Review article: the measurement of non-acid gastro-oesophageal reflux

Alimentary Pharmacology & Therapeutics Review article: the measurement of non-acid gastro-oesophageal reflux A. J. P. M. SMOUT Department of Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands Correspondence to: Dr A. J. P. M. Smout, Department of Gastroenterology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail: asmout@umcutrecht.nl Conflicts of interest: The author has declared no conflicts of interest. This article appeared as part of a supplement sponsored by Nycomed bv. Publication data Submitted 16 August 2007 Accepted 24 September 2007 SUMMARY Background Oesophageal ph monitoring has been used for three decades to study gastro-oesophageal reflux, but it does not allow detection of non-acid reflux episodes. Aim To discuss the techniques by which non-acid reflux can be measured and to evaluate the clinical relevance of such measurements. Methods Review of the literature on non-acid reflux monitoring. Results Ambulatory oesophageal impedance monitoring (using a catheter with ring electrodes) allows one to detect all types of gastro-oesophageal reflux, acid as well as non-acid. Measurement of intra-oesophageal bilirubin concentration also detects reflux irrespective of the ph, but only when there is bilirubin in the gastric juice and technical short-comings limit the applicability of this technique. In untreated subjects, about 50% of reflux episodes are non-acid (nadir ph > 4). In patients on acid inhibition, up to 95% of reflux episodes are non-acid. Treatment with an acid inhibitor leads to a significant decrease in the incidence of acid reflux episodes, but not to a reduction in the total number of reflux episodes. This shift is associated with a shift in symptoms from heartburn to regurgitation. With impedance monitoring, the temporal association between symptoms that persist during inhibition of acid secretion and non-acid reflux events can be demonstrated. In a proportion of patients with chronic cough, the coughing episodes are preceded by non-acid reflux. Conclusions Intraluminal impedance monitoring of gastro-oesophageal reflux is a feasible technique, which provides clinically important information about the relationships between symptoms and non-acid reflux events. Aliment Pharmacol Ther 26 (Suppl 2), 7 12 ª 2007 The Author 7 doi:10.1111/j.1365-2036.2007.03527.x

8 A. J. P. M. SMOUT INTRODUCTION During the past decades, our concepts of gastrooesophageal reflux and gastro-oesophageal reflux disease (GERD) have been determined, to a large extent, by the results of studies in which oesophageal ph monitoring was used to assess reflux. Traditionally, oesophageal ph monitoring is carried out with a catheter-mounted ph electrode placed at 5 cm above the lower oesophageal sphincter (LOS). Nowadays, it is also possible to record oesophageal ph using a radiotelemetric capsule (Bravo Ò, Medtronic, Minneapolis, MN, USA) attached to the oesophageal mucosa, most commonly at 6 cm above the squamocolumnar junction. 1 Capsule ph-metry is better tolerated than catheter ph-metry and allows for prolonged recording periods (48 h or longer). 2 With both techniques, the ph data are recorded in digital format in a portable datalogger and automated data analysis takes place after transfer of the data to a computer. Oesophageal ph monitoring provides two types of information. Firstly, the severity of oesophageal acid exposure can be measured. This is usually expressed as percentage of time with ph 4. Secondly, and often more importantly, oesophageal ph monitoring makes it possible to study the association between symptoms and acid reflux events. This association can be expressed numerically in the form of several indices, among which the symptom index (SI) and the symptom association probability (SAP) are the most popular. 3, 4 Although oesophageal ph monitoring has taught us much about reflux and GERD, it is important to realise that the technique may fail to detect reflux when the ph of the refluxate is high (non-acid reflux). This can occur after a meal (buffering effect of food), in neonates and infants (in whom gastric acid secretion is still limited and frequent milk feedings buffer the gastric contents almost continuously), during the use of an acid secretion-inhibiting drug, i.e. an H 2 -receptor antagonist or a proton pump inhibitor (PPI), after gastric resection (e.g. Billroth I, Billroth II and total gastric resection) and in atrophic gastritis (auto-immune or Helicobacter pylori infection-associated). TECHNIQUES FOR MEASUREMENT OF NON-ACID REFLUX In recent years, two techniques have emerged that make it possible to monitor non-acid reflux in ambulatory individuals. The first of these is the bilirubin absorption monitoring technique (marketed as Bilitec Ò, Medtronic, Minneapolis, MN, USA). 