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Transient Lower Esophageal Sphincter Relaxations Do Not Result From Passive Opening of the Cardia by Gastric Distention

2006; Elsevier BV; Volume: 130; Issue: 1 Linguagem: Inglês

10.1053/j.gastro.2005.11.003

1528-0012

Benson T. Massey, Chelsey Simuncak, Nicole J. Lecapitaine-Dana, Sudhindra Pudur,

Dysphagia Assessment and Management

Background & Aims: Transient lower esophageal sphincter relaxation is the main mechanism for gastroesophageal reflux. Although there is evidence that transient lower esophageal sphincter relaxations are neurally mediated, another school of thought is that transient lower esophageal sphincter relaxations result from gastric distention, which shortens the sphincter to the point where it opens and the pressure decreases. We assessed the relationship of transient lower esophageal sphincter relaxation to gastroesophageal junction opening in an unsedated human model.Methods: Seven healthy volunteers (6 men and 1 woman, aged 18–53 years) were studied while they were sitting. Manometry was performed by using a sleeve catheter passed through 1 nostril. A 5.3-mm endoscope was placed through the other nostril to obtain a retroflexed view of the cardia. The biopsy channel was connected to a barostat to distend the stomach with air at 15 mm Hg for 30 minutes. Manometric and endoscopic video-recording times were synchronized but scored independently.Results: The transient lower esophageal sphincter relaxation onset invariably preceded gastroesophageal junction opening (median, 5.0 seconds; range, 0.5–20.7 seconds; P < .001). The transient lower esophageal sphincter relaxation nadir also typically occurred before gastroesophageal junction opening (median, 2.1 seconds; range, −4.2 to +19.5 seconds; P < .001). Once open, the gastroesophageal junction moved proximally for the duration of the transient lower esophageal sphincter relaxation. Termination of transient lower esophageal sphincter relaxations occurred about the time the time of gastroesophageal junction closure.Conclusions: These data refute the hypothesis that transient lower esophageal sphincter relaxations result from passive mechanical distraction of the gastroesophageal junction. Rather, transient lower esophageal sphincter relaxations must occur before the gastroesophageal junction can open. Background & Aims: Transient lower esophageal sphincter relaxation is the main mechanism for gastroesophageal reflux. Although there is evidence that transient lower esophageal sphincter relaxations are neurally mediated, another school of thought is that transient lower esophageal sphincter relaxations result from gastric distention, which shortens the sphincter to the point where it opens and the pressure decreases. We assessed the relationship of transient lower esophageal sphincter relaxation to gastroesophageal junction opening in an unsedated human model. Methods: Seven healthy volunteers (6 men and 1 woman, aged 18–53 years) were studied while they were sitting. Manometry was performed by using a sleeve catheter passed through 1 nostril. A 5.3-mm endoscope was placed through the other nostril to obtain a retroflexed view of the cardia. The biopsy channel was connected to a barostat to distend the stomach with air at 15 mm Hg for 30 minutes. Manometric and endoscopic video-recording times were synchronized but scored independently. Results: The transient lower esophageal sphincter relaxation onset invariably preceded gastroesophageal junction opening (median, 5.0 seconds; range, 0.5–20.7 seconds; P < .001). The transient lower esophageal sphincter relaxation nadir also typically occurred before gastroesophageal junction opening (median, 2.1 seconds; range, −4.2 to +19.5 seconds; P < .001). Once open, the gastroesophageal junction moved proximally for the duration of the transient lower esophageal sphincter relaxation. Termination of transient lower esophageal sphincter relaxations occurred about the time the time of gastroesophageal junction closure. Conclusions: These data refute the hypothesis that transient lower esophageal sphincter relaxations result from passive mechanical distraction of the gastroesophageal junction. Rather, transient lower esophageal sphincter relaxations must occur before the gastroesophageal junction can open. Transient lower esophageal sphincter relaxation (TLESR) is the principal mechanism for gastroesophageal reflux, both in healthy subjects1Dent J. Dodds W.J. Friedman R.H. Sekiguchi T. Hogan W.J. Arndorfer R.C. Petrie D.J. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects.J Clin Invest. 1980; 65: 256-267Crossref PubMed Scopus (800) Google Scholar, 2Schoeman M.N. Tippett M.D. Akkermans L.M. Dent J. Holloway R.H. Mechanisms of gastroesophageal reflux in ambulant healthy human subjects.Gastroenterology. 