Transient Lower Esophageal Sphincter Relaxations and Reflux: Mechanistic Analysis Using Concurrent Fluoroscopy and High-Resolution Manometry
2006; Elsevier BV; Volume: 131; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2006.09.009
ISSN1528-0012
AutoresJohn E. Pandolfino, Qing G. Zhang, Sudip Kumar Ghosh, Alexander Han, Christopher Boniquit, Peter J. Kahrilas,
Tópico(s)Eosinophilic Esophagitis
ResumoBackground & AimsThe aim of this study was to perform a detailed analysis of the mechanics leading to esophagogastric junction (EGJ) opening during transient lower esophageal sphincter relaxations (tLESRs) using high-resolution manometry coupled with simultaneous fluoroscopy. Methods Six subjects without hiatus hernia had endoclips placed at the squamocolumnar junction and 10 cm proximal. A 36-channel solid-state manometric assembly was placed spanning from stomach to pharynx, and subjects were studied for 2 hours after a high-fat meal. An esophageal pH electrode also was placed and fluoroscopy was initiated at the onset of a tLESR. Axial clip movement was measured during replay of the videotaped fluoroscopy and was correlated with manometric data. Results Ninety-three tLESRs were recorded, 62 tLESRs of which had good fluoroscopic visualization. Seventy-eight tLESRs had manometric evidence of flow and the majority had evidence of a common cavity (88%), but few were detected by the pH electrode. Esophageal shortening and crural diaphragm inhibition always preceded EGJ opening and common cavity. A positive pressure gradient between the stomach and the EGJ lumen of 7.1 mm Hg (interquartile range, 4.1–9.1 mm Hg) preceded the EGJ opening. Conclusions Key events leading to the EGJ opening during tLESRs were LES relaxation, crural diaphragm inhibition, esophageal shortening, and a positive pressure gradient between the stomach and the EGJ lumen. The manometric signature of opening was pressure equalization within the EGJ, but this only occasionally was associated with pH evidence of reflux. Future investigations will need to analyze how this delicately balanced anatomic–physiologic system is perturbed in subjects with reflux disease. Background & AimsThe aim of this study was to perform a detailed analysis of the mechanics leading to esophagogastric junction (EGJ) opening during transient lower esophageal sphincter relaxations (tLESRs) using high-resolution manometry coupled with simultaneous fluoroscopy. Methods Six subjects without hiatus hernia had endoclips placed at the squamocolumnar junction and 10 cm proximal. A 36-channel solid-state manometric assembly was placed spanning from stomach to pharynx, and subjects were studied for 2 hours after a high-fat meal. An esophageal pH electrode also was placed and fluoroscopy was initiated at the onset of a tLESR. Axial clip movement was measured during replay of the videotaped fluoroscopy and was correlated with manometric data. Results Ninety-three tLESRs were recorded, 62 tLESRs of which had good fluoroscopic visualization. Seventy-eight tLESRs had manometric evidence of flow and the majority had evidence of a common cavity (88%), but few were detected by the pH electrode. Esophageal shortening and crural diaphragm inhibition always preceded EGJ opening and common cavity. A positive pressure gradient between the stomach and the EGJ lumen of 7.1 mm Hg (interquartile range, 4.1–9.1 mm Hg) preceded the EGJ opening. Conclusions Key events leading to the EGJ opening during tLESRs were LES relaxation, crural diaphragm inhibition, esophageal shortening, and a positive pressure gradient between the stomach and the EGJ lumen. The manometric signature of opening was pressure equalization within the EGJ, but this only occasionally was associated with pH evidence of reflux. Future investigations will need to analyze how this delicately balanced anatomic–physiologic system is perturbed in subjects with reflux disease. Compelling evidence exists that transient lower esophageal sphincter relaxations (tLESRs) are the most frequent mechanism for reflux and essentially the only operant mechanism during periods of normal LES pressure (>10 mm Hg). Transient LES relaxations occur independently of swallowing, are not accompanied by peristalsis, are accompanied by diaphragmatic inhibition, and persist for longer periods than do swallow-induced LES relaxations (>10 s).1Mittal R.K. Holloway R.H. Penagini R. Blackshaw L.A. Dent J. Transient lower esophageal sphincter relaxation.Gastroenterology. 1995; 109: 601-610Google Scholar, 2Holloway R.H. Penagini R. Ireland A.C. Criteria for objective definition of transient lower esophageal sphincter relaxation.Am J Physiol. 