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Effect of prolonged gastric distention on lower esophageal sphincter function and gastroesophageal reflux
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2003 by Am. Coll. of Gastroenterology Published by Elsevier Inc.
Vol. 98, No. 8, 2003 ISSN 0002-9270/03/$30.00 doi:10.1016/S0002-9270(03)00437-4
Effect of Prolonged Gastric Distention on Lower Esophageal Sphincter Function and Gastroesophageal Reflux D. P. Hirsch, M.D., Ph.D., E. M. H. Mathus-Vliegen, M.D., Ph.D., U. Dagli, M.D., G. N. J. Tytgat, M.D., Ph.D., and G. E. E. Boeckxstaens, M.D., Ph.D. Division of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
OBJECTIVES: Morbidly obese patients treated with an intragastric balloon report a transient increase in gastroesophageal reflux (GER) symptoms. In the present study, we evaluated the underlying mechanisms of GER and examined the effect of prolonged gastric distention on lower esophageal sphincter function. METHODS: Fasting and postprandial manometric studies were performed in obese subjects (n ⫽ 15) before, immediately after, and 10 and 20 wk after placement of a 500-ml water-filled balloon. RESULTS: Residual lower esophageal sphincter (LES) pressure after water swallows was not affected after balloon placement, excluding mechanical interaction with sleeve function. Postprandial LES pressure was significantly increased after 10 and 20 wk. GER was increased in the right recumbent position until 10 wk after balloon placement, mainly because of an increased percentage of transient lower esophageal sphincter relaxations (TLESRs) accompanied by GER. TLESRs were the main mechanisms underlying reflux both before and after balloon placement. The rate of TLESRs was increased significantly immediately after introduction of the balloon, returning to baseline values after 20 wk. After balloon placement, reflux episodes were evoked by gastric contractions that were not inhibited by meals. CONCLUSIONS: Chronic distention by an intragastric balloon increased reflux up to 10 wk after placement because of an increase in the percentage of TLESRs accompanied by a reflux episode. In addition, prolonged balloon distention increased the rate of TLESRs and created a postprandial state even 10 wk after balloon placement. After 20 wk these effects largely resolved, illustrating adaptation to this artificial situation. (Am J Gastroenterol 2003;98:1696 –1704. © 2003 by Am. Coll. of Gastroenterology)
INTRODUCTION Gastroesophageal reflux disease (GERD) is a common disorder, with heartburn, retrosternal pain, and regurgitation as the main symptoms (1). These symptoms are evoked by
acidic gastric contents crossing the lower esophageal sphincter (LES) and subsequently irritating the esophageal mucosa. The LES is the main barrier against gastroesophageal reflux (GER), and it has traditionally been throught that a persistently low LES pressure was the main mechanism underlying reflux. However, it is now well established that both GERD patients and healthy volunteers have GER primarily during transient relaxations of the LES (TLESRs) (2, 3). A TLESR is a period of prolonged and complete relaxation of the LES that is not associated with swallowing (4). The abrupt relaxation of the LES is a preprogrammed motor action that is located in the brainstem and that is triggered by distention of the stomach wall. After a meal, the rate of TLESRs is increased, presumably by distention of the proximal stomach (5). The rate of TLESRs can also be increased artificially by distending the stomach with free air or an intragastric balloon (6, 7). Upon distention of the stomach wall, mechanoreceptors are activated, sending information via vagal afferents to the medulla oblongata. The visceral information is processed in the medulla oblongata, and subsequently vagal efferent neurons are activated, relaxing the LES (8, 9). To reduce weight, morbidly obese patients are treated with a water-filled intragastric balloon (10). The intragastric balloon is thought to exert its action by occupying a large volume of the stomach. This should theoretically result in a decreased capacity to store food and subsequently to result in early satiety, a reduction in caloric intake, and ultimately weight loss. This balloon is introduced endoscopically and remains in the stomach for at least 20 wk. On average, this results in a weight reduction of 26 kg (10, 11). However, immediately after balloon placement such patients experience severe reflux, in some cases necessitating removal of the balloon (12, 13). In the remaining patients, GER was increased up to 13–26 wk after balloon placement and slowly declined in time (13). Although the effect of acute gastric distention on LES function is well established, the effect of the prolonged distention by an intragastric balloon on LES function and the mechanisms underlying the increase in GER are unknown. We hypothesized that this
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balloon, with a content of 500 ml, would continuously distend the stomach and would represent a human model of chronic distention. Therefore, the present study was designed to evaluate prospectively the effect of prolonged gastric distention on LES function, especially on the rate of TLESRs and reflux.
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Intragastric Balloon The intragastric balloon (Bio Enterics, Santa Barbara, CA) is composed of smooth silicon with radiopaque markings. Using an insertion system, the balloon is introduced orally and positioned in the stomach. The balloon is filled via the filling catheter with 500 ml of sterile saline under endoscopic view. The filling catheter is subsequently removed with a short pull.
MATERIALS AND METHODS Subjects Eighteen consecutive, morbidly obese subjects with an average age of 34 yr (range 21–56 yr) and a mean body mass index of 42 ⫾ 1 kg/m2 were included in the study. To minimize the number of study days, three groups were created: one group (n ⫽ 6) was only studied before, immediately after balloon placement and at 10 wk; the second group (n ⫽ 6) was studied before and at 10 and 20 wk; and a third group (n ⫽ 6) was also studied before and at 10 and 20 wk, but only postprandially. Although the balloon was well tolerated in the majority of the patients, two subjects experienced sustained severe pyrosis, vomiting, and abdominal cramping, for which the balloon had to be removed prematurely. Because of abdominal cramping, a third subject could only be studied during the fasting right recumbent period after 10 wk. These subjects, one from each study group, were excluded for analysis of the effect of prolonged gastric distention. Subjects did not take any medication known to interact with GI motility. Gastric acid suppressive therapy, if used, was stopped at least 5 days before the studies. Each subject gave written informed consent, and the study was approved by the Medical Ethical Committee of the Academic Medical Center of Amsterdam. Esophageal Manometry Manometric recordings were performed using a 10-lumen assembly that incorporated a sleeve sensor at its distal end to monitor LES pressure (Dentsleeve, Belair, South Australia). Side holes monitored pressure in the stomach (1 cm below the distal margin of the sleeve) and at 2, 5, 8, 11, 14, 17, and 20 cm above the LES. A side hole in the pharynx monitored swallows. The gastric and esophageal side holes were perfused at 0.3 ml/min and the sleeve at 0.6 ml/min with degassed distilled water by a pneumohydraulic capillary perfusion pump (Dentsleeve). The pharyngeal side hole was perfused by air at 0.3 ml/min to reduce pharyngeal triggering of TLESRs (14). Pressures were sensed by external transducers connected to a polygraph (Synectics Medical, Stockholm, Sweden). Intraesophageal pH was monitored using a one-sensor, monocrystalline antimony pH electrode (Synectics Medical). The pH probe was calibrated at pH 1 and 7 using standard buffer solutions (Synectics Medical). Signals were digitized, computer-processed, and stored using commercially available software (Polygram for Windows, Synectics Medical).
