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Reflux monitoring: pH-metry, Bilitec and Oesophageal impedance measurements
Best Practice & Research Clinical Gastroenterology 23 (2009) 299–311
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Best Practice & Research Clinical Gastroenterology
2
Reflux monitoring: pH-metry, Bilitec and Oesophageal impedance measurements Daniel Pohl, MD, Research Fellow a, Radu Tutuian, MD, Clinical Lead Functional GI Disorders b, * a b
Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425, USA University Clinic for Visceral Surgery and Medicine, Bern University Hospital, Inselspital, CH-3010 Bern, Switzerland
Keywords: gastro-oesophageal reflux disease pH monitoring impedance–pH monitoring bilirubin monitoring proton pump inhibitors
Gastro-oesophageal reflux disease (GERD) is a highly prevalent condition in Western countries leading to millions of outpatient visits per year. GERD symptoms including heartburn, regurgitation and chest pain are caused by reflux of gastric content in the oesophagus even in the absence of endoscopically visible mucosal lesions. Several procedures are used to identify gastro-oesophageal reflux, the clinically widely used are: conventional (catheterbased) pH monitoring, wireless oesophageal pH monitoring (Bravo), bilirubin monitoring (Bilitec), and combined multichannel intraluminal impedance–pH monitoring (MII–pH). Each technique has strengths and limitations of which clinicians and investigators should be aware when deciding which to choose in a particular patient. Important is the ability to quantify gastro-oesophageal reflux and evaluate the relationship between symptoms and reflux episodes. The present review summarises the technical aspects in performing and interpreting esophageal reflux monitoring procedures. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Gastro-oesophageal reflux disease (GERD) is a highly prevalent condition in industrialised countries amounting to millions of visits to gastrointestinal specialists each year [1]. Due to the high prevalence of disease, the financial burden caused alone by acid supressive therapy exceeds 10 billion $ per year in the United States [2].
* Corresponding author. Tel.: þ41 31 632 2403; Fax: þ41 31 632 9723. E-mail address: [email protected] (R. Tutuian). 1521-6918/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2009.04.003
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The first description of lesions induced by gastric content refluxing into the oesophagus comes from Allison in the mid-1940s [3]. Apart from recognising mucosal damage as the pathology to treat, it was soon realised that symptoms suggestive of GERD such as heartburn, regurgitation, chest pain and dysphagia could be caused by reflux of gastric content in the oesophagus even when there was no evidence of mucosal pathology during endoscopy. Thus, approaches other than endoscopy to monitor gastro-oesophageal reflux were needed. Quantifying gastro-oesophageal refluxate independent of mucosal lesions was first achieved using intraoesophageal pH monitoring in the distal oesophagus. This technique was soon accepted by investigators and clinicians as the gold standard to diagnose and monitor therapeutic interventions aimed at reducing distal esophageal acid exposure and number of gastro-oesophageal reflux episodes. Parallel to this was the development of potent gastric acid inhibitors – first histamine receptor 2 antagonists (H2-RA) and in the 1980 the even more potent proton pump inhibitors (PPI) – to treat GERD. The development of these potent gastric acid inhibitors with excellent patient tolerability had a major impact not only on treatment but also on the diagnosis of GERD. Empiric treatment with PPIs became the approach of choice in the primary care setting leading to a selection of patients referred for further testing to mainly those with persistent symptoms despite acid suppressive therapy. This development revealed the limitations of ‘simple’ esophageal pH monitoring, calling for the development of more advanced tools to monitor gastro-oesophageal reflux in these patients. The present paper reviews technical aspects, procedure and interpretation of widely used techniques to monitor gastro-oesophageal reflux starting with conventional pH monitoring, wireless esophageal pH monitoring (Bravo), bilirubin monitoring (Bilitec) and combined multichannel intraluminal impedance–pH monitoring (MII–pH). Oesophageal pH monitoring Esophageal pH monitoring is still the most widely used clinical tool to monitor gastro-oesophageal reflux. Prolonged intraoesophageal pH-measurements were first described by Spencer and colleagues in the late 1960s [4]. The technique became widely spread both in clinical and research setting after normal values were published by Johnson and DeMeester a decade later [5]. Over time esophageal pH monitoring became the gold standard in diagnosing GERD providing information on distal esophageal acid exposure and later in evaluation of symptom association with acid reflux episodes. Esophageal pH monitoring is now used in stationary and ambulatory practice with catheter-based and more recently catheter-free systems. Conventional, catheter-based pH monitoring For catheter-based pH monitoring one or more esophageal pH sensors are mounted on a flexible catheter and connected to a data storage device. The pH is measured either by glass or most often by antimony pH sensors with internal or external reference electrodes. Internal reference systems are preferred as the reference electrode is mounted on the same catheter that is positioned in the oesophagus or stomach, thus reducing the number of ‘wires’ connected to the patient. External reference systems use an electrode placed to the skin of the subject and are therefore influenced by factors influencing skin conductivity (i.e. dry or over-moistured skin, cutaneous lesions, accidental disconnection during movement, etc.). In vitro studies suggest that glass-electrodes are superior to monocrystalline antimony electrodes as they respond much quicker to changes in pH, have less drift and a better linear response [6]. Nevertheless in clinical practice, antimony electrodes provide similar results and have been shown to offer better insertion and study comfort compared to the larger glasselectrodes [7]. Antimony electrodes are less expensive allowing the production of more convenient and hygienic single-use, disposable catheters. The pH electrodes are calibrated using buffer solutions with determined pH values prior to examination. Two calibration substances are usually used – one in the acidic range (pH 1–4) and one in the neutral range (pH 6–7). After calibration the catheter is inserted transnasally into the oesophagus until the lower tip has reached the gastric cavity. Catheters may have one or more acid-sensing electrodes: in catheters with one pH electrode it is passed to come to rest 5 cm above the upper border
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of the lower esophageal sphincter. This position was chosen by global consensus and is regarded as the optimal position for distal esophageal acid exposure with limited risk of accidental slippage into the stomach. Most laboratories use dual pH electrodes (Fig. 1). Spacing pH sensors 10–15 cm apart allows placement of a pH electrode in the proximal and distal oesophagus or in the distal oesophagus and stomach. This allows using dual pH monitoring systems for either monitoring proximal and distal esophageal acid exposure or distal esophageal and gastric acid control. After the correct placement of the pH electrodes, patient instruction is of pivotal importance in having an optimal reflux recording. Patients are asked to undergo the same daily routines as usual and try to reproduce situations that cause the symptoms for which she/he underwent reflux monitoring. This is aimed at reproducing, as good as possible, normal daily activities and tries to maximise the ability to evaluate the relationship between symptoms and reflux. Beside symptoms patients are asked to record information on time of meals, medication and changes in body position. Most devices allow digital storage of events on the data logger using pre-coded softkeys for meals, body position and symptoms. For an ambulatory esophageal pH monitoring patients are asked to return the diary and data logger the following day. While most centres aim at 22–24 h of recording, recent data suggest that shorter studies (16 h) provide accurate information and improve patient compliance [8]. Catheter-free pH monitoring (BravoÒ System) Catheter-based pH-recording systems are not tolerated by all patients and limit the length of examination in even more patients. In the 1960s the first catheter-free device was released (the Heidelberg capsule) allowing telemetric recordings of intragastric pH [9,10]. Still, catheter-free oesophageal pH monitoring systems established their use in clinical practice only in recent years [11]. The Bravo system (Medtronic Inc., USA) includes a 26 mm 5.5 mm 6.5 mm capsule containing an antimony pH electrode with internal reference, miniaturised electronics with radiofrequency transmitter and battery, a capsule delivery system as well as an external receiver to monitor intraoesophageal pH (Fig. 2). Using a customised delivery system, the capsule is passed transorally during upper GI endoscopy and positioned in the distal oesophagus 6 cm above the gastro-oesophageal mucosal separation (‘Z-line’). The capsule is then attached (i.e. ‘pierced’) to the esophageal mucosa. Once released from the delivery system pH data are recorded. Bravo appears to be safe and patients including
Fig. 1. Conventional oesophageal pH monitoring using a 2-channel catheter with sensors in the distal (5 cm above LES) and proximal (15 cm above LES) oesophagus. The box shows examples of gastro-oesophageal reflux episodes defined as abrupt drop in pH from above to below 4.0 followed by gradual recovery of pH to baseline.
302 D. Pohl, R. Tutuian / Best Practice & Research Clinical Gastroenterology 23 (2009) 299–311 Fig. 2. Wireless pH monitoring system using a capsule with antimony pH electrode attached in the distal oesophagus 6 cm above the ‘Z-Line’. Data are transmitted to an external receiver allowing monitoring up to 4 days.
