Four-Day Bravo ph Capsule Monitoring With and Without Proton Pump Inhibitor Therapy

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3:1083 1088 Four-Day Bravo ph Capsule Monitoring With and Without Proton Pump Inhibitor Therapy IKUO HIRANO, QING ZHANG, JOHN E. PANDOLFINO, and PETER J. KAHRILAS Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois Background & Aims: Ambulatory ph testing often is used to guide the management of reflux symptoms that do not respond to proton pump inhibitor (PPI) therapy and to evaluate the contribution of acid reflux to atypical symptoms. Controversy exists as to whether such clinical studies are performed optimally off or on PPI therapy. The aim of the present study was to determine the feasibility of 4-day ph recordings using a ph system that would encompass time periods both before and during PPI therapy. Methods: Eighteen patients underwent 4-day ambulatory ph testing using 2 separate receivers calibrated to a single Bravo ph capsule. Rabeprazole was administered on days 2 4 of the study (20 mg orally twice a day). Results: Indications for ph testing were refractory heartburn, chest pain, or chronic cough. ph recordings showed that 9 patients (53%) had esophageal acid exposure values that exceeded 4% on day 1 and 7 patients (41%) had values that exceeded 5.3%. Patients showed significant and progressive reductions in acid exposure on days 2 4 of the recording period. Of the 7 patients with quantitatively abnormal levels of acid exposure on day 1, 86% had normalization by day 3. Conclusions: Prolonged, esophageal ph recordings using the Bravo ph system are feasible and allow for combined testing both off and on a therapeutic trial of PPI. Such studies may allow for the acquisition of complementary information in a single test that may be useful in the management of patients with suspected gastroesophageal reflux disease symptoms. Ambulatory ph testing is considered the most objective means of diagnosing gastroesophageal reflux disease (GERD) with greater sensitivity than endoscopy and greater specificity than therapeutic trials with proton pump inhibitors (PPIs). 1,2 ph testing often is used to guide the management of typical reflux symptoms that do not respond to PPI therapy and to evaluate atypical symptoms such as chest pain, asthma, and chronic laryngeal symptoms. 1,3 Limitations of conventional catheterbased ph testing include patient intolerance, potential for catheter migration, and limitation in patients physical and dietary activity owing to discomfort. 4,5 The development of the Bravo wireless ph capsule (Medtronic, Shoreview, MN) has circumvented some of these problems and has the additional advantage of allowing for 48-hour recording periods, which may increase its sensitivity in the diagnosis of GERD. 5,6 The Bravo ph system, although designed for 48-hour recordings, may be capable of recording for longer periods of time. Lengthening the recording period to an interval of several days might allow for ph testing in patients initially off and subsequently on PPI therapy. Such recordings would allow for both the detection of the presence of quantitatively abnormal reflux and for assessment of the adequacy of PPI therapy, should it be present. Furthermore, the longer sampling period might increase the diagnostic sensitivity of ph recordings and enable prolonged assessments of symptom correlation with reflux events. The aim of the present study was to test the feasibility of using the Bravo ph system for a 4-day recording period that encompassed sequential recording periods both off and on PPI therapy. Methods Eighteen patients were selected from those undergoing ph testing for the clinical evaluation of reflux disease. Because the feasibility and accuracy of recordings beyond 48 hours has not yet been ascertained, only patients in whom ph testing was requested off therapy were included. In this manner, the primary clinical objective would not be affected by the additional testing protocol. Patients were required to be off PPI therapy for a minimum of 2 weeks before the study. Informed consent was obtained for all procedures. ph Study Protocol Two Bravo ph receivers were calibrated simultaneously to 1 ph capsule. After the calibration, 1 receiver (R2) was turned off. The Bravo capsule then was placed 6 cm above the endoscopically determined squamocolumnar junction as previously described. 6 Recording was started with the first Abbreviations used in this paper: GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor. 2005 by the American Gastroenterological Association 1542-3565/05/$30.00 PII: 10.1053/S1542-3565(05)00529-X