Study Design Subjects were studied before, immediately after, and 10 and 20 wk after balloon placement. All subjects attended the laboratory at 8:30 AM after an overnight fast. The manometric assembly and pH electrode were passed through an anesthetized nostril and positioned with the sleeve straddling the LES. The pH probe was positioned 5 cm above the upper margin of the LES. Acute Study In previous studies, the majority of the subjects experienced severe nausea, abdominal cramping, and vomiting immediately after balloon placement, making recording difficult and uncomfortable for the subjects. Therefore, only six subjects were asked to participate in an acute study design. Subjects arrived at 8 AM after an overnight fast. To prevent interference of sedation and inflated air during endoscopic placement, the balloon was positioned orally without endoscopic guidance. The position of the unfolded balloon was controlled using fluoroscopy. When the balloon was located in the stomach, the balloon was slowly filled with 500 ml of saline under fluoroscopic control. After complete filling, the filling catheter was removed with a short pull. The recordings of the subjects in the acute study were started within 30 min after balloon placement. In this group, esophageal motility and pH were recorded during 60 min in the right recumbent position, and no meal was given. Studies Before and 10 and 20 wk After Balloon Placement After an overnight fast, the subjects arrived at the laboratory at 8:30 AM. After 10 and 20 wk, the subjects arrived at 8 AM and a plain abdominal x-ray was taken in the upright and supine position to determine the location of the balloon. The esophageal manometry catheter and pH electrode were positioned as described above. Because the balloon is free to move, the body position of the subjects may influence the location of the balloon and subsequently may affect LES function and GER. Therefore, after a 10-min adaptation period, subjects were studied for 60 min in the right recumbent and for 60 min in the sitting position (before, n ⫽ 11; at 10 wk, n ⫽ 11; at 20 wk, n ⫽ 5). The order of the sitting and right recumbent position was randomized. To assess possible mechanical interference of the balloon with LES relaxation and sleeve function, subjects swallowed 5 ml of water 10 times. Subsequently, subjects consumed a pancake (650 kcal) in the sitting position and were studied in the
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right recumbent position for an additional 120 min (before, n ⫽ 18; at 10 wk, n ⫽ 15; at 20 wk, n ⫽ 10). Data Analysis LES Pressure. LES pressure was measured at end-expiration relative to intragastric pressure. Basal LES pressure was determined as visual means of 1-min periods every 15 min. The average was calculated for the fasting recording in the right recumbent and sitting position and the postprandial period. Residual LES pressure after a 5-ml water swallow was calculated at the nadir of the relaxation, and the average was calculated for the 10 water swallows. TLESRs. TLESRs were scored according to previously published criteria (4): 1) absence of swallowing for 4 s before to 2 s after the onset of LES relaxation, 2) relaxation rate of ⱖ1 mm Hg/s, 3) time from onset to complete relaxation of ⱕ10 s, and 4) nadir pressure of ⱕ2 mm Hg. LES relaxations associated with a single swallow and fulfilling criteria 2– 4 and a duration of ⬎10 s were classified as TLESRs. TLESRs were counted for each subject during the fasting recording in the right recumbent (60 min) and sitting (60 min) position and during the first and second postprandial hour. In addition, the percentage of TLESRs accompanied by a reflux episode was determined. Furthermore, the increase in TLESRs and the percentage of TLESRs accompanied with reflux by the meal was determined. GER. A decrease in esophageal pH was scored as a reflux episode if the pH drop was ⬎1 pH unit and lasted ⱖ10 s. The mechanism underlying each reflux episode was characterized as follows: TLESR, swallow-associated, a period of sustained absence of LES pressure (ⱕ5 mm Hg), a period of apparently stable LES pressure (⬎5 mm Hg), associated with an intragastric pressure rise, or not interpretable. The duration of all pH drops to ⬍4 was calculated, and the percentage of total time at pH ⬍4 was determined. In addition, the increase in reflux and percentage of the time that pH was ⬍4 by the meal was determined. Statistical Analysis The subjects participating in the acute experiments experienced acute severe nausea immediately after balloon placement. As a consequence, some studies had to be stopped prematurely. In that case, the number of recorded events (TLESRs, reflux episodes) was divided by the recording period (ranging from 32 to 55 min) and multiplied by 60 min to normalize the data. At 20 wk, only five subjects were studied in the fasting period. As this number is too small for statistical analysis, these data are only described but were not statistically analyzed. Data are presented as median and interquartile range. The effect of the intragastric balloon in time on LES function and reflux was evaluated using a general linear model with repeated measurements. Wilcoxon matched pairs, signed rank tests and 2 tests were used. A p value ⬍ 0.05 was considered to be statistically significant.
Figure 1. Plain abdominal x-ray film immediately after placement of intragastric balloon. Note the large volume of stomach being occupied by the balloon. A coin 25 mm in diameter is attached at the level of the sternum to illustrate actual size of the balloon.
RESULTS Subjects The balloon was positioned in the stomach in all 18 subjects without difficulty. After being filled with 500 ml of saline, the balloon occupied a large volume of the stomach, as shown in Figure 1. During the day of balloon placement, most subjects developed severe pyrosis (89%), nausea (83%), vomiting (89%), abdominal cramping (72%), and belching (89%). After 10 wk 50% of the subjects still reported belching and 38% pyrosis. Interestingly, 25% could feel the balloon moving in the stomach. After 20 wk symptoms were further reduced, and only 20% of subjects reported belching and pyrosis. After 10 wk subjects lost 9 ⫾ 1 kg (p ⬍ 0.05); however their weight was not further reduced after 20 wk (total weight reduction 12 ⫾ 1 kg). Effect of Intragastric Balloon on LES Function and GER Fasting LES Function. To evaluate the possible interference of the balloon with sleeve function, we first evaluated the effect of the balloon on water swallow–induced LES relaxation. Before balloon placement, residual LES pressure was 2 mm Hg (range 0 –3 mm Hg). At 10 and 20 wk after balloon placement, residual LES pressure was 2 mm Hg (range 0 –3 mm Hg) and 1 mm Hg (range 0 –2 mm Hg), respectively, which was not statistically different from before. This indicates that LES relaxation was preserved and that the balloon did not mechanically interact with sleeve function. The fasting LES pressure before balloon placement was 14 mm Hg (range 8 –24 mm Hg). Immediately after introduction of the balloon, fasting LES pressure was 16 mm Hg (range 11–25 mm Hg) and did not differ from before. At 10
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Figure 2. Effect of acute and prolonged gastric distention on (A) rate of TLESRs and (B) percentage of TLESRs accompanied by a reflux episode during fasting period in right recumbent position before (n ⫽ 11), during (n ⫽ 6), and 10 wk (n ⫽ 11) and 20 wk (n ⫽ 5) after balloon placement. Results are shown as median and interquartile range. *p ⬍ 0.05.
wk after balloon placement, fasting LES pressure was 29 mm Hg (range 12–36 mm Hg), and after 20 wk was 22 mm Hg (range 15–34 mm Hg). Fasting TLESRs and Percentage of TLESRs WITH GER. Under fasting conditions, 3.0 n/h (range 2.0 –7.0 n/h). TLESRs were recorded before the balloon was introduced. Immediately after balloon placement, the rate of TLESRs was significantly increased to 9.4 n/h (7.7–12.1n/h (Fig. 2A). At 10 wk after balloon placement the rate of TLESRs was 6.0 n/h (range 2.0 – 6.0 n/h. Only at 20 wk did the rate of TLESRs return to baseline levels (Fig. 2A). Before balloon placement, 31% (range 15– 49%) of the TLESRs were accompanied by a reflux episode. At 10 wk after balloon placement, this percentage increased to 100% (range 63– 100%; p ⬍ 0.05), and after 20 wk it was 67% (range 25–100%) (Fig. 2B). Fasting GER. The number of reflux episodes was low before balloon placement at 1.0 n/h (range 0 –3.0n/h), with a
pH of ⬍4 during 1% (range 0 –2%) of the recording period (Fig. 3A). The rate of reflux episodes and the percentage of time that pH ⬍4 were not increased significantly immediately after balloon placement. At 10 wk after placement, however, the number of reflux episodes was significantly increased to 5.0 n/h (range 2.0 – 6.0 n/h; p ⬍ 0.05), although the percentage of time that pH was ⬍4 (9%, range 6 –10%) was not increased. At 20 wk, both the rate of reflux episodes and the percentage of time that pH was ⬍4 had returned to baseline values (Fig. 3B). Effect of Body Position While Fasting. Before balloon placement, body position had no effect on LES pressure, rate of TLESRs, percentage TLESRs with reflux, rate of reflux episodes, and percentage of time that pH was ⬍4. In contrast, at 10 and 20 wk, the percentage of TLESRs accompanied with reflux was significantly increased during the right recumbent but not the sitting position (Fig. 4A). Similarly, at 10 wk, the increase in the rate of reflux epi-
Figure 3. Effect of acute and prolonged gastric distention on (A) rate of reflux episodes and (B) percentage of time that pH was ⬍4 during fasting in recumbent position, before (n ⫽ 11), during (n ⫽ 6), and 10 wk (n ⫽ 11) and 20 wk (n ⫽ 5) after balloon placement. Results are shown as median and interquartile range. *p ⬍ 0.05.