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children have been shown to tolerate Bravo measurements well [44–46]. Apart from offering more patient comfort, fixation of the capsule in the distal oesophagus avoids slippage into the stomach reducing position-and motion-induced changes and allowing longer recording times up to 96 hours. Length of recording is limited by battery life and spontaneous detachment of the probe from the esophageal mucosa. A recent study evaluating the feasibility of prolonged recordings in the clinical practice revealed that complete 96-h recordings were available in only 34/83 (41%) patients [12]. Current disadvantages of the system are the high cost of the pH capsule, need of upper endoscopy for accurate placement and impracticability of multiple recording sites. Questions answered by prolonged wireless esophageal pH-metry are distal esophageal acid exposure and the relationship between symptoms and gastro-oesophageal reflux episodes. Oesophageal pH data interpretation Once acquired by either catheter-based or catheter-free pH oesophageal pH systems, pH data are transferred from the logger to a work station to be analysed using dedicated software. Reflux episodes are characterised by an abrupt decline in intraoesophageal pH in the distal oesophagus. A cutoff pH 4.0 is used by most laboratories to identify acid reflux episodes (Fig. 1). Reasons for using the cutoff of 4.0 as a clinically useful parameter in gastroenterological practice include observations that proteolytic activity of pepsin rapidly decreases in solutions with a pH above 4.0 [13] and typical reflux symptoms (i.e. heartburn) are more often reported at intraoesophageal pH values below 4.0 [14]. This cutoff value has been challenged over the years by studies suggesting that a pH value of 5 may provide better discrimination between healthy volunteers and patients with reflux symptoms [15]. Other authors have suggested that the best discrimination between patients with reflux symptoms and healthy volunteers occurs within the full range between pH 3 and 6 rather than using one single pH value [16] or by studies proposing different pH threshold values for different positions based on pH distribution curves [17]. However the simplicity of using a single cutoff value prevailed and pH 4.0 is currently the most widely used cutoff value to identify gastro-oesophageal reflux episodes in ambulatory oesophageal pH monitoring. Based on this cutoff the number of gastro-oesophageal reflux episodes, number of reflux episodes exceeding 5 min and duration of intraoesophageal pH below 4 are used to define gastro-oesophageal reflux. These parameters are reported separately for total recording time, time spent in the upright and recumbent position. Since upright, recumbent periods and total duration of recording varies from one to another patient, reporting a ‘normalized’ percent time (i.e. duration of intraoesophageal pH < 4 divided by the total recording time) is preferred. Meal periods are generally excluded from analysis in order to avoid artefactual increase in oesophageal acid exposure time determined by the ingestion of acidic foods and drinks [18]. Nevertheless patients are asked to follow their usual diet and even encouraged to consume foods that typically cause symptoms and mark these ingestion periods accordingly. Based on studies in healthy volunteers, normal values for percent time pH < 4 have been established for both catheter-based and catheter-free systems (Table 1). Recordings in patients are compared against these values and classified as normal or abnormal. Several authors have proposed using scores to quantify distal oesophageal acid exposure. The most commonly used scores for adult patients are the Johnson/DeMeester and DeMeester score [5]. These scores are frequently used by surgical colleagues and are automatically calculated by most pH monitoring softwares based on the following six parameters: (1) total % time pH < 4, (2) % time pH < 4 in the upright period, (3) % time pH < 4 in the recumbent period, (4) total number of reflux episodes, (5) total number of reflux episodes longer than 5 min and (6) duration of the longest reflux episode. Recent studies show that these scores are not necessarily superior to percent time pH < 4 in discriminating between healthy volunteers and GERD patients [19,20]. Regardless whether one uses the composite score or individual acid exposure times a detailed evaluation of the pH tracing is of pivotal importance to recognise and exclude artifacts and to assess symptom association. Apart from quantification of distal oesophageal acid exposure and number of reflux symptoms the importance of association between symptoms, that drive the patient to seek medical care, and actual reflux events is being more and more recognised. Multiple assessment tools have been developed for
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Table 1 Normal values for oesophageal pH monitoring (catheter-based and wireless) and combined MII–pH monitoring based on 95th percentile data in healthy volunteers not taking acid suppressive therapy. pH monitoring
Impedance–pH monitoring
Catheter-based [5] Wireless [10] US–Belgian [32] French–Belgian [33] Italian [34] (N ¼ 52) (N ¼ 39) (N ¼ 60) (N ¼ 72) (N ¼ 25) Oesophageal pH data % time pH < 4 Total Upright Recumbent
4.2% 6.3% 1.2%
5.3% 6.9% 3.2%
6.7% 9.7% 2.1%
5.0% 6.2% 5.3%
4.0% 5.0% 3.0%
Oesophageal MII-data # Reflux episodes Total Acid Weakly acid Weakly alkaline
– – – –
– – – –
73 55 26 1
75 50 33 15
48 51 38 18
this purpose; the most commonly used ones are the symptom index (SI) and the symptom association probability (SAP). The symptom index constitutes a very simple and straightforward assessment tool. The SI, first described by Meyer et al, is the proportion of symptoms preceded by acid reflux episodes (i.e. drop in pH from above to below 4) within a 5-min time window out of the total number of symptoms. The SI may be determined separately for different symptoms and is declared positive if greater or equal to 50% (i.e. meaning that at least half of the reported symptoms are preceded by gastro-oesophageal reflux). This definition of symptom index is not uniformly accepted – especially regarding more atypical symptoms of reflux disease: for patients with chest pain Lam et proposed a shorter, 2-min time window, for a positive symptom association [21]. Recognising that using the symptom index (SI) the likelihood of a false positive association rises with increasing number of reflux episodes and decreasing number of symptoms, Breumelhof and Smout proposed the symptom sensitivity index (SSI) as additional parameter to evaluate symptom association during 24-h oesophageal pH monitoring [22]. The symptom sensitivity index is defined as the percentage of reflux episodes associated with symptoms out of the total number of reflux episodes. A symptom sensitivity index greater than 10% would further strengthen the association between symptoms and reflux in a given patient. Weusten et al developed the mathematically more complex symptom association probability (SAP) in search of a more robust parameter to evaluate symptom association [23]. The SAP evaluates if the distribution of reflux episodes and symptoms during the monitoring period occurs by chance or not. Commercially available software programs have the ability to calculate the SAP in percentage based on the methodology described by Weusten et al [23]. It is important to recognise that the SAP is a statistical analysis tool indicating the statistical probability of symptom–reflux association. To ensure a valid result and reduce the probability of symptom–reflux association by chance alone, only a SAP greater than 95% should be considered positive [24]. In summary, both catheter-based and wireless pH-metry uses the high acid concentration (i.e. low pH) of gastric content to detect gastro-oesophageal reflux. This allows quantifying distal oesophageal acid exposure and assessing the association between symptoms and acid reflux episodes. There is a wide and long experience with this method, establishing oesophageal pH monitoring as the gold standard in monitoring gastro-oesophageal reflux. Bilirubin monitoring (Bilitec) Oesophageal pH monitoring provides information on acid reflux episodes reaching the distal oesophagus. Still, other components of the gastric content play a role in the development of oesophageal lesions and markers other than pH levels are warranted when monitoring patients on acid suppressive therapy. Along these lines, one of the first alternative methods is bilirubin monitoring in the distal oesophagus. The role of duodeno-gastro-oesophageal reflux (DGER) or bile reflux in GERD pathology has been the subject of numerous investigations and has re-emerged as a topic of recent
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studies. Currently the best available method for clinical use is the spectrophotometric method Bilitec 2000 (Medtronic, Inc.). The system incorporates a small fibre-optic spectrophotometric chamber measuring the absorbance of light at a wavelength of 470 nm. Absorbance values exceeding 0.14 are considered indicative of the presence of bilirubin in the refluxate (Fig. 3). Similar to pH monitoring, the bilirubin sensor mounted on a catheter is placed transnasally in the distal oesophagus and positioned 5 cm above the proximal border of the lower oesophageal sphincter. The ambulatory procedure is also similar to catheter-based pH monitoring with the difference that patients are instructed to follow a ‘white’ diet since coloured foods and drinks are known to influence the spectrophotometric bilirubin measurements [25]. Although bilirubin monitoring can be used as stand-alone tool, in clinical practice it is often combined with pH monitoring in order to assess both gastro-oesophageal and duodeno-gastrooesophageal reflux. Bilitec data interpretation In analogy to distal oesophageal acid exposure, Bilitec monitoring will provide information on the distal oesophageal bile exposure as percentage of time bilirubin absorbance > 0.14. In terms of symptom association the rise and decline in bilirubin absorbance are not as rapid as for changes in oesophageal pH. While, in theory the same symptom association parameters as for pH monitoring could be calculated for bilirubin monitoring, these parameters have inherent shortcomings given the above mentioned ‘sluggishness’ of the changes in bilirubin absorbance. Clinical relevance of bilirubin monitoring Vaezi and Richter were among the first to report the prevalence of DGER in GERD and the relationship between pH, bile and oesophageal damage in 20 healthy subjects, 30 patients with GERD (both
Fig. 3. Bilirubin monitoring in the distal oesophagus. A small photometric cell is placed in the distal oesophagus (most common 5 cm above LES). Absorbance values exceeding 0.14 are considered indicative of the presence of bilirubin in the refluxate.