1995; 108: 83-91Abstract Full Text PDF PubMed Scopus (296) Google Scholar and in those with gastroesophageal reflux disease.3Dodds W.J. Dent J. Hogan W.J. Helm J.F. Hauser R. Patel G.K. Egide M.S. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis.N Engl J Med. 1982; 307: 1547-1552Crossref PubMed Scopus (906) Google Scholar, 4Mittal R.K. McCallum R.W. Characteristics and frequency of transient relaxations of the lower esophageal sphincter in patients with reflux esophagitis.Gastroenterology. 1988; 95: 593-599Abstract Full Text PDF PubMed Scopus (284) Google Scholar, 5Penagini R. Schoeman M.N. Dent J. Tippett M.D. Holloway R.H. Motor events underlying gastro-oesophageal reflux in ambulant patients with reflux oesophagitis.Neurogastroenterol Motil. 1996; 8: 131-141Crossref PubMed Scopus (133) Google Scholar A substantial body of evidence indicates that this is a neurally mediated event. In dogs, vagotomy abolishes gastroesophageal gas venting,6Strombeck D.R. Harrold D. Ferrier W. Eructation of gas through the gastroesophageal sphincter before and after truncal vagotomy in dogs.Am J Vet Res. 1987; 48: 207-210PubMed Google Scholar and vagal cooling abolishes TLESRs.7Martin C.J. Patrikios J. Dent J. Abolition of gas reflux and transient lower esophageal sphincter relaxation by vagal blockade in the dog.Gastroenterology. 1986; 91: 890-896PubMed Google Scholar In addition, several pharmacological agents acting via cholecystokinin A,8Boulant J. Fioramonti J. Dapoigny M. Bommelaer G. Bueno L. Cholecystokinin and nitric oxide in transient lower esophageal sphincter relaxation to gastric distention in dogs.Gastroenterology. 1994; 107: 1059-1066PubMed Google Scholar, 9Boulant J. Mathieu S. D'Amato M. Abergel A. Dapoigny M. Bommelaer G. Cholecystokinin in transient lower oesophageal sphincter relaxation due to gastric distension in humans.Gut. 1997; 40: 575-581Crossref PubMed Scopus (108) Google Scholar, 10Clave P. Gonzalez A. Moreno A. Lopez R. Farre A. Cusso X. D'mato M. Azpiroz F. Lluis F. Endogenous cholecystokinin enhances postprandial gastroesophageal reflux in humans through extrasphincteric receptors.Gastroenterology. 1998; 115: 597-604Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 11Boeckxstaens G.E. Hirsch D.P. Fakhry N. Holloway R.H. D'Amato M. Tytgat G.N. Involvement of cholecystokininA receptors in transient lower esophageal sphincter relaxations triggered by gastric distension.Am J Gastroenterol. 1998; 93: 1823-1828Crossref PubMed Scopus (93) Google Scholar, 12Zerbib F. Des Varannes S.B. Scarpignato C. Leray V. D'Amato M. Roze C. Galmiche J.P. Endogenous cholecystokinin in postprandial lower esophageal sphincter function and fundic tone in humans.Am J Physiol Gastrointest Liver Physiol. 1998; 38: G1266-G1273Google Scholar cholinergic,13Mittal R.K. Holloway R. Dent J. Effect of atropine on the frequency of reflux and transient lower esophageal sphincter relaxation in normal subjects.Gastroenterology. 1995; 109: 1547-1554Abstract Full Text PDF PubMed Scopus (149) Google Scholar, 14Mittal R.K. Chiareli C. Liu J. Holloway R.H. Dixon S. Atropine inhibits gastric distension and pharyngeal receptor mediated lower oesophageal sphincter relaxation.Gut. 1997; 41: 285-290Crossref PubMed Scopus (45) Google Scholar, 15Lidums I. Checklin H. Mittal R.K. Holloway R.H. Effect of atropine on gastro-oesophageal reflux and transient lower oesophageal sphincter relaxations in patients with gastro-oesophageal reflux disease.Gut. 1998; 43: 12-16Crossref PubMed Scopus (74) Google Scholar opioid,16Penagini R. Bianchi P.A. Effect of morphine on gastroesophageal reflux and transient lower esophageal sphincter relaxation.Gastroenterology. 1997; 113: 409-414Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar nitric oxide,8Boulant J. Fioramonti J. Dapoigny M. Bommelaer G. Bueno L. Cholecystokinin and nitric oxide in transient lower esophageal sphincter relaxation to gastric distention in dogs.Gastroenterology. 1994; 107: 1059-1066PubMed Google Scholar, 17Hirsch D.P. Holloway R.H. Tytgat G.N.J. Boeckxstaens G.E.E. Involvement of nitric oxide in human transient lower esophageal sphincter relaxations and esophageal primary peristalsis.Gastroenterology. 1998; 115: 1374-1380Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar and γ-aminobutyric acid B18Lehmann A. Antonsson M. Bremner-Danielsen M. Flardh M. Hansson-Branden L. Karrberg L. Activation of the GABA(B) receptor inhibits transient lower esophageal sphincter relaxations in dogs.Gastroenterology. 1999; 117: 1147-1154Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 19Lidums I. Lehmann A. Checklin H. Dent J. Holloway R.H. Control of transient lower esophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in normal subjects.Gastroenterology. 