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Figure 4. Effect of body position on (A) percentage of TLESRs with reflux and (B) rate of reflux episodes in the fasting period before (open bars) and at 10 wk (hatched bars) and 20 wk (filled bars) after balloon placement. Results are shown as median and interquartile range. *p ⬍ 0.05.
sodes (Fig. 4B) and the percentage of time that pH was ⬍4 (data not shown) were observed only in the right recumbent position. After 10 wk, no reflux episodes were recorded in the sitting position. Postprandial LES Function. Before placement of the balloon, LES pressure decreased from 14 mm Hg (range 8 –24 mm Hg) to a minimum of 7 mm Hg (range 3–13 mm Hg) during the postprandial recording period (p ⬍ 0.05). At 10 and 20 wk after balloon placement, postprandial LES pressure was significantly higher at 22 mm Hg (range 13–38 mm Hg; p ⬍ 0.05) and 21 mm Hg (range 9 –26 mm Hg; p ⬍ 0.05), respectively. In addition, the postprandial decrease in LES pressure was attenuated. Postprandial TLESRs and Percentage of TLESRs with GER. Before balloon placement, ingestion of the meal resulted in a significant increase in the rate of TLESRs during
the first hour (6 n/h [range 4.8 –7.3 n/h], p ⬍ 0.05) but not during the second hour (4.0 n/h [range 2.0 – 4.5 n/h]) compared with fasting in the right recumbent position (3.0 n/h [range 2.0 –7.0 n/h]) (Fig. 5A). Furthermore, the percentage of TLESRs accompanied by a reflux episode was significantly increased in the postprandial period (p ⬍ 0.05) (Fig. 5B). At 10 wk, ingestion of the meal did not further increase the rate of TLESRs or the percentage TLESRs accompanied by a reflux episode (Fig. 5A, 5B). The rate of TLESRs and the percentage TLESRs accompanied by reflux in the postprandial period were not significantly different compared with values before balloon placement (Fig. 5A, 5B). At 20 wk, ingestion of the meal again resulted in an increase in the rate of TLESRs during the first hour (p ⬍ 0.05) (Fig. 5A). The percentage of TLESRs accompanied by a reflux episode was not increased after the meal.
Figure 5. Effect of meal ingestion on (A) rate of TLESRs, (B) percentage of TLESRs accompanied by a reflux episode, and (C) rate of reflux episodes in right recumbent position during fasting period (open bars) and postprandial periods (hatched bars, first hour of postprandial period; filled bars, second hour of posprandial period). Results are shown as median and interquartile range. *p ⬍ 0.05.
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Figure 6. Mechanisms underlying reflux episodes. Fasting and postprandial data are summated as follows: TLESR, swallow, low (ⱕ5 mm Hg) and high (⬎5 mm Hg) LES pressure, intragastric pressure wave (IPW), not interpretable (NI). Before balloon placement (open bars) and at 10 wk (hatched bars) and 20 wk (filled bars) after balloon placement.
Postprandial GER. Before placement of the balloon, ingestion of the meal resulted in a significant increase in the rate of reflux episodes and the percentage of time that pH was ⬍4 (p ⬍ 0.05). At 10 wk after balloon placement, the rate of reflux episodes (Fig. 5C) and the percentage of time that pH was ⬍4 were increased and equaled postprandial values during the fasting recumbent period (p ⬍ 0.05). Ingestion of the meal did not further increase the rate of reflux episodes and the percentage of time that pH was ⬍4 (Fig. 5). At 20 wk, the percentage of time that pH was ⬍4 was increased after the meal (p ⬍ 0.05). In all, 78% of all reflux episodes (n ⫽ 581 total) occurred during the postprandial period. Because the distribution of each mechanism was not influenced by the meal or by body position, the episodes during the fasting and postprandial recording period were summated. TLESRs were the main mechanism underlying GER both before (70%) and after balloon placement (10 wk, 75%; 20 wk, 65%) (Fig. 6). Gastric pressure waves accounted for 9% and 14% of the reflux episodes at 10 and 20 wk after balloon placement, as discussed below.
Meal Intake. Before placement of the balloon, most subjects consumed the entire pancake. After balloon placement, subjects experienced early satiety and were able to consume significantly less of the pancake (10 wk, 61% [range 46 – 84%] of the pancake; 20 wk, 55% [range 43– 88%] of the pancake). At 10 and 20 wk after balloon placement, there was no relationship between the percentage of the meal consumed and LES pressure (r ⫽ ⫺0.3, p ⫽ 0.27), rate of TLESRs (r ⫽ ⫺0.4, p ⫽ 0.1), percentage of TLESRs with reflux (r ⫽ ⫺0.4, p ⫽ 0.17), rate of reflux (r ⫽ ⫺0.5, p ⫽ 0.07), and percentage of time that pH was ⬍4 (r ⫽ ⫺0.3, p ⫽ 0.24) (data not shown). Effect of Intragastric Balloon on Gastric Pressure In all subjects, pressure waves were recorded in the gastric and sleeve channel during the fasting recording period. The pressure waves occurred episodically and had a phase III– like appearance (Fig. 7A). These rises in intragastric pressure were not accompanied by a reflux episode and resolved after ingestion of the meal (Fig. 7B). In contrast, at 10 and 20 wk after balloon placement, the episodes of contractile
Figure 7. Typical tracing with intragastric pressure recordings in the fasting (A) and postprandial (B) recording periods. Same individual at 10 wk after balloon placement before (C) and after (D) meal ingestion. Horizontal lines indicates baseline.
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Figure 8. Typical tracing showing a phasic gastric pressure wave accompanied by a reflux episode (A) and a TLESR with reflux (B). Horizontal line indicates baseline.
activity lasted 45 min (range 31– 60 min) at 10 wk and 30 min (range 18 – 43 min) at 20 wk, which was significantly longer than before (Fig. 7C). In addition, in 80% and 70% of the subjects at 10 and 20 wk, respectively, intragastric pressure waves persisted during the postprandial period (Fig. 7D). Although, on average, meal intake was reduced after 10 and 20 wk, no relationship was found between the occurrence of pressure waves and the percentage of the meal ingested. Furthermore, in contrast to values before balloon placement, 40% of the patients had one or more periods of GER associated with a gastric pressure wave in the fasting and 33% in the postprandial period (Fig. 8A). Of these contractions, 49% were associated with a swallow, and 31% of these contractions were immediately followed by a TLESR with reflux (Fig. 8B). Balloon Location and Body Position Radiological studies showed that immediately after balloon placement, the balloon was located in the fundic region in five subjects and in the corporal region in one subject. At 10 wk, the balloon was in the fundic region in 31% of the patients in the supine position and in 21% in the upright position, with the remainder in the corporal region. After 20 wk, the balloon was in the fundic region in 67% of the patients when supine and in 33% when upright. There was no relationship between the location of the balloon and LES pressure, rate of TLESRs, percentage TLESRs with reflux, rate of reflux episodes, and percentage of time that pH was ⬍4.
