Esophageal and Airway pH Monitoring

Number: 0667

Policy

  1. Aetna considers esophageal pH monitoring medically necessary for any of the following indications:

    1. To detect refractory reflux in members with chest pain after cardiac evaluation using a symptom reflux association scheme, preferably the symptom association probability calculation (pH study done after a trial of proton pump inhibitor [PPI] therapy for at least 4 weeks); or
    2. To document abnormal esophageal acid exposure in an endoscopy-negative member being considered for surgical anti-reflux repair (pH study done after withholding anti-secretory drug regimen for more than 1 week); or
    3. To document concomitant gastro-esophageal reflux disease (GERD) in an adult onset, non-allergic asthmatic suspected of having reflux-induced asthma (pH study done after withholding anti-secretory drugs for more than 1 week).  Note: a positive test does not prove causality; or
    4. To evaluate a member with suspected otolaryngologic manifestations (chronic cough, laryngitis, pharyngitis) of GERD after symptoms have failed to respond to at least 4 weeks of PPI therapy (pH study done while the member continues taking their anti-secretory drug regimen to document the adequacy of therapy); or
    5. To evaluate vomiting in infants up to 3 months of age; or
    6. To evaluate members after anti-reflux surgery who are suspected to have ongoing abnormal reflux (pH study done after withholding anti-secretory drug regimen for more than 1 week); or
    7. To evaluate members with either normal or equivocal endoscopic findings and reflux symptoms that are refractory to PPI therapy (pH study done after withholding anti-secretory drug regimen for 1 week or more if the study is done to confirm excessive acid exposure or while taking the anti-secretory drug regimen if symptom-reflux correlation is to be scored).

    The disposable capsule pH monitor (Bravo pH Monitoring System) is considered an acceptable alternative to standard catheter-based ambulatory pH monitoring for the medically necessary indications listed above except for evaluating vomiting for infants. The Bravo pH Monitoring System is considered experimental and investigational for evaluating vomiting in infants because it has not been approved for use in this age group.

  2. Aetna considers esophageal pH recording experimental and investigational for all other indications, including any of the following indications because its effectiveness for these indications has not been established:

    1. To detect or verify reflux esophagitis in adults (this is an endoscopic diagnosis); or
    2. To evaluate “alkaline reflux” in adults; or
    3. To titrate PPI dosing in the management of Barrett's esophagus. 
  3. Aetna considers airway pH monitoring for detection of laryngo-pharyngeal reflux and other indications experimental and investigational because its effectiveness for these indications has not been established.

  4. Aetna considers multichannel intraluminal pH impedence testing medically necessary for evaluation of GERD in children and adolescents 18 years of age or younger.

  5. Aetna considers multichannel intraluminal impedance in the evaluation of GERD in adults experimental and investigational because there is inadequate evidence in the peer-reviewed published clinical literature regarding its effectiveness. Aetna considers mutichannel intraluminal impedance testing experimental and investigational for all other indications (e.g., achalasia, and laryngo-pharyngeal reflux). 

  6. Aetna considers pharyngeal pH monitoring experimental and investigational for diagnosis of extra-esophageal reflux disease because the effectiveness of this approach has not been established.

Background

Esophageal pH recording provides quantitative data on both esophageal acid exposure and on the correlation between patient symptoms and reflux events.  Despite these strengths, the inherent weakness of the technique is its inability to prove causality between symptoms and acid reflux.  Alternatively, causality is reasonably assumed in clinical practice by the alleviation of suspected reflux symptoms during a therapeutic trial of a proton pump inhibitor (PPI).  In view of this viable alternative, the AGA (2001) has concluded that the major indications for esophageal pH monitoring are in documenting the failure of either medical or surgical therapy.

For standard ambulatory esophageal pH monitoring, a nasogastric catheter fitted with a pH probe is inserted through the nose into the lower esophagus.  The catheter is attached to a data logger that is worn on the body.  The catheter is left in place for 24 to 48 hrs.  Over this period, the probe measures the amount of acid refluxing in the esophagus and the pattern of occurrence throughout the day.  The patient reports any symptoms, such as pain, waterbrash, wheezing and coughing, and their timing.  Some ambulatory pH monitors have a button for the patient to press when he/she is having symptoms in order to alert the physician reading the study that they were having symptoms at a particular time.  This helps the physician to determine if symptoms are related to acid reflux.

Because the use of a nasogastric catheter is awkward and distressing to the patient, a newer catheter-free approach has been developed (the Bravo pH Monitoring System, Medtronic, Minneapolis, MN) that uses a tiny disposable capsule pH monitor that is pinned to the lower esophagus via an endoscopic approach.  The capsule transmits pH data to a data logger that is worn on the body.  After several days, the disposable capsule is sloughed off the esophagus and passes out of the digestive tract.

An assessment of the evidence supporting catheterless esophageal pH monitoring by the National Institute for Health and Clinical Excellence (NICE, 2006) concluded that “[c]urrent evidence on the safety and efficacy of catheterless oesophageal pH monitoring appears adequate to support the use of this technique provided that normal arrangements are in place for consent, audit and clinical governance.”  The assessment noted that catheterless pH monitoring would be particularly appropriate in children and other patients who may not tolerate the nasal intubation required for catheter-based monitoring.  The assessment also noted that catheterless pH monitoring may be unsuitable for some patients, for example patients with pacemakers.

Dickman and Fass (2006) stated that "pH testing remains a commonly used evaluative tool in clinical practice.  However, the original tool that included a nasally placed pH catheter was plagued with a variety of shortcomings, primarily the effect of the procedure on patients' lifestyle and thus on reflux-provoking activities.  The miniaturization of evaluative techniques in gastroenterology was the impetus for the development of the wireless pH capsule and the SmartPill.  These modalities improve patients' tolerability of the required test and provide a unique opportunity for expansion of indications and data collection.  The introduction of the multi-channel intraluminal impedance with a pH sensor allowed the detection of gastroesophageal reflux (GER) that is non-acidic.  However, the value of the technique beyond the realm of academic gastroenterology remains to be elucidated.  Recently, there was a renewal of interest in Bilitec 2000.  The technique, which has never found a clear clinical role, has been recommended as an important tool in evaluating patients who failed PPI therapy.  However, data to support its clinical value in this situation have remained scant".