5 With this technique, a cathetermounted sensor placed in the distal oesophagus measures the absorbance of light with a wavelength, which is the same as that of bilirubin. The actual measuring device consists of a small cup in which a beam of light is reflected. The more the injected light is absorbed (i.e. not reflected), the higher the concentration of bilirubin in the cup is supposed to be. This technique has several disadvantages. Firstly, a liquid diet that is free of components that have a wavelength similar to that of bilirubin is required. Secondly, even when such a diet is used, the cup in which the reflection of the light takes place easily becomes clogged by small particles. This leads to light absorbance that can be falsely interpreted as presence of bilirubin. Thirdly, because the cup is not equipped with a cleansing mechanism, bilirubin-containing material is likely to remain in the cup longer than in the oesophageal body itself, leading to falsely prolonged periods of bilirubin absorbance. The above described technical limitations make the bilirubin absorption monitoring technique less suitable for the detection of rapid and short-lived events, such as episodes of gastro-oesophageal reflux. Consequently, analysis of the association between symptoms and reflux events with this technique is hampered. 6 Intra-oesophageal impedance monitoring is a technique pioneered by Silny et al. 7 in Aachen, Germany, in which the resistance to an alternating current (impedance) is measured at multiple sites in the oesophageal body. This is performed with a thin catheter on which ring electrodes are mounted (Figure 1). Most commonly, a catheter is used that allows recording from six impedance measurement segments that cover the entire oesophageal body and one ph electrode at 5 cm above the LOS (Figure 2). As all types of liquids that enter the oesophagus (saliva, drinks and gastric contents) have an impedance that is lower than that of the oesophageal wall, passage of liquids is seen as decrease in impedance. In case of aboral passage (i.e. transit of a swallowed bolus), the impedance fall is seen first in the most proximal recording sites and shortly afterwards in progressively more distal recording sites. In contrast, gastro-oesophageal reflux of liquid material gives rise to an impedance fall that is observed in the distal channels first (Figure 1). Using impedance monitoring, gastro-oesophageal reflux events can be detected irrespective of their acidity. Reflux with a nadir ph > 4

REVIEW: NON-ACID REFLUX 9 Figure 1. Detail of catheter for ambulatory combined ph and impedance monitoring. Metal rings placed at 2-cm intervals serve as electrodes for impedance measurement. An antimony ph electrode is positioned between two of these rings. has been named non-acid, but a consensus group gathering in Porto recently decided that it is more appropriate to use the term weakly acidic reflux. 8 As air and gas are poor conductors, passage of an air or gas bolus is seen as an impedance rise (often to values higher than 10 000 W). Swallowed air will be seen as an impedance rise that travels in distal direction; regurgitated air (belch) gives rise to a rapid increase in impedance that extends in oral direction. Quite often, liquid reflux events are accompanied by gas reflux (Figure 3). This type of reflux can be referred to as mixed reflux. Presently, two companies, Sandhill Scientific, Inc., Highlands Ranch, CO, USA and Medical Measurement Systems (MMS), Enschede, the Netherlands, provide equipment for ambulatory oesophageal impedance-ph monitoring. Both systems allow recording at adequate sampling rate (50 Hz minimum) and offer automated signal analysis. PREVALENCE OF NON-ACID REFLUX Recent studies using the impedance monitoring technique have shown that non-acid reflux ph > 4) is far from rare, neither in healthy subjects nor in patients with GERD. In fact, under many circumstances, nonacid reflux episodes may outnumber acid reflux episodes, an observation that severely corrodes the position of oesophageal ph-metry as the gold standard technique for reflux assessment. In healthy subjects, 25 34% of reflux episodes have a nadir ph < 4. 9 12 Upper limits of normal for 24-h ambulatory impedance-ph monitoring in adults were published by Figure 2. Commonly used catheter configuration for ambulatory ph impedance monitoring of the oesophagus. Z: impedance. three independent groups. These reflect the frequent occurrence of non-acid reflux in healthy individuals 10 12 (Table 1). In untreated GERD patients, the proportion of non-acid reflux appears to be slightly higer: 45 50% of reflux episodes were found to be nonacid. 9, 13 In GERD patients, treatment with a PPI does not lead to a significant reduction in the number of