DISCUSSION Endoscopic placement of an intragastric balloon is one of a number of treatments to reduce weight in morbidly obese patients (10). This treatment, however, is often accompanied
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by increased symptoms of GER. In the present study, we confirmed the increase in reflux and clarified the mechanisms underlying this increase, showing that this increase results mainly from an increase in the percentage of TLESRs accompanied by reflux. We further illustrated that prolonged balloon distention can increase the rate of TLESRs and can create a postprandial state even 10 wk after balloon placement. After 20 wk, these effects largely resolve, illustrating adaptation to this artificial situation. GER with symptoms of heartburn, retrosternal pain, and even esophagitis have been reported in obese patients treated with intragastric balloons (11, 13). In the present study, approximately 40% of the subjects complained of heartburn (especially in the first 10 wk), leading to removal of the balloon in three patients. In the remaining subjects, the balloon induced GER, as shown by the increased number of reflux events. One of the possible mechanisms underlying this increase in GER could be interference of the balloon with LES function, leading to lowered LES pressure. However, LES pressure was even significantly increased after balloon placement, thereby excluding this possibility. Furthermore, swallow-induced relaxation remained unaffected, illustrating preserved LES function and excluding mechanical interaction by the balloon with sleeve function. Interestingly, we noticed an increased percentage of TLESRs accompanied by a reflux episode. This finding is similar to that reported in patients with GERD. Although controversy exists whether the rate of TLESRs is increased in patients with GERD, evidence clearly illustrates that the percentage of reflux during TLESRs is increased in such patients (3, 15–19). The exact mechanisms underlying this observation are still unclear, although the increase in the percentage of TLESRs accompanied by reflux was especially seen in the right recumbent position, suggesting that body position might play an important role. Indeed, previous studies have also reported a significantly increase in reflux during the right compared with the left recumbent position, because of an increase in TLESRs and the percentage of TLESRs accompanied by a reflux episode (20 – 22). This indicates that distribution of intragastric contents may play an important role in the pathogenesis of reflux. By occupying a large volume of the stomach, the intragastric balloon might have resulted in pooling of intragastric contents in the cardiac region during the right recumbent position. One could speculate that this might have triggered TLESRs or increased the risk and the volume of refluxate during a TLESR. Comparable to acute distention of the stomach using free air or a barostat balloon (6, 7), the rate of TLESRs drastically increased immediately after balloon placement. The increased rate of TLESRs most likely results from gastric distention, a well known trigger of TLESRs. Radiographic studies indeed showed that the balloon largely filled the stomach, preferentially the proximal part. The rate of TLESRs was comparable to the rates observed during acute distention by air insufflation or barostat distention. In these
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experiments, the stomach rapidly adapts to distention within 15 min (6, 23). Surprisingly, in the present study, even after 10 wk, the fasting rate of TLESRs was still increased, although not statistically significantly. Adaptation with return to a comparable rate of TLESRs as before balloon placement was only obtained after 20 wk. Although we have no explanation for this observation, one might speculate that the balloon shifted between the corpus and the fundus of the stomach, thereby delaying adaptation. Some patients indeed reported a sensation of movement of the balloon up and down. Whether this adaptation to distention explains or contributes to the symptomatic improvement observed over time also remains speculative. It is interesting, however, to note that most of the weight is lost during the first 10 wk, when adaptation is incomplete and the balloon still induces a postprandial condition. The cardiac region is believed to have the lowest threshold for TLESRs (8). The position of the balloon could have influenced the number of TLESRs observed. At 20 wk after placement, 67% of the balloons were localized in the fundic region, compared with 31% at 10 wk. Inasmuch as the cardiac region is the most sensitive part of the stomach, one would expect a higher rate of TLESRs; however, after 20 wk, the rate of TLESRs was returned to predistention levels. Furthermore, analysis showed that there was no relationship between the localization of the balloon and the number of TLESRs observed, illustrating that balloon position had no major impact. After 10 wk, the fasting rates of TLESRs and reflux parameters reached values comparable to those observed in the postprandial period before balloon placement. Ingestion of a meal did not further increase these values above those before balloon placement, which might have been explained by the reduction in meal intake after 10 and 20 wk. There was, however, no relation between the percentage of the meal consumed and LES pressure, rate of TLESRs, percentage of TLESRs with reflux, rate of reflux episodes, and percentage of time that pH was ⬍4. These findings suggest that the intragastric balloon induced a “postprandial” situation during the fasting state by occupying a large volume of the stomach. This should theoretically result in a decreased capacity to store food and subsequently result in early satiety, a reduction in caloric intake, and, ultimately, weight loss. Indeed, meal ingestion and body weight were significantly decreased after balloon placement. Finally, gastric pressure waves were recorded that were different from gastric contractions observed during phases II and III of the interdigestive motor pattern. Similar irregular contractions were previously reported during gastric distention in a canine model, suggesting that this motor pattern is another compensatory mechanism of the stomach to this artificial condition of chronic distention (24, 25). In conclusion, we showed that the increase in GER after prolonged balloon placement resulted from a transient increase in the percentage of TLESRs associated with GER. We further illustrated that prolonged balloon distention can
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increase the rate of TLESRs and can create a postprandial state, even 10 wk after balloon placement. After 20 wk these effects largely resolve, illustrating adaptation to this artificial situation.
ACKNOWLEDGMENTS This work was supported by the Netherlands Digestive Diseases Foundation grant WS 97-28 (to D.P.H.). Reprint requests and correspondence: Guy E. E. Boeckxstaens, M.D., Ph.D., Academic Medical Center, Division of Gastroenterology and Hepatology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Received June 11, 2002; accepted Apr. 14, 2003.
REFERENCES 1. Heading RC. Prevalence of upper gastrointestinal symptoms in the general population: A systematic review. Scand J Gastroenterol 1999;231(suppl):3–8. 2. Dent J, Dodds WJ, Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980;65:256 –67. 3. Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982;307:1547–52. 4. Holloway RH, Penagini R, Ireland AC. Criteria for objective definition of transient lower esophageal sphincter relaxation. Am J Physiol 1995;268:G128 –38. 5. Holloway RH, Kocyan P, Dent J. Provocation of transient lower esophageal sphincter relaxations by meals in patients with symptomatic gastroesophageal reflux. Dig Dis Sci 1991; 36:1034 –9. 6. Boeckxstaens GE, Hirsch DP, Fakhry N, et al. Involvement of cholecystokinin-A receptors in transient lower esophageal sphincter relaxations triggered by gastric distension. Am J Gastroenterol 1998;93:1823–8. 7. Holloway RH, Hongo M, Berger K, et al. Gastric distension: A mechanism for postprandial gastroesophageal reflux. Gastroenterology 1985;89:779 –84. 8. Franzi SJ, Martin CJ, Cox MR, et al. Response of canine lower esophageal sphincter to gastric distension. Am J Physiol 1990; 259:G380 –5. 9. Mittal RK, Holloway RH, Penagini R, et al. Transient lower esophageal sphincter relaxation. Gastroenterology 1995;109: 601–10. 10. Mathus-Vliegen EMH. Efficacy in bioenterics balloon treatment in a prospective 2-year follow-up study. Int J Obesity 1997;21(suppl 2):S67. 11. Mathus-Vliegen EMH, Tytgat GNJ. A newly designed intragastric balloon: Results, safety and tolerance in treatment refractory obese patients. (Submitted for publication.). 12. Mathus-Vliegen EMH. Tolerance and safety of bioenterics intragsatric balloons. Int J Obesity 2000;21(suppl 2):S66. 13. Mathus-Vliegen EM, Tygat GN. Gastro-oesophageal reflux in obese subjects: Influence of overweight, weight loss and chronic gastric balloon distension. Scand J Gastroenterol 2002;37:1246 –52. 14. Mittal RK, Chiareli C, Liu J, et al. Characteristics of lower esophageal sphincter relaxation induced by pharyngeal stimulation with minute amounts of water. Gastroenterology 1996; 111:378 –84.
