Clara Loots and Marije Smits contributed equally to this paper.
Address for Correspondence Clara Loots, Department of Pediatric Gastroenterology and Nutrition, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel: +31 20 5665270; fax: +31 20 5669478; e-mail: firstname.lastname@example.org
Background Posture has been shown to influence the number of transient lower esophageal sphincter relaxation (TLESRs) and gastroesophageal reflux (GER), however, the physiology explaining the influence of right lateral position (RLP), and left lateral position (LLP) is not clear. The aim of this study was to determine the influence of RLP and LLP on TLESRs and GERD after a meal in GER disease (GERD) patients and healthy controls (HC) while monitoring gastric distension and emptying.
Methods Ten GERD patients and 10 HC were studied for 90 min (30 min test meal infusion, 30 min postprandial in either RLP or LLP (randomly assigned) and 30 min in alternate position). The study was repeated on a separate day in reverse position order. TLESRs, GER, and gastric emptying rate were recorded using manometry, multichannel intraluminal impedance, and 13C-octanoate breath tests. Gastric distension was visualized by five serial gastric volume scintigraphy scans during the first 30 min.
Key Results Gastroesophageal reflux, (GER) disease patients had increased numbers of TLESRs in RLP compared to LLP in the first postprandial hour [5 (4–14) and 4.5 (2–6), respectively, P = 0.046] whereas the number of TLESRs was not different in RLP and LLP [4 (2–4) and 4 (3–6), respectively, P = 0.7] in HC. Numbers of GER increased similar to TLESRs in GERD patients. In GERD patients, gastric emptying reached peak 13CO2 excretion faster and proximal gastric distension was more pronounced.
Conclusions & Inferences In GERD patients, TLESRs, GER, distension of proximal stomach, and gastric emptying are increased in RLP compared to LLP. This effect is not seen in HC.
weakly acid and weakly alkaline gastroesophageal reflux
Gastroesophageal reflux (GER) occurs in both patients and healthy controls. When GER causes symptoms or complications it is referred to as GER disease (GERD).1,2 The most important underlying mechanism of GER is transient lower esophageal sphincter relaxation (TLESR), a vago-vagally mediated relaxation of the lower esophageal sphincter (LES) and the crural diaphragm.3–7 These structures form the esophagogastric junction (EGJ), the main anti reflux barrier. TLESRs are a physiological mechanism thought to allow gas to vent from the stomach.7 There is no clear difference in the number of TLESRs in HC or GERD patients, however, TLESRs are more likely to be associated with liquid and acidic GER in GERD patients.8–11
Several factors are known to trigger TLESRs.12 Mechanoreceptors located in the proximal stomach trigger TLESRs via a vago-vagal pathway.6,13 These receptors are activated after a meal due to a combination of gastric distension and gastric accommodation, caused by mechanic distension after volume increase, the reduced gastric tone, and enhanced gastric compliance as a response to food intake.14,15
Another factor influencing TLESRs, is cholecystokinin (CCK). CCK is released when nutrients (especially fat) enter the duodenum, causing a decrease in LES pressure, fundic relaxation, and an increase in TLESRs.16,17 This effect can be blocked by a CCK-A antagonist.17 The increase in TLESRs after a meal is most likely modulated by both fundic relaxation and by direct interaction of CCK with the vagal afferent system.
It has been shown that lateral positioning affects TLESR triggering, although not significantly in all studies.18–21 In GERD patients and healthy adults, TLESRs and GER have been shown to occur more frequently in right lateral position (RLP) compared to left lateral position (LLP).19,21
Recently, we showed that TLESRs occurred more frequently and were more likely to cause liquid GER in RLP in healthy premature infants, despite more rapid gastric emptying.22,23 In addition, small volumes of a liquid meal caused a significantly faster onset of TLESR triggering after the start of a meal infusion in RLP compared to LLP.24
The underlying mechanisms of these observations are not completely understood. The effects of body positioning in adults may provide more insights into factors that are known to influence TLESR triggering. These factors include the activation of the mechanoreceptor by distension and accommodation of the stomach, distribution of gastric contents within the stomach, and the rate of gastric emptying, all of which are likely to be influenced by different body positions. On the basis of the above, we hypothesize that the increased number of TLESRs in RLP compared to LLP could be caused by more rapid emptying of nutrients in RLP due to the anatomical position of the pylorus, difference in activation of mechanoreceptors, pooling of gastric contents in the proximal stomach or a combination of these factors. Furthermore, we hypothesize that interaction of the involved factors may be disrupted in GERD patients.
