The American Journal of Gastroenterology (2007) 102, 668–685; doi:10.1111/j.1572-0241.2006.00936.x
ACG Practice Guidelines: Esophageal Reflux Testing
12Ikuo Hirano MD, Joel E Richter MD and the Practice Parameters Committee of the
*American College of Gastroenterology
11. Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
22. Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania Correspondence: Ikuo Hirano, MD, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 North St Clair Street, Suite 1400, Chicago, Illinois 60611-2951. *The members of the Practice Parameters Committee of the American College of Gastroenterology are listed in the Appendix.
Received 26 April 2006; Accepted 28 August 2006.
Investigations and technical advances have enhanced our understanding and management of gastroesophageal reflux disease. The recognition of the prevalence and importance of patients with endoscopy-negative reflux disease as well as those refractory to proton pump inhibitor therapy have led to an increasing need for objective tests of esophageal reflux. Guidelines for esophageal reflux testing are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the Board of Trustees. Issues regarding the utilization of conventional, catheter-based pH monitoring are discussed. Improvements in the interpretation of esophageal pH recordings through the use of symptom-reflux association analyses as well as limitations gleaned from recent studies are reviewed. The clinical utility of pH recordings in the proximal esophagus and stomach is examined. Newly introduced techniques of
duodenogastroesophageal reflux, wireless pH capsule monitoring and esophageal impedance testing are assessed and put into the context of traditional methodology. Finally, recommendations on the clinical applications of esophageal reflux testing are presented.
ACG Guidelines on the clinical applications of ambulatory esophageal pH monitoring were
1last published 10 yr ago (). Since that time, research investigations and technical
advances have enhanced our understanding of both the utility and limitations of this diagnostic modality. Studies have examined whether placement of pH probes in the pharynx, cervical esophagus, and proximal stomach yield information that alters the management of gastroesophageal reflux disease (GERD). Newer techniques for esophageal functional testing such as wireless pH capsule monitoring,
duodenogastroesophageal (formerly referred to as alkaline or bile reflux) reflux detection, and esophageal impedance testing have been introduced over the past decade and are currently available in clinical practice. A recent, prospective study compared the indications for esophageal pH monitoring in clinical practice with the indications in
2,3practice guidelines (). Less than half of the studies performed were in accordance with the recommendations. Two studies reported that pH testing resulted in a change in management in approximately 50% of investigated patients, although such changes were
4,5maintained in only half of the cohort ().
This second practice guidelines summarizes advances in GERD diagnostic testing and how they have modified the clinical management of esophageal disorders. A literature search was conducted for English-language articles dealing with functional evaluation of the esophagus from 1994 to 2006. Databases included Medline and PubMed with search terms that included esophageal pH monitoring, GERD, esophageal impedance, asthma, laryngitis, chest pain, Bilitec, and bile reflux.
WIRELESS pH MONITORING.
First introduced over 30 years ago, catheter-based esophageal pH recording remains both a widely accepted and available technique for quantifying esophageal acid exposure. The technique has been extensively examined and critically reviewed in earlier clinical
1,2guidelines (). The most significant recent technical advance in pH recording has been the incorporation of the antimony electrode into a wireless capsule that transmits pH data to an external receiver via radiofrequency telemetry (433 MHz). The current data sampling at 6-s intervals of the wireless pH capsule (Bravo system, Medtronic, Minneapolis, MN) (0.17Hz) is slower than the 4-s intervals used by the Slimline pH catheter systems (0.25Hz) (Medtronic, Minneapolis, MN) and 5-s intervals used by the Sandhill pH catheter system (0.20 Hz) (Sandhill Scientific, Highlands Ranch, CO). Prior studies have demonstrated that faster sampling frequencies up to 1 Hz lead to the detection of a greater total number of reflux events but do not change the overall acid
6exposure values (). Using the wireless pH system, the 95th percentile for distal esophageal acid exposure for control subjects was 5.3%, a value higher than values
2,7,8reported in several although not all catheter-based system studies (). The higher acid
exposure threshold reported in healthy controls using the wireless pH system may be the consequence of less restriction in daily activities or the result of a thermal calibration error that existed in the pH catheter systems. Both of these issues will now be addressed. A major advantage of the wireless pH system is patient tolerability. Nasally passed pH electrodes are both uncomfortable and conspicuous leading patients to avoid potentially
9reflux provoking stimuli such as meals and physical activity (). However, a second study
from Spain reported that patients' dietary, sleep, and tobacco use did not vary during the performance of pH studies, although 65% of patients did report diminished physical
10activity (). Wong et al. randomized 50 patients to either catheter-based or wireless pH monitoring and reported less interference with daily activity and improved overall
11satisfaction with the pH capsule (). Taking advantage of the improved patient comfort
with the wireless pH system, Pandolfino et al. demonstrated a threefold increase in acid
12exposure during physical exercise compared with nonexercise periods (). Therefore, pH
recordings using the wireless pH system improve patients' ability to perform their daily activities and thus provide a more accurate picture of their acid exposure profile as well as improve their compliance with the study.