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15. Mittal RK, McCallum RW. Characteristics and frequency of transient relaxations of the lower esophageal sphincter in patients with reflux esophagitis. Gastroenterology 1988;95: 593–9. 16. Schoeman MN, Tippett M, Akkermans LMA, et al. Mechanisms of gastroesophageal reflux in ambulant healthy human subjects. Gastroenterology 1995;108:83–91. 17. Penagini R, Mangano M, Bianchi PA. Effect of increasing the fat content but not the energy load of a meal on gastrooesophageal reflux and lower oesophageal sphincter motor function. Gut 1998;42:330 –3. 18. Sifrim D, Holloway R, Silny J, et al. Composition of the postprandial refluxate in patients with gastroesophageal reflux disease. Am J Gastroenterol 2001;96:647–55. 19. Trudgill NJ, Riley SA. Transient lower esophageal sphincter relaxations are no more frequent in patients with gastroesophageal reflux disease than in asymptomatic volunteers. Am J Gastroenterol 2001;96:2569 –74.
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20. Herwaarden MA, Katzka D, Smout AJPM, et al. Underlying mechanisms responsible for the higher incidence of esophageal reflux in the right supine body position. Eur J Gastroenterol Hepatol 1999;11:A108. 21. Katz LC, Just R, Castell DO. Body position affects recumbent postprandial reflux. J Clin Gastroenterol 1994;18:280 –3. 22. Pattrick FG. Investigation of gastroesophageal reflux in various positions with a two-lumen pH electrode. Gut 1970;11: 659 –67. 23. Alloca M, Mangano M, Bianchi PA, et al. Rate of transient lower esophageal sphincter relaxations during prolonged gastric distension. Gastroenterology 1999;116:A111. 24. Grundy D, Hutson D, Rudge LJ, et al. Pre-pyloric mechanisms regulating gastric motor function in the conscious dog. Q J Exp Physiol 1989;74:857–65. 25. Azpiroz F, Malagelada JR. Pressure activity patterns in the canine proximal stomach: Response to distension. Am J Physiol 1984;247:G265–72.
Vol. 98, No. 8, 2003 ISSN 0002-9270/03/$30.00 doi:10.1016/S0002-9270(03)00437-4
Effect of Prolonged Gastric Distention on Lower Esophageal Sphincter Function and Gastroesophageal Reflux D. P. Hirsch, M.D., Ph.D., E. M. H. Mathus-Vliegen, M.D., Ph.D., U. Dagli, M.D., G. N. J. Tytgat, M.D., Ph.D., and G. E. E. Boeckxstaens, M.D., Ph.D. Division of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
OBJECTIVES: Morbidly obese patients treated with an intragastric balloon report a transient increase in gastroesophageal reflux (GER) symptoms. In the present study, we evaluated the underlying mechanisms of GER and examined the effect of prolonged gastric distention on lower esophageal sphincter function. METHODS: Fasting and postprandial manometric studies were performed in obese subjects (n ⫽ 15) before, immediately after, and 10 and 20 wk after placement of a 500-ml water-filled balloon. RESULTS: Residual lower esophageal sphincter (LES) pressure after water swallows was not affected after balloon placement, excluding mechanical interaction with sleeve function. Postprandial LES pressure was significantly increased after 10 and 20 wk. GER was increased in the right recumbent position until 10 wk after balloon placement, mainly because of an increased percentage of transient lower esophageal sphincter relaxations (TLESRs) accompanied by GER. TLESRs were the main mechanisms underlying reflux both before and after balloon placement. The rate of TLESRs was increased significantly immediately after introduction of the balloon, returning to baseline values after 20 wk. After balloon placement, reflux episodes were evoked by gastric contractions that were not inhibited by meals. CONCLUSIONS: Chronic distention by an intragastric balloon increased reflux up to 10 wk after placement because of an increase in the percentage of TLESRs accompanied by a reflux episode. In addition, prolonged balloon distention increased the rate of TLESRs and created a postprandial state even 10 wk after balloon placement. After 20 wk these effects largely resolved, illustrating adaptation to this artificial situation. (Am J Gastroenterol 2003;98:1696 –1704. © 2003 by Am. Coll. of Gastroenterology)
INTRODUCTION Gastroesophageal reflux disease (GERD) is a common disorder, with heartburn, retrosternal pain, and regurgitation as the main symptoms (1). These symptoms are evoked by
acidic gastric contents crossing the lower esophageal sphincter (LES) and subsequently irritating the esophageal mucosa. The LES is the main barrier against gastroesophageal reflux (GER), and it has traditionally been throught that a persistently low LES pressure was the main mechanism underlying reflux. However, it is now well established that both GERD patients and healthy volunteers have GER primarily during transient relaxations of the LES (TLESRs) (2, 3). A TLESR is a period of prolonged and complete relaxation of the LES that is not associated with swallowing (4). The abrupt relaxation of the LES is a preprogrammed motor action that is located in the brainstem and that is triggered by distention of the stomach wall. After a meal, the rate of TLESRs is increased, presumably by distention of the proximal stomach (5). The rate of TLESRs can also be increased artificially by distending the stomach with free air or an intragastric balloon (6, 7). Upon distention of the stomach wall, mechanoreceptors are activated, sending information via vagal afferents to the medulla oblongata. The visceral information is processed in the medulla oblongata, and subsequently vagal efferent neurons are activated, relaxing the LES (8, 9). To reduce weight, morbidly obese patients are treated with a water-filled intragastric balloon (10). The intragastric balloon is thought to exert its action by occupying a large volume of the stomach. This should theoretically result in a decreased capacity to store food and subsequently to result in early satiety, a reduction in caloric intake, and ultimately weight loss. This balloon is introduced endoscopically and remains in the stomach for at least 20 wk. On average, this results in a weight reduction of 26 kg (10, 11). However, immediately after balloon placement such patients experience severe reflux, in some cases necessitating removal of the balloon (12, 13). In the remaining patients, GER was increased up to 13–26 wk after balloon placement and slowly declined in time (13). Although the effect of acute gastric distention on LES function is well established, the effect of the prolonged distention by an intragastric balloon on LES function and the mechanisms underlying the increase in GER are unknown. We hypothesized that this
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balloon, with a content of 500 ml, would continuously distend the stomach and would represent a human model of chronic distention. Therefore, the present study was designed to evaluate prospectively the effect of prolonged gastric distention on LES function, especially on the rate of TLESRs and reflux.
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Intragastric Balloon The intragastric balloon (Bio Enterics, Santa Barbara, CA) is composed of smooth silicon with radiopaque markings. Using an insertion system, the balloon is introduced orally and positioned in the stomach. The balloon is filled via the filling catheter with 500 ml of sterile saline under endoscopic view. The filling catheter is subsequently removed with a short pull.