Wenner et al (2007) evaluated and compared the subjective experience of patients undergoing esophageal pH monitoring by means of the wireless pH capsule method or the conventional catheter-based method.  Using a randomized study design, patients referred for esophageal pH testing underwent both wireless and traditional catheter-based 24-hr pH recording with a 7-day interval.  The wireless pH capsule was placed during endoscopy and followed by 48-hr pH recording. All patients answered a questionnaire, including a 10-cm visual analog scale (VAS), which described the perceived severity of symptoms and the degree of interference with normal daily activities during the pH tests.  A total of 31 patients (16 women and 15 men) were included in the analysis.  The severity of all adverse symptoms associated with the wireless technique was significantly lower compared with the catheter-based technique (median VAS 2.1 versus 5.1, p < 0.001).  Wireless pH recording was associated with less interference with off-work activities and normal daily life, median VAS 0.6 and 0.7 compared with 5.0 and 5.7, respectively, for the catheter-based technique (p < 0.0001).  Patients actively working during both tests reported less interference with normal work during the capsule-based test than during the catheter-based pH test (median VAS 0.3 versus 6.8, p = 0.005).  Twenty-seven patients (87 %) stated that, if they had to undergo esophageal pH monitoring again, they preferred the wireless test over the catheter-based pH test (p < 0.0001).  The authors concluded that these findings showed that a significant majority of patients undergoing esophageal pH monitoring preferred the wireless pH capsule over the traditional catheter-based technique because of less adverse symptoms and less interference with normal daily life.

Davids and colleagues (2008) stated that laryngo-pharyngeal reflux (LPR) -- GER above the upper esophageal sphincter -- is a common problem encountered by otolaryngologists.  Despite consensus guidelines, the presentation, diagnosis, and treatment remain controversial.  These researchers surveyed Canadian otolaryngologists to assess current perspectives.  Web-based questionnaires were e-mailed to 135 otolaryngologists.  Respondents were categorized by subspecialty as head and neck (H&N) or non-H&N (rhinology, otology, laryngology, facial plastics, general and pediatric otolaryngology).  Data were analyzed to determine differences in proportions between groups.  The response rate was 48 of 135 otolaryngologists.  Symptoms considered to be strongly or moderately associated with LPR included globus sensation, excessive throat clearing, sore or burning throat, hoarseness, chronic cough, and dysphonia.  The laryngoscopic signs considered strongly associated with LPR were edema, intra-arytenoid changes, and granulomata.  The majority of otolaryngologists in both the H&N (12 of 15) and non-H&N groups (27 of 32) use flexible laryngoscopy for investigation and diagnosis of LPR.  Proton pump inhibitors in addition to lifestyle modifications are recommended by both groups as 1st- and 2nd-line therapy for an initial course of 6 to 12 weeks, with long-term therapy extended for 4 to 12 months.  The authors concluded that Canadian otolaryngologists do correlate specific signs and symptoms with LPR patients.  This is consistent across sub-specialties within the field.  Flexible fibre-optic laryngoscopy is the preferred diagnostic tool.  Although evidence based on randomized controlled trials has yet to demonstrate a reproducible, statistically significant improvement in LPR from treatment, 1st-line pharmacotherapy (in addition to lifestyle changes) is generally provided as a PPI, with the duration of therapy being somewhat variable and less than that recommended by the current literature.

Mel-S (2008) stated that LPR is a a widely recognized disorder in otolaryngological practice.  However, the signs and symptoms attributed to this disorder are non-specific and treatment is usually empirical.  The author noted that there is still much to learn about the pathophysiological mechanisms of LPR and there is still much controversy on diagnostic as well as therapeutic parameters for this condition.  There is no consensus on the diagnosis and treatment of LPR and the majority of clinicians depend mainly on clinical findings and empirical treatments rather than more specific investigations.  The author concluded that the concept of LPR is still controversial.  The current practice of empirical treatment with PPIs is based on weak evidence.  However, this practice seems to be widely accepted and will not change until further clinical and laboratory studies improve the understanding of this condition.

Gupta and Sataloff (2009) shared the same view on LPR as Mel-S (2008).  These investigators noted that despite numerous research efforts, the diagnosis and treatment of LPR remain elusive and unproven.  Acid-induced changes in laryngo-pharyngeal mucosa have been confirmed by histological evidence.  However, the implications of this for laryngeal signs and symptoms are unclear.  Diagnosis remains controversial, confounded by a lack of standardization and accepted evidence-based norms.  Whereas treatment is generally believed by clinicians to be effective in alleviating signs and symptoms attributed to LPR, incontrovertible data confirming efficacy are scarce.  Confounding the issues further, there are numerous studies that purport to show that various widely used treatments are not effective, although the scientific merit of virtually all of these studies has been challenged.  The authors concluded that LPR remains a controversial diagnosis.  Treatment with PPIs persists despite weak evidence supporting or refuting their utility, and well-designed studies are needed to understand diagnosis, treatment, pathyophysiology, and long-term health consequences of LPR and its treatment.

DiFiore et al (2005) examined the temporal relationship between apnea and gastro-esophageal reflux (GER) and assessed the effect of GER on apnea duration.  A total of 119 preterm infants underwent 12-hour cardiorespiratory monitoring studies using respiratory inductance plethysmography, heart rate, oxygen saturation (SaO2), and esophageal pH.  The studies were scored for GER (pH less than 4 for greater than or equal to 5 seconds) and apnea greater than or equal to 15 seconds or greater than or equal to 10 seconds that occurred within 30 seconds of GER.  Apnea greater than or equal to 10 seconds was used to assess whether GER would prolong apnea duration.  There were a total of 6,255 episodes of GER.  Only 1 % of GER episodes were associated with apnea greater than or equal to 15 seconds, and there was no difference in apnea rate before, during, or after GER.  There was also no difference in rate of apnea greater than or equal to 10 seconds before versus during GER; however, there was a decrease in apnea rate immediately after GER.  The presence of GER during apnea did not prolong apnea duration, and GER had no effect on the lowest SaO2 or heart rate during apnea.  The authors concluded that there is no evidence of a temporal relationship between acid-based GER and apnea in preterm infants.  In addition, GER does not prolong apnea duration and does not exacerbate the resultant decrease in heart rate and SaO2.  Moreover, the 2006 summary proceedings from the Apnea Prematurity Group of the National Institutes of Child Health and Human Development (Finer et al, 2006) termed the relationship between apnea of prematurity (AOP) and GERD unsubstantiated.

Slocum et al (2007) stated that GER and AOP are both common occurrences in premature infants.  However, a causal relationship between the 2 remains controversial.  Strong physiologic evidence indicates that a variety of protective reflex responses may elicit laryngeal adduction and apnea.  Although a potential link between GER and apnea may exist through this pathway, clinical studies can be cited to either support or refute such a link in premature infants.  The majority of GER episodes do not appear to be related to apnea.  In a specific subset of events, a causal relationship may exist.  Whether this is related to the character of the reflux episode or to a predisposition in a subpopulation of infants is unclear.  The authors presented the evidence for and against an association between GER and apnea, discussed techniques used in their evaluation, and identified approaches for future investigation.