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erosive and non-erosive forms) and 20 patients with Barrett’s oesophagus (BE) [26]. Bilirubin and oesophageal pH values were monitored for 24 h while all subjects were asked to discontinue acid suppressive medications prior to the study (PPI 1 week and H2RA’s 48 h prior to testing). The authors noted a graded increase in oesophageal %time pH < 4 parallel to the severity of the disease: healthy subjects, 1.5%; patients with NERD, 7.0%; patients with EE, 15.4%; patients with uncomplicated BE, 14.7% and patients with complicated BE, 22.8%. The median percentage of the total time with bilirubin absorbance exceeding 0.14 also increased with disease severity: 0.4% in healthy subjects, 3.2% in NERD patients, 14.6% in EE patients, 23.0% in patients with uncomplicated BE and 46.0% in patients with complicated BE. Linear regression analysis showed a significant correlation (r ¼ 0.73; P < 0.01) between percentage of time with oesophageal pH < 4 and bilirubin absorbance > 0.14. These findings strengthen the concept of synergy between acid and duodenal content (in particular bile acids) in causing oesophageal lesions. Marshall et al investigated the relationship between acid and bile reflux in 113 patients with reflux symptoms [63 without erosive oesophagitis (group 1), 23 with erosive oesophagitis (group 2), 27 Barrett’s oesophagus (group 3)] and 15 controls [27] undergoing oesophageal pH and bilirubin and gastric pH monitoring. In an attempt to clarify the circadian variations of gastric (pH monitoring) and duodeno-gastric reflux the authors focussed on the overlap between acid and bilirubin exposure in the distal oesophagus in particular during the night. They found that nocturnal oesophageal bile reflux occurs mostly at times when the oesophageal pH was between 4 and 7 in all groups: 67.6%, 76.5% and 41.4% of the supine period for groups 1, 2 and 3 respectively. In addition they noted that individual oesophageal bile reflux and oesophageal or gastric alkaline shift episodes rarely coincided. Acid reflux predominated in the first half of the night (P < 0.001) while oesophageal bile reflux and alkaline shift continued throughout the night and gastric alkaline shift increased towards the end of the night (P < 0.001). Based on these findings the authors concluded that duodenal contents in the oesophagus exist at a wide pH range, and passes through an acid or an alkaline stomach implying that constituents of duodenal refluxate are involved in causing oesophageal damage independent of gastric acidity. Bilirubin monitoring has been used to evaluate gastro-oesophageal reflux in patients taking acid suppressive medication since Bilitec detects gastro-oesophageal reflux independent of the acid content of the refluxate. Tack et al reported the results of bilirubin monitoring in 65 patients with persistent typical reflux symptoms (heartburn or regurgitation) while on therapy with standard dose PPI [28]. The results of Bilitec monitoring revealed that 11% of patients had pathologic acid reflux, 38% pathologic bile reflux and 26% pathologic acid and bile reflux. Based on these results the authors concluded that combined bilirubin and pH monitoring is superior to pH monitoring alone to demonstrate pathologic reflux in patients with persistent reflux symptoms despite standard PPI therapy. In another study Koek et al used bilirubin monitoring to evaluate the response to therapy with baclofen in patients with persistent symptoms on PPI therapy [29]. Sixteen patients with persistent heartburn and/or regurgitation on PPI therapy underwent bilirubin and pH monitoring while on acid suppressive therapy. While patients had normal distal oesophageal acid exposure (total % time pH < 4 0.3% [0.05–2.2%]) they had abnormal DGER (total % time bilirubin absorbance > 0.14, 13.8% [11.8–15.5]) on acid suppressive therapy. Adding 5–20 mg baclofen tid maintained a normal distal oesophageal acid exposure but also decreased DGER (total % time bilirubin absorbance > 0.14, 6.1% [0.8–10.3]; P < 0.05). Based on these results the authors concluded that baclofen improves (duodeno-) gastro-oesophageal reflux in patients with persistent symptoms on acid suppressive therapy and bilirubin monitoring is important in documenting ongoing reflux on PPI therapy. In summary, Bilitec monitoring expands the ability to monitor gastro-oesophageal reflux by including data on bile-containing refluxate (i.e. duodenal gastro-oesophageal reflux; DGER). While DGER alone is an infrequent cause of erosive oesophagitis bile-containing reflux appears to contribute to the pathogenesis of erosive oesophagitis and Barrett’s oesophagus. By detecting gastro-oesophageal reflux independent of acid content Bilitec can be used to detect gastro-oesophageal reflux in patients on acid suppressive therapy or following gastric surgery. Still, the rather ‘sluggish’ reaction and in particular clearance of bilirubin out of the oesophagus represents a limitation in the assessment of symptom association.
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Multichannel intraluminal impedance As discussed above, in recent years the increasing number of patients with persistent symptoms on acid suppressive therapy revealed the limitations of solely pH monitoring to detect gastro-oesophageal reflux. A further development was multichannel intraluminal impedance (MII) first described by Silny et al in 1991 [30]. MII-monitoring detects changes in intraluminal electrical conductivity of the oesophageal content providing information on presence of liquids and gas in the oesophagus. The basic component of MII technology is an impedance circuit. Alternating electrical current is applied between two metal rings mounted on a catheter which acts as an electrical isolator and the electrical circuit is closed by electrical charges in the oesophageal mucosa surrounding the catheter. In an empty oesophagus the system will measure a baseline oesophageal impedance of 1500–2000 Ohm. The appearance of liquid bolus in the impedance measuring segment leads to a decline in impedance from baseline that persists as long as the bolus is present between the pair of metal rings. Once the liquid has passed by this segment, impedance returns back to its baseline value. Incorporating multiple impedance measuring segments allows detecting the direction of bolus movement. A rapid decline in intraoesophageal impedance starting in the proximal channels and advancing over time to the distal channel signals bolus movement in anterograde (aboral) movement. Vice versa a decline starting in the distal oesophagus and moving towards the proximal oesophagus indicates bolus transit in retrograde (oral) direction. The differentiation in direction of bolus movement allows identification of swallows (anterograde) and reflux events (retrograde). Combining multichannel intraluminal impedance with pH monitoring (i.e. MII–pH) becomes an important tool to identify and validate gastro-oesophageal reflux episodes of all types, independent of their acidity [31]. Combined impedance–pH monitoring systems Oesophageal MII–pH monitoring systems use a thin flexible catheter similar to conventional pH monitoring catheters. The procedure of transnasal insertion of the catheter with intubation of oesophagus and stomach, time of measurement and patient activities does not differ to standard 24 h pH monitoring. Besides a pH sensor, multiple rings are mounted on the catheter and electrical impedance data are measured between two adjacent rings. The most common design used in clinical practice uses impedance rings placed at 2, 4, 6, 8, 10, 14, 16 and 18 cm and a pH sensor at 5 cm from the tip of the catheters. This catheter therefore collects impedance data at 3, 5, 7, 9, 15 and 17 cm above the LES in addition to pH data at the usual position 5 cm above the LES (Fig. 4). During monitoring the MII–pH catheter is connected to an external data logger and data are sampled at 50 Hz. Data are stored on a flash memory card and transferred after the monitoring period to a computer work station with dedicated interpretation software. Oesophageal impedance–pH data: use and interpretation Combined MII–pH monitoring provides information on: (1) the number of gastro-oesophageal reflux episodes (both acid and non-acid), (2) the physical condition of reflux episodes (i.e. liquid, gas or mixed liquid–gas), (3) the height of the reflux column inside the oesophagus and (4) the association between symptoms and reflux episodes (i.e. using symptom index or symptom association probability). To date normal values for these parameters are available from US–Belgian [32], French–Belgian [33] and Italian [34] cohorts of healthy volunteers not taking any acid suppressive therapy (Table 1). There have been attempts to provide information on the amount (i.e. volume) of the refluxate however changes in impedance, once the area between two metal rings is covered, are independent of volume [35]. MII–pH monitoring appears most useful in evaluating patients with persistent symptoms on acid suppressive therapy. On one hand it clarifies the effectiveness of acid suppression by assessing distal oesophageal acid exposure, on the other hand it provides information on the relationship between gastro-oesophageal reflux of any type (acid, non-acid, liquid, mixed, gaseous) and symptoms. The evaluation of patients on acid suppressive therapy changed the paradigm of reflux testing in GERD: impedance allows detection of virtually all types of reflux whereas pH data are used in the categorisation of impedance detected reflux episodes; acid and non-acid. To date published normal values of
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Fig. 4. Combined multichannel intraluminal impedance and pH (MII–pH) monitoring. Impedance measuring channels are centred around 3, 5, 7, 9, 15 and 17 cm above the lower oesophageal sphincter (LES) and pH sensor is located at 5 cm above the LES. Combined impedance–pH monitoring identifies reflux episodes as rapid declines in intraluminal impedance progressing over time from distal to proximal. Information from the pH channel is used to distinguish between acid (nadir pH < 4) and non-acid (nadir pH > 4) reflux episodes.
