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NEUROREGULATION AND MOTILITY
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois
Submitted 28 October 2005 ; accepted in final form 4 January 2006
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ABSTRACT |
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intraluminal pressure gradient; peristalic amplitude; esophageal transition zone
Esophageal peristalsis can be studied quantitatively using manometry in which spatial variations of intraluminal pressure are recorded over time. Conventionally, this is done with devices incorporating three to eight pressure sensors spaced at 3- to 5-cm intervals within the esophagus, each characterizing the contraction in the region in which it resides; luminal contractile activity between sensors can only be inferred. However, a major evolution in manometric methodology has been the introduction of high-resolution manometry (HRM); the basic concept being that by vastly increasing the number of recording sites and decreasing the spacing between them, one can more completely define the intraluminal pressure environment, minimizing the impact of spatial gaps between recording sites. Of course, the vastly increased quantity of data associated with HRM studies creates new challenges with respect to data display and data analysis. Hence, algorithms have been devised to smoothly interpolate HRM data, making it appear as a space-time continuum that can be displayed as isobaric contour plots (2–4). The advantages of isobaric contour plots are multiple, but the most evident is that it provides a seamless, dynamic representation of peristalsis at every axial position within and across the esophagus, as shown in Fig. 1. When so imaged, it becomes apparent that peristalsis is comprised of several distinct yet integrated elements: 1) a proximal propagated contraction, corresponding to the striated muscle portion of the esophagus; 2) a distal propagated contraction, corresponding to the smooth muscle esophagus; and 3) a zone of transition between the two (5, 7, 13). Not only does each of these elements occur in a reasonably stereotyped pattern but each is also timed in a stereotyped fashion for a given individual, in essence defining the functional limits of peristalsis.
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METHODS |
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Manometric studies were done on 75 asymptomatic subjects (40 men and 35 women, age: 19–48 yr). Subjects consisted of volunteers recruited by advertisement or word of mouth with no history of gastrointestinal symptoms, upper gastrointestinal tract surgery, or significant medical conditions. The study protocol was approved by the Northwestern University Institutional Review Board, and informed consent was obtained from each subject.
High-Resolution Manometry
A solid-state manometric assembly with 36 circumferential sensors spaced at 1-cm intervals (4.2-mm outer diameter) was used (Sierra Scientific Instruments; Los Angeles, CA). This device uses proprietary pressure transduction technology (TactArray) that allows each of the 36 pressure-sensing elements to detect pressure over a length of 2.5 mm in each of 12 circumferentially dispersed sectors. The sector pressures are then averaged to obtain a mean pressure measurement, making each of the 36 sensors a circumferential pressure detector with the extended frequency response characteristic of solid-state manometric systems. Before the recording, transducers were calibrated at 0 and 100 mmHg using externally applied pressure. The response characteristics of each sensing element were such that they could record pressure transients in excess of 6,000 mmHg/s and were accurate to within 1 mmHg of atmospheric pressure for measurements obtained for at least the final 5 min of the study, immediately before thermal recalibration (see Study Protocol). The data-acquisition frequency was 35 Hz for each sensor.
Study Protocol
After a brief interview and examination to ensure the absence of gastrointestinal symptoms and to make anthropometric measurements, subjects underwent transnasal placement of the manometric assembly. Studies were done in a supine position after at least a 6-h fast, and the manometric assembly was positioned to record from the hypopharynx to the stomach with about five intragastric sensors. The catheter was fixed in place by taping it to the nose. The manometric protocol included a 5-min period to assess basal sphincter pressure, 10 water swallows of 5 ml, and 1 water swallow each of 1 (dry), 10, and 20 ml.
HRM. Manometric data were initially analyzed using ManoView analysis software (Sierra Scientific Instruments). First, data were corrected for the thermal sensitivity of the pressure-sensing elements using the thermal compensation function of ManoView. This was done by visually identifying the instant when the assembly was pulled from the nose at the end of the recording. Immediately after that instant, the catheter was still at body temperature but all pressure sensors were exposed to atmospheric pressure. The software routine then set this pressure as zero and calculated the magnitude of the pressure correction required for each sensing element. Those sensor-specific thermal correction factors were then applied to the entire manometric data set, in essence correcting it for temperature-dependent calibration drift. Note that although this sensor technology is subject to thermal drift, that effect is almost linear so that the correction factors applied to reestablish the zero reference also correct error attributable to thermal drift in the entire data set.
