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Usefulness of low- and high-volume multiple rapid swallowing during high-resolution manometry
Digestive and Liver Disease 47 (2015) 103–107
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Usefulness of low- and high-volume multiple rapid swallowing during high-resolution manometry Alessandra Elvevi a , Aurelio Mauro a , Delia Pugliese a , Ivana Bravi a , Andrea Tenca a , Dario Consonni b , Dario Conte a , Roberto Penagini a,∗ a b
Gastrointestinal and Digestive Endoscopy Unit, Università degli Studi and Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy Epidemiology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
a r t i c l e
i n f o
Article history: Received 10 March 2014 Accepted 1 October 2014 Available online 12 November 2014 Keywords: High-resolution manometry Multiple rapid swallowing Oesophageal motility
a b s t r a c t Background: It has been suggested that multiple rapid swallowing should be added to oesophageal manometry. Aim: To prospectively evaluate whether 10 and 200 mL multiple rapid swallowing provide different information concerning motor function. Methods: 30 consecutive patients with oesophageal symptoms, 13 achalasia patients after successful pneumatic dilation and 19 healthy subjects performed eight 5 mL single swallows, two 10 mL and one 200 mL multiple rapid swallowing. Results: Almost all of the healthy subjects and two-thirds of the patients with oesophageal symptoms showed motor inhibition during both 10 and 200 mL multiple rapid swallowing. The oesophago-gastric pressure gradient was significantly higher during 200 mL multiple rapid swallowing within each group (p < 0.01), and significantly higher in the achalasia patients than in the other two groups (p < 0.0001). Presence of a contraction and increased contraction strength in comparison with single swallows were both more frequent after 10 mL than after 200 mL multiple rapid swallowing in the healthy subjects and the patients (p < 0.05). Conclusion: Motor inhibition could be similarly evaluated by means of 10 and 200 mL multiple rapid swallowing; 10 mL evaluated the after-contraction, whereas 200 mL multiple rapid swallowing was more valuable in identifying increased resistance to outflow. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Patients with oesophageal symptoms are often referred for oesophageal manometry in order to investigate the cause of the symptoms, and a motility disorder is diagnosed in a variable proportion of cases depending on the series [1–3]. Highresolution manometry (HRM) has improved the diagnostic yield of oesophageal motility studies, and led to the further characterisation of clinically relevant phenotypes [3,4]. Various tests have been proposed as a means of further characterising patients with oesophageal symptoms and detecting motor abnormalities in those with normal oesophageal manometry
∗ Corresponding author at: Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Pad. Granelli, Via F. Sforza 35, 20122 Milano, Italy. Tel.: +39 02 55033595; fax: +39 02 50320403. E-mail address: [email protected] (R. Penagini).
findings, including low (10 mL) or high volume (200 mL) multiple rapid swallowing (MRS) [5–8] and the ingestion of a solid bolus [8–10]. When swallows are made in rapid succession (with an interval of <4 s between them) [11,12], no peristaltic wave appears until the last swallow because new deglutition inhibits the activity of a previous swallow as a result of neural inhibition and smooth muscle refractoriness [13]. The lower oesophageal sphincter (LOS) relaxes from the first deglutition onward, and remains relaxed throughout the whole series [13]. The last swallow of a MRS series is followed by a powerful peristaltic sequence in the oesophageal body together with post-relaxation contraction in the LOS [6,11,13]. A normal response to MRS requires not only the integrity of both the inhibitory and excitatory neural pathways, but also the integrity of the oesophageal muscle in order to allow inhibition during MRS and powerful contraction afterwards. It is known that 10 mL MRS during oesophageal manometry can be used to evaluate the motor reserve in patients with oesophageal
http://dx.doi.org/10.1016/j.dld.2014.10.007 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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symptoms and hypotensive peristalsis [6], and MRS can be useful for predicting the development of dysphagia in patients who have undergone anti-reflux surgery [7]. In addition to motor inhibition and after-contraction, 200 mL MRS could also be used to detect increased oesophageal resistance to outflow, as assessed by the oesophago-gastric pressure gradient because of the high volume of water flowing through the oesophagus. However, it is not known whether the use of 10 or 200 mL MRS as a provocative test provides clinicians with the same or complementary information about oesophageal motor function. The aim of this study was to elucidate this point using HRM.
2. Materials and methods 2.1. Study population We prospectively enrolled all of the patients with oesophageal symptoms (i.e. dysphagia, chest pain, heartburn and regurgitation) referred to our Centre for oesophageal manometry between September and December 2012, and all of the routinely followed-up achalasia patients successfully treated by means of pneumatic dilation who underwent oesophageal manometry between September 2012 and May 2013. The latter group was included in the study as a model of patients with increased oesophageal resistance to outflow because it is known that they have decreased oesophago-gastric junction distensibility [14,15]. Healthy subjects were enrolled as a control group. Written informed consent was obtained from all of the study participants, and the study was approved by the Human Research Review Committee of the Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico of Milan.
2.4. Data analysis 2.4.1. Oesophageal manometry Oesophageal motility after the SS was characterised using the Chicago Classification [16]. 2.4.2. Analyses during MRS (1) The presence of motor inhibition, defined as the absence of any motor activity ≥20 mmHg of amplitude in the distal oesophageal body. (2) The oesophago-gastric pressure gradient (OGPG), defined as the difference between intra-oesophageal and intragastric pressure, with the first being measured 3 cm above the upper border of the LOS during the last five seconds of MRS or, in the presence of contractions, during the last five seconds of suppressed motility [8]. (3) LOS relaxation, measured as the 4-second integrated relaxation pressure (4s IRP) during the last 10 s of MRS. 2.4.3. Analyses after MRS After seeking the presence of an after-contraction of the oesophageal body (defined as the presence of a pressure wave of >20 mmHg of amplitude in the distal oesophageal body), the ratio between the distal contractile integral (DCI) of the identified aftercontraction and the mean DCI of a SS (the MRS/SS DCI ratio) was calculated. A contraction of the oesophageal body was considered to be related to MRS (i.e. an after-contraction) if it reached the upper border of the LOS within 10 s of the last swallow. As the majority of achalasia patients did not have proper contraction waves of the oesophageal body, their MRS analyses only included the OGPG and LOS relaxation. 2.5. Statistical analysis
2.2. Oesophageal manometry HRM (Solar HRM, MMS, The Netherlands) was performed using a disposable 20-sensor catheter (MMS G-90500). The most distal side hole (2 cm from the tip of the catheter) recorded intragastric pressure; 5 cm more proximally, five side holes spaced 1 cm apart recorded the motor activity of the oesophago-gastric junction; and the remaining 13 side holes spaced 2 cm apart recorded the motor activity of the oesophageal body, the upper oesophageal sphincter and the pharynx. The catheter lumens were perfused with degassed distilled water at a rate of 0.1 mL/min, and were all connected to a pressure transducer (DTX Plus TNF-R). The manometric signals were visualised as isobaric contour plots on a dedicated screen, and were stored for subsequent analysis using commercial software (MMS Investigation & Diagnostic Software, Version 8.19, build 2188). 2.3. Study protocol In all cases, the oesophageal manometry catheter was passed trans-nasally under topical anaesthesia (Lidocaine spray 10%) after an overnight fast, and positioned so that it straddled the LOS. The whole test was performed the patients in a recumbent position on their right side. Each test started with eight 5 mL single swallows (SS) of water at intervals of 20–30 s, followed by two 10 mL MRS as follows: swallows of 2 mL of water were administered through a syringe at intervals of 2–3 s, while the physician indicated the rhythm of swallowing [5]. Finally, one multiple rapid swallowing of 200 mL of water within 30 s was administered using a straw [8].
The results are expressed as median values, and their 25th and 75th percentiles. The continuous variables were compared using non-parametric tests (Wilcoxon’s signed-rank for paired comparisons and the Wilcoxon–Mann–Whitney test for comparisons between groups). The frequency of motor inhibition during 10 and 200 mL MRS, and motor activity afterwards, was compared within each group using McNemar’s test, and between groups using Pearson’s chi-squared test. The Kruskal–Wallis test was used to correlate the patients’ symptoms and the manometric variables. 3. Results Thirty-eight patients with oesophageal symptoms and 19 achalasia patients were originally enrolled, but eight with oesophageal symptoms and six achalasia patients were excluded because they did not manage to drink 200 mL of water or drank it in more than 30 s (n = 12) or because they had undergone anti-reflux surgery (n = 2). The final analysis was therefore based on 30 patients with oesophageal symptoms (15 men; mean age 56 years, range 20–74) and 13 achalasia patients (seven men; mean age 58 years, range 28 to 73). On the basis of the Chicago Classification [16], the patients with oesophageal symptoms were diagnosed as having weak peristalsis with small or large peristaltic defects (n = 18), frequently failing peristalsis (n = 2), oesophago-gastric junction outflow obstruction (n = 2), no peristalsis (n = 1), or jackhammer oesophagus (n = 1); the remaining were classified as normal. Of the 13 achalasia patients, one had type 1 and twelve type 2 achalasia at the time of diagnosis; peristaltic motor activity had been restored after pneumatic dilation in four of the 12 patients with type 2 achalasia. The achalasia patients had a negative intra-oesophageal pressure of −5 (from −10 to −1) mmHg, a non-dilated oesophagus
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at barium oesophagogram with a diameter of 2.0 (1.9 to 2.6) cm, and a 4s IRP of <15 mmHg. The control group consisted of 19 healthy subjects: seven men and 12 women with a mean age of 28 years (range 23–33). 3.1. Motor inhibition during MRS Eighteen of the 19 healthy subjects showed complete motor inhibition during both 10 and 200 mL MRS. Twenty-one of the 30 patients with oesophageal symptoms showed complete motor inhibition during 10 mL MRS and 20 patients during 200 mL MRS. More patients than healthy subjects had impaired motor inhibition during both 10 and 200 mL MRS: respectively 9 (30%) and 10 (33%) vs 1 (5%) and 1 (5%) (p < 0.05). Three (50%) of the six patients with oesophageal symptoms and normal peristalsis after SS had impaired motor inhibition during both 10 and 200 mL MRS. 3.2. Oesophago-gastric pressure gradient during MRS The OGPG was significantly higher during 200 mL MRS than during 10 mL MRS in all of the groups: 1 (0 to 2.8) vs −0.5 (−1.9 to 0) mmHg (p < 0.001) in the healthy subjects; 1 (−1 to 4) vs −1 (−4 to 2) mmHg (p < 0.01) in the symptomatic patients; and 9 (4 to 13) vs −0.5 (−2.5 to 2.8) mmHg (p < 0.01) in the achalasia patients (Fig. 1). Although the OGPG of the symptomatic patients as a whole was not different from that of the healthy subjects, four, including one with normal SS manometry, had a higher OGPG during 10 mL MRS, and six, including two with normal SS manometry, had a higher OGPG during 200 mL MRS. The achalasia patients had higher OGPG values than both the healthy subjects and symptomatic patients only during 200 mL MRS (p < 0.0001).
Fig. 1. Oesophago-gastric pressure gradient during 10 mL and 200 mL multiple rapid swallowing in healthy subjects, patients with oesophageal symptoms and achalasia patients; *p < 0.01 vs 10 mL in the same group. †p < 0.0001 vs 200 mL in healthy subjects and patients with oesophageal symptoms. OGPG, oesophago-gastric pressure gradient; HS, healthy subjects; pts, patients.
1.5 (−0.5 to 4.9) mmHg during 10 mL MRS (p < 0.05) and 1.4 (−0.8 to 2.5) mmHg during 200 mL MRS (p < 0.001) in the symptomatic patients. In the achalasia patients, the corresponding values were respectively 4.9 (1.7 to 6.0) mmHg, 5.9 (3.6 to 7.4) mmHg (p = 0.2 vs SS) and 5.3 (1.3 to 7.2) mmHg (p = 0.5 vs SS). The achalasia patients had higher 4s IRP values than the healthy subjects during SS (p < 0.5), 10 mL MRS (p < 0.01) and 200 mL MRS (p < 0.01), and higher values than the patients with oesophageal symptoms during 10 mL (p < 0.05) and 200 mL MRS (p < 0.001). 3.4. After-contraction
3.3. LOS relaxation during MRS There was no difference in 4s IRP between SS, 2.0 (0.9 to 2.8) mmHg, and 10 mL, 1.6 (0.3 to 2.4) mmHg; p = 0.1 vs SS or 200 mL MRS, 2.0 (0.8 to 2.9) mmHg; p = 0.9 vs SS in the healthy subjects, but it significantly decreased from 2.6 (1.0 to 4.9) mmHg during SS to
All of the 19 healthy subjects showed an after-contraction after 10 mL MRS, but only 13 (68%) after 200 mL MRS (p < 0.05). Among the 30 patients with oesophageal symptoms, 28 (93%) showed an after-contraction after 10 mL MRS, and only 16 (53%) after 200 mL MRS (p < 0.0005) (see example in Fig. 2). The between-group
Fig. 2. Examples in a patient with weak peristalsis: (a) single swallow; (b) 10 mL multiple rapid swallowing (note the presence of a stronger contraction in comparison with a single swallow; (c) 200 mL multiple rapid swallowing (note the absence of an after-contraction).
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Fig. 3. Ratio between the distal contractile integral after multiple rapid swallowing and the distal contractile integral after a single swallow (the multiple rapid swallowing/single swallow distal contractile integral ratio) in healthy subjects and patients with oesophageal symptom. †p < 0.05 vs 10 mL in healthy subjects. DCI, distal contractile integral; MRS, multiple rapid swallowing; SS, single swallow; HS: healthy subjects; pts, patients.
difference in the percentage of subjects without an aftercontraction after 200 mL MRS was significant (p < 0.0001). Fig. 3 shows the MRS/SSDCI ratios. Seventy-nine percent of the healthy subjects had an MRS/SS DCI ratio of >1 after 10 mL MRS, but only 26% after 200 mL MRS (p < 0.01). The corresponding figures among the symptomatic patients were 50% and 23% (p < 0.01), and 67% and 29% (p < 0.05) in the subgroup with weak peristalsis. The MRS/SS DCI ratio after 10 mL MRS was significantly higher in the healthy subjects than in the patients with oesophageal symptoms (p < 0.05) whereas the ratio after 200 mL MRS was similar in the two groups (p = 0.3). 3.5. Correlation between patient symptoms and the manometric findings When comparing dysphagia patients with the other symptomatic patients a higher (p < 0.05) MRS/SS DCI ratio both after 10 and 200 mL MRS was found, 1.5 (1.0 to 2.5) vs 0.9 (0.7 to 1.2) and 1.4 (0.8 to 1.9) vs 0.6 (0.3 to 1.0) respectively. No differences regarding OGPG or 4s IRP were found. 4. Discussion Our study provides an insight into the usefulness of low and high volume MRS incorporated into routine oesophageal HRM. Both types of MRS are useful for evaluating motor inhibition during swallowing, but 10 mL MRS detected more symptomatic patients who increased the strength of their after-contraction in comparison with SS, and 200 mL MRS differentiated the patients known to have increased resistance to outflow (i.e. achalasia patients). With regard to the inhibition of oesophageal body motility, our findings confirm those obtained using standard manometry [6] insofar as motor inhibition during 10 mL MRS occurred in almost of the healthy subjects, whereas it was altered in a substantial proportion of patients, including those with normal manometry findings after SS. We obtained similar results with 200 mL MRS, which suggests that the two types of MRS are similarly valuable when testing the integrity of the inhibitory pathways of the oesophageal body. The clinical relevance of incomplete inhibition during MRS is still unclear, but it is possibly involved in the perception of obstructive symptoms due to impaired oesophageal clearance of liquids and solids when rapidly swallowing during meals.
As expected, swallowing a higher volume of water led to higher OGPG values in all three groups: i.e. healthy subjects, patients with oesophageal symptoms and achalasia patients after successful pneumatic dilation. The last group was included because it is known that they have less oesophago-gastric junction distensibility than healthy subjects [14,15], which is in line with higher 4s IRP in our series even though it was <15 mmHg, their oesophagus was non-dilated and basal intra-oesophageal pressure was negative. They therefore represented an ideal group for testing the ability of 10 and 200 mL MRS to detect impaired outflow of swallowed water. Only 200 mL MRS proved to be able to differentiate our achalasia patients from the healthy subjects and patients with oesophageal symptoms, which suggests that a high volume of water has to be swallowed in a short time in order to be able to differentiate patients with impaired outflow. In order to gain an insight into the clinical usefulness of this variable, we looked for differences between the patients with non-obstructive dysphagia and those with other oesophageal symptoms, but the small numbers prevented from us finding any. In order to investigate the existence and frequency of patients with increased OGPG at 200 mL MRS, this test should be evaluated in a larger cohort of patients with endoscopy negative dysphagia and with no diagnosis of achalasia or OG junction outflow obstruction at routine HRM. It can be hypothesised that such patients may benefit from the use of smooth muscle relaxants, Botox injections or pneumatic dilation, but this to be verified in a controlled trial. Neither 10 nor 200 mL MRS had any effect on 4s IRP in healthy subjects, which was already maximal after SS. In the symptomatic patients, in whom 4s IRP was more variable after SS and >15 mmHg in two, MRS decreased 4s IRP presumably as a result of greater stimulation of the inhibitory neural pathways, as suggested by previously published traditional manometry data [5]. In the achalasia patients, 4s IRP was higher than in healthy subjects and did not change after MRS, most likely because of severe damage to the inhibitory neural pathways. Our findings confirm previous observations that 10 mL MRS increases the strength of oesophageal body contraction in comparison with SS in the majority of healthy subjects, and in half of the patients with oesophageal symptoms, in which the MRS/SS DCI ratio was significantly lower. Unlike 10 mL MRS, 200 mL MRS did not induce a contraction in one-third of our healthy subjects and half of the patients. The reason for this is unknown, but it can be postulated that the marked oesophageal distension caused by rapidly swallowing a large volume of water had an inhibitory effect or prevented oesophageal contraction, especially if weak, to occlude the lumen. Furthermore, there was no difference in the MRS/SS DCI ratio between the healthy subjects and the patients. Our findings strongly suggest that 10 mL MRS is better than 200 mL MRS in selecting patients with a “motor reserve” (i.e. those in whom the strength of peristalsis is increased in response to a stronger stimulus). This is clinically relevant especially in patients with weak peristalsis, and Shaker et al. [7] have shown that the absence of a reserve in patients referred for anti-reflux surgery predicts post-surgical dysphagia. Furthermore, as it has been reported that prokinetic drugs lead to disappointing results in patients with weak peristalsis [17], ongoing studies are testing the hypothesis that the presence of a motor reserve at MRS identifies patients who may benefit from such drugs. The limitations of the study include the relatively small number of enrolled patients and their heterogeneity; this may have meant that there were different pathophysiological mechanisms at play. Finally, it needs to be pointed out that, in order to be useful, patients must rapidly swallow the high volume of water within the allocated time. Physicians and their motility technicians/nurses therefore need to ensure the quality of MRS, and be prepared to repeat the tests or discard the results of those that are not
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performed correctly. On the basis of our experience, 10 mL MRS is performed correctly by more than 95% of patients, and 200 mL MRS by 80%. In conclusion, our observations suggest that 10 and 200 mL MRS tests are a rapid and inexpensive means of acquiring additional information concerning oesophageal motor function, and can help in the management of selected cases. Both can be used to evaluate motor inhibition, 10 mL MRS evaluates the presence and strength of after-contractions, and 200 mL MRS is more valuable in identifying patients with increased resistance to outflow. Although studies of larger patient cohorts with various motility disorders would shed more light on the clinical implications of MRS, the existing data support incorporating both forms into routine oesophageal manometry. Conflict of interest None declared. References [1] Dekel R, Pearson T, Wendel C, et al. Assessment of oesophageal motor function in patients with dysphagia or chest pain – the clinical outcomes research initiative experience. Alimentary Pharmacology and Therapeutics 2003;18:1083–9. [2] Katz PO, Dalton CB, Richter JE, et al. Esophageal testing of patients with noncardiac chest pain or dysphagia. Results of three years’ experience with 1161 patients. Annals of Internal Medicine 1987;106:593–7. [3] Pandolfino JE, Ghosh SH, Rice J, et al. Classifying esophageal motility by pressure topography characteristics: a study of 400 patients and 75 controls. American Journal of Gastroenterology 2008;103:27–37. [4] Fox MR, Bredenoord AJ. Oesophageal high-resolution manometry: moving from research into clinical practice. Gut 2008;57:405–23.