1995; 268: G128-G133Google Scholar Of note, prolonged manometric recordings have not consistently shown an increased frequency of tLESR in gastroesophageal reflux disease patients compared with normal controls.3Sifrim D. Holloway R. Transient lower esophageal sphincter relaxations: how many or how harmful?.Am J Gastroenterol. 2001; 96: 2529-2532Google Scholar However, the frequency of acid reflux (as opposed to gas reflux) during tLESRs has been reported to be greater in gastroesophageal reflux disease patients.3Sifrim D. Holloway R. Transient lower esophageal sphincter relaxations: how many or how harmful?.Am J Gastroenterol. 2001; 96: 2529-2532Google Scholar Our current understanding of gastroesophageal reflux draws a fundamental distinction between LES relaxation and esophagogastric junction (EGJ) opening, the latter being essential for reflux to occur. During swallow-induced LES relaxation, for instance, EGJ opening occurs well after relaxation in response to a transmural pressure gradient attributable to peristalsis and intrabolus pressure. However, this mechanism is not operational during tLESR, leaving open the question of how EGJ opening occurs in that circumstance. Hence, other elements of the tLESR reflex such as esophageal shortening and crural diaphragm inhibition have been invoked. Studies in cats and human beings have suggested that esophageal shortening preceded gastroesophageal reflux during tLESRs and it was hypothesized that proximal migration of the EGJ may be involved in the EGJ opening mechanism.4Torrance H.B. Studies on the mechanism of gastro-oesophageal regurgitation.J R Coll Surg. 1958; 4: 54-62Google Scholar, 5Sifrim D. Tack J. Zhang X. Huysmans W. Janssens J. Continuous monitoring of esophageal shortening in man during swallowing, transient LES relaxations and intraesophageal acid perfusion.Gastroenterology. 2002; 122: A188Abstract Full Text Full Text PDF Scopus (161) Google Scholar However, other studies did not confirm that temporal relationship, suggesting that shortening was a response to common cavity formation after a reflux event.6Martin 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-G557Google Scholar, 7Massey B. Simuncak C. Lecapitaine-Dana N.J. Pudur S. Transient LES relaxations are not the results of mechanical opening of the cardia during gastric distention.Gastroenterology. 2001; 120: A112Google Scholar, 8Shi 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 oesophageal sphincter relaxation.Neurogastroenterol Motil. 2002; 14: 505-512Google Scholar These conflicting results may be attributable to methodologic difficulties pertaining to the difficulty of simultaneously detecting and timing reflux, LES relaxation, and esophageal shortening. The aim of this study was to apply state-of-the-art manometry coupled with simultaneous fluoroscopy in a detailed analysis of the mechanics leading to EGJ opening during tLESRs. We used solid-state high-resolution manometry to provide a dynamic pressure profile across the EGJ, free of hydrostatic influence or movement artifact. This technology was combined with digital image analysis of endoclip movement during tLESRs to elucidate the temporal relationship between EGJ opening and esophageal shortening with the hypothesis that esophageal shortening is a prerequisite for EGJ opening. Secondary goals of this study focused on quantifying the pressure gradient across the EGJ during tLESR and ascertaining whether or not common cavity events, often highlighted as an ancillary feature of a tLESR, truly indicate isobaric conditions between the stomach and esophagus. Six subjects without manometric, fluoroscopic, or endoscopic evidence of hiatus hernia (3 men; ages, 25–46 years) were studied using simultaneous manometry, pH monitoring, and fluoroscopy. None of the subjects had previous gastrointestinal surgery or were taking medications known to affect gastrointestinal motor function or acid secretion. Subjects were enrolled from the gastrointestinal diagnostic laboratory at Northwestern Memorial Hospital. The study protocol was approved by the Northwestern University Institutional Review Board, and informed consent was obtained from each subject. Upper endoscopy was performed with a 27 F endoscope in the left lateral decubitus position after at least a 6-hour fast. During endoscopy, performed either without sedation or under moderate sedation with 1–4 mg of midazolam, the squamocolumnar junction (SCJ) was marked by placement of an 11-mm stainless steel clip using a clipping device passed through the working channel of the endoscope (Olympus HX-SLR-1 clip fixing device; Tokyo, Japan). A second clip was placed about 10 cm proximal to the SCJ in 5 subjects. A solid-state manometric assembly with 36 circumferential sensors spaced at 1-cm intervals (outer diameter, 4.2 mm) was used (Sierra Scientific Instruments Inc., Los Angeles, CA). This device uses proprietary pressure transduction technology (TactArray, Sierra Scientific Instruments Inc.) that allows each of the 36 pressure-sensing elements to detect pressure over a length of 2.5 mm in each of 12 radially dispersed sectors.9Pandolfino J.E. El-Serag H.B. Zhang Q. Shah N. Ghosh S.K. Kahrilas P.J. Obesity: a challenge to esophagogastric junction integrity.Gastroenterology. 