Various techniques have been devised to diagnose, characterize, and classify gastroesophageal reflux (GER). Stationary techniques, such as fluoroscopy and scintigraphy, provide interesting anatomic and functional information related to GER but are not sensitive enough and are usually performed in nonphysiologic conditions. Ambulatory techniques for GER monitoring have been developed and used since 1974. The current available techniques include catheter and wireless pH-metry, Bilitec, and impedance-pH monitoring. Prolonged wireless pH monitoring can be useful to evaluate patients off and on proton pump inhibitor (PPI) treatment. Impedance-pH monitoring is being used increasingly in patients who have persistent symptoms on PPI therapy because it can establish an association between symptoms and weakly acidic or nonacid reflux. Bilitec is performed in patients suspected to have increased duodenogastroesophageal reflux (DGER). This article discusses the technical details, clinical indications, and applications of these diagnostic techniques.
Gastroesophageal reflux disease (GERD) consists of the reflux of gastric contents into the esophagus leading to symptoms and complications. GERD is one of the most common conditions that affect the gastrointestinal tract. Various techniques have been devised to diagnose, characterize, and classify gastroesophageal reflux (GER). Reflux episodes can be detected using stationary techniques such as barium swallows and video-fluoroscopy or scintigraphy. Although these techniques provide interesting anatomic and functional information related to GERD (hiatal hernia, esophageal clearance, or gastric emptying), they are insufficiently sensitive and usually performed in nonphysiologic conditions. To overcome these limitations, ambulatory techniques for GER monitoring have been developed and used since 1974. Currently available techniques include catheter and wireless pH-metry, Bilitec, and impedance-pH monitoring. This article discusses the technical details, clinical indications and applications of these diagnostic techniques.
General principles and requirements for ambulatory monitoring of gastroesophageal reflux disease
In patients who have GERD, the occurrence of both reflux episodes and symptoms can be intermittent, unpredictable, or related to type or intensity of physical activities or quantity and nature of meals. Furthermore, many patients show a significant daily variability in reflux and symptoms. Therefore, an ideal GER monitoring technique should be ambulatory and consist of a long-lasting continuous recording at an adequate sampling frequency to detect slow long-lasting and fast short-lasting reflux events that might eventually be associated with symptoms during the study period. The ambulatory technique should allow for normal physical activities and patients should be able to have their habitual meals.
Several relevant clinical parameters can be assessed with most GER monitoring techniques. A quantitative evaluation of the efficiency of the antireflux barrier is best performed analyzing the number of reflux events and proximal extent of reflux. The esophageal exposure time (percent of 24 hours) is the most frequently used parameter and expresses a combination of antireflux barrier and esophageal clearance failure. In addition, a more qualitative analysis of the relationship between reflux episodes and symptoms is mandatory, particularly in patients who have a normal esophageal exposure or number of reflux events. The most commonly used tools are the symptom index (SI) and the symptom association probability analysis (SAP). The statistical validity of the SAP makes this technique more beneficial.
pH monitoring
Esophageal pH monitoring is considered to be the gold standard for GER detection. Currently, it can be performed using either a catheter- or capsule-based wireless system. The catheter-based measurements are conventionally performed with the pH sensor located at 5 cm above the proximal border of the lower esophageal sphincter (LES) as determined with manometry. This position was chosen to decrease the risk for the pH sensor to slip into the stomach during swallow-induced shortening of the esophagus. This displacement does not occur with the wireless method, wherein the clipped capsule sensor locates the pH sensor at 5 to 6 cm above the squamocolumnar junction (SCJ) as previously determined endoscopically.
Catheter-Based Method
Catheter-based esophageal pH monitoring is the most widely available and commonly used method. The correct positioning of the catheter is achieved using either standard manometry before the test to determine the location of the LES or LES-locator pH catheters that have a pressure sensor in the tip.
The pH electrodes must be calibrated before and after the test using reference buffer solutions at pH 7 and 1. The patient wears a data-logger, which samples esophageal pH every 4 to 6 seconds (0.2 Hz) during the 24 hours of measurement. Compared with higher sampling frequencies (ie, 1 Hz), the current method can miss fast short-lasting reflux events of unknown clinical relevance, but the calculation of overall acid exposure time is not affected. Patients record symptoms, meal times, medications taken, and changes in position in a diary and on the data-logger. Patients are advised to eat their usual diet and perform usual activities on the day of the test.