MII–pH parameters on acid suppressive therapy are available only from a small group of healthy volunteers [36]. In patients not taking acid suppressive therapy most reflux episodes are acid, with the majority of non-acid reflux episodes occurring post-prandially [37]. Most patients seen in GI practice have been put on (empiric) acid suppressive therapy. However acid suppressive therapy only changes the acidity of the gastro-oesophageal refluxate without seeming to affect the mechanisms leading to gastric content refluxing into the oesophagus. Studies on post-prandial reflux have shown a shift from acid to non-acid reflux without significant reduction of the total number of gastro-oesophageal reflux events [38]. Partly contradicting these findings have been studies on healthy volunteers on acid suppressive therapy reporting a reduction in the number of acid reflux episodes but no change in the number of non-acid reflux episodes [30]. This may be explained by PPIs inducing a decrease of volume of gastric secretions, hence less gastric distension and less tLESRs leading to a decrease in the total number of gastro-oesophageal reflux episodes. Conversely, in the post-prandial period the volume of gastric content is determined primarily by the volume of the meal whereas the main effect of a PPI in that period may be attributed to a decrease in intragastric acidity. As discussed above gastro-oesophageal reflux episodes with a pH above 4.0 are generally considered non-acid in order to underscore the difference to the acid reflux episodes detected by conventional pH monitoring. Acknowledging the chemically correct definition of acid and non-acid, gastro-oesophageal reflux episodes detected by MII may be differentiated in acidic (if pH drops below 4.0), weakly acidic (if pH is between 4.0 and 7.0) and weakly alkaline (if intraoesophageal pH during an MII-detected reflux episode is above 7.0) [25]. The clinical relevance of this separation of non-acid reflux into weakly acidic and weakly alkaline remains to be established. The clinical relevance of gastric acid in the development of oesophageal mucosal erosions is well established. Reducing the acid content as done by PPI therapy has shown healing rates of close to 90% in GERD [39]. The relevant role of non-acid reflux as appreciated today is, rather than a possible effect on structural integrity of oesophageal mucosa, the evaluation of symptom–reflux association in patients under acid suppressive therapy. This is important as one-third of patients diagnosed with erosive GERD [33] and up to 65% of patients with non-erosive GERD have persistent symptoms on daily dose of PPI independent of endoscopic visual integrity [40].
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Mainie et al [41] and Zerbib et al [42] documented that in up to 50% of patients on therapy with PPI twice daily, oesophageal symptoms during 24-h combined MII–pH monitoring were associated with ongoing gastro-oesophageal reflux. Recently Becker et al [43] evaluated patients with ongoing symptoms under acid suppressive therapy and found abnormal MII–pH findings (abnormal distal oesophageal acid exposure or abnormal number of MII-detected reflux episodes) in 39% of patients taking standard dose PPI once daily. Patients were followed up for at least 3 months after the dose of PPI was increased. The authors were able to document a significantly better symptomatic relief in patients with abnormal MII–pH results (90%) compared to patients with normal MII–pH findings (43%), concluding that combined MII–pH monitoring facilitates a more focussed therapeutic approach to patients with PPI-resistant GERD possibly avoiding PPI overuse. The clinical utility of a positive association between symptoms and reflux is supported by the finding of an observational study by Mainie et al evaluating symptom response 7–25 months following anti-reflux surgery in 19 patients undergoing laparoscopic Nissen fundoplication for symptomatic nonacid reflux. Before surgery patients were examined using 24 h MII–pH. Most patients (94%) had a positive SI and one (6%) a negative SI. Patients were operated and followed up for a median period of 14 months. In this group 16/17 (94%) patients with a pre-op positive SI were asymptomatic or markedly improved (one patient was lost to follow up). The one patient operated despite negative SI had persistent symptoms and atypical ENT complaints recurred 9 months after fundoplication in a patient with positive symptom association. Despite the technical limitations of an observational study, this report yields important data on the efficacy of anti-reflux surgery in patients with symptomatic nonacid reflux on PPI therapy, which should be mandatory until proven otherwise in randomised, controlled studies in this group of patients. Summary and conclusion Oesophageal reflux testing – involving conventional 24-h pH monitoring, the wireless Bravo system, Bilitec and recently developed combined 24-h pH impedance testing – is an integral part in the evaluation of GERD and related symptoms. Empiric treatment with acid suppressive therapy is a practical and widely used approach in clinically suspected GERD. Oesophageal reflux monitoring is used to quantify oesophageal acid exposure in patients with reflux symptoms and normal endoscopic findings, part of pre-operative evaluation in patients planned for anti-reflux surgery and in patients with persistent reflux symptoms despite acid suppressive therapy. Conventional and wireless oesophageal pH monitoring should be performed in patients off acid suppressive therapy as it allows quantifying distal oesophageal acid exposure and the association of symptoms with acid reflux episodes. Wireless oesophageal pH testing increases patient comfort and mobility and allows measurements over prolonged periods of time. Patients complaining of oesophageal symptoms despite sufficient acid suppressive therapy should be evaluated using combined 24-h MII–pH monitoring, as it identifies reflux episodes independent of acidity and allows a better insight into symptom–reflux association. Specialised oesophageal function test centres should offer (wireless) pH testing and 24-h MII–pH as the current state of the art tools in the evaluation of GERD and related symptoms.
Practice points Conventional pH-metry measures oesophageal acid exposure using up to 3 (usually 1 or 2) electrodes mounted to a catheter that is inserted transnasally for 24 h recording. Wireless pH-metry improves patient comfort and prolongs the period of time for data acquisition but is more expensive and requires upper GI endoscopy. Regardless of the methodology used for pH-metry, not only quantification of distal oesophageal acid exposure but also analysis of the association between symptoms and reflux episodes is of importance.
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The catheter-based Bilitec system incorporates a small fibre-optic spectrophotometric chamber. High absorbance is considered indicative of the presence of bilirubin in the refluxate. Thus, Bilitec monitoring expands the ability to monitor gastro-oesophageal reflux by including data on bile-containing refluxate. MII-monitoring detects changes in intraluminal electrical conductivity of the oesophageal content providing information on presence of liquids and gas in the oesophagus. A rapid decline in intraoesophageal impedance starting in the distal oesophagus and moving towards the proximal oesophagus indicates liquid bolus transit in retrograde (oral) direction. Combining multichannel intraluminal impedance with pH monitoring (i.e. MII–pH) is an important tool to identify and validate gastro-oesophageal reflux episodes of all types independent of acidity.
References *[1] Locke GR, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population based study in Olmsted County, Minnesota. Gastroenterology 1997;112:1448–56. [2] Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal and liver diseases, 2006. Am J Gastroenterol 2006;101:2128–38. [3] Allison PR. Peptic ulcer of the esophagus. J Thorac Cardiovasc Surg 1946;15:308–17. [4] Spencer J. Prolonged pH recording in the study of gastro-oesophageal reflux. Br J Surg 1969;56:912–4. *[5] Johnson LF, DeMeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974;62:325–32. [6] McLauchlan G, Rawlings JM, Lucas ML, et al. Electrodes for 24 hours pH monitoring – a comparative study. Gut 1987;28: 935–9. [7] Ward BW, Wu WC, Richter JE, et al. Ambulatory 24-hour esophageal pH monitoring. Technology searching for a clinical application. J Clin Gastroenterol 1986;8(Suppl. 1):59–67. [8] Dobhan R, Castell DO. Prolonged intraesophageal pH monitoring with 16-hr overnight recording. Comparison with ‘24hr’ analysis. Dig Dis Sci 1992;37:857–64. [9] Gureneis P, Orleanski A. On determination of the pH value of gastric juice by means of the internal radio sound, according to the H.G. Noeller (Heidelberg capsule). Wien Z Inn Med 1964;45:368–72. *[10] Pandolfino JE, Richter JE, Ours T, et al. Ambulatory esophageal pH monitoring using a wireless system. Am J Gastroenterol 2003;98:740–9. [11] Connell AM, Waters TE. Assessment of gastric function by pH telemetring capsule. Lancet 1964;189:227–30. *[12] Scarpulla G, Camilleri S, Galante P, et al. The impact of prolonged pH measurements on the diagnosis of gastroesophageal reflux disease: 4-day wireless pH studies. Am J Gastroenterol 2007;102:2642–7. [13] Piper DW, Fenton BH. pH stability and activity curves of pepsin with special reference to their clinical importance. Gut 1965;6:506–8. [14] Tuttle SG, Rufin F, Bettarello A. The physiology of heartburn. Ann Intern Med 1961;55:292–300. [15] Stanciu C, Hoare RC, Bennett JR. Correlation between manometric and pH tests for gastro-oesophageal reflux. Gut 1977; 18:536–40. [16] Vitale GC, Sadek S, Tulley FM, et al. Computerized 24-hour esophageal pH monitoring: a new ambulatory technique using radiotelemetry. J Lab Clin Med 1985;105:686–93. [17] Weusten BL, Roelofs JM, Akkermans LM, et al. Objective determination of pH thresholds in the analysis of 24 h ambulatory oesophageal pH monitoring. Eur J Clin Invest 1996;26:151–8. [18] Agrawal A, Tutuian R, Hila A, et al. Ingestion of acidic foods mimics gastroesophageal reflux during pH monitoring. Dig Dis Sci 2005;50:1916–20. *[19] Johnsson F, Joelsson B, Isberg PE. Ambulatory 24 hour intraesophageal pH-monitoring in the diagnosis of gastroesophageal reflux disease. Gut 1987;28:1145–50. [20] Schindlbeck NE, Heinrich C, Konig A, et al. Optimal thresholds, sensitivity, and specificity of long-term pH-metry for the detection of gastroesophageal reflux disease. Gastroenterology 1987;93:85–90. [21] Lam HG, Breumelhof R, Roelofs JM, et al. What is the optimal time window in symptom analysis of 24-h esophageal pressure and pH data? Dig Dis Sci 1994;39:402–9. [22] Breumelhof R, Smout AJ. The symptom sensitivity index: a valuable additional parameter in 24-h esophageal pH recording. Am J Gastroenterol 1991;86:160–4. [23] Weusten BL, Roelofs JM, Akkermans LM, et al. The symptom-association probability: an improved method for symptom analysis of 24-h esophageal pH data. Gastroenterology 1994;107:1741–5. *[24] Bredenoord AJ, Weusten BL, Smout AJ. Symptom association analysis in ambulatory gastro-oesophageal reflux monitoring. Gut 2005;54:1810–7. [25] Barrett MW, Myers JC, Watson DI, et al. Dietary interference with the use of Bilitec to assess bile reflux. Dis Esophagus 1999;12:60–4. *[26] Vaezi MF, Richter JE. Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 1996;111:1192–9. [27] Marshall RE, Anggiansah A, Owen WA, et al. The temporal relationship between oesophageal bile reflux and pH in gastrooesophageal reflux disease. Eur J Gastroenterol Hepatol 1998;10:385–92.