2000; 118: 7-13Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar pathways modulate the occurrence of TLESRs in animals and humans. It is also known that fundoplication decreases the occurrence of TLESRs, both in humans20Ireland A.C. Holloway R.H. Toouli J. Dent J. Mechanisms underlying the antireflux action of fundoplication.Gut. 1993; 34: 303-308Crossref PubMed Scopus (168) Google Scholar, 21Johnsson F. Holloway R.H. Ireland A.C. Jamieson G.G. Dent J. Effect of fundoplication on transient lower oesophageal sphincter relaxation and gas reflux.Br J Surg. 1997; 84: 686-689Crossref PubMed Scopus (89) Google Scholar and a dog model.22Cox M.R. Franzi S.J. Martin C.J. The effect of fundoplication on the motility of the canine lower oesophageal sphincter.Aust N Z J Surg. 2000; 70: 68-72Crossref PubMed Scopus (10) Google Scholar It has been believed that fundoplication serves to decrease distention of the cardia, which is the region of the stomach where distention most easily produces TLESRs.23Franzi S.J. Martin C.J. Cox M.R. Dent J. Response of canine lower esophageal sphincter to gastric distension.Am J Physiol. 1990; 259: G380-G385PubMed Google Scholar Conversely, in a cadaveric human model, fundoplication prevents gastroesophageal venting purely by the mechanical properties of the wrap itself.24Farrell T.M. Smith C.D. Metreveli R.E. Richardson W.S. Johnson A.B. Hunter J.G. Fundoplications resist reflux independent of in vivo anatomic relationships.Am J Surg. 1999; 177: 107-110Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Ex vivo25Pettersson G.B. Bombeck C.T. Nyhus L.M. The lower esophageal sphincter mechanisms of opening and closure.Surgery. 1980; 88: 307-314PubMed Google Scholar and in vivo26Mason R.J. Demeester T.R. Lund R.J. Peters J.H. Crookes P. Ritter M. Gadenstatter M. Hagen J.A. Nissen fundoplication prevents shortening of the sphincter during gastric distention.Arch Surg. 1997; 132: 719-724Crossref PubMed Scopus (57) Google Scholar animal models of the gastroesophageal junction suggest that gastric distention results in a reduction of lower esophageal sphincter (LES) length. In some models, resting LES pressure (LESP) is related to LES length,25Pettersson G.B. Bombeck C.T. Nyhus L.M. The lower esophageal sphincter mechanisms of opening and closure.Surgery. 1980; 88: 307-314PubMed Google Scholar with gastric distention resulting in a decrease in LESP to the gastric opening pressure. Thus, it has been argued that a neural mechanism is not needed to explain TLESR. Rather, TLESRs ensue from the gastric distention–induced reduction of the LES length to the point where mechanical forces open the sphincter.26Mason R.J. Demeester T.R. Lund R.J. Peters J.H. Crookes P. Ritter M. Gadenstatter M. Hagen J.A. Nissen fundoplication prevents shortening of the sphincter during gastric distention.Arch Surg. 1997; 132: 719-724Crossref PubMed Scopus (57) Google Scholar The previous models have been limited by the fact that they have not recorded TLESRs directly, which requires continuous monitoring of the LES, typically with a sleeve device.27Dent J. A new technique for continuous sphincter pressure measurement.Gastroenterology. 1976; 71: 263-267Abstract Full Text PDF PubMed Scopus (429) Google Scholar Moreover, the relationships among gastric distention, LESP, and gastroesophageal junction (GEJ) opening have not been assessed in a conscious human model. This study used a novel technique of concurrent manometry and ultrathin endoscopy techniques to address the hypothesis of whether, in the setting of gastric distention, TLESRs resulted in opening of the cardia or vice versa. Seven healthy volunteers (6 men and 1 woman, aged 18–53 years) without symptoms of heartburn or dysphagia were recruited for the study. The study was approved by the Institutional Review Board of the Medical College of Wisconsin, and volunteers were compensated for their time. All subjects had esophageal manometry that confirmed normal motility and unsedated transnasal endoscopy,28Shaker R. Unsedated trans-nasal pharyngoesophagogastroduodenoscopy (T-EGD) technique.Gastrointest Endosc. 1994; 40: 346-348Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar thus confirming a lack of esophagitis and hiatal hernia. Subjects were studied in a sitting position after at least a 6-hour fast. Both nostrils were anesthetized with 2% lidocaine jelly. Through 1 nostril, a manometry catheter with a sleeve device (Arndorfer Medical Specialties, Greendale, WI) was placed so that the sleeve was at the level of the LES. Perfused side holes on the catheter recorded intragastric pressure (IGP) and esophageal body pressure above the sleeve device, and an intermittently perfused sidehole in the pharynx served as a swallow marker. The catheter was connected to a pneumohydraulic capillary infusion system29Arndorfer R.C. Stef J.J. Dodds W.J. Linehan J.H. Hogan W.J. Improved infusion system for intraluminal esophageal manometry.Gastroenterology. 