Patient acceptance and clinical impact of Bravo monitoring in patients with previous failed catheter-based studies

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1 Alimentary Pharmacology & Therapeutics Patient acceptance and clinical impact of monitoring in patients with previous failed catheter-based studies R. SWEISà, M.FOX*,, à,r.anggiansahà, A.ANGGIANSAHà, K. BASAVARAJUà, R. CANAVANà & T. WONGà *Functional GI Disease Unit, Clinic for Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland; Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; àoesophageal Laboratory, Department of Gastroenterology, Guys and St Thomas NHS Foundation Trust, London, UK Correspondence to: Dr T. Wong, St Thomas Hospital, Department of Gastroenterology, Westminster Bridge Road, London SE1 7EH, UK. Publication data Submitted 11 September 8 First decision 2 October 8 Resubmitted 31 October 8 Resubmitted 1 December 8 Accepted 15 December 8 Epub Accepted Article 22 December 8 SUMMARY Background Standard ph monitoring is performed over 24 h with a naso-oesophageal catheter (C-pH). Limitations include naso-pharyngeal discomfort, nausea and social embarrassment resulting in reduced reflux-provoking activities. Recently a catheter-free ph-monitoring technique has become available. The tolerability and diagnostic yield of this system in patients who failed standard monitoring remain unknown. Aim To examine the tolerability and diagnostic outcome of catheter-free phmonitoring technique in patients who failed standard monitoring. Methods Patients referred for C-pH and catheter-free ph monitoring completed a tolerability questionnaire. Acid exposure in the distal oesophagus and symptom index (SI) were reviewed. Results Over 4 years, (%) of patients with typical reflux symptoms referred for C-pH were diagnosed with gastro-oesophageal reflux disease (GERD) based on a pathological percentage time acid exposure (%time ph <4);134 (8%) patients failed C-pH and, of these, 129 successfully completed 2-day catheter-free ph monitoring. Ninety-eight (76%) of these patients had a pathological percentage ph <4 on either day compared with 49 2 (49%) of contemporaneous C-pH patients (P <.1). There was no difference in SI for heartburn (35% vs. 42%; P =.49). The questionnaire demonstrated a preference for catheter-free ph monitoring (96%) with less restriction in activities of daily living, naso-pharyngeal discomfort, dysphagia and chest pain. Conclusions Tolerance and satisfaction with catheter-free ph monitoring are high in patients who had previously failed C-pH; catheter-free ph monitoring assists the definitive diagnosis of GERD in this group. 669 doi:.1111/j x

2 67 R. SWEIS et al. INTRODUCTION Monitoring oesophageal ph is a valuable tool in the diagnosis of patients with gastro-oesophageal reflux disease (GERD), especially those in whom the association between reflux and symptoms is uncertain and those under consideration for anti-reflux surgery. Standard ambulatory investigation is normally performed by naso-oesophageal catheter with a ph electrode (C-pH) placed 5 cm above the lower oesophageal sphincter (LOS) identified by manometry. 1, 2 Limitations of this procedure are nasal and pharyngeal discomfort with gagging, nausea and vomiting in some patients. C-pH is also considered socially embarrassing and can result in a modified diet and lifestyle, which may not be representative of normal daily life and reduce reflux provoking activities. 3, 4 No study has been performed to assess factors affecting tolerance of nasal intubation; however, intolerance for other invasive diagnostic procedures such as colonoscopy is more common in the presence of functional gastrointestinal disease. 5 Similarly, individuals who are intolerant to C-pH are often considered to have heightened sensitivity, functional oesophageal symptoms or psychological disease. Especially in many patients with nondiagnostic findings on endoscopy, failure to tolerate the nasooesophageal catheter prevents an objective assessment of oesophageal ph and symptom-association with reflux events. Failure to obtain a definitive diagnosis of GERD and subjective interpretation of patient behaviour on the part of physicians may result in inappropriate management decisions. The system (Medtronic Inc., Shoreview, MN, USA) is an endoscopically placed, catheter-free phmonitoring system. A radiotelemetric capsule is attached to oesophageal mucosa 6 cm above the z-line identified at endoscopy using a specially designed trans-oral delivery device. Oesophageal ph data are then transmitted to a portable receiver attached to the patient s belt for 48 h. Prolonged measurement increases diagnostic reproducibility and is, therefore, most suitable in patients with intermittent symptoms in view of the wide day-to-day variability in symptom frequency. 6 8 It is less suitable for patients with prominent postprandial symptoms or for the investigation of patients on anti-secretory medication as most reflux events in these situations are weak or non-acidic. The catheter-free system is better tolerated than catheterbased ph measurement and is preferred by unselected patients referred for ph investigation. 1, 9 The disadvantage of the system is higher costs. As a result, recent UK guidelines state that catheterfree oesophageal ph monitoring is particularly suitable for patients who do not tolerate nasal intubation. Patients who fail to tolerate C-pH can be offered catheter-free ph monitoring; however, it is not known whether this cohort of patients tolerate catheter-free ph monitoring and whether the diagnostic yield in terms of pathological oesophageal acid exposure or symptom association justifies this investigation. This study prospectively examined the technical success, patient satisfaction and results of ph measurement in patients intolerant of C-pH and compared them with a contemporaneous group of patients who tolerated C-pH. METHOD Patients Between 3 March 4 and 24 January 8, details of 2749 consecutive patients referred to a tertiary centre for oesophageal manometry and ph studies were recorded in a database and on paper records. Patients with primary motility disorders such as achalasia on manometry were excluded from the study; 2366 were referred for conventional 24 h ph monitoring via a nasal catheter; 615 cancelled or did not attend for their investigation. In the same period, 185 patients were referred for wireless studies. Of these, 156 (84%) patients underwent the investigation; (99%) of those investigated successfully completed the standard 48 h ph monitoring. A majority of patients [ (86%)] were offered having failed 24-h C-pH. Digitrapper catheter ph monitoring (C-pH) Prior to its passage, an antimony ph catheter (Slimline; Medtronic Inc.) was calibrated at 25 C in phs 7.1 and 1.7 buffer solutions as per the manufacturer s protocol (Medtronic Inc.). This was then passed trans-nasally and positioned so that the ph sensor was 5 cm above the lower oesophageal high pressure zone, which was obtained at conventional or high resolution manometry. The catheter was then connected to a portable digital data recorder (Digitrapper ph ; Medtronic Inc.). A new catheter was used for every patient.

3 TOLERABILITY OF BRAVO 671 All patients were asked to return in 24 h when the catheter is removed and the data downloaded. capsule ph monitoring Prior to placement of the capsule, the device was activated by a magnetic switch and calibrated at 25 C according to the manufacturer s protocol (Medtronic Inc.). The capsule and receiver were also checked to confirm transmission of data. After an initial endoscopy to confirm the position of the squamocolumnar junction (SCJ) and document endoscopic findings, the delivery system was passed orally with the patients lying in the left lateral decubitus position. The capsule was then deployed 6 cm proximal to the SCJ after 1 min of suction to stabilize the position. 1 The distance to the attachment site was measured from the incisor teeth. Capsule attachment and accuracy of position was then confirmed by direct vision with a repeat endoscopy; a picture was taken for objective analysis. Mean doses for sedation [midazolam 7 mg ( mg) and fentanyl 67 lg ( 1)] were somewhat higher than those for the diagnostic endoscopy [midazolam 4 mg ( 5 mg)]. The receiver was then reconfirmed to be transmitting successfully and the patient was asked to return in 48 h. ph capsule and C-pH Prior to the study, patients in both groups were provided with detailed dietary advice to avoid ingestion of food and fluids with low ph to eliminate swallowassociated artefacts. Patients who were not excluded proceeded to C-pH and completed a tolerability questionnaire on their return to the oesophageal laboratory 24 h later (See Appendix S1 online). Those who failed manometry or C-pH and proceeded to also completed the same questionnaire on their return at 48 h (See Appendix S1 online). Endoscopic results (Los Angeles (LA) classification), %time ph <4 24 h and symptom index (SI) of the C-pH and group were assessed. (e.g. number of reflux episodes) were not analysed separately to reduce the chance of type I errors related to multiple comparisons. The primary outcome was the %time ph <4 of the 24-h period with the highest acid exposure within the 48 h catheter-free study. Average 48 h results are also presented for comparison. It has been shown that different cut-off values between C-pH and should be employed for diagnostic accuracy. However, this has not yet become a standard method of interpreting ph measurement. Furthermore, as normal cut-off values for this parameter differ between practitioners, studying the effects of altering the cutoff value on diagnostic yield is of interest. Therefore, for categorical analysis, we applied (i) a standard cutoff value of 4.2% for both procedures and (ii) specific cut-off values of 4.2% for C-pH and >5.3% for in accordance with published values. 1 Symptom index Symptom index is the percentage of reflux symptoms associated with reflux episodes. Recent evidence suggests that this parameter provides a clinically useful assessment of visceral sensitivity. 12 SI is preferred to symptom association probability (SAP) in this study because SAP increases with study duration (significance of association increases with number of observations) and thus cannot be used for comparing 24- and 48-h data. 13 Symptoms were considered to be associated to reflux if they occurred within 2 min of the reflux episode. The cut-off value used for positive SI was %. Statistical analysis Student s t-test was used for quantitative variables and the chi-squared test and Fisher s exact test for qualitative variables. Mann Whitney U-test was used for nonparametric analysis of %time ph <4 and SI. P <.5 was considered statistically significant. Statistical analysis was performed using commercial statistical software SPSS 16. (SPSS Inc., Chicago, IL, USA) for Windows. DATA ANALYSIS Oesophageal acid exposure measurements Per cent time ph <4 24 h is the single most robust and reproducible diagnostic marker of GERD and was the primary outcome measurement. 11 Other parameters Power Assuming a % variation in symptom reporting (typical in GERD trials), patients give a 9% (b =.9) chance of detecting a % difference in tolerability between C-pH and measurements at a <.5. Assuming a % day-to-day variation in oesophageal

4 672 R. SWEIS et al. acid exposure, 8 a sample size of patients gives an 8% (b =.8) chance of detecting a % difference between C-pH and measurements. This equates a similar change in diagnostic classification at typical diagnostic cut-offs in the mid-range of the population distribution in the population tested (i.e. 4 6% acid exposure), estimated from 2 2 tables. RESULTS From the 1751 patients who had the catheter-based test, 883 (%) had a diagnosis of GERD based on a pathological %time ph <4. Of the 1751 patients, 134 (7.7%) could not tolerate the nasal catheter. This is consistent with the published data that 5 % of patients are intolerant of C-pH or fail to complete the 24-h study. 14 Reasons for failure in this cohort were intolerance of catheter insertion (84%), intolerance of the catheter after intubation (7%) and vomiting of the catheter within the 24 h monitoring period (9%). The remaining 22 had performed either because of ongoing symptoms despite a negative 24-h test (11 22), a contraindication to nasal catheterization, e.g. recent rhinoplasty (three of 22) or a wish to avoid nasal intubation (eight of 22). These were not included in the study. From the 134 patients intolerant of C-pH who completed the procedure, the mean age was 6 (range 18 76; 58 males). These were compared with 1 consecutive C-pH controls with a mean age of 57 (range 16 85; 44 males). Ninety-four of 134 (7%) patients completed the tolerability questionnaire. There was no difference in age and gender between the two groups (P =.11 and.78 respectively). Endoscopy results were recorded in patients undergoing and 95 1 patients undergoing C- ph (Table 1). There was no difference in endoscopic findings between the two groups (P =.92); however, Table 1. Endoscopy findings (%) CP-H (%) Normal 81 (64) 68 (72) Oesophagitis 37 (29) 16 (17) LA classification A 23 (18) 11 (12) LA classification B 14 (11) 5 (5) Barrett s 5 (4) 8 (8) Schatzki s ring 1 (1) 1 (1) Stricture 2 (2) 2 (2) n it is important to note that almost all patients were on anti-secretory medication with proton pump inhibitors until 1 week prior to the procedure. In addition, most of the C-pH group had their endoscopy performed at regional hospitals, whereas the patients had their endoscopies performed at tertiary referral centres by an endoscopist who took particular note of mucosal disease prior to capsule deployment. Oesophageal acid exposure Analysis of continuous data from ambulatory ph studies showed a significantly higher median (IQR) %time ph <4 between the 48 h and 24 h C-pH groups [6.9 (3.8) vs. 4.1 ( ); P =.1]. Categorical analysis (Table 2) also showed a higher prevalence of pathological oesophageal acid exposure on at least 1 day during 48-h catheter-free ph monitoring as defined by a standard cut-off value of 4.2% for both techniques (98 129; 76% vs. 49 2; 48% respectively; P <.1). Using a specific cut-off value of 5.3% for and 4.2% for C-pH, the prevalence of pathological oesophageal acid exposure on at least 1 day remained higher in the group. (92 129; 71% vs. 49 2; 48% respectively; P <.1). Average 48 h results showed a similar finding with higher prevalence of oesophageal acid exposure in the group using 4.2% as a standard cut-off value [ (68%); P =.3]; however, this difference was not significant using a cut-off of 5.3% [ (58%); P =.18]. There was no systematic difference in the Table 2. Categorical analysis of diagnostic yield applying different cut-off values for %time ph <4 to define gastrooesophageal reflux disease C-pH Cut-off 5.3% Cut-off 4.2% Cut-off 4.2% time ph <4 time ph <4 time ph <4 pos 92 (71%) 98 (76%) 49 (48%) neg 37 (29%) 31 (24%) 53 (52%) n Median IQR Pathological oesophageal acid exposure was higher on at least 1 day in the 48-h group than in the 24-h C-pH group using uniform (4.2% time ph <4) or technique-specific cut-off values (5.3% and 4.2% time ph <4); P <.1 for both comparisons.

5 TOLERABILITY OF BRAVO 673 Table 3. Categorical analysis of symptom index for heartburn symptoms HB 48 h SI >% C-pH HB 24 h SI >% pos 34 (35%) 22 (42%) neg 63 (65%) (58%) n Median IQR There was no significant difference in diagnostic yield for gastro-oesophageal reflux disease based on symptom index (positive SI %) for heartburn (HB) or pooled reflux associated symptoms between the two procedures (P =.488 and.328 respectively). Similarly, there was no difference in median scores (38.5 vs. 33; P =.8). incidence of pathological oesophageal acid exposure between the first and second day of measurements using 4.2% and 5.3% as cut-off values (P = N.S. for both). Fifteen of 129 (11.6%) patients had a different outcome on days 1 and 2 using 4.2% as a cut-off value and (12.4%) using 5.3% as a cut-off value. Continuous analysis of SI showed that there was no significant difference in the median SI for heartburn (HB, the most common symptom) between the group at 48 h and C-pH group [38.5 ( ) vs. 33 ( ); P =.8]. Categorical analysis also showed no difference in SI for HB between and C-pH [34 97 (35%) and (42%) respectively; P =.49; Table 3]. When SI for all potential reflux-associated symptoms (HB, regurgitation, chest pain and cough) was pooled, there was also no significant difference between the (47 116; 41%) and C-pH groups (32 65; 49%) (P =.33). Similarly, there was no difference for SI between day 1 and 2 or between either day and average SI over 48-h wireless measurement for HB or pooled symptoms (P = N.S.), or with SI assessed during 24-h C-pH (P = N.S.). Thus, consistent with previous results, there was important day-to-day variability for oesophageal acid measurements or SI, 6, 8 but no systematic difference over the measurement period was present. Tolerance of procedure There was no difference in oesophageal acid exposure or SI between the patients who answered the Figure 1. Overall experience of and C-pH groups (1 = very unhappy, 5 = very satisfied) favoured the catheter-free technique (P <.1). questionnaire compared with those who did not (P = N.S.). The results of the tolerability questionnaire demonstrated a significant preference for the system compared with C-pH in almost all responses (Figures 1 5), with an overall satisfaction score of vs ; P <.1 (Figure 1). All but one respondent who had undergone the catheter-free ph monitoring said that they would recommend the procedure to another person compared to 73% who underwent C-pH (P <.1). Moreover, 96% of patients who underwent both procedures preferred to C-pH. There was markedly less restriction of daily activities (Figure 2), throat (Figure 3), nasal discomfort and swallowing difficulty (Figure 4) during 7 6 Figure 2. Restriction of everyday activities in and C-pH groups (1 = very severe, 5 = normal for patient) favoured the catheter-free technique (P <.1).

6 674 R. SWEIS et al. 6 6 Figure 3. Throat discomfort in and C-pH groups (1 = very severe, 5 = none) favoured the catheter-free technique (P <.1) the catheter-free procedure than during the catheterbased procedure (P <.1 for all comparisons). There were also less reports of chest pain immediately after placement of the capsule compared with C-pH (P =.4; Figure 5). No complications occurred with the system (capsule retention, bleeding, perforation) and no capsule required endoscopic removal. DISCUSSION Figure 4. Swallowing difficulty immediately after insertion of and C-pH (1 = very severe unable to swallow, 5 = normal) favoured the catheter-free technique (P <.1). Published data indicate that between 5% and % of patients are intolerant of naso-gastric intubation or fail to complete 24 h ambulatory catheter-based ph Figure 5. Chest pain immediately after insertion of and C-pH (1 = very severe, 5 = none) (P =.35). monitoring. 14 The system provides the means to obtain definitive diagnosis of GERD in this cohort. This study demonstrates that the technique is well tolerated and that ph measurement has a high diagnostic yield in these individuals. Two groups of patients referred for oesophageal studies to a large tertiary referral unit were studied: (i) patients who successfully completed a 24 h catheterbased ph monitoring and (ii) patients who failed to tolerate the nasal catheter (almost all performed in our institution) and underwent catheter-free ph monitoring. There were no differences in baseline demographic or clinical characteristics between these two groups. Ambulatory ph measurements were successful in the vast majority of patients. Patient tolerance was improved and activities of daily living were better preserved for the catheter-free procedure compared with the catheter-based study (Figures 1 5). Although some studies have reported chest pain to be increased in patients undergoing the procedure, 1, 4 pain is not serious in the vast majority with very few requiring removal. Our study found little difference in this parameter between the two procedures. The relatively high dose of sedation required for capsule placement is likely to reflect intolerance of oropharyngeal intubation in patients who failed to tolerate nasopharyngeal intubation. Patients who undergo as a primary investigation usually require no greater dose than at routine endoscopy. As reported by the previous comparative studies, oesophageal acid exposure was higher in the group than in the C-pH group [6.9% (3.8) vs. 4.1%

7 TOLERABILITY OF BRAVO 675 ( ); P =.1]. Applying a diagnostic cut-off for the diagnosis of GERD (i.e. categorical analysis) revealed that the prevalence of pathological acid exposure on at least one 24-h period during 48-h catheterfree ph monitoring was higher than that of the 24-h C-pH measurement. This is consistent with the studies by Pandolfino et al. 1 and Scarpulla et al. 6 that showed that analysis of the worst day increases diagnostic sensitivity in prolonged ph monitoring. In contrast, if the diagnosis based on the average ph exposure over 48 h was compared with 24-h ph monitoring using normal values specific for both techniques (i.e. 5.3% and 4.2% for and C-pH respectively), then no significant increase in diagnostic yield was found. Sixteen of 129 (12.4%) patients had different outcomes on days 1 and 2 using 5.3% as a cut-off value respectively. This is consistent with a recent study by Gillies et al. 15 in which % of patients had their diagnosis changed when second day data were included. There was no significant difference in the SI for HB or pooled reflux-related symptoms during 48-h catheter-free and 24-h C-pH monitoring (Table 2). In contrast, as reported by other authors, 13, 16 the ability to detect a significant reflux symptom association probability increased with test duration. These findings illustrate the important day-to-day variability of oesophageal acid exposure. 17 Prolonged study duration reduces measurement variations, increases the number of events available for analysis and improves test retest reproducibilty. 6, 8 It is important to note that this case series was not designed to address diagnostic yield of ph studies and it is not clear whether the average or worst day analysis of prolonged ph studies is most clinically relevant. 6 There are several possible explanations for the increased acid reflux observed in the group compared with the demographically and clinically similar C-pH group. First, improved comfort and the lack of a catheter during ph measurement facilitate more normal dietary and physical activity. This increases the number of reflux events and overall oesophageal acid exposure. 3, 4 Second, as described above, prolonged monitoring may increase the diagnostic yield of GERD. 6 Finally, although endoscopic findings were similar in both groups, we cannot exclude a selection bias by which only those with more severe symptoms attended for further testing by the procedure. These findings do not support the contention that patients who fail to tolerate C-pH have heightened sensitivity to distal oesophageal acid reflux. On the contrary, this group had at least as high a prevalence of pathological acid exposure and no evidence of visceral hypersensitivity as assessed by SI. 12 Thus, failure to tolerate intubation with a naso-oesophageal catheter was independent of the severity of acid exposure or reflux symptoms. Some patients did not complete the tolerability questionnaire; however, there was no evidence of selection bias on subgroup analysis. Indeed, a minority of patients who did not report had a numerically higher prevalence of pathological acid exposure than the other groups. In conclusion, this study compared a cohort of patients investigated by who had failed catheter ph monitoring with a contemporaneous, well-matched group of patients who successfully completed this investigation. Patient satisfaction with ph monitoring was high and the technique was well tolerated, even in a patient group that had previously failed to complete C-pH. There was no evidence to support that patients had higher oesophageal sensitivity to reflux events; rather, this group was unable to tolerate naso-pharyngeal intubation without sedation. This study has important clinical consequences. entails a greater cost than C-pH and, in many cases (as here), an additional visit to hospital for endoscopic placement. Nevertheless, had ph measurement not been available, many patients with pathological ph exposure would not have received a definitive diagnosis of GERD. This is likely to have an adverse impact on care and management decisions in many individuals, for example, those under consideration for anti-reflux surgery. These findings support the recommendation that patients who fail to tolerate catheter-based testing should be offered catheter-free ph monitoring. ACKNOWLEDGEMENTS We are grateful to Dr Maxwell Asante, Consultant Gastroenterologist at Princess Royal University Hospital, Orpington, UK for his help with funding research at the oesophageal lab for one year through the Maxwell Asante Foundation; Dr Jeremy Sanderson, Consultant Gastroenterologist at Guy s and St Thomas Hospitals, London, UK and Senior Clinical Research Fellow at King s College London for his support and advice; Siobhan Crichton in the Division of Health and Social Care Research at Kings College London for statistics advice; and The Manoukian Foundation for its support of the St. Thomas Hospital Oesophageal

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