Wireless ph capsule yield in clinical practice

Transcription

1 270 Wireless ph capsule yield in clinical practice Authors S. Roman 1,F.Mion 1, F. Zerbib 2, R. Benamouzig 3, J. C. Letard 4, S. Bruley des Varannes 5 Institutions Institutions are listed at the end of article. submitted 13. March 2011 accepted after revision 14. October 2011 Bibliography DOI /s Published online: Endoscopy 2012; 44: Georg Thieme Verlag KG Stuttgart New York ISSN X Corresponding author S. Roman, MD, PhD Digestive Physiology Hôpital Edouard Herriot Pavillon H 5 place d Arsonval Lyon Cedex 03 France Fax: roman.sabine@gmail.com Wireless ph monitoring is one of the recent technologies that focus on improving the diagnosis of gastroesophageal reflux disease (GERD). The capsule, which is fixed within the esophagus, transmits data via telemetry to an external receiver. The capsule is usually inserted 6 cm above the squamocolumnar junction during an upper endoscopy. The standard recording duration is 48 hours but this can be extended to 96 hours. The wireless capsule has been shown to be at least as accurate as the conventional catheter for the monitoring of esophageal ph. Normal ph values have been established in three different series. The use of a wireless capsule provides an increased diagnostic yield for GERD compared with the conventional catheter. The increased yield is the result of higher sensitivity to detect both abnormal acid esophageal exposure and positive Introduction The definition of gastroesophageal reflux disease (GERD) is based on clinical symptoms. In order to differentiate pathological gastric content reflux into the esophagus from functional disorder, an objective diagnosis of GERD is required. In the absence of esophagitis, the diagnosis of pathological GERD is based on the detection of gastric content reflux into the esophagus using esophageal ph and/or impedance monitoring. An esophageal ph of < 4 or retrograde esophageal bolus detected by impedance define a reflux episode [1]. With the introduction of new technologies, endoscopists are now involved in the diagnosis of functional esophageal disorders. The functional luminal imaging probe (FLIP) represents a promising tool for the evaluation of esophagogastric junction (EGJ) compliance using impedance planimetry [2]. It may be performed during an upper endoscopy but its use is currently limited to research protocols. Wireless esophageal ph monitoring, symptom reflux association. This may be related both to the prolonged recording duration and to fewer dietary modifications and restrictions on activities. Several studies have shown that the ph capsule was better tolerated by patients than the conventional ph catheter. Mild-to-moderate chest pain represents the main side effect of the ph capsule: severe chest pain requiring endoscopic removal of the capsule is rare. The main indication for wireless capsule application is monitoring of distal esophageal ph for diagnostic purpose, particularly in patients with a normal endoscopic examination. The capsule technique has some limitations: costs are higher than conventional ph monitoring, misplacement may occur, and the sampling rate is lower. Finally, compared with ph-impedance monitoring, only acid reflux events can be evaluated. developed initially to improve the tolerance of ph monitoring, is a technique of interest to the endoscopist. The wireless ph capsule ( " Fig. 1) is fixed to the esophageal mucosa usually during an upper endoscopy. Thus, a positive diagnosis of GERD may be made by endoscopists even in the absence of esophagitis. The aims of this review were: 1) to describe the technical aspects of the wireless capsule; 2) to determine the accuracy of the wireless capsule; 3) to compare the capsule with other techniques of reflux detection; and 4) to evaluate medico-economic aspects. methodology Key words including wireless ph and Bravo ph were used to search the PubMed database through to January 2011, with limits set to articles published in English. A total of 141 publications were found: 83 original articles, 28 reviews