COMPARISON OF WIRELESS pH CAPSULE AND CATHETER-BASED pH
During studies simultaneously using the wireless pH and Slimline catheter pH systems, a
13,14,15significant offset was noted in the pH values reported by the two systems (). As a
result of this offset, the Slimline system reported a median percent time pH <4 of 3.5% in a group of healthy subjects compared with 1.75% with the wireless pH system. Swallowed orange juice with pH of 3.88 measured ex vivo using a benchtop pH glass
electrode was used as a reference standard and demonstrated that the wireless pH system gave a median pH value of 3.84 compared with 3.11 for the Slimline catheter. This difference in calibration has been determined to be due to a thermal calibration correction factor error inherent to the Slimline software. This error has since been corrected. Another difference noted between the wireless pH capsule and Slimline catheter was in the detection of number of acid reflux events. The Slimline recorded a significantly greater number of events that could only partly be explained by the thermal
14correction factor error (). The difference was due to a higher detection of short reflux episodes and likely secondary to the lower sampling rate of the wireless pH compared with Slimline catheter system. It should be noted that both the wireless pH and Slimline systems miss a proportion of short reflux events due to their sampling frequencies being
6lower than the optimal frequency of 1 Hz (). Whether the short reflux episodes are
associated with symptoms and may affect the sensitivity of symptom association of pH testing with the wireless pH system is uncertain. Moreover, such short events do not alter the overall acid exposure times.
LIMITATIONS OF WIRELESS pH TESTING.
Disadvantages of the wireless pH system exist. The current capsule size does not allow for reliable nasal passage such that oral passage of the delivery catheter is necessary. Endoscopy is generally performed immediately prior to wireless pH capsule placement to determine the position of the squamocolumnar junction, thereby adding cost to the procedure. Early capsule detachment prior to 24 h is uncommon but can add additional costs for incomplete data acquisition. In one report, 12% of capsules failed to attach properly on first attempt necessitating a replacement capsule. Modifications to the catheter delivery system have since been performed by the manufacturer. A second report from two centers reported capsule detachment prior to 16 h in 3/85 subjects and
7prior to 36 h in 9/85 subjects (). Detachment that occurs during the 48-h recording
period could lead to erroneous interpretation of the acid exposure time consequent to intragastric pH recording (Fig. 1). This potential error can be minimized by manual
inspection of the pH tracing as well as querying the patient regarding the timing of loss of esophageal foreign body sensation. Finally, a single case report described a proximal
17esophageal perforation following an attempted wireless pH capsule placement ().
Serious complications including perforation have not been reported in the published
7,12,13,15,16,18,19,20,21,22,23,24,25series totaling over 850 subjects ().
Early detachment of the wireless pH capsule in a GERD patient. Note the sudden prolonged drop
in pH representing the capsule in the stomach and then the sharp rise as the capsule enters the
small intestine through the pylorus. In addition, there are two small areas indicating data loss
Full figure and legend (44K)
Additional drawbacks are minor. The validity of using the squamocolumnar junction as a reference point for the gastroesophageal junction has not been subject to the same scrutiny as the manometric positioning of the catheter-based pH electrodes. However, prior studies have demonstrated consistency of the positioning of the proximal margin of the lower esophageal sphincter (LES) 1 to 1.5 cm above the squamocolumnar junction 26(). The reliability of using other markers such as the proximal margin of the gastric folds in patients with Barrett's esophagus has not been determined. Patient discomfort from the pH capsule has been reported with many patients noting a foreign body
21,22sensation, especially with deglutition (). This is generally of little consequence with
7,11rare patients requiring early capsule removal by endoscopy secondary to discomfort ().