In this study, we investigated the influence of lateral positioning on the onset of TLESRs and the type of GER after a test meal in both adult GERD patients and healthy adult controls while simultaneously monitoring potential underlying of mechanisms of gastric distension and gastric emptying.
Ten GERD patients and 10 healthy controls (HC) were included. GERD patients were required to meet ≥2 of the following criteria: (i) experience heartburn and regurgitation for >3 months and >2 times a week, (ii) diagnostic pH monitoring with acid exposure in the distal esophagus of >5, 8%,25 (iii) combined pH MII monitoring with a SAP>95% or (iv) reflux esophagitis ≥grade 1 confirmed by endoscopy. GERD patients ceased any anti reflux and prokinetic medication 5 days prior to the study. HC had no history of GERD or symptoms related to GERD. Subjects, who had undergone previous gastro-intestinal surgery (with exception of appendectomy), congenital abnormalities affecting the gastro-intestinal tract, neurological impairment, known large hiatus hernia (>3 cm), were pregnant and/or had any condition making discontinuation of anti reflux medication impossible, were excluded.
Subjects provided a written informed consent and the protocol was approved by the Medical Ethics Committee of the Academic Medical Center, Amsterdam.
Patients and controls completed a validated GERD questionnaire (Reflux Disease Questionnaire, RDQ) prior to commencement of the study.26 Subjects were studied twice on separate days and underwent both positioning protocols in a randomized crossover fashion, either LLP or RLP first. Study procedures were identical for both GERD patients and HC.
Subjects fasted for at least 6 h prior to the commencement of the study (Fig. 1). – They received an intravenous injection with 99mTc-pertechnetate, 30-40 min before the start of the study.
An assembly of a manometry and pH-MII catheter was transnasally positioned under topical nasal anesthesia with the sleeve sensor straddling the LES. Subjects were then randomly positioned in either LLP or RLP in the Single Photon Emission Computer Tomography (SPECT) scanner and baseline gastric volume was assessed during the first SPECT scan. After the baseline SPECT scan, a liquid test meal (Nestle nutrition Isosource Protein, 512 kJ, 14 g carbohydrate, 6 g protein, 4 g fat per 100 mL) was infused in the stomach, at a constant rate, initially of 100 mL during the first 15 min (slow infusion) followed by 300 mL during the next 15 min (fast infusion). During the meal infusion four SPECT scans were taken (two during slow and two during fast infusion). Furthermore, the 13C Na-Octanoate breath test was performed. After 60 min, 30 min after the end of the meal infusion, subjects changed over to the other lateral position for 30 min.
Recording methods and raw data analysis
Manometry and esophageal impedance
A water perfused manometry catheter with eight esophageal channels spaced 3 cm apart, a 7 cm sleeve, a gastric channel, and a central lumen allowing liquid meal infusion and a single use pH-MII catheter (Unisensor pHTip ™disposable catheter) were used. The manometric assembly was positioned with the tip in the stomach and the sleeve straddling the high pressure zone at the EGJ. The pH-MII catheter was placed in the esophagus with its pH sensor 5 cm above the proximal border of the manometrically established high-pressure zone. Data acquisition and analysis were performed using the Stationary Solar Gastro System (MMS Inc., Enschede, The Netherlands).
All pH-MII tracings were analyzed for GER episodes, which were qualified as liquid, mixed or gas, and acidic (pH < 4), weakly acidic (4 < pH < 7) or weakly alkaline (pH > 7) according to accepted standards.9,27,28 For analysis, liquid and mixed GER episodes were grouped (liquid/mixed GER) as well as weakly acidic and weakly alkaline GER (WA GER). Manometry tracings were analyzed for TLESRs and LES resting pressure. The data were analyzed for different periods: slow infusion, fast infusion, total infusion, postprandial period first position (30–60 min), postprandial period second position (60–90 min).
Gastric emptying breath test (GEBT)
To assess gastric emptying rate, a 13C Na-Octanoate breath test (GEBT) was performed. 100 mg 13C labeled Na-Octanoate (a stable isotope) was added to the liquid study meal by injecting it as a bolus within 1 min at the start of meal infusion. Breath samples were taken at 1-min intervals during the first 15 min of the study and at 5 min intervals during the remaining 75 min.
Obtained breath samples were analyzed for the ratio between 12CO2 and 13CO2 content using an isotope ratio mass spectrometer. 13CO2 concentration was used to calculate gastric emptying time as previously described.29 Three parameters to express gastric emptying time were used; time to reach peak 13C excretion (Time to Tmax), the maximum 13C excretion (%dose 13C at Tmax), a fitted curve was made and the slope of the onset of 13C excretion (GEonset) was calculated as %dose 13C at Tmax/Time to Tmax.
