Detection of acid and nonacid reflux using esophageal reflux monitoring, which includes conventional and wireless pH monitoring and pH impedance, can be a valuable diagnostic tool when used appropriately in the assessment of patients with gastroesophageal reflux disease. Reflux monitoring may be especially helpful if a management change is desired, such as when initial or empirical treatment is ineffective. However, each of these methods has its limitations, which need to be accounted for in their clinical use. Indications, test performance, interpretation, and clinical applications of esophageal reflux monitoring, as well as their limitations, are discussed in this review.
Key points
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Esophageal reflux monitoring, although helpful in the diagnostic assessment of gastroesophageal reflux disease, has its limitations and should be used as a supporting component in the diagnosis.
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Not all reflux events cause symptoms, and not all symptoms are caused by reflux.
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Acid reflux is uncommon while on proton pump inhibitor (PPI) therapy; thus, pH monitoring without impedance may have limited usefulness if performed on patients on PPIs.
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Detection of nonacid reflux may be helpful diagnostically, however, data regarding efficacy of treatments focused on this entity are lacking.
Introduction
Gastroesophageal reflux disease (GERD), which is defined as a condition that develops when the reflux of gastric contents causes troublesome symptoms or complications, is one of the most common diagnoses made in gastroenterology and primary care clinics. The diagnosis of GERD is often based on the presence of typical symptoms (heartburn and regurgitation) or atypical or extraesophageal symptoms, such as noncardiac chest pain, cough, sore throat, or hoarseness, and a response to acid suppressive therapy. In the absence of endoscopic evidence of GERD, or an alternative cause of symptoms, esophageal reflux monitoring can be used to assist in diagnostic evaluation.
Ambulatory esophageal reflux monitoring can be performed via several different methods. pH monitoring is available via transnasal catheter or wireless sensors and can detect reflux episodes by measuring decreases in esophageal pH. Impedance pH catheters, placed transnasally into the esophagus, measure the change in electrical resistance between closely spaced electrodes and thus can determine the composition of intraesophageal contents (liquid, gas, or mixed), and measure direction of flow (antegrade or retrograde), as well as esophageal pH. Thus, pH monitors are able to measure acid reflux, which is defined as refluxed gastric contents with a pH less than 4, whereas impedance pH can detect both acid reflux and nonacid reflux, which is defined as refluxed contents with pH 4 or greater and sometimes further classified as weakly acidic (pH 4–7) and weakly alkaline (pH ≥7) reflux. Although esophageal reflux monitoring can be a valuable tool for assessing patients with suspected GERD, each testing modality has its limitations, which need to be considered when deciding when and how to use these tests. This review covers the indications for reflux monitoring, which test to choose, including characteristics and technical details of each modality, and how to interpret results and incorporate them into clinical practice.
Introduction
Gastroesophageal reflux disease (GERD), which is defined as a condition that develops when the reflux of gastric contents causes troublesome symptoms or complications, is one of the most common diagnoses made in gastroenterology and primary care clinics. The diagnosis of GERD is often based on the presence of typical symptoms (heartburn and regurgitation) or atypical or extraesophageal symptoms, such as noncardiac chest pain, cough, sore throat, or hoarseness, and a response to acid suppressive therapy. In the absence of endoscopic evidence of GERD, or an alternative cause of symptoms, esophageal reflux monitoring can be used to assist in diagnostic evaluation.
Ambulatory esophageal reflux monitoring can be performed via several different methods. pH monitoring is available via transnasal catheter or wireless sensors and can detect reflux episodes by measuring decreases in esophageal pH. Impedance pH catheters, placed transnasally into the esophagus, measure the change in electrical resistance between closely spaced electrodes and thus can determine the composition of intraesophageal contents (liquid, gas, or mixed), and measure direction of flow (antegrade or retrograde), as well as esophageal pH. Thus, pH monitors are able to measure acid reflux, which is defined as refluxed gastric contents with a pH less than 4, whereas impedance pH can detect both acid reflux and nonacid reflux, which is defined as refluxed contents with pH 4 or greater and sometimes further classified as weakly acidic (pH 4–7) and weakly alkaline (pH ≥7) reflux. Although esophageal reflux monitoring can be a valuable tool for assessing patients with suspected GERD, each testing modality has its limitations, which need to be considered when deciding when and how to use these tests. This review covers the indications for reflux monitoring, which test to choose, including characteristics and technical details of each modality, and how to interpret results and incorporate them into clinical practice.