2006; 130: 639-649Abstract Full Text Full Text PDF Scopus (435) Google Scholar The sector pressures then are averaged, making each of the 36 sensors a circumferential pressure detector with the extended frequency response characteristic of solid-state manometric systems and free of the hydrostatic influences characteristic of water-perfused systems. Before the recording, the transducers were calibrated at 0 and 100 mm Hg using externally applied pressure. The response characteristics of each sensing element were such that they could record pressure transients in excess of 6000 mm Hg/s and were accurate to within 1 mm Hg of atmospheric pressure after thermal recalibration.9Pandolfino J.E. El-Serag H.B. Zhang Q. Shah N. Ghosh S.K. Kahrilas P.J. Obesity: a challenge to esophagogastric junction integrity.Gastroenterology. 2006; 130: 639-649Abstract Full Text Full Text PDF Scopus (435) Google Scholar After endoscopy, the manometric assembly was positioned to record from the hypopharynx to the stomach and a catheter pH electrode was placed 5 cm above the LES. After recording 10 water swallows in a supine position and a 30-minute accommodation period in a sitting position, subjects ate a 1000-calorie high-fat meal (2 cheeseburgers). They then were shielded below the umbilicus with a lead apron and positioned within the C arm of a fluoroscope (Easy Diagnostics, Phillips Medical Systems, Shelton, CT). During the subsequent 120 minutes, fluoroscopy was initiated and recorded each time the onset of a tLESR was suspected on the real-time manometric recording by either of the 2 investigators watching the manometric recordings for evidence of LES relaxation. Once fluoroscopy was initiated, it was continued until LES relaxation ended in the case of a tLESR or until it became clear that the LES relaxation was unrelated to a tLESR (swallow or spontaneous pressure variation). Maximal fluoroscopic exposure for each subject was less than 5 minutes. Fluoroscopic images were recorded using a videotape recorder (Panasonic VO 9800; Panasonic, Osaka, Japan) and synchronized with manometric data using an event marker each time fluoroscopy was initiated. Images later were downloaded to a G4 Macintosh computer (Apple Inc., Cupertino, CA) and analyzed using National Institutes of Health (Bethesda, MD) image software. Characterization of the pressure morphology across the EGJ was performed with a computer program (Matlab, The MathWorks Inc., Natick, MA) customized for processing binary manometric data into isocontour pressure plots and spatial pressure variation plots. This was performed by first exporting the binary manometry data from ManoView (Sierra Scientific Instruments Inc.) in ASCII text format for processing and storage. These ASCII files then were reconverted into a known binary format for use in Matlab and isocontour (Figure 1A) and spatial pressure variation plots were generated (Figure 1B). For these plots to appear smooth (as opposed to notched), the data sets were enhanced both in the time dimension (between sampling times) and in the spatial dimension (between pressure recording sites). This interpolation was performed using a cubic spline algorithm implemented on a finely resolved rectilinear space-time grid to generate intermediate data points, resulting in a virtual increase in the spatial data from 1 to 10 recording sites per cm and doubling the temporal sampling from 35 to 70 Hz.10Clouse R.E. Staiano A. Topography of the esophageal peristaltic pressure wave.Am J Physiol. 1991; 261: G677-G784Google Scholar The analysis of manometric evidence of flow across the EGJ and the measurement of the trans-sphincteric pressure gradient during a tLESR were performed by converting the manometric data into spatial pressure variation plots with a sampling frequency of 5 Hz (Figure 1B). For each vertical line of the spatial pressure variation plot, position along the y-axis indicates spatial position of the pressure sensor and deflection along the x-axis indicates pressure magnitude. As with isobaric contour plots, spatial data resolution is enhanced by interpolation between adjacent sensor positions with a smoothing function. In addition, a computer program was developed using Matlab to correlate manometry with fluoroscopy data and plot the position of the endoclips relative to the manometric sensors. In a point-and-click environment, axial clip movement was quantified and correlated temporally with manometry. Isocontour and spatial pressure variation plots were overlaid with clip data (Figure 1). tLESRs were defined according to standard criteria2Holloway R.H. Penagini R. Ireland A.C. Criteria for objective definition of transient lower esophageal sphincter relaxation.Am J Physiol. 