1084 HIRANO ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 11 Table 1. Indications for Bravo Study and ph Study Results Patient Indication (primary/secondary) Day 1 Day 2 Day 3 Day 4 % Symptom index % Symptom index % Symptom index % Symptom index 1 Chest pain 4.8 1/1 0 0/0 0 0/0 0 1/2 2 Chest pain 10.2 1/2 2 0/5.7 0/6.3 1/5 3 Chest pain.5 1/2 0.5 1/2.5 1/3.7 2/10 4 Chest pain 13.6 1/2 11 1/1 0 0/2.1 0/0 5 Chest pain 6.7 0/1.5 0/0 0 0/0.2 0/2 6 Chest pain 1.1 1/3.2 1/5 0 0/2.8 0/0 7 Chest pain 4.1 7/7.3 2/2.6 1/1 0 1/2 8 Chronic cough/chest pain 1.9 3/6.4 1/6.2 0/4 0 0/3 9 Chronic cough 3.7 NA 1 NA.3 NA.1 NA 10 Chronic cough 15.3 NA 1.3 NA 1 NA.5 NA 11 Refractory heartburn, chronic cough.6 4/14.3 1/6 2 0/2 - - 12 Refractory heartburn 14.2 2/2 3.3 2/2 1.4 0/0 1.3 0/0 13 Refractory heartburn 12.5 1/5 3.9 2/5 2.4 0/3 4.5 2/4 14 Refractory heartburn 1.7 1/7 1.1 1/5.5 0/3.2 0/4 15 Refractory heartburn.9 4/13.5 3/7.2 1/1.3 2/4 16 Refractory heartburn 20.5 3/4 10.2 2/2 8.7 2/4 8.2 2/2 17 Refractory heartburn.3 0/1.2 0/1.1 0/1 0 0/1 Median (interquartile range) 4.1 (1.1 13.1).5 (.3 2.7).5 (.1 1.2).3 (.1.8) NOTE. Total percent of time ph level was less than 4 is shown. receiver (R1) immediately after capsule placement. The patients were instructed to begin rabeprazole 20 mg orally twice a day starting 24 hours later. At 48 hours, the patients were instructed to turn on the second receiver. The patient returned both receivers after day 4 of the study. Patients also kept standard symptom, activity, and dietary diaries during the 4-day period. Symptom-reflux associations were expressed using the symptom index defined by the number of reflux-related symptom episodes divided by the total number of symptom episodes. 7 This analysis was applied to patients with indications of chest pain and refractory reflux, but not chronic cough. To assess for potential ph calibration errors and electrode drift, 5 patients swallowed 50 cc of orange juice warmed to 37 C at both the beginning and the end of the 4-day period. The ph of the swallowed orange juice was compared with values measured ex vivo with the orange juice containers immersed in a water bath heated to 37 C using a bench-top glass ph electrode (Scholar Model 425; Corning, Corning, NY). In addition, 8 Bravo capsules were studied ex vivo over a 48-hour period with repeated calibrations recorded using buffer solutions with a ph of 1, 4, and 7. The receivers were switched off after each calibration to determine if this would affect the recorded values. The institutional review board of Northwestern University approved the study protocol. Statistical Analysis The data distribution characteristics were checked before statistical analysis. Nonparametric group data were presented as the median (interquartile range) and paired data were compared with the Wilcoxon signed-rank test. Comparisons involving more than 2 datasets were made using repeatedmeasures analysis of variance (SAS Institute Inc., Cary, NC). A P value of less than.05 was accepted as indicative of statistical significance. Results Eighteen patients were studied using the 2 receivers and the 4-day recording protocol. In 2 patients, the early detachment of the Bravo capsule prevented complete data analysis. One probe detached after 2 days and the second probe detached after the third day. The patient who only completed 2 days of recording was excluded from the data analysis, however, the patient whose probe detached at the end of day 3 was included. The remaining 16 patients completed the 4-day study. None of the 18 patients had endoscopic evidence of esophagitis. No patient reported any adverse effects of the Bravo procedure such as chest pain, dysphagia, or bleeding. The indications for ph testing were chest pain, refractory heartburn, and laryngeal symptoms (Table 1). Seven patients were studied for chest pain that was not typical of reflux and who had not responded previously to empiric PPI therapy. Seven patients complained of heartburn despite treatment with PPI therapy or fundoplication. Four patients were being evaluated for laryngeal symptoms dominated by chronic cough in the absence of heartburn that had not responded to a prolonged course of twice-daily PPI therapy. Six men and 12 women were included with a median age of 52 years. Analysis of the ph recordings showed that 9 (53%) patients had esophageal acid exposure that exceeded 4% on day 1 and 7 patients (41%) had values that exceeded 5.3%. A previous study from our laboratory showed that the 95th percentile for a Bravo 2-day recording in control patients was 5.3%, a value higher than that obtained