Gastric distension SPECT scans and assessment of gastric acid distribution
Gastric mucosa was labeled with 200 MBq 99 mTc-pertechnetate, a monovalant negatively charged molecule accumulated and secreted by the gastric parietal cells, closely in parallel with gastric acid secretion. This was previously used and validated to visualize gastric volume change (as a marker for gastric distension and accommodation) and intragastric acid distribution on single photon emission computer tomography (SPECT).30–32
Subjects were positioned in lateral position on the imaging table of a large field-of-view (GE Infinia II, ‘s Hertogenbosch, The Netherlands) gamma camera equipped with low-energy high-resolution collimators with the stomach in the middle of the field-of-view. Five fast SPECT scans were acquired (7 min, 72 views, 10 sec/view, 128 × 128 matrix). After completion of the acquisition, data were reconstructed on a Hermes computer (Hermes Medical Solutions, Stockholm, Sweden).
From the acquired SPECT scans, the fasting (baseline) gastric volume was calculated as previously described.33 Total, proximal (fundus), and distal (antrum) gastric volume change were calculated relative to baseline volume as a marker of activation of mechanoreceptors through gastric distension and accommodation. Throughout this article this will be referred to as gastric distension.
On the fifth scan, the distribution of gastric acid was analyzed visually to assess patterns of gastric acid pooling.
Analysis was performed blinded to the identity of the subject (GERD patient/HC) and position of the subject (LLP/RLP). Data of the first hour postprandial were grouped, including the postprandial period first position (30–60 min) of the first study and the matching lateral position of the postprandial period (60–90 min) of the second study.
Time to first TLESR after the start of the liquid test meal infusion, numbers of TLESRs and GER episodes, the type (acidic, WA) of GER episodes, gastric emptying time, and gastric distension (total, proximal and distal) were compared between groups (GERD patients vs HC) and position (LLP vs RLP). Furthermore, correlations between TLESRs, GER, gastric emptying, and gastric distension were assessed.
As the data were non-Gaussian, all parameters were described using medians and interquartile ranges (IQR) unless otherwise stated and were compared using the Wilcoxon’s signed rank test for paired data and the Mann–Whitney-U for non-paired data. Dichotomous data were analyzed using a Fisher’s exact test. Correlations were calculated using Spearman’s correlation. A P-value <0.05 was considered statistically significant.
Ten GERD patients [seven men, median (range) age: 31 (18–57) years, median (range) BMI: 24 (21–29)] and 10 healthy controls [four men, median (range) age: 22 (19–57) years, median (range) BMI: 23 (19–28)] were included in the study. BMI was not different between the groups (P = 0.39). One GERD patient did not complete the study protocol due to severe nausea and vomiting when turning to RLP. Data obtained during the first hour of his study in both RLP and LLP are reported. All HC completed the study protocol without problems. HC had median (IQR) RDQ scores of 0 (0–0). The GERD patients had a median RDQ score of 15 (9–21). One GERD patient had a hiatal hernia of <3 cm as diagnosed by endoscopy.
Onset of TLESRs after infusion start
The time of onset of the first TLESR after the constant infusion of a liquid meal was comparable between GERD patients and HC both in LLP (25 (10–43) vs 19 (1–36) min) and RLP (24 (9–39) vs 23 (4–41) min). Time of onset of TLESRs did not correlate with gastric emptying or gastric distension.
Postprandial TLESRs and GER
Gastroesophageal reflux disease patients had an increased number of TLESRs in the first postprandial hour in RLP compared to LLP (5 (4–14) and 4.5 (2–6), respectively, P = 0.046) whereas HC did not exhibit this difference between RLP and LLP (4 (2–4) and 4 (3–6), respectively, P = 0.7) (Fig. 2). The difference in TLESRs and GER episodes in RLP between GERD patients and HC did not reach statistical significance (P = 0.089 and P = 0.123, respectively). In GERD patients the majority of GER episodes were liquid/mixed irrespective of position, while in HC, LLP was associated with significantly less liquid GER (47% (11–69%) of liquid/mixed GER compared to 80% (73–100%) in RLP, P = 0.015 (Fig. 3). In both LLP and RLP, GERD patients have more acid GER episodes [LLP and RLP combined: 2 (2–5) vs 0.5 (0–1), P = 0.008] and more liquid/mixed GER episodes [5 (4–14) vs 3.5(1–7) P = 0.01] compared to HC.