Wireless Capsule Method
Experts recognize that patients may sometimes subconsciously alter their meals and physical activity during a catheter-based 24-hour pH monitoring. Therefore, a wireless pH monitoring method was recently devised that is more comfortable for patients and thus less likely to affect the pH measurement. A wireless capsule (Bravo system, Medtronic, Minneapolis, Minnesota) containing an antimony electrode transmits esophageal pH data through radiofrequency telemetry to an external receiver worn by the patient. The sampling frequency is every 6 seconds. The capsule containing the pH sensor is attached to the esophageal mucosa at 5 cm above the SCJ. The 95th percentile for esophageal acid exposure at 5 cm above the LES in control subjects using the Bravo system was 5.3%. This value is higher than reported in many studies using the catheter system. This difference seen in healthy controls may be caused by the increased tolerability of the capsule leading to less restriction in daily activities by the test subject. However, some patients experience a vague chest discomfort or foreign body sensation while the capsule is in place. Other disadvantages of the wireless pH system are the need for an endoscopy to determine the position of the SCJ and early capsule detachment.
Distal and Proximal Esophageal pH Monitoring
Ambulatory pH-metry is generally used to assess reflux in the distal esophagus. Proximal esophageal or pharyngeal pH-metry can be used to assess the proximal extent of acid reflux and its association with extraesophageal GERD symptoms.
The conventional location of the pH sensor to assess distal acid reflux is at 5 cm above the LES. This position was chosen to balance increasing the sensitivity of the test with decreasing false-positive measurements from possible displacement of the electrode into the stomach, particularly during a swallow.
Recent studies have compared the acid exposure at 5 cm above the LES with more distal locations in the esophagus, such as 1 cm above the SCJ. These studies showed numerous acid reflux episodes that reached the very distal esophagus but not the conventional study site at 5 cm. These episodes are called short-segment reflux episodes. Greater acid exposure in the most distal esophagus is compatible with the greater frequency of complications of GERD in this area compared with the more proximal esophagus. For example, short-segment Barrett’s esophagus is more common than long-segment.
Controversial data exist about the association of short-segment reflux episodes with symptoms. One study found that patients who had typical reflux symptoms, normal acid exposure at 5 cm above the LES, and a positive SAP for acid reflux have a better response to acid suppressive treatment than those with a negative SAP. These patients may have had short-segment acid reflux not detected using conventional pH-metry but responsive to acid suppressive therapy. However, further studies are required to determine the clinical relevance of short-segment reflux episodes. Moving the position of esophageal pH monitoring distal to the current one at 5 cm above the LES would likely increase sensitivity but decrease specificity and require clipping of the sensor to avoid the effect of esophageal shortening.
Measuring proximal esophageal pH has also been suggested in studying the relationship between oropharyngeal and respiratory symptoms to GER. The yield of proximal pH measurements is controversial. In addition, the location of the pH sensor in the proximal esophagus is often unreliable and inconsistent.
Duration of pH Monitoring
Currently, catheter-based pH monitoring is performed for 24 hours. The wireless capsule method has made it possible for patients to tolerate longer periods of recording. The Bravo capsule can generally record for 48 hours, although up to 10% to 15% of capsules detach from the esophageal mucosa sooner. Studies with 48 hours to 4 days of pH monitoring have shown daily variability in reflux episodes. This variability is likely caused by lifestyle and dietary factors.
Experts have suggested that multiple-day recording data could be analyzed as the average of the days or through reporting just the 24-hour period with the greatest esophageal acid exposure. The latter method leads to a significant increase in sensitivity and slight decrease in specificity compared with either the first 24 hours or the overall 48-hour data in patients who have GERD and controls. Prolonged studies increase the likelihood of finding positive reflux symptom associations and also allow evaluation of the effect of treatment (ie, study patients off and on proton pump inhibitor [PPI] therapy sequentially).
Conversely, some researchers have raised the possibility of reducing the pH testing period to less than 24 hours. Arora and colleagues performed a 3-hour postprandial pH test in patients who had GERD. Compared with a standard 24-hour ambulatory pH study, the 3-hour study had a sensitivity of 88% and specificity of 98%. Further studies are needed to confirm this and determine the optimal duration of pH monitoring.