2 271 Fig. 1 Wireless ph capsule and delivery system. The capsule is oblong in shape ( mm). An antimony ph electrode and a reference electrode are located on the distal tip of the epoxy-coated capsule. The capsule also contains an internal battery and a transmitter located within the epoxy-covered capsule. A 4-mm diameter 3.5-mm deep well is located on the superior lateral aspect of the probe and contains the attachment system. The ph electrode samples esophageal ph every 6 seconds and data are transmitted to an external receiver via telemetry every 12 seconds. The receiver can be clipped onto a patient s belt (Photograph courtesy of Given Imaging.) (5 specifically on the wireless capsule), 15 letters or comments, 11 case reports, and 4 technical notes. Technical aspects Capsule placement Before placing the wireless capsule, some contraindications should be considered: bleeding diathesis, anticoagulation, stricture, severe esophagitis, esophageal varices, history of bowel obstruction, and implanted pacemaker or defibrillator. After calibration in reference solutions, the wireless capsule is placed transorally 6 cm above the squamocolumnar junction (SCJ) during an upper endoscopy, usually under sedation [3]. Lacy et al. have proposed inserting the capsule transorally without endoscopy [4]. For this, an esophageal manometry was undertaken transnasally in order to locate the lower esophageal sphincter (LES). The authors then calculated and validated a 4- cm additive factor to use when inserting the capsule transorally, which accounts for the difference in distance between the LES and nose (manometry) and between the LES and teeth (wireless ph capsule system). The wireless ph capsule can also be placed transnasally [5 7]. Local anesthesia with lidocaine and nasal vasoconstriction with oxymetazoline may be used. However, this placement may be associated with a higher insertion failure rate (up to 20 % in the study by Wong et al. [7]) and with mild transient nose bleeds (5 %) [6]. " Fig. 2 summarizes the different possibilities for the insertion of the wireless ph capsule. A defect in capsule attachment has been observed in 0 12 % of cases [3, 6,8], requiring the use of a second capsule. Different hypotheses have been proposed to explain this attachment defect: insufficient sedation, operator with limited experience, inadequate lubrication of capsule or system, and dysfunction of the delivery system. Therefore, some authors recommend a systematic endoscopic examination to confirm capsule attachment [9]. Capsule location The capsule is usually located 5 cm above the proximal border of the LES (identified by manometry) or 6 cm above the SCJ (identified by endoscopy). A placement closer to the EGJ has been reported in different studies: 1cm above the SCJ [10, 11] and immediately above the SCJ [12, 13]. Using a predefined specificity of 90 % for GERD diagnosis, Wenner et al. found that capsule placement just above the EGJ increased the sensitivity to detect pathological GERD from 78 % to 97 % in patients with esophagitis and from 47 % to 73 % in patients with nonerosive reflux disease (NERD) [12]. However, Bansal et al. showed that a distal ph measurement improved the diagnostic accuracy for patients with esophagitis (sensitivity 84 % and specificity 92 % vs. 75 % and 81 %, respectively, for the proximal measurement) but not for patients with NERD (sensitivity 58 % and specificity 66 % vs. 61 % and 67 %, respectively, for the proximal measurement) [11]. Based on these data, a placement closer to the EGJ should not be recommended to improve the diagnostic yield in patients with NERD. Finally, a retrospective study suggested that endoscopic misplacement of wireless capsules was common [14]. The authors de- During an upper GI endoscopy Capsule insertion Previous endoscopy SCJ location (from incisors) Without endoscopy No SCJ location during previous endoscopy Fig. 2 Algorithm for the insertion of a wireless ph capsule in the distal esophagus. The capsule can be inserted with or without endoscopy. The landmarks used are the squamocolumnar junction (SCJ), as identified during an upper endoscopy or the proximal border of the lower esophageal sphincter (LES), as identified during an esophageal manometry. Esophageal manometry LES location (from nares) Transoral insertion Location 6 cm above SCJ Transoral insertion Location 6 cm above SCJ Transoral insertion Location = manometrically measured distance to the upper border of LES minus 9 cm OR Transnasal insertion Location = manometrically measured distance to the upper border of LES minus 5 cm Roman S et al. Wireless ph capsule Endoscopy 2012; 44:

3 272 fined the ideal capsule location based on manometry performed on the same day as the endoscopic capsule placement. The capsule was positioned more than 3cm from the ideal location in 38 % of patients. This misplacement was proximal in 92.9%. Recording duration The recording duration of the wireless capsule is usually 48 hours. The reproducibility between the 2 days of recording has been reported as being good [3, 6,8,15]. However, day-to-day variability has also been reported and is responsible for discrepancies in acid esophageal exposure between the first and the second day of recording [3, 4,8,15 17]. Some authors have hypothesized that anesthesia could explain this difference. In the study by Bhat et al., the difference in acid exposure occurred only in the first 6 hours of recording following capsule insertion under anesthesia, with a higher esophageal acid exposure during this period [8]. However, Lacy et al. did not find any difference between individuals with capsules inserted under sedation and those without sedation [4]. Of note, the acid esophageal exposure was similar between the 2 days in this latter study. Finally, Belafsky et al. did not observe any change associated with sedation for any parameter recorded with wireless capsules [15]. Wenner et al. proposed a modification of activity to explain the increase in acid esophageal exposure in healthy volunteers during the second day of recording [17]. Extending ambulatory ph monitoring beyond 24 hours improves the sensitivity of reflux detection by distinguishing day-to-day variability and by reducing the potential for false-negative studies. Prakash and Clouse reported that extending the recording to 2 days increased the detection of patients with elevated acid esophageal exposure (12.5 % increase), the number of patients reporting symptoms (5.2 % increase), and the proportion of patients with a positive symptom association in the absence of anti-reflux therapy [18]. This increased diagnostic yield was also observed in patients on anti-reflux therapy [18], in patients with GERD symptoms and normal upper endoscopy [19], and in patients with unexplained chest pain [20]. The recording duration may be extended up to 96 hours, with significant improvements in diagnostic yield [21 23]. Capsule detachment occurred in 0 to 41 % after 96 hours [22, 23]. Grigolon et al. showed that analysis of the worst day out of a 3-day recording led to a higher proportion of patients with pathological reflux or positive symptom association than analysis of the entire recording period [24]. Extension of the recording duration to 48 or 96 hours can also test the efficacy of proton pump inhibitors (PPIs) on esophageal acid exposure and reflux symptom association. Thus, studies were performed both off and on medical therapy during a single recording [21, 25]. This may represent an efficient approach to address the controversy regarding ph assessment on or off therapy in refractory GERD. Capsule removal Capsule detachment occurs spontaneously in most cases between 2 3 days and 2 weeks [6]. Endoscopic removal may be required due to complications (severe or persistent chest pain) or if the capsule is still attached after 2 weeks (1 % to 2 %) [3]. Systematic radiographic checking is not usually recommended unless unusual symptoms are present. Different techniques have been used for capsule removal: gentle pressure application with the tip of the endoscope [26, 27], cold or hot snare [26, 28], retrieval net [29] or endoscopic scissors [30]. No major complications have a b Capsule falls down in the stomach Capsule passes trough in the intestine Time 2 hours 2 hours Fig. 3 Examples of 48-hour wireless ph recording in patients off proton pomp inhibitor