Gastric emptying reached peak 13C -excretion faster in RLP compared to LLP in both GERD patients [Time to Tmax in RLP: 36 (26–46) min and in LLP: 49 (41–74) min, respectively, P = 0.007] and HC [Time to Tmax in RLP: 43 (35–54) min and in LLP: 48.5 (43–73) min, respectively, P = 0.017]. In RLP GERD patients had a significantly faster GE onset (P = 0.008) and Time to Tmax is shorter (P = 0.028) compared to HC (Fig. 4, gastric emptying curves). In LLP no difference was found between HC and GERD patients.
Lower esophageal sphincter pressure was reduced significantly in the first postprandial 30 min in RLP [from 11 (8–15) mmHg to 7 (4–12) mmHg after infusion, P = 0.007] and in LLP [from 11 (10–17) mmHg to 10 (6–15) mmHg after infusion, P = 0.004]. There were no significant differences between HC and GERD patients in LLP or RLP. When starting in RLP, LES pressure [from 11 (9–13) to 9 (7–13) mmHg, P = 0.55] did not change after turning to LLP. Alternatively, turning from LLP to RLP resulted in a decrease of LES pressure [from 10 (5–18) to 7 (4–10) mmHg, P = 0.001] in all patients.
Gastric distension and acid distribution
When assessing the whole stomach, more gastric distension was observed in LLP compared to RLP (ratio scan 5 vs scan 1 in GERD patients and HC combined, P = 0.05). GERD patients exhibited a more pronounced increase in distension in RLP than HC. GERD patients had significantly greater distension of the stomach compared to HC after slow infusion (P = 0.015) and during the start of the fast infusion (P = 0.023). Interestingly, proximal stomach distension was significantly enhanced during the last scan in RLP in GERD patients compared to HC, P = 0.034 (Fig. 4, proximal gastric distension curves).
On the fifth scan, the distribution of gastric acid was analyzed visually to assess patterns of gastric acid pooling. Two distinct patterns were observed; one pattern with a proximal and distal acid pool (two high pertechnetate signal intensity zones) and one pattern with one acid pool (one high pertechnetate signal intensity zone; Fig. 5). The fifth scan of every study was classified into one of these two patterns. These patterns were significantly different (Fisher’s exact test P < 0.001) in LLP compared to RLP in both GERD patients and healthy volunteers. Pattern one (proximal and distal pooling of acid, Fig. 5A) was observed in 16 of 20 scans in LLP, while pattern two (one homogenous acid pool, Fig. 5C) was observed in 20 of 20 scans in RLP. There was no difference between GERD patients and HC.
In this study, we have shown that the effect of lateral position on GER and its underlying mechanisms is significantly different in GERD patients compared to HC. Body position is known to increase the number of TLESRs and GER in RLP.21,23 We indeed observed that TLESRs and GER are more prevalent in RLP in GERD patients, however, this effect was not observed in HC. We also observed more rapid gastric emptying in the RLP in both GERD patients and HC with GERD patients having more rapid early gastric emptying. Furthermore, we demonstrate, that postprandial proximal gastric distension in RLP is more pronounced in GERD patients.
In line with our previous studies investigating the influence of lateral positioning on gastric emptying and GER in premature infants,22,23 we demonstrated that in RLP the incidence of GER is increased while gastric emptying is accelerated.
Gastric emptying was measured by adding the 13C octanoate marker at the beginning of the infused test meal. This experimental setup was chosen to measure the onset on gastric emptying most accurately. In LLP, the onset of gastric emptying was later than that in RLP. This may have allowed the octanoate to dilute in the meal, leading to a more delayed measurement of an increase in octanoate.34 Passive factors such as gravity or buoyancy may have had a delaying effect on the early emptying phase in LLP due to independent effects of position on gastric function.35 However, in this study protocol we were most interested in the onset of gastric emptying the difference between GERD patients and HC in the respective positions. The onset of gastric emptying is less influenced by the dilution of the marker in the meal supported by the fact that there was no significant difference in the onset of gastric emptying in LLP compared to RLP. Furthermore, the difference between GERD patients and HC was observed in RLP.
An increase in TLESRs and GER, in a setting of accelerated GE may be explained by the now well characterized mechanism of gastric distension following nutrient presentation to the duodenum. This may largely be due to CCK release, which is known to decrease LES pressure and augment gastric distension, the latter mechanism enhances TLESRs.16 However, CCK can also down regulate gastric emptying17 via stimulation of isolated pyloric pressure waves and increase basal pyloric tone.36,37 This response may explain the convergence of the gastric emptying curves of GERD compared to those of the HC in the 30–60 min following the meal infusion in RLP (Fig. 4B). Although gastric emptying rate differences may influence CCK release, we did not measure serum CCK in this experiment and therefore we are unable to draw further conclusions with respect to the precise role of CCK and other gut hormones.