Simultaneous Esophageal and Gastric pH Monitoring
The catheter-based method allows for simultaneous esophageal and gastric pH monitoring. The distal pH electrode can be located at the tip of the catheter and placed 10 cm distal to the proximal end of the LES. In patients taking a PPI, the information gathered from this electrode is twofold: whether the PPI adequately suppresses gastric acid secretion (keeping pH > 4) and whether nocturnal acid breakthrough occurs, defined as gastric pH less than 4 for a least 1 hour overnight. Studies have shown that single dose PPIs succeed in keeping gastric pH greater than 4 for less than 50% of the time, whereas twice-daily dosing increases the efficacy to 70% of the time. Ongoing controversy exists as to whether nocturnal acid breakthrough has any clinical relevance to GERD. Intragastric acid exposure does not seem to predict esophageal acid exposure. Furthermore, correlation between nocturnal acid breakthrough and esophageal reflux episodes and symptoms is poor.
pH Monitoring on Versus Off Proton Pump Inhibitor Therapy
Great debate exists about whether to perform pH monitoring on or off PPI. Generally, this decision depends on the reason for performing the test and the pretest probability of GERD. Many patients are referred for pH monitoring after they have already been prescribed PPIs by their primary care physician or another gastroenterologist. If the pretest probability of GERD in a patient is low, pH monitoring off PPI can help rule out GERD if the test and the symptom analysis are negative. Patients who do not have esophagitis who are being considered for a surgical or endoscopic antireflux procedure should also be tested off PPI. Off-PPI pH monitoring is more difficult to interpret when it is abnormal. Abnormal reflux is not necessarily the cause of the patient’s symptoms. In these instances, performing a symptom-reflux analysis is important to determine whether a relationship exists between the two.
If a patient has a high pretest probability of GERD with refractory typical symptoms while on an adequate dose of PPIs, it is useful to perform pH monitoring on PPI. Although uncommon, acid reflux can persist despite twice-daily PPIs in a minority of patients. These patients can then be managed with increased acid suppression or referral for a surgical antireflux procedure. However, most patients who have refractory symptoms on PPIs have a normal number of acid reflux episodes.
Currently, the American College of Gastroenterology practice guideline for esophageal reflux testing cites three reasons for performing pH monitoring on–PPI therapy: (1) ongoing abnormal esophageal acid exposure frequently occurs in patients taking once-daily PPI therapy; (2) patients who have more severe complications of reflux (higher grades of esophagitis and Barrett’s esophagus) have substantially lower rates of pH normalization, even on twice-daily PPI therapy; and (3) the diagnostic yield of pH-metry is greater in patients presenting with typical reflux symptoms than in those presenting with extraesophageal symptoms.
Reflux Symptom Association Analysis
An abnormal number of acid reflux episodes or increased acid exposure does not automatically imply that acid reflux is the cause of a patient’s symptoms. More importantly, a normal number of reflux events or normal acid exposure does not exclude reflux as the cause of symptoms. Several methods of symptom-reflux correlation have been devised. The SI is calculated by dividing the number of symptoms associated with an esophageal pH less than 4 by the total number of symptoms reported by the patient yielding a percentage of episodes that correlate with GER. This can be done for each particular symptom of the patient. The optimal sensitivity and specificity are obtained when an arbitrary 50% SI threshold is used. A limitation of the SI is that it does not account for the total number of reflux episodes and does not include a statistical validation procedure. Therefore, the likelihood of obtaining a positive SI by chance is significant. The SSI is calculated by dividing the total number of reflux episodes associated with symptoms by the total number of reflux episodes. However, the SSI is limited by not accounting for the total number of symptoms.
The SAP analysis divides the 24-hour period of monitoring into 2-minute intervals. Each interval is put into one of four categories: (1) reflux positive, symptom positive; (2) reflux positive, symptom negative; (3) reflux negative, symptom positive; and (4) reflux negative, symptom negative. A Fisher’s exact test is then performed, and an SAP value greater than 95% means that the association between symptoms and reflux can be attributed to chance less than 5% of the time. Unfortunately, all three indices are suboptimal in predicting response to PPIs. The results are better in certain groups of patients than in others. For example, patients who have normal esophageal exposure and a high SI for acid reflux experience better response to PPIs than similar patients who have a low SI.
Impedance-pH monitoring
While esophageal pH monitoring is considered the gold standard for gastroesophageal reflux detection, it may not accurately detect GER when little or no acid is present in the refluxate. Esophageal impedance monitoring is a technique that can be used to detect all types of GER (acidic, weakly acidic, and weakly alkaline).