MATERIALS AND METHODS Subjects Eighteen consecutive, morbidly obese subjects with an average age of 34 yr (range 21–56 yr) and a mean body mass index of 42 ⫾ 1 kg/m2 were included in the study. To minimize the number of study days, three groups were created: one group (n ⫽ 6) was only studied before, immediately after balloon placement and at 10 wk; the second group (n ⫽ 6) was studied before and at 10 and 20 wk; and a third group (n ⫽ 6) was also studied before and at 10 and 20 wk, but only postprandially. Although the balloon was well tolerated in the majority of the patients, two subjects experienced sustained severe pyrosis, vomiting, and abdominal cramping, for which the balloon had to be removed prematurely. Because of abdominal cramping, a third subject could only be studied during the fasting right recumbent period after 10 wk. These subjects, one from each study group, were excluded for analysis of the effect of prolonged gastric distention. Subjects did not take any medication known to interact with GI motility. Gastric acid suppressive therapy, if used, was stopped at least 5 days before the studies. Each subject gave written informed consent, and the study was approved by the Medical Ethical Committee of the Academic Medical Center of Amsterdam. Esophageal Manometry Manometric recordings were performed using a 10-lumen assembly that incorporated a sleeve sensor at its distal end to monitor LES pressure (Dentsleeve, Belair, South Australia). Side holes monitored pressure in the stomach (1 cm below the distal margin of the sleeve) and at 2, 5, 8, 11, 14, 17, and 20 cm above the LES. A side hole in the pharynx monitored swallows. The gastric and esophageal side holes were perfused at 0.3 ml/min and the sleeve at 0.6 ml/min with degassed distilled water by a pneumohydraulic capillary perfusion pump (Dentsleeve). The pharyngeal side hole was perfused by air at 0.3 ml/min to reduce pharyngeal triggering of TLESRs (14). Pressures were sensed by external transducers connected to a polygraph (Synectics Medical, Stockholm, Sweden). Intraesophageal pH was monitored using a one-sensor, monocrystalline antimony pH electrode (Synectics Medical). The pH probe was calibrated at pH 1 and 7 using standard buffer solutions (Synectics Medical). Signals were digitized, computer-processed, and stored using commercially available software (Polygram for Windows, Synectics Medical).
Study Design Subjects were studied before, immediately after, and 10 and 20 wk after balloon placement. All subjects attended the laboratory at 8:30 AM after an overnight fast. The manometric assembly and pH electrode were passed through an anesthetized nostril and positioned with the sleeve straddling the LES. The pH probe was positioned 5 cm above the upper margin of the LES. Acute Study In previous studies, the majority of the subjects experienced severe nausea, abdominal cramping, and vomiting immediately after balloon placement, making recording difficult and uncomfortable for the subjects. Therefore, only six subjects were asked to participate in an acute study design. Subjects arrived at 8 AM after an overnight fast. To prevent interference of sedation and inflated air during endoscopic placement, the balloon was positioned orally without endoscopic guidance. The position of the unfolded balloon was controlled using fluoroscopy. When the balloon was located in the stomach, the balloon was slowly filled with 500 ml of saline under fluoroscopic control. After complete filling, the filling catheter was removed with a short pull. The recordings of the subjects in the acute study were started within 30 min after balloon placement. In this group, esophageal motility and pH were recorded during 60 min in the right recumbent position, and no meal was given. Studies Before and 10 and 20 wk After Balloon Placement After an overnight fast, the subjects arrived at the laboratory at 8:30 AM. After 10 and 20 wk, the subjects arrived at 8 AM and a plain abdominal x-ray was taken in the upright and supine position to determine the location of the balloon. The esophageal manometry catheter and pH electrode were positioned as described above. Because the balloon is free to move, the body position of the subjects may influence the location of the balloon and subsequently may affect LES function and GER. Therefore, after a 10-min adaptation period, subjects were studied for 60 min in the right recumbent and for 60 min in the sitting position (before, n ⫽ 11; at 10 wk, n ⫽ 11; at 20 wk, n ⫽ 5). The order of the sitting and right recumbent position was randomized. To assess possible mechanical interference of the balloon with LES relaxation and sleeve function, subjects swallowed 5 ml of water 10 times. Subsequently, subjects consumed a pancake (650 kcal) in the sitting position and were studied in the
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right recumbent position for an additional 120 min (before, n ⫽ 18; at 10 wk, n ⫽ 15; at 20 wk, n ⫽ 10). Data Analysis LES Pressure. LES pressure was measured at end-expiration relative to intragastric pressure. Basal LES pressure was determined as visual means of 1-min periods every 15 min. The average was calculated for the fasting recording in the right recumbent and sitting position and the postprandial period. Residual LES pressure after a 5-ml water swallow was calculated at the nadir of the relaxation, and the average was calculated for the 10 water swallows. TLESRs. TLESRs were scored according to previously published criteria (4): 1) absence of swallowing for 4 s before to 2 s after the onset of LES relaxation, 2) relaxation rate of ⱖ1 mm Hg/s, 3) time from onset to complete relaxation of ⱕ10 s, and 4) nadir pressure of ⱕ2 mm Hg. LES relaxations associated with a single swallow and fulfilling criteria 2– 4 and a duration of ⬎10 s were classified as TLESRs. TLESRs were counted for each subject during the fasting recording in the right recumbent (60 min) and sitting (60 min) position and during the first and second postprandial hour. In addition, the percentage of TLESRs accompanied by a reflux episode was determined. Furthermore, the increase in TLESRs and the percentage of TLESRs accompanied with reflux by the meal was determined. GER. A decrease in esophageal pH was scored as a reflux episode if the pH drop was ⬎1 pH unit and lasted ⱖ10 s. The mechanism underlying each reflux episode was characterized as follows: TLESR, swallow-associated, a period of sustained absence of LES pressure (ⱕ5 mm Hg), a period of apparently stable LES pressure (⬎5 mm Hg), associated with an intragastric pressure rise, or not interpretable. The duration of all pH drops to ⬍4 was calculated, and the percentage of total time at pH ⬍4 was determined. In addition, the increase in reflux and percentage of the time that pH was ⬍4 by the meal was determined. Statistical Analysis The subjects participating in the acute experiments experienced acute severe nausea immediately after balloon placement. As a consequence, some studies had to be stopped prematurely. In that case, the number of recorded events (TLESRs, reflux episodes) was divided by the recording period (ranging from 32 to 55 min) and multiplied by 60 min to normalize the data. At 20 wk, only five subjects were studied in the fasting period. As this number is too small for statistical analysis, these data are only described but were not statistically analyzed. Data are presented as median and interquartile range. The effect of the intragastric balloon in time on LES function and reflux was evaluated using a general linear model with repeated measurements. Wilcoxon matched pairs, signed rank tests and 2 tests were used. A p value ⬍ 0.05 was considered to be statistically significant.
Figure 1. Plain abdominal x-ray film immediately after placement of intragastric balloon. Note the large volume of stomach being occupied by the balloon. A coin 25 mm in diameter is attached at the level of the sternum to illustrate actual size of the balloon.
RESULTS Subjects The balloon was positioned in the stomach in all 18 subjects without difficulty. After being filled with 500 ml of saline, the balloon occupied a large volume of the stomach, as shown in Figure 1. During the day of balloon placement, most subjects developed severe pyrosis (89%), nausea (83%), vomiting (89%), abdominal cramping (72%), and belching (89%). After 10 wk 50% of the subjects still reported belching and 38% pyrosis. Interestingly, 25% could feel the balloon moving in the stomach. After 20 wk symptoms were further reduced, and only 20% of subjects reported belching and pyrosis. After 10 wk subjects lost 9 ⫾ 1 kg (p ⬍ 0.05); however their weight was not further reduced after 20 wk (total weight reduction 12 ⫾ 1 kg). Effect of Intragastric Balloon on LES Function and GER Fasting LES Function. To evaluate the possible interference of the balloon with sleeve function, we first evaluated the effect of the balloon on water swallow–induced LES relaxation. Before balloon placement, residual LES pressure was 2 mm Hg (range 0 –3 mm Hg). At 10 and 20 wk after balloon placement, residual LES pressure was 2 mm Hg (range 0 –3 mm Hg) and 1 mm Hg (range 0 –2 mm Hg), respectively, which was not statistically different from before. This indicates that LES relaxation was preserved and that the balloon did not mechanically interact with sleeve function. The fasting LES pressure before balloon placement was 14 mm Hg (range 8 –24 mm Hg). Immediately after introduction of the balloon, fasting LES pressure was 16 mm Hg (range 11–25 mm Hg) and did not differ from before. At 10
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Figure 2. Effect of acute and prolonged gastric distention on (A) rate of TLESRs and (B) percentage of TLESRs accompanied by a reflux episode during fasting period in right recumbent position before (n ⫽ 11), during (n ⫽ 6), and 10 wk (n ⫽ 11) and 20 wk (n ⫽ 5) after balloon placement. Results are shown as median and interquartile range. *p ⬍ 0.05.