Manometry data analysis. Further characterization of esophageal peristalsis was performed with a computer program (MATLAB, The MathWorks; Natick, MA) customized for processing binary manometric data into isocontour pressure plots and spatial pressure variation plots. This was done by first exporting the binary manometry data from ManoView in ASCII text format for processing and storage. These ASCII files were then reconverted into a double-precision binary format for use in MATLAB, and isocontour or spatial pressure variation plots were generated. In order for these plots to appear smooth (as opposed to notched), the data set was enhanced in both the time dimension (between sampling times) and spatial dimension (between pressure-recording sites). This interpolation was done using a cubic hermite interpolating polynomial in MATLAB implemented on a finely resolved rectilinear space-time grid to generate intermediate data points, resulting in a virtual increase in the spatial data from 1 to 10 recording sites per centimeter and doubling the temporal sampling rate from 35 to 70 Hz (3, 9).
After thermal correction, peristaltic characteristics were analyzed according to the scheme defined in Fig. 1. The peristaltic contraction wave was considered to consist of three characteristic elements: proximal (striated muscle) esophageal peristalsis, distal (smooth muscle) esophageal peristalsis, and the transition between the two (3, 7). For each of these peristaltic elements, secondary programs were written in MATLAB to facilitate an automated analysis, calculating the parameters described in the following sections. In every case, the results of the automated analyses were then scrutinized on a case-by-case basis to insure that the programmed algorithms had functioned properly. In the unusual cases that they had not and the error could not be corrected by further refinement of the automated analysis, that particular instance was manually analyzed. All pressure measurements of peristaltic performance were referenced to atmospheric pressure.
The isobaric contour analysis tool (incorporated within ManoView and MATLAB software) was extensively used in our analysis. Two examples of isobaric contours at 20 and 40 mmHg are shown in Fig. 2.
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The propagation rate of the contractile front through the proximal esophageal segment was also derived from the isobaric contour plots and characterized as the proximal contraction propagation velocity (PCPV). Because contraction wave velocity varies along the length of the esophagus (5), PCPV was also calculated at many locations along a normalized grid, although in this case only at 10 equally spaced loci to reduce artifacts. At isobaric contour levels of 20, 30, and 40 mmHg, propagation velocity was calculated (in cm/s) between each adjacent pair of proximal segment loci. The PCPV plot was then constructed with propagation velocity on the y-axis and normalized length of the proximal esophageal segment on the x-axis.
In addition to the parameters defined above, three measures summarizing the magnitude of the proximal peristaltic contraction were derived. The maximal contractile pressure was the greatest pressure within the proximal peristaltic segment. The maximal contractile duration was the duration of contraction at the same locus as the maximal contractile pressure. Finally, the proximal contractile integral was calculated as follows. If the isobaric contour map is envisioned as a solid, the footprint of the solid would be time (in s) multiplied by axial domain (in cm) and the height of the solid would be pressure (in mmHg). The proximal contractile integral was the volume of that solid spanning from 10 mmHg at the base to the maximal contractile pressure (expressed as mmHg·s·cm).
Distal esophageal peristalsis. The analysis of distal esophageal peristalsis largely mirrored that of proximal peristalsis with a few requisite refinements. In this case, we used the resting state of the esophagus (Fig. 1A) to define the lower margin of the esophagogastric junction (EGJ) and defined the span of the distal esophagus as from that point to the center of the transition zone. Again, a normalized grid of 50 equally spaced loci was created along the segment, and distal esophageal peristaltic amplitude (DEPA) was measured at each locus. Similarly, the distal contraction propagation velocity (DCPV) was analogous to the PCPV, representing an expression of the propagation velocity of the contractile front as a function of isobaric contour pressure.
Recognizing that bolus transport is effected by a combination of esophageal closure pressure and intraluminal pressure gradients (10), we plotted the manometric data as spatial variations of intraluminal pressure over time (Fig. 3). Spatial pressure variation plots have the advantage of clearly illustrating the relationship among closure pressure (peristaltic amplitude), intrabolus pressure, and EGJ outflow resistance. The instantaneous relationship among these pressures defines whether flow is likely to occur and, if so, in which direction. While DEPA defined the magnitude of distal esophageal peristaltic force, the efficacy of that force in achieving esophageal emptying depends on its coordination with EGJ relaxation. The outflow permissive pressure gradient (OPPG) was derived as an assessment of the balance between distal peristalsis and swallow-induced EGJ relaxation. OPPG parameters were derived from a plot with time on the x-axis (time 0 being the onset of maximal UES relaxation) and three pressure tracings on the y-axis: 1) instantaneous E-sleeve relaxation pressure, 2) instantaneous intrabolus pressure at a location 2 cm above the upper margin of the resting state EGJ, and 3) instantaneous distal peristaltic amplitude (Fig. 3C). Thus conditions are permissive of esophageal emptying (antegrade flow permissive) during periods when the peristaltic amplitude exceeded intrabolus pressure (measured 2 cm proximal to the EGJ), which in turn exceeded E-sleeve pressure. On the other hand, periods during which the peristaltic amplitude was less than intrabolus pressure, which was in turn less than E-sleeve pressure, were considered consistent with retrograde flow and permissive for retrograde "escape" of the bolus. Summary statistics of the OPPG are 1) the duration of time that pressure conditions are optimal for esophageal emptying (antegrade flow permissive), 2) the mean emptying pressure during the potential emptying period (intrabolus pressure 2 cm proximal to the EGJ minus E-sleeve pressure), and 3) the duration of time that conditions are right for retrograde escape to occur (retrograde flow permissive time).