1977; 73: 23-27PubMed Google Scholar and a 12-channel strip chart recorder (Model 7E Polygraph; Grass Instrument Co, Quincy, MA). At the end of the study, the perfused catheter was held at its intubation level outside the subject to obtain baseline pressures, to adjust for the different heights of the recording sites above and below the pressure transducers. The other nostril was used for passage of a 5.3-mm diameter fiberoptic endoscope (model FG-16X; Pentax Precision Instruments Corp, Orangeburg, NY). The endoscope was first used to aspirate any residual fluid from the gastric lumen. Next, the tip of this endoscope was positioned in the stomach to obtain a retroflexed view of the cardia (as well as the shaft of the endoscope and the manometry catheter tip as they exited the GEJ). The endoscope was held in a stationary position and was adjusted only when necessary to reorient the view of the cardia; these times were noted on the strip chart. A video adaptor was connected to the endoscope to allow video recording (Panasonic model AG-1980P; Matsushita Electronic Ind Co Ltd, Osaka, Japan) of the endoscopic image. A modified timing device (model VC-436; Thalner Electronics Laboratories Inc, Ann Arbor, MI) sent a digital timing signal to the video recorder at a frequency of 0.01 seconds while sending an impulse to the strip chart recorder each second, thus allowing synchronization of endoscopic and manometric data recording. Gastric distention was performed with an electronic barostat (G&J Electronics, Toronto, Ontario, Canada). Low-compliance tubing was connected from the barostat to the biopsy channel of the endoscope. Prior bench testing had shown that this connection could maintain a pressure of 50 mm Hg in a closed system without leakage. The barostat was configured so that this large-diameter, low-compliance channel was used both for sensing gastric pressure and delivering air to the stomach to maintain gastric pressure. A target gastric distention pressure of 15 mm Hg relative to atmospheric pressure (not gastric basal pressure) was used, because pilot data had shown that this resulted in a high rate of TLESRs.30Massey B.T. Gorny J.M. Hofmann C. Arndorfer R.C. Effect of intragastric pressure on belch-associated esophageal common cavity reflux events.Gastroenterology. 1998; 114: A799Google Scholar Gastric pressure was monitored at 25 Hz for rapid addition/withdrawal of air from the stomach as needed to achieve the target pressure. Subjects were studied on 2 separate days for 30-minute distention periods, although for 1 subject the video-recording data from 1 distention period were lost. Manometric and endoscopic video recordings were analyzed and scored independently of each other by different observers; the endoscopic observer did not have access to the manometric scoring while scoring the endoscopic recording, and vice versa. On the manometric tracing, TLESRs were identified by previously published criteria.31Holloway R.H. Penagini R. Ireland A.C. Criteria for objective definition of transient lower esophageal sphincter relaxation.Am J Physiol. 1995; 268: G128-G133PubMed Google Scholar The times of TLESR onset and when LESP first reached IGP were noted, as was the time of termination of the TLESR, which was defined as the onset of the terminating peristaltic wave on the sleeve channel. Similarly, the time at which a common cavity pressure was first recorded in the esophageal channels was recorded. Recordings with artifacts were excluded from analysis. On the video recording, the times of opening and closing of the GEJ were studied by slow motion and frame-by-frame playback. Opening of the GEJ was determined to occur on the frame in which a gap first appeared between the manometric catheter or endoscope shaft and the gastric mucosa. Closure of the GEJ was recognized on the frame in which no further fluid or foam exited through the cardia and no gap was visible between the mucosa and either the endoscope or catheter. Differences in time between the onset and nadir of the TLESR, as well as the common cavity onset, were compared with the time of GEJ opening by using the paired t test or sign test, depending on whether the data were normally distributed, with P < .05 considered significant. Differences in values between subjects were analyzed by analysis of variance. From the recording sessions in the 7 subjects, a total of 142 TLESRs were available for analysis. The endoscope position to view the cardia in retroflexion could be maintained throughout the study. Although the endoscope was located adjacent to the manometry catheter as it passed through the GEJ, this did not interfere with the ability to record basal LESP, as well as deglutitive LES relaxations and TLESRs. Because the stomach was distended with air, an unencumbered view of the cardia was achieved, although for some TLESRs, vigorous belching or swallows moved foam temporarily into the region of the cardia