Manometric studies have recorded high amplitude foci of esophageal body contractions in the vicinity of the pH capsule that may account for symptoms of chest pain in some
27patients (). Inadequate data reception resulting in periods of missing data is most
commonly the result of the receiver being out of range of the capsule. Modifications to the hardware have reduced this problem and the current software automatically deletes such periods from the final analysis. Finally, failure of capsule detachment, albeit rare, can necessitate endoscopic extraction.
OPTIMAL DURATION OF pH MONITORING.
The standard duration of recording for esophageal pH testing is 24 h. With the introduction of the wireless pH system, prolonged recording periods extending beyond 24 and even 48 h are now both well tolerated and feasible. The wireless pH system routinely records for 48 h although early detachment prior to 48 h occurs in about 10% of patients 7,19(). The 48-h data could be interpreted using an average of the 2 days or only the 24-h period with the greatest acid exposure (worst day analysis). A significant increase in the sensitivity of pH testing and small decrease in specificity were evident when utilizing the worst day data compared with either the initial 24-h or overall 48-h data in comparing controls with GERD patients. Defining GERD as the presence of erosive esophagitis and an abnormal pH study as greater than 5.3% exposure time, the sensitivity of day 1 testing was 74% and specificity 90%. By using the worst day of the 2-day recording
7window, the sensitivity increased to 100% with a decrease in specificity to 85% (). A
similar increase in reflux detection was recently reported for a 2-day compared with
22single-day reflux study using the wireless pH system (). Of note, earlier catheter-based
studies examining the reproducibility of pH testing over two different study days reported
28,29concordance of between 73 and 89% (). The differences in lifestyle and dietary
factors that likely account for this variability are reduced by the prolonged recording window with the wireless pH system.
A shorter recording period utilizing the pH catheter system has been proposed as an accurate means of assessing reflux that allows for improved patient tolerance. Arora and Murray described a 3-h postprandial pH test in a series of patients with GERD and reported a sensitivity of 88% and specificity of 98% using the results of the entire 24-h
30ambulatory study as the reference standard (). Although this may be an alternative for
some patients, the wireless pH capsule circumvents many of the tolerability problems of catheter-based studies. Furthermore, the 24- to 48-h recording windows allow for assessment of supine and upright patterns of reflux as well as increased detection of
31symptoms for symptom association calculations ().
pH ELECTRODE CALIBRATION.
Calibration is performed on all pH systems prior to each study using reference buffer solutions. An analysis of 100 consecutive pH studies using posttest calibration testing of catheter-based antimony pH electrodes found drift of greater than 0.4 pH units in 5%
and a change in study interpretation in 6% of studies when the drift was factored into the
32final analysis (). Posttest calibration is currently not routinely performed for clinical studies with the wireless pH capsule due to the in vivo fixation of the capsule that does
not allow for posttest immersion into buffer solutions. Recently, a protocol involving the
13,14,19use of swallowed juice has been reported (). This method involves measuring the
pH of orange juice or a similar acidic beverage using a benchtop glass pH electrode. The juice is then swallowed and the nadir pH is recorded on the wireless pH device both at the beginning and termination of the study period. This technique has been validated in comparisons with catheter-based pH electrodes both in vivo and ex vivo. Calibration drift
can be corrected prior to final data analysis. However, the optimal manner by which to recalculate data that is obtained in the setting of a significant pH baseline drift has not been determined. Therefore, the utility of posttest calibration for the wireless pH capsule has not yet been determined and is currently not routinely performed. For catheter-based pH recordings, posttest calibration is easily performed and analysis should factor in large deviations in the baseline pH measurements.