Corvaglia et al (2009) evaluated the relationship between GER detected by combined multi-channel intraluminal impedance-pH measurement and AOP in 26 preterm infants.  Although the findings showed that 154 apneas out of 1,136 were triggered by GER (p = 0.034), the authors concluded that further studies are needed to recognize clinical features that identify those patients who are more susceptible to GER-triggered apneas.

The American College of Radiology's Appropriateness Criteria on "Vomiting in infants up to 3 months of age" (Bulas et al, 2011) stated that "The role of imaging in evaluating the vomiting infant is to define whether and where there is a point of anatomic obstruction.  Secondarily, one should note whether there is GER or delayed gastric emptying.  Diagnostic studies that are complementary to imaging examinations include esophageal pH monitoring, esophageal motility studies, endoscopic evaluation of the esophagus, and multichannel intraluminal impedance".

The AGA's medical position statement on the management of Barrett's esophagus (2011) noted that "The guideline developers recommend against attempts to eliminate esophageal acid exposure (proton pump inhibitors [PPIs] in doses greater than once daily, esophageal pH monitoring to titrate PPI dosing, or antireflux surgery) for the prevention of esophageal adenocarcinoma (strong recommendation, moderate-quality evidence)".

Multichannel Intraluminal Impedance (MII) technology was designed to allow characterization of bolus movement within the esophagus regardless of the pH level. It provides 2 testing modalities in the evaluation of GERD. Esophageal function testing (EFT) combines MII with standard pressure manometry. Gastroesophageal reflux (GER) monitoring (Sleuth) combines MII with standard pH testing. Combined manometry and impedance is intended to provide an assessment of esophageal function without the need for radiation. MII with pH is intended to determine whether a patient has non-acid reflux and help to determine why a patient continues to have symptoms while on adequate medical therapy. It also is intended to sort out which patients with continuing symptoms on medical therapy do not have reflux as the cause of their symptoms. Multichannel intraluminal impedance in combination with pH monitoring in the evaluation of GERD is considered investigational/experimental because there is inadequate evidence in the peer-reviewed published clinical literature regarding its effectiveness.

An AHRQ assessment on the management of gastroesophageal reflux disease (Ip, et al., 2011) concluded: "There is a lack of consensus among clinical practitioners around the issue of selecting the best diagnostic method to use, and its timing, in identifying acid and nonacid reflux during symptomatic episodes. The role of newer methods, such as impedance monitoring, needs to be examined in terms of impact in the areas of diagnosis and treatment."

A technology assessment of impedance monitoring in GERD by the Centre for Evidence-based Purchasing (Talboys, et al., 2010) found the evidence for impedance monitoring to be inconclusive: "Although there is some evidence to support the use of multi-channel intraluminal impedance-pH (MII-pH) measurements, the quality of the studies is generally poor. Most of the studies do not have any case controls and there is variation between studies in the equipment and criteria used for assigning patients into different sub-groups. High quality studies are required to determine the optimum testing protocol, on or off therapy. Only one poor quality study discussed the outcome of changing patient management following MII-pH investigation. At present the evidence is inconclusive for the use of MII-pH devices in patients with persistent symptoms while being treated for GORD."

An American Gastroenterology Association technical review on the management of GERD (Kahrilas, et al., 2008) stated: "Very little of the literature focused on testing management strategy trials but rather tended to demonstrate the capabilities of new technologies without rigorously testing the clinical validity of the result. This was especially true of impedance monitoring where, despite the large number of citations, there were no high-quality outcome trials. Hence, there was only one B-level recommendation regarding the reflux testing methodologies and it failed to distinguish among them; with respect to the unique capabilities of impedance monitoring, only an 'I' level recommendation could be made."

A guideline on surgical treatment of gastroesphageal reflux disease by the Society of American Gastrointestinal and Endoscopic Surgeons (2010) stated: "Based on the available evidence, the diagnosis of gastroesophageal reflux disease (GERD) can be confirmed if at least one of the following conditions exists: a mucosal break seen on endoscopy in a patient with typical symptoms, Barrett's esophagus on biopsy, a peptic stricture in the absence of malignancy, or positive pH-metry (Grade A). A newer test to objectively document gastroesophageal reflux is multichannel intraluminal esophageal impedance but the available evidence is insufficient to provide firm recommendations."

A critical review of esophageal impedance monitoring by Herbella (2012) found a lack of evidence for clinical utility of esophageal impedance measurements: "MII made great contributions for the understanding of esophageal physiology; however, direct clinical applications are few. MII-pH was expected to identify patients with normal acid reflux and abnormal nonacidic reflux. Unfortunately, these patients are rarely found off therapy, that is, nonacidic reflux parallels acid reflux; and the significance of isolated nonacidic reflux is unclear. Repeating words by Sifrim and Zerbib: 'Combined pH-impedance has little added value in patients ‘off’ therapy and virtually no outcome data exist to determine the optimal pH-impedance parameters.' The significance of bolus transit is elusive. MII-manometry findings that contradicts manometry lacks better understanding and clinical implication."

Guidelines from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Vandenplas, et al., 2009) indicated the use of multichannel intralumian esophageal impedance with pH monitoring for evaluation of the temporal relation between symptoms and gastroesophageal reflux in children. In children, pHMII is useful to correlate symptoms with reflux (particularly nonacid reflux), to quantify reflux during tube feedings and the postprandial period, and to assess efficacy of antireflux therapy."

Frohlich et al (2008) conducted a study in 24 patients aged 4 months to 23 years to evaluate GERD and it's association with gastrointestinal or extraintestinal symptoms using combined multichannel intraluminal impedance  and pH measurement. The 24 hour multichannel intraluminal impedance and pH measurement evaluation was performed with a single catheter comprised of 6 impedance channels and 1 pH channel. The authors detected a total of 911 episodes of retrograde bolus movement, including 379 acidic and 532 weakly acidic bolus movements. Of the 201 symptom events recorded, 42% were associated with retrograde bolus movements, 24% with weakly acidic reflux, and 16% with acid reflux episodes.  Esophageal atresia patients showed significantly fewer complete swallows of liquid than patients without esophageal surgery (42% vs 98%).  The authors concluded that in patients with corrected esophageal atresia, half of the reflux events could be detected only by multichannel intraluminal impedance and that weakly acidic reflux can be responsible for the patients' syumptoms. However, the authors also noted that patients may have few or no symptoms despite poor esophageal function and extensive GERD.