treatment. The horizontal red line represents ph 4. Vertical lines indicate patient symptoms. a The ph was recorded in the distal esophagus. The patient presented prolonged reflux events. b The capsule was inserted in the distal esophagus during the brief first part of the recordings (purple box). The ph baseline was around 6, which corresponded to the esophageal ph. The capsule fell down into the stomach. The drop around 1 was prolonged and corresponded to the gastric ph recording (yellow box). When the capsule reached the duodenum, the ph suddenly increased to 8, which corresponded to a normal duodenal ph (red box). been reported for endoscopic removal. One case of bleeding was resolved after epinephrine injection [26]. Accuracy Feasibility Several groups have reported their experience in cohort studies [3, 4, 6, 8, 15, 31]: successful capsule placement and recording was achieved in 85 % 97 %. A second capsule was required in up to 12 % of patients. Failure causes were: capsule attachment not possible, capsule misplacement, and early detachment within the first 24 hours (0 5%). One study emphasized that early detachment of the capsule induced an over-estimation of esophageal acid exposure due to passage of the capsule into the stomach [32]. " Fig. 3 shows an example of the drop in ph due to gastric passage of the capsule. Therefore, a careful examination of ph tracings is mandatory. Normal values Normal values for 48-hour recordings from the wireless ph capsule have been established in three different studies and are reported in " Table 1. In the studies by Pandolfino [3] and Wenner [17], the capsule was inserted 6cm above the SCJ, as identified by endoscopy, whereas in the study by Ayazi [16] it was inserted 5 cm above the proximal border of the LES, as identified by manometry. Wenner et al. used receiver operating characteristic curves to determine the optimal threshold for the diagnosis of pathological GERD with the wireless capsule [33]. The best criterion to distinguish patients and controls was the percentage of total time with an esophageal ph <4 within a 48-hour recording. A threshold of 4% permitted the diagnosis of pathological GERD with a sensitivity of 59 % and a specificity of 93.5 %. Ayazi et al. found that the best diagnostic accuracy was obtained using an

4 273 Table1 Normal values for 48-hour recordings with wireless ph capsule. Study Capsule location No.of controls Median % total time with ph <4 (95th percentile), % Pandolfino et al., 2003 [3] 6cm above SCJ (5.3) Wenner et al., 2005 [17] 6cm above SCJ (4.4) 26 (93) Ayazi et al., 2009 [16] 5cm above proximal border of LES (4.85) 37 (104) LES, lower esophageal sphincter; SCJ, squamo-columnar junction. Median no.of acid reflux events (95th percentile) Table 2 Comparison between the wireless ph capsule and conventional ph catheter. Percentage of total time with ph 4 is expressed as the median. Study Study design % of total time with ph <4, median % P value Bruley des Varannes et al., 2005 [34] Pandolfino et al., 2005 [35] Håkanson et al., 2009 [37] Schneider et al., 2007 [42] Sweis et al., 2009 [9] Wong et al., 2005 [7] Wenner et al., 2007 [40] abnormal DeMeester score ( > 14) on the first or the second day of examination (sensitivity 93 %, specificity 100 %) [16]. Comparison with other techniques of reflux detection Conventional ph-metry Diagnostic yield Esophageal acid exposures recorded with the wireless capsule and conventional ph catheter are compared in " Table 2. In control individuals and in GERD patients the correlation between the two techniques was good when esophageal ph was simultaneously recorded with the conventional catheter and the wireless capsule [34 37]. However, in the studies by Pandolfino et al. [35, 36] and Bruley des Varannes et al. [34], esophageal acid exposure was overestimated by the conventional ph catheter because of a flawed software scheme for electrode thermal calibration. This abnormality has since been corrected by the manufacturer. The wireless ph capsule had a propensity to detect fewer reflux events than the catheter-based system [34, 36]. Brief events were probably missed by the capsule because of a