1995; 268: G128-G133Google Scholar and required agreement between at least 2 of 3 investigators (J.E.P., P.J.K., and Q.Z.). Common cavities were defined by an abrupt increase in esophageal pressure of at least 5 mm Hg above esophageal baseline. Pressure in the proximal esophagus during a common cavity was measured 5 cm below the lower margin of the upper esophageal sphincter (UES), whereas distal esophageal pressure during a common cavity was measured 5 cm above the proximal margin of the LES. Common cavities were classified as gastroesophageal common cavities (GECCs) if the pressurization of the esophagus occurred in association with manometric evidence of EGJ flow or esophageal common cavities (ECCs) if pressurization occurred in the context of a compartmentalized esophagus with manometric evidence of a closed EGJ. Manometric evidence of flow across the EGJ was defined by analyzing the spatial pressure variation plots at maximal resolution (40 Hz) and assessing pressure gradient changes across the EGJ. Instances in which esophageal pressure increased and the gastroesophageal pressure gradient decreased during EGJ relaxation were considered manometric evidence of flow (Figure 2). Validation of this definition is found in a previously published report11Pandolfino 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: 200-206Google Scholar using concurrent high-resolution manometry and high-resolution impedance within and across the EGJ during reflux events (Figure 2). Note that in Figure 2, manometric evidence of flow occurs simultaneously with impedance evidence of EGJ opening and liquid reflux during a tLESR. Equalization of pressure between the stomach and esophagus was defined when esophageal pressure increased to within 2 mm Hg of the gastric pressure. The trans-EGJ pressure gradient was measured at rest and during tLESRs, 0.2 seconds before the instant at which there was manometric evidence of trans-EGJ flow. The resting trans-EGJ pressure gradient was determined by subtracting the average end-expiratory esophageal pressure 2 cm proximal to the EGJ from the average end-expiratory gastric pressure 2 cm distal to the EGJ for a 30-second period before the occurrence of a tLESR. To account for EGJ movement, the trans-EGJ pressure gradient at the instant of trans-EGJ flow was measured between the transducers that were nearest 4 cm proximal and 2 cm distal to the SCJ clip. Acid reflux was defined by a decrease of intraesophageal pH to less than 4, and clearance was defined as recovery above pH 4.0. Furthermore, all pH decreases by 1 pH unit or more with a nadir pH greater than 4 but less than 7 were recorded and classified as weakly acidic. Secondary peristalsis at the termination of a tLESR was assessed using the isobaric contour tool in Manoscan (Sierra Scientific Instruments Inc.) to assess propagation of the contractile wavefront. The isobaric contour was set at 30 mm Hg to analyze peristaltic integrity and whether contractile activity was predominantly located in the distal 50% of the esophagus. Shortening of the esophagus was defined by reduced separation between the SCJ clip and the more proximal clip (or the UES) evident during replay of the videotaped fluoroscopy. Distance was calculated from the digitized videofluorographic images using the 10-mm separation between manometric sensors as a reference (Figure 3). The proximal migration of the SCJ clip before the onset of shortening and during maximal shortening were measured and correlated with the timing of the EGJ opening, common cavity if present, and acid reflux if detected. The estimated percent increase in distal esophageal muscularis propria cross-section area during the tLESR and/or ensuing secondary peristalsis (when it occurred) were calculated from the shortening data as described by Nicosia et al.12Nicosia M.A. Brasseur J.G. Liu J.B. Miller L.S. Local longitudinal muscle shortening of the human esophagus from high-frequency ultrasonography.Am J Physiol. 