Background: Whereas it is well documented that fundoplication reduces acid reflux, the effects of the procedure on non-acid and gas reflux and the mechanisms through which this is achieved have not been fully elucidated.
Methods: In 14 patients, reflux was measured with impedance–pH monitoring during a postprandial 90 min stationary recording period before and 3 months after fundoplication. Concomitantly, the occurrence of transient lower oesophageal sphincter relaxations (TLOSRs) and morphology of the oesophagogastric junction were studied with high-resolution manometry. This was followed by 24 h ambulatory impedance–pH monitoring.
Results: Before fundoplication, two separate high-pressure zones (hernia profile) were detected during 24.9% of total time, during which there was a large increase in reflux rate. After fundoplication, the hernia profile did not occur. Fundoplication decreased the number of TLOSRs (from 10.5 (SEM 1.2) to 4.5 (0.7), p<0.01) and also the percentage of TLOSRs associated with acidic or weakly acidic reflux (from 72.7% to 4.1%, p<0.01). Nadir pressure during TLOSRs increased after surgery (from 0 (0–0) to 1.0 (1–2) kPa, p<0.05). In the ambulatory study, there was a large decrease in prevalence of both acid (−96%, from 47.0 (5.9) to 1.8 (0.5), p<0.01) and weakly acidic reflux (−92%, from 25.0 (9.7) to 2.3 (0.9), p<0.01). The decrease in gas reflux was less pronounced (−53%, from 24.2 (4.9) to 11.3 (3.0), p<0.01).
Conclusions: Fundoplication greatly reduces both acid and weakly acidic liquid reflux; gas reflux is reduced to a lesser extent. Three mechanisms play a role: (1) abolition of the double high-pressure zone profile (hiatal hernia); (2) reduced incidence of TLOSRs; and (3) decreased percentage of TLOSRs associated with reflux.
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Fundoplication is an alternative method for medical treatment of reflux disease. The procedure is highly effective in reducing oesophageal acid exposure time and reflux symptoms.1 The mechanisms through which fundoplication reduces gastro-oesophageal reflux (GORD) are complex and incompletely understood. It has been shown that fundoplication reduces the volume of the proximal stomach and affects the rate of transient lower oesophageal sphincter relaxations (TLOSRs).2 3 TLOSRs are the most important mechanism through which reflux of acidic gastric contents can occur.4 5 TLOSRs differ from swallow-associated lower oesophageal sphincter (LOS) relaxations in various aspects. TLOSRs are not triggered by a swallow but by gastric distention-activated stretch receptors in the gastric wall, and the duration of TLOSRs is longer than that of swallow-associated LOS relaxations. Besides acidic gastric contents, air and non-acid liquids can also escape from the stomach during a TLOSR.6 7
Spatial separation of the LOS and the diaphragm is regarded as an important pathophysiological factor in GORD.8 Recently, we have shown that intermittent spatial separation of the LOS and the diaphragm occurs frequently in patients with a small hiatal hernia and leads to a twofold increase of acidic and weakly acidic reflux episodes but not of pure gas reflux.9 Spatial separation of the two components of the anti-reflux barrier can be detected by high-resolution manometry. In theory, surgical reduction of the hiatal hernia could therefore contribute significantly to the reduction of acidic and weakly acidic reflux episodes brought about by anti-reflux surgery. It can also be hypothesised that the inhibitory effect of fundoplication on gas reflux would be less pronounced, as gas reflux is likely to be less affected by the repositioning of the LOS to the level of the diaphragm.
