Esophageal-reflux monitoring

TECHNICAL REVIEW

Esophageal-reflux monitoring John E. Pandolfino, MD, Marcelo F. Vela, MD Chicago, Illinois, Charleston, South Carolina, USA

It is neither practical nor necessary to initiate a diagnostic evaluation of every patient with symptoms of GERD. Management, by and large, is focused on empiric therapy, with lifestyle modification and medication if the clinical presentation is compatible with uncomplicated GERD symptoms. Further testing is only required when complications are suspected, patients fail therapy, or the diagnosis must be confirmed before a change in treatment strategy. Documenting the role of reflux in GERD symptoms, however, is not an easy task. Certainly, evidence of esophagitis on endoscopy is highly specific; however, the majority of patients with GERD will have a normal endoscopy. Therefore, in most cases, our diagnostic focus must be redirected to concentrate on documenting abnormal gastroesophageal reflux. This endeavor is also not straightforward, because there currently is no criterion standard for defining abnormal reflux. The diagnosis of GERD would be simple if the causative factor, gastric refluxate, were easily measured and a reliable threshold for symptom generation and complications were known. Unfortunately, this is not the case, and our current armamentarium consists of techniques that are limited in their ability in that they only provide surrogate information that reflux is occurring. Ambulatory pH monitoring provides evidence for reflux by measuring periods when the pH drops below a certain threshold, whereas combined multichannel intraluminal impedance and pH (MII-pH) detects reflux by measuring the direction and extent of changes in impedance along a catheter and qualifies reflux as acid or nonacid based upon the concomitant pH changes. Although these techAbbreviations: ISFET, ion-sensitive field effect; LES, lower-esophageal sphincter; MII, multichannel intraluminal impedance; MII-pH, combined multichannel intraluminal impedance and pH; PPI, proton pump inhibitor; SAP, symptom association probability; SCJ, squamocolumnar junction; SI, symptom index. DISCLOSURE: The authors disclosed financial relationships relevant to this publication: J. Pandolfino is with the speaker bureaus of Astra Zeneca, Medtronic, Santarus, is a consultant for Astra Zeneca, TAP, Santarus, Medtronic, Crospon, and received grant support from Astra Zeneca, Medtronic. M. Vela is with the speaker bureaus of Astra Zeneca, Sandhill Scientific, is a consultant for Medtronic, and received grant support from Astra Zeneca.

niques are helpful in clinical practice, it is important to understand their limitations. It must also be kept in mind that, currently, there is no consensus regarding the optimal technique or methodology, because there are no well-done randomized controlled trials that compare pH alone with combined pH and impedance in predicting clinical outcomes. With these limitations, the focus of this technical review on ambulatory pH monitoring will be concentrated on reviewing 3 specific issues: (1) the appropriate equipment and methodology for clinical studies, (2) the accuracy and quality of the information obtained, and (3) how ambulatory reflux monitoring can help guide clinical practice. Our ultimate goal is to familiarize practicing gastroenterologists with the current techniques available and also to highlight how these tools can improve management in the context of their imperfections.

REVIEW METHODOLOGY Key words, including ‘‘pH monitoring,’’ ‘‘pH electrodes,’’ ’’reflux testing,’’ ‘‘impedance,’’ ‘‘Bravo,’’ ‘‘esophageal acid exposure,’’ and ‘‘nonacid reflux’’ were used to search the PubMed database through February 2008, with limits set to human trials published in English. A manual search from relevant articles was also performed for each specific section of the review. Data were classified according to the guidelines of the U.S. Preventive Services Task Force, with 5 classifications (A, B, C, D, and insufficient) used to determine the strength of evidence and magnitude of net benefit for each recommendation (Appendix 1). The quality of evidence is graded separately by using 3 classifications (good, fair, and poor). There was a paucity of large-scale randomized controlled data that compared various modalities and measurement parameters; thus, most of the evidence is classified as fair.

TECHNICAL ASPECTS

See CME section; p. 914. Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2008.09.022

Reflux monitoring can be performed by using a variety of devices, and, currently, there is no uniform consensus regarding the optimal system. These reflux monitoring systems differ in many ways and can be categorized based on the following characteristics: (1) pH-electrode type, (2)

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spacing and position of the pH electrode, (3) the need for an indwelling transnasal catheter, and (4) incorporation of MII to enable measurement of nonacid reflux. In addition, there is also no consensus regarding the optimal technique in terms of duration of pH monitoring, position of the pH electrodes within the upper-GI tract, and how to instruct patients regarding meals and activities. Given that these issues could potentially alter accuracy and reproducibility, this section will review these variables and their potential impact on performance of reflux monitoring in clinical practice (Table 1).

pH monitoring electrodes pH monitoring systems use 2 electrodes that function as a galvanic cell. One electrode acts as a reference electrode with a constant potential, and the other acts as an indicator electrode whose potential is sensitive to changes in hydrogen ion concentration. The electrodes are typically connected to a device that can translate the potential difference between the 2 electrodes into a concentration gradient of hydrogen ions (pH). Several types of pH electrodes are available for ambulatory esophageal pH recording: (1) antimony monocrystalline electrodes, (2) combined glass electrodes (built-in reference electrode), and (3) ion-sensitive field effect (ISFET). Glass electrodes are generally the most accurate of the electrodes available1; however, they are limited by a restriction to a single sensor and require careful handling. Although antimony pH electrodes are inferior to glass in terms of sensitivity, drift, temperature effect, and response rate, they are cheaper and smaller, which makes them more suited for ambulatory clinical studies. The lack of accuracy and significant hysteresis make antimony electrodes unsuitable for research studies and intragastric pH measurement.2,3 ISFET electrodes are now becoming clinically available in various systems, and these catheters may soon replace antimony as the electrode of choice in clinical studies. They combine the accuracy and stability of glass catheters with the flexibility and size of antimony-electrode catheters and, thus, may represent the best of both worlds.4 Regardless, all of these electrodes can be used satisfactorily for clinical esophageal pH monitoring.3,5,6 (grade B, fair)

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TABLE 1. Summary of technical aspects of pH monitoring pH electrode type All pH electrodes are adequate for clinical ambulatory studies that assess distal esophageal-acid exposure. The accuracy of the Bravo wireless antimony pH electrode has been validated. Position and placement of the electrode Distal esophageal-acid exposure should be measured 5 cm above the proximal aspect of the LES or 6 cm above the SCJ. Catheter-based systems (pH alone or combined pH and impedance) should use manometric assessment of the proximal aspect of the LES for placement. Transoral wireless capsule placement can be placed with both endoscopic measurements (6 cm above the SCJ) and transnasal manometric landmarks (9 cm above the proximal aspect of the LES). Proximal esophageal pH measurement is technically limited and not helpful for routine clinical use. Gastric pH should be measured 7-10 cm below the LES; although gastric pH monitoring can provide information regarding the efficacy of acid-suppressive medications or suggest poor compliance, its clinical significance is not clear. Duration of studies Ambulatory pH studies should be performed with a goal of 24 h. Extending ambulatory pH monitoring beyond 24 h improves sensitivity of reflux correlation and can be used to perform studies while ‘‘off’’ and while ‘‘on’’ medical therapy. Diet and activity Diet and activity should not be limited during the study period; however, a careful diary must be kept to reduce false positives that may occur with ingestion of acidic foods in-between meals. Monitoring with impedance-pH enables distinction between swallowed acidic material and reflux.

