Patterns of esophageal inhibition during swallowing, pharyngeal stimulation, and transient LES relaxation

Philippe Pouderoux1, Eric Verdier1, and Peter J. Kahrilas2

1 Service d'Hépato-Gastroentérologie et Alcoologie, Hôpital Caremeau, Centre Hospitalier et Universitaire de Nîmes, 30900 France; and 2 Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Lower esophageal sphincter (LES) relaxation and esophageal body inhibition co-occur during esophageal peristalsis but not necessarily during pharyngeal stimulation or transient LES relaxation (tLESR). This study examined these relationships and the impact on reflux. Nine young volunteers were studied. An artificial high-pressure zone (HPZ) was established, and pH was recorded 8 and 5 cm proximal to the LES. Pharyngeal stimulation was by water injection and gastric distension with liquid or gas. Peristalsis, pharyngeal stimulation, and spontaneous events were recorded. Swallowing relaxed the LES in 100% of trials (the HPZ in 80%) and caused no reflux. Pharyngeal stimulation relaxed the LES in two-thirds of trials, had no effect on the HPZ, and caused no reflux. Gastric distension was associated with 117 tLESRs, 48% with acid reflux, and 32% with gas reflux; there was no effect on the HPZ. We conclude that LES relaxation is a necessary but not sufficient condition for reflux. LES relaxation and esophageal body inhibition are independent events that may be concurrent (swallowing) or dissociated (tLESR).

esophageal primary peristalsis; transient LES relaxation; gastroesophageal reflux; pharynx; swallow


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

NEUROPHYSIOLOGICAL STUDIES in animals have demonstrated that esophageal primary peristalsis is comprised of deglutitive inhibition followed by a sequenced esophageal contraction. Evidence that both esophageal inhibition and contraction are centrally mediated comes from vagal efferent fiber recording demonstrating populations of short- and long-latency neurons whose activity temporally corresponds with inhibition and contraction, respectively. Furthermore, the long-latency neurons to the striated and smooth muscles are sequentially activated. Sequence of inhibition followed by contraction can also be elicited by electrical stimulation of the vagus or even of the esophagus itself (4).

The phenomenon of deglutitive inhibition has been studied in humans by using repetitive swallows (16) and, more recently, by the techniques of subthreshold pharyngeal stimulation (13) and creation of an artificial high-pressure zone (HPZ) within the esophagus (11). Stimulation of the pharynx with small volumes of water was shown to inhibit ongoing primary peristalsis, and this effect was hypothesized to be a variant of deglutitive inhibition (13). Inflation of a balloon in the esophageal lumen creates an artificial HPZ as a result of focal-sustained contraction. Tone of the artificial HPZ can be measured with a pressure sensor wedged between the balloon and the esophageal wall, and relaxation of the HPZ is thought to be a direct measurement of active inhibition of the esophageal body (11). Transient lower esophageal sphincter (LES) relaxation (tLESR) has also been reported to inhibit ongoing peristalsis in the distal esophagus (2). However, an experiment utilizing the artificial HPZ technique did not find esophageal inhibition of the artificial HPZ during tLESR unless the tLESR was associated with reflux-induced esophageal distension as can occur during gas or fluid reflux (12).

tLESR is a unique motor response comprised of both LES and crural diaphragm inhibition (9). Numerous experiments involving prolonged manometric recordings have confirmed that tLESRs are the most frequent mechanism by which gastroesophageal reflux occurs, both in normal individuals and in patients with gastroesophageal reflux disease (GERD) (1, 3). However, debate persists regarding the triggering mechanisms of tLESRs. Gastric distension is indisputably a potent stimulus for tLESR, regardless of whether distension is resultant from a balloon, air, or a meal (8). Pharyngeal sensory stimulation by water or air instillation at intensity less than that necessary to elicit swallowing can elicit LES relaxations that resemble tLESRs (7, 10, 14). However, unlike the tLESRs associated with gastric distension that are clearly associated with reflux events, the role of pharyngeal stimulation in triggering reflux remains unclear (8). The aims of this study were to clarify the patterns of esophageal- and LES inhibition-associated pharyngeal stimulation, peristalsis, and gastric distension in normal individuals. We also sought to determine which patterns of inhibition were potentially associated with gastroesophageal reflux.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Patients and materials. Nine healthy volunteers (5 male and 4 female) aged 18-35 yr (mean, 25 yr) were studied. The study protocol was approved by the Northwestern University Institutional Review Board, and informed consent was obtained from each subject. No subject was taking any medications that could affect esophageal motility. Smoking was not permitted on the day of the study.