wk after balloon placement, fasting LES pressure was 29 mm Hg (range 12–36 mm Hg), and after 20 wk was 22 mm Hg (range 15–34 mm Hg). Fasting TLESRs and Percentage of TLESRs WITH GER. Under fasting conditions, 3.0 n/h (range 2.0 –7.0 n/h). TLESRs were recorded before the balloon was introduced. Immediately after balloon placement, the rate of TLESRs was significantly increased to 9.4 n/h (7.7–12.1n/h (Fig. 2A). At 10 wk after balloon placement the rate of TLESRs was 6.0 n/h (range 2.0 – 6.0 n/h. Only at 20 wk did the rate of TLESRs return to baseline levels (Fig. 2A). Before balloon placement, 31% (range 15– 49%) of the TLESRs were accompanied by a reflux episode. At 10 wk after balloon placement, this percentage increased to 100% (range 63– 100%; p ⬍ 0.05), and after 20 wk it was 67% (range 25–100%) (Fig. 2B). Fasting GER. The number of reflux episodes was low before balloon placement at 1.0 n/h (range 0 –3.0n/h), with a
pH of ⬍4 during 1% (range 0 –2%) of the recording period (Fig. 3A). The rate of reflux episodes and the percentage of time that pH ⬍4 were not increased significantly immediately after balloon placement. At 10 wk after placement, however, the number of reflux episodes was significantly increased to 5.0 n/h (range 2.0 – 6.0 n/h; p ⬍ 0.05), although the percentage of time that pH was ⬍4 (9%, range 6 –10%) was not increased. At 20 wk, both the rate of reflux episodes and the percentage of time that pH was ⬍4 had returned to baseline values (Fig. 3B). Effect of Body Position While Fasting. Before balloon placement, body position had no effect on LES pressure, rate of TLESRs, percentage TLESRs with reflux, rate of reflux episodes, and percentage of time that pH was ⬍4. In contrast, at 10 and 20 wk, the percentage of TLESRs accompanied with reflux was significantly increased during the right recumbent but not the sitting position (Fig. 4A). Similarly, at 10 wk, the increase in the rate of reflux epi-
Figure 3. Effect of acute and prolonged gastric distention on (A) rate of reflux episodes and (B) percentage of time that pH was ⬍4 during fasting in recumbent position, before (n ⫽ 11), during (n ⫽ 6), and 10 wk (n ⫽ 11) and 20 wk (n ⫽ 5) after balloon placement. Results are shown as median and interquartile range. *p ⬍ 0.05.
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Figure 4. Effect of body position on (A) percentage of TLESRs with reflux and (B) rate of reflux episodes in the fasting period before (open bars) and at 10 wk (hatched bars) and 20 wk (filled bars) after balloon placement. Results are shown as median and interquartile range. *p ⬍ 0.05.
sodes (Fig. 4B) and the percentage of time that pH was ⬍4 (data not shown) were observed only in the right recumbent position. After 10 wk, no reflux episodes were recorded in the sitting position. Postprandial LES Function. Before placement of the balloon, LES pressure decreased from 14 mm Hg (range 8 –24 mm Hg) to a minimum of 7 mm Hg (range 3–13 mm Hg) during the postprandial recording period (p ⬍ 0.05). At 10 and 20 wk after balloon placement, postprandial LES pressure was significantly higher at 22 mm Hg (range 13–38 mm Hg; p ⬍ 0.05) and 21 mm Hg (range 9 –26 mm Hg; p ⬍ 0.05), respectively. In addition, the postprandial decrease in LES pressure was attenuated. Postprandial TLESRs and Percentage of TLESRs with GER. Before balloon placement, ingestion of the meal resulted in a significant increase in the rate of TLESRs during
the first hour (6 n/h [range 4.8 –7.3 n/h], p ⬍ 0.05) but not during the second hour (4.0 n/h [range 2.0 – 4.5 n/h]) compared with fasting in the right recumbent position (3.0 n/h [range 2.0 –7.0 n/h]) (Fig. 5A). Furthermore, the percentage of TLESRs accompanied by a reflux episode was significantly increased in the postprandial period (p ⬍ 0.05) (Fig. 5B). At 10 wk, ingestion of the meal did not further increase the rate of TLESRs or the percentage TLESRs accompanied by a reflux episode (Fig. 5A, 5B). The rate of TLESRs and the percentage TLESRs accompanied by reflux in the postprandial period were not significantly different compared with values before balloon placement (Fig. 5A, 5B). At 20 wk, ingestion of the meal again resulted in an increase in the rate of TLESRs during the first hour (p ⬍ 0.05) (Fig. 5A). The percentage of TLESRs accompanied by a reflux episode was not increased after the meal.
Figure 5. Effect of meal ingestion on (A) rate of TLESRs, (B) percentage of TLESRs accompanied by a reflux episode, and (C) rate of reflux episodes in right recumbent position during fasting period (open bars) and postprandial periods (hatched bars, first hour of postprandial period; filled bars, second hour of posprandial period). Results are shown as median and interquartile range. *p ⬍ 0.05.
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Figure 6. Mechanisms underlying reflux episodes. Fasting and postprandial data are summated as follows: TLESR, swallow, low (ⱕ5 mm Hg) and high (⬎5 mm Hg) LES pressure, intragastric pressure wave (IPW), not interpretable (NI). Before balloon placement (open bars) and at 10 wk (hatched bars) and 20 wk (filled bars) after balloon placement.
Postprandial GER. Before placement of the balloon, ingestion of the meal resulted in a significant increase in the rate of reflux episodes and the percentage of time that pH was ⬍4 (p ⬍ 0.05). At 10 wk after balloon placement, the rate of reflux episodes (Fig. 5C) and the percentage of time that pH was ⬍4 were increased and equaled postprandial values during the fasting recumbent period (p ⬍ 0.05). Ingestion of the meal did not further increase the rate of reflux episodes and the percentage of time that pH was ⬍4 (Fig. 5). At 20 wk, the percentage of time that pH was ⬍4 was increased after the meal (p ⬍ 0.05). In all, 78% of all reflux episodes (n ⫽ 581 total) occurred during the postprandial period. Because the distribution of each mechanism was not influenced by the meal or by body position, the episodes during the fasting and postprandial recording period were summated. TLESRs were the main mechanism underlying GER both before (70%) and after balloon placement (10 wk, 75%; 20 wk, 65%) (Fig. 6). Gastric pressure waves accounted for 9% and 14% of the reflux episodes at 10 and 20 wk after balloon placement, as discussed below.
Meal Intake. Before placement of the balloon, most subjects consumed the entire pancake. After balloon placement, subjects experienced early satiety and were able to consume significantly less of the pancake (10 wk, 61% [range 46 – 84%] of the pancake; 20 wk, 55% [range 43– 88%] of the pancake). At 10 and 20 wk after balloon placement, there was no relationship between the percentage of the meal consumed and LES pressure (r ⫽ ⫺0.3, p ⫽ 0.27), rate of TLESRs (r ⫽ ⫺0.4, p ⫽ 0.1), percentage of TLESRs with reflux (r ⫽ ⫺0.4, p ⫽ 0.17), rate of reflux (r ⫽ ⫺0.5, p ⫽ 0.07), and percentage of time that pH was ⬍4 (r ⫽ ⫺0.3, p ⫽ 0.24) (data not shown). Effect of Intragastric Balloon on Gastric Pressure In all subjects, pressure waves were recorded in the gastric and sleeve channel during the fasting recording period. The pressure waves occurred episodically and had a phase III– like appearance (Fig. 7A). These rises in intragastric pressure were not accompanied by a reflux episode and resolved after ingestion of the meal (Fig. 7B). In contrast, at 10 and 20 wk after balloon placement, the episodes of contractile
Figure 7. Typical tracing with intragastric pressure recordings in the fasting (A) and postprandial (B) recording periods. Same individual at 10 wk after balloon placement before (C) and after (D) meal ingestion. Horizontal lines indicates baseline.