November 2005 EXTENDED BRAVO ph MONITORING 1085 Figure 1. Percent time of ph less than 4 for each day of the 4-day study. A significant reduction in distal esophageal acid exposure occurred within the first day of administration of rabeprazole (day 2) and was maintained throughout the remainder of the recording period. Only 1 patient (6%) failed to normalize acid exposure levels during the treatment phase. The horizontal bars represent the median acid exposure for each day. *Significance at the P.005 level. with catheter-based ph recordings. 6 All patients were noted to have a reduction in acid exposure with each successive day of the recording period, with all but 1 patient showing normal acid exposure by day 3 (Table 1). Significant reductions in acid exposure occurred on day 2 (first day of rabeprazole) and continued on days 3 and 4 (Table 1, Figure 1). Figure 2 shows a 96-hour ph tracing of a patient with the indication of chest pain (patient 2) with abnormal baseline acid exposure showing the marked reduction in reflux events on successive days after the initiation of rabeprazole at 20 mg twice daily. Only 1 patient (6%) did not normalize distal acid exposure by day 4 of the study period (patient 16). The indication for ph testing in this individual was that of heartburn refractory to PPI therapy. Of the 7 patients with pathologic amounts of acid exposure, 6 patients (86%) achieved normalization of acid exposure on both days 3 and 4 of the study. Symptom indices are shown in Table 1 for each study indication. For the 7 patients with chest pain as the primary indication for ph testing, only 1 patient (patient 7) showed a symptom index greater than 50% during the course of the study period. Although this patient did not have an abnormal baseline acid exposure, she did show a reduction in the frequency of chest pain episodes with suppression of distal acid exposure. Three patients with chest pain and abnormal baseline acid exposure showed persistent chest pain despite suppression of acid exposure to less than.3%. For the 7 patients with refractory heartburn, 3 patients had abnormal baseline esophageal acid exposure values, of whom 2 had symptom indices greater than 75%. Calibration testing in 5 patients using swallowed orange juice warmed to body temperature allowed for verification of the stability of the ph recording system over the 4-day recording window. On day 1, the ph values of the juice measured by the Bravo capsule (median ph, 3.84) registered.11 units higher than the values determined ex vivo using a bench-top glass ph electrode (median ph, 3.73). In contrast, the ph values Figure 2. Representative 96-hour Bravo ph tracing from a patient with significant GERD on day 1. The shaded regions represent supine periods. Initial esophageal exposure was 10.2% on day 1 and showed an upright reflux pattern. After the administration of rabeprazole at 20 mg orally twice a day, the acid exposure decreased to 2% on day 2,.7% on day 3, and.3% on day 4.

1086 HIRANO ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 11 of the juice measured by the Bravo capsule on day 4 (median ph, 4.07) were.36 units higher than the ex vivo value (median ph, 3.71). These differences were not statistically significant (P.08). Furthermore, recalculation of the distal esophageal acid exposure times using a threshold for abnormality that corrected for the ph drift did not change the overall test interpretation for any individual patient. The ex vivo calibration tests of 8 Bravo ph capsules were performed using standard buffer solutions and showed stability of the recordings over 48 hours. The mean values for buffer solutions of ph values of 1, 4, and 7 were 1.0, 4.0, and 6.9 on day 1, respectively, and 1.1, 4.0, and 7.0 on day 3, respectively. Discussion We have shown the feasibility of prolonged 4-day ambulatory ph recordings of esophageal acid exposure in patients undergoing clinical evaluation for GERD. Recordings were completed in 89% of patients; however, 2 patients experienced incomplete recordings because of capsule detachment after 2 and 3 days. The prolonged recording window was used to allow combined ph testing of patients both off and on PPI therapy. Rabeprazole was chosen for this study because of its more rapid onset of acid suppression compared with omeprazole. 8,9 In vitro experiments have shown a shorter chemical activation half-life and faster rate of inhibition of the H /K adenosine triphosphatase for rabeprazole compared with other PPIs attributed to a higher pka. 10,11 In the present study, the suppressive effects of rabeprazole on esophageal acid exposure were evident within 24 hours of administration and were significant on days 2 4 of the recording period. Acid exposure times improved in all patients, regardless of the degree of initial acid exposure. In 6 of 7 patients with quantitatively abnormal esophageal acid exposure (86%), normalization of these values was achieved on rabeprazole within 24 hours and was maintained throughout the remainder of the 96-hour recording period. Presently, controversy exists as to whether ph testing is more useful when performed with patients on or off PPI therapy. Testing off-therapy often is recommended for patients in whom there is a low index of suspicion for reflux disease and to rule out the disease on the basis of quantitatively normal esophageal acid exposure. Offtherapy testing also is used to document the presence of reflux in patients without esophagitis who are being evaluated for antireflux surgery. A limitation of testing off-therapy is interpreting causality. Given the high prevalence of GERD in the general population, an individual patient may show abnormal esophageal acid exposure without this being the basis of his or her symptoms. 1 ph testing on-therapy, on the other hand, is used in the evaluation of patients whose typical or atypical reflux symptoms do not respond to therapeutic trials of PPI therapy. Evidence of significant reflux events on PPI therapy, although uncommon, is used to support the use of more aggressive medical, endoscopic, or surgical therapies for GERD. 1,3 A potential limitation of on-therapy ph testing pertains to the evaluation of patients in whom refractory symptoms may be attributed to nonacid reflux. Regurgitation of food, bile, pancreatic enzymes, and excessive gastric volume have been reported to produce symptoms in some patients. By significantly reducing gastric acidity, a greater proportion of reflux events may go undetected by conventional ph testing on PPI therapy. Such nonacid reflux events can be detected by using esophageal impedance or bile-acid recording devices. 12 The present study was neither designed nor powered to address specifically the role of GERD in chest pain, refractory reflux, or reflux laryngitis. However, the prolonged ph recording period combined with an analysis of symptom occurrence both on and off PPI therapy should enhance the interpretation of symptom causality. In the present study, analysis of the reflux-symptom association was performed using the symptom index. 7 Although there are limitations to this measure, 1 it was used for reasons of simplicity and was expressed as a proportion. The symptom index allows for the correlation of acid-reflux events and a specific typical or atypical reflux symptom. It is of value in the analysis of patients who may exhibit visceral hypersensitivity with acid exposure times that are within the normal range. 13 In the current series for the indication of chest pain, only 1 of 7 patients showed a symptom index greater than 50%. Moreover, acid suppression on PPI therapy was effective in all 7 chest pain patients despite persistent symptoms. Although GERD is a well-recognized cause of atypical or noncardiac chest pain, it is likely that the inclusion of patients who had not responded to empiric therapy with PPIs accounts for the low incidence of symptom-based therapeutic success in the chest-pain patients examined. 14 For the 7 patients studied with an indication of refractory heartburn, only 1 patient had persistently abnormal acid exposure values on PPI therapy. This same patient also showed a symptom index that ranged from 50% to 100% for each day of the study. No patient with chronic cough had persistent abnormal acid exposure on PPI therapy. Overall, these data support previous observations that persistent GERD, as defined by abnormal

November 2005 EXTENDED BRAVO ph MONITORING 1087 acid exposure or positive symptom index, is an uncommon explanation for chest pain, refractory heartburn, or chronic cough that does not respond to an empiric trial of PPI therapy. ph drift, defined as the fluctuation in an absolute reference point for measuring ph level, has been reported to occur during the course of ambulatory esophageal ph studies. 15 17 It has been reported more frequently with antimony than glass-electrode catheter systems. Because the Bravo capsule incorporates an antimony electrode and the current study is 4 times the duration of catheterbased studies, we thought that it was important to document the stability of the ph recording during the 4-day recording. Although catheter ph electrode calibration easily can be rechecked ex vivo at the termination of the study, the in vivo attachment of the Bravo capsule makes repeat calibration problematic. This was the rationale for the use of orange juice prewarmed to body temperature as a reference standard. Patients swallowed the orange juice and recordings of ph were measured both at the time of capsule placement and again at the completion of the recording period. We found a ph drift of.11 units on day 1 and.36 units on day 4. This difference was not statistically significant. Furthermore, re-analysis of the data using a correction factor to account for this drift did not affect the overall test interpretation in any of these patients. Although such electrode drift can be corrected mathematically in post hoc data analysis, additional studies with greater numbers are needed to address its significance. Several limitations exist regarding the study results. First, the reliability of ph recordings beyond 48 hours using 2 different receivers with a single Bravo capsule has not been validated previously. Although both receivers were calibrated at the onset of the study, the second receiver was turned off for the initial 2 days of the study to prolong its battery life. To determine if the calibration of the Bravo receiver was affected by turning the unit off, we studied a series of 8 Bravo capsules ex vivo. The recordings showed stable measurements of buffer solutions of ph levels of 1, 4, and 7. As mentioned previously, we also have begun to assess routinely the in vivo stability of the ph calibration of Bravo ph recordings. A second limitation of the study is the fact that the observations on the effect of PPI therapy were not controlled. Day-to-day variability in distal esophageal exposure can affect the classification of normal and abnormal readings. However, in the initial Bravo series of 85 patients, the overall acid exposure values were not significantly different when comparing day 1 and day 2 values. 