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Devices for esophageal function testing

Open AccessPublished:October 22, 2021DOI:https://doi.org/10.1016/j.vgie.2021.08.012

      Background and Aims

      Esophageal function testing is an integral component of the evaluation of refractory GERD and esophageal motility disorders. This review summarizes the current technologies available for esophageal function testing, including the functional luminal imaging probe (FLIP), high-resolution esophageal manometry (HRM), and multichannel intraluminal impedance (MII) and pH monitoring.

      Methods

      We performed a MEDLINE, PubMed, and MAUDE database literature search to identify pertinent clinical studies through March 2021 using the following key words: esophageal manometry, HRM, esophageal impedance, FLIP, MII, and esophageal pH testing. Technical data were gathered from traditional and web-based publications, proprietary publications, and informal communications with pertinent vendors. The report was drafted, reviewed, and edited by the American Society for Gastrointestinal Endoscopy Technology Committee and approved by the Governing Board of the American Society for Gastrointestinal Endoscopy.

      Results

      FLIP is a high-resolution impedance planimetry system used for pressure and dimension measurement in the esophagus, pylorus, and anal sphincter. FLIP provides complementary information to HRM for esophageal motility disorders, especially achalasia. The Chicago classification, based on HRM data, is a widely adopted algorithmic scheme used to diagnose esophageal motility disorders. MII detects intraluminal bolus movement and, combined with pH measurement or manometry, provides information on acid and non-acid gastroesophageal reflux and bolus transit in patients with refractory GERD and for preoperative evaluation for anti-reflux procedures.

      Conclusions

      Esophageal function testing techniques (FLIP, HRM, and MII-pH) have diagnostic and prognostic value in the evaluation of esophageal motility disorders and refractory GERD. Newer technologies and classification systems have enabled an increased understanding of these diseases.

      Video

      (mp4, (41.32 MB)

      Endoscopic video of ENDOFLIP procedure.

      Abbreviations:

      AET (acid exposure time), ASGE (American Society for Gastrointestinal Endoscopy), BMI (body mass index), CC (Chicago classification), CD (contractile deceleration), CSA (cross-sectional area), DI (distensibility index), DP (distensibility plateau), DRI (dysphagia risk index), EGJ (esophagogastric junction), EGJOO (esophagogastric junction outflow obstruction), EoE (eosinophilic esophagitis), EM (esophageal manometry), EPT (esophageal pressure topography plots), FLIP (functional luminal imaging probe), HRM (high-resolution esophageal manometry), IEM (ineffective esophageal motility), IRP (integrated relaxation pressure), LES (lower esophageal sphincter), LHM (laparoscopic Heller myotomy), MII (multichannel intraluminal impedance), MRS (multiple rapid swallows), MSA (magnetic sphincter augmentation), NOD (nonobstructive dysphagia), POEM (peroral endoscopic myotomy), PPI (proton pump inhibitors), SAP (symptom association probability), SI (Symptom index), UES (upper esophageal sphincter)
      The American Society for Gastrointestinal Endoscopy (ASGE) Technology Committee provides reviews of existing, new, or emerging endoscopic technologies that have an impact on the practice of GI endoscopy. Evidence-based methodology is used, performing a MEDLINE literature search to identify pertinent clinical studies on the topic and a Manufacturer and User Facility Device Experience (MAUDE) (U.S. Food and Drug Administration Center for Devices and Radiological Health) database search to identify the reported adverse events of a given technology. Both are supplemented by accessing the “related articles” feature of PubMed and by scrutinizing pertinent references cited by the identified studies. Controlled clinical trials are emphasized, but in many cases, data from randomized, controlled trials are lacking. In such cases, large case series, preliminary clinical studies, and expert opinions are used. Technical data are gathered from traditional and web-based publications, proprietary publications, and informal communications with pertinent vendors. Technology Status Evaluation Reports are drafted by a small group of members of the ASGE Technology Committee, reviewed and edited by the committee as a whole, and approved by the Governing Board of the ASGE. When financial guidance is indicated, the most recent coding data and list prices at the time of publication are provided. For this review, the MEDLINE database was searched through March 2021 for relevant articles by using the key words esophageal manometry, high resolution manometry, esophageal impedance, functional luminal imaging probe, MII, and esophageal pH testing.
      Technology Status Evaluation Reports are scientific reviews provided solely for educational and informational purposes. Technology Status Evaluation Reports are not rules and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment or payment for such treatment.

      Background

      GERD is the most common GI diagnosis associated with outpatient visits in the United States, and approximately 20% of the U.S. population report at least weekly symptoms of GERD.
      • El-Serag H.B.
      • Sweet S.
      • Winchester C.C.
      • et al.
      Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review.
      ,
      • Richter J.E.
      • Rubenstein J.H.
      Presentation and epidemiology of gastroesophageal reflux disease.
      Esophageal function testing is an integral component of the evaluation of refractory GERD and esophageal motility disorders such as achalasia. Measurement of esophageal distensibility and compliance is also increasingly used for the evaluation of esophageal motility disorders, as well as other esophageal conditions such as eosinophilic esophagitis (EoE) and after endoscopic or surgical esophageal interventions.
      In recent years, new technologies have expanded our understanding of esophageal motility and gastroesophageal reflux and are now rapidly being integrated into routine clinical practice. This review summarizes the current technologies available for esophageal function testing, including the functional luminal imaging probe (FLIP), high-resolution esophageal manometry (HRM), and multichannel intraluminal impedance (MII) and pH monitoring. This is an update of a previously published American Society for Gastrointestinal Endoscopy (ASGE) technology document on esophageal function testing.
      • Wang A.
      • Pleskow D.K.
      • Banerjee S.
      • et al.
      Esophageal function testing.
      Wireless pH testing has been addressed in a previous ASGE technology document
      • Chotiprashidi P.
      • Liu J.
      • Carpenter S.
      • et al.
      ASGE technology status evaluation report: wireless esophageal pH monitoring system.
      and is not reviewed here.

      Technology under Review

      Functional luminal imaging probe

      FLIP uses high-resolution impedance planimetry during volume-controlled distension to quantify the relationship between luminal geometry and pressure in the assessment of the mechanical properties of the esophageal wall and esophagogastric junction (EGJ).
      • Savarino E.
      • di Pietro M.
      • Bredenoord A.J.
      • et al.
      Use of the functional lumen imaging probe in clinical esophagology.
      Specifically, FLIP analyzes the relationship between luminal cross-sectional area (CSA) and pressure, which provides a measure of luminal distensibility (CSA/pressure). The technology consists of a multielectrode probe and proprietary software that measures the dynamic geometrical changes of the EGJ and esophageal body during peristalsis.
      • McMahon B.P.
      • Frøkjær J.B.
      • Drewes A.M.
      • et al.
      A new measurement of oesophago-gastric junction competence.
      The EndoFLIP system (Medtronic Inc, Minneapolis, Minn, USA) is cleared by the U.S. Food and Drug Administration for pressure and dimension measurement in the esophagus, pylorus, and anal sphincter (Fig. 1). The system is intended for use as an adjunct to other diagnostic methods in the evaluation of patients with symptoms consistent with GI dysmotility. Additional applications include assessment of pylorus distensibility before or during gastric peroral endoscopic myotomy (POEM) or surgical pyloromyotomy, estimation of the size of the stoma after gastric band placement, intraoperative assessment for fundoplