). In addition, contraction amplitude 5 cm above the LES was also reproducible (W = 0.86, P = 0.03). In the conventional (virtual) line tracings, only LES resting pressure was statistically significant (W = 0.84, P = 0.03).
Table 1. Reproducibility of HRM parameters in 20 normal subjects
Concordance values for DCI, IBP, IRPs1–4, CFV, and peristalsis neither reached levels of statistical significance nor did concordance for LES relaxation pressure and relative relaxation pressure in the conventional line tracings. Figs 2–5 show Bland–Altman plots for UES resting pressure, LES resting pressure, LES relaxation pressure, and contraction amplitude 5 cm above the LES. In these figures data points are relatively closely scattered around the x-axis, indicative of a small difference between the two measurements as compared to the mean of the two measurements.
Table 2 shows the concordance of normal and abnormal findings of each parameter in the two measurements in the 20 subjects. A concordance of 1.0 implies that the value was both normal in the first and in the second measurement in all subjects. In total, 307 out of 400 swallows were classified as being peristaltic, 39 as hypotensive peristalsis, 25 as absent peristalsis, 19 as simultaneous contractions, 7 as hypertensive peristalsis, 2 as non-transmitted contractions, and in one swallow in one subject panesophageal pressurization was seen. Fig. 6 shows examples of disconcordant findings in these subjects.
Table 2. Concordance of HRM parameters in 20 normal subjects
A concordance of 1.0 implies that the value was both normal in the first and in the second measurement in all subjects. DCI,distal contractile integral; IRPs4,integrated relaxation pressure; CFV,contractile front velocity; IBP,intrabolus pressure; LES,lower esophageal sphincter.
LES relaxation pressure
The introduction of HRM has provided new insights into esophageal physiology and pathophysiology. Normal values have been determined and a new classification of esophageal motor disorders has been introduced and modified, the so-called Chicago Classification. 8,9 However, it has not yet been determined whether the newly introduced parameters used to classify these disorders are reproducible. This is the first study in which the reproducibility of these parameters was assessed.
One of the most important aspects of performing and interpreting measurements is good reliability of a method. This can be achieved by performing these measurements in the same subjects to establish re-test reliability as a measure of reproducibility. Reproducibility is not only influenced by patient-related factors, but also by technical factors. Differences in data acquisition and data analysis can greatly influence the results in any test. In this study, overall reproducibility of HRM data was good and this can be considered as an important validation of the reliability of this new technique.
As was shown, %COV was much larger between subjects than it is within subjects. In addition, concordance testing using Kendall’s W test showed that concordance of parameters representing anatomic landmarks such as LES and UES pressures was statistically significant; whereas, several contraction wave parameters showed a tendency toward significance. In order to establish an insight in the concordance of the latter, a separate analysis was performed in which concordance values were calculated. These parameters proved to have high concordance values. This implies that although considerable absolute variations occurred between the first and the second measurement, the values stayed within the normal range in these healthy subjects, limiting the importance of these variations. Most importantly, in the first and the second measurements, no large differences were found for parameters such as DCI, CFV, IBP, and IRP.
One could argue that the observed moderate reproducibility that was found for some parameters may limit the diagnostic value of HRM. However, it should be realized that even large variations in certain parameters between different days are only of importance when they change the overall conclusion of the measurement, i.e., the manometric diagnosis. Whether the observed day-to-day changes in the measured parameters will affect diagnosis can only be answered in a study in which patients are measured twice. Our concordance data showed that at least in healthy volunteers, the day-to-day variability does not frequently change values in a way that they would alter the final conclusion of the test. This supports the use of HRM as a tool in the clinical evaluation of patients with esophageal motor disorders. Furthermore, the evaluation of a patient consists of evaluating the entire measurement, including the evaluation of 10 separate swallows and global assessment of peristalsis and sphincter function.
Reproducibility in this study was measured using MMS software and hardware. However, normative values were derived making use of the Chicago Classification, which is established with Sierra software and hardware. Looking for example closely at IRP in the automated analysis, the generated mean values seem much higher than the normative values produced by Sierra. The discrepancy suggests that the data derived in this study are not to be generalized to other software and hardware such as Sierra and Sandhill until more data on this subject are available.
Surprisingly, peristalsis itself showed to be less reproducible. This is mainly due to two individuals who showed 100% peristalsis on one of the measurement days and 40% and 60% peristalsis on the other day of the measurement (see Fig. 6). The cause for this difference is not clear.
Relaxation pressure and relative relaxation pressure on the other hand were reproducible when measured with HRM, but not when measured in conventional line tracings. This might be circumstantial evidence that HRM, in contrast to conventional stationary manometry, is more reproducible for certain parameters and further supports its clinical use.
In conclusion, HRM is a reproducible method for studying esophageal motor disorders and supports its clinical use but considerable day-to-day variability may occur. This should be taken into account when borderline findings are made during HRM. The reproducibility of several parameters assessed with HRM is better than with conventional manometry and further supports the clinical use of this new technique.
AB, AJB, PS and AS were responsible for study concept and design, revision and drafting the paper, analysis and interpretation of data, and statistical analysis. JO was responsible for acquisition of data; AB had access to all of the data and takes responsibility for the integrity of the data and accuracy of the analysis. He is the guarantor of the article.
AB, JO and AS have no funding interests to declare. AJB has served as a consultant to Janssen–Cilag, AstraZeneca and Movetis and is supported by The Netherlands Organization for Scientific Research. He has received speaker fees from MMS International. PS has served as a consultant to Janssen–Cilag and has received unrestricted grants from AstraZeneca, Nycomed and Janssen–Cilag, The Netherlands.
The sponsors did not have a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the paper.