2001; 281: G1022-G1033Google Scholar If the resting-state segment length immediately before the initiation of the tLESR had not been imaged, the corresponding data were obtained from the ending stage when the esophagus returned to its resting state. Descriptive data for each measured parameter were expressed as median with interquartile range (IQR) for the entire tLESR data set. Comparisons of tLESRs associated with and without EGJ flow were performed by comparing the median values for each subject using Wilcoxon nonparametric studies. A total of 93 tLESRs were identified during the 2-hour postprandial recording periods (range, 9–24 tLESRs/subject). The median residual nadir pressure during tLESRs was 0.0 mm Hg (IQR, 0.0–2.0 mm Hg) and the median duration was 19.3 seconds (IQR, 15.8–24.1 s). Median percent crural inhibition, calculated by comparing the inspiratory augmentation of EGJ pressure during tLESR with that measured before the tLESR, was 90% (IQR, 70%–100%). Seventy-eight of the 93 tLESRs had manometric evidence of flow across the EGJ with pressure equalization of the distal esophagus whereas 15 had no evidence of flow. tLESRs with manometric evidence of flow had significantly longer relaxation duration than those without flow but similar median nadir pressure (Table 1). Although there was no statistical difference, it appeared that tLESRs with flow had more complete crural inhibition when compared with tLESRs without flow (Table 1). By comparison, swallowing was associated with similar nadir relaxation pressure, shorter relaxation periods, and significantly less inhibition of the crural diaphragm than observed during tLESRs (Table 1).Table 1Relaxation Characteristics of tLESRs and SwallowstLESR with manometric evidence of flow (n = 78)tLESR without manometric evidence of flow (n = 15)SwallowsNadir pressure, mm Hg0 (0–0.8)0.75 (0.1–1)1.0 (0.5–2.5)Relaxation duration, s20.1 (18.8–21.1)17.3 (12.3–19.1)aP < .05 vs with flow.6.75 (6.65–7.25)bP < .05 vs tLESRs.Median % crural inhibition95.9 (80.2–100)73.2 (66.6–78.3)22.4%bP < .05 vs tLESRs.NOTE. Median values shown (IQR), nadir LES pressure is referenced to gastric pressure.a P < .05 vs with flow.b P < .05 vs tLESRs. Open table in a new tab NOTE. Median values shown (IQR), nadir LES pressure is referenced to gastric pressure. Common cavities (GECC or ECC) were identified in 68 of the 78 tLESRs with manometric evidence of trans-EGJ flow. No common cavities were identified during tLESRs without manometric evidence of flow. The majority of common cavities (88%) were classified as GECCs (Figure 4, Figure 5), suggesting direct communication between the stomach and esophagus. These events predominantly occurred in relation to either abdominal strain events (Figure 4) during the relaxation period (27%) or during inspiration (Figure 5) when the gastroesophageal pressure gradient was flow permissive (60%). Eight tLESRs were associated with common cavities that were compartmentalized within the esophagus without direct communication with the stomach (ECCs, Figure 6). ECCs occurred during expiration, often in conjunction with EGJ and UES contraction. Sixty-nine tLESRs had evaluable pH data and 29 reflux events (9 acid; 20 weakly acidic) were recorded. All of the reflux events were recorded after a GECC and manometric evidence of trans-EGJ flow.Figure 5GECC during inspiration with detailed pressure characterization during the time interval that the common cavity is generated. Figure layout is as in Figure 4. Note that the distal esophageal segment shortens from a baseline length of 11.5 to 9.5 cm at the instant of manometric evidence of flow and 9.0 cm at the instant of maximal shortening. The instant of manometric evidence of flow (EGJ opening) and the formation of the GECC are highlighted by the first orange shaded line evidenced by an increase in distal esophageal pressure from -4 to 3 mm Hg. Propagation of the GECC into the proximal esophagus occurs in the second orange shaded line as the pressure in the proximal esophagus increases from -7 to 2 mm Hg. Note that after the EGJ opening, a flow-permissive pressure gradient exists from the stomach into the esophagus.View Large Image Figure ViewerDownload (PPT)Figure 6Example of ECC shown on an isocontour plot with detailed pressure characterization during the time interval when the ECC is generated, again using the same layout as Figure 4. Note that the formation of the ECC is shown by an increase in esophageal pressure from subatmospheric to 14 mm Hg and that this is compartmentalized within the esophagus as evident by greater pressures at the UES and EGJ.View Large Image Figure ViewerDownload (PPT) Sixty-two tLESRs had sufficient fluoroscopic visualization to accurately assess the associated SCJ movement. The pattern of SCJ clip movement mirrored movement of the high-pressure band indicative of the LES on high-resolution manometry isocontour plots (Figure 3). Esophageal shortening was most prominent in the distal segment isolated by the clips. The median maximal proximal SCJ excursion was 3.0 cm (range, 0–9 cm) whereas the proximal clip showed minimal proximal movement (1.2 cm; IQR, 1.0–2.0 cm) relative to the stationary pressure band of the UES evident on the high-resolution manometry