Introduction

Gastroesophageal reflux disease (GERD) is a common disorder of the gastrointestinal tract that involves the movement of stomach contents into the esophagus or mouth, causing discomfort or complications.[1] Population-based studies have identified GERD as one of the most common upper gastrointestinal (GI) tract disorders, with a prevalence of about 20% in the United States.[2] Patients may present with typical symptoms, including heartburn or regurgitation, or atypical symptoms such as cough, asthma, hoarseness, chronic laryngitis, throat-clearing, chest pain, dyspepsia, and nausea.[3] 

Typically, GERD is diagnosed clinically and treated with a trial of proton-pump inhibitor (PPI) therapy. Relief of heartburn and regurgitation after a 6 to 8 week trial of PPI therapy is a reliable indicator of GERD. This approach has a sensitivity of 78% and a specificity of 54%; hence a negative trial does not rule-out GERD.[4] However, this is a cost-effective approach to diagnosing GERD rather than proceeding directly to endoscopic or alternative diagnostic testing.[5] If patients present with alarm features (i.e., new-onset dyspepsia at age greater than 60, GI bleeding, dysphagia, odynophagia, weight loss, anemia, persistent vomiting), a trial of PPI therapy is not necessary, and the work-up should directly proceed to early endoscopy.[3]

Ambulatory esophageal pH testing is done with a wireless pH capsule or a traditional pH probe and is the gold standard test for GERD diagnosis.[3] Some patients with typical or atypical GERD symptoms have a normal upper endoscopy and normal ambulatory esophageal pH testing but are unresponsive to standard PPI therapy. Ambulatory pH testing does not detect all types of reflux, especially when the refluxate contains little or no acid.[6] It relies on the acidification of intraesophageal pH to less than 4 as a marker for the presence of gastric contents in the esophagus to diagnose gastroesophageal reflux (GER) episodes. Hence, it has limited use in detecting episodes where the pH fails to fall below 4.[7]

A newer technique combining multichannel intraluminal impedance (MII) testing with pH testing allows for the detailed characterization of the refluxate, including its physical and chemical properties.[2] The MII detects the intraluminal bolus movement with the esophagus via strategic placement of a catheter. It can characterize, in combination with pH testing, whether the bolus is composed of liquid, gas, or mixed components as well as its pH.[2]

Specimen Collection

There is no specific specimen that is collected. The study lasts for 24 hours, and once it is complete, the recording unit is returned to the provider. The information is downloaded to a computer, and subsequent data analysis follows using a software system.[8]

Procedures

Patient Protocol[7][8] 

• Instructed to fast 4 to 6 hours before probe insertion
• Provided with a diary to record: time of the meal, the content of the meal, time of upright and recumbent periods, time of administration of acid-suppressing medication, time of symptom occurrence
• No clear guidelines on dietary restrictions exist; it varies from provider to provider
• Patients are encouraged to continue their usual eating habits or engage in ordinary activities that are known to induce symptoms

Testing On/Off PPI therapy[9][10]

• The decision to perform testing on or off PPI therapy depends on the indication for testing.
• If a patient has a known history of GERD that is refractory to treatment, and the indication for MII-pH testing is to diagnose weakly acidic (non-acid) reflux, PPI therapy continues. Usually, patients remain on high-dose acid-suppressive therapy for at least one week before testing and on the day of testing.
• If it is unclear whether GERD is the cause of a patient’s symptoms, MII-pH testing is done off PPI therapy to detect acid reflux events.

Insertion Technique[7][8]

• The MII-pH probe placement is transnasally into the esophagus
• The probes are 2.1 mm in diameter and allow for pH sensors to be placed 5 cm superior to the lower esophageal sphincter (LES) and 10 cm below the LES
• Impedance measurements are taken at various segments throughout the esophagus with four impedance-measuring segments in the distal esophagus (3, 5, 7, and 9 cm above the LES) and two segments in the proximal esophagus (at 15 and 17 cm above the LES)
• The testing usually lasts 24 hours, and once the study is complete, the recording unit is returned to the provider
• There is subsequent data analysis using a software system

Indications

Clinical indications for combined MII-pH testing include[7][9][11][12][13]:

1. To quantify and characterize gastroesophageal reflux in patients who have had a minimal or lack of response to acid-suppressive therapy with a proton pump inhibitor (PPI) and who have normal endoscopic findings.
2. To evaluate patients with atypical gastroesophageal reflux symptoms
3. To evaluate patients with reflux symptoms and achlorhydria (i.e., atrophic gastritis)
4. To evaluate patients with reflux symptoms after surgical gastrectomy
5. To evaluate patients with primary postprandial symptoms
6. To evaluate patients with reflux symptoms and frequent meal ingestion (i.e., infants)

Potential Diagnosis

Types of Reflux[6][14]