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[28] Tack J, Koek G, Demedts I, et al. Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett’s esophagus: acid reflux, bile reflux, or both? Am J Gastroenterol 2004;99:981–8. [29] Koek GH, Sifrim D, Lerut T, et al. Effect of the GABA(B) agonist baclofen in patients with symptoms and duodeno-gastrooesophageal reflux refractory to proton pump inhibitors. Gut 2003;52:1397–402. [30] Silny J. Intraluminal multiple electric impedance procedure for measurement of gastrointestinal motility. J Gastrointest Motil 1991;3:151–62. [31] Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004;53:1024–31. *[32] Shay SS, Tutuian R, Sifrim D, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol 2004;99:1037–43. [33] Zerbib F, des Varannes SB, Roman S, et al. Normal values and day-to-day variability of 24-h ambulatory oesophageal impedance-pH monitoring in a Belgian-French cohort of healthy subjects. Aliment Pharmacol Ther 2005;22:1011–21. [34] Zentilin P, Iiritano E, Dulbecco P, et al. Normal values of 24-h ambulatory intraluminal impedance combined with pHmetry in subjects eating a Mediterranean diet. Dig Liver Dis 2006;38:226–32. *[35] Srinivasan R, Vela MF, Katz PO, et al. Esophageal function testing using multichannel intraluminal impedance. Am J Physiol Gastrointest Liver Physiol 2001;280:G457–62. [36] Tutuian R, Mainie I, Agrawal A, et al. Normal values for ambulatory 24-h combined impedance-pH monitoring on acid suppressive therapy. Gastroenterology 2006;130(Suppl. 2):A-171 [abstract]. [37] Wildi SM, Tutuian R, Castell DO. The influence of rapid food intake on postprandial reflux: studies in healthy volunteers. Am J Gastroenterol 2004;99:1645–51. [38] Vela MF, Camacho-Lobato L, Srinivasan R, et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastro-esophageal reflux: effect of omeprazole. Gastroenterology 2001;120:1599–606. [39] Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002;97:575–83. [40] Dean BB, Gano Jr AD, Knight K, et al. Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol 2004;2:656–64. *[41] Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance–pH monitoring. Gut 2006;55:1398–402. [42] Zerbib F, Roman S, Ropert A, et al. Esophageal pH–impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol 2006;101:1956–63. [43] Becker V, Bajbouj M, Waller K, et al. Clinical trial: persistent gastro-oesophageal reflux symptoms despite standard therapy with proton pump inhibitors – a follow-up study of intraluminal-impedance guided therapy. Aliment Pharmacol Ther 2007;26:1355–60. [44] Wenner J, Johnsson F, Johansson J, Oberg S. Wireless oesophageal pH monitoring: feasibility, safety and normal values in healthy subjects. Scand J Gastroenterol 2005;40:768–74. [45] Sweis R, Fox M, Anggiansah R, et al. Patient acceptance and clinical impact of Bravo monitoring in patients with previous failed catheter-based studies. Aliment Pharmacol Ther 2009;29:669–76. [46] Lacy BE, Edwards S, Paquette L, et al. Tolerability and Clinical Utility of the Bravo pH Capsule in Children. J Clin Gastroenterol [Epub ahead of print].
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
2
Reflux monitoring: pH-metry, Bilitec and Oesophageal impedance measurements Daniel Pohl, MD, Research Fellow a, Radu Tutuian, MD, Clinical Lead Functional GI Disorders b, * a b
Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425, USA University Clinic for Visceral Surgery and Medicine, Bern University Hospital, Inselspital, CH-3010 Bern, Switzerland
Keywords: gastro-oesophageal reflux disease pH monitoring impedance–pH monitoring bilirubin monitoring proton pump inhibitors
Gastro-oesophageal reflux disease (GERD) is a highly prevalent condition in Western countries leading to millions of outpatient visits per year. GERD symptoms including heartburn, regurgitation and chest pain are caused by reflux of gastric content in the oesophagus even in the absence of endoscopically visible mucosal lesions. Several procedures are used to identify gastro-oesophageal reflux, the clinically widely used are: conventional (catheterbased) pH monitoring, wireless oesophageal pH monitoring (Bravo), bilirubin monitoring (Bilitec), and combined multichannel intraluminal impedance–pH monitoring (MII–pH). Each technique has strengths and limitations of which clinicians and investigators should be aware when deciding which to choose in a particular patient. Important is the ability to quantify gastro-oesophageal reflux and evaluate the relationship between symptoms and reflux episodes. The present review summarises the technical aspects in performing and interpreting esophageal reflux monitoring procedures. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Gastro-oesophageal reflux disease (GERD) is a highly prevalent condition in industrialised countries amounting to millions of visits to gastrointestinal specialists each year [1]. Due to the high prevalence of disease, the financial burden caused alone by acid supressive therapy exceeds 10 billion $ per year in the United States [2].
* Corresponding author. Tel.: þ41 31 632 2403; Fax: þ41 31 632 9723. E-mail address: [email protected] (R. Tutuian). 1521-6918/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2009.04.003
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The first description of lesions induced by gastric content refluxing into the oesophagus comes from Allison in the mid-1940s [3]. Apart from recognising mucosal damage as the pathology to treat, it was soon realised that symptoms suggestive of GERD such as heartburn, regurgitation, chest pain and dysphagia could be caused by reflux of gastric content in the oesophagus even when there was no evidence of mucosal pathology during endoscopy. Thus, approaches other than endoscopy to monitor gastro-oesophageal reflux were needed. Quantifying gastro-oesophageal refluxate independent of mucosal lesions was first achieved using intraoesophageal pH monitoring in the distal oesophagus. This technique was soon accepted by investigators and clinicians as the gold standard to diagnose and monitor therapeutic interventions aimed at reducing distal esophageal acid exposure and number of gastro-oesophageal reflux episodes. Parallel to this was the development of potent gastric acid inhibitors – first histamine receptor 2 antagonists (H2-RA) and in the 1980 the even more potent proton pump inhibitors (PPI) – to treat GERD. The development of these potent gastric acid inhibitors with excellent patient tolerability had a major impact not only on treatment but also on the diagnosis of GERD. Empiric treatment with PPIs became the approach of choice in the primary care setting leading to a selection of patients referred for further testing to mainly those with persistent symptoms despite acid suppressive therapy. This development revealed the limitations of ‘simple’ esophageal pH monitoring, calling for the development of more advanced tools to monitor gastro-oesophageal reflux in these patients. The present paper reviews technical aspects, procedure and interpretation of widely used techniques to monitor gastro-oesophageal reflux starting with conventional pH monitoring, wireless esophageal pH monitoring (Bravo), bilirubin monitoring (Bilitec) and combined multichannel intraluminal impedance–pH monitoring (MII–pH). Oesophageal pH monitoring Esophageal pH monitoring is still the most widely used clinical tool to monitor gastro-oesophageal reflux. Prolonged intraoesophageal pH-measurements were first described by Spencer and colleagues in the late 1960s [4]. The technique became widely spread both in clinical and research setting after normal values were published by Johnson and DeMeester a decade later [5]. Over time esophageal pH monitoring became the gold standard in diagnosing GERD providing information on distal esophageal acid exposure and later in evaluation of symptom association with acid reflux episodes. Esophageal pH monitoring is now used in stationary and ambulatory practice with catheter-based and more recently catheter-free systems. Conventional, catheter-based pH monitoring For catheter-based pH monitoring one or more esophageal pH sensors are mounted on a flexible catheter and connected to a data storage device. The pH is measured either by glass or most often by antimony pH sensors with internal or external reference electrodes. Internal reference systems are preferred as the reference electrode is mounted on the same catheter that is positioned in the oesophagus or stomach, thus reducing the number of ‘wires’ connected to the patient. External reference systems use an electrode placed to the skin of the subject and are therefore influenced by factors influencing skin conductivity (i.e. dry or over-moistured skin, cutaneous lesions, accidental disconnection during movement, etc.). In vitro studies suggest that glass-electrodes are superior to monocrystalline antimony electrodes as they respond much quicker to changes in pH, have less drift and a better linear response [6]. Nevertheless in clinical practice, antimony electrodes provide similar results and have been shown to offer better insertion and study comfort compared to the larger glasselectrodes [7]. Antimony electrodes are less expensive allowing the production of more convenient and hygienic single-use, disposable catheters. The pH electrodes are calibrated using buffer solutions with determined pH values prior to examination. Two calibration substances are usually used – one in the acidic range (pH 1–4) and one in the neutral range (pH 6–7). After calibration the catheter is inserted transnasally into the oesophagus until the lower tip has reached the gastric cavity. Catheters may have one or more acid-sensing electrodes: in catheters with one pH electrode it is passed to come to rest 5 cm above the upper border