Wireless pH electrodes The Bravo pH monitoring system (Medtronic, Minneapolis, Minn) uses a radiotelemetry pH sensing capsule that is attached to the mucosa of the distal esophagus. The oblong capsule is 25 mm in length and has an antimony pH electrode and a reference electrode located at its distal tip, with an internal battery and transmitter located within the epoxy covered capsule. The capsule simultaneously measures pH and transmits data via a radiofrequency signal to a pager-sized receiver clipped onto the patient’s belt. The performance of the catheter-free wireless pH electrode in measuring esophageal-acid exposure has been validated against catheter-based antimony pH electrode systems in simultaneous controlled trials.7-9

The main advantages of this system are the lack of a catheter and that its position can be fixed. Tolerability has been shown to be better with the wireless system when compared with catheter-based pH monitoring in both randomized10 and uncontrolled comparison studies.11 However, there are some drawbacks to the wireless system that deserve mention. Accuracy of a single sensor may overestimate reflux by including swallow events, and early detachment can also alter results and may require repeated placement. Furthermore, additional endoscopic procedures may be required for patients who report severe chest pain (5%), odynophagia, or failure of the capsule to detach.11-13 Thus, wireless pH monitoring

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is a validated alternative to catheter-based pH monitoring and may be very helpful in patients who do not tolerate catheter placement or in whom longer-duration pH monitoring is required (grade B, good).

Esophageal-reflux monitoring

Distal esophagus. Consistent placement and positioning of the pH electrode is paramount for reliable assessment of esophageal pH data. Typically, the pH electrode should be placed close enough to the stomach to sample the region of esophageal mucosa most affected by gastroesophageal reflux, without being repositioned to the stomach during the course of the study. By convention, the pH electrode is placed 5 cm proximal to the upper margin of lower esophageal sphincter (LES), seen on esophageal manometry as the upper margin of LES high-pressure zone.1,5,14,15 This position should avoid displacement into the stomach during swallowing, breathing, and transient LES relaxations. Thus, pH monitoring to assess acid exposure in the distal esophagus should be performed at 5 cm above the proximal margin of the LES, because most of our standard normative diagnostic values were obtained from studies that used this position (grade B, good). Many placement techniques are available to position the pH electrode in the distal esophagus; however, manometric technique appears to be the most reliable when using a transnasal catheter pH system. Fluoroscopy and upper endoscopy have a poor correlation with transnasal manometry in localizing the esophagogastric junction.16,17 Although there was initial interest in using the pH change from intragastric pH to intraesophageal pH because of its simplicity and use of a single transnasal intubation, this technique was also found to have a poor correlation with manometric assessment in patients with GERD.16,17 However, there are cases in which the LES is not easily identified and the alternative approaches, such as the pH step-up, may be helpful. The data support that manometric assessment of the LES is the most accurate and reproducible method to place a transnasal pH catheter if accurate measurements can be obtained (grade B, good). With the introduction of a wireless pH system, there has been renewed interest in pH-electrode–placement techniques, given that the majority of catheter-free wireless pH capsules are transorally placed. A controlled trial that assesses the accuracy of endoscopic placement of catheterfree wireless pH electrodes versus transnasal pH-catheter– electrode placement by using a conventional manometric technique revealed that the techniques are comparable.7 The average difference in position was negligible and did not have a significant bearing on the total number of reflux events detected by both systems. Recently, a correction factor of approximately 3.74 cm was reported and validated, which accounts for the difference in distance between the transnasopharyngeal catheter and the transoropharyngeal Bravo delivery system.18 Alternatively, the wireless pH cap-

sule can be transnasally placed by using manometry; however, this may be associated with failure to intubate in 2.5% to 13% of patients.19,20 In addition, mild transient nosebleeds have been reported in 86% of subjects.20 Transoral placement of the catheter-free wireless pH capsule 6 cm above the squamocolumnar junction (SCJ) via endoscopy or 9 cm above the proximal aspect of the LES via a transnasal manometric measurement of the position of the LES has been validated (grade B, good). Proximal esophagus or oropharyngeal placement. Although pathophysiologic studies support that proximal reflux and regurgitation into the hypopharynx is associated with otolaryngologic manifestations of GERD, current methodology for documenting proximal reflux is limited by technical issues related to position and a paucity of consistent normative data to distinguish abnormal proximal acid exposure. Data support that the spatiotemporal characteristics of reflux are consistent with a linear decrease in both acid-exposure time and the number of reflux events as one progresses further away from the LES.21 Thus, the position of the proximal pH recording site is extremely important when interpreting results, and one cannot compare data obtained at different points along the pharyngoesophageal segment. Furthermore, data also suggest that the current techniques do not allow a consistent and accurate position of the proximal recording probe, because there is great variability in esophageal length and position and pressure topography of the upper esophageal sphincter.22 Despite these challenges, results of data reported normative ranges of pH!4 of 0% to 1.4% with the probe positioned 20 cm above the LES,23,24 and 0% to 1.0% with the probe positioned just above the upper esophageal sphincter.25,26 Because these numbers are quite low, it is also prudent to carefully analyze the pH tracing to determine whether the pH drops represent true proximal reflux versus artifact.26-28 Criteria, such as a pH drop O2 to 3 units, an abrupt decrease within 30 seconds, and a good temporal correlation with distal acidification may help to distinguish true gastropharyngeal reflux.28 In addition, combined MII and pH may obviate the need for a proximal probe as proximal extent can be determined without a proximal pH recording site. Given these limitations, there is insufficient evidence to recommend for or against routinely providing proximal esophageal or oropharyngeal pH monitoring to assess GERD severity (grade insufficient, poor). Intragastric pH monitoring. Intragastric pH monitoring is performed by placing a pH electrode in the gastric fundus 7 to 10 cm below the manometrically determined LES,29 typically by using a transnasally placed dual pH catheter to monitor both distal esophageal and gastric pH. Wireless gastric pH monitoring with the catheter-free wireless pH capsule appears to be feasible, but the data supporting this approach are very limited and require further validation.30 Although intragastric pH can help determine the efficacy of acid suppressive medications or suggest poor compliance, its clinical

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pH-electrode positioning and placement techniques

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relevance is unclear, because data that show a correlation between intragastric pH and gastroesophageal reflux is scarce, and the findings are inconsistent.31,32 Thus, there is insufficient evidence to recommend for or against routinely performing intragastric pH monitoring (grade insufficient, poor).

Duration of pH monitoring

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most doubled the number of symptoms available for association with reflux events. They also reported that 1 in 5 patients either developed or lost evidence of a symptom-reflux correlation and that extending the test overall led to an increased yield of 31% in incriminating reflux as causative in their GERD symptoms. Extending the recording duration to 4 days can also be used for a more involved single evaluation of reflux both off and on antisecretory medication.49,50 Although only 2 reports are available, one based on results from 18 patients on rabeprazole taken on the second day49 and a more recent one from 14 patients on omeprazole and sodium bicarbonate taken at the end of day 2,50 this approach provided a relatively efficient method to address the controversy regarding pH assessment on and/or off therapy (Fig. 1). Thus, patients can be assessed while off medicine to confirm abnormal acid reflux and then assessed while on medicine to document whether ongoing acid reflux is present in the context of therapy.