This technique is based on the measurement of electrical impedance between closely arranged electrodes mounted on a thin intraluminal probe. Pairs of electrodes representing an impedance segment are connected to an impedance voltage transducer, which delivers a measuring current. The output of the measurement represents the electrical impedance around the catheter in the section between the pair of electrodes. The impedance is inversely proportional to the electrical conductivity of the luminal contents and the cross-sectional area between the two electrodes. Air has a low conductivity and yields an impedance increase, whereas swallowed or refluxed material has a high conductivity and yields an impedance drop. When the esophagus is empty, the impedance catheter measures the conductivity of the esophageal wall. As a result, impedance can be modified by mucosal inflammation and altered muscle tone. Furthermore, luminal dilation, such as induced by a bolus entering the measuring segment, results in an impedance drop, whereas luminal narrowing, such as during an occlusive contraction, causes an impedance increase.
Changes in temporal–spatial patterns in impedance are identified at various levels within the esophagus allowing differentiation between antegrade (ie, swallow) and retrograde (ie, reflux) bolus movement. In this way, impedance can be used to evaluate intraesophageal liquid movements (bolus transit tests and reflux monitoring) or gas movement (aerophagia and belching).
Animal and human validation studies have confirmed the high sensitivity and accuracy of impedance for reflux detection and tracking of intraesophageal bolus movement. However, impedance is very sensitive to small variations in intraluminal volumes of liquids and gas or catheter movements. Similar drops in impedance are observed with liquid boluses of 1 and 10 mL and fast rises in impedance may be caused by gas movement or catheter displacement from abrupt esophageal distension. Therefore, quantifying the volume of gastroesophageal reflux using impedance is not currently possible.
Definitions
Gastroesophageal reflux of liquid is detected as an orally progressing drop in impedance, starting at the level of the lower esophageal sphincter and propagating to more proximal impedance measuring segments. Gastroesophageal reflux of gas is detected as an almost simultaneous or rapidly orally progressing rise in impedance in at least two impedance segments. A recent consensus report provided a detailed nomenclature for reflux patterns detected by impedance-pH monitoring. An impedance-detected reflux episode is defined as acidic when the reflux episode decreases esophageal pH below 4 or reflux occurs when esophageal pH is already below 4. In cases where the pH falls by at least one unit, but does not fall below 4, it is called weakly acidic reflux ; weakly alkaline reflux denotes reflux episodes during which nadir esophageal pH does not drop below 7.
A clinically simpler classification considers acid (nadir pH < 4) and nonacid (nadir pH > 4) reflux. Nonacid reflux can further be separated into weakly acidic (nadir pH 4–7) or weakly alkaline (nadir pH ≥ 7).
The rationale for combining impedance and pH monitoring is to better characterize reflux episodes. Esophageal impedance identifies retrograde bolus movements (reflux) and makes it possible to detect the nature (liquid, gas, or mixed liquid–gas) and proximal extent of reflux. Impedance is a very sensitive technique for detecting individual reflux events (acidic or weakly acidic), and the typical impedance pattern of reflux matches consistently with reflux detected by other techniques, such as fluoroscopy.
Recent pediatric and adult studies have reported pH-only reflux events (related or not to swallowed acidic solutions) or, less frequently, slow drifts of pH from baselines around five to values below four. These changes are not accompanied by a typical impedance pattern of reflux but are associated with slow drifts in impedance in one or two channels. Formal analysis of nontypical impedance changes during pH-only drift events is needed to establish the definite sensitivity and specificity of impedance for diagnosing minute volumes of acid reflux. These findings suggest that combining impedance with pH monitoring is required to obtain the most complete evaluation of GER.
Impedance-pH Monitoring in Clinical Reflux Testing
Normal values for several parameters of impedance-pH monitoring have been determined using healthy asymptomatic adults and neonates. In healthy adults, the total rate of reflux episodes measured with impedance-pH is approximately 40 over 24 hours with a third being acid and two thirds weakly acidic and weakly alkaline. Impedance-pH monitoring shows good reproducibility both in stationary postprandial and 24-hour ambulatory conditions. Impedance-pH monitoring should be analyzed in a quantitative fashion, similar to 24-hour pH-metry, by searching for increased numbers of reflux episodes, prolonged acid or volume exposures, or increased numbers of proximal reflux events. In addition, particularly in patients on PPI, qualitative analysis of the reflux–symptom association, using SI or SAP, is mandatory. When analyzed in this fashion, the primary intent of the study is to confirm an unclear diagnosis of GERD and most investigators prefer to have withheld PPI therapy for 7 days leading into the study. In this context, the added yield of impedance-pH monitoring compared with conventional pH-metry is relatively slight. Nonetheless, impedance-pH monitoring provides the equivalent pH-metry information and adds for the possibility of detecting the occasional patient who has a positive association between heartburn or regurgitation and weakly acidic or gas reflux.