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of the lower esophageal sphincter. This position was chosen by global consensus and is regarded as the optimal position for distal esophageal acid exposure with limited risk of accidental slippage into the stomach. Most laboratories use dual pH electrodes (Fig. 1). Spacing pH sensors 10–15 cm apart allows placement of a pH electrode in the proximal and distal oesophagus or in the distal oesophagus and stomach. This allows using dual pH monitoring systems for either monitoring proximal and distal esophageal acid exposure or distal esophageal and gastric acid control. After the correct placement of the pH electrodes, patient instruction is of pivotal importance in having an optimal reflux recording. Patients are asked to undergo the same daily routines as usual and try to reproduce situations that cause the symptoms for which she/he underwent reflux monitoring. This is aimed at reproducing, as good as possible, normal daily activities and tries to maximise the ability to evaluate the relationship between symptoms and reflux. Beside symptoms patients are asked to record information on time of meals, medication and changes in body position. Most devices allow digital storage of events on the data logger using pre-coded softkeys for meals, body position and symptoms. For an ambulatory esophageal pH monitoring patients are asked to return the diary and data logger the following day. While most centres aim at 22–24 h of recording, recent data suggest that shorter studies (16 h) provide accurate information and improve patient compliance [8]. Catheter-free pH monitoring (BravoÒ System) Catheter-based pH-recording systems are not tolerated by all patients and limit the length of examination in even more patients. In the 1960s the first catheter-free device was released (the Heidelberg capsule) allowing telemetric recordings of intragastric pH [9,10]. Still, catheter-free oesophageal pH monitoring systems established their use in clinical practice only in recent years [11]. The Bravo system (Medtronic Inc., USA) includes a 26 mm 5.5 mm 6.5 mm capsule containing an antimony pH electrode with internal reference, miniaturised electronics with radiofrequency transmitter and battery, a capsule delivery system as well as an external receiver to monitor intraoesophageal pH (Fig. 2). Using a customised delivery system, the capsule is passed transorally during upper GI endoscopy and positioned in the distal oesophagus 6 cm above the gastro-oesophageal mucosal separation (‘Z-line’). The capsule is then attached (i.e. ‘pierced’) to the esophageal mucosa. Once released from the delivery system pH data are recorded. Bravo appears to be safe and patients including
Fig. 1. Conventional oesophageal pH monitoring using a 2-channel catheter with sensors in the distal (5 cm above LES) and proximal (15 cm above LES) oesophagus. The box shows examples of gastro-oesophageal reflux episodes defined as abrupt drop in pH from above to below 4.0 followed by gradual recovery of pH to baseline.
302 D. Pohl, R. Tutuian / Best Practice & Research Clinical Gastroenterology 23 (2009) 299–311 Fig. 2. Wireless pH monitoring system using a capsule with antimony pH electrode attached in the distal oesophagus 6 cm above the ‘Z-Line’. Data are transmitted to an external receiver allowing monitoring up to 4 days.
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children have been shown to tolerate Bravo measurements well [44–46]. Apart from offering more patient comfort, fixation of the capsule in the distal oesophagus avoids slippage into the stomach reducing position-and motion-induced changes and allowing longer recording times up to 96 hours. Length of recording is limited by battery life and spontaneous detachment of the probe from the esophageal mucosa. A recent study evaluating the feasibility of prolonged recordings in the clinical practice revealed that complete 96-h recordings were available in only 34/83 (41%) patients [12]. Current disadvantages of the system are the high cost of the pH capsule, need of upper endoscopy for accurate placement and impracticability of multiple recording sites. Questions answered by prolonged wireless esophageal pH-metry are distal esophageal acid exposure and the relationship between symptoms and gastro-oesophageal reflux episodes. Oesophageal pH data interpretation Once acquired by either catheter-based or catheter-free pH oesophageal pH systems, pH data are transferred from the logger to a work station to be analysed using dedicated software. Reflux episodes are characterised by an abrupt decline in intraoesophageal pH in the distal oesophagus. A cutoff pH 4.0 is used by most laboratories to identify acid reflux episodes (Fig. 1). Reasons for using the cutoff of 4.0 as a clinically useful parameter in gastroenterological practice include observations that proteolytic activity of pepsin rapidly decreases in solutions with a pH above 4.0 [13] and typical reflux symptoms (i.e. heartburn) are more often reported at intraoesophageal pH values below 4.0 [14]. This cutoff value has been challenged over the years by studies suggesting that a pH value of 5 may provide better discrimination between healthy volunteers and patients with reflux symptoms [15]. Other authors have suggested that the best discrimination between patients with reflux symptoms and healthy volunteers occurs within the full range between pH 3 and 6 rather than using one single pH value [16] or by studies proposing different pH threshold values for different positions based on pH distribution curves [17]. However the simplicity of using a single cutoff value prevailed and pH 4.0 is currently the most widely used cutoff value to identify gastro-oesophageal reflux episodes in ambulatory oesophageal pH monitoring. Based on this cutoff the number of gastro-oesophageal reflux episodes, number of reflux episodes exceeding 5 min and duration of intraoesophageal pH below 4 are used to define gastro-oesophageal reflux. These parameters are reported separately for total recording time, time spent in the upright and recumbent position. Since upright, recumbent periods and total duration of recording varies from one to another patient, reporting a ‘normalized’ percent time (i.e. duration of intraoesophageal pH < 4 divided by the total recording time) is preferred. Meal periods are generally excluded from analysis in order to avoid artefactual increase in oesophageal acid exposure time determined by the ingestion of acidic foods and drinks [18]. Nevertheless patients are asked to follow their usual diet and even encouraged to consume foods that typically cause symptoms and mark these ingestion periods accordingly. Based on studies in healthy volunteers, normal values for percent time pH < 4 have been established for both catheter-based and catheter-free systems (Table 1). Recordings in patients are compared against these values and classified as normal or abnormal. Several authors have proposed using scores to quantify distal oesophageal acid exposure. The most commonly used scores for adult patients are the Johnson/DeMeester and DeMeester score [5]. These scores are frequently used by surgical colleagues and are automatically calculated by most pH monitoring softwares based on the following six parameters: (1) total % time pH < 4, (2) % time pH < 4 in the upright period, (3) % time pH < 4 in the recumbent period, (4) total number of reflux episodes, (5) total number of reflux episodes longer than 5 min and (6) duration of the longest reflux episode. Recent studies show that these scores are not necessarily superior to percent time pH < 4 in discriminating between healthy volunteers and GERD patients [19,20]. Regardless whether one uses the composite score or individual acid exposure times a detailed evaluation of the pH tracing is of pivotal importance to recognise and exclude artifacts and to assess symptom association. Apart from quantification of distal oesophageal acid exposure and number of reflux symptoms the importance of association between symptoms, that drive the patient to seek medical care, and actual reflux events is being more and more recognised. Multiple assessment tools have been developed for
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Table 1 Normal values for oesophageal pH monitoring (catheter-based and wireless) and combined MII–pH monitoring based on 95th percentile data in healthy volunteers not taking acid suppressive therapy. pH monitoring
Impedance–pH monitoring
Catheter-based [5] Wireless [10] US–Belgian [32] French–Belgian [33] Italian [34] (N ¼ 52) (N ¼ 39) (N ¼ 60) (N ¼ 72) (N ¼ 25) Oesophageal pH data % time pH < 4 Total Upright Recumbent
4.2% 6.3% 1.2%
5.3% 6.9% 3.2%
6.7% 9.7% 2.1%
5.0% 6.2% 5.3%
4.0% 5.0% 3.0%
Oesophageal MII-data # Reflux episodes Total Acid Weakly acid Weakly alkaline
– – – –
– – – –
73 55 26 1
75 50 33 15
48 51 38 18