Indications for esophageal reflux monitoring
Esophageal reflux monitoring can be used to support a diagnosis of GERD, such as before antireflux procedures, or when the diagnosis of GERD may be in question, such as when there is a lack of response to effective therapy. After an empirical trial of acid suppression therapy, generally with proton pump inhibitors (PPIs), upper endoscopy is the initial diagnostic test performed, because it can assess for complications (especially if patients show alarm symptoms, eg, dysphagia) and also confirm a diagnosis by identifying complications, such as erosive esophagitis or Barrett esophagus, which are specific, although not sensitive, features of GERD. Thus, if erosive esophagitis or Barrett esophagus are present, additional esophageal reflux testing is not necessary to diagnose GERD. In addition, endoscopy can identify an alternative diagnosis for patient symptoms, such as pill, infectious, or eosinophilic esophagitis. If an antireflux procedure is being considered, esophageal manometry is then often performed next to identify achalasia or esophageal aperistalsis; manometry can also play a role in localization of the lower esophageal sphincter (LES), which may be needed to place an esophageal reflux monitoring device. Typical indications for esophageal reflux monitoring included below.
Before Antireflux Surgery
If endoscopy is normal, which is often the case, and an antireflux procedure is being considered, esophageal reflux monitoring is then indicated. PPIs are the staple of GERD treatment and are effective in the treatment of typical GERD symptoms and healing of esophagitis. Thus, a response to PPIs is often used as the confirmatory test for GERD. However, although a positive response to a PPI trial is supportive of a diagnosis of GERD and predicts a positive response to antireflux therapy, there is also potential for a placebo effect and thus false-positive results of a PPI trial test. Therefore, even when patients have a positive response to a PPI trial, esophageal reflux monitoring should be performed in patients with endoscopy-negative (presumed) reflux disease before pursuing antireflux endoscopic or surgical interventions with their inherent procedural risks.
PPI-Refractory GERD Symptoms
The definition of PPI-refractory GERD or PPI-nonresponsive GERD can vary, often differing in whether this includes patients who do not respond to daily PPI, or more commonly, only to patients with continued symptoms on high-dose, twice-daily PPI. Regardless of definition, refractory symptoms are the most common use for esophageal reflux monitoring. The lack of a response to high-dose PPI treatment (after confirming patient adherence and correct premeal dosing) raises several clinical possibilities: the symptoms are related to GERD, which may be either caused by breakthrough acid reflux or nonacid reflux; or, there is another explanation (not GERD, eg, functional heartburn) for the patient’s continued symptoms. Reflux monitoring can be helpful to differentiate these possibilities.
A special situation exists if patients develop GERD symptoms after antireflux surgery. In general, a similar diagnostic algorithm is followed as for patients with GERD without previous surgery, including a PPI trial, but with earlier use of endoscopy and imaging to assess postsurgical anatomy. If the anatomy is appropriate and an empirical trial of PPIs is ineffective, reflux monitoring, perhaps a different method than used preoperatively, again can be useful to assess for the cause of symptoms.
Noncardiac Chest Pain
Once cardiac causes have been thoroughly evaluated for and excluded, the possibility of GERD-related chest pain can be entertained. Meta-analyses have shown that GERD-related (based on abnormal pH monitoring or endoscopy) chest pain frequently responds to PPI therapy. However, if chest pain persists or symptom cause is still unclear after a 4-week trial of PPI, esophageal reflux testing is likely the most useful test in determining the cause of the patient’s chest pain.