The effective reduction in reflux episodes brought about by fundoplication usually leads to an impressive effect on reflux symptoms. However, some patients develop new symptoms after the procedure. One of the most common complaints after anti-reflux surgery is the subjective sensation of bloating, often associated with an inability to belch.10 11 This condition, first described by Woodward and colleagues, is usually referred to as the gas-bloat syndrome.12 It occurs in 6–49% of all patients after fundoplication, sometimes requiring hospitalisation.13–15 It is hypothesised that gas-related symptoms after anti-reflux surgery are related to intragastric accumulation of swallowed air due to an impairment of venting air from the stomach.16 17 Stationary laboratory-based studies have confirmed that there is an air venting defect with a pronounced decrease in TLOSRs as well as a decreased volume and number of gas reflux episodes in patients who underwent fundoplication; data in an ambulatory outpatient setting are lacking.18–20 Others have suggested that symptoms of bloating and flatulence are the result of an increased ingestion of air caused by excessive postoperative air swallowing.21
In some patients, reflux symptoms persist after anti-reflux surgery despite a marked decrease in acid reflux, and a subset of patients continue to use their acid-suppressive medication postoperatively.22 It has been described that non-acid reflux can elicit heartburn and regurgitation, and it is possible that persistent reflux symptoms after anti-reflux surgery are caused by non-acid (weakly acidic) reflux episodes.23 24 Thus far, the effect of fundoplication on weakly acidic reflux has not been studied.
The aim of this study was therefore to investigate the effect of Nissen fundoplication on the prevalence and mechanisms of acidic, weakly acidic and gas reflux.
We studied 14 patients with GORD (7 men: mean age 47 years, range 28–73 years). All patients had symptoms of heartburn, regurgitation and/or chest pain, and 12 out of 14 had a positive relationship between the occurrence of their primary symptom and reflux events (symptom association probability ⩾95%). Furthermore, all had a pathological oesophageal acid exposure (time with pH <4 greater than 6.0%). Eight patients had evidence of a small hiatal hernia on endoscopy. Written informed consent was obtained from all subjects, and the protocol was approved by the medical ethical committee of the University Medical Center Utrecht.
All patients were studied 1 month before and 3 months after laparoscopic Nissen fundoplication. Each study day consisted of two parts and started with a stationary part in which the mechanisms and frequency of reflux were identified after a meal and after provocation with intragastric air inflation. This was followed by an ambulatory 24 h impedance–pH study in which air swallowing and gastro-oesophageal reflux of gas and liquids were monitored for 24 h (fig 1).
The use of gastric acid-inhibitory drugs and drugs that influence gastrointestinal motility was discontinued 5 days before each study. After an overnight fast, the manometry catheter was introduced transnasally. Thereafter, the impedance and the pH catheter were introduced transnasally and positioned based on the manometric findings (see below). Subjects were in an upright position and were asked to minimise head movements in order to avoid axial displacement of the catheters. The subjects consumed a standardised meal comprising a hamburger (McDonald’s Quarter Pounder consisting of a bun, sauce, meat, pickle and cheese), 20 g of fresh onions, 44 g of potato chips and 475 ml of orange juice (in total 967 kcal). The meal had to be finished in 30 min. After the meal, a 90 min period of pressure, impedance and pH recording was started. This was followed by manual inflation of 600 ml of air in the stomach over 5 min through a channel in the manometry catheter, using a syringe. After the air was insufflated, recording was continued for another 20 min. Thereafter, the manometry catheter was removed and a 24 h ambulatory impedance–pH measurement was carried out. The first 2 h of the 24 h recording were excluded from the analysis in order to minimise the effect of the previously inflated air.
Patients were asked to fill in a questionnaire on the days of the 24 h study, in which they were asked to indicate the presence of symptoms of heartburn, regurgitation, chest pain, flatulence and the sensation of bloating on a 5-point scale (0–4), and the inability to belch and/or vomit on a binary scale (present/absent).
The operations were carried out by the same surgeon in the University Medical Center Utrecht. All subjects underwent a laparoscopic floppy 360° Nissen fundoplication.