The typical duration for clinical catheter-based reflux monitoring is 24 hours. With the poor tolerance of pH catheters as the main impetus, there has been substantial interest in shorter study periods (3-16 hours). These shorter study periods were shown to have variable sensitivity (54%-100%) when referenced to 24-hour pH monitoring.17,33-37 Although an attractive option for patients, short study periods of 3 hours limited to the postprandial period were reported to have limited sensitivity.38 Sensitivity of postprandial studies ranged anywhere from 54% to 88% compared with 24-hour pH studies, and these results varied based on the type of meal.33,37,39 Increasing the study period to at least 2 postprandial periods or 8 hours has been shown to increase sensitivity to 79% to 100% when compared with 24-hour monitoring periods. Despite this moderate improvement in sensitivity, these shorter studies lacked a supine period to assess supine or nocturnal reflux and are also associated with poor reproducibility. The reproducibility of a 24-hour pH test was estimated at 77% to 83% in various studies and has been shown to decrease significantly when studies are less than 10 hours.17,35,40-42 Given these limitations and the potential that shorter studies may not provide adequate time to document a symptom-reflux correlation, ambulatory pH studies that use catheters should be performed with a goal of 24 hours (grade B, fair). With the introduction of the Bravo catheter-free wireless pH monitoring system, ambulatory pH monitoring beyond 24 hours is both feasible and well tolerated.11,43-47 Extending studies to longer than 24 hours is associated with greater sensitivity by distinguishing day-to-day variability and reducing the potential for false-negative studies. By using the 24-hour time period with the ‘‘worst day’’ of acid exposure as a positive result was associated with a sensitivity of 100% when using both esophagitis (2-day study)11 and an abnormal 96-hour study period (4-day study) as a criterion standard.47 Although these results are associated with excellent negative-predictive values, specificity is not perfect, and the rate of false positives is too high to consider this an appropriate test to rule in GERD. Prolongation of pH monitoring beyond 24 hours can also help increase the likelihood of determining a significant symptom-reflux correlation and may also allow for comparison studies with the patient off and then on antisecretory therapy. Recently, Prakash and Clouse48 reported that extending the duration of pH studies by using the catheter-free wireless pH system to 2 days al-

Although diet and activity have an impact on gastroesophageal reflux, there currently are no guidelines regarding diet or activity restrictions during reflux monitoring. The optimal test should obtain a representative measure of reflux activity by allowing testing in ordinary conditions (normal diet and daily activities). Because ingestion of foods or liquids with a pH !4.0 may mimic reflux events and produce false-positive results,51 meals should be excluded from the analysis period, and acidic foods and drinks should be restricted between meal periods or be accurately noted on the pH diary. Combined MII-pH can differentiate reflux from swallow-induced pH changes and may not require the same restrictions. In a study of 60 patients who were undergoing MII-pH testing while off acid-suppressive medication, 81% of acid-reflux episodes detected by pH alone were associated with impedance-detected swallows and in 22% of patients with GERD was erroneously diagnosed because of increased esophageal-acid exposure detected by pH alone.52 Activity, however, should not be limited, except to prevent damage to the testing equipment. Wireless pH monitoring is better tolerated than catheter-based tests and may result in less restriction in activity for the patient.10 Regardless of the device used, patients should be encouraged to maintain a normal level of activity during testing. Meals should be excluded from the analysis of pH or impedance-pH studies. Ingestion of acidic foods should be limited and carefully recorded by the patient during testing, although this may be less important when using impedance-pH, which can distinguish between swallowed acidic food and reflux (grade B, fair); activity should not be restricted during testing except to prevent damage to the equipment (grade B, fair).

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Diet and activity

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Esophageal-reflux monitoring

Figure 1. Extended use of the Bravo pH monitoring system to monitor esophageal-acid exposure over a 96-hour period, with patients off therapy on the first 2 days followed by intake of omeprazole and sodium bicarbonate 40 mg twice a day for days 3 and 4. The percentage of time with esophageal pH !4 can be monitored over each day, delineating patients with significant esophageal-acid exposure while off therapy and to determine whether esophageal-acid exposure is appropriately reduced with PPI therapy (courtesy of Ikuo Hirano).

MII-pH Principles of MII-pH monitoring. MII-pH monitoring has the advantage of detecting reflux at all pH levels (acid or nonacid). Intraesophageal impedance, determined by measuring electrical conductivity across a pair of closely spaced electrodes within the esophageal lumen, depends on the conductivity of the material through which the current travels. A catheter with multiple pairs of impedance electrodes can record impedance changes in response to movement of intraesophageal material in either antegrade or retrograde direction.53,54 Because the esophageal wall, air, and different bolus materials (swallowed food or refluxed gastric contents) each produce different impedance changes, the technique characterizes reflux episodes in great detail, including their composition (air or liquid, or mixed), proximal extent, velocity, and clearance time. During MII-pH monitoring, impedance detects retrograde bolus movement, whereas pH measurement establishes the acidity of the reflux episode (acid if pH! 4.0, nonacid otherwise) (Fig. 2). Some investigators classify reflux with a pH above 4.0 as either weakly acidic (pH R 4 but!7) or weakly alkaline (pH R 7).54 In www.giejournal.org

Figure 2. Impedance changes in 6 measuring segments that span the esophagus (Z1 to Z6), and pH changes from a single sensor in the distal esophagus are shown; the dotted line represents a pH of 4.0. The dotted arrow shows the direction of flow detected by impedance (retrograde or antegrade). A, Acid reflux. A typical impedance reflux pattern of sequential impedance drops in a retrograde direction that reaches the third impedance measuring segment (Z3) is associated with a pH fall to below 4.0. This episode did not cause symptoms. B, Nonacid reflux. Typical impedance reflux pattern reaching Z1, pH remains above 4. The patient reported regurgitation during this reflux episode, which would have been missed by conventional pH without impedance. C. Acidic food swallow. A typical impedance swallow pattern with sequential impedance drops in an antegrade direction, beginning in the most proximal impedance measuring segment (Z1); this is associated with a pH fall to below 4.0, which indicates that the swallowed material is acidic. This pH drop may have been misinterpreted as acid reflux by conventional pH without impedance.

this current technical review, nonacid reflux refers to any reflux with pH R 4. MII-pH monitoring was recognized as the most sensitive tool for measuring reflux by a recently convened Volume 69, No. 4 : 2009 GASTROINTESTINAL ENDOSCOPY 921

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TABLE 2. Normative data for reflux by using combined impedance-pH monitoring*

manual analysis until accuracy of automated analysis software improves (grade B, fair).