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Figure 8. Typical tracing showing a phasic gastric pressure wave accompanied by a reflux episode (A) and a TLESR with reflux (B). Horizontal line indicates baseline.
activity lasted 45 min (range 31– 60 min) at 10 wk and 30 min (range 18 – 43 min) at 20 wk, which was significantly longer than before (Fig. 7C). In addition, in 80% and 70% of the subjects at 10 and 20 wk, respectively, intragastric pressure waves persisted during the postprandial period (Fig. 7D). Although, on average, meal intake was reduced after 10 and 20 wk, no relationship was found between the occurrence of pressure waves and the percentage of the meal ingested. Furthermore, in contrast to values before balloon placement, 40% of the patients had one or more periods of GER associated with a gastric pressure wave in the fasting and 33% in the postprandial period (Fig. 8A). Of these contractions, 49% were associated with a swallow, and 31% of these contractions were immediately followed by a TLESR with reflux (Fig. 8B). Balloon Location and Body Position Radiological studies showed that immediately after balloon placement, the balloon was located in the fundic region in five subjects and in the corporal region in one subject. At 10 wk, the balloon was in the fundic region in 31% of the patients in the supine position and in 21% in the upright position, with the remainder in the corporal region. After 20 wk, the balloon was in the fundic region in 67% of the patients when supine and in 33% when upright. There was no relationship between the location of the balloon and LES pressure, rate of TLESRs, percentage TLESRs with reflux, rate of reflux episodes, and percentage of time that pH was ⬍4.
DISCUSSION Endoscopic placement of an intragastric balloon is one of a number of treatments to reduce weight in morbidly obese patients (10). This treatment, however, is often accompanied
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by increased symptoms of GER. In the present study, we confirmed the increase in reflux and clarified the mechanisms underlying this increase, showing that this increase results mainly from an increase in the percentage of TLESRs accompanied by reflux. We further illustrated that prolonged balloon distention can increase the rate of TLESRs and can create a postprandial state even 10 wk after balloon placement. After 20 wk, these effects largely resolve, illustrating adaptation to this artificial situation. GER with symptoms of heartburn, retrosternal pain, and even esophagitis have been reported in obese patients treated with intragastric balloons (11, 13). In the present study, approximately 40% of the subjects complained of heartburn (especially in the first 10 wk), leading to removal of the balloon in three patients. In the remaining subjects, the balloon induced GER, as shown by the increased number of reflux events. One of the possible mechanisms underlying this increase in GER could be interference of the balloon with LES function, leading to lowered LES pressure. However, LES pressure was even significantly increased after balloon placement, thereby excluding this possibility. Furthermore, swallow-induced relaxation remained unaffected, illustrating preserved LES function and excluding mechanical interaction by the balloon with sleeve function. Interestingly, we noticed an increased percentage of TLESRs accompanied by a reflux episode. This finding is similar to that reported in patients with GERD. Although controversy exists whether the rate of TLESRs is increased in patients with GERD, evidence clearly illustrates that the percentage of reflux during TLESRs is increased in such patients (3, 15–19). The exact mechanisms underlying this observation are still unclear, although the increase in the percentage of TLESRs accompanied by reflux was especially seen in the right recumbent position, suggesting that body position might play an important role. Indeed, previous studies have also reported a significantly increase in reflux during the right compared with the left recumbent position, because of an increase in TLESRs and the percentage of TLESRs accompanied by a reflux episode (20 – 22). This indicates that distribution of intragastric contents may play an important role in the pathogenesis of reflux. By occupying a large volume of the stomach, the intragastric balloon might have resulted in pooling of intragastric contents in the cardiac region during the right recumbent position. One could speculate that this might have triggered TLESRs or increased the risk and the volume of refluxate during a TLESR. Comparable to acute distention of the stomach using free air or a barostat balloon (6, 7), the rate of TLESRs drastically increased immediately after balloon placement. The increased rate of TLESRs most likely results from gastric distention, a well known trigger of TLESRs. Radiographic studies indeed showed that the balloon largely filled the stomach, preferentially the proximal part. The rate of TLESRs was comparable to the rates observed during acute distention by air insufflation or barostat distention. In these
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experiments, the stomach rapidly adapts to distention within 15 min (6, 23). Surprisingly, in the present study, even after 10 wk, the fasting rate of TLESRs was still increased, although not statistically significantly. Adaptation with return to a comparable rate of TLESRs as before balloon placement was only obtained after 20 wk. Although we have no explanation for this observation, one might speculate that the balloon shifted between the corpus and the fundus of the stomach, thereby delaying adaptation. Some patients indeed reported a sensation of movement of the balloon up and down. Whether this adaptation to distention explains or contributes to the symptomatic improvement observed over time also remains speculative. It is interesting, however, to note that most of the weight is lost during the first 10 wk, when adaptation is incomplete and the balloon still induces a postprandial condition. The cardiac region is believed to have the lowest threshold for TLESRs (8). The position of the balloon could have influenced the number of TLESRs observed. At 20 wk after placement, 67% of the balloons were localized in the fundic region, compared with 31% at 10 wk. Inasmuch as the cardiac region is the most sensitive part of the stomach, one would expect a higher rate of TLESRs; however, after 20 wk, the rate of TLESRs was returned to predistention levels. Furthermore, analysis showed that there was no relationship between the localization of the balloon and the number of TLESRs observed, illustrating that balloon position had no major impact. After 10 wk, the fasting rates of TLESRs and reflux parameters reached values comparable to those observed in the postprandial period before balloon placement. Ingestion of a meal did not further increase these values above those before balloon placement, which might have been explained by the reduction in meal intake after 10 and 20 wk. There was, however, no relation between the percentage of the meal consumed and LES pressure, rate of TLESRs, percentage of TLESRs with reflux, rate of reflux episodes, and percentage of time that pH was ⬍4. These findings suggest that the intragastric balloon induced a “postprandial” situation during the fasting state by occupying a large volume of the stomach. This should theoretically result in a decreased capacity to store food and subsequently result in early satiety, a reduction in caloric intake, and, ultimately, weight loss. Indeed, meal ingestion and body weight were significantly decreased after balloon placement. Finally, gastric pressure waves were recorded that were different from gastric contractions observed during phases II and III of the interdigestive motor pattern. Similar irregular contractions were previously reported during gastric distention in a canine model, suggesting that this motor pattern is another compensatory mechanism of the stomach to this artificial condition of chronic distention (24, 25). In conclusion, we showed that the increase in GER after prolonged balloon placement resulted from a transient increase in the percentage of TLESRs associated with GER. We further illustrated that prolonged balloon distention can
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increase the rate of TLESRs and can create a postprandial state, even 10 wk after balloon placement. After 20 wk these effects largely resolve, illustrating adaptation to this artificial situation.
ACKNOWLEDGMENTS This work was supported by the Netherlands Digestive Diseases Foundation grant WS 97-28 (to D.P.H.). Reprint requests and correspondence: Guy E. E. Boeckxstaens, M.D., Ph.D., Academic Medical Center, Division of Gastroenterology and Hepatology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Received June 11, 2002; accepted Apr. 14, 2003.
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