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[5] Savojardo D, Mangano M, Cantu P, et al. Multiple rapid swallowing in idiopathic achalasia: evidence for patients’ heterogeneity. Neurogastroenterology and Motility 2007;19:263–9. [6] Fornari F, Bravi I, Penagini R, et al. Multiple rapid swallowing: a complementary test during standard oesophageal manometry. Neurogastroenterology and Motility 2009;21:718–41. [7] Shaker A, Stoikes N, Drapekin J, et al. Multiple rapid swallow responses during esophageal high-resolution manometry reflect esophageal body peristaltic reserve. American Journal of Gastroenterology 2013;108:1706–12. [8] Daum C, Sweis R, Kaufman E, et al. Failure to respond to physiologic challenge characterizes esophageal motility in erosive gastro-esophageal reflux disease. Neurogastroenterology and Motility 2011;23, 517-e200. [9] Xiao Y, Nicodeme F, Kahrilas PJ, et al. Optimizing the swallow protocol of clinical high-resolution esophageal manometry studies. Neurogastroenterology and Motility 2012;24:e489–96. [10] Bogte A, Bredenoord AJ, Oors J, et al. Relationship between esophageal contraction patterns and clearance of swallowed liquid and solid boluses in healthy controls and patients with dysphagia. Neurogastroenterology and Motility 2012;24:e364–72. [11] Ask P, Tibbling L. Effect of time interval between swallows on esophageal peristalsis. American Journal of Physiology 1980;238:G485–90. [12] Vanek AW, Diamant NE. Responses of the human esophagus to paired swallows. Gastroenterology 1987;92:643–50. [13] Meyer GW, Gerhardt DC, Castell DO. Human esophageal response to rapid swallowing: muscle refractory period or neural inhibition? American Journal of Physiology 1981;241:G129–36. [14] Rohof WO, Hrisch DP, Kessing BF, et al. Efficacy of treatment for patients with achalasia depends on the distensibility of the esophagogastric junction. Gastroenterology 2012;143:328–35. [15] Pandolfino JE, de Ruigh A, Nicodème F, et al. Distensibility of the esophagogastric junction assessed with the functional lumen imaging probe (FLIP) in achalasia patients. Neurogastroenterology and Motility 2013;25:496–501. [16] Bredenoord AJ, Fox M, Kahrilas PJ, et al. Chicago classification criteria of esophageal motility disorders defined in high resolution esophageal pressure topography. Neurogastroenterology and Motility 2012;24(Suppl. 1):57–65. [17] Allescher HD, Ravich WJ. Medical treatment of esophageal motility disorders. Dysphagia 1993;8:125–34.
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Usefulness of low- and high-volume multiple rapid swallowing during high-resolution manometry Alessandra Elvevi a , Aurelio Mauro a , Delia Pugliese a , Ivana Bravi a , Andrea Tenca a , Dario Consonni b , Dario Conte a , Roberto Penagini a,∗ a b
Gastrointestinal and Digestive Endoscopy Unit, Università degli Studi and Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy Epidemiology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
a r t i c l e
i n f o
Article history: Received 10 March 2014 Accepted 1 October 2014 Available online 12 November 2014 Keywords: High-resolution manometry Multiple rapid swallowing Oesophageal motility
a b s t r a c t Background: It has been suggested that multiple rapid swallowing should be added to oesophageal manometry. Aim: To prospectively evaluate whether 10 and 200 mL multiple rapid swallowing provide different information concerning motor function. Methods: 30 consecutive patients with oesophageal symptoms, 13 achalasia patients after successful pneumatic dilation and 19 healthy subjects performed eight 5 mL single swallows, two 10 mL and one 200 mL multiple rapid swallowing. Results: Almost all of the healthy subjects and two-thirds of the patients with oesophageal symptoms showed motor inhibition during both 10 and 200 mL multiple rapid swallowing. The oesophago-gastric pressure gradient was significantly higher during 200 mL multiple rapid swallowing within each group (p < 0.01), and significantly higher in the achalasia patients than in the other two groups (p < 0.0001). Presence of a contraction and increased contraction strength in comparison with single swallows were both more frequent after 10 mL than after 200 mL multiple rapid swallowing in the healthy subjects and the patients (p < 0.05). Conclusion: Motor inhibition could be similarly evaluated by means of 10 and 200 mL multiple rapid swallowing; 10 mL evaluated the after-contraction, whereas 200 mL multiple rapid swallowing was more valuable in identifying increased resistance to outflow. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Patients with oesophageal symptoms are often referred for oesophageal manometry in order to investigate the cause of the symptoms, and a motility disorder is diagnosed in a variable proportion of cases depending on the series [1–3]. Highresolution manometry (HRM) has improved the diagnostic yield of oesophageal motility studies, and led to the further characterisation of clinically relevant phenotypes [3,4]. Various tests have been proposed as a means of further characterising patients with oesophageal symptoms and detecting motor abnormalities in those with normal oesophageal manometry
∗ Corresponding author at: Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Pad. Granelli, Via F. Sforza 35, 20122 Milano, Italy. Tel.: +39 02 55033595; fax: +39 02 50320403. E-mail address: [email protected] (R. Penagini).
findings, including low (10 mL) or high volume (200 mL) multiple rapid swallowing (MRS) [5–8] and the ingestion of a solid bolus [8–10]. When swallows are made in rapid succession (with an interval of <4 s between them) [11,12], no peristaltic wave appears until the last swallow because new deglutition inhibits the activity of a previous swallow as a result of neural inhibition and smooth muscle refractoriness [13]. The lower oesophageal sphincter (LOS) relaxes from the first deglutition onward, and remains relaxed throughout the whole series [13]. The last swallow of a MRS series is followed by a powerful peristaltic sequence in the oesophageal body together with post-relaxation contraction in the LOS [6,11,13]. A normal response to MRS requires not only the integrity of both the inhibitory and excitatory neural pathways, but also the integrity of the oesophageal muscle in order to allow inhibition during MRS and powerful contraction afterwards. It is known that 10 mL MRS during oesophageal manometry can be used to evaluate the motor reserve in patients with oesophageal
http://dx.doi.org/10.1016/j.dld.2014.10.007 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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symptoms and hypotensive peristalsis [6], and MRS can be useful for predicting the development of dysphagia in patients who have undergone anti-reflux surgery [7]. In addition to motor inhibition and after-contraction, 200 mL MRS could also be used to detect increased oesophageal resistance to outflow, as assessed by the oesophago-gastric pressure gradient because of the high volume of water flowing through the oesophagus. However, it is not known whether the use of 10 or 200 mL MRS as a provocative test provides clinicians with the same or complementary information about oesophageal motor function. The aim of this study was to elucidate this point using HRM.