It should be recognized that, although consistent with known physiological effects, our findings are inconsistent with clinical dogma that gastric emptying is delayed in GERD patients and, therefore, accelerating GE will lead to a reduction in GER. This clinical impression is widespread and has led to prokinetic agents being used to treat GER symptoms despite the lack of evidence for its effectiveness.38 The findings of this study do not support the rationale for the use of prokinetics in the treatment of GERD, it should, however, be recognized that this study was not performed in a physiological setting and this study design differed from standard test settings. Prokinetics may have a more complex, yet unknown, effect on gastric function and GERD.
The increase in gastric distension of the whole stomach after constant infusion of a liquid meal was more pronounced in LLP compared to RLP and there was no difference between GERD patients and HC. However, the proximal gastric distension was significantly greater in RLP compared to LLP in GERD patients as has been observed by others.38–40 The increased distension in GERD patients may have contributed to the increased numbers of TLESRs although this effect was less pronounced (P = 0.089). Not only distension of the proximal stomach but also distension of the EGJ has been reported to play a role in GER. Pandolfino et al. showed that the EGJ is more compliant in GERD patients than in controls.41 They propose that the anatomic degradation leading to wider opening of the EGJ during TLESRs may partly explain the difference in the type of the refluxate between GERD patients and controls. This hypothesis could explain our finding of TLESRs resulting in more liquid GER in GERD patients in RLP.
Van Herwaarden et al.21 observed that HC had increased TLESRs and GER in RLP, whereas we did not show a difference in TLESR in RLP vs LLP in our HC group. This discrepancy may be explained by differences in the protocols used. Van Herwaarden studied patients over a longer period and incorporated a refluxogenic meal, both resulting in more GER events in the subjects they studied.
Our results also differ with the papers by Mittal and Sifrim in which the authors report that TLESRs are equally frequent in GERD patients and HC.10,42,43 Although not statistically significant, we observed a trend toward TLESRs being more frequent in RLP in GERD patients than that in controls. It is important to note that the studies which originally described TLESR as a reflux mechanism, also reported greater numbers of TLESRs in GERD patients vs controls.3–5 In these and subsequent studies subjects stayed in recumbent position or undergoing 24 h measurement, TLESRs were more prevalent in GERD patients than those in HC.44,45 In contrast, subjects in the studies of Sifrim and Mittal were studied in sitting position, possibly explaining the different findings in those studies.
Gastric acid distribution has been suggested to be an important determinant of the type of GER in GERD patients and HC.32,46–49 We observed a distinctly different pattern of 99mTc-pertechnetate pooling as a marker of gastric acid in LLP vs RLP, with more pooling in the proximal and distal stomach in LLP suggesting that the acid pool floats on top of the gastric contents. Our experimental setting was not specifically designed to measure pooling of gastric acid and, therefore, we were unable to visualize the position of the acid pool in relation to the EGJ. However, our results indicate that the location of the acid pool is dependent on body position.
There are some limitations to this study. The study groups are relatively small, although the robust crossover design yielded significant differences between the groups. Furthermore, this study was performed in non-physiological test settings. It is important to recognize the benefits and limitations of this setting. The two-phase infusion protocol was chosen for the following reasons; the initial, slow phase was designed to ensure accurate measurement of the first onset on gastric emptying. The second, more rapid infusion rate was chosen to promote gastric distension and, therefore, the triggering of TLESRs due to this mechanism. This design may have promoted more pronounced differences in onset of gastric emptying and in number of TLESRs.
In conclusion, TLESRs, GER, distension of proximal stomach, and gastric emptying are increased in RLP in GERD patients compared to HC. The underlying mechanism for these effects may relate to increased gastric distension in RLP enhanced by more rapid delivery of nutrients to the duodenum in GERD patients and possibly by pooling of gastric contents in the fundus in RLP. There was no difference in time to onset of GER between GERD patients and HC or RLP and LLP nor did we observe a correlation with gastric emptying or gastric distension suggesting the interaction between these factors may be not be explained by a simple model. Furthermore, this study suggests that the interaction of the factors regulating the number of TLESRs may be disrupted in GERD patients. In future studies, investigators should carefully consider positioning of the study subject as this study suggests that differences between HC and GERD patients are most pronounced in RLP.
The authors have no competing interests.
All authors took part in the design of the study and critically reviewed the final manuscript. CL and MS recruited patients, performed the measurement, analyzed, and wrote the manuscript. CL and MS contributed equally to the manuscript.