Extraesophageal GERD Symptoms
Some disagreement exists regarding the use or timing of esophageal reflux monitoring for extraesophageal GERD symptoms. GERD is frequently associated with patients who have chronic cough, laryngitis, or asthma. However, it is less clear if these observations are truly recognizing a causal relationship between GERD and these symptoms. Thus, recent guidelines recommend consideration of esophageal reflux monitoring before an empirical trial of PPIs for extraesophageal symptoms in the absence of concurrent typical GERD symptoms. Others suggest that testing be considered if symptoms are refractory to PPI therapy, although testing in this scenario may carry a low yield.
Assessing Effectiveness of Reflux Therapy
Reflux monitoring may also be helpful to assess the effectiveness of antisecretory therapy in patients with refractory esophagitis or stricture formation. Patients not responding to high-dose therapy may have PPI-refractory disease and may require antireflux surgery.
Performance of esophageal reflux monitoring
Once the decision to pursue reflux monitoring has been made, the next step is to choose which type of device to use ( Fig. 1 ): pH monitoring, either catheter-based (conventional) or wireless (Bravo pH monitoring system, Given Imaging, Yoqneam, Israel), or impedance pH. The basic equipment needed to perform any type of reflux monitoring includes a portable data logger, the sensor (pH or impedance pH), a computer, and analysis software.
There are also tests available to measure gastroduodenal or bile reflux; the most commonly referenced is the Bilitec (Medtronic Instruments, Minneapolis, MN) system. This transnasal catheter is placed with the sensor positioned at 5 cm above the proximal border of the LES, with goal test duration of 24 hours. Although bile acid reflux has been reported to cause esophageal mucosal damage and typical GERD symptoms, bile reflux is commonly seen occurring with acid reflux and is also successfully treated with PPI, and thus, its use may not add much beyond standard pH monitoring. In addition, the Bilitec system is limited by dietary restrictions during the test and a decreased sensitivity for bile reflux events associated with acid reflux with pH less than 3.5. With impedance pH testing being able to detect nonacid reflux, the clinical usefulness for bile reflux testing is diminishing, and thus is not discussed further in this review.
To perform esophageal reflux monitoring, the sensor is first calibrated according to product-specific instructions, and the sensor is placed (further details are presented later) after a 4-hour to 8-hour fast. Regardless of which testing modality is used, several aspects of esophageal reflux monitoring are consistently recommended :
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The pH sensor should be positioned 5 cm above the proximal border of the LES or 6 cm above the squamocolumnar junction (SCJ)
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Goal test duration should be at least 24 hours
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Patient instructions during the study should include:
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Diet and activity should not be limited
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Patients should record symptoms, meals, activities (including sleep), and position (supine, upright)
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Symptom association assessment should be used to statistically interpret studies
Various features of the reflux monitoring modalities are summarized in Table 1 .
| Conventional pH Monitoring | Wireless pH Monitoring | pH Impedance Monitoring | |
|---|---|---|---|
| Transnasal catheter? | Yes | No | Yes |
| pH sensor placement | 5 cm from LES | 6 cm from SCJ (endoscopically) | 5 cm from LES |
| Duration (h) | 24 | 24–96 | 24 |
| Measures | Acid reflux | Acid reflux | Acid and nonacid reflux |
| Interpretation | Automated | Automated | Automated, but requires manual review |
Sensor Placement and Positioning
The primary basis for sensor placement at 5 cm above the proximal border of the LES is to avoid migration of the sensor into the stomach; up to 2 cm of sensor migration has been observed during swallowing, and this potential also exists with other activities. In addition, normative values of reflux monitoring modalities have been determined with these sensor positions, and thus, accurate reproduction is needed for application of normative standards. Although wireless pH sensors, which are fixed to the esophageal wall, may offer the ability for catheter placement without risk for migration during the testing period, they are conventionally also placed 6 cm above the SCJ, because normative data are also produced for placement at this positioning.
Limitation of conventional placement location
Conventional intraesophageal placement of the pH sensor at 5 cm above the LES may limit the sensitivity of reflux monitoring by missing short-segment reflux events, because studies have shown higher esophageal acid exposures at sensor placements just above the LES (0.5 cm) or SCJ (1 cm), than at placement at 5.5 cm above the LES or 6 cm above the SCJ, respectively. Thus, although sensitivity of reflux monitoring could be increased with placement of a wireless sensor closer to the SCJ, further study is needed to validate this technique.