MEASUREMENTS No. reflux events: upper limit of normal Study

N Total Acid Nonacid

United States (Shay et al56) 57

France-Belgium (Zerbib et al )

60 73

59

27

72 75

50

48

*Modified from Refs. 56 and 57.

panel of experts, the ‘‘Porto Consensus.’’54 Assessment of reflux with impedance-pH is reproducible,55 and normal values for ambulatory 24-hour impedance-pH monitoring obtained by 2 independent multicenter studies were similar (Table 2).56,57 MII-pH catheters. MII-pH monitoring can be performed with several different catheters, which incorporate a varying number of impedance and pH electrodes in different configurations. Ordinarily, the catheter has a pH electrode for placement 5 cm above the LES (similar to conventional pH testing), with the possibility of additional pH sensors in the stomach or the proximal esophagus. Catheters may incorporate 6 or more impedance measuring segments (each composed of 2 metal electrodes, usually spaced 2 cm apart) to detect impedance changes along variable lengths of the esophagus. Although there are no published studies that compared the accuracy of different catheter configurations, a catheter with 6-impedance measuring segments and 1 pH electrode enables accurate detection of reflux episodes, with an assessment of the proximal extent of reflux, and it permits distinction between swallowing and reflux episodes. A smaller number of impedance measuring segments may compromise accuracy. As a minimum, impedance-pH catheters should have 6 impedance measuring segments and one pH electrode (grade C, fair). Interpretation of MII-pH monitoring. Identification of reflux episodes requires visual analysis of impedance changes and is more laborious than that of the fully automated conventional pH test. Automated impedance-pH analysis software is available (Sandhill Scientific, Inc, Highlands Ranch, Colo), but, in its current state of development, it overestimates the number of reflux episodes58 and should be used to mark the impedance-pH tracing and to shorten the time required to interpret it; manual review and editing is required for accurate results, and relying solely on this software cannot be currently recommended. It is possible that full and dependable automation will be available in the future through further software refinements. Also, it is important to mention that a low baseline impedance, often seen in patients with severe reflux or Barrett’s esophagus, can make interpretation of the impedance-pH tracings more arduous. Thus, combined impedance-pH should incorporate a careful 922 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 4 : 2009

The utility of a diagnostic test is based on 2 main factors: (1) its technical performance and (2) its diagnostic impact. Although technical performance focuses on how accurate and reliable the technique is in measuring the variable of interest, the diagnostic impact focuses on how well the variable of interest will alter therapeutic direction and patient outcome. Although these factors are not mutually exclusive, the starting point is always going to hinge on the accuracy and reliability of the test. Given this relationship, the next section will focus first on how accurate and reliable pH and MII monitoring are in defining both abnormal reflux and a symptom-reflux association. In addition, we will also discuss how well these measurements perform in predicting whether reflux should be implicated in the patient’s symptoms.

Esophageal-acid exposure Ambulatory pH monitoring does not directly quantify the amount of gastric juice delivered to the esophagus, because there is no determination of volume. It instead provides a marker that acid is present in the esophagus and expresses this as a function of time. The original analysis scheme was devised by Johnson and DeMeester59 and examined 6 variables: (1) the percentage of total time that the pH was !4, (2) the percentage of upright time that the pH was!4, (3) the percentage of supine time that the pH was!4, (4) the number of reflux events, (5) the number of reflux events longer than 5 minutes, and (6) the longest reflux event. Current consensus is that the total percentage of time the pH is less than 4 is the most useful single discriminator between physiologic and pathologic reflux.5 An abnormal test is described as a value greater than an established threshold, which is typically more than 2 SDs above the mean or 95th percentile of normal controls. The most referenced threshold for abnormal acid exposure by using conventional catheter-based systems is a pH!4 for more than 4.2% of the duration of the study.60 The most referenced value for an abnormal DeMeester composite score is a value larger than 14.7. Studies that used the catheter-free wireless pH system reported similar normative ranges of 5.3% to 4.4% for the 48-hour period when compared with the 24-hour ambulatory catheter-based systems.11,61 It should be noted, however, that multiple studies had varying normal ranges and these values should be interpreted in the context of other variables included in the composite score and reflux-symptom correlation.62-65 Data support that esophageal-acid exposure (contact time) during ambulatory pH monitoring is associated with a graded increase in severity across the GERD spectrum.66,67 However, there is marked variability in esophageal-acid www.giejournal.org

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exposure in patients with reflux, and substantial overlap exists with normative values obtained in asymptomatic controls. For example, up to 10% to 30% of patients with reflux esophagitis may have normal esophageal-acid exposure.62,63 This lack of sensitivity can be related to technical limitations of pH monitoring or possibly to the fact that these patients may develop symptoms or erosions at lower pH threshold values. Although esophageal-acid exposure by itself cannot predict the presence of GERD or its severity, it may help to predict response to antireflux therapy. Campos et al68 performed a multivariate analysis of factors that predicts outcomes after fundoplication and found that an abnormal 24-hour pH score significantly predicted a successful outcome, with an odds ratio of 5.4 (95% CI, 1.9-15.3). Similarly, Khajanchee et al69 also reported that patients with symptomatic GERD and with a normal preoperative 24-hour pH score had significantly worse symptomatic outcomes than patients with abnormal pH scores and recommended a policy of routine pH testing before fundoplication. Thus, although overall acid exposure or contact time does not clearly distinguish patients with GERD from asymptomatic normal subjects, it is a valid measurement to help predict response to therapy (grade B, good).

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TABLE 3. Comparison between the 3 available technologies, highlighting the specific differences between the catheter and wire-based systems and also the addition of impedance Conventional Wireless pH Bravo pH monitoring monitoring Impedance pH Catheter required

Yes

No

Yes

Standard

Improved

Same

Detects nonacid reflux

No

No

Yes

Distinguish acid reflux from acidic food swallow

No

No

Yes

Prolonged monitoring O24 h

No

Yes

No

Automated interpretation

Yes

Yes

Software available but requires manual review and/or editing

Patient tolerability

Reflux episodes Measuring distal esophageal percentage time pH !4 is considered the most useful variable for distinguishing physiologic from pathologic reflux. Alternatively, the number of reflux episodes (acid or nonacid) over the monitoring period can be quantified. Of note, nonacid reflux (seen during buffering of stomach contents by food in the postprandial period or through pharmacologic acid suppression) cannot be reliably detected by conventional pH monitoring.70,71 MII-pH is more accurate for quantifying reflux episodes, because it detects reflux (acid or nonacid) regardless of pH changes. In addition, MII-pH can differentiate swallowed acidic foods from true reflux. A comparison of the various technologies available to perform reflux monitoring is provided in Table 3. Three multicenter studies established normal values for ambulatory 24-hour impedance-pH monitoring based on the 95th percentile of normal controls, with similar results (Table 2).56,57,72 A large U.S. study defined abnormal reflux as O73 total reflux episodes, O59 acid-reflux episodes, or O27 nonacid-reflux episodes.56 The clinical utility of these thresholds is unclear, and outcome studies that prove that treating patients based upon these end points is beneficial are lacking. Furthermore, although one of the main advantages of MII-pH is its ability to measure nonacid reflux, normal MII-pH values in acid-suppressed subjects are not available. Moreover, whether nonacid reflux can injure the esophageal mucosa is questionable, and the presence of an abnormal number of reflux episodes (acid or nonacid) does not establish that this is the cause of a patient’s symptoms. Therefore, although impedance-pH consti-

Establishing pathologic amounts of reflux by detecting increased distal esophageal-acid exposure is important and can guide treatment decisions. However, a critical clinical question is whether a patient’s symptoms are from reflux, particularly in patients with normal acid exposure (or a normal number of reflux episodes) but with a strong association between symptoms and reflux (the ‘‘acid-sensitive’’ or ‘‘reflux-sensitive’’ esophagus). A symptom event is conventionally considered to be associated with a reflux episode if it occurs within 2 minutes of the reflux episode. The two most commonly used methods to evaluate the temporal association between symptoms and reflux are the symptom index (SI)73 and the symptom association probability (SAP).74 The SI is defined as the percentage of symptom events that are temporally related to a reflux episode ([number of reflux-related symptom events/total number of symptom events]  100%). An SI of 50% is considered positive, meaning that the symptom is related to reflux. This value was derived from receiver operating characteristic curves that found this threshold to be sensitive and specific for heartburn.75 The SAP is calculated by dividing the pH or impedance-pH tracing

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tutes the most accurate tool for quantifying the number of reflux episodes, the clinical utility of this measurement remains unproven (grade insufficient, poor).