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Transition zone. The proximal and distal esophageal contractions sometimes smoothly blended with one another and at other times exhibited a spatial gap and/or temporal delay between the termination of the proximal contraction and the initiation of the distal contraction. Even in instances in that they smoothly blended, there was characteristically a pressure trough between them. The duration of this delay (or the persistence of the trough) increased when analyzed at increased isobaric contour pressures. Parameters of the transition zone were calculated based on the scheme shown in Fig. 2. At each isobaric contour pressure, beginning at 10 mmHg and increasing in increments of 5 mmHg, the transition delay was (td – tp) in duration spanning a length of (xd – xp) cm (Fig. 2). Each of these variables, defining the length and duration of the transition zone, was then plotted as a function of contractile pressure.
Statistical Analysis
Means, SD, SE, and median and interquartile ranges were calculated for all the paradigms developed above and are summarized in the ensuing figures and tables. In addition, coefficient of variation (CV) analysis was used to assess the intrasubject variability for each paradigm. The CV was calculated as the SD divided by the mean for each subject and expressed as a percentage. The mean CV from all 75 subjects is presented.
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RESULTS |
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As evident in Table 1, the proximal esophageal contractile zone averaged 6.1 cm in length. This is consistent with observations made by Clouse and Staiano (3) and Meyer et al. (13), who quantified the location of the pressure trough as 
6 cm from the lower margin of the UES. The characteristics of the proximal esophageal contraction are depicted in Fig. 4. The 50th percentile value for the PEPA at the midpoint of the proximal segment was 70.1 mmHg. PCPV was remarkably uniform at an average of about 2.4 cm/s across the 20- to 40-mmHg range of pressures analyzed. Note that there were no instances of a failed contraction through this region in any subject. Table 2 summarizes the characteristics of the contraction through the proximal segment in terms of maximal pressure, duration, and contractile integral.
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As evident in Table 1, the distal esophageal contractile zone, spanning from the transition zone to the lower margin of the EGJ, encompassed most of the length of the esophagus, averaging 19.9 cm in length. The characteristics of the distal esophageal contraction are depicted in Fig. 5. When the DEPA plot (Fig. 5) was compared with the PEPA plot (Fig. 4), distal esophageal peristalsis was less uniform than proximal peristalsis but similar in the sense that both gradually diminished with proximity to the transition zone. Peristaltic amplitude also diminished approaching and within the EGJ. DCPV, on average, similar to that through the proximal segment with the caveat that it was markedly slower emerging from the transition zone and approaching the EGJ. Table 3 summarizes the characteristics of the contraction through the distal segment in terms of maximal pressure, duration, and contractile integral.
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The transition zone is represented in Fig. 1 as the region of the isocontour plot bridging the proximal and distal esophageal segments centered at the nadir pressure along the spatial pressure variation plot of Fig. 1C. The spatial and temporal characteristics of the transition zone varied with isocontour pressure, as evident in Fig. 2. In Fig. 2, the length of the transition zone is xd(20) – xp(20) cm for the 20-mmHg isobaric contour and xd(40) – xp(40) cm for the 40-mmHg isobaric contour. Similarly, the duration of the transition zone was td(20)– tp(20) s for the 20-mmHg isobaric contour and td(40) – tp(40) s for the 40-mmHg isobaric contour. Summary data for the length and duration of the transition zone as a function of isocontour pressure are shown in Fig. 7. Following the 50th percentile values of Fig. 7, the transition zone was first definable at an isocontour pressure of 30 mmHg and gradually increased to a magnitude of 2.5 cm and 1.5 s as the isocontour pressure increased to 50 mmHg. On the other hand, by examining the 5th percentile values of Fig. 7, the transition zone was already evident at the 10-mmHg icocontour and expanded to 3.5 cm and 7 s as the isocontour pressure increased to 50 mmHg. Note that none of the subjects had a transition zone pressure lower than 10 mmHg and the duration was 0 at pressures 
20 mmHg.
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The CV analysis, presented as the mean CV from 75 subjects, is summarized in Table 5. The CV ranged between 5% and 20% with the contractile integral showing the greatest intrasubject variability in both esophageal segments, probably because of its sensitivity to variations in all three components of peristalsis: space, time, and pressure. The length of the contractile segment exhibited the lowest variability among all parameters, most likely because of the concordance of the esophageal segments with the neuromuscular anatomy of the esophagus. On average, the distal esophagus exhibited higher intrasubject variability compared with the proximal esophagus in all paradigms.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The key physiological function of peristalsis is bolus transport, effected by a sequenced contraction propagated through the esophagus. Abnormal peristalsis can be characterized by abnormal propagation, inadequate contractility, or excessive contractility. Examining first the concept of adequacy, effective bolus clearance is contingent on the presence of a seamless contractile front of appropriate amplitude and velocity propagating over a length of the esophagus. Furthermore, although relatively tightly integrated, we know from a wide array of investigations that the proximal and distal esophagus have distinct characteristics with respect to neural control, muscle type, and manometric attributes (Fig. 1) (5, 7, 12, 13): hence, the concept of PEPA and DEPA, HRM paradigms for quantifying spatial variation in peristaltic amplitude. Summary data on PEPA and DEPA, shown in Figs. 4A and 5A, respectively, are presented in a format such that the range of normal values are readily evident, thus serving as a yardstick against which to measure patient data.
The success or failure of the contractile front to effect clearance is further dependent on the downstream resistance that must be overcome. More specifically, owing to the timed nature of peristalsis, clearance is dependent on the instantaneous intraluminal relationship among clearance force (intrabolus pressure), closure force (peristaltic amplitude), and outflow resistance (E-sleeve pressure). An earlier study (8) combining manometry with fluoroscopy demonstrated that most instances of impaired bolus clearance occurred in the distal esophagus, suggesting that the downstream resistance from the proximal esophagus was minimal compared with that at the EGJ. Hence, the concept of OPPG, a HRM paradigm quantifying the window of opportunity for bolus flow across the EGJ, was developed. The data shown in Table 4 and Figs. 3 and 6 explain this concept and again provide a yardstick against which to gauge abnormality. Note that a much fuller description of EGJ relaxation characteristics defined in HRM paradigms is to be published in another study (15).
Other than clearance function, the analysis of abnormal esophageal motility has historically focused on states of abnormally propagated or excessive contractility: distal esophageal spasm, nutcracker esophagus, etc. Two parameters of the esophageal contraction define these states: propagation velocity and the magnitude of the contraction, as gauged by some combination of amplitude and duration. With respect to propagation, the issue is complicated by the nonuniform nature of propagation through the esophagus. Hence, the data shown in Figs. 4B and 5B completely describe the propagation velocity through the esophagus, leveraging the spatial resolution of the HRM method. Again, data are presented in a format such that the range of normal values are readily evident, thus serving as a yardstick against which to measure patient data. With respect to the magnitude of the peristaltic contraction, the enhanced spatial resolution of HRM allows localization of the maximal contraction within each esophageal region and thereby an establishment of normal limits (proximal esophagus, Table 2; distal esophagus, Table 3). Furthermore, a unique opportunity exists to quantify the integrated contractile activity of each esophageal segment and introduce a unique HRM paradigm, the contractile integral as a way of quantifying the overall vigor of the contraction. This paradigm is intended to be particularly sensitive in delineating focal or generalized abnormalities involving sustained and/or hypertensive esophageal contractions.
The final element of peristalsis to be characterized is the transition zone. The transition zone was in essence first defined using HRM techniques (5), although the existence of a pressure trough in the midesophagus was recognized before this (3, 11). However, the normal characteristics of this transition zone have not been previously defined. Again, leveraging the spatial and temporal resolution of HRM to analyze transition zone characteristics according to the paradigm illustrated in Fig. 2, we quantified the normal characteristics of the transition zone shown in Fig. 7. Once again, data are presented in a format such that the range of normal values is readily evident, thus serving as a yardstick against which to measure patient data.
In conclusion, HRM represents an evolution in manometric technology presenting the opportunity to redefine this clinical test in enhanced quantitative paradigms that may ultimately lead to more objective, consistent, and reproducible interpretation. With the use of a state-of-the-art manometric probe along with an extensive computational exercise, we performed a detailed analysis of esophageal peristalsis aimed at quantifying its essential features. In so doing, new paradigms for the quantification of peristaltic function during swallowing were devised that will hopefully optimize the utility of HRM in clinical and investigative studies. This, along with a companion study (15) on the HRM characteristics of the EGJ, are intended to set the stage for a reassessment of what constitutes normal and abnormal esophageal motor function.
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GRANTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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