Various methods can be used for localization of the LES and subsequent placement of the pH sensor. For catheter-based systems (pH or impedance pH), esophageal manometry is typically used. Wireless pH sensors can be placed either endoscopically or via transnasal or transoral deployment assembly either after endoscopic identification of the SCJ or after manometric localization of the LES. Transoral placement without sedation is possible (with a correction factor of 4 cm if using transnasal manometry to localize the LES) and is successful in more than 90% of cases. Transnasal placement of the wireless pH sensor may be complicated by minor epistaxis (up to 85%) and possibly a higher insertion failure rate (8%–20% of attempts).
Intragastric and proximal esophageal or oropharyngeal sensor placement may be of interest in specific circumstances. Intragastric pH monitoring is often performed with a sensor at 7 to 10 cm below the LES (which corresponds to the gastric fundus). Various sites for proximal esophageal or oropharyngeal sensor sites have been reported, including 15 to 20 cm above the LES, as well as various locations relative to the upper esophageal sphincter. Although there is some association of gastric pH effect on esophagitis healing, and proximal acid reflux has been associated with extraesophageal symptoms of GERD, there are sufficient limitations in regards to technical aspects, standardized normative values, and proven clinical relevance. Thus, the routine use of intragastric or proximal esophageal or oropharyngeal pH sensors does not have sufficient evidence for society guidelines to recommend for or against. Use of esophageal impedance testing, which can measure the proximal extent of reflux events, may further negate the use of proximal esophageal pH sensors, although the addition of hypopharyngeal impedance pH measurements may have a role in the assessment of patients with extraesophageal symptoms.
Test Duration
Although a test duration of 24 hours or greater is recommended, there has been discussion of tests of both shorter and longer duration. In general, catheter-based tests are performed for up to 24 hours and wireless tests are performed for 48 hours. When determining test duration, factors that limit test duration, such as patient tolerance and (less so) equipment/battery longevity, are weighed against the potential advantages of longer tests, which include possible increased test sensitivity and specificity, increased symptoms for association assessment, as well as the potential for performing a single study both on and off PPI.
Patient tolerance
Patient tolerance is the primary factor limiting test duration. In studies comparing conventional catheter-based pH systems with wireless pH monitoring, patients report more nasal and throat discomfort (including more runny nose, discomfort and difficulty with swallowing, and headaches) with the catheter-based systems and more chest or esophageal discomfort (esophageal foreign body sensation or chest pain) with wireless systems. Few patients (<4%) in wireless pH sensor groups required endoscopic removal of the pH probe. Overall, patients tolerated and preferred the wireless system over the catheter-based systems. They also reported being more active, with less change in their daily activities with wireless than catheter-based pH testing; maintenance of normal activity is important during reflux monitoring, not only to help assess esophageal components in real-life situations but also because exercise can often increase reflux events.
Thus, because the primary limitation for longer duration of catheter-based studies is patient tolerability, shorter study durations have been assessed, and a range of durations (3–12 hours) and protocols have been reported (with varying inclusion of postprandial and supine periods). Studies of these shorter protocols have reported sensitivities ranging from 53% up to 97% (compared with 24-hour studies), with improved sensitivities when including both postprandial and supine periods. Thus, if patients are unable to tolerate a complete 24-hour study protocol, some inferences may be able to be made from the shortened test data. However, limitations of these shorter duration tests, which include poor reproducibility and a diminished time frame to perform symptom association assessment, need to be accounted for, especially if a test is normal. Longer pH study durations (48–96 hours) are available with the better-tolerated wireless pH monitoring systems, which may increase test sensitivity. Wireless data receivers are capable of recording for 48 hours, but by calibrating the pH sensor simultaneously to 2 data receivers and turning the second receiver on after 48 hours, measurement for up to 96 hours is possible. Most patients are able to complete 48-hour (>85%), and even 96-hour (41%–100%), studies. These tests of greater than 24 hours have shown increased detection of abnormal studies, identification of day-to-day variability, increasing symptom association, and subsequently, overall improved diagnostic yield. Extending the testing period to 96 hours also allows for a single test to be completed both on (2 days) and off (2 days) PPI.