OPTIMAL pH ELECTRODE LOCALIZATION.
Catheter-based pH electrodes are by convention positioned 5 cm above the proximal border of the LES. This localization minimizes potential artifact that could result from catheter migration into the proximal stomach during swallowing but may not be the optimal site to maximize the sensitivity of pH testing. Using videoradiography, pH probe migration by up to 2 cm cephalad as well as 2 cm caudad was observed during
33deglutition (). Furthermore, improper positioning of the pH catheter electrode has been detected by fluoroscopic imaging in up to 5% of patients due to buckling of the catheter
34in either the pharynx or esophagus (). Inadvertent pH probe migration into the
proximal stomach has also been reported, presumably as a result of slippage of the nasal fixation.
As would be expected given effects of gravity, esophageal peristalsis, and salivary
35buffering, proximal esophageal acid exposure is significantly less than distal exposure ().
In a study by Fletcher et al., esophageal acid exposure was over six times greater with a pH catheter fixed by means of metal clips at 0.5 cm compared with 5.5 cm above the
36LES (). Positioning the pH electrode immediately above the squamocolumnar junction has theoretical advantages in that the endoscopic changes of reflux esophagitis are typically most apparent at this level and not 5 cm above the proximal border of the LES. Currently, the wireless pH capsule is positioned 6 cm above the squamocolumnar junction, which closely approximates the conventional pH electrode positioning of
13catheter-based pH studies (). A potential advantage of the wireless pH capsule is its ability to be affixed to the mucosal wall in closer proximity to the squamocolumnar junction. A study of nine patients with GERD compared acid exposure profiles of a
37capsules affixed 1 cm and 6 cm above the squamocolumnar junction (). Significantly
greater acid exposure times were recorded with the 1-cm probe, most apparent in the
postprandial period where the acid exposure times were nine times greater at the 1-cm compared with 6-cm site. While this may improve the sensitivity of pH monitoring in the diagnosis of GERD, the technique needs to be validated and will likely compromise test specificity to some extent. Thus, at this time, conventional positioning of the wireless pH capsule 6 cm above the squamocolumnar junction and catheter electrode 5 cm above the proximal LES are recommended for clinical studies.
pH TESTING: ON- VERSUS OFF-PROTON PUMP INHIBITOR (PPI) THERAPY.
Presently, controversy exists as to whether pH testing is more useful when performed with patients on or off PPI therapy. Testing off-therapy is often recommended for patients in whom there is a low index of suspicion for reflux disease, to "rule out GERD" on the basis of quantitatively normal esophageal acid exposure. A negative pH study performed with the patient off PPI therapy is generally considered evidence that a patient does not have pathologic reflux disease, especially when combined with a negative symptom correlation measure. Off-therapy testing is also utilized to document the presence of reflux in patients without esophagitis who are being evaluated for antireflux endoscopic treatment or surgical fundoplication. A limitation of off-therapy pH testing is the interpretation of an abnormal study. Off-therapy pH testing may demonstrate abnormal reflux but this does not indicate causality between the reflux and the patient's symptoms. Symptom–reflux correlation using a symptom index (SI) can help but can also be inaccurate in the setting of frequent reflux episodes that result in a high SI on the basis of chance associations. The symptom association probability (SAP) is a better statistical method that can limit misinterpretation of false-positive chance associations. The yield of the SI and SAP is greater when done off- rather than on-PPI therapy. On-therapy testing is more commonly used to evaluate patients with refractory reflux symptoms. The intent is to investigate the possibility that an individual patient is having persistently abnormal distal esophageal acid exposure in spite of PPI therapy. Evidence of significant reflux events on PPI therapy, although uncommon, is used to support the use
2,38of more aggressive medical, endoscopic, or surgical therapies for GERD (). The
likelihood of having an abnormal pH study on PPI therapy is variable and depends upon the clinical setting and indication for which the test is being performed. On twice-daily
39PPI therapy, only 4% of patients had abnormal pH monitoring in one study (). Another
recent study reported much higher failure rates of 50% of patients who were
40asymptomatic on PPI therapy, three quarters of whom were on b.i.d. PPI therapy ().