10 A. J. P. M. SMOUT Figure 3. Example of impedance ph signals showing a reflux event (left) and a swallow (right) with a gaseous component. Liquid reflux events associated with a gas component are often labelled mixed reflux events. Table 1. Median values and upper limits of normal (95th percentile) for reflux episodes (number per 24 h) observed in ambulatory 24-h impedance-ph monitoring in adults Number of reflux events 24 h All Acid Weakly acidic Shay et al. (2004) Median 30 18 9 95th percentile 73 55 26 Zerbib et al. (2005) Median 44 22 11 95th percentile 75 50 33 Zentilin et al. (2006) Median 16 18 14 95th percentile 48 53 38 reflux episodes, but the percentage of acid reflux episodes (i.e. episodes with a nadir ph < 4) is dramatically reduced, from 50% to 5% approximately. 13 CLINICAL RELEVANCE OF NON-ACID REFLUX Whereas it is clear that the possibility to measure nonacid (weakly acidic) reflux is of great interest to researchers, the most important question to the clinician is whether or not non-acid reflux is clinically relevant. It is obvious that the noxious effect of non-acid material on the oesophageal mucosa is less than that of acid material: the fact that acid secretion-inhibiting drugs effectively promote the healing of oesophageal lesions testifies to this. An exception to this rule can be found in patients in whom the distal stomach or the entire stomach has been removed. In these patients, duodenal contents with high concentrations of pancreatic and biliary secretions can easily reflux into the distal oesophagus and cause oesophagitis, even in the absence of acid. However, whereas non-acid reflux appears to be relatively harmless to the oesophageal mucosa, there is an increasing body of evidence that it may cause symptoms. NON-ACID REFLUX AND TYPICAL REFLUX SYMPTOMS The question whether non-acid reflux causes symptoms, in particular typical reflux symptoms such as heartburn, has been addressed in several studies. In a study by Bredenoord et al. 14, it was found that the lower the ph of the refluxate, the higher the chance that it is perceived by patients with reflux disease. However, there now is incontrovertible evidence that non-acid reflux (ph > 4) can indeed cause symptoms. This has been demonstrated for the symptoms regurgitation, cough and heartburn. 13 15 As non-acid reflux episodes may be associated with symptoms and as these episodes can be missed during ph monitoring, it was felt to be likely that the addition of impedance monitoring to ph monitoring would increase the yield of 24-h monitoring. In particular, it was anticipated that the assessment of the temporal relationship between reflux episodes and symptoms would benefit from the addition of impedance monitoring. Recently, evidence for such an increased yield of impedance monitoring has indeed been produced. In GERD patients studied after stopping PPI treatment (off

REVIEW: NON-ACID REFLUX 11 PPI), the percentage of patients with a positive SI was found to be increased from 48% to 63% by the addition of impedance monitoring to ph monitoring only. Likewise, the percentage of patients with a positive SAP had increased from 67% to 75%. 16 An even greater increase in the yield of symptom analysis was found in patients who were studied while continuing their acid secretion inhibiting therapy (on PPI). The percentage of patients with a positive SI increased from 18% to 64% by the addition of impedance monitoring to ph monitoring. The percentage of patients with a positive SAP increased from 18% to 45%. 17 Other recent studies confirmed the value of including non-acid reflux episodes in the analysis of the association between symptoms and reflux. Mainie et al. 18 studied 168 patients with symptoms that persisted despite PPI therapy. During the 24-h ph impedance study, 144 patients on PPI had one or more symptom episodes. A positive SI was found in 69 of these patients. In 53 of the 69 patients with a positive SI, this was based on an association with non-acid reflux. Hila et al. 19 concluded from their study in 60 consecutive patients studied off PPI that, for the detection of acid reflux, ph monitoring alone is very sensitive, but not specific. Compared to impedance monitoring, ph monitoring yielded a