1. Acidic: pH < 4
2. Weakly acidic: pH 4 to 7
3. Weakly alkaline: pH >7

Causes

Insufficient Acid Suppression

• Medication-related factors
  • Poor compliance with PPI timing (i.e., not taking PPI 30-60 minutes before breakfast as instructed), or poor medication adherence.[15]
  • Certain populations of people who have CYP2C19 mutations could be slow or rapid metabolizers of PPIs, which could ultimately affect the duration of action. Rapid metabolizers could classify into the group with “PPI failure.”[16]
• Residual acid reflux
  • Research has noted residual acid reflux in some patients despite being on PPI therapy. However, some patients respond better to twice daily therapy rather than once-daily therapy. In a retrospective study done on 135 patients with typical GERD symptoms refractory to once or twice daily PPI therapy, results were abnormal in 31% and 4%, respectively.[17]
• Weakly acidic or alkaline reflux[18][19]
  • Usually occurs in the postprandial period due to transient lower esophageal sphincter relaxation occurring more often following meal-induced gastric fundus distension.
  • Individuals on PPI therapy - the PPI reduces the acidity level in the stomach; however, the patient continues to have reflux due to structural and motility abnormalities. 
  • Individuals off PPI therapy - usually occur when the food contents buffer gastric acid in the postprandial period, and there is transient lower esophageal sphincter relaxation. 

Reflux Hypersensitivity

• The diagnosis is made when all of the Rome IV criteria are met for the last three months with symptomatic onset at least six months before the diagnosis [20]:
• Retrosternal symptoms including heartburn or chest pain
• Normal endoscopy and eosinophilic esophagitis has been ruled out as a cause 
• Absence of major esophageal motor disorders
• Reflux events trigger symptoms despite normal acid exposure on pH or pH-impedance monitoring.

Functional Heartburn

• The diagnosis is made when all of the Rome IV criteria listed below are met for the last three months with symptomatic onset at least six months before diagnosis and at a frequency of at least twice per week.[21] 
• Burning retrosternal discomfort or pain
• No symptom relief despite optimal anti-secretory therapy
• Absence of evidence that GERD or eosinophilic esophagitis is the cause of the symptoms
• Lack of major esophageal motor disorders (achalasia, esophagogastric junction outflow obstruction, distal esophageal spasm, jackhammer esophagus, absent contractility)

Alternative Diagnosis

• Achalasia
• Eosinophilic esophagitis
• Pill-induced esophagitis
• Gastroparesis
• Stricture
• Malignancy

Normal and Critical Findings

The overall interpretation of the study is based on normal data obtained from healthy volunteers, which serve to establish reference values.[22] Because acid-suppressive therapy alters the ratio of acid versus non-acid reflux episodes in the postprandial period and reduces the total number of reflux episodes, different normal values are utilized when interpreting the total number of reflux episodes “on” and “off” acid-suppressive therapy.[18][23]  

The symptom index and symptom association probability are two indices that help assess the association of a patient’s symptoms with gastroesophageal reflux episodes (acid and non-acid).[24] The symptom index measures the overall strength of the relationship between symptoms and reflux episodes, and the symptom association probability determines whether this relationship is due to chance.[3] 

Symptom index (SI): number of symptoms associated with reflux occurring in the preceding 5-minute interval divided by the total number of symptoms recorded by the patient during the monitoring period.[24]

• SI greater than 50% is considered a positive test (i.e., more than half of the total number of reflux events was symptomatic). In this case, patients are considered to have symptomatic gastroesophageal reflux on PPI therapy.
• SI less than 50% is considered to be a negative test. In this case, patients are considered to have persistent symptoms while on PPI therapy due to causes other than gastroesophageal reflux.

Symptom association probability (SAP): the total measuring time divides into two-minute intervals. A contingency table with four fields listed below assesses correlation with the Fisher exact test.[25] 

• Number of intervals with GER and symptoms
• Number of intervals with GER without symptoms
• Number of intervals without GER and with symptoms
• Number of intervals without both GER and symptoms

A positive SAP (greater than 95%) is considered statistically significant and is interpreted as an adequate temporal association between GER and the recorded symptom.[25]

Interfering Factors

Although MII-pH testing is a great tool to assess and diagnose GERD-related symptoms, there are some limitations and drawbacks to the test.[2]

• There is a day-to-day variability of the test.[26][27]
• Assessment of the reflux-symptom correlation uses the SI and SAP indices; however, the validity of these indices is still uncertain.[2]
• When performing the test off PPI therapy, MII-pH findings are not always able to predict the response to PPIs in patients with typical reflux-related symptoms.[28]
• The inability to assess the volume of refluxate[8]
• Difficulty in measuring changes in impedance in patients that have a low baseline impedance (i.e., Barrett esophagus, severe esophagitis, poor esophageal motility)[8]

Complications

Complications of MII-pH testing include bleeding, infection, and trauma to the nasopharynx or esophagus. 

Patient Safety and Education

The procedure is relatively safe; however, the placement of a transnasal catheter may produce some nasopharyngeal discomfort. It may also alter the usual activities of a patient, including food and drink consumption. Despite this, patients are usually able to complete the entire 24-hour examination. Before the procedure, patients should receive counsel on expectations before the day of the examination and how and what to log into a diary.[7][8]

The contraindications for placement of a transnasal MII catheter include prior nasal surgery or trauma, concurrent use of anticoagulants, or coagulopathy. Safety data on the use of impedance in patients with implantable cardiac defibrillators and pacemakers are yet to be studied.[8]

Clinical Significance

In conclusion, MII-pH is a helpful tool to diagnose GERD as it is more accurately able to detect the variances in refluxate composition at various pH levels than pH metering alone. It has a high sensitivity in identifying all types of reflux episodes.[29] This data collection allows the provider to be better equipped with information to personalize treatment for the patient depending on the underlying cause of their symptoms.