Even if the overall percentage of patients with persistent acid reflux on PPI therapy is small, one could argue that pH monitoring is still of clinical utility to identify the population of truly refractory patients who may benefit from additional medical, endoscopic, or surgical therapy. A potential limitation of on-therapy testing is that the reduction in gastric acidity converts acid to weakly acid or nonacid reflux episodes that are not detected by pH monitoring. The clinical importance of such episodes is a matter
of current controversy best addressed through ongoing investigations using esophageal impedance monitoring.
The threshold acid exposure time for an abnormal pH study done on PPI therapy is not established. While the conventional, off-therapy thresholds of percent time pH <4 of 4–
5% have been commonly used, Kuo and Castell suggested a more stringent cutoff of 1.6% based on the 95% confidence interval using a pH catheter-based study of healthy
41controls treated with omeprazole 40 mg (). Whether the relative rather than absolute
decrease in acid exposure time off and on PPI therapy is relevant for symptom relief has not been determined. Furthermore, assessment of symptom association with reflux episodes on therapy may be more relevant than the actual percent time of distal acid exposure.
A recent study took advantage of the prolonged recording capabilities of the wireless pH
19system to allow for pH monitoring both off and on PPI therapy in a single test ().
Patients with suspected GERD underwent wireless pH testing off PPI therapy for the first 24 h followed by three additional recording days on rabeprazole 20 mg PO b.i.d. (Fig. 2).
Two wireless pH receivers were calibrated to a single pH capsule to allow for the prolonged recording. All patients had demonstrable reductions in distal esophageal acid exposure by day 3 with only 5% failing to normalize acid exposure values by day 4. Early capsule detachment that prevented complete analysis on therapy occurred in 5%. By combining pH monitoring both off and on therapy, two distinct questions can be answered in a single study: (a) Does the patient have abnormal distal esophageal acid exposure consistent with GERD? and (b) If reflux is present, is it being suppressed by PPI therapy? The prolonged recording period can also increase the sensitivity for the
31detection of symptoms for correlation with reflux episodes (). A disadvantage of this 4-
day protocol is the lower sensitivity for the diagnosis of GERD afforded by the 24-h rather than 48-h recording period off therapy. Studies with the wireless pH system have demonstrated an increase in test sensitivity between 12 to 25% when incorporating the
7,3148-h recording period (). To circumvent this limitation, a 48-h-off and 48-h-on PPI therapy protocol is being investigated but could be limited by failure to achieve a steady-state PPI effect on acid secretion or visceral sensitivity. In addition, early capsule detachment, although uncommon, may be an issue especially in patients in whom the on-therapy data are considered more important than off-therapy data.
Ninety-six-hour wireless pH recording combining periods both off and on PPI therapy from a
patient with significant GERD. Initial esophageal exposure was 15.3% on day 1 and demonstrated
an upright reflux pattern. Following the administration of rabeprazole at 20 mg PO b.i.d., the acid
exposure decreased to 1.3% on day 2, 1.0% on day 3, and 0.5% on day 4.
Full figure and legend (108K)
An advantage of the 24-h pH test over other diagnostic modalities is the ability to correlate symptoms with acid exposure events. Multiple methods have been devised to use statistical calculations to correlate symptoms with acid reflux. The first scheme was
42the SI (). This involves dividing the number of symptoms associated with pH <4 by the total number of symptoms yielding a percentage of symptom episodes that correlate with GERD. Symptom indices can be separately calculated for each symptom attributable to reflux including heartburn, regurgitation, or chest pain. Analysis using receiver operating characteristic curves designed to optimize sensitivity and specificity derived a value of 50% as the optimal threshold for a positive SI for patients with multiple episodes of
43heartburn (). The SI has important limitations. It does not take into account the total number of reflux episodes. Thus, a patient with multiple reflux episodes but only one symptomatic reflux event will have an SI of 100%. Reporting the SI as a ratio of events as well as percentage circumvents this limitation. However, in patients with frequent reflux episodes, random, temporal associations between reflux and symptoms may produce a high SI in the absence of any true association. The second devised scheme
44was the symptom sensitivity index (SSI) (). This involves dividing the total number of
reflux episodes associated with symptoms by the total number of reflux episodes. This system is also limited and failed to take into account the total number of symptom episodes. The proposed scheme with the best statistical validity for symptom–reflux
45correlation is the symptom probability analysis (SAP) (). This involves constructing a
contingency table with four fields: (a) positive symptom, positive reflux; (b) negative symptom, positive reflux; (c) positive symptom, negative reflux; and (d) negative symptom, negative reflux. The Fisher's exact test is then applied to calculate the probability that the observed association between reflux and symptoms occurred by chance. Therefore the SAP determines the statistical validity of symptom–reflux
associations while the SI and SSI provide data on the strength of the association. An SAP value of >95% indicates that the probability that the observed association between reflux and the symptom occurred by chance is <5%.
Attempts have been made to validate the utility of the symptom indices. Two groups have reported that patients with a high SI but normal esophageal acid exposure time
46,47respond better to PPI therapy than patients with a low index (). Prakash and Clouse
reported that the use of a 2-day recording window with the wireless pH system allowed for increased detection of symptom events, thereby improving the reflux-associated
31symptom probability analysis (). Arguing against the usefulness of the indices, Taghavi et al. prospectively compared the SI, SSI, and SAP using a symptom response to high-dose omeprazole as a relatively objective independent measure defining reflux disease 48(). All three indices performed poorly in predicting the response to PPI therapy. The sensitivities of the SI, SSI, and SAP in comparison to the omeprazole test were 35%, 74%, and 65% while the specificities were 80%, 73%, and 73%, respectively. This
observation highlights limitations in not only the indices but also the lack of a diagnostic standard for defining symptomatic reflux disease.
A major shortcoming in using any of the available symptom indices is in the completeness by which patients record their symptom events. Symptoms may occur as prolonged rather than transitory events, which can lead to inaccuracies in their association with short-lived pH drops. On the other hand, symptom indices rely on correlation with acid reflux events that may go undetected with less frequent sampling rates of currently used pH monitoring systems. Furthermore, it should be emphasized that the utilization of symptom association depends upon the specific symptom being analyzed. Interpretation of reflux association with heartburn is more straightforward than cough or other laryngeal symptoms. Cough can be induced by reflux but can also cause reflux via an increase in the gastroesophageal pressure gradient. Laryngeal symptoms are generally chronic symptoms that may not demonstrate direct association with individual reflux episodes.
Overall, symptom indices add an important dimension to the interpretation of pH monitoring. While the percent time pH >4 indicates whether abnormal degrees of acid reflux are present, it does not indicate causality between the reflux and an individual patient's complaints. Likewise, normal degrees of acid reflux may still be clinically significant if they are strongly associated with symptoms. The SI has intuitive appeal and is readily calculated. The SAP is more statistically robust and is now included on automated analysis routines on currently available pH analysis software systems. However, as none of the symptom association schemes have been well validated, they should currently be viewed as complementary information that statistically links a particular symptom to reflux events but does not guarantee response to medical or surgical antireflux therapies.
Investigators from Italy have reported on a new parameter by which to analyze esophageal acid exposure. Instead of using a fixed parameter of percent time pH <4, the
49,50authors used the area under the curve of hydrogen ion activity (). Such methodology
accounts for not only the duration of acid exposure but also the degree of esophageal acidification, with greater significance placed on a pH value of 2 compared with 3, for example. In a study of 30 controls and 60 patients with GERD, the authors reported an
50increase in diagnostic sensitivity by 17% for nonerosive and 10% for erosive GERD ().
Additional studies have demonstrated a correlation between esophagitis grade and
51magnitude of integrated esophageal acidity (). The integrated esophageal acidity is not
calculated on currently available data analysis programs for clinical practice and its clinical utility is still being investigated.
Intragastric pH Monitoring
Intragastric pH recording is most commonly performed by placement of a pH probe 10 cm below the proximal margin of the LES. This manometrically guided placement results
52in positioning of the probe in the gastric fundus (). An esophageal sensor 5 cm above
the LES simultaneously records esophageal acid exposure. Limited studies have shown