2. Materials and methods 2.1. Study population We prospectively enrolled all of the patients with oesophageal symptoms (i.e. dysphagia, chest pain, heartburn and regurgitation) referred to our Centre for oesophageal manometry between September and December 2012, and all of the routinely followed-up achalasia patients successfully treated by means of pneumatic dilation who underwent oesophageal manometry between September 2012 and May 2013. The latter group was included in the study as a model of patients with increased oesophageal resistance to outflow because it is known that they have decreased oesophago-gastric junction distensibility [14,15]. Healthy subjects were enrolled as a control group. Written informed consent was obtained from all of the study participants, and the study was approved by the Human Research Review Committee of the Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico of Milan.
2.4. Data analysis 2.4.1. Oesophageal manometry Oesophageal motility after the SS was characterised using the Chicago Classification [16]. 2.4.2. Analyses during MRS (1) The presence of motor inhibition, defined as the absence of any motor activity ≥20 mmHg of amplitude in the distal oesophageal body. (2) The oesophago-gastric pressure gradient (OGPG), defined as the difference between intra-oesophageal and intragastric pressure, with the first being measured 3 cm above the upper border of the LOS during the last five seconds of MRS or, in the presence of contractions, during the last five seconds of suppressed motility [8]. (3) LOS relaxation, measured as the 4-second integrated relaxation pressure (4s IRP) during the last 10 s of MRS. 2.4.3. Analyses after MRS After seeking the presence of an after-contraction of the oesophageal body (defined as the presence of a pressure wave of >20 mmHg of amplitude in the distal oesophageal body), the ratio between the distal contractile integral (DCI) of the identified aftercontraction and the mean DCI of a SS (the MRS/SS DCI ratio) was calculated. A contraction of the oesophageal body was considered to be related to MRS (i.e. an after-contraction) if it reached the upper border of the LOS within 10 s of the last swallow. As the majority of achalasia patients did not have proper contraction waves of the oesophageal body, their MRS analyses only included the OGPG and LOS relaxation. 2.5. Statistical analysis
2.2. Oesophageal manometry HRM (Solar HRM, MMS, The Netherlands) was performed using a disposable 20-sensor catheter (MMS G-90500). The most distal side hole (2 cm from the tip of the catheter) recorded intragastric pressure; 5 cm more proximally, five side holes spaced 1 cm apart recorded the motor activity of the oesophago-gastric junction; and the remaining 13 side holes spaced 2 cm apart recorded the motor activity of the oesophageal body, the upper oesophageal sphincter and the pharynx. The catheter lumens were perfused with degassed distilled water at a rate of 0.1 mL/min, and were all connected to a pressure transducer (DTX Plus TNF-R). The manometric signals were visualised as isobaric contour plots on a dedicated screen, and were stored for subsequent analysis using commercial software (MMS Investigation & Diagnostic Software, Version 8.19, build 2188). 2.3. Study protocol In all cases, the oesophageal manometry catheter was passed trans-nasally under topical anaesthesia (Lidocaine spray 10%) after an overnight fast, and positioned so that it straddled the LOS. The whole test was performed the patients in a recumbent position on their right side. Each test started with eight 5 mL single swallows (SS) of water at intervals of 20–30 s, followed by two 10 mL MRS as follows: swallows of 2 mL of water were administered through a syringe at intervals of 2–3 s, while the physician indicated the rhythm of swallowing [5]. Finally, one multiple rapid swallowing of 200 mL of water within 30 s was administered using a straw [8].
The results are expressed as median values, and their 25th and 75th percentiles. The continuous variables were compared using non-parametric tests (Wilcoxon’s signed-rank for paired comparisons and the Wilcoxon–Mann–Whitney test for comparisons between groups). The frequency of motor inhibition during 10 and 200 mL MRS, and motor activity afterwards, was compared within each group using McNemar’s test, and between groups using Pearson’s chi-squared test. The Kruskal–Wallis test was used to correlate the patients’ symptoms and the manometric variables. 3. Results Thirty-eight patients with oesophageal symptoms and 19 achalasia patients were originally enrolled, but eight with oesophageal symptoms and six achalasia patients were excluded because they did not manage to drink 200 mL of water or drank it in more than 30 s (n = 12) or because they had undergone anti-reflux surgery (n = 2). The final analysis was therefore based on 30 patients with oesophageal symptoms (15 men; mean age 56 years, range 20–74) and 13 achalasia patients (seven men; mean age 58 years, range 28 to 73). On the basis of the Chicago Classification [16], the patients with oesophageal symptoms were diagnosed as having weak peristalsis with small or large peristaltic defects (n = 18), frequently failing peristalsis (n = 2), oesophago-gastric junction outflow obstruction (n = 2), no peristalsis (n = 1), or jackhammer oesophagus (n = 1); the remaining were classified as normal. Of the 13 achalasia patients, one had type 1 and twelve type 2 achalasia at the time of diagnosis; peristaltic motor activity had been restored after pneumatic dilation in four of the 12 patients with type 2 achalasia. The achalasia patients had a negative intra-oesophageal pressure of −5 (from −10 to −1) mmHg, a non-dilated oesophagus
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at barium oesophagogram with a diameter of 2.0 (1.9 to 2.6) cm, and a 4s IRP of <15 mmHg. The control group consisted of 19 healthy subjects: seven men and 12 women with a mean age of 28 years (range 23–33). 3.1. Motor inhibition during MRS Eighteen of the 19 healthy subjects showed complete motor inhibition during both 10 and 200 mL MRS. Twenty-one of the 30 patients with oesophageal symptoms showed complete motor inhibition during 10 mL MRS and 20 patients during 200 mL MRS. More patients than healthy subjects had impaired motor inhibition during both 10 and 200 mL MRS: respectively 9 (30%) and 10 (33%) vs 1 (5%) and 1 (5%) (p < 0.05). Three (50%) of the six patients with oesophageal symptoms and normal peristalsis after SS had impaired motor inhibition during both 10 and 200 mL MRS. 3.2. Oesophago-gastric pressure gradient during MRS The OGPG was significantly higher during 200 mL MRS than during 10 mL MRS in all of the groups: 1 (0 to 2.8) vs −0.5 (−1.9 to 0) mmHg (p < 0.001) in the healthy subjects; 1 (−1 to 4) vs −1 (−4 to 2) mmHg (p < 0.01) in the symptomatic patients; and 9 (4 to 13) vs −0.5 (−2.5 to 2.8) mmHg (p < 0.01) in the achalasia patients (Fig. 1). Although the OGPG of the symptomatic patients as a whole was not different from that of the healthy subjects, four, including one with normal SS manometry, had a higher OGPG during 10 mL MRS, and six, including two with normal SS manometry, had a higher OGPG during 200 mL MRS. The achalasia patients had higher OGPG values than both the healthy subjects and symptomatic patients only during 200 mL MRS (p < 0.0001).