Symptom-reflux correlation

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in 2-minute segments and by determining whether a reflux episode and/or a symptom occurred in each 2-minute segment. A 2  2 contingency table with the number of 2minute segments with and without symptoms and with and without reflux has been built; the probability that a positive association between reflux and symptoms occurs by more than chance is evaluated through a modified c2 test, with an SAP greater than 95% considered positive.74 Although determining the SAP is more complex, available software provides automated calculation. Of note, both the SI and the SAP rely on precise and timely symptom recording by the patient, along with accurate reflux detection by the testing device. In addition, prospective data to validate the ability of these symptom association measures to predict response to treatment is scarce. Nonetheless, they are thought to be useful, and they are commonly used both for research and clinical purposes. A very strong symptom association measure (SI or SAP) can support a therapeutic intervention. Catheter-free wireless pH monitoring and impedancepH studies both enhanced our ability to assess the symptom-reflux association. The catheter-free wireless pH system is better tolerated by adult76 and pediatric77 patients, which enables testing with fewer limitations on diet and activity,44 while allowing prolonged monitoring (up to 96 hours), all of which increases the likelihood of detecting reflux events with improved symptom-association determination. However, the catheter-free wireless pH system has not been validated with any symptom association scheme and has a propensity to detect fewer and only longer-duration reflux events, which makes it somewhat imprecise for analyzing symptom-reflux correlations.78 Two recent studies used 24-hour impedance-pH to evaluate the association between symptoms and reflux in patients while off and then while on acid suppressive medication. In a study of 144 patients with persistent reflux symptoms despite twice daily proton pump inhibitor (PPI) therapy, SI was positive for acid reflux in 11% of the patients and positive for nonacid reflux in 37%; 52% of the patients had a negative SI.79 Another study that evaluated 60 patients with heartburn and regurgitation by performing MII-pH monitoring after stopping acid suppression found that the proportion of patients with a positive SAP was higher if both impedance and pH parameters were used in the analysis, as opposed to pH alone (77% vs 67%, P ! .05).80 The first study emphasizes the importance of nonacid reflux as a potential cause of symptoms in patients who use acid suppression, whereas the second study highlights how adding impedance to pH monitoring increases the diagnostic yield and enables better symptom analysis. However, MII-pH comes with the limitations of catheter-based systems: decreased patient tolerance, monitoring limited to 24 hours, relatively limited availability, and time-consuming interpretation. Therefore, there is fair evidence to suggest that impedance-pH improves the yield of symptom association studies during reflux 924 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 4 : 2009

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monitoring, but the data supporting an improvement in clinical utility are still limited (grade C, fair).

CLINICAL UTILITY Although current esophageal-reflux monitoring techniques are far from a criterion standard for the diagnosis of GERD, they still can provide useful clinical information for the management of patients who present with GERD symptoms. By focusing on the strengths of the various technologies and the information they provide, one can give supporting evidence to their clinical impression and better define treatment strategies. The following section will focus on 4 general clinical questions that may be answered by using esophageal-reflux testing.

Question 1: does the patient have abnormal acid exposure? The importance of gastric acid in GERD has been substantiated by the excellent response of both GERD symptoms and esophagitis healing to acid-suppression therapy.81 Reflux of gastric acid represents an essential mechanism in the pathophysiology of GERD, and, thus, the measurement of esophageal-acid exposure represents an important variable in the management of GERD. The most well-validated single quantitative measurement for assessing abnormal gastroesophageal-acid reflux is the overall percentage time when the pH is !4 in the esophagus during the ambulatory monitoring period.5 This measurement may be combined with other variables, such as the number of reflux events and the duration of acid exposure during these events, to provide a composite score to assess the acid burden in the esophagus and potentially may improve the yield.59 By using the 95th percentile of normative ranges, one can determine whether the patient has numerical abnormal acid reflux by using the percentage time that the pH is !4 or the DeMeester composite score; however, these results should not be viewed as dichotomous and, thus, do not prove causality. Documenting esophageal-acid exposure while off medication. Documenting abnormal esophageal acid exposure by itself can be very helpful in determining whether a patient has abnormal gastroesophageal reflux if the patients are studied while off the medication. This is probably the most important question in the management of GERD, because abnormal movement of gastric juice into the esophagus is the prerequisite for GERD. Although GERD symptoms could be elicited by reflux episodes with a pH O4, these reflux episodes are responsible for a very small proportion of symptomatic events when patients are studied while off medication.82 Thus, documenting patient’s abnormal esophageal-acid exposure while off medication by using the total percentage time the pH !4 or a composite score will likely www.giejournal.org

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differentiate the majority of patients into abnormal reflux or normal reflux. Although MII-pH improves the accuracy of detecting all types of reflux events,54 there is little evidence to support that the addition of impedance will improve documentation of abnormal esophageal-acid reflux in patients while off medication. Similarly, there is also no validated data to support that the catheter-free wireless pH system will improve our ability to distinguish patients with true GERD from patients with symptoms related to nonreflux pathology. The catheter-free wireless pH system could potentially reduce false-negative results from reduced activity and day-to-day variability; however, the data for this benefit are limited. Thus, all the available reflux monitoring systems that currently incorporate a pH sensor can be used to determine the presence or absence of abnormal reflux while off medication (grade B, good). Documenting esophageal-acid exposure while on medication. Documenting abnormal esophageal-acid exposure while patients are on medication has very limited use in the evaluation of GERD.83 This is secondary to extreme variability in esophageal-acid exposure in both symptomatic84 and asymptomatic patients85 on PPI therapy. The utility of studying acid exposure on PPI therapy is further complicated because there are no validated thresholds for what is considered abnormal or pathologic in the context of PPI therapy. Normative values in asymptomatic controls while on PPI therapy have been reported with the 95th percentile of the normal range for a total percentage time pH!4 of 1.6%.86 Unfortunately, outcome data that validate this threshold are limited to a single study focused on escalating PPI therapy from twice a day to 4 times a day in patients with a percentage time the pH !4 greater than 1.6%. In this study, 5 of 10 patients with typical symptoms were noted to have esophagealacid exposure greater than 1.6%, and 3 responded to an escalation of PPI therapy.86 Given the lack of valid outcome predictors and the variability of esophageal-acid exposure in symptomatic patients on PPI therapy, esophageal-acid exposure while on medication should be interpreted with caution. Although the threshold for abnormality is unclear, patients who present with values well above normal ranges while on medication will likely require an escalation of antireflux therapy or a more detailed evaluation of compliance with medication instructions. Normal or negligible levels of esophageal-acid exposure while on medication supports that patients will likely not benefit from further acid suppression. However, this test result does not rule out GERD as a potential cause, because patients with normal acid exposure on medication may well have abnormal acid exposure while off medication, and the current symptoms may be related to nonacid causes. Performing a 4-day catheter-free pH-monitoring test with the patient while off and then while on medication may be helpful in documenting the presence of GERD and also whether the pa-

tient will require an escalation of therapy focused on reducing esophageal-acid exposure. However, it does not determine whether ongoing nonacid reflux in the context of adequate acid suppression is responsible for refractory symptoms. Although studying patients while on medication will determine whether abnormal acid exposure is present despite medication, it is still limited in evaluating nonacid reflux and in documenting GERD, and its utility cannot be determined (grade insufficient, fair).