Di Pace et al (2011) described the use of impedance measurements in healthy children and in a pediatric population with GERD. The authors evaluated 60 children who submitted to multichannel intraluminal impedance pH monitoring for 24 hours for suspected GERD.  The results showed that patients fell into two groups, one being acid GERD and a second group which had negative multichannel intraluminal impedance pH monitoring analysis for GERD, despite being symptomatic.  The group showing acid GERD had a median mean acid clearing time of 151 seconds and a median mean bolus clearing time of 25 seconds. The group which was neative per the multichannel intraluminal impedance pH monitoring analysis had normal values. The authors concluded that multichannel intraluminal impedance pH monitoring is "an ideal test in children because it studies GER[D]with its characteristics and motility pattern."

Catalano et al (2011) evaluated 22 children treated for esophageal atresia at birth and 20 normal children of similar age with suspected GERD using multichannel intraluminal impedance and pH measurement. The goal of the study was to evaluate characteristics of GERD and esophageal clearance in children treated for esophageal atresia with distal tracheoesophageal fistula.  A significant diference was found between the two groups, with  the median mean bolus clearing time and mean acid clearing time longer in the esophageal atresia group.Thus, the investigators concluded that the incidence of GERD may be underestimated if pH - metry is used and that the pH multichannel intraluminal impedance is an ideal test in children because it studies GERD both for its characteristics and its motility pattern.

Salvatore et al (2013) analyzed the age effect on impedance baseline in multichannel intraluminal impedance testing in a large population of pediatric patients. A total of 816 children with GERD symptoms were evaluated using multichannel intraluminal impedance testing, with mean impedance baseline automatically calculated in the different multichannel intraluminal impedance channels through 24 hour tracings. Mean inpedance baseline was significantly lower in younger compared with older children up to 48 months (P < 0.001). The mean increase of impedance baseline per month was 2.9 in the group positive for multichannel intraluminal impedance testing and 2.3 in the group with normal tested values. From 48 months onward, there was no significant difference between the two groujps. The authors concluded that impedance baseline is significantly lower in infants compared with older children and that low impedance baseline in both the proximal and distal esophagus in young infants may be related to anatomical and functional differences due to etiologies other than the presence of esophagitis.

Although recent studies have provided some encouraging data regarding use of multichannel intraluminal impedance testing in achalasia, further studies in a wider group of patients with achalasia are needed (Burgess & Wyeth, 2011).

Multichannel Intraluminal Impedance Testing Laryngo-Pharyngeal Reflux

Wan and associates (2014) sought a deeper and more comprehensive understanding of 2 major diagnostic methods for laryngo-pharyngeal reflux (LPR) by exploring whether and how differences exist before and after treatment between patients diagnosed by either Reflux Symptom Index (RSI) and Reflux Finding Score (RFS) or 24-hour pH monitoring.  Two groups of patients with confirmed LPR disease (LPRD) by either a combination of RSI and RFS (Questionnaire group, 35 patients) or 24-hour MII-pH monitoring (pH Group, 23 patients) were recruited.  All patients were prescribed esomeprazole 20 mg twice-daily for 1 month; RSI, RFS, and acoustic parameters before and after treatment were compared between the 2 groups.  Intrinsic correlations involving multiple parameters were investigated as well.  Except for excess throat mucus (p = 0.019) and subglottic edema (p = 0.042), most RSI and RFS items before treatment were not significantly different between the Questionnaire and pH Groups, and nearly all such items in both groups exhibited distinct remission after therapy (p < 0.05).  Absolute value of remission in RSI after treatment was more prominent in pH Group than in the Questionnaire group (p = 0.007).  Jitter (p = 0.252), shimmer (p = 0.815), and harmonics-to-noise ratio (p = 0.117) descended to normal value after treatment.  Moderate-to-high levels of correlation were found between the patient's original status and the absolute value of remission in most items of RSI and RFS as well as voice parameters.  The authors concluded that 24-hour MII-pH monitoring and a combination of RSI and RFS were quite competitive with each other in selecting LPRD patients.  Although treatment worked out on nearly all the symptoms, laryngeal images and voice parameters, 24-hour MII pH appeared to be more promising in a greater symptom relief.  The extent of relief that could take place in most of the measurements was considerably determined by their initial status.

In a prospective cohort study without controls, Kim and colleagues (2017) evaluated the association between the parameters of 24-hour MII-pH monitoring and the symptoms or quality of life (QoL) in patients with LPR.  A total of 45 patients were selected from subjects who underwent 24-hour MII-pH monitoring and were diagnosed with LPR from September 2014 to May 2015.  Outcome measures included RSI, health-related QoL (HRQoL), short form 12 (SF-12) survey questionnaires.  Spearman's correlation was used to analyze the association between the symptoms or QoL and 24-hour MII-pH monitoring.  Most parameters in 24-hour MII-pH monitoring showed weak or no correlation with RSI, HRQoL and SF-12.  Only number of non-acid reflux events that reached the larynx and pharynx (LPR-non-acid) and number of total reflux events that reached the larynx and pharynx (LPR-total) parameters showed strong correlation with heart-burn in RSI (R = 0.520, p < 0.001, R = 0.478, p = 0.001, respectively).  Multiple regression analysis showed that there was only 1 significant regression coefficient between LPR-non-acid and voice/hoarseness portion of HRQoL (b = 1.719, p = 0.022).  The authors concluded that most parameters of 24-hour MII-pH monitoring did not reflect subjective symptoms or QoL in patients with LPR. 

Furthermore, an UpToDate review on “Laryngopharyngeal reflux” (Franco, 2018) does not mention multichannel intraluminal impedance testing as a diagnostic tool.