Fig. 1. Oesophago-gastric pressure gradient during 10 mL and 200 mL multiple rapid swallowing in healthy subjects, patients with oesophageal symptoms and achalasia patients; *p < 0.01 vs 10 mL in the same group. †p < 0.0001 vs 200 mL in healthy subjects and patients with oesophageal symptoms. OGPG, oesophago-gastric pressure gradient; HS, healthy subjects; pts, patients.
1.5 (−0.5 to 4.9) mmHg during 10 mL MRS (p < 0.05) and 1.4 (−0.8 to 2.5) mmHg during 200 mL MRS (p < 0.001) in the symptomatic patients. In the achalasia patients, the corresponding values were respectively 4.9 (1.7 to 6.0) mmHg, 5.9 (3.6 to 7.4) mmHg (p = 0.2 vs SS) and 5.3 (1.3 to 7.2) mmHg (p = 0.5 vs SS). The achalasia patients had higher 4s IRP values than the healthy subjects during SS (p < 0.5), 10 mL MRS (p < 0.01) and 200 mL MRS (p < 0.01), and higher values than the patients with oesophageal symptoms during 10 mL (p < 0.05) and 200 mL MRS (p < 0.001). 3.4. After-contraction
3.3. LOS relaxation during MRS There was no difference in 4s IRP between SS, 2.0 (0.9 to 2.8) mmHg, and 10 mL, 1.6 (0.3 to 2.4) mmHg; p = 0.1 vs SS or 200 mL MRS, 2.0 (0.8 to 2.9) mmHg; p = 0.9 vs SS in the healthy subjects, but it significantly decreased from 2.6 (1.0 to 4.9) mmHg during SS to
All of the 19 healthy subjects showed an after-contraction after 10 mL MRS, but only 13 (68%) after 200 mL MRS (p < 0.05). Among the 30 patients with oesophageal symptoms, 28 (93%) showed an after-contraction after 10 mL MRS, and only 16 (53%) after 200 mL MRS (p < 0.0005) (see example in Fig. 2). The between-group
Fig. 2. Examples in a patient with weak peristalsis: (a) single swallow; (b) 10 mL multiple rapid swallowing (note the presence of a stronger contraction in comparison with a single swallow; (c) 200 mL multiple rapid swallowing (note the absence of an after-contraction).
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Fig. 3. Ratio between the distal contractile integral after multiple rapid swallowing and the distal contractile integral after a single swallow (the multiple rapid swallowing/single swallow distal contractile integral ratio) in healthy subjects and patients with oesophageal symptom. †p < 0.05 vs 10 mL in healthy subjects. DCI, distal contractile integral; MRS, multiple rapid swallowing; SS, single swallow; HS: healthy subjects; pts, patients.
difference in the percentage of subjects without an aftercontraction after 200 mL MRS was significant (p < 0.0001). Fig. 3 shows the MRS/SSDCI ratios. Seventy-nine percent of the healthy subjects had an MRS/SS DCI ratio of >1 after 10 mL MRS, but only 26% after 200 mL MRS (p < 0.01). The corresponding figures among the symptomatic patients were 50% and 23% (p < 0.01), and 67% and 29% (p < 0.05) in the subgroup with weak peristalsis. The MRS/SS DCI ratio after 10 mL MRS was significantly higher in the healthy subjects than in the patients with oesophageal symptoms (p < 0.05) whereas the ratio after 200 mL MRS was similar in the two groups (p = 0.3). 3.5. Correlation between patient symptoms and the manometric findings When comparing dysphagia patients with the other symptomatic patients a higher (p < 0.05) MRS/SS DCI ratio both after 10 and 200 mL MRS was found, 1.5 (1.0 to 2.5) vs 0.9 (0.7 to 1.2) and 1.4 (0.8 to 1.9) vs 0.6 (0.3 to 1.0) respectively. No differences regarding OGPG or 4s IRP were found. 4. Discussion Our study provides an insight into the usefulness of low and high volume MRS incorporated into routine oesophageal HRM. Both types of MRS are useful for evaluating motor inhibition during swallowing, but 10 mL MRS detected more symptomatic patients who increased the strength of their after-contraction in comparison with SS, and 200 mL MRS differentiated the patients known to have increased resistance to outflow (i.e. achalasia patients). With regard to the inhibition of oesophageal body motility, our findings confirm those obtained using standard manometry [6] insofar as motor inhibition during 10 mL MRS occurred in almost of the healthy subjects, whereas it was altered in a substantial proportion of patients, including those with normal manometry findings after SS. We obtained similar results with 200 mL MRS, which suggests that the two types of MRS are similarly valuable when testing the integrity of the inhibitory pathways of the oesophageal body. The clinical relevance of incomplete inhibition during MRS is still unclear, but it is possibly involved in the perception of obstructive symptoms due to impaired oesophageal clearance of liquids and solids when rapidly swallowing during meals.