and precluded measurement of endoscopic events. The relative timing of events was not significantly different among subjects, so that data from all subjects were pooled for analysis. On videoendoscopy, TLESRs had characteristic features (Figure 1). The cardia was seen to snap open abruptly, resulting in a wide circular opening of the GEJ that was at least 2–3 times the endoscope diameter. Occasionally, fluid retained in the esophagus would fall through the GEJ soon after it opened. Upon opening, the GEJ was seen to move orad, according to movement relative to markings on the endoscope shaft. If the subject belched during the TLESR, there was abrupt, temporary movement of the GEJ and fundus downward with the straining, after which the GEJ returned to a more orad location. Orad positioning of the GEJ persisted until the TLESR was terminated by a primary or secondary peristaltic wave, at which point the GEJ moved aborad. During this aborad movement, fluid and/or foam was seen to pass through the opening of the GEJ before it closed. Closure frequently occurred before the GEJ had finished its aborad excursion. No consistent change in the anatomy of the cardia could be detected in the several seconds before it opened abruptly. A tight circular mucosal cuff surrounded the endoscope shaft and manometry catheter. This mucosal cuff was usually no more than 1 endoscope diameter thick, and it disappeared when the cardia opened. A classic transverse mucosal fold32Hill L.D. Kozarek R.A. Kraemer S.J. Aye R.W. Mercer C.D. Low D.E. Pope II, C.E. The gastroesophageal flap valve in vitro and in vivo observations.Gastrointest Endosc. 1996; 44: 541-547Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar could not be identified. Axial movements of this mucosal cuff could be seen during respiration or deglutition; these were not discernible during the period of the TLESR itself, once the GEJ had opened wide. The temporospatial changes in cardia anatomy during TLESRs showed striking differences compared with those seen during a swallow. Compared with a typical swallow, the opening of the GEJ was much longer during a TLESR. Furthermore, most swallows did not show the wide opening of the GEJ seen during TLESRs. Instead, the mucosal seal between the endoscope and catheter was pushed open minimally by the thin stream of fluid being propelled into the stomach by the peristaltic wave. Swallows in which a common cavity pressure appeared in the esophagus ahead of the peristaltic wave could show a wide opening of the GEJ. An example of the typical temporal association between manometric and endoscopic events is shown during a TLESR in Figure 2. The TLESR onset begins several seconds before the GEJ is seen to open. The LESP also first reaches IGP before the GEJ opens. Opening of the GEJ is closely associated with the onset of the common cavity pressure in the esophageal body. Termination of the TLESR by a peristaltic wave occurs close to the time that the GEJ is observed to close. Data for the relative timing of endoscopic and manometric events are shown in Figure 3.Figure 3Time differentials between endoscopic and manometric events. Boxes depict the 25th–75th percentiles, and whiskers depict the 10th–90th percentiles. The line in the box depicts the median value for the net time difference. Times of TLESR onset and nadir occur significantly (*P < .001) before the opening of the GEJ. Times of common cavity (CC) onset and GEJ opening do not differ significantly (#P > .1), nor do those for TLESR end and GEJ closure.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The manometric onset of TLESRs invariably occurred before the GEJ was seen to open (126 observations; median time, 6.3 seconds; range, 0.5–20.7 seconds; P < .001). Typically during the TLESR, LESP also reached its nadir a few seconds before GEJ opening, although opening could occur while LESP was decreasing (113 observations; median time, 2.1 seconds; range, −4.2 to +19.5 seconds; P < .001). Although the esophageal common cavity tended to occur shortly after GEJ opening, the difference in time between these 2 events was quite variable and not significantly different (116 observations; median, 0.5 seconds; range, −10.1 to +12.3 seconds; P > .1). Likewise, the differences in times of TLESR termination and GEJ closure were not significantly different (105 observations; median difference, GEJ closure − TLESR termination, −0.1 seconds; range, −17.9 to +4.6 seconds; P > .1). Overall, the duration of the TLESR event was longer than the period that the GEJ remained open (median, 17.0 vs 12.6 seconds; P < .001). In this study, we used the novel combination of manometric and videoendoscopic methodologies to address the question of whether gastric distention acts to efface and pull open the cardia, thus resulting in the decrease in pressure at the GEJ that has been termed a TLESR. Contrary