A water-perfused silicone rubber catheter (outer diameter 4.0 mm, length 75 cm, channel diameter 0.4 mm) was used for manometric recording (Dentsleeve Pty Ltd, Wayville, South Australia). The catheter was positioned in such a way that its distal seven sideholes, spaced at 1 cm intervals, straddled the oesophagogastric junction and the most distal sidehole was positioned intragastrically. The proximal part of the assembly incorporated five sideholes at 1 cm intervals. Of these, the sidehole most clearly showing pharyngeal contractions was selected for recording swallows. After selection of this sidehole, perfusion of the other four pharyngeal sideholes was discontinued since it has been suggested that pharyngeal stimulation with water may trigger TLOSRs.25 The middle part of the catheter contained four oesophageal sideholes at 5 cm intervals. All sideholes were perfused at a rate of 0.08 ml/min using a pneumohydraulic perfusion system (Dentsleeve Pty Ltd, Wayville, South Australia).
Pressures were measured with external pressure transducers (Abbott, Sligo, Ireland). Pressure data were stored in digital format in two 12-channel dataloggers (Medical Measurement Systems, Enschede, The Netherlands), using a sample frequency of 8 Hz. At the end of the study, all data were transferred to the hard disc of a computer.
Intraluminal impedance and pH monitoring
For intraluminal impedance monitoring, a seven-channel impedance catheter was used (Aachen University of Technology, FEMU, Aachen, Germany). This catheter (outer diameter 2.3 mm) enabled recording from seven segments, each recording segment being 2 cm long. The recording segments were located at 0–2, 2–4, 4–6, 8–10, 10–12, 14–16 and 17–19 cm above the upper border of the manometrically localised LOS. Impedance signals were stored in a digital system (Aachen University of Technology, FEMU, Aachen, Germany) using a sample frequency of 50 Hz. Intraluminal pH monitoring was performed with a glass pH electrode (Ingold AG, Urdorf, Switzerland) and data were stored in a digital datalogger (Orion, MMS, Enschede, The Netherlands) using a sampling frequency of 2 Hz. The pH glass catheter was positioned 5 cm above the upper border of the LOS. Using a cable that connected the pH datalogger with the impedance datalogger, the pH signals were stored on both dataloggers to enable synchronisation.
In the analysis of the impedance tracings, gas reflux was defined as a rapid (>3000 Ω/s) and pronounced rise in impedance that moved in the retrograde direction over at least two consecutive impedance sites.26 Liquid reflux was defined as a fall in impedance of ⩾50% of baseline impedance that moved in the retrograde direction over the two distal impedance sites. Mixed liquid–gas reflux was defined as gas reflux occurring during or immediately preceding liquid reflux. Liquid and mixed reflux episodes were classified as acid when the pH dropped below 4; reflux episodes were classified as weakly acidic when the nadir pH was between 4 and 7.27
In the impedance tracings, all swallows were identified. Air-containing swallows (air swallows) were defined as swallows that were preceded by an impedance peak of >1000 Ω above baseline, measured in the most distal impedance segment. Detection of air swallows with impedance monitoring was validated previously and has been shown to be reproducible.28 29
For each reflux episode identified with combined pH–impedance monitoring, the underlying mechanism responsible for the episode was identified. Reflux mechanisms were classified into five categories: TLOSR-associated, swallow-associated, strain-associated, low LOS pressure-associated and other/unknown. For detection of TLOSRs, we used the criteria developed by Holloway et al. modified for high-resolution manometry.30 31 Furthermore, TLOSRs were scored if the nadir pressure during relaxation was equal to or less than the residual relaxation pressure determined during repeated water swallows. Reflux was considered to be swallow-associated if it occurred in the period between 2 s before and 4 s after a pharyngeal contraction. Straining was defined as a simultaneous increase in pressure in all channels, including the gastric channel. LOS pressure was classified as low when basal end-expiratory LOS pressure was <0.5 kPa. End-expiratory LOS pressure was calculated using the intragastric pressure as reference.
In the analysis, the periods of meal consumption were disregarded.