As expected, swallowing a higher volume of water led to higher OGPG values in all three groups: i.e. healthy subjects, patients with oesophageal symptoms and achalasia patients after successful pneumatic dilation. The last group was included because it is known that they have less oesophago-gastric junction distensibility than healthy subjects [14,15], which is in line with higher 4s IRP in our series even though it was <15 mmHg, their oesophagus was non-dilated and basal intra-oesophageal pressure was negative. They therefore represented an ideal group for testing the ability of 10 and 200 mL MRS to detect impaired outflow of swallowed water. Only 200 mL MRS proved to be able to differentiate our achalasia patients from the healthy subjects and patients with oesophageal symptoms, which suggests that a high volume of water has to be swallowed in a short time in order to be able to differentiate patients with impaired outflow. In order to gain an insight into the clinical usefulness of this variable, we looked for differences between the patients with non-obstructive dysphagia and those with other oesophageal symptoms, but the small numbers prevented from us finding any. In order to investigate the existence and frequency of patients with increased OGPG at 200 mL MRS, this test should be evaluated in a larger cohort of patients with endoscopy negative dysphagia and with no diagnosis of achalasia or OG junction outflow obstruction at routine HRM. It can be hypothesised that such patients may benefit from the use of smooth muscle relaxants, Botox injections or pneumatic dilation, but this to be verified in a controlled trial. Neither 10 nor 200 mL MRS had any effect on 4s IRP in healthy subjects, which was already maximal after SS. In the symptomatic patients, in whom 4s IRP was more variable after SS and >15 mmHg in two, MRS decreased 4s IRP presumably as a result of greater stimulation of the inhibitory neural pathways, as suggested by previously published traditional manometry data [5]. In the achalasia patients, 4s IRP was higher than in healthy subjects and did not change after MRS, most likely because of severe damage to the inhibitory neural pathways. Our findings confirm previous observations that 10 mL MRS increases the strength of oesophageal body contraction in comparison with SS in the majority of healthy subjects, and in half of the patients with oesophageal symptoms, in which the MRS/SS DCI ratio was significantly lower. Unlike 10 mL MRS, 200 mL MRS did not induce a contraction in one-third of our healthy subjects and half of the patients. The reason for this is unknown, but it can be postulated that the marked oesophageal distension caused by rapidly swallowing a large volume of water had an inhibitory effect or prevented oesophageal contraction, especially if weak, to occlude the lumen. Furthermore, there was no difference in the MRS/SS DCI ratio between the healthy subjects and the patients. Our findings strongly suggest that 10 mL MRS is better than 200 mL MRS in selecting patients with a “motor reserve” (i.e. those in whom the strength of peristalsis is increased in response to a stronger stimulus). This is clinically relevant especially in patients with weak peristalsis, and Shaker et al. [7] have shown that the absence of a reserve in patients referred for anti-reflux surgery predicts post-surgical dysphagia. Furthermore, as it has been reported that prokinetic drugs lead to disappointing results in patients with weak peristalsis [17], ongoing studies are testing the hypothesis that the presence of a motor reserve at MRS identifies patients who may benefit from such drugs. The limitations of the study include the relatively small number of enrolled patients and their heterogeneity; this may have meant that there were different pathophysiological mechanisms at play. Finally, it needs to be pointed out that, in order to be useful, patients must rapidly swallow the high volume of water within the allocated time. Physicians and their motility technicians/nurses therefore need to ensure the quality of MRS, and be prepared to repeat the tests or discard the results of those that are not
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performed correctly. On the basis of our experience, 10 mL MRS is performed correctly by more than 95% of patients, and 200 mL MRS by 80%. In conclusion, our observations suggest that 10 and 200 mL MRS tests are a rapid and inexpensive means of acquiring additional information concerning oesophageal motor function, and can help in the management of selected cases. Both can be used to evaluate motor inhibition, 10 mL MRS evaluates the presence and strength of after-contractions, and 200 mL MRS is more valuable in identifying patients with increased resistance to outflow. Although studies of larger patient cohorts with various motility disorders would shed more light on the clinical implications of MRS, the existing data support incorporating both forms into routine oesophageal manometry. Conflict of interest None declared. References [1] Dekel R, Pearson T, Wendel C, et al. Assessment of oesophageal motor function in patients with dysphagia or chest pain – the clinical outcomes research initiative experience. Alimentary Pharmacology and Therapeutics 2003;18:1083–9. [2] Katz PO, Dalton CB, Richter JE, et al. Esophageal testing of patients with noncardiac chest pain or dysphagia. Results of three years’ experience with 1161 patients. Annals of Internal Medicine 1987;106:593–7. [3] Pandolfino JE, Ghosh SH, Rice J, et al. Classifying esophageal motility by pressure topography characteristics: a study of 400 patients and 75 controls. American Journal of Gastroenterology 2008;103:27–37. [4] Fox MR, Bredenoord AJ. Oesophageal high-resolution manometry: moving from research into clinical practice. Gut 2008;57:405–23.
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