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Question 2: are the patient’s symptoms from reflux? Although documenting abnormal acid exposure is important and this information can guide therapeutic interventions, it must be kept in mind that not all reflux episodes cause symptoms. Conversely, not all symptoms are from reflux. Therefore, a very important question in the management of patients with complaints attributable to GERD is whether their symptoms are indeed caused by reflux. The details regarding the calculation of the SI73 and SAP74 are explained in earlier in this review. Two studies compared these indices, and both were shown to predict a response to treatment in different settings. A recent study of 74 patients with heartburn found a statistically significant greater decrease in symptom scores after PPI treatment in patients with a positive versus a negative index, regardless of whether the SI or SAP was used.87 A different study of 38 patients with heartburn found that the SAP had better positive and negative predictive values compared with the SI for identifying patients who will respond to PPI therapy (79% vs 73% and 58% vs 44%, respectively), but these numbers show the SAP certainly was not perfect.88 In contrast, small uncontrolled studies that used MII-pH to study refractory patients found the SI to be a good predictor of treatment response. Both the SI and the SAP have methodologic shortcomings, but they are useful and commonly used in clinical practice.89 A strongly positive SI or SAP may suggest the need for a therapeutic intervention, and a negative result supports the notion that the patient’s symptoms are not likely from reflux. It is hoped that further research will improve the performance characteristics of these or new indices, so as to enhance our ability to assess the relationship between reflux and symptoms. Analysis of symptomreflux association is an important component of reflux testing and should be performed on all studies (grade B, good); although the SAP has an advantage over the SI by having an objective cutoff based on statistical analysis of chance, there is no clear data to support one scoring system over another (grade C, fair).

Question 3: what is the role of reflux monitoring in patients with refractory symptoms? In the present era of frequent use and sometimes overuse of empiric acid suppression with PPIs for symptoms

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ting.84 A negative pH test in treated patients excludes ongoing acid reflux as the cause of their symptoms, but it does not allow a distinction between patients with symptomatic nonacid reflux versus those with no reflux. Therefore, impedance-pH monitoring is superior for testing patients with acid suppression because of its ability to detect nonacid reflux. Impedance-pH may reveal persistent symptoms from reflux, either acid or nonacid. A negative impedance-pH test of the patient while on medication establishes that the patient’s complaints are not from GERD, but it does not provide information regarding whether PPIs can be discontinued (this finding may be the result of GERD adequately treated by PPIs with ongoing symptoms from a nonreflux cause). Who to test while on versus while off PPI. Fourday catheter-free wireless pH monitoring with 2 days off medication followed by 2 days on treatment enables evaluation while off and then while on therapy in a single test (Fig. 1) but is limited by the inability to detect nonacid reflux. Performing pH-metry after cessation of therapy, along with impedance-pH while on medication, would provide the greatest possible amount of information about reflux in the untreated state, as well as the response to acid suppression. This will be necessary in some challenging patients, but limiting the evaluation to a single test is preferable. Although studies that compare the yield of ‘‘off versus on’’ therapy reflux monitoring are not available, choosing patients based upon their clinical presentation may be helpful. Patients in whom GERD is less likely (atypical presentations, with the possible exception of cough) may be best served by pH monitoring while off medication. In contrast, those in whom GERD is more likely (typical symptoms) should be considered for impedance-pH testing while on therapy, because testing in these patients is more likely to reveal ongoing reflux (either acid or nonacid), despite medication. It is hoped that a clearer consensus regarding the most effective approach for each clinical scenario will emerge from high-quality studies that address these questions.

thought to be from reflux, we are seeing increasing numbers of patients who do not respond to these medications. Between 25% and 42% of patients on a once daily PPI fail to respond to treatment; of these, only 20% to 25% will improve after increasing the dose to twice daily.90,91 If compliance can be ascertained and endoscopy rules out nonreflux etiologies, then reflux monitoring further characterizes the refractory patient, with 3 possible explanations for persistent symptoms despite therapy: (1) failure of acid suppression with ongoing acid reflux, which will require further acid suppression through increased dosing or a different therapeutic approach, (2) adequate acid control but ongoing nonacid reflux, which, in the presence of a positive reflux-symptom association, will require specific treatment, or (3) no reflux of any kind (acid or nonacid) and/or no relationship between reflux and the patient’s complaints. Two key issues are whether testing should be performed after stopping acid suppressive therapy or while on medication, and what technique to use (catheter-based pH, Bravo, or impedance-pH). The findings that each approach may yield, along with their clinical implications, are explored below and summarized in Figure 3. The approach chosen will depend, in part, on the available technology and expertise. At the present time, there is no clear consensus regarding the optimal testing methodology for refractory reflux, and, in a few patients, a clear diagnosis will only emerge after testing both while off medication and while on medication. Reflux monitoring while off medication. For testing patients while off therapy (5-7 days after discontinuing PPI), pH measurement is sufficient, because nonacid reflux is only relevant during acid suppression. Although catheter-free wireless pH monitoring allows prolonged testing under more physiologic conditions and impedance-pH may be more accurate by excluding pH drops from acidic food, catheter-based pH-metry is acceptable to study refractory patients while off therapy. If pH monitoring of patients while off medication is negative (normal distal esophageal-acid exposure and a negative symptomreflux association), GERD is very unlikely, and patients with heartburn as the predominant symptom may be labeled as ‘‘functional heartburn,’’ whereas those with atypical symptoms (such as laryngitis) will require a workup for other etiologies, including allergic, otorhinolaryngologic, and pulmonary disorders. A negative test while off therapy is very useful, because it directs the diagnostic workup toward other causes, and it enables cessation of unnecessary PPI therapy. Reflux monitoring while on PPI. An abnormal pH test in a compliant patient who is taking a PPI is evidence of therapeutic failure (ie, ongoing acid reflux despite treatment). However, this is infrequently found, because on PPI-therapy reflux becomes predominantly nonacid70,71 and thus not readily detected by pH testing, with very low pretest likelihood of a positive pH test in this set-

An important indication for reflux monitoring is the documentation of abnormal reflux and/or a strong symptom-reflux correlation before antireflux surgery in a patient without endoscopic evidence of GERD (esophagitis, stricture, Barrett’s esophagus). The best predictors of outcome after fundoplication are response to antisecretory medication, typical symptoms, and abnormal esophagealacid exposure.92 Taken together these factors can provide a reasonable assessment of which patients respond to antireflux therapy, however, there is no guarantee that 100% of these patients will respond. Negative results that support that ongoing reflux is not the cause of the

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Question 4: will the patient benefit from antireflux surgery?