Statistical analysis and presentation of data
Sample size calculations were performed on the basis of changes in gas reflux episodes, as these changes are expected to be smaller than changes in acidic and weakly acidic reflux episodes. This study was designed to detect a 50% decrease in gas reflux episodes postoperatively with a power of 80%, given an estimated frequency of gas reflux episodes of 20 and an SD of 14. Comparisons were performed using the Wilcoxon signed rank test unless stated otherwise. Comparisons between nadir pressures of TLOSRs before and after surgery were performed using the Wilcoxon rank sum test. Differences were considered statistically significant when p⩽0.05. Parametric data are presented as mean and SEM, and non-parametric data as median (interquartile range).
During the 90 min postprandial measurement period, pronounced effects of Nissen fundoplication on gastro-oesophageal reflux and refluxogenic mechanisms were observed. Fundoplication greatly reduced the total (acid and weakly acidic) number of reflux episodes (from 12.2 (2.7) to 0.7 (0.5), p<0.005). Before the operation, two separate high-pressure zones (hernia profile) were detected in 10 subjects during 34.9% of total time, during which there was a much higher reflux rate compared with the periods with a single high-pressure zone (reduced hernia) (13.0 (4.0) episodes/h vs 7.7 (1.1) episodes/h) (fig 2). After fundoplication, no double high-pressure zones were identified.
Fundoplication significantly decreased both the number of TLOSRs (from 10.5 (1.2) to 4.5 (0.7) per 90 min, p<0.01) and the percentage of TLOSRs accompanied by acid or weakly acidic reflux (from 72.7% to 4.1%, p<0.005). The numbers of TLOSRs with liquid or mixed reflux were both reduced, while the number of TLOSRs accompanied by gas reflux was not affected by the operation (fig 3). Surgery increased the nadir pressure during TLOSRs (from 0 (0–0) to 1.0 (1–2) kPa, p<0.05) (fig 4). The duration of TLOSRs was not affected (18.0 (0.8) s vs 16.8 (0.8) s, p = 0.13).
In the 90 min period, the number of reflux episodes induced by TLOSRs decreased from 9.0 (1.1) to 1.5 (0.5), while the proportion of reflux episodes that was induced by a TLOSR remained constant (64.7% vs 62.5%). The number of swallow-associated reflux episodes decreased from 2.3 (1.0) to 0.3 (0.2), but swallows were responsible for a similar proportion of reflux episodes after surgery (16.5% vs 13.8%). Low LOS pressure was responsible for 1.0 (0.4) reflux episodes at baseline (7.2% of all reflux), whereas after surgery no low LOS pressure-associated reflux occurred. The absolute number of strain-associated reflux episodes decreased from 0.4 (0.2) to 0.1 (0.1) (p<0.05), while the proportion of reflux episodes that was associated with a strain was not affected (2.9% vs 4.2%).
In the air infusion study it was observed that fundoplication greatly reduced the occurrence of all types of reflux events after air inflation (table 1). However, the decrease in pure liquid and mixed liquid–gas reflux episodes was more pronounced than the decrease in pure gas reflux episodes.
Ambulatory 24 h impedance–pH study
In the ambulatory study, fundoplication was found to lead to an impressive decrease in the prevalence of both acid (−96%, from 47.0 (5.9) to 1.8 (0.5), p<0.01) and weakly acidic reflux episodes (−92%, from 25.0 (9.7) to 2.3 (0.9), p<0.01) (fig 5). Likewise, there was a substantial decrease in pure liquid and mixed gas–liquid reflux episodes (table 2). The decrease in gas reflux was less pronounced, albeit statistically significant (−53%, from 24.2 (4.9) to 11.3 (3.0), p<0.01). There was a larger decrease in reflux events reaching the proximal oesophagus (−99%, from 16.4 (4.4) to 0.1 (0.1), p<0.01) than in events reaching the distal oesophagus (−79%, from 11.5 (1.5) to 2.4 (0.7), p<0.01). Fundoplication significantly decreased both bolus and acid clearance times (from 18.2 (1.4) s to 15.6 (1.4) s, p<0.05 and from 119.7 (22.1) s to 18.1 (6.1) s, p<0.01). The numbers of swallows and air-containing swallows were not affected by the operation (920 (86) vs 914 (86), NS; 325 (30) vs 365 (48), NS). In four patients, acid and weakly acidic reflux were abolished completely by the operation, and in one patient there was also a total abolition of pure gas reflux.