6 A third limitation to the protocol is potential premature Bravo capsule detachment. In the present study, 2 patients had detachment at 2 and 3 days that did not allow for completion of the 96-hour recording period. Finally, further studies are needed to determine optimal PPI dosing. Single doses rather than twice-daily doses of PPI therapy may be appropriate under certain circumstances. It also is unclear if symptom profiles after 3 days of acid suppression can be interpreted with the same certainty as those after longer courses of therapy that allow for improvement in abnormal tissue resistance of patients with symptomatic reflux. 18 In summary, this report shows the feasibility of 4-day ambulatory esophageal Bravo ph monitoring that allows for assessment of distal esophageal acid exposure both off and on PPI therapy in a single study. The use of such a recording protocol should enhance the diagnostic yield of ph testing for both typical and atypical reflux manifestations. Further studies are necessary to confirm the validity of the recording technique, optimal pharmacologic intervention, and stability of the ph calibration. References 1. Kahrilas PJ, Quigley EM. Clinical esophageal ph recording: a technical review for practice guideline development. Gastroenterology 1996;110:1982 1996. 2. Numans ME, Lau J, de Wit NJ, et al. Short-term treatment of gastroesophageal reflux disease. Ann Intern Med 2004;140: 518 527. 3. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999;94:1434 1442. 4. Fennerty MB, Johnson C, Camargo L, et al. Effect of ambulatory 24-hour esophageal ph monitoring on reflux-provoking activities. J Clin Gastroenterol 1999;28:36 39. 5. Pandolfino JE, Bianchi LK, Lee TJ, et al. Esophagogastric junction morphology predicts susceptibility to exercise-induced reflux. Am J Gastroenterol 2004;99:1430 1436. 6. Pandolfino JE, Richter JE, Ours T, et al. Ambulatory esophageal ph monitoring using a wireless system. Am J Gastroenterol 2003; 98:740 749. 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;8:59 67. 8. Williams MP, Sercombe J, Hamilton MI, et al. A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther 1998;12:1079 1089. 9. Gardner JD, Sloan S, Miner PB, et al. Determination of the reduction in gastric acidity necessary to prevent pathological oesophageal reflux in patients with gastro-oesophageal reflux disease treated with a proton pump inhibitor. Aliment Pharmacol Ther 2003;17:955 964. 10. Kromer W, Kruger U, Huber R, et al. Differences in ph-dependent activation rates of substituted benzimidazoles and biological in vitro correlates. Pharmacology 1998;56:57 70. 11. Besancon M, Simon A, Sachs G, et al. Sites of reaction of the gastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem 1997;272:22438 22446.

1088 HIRANO ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 11 12. Tutuian R, Katz PO, Castell DO. Dose-dependent control of intragastric ph by pantoprazole, 10, 20 or 40 mg, in healthy volunteers. Aliment Pharmacol Ther 2003;17:243 251. 13. Fass R, Naliboff B, Higa L, et al. Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans. Gastroenterology 1998;115:1363 1373. 14. Fass R, Fennerty MB, Ofman JJ, et al. The clinical and economic value of a short course of omeprazole in patients with noncardiac chest pain. Gastroenterology 1998;115:42 49. 15. Vandenplas Y, Helven R, Goyvaerts H. Comparative study of glass and antimony electrodes for continuous oesophageal ph monitoring. Gut 1991;32:708 712. 16. Wise JL, Kammer PK, Murray JA. Post-test calibration of singleuse, antimony, 24-hour ambulatory esophageal ph probes is necessary. Dig Dis Sci 2004;49:688 692. 17. Sjoberg F, Gustafsson U, Tibbling L. Alkaline oesophageal reflux an artefact due to oxygen corrosion of antimony ph electrodes. Scand J Gastroenterol 1992;27:1084 1088. 18. Barlow WJ, Orlando RC. The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis. Gastroenterology 2005;128:771 778. Address requests for reprints to: Ikuo Hirano, MD, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 North St Clair Street, Suite 1400, Chicago, Illinois 60611-2951. e-mail: i-hirano@northwestern.edu; fax: (312) 695-3999. J.E.P. has received a research grant from Medtronic.