Esophageal manometry was performed by using a 5-mm OD multilumen assembly that incorporated a sleeve sensor for monitoring LES pressure (Arndorfer Medical Specialties, Greendale, WI). Side-hole recording sites at the proximal and distal ends of the sleeve recorded distal esophageal and intragastric pressure, respectively. Additional side-hole recording sites were situated 3, 6, and 9 cm above the proximal margin of the sleeve. Pharyngeal stimulation was accomplished with a second manometry catheter (3 mm OD) with an injection port located 2 cm above the upper limit of the upper esophageal sphincter (UES) and a pressure recording site in the pharynx 1 cm above the injection port. Each manometric channel was perfused at 0.5 ml/min by a low- compliance pneumohydraulic pump (Mui Scientific, Mississauga, ON, Canada). Esophageal pH was monitored with a unipolar glass electrode (Microelectrodes, Bedford, NH) positioned 5 cm above the upper margin of the LES and a skin Ag/AgCl reference electrode (Synectics Medical, Irving, TX). Before each study, the electrode was calibrated in buffer solutions of pH 1 and 7 (Synectics). Manometric assemblies were connected to external pressure transducers (Medex, Hilliard, OH), and both pressure and pH output were recorded on a computer polygraph set at a sampling frequency of 40 Hz and processed by using Gastromac 3.3.3 software (Neomedix Systems, Warriewood, NSW, Australia).

A balloon made from the finger of a latex glove (35-mm length) was constructed at the end of a 0.8-mm OD polyvinyl tube. The tube was then glued to the manometric catheter such that the balloon was positioned opposite the side hole located 6 cm above the sleeve. The diameter of the balloon and intraballoon pressure were measured in vitro at room temperature by inflating the balloon with air at 1-ml increments. When inflated with 1, 2, 3, 4, and 5 ml, the diameter of the balloon was 11.1 ± 0.2, 13.3 ± 0.2, 15.2 ± 0.3, 17.0 ± 0.5, and 20.5 ± 0.5 mm, and intraballoon pressure was 4.7 ± 0.4, 9.7 ± 0.4, 13.7 ± 0.6, 20.0 ± 0.7, and 27.9 ± 1.8 mmHg, respectively (measurements made in triplicate; means ± SD).

For gastric distension experiments, two 0.8-mm OD lines were glued to the esophageal manometric catheter with their end holes located in the stomach 3 cm below the distal end of the sleeve. Each line was connected to a pneuhydraulic low- compliance pump (Arndorfer). One pump infused a 10% dextrose solution at a rate of 5 ml/min. Dextrose was mixed with a few milliliters of 5 N HCl to obtain a solution at pH 2, stocked frozen, and thawed the day of the study. The other pump infused compressed air at a rate of 1 l/h.

Experimental procedure. Subjects were studied in a supine posture after an overnight fast. The two manometric assemblies and the pH electrode were passed transnasally after light local anesthesia with lidocaine. The stomach was loaded with 200 ml 10% dextrose at pH 2. The balloon was slowly inflated with 1-ml increments of air to induce a local sustained increase in esophageal pressure as measured by the side hole located 6 cm above the sleeve between the balloon and the esophageal wall. The magnitude of the HPZ was 10-15 mmHg, and deglutitive inhibition was visualized as a relaxation (11).