Pharyngeal pH Monitoring in the Diagnosis of Extraesophageal Reflux in Children

Chiou and associates (2011) noted that oropharyngeal (OP) pH monitoring has been developed as a new way to diagnose supra-esophageal gastric reflux (SEGR), however, this approach has not been well-validated.  these investigators examined the correlation between OP pH and GER events detected by MII-pH.  A total of 15 patients (11 males, median age of 10.8 years) with suspected GER were prospectively evaluated with ambulatory 24-hour OP pH monitoring (positioned at the level of the uvula) and concomitant esophageal MII-pH monitoring.  Potential OP events were identified by the conventional pH threshold of less than 4 and by the following alternative criteria: relative pH drop of greater than 10 % from 15-min baseline; and absolute pH drop below thresholds of less than 5.5, 5.0, and 4.5.  The 2-min window preceding each OP event was analyzed for correlation with an episode of GER detected by MII-pH.  A total of 926 GER events were detected by MII-pH.  Application of alternative pH criteria increased the identification of potential OP pH events; however, a higher proportion of OP events had no temporal correlation with GER (45 to 81 %), compared with the conventional definition of pH of less than 4 (40 %).  A total of 306 full-column acid reflux episodes were detected by MII-pH, of which 10 (3.3 %) were also identified by OP pH monitoring.  The authors concluded that findings of this study indicated that traditional acid reflux (pH less than 4) to the level of the oropharynx is rare, even in children with suspected reflux.  Application of extended pH criteria significantly increased the detection of pH events in the oropharynx qualifying as SEGR.  However, the majority of acidic and weakly-acidic changes in OP pH were not temporally correlated with GER episodes, especially when subjects were in the supine position, suggesting that they may be artifactual and occurred independently of reflux.  Thus, 24-hour pH monitoring of the oropharynx without concurrent esophageal monitoring may over-estimate the presence of SEGR in children.  Future studies are needed to determine the optimal pH criteria for oropharyngeal pH events, and whether oropharyngeal monitoring could be used to more accurately identify patients with abnormal SEGR.

The authors stated that this study had several drawbacks.  First, these researchers were unable to confirm whether full-column episodes extended proximally above the upper esophageal sphincter (UES) in order to be truly considered supra-esophageal.  Indeed, episodes of reflux which reached the proximal-most pair of impedance sensors but remained distal to the UES may or may not result in a significant change in OP pH.  Furthermore, because of the fixed spacing of sensors on the impedance catheter, these investigators were unable to standardize the gap in distance between the proximal sensor and the OP pH electrode, which was consistently placed at the level of the uvula.  This may have accounted for some of the variability in correlation between esophageal and OP measurements.  Although this limitation may have led to an under-estimation of the Restech probe’s sensitivity for full-column acid reflux, it was clearly unrelated to the Restech’s probe’s poor specificity (i.e., 40 to 81 % of oropharyngeal events had no correlation with any reflux detected by MII-pH).  Future studies should consider incorporating pharyngeal impedance in order to better characterize changes in OP pH in the context of liquid or gaseous reflux in areas above the UES.  Second, because there was no separate control group, these researchers could not comment directly on how the frequency of oropharyngeal reflux in children with suspected reflux compared with healthy controls.  Although normative data are helpful in establishing optimal pH criteria, this was not within the scope this study.  Aside from the challenges of performing invasive tests on healthy children, the authors chose to focus on children with suspected GER in order to maximize encounters with potential SEGR events and gain information regarding the relationship between OP pH and GER.  Finally, the use of 2 different technologies together raised the possibility of differences in pH sampling rates as well as lack of synchronization between studies leading to errors in correlation.  These researchers employed several measures in their protocol to ensure that the 2 probes were electronically synchronized.  Furthermore, the addition of esophageal impedance monitoring allowed these investigators to detect the presence of all GER episodes, independent of the distal pH probe.

Plocek and colleagues (2019) stated that various clinical symptoms are attributed to extra-esophageal reflux disease (EERD).  Multi-channel intraluminal impedance-pH monitoring (MII-pH) is considered to correlate symptoms with acid and non-acid GER events.  Pharyngeal pH monitoring (Dx-pH) is considered to correlate the decrease in the pH level in the oropharynx with reported symptoms and to diagnose supra-esophageal reflux.  These researchers examined the correlation between acid reflux episodes recorded by Dx-pH and GER detected via MII-pH in children with suspected EERD.  The study enrolled 23 consecutive children (15 boys and 8 girls; median age of 8.25 [range of 3 to 16.5] years) with suspected EERD.  MII-pH and Dx-pH were conducted concurrently in all patients.  A total of 1,228 reflux episodes were recorded by MII-pH.  With the antimonic sensor placed inside the impedance probe, 1,272 pH-only reflux episodes were recorded.  Of these, 977 (76.81 %) were associated with a retrograde bolus transit.  Regarding GER, 630 full-column episodes extended to the most proximal pair of impedance sensors; 500 (83.33 %) demonstrated an acidic character.  The following acid reflux numbers were determined by the Dx-pH system: for pH less than 4, n = 126; pH less than 4.5, n = 136; pH less than 5, n = 167; and pH less than 5.5, n = 304, and for a decrease in pH of greater than 10 % relative to the baseline, n = 324.  There was no significant correlation between the number of pharyngeal reflux episodes detected by Dx-pH and that of GERs identified by MII-pH.  The proportion of oropharyngeal pH events that were temporally related to a GER episode increased with the extended pH criteria.  The highest proportion was observed for a pH decrease of greater than or equal to 10 % from the baseline and did not exceed 5.2 %.  The application of the extended pH criteria in the Dx-pH system resulted in an increase in the number of diagnosed laryngo-pharyngeal refluxes; most were not temporally associated with GER episodes confirmed by MII-pH.  Thus, the authors concluded that the efficacy of the exclusive application of Dx-pH for supra-esophageal gastric reflux diagnosis is uncertain.


Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Esophageal pH Monitoring:

CPT codes covered when selection criteria are met:

91034 Esophagus, gastroesophageal reflux test; with nasal catheter pH electrode(s) placement, recording, analysis and interpretation
91035     with mucosal attached telemetry pH electrode placement, recording, analysis and interpretation

ICD-10 codes covered if selection criteria are met:

J02.0 - J02.9 Acute pharyngitis
J04.0 Acute laryngitis
J31.2 Chronic pharyngitis
J37.0 Chronic laryngitis
J45.20 - J45.50 Intermittent and persistent asthma, uncomplicated
K21.9 Gastro-esophageal reflux disease without esophagitis
R05 Cough
R07.9 Chest pain, unspecified

ICD-10 codes not covered for indications in the CPB:

K21.0 Gastro-esophageal reflux disease with esophagitis
K22.70 - K22.719 Barrett's esophagus
P28.3 - P28.4 Primary and other apnea of newborn
P92.01 - P92.09 Bilious and other vomiting in newborn
R11.10 - R11.14 Vomiting
R11.2 Nausea with vomiting, unspecified

Airway pH Monitoring:

There is no specific code for airway pH monitoring:

Multichannel intraluminal impedance in combination with pH monitoring, 19 years and older:

CPT codes not covered for indications in the CPB:

91037 Esophageal function test, gastroesophageal reflux test with nasal catheter intraluminal impedance electrode(s) placement, recording, analysis and interpretation
91038 Esophageal function test, gastroesophageal reflux test with nasal catheter intraluminal impedance electrode(s) placement, recording, analysis and interpretation; prolonged (greater than 1 hour, up to 24 hours)