specificity of 68%, 67% and 58%, respectively, for either an abnormal percentage time of ph < 4, a positive SI or both. For the detection of weakly acidic reflux, ph monitoring had a sensitivity of only 28%. NON-ACID REFLUX AND COUGH It is a widespread belief that unexplained chronic cough can be caused by gastro-oesophageal reflux. Oesophageal ph monitoring with analysis of the association between reflux events and cough events has provided evidence that, in a subset of patients, acid reflux is indeed the cause of their symptoms. Recently, the question whether non-acid reflux may also induce cough was also addressed. Sifrim et al. 20 used combined impedance and ph monitoring to identify the reflux and concurrent oesophageal pressure monitoring to identify the coughing episodes in a group of 22 patients with chronic unexplained cough. Six patients were found to have a positive SAP for the sequence cough preceding reflux and 10 patients had a positive SAP for the sequence reflux preceding cough. In five of the 10 patients with a positive SAP for the refluxcough sequence, the association was brought about by acid reflux episodes, but in the other five patients, weakly acidic reflux episodes or a combination of weakly acidic and acid reflux episodes were associated with cough. This study showed that gastro-oesophageal reflux can induce coughing spells even when the ph of the refluxate is above 4. In addition, the study confirmed that combined 24-h impedance ph pressure monitoring is a useful diagnostic technique in these patients. Tutuian et al. 21 retrospectively reviewed data from 50 patients with persistent cough despite acid inhibition. All patients were studied while taking a PPI twice daily. The SI for cough was positive ( 50%) in 13 of the 50 patients (26%). The authors argue that, for PPI-resistant cough, impedance ph monitoring should be performed while continuing PPI treatment, because demonstration of a relationship off PPI does not explain why symptoms persist on PPI. If non-acid reflux is a cause of chronic cough, it is not surprising that the effect of proton pump inhibition in this condition can be disappointing. Fundoplication, which abolishes all types of reflux, was carried out in six patients with chronic cough and a positive SI for the association between symptoms and cough. Five of these patients were asymptomatic after the 21, 22 procedure; the sixth patient was lost to follow-up. CLINICAL IMPLICATIONS The advent of oesophageal impedance monitoring had a profound influence on the approach to GERD patients with persistent symptoms despite PPI therapy. In the traditional approach, ph monitoring was performed after stopping the PPI. This provided answers to the questions whether the patient s symptoms were indeed related to acid reflux and, secondly and less importantly, whether the patient s reflux was excessive or not. Nowadays, the alternative option is to investigate these patients on PPI with combined ph and impedance monitoring. Such a study provides answers to two clinically relevant questions: (i) is the patient s acid reflux adequately suppressed by the PPI? and (ii) is reflux (either acid or non-acid) the cause of the remaining symptoms on PPI? Before considering the addition of impedance monitoring to one s diagnostic armamentarium, however, one should take into account that the automated analysis of oesophageal impedance signals is not yet perfect. 23 This implies that the signals must be visually inspected and that the results of automated analysis of the association between symptoms and reflux episodes should always be verified.

12 A. J. P. M. SMOUT CONCLUSIONS Intraluminal impedance monitoring of reflux of gastric material into the oesophagus is a clinically feasible technique. With this technique, it has been shown that approximately 50% of reflux episodes in GERD patients off PPI and 95% of reflux episodes on PPI are non-acid (ph > 4). Non-acid reflux can induce symptoms such as regurgitation, heartburn and cough. In patients with symptoms that persist during PPI treatment, non-acid reflux causes symptoms more often than acid reflux and, as a consequence, impedance monitoring provides more clinically relevant information than ph monitoring. REFERENCES 1 Kahrilas PJ, Pandolfino JE. Review article: oesophageal ph monitoring technologies, interpretation and correlationg with clinical outcomes. Aliment Pharmacol Ther 2005; 22(Suppl. 3): 2 9. 2 Hirano I, Zhang Q, Pandolfino JE, Kahrilas PJ. Four-day bravo ph capsule monitoring with and without proton pump inhibitor therapy. 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