After stabilization of the HPZ, subjects swallowed 10 water boluses (5-ml) from a graduated syringe. Swallows were separated by at least 20 s. Pharyngeal stimulation was begun with 0.2 ml water and increased by 0.2-ml increments with the subjects instructed to refrain from swallowing. Ten iterations of pharyngeal stimulation were obtained on each subject.

At the completion of the swallowing and pharyngeal stimulation studies, the gastric fundus was distended by loading 200 ml of air with a syringe, followed by a continuous infusion of air and acid dextrose. Air infusion was discontinued if the subject complained of abdominal discomfort or when the epigastrium was noted to be tense to palpation or percussion and was resumed when the symptoms or physical signs disappeared. Recordings were made for 2 h, during which subjects were on their back for 1 h and seated in a chair for 1 h. The sequence of position was determined randomly.

Data analysis. LES pressure was measured as the mean pressure during the 5- to 10-s period that preceded the pharyngeal swallow by 4 s and was referenced to intragastric pressure. tLESRs were analyzed according to criteria described by Holloway et al. (5). Basal HPZ pressure was also determined in the 5- to 10-s interval 4 s before the test event and referenced to the mean baseline pressure with the balloon deflated. Pressure within the HPZ was determined during three different 10-s periods at the beginning, middle, and end of the test procedure. Analysis of the relaxation in the HPZ was similar to that carried out in the LES. Onset of HPZ relaxation was determined as the point at which pressure decreased by >= 3 mmHg relative to the minimal pressure determined during the 5- to 10-s baseline recorded 4 s before swallowing, and the offset of relaxation was the instant at which the pressure increased to a value greater than the minimal value recorded before swallowing. Duration of HPZ relaxation was the interval between onset and offset. Magnitude of HPZ relaxation was expressed both as a percent (100% inhibition being defined as a decrease to the baseline with the balloon deflated) and as numerical values. The nadir pressure was the lowest pressure value recorded during relaxation. Mean pressure values during HPZ relaxation were obtained from the intervals between the onset and offset of relaxation and between the onset of swallowing and the onset of the peristaltic pressure wave at the HPZ port.

During the pharyngeal stimulation procedure, analyzed LES pressure variables included the interval between the pharyngeal water stimulation and the onset of LES relaxation, mean LES pressure, duration of relaxation, nadir pressure, duration during which LES pressure was <= 4, and the mean pressure during the interval between the onset of stimulation and the arrival of peristalsis. LES relaxation was considered complete when <= 4 mmHg on the basis of the observation that gastroesophageal reflux most frequently occurs when LES pressure is below this value (9). When LES relaxation ended with a swallow-induced peristaltic sequence, only the interval extending to 4 s before the swallow was analyzed. The HPZ tracing was similarly analyzed for the presence, extent, and duration of relaxation; mean pressure during LES relaxation; and mean pressure during the interval between the onset of the stimulus and the arrival of peristalsis.

Reflux episodes were defined as a decrease in pH to <4 for >= 4 s or, if basal esophageal pH was already <4, a further decrease of >= 1 pH unit. Common cavity phenomena were defined as abrupt increases in esophageal body pressure to intragastric pressure observed in at least the two distal esophageal body recording sites persisting until the subsequent occurrence of either primary or secondary peristalsis.

Statistical analysis was performed with either one-way or two-way analysis of variance followed by Student-Newman- Keuls multiple comparisons procedure to identify significant differences among groups, or chi -square as appropriate. The threshold for statistical significance was P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

One subject was excluded from analysis, because despite persistent effort it was not possible to maintain a HPZ without triggering spontaneous esophageal contractions with balloon inflation. For the remainder of the subjects, a HPZ was relatively easily obtained by progressive inflation of the balloon to a threshold diameter less than that associated with local muscle contraction. The mean pressure of the HPZ among subjects was 12 ± 2 mmHg associated with balloon volumes ranging from 2-4 ml. Higher pressures tended to trigger simultaneous esophageal contractions or result in obstructing the passage of the swallowed bolus, as evidenced by intrabolus pressures >10 mmHg. During experimentation, HPZ pressure was relatively unstable over time and frequent adjustments of balloon inflation were necessary. Similarly, HPZ pressure was frequently altered or abolished with change of posture, requiring that the balloon be deflated and reinflated before continuing with the experimental protocol.