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Figure 3. Proposed algorithm for the evaluation of patients with persistent symptoms, despite acid suppression with a PPI. Studying patients while off medication (feasible with pH alone or impedance-pH) may be preferable when GERD is unlikely, because this approach enables distinction between patients with GERD and patients without GERD; in the latter, the evaluation can be directed to nonreflux causes after a negative reflux monitoring study. For patients with ongoing symptoms despite therapy in whom GERD is more likely, impedance-pH monitoring on medication is preferable, because it will document persistent reflux (either acid or nonacid); pH alone will miss nonacid reflux and, therefore, is inadequate for this purpose.

patient’s symptoms can be as helpful as positive results in determining outcome, and, thus, the negative predictive value of these tests should not be ignored. Below are indications in which esophageal-reflux testing may be helpful in patient selection for fundoplication. Treatment success in this section is defined by symptom response and not the success of an operation in terms of technical issues, such as operative complications and fundoplication associated bowel complaints. In addition,

we are not assessing the data regarding the validity of the indication in terms of risk and benefit, and are only assessing how esophageal-reflux monitoring can be used in these situations. Patients with a negative endoscopy and with typical or atypical symptoms that responded to PPI therapy and are requesting surgery for maintenance therapy. Although patients with both typical symptoms and a positive response to medical therapy

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represent a group that has a high probability of symptom resolution with antireflux surgery,92 esophageal-reflux testing with the patient off medication may provide additional data supportive of a positive outcome. Placebo response rates with PPI therapy can be high, and, given the inherent risk of surgery and the possibility of new complications, it is not unreasonable to obtain preoperative data to confirm abnormal reflux. In contrast, patients with atypical complaints have a lower probability of treatment success and, therefore, esophageal-reflux monitoring with the patient off medication should be encouraged to document that the patient has abnormal gastroesophageal reflux. This can be accomplished with a conventional pH catheter system, catheter-free wireless pH sensor, or a combined impedance-pH system. Evaluation of patients with a negative endoscopy with typical and atypical symptoms not responding to PPI therapy. Although refractory GERD represents a common indication for antireflux surgery, these patients have a lower probability of symptom resolution with antireflux surgery.92 This poor outcome is because a large proportion of these patients do not have abnormal GERD and are suffering from an alternative diagnosis. Thus, surgery should only be contemplated when there is strong evidence that the patient’s symptoms are truly related to reflux despite PPI therapy. Esophageal-reflux monitoring should be performed with the patient off medication if pH alone is used, because total esophageal-acid exposure has the best predictive value in determining outcome. Patients with normal acid exposure and a negative symptom reflux correlation while off medication should be evaluated for alternative diagnoses, such as functional heartburn, esophageal motor disease, or eosinophilic esophagitis. Patients with abnormal acid exposure and/or a positive symptom-reflux correlation have a higher likelihood of responding to antireflux surgery than patients with a negative study68,69; however, this does not provide definitive proof that patient’s symptoms while on PPI therapy are related to reflux. Patients who are unable to stop PPI therapy can be evaluated while on medication with combined impedance-pH to determine whether their continued symptoms on medication are from abnormal reflux. The benefit of this methodology is that patients can be evaluated for both breakthrough acid reflux and a symptom correlation with nonacid reflux. Patients found to have abnormal acid exposure while on medication may represent patients who are noncompliant or patients with PPI resistance. Patients with ‘‘true’’ PPI resistance can be offered an escalation of antireflux therapy, which may include an increased dose or surgery. Patients found to have normal acid exposure and a positive symptom-reflux correlation for nonacid reflux during combined impedance-pH represent a group that theoretically could respond to therapy focused on reflux inhibition. 928 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 4 : 2009

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SUMMARY Esophageal-reflux monitoring can be very helpful in the evaluation and management of GERD if one understands the strengths and limitations of the available technologies. Each specific device can provide the practicing clinician with important information regarding the presence of abnormal reflux and whether or not there is a consistent relationship between reflux events and symptoms. Choosing the right test and the right setting (off or on medication) relies heavily on the pretest probability of GERD and the question that needs to be answered. However, even this is not straightforward, and occasionally a test may need to be repeated under a different circumstance or to look for a different outcome measurement (nonacid reflux). Given these unclear issues, reflux testing should be performed with some degree of flexibility, and a single test or technology may not be enough to satisfy all of our needs. Thus, one should use reflux monitoring to support management decisions but should never rely solely on this technology to make a clinical decision.

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35. Choiniere L, Miller L, Ilves R, et al. A simplified method of esophageal pH monitoring for assessment of gastroesophageal reflux. Ann Thorac Surg 1983;36:596-603. 36. Grande L, Pujol A, Ros E, et al. Intraesophageal pH monitoring after breakfast þ lunch in gastroesophageal reflux. J Clin Gastroenterol 1988;10:373-6. 37. Fink SM, McCallum RW. The role of prolonged esophageal pH monitoring in the diagnosis of gastroesophageal reflux. JAMA 1984;252:1160-4. 38. Galmiche JP, Guillard JF, Denis P, et al. A study of post-prandial oesophageal pH in healthy subjects and in patients with gastro-oesophageal reflux. Diagnostic value of a scoring index of acid reflux [French]. Gastroenterol Clin Biol 1980;4:531-9. 39. Arora AS, Murray JA. Streamlining 24-hour pH study for GERD: use of a 3-hour postprandial test. Dig Dis Sci 2003;48:10-5. 40. Johnsson F, Joelsson B. Reproducibility of ambulatory oesophageal pH monitoring. Gut 1988;29:886-9. 41. Dalby K, Nielsen RG, Markoew S, et al. Reproducibility of 24-hour combined multiple intraluminal impedance (MII) and pH measurements in infants and children. Evaluation of a diagnostic procedure for gastroesophageal reflux disease. Dig Dis Sci 2007;52:2159-65. 42. Dhiman RK, Saraswat VA, Mishra A, et al. Inclusion of supine period in short-duration pH monitoring is essential in diagnosis of gastroesophageal reflux disease. Dig Dis Sci 1996;41:764-72. 43. Ahlawat SK, Novak DJ, Williams DC, et al. Day-to-day variability in acid reflux patterns using the BRAVO pH monitoring system. J Clin Gastroenterol 2006;40:20-4. 44. Ward EM, Devault KR, Bouras EP, et al. Successful oesophageal pH monitoring with a catheter-free system. Aliment Pharmacol Ther 2004;19:449-54. 45. Hirano I. Dual receiver, Four-day Bravo pH probe combining testing off and on PPI. Clin Gastroenterol Hepatol 2005;3:1083-8. 46. Hirano I. Review article: modern technology in the diagnosis of gastro-oesophageal reflux diseasedBilitec, intraluminal impedance and Bravo capsule pH monitoring. Aliment Pharmacol Ther 2006;23(Suppl 1):12-24. 47. Scarpulla G, Camilleri S, Galante P, et al. The impact of prolonged pH measurements on the diagnosis of gastroesophageal reflux disease: 4-day wireless pH studies. Am J Gastroenterol 2007;102:2642-7. 48. Prakash C, Clouse RE. Value of extended recording time with wireless pH monitoring in evaluating gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2005;3:329-34. 49. 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;3:1083-8. 50. Garrean CP, Gonsalves N, Hirano I. Bravo pH testing on and off treatment with immediate-release omeprazole. Gastroenterol Hepatol 2007;3:4-7. 51. Agrawal A, Tutuian R, Hila A, et al. Ingestion of acidic foods mimics gastroesophageal reflux during pH monitoring. Dig Dis Sci 2005;50: 1916-20. 52. Hila A, Agrawal A, Castell DO. Combined multichannel intraluminal impedance and pH esophageal testing compared to pH alone for diagnosing both acid and weakly acidic gastroesophageal reflux. Clin Gastroenterol Hepatol 2007;5:172-7. 53. Fass J, Silny J, Braun J, et al. Measuring esophageal motility with a new intraluminal impedance device. First clinical results in reflux patients. Scand J Gastroenterol 1994;29:693-702. 54. Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004;53:1024-31. 55. Bredenoord AJ, Weusten BL, Timmer R, et al. Reproducibility of multichannel intraluminal electrical impedance monitoring of gastroesophageal reflux. Am J Gastroenterol 2005;100:265-9. 56. Shay S, Tutuian R, Sifrim D, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol 2004;99:1037-43.