this purpose; the most commonly used ones are the symptom index (SI) and the symptom association probability (SAP). The symptom index constitutes a very simple and straightforward assessment tool. The SI, first described by Meyer et al, is the proportion of symptoms preceded by acid reflux episodes (i.e. drop in pH from above to below 4) within a 5-min time window out of the total number of symptoms. The SI may be determined separately for different symptoms and is declared positive if greater or equal to 50% (i.e. meaning that at least half of the reported symptoms are preceded by gastro-oesophageal reflux). This definition of symptom index is not uniformly accepted – especially regarding more atypical symptoms of reflux disease: for patients with chest pain Lam et proposed a shorter, 2-min time window, for a positive symptom association [21]. Recognising that using the symptom index (SI) the likelihood of a false positive association rises with increasing number of reflux episodes and decreasing number of symptoms, Breumelhof and Smout proposed the symptom sensitivity index (SSI) as additional parameter to evaluate symptom association during 24-h oesophageal pH monitoring [22]. The symptom sensitivity index is defined as the percentage of reflux episodes associated with symptoms out of the total number of reflux episodes. A symptom sensitivity index greater than 10% would further strengthen the association between symptoms and reflux in a given patient. Weusten et al developed the mathematically more complex symptom association probability (SAP) in search of a more robust parameter to evaluate symptom association [23]. The SAP evaluates if the distribution of reflux episodes and symptoms during the monitoring period occurs by chance or not. Commercially available software programs have the ability to calculate the SAP in percentage based on the methodology described by Weusten et al [23]. It is important to recognise that the SAP is a statistical analysis tool indicating the statistical probability of symptom–reflux association. To ensure a valid result and reduce the probability of symptom–reflux association by chance alone, only a SAP greater than 95% should be considered positive [24]. In summary, both catheter-based and wireless pH-metry uses the high acid concentration (i.e. low pH) of gastric content to detect gastro-oesophageal reflux. This allows quantifying distal oesophageal acid exposure and assessing the association between symptoms and acid reflux episodes. There is a wide and long experience with this method, establishing oesophageal pH monitoring as the gold standard in monitoring gastro-oesophageal reflux. Bilirubin monitoring (Bilitec) Oesophageal pH monitoring provides information on acid reflux episodes reaching the distal oesophagus. Still, other components of the gastric content play a role in the development of oesophageal lesions and markers other than pH levels are warranted when monitoring patients on acid suppressive therapy. Along these lines, one of the first alternative methods is bilirubin monitoring in the distal oesophagus. The role of duodeno-gastro-oesophageal reflux (DGER) or bile reflux in GERD pathology has been the subject of numerous investigations and has re-emerged as a topic of recent
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studies. Currently the best available method for clinical use is the spectrophotometric method Bilitec 2000 (Medtronic, Inc.). The system incorporates a small fibre-optic spectrophotometric chamber measuring the absorbance of light at a wavelength of 470 nm. Absorbance values exceeding 0.14 are considered indicative of the presence of bilirubin in the refluxate (Fig. 3). Similar to pH monitoring, the bilirubin sensor mounted on a catheter is placed transnasally in the distal oesophagus and positioned 5 cm above the proximal border of the lower oesophageal sphincter. The ambulatory procedure is also similar to catheter-based pH monitoring with the difference that patients are instructed to follow a ‘white’ diet since coloured foods and drinks are known to influence the spectrophotometric bilirubin measurements [25]. Although bilirubin monitoring can be used as stand-alone tool, in clinical practice it is often combined with pH monitoring in order to assess both gastro-oesophageal and duodeno-gastrooesophageal reflux. Bilitec data interpretation In analogy to distal oesophageal acid exposure, Bilitec monitoring will provide information on the distal oesophageal bile exposure as percentage of time bilirubin absorbance > 0.14. In terms of symptom association the rise and decline in bilirubin absorbance are not as rapid as for changes in oesophageal pH. While, in theory the same symptom association parameters as for pH monitoring could be calculated for bilirubin monitoring, these parameters have inherent shortcomings given the above mentioned ‘sluggishness’ of the changes in bilirubin absorbance. Clinical relevance of bilirubin monitoring Vaezi and Richter were among the first to report the prevalence of DGER in GERD and the relationship between pH, bile and oesophageal damage in 20 healthy subjects, 30 patients with GERD (both
Fig. 3. Bilirubin monitoring in the distal oesophagus. A small photometric cell is placed in the distal oesophagus (most common 5 cm above LES). Absorbance values exceeding 0.14 are considered indicative of the presence of bilirubin in the refluxate.
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erosive and non-erosive forms) and 20 patients with Barrett’s oesophagus (BE) [26]. Bilirubin and oesophageal pH values were monitored for 24 h while all subjects were asked to discontinue acid suppressive medications prior to the study (PPI 1 week and H2RA’s 48 h prior to testing). The authors noted a graded increase in oesophageal %time pH < 4 parallel to the severity of the disease: healthy subjects, 1.5%; patients with NERD, 7.0%; patients with EE, 15.4%; patients with uncomplicated BE, 14.7% and patients with complicated BE, 22.8%. The median percentage of the total time with bilirubin absorbance exceeding 0.14 also increased with disease severity: 0.4% in healthy subjects, 3.2% in NERD patients, 14.6% in EE patients, 23.0% in patients with uncomplicated BE and 46.0% in patients with complicated BE. Linear regression analysis showed a significant correlation (r ¼ 0.73; P < 0.01) between percentage of time with oesophageal pH < 4 and bilirubin absorbance > 0.14. These findings strengthen the concept of synergy between acid and duodenal content (in particular bile acids) in causing oesophageal lesions. Marshall et al investigated the relationship between acid and bile reflux in 113 patients with reflux symptoms [63 without erosive oesophagitis (group 1), 23 with erosive oesophagitis (group 2), 27 Barrett’s oesophagus (group 3)] and 15 controls [27] undergoing oesophageal pH and bilirubin and gastric pH monitoring. In an attempt to clarify the circadian variations of gastric (pH monitoring) and duodeno-gastric reflux the authors focussed on the overlap between acid and bilirubin exposure in the distal oesophagus in particular during the night. They found that nocturnal oesophageal bile reflux occurs mostly at times when the oesophageal pH was between 4 and 7 in all groups: 67.6%, 76.5% and 41.4% of the supine period for groups 1, 2 and 3 respectively. In addition they noted that individual oesophageal bile reflux and oesophageal or gastric alkaline shift episodes rarely coincided. Acid reflux predominated in the first half of the night (P < 0.001) while oesophageal bile reflux and alkaline shift continued throughout the night and gastric alkaline shift increased towards the end of the night (P < 0.001). Based on these findings the authors concluded that duodenal contents in the oesophagus exist at a wide pH range, and passes through an acid or an alkaline stomach implying that constituents of duodenal refluxate are involved in causing oesophageal damage independent of gastric acidity. Bilirubin monitoring has been used to evaluate gastro-oesophageal reflux in patients taking acid suppressive medication since Bilitec detects gastro-oesophageal reflux independent of the acid content of the refluxate. Tack et al reported the results of bilirubin monitoring in 65 patients with persistent typical reflux symptoms (heartburn or regurgitation) while on therapy with standard dose PPI [28]. The results of Bilitec monitoring revealed that 11% of patients had pathologic acid reflux, 38% pathologic bile reflux and 26% pathologic acid and bile reflux. Based on these results the authors concluded that combined bilirubin and pH monitoring is superior to pH monitoring alone to demonstrate pathologic reflux in patients with persistent reflux symptoms despite standard PPI therapy. In another study Koek et al used bilirubin monitoring to evaluate the response to therapy with baclofen in patients with persistent symptoms on PPI therapy [29]. Sixteen patients with persistent heartburn and/or regurgitation on PPI therapy underwent bilirubin and pH monitoring while on acid suppressive therapy. While patients had normal distal oesophageal acid exposure (total % time pH < 4 0.3% [0.05–2.2%]) they had abnormal DGER (total % time bilirubin absorbance > 0.14, 13.8% [11.8–15.5]) on acid suppressive therapy. Adding 5–20 mg baclofen tid maintained a normal distal oesophageal acid exposure but also decreased DGER (total % time bilirubin absorbance > 0.14, 6.1% [0.8–10.3]; P < 0.05). Based on these results the authors concluded that baclofen improves (duodeno-) gastro-oesophageal reflux in patients with persistent symptoms on acid suppressive therapy and bilirubin monitoring is important in documenting ongoing reflux on PPI therapy. In summary, Bilitec monitoring expands the ability to monitor gastro-oesophageal reflux by including data on bile-containing refluxate (i.e. duodenal gastro-oesophageal reflux; DGER). While DGER alone is an infrequent cause of erosive oesophagitis bile-containing reflux appears to contribute to the pathogenesis of erosive oesophagitis and Barrett’s oesophagus. By detecting gastro-oesophageal reflux independent of acid content Bilitec can be used to detect gastro-oesophageal reflux in patients on acid suppressive therapy or following gastric surgery. Still, the rather ‘sluggish’ reaction and in particular clearance of bilirubin out of the oesophagus represents a limitation in the assessment of symptom association.