Primary peristalsis. During swallowing, complete LES relaxation was observed in 99% of iterations, whereas HPZ relaxation occurred in 80%. Relaxation was complete (pressure drop >80% of the baseline value) in 59% of HPZ relaxations (Fig. 1). HPZ relaxation occurred 0.6 ± 0.5 s before that of the LES, had a shorter duration (5.2 ± 0.7 vs. 7.5 ± 0.5 s, P < 0.01), and always ended with the peristaltic contraction. Incomplete or absent HPZ relaxation occurred without any observable alteration of primary peristalsis or LES relaxation. No acid reflux or common cavity events were observed during swallowing studies.


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Fig. 1.   Relaxation of the lower esophageal sphincter (LES) and the high-pressure zone (HPZ) during primary peristalsis. The HPZ was obtained between an inflated latex balloon and the esophageal (Eso) wall 8 cm above the LES. Swallow is indicated by the pharyngeal (Phar) contraction (arrow). Relaxation of the HPZ was complete, occurred before LES relaxation, and terminated with primary peristalsis.

Pharyngeal stimulation. During pharyngeal stimulation, LES relaxation occurred in 63% of trials (Fig. 2). The interval between the onset of pharyngeal stimulation and LES relaxation was 4.6 ± 0.8 s and the duration of relaxation was 20.8 ± 4.3 s, significantly longer than swallow-induced relaxations (7.5 ± 0.5 s, P < 0.01). However, complete LES relaxation (nadir <= 4 mmHg) was observed in only 36.2% of the trials and lasted only 9.5 ± 6 s. LES relaxation was terminated by: 1) spontaneous return of LES pressure to baseline, 2) primary peristalsis, or 3) simultaneous esophageal contraction (Table 1). No HPZ relaxation was observed during pharyngeal stimulation, and no acid reflux or common cavity events were observed.


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Fig. 2.   LES relaxation induced by pharyngeal stimulation illustrated with the same recording setup as in Fig. 1. Rapid injection of water (arrow) 2 cm above the upper esophageal sphincter (UES) is followed by LES relaxation lasting 18 s. Relaxation is complete, shown by nadir pressure relative to the stomach being <= 4 mmHg. Pharyngeal stimulation is not associated with relaxation of the HPZ.


                              
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Table 1.   Mode of termination of lower esophageal sphincter relaxation and occurrence of reflux with each type of relaxation

Gastric distension. During gastric distension studies 117 episodes of spontaneous LES relaxation were recorded, all of which met the criteria for tLESRs (5) with a mean duration of 23 ± 4 s. Among these, 56 were associated with acid reflux, always in association with a common cavity. Gas reflux events, defined by the occurrence of a common cavity without a concomitant decrease of pH to a value <4, were associated with 37 tLESRs. Twenty-four tLESRs were free of detectable gas or acid reflux. LES relaxation terminated with either primary peristalsis, secondary peristalsis, simultaneous contraction, or spontaneously (Fig. 3 and Table 1). tLESR was not associated with any consistent pattern of HPZ relaxation regardless of the presence or constituents of the refluxate. During tLESRs, the mean pressure variation in the HPZ was 2.6 ± 1 mmHg (tLESR without reflux) 5 ± 0.8 mmHg (tLESR + acid reflux), and 4.9 ± 0.8 mmHg (tLESR + gas reflux) (P < 0.05). Mean pressure of the HPZ was inferior to basal pressure during 30% of tLESRs without reflux, 14.8% of tLESRs with acid reflux, and 32% of the tLESRs with gas reflux. Secondary peristalsis was uniformly associated with HPZ relaxation.