to the implications from other models, we found that in awake, seated, healthy humans during gastric air distention, the decrease in LESP to IGP seen with a TLESR always begins before GEJ opening. Furthermore, the LESP usually reaches IGP before GEJ opening. Although the sleeve device, which records the highest pressure present along its length, would be insensitive to an orally propagated shortening of the high-pressure zone, such a shortening might be expected to efface the squamocolumnar junction, which lies distal to the point of peak LESP.33Kahrilas P.J. Lin S. Chen J. Manka M. The effect of hiatus hernia on gastro-oesophageal junction pressure.Gut. 1999; 44: 476-482Crossref PubMed Scopus (261) Google Scholar At the distending pressures used in this study, such effacement was not seen before GEJ opening, which occurred after TLESR onset. Previous models of GEJ opening during gastric distention have had several limitations that may make them irrelevant for study of the TLESR mechanism. First, these models did not actually record LESP at the instant of GEJ opening but inferred a relaxation based on equalization of gastric and esophageal pressures.25Pettersson G.B. Bombeck C.T. Nyhus L.M. The lower esophageal sphincter mechanisms of opening and closure.Surgery. 1980; 88: 307-314PubMed Google Scholar, 26Mason R.J. Demeester T.R. Lund R.J. Peters J.H. Crookes P. Ritter M. Gadenstatter M. Hagen J.A. Nissen fundoplication prevents shortening of the sphincter during gastric distention.Arch Surg. 1997; 132: 719-724Crossref PubMed Scopus (57) Google Scholar Thus, no information was obtained about the time course of LESP in the seconds preceding GEJ opening. Second, these studies have used ex vivo organ blocks or animals that have been anesthetized. It is known that anesthesia abolishes the TLESR response in a dog model.34Cox M.R. Martin C.J. Dent J. Westmore M. Effect of general anaesthesia on transient lower oesophageal sphincter relaxations in the dog.Aust N Z J Surg. 1988; 58: 825-830Crossref PubMed Scopus (56) Google Scholar Finally, a major limitation of these models is that they ignore the effect of the diaphragmatic crura, which serves as an external sphincter to maintain the competence of the GEJ during intra-abdominal pressure transients.35Mittal R.K. Fisher M. McCallum R.W. Rochester D.F. Dent J. Sluss J. Human lower esophageal sphincter pressure response to increased intra-abdominal pressure.Am J Physiol. 1990; 258: G624-G630PubMed Google Scholar Inhibition of the diaphragmatic crura is also a component of the TLESR, and this inhibition is critical for reflux to occur.36Mittal R.K. Fisher M.J. Electrical and mechanical inhibition of the crural diaphragm during transient relaxation of the lower esophageal sphincter.Gastroenterology. 1990; 99: 1265-1268PubMed Google Scholar, 37Mittal R.K. Chiareli C. Liu J.M. Shaker R. Characteristics of lower esophageal sphincter relaxation induced by pharyngeal stimulation with minute amounts of water.Gastroenterology. 1996; 111: 378-384Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 38Pandolfino J.E. Shi G. Zhang Q. Ghosh S. Brasseur J.G. Kahrilas P.J. Measuring EGJ opening patterns using high resolution intraluminal impedance.Neurogastroenterol Motil. 2005; 17: 200-206Crossref PubMed Scopus (28) Google Scholar Crural activity persists after deglutition,36Mittal R.K. Fisher M.J. Electrical and mechanical inhibition of the crural diaphragm during transient relaxation of the lower esophageal sphincter.Gastroenterology. 1990; 99: 1265-1268PubMed Google Scholar which may explain the observation during this study that the GEJ often opened minimally with a swallow but opened widely during a TLESR. Although not specifically studied, crural activity may explain why, in 1 model, higher gastric distention pressures were associated with increased LESP, even though LES length shortened.26Mason R.J. Demeester T.R. Lund R.J. Peters J.H. Crookes P. Ritter M. Gadenstatter M. Hagen J.A. Nissen fundoplication prevents shortening of the sphincter during gastric distention.Arch Surg. 1997; 132: 719-724Crossref PubMed Scopus (57) Google Scholar Some of the controversy regarding the genesis of the TLESR seems to be triggered by the issue of whether fundoplication, which should correct abnormal opening of a mechanically defective GEJ, has a role in preventing the neurally mediated opening of a mechanically normal sphincter. Certainly, fundoplication has been shown to reduce the rate of TLESR, both in patients with reflux disease20Ireland A.C. Holloway R.H. Toouli J. Dent J. Mechanisms underlying the antireflux action of fundoplication.Gut. 1993; 34: 303-308Crossref PubMed Scopus (168) Google Scholar, 21Johnsson F. Holloway R.H. Ireland A.C. Jamieson G.G. Dent J. Effect of fundoplication on transient lower oesophageal sphincter relaxation and gas reflux.Br J Surg. 1997; 84: 686-689Crossref PubMed Scopus (89) Google Scholar and in a canine model.22Cox M.R. Franzi S.J. Martin C.J. The effect of fundoplication on the motility of the canine lower oesophageal sphincter.Aust N Z J Surg. 2000; 70: 68-72Crossref PubMed Scopus (10) Google Scholar This may be because the wrap prevents distention of that portion of the stomach where TLESRs are most easily elicited.23Franzi S.J. Martin C.J. Cox M.R. Dent J. Response of canine lower esophageal sphincter to gastric distension.Am J Physiol. 1990; 259: G380-G385PubMed Google Scholar However, sham fundoplication also decreases the rate of TLESRs,22Cox M.R. Franzi S.J. Martin C.J. The effect of fundoplication on the motility of the canine lower oesophageal sphincter.Aust N Z J Surg. 2000; 70: 68-72Crossref PubMed Scopus (10) Google Scholar thus raising the possibility that the act of surgery may, at least in the short term, disrupt the neural pathways that facilitate TLESRs. In our model of gastric air distention for inducing TLESRs, we observed endoscopically fairly abrupt opening of the GEJ. A recent paper by Pandolfino et al,38Pandolfino J.E. Shi G. Zhang Q. Ghosh S. Brasseur J.G. Kahrilas P.J. Measuring EGJ opening patterns using high resolution intraluminal impedance.Neurogastroenterol Motil. 2005; 17: 200-206Crossref PubMed Scopus (28) Google Scholar using high-resolution intraluminal impedance at the GEJ, suggested that the opening could be a more gradual process, taking up to 7.7 seconds, that proceeded in an orad direction. However, the criteria for impedance change that were used in that study to signify GEJ opening have not been validated by concurrent fluoroscopy or endoscopy, and because the higher intraluminal pressure at the GEJ is associated with a higher impedance, it is unclear how to distinguish impedance changes related to pressure changes from those due to bolus movement. Likewise, it is difficult to distinguish distal GEJ opening from sensor displacement into the stomach from movement or gastric distention with high-resolution impedance. It is also possible that the difference in subject position between our study and that of Pandolfino et al (upright vs lying on the right side) could contribute to the differences in observations. Once the GEJ opened wide, we observed proximal movement of the cardia, as has been observed previously in a canine model of reflux.39Martin C.J. Dodds W.J. Liem H.H. Dantas R.O. Layman R.D. Dent J. Diaphragmatic contribution to gastroesophageal competence and reflux in dogs.Am J Physiol. 1992; 263: G551-G557PubMed Google Scholar Using the technique of fluoroscopically recorded movement of mucosally placed markers, Shi et al40Shi G. Pandolfino J.E. Joehl R.J. Brasseur J.G. Kahrilas P.J. Distinct patterns of oesophageal shortening during primary peristalsis, secondary peristalsis and transient lower esophageal sphincter relaxation.Neurogastroenterol Motil. 2002; 14: 505-512Crossref PubMed Scopus (38) Google Scholar have also shown proximal movement of the squamocolumnar junction during TLESRs. This was associated with segmental esophageal shortening, which likely results from esophageal longitudinal muscle contraction and is also observed with deglutition.41Edmundowicz S.A. Clouse R.E. Shortening of the esophagus in response to swallowing.Am J Physiol. 1991; 260: G512-G516PubMed Google Scholar Shi et al40Shi G. Pandolfino J.E. Joehl R.J. Brasseur J.G. Kahrilas P.J. Distinct patterns of oesophageal shortening during primary peristalsis, secondary peristalsis and transient lower esophageal sphincter relaxation.Neurogastroenterol Motil. 2002; 14: 505-512Crossref PubMed Scopus (38) Google Scholar also described a slight shortening of the distal esophageal segment before GEJ opening; although we did not recognize such shortening, this was associated with only a 3-mm movement of the squamocolumnar junction and may have been difficult to discern with the endoscope. Similar to swallowing, the upward position of the cardia persisted until around the time of the peristaltic wave that terminated the TLESR, at which point the GEJ closed as it moved back toward its rest position. This upward movement occurred after the TLESR had reached IGP and so was likely a response to esophageal distention,40Shi G. Pandolfino J.E. Joehl R.J. Brasseur J.G. Kahrilas P.J. Distinct patterns of oesophageal shortening during primary peristalsis, secondary peristalsis and transient lower esophageal sphincter relaxation.Neurogastroenterol Motil. 2002; 14: 505-512Crossref PubMed Scopus (38) Google Scholar, 42Staff D.M. Massey B.T. Arndorfer R.C. Hofmann C. Ryan C. Kern M. Effect of balloon distension on esophageal shortening in man.Gastroenterology. 1996; 110: A763Google Scholar rather than an intrinsic component of the TLESR event itself. Likewise, this upward movement could not have facilitated GEJ opening, because the opening had already occurred. During endoscopic observations of the cardia in the distended stomach, we did not observe the 3–4-cm–long transverse fold at the cardia that has been termed a grade 1 flap valve appearance by Hill et al.32Hill L.D. Kozarek R.A. Kraemer S.J. Aye R.W. Mercer C.D. Low D.E. Pope II, C.E. The gastroesophageal flap valve in vitro and in vivo observations.Gastrointest Endosc. 1996; 44: 541-547Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar This may be because the narrower endoscope produced less distention of the intra-abdominal segment of the esophagus, thus making this fold less obvious. Alternatively, gastric distention in a sitting position may alter the anatomy and endoscopic appearance of the transverse fold compared with the standard left lateral decubitus view; future correlative endoscopic observations of sitting and recumbent subjects may be able to resolve this issue. It is unclear whether the GEJ openings observed during TLESRs in our study are akin to these seen with a grade 2 flap valve in Hill and colleagues' study, because the durations of opening were not described in that study. Certainly, we did not see opening and closure of the GEJ with respiration. A snug, but narrow, mucosal cuff apposed the endoscope and manometry catheter during respiratory movements of the cardia, opening up only with swallows and TLESRs. If a grade 2 classification is, in fact, predicated on the occurrence of a TLESR, then the difference between grade 1 and 2 may have to do with the duration of observation and the body position during the study, because TLESRs are more easily elicited in the upright position.43Wyman J.B. Dent J. Heddle R. Dodds W.J. Toouli J. Downton J. Control of belching by the lower oesophageal sphincter.Gut. 1990; 31: 639-646Crossref PubMed Scopus (201) Google Scholar, 44Ireland A.C. Dent J. Holloway R.H. Preservation of postural control of transient lower oesophageal sphincter relaxations in patients with reflux oesophagitis.Gut. 1999; 44: 313-316Crossref PubMed Scopus (24) Google Scholar Although we showed that the TLESR begins before the GEJ opens, the factors that determine exactly when the GEJ opens are unclear from this study. Once the LESP reached IGP, it often seemed to remain there for several seconds without a change in the appearance of the cardia before the GEJ opened. The study by Pandolfino et al38Pandolfino J.E. Shi G. Zhang Q. Ghosh S. Brasseur J.G. Kahrilas P.J. Measuring EGJ opening patterns using high resolution intraluminal impedance.Neurogastroenterol Motil. 2005; 17: 200-206Crossref PubMed Scopus (28) Google Scholar found a similar variability in the relationship between the time of the TLESR nadir and that of GEJ opening, as determined by a change in impedance at the GEJ. Although on some occasions the strain associated with belching would occur right at the start of the common cavity wave and GEJ opening, such straining often occurred after the GEJ was already open. It is plausible that pressure at the GEJ actually has to decrease to a critical value below IGP before the GEJ opens. This could not normally be detected with the sleeve, which records the highest pressure occurring along its length45Linehan J.H. Dent J. Dodds W.J. Hogan W.J. Sleeve device functions as a Starling resistor to record sphincter pressure.Am J Physiol. 1985; 248: G251-G255PubMed Google Scholar and so would tend to record IGP as LESP decreased below this. This study examined only healthy volunteers with an intact LES and no hiatal hernia. It is possible that, in reflux patients with low sphincter pressures or hiatal hernias, GEJ opening events may show a different temporal relationship to pressure changes. It is known that in such patients, mechanisms other than TLESR play an increasing role in acid reflux events.46Dent J. Holloway R.H. Toouli J. Dodds W.J. Mechanisms of lower oesophageal sphincter incompetence in patients with gastroesophageal reflux.Gut. 1988; 29: 1020-1028Crossref PubMed Scopus (560) Google Scholar, 47van Herwaarden M.A. Samson M. Smout A.J. Excess gastroesophageal reflux in patients with hiatal hernia is caused by mechanisms other than transient LES relaxations.Gastroenterology. 2000; 119: 1439-1446Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar In summary, we have shown that TLESRs do not result from the passive opening of the cardia during gastric distention. In the setting on ongoing gastric distention, the anatomic configuration of the GEJ remains relatively unchanged, and effacement of the mucosa at the GEJ is not a necessary event for the initiation of TLESRs. Rather, the pressure decrease with a TLESR is a rapid event that must commence before the cardia can open. The opening of the cardia is itself an abrupt event that shows a highly variable temporal relationship to the onset of the TLESR—except that the TLESR always starts first.