ICD-10 codes covered if selection criteria are met:

K21.9 Gastro-esophageal reflux disease without esophagitis [covered for patients 12 years of age or younger; not covered for adolescents and adults]

ICD-10 codes not covered for indications listed in the CPB:

J38.7 Other diseases of larynx [laryngo-pharyngeal reflux]
J39.2 Other diseases of larynx [laryngo-pharyngeal reflux]

Multichannel intraluminal impedance in combination with pH monitoring, 0 - 18 years of age :

CPT codes covered when selection criteria are met :

91037 Esophageal function test, gastroesophageal reflux test with nasal catheter intraluminal impedance electrode(s) placement, recording, analysis and interpretation
91038 Esophageal function test, gastroesophageal reflux test with nasal catheter intraluminal impedance electrode(s) placement, recording, analysis and interpretation; prolonged (greater than 1 hour, up to 24 hours)

ICD-10 codes covered for indications listed in the CPB:

K21.9 Gastro-esophageal reflux disease without esophagitis
R05 Cough [frequent or persistent cough]
R06.2 Wheezing [frequent or persistent wheezing]
R10.0 - R10.13, R10.30 - R10.9 Abdominal pain
R11.11 Vomiting without nausea [frequent or recurrent vomiting] [regurgitation and re-swallowing]
R12 Heartburn
R14.0 - R14.3 Flatulence and related conditions
R43.8 Other disturbances of smell and taste [sour mouth]
R62.50 Unspecified lack of expected normal physiological development in childhood [poor growth]
R63.3 Feeding difficulties [difficulty eating]

ICD-10 code not covered for indications in the CPB (not all inclusive):

J38.7 Other diseases of larynx [laryngo-pharyngeal reflux]
J39.2 Other diseases of pharynx [laryngo-pharyngeal reflux]
K22.0 Achalasia of cardia

Pharyngeal pH Monitoring:

CPT codes not covered for indications in the CPB:

Pharyngeal pH monitoring – no specific code:

ICD-10 codes not covered for indications listed in the CPB:

K21.9 Gastro-esophageal reflux disease without esophagitis [extra-esophageal reflux disease]

The above policy is based on the following references:

  1. American Gastroenterological Association (AGA). American Gastroenterological Association medical position statement: Guidelines on the use of esophageal pH recording. Gastroenterology. 1996;110(6):1981 (reviewed 2001).
  2. Kahrilas PJ, Quigley EMM. Clinical esophageal pH recording: A technical review for practice guideline development. Gastroenterology 1996;110:1982-1996.
  3. British Society of Gastroenterology (BSG). Guidelines for oesophageal manometry and pH monitoring. Clinical Practice Guidelines. London, UK: BSG; 1996. 
  4. Pandolfino JE, Richter JE, Ours T, et al. Ambulatory esophageal pH monitoring using a wireless system. Am J Gastroenterol. 2003;98(4):740-749.
  5. DeVault KR, Castell DO and the Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. American College of Gastroenterology Treatment Guidelines. Am J Gastroenterol. 1999;94(6):1434-1442.
  6. Streets CG, DeMeester TR. Ambulatory 24-hour esophageal pH monitoring: Why, when, and what to do. J Clin Gastroenterol. 2003;37(1):14-22.
  7. Soll AH, Fass R. Gastroesophageal reflux disease: Presentation and assessment of a common, challenging disorder. Clin Cornerstone. 2003;5(4):2-14; discussion 14-17.
  8. DiMarino AJ Jr, Cohen S. Clinical relevance of esophageal and gastric pH measurements in patients with gastro-esophageal reflux disease (GERD). Curr Med Res Opin. 2005;21(1):27-36.
  9. Jiang SP, Huang LW. Role of gastroesophageal reflux disease in asthmatic patients. Eur Rev Med Pharmacol Sci. 20059(3):151-160.
  10. Irwin RS. Chronic cough due to gastroesophageal reflux disease: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl):80S-94S.
  11. 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(1):20-24.
  12. National Institute for Health and Clinical Excellence (NICE). Catheterless oesophageal pH monitoring. Interventional Procedure Guidance 187. London, UK: NICE; July 2006.
  13. BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). Special report: Wireless esophageal pH monitoring. TEC Assessment Program. Chicago, IL: BCBSA; May 2006;21(2).
  14. Dickman R, Fass R. Ambulatory esophageal pH monitoring: New directions. Dig Dis. 2006;24(3-4):313-318.
  15. Wenner J, Johnsson F, Johansson J, Oberg S. Wireless esophageal pH monitoring is better tolerated than the catheter-based technique: Results from a randomized cross-over trial. Am J Gastroenterol. 2007;102(2):239-245.
  16. Hirano I, Richter JE; Practice Parameters Committee of the American College of Gastroenterology. ACG practice guidelines: Esophageal reflux testing. Am J Gastroenterol. 2007;102(3):668-685.
  17. Semeniuk J, Kaczmarski M. 24-hour esophageal pH-monitoring in children suspected of gastroesophageal reflux disease: Analysis of intraesophageal pH monitoring values recorded in distal and proximal channel at diagnosis. World J Gastroenterol. 2007;13(38):5108-5115.
  18. Croffie JM, Fitzgerald JF, Molleston JP, et al. Accuracy and tolerability of the Bravo catheter-free pH capsule in patients between the ages of 4 and 18 years. J Pediatr Gastroenterol Nutr. 2007;45(5):559-563.
  19. Davids T, Sommer DD, Armstrong D. Survey of current perspectives on laryngopharyngeal reflux among Canadian otolaryngologists. J Otolaryngol Head Neck Surg. 2008;37(2):196-202.
  20. Ali Mel-S. Laryngopharyngeal reflux: Diagnosis and treatment of a controversial disease. Curr Opin Allergy Clin Immunol. 2008;8(1):28-33.
  21. Gupta R, Sataloff RT. Laryngopharyngeal reflux: Current concepts and questions. Curr Opin Otolaryngol Head Neck Surg. 2009;17(3):143-148.
  22. Lacy BE, Edwards S, Paquette L, et al. Tolerability and clinical utility of the Bravo pH capsule in children. J Clin Gastroenterol. 2009;43(6):514-519.
  23. Monkemüller K, Neumann H, Fry LC, et al. Catheter-free pH-metry using the Bravo capsule versus standard pH-metry in patients with non-erosive reflux disease (NERD). Z Gastroenterol. 2009;47(4):351-356.
  24. Di Fiore JM, Arko M, Whitehouse M, et al. Apnea is not prolonged by acid gastroesophageal reflux in preterm infants. Pediatrics. 2005;116(5):1059-1063.
  25. Finer NN, Higgins  R, Kattwinkel J, Martin RJ. Summary proceedings from the Apnea-of-Prematurity Group. Pediatrics. 2006;117(Supplement 1):S47-S51. 
  26. Slocum C, Hibbs AM, Martin RJ, Orenstein SR. Infant apnea and gastroesophageal reflux: A critical review and framework for further investigation. Curr Gastroenterol Rep. 2007;9(3):219-224.
  27. Corvaglia L, Zama D, Gualdi S, et al. Gastro-oesophageal reflux increases the number of apnoeas in very preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94(3):F188-F192.
  28. Pilic D, Frohlich T, Noh F, et al. Detection of gastroesophageal reflux in children using combined multichannel intraluminal impedance and pH measurement: Data from the German Pediatric Impedance Group. J Pediatr. 2011;158(4):650-654.
  29. Bulas D, McGrane SL, Coley BD, et al, Expert Panel on Pediatric Imaging. ACR Appropriateness Criteria® vomiting in infants up to 3 months of age. [online publication]. Reston, VA: American College of Radiology (ACR); 2011.
  30. American Gastroenterological Association, Spechler SJ, Sharma P, Souza RF, et al. American Gastroenterological Association medical position statement on the management of Barrett's esophagus. Gastroenterology 2011;140(3):1084-1091.
  31. Blanco FC, Davenport KP, Kane TD. Pediatric gastroesophageal reflux disease. Surgical Clinics of North America. 2012;92(3:541-558.
  32. Cappell MS. Clinical presentation, diagnosis, and management of gastroesophageal reflux disease. Medical Clinics of North America. 2005;89(2):243-291.
  33. Carroll TL, Fedore LW, Aldahlawi MM. pH Impedance and high-resolution manometry in laryngopharyngeal reflux disease high-dose proton pump inhibitor failures. Laryngoscope. 2012;122(11): 2473-2481.
  34. Castell DO, Mainie I, Tutuian R. Non-acid gastroesophageal reflux: documenting its relationship to symptoms using multichannel intraluminal impedance (MII). Trans Am Clin Climatol Assoc. 2005;116:321-333; discussion 333-334.
  35. Castell DO, Vela M. Combined multichannel intraluminal impedence and ph-metry: An evolving technique to measure type and proximal extent of esophageal reflux. The American Journal of Medicine. 2001;111(Suppl 8A):157S-159S.
  36. Condino AA, Sondheimer J, Pan Z, et al. Evaluation of infantile acid and nonacid gastroesophageal reflux using combined pH monitoring and impedance measurement. J Pediatr Gastroenterol Nutr. 2006;42(1):16-21.
  37. Cresi F, Locatelli E, Marinaccio C, et al. Prognostic values of Multichannel Intraluminal Impedance and pH monitoring in newborns with symptoms of gastroesophageal reflux disease. J Pediatr. 2013;162(Issue 4):.
  38. 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(9):2159-2165.
  39. Del Genio, et al. Prospective assessment of patient selection for antireflux surgery by combined multichannel intraluminal impedance pH monitoring. J Gastrointest Surg, 12(9): 1491-6  2008.
  40. Di Pace MR, Caruso AM, Farina F, et al. Evaluation of esophageal motility and reflux in children treated for congenital diaphragmatic hernia with the use of combined multichannel intraluminal impedance and pH monitoring. J Pediatr Surg. 2011;46(10):1881-1886.
  41. Di Pace MR, Caruso AM, Catalano P, et al. Evaluation of esophageal motility and reflux in children treated for esophageal atresia with the use of combined multichannel intraluminal impedance and pH monitoring. J Pediatr Surg. 2011;46(3):443-451.
  42. Di Pace MR, Caruso AM, Catalano P, et al. Evaluation of esophageal motility using multichannel intraluminal impedance in healthy children and children with gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52(1):26-30.
  43. Fike FB, Pettiford JN, St Peter SD, et al. Utility of pH/multichannel intraluminal impedance probe in identifying operative patients in infants with gastroesophageal reflux disease. J Laparoendosc Adv Surg Tech A. 2012;22(5):518-520.
  44. Francavilla R, Magista AM, Bucci N, et al. Comparison of esophageal pH and multichannel intraluminal impedance testing in pediatric patients with suspected gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2010;50(2):154-160.