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Fig. 3.   Transient LES relaxation associated with acid reflux. LES relaxation (arrow) is associated with a drop of intraluminal pH, consistent with acid reflux. Pressure in the HPZ persists unchanged during the 22 s of LES relaxation. LES relaxation terminates with secondary peristalsis associated with HPZ relaxation.

Factors that tended to promote the occurrence of tLESRs were distension with air and acid rather than acid only and the sitting position; 7% of acid reflux events and 90% of gas reflux episodes occurred in the sitting position (Table 2). On the other hand, 70% of tLESRs not accompanied by reflux occurred in the supine posture. tLESRs were shorter in duration in the sitting position and with gastric air insufflation (20.6 s with gas infusion and sitting position, 22.6 s with gas infusion and supine position, 27.8 s with liquid infusion and supine position, P > 0.05 by two-way ANOVA). tLESRs not accompanied by reflux appeared to last longer than with reflux (30.8 vs. 20.25 s; P > 0.05 by two-way ANOVA).

                              
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Table 2.   Effect of position on the incidence of transient LES relaxation and on the likelihood of associated reflux


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The major finding of this study was that, although LES relaxation could be elicited by primary or secondary peristalsis, pharyngeal stimulation, or gastric distension, the associated patterns of esophageal inhibition and the likelihood of there being associated gastroesophageal reflux are unique in each case. Only peristalsis was consistently associated with inhibition of an artificial HPZ in the distal esophagus as described by Sifrim et al. (11), and only tLESR as elicited by gastric distension was associated with gastroesophageal reflux.

The unique association of gastroesophageal reflux with tLESR observed in this study of normal volunteers strongly corroborates the hypothesis that LES relaxation is a necessary but not sufficient condition for the occurrence of gastroesophageal reflux. Inhibition of the crural diaphragm is a necessary cofactor. Previous work has demonstrated that crural diaphragm inhibition is a feature of tLESR but not of peristalsis-induced relaxation (9) or of LES relaxation induced by pharyngeal stimulation (7). In fact, in the latter study, pharyngeal stimulation was shown to augment crural diaphragm contraction. Thus combining the current observations with those gleaned from the literature leads to the synthesis of patterns of esophageal and LES inhibition summarized in Table 3.

                              
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Table 3.   Patterns of inhibition elicited by swallowing, gastric distention, pharyngeal stimulation, and secondary peristalsis

In contemplating the construct of Table 3, it is essential to recognize that the unique association of reflux with tLESRs pertains to normal individuals but not necessarily to individuals with reflux disease; especially if those individuals have a hiatal hernia. The ambulatory manometry study of GERD patients with and without hiatus hernia recently published by van Herwaarden et al. (15) nicely demonstrates this point. Although reflux associated with events other than tLESR was a relative rarity in GERD patients without hiatus hernia, they became the dominant mechanisms in patients with hiatus hernia, especially in the postprandial period. A frequent mechanism observed among the hernia patients was swallow-induced reflux, which is decidedly rare among normal individuals. There is one conflicting report on the ability of pharyngeal stimulation to induce reflux (17). In that study, 16-44% of pharyngeal stimuli were associated with acid reflux, and this was noted to be more frequent in the elderly. However, it would be reasonable to assume a higher incidence of hiatus hernia among the elderly, and that variable was not controlled for in that investigation. Additionally, the reflux events observed occurred primarily in the postprandial period, and in some instances, these could be attributable to the chance co-occurrence of a gastric distension-induced tLESR. In the current protocol, the stomach was initially filled with acid, but the volume of acid was not great enough to increase the rate of tLESRs on the basis of distension; it was only enough to favor acid reflux in the setting of LES relaxation. Continuous gastric air infusion has been shown to be a potent mechanism to trigger tLESRs (6), and we induced a rate of tLESRs similar to that previously reported with the same experimental protocol. tLESRs were more frequent in the sitting position, which is consistent with observations made with other techniques of gastric distension, including meals. The reasons why the frequency of tLESRs seems higher with continuous gastric distension compared with meals or balloon distension remains speculative. Intuitively, continuous gastric distension with air induces a high level of distension marked by abdominal discomfort. The whole stomach is distended with air infusion compared with focal distension obtained with a balloon, and the stimulus constantly renews itself, should it be relieved by belching.