No relationship was found between the number of acid and weakly acidic reflux episodes postoperatively and the number of pure gas reflux episodes postoperatively (r = 0.40, p = 0.2). However, a strong relationship was found between the number of weakly acidic reflux episodes that occurred postoperatively and the number of acidic reflux episodes (r = 0.85, p<0.001).
Fundoplication reduced the symptom scores for heartburn (from 3 (2–4) to 0 (0–0)), regurgitation (from 4 (2–4) to 0 (0–0)) and chest pain (from 3.0 (3–4) to 0 (0–0)). None of the patients had a positive symptom association probability after the operation. Two patients had persistent symptoms of chest pain and two patients continued to experience symptoms of heartburn while their sensation of regurgitation had disappeared (for which they did have a positive symptom association probability preoperatively). One of the patients with persistent symptoms of heartburn had complete inhibition of acidic and weakly acidic reflux, while the other one had a moderate reduction in reflux episodes (91%). Both the patients with persistent chest pain had a large (93% and 89%) reduction in weakly acidic and acidic reflux episodes. Two subjects continued to use their acid-suppressive medication postoperatively.
At 3 months postoperatively, four patients reported that they were unable to belch and/or vomit. Bloating scores increased from 0 (0–1) to 1.5 (0–3), with six subjects reporting newly developed bloating. Five patients reported increased flatulence, and the flatulence score increased from 0 (0–0) to 1.5 (0–3). However, no differences were found in the frequency of air swallowing or the frequency of gas reflux between the patients with and without various symptoms. For example, the number of gas reflux episodes in patients who reported an inability to belch (10.7 (5.2)) did not differ from the number of gas reflux episodes in those who did not suffer from impaired belching (12.9 (3.6)). Furthermore, the proportional postoperative reduction in gas reflux episodes was not related to specific symptoms either.
In patients with documented reflux disease who do not respond sufficiently to high dosages of proton pump inhibitors, Nissen fundoplication is considered a well-accepted alternative treatment. The operation can be performed laparoscopically and is highly effective in reducing reflux symptoms. However, after the procedure, a subset of patients develop gas-related symptoms such as bloating and flatulence, which are postulated to result from the inability to vent gastric air.14 18 32 The effect of anti-reflux surgery on oesophageal acid exposure has been studied extensively, but data on the effect on weakly acidic reflux and gas reflux are sparse. One study has suggested that the operation primarily affects acid reflux and that persisting weakly acidic reflux episodes would be responsible for therapy-resistant symptoms.33
This is the first study showing that fundoplication reduces both acid and weakly acidic reflux and also pure gas reflux, and that in some patients it abolishes all types of reflux completely. However, the observed reduction in reflux episodes was found to be selective as the reduction in liquid-containing (pure liquid and mixed liquid–gas) reflux was larger than the reduction in pure gas reflux. Gas reflux thus seems to occur more easily after surgery than liquid-containing reflux. This can be explained by the observation that gaseous substances pass a highly compliant oesophagogastric junction more easily than liquids do.34
Although gas reflux is less affected by a fundoplication compared with liquid reflux, there is still a large decrease in the occurrence of gas reflux episodes. The decreased ability to vent gastric air is likely to lead to symptoms of bloating and flatulence. While Nissen fundoplication did not affect the frequency of air swallowing, the frequency of gas reflux was markedly reduced, suggesting that larger volumes of air entered the small intestine. This was accompanied by subjective sensations such as the inability to belch, bloating and increased flatulence, but there were no relationships between the presence and severity of these symptoms and the reduction in gas reflux frequency. In fact, in all patients who reported an inability to belch, some gas reflux episodes did still occur. Furthermore, the patient with a complete abolition of reflux episodes did not report such symptoms. It can be concluded that differences in reflux patterns cannot adequately predict postoperative symptoms. Perhaps the presence of gas-bloat symptoms can be explained by differences in visceral sensitivity between the subjects with and without these symptoms, as it cannot be explained by differences in air swallowing and gas reflux patterns.19 35