  45. Gawron AJ, Rothe J, Fought AJ, et al. Many patients continue using proton pump inhibitors after negative results from tests for reflux disease. Clin Gastroenterol Hepatol. 2012;10(6):620-625.
  46. Hajar N, Castell DO, Ghomrawi H, et al. Impedance pH confirms the relationship between GERD and BMI. Dig Dis Sci. 2012;57(7):1875-1879.
  47. Hila A, Agrawal A, Castell D.. 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(2):172-177.
  48. Kline MM, Ewing M, Simpson N, Laine L. The utility of intraluminal impedance in patients with gastroesophageal reflux disease-like symptoms but normal endoscopy and 24-hour pH testing. Clin Gastroenterol Hepatol. 2008;6(8):880-885; quiz 836.
  49. Loots CM, van Wijk MP, Blondeau K, et al. Interobserver and intraobserver variability in pH-impedance analysis between 10 experts and automated analysis. Journal of Pediatrics. 2012;160(3):441-446.
  50. Loots CM, Benninga MA, Davidson GP, Omari TI. Addition of pH-impedance monitoring to standard pH monitoring increases the yield of symptom association analysis in infants and children with gastroesophageal reflux. J Pediatr. 2009;154(2):248-252.
  51. Malhotra A, Freston JW, Aziz K. Use of pH-impedance testing to evaluate patients with suspected extraesophageal manifestations of gastroesophageal reflux disease. J Clin Gastroenterol. 2008;42(3):271-278.
  52. Mattioli G, Pini-Prato A, Gentilino V, et al. Esophageal impedance/pH monitoring in pediatric patients: preliminary experience with 50 cases. Dig Dis Sci. 2006;51(12):2341-2347.
  53. Pandolfino JE, Vela MF. Esophageal-reflux monitoring. Gastrointestinal Endoscopy. 2009;69(4):917-930.
  54. Park W, Vaezi MF. Esophageal impedance recording: clinical utility and limitations. Curr Gastroenterol Rep. 2005;7(3):182-189.
  55. Pilic D, Frohlich T, Noh F, e al. Detection of gastroesophageal reflux in children using combined multichannel intraluminal impedance and pH measurement: Data from the German Pediatric Impedance Group. J Pediatr. 2011;158(4):650-654.
  56. ASGE Technology Committee, Wang A, Pleskow DK, Banerjee S, et al. Esophageal function testing. Gastrointestinal Endoscopy. 2012;76(2):231-243.
  57. Rosen R, Hart K, Nurko S. Does reflux monitoring with multichannel intraluminal impedance change clinical decision making? J Pediatr Gastroenterol Nutr. 2011;52(4):404-407.
  58. Rosen R, Lord C, Nurko S. The sensitivity of multichannel intraluminal impedance and the pH probe in the evaluation of gastroesophageal reflux in children. Clin Gastroenterol Hepatol. 2006;4(2):167-172.
  59. Shay SS, Bomeli S, Richter J. Multichannel intraluminal impedance accurately detects fasting, recumbent reflux events and their clearing. Am J Physiol Gastrointest Liver Physiol. 2002;283(2):G376-G383.
  60. Tutuian R, Castell DO. Reflux monitoring: role of combined multichannel intraluminal impedance and pH. Gastrointest Endosc Clin N Am,. 2005;15(2):361-371.
  61. Villa N, Vela MF. Impedance-pH testing. Gastroenterology Clinics. 2013;42(1):17-26.
  62. Wenzl TG,  Loots CM, Salvatore S, Vandenplas Y; ESPGHAN EURO-PIG Working Group. Indications, methodology, and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol. J Pediatr Gastroenterol Nutr. 2012;55(2):230-234.
  63. Woodley FW, Mousa H. Acid gastroesophageal reflux reports in infants: a comparison of esophageal pH monitoring and multichannel intraluminal impedance measurements. Dig Dis Sci. 2006;51(11):1910-1916.
  64. Vandenplas Y, Rudolph CD, Di Lorenzo C, et al.; North American Society for Pediatric Gastroenterology Hepatology and Nutrition, European Society for Pediatric Gastroenterology Hepatology and Nutrition. Pediatric gastroesophageal reflux clinical practice guidelines: Joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. 2009;49(4):498-547.
  65. Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Guidelines for surgical treatment of gastroesophageal reflux disease. Los Angeles, CA: Society of American Gastrointestinal and Endoscopic Surgeons (SAGES); 2010.
  66. Ip S, Chung M, Moorthy D, et al. Comparative Effectiveness of Management Strategies for Gastroesophageal Reflux Disease: Update. Comparative Effectiveness Review No. 29. Prepared by Tufts Medical Center Evidence-based Practice Center under Contract No. HHSA 290-2007-10055-I. AHRQ Publication No. 11-EHC049-EF. Rockville, MD: Agency for Healthcare Research and Quality; September 2011.
  67. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology. 2008;135(4):1383-1391, 1391.e1-5.
  68. Frohlich T, Otto S, Weber P et al. Combined esophageal multichannel intraluminal impedance and pH monitoring after repair of esophageal atresia. J Pediatr Gastroenterol Nutr. 2008;47(4):443-449.
  69. Talboys M, Carolan-Rees G, Williams J, et al.; National Health Service (NHS), Purchasing and Supply Agency, Centre for Evidence-based Purchasing. Oesophageal multichannel intra-luminal impedance and pH measurement. Evidence Review. CEP10028. Cardiff, UK: Cardiff Medicentre, Clinical Engineering Device Assessment and Reporting (CEDAR); March 2010.
  70. Sifrim D, Zerbib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut. 2012;61(9):1340-1354.
  71. Herbella FAM. Critical analysis of esophageal multichannel intraluminal impedance monitoring 20 years later. ISRN Gastroenterol. 2012;2012(903240).
  72. Di Pace MR, Caruso AM, Catalano P, et al. Evaluation of esophageal motility using multichannel intraluminal impedance in healthy children and children with gastroesophageal reflux. J Pediatri Gastroenterol Nutr. 2011;51(1):26-30.
  73. Catalano P, Di Pace MR, Caruso AM, et al. Gastroesophageal reflux in young children treated for esophageal atresia: evaluation with pH-multichannel intraluminal impedance. J Pediatr Gastroenterol Nutr. 2011;52(6):686-690.
  74. Salvatore S, Salvatoni A, Van Berkel M, et al. Esophageal impedance baseline is age dependent. J Pediatr Gastroenterol Nutr. 2013;57(4):506-513.
  75. Burgess NG, Wyeth JW. An audit of combined multichannel intraluminal impedance manometry in the assessment of dysphagia. J Gastroenterol Hepatol. 2011;26 Suppl 3:79-82.
  76. Afaneh C, Zoghbi V, Finnerty BM, et al. BRAVO esophageal pH monitoring: more cost-effective than empiric medical therapy for suspected gastroesophageal reflux. Surg Endosc. 2016;30(8):3454-3460.
  77. Iluyomade A, Olowoyeye A, Fadahunsi O, et al. Interference with daily activities and major adverse events during esophageal pH monitoring with bravo wireless capsule versus conventional intranasal catheter: A systematic review of randomized controlled trials. Dis Esophagus. 2017;30(3):1-9.
  78. Hoshino M, Omura N, Yano F, et al. Comparison of the multichannel intraluminal impedance pH and conventional pH for measuring esophageal acid exposure: a propensity score-matched analysis. Surg Endosc. 2017;31(12):5241-5247.
  79. Wan Y, Yan Y, Ma F, et al. LPR: how different diagnostic tools shape the outcomes of treatment. J Voice. 2014;28(3):362-368.
  80. Pavic I, Babic I, Cepin Bogovic J, Hojsak I. The importance of combined 24-hour multichannel intraluminal impedance-pH monitoring in the evaluation of children with suspected laryngopharyngeal reflux. Clin Otolaryngol. 2017;42(3):544-549.
  81. Kim SI, Kwon OE, Na SY, et al. Association between 24-hour combined multichannel intraluminal impedance-pH monitoring and symptoms or quality of life in patients with laryngopharyngeal reflux. Clin Otolaryngol. 2017;42(3):584-591.
  82. Franco RA, Jr.Laryngopharyngeal reflux. UpToDate Inc., Waltham, MA. Last reviewed May 2018.
  83. Chiou E, Rosen R, Jiang H, Nurko S. Diagnosis of supra-esophageal gastric reflux: Correlation of oropharyngeal pH with esophageal impedance monitoring for gastro-esophageal reflux. Neurogastroenterol Motil. 2011;23(8):717-e326.
  84. Plocek A, Gębora-Kowalska B, Białek J, et al. Esophageal impedance-pH monitoring and pharyngeal pH monitoring in the diagnosis of extraesophageal reflux in children. Gastroenterol Res Pract. 2019;2019:6271910.