isocontour plots (Figure 3). There were 9 instances in which proximal clip movement was 1 cm or less. The median separation between the clips during maximal SCJ excursion was 6.75 cm (IQR, 6.0–8.5 cm). Of the 62 tLESRs with fluoroscopic visualization, 52 (84%) were associated with manometric evidence of trans-EGJ flow and 47 (76%) were associated with a GECC. Two distinct patterns of esophageal shortening were noted: (1) an initial slow proximal migration of the SCJ with a rate increase of 0.36 cm/s noted at the onset of the tLESR before manometric evidence of retrograde flow and (2) more rapid proximal SCJ movement at a rate of 0.46 cm/s that occurred after a GECC (Figure 3). Manometric evidence of retrograde flow always occurred after the onset of esophageal shortening and occurred when 56% (1.7 cm; IQR, 0.5–2.5 cm) of maximal shortening was achieved. The majority of EGJ opening (GECC onset) occurred when the SCJ had moved above the crural diaphragm (71%) vs at the level of or below the crural diaphragm (29%). The median trans-EGJ pressure gradient before the occurrence of a tLESR was similar between tLESRs with and without manometric evidence of gastroesophageal flow (n = 78; median, 8.0 mm Hg; IQR, 7.0–10.0; n = 15; median, 7.0 mm Hg; IQR, 5.5–8.5, respectively). However, all of the events associated with manometric evidence of gastroesophageal flow were preceded by a positive pressure gradient between the stomach and the residual 3-cm LES pressure band tracked and measured along the SCJ excursion path (median, 7.1 mm Hg; IQR, 4.1–9.1 mm Hg measured 0.2 seconds before gastroesophageal flow) (Figure 7A), whereas none of the events without manometric evidence of flow were associated with a positive gradient (median maximum gradient achieved, -1.6 mm Hg; IQR, -3.1 to -0.9 mm Hg) (Figure 7B). Termination of the LES relaxation period during tLESRs occurred via 3 contractile mechanisms: (1) secondary peristalsis (56%) (Figure 8), (2) isolated contractions limited to the distal esophagus (17%) (Figure 9), and (3) primary peristalsis (27%) (Figure 10). The most extreme instances of esophageal shortening (and the maximal extent of shortening in 79% of instances) were associated with either secondary peristalsis or focal esophageal contractions and occurred well after the onset of the GECC as illustrated in Figure 9. In the remaining instances, maximal shortening was less extreme and was associated with the GECC.Figure 9Termination of a tLESR with an isolated contractile event limited to the distal esophagus. This focal contraction in the distal esophagus is associated with a greater degree of distal esophageal shortening compared with either primary or secondary peristalsis (Table 2).View Large Image Figure ViewerDownload (PPT)Figure 10Termination of a tLESR with primary peristalsis. In this example, the observed magnitude of esophageal shortening is similar to that observed in a normal swallow.View Large Image Figure ViewerDownload (PPT) The magnitude of the calculated increase in the muscularis propria cross-sectional area varied depending on the terminal event of the tLESR. The change in cross-sectional area was modeled for the distal esophageal segment isolated by the 2 mucosal clips, assuming that it was uniform along the length of that segment. The maximal increase in cross-sectional area occurred with isolated esophageal contractions (median, 52.7%; IQR, 26.4%–77.4 %), whereas lesser degrees were seen in association with secondary peristalsis (median, 40.0%; IQR, 25.9%–52.2 %) or primary peristalsis (median, 41.7%; IQR, 33.9%–50.0%) (Table 2).Table 2Length and Cross-Sectional Area Changes of the Distal Esophageal Segment at the Termination of tLESRsTerminating eventtLESR duration, sMaximal % shorteningMaximal % increase in cross-sectional areaPrimary peristalsis22.8 (20.7–24.4)29.4 (25.4–33.3)41.7 (33.9–50.0)Secondary peristalsis19.8 (16.15–28.15)28.9 (20.6–34.2)40.0 (25.9–52.2)Isolated distal contraction16.7 (11.25–18.4)34.1 (20.9–43.2)52.7 (26.4–77.4)NOTE. Median values shown (IQR). Open table in a new tab NOTE. Median values shown (IQR). This study examined the complex motor patterns associated with tLESR in normal subjects without hiatal hernia. Our findings suggest that EGJ opening occurs as a consequence of 3 elements of a tLESR; LES relaxation, crural diaphragm inhibition, and distal longitudinal muscle contraction (evident by esophageal shortening). Furthermore, even in conjunction with these 3 prerequisites, EGJ opening did not always occur. The fourth necessary criterion was the development of an axial pressure gradient such that pressure within the gastric lumen exceeded that within the EGJ at and proximal to the SCJ. There were several potential mechanisms for the development of that pressure gradient that variably included: abdominal straining, axial movement of the EGJ above the crural diaphragm, or inspiration. The phenomenon of esophageal shortening during tLESRs has been reported in both cat and human studies, leading to the hypothesis that shortening was related mechanistically to LES opening.4Torrance H.B. Studies on the mechanism of gastro-oesophageal regurgitation.J R Coll Surg. 1958; 4: 54-62Google Scholar, 5Sifrim D. Tack J. Zhang X. Huysmans W. Janssens J. Continuous monitoring of esophageal shortening in man during swallowing, transient LES relaxations and intraesophageal acid perfusion.Gastroenterology. 