Another finding of the present study was that the distal esophageal HPZ was uniquely inhibited by peristalsis, be it primary or secondary. As initially described, the artificial HPZ is a method for directly demonstrating deglutitive inhibition (11). Supporting that contention, HPZ relaxation was observed with swallowing before LES relaxation and for a shorter duration. However, although we maintained a slightly lower magnitude of HPZ than described by Sifrim et al. (12), the HPZ failed to relax completely in a substantial number of swallows, despite normal LES relaxation in these young individuals without evidence of abnormal esophageal motility. This observation suggests that deglutitive inhibition may be insufficient to negate the contraction induced by focal distension in some cases, the extreme case being the one individual in whom we could not conduct the experiment at all, because of sustained esophageal contraction with any balloon distension. In contradistinction to the case with peristalsis, inhibition of the HPZ was not observed in the setting of either pharyngeal stimulation or tLESR. However, both of these stimuli have been reported to inhibit ongoing peristalsis (13). This apparent discrepancy has a number of possible explanations. As invoked to explain the variability in the peristaltic response of the HPZ, the sustained contraction around the balloon may be more resistant to inhibition than peristaltic contraction. Alternatively, the distal esophagus may be less susceptible to inhibition than the proximal esophagus. Supportive of this, inhibition of swallowing by a pharyngeal stimulus or repetitive swallowing is not always possible, once the peristaltic wave has progressed to the distal esophagus (13). Similarly, in the case of tLESRs, our findings of absent HPZ inhibition are consistent with those of Sifrim et al. (12) with the only caveat being that they did report HPZ inhibition of the tLESR accompanied by reflux. However, we observed partial relaxation in that setting, and the difference in findings may be a matter of interpretation. To eliminate a bias in the determination of the nadir HPZ pressure (which was subject to much spontaneous fluctuation with respiration, movement, etc.) we reported the mean rather than the nadir HPZ pressure during the period of tLESR.

In summary, this study showed that only LES relaxation induced by gastric distension, but not that elicited by either peristalsis or pharyngeal stimulation, was associated with reflux in young, normal asymptomatic individuals. On the other hand, relaxation of an artificial HPZ within the esophageal body consistently occurred only with primary or secondary peristalsis, suggesting relevance mainly to the phenomenon of deglutitive inhibition. Thus there is clear distinction among the inhibitory mechanisms controlling the LES, the crural diaphragm, and the esophageal body. Furthermore, the significance of LES relaxation varies with the concomitant activity of the esophagus, and crural diaphragm and LES relaxation is a necessary but not adequate condition for gastroesophageal reflux.


    ACKNOWLEDGEMENTS

This study was supported, in part, by United States Public Health Service Grant RO1-DC-00646 (to P. J. Kahrilas).


    FOOTNOTES

Address for reprint requests and other correspondence: P. Pouderoux, Service d'Hépato-Gastroentérologie et Alcoologie, Centre Hospitalier et Universitaire de Nîmes, Hôpital Caremeau, Ave. du Professeur Robert Debré, 30900 Nîmes, France (E-mail: philippe.pouderoux{at}chu-nimes.fr).

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.

First published October 15, 2002;10.1152/ajpgi.00301.2002

Received 24 July 2002; accepted in final form 1 October 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Gastrointest Liver Physiol 284(2):G242-G247
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