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Multichannel intraluminal impedance As discussed above, in recent years the increasing number of patients with persistent symptoms on acid suppressive therapy revealed the limitations of solely pH monitoring to detect gastro-oesophageal reflux. A further development was multichannel intraluminal impedance (MII) first described by Silny et al in 1991 [30]. MII-monitoring detects changes in intraluminal electrical conductivity of the oesophageal content providing information on presence of liquids and gas in the oesophagus. The basic component of MII technology is an impedance circuit. Alternating electrical current is applied between two metal rings mounted on a catheter which acts as an electrical isolator and the electrical circuit is closed by electrical charges in the oesophageal mucosa surrounding the catheter. In an empty oesophagus the system will measure a baseline oesophageal impedance of 1500–2000 Ohm. The appearance of liquid bolus in the impedance measuring segment leads to a decline in impedance from baseline that persists as long as the bolus is present between the pair of metal rings. Once the liquid has passed by this segment, impedance returns back to its baseline value. Incorporating multiple impedance measuring segments allows detecting the direction of bolus movement. A rapid decline in intraoesophageal impedance starting in the proximal channels and advancing over time to the distal channel signals bolus movement in anterograde (aboral) movement. Vice versa a decline starting in the distal oesophagus and moving towards the proximal oesophagus indicates bolus transit in retrograde (oral) direction. The differentiation in direction of bolus movement allows identification of swallows (anterograde) and reflux events (retrograde). Combining multichannel intraluminal impedance with pH monitoring (i.e. MII–pH) becomes an important tool to identify and validate gastro-oesophageal reflux episodes of all types, independent of their acidity [31]. Combined impedance–pH monitoring systems Oesophageal MII–pH monitoring systems use a thin flexible catheter similar to conventional pH monitoring catheters. The procedure of transnasal insertion of the catheter with intubation of oesophagus and stomach, time of measurement and patient activities does not differ to standard 24 h pH monitoring. Besides a pH sensor, multiple rings are mounted on the catheter and electrical impedance data are measured between two adjacent rings. The most common design used in clinical practice uses impedance rings placed at 2, 4, 6, 8, 10, 14, 16 and 18 cm and a pH sensor at 5 cm from the tip of the catheters. This catheter therefore collects impedance data at 3, 5, 7, 9, 15 and 17 cm above the LES in addition to pH data at the usual position 5 cm above the LES (Fig. 4). During monitoring the MII–pH catheter is connected to an external data logger and data are sampled at 50 Hz. Data are stored on a flash memory card and transferred after the monitoring period to a computer work station with dedicated interpretation software. Oesophageal impedance–pH data: use and interpretation Combined MII–pH monitoring provides information on: (1) the number of gastro-oesophageal reflux episodes (both acid and non-acid), (2) the physical condition of reflux episodes (i.e. liquid, gas or mixed liquid–gas), (3) the height of the reflux column inside the oesophagus and (4) the association between symptoms and reflux episodes (i.e. using symptom index or symptom association probability). To date normal values for these parameters are available from US–Belgian [32], French–Belgian [33] and Italian [34] cohorts of healthy volunteers not taking any acid suppressive therapy (Table 1). There have been attempts to provide information on the amount (i.e. volume) of the refluxate however changes in impedance, once the area between two metal rings is covered, are independent of volume [35]. MII–pH monitoring appears most useful in evaluating patients with persistent symptoms on acid suppressive therapy. On one hand it clarifies the effectiveness of acid suppression by assessing distal oesophageal acid exposure, on the other hand it provides information on the relationship between gastro-oesophageal reflux of any type (acid, non-acid, liquid, mixed, gaseous) and symptoms. The evaluation of patients on acid suppressive therapy changed the paradigm of reflux testing in GERD: impedance allows detection of virtually all types of reflux whereas pH data are used in the categorisation of impedance detected reflux episodes; acid and non-acid. To date published normal values of
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Fig. 4. Combined multichannel intraluminal impedance and pH (MII–pH) monitoring. Impedance measuring channels are centred around 3, 5, 7, 9, 15 and 17 cm above the lower oesophageal sphincter (LES) and pH sensor is located at 5 cm above the LES. Combined impedance–pH monitoring identifies reflux episodes as rapid declines in intraluminal impedance progressing over time from distal to proximal. Information from the pH channel is used to distinguish between acid (nadir pH < 4) and non-acid (nadir pH > 4) reflux episodes.
MII–pH parameters on acid suppressive therapy are available only from a small group of healthy volunteers [36]. In patients not taking acid suppressive therapy most reflux episodes are acid, with the majority of non-acid reflux episodes occurring post-prandially [37]. Most patients seen in GI practice have been put on (empiric) acid suppressive therapy. However acid suppressive therapy only changes the acidity of the gastro-oesophageal refluxate without seeming to affect the mechanisms leading to gastric content refluxing into the oesophagus. Studies on post-prandial reflux have shown a shift from acid to non-acid reflux without significant reduction of the total number of gastro-oesophageal reflux events [38]. Partly contradicting these findings have been studies on healthy volunteers on acid suppressive therapy reporting a reduction in the number of acid reflux episodes but no change in the number of non-acid reflux episodes [30]. This may be explained by PPIs inducing a decrease of volume of gastric secretions, hence less gastric distension and less tLESRs leading to a decrease in the total number of gastro-oesophageal reflux episodes. Conversely, in the post-prandial period the volume of gastric content is determined primarily by the volume of the meal whereas the main effect of a PPI in that period may be attributed to a decrease in intragastric acidity. As discussed above gastro-oesophageal reflux episodes with a pH above 4.0 are generally considered non-acid in order to underscore the difference to the acid reflux episodes detected by conventional pH monitoring. Acknowledging the chemically correct definition of acid and non-acid, gastro-oesophageal reflux episodes detected by MII may be differentiated in acidic (if pH drops below 4.0), weakly acidic (if pH is between 4.0 and 7.0) and weakly alkaline (if intraoesophageal pH during an MII-detected reflux episode is above 7.0) [25]. The clinical relevance of this separation of non-acid reflux into weakly acidic and weakly alkaline remains to be established. The clinical relevance of gastric acid in the development of oesophageal mucosal erosions is well established. Reducing the acid content as done by PPI therapy has shown healing rates of close to 90% in GERD [39]. The relevant role of non-acid reflux as appreciated today is, rather than a possible effect on structural integrity of oesophageal mucosa, the evaluation of symptom–reflux association in patients under acid suppressive therapy. This is important as one-third of patients diagnosed with erosive GERD [33] and up to 65% of patients with non-erosive GERD have persistent symptoms on daily dose of PPI independent of endoscopic visual integrity [40].
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Mainie et al [41] and Zerbib et al [42] documented that in up to 50% of patients on therapy with PPI twice daily, oesophageal symptoms during 24-h combined MII–pH monitoring were associated with ongoing gastro-oesophageal reflux. Recently Becker et al [43] evaluated patients with ongoing symptoms under acid suppressive therapy and found abnormal MII–pH findings (abnormal distal oesophageal acid exposure or abnormal number of MII-detected reflux episodes) in 39% of patients taking standard dose PPI once daily. Patients were followed up for at least 3 months after the dose of PPI was increased. The authors were able to document a significantly better symptomatic relief in patients with abnormal MII–pH results (90%) compared to patients with normal MII–pH findings (43%), concluding that combined MII–pH monitoring facilitates a more focussed therapeutic approach to patients with PPI-resistant GERD possibly avoiding PPI overuse. The clinical utility of a positive association between symptoms and reflux is supported by the finding of an observational study by Mainie et al evaluating symptom response 7–25 months following anti-reflux surgery in 19 patients undergoing laparoscopic Nissen fundoplication for symptomatic nonacid reflux. Before surgery patients were examined using 24 h MII–pH. Most patients (94%) had a positive SI and one (6%) a negative SI. Patients were operated and followed up for a median period of 14 months. In this group 16/17 (94%) patients with a pre-op positive SI were asymptomatic or markedly improved (one patient was lost to follow up). The one patient operated despite negative SI had persistent symptoms and atypical ENT complaints recurred 9 months after fundoplication in a patient with positive symptom association. Despite the technical limitations of an observational study, this report yields important data on the efficacy of anti-reflux surgery in patients with symptomatic nonacid reflux on PPI therapy, which should be mandatory until proven otherwise in randomised, controlled studies in this group of patients. Summary and conclusion Oesophageal reflux testing – involving conventional 24-h pH monitoring, the wireless Bravo system, Bilitec and recently developed combined 24-h pH impedance testing – is an integral part in the evaluation of GERD and related symptoms. Empiric treatment with acid suppressive therapy is a practical and widely used approach in clinically suspected GERD. Oesophageal reflux monitoring is used to quantify oesophageal acid exposure in patients with reflux symptoms and normal endoscopic findings, part of pre-operative evaluation in patients planned for anti-reflux surgery and in patients with persistent reflux symptoms despite acid suppressive therapy. Conventional and wireless oesophageal pH monitoring should be performed in patients off acid suppressive therapy as it allows quantifying distal oesophageal acid exposure and the association of symptoms with acid reflux episodes. Wireless oesophageal pH testing increases patient comfort and mobility and allows measurements over prolonged periods of time. Patients complaining of oesophageal symptoms despite sufficient acid suppressive therapy should be evaluated using combined 24-h MII–pH monitoring, as it identifies reflux episodes independent of acidity and allows a better insight into symptom–reflux association. Specialised oesophageal function test centres should offer (wireless) pH testing and 24-h MII–pH as the current state of the art tools in the evaluation of GERD and related symptoms.
Practice points Conventional pH-metry measures oesophageal acid exposure using up to 3 (usually 1 or 2) electrodes mounted to a catheter that is inserted transnasally for 24 h recording. Wireless pH-metry improves patient comfort and prolongs the period of time for data acquisition but is more expensive and requires upper GI endoscopy. Regardless of the methodology used for pH-metry, not only quantification of distal oesophageal acid exposure but also analysis of the association between symptoms and reflux episodes is of importance.
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The catheter-based Bilitec system incorporates a small fibre-optic spectrophotometric chamber. High absorbance is considered indicative of the presence of bilirubin in the refluxate. Thus, Bilitec monitoring expands the ability to monitor gastro-oesophageal reflux by including data on bile-containing refluxate. MII-monitoring detects changes in intraluminal electrical conductivity of the oesophageal content providing information on presence of liquids and gas in the oesophagus. A rapid decline in intraoesophageal impedance starting in the distal oesophagus and moving towards the proximal oesophagus indicates liquid bolus transit in retrograde (oral) direction. Combining multichannel intraluminal impedance with pH monitoring (i.e. MII–pH) is an important tool to identify and validate gastro-oesophageal reflux episodes of all types independent of acidity.
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