Refractory Gastroesophageal Reflux Disease
Impedance-pH monitoring is useful in reaching a diagnosis in patients with refractory GERD. For example, an American multicenter study of 168 patients who have refractory GERD used ambulatory impedance-pH monitoring on PPI and showed that 11% of patients had a positive SI for acid reflux and 37% had a positive SI for non–acid reflux.
A French-Belgian multicenter study found similar results and showed that adding impedance to pH monitoring improves the diagnostic yield by 15% to 20% and allows better symptom analysis than pH-metry alone. A recent study by Sharma and colleagues tried to further characterize symptoms in patients refractory to PPIs. It found that only 27% of the symptoms reported by patients on PPI during combined impedance-pH monitoring were typical of GERD (eg, heartburn, regurgitation). These typical symptoms were more likely to have a positive SI than atypical symptoms, such as throat clearing, indigestion, and belching.
Most patients whose symptoms are associated with weakly acidic reflux do not have an increased number of reflux events, suggesting that they have hypersensitivity of the esophagus to less-acidic refluxate. The most important factor associated with perception of weakly acidic reflux is high proximal extent, suggesting an increased sensitivity of the proximal esophagus in certain patients.
Erosive and Nonerosive Reflux Disease
Distal esophageal exposure to weakly acidic refluxate is similar in esophagitis and patients who have nonerosive reflux disease (NERD), supporting the notion that weakly acidic reflux is not associated with severe esophageal mucosal damage. In patients who have NERD, heartburn and regurgitation are mostly attributed to acid reflux. Recent studies assessed the role of weakly acidic and gas reflux in NERD.
Conchillo and colleagues found that patients who have esophagitis have more acid reflux in the supine position than those who have NERD, but both groups have identical patterns of non–acid reflux. Emerenziani and colleagues confirmed that most symptoms in patients who have NERD were related to acid reflux. However, these patients were more sensitive to weakly acidic reflux than those who had esophagitis, and the presence of gas in the refluxate significantly enhanced the probability of reflux perception.
Atypical Gastroesophageal Reflux Disease
The relationship between weakly acidic reflux and extraesophageal manifestations of GERD has been assessed with combined impedance-pH monitoring in adults and children. No data suggest an association between weakly acidic or gas reflux and episodes of noncardiac chest pain. Weakly acidic reflux was found to precede cough in a subgroup of adult patients who had unexplained chronic cough, and could also be relevant in patients post–lung transplantation. Preliminary studies using impedance-pH monitoring to assess laryngeal symptoms and globus suggest that an increased prevalence of high proximal extent of reflux and the presence of gas reflux episodes with weak acidity might underlie symptoms in these patients.
Antireflux Therapy
The objective evaluation of antireflux therapies in GERD includes demonstration of endoscopic healing or reduction in esophageal acid exposure during pH-metry. Combined impedance-pH monitoring adds the possibility of evaluating the reduction in acidic and weakly acidic reflux, the reduction in the proximal extent of reflux, and any modification in volume exposure of the distal esophagus.
Two recent studies used impedance-pH monitoring to evaluate postoperative reflux after Nissen fundoplication. The first study showed that the number of reflux events and the proximal extent of reflux were clearly diminished in patients who underwent surgery compared with healthy controls. The remaining postoperative reflux was nonacidic, and persistent symptoms in a subgroup of patients were associated with non–acid reflux. The second study compared reflux before and after surgery in similar patients and found a clear postoperative abolition of acidic and weakly acidic reflux after surgery. Two other studies suggest that impedance-pH monitoring may also predict favorable outcome with medical or surgical therapy. Both studies were uncontrolled and did not clearly describe whether symptoms were caused by remaining acidic reflux (that could be detected with simple pH-metry and treated with higher-dose PPI) or weakly acidic reflux (that could only be detected with impedance-pH monitoring).
Despite establishing some association, accepting the causal role of weakly acidic reflux in GERD symptoms may be premature until specific controlled outcome studies are available.
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