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57. Zerbib F, des Varannes SB, Roman S, et al. Normal values and day-to-day variability of 24-h ambulatory oesophageal impedance-pH monitoring in a Belgian-French cohort of healthy subjects. Aliment Pharmacol Ther 2005;22:1011-21. 58. Roman S, Bruley des Varannes S, Pouderoux P, et al. Ambulatory 24-h oesophageal impedance-pH recordings: reliability of automatic analysis for gastro-oesophageal reflux assessment. Neurogastroenterol Motil 2006;18:978-86. 59. Johnson LF, DeMeester TR. Development of the 24-hour intraesophageal pH monitoring composite scoring system. J Clin Gastroenterol 1986;8(Suppl 1):52-8. 60. Johnson LF, Demeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974;62:325-32. 61. Wenner J, Johnsson F, Johansson J, et al. Wireless oesophageal pH monitoring: feasibility, safety and normal values in healthy subjects. Scand J Gastroenterol 2005;40:768-74. 62. Vitale GC, Cheadle WG, Sadek S, et al. Computerized 24-hour ambulatory esophageal pH monitoring and esophagogastroduodenoscopy in the reflux patient. A comparative study. Ann Surg 1984;200:724-8. 63. Mattioli S, Pilotti V, Spangaro M, et al. Reliability of 24-hour home esophageal pH monitoring in diagnosis of gastroesophageal reflux. Dig Dis Sci 1989;34:71-8. 64. Baldi F, Ferrarini F, Longanesi A, et al. Ambulatory 24-hour oesophageal pH monitoring in normal subjects: a multicentre study in Italy. G.I.S.M.A.D. GOR Study Group. Ital J Gastroenterol 1991;23:477-80. 65. Richter JE, Bradley LA, DeMeester TR, et al. Normal 24-hr ambulatory esophageal pH values. Influence of study center, pH electrode, age, and gender. Dig Dis Sci 1992;37:849-56. 66. Vaezi MF, Richter JE. Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 1996;111:1192-9. 67. Avidan B, Sonnenberg A, Schnell TG, et al. Hiatal hernia and acid reflux frequency predict presence and length of Barrett’s esophagus. Dig Dis Sci 2002;47:256-64. 68. Campos GM, Peters JH, DeMeester TR, et al. Multivariate analysis of factors predicting outcome after laparoscopic Nissen fundoplication. J Gastrointest Surg 1999;3:292-300. 69. Khajanchee YS, Hong D, Hansen PD, et al. Outcomes of antireflux surgery in patients with normal preoperative 24-hour pH test results. Am J Surg 2004;187:599-603. 70. Vela MF, Camacho-Lobato L, Srinivasan R, et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology 2001;120:1599-606. 71. Sifrim D, Holloway R, Silny J, et al. Composition of the postprandial refluxate in patients with gastroesophageal reflux disease. Am J Gastroenterol 2001;96:647-55. 72. Zentilin P, Iiritano E, Dulbecco P, et al. Normal values of 24-h ambulatory intraluminal impedance combined with pH-metry in subjects eating a Mediterranean diet. Dig Liver Dis 2006;38:226-32. 73. Wiener GJ, Morgan TM, Copper JB, et al. Ambulatory 24-hour esophageal pH monitoring. Reproducibility and variability of pH parameters. Dig Dis Sci 1988;33:1127-33. 74. Weusten BL, Roelofs JM, Akkermans LM, et al. The symptom-association probability: an improved method for symptom analysis of 24-hour esophageal pH data. Gastroenterology 1994;107:1741-5. 75. Singh S, Richter JE, Bradley LA, et al. The symptom index. Differential usefulness in suspected acid-related complaints of heartburn and chest pain. Dig Dis Sci 1993;38:1402-8. 76. Wenner J, Johnsson F, Johansson J, et al. Wireless esophageal pH monitoring is better tolerated than the catheter-based technique: results from a randomized cross-over trial. Am J Gastroenterol 2007;102: 239-45.

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930 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 4 : 2009

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Received June 24, 2008. Accepted September 13, 2008. Current affiliations: Division of Gastroenterology, Department of Medicine (J.E.P.), The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, Gastroenterology and Hepatology, Department of Medicine (M.F.V.), Medical University of South Carolina, Charleston, South Carolina, USA. Reprint requests: Reprints not available from the authors.

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Esophageal-reflux monitoring

APPENDIX 1. RECOMMENDATIONS WITHIN THIS REVIEW ARE BASED UPON A MODIFICATION OF THE U.S. PREVENTIVE SERVICES TASK FORCE (USPSTF) GRADING SYSTEM (http://www.ahrq.gov/clinic/pocketgd.pdf), according to one of five classifications (A, B, C, D, Insufficient) reflecting the strength of evidence and magnitude of net benefit (benefits minus harms).

Strength of Recommendations A.d The authors strongly recommend that clinicians provide [the service] to eligible patients. The authors found good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms. B.d The authors recommend that clinicians provide [this service] to eligible patients. The authors found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms. C.d The authors make no recommendation for or against routine provision of [the service]. The authors found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation. D.d The authors recommend against routinely providing [the service] to asymptomatic patients. The authors found at least fair evidence that [the service] is ineffective or that harms outweigh benefits. Insufficient.d The authors conclude that the evidence is insufficient to recommend for or against routinely providing [the service]. Evidence that the [service] is effective is lacking, of poor quality, or conflicting and the balance of benefits and harms cannot be determined.

Quality of Evidence The authors graded the quality of the overall evidence for a service on a 3-point scale (good, fair, poor): Good: Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes. Fair: Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or indirect nature of the evidence on health outcomes. Poor: Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.

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