decreased sampling rate of the wireless system (every 6 seconds Wireless capsule Conventional ph catheter Simultaneous recording (n=33 patients) Simultaneous recording (n=22 controls) 1.76 (1.15 after calibration correction) Simultaneous recording 1 st series (26 patients, 27 controls) Patients: 3.2 Controls: nd series with control of ph capsule and catheter location (21 patients, 18 controls) Simultaneous recording 10 controls 43 post-360 floppy Nissen Cohort of patients with esophagitis: wireless capsule (n =68 patients) or conventional catheter (n =55 patients) Cohort Wireless capsule (n= 134 patients) or conventional catheter (n = 110 patients) Randomized study Wireless capsule (n= 25 patients) or conventional catheter (n = 25 patients) Randomized cross over study (n=31 patients) Patients: 2.4 Controls: (0.90 after calibration correction) Patients: 6.8 Controls: 2.1 Patients: 7.1 Controls: P <0.05 (n.s. after calibration correction) P =0.1 P = P = P = P = P =0.837 for the wireless ph capsule vs. every 4 seconds for the conventional catheter). Another explanation for the discrepancies between the capsule and the catheter may be brief esophageal shortening episodes. Fox showed that during the brief esophageal shortening that occurs with transient LES relaxations, the position of the capsule remained constant relative to the LES whereas the catheter electrode approached the LES and recorded a short ph drop as it entered into the acid pocket [38]. Finally, the algorithm used by the analysis software to detect reflux events might differ between conventional and wireless ph systems. Even if brief events were missed with the capsule, this had few consequences on the total acid exposure [35]. However, no symptom reflux association test has been validated for the capsule. In a cohort study, Sweis et al. observed a significantly more frequent diagnosis of pathological GERD in the group of patients who underwent wireless ph recording compared with the group who underwent ph catheter recording (71 % vs. 48 %, respectively, with a threshold of 5.3 % of time with esophageal ph <4 for the capsule and 4.2% for the catheter; P<0.01) [9]. A recent study by the same group emphasized the importance of prolonged recordings with wireless capsules in 38 patients with negative conventional ph monitoring [39]. Using average and worst-day analysis, Roman S et al. Wireless ph capsule Endoscopy 2012; 44:

5 274 Esophagitis Anti-reflux therapy Patient with GERD symptoms refered for upper endoscopy PPI therapy Failure Normal Wireless ph-monitoring OFF PPI just after the endoscopy Abnormal acid esophageal exposure or positive symptomreflux association Normal acid esophageal exposure Fig. 4 Proposition of diagnostic strategy in patients with gastroesophageal reflux disease (GERD) symptoms. If the patient has persistent symptoms despite proton-pump inhibitor (PPI) therapy or presents atypical symptoms, wireless ph monitoring may be implemented just after the endoscopy. According to Rome III criteria, the diagnosis of GERD is considered to be positive if patients present abnormal esophageal acid exposure or positive symptom reflux association when off PPI therapy. Atypical symptoms Typical symptoms PPI therapy ph monitoring (conventional or wireless) or ph-impedance OFF PPI ph-impedance ON PPI Failure Absence of pathological GERD Alternative diagnosis (functional disorder?) esophageal acid exposure was pathological in 37 % and 47 %, and symptom association probability was positive in 34 % and 63 %, respectively. The median recording duration was 72 hours. Tolerability Wireless ph monitoring was better tolerated by patients than catheter-based tests [3, 7, 9, 40 42]. Sweis et al. reported that 96 % of patients who underwent both procedures preferred the wireless capsule [9]. However, the capsule presents some specific side effects. Chest pain was reported in 9 % 70 %, and foreign body sensation in 10 % 56 % [3,5, 6,8, 26,41, 43]. Most of the time chest pain was moderate, but in some cases severe pain led to the endoscopic removal of the capsule (0 75 % of cases of severe chest pain) [3, 4,6, 8]. The other side effects reported