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
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ABSTRACT |
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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
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INTRODUCTION |
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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.
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MATERIALS AND METHODS |
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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.
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RESULTS |
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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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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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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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DISCUSSION |
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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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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.
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ACKNOWLEDGEMENTS |
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This study was supported, in part, by United States Public Health Service Grant RO1-DC-00646 (to P. J. Kahrilas).
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FOOTNOTES |
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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.
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