Various mechanisms were responsible for the observed decrease in reflux frequency after fundoplication. First, there was a pronounced decrease in TLOSRs, as described previously.2 36 Furthermore, the proportion of TLOSRs leading to reflux was substantially decreased after surgery. It is likely that this is due to the observed increase in nadir pressure during TLOSRs. Finally, after surgery, the double high-pressure zone at the oesophagogastric junction was no longer observed, indicating that spatial separation of the LOS and diaphragm had been reduced effectively. Intermittent spatial separation of the LOS and diaphragm predisposes to acid and weakly acidic reflux, but not to gas reflux, and this increase in reflux episodes is due to reflux mechanisms other than TLOSRs.9 Thus, the large reduction in reflux episodes that occurred during swallowing and straining might occur through reduction of spatial separation of the LOS and diaphragm. Indeed, a large decrease in swallow-induced reflux and strain-induced reflux was observed postoperatively, likely to result from the abolition of the double high-pressure zone profile after the fundoplication. It also explains why the reduction in gas reflux episodes is much less pronounced, as these type of reflux episodes are less affected by spatial separation of the LOS and diaphragm.
We observed that Nissen fundoplication leads to a larger reduction in reflux episodes reaching the proximal oesophagus than in reflux episodes reaching no further than the distal oesophagus. Furthermore, the acid and bolus clearance times of the individual reflux episodes are decreased after fundoplication. We have suggested previously that bolus clearance time and proximal extent of reflux episodes are partly dependent on the volume of the refluxate and both are important determinants of whether or not a reflux episode will be symptomatic.24 Thus, these findings suggest that Nissen fundoplication leads not only to a decrease in number of reflux episodes but also to reduction in volume of the refluxate. This phenomenon is reflected by the observed decrease in bolus clearance time. It has to be mentioned, however, that with impedance monitoring bolus volume cannot be measured and only indirect information on the volume of the refluxate is gathered. Both effects might contribute to the effective symptom reduction that is brought about by the operation.
In the few patients with persistent symptoms after the operation, a large reduction of acid and weakly acidic reflux episodes was achieved postoperatively. Furthermore, in all patients, the decrease in weakly acidic reflux was proportional to the decrease in acid reflux. In none of the patients was evidence found that the effect of anti-reflux surgery differed between acid or weakly acidic reflux. Furthermore, a strong relationship was found between the number of weakly acidic reflux episodes and the number of acid reflux episodes after the operation. We therefore conclude that it is highly unlikely that patients who remain symptomatic after fundoplication despite a negative 24 h pH study suffer from reflux symptoms induced by weakly acidic reflux.
Several limitations of this study need to be addressed. First, the sample size of this study is relatively small. However, since large differences were expected to occur after the operation the study is sufficiently powered to allow conclusions to be drawn, and indeed large statistically significant differences were found. Furthermore, the follow-up time of 3 months seems relatively short to determine the effects of the operation. In a large study with a follow-up of 5 years, the effect at 3 months was predictive for the effect of the operation in the long term.1 Finally, rapid insufflation of a large volume of air into the stomach does not resemble the normal physiological situation in which small volumes of air are transported gradually to the stomach with swallows. However, it can be regarded as a useful technique to study the mechanism of gastric air venting, and the results are complementary to the results of the ambulatory study.
In conclusion, fundoplication greatly reduces gastro-oesophageal reflux by a complete abolition of the double high-pressure zone profile (hiatal hernia) and reduction of both the number of TLOSRs and the percentage of TLOSRs that are accompanied by reflux. The effect of Nissen fundoplication is refluxate dependent: acid and weakly acidic reflux are reduced more effectively than pure gas reflux.
Competing interests: None declared
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