So, although shorter catheter study duration may be an option in selective situations, it is recommended for reflux monitoring studies to be performed for at least 24 hours, keeping in mind that improved diagnostic information may become available with longer test durations.
Comparisons of Esophageal Reflux Monitoring Modalities
Several characteristics of esophageal reflux monitoring modalities need to be considered when choosing which test to pursue. These characteristics generally include whether to use a catheter-based or wireless sensor and whether or not to use impedance testing. In addition to some differences in diagnostic yield, there are other limitations to esophageal reflux testing modalities that need to be considered.
Other limitations
When using either pH monitoring method, there is the potential to overestimate esophageal acid exposure and reflux caused by ingestion of acid foods (which may not be reported by patients). Studies using impedance are able to differentiate these events by detection of antegrade flow. In addition, pH monitoring may underestimate the number of reflux events if they occur when esophageal pH is already less than 4.0.
Neither pH nor impedance pH testing are able to measure the volume of the refluxate. In addition, although pH electrode drift is sometimes a concern, it does not seem to cause major changes in test results, regardless of sensor type and even during prolonged test durations.
Impedance testing may be limited by difficult interpretation or missed reflux events in patients who have low baseline impedance, such as in the setting of esophagitis or Barrett esophagus. However, low baseline impedance is an uncommon finding (only 1.4% reported in 1 study), and the use of reflux monitoring in these patients with endoscopic evidence of GERD may be questioned. Furthermore, impedance testing is more cumbersome on the interpreting physician, because manual interpretation is required (see further discussion later).
The wireless pH sensor is also reported to cost approximately 3 to 5 times as much as the standard catheter-based pH monitor, which is another issue that should be considered when choosing between tests. Additional cost may also be accrued if endoscopic placement is used or required.
The goals of any diagnostic test are to make a diagnosis and to help dictate management decisions. Herein lies potentially the greatest limitation to esophageal reflux monitoring. Although detailed discussion of specific therapies for GERD is beyond the scope of this review, a question that should be asked before pursuing esophageal reflux monitoring is how the potential results may alter future therapy. This question is pertinent in the case of nonacid reflux in which treatments for reflux inhibition, such as baclofen or antireflux surgery, may be limited by potential side effects or strong efficacy data.
Several studies have been performed comparing the diagnostic yield of the various reflux monitoring modalities. Studies using concurrent or crossover measurements with wireless and catheter-based pH monitoring showed similar measurements of 24-hour esophageal acid exposure in patients tested off PPIs.
One of the primary advantages of using combined impedance pH is the ability to detect reflux episodes regardless of their pH (and then characterize reflux events as acid or nonacid). Several studies have examined the use of impedance pH both on and off PPI therapy. Although there are some minor variations among methodology, results, and conclusions in these studies, in general, they show that the addition of impedance to pH monitoring on patients both on and off PPI increases the diagnostic yield of the procedure (generally with increased symptom associations of approximately 10%–20%), although this increased yield may be more pronounced in patients actively taking PPIs.
There are no studies comparing concurrent use of impedance pH and wireless pH monitoring; however, corresponding features, such as improved patient tolerance with a wireless system, can likely be inferred from the comparisons of wireless and catheter-based systems. Although further testing and validation are needed before clinical use, a prototype of a wireless impedance pH system has been developed and may provide exciting diagnostic advantages in the future.
On or Off PPIs?
The decision to test on or off PPI can be derived from the clinical question(s) and based on the clinical scenario ( Fig. 2 ). Studies have consistently shown that the total number of reflux events is similar whether on or off PPI therapy. However, for patients off PPI, acid reflux made up most reflux events (although nonacid reflux events do sometimes occur). In studies of patients on PPI, few patients had abnormal distal esophageal acid exposure, nonacid reflux made up most of the reflux events and symptomatic reflux episodes, and acid reflux on PPIs was rare. Thus, in patients on PPI, pH monitoring performed without impedance is likely to have a low yield.