2002; 122: A188Abstract Full Text Full Text PDF Scopus (161) Google Scholar Certainly, the notion that EGJ opening is facilitated by a transmural pressure gradient achieved by repositioning the sphincter to a supradiaphragmatic position is mechanistically appealing. However, other animal and human studies have suggested that shortening occurs as a consequence of reflux rather than a preamble to it.6Martin 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-G557Google Scholar, 7Massey B. Simuncak C. Lecapitaine-Dana N.J. Pudur S. Transient LES relaxations are not the results of mechanical opening of the cardia during gastric distention.Gastroenterology. 2001; 120: A112Google Scholar, 8Shi 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 oesophageal sphincter relaxation.Neurogastroenterol Motil. 2002; 14: 505-512Google Scholar Our current findings, in fact, support both observations. Based on a large number of observations, we concluded that some degree of esophageal shortening is a necessary component of the opening mechanism in normal individuals because it was always noted to occur before manometric evidence of EGJ flow evident by a GECC. This initial shortening noted at the onset of a tLESR may represent an efferent component of the centrally mediated tLESR reflex. We also observed a more substantial degree of esophageal shortening after manometric evidence of EGJ opening, likely as a consequence of esophageal distention with a GECC, secondary peristalsis, or focal contraction of the distal esophagus. This second pattern of esophageal shortening likely is mediated through the same intramural neuromuscular control mechanism responsible for secondary peristalsis in the smooth muscle esophagus because it appears confined to the distal 10-cm segment delineated by the endoclips. EGJ opening and flow were not defined by impedance or ultrasound. Instead EGJ opening associated with flow through the EGJ during a tLESR was defined indirectly using manometric criteria. Although this is a limitation, it is difficult to imagine another scenario in which the pressure in the distal esophagus would increase and the gastroesophageal pressure gradient across the EGJ would decrease during EGJ relaxation. In this study we identified 78 instances in which we noted manometric evidence of flow during tLESRs. Of these 78 events, 60 events were followed-up closely by a GECC, suggesting that the GECC resulted from direct communication between the stomach and the esophagus. Our findings suggested that the pressure differential between gastric and residual EGJ pressure (typically about 7 mm Hg in tLESRs with EGJ opening) was a necessary prerequisite and a more important predictor of EGJ opening and common cavity generation than was the trans-sphincteric pressure gradient as has been suggested recently.13Scheffer R.C. Gooszen H.G. Hebbard G.S. Samsom M. The role of transsphincteric pressure and proximal gastric volume in acid reflux before and after fundoplication.Gastroenterology. 2005; 129: 1900-1909Abstract Full Text Full Text PDF Scopus (46) Google Scholar Furthermore, consistent with numerous observations made from intraluminal impedance studies, relatively few manometrically evident reflux events were detected by the pH electrode positioned 5 cm proximal to the EGJ, emphasizing the limited sensitivity of pH monitoring as a reflux event detector.14Shay S. Tutuian R. Sifrim D. Vela M. Wise J. Balaji N. Zhang X. Adhami T. Murray J. Peters J. Castell D. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers.Am J Gastroenterol. 2004; 99: 1037-1043Google Scholar, 15Sifrim D. Castell D. Dent J. Kahrilas P.J. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux.Gut. 2004; 53: 1024-1031Google Scholar However, pH monitoring was very specific for reflux in that every reflux event detected by the pH electrode was first evident by manometric evidence of EGJ opening with flow through the EGJ and subsequent development of a GECC. tLESRs that were associated with EGJ opening or a GECC tended to show proximal migration of the SCJ of sufficient magnitude to position the SCJ above the diaphragm at the instant of opening. This observation extends to a higher spatial and temporal resolution the findings recently reported monitoring LES–crural diaphragm separation in gastroesophageal reflux disease patients. In that ambulatory high-resolution manometric study, reflux occurred more frequently during intermittent episodes of manometrically evident LES–crural diaphragm separation.16Bredenoord A.J. Weusten B.L. Timmer R. Smout A.J. Intermittent spatial separation of diaphragm and lower esophageal sphincter favors acidic and weakly acidic reflux.Gastroenterology. 2006; 130: 334-340Google Scholar Although the mechanism by which separation was achieved was not ascertained in that investigation, it is tempting to speculate that the patients studied had laxity of their phrenoesophageal attachment, putting them somewhere in a continuum between normal and overt hiatus hernia. The current findings suggest that, in the setting of normal anatomy, conceptually similar repositioning of the EGJ occurs as a result of distal esophageal longitudinal muscle contraction. In the setting of overt hiatus hernia the component separation is pre-existent and EGJ opening may not require any longitudinal muscle contraction. In contrast, fundoplication may prevent EGJ opening by restricting proximal movement of the EGJ. Another advantage of the concurrent fluoroscopy/high-resolution manometry method used in this investigation was in the ability to reliably distinguish between events leading to EGJ opening during tLESR (discussed previously) from those that resulted from it. Events resulting from EGJ opening included secondary peristalsis (Figure 8), vigorous contractions isolated to the distal esophagus (Figure 9), and ECC (Figure 6). Parenthetically, ECCs are the likely explanation for findings recently reported by Tipnis et al17Tipnis N.A. Liu J. Puckett J.L. Mittal R.K. Common cavity pressure during gastro-esophageal reflux: reassessment using simultaneous pressure, impedance and ultrasound imaging.Am J Physiol. 2006; 290: G1149-G1156Google Scholar in a study using concurrent manometry, impedance, and intraluminal ultrasound. Those investigators hypothesized that, rather than being indicative of reflux, common cavity could be secondary to compliance and volume changes induced by esophageal longitudinal muscle shortening. Although this was a novel concept, without concurrent EGJ pressure recordings those investigators could not differentiate between the ECCs they studied and the more frequent GECCs that are indicative of reflux. Another ultrasound finding, perhaps explained by the current investigations, is sustained esophageal contractions.18Pehlivanov N. Liu J. Mittal R.K. Sustained esophageal contraction: a motor correlate of heartburn symptom.Am J Physiol. 2001; 281: G743-G751Google Scholar, 19Bhalla V. Liu J. Puckett J.L. Mittal R.K. Symptom hypersensitivity to acid infusion is associated with hypersensitivity of esophageal contractility.Am J Physiol. 2004; 287: G65-G71Google Scholar The occasional isolated distal esophageal contractions (Figure 9) observed as a consequence of some tLESRs with reflux result in profound, relatively prolonged shortening and our calculations (Table 2) suggest that these likely would meet criteria for sustained esophageal contractions seen with intraluminal ultrasound.18Pehlivanov N. Liu J. Mittal R.K. Sustained esophageal contraction: a motor correlate of heartburn symptom.Am J Physiol. 2001; 281: G743-G751Google Scholar In conclusion, this investigation used concurrent fluoroscopy and high-resolution manometry to investigate the mechanism of EGJ opening during the postprandial period in normal subjects. The key events leading to EGJ opening were LES relaxation, crural diaphragm inhibition, distal esophageal longitudinal muscle contraction, and the generation of positive pressure gradient between the stomach and the lumen of the EGJ. The manometric signature of opening was of pressure equalization within the EGJ, extending proximally into the esophageal lumen to varying degrees, but only occasionally associated with pH electrode evidence of reflux. Future investigations will need to analyze how this delicately balanced anatomic–physiologic system is perturbed in subjects with varying degrees of reflux disease. The authors would like to thank Dr Ray E. Clouse (Washington University School of Medicine, St. Louis, MO) for his intellectual contributions in refining the analysis of high resolution manometry and for critiquing the paradigms for the analysis of sphincter function presented herein. The authors also wish to thank Dr Tom Parks (Sierra Scientific Instruments Inc., Los Angeles, CA) for extensive technical assistance with respect to the design and function of the manometry hardware used for this study.
Referência(s)