in the literature are: one case of esophageal perforation, which occurred during capsule insertion and was treated medically [44], one capsule aspiration in a sedated patient, which was spontaneously expelled into the nasopharynx during coughing [45], and one case of minor mucosal injury caused by inadvertent capsule extraction [31]. ph impedance monitoring Compared with ph monitoring, ph impedance monitoring allows the detection of non-acid reflux events. Monitoring of this nature might be particularly relevant in patients with persistent GERD symptoms despite anti-reflux therapy. No randomized trial comparing wireless ph and ph impedance monitoring is available. The only study comparing ph impedance and wireless ph monitoring was conducted by Pritchett et al. in 39 patients with refractory GERD symptoms [46]. These patients were evaluated with ph impedance monitoring on PPI therapy followed by wireless ph monitoring off therapy. ph impedance monitoring was abnormal in 14 patients (36 %) and wireless ph monitoring was abnormal in 28 patients (72 %). In all, 93 % of patients with abnormal impedance on therapy also had abnormal acid reflux off therapy. The authors concluded that ph impedance monitoring on therapy might provide the single best strategy for patients with refractory GERD symptoms. However, these two techniques might be complementary. Prospective randomized trials might be useful to compare these techniques in the same conditions (on or off therapy) in order to determine the best strategy for the diagnosis of GERD. Medico-economic evaluation The medico-economic data on ph monitoring by telemetric capsule are scarce. The cost of the wireless capsule is higher than the conventional ph catheter (by about five times). Moreover, the cost of the upper endoscopy and potentially of the general anesthesia should be added when the capsule is inserted endoscopically. The financial impact of ph monitoring with the wireless capsule on a managed care organization was assessed in only one study in the USA [47]. A decision model was constructed to project total 1-year costs to manage GERD symptoms with or without using the wireless ph capsule in a hypothetical managed care organization, with eligible adult enrollees of whom 600 presented GERD symptoms. An increase of 10 % in the use of ph monitoring with wireless capsules yielded incremental permember-per-month costs of US$0.029 and per-treated-memberper-month costs of US$ The costs of PPI therapy dropped from US$ to US$236363, while increases were observed in ph monitoring (from US$ to US$21 973). Thus, an increased use of ph monitoring would lead to less unnecessary use of PPIs with a modest budgetary impact. Conclusions Wireless capsule ph monitoring represents an interesting tool for endoscopists in the diagnosis of GERD. The tolerability of the examination is improved compared with the conventional ph catheter. The standard recording duration is 48 hours. The sensitivity of pathological esophageal acid exposure detection and positive symptom association is increased. Thus, in a patient referred for upper endoscopy due to GERD symptoms, a wireless capsule might be placed in the esophagus at the time of the endoscopy to diagnose GERD in the absence of esophagitis ( " Fig. 4). However, the wireless capsule has not yet been validated with any symptom association to predict clinical outcomes. The cost of the capsule is higher than the conventional catheter. In contrast

6 275 to ph impedance monitoring, non-acid reflux is not detected. Further evaluations are required to determine the place of wireless capsule examination in GERD diagnosis strategy, especially in comparison with ph impedance monitoring. Competing interests: All authors have served as consultants for Given Imaging. Institutions 1 Digestive Physiology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon; Université Claude Bernard Lyon 1, Lyon, France 2 Department of Gastroenterology and Hepatology, CHU Bordeaux, Saint André Hospital, Bordeaux ; Université Victor Segalen Bordeaux 2, Bordeaux, France 3 Gastroenterology Department, Assistance Publique Hôpitaux de Paris, Avicenne Hospital, Bobigny; Université Paris 13, Bobigny, France 4 Polyclinique de Poitiers, Poitiers, France 5 CHU Nantes, Institut des Maladies de l Appareil Digestif, CIC-INSERM, Nantes; Université de Nantes, Nantes, France References 1 Sifrim D, Castell D, Dent J et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, nonacid, and gas reflux. Gut 2004; 53: Kwiatek MA, Pandolfino JE, Hirano I et al. Esophagogastric junction distensibility assessed with an endoscopic functional luminal imaging probe (EndoFLIP). Gastrointest Endosc 2010; 72: Pandolfino JE, Richter JE, Ours T et al. Ambulatory esophageal ph monitoring using a wireless system. Am J Gastroenterol 2003; 98: Lacy BE, O Shana T, Hynes M et al. Safety and tolerability of transoral Bravo capsule placement after transnasal manometry using a validated conversion factor. Am J Gastroenterol 2007; 102: Belafsky PC, Allen K, Castro-Del Rosario L et al. Wireless ph testing as an adjunct to unsedated transnasal esophagoscopy: the safety and efficacy of transnasal telemetry capsule placement. Otolaryngol Head Neck Surg 2004; 131: Marchese M, Spada C, Iacopini F et al. Nonendoscopic transnasal placement of a wireless capsule for esophageal ph monitoring: feasibility, safety, and efficacy of a manometry-guided procedure. Endoscopy 2006; 38: Wong WM, Bautista J, Dekel R et al. Feasibility and tolerability of transnasal/per-oral placement of the wireless ph capsule vs. traditional 24- h oesophageal ph monitoring a randomized trial.. Aliment Pharmacol Ther 2005; 21: Bhat YM, McGrath KM, Bielefeldt K. Wireless esophageal ph monitoring: new technique means new questions. J Clin Gastroenterol 2006; 40: Sweis R, Fox M, Anggiansah R et al. Patient acceptance and clinical impact of Bravo monitoring in patients with previous failed catheterbased studies. Aliment Pharmacol Ther 2009; 29: Pandolfino JE, Lee TJ, Schreiner MA et al. Comparison of esophageal acid exposure at 1 cm and 6 cm above the squamocolumnar junction using the Bravo ph monitoring system. Dis Esophagus 2006; 19: Bansal A, Wani S, Rastogi A et al. Impact of measurement of esophageal acid exposure close to the gastroesophageal junction on diagnostic accuracy and event-symptom correlation: a prospective study using wireless dual ph monitoring. Am J Gastroenterol 2009; 104: Wenner J, Hall M, Hoglund P et al. Wireless ph recording immediately above the squamocolumnar junction improves the diagnostic performance of esophageal ph studies. Am J Gastroenterol 2008; 103: Wenner J, Johnsson F, Johansson J et al. Acid reflux immediately above the squamocolumnar junction and in the distal esophagus: simultaneous ph monitoring using the wireless capsule ph system. Am J Gastroenterol 2006; 101: Doma S, Paladugu S, Parkman HP et al. Wireless capsules for esophageal ph monitoring: are we placing them correctly? Digestion 2010; 82: Belafsky PC, Godin DA, Garcia JC et al. Comparison of data obtained from sedated versus unsedated wireless telemetry capsule placement: does sedation affect the results of ambulatory 48-hour ph testing? Laryngoscope 2005; 115: Ayazi S, Lipham JC, Portale G et al. Bravo catheter-free ph monitoring: normal values, concordance, optimal diagnostic thresholds, and accuracy. Clin Gastroenterol Hepatol 2009; 7: Wenner J, Johnsson F, Johansson J et al. Wireless oesophageal ph monitoring: feasibility, safety and normal values in healthy subjects. Scand J Gastroenterol 2005; 40: Prakash C, Clouse RE. Value of extended recording time with wireless ph monitoring in evaluating gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2005; 3: Ang D, Teo EK, Ang TL et al. To Bravo or not? A comparison of wireless esophageal ph monitoring and conventional ph catheter to evaluate non-erosive gastroesophageal reflux disease in a multiracial Asian cohort. J Dig Dis 2010; 11: Prakash C, Clouse RE. Wireless ph monitoring in patients with non-cardiac chest pain. Am J Gastroenterol 2006; 101: Hirano I, Zhang Q, Pandolfino JE et al. Four-day Bravo ph capsule monitoring with and without proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2005; 3: Calabrese C, Liguori G, Gabusi V et al. Ninety-six-hour wireless oesophageal ph monitoring following proton pump inhibitor administration in NERD patients. Aliment Pharmacol Ther 2008; 28: 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: Grigolon A, Bravi I, Duca P et al. Prolonged wireless ph monitoring: importance of how to analyse oesophageal acid exposure. Scand J Gastroenterol 2010; 45: Garrean CP, Zhang Q, Gonsalves N et al. Acid reflux detection and symptom-reflux association using 4-day wireless ph recording combining 48-hour periods off and on PPI therapy. Am J Gastroenterol 2008; 103: Prakash C, Jonnalagadda S, Azar R et al. Endoscopic removal of the wireless ph monitoring capsule in patients with severe discomfort. Gastrointest Endosc 2006; 64: Triester SL, Leighton JA, Budavari AI et al. Severe chest pain from an indwelling Bravo ph probe. Gastrointest Endosc 2005; 61: Fischer A, Baier PK, Utzolino S et al. Management of severe chest pain caused by a Bravo ph monitoring capsule. Endoscopy 2008; 40: 02E Wells CD, Heigh RI, Burdick GE et al. Symptomatic esophageal ulceration caused by a Bravo wireless ph probe and subsequent endoscopic removal of the probe using a retrieval net. Endoscopy 2006; 38: 02E97 30 Agrawal D, Akerman PA, Rich H. Removal of a Bravo 24-hour ph capsule with endoscopic scissors. Gastrointest Endosc 2009; 70: Tu CH, Lee YC, Wang HP et al. Ambulatory esophageal ph monitoring by using a wireless system: a pilot study in Taiwan. Hepatogastroenterology 2004; 51: Iqbal A, LeeYK, Vitamvas M et al. 48-Hour ph monitoring increases the risk of false positive studies when the capsule is prematurely passed. J Gastrointest Surg 2007; 11: Wenner J, Johansson J, Johnsson F et al. Optimal thresholds and discriminatory power of 48-h wireless esophageal ph monitoring in the diagnosis of GERD. Am J Gastroenterol 2007; 102: Bruley des Varannes S, Mion F, Ducrotte P et al. Simultaneous recordings of oesophageal acid exposure with conventional ph monitoring and a wireless system (Bravo). Gut 2005; 54: Pandolfino JE, Schreiner MA, Lee TJ et al. Comparison of the Bravo wireless and Digitrapper catheter-based ph monitoring systems for measuring esophageal acid exposure. Am J Gastroenterol 2005; 100: Pandolfino JE, Zhang Q, Schreiner MA et al. Acid reflux event detection using the Bravo wireless versus the Slimline catheter ph systems: why are the numbers so different? Gut 2005; 54: Håkanson BS, Berggren P, Granqvist S et al. Comparison of wireless 48-h (Bravo) versus traditional ambulatory 24-h esophageal ph monitoring. Scand J Gastroenterol 2009; 44: Fox M. Bravo wireless versus catheter ph monitoring systems. Gut 2006; 55: Sweis R, Fox M, Anggiansah A et al. Prolonged, wireless ph-studies have a high diagnostic yield in patients with reflux symptoms and negative 24-h catheter-based ph-studies. Neurogastroenterol Motil 2011; 23: Wenner J, Johnsson F, Johansson J et al. Wireless esophageal ph monitoring is better tolerated than the catheter-based technique: results Roman S et al. Wireless ph capsule Endoscopy 2012; 44:

7 276 from a randomized cross-over trial. Am J Gastroenterol 2007; 102: Grigolon A, Bravi I, Cantu P et al. Wireless ph monitoring: better tolerability and lower impact on daily habits. Dig Liver Dis 2007; 39: Schneider JH, Kramer KM, Konigsrainer A et al. Ambulatory ph: monitoring with a wireless system. Surg Endosc 2007; 21: Crowell MD, Bradley A, Hansel S et al. Obesity is associated with increased 48-h esophageal acid exposure in patients with symptomatic gastroesophageal reflux. Am J Gastroenterol 2009; 104: Fajardo NR, Wise JL, Locke GR et al. Esophageal perforation after placement of wireless Bravo ph probe. Gastrointest Endosc 2006; 63: Von Renteln D, Kayser T, Riecken B et al. An unusual case of Bravo capsule aspiration. Endoscopy 2008; 40 Suppl. 2: E Pritchett JM, Aslam M, Slaughter JC et al. Efficacy of esophageal impedance/ph monitoring in patients with refractory gastroesophageal reflux disease, on and off therapy. Clin Gastroenterol Hepatol 2009; 7: Lee WC, Yeh YC, Lacy BE et al. Timely confirmation of gastro-esophageal reflux disease via ph monitoring: estimating budget impact on managed care organizations. Curr Med Res Opin 2008; 24: