Distension-evoked motility analysis in human esophagus

Authors


Address for Correspondence

Donghua Liao, Mech-Sense, Aalborg Hospital Science and Innovation Centre, Sdr. Skovvej 15, DK-9000 Aalborg, Denmark.

Tel: +45 99326907; fax: +45 99326801;

e-mail: dl@rn.dk

Abstract

Background

The major function of the esophagus is to transport food from the mouth to the stomach by peristaltic muscle action. However, only few techniques exist for detailed evaluation of motor activity of the esophagus in vivo. The aim of this study is to use distension combined with manometry and impedance planimetry [pressure–cross-sectional area (P-CSA) recordings] to assess esophageal peristaltic motor function in terms of the mechanical energy output, and to examine the change in the motor activity of the esophagus in response to butylscopolamine, an anticholinergic drug known to impair the smooth muscle contraction in the gastrointestinal tract.

Methods

The probe with CSA measurements was positioned 7 cm above the lower esophageal sphincter in 16 healthy volunteers before and during butylscopolamine administration. Distension-evoked esophageal peristalsis was analyzed using P-CSA data during distension up to pressures of 5 kPa. The P-CSA, work output (area of the tension-CSA curves), and propulsive tension were analyzed.

Key Results

The wave-like peristalsis resulted in P-CSA loops consisting of relaxation and contraction phases. The work increased with the distension pressure (from 1311 ± 198 to 16 330 ± 1845 μJ before butylscopolamine vs from 2615 ± 756 to 11 404 ± 1335 μJ during butylscopolamine administration), and propulsive tension increased from 18.7 ± 1.9 to 88.5 ± 5.5 N m−1 before the drug and from 23.1 ± 3.9 to 79.5 ± 3.3 N m−1 during butylscopolamine administration). Significantly, lower values were found during butylscopolamine administration compared with the distension before using the drug (P < 0.01).

Conclusions & Inferences

Esophageal muscle properties during peristalsis can be assessed in vivo in terms of mechanical energy output parameters. Butylscopolamine impaired muscle contraction which could be detected as altered contraction parameters. The analysis can be further used as an adjunct tool of the combined manometry and impedance planimetry recordings to derive advanced esophageal motor function parameters for studying the physiological and pathophysiological mechanical consequences of esophageal contractions.

Introduction

The major function of the esophagus is to transport food from the mouth to the stomach. A powerful, synchronized peristaltic contraction follows each swallow to accomplish this task. Peristalsis is a motor pattern, a type of esophageal locomotion based on neuromechanical feedback rather than a simple reflex.[1] Assessment of the muscle and connective tissue mechanics of the esophagus is fundamental for advancing the understanding of esophageal pathophysiology related to failure of esophageal function. Manometry and fluoroscopy are commonly used tools for evaluation of esophageal motor function in vivo where simple dynamic properties, such as frequency and amplitude of the esophageal contraction and propulsive force can be obtained.[2-6] However, the information obtained by manometry and fluoroscopy does not, from a mechanical point of view, provide detailed data on the association between the temporal patterns of the dynamic changes in the wall and the force that stimulates the contraction. Understanding muscle function under dynamic conditions requires recording of in vivo length changes and forces developed during the muscles contraction. This approach provides a direct means for assessing the mechanical energy output of muscle activity.

Studies on the dynamic motor activity and mechanical energy output of the gastrointestinal (GI) tract have lagged behind those of the force–deformation behavior in striated muscles and in the left ventricle, where force–length and pressure–volume (PV) analysis for a long time has been the standard in studies of the muscle and ventricular function.[7-12] Advanced force–deformation analysis requires measurement of the temporal patterns of muscle force and the associated changes in muscle length to quantify mechanical work generated by the muscle. The combined impedance planimetry and manometry technology with measurement of pressure–cross-sectional area (P–CSA) relations of the distending bag provides the needed data in vivo for force–deformation analysis in the esophagus.[13-15] In our recent studies, we made a first attempt of applying P–CSA recordings to study the mechanical energy output of esophageal secondary peristaltic contractions in healthy volunteers and in patients with systemic sclerosis (SS).[16] In a recent study done using cardiac pump function analysis, we found that SS patients had different P–CSA loop shapes with smaller work output. However, the study showed that the P–CSA loop recorded in the esophagus was different from the PV loop in the left ventricle. The PV loop of the left ventricle demonstrates four distinct and stable phases, i.e., ventricular filling, isovolumetric contraction, ejection, and isovolumetric relaxation whereas such phases cannot be easily identified in the esophageal P–CSA curves. Consequently, in the current study, we apply mechanical energy analysis to define the motor activity of the esophagus with only two phases, i.e., a contraction phase and a relaxation phase defined for a contraction cycle. To quantify the distension-evoked motility of the esophagus in vivo, we studied the P–CSA relationship of the wave-like contractions evoked by bag distension in the esophagus of healthy volunteers before and after administration of the anticholinergic drug butylscopolamine. The P–CSA relationship, propulsive tension, work output, and power output during cyclic contractions were analyzed using advanced distension protocols and novel muscle contraction analysis method. We hypothesized that distension-evoked motor response of the esophagus can be quantified by the mechanical energy generated by the muscle. The long-term perspective of the new analysis is to be capable of quantitatively conducting analysis of disease-related motor function changes in response to esophageal disease.

Materials & Methods

Subjects

The volunteers included in this study have been described in detail by Villadsen and coworkers.[4, 17] In brief, 16 healthy volunteers (10 women and 6 men, average age 48.4 ± 1.5 years) without any symptoms or history of esophageal diseases were included in this study. The volunteers were studied twice with approximately 2 weeks between studies to avoid mechanical preconditioning effects. On one occasion they were studied without any medication. On the other occasion they received the anticholinergic drug butylscopolamine. The protocol was approved by the Danish Ethics Committee for Aarhus County. All healthy volunteers gave informed consent.

Experimental probe design

A four-electrode impedance measuring system located inside a bag on a 0.85-m long 15-French probe (W.Cook, Europe A/S, Bjaeverskov, Denmark) was used for measurements of luminal CSA in the esophagus.[4, 17] The bag was 4 cm long and made of 50-μm thick non-conducting polyurethane. The bag was connected via two infusion channels (2 mm each in diameter) to a level container to be raised and lowered to alter the bag pressure. The bag could be inflated with diluted saline solution to a maximum CSA of approximately 2000 mm2 (diameter 50 mm) without stretching the bag wall. The size of the bag was chosen on the basis of pilot studies on the healthy volunteers. The probe contained three channels for pressure measurements. One pressure was measured inside the bag whereas the other two pressures were measured 4 cm proximal and distal to the bag. Records of CSA and pressure were amplified, analog-to-digital converted and stored on a computer for later analysis.

Study protocol

The subjects fasted 8 h prior to the study. After calibration of the measurement system, the tube was passed into the esophagus via the nostrils and pharynx. A conventional manometric measurement of esophageal body and lower esophageal sphincter (LES) pressures during wet swallows was done before the distension test. The distal pressure was used only to identify the LES or pressure inversion point prior to the positioning of the bag at the distal distension site and the proximal pressure were used for evaluation of secondary peristalsis during the bag distension. The middle of the bag was placed approximately 7 cm above the high pressure zone representing the LES. Distensions were done by raising the pressure in the bag in steps from 0.5 to 1.0, 2.0 3.0, 4.0, and 5.0 kPa by altering the height of the level container above the zero pressure level (Fig. 1).[4] A maximum value of 5.0 kPa was chosen as pilot studies in healthy volunteers showed that the threshold for nasopharyngeal and retrosternal discomfort was reached at this pressure level. The pressure and CSA were recorded simultaneously for further analysis. About 2 weeks later, the same volunteer was asked to repeat the distension test with administration of the anticholinergic drug butylscopolamine for inhibiting distension-evoked smooth muscle contractions. Forty milligrams of butylscopolamine was given intravenously. This resulted in decreased contractility and by the development of classic anticholinergic side effects. An additional 20 mL dose was given if the contractions were not significantly inhibited provided that the subjects did not have major side effects. The subjects were asked to avoid swallowing and to signal any sensation during the distensions.

Figure 1.

A schematic diagram of the experimental set up for pressure and CSA measurement (A) and a flowchart of the distension protocols (B). The numbers from 0.5 to 5 are distension pressures in kPa. Details on the experimental setup and the study protocol appear in the main text.

Data analysis of pressure and CSA recordings

Recordings of CSA and pressure in the bag during the distension were used for data analysis. The CSA and pressure recorded at the distension pressure of 0.5 kPa were used as the reference state. Distension-evoked cyclic contractions at distension steps of 1.0, 2.0, 3.0, 4.0, and 5.0 kPa were selected cycle-by-cycle from the recorded CSA curves. The pressure and CSA recordings from each selected cyclic contraction were used for the tension analysis and motor function analysis.

Circumferential wall tension

The circumferential stress resultant (the circumferential wall tension) was calculated according to the Law of LaPlace for a circular cylindrical structure as[14]:

display math(1)

where T is the circumferential wall tension, r is the bag radius, and ΔP is the transmural pressure. The geometry of the esophageal cross-section during the distensions is considered as circular. Therefore, the bag radius was determined as:

display math(2)

The transmural pressure was determined by subtracting the esophageal pressure at the resting state (representative of the intrathoracic pressure) from the recorded bag pressure during the distension.

Muscle motor function analysis

The motor activity was analyzed in terms of positive work output, power output, preload tension, afterload tension, and propulsive tension on the basis of the calculated wall tension and recorded CSA. The definitions of the parameters are illustrated in Fig. 2 as:

Figure 2.

Illustration of the parameters used in the motor function analysis. (A) The tension-CSA loop area is the work output. (B) The hollow triangles and solid triangles in the tension curve indicate the preload tension before the distension-evoked contractions and afterload tension developed during a peristaltic cycle. The difference between the afterload tension and the preload tension is the propulsive tension.

  • Work output: the area of the tension-CSA loop during a contraction cycle.
  • Preload tension: the tension just prior to a contraction.
  • Afterload tension: the maximum tension developed during a single contraction.
  • Propulsive tension (∆tension): the tension difference between the afterload tension and the preload tension during a single contraction.
  • Power output: preload tension*CSA change rate, where CSA change rate represents the CSA decrease rate during a single contraction. It can be expressed as = (CSAafterload − CSApreload)/(tafterload − tpreload), CSApreload, tpreload are the CSA and time at the preload tension point, and CSAafterload, tafterload are the CSA and time at the afterload tension point.

Statistical analysis

The results are expressed as mean ± SEM. Two-way anova was used with factor 1 = before vs during butylscopolamine, factor 2 = distension pressures. The Tukey test was used for post hoc analysis. Data were considered different when < 0.05. All analyses were done using the software package Sigma Stat 2.0 (SPSS Inc. Chicago, IL, CSA).

Results

In vivo pressure and CSA recordings

Distension increased pressure and CSA to higher levels where contractions caused variations in pressure and CSA until deflation of the bag (Fig. 3A, B). The drug butylscopolamine significantly inhibited esophageal motility resulting in weak to absent response to contraction (Fig. 3B). A representative pressure recording with distension step of 5 kPa shows the distension-evoked wave-like cyclic contraction which propagated aborally along the esophagus (Fig. 3C). At all distension levels, the number of observed cyclic contractions during butylscopolamine is much less than that before the drug (23 vs 90 contractions at the distension pressure of 5 kPa), and with impaired pressure amplitude (5.65 ± 0.2 vs 6.74 ± 0.28 kPa at distension pressure of 5 kPa) and impaired CSA amplitudes (314.1 ± 24.2 vs 562.1 ± 30.8 mm2 at distension pressure of 5 kPa) (Fig. 4, F = 35.56, < 0.001).

Figure 3.

Representative CSA curves during distensions before (A) and during (B) butylscopolamine administration and representative pressure curves from three sites in the esophagus before drug administration (C). The seven pressure steps were 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, and 5.0 kPa. Impaired contraction amplitudes were observed after administration of butylscopolamine (B). The phase difference of the peristaltic contractions along the esophagus is clearly seen in (C).

Figure 4.

The total number of detected single cyclic contractions (A), the averaged contraction CSA amplitude (B), and the averaged contraction pressure amplitude (C) at all distension pressure steps before and during butylscopolamine administration. The drug significantly lowered the contraction activity.

Pressure–CSA relationships

A representative recording of the bag pressure and CSA at the pressure step of 4 kPa clearly demonstrated the cyclic wave-like esophageal contractions before and during butylscopolamine administration (Fig. 5A, C, E). A parametric plot of pressure against CSA from one cyclic contraction generated an anticlockwise loop demonstrating the positive mechanical work during the contraction (Fig. 5B, D, F). The lower contraction amplitudes (3.11 ± 0.20 vs 5.91 ± 0.32 kPa for pressure) and the smaller P–CSA loop during butylscopolamine reflect the lesser mechanical work (Fig. 5D–F). However, the maximum pressure and the minimum CSA in one cyclic contraction were not reached at exactly the same time due to the muscles deforming earlier than the pressure change (Fig. 5A, C, E). As shown in the figure, there is approximately 3 s delay of the pressure curve.

Figure 5.

Simultaneous pressure-time and CSA-time recordings at a pressure step of 4 kPa in a representative healthy volunteer before (A, B, D, E) and during (C, F) butylscopolamine administration. The P–CSA behavior was plotted on the basis of the contraction cycle marked by the gray box before (D, E) and during butylscopolamine (F). The curves in panels A and D show the raw experimental recording and curves in panels B and E are smoothed curves from panels A and D. Only the smoothed curves are shown in recording during butylscopolamine (C and F). Solid arrows show the path of CSA change during pressure development and the hollow arrows show the start of the contraction cycle (D–F).

Motor contraction analysis

The average work output, power, and propulsive tension increased with the pressure level with significant lower values during the butylscopolamine administration (F = 18.46, < 0.01, Fig. 6A–C). The relationships between the pressure and work output, power and propulsive tension showed a sigmoid curve pattern before the butylscopolamine administration, whereas the relationships during the drug administration showed an exponential curve pattern.

Figure 6.

The average work output (A), propulsive tension (B), and power output (C) as function of the distension pressure steps before and during butylscopolamine. Lines with markers represent the calculated data. The heavy solid lines are the sigmoid growth curve fitting and exponential curve fitting of the data before and during butylscopolamine administration.

Discussion

This study quantitatively characterized distension-evoked muscle contractile function of the human esophagus using analysis of simultaneous pressure and CSA recordings at normal conditions and during administration of the anticholinergic drug butylscopolamine. The analysis showed that advanced contraction analysis can provide quantitative parameters as the work output, propulsive tension, and power output to assess the in vivo contractility of human esophagus.

Smooth muscle contractility in the esophagus results in hysteresis in the P–CSA plot due to an unsteady state of the muscle contractions. Such findings are similar to those found in the force-ca2+ plot in the esophageal smooth muscle cell.[18, 19] Stored mechanical energy in terms of force–length plots (mechanical work loops with hysteresis) have been used in decades in analysis of striated muscles[7-9, 11] and in cardiac muscle for evaluation of left ventricular pump function.[12, 20, 21] Consequently, novel esophageal mechanical energy parameters such as work output and power output as used in this study will shed light on the muscle behavior in the esophagus.

Previous studies on the esophageal propulsive force in response to an acute obstruction demonstrated that distension-evoked propulsive force was not by itself a peristaltic wave, as it may persist locally for long periods and not progress down the esophagus.[6] In contrast, the current study showed the contraction waves propagated along the esophagus passing the distended bag even at the highest distension pressure. A cause of the persisting contraction in the study by Winship could be the use of thick-walled rubber material for the balloon, resulting in a solid balloon that did not allow contractions to pass during the distension. The longer contraction duration in the bag (Fig. 3C) likely implies that the contraction at the bag location could be a combination of both peristaltic contraction and esophageal obstruction caused propulsive force (a stationary contraction). However, to reveal the esophageal obstruction caused propulsive force during bag distension, studies with simultaneous recording of the propulsive force are needed. Different performance of the work output and distension pressure relationship before and during butylscopolamine administration demonstrated the drug-induced change in the esophageal wall mechanical behavior (Fig. 6). The exponential work output and pressure relationship during the butylscopolamine administration agrees well with the passive force–deformation curves presented in our previous length-tension studies in the esophagus.[22] Moreover, in our recent studies on mechanical energy output based on esophageal secondary peristaltic contraction analysis in patients with SS, we found that SS patients had different work loop shapes with smaller work output. Those results indicate reduced muscle function when compared with healthy volunteers.[16] Therefore, such promising results lead us to hypothesize that mechanical energy-based motor function analysis can be used in the future to assess various esophageal motor diseases and drug-induced esophageal motility changes.

In the current study, the luminal geometry changes as well as the corresponding circumferential propulsive tension were determined to demonstrate the peristalsis contractions in the esophagus. Propulsion of the bolus is associated with the change of the axial length of the esophagus and the changes in the wall thickness in both circular muscle and longitudinal muscle layers.[23] The current developed analysis can be advanced by combination with endoscopic ultrasonography for wall thickness and axial length change determination. However, such analysis will be considerably more cumbersome.

Esophageal muscle and connective tissue mechanical assessment is fundamental to advance the understanding of the esophageal pathophysiology and therapeutics, especially for failure of esophageal function. The test of muscle activity in vivo would help to assess the occurrence, duration, and extent of involvement of the GI tract in diseases such as scleroderma[16], diabetic viscera neuropathy and dysphagia. This study represents a quantitative method to assess the in vivo contractility of human esophagus with step controlled mechanical stimuli. Such data cannot be generated using manometry as a stand-alone tool. The contraction properties were defined from a single cyclic contraction in terms of several novel mechanical measures. The impaired muscle activities and the changed muscle mechanical behavior after the administration of butylscopolamine were quantitatively described. The developed esophageal muscle contraction analysis can likely be used as an adjunct tool of the combined manometry and impedance planimetry recordings to provide advanced parameters for new understanding of esophageal motor function. It may have clinical relevance in diagnosing patients with symptoms of chest pain and dysphagia.[24]

Acknowledgment

The study was supported by grants from Karen Elise Jensens Foundation and Det Obelske Familiefond.

Funding

The study was supported by grants from Karen Elise Jensens Foundation and Det Obelske Familiefond.

Disclosures

The authors have no competing interests.

Author Contributions

DL did all analysis and wrote part of the manuscript; HG designed the study and reviewed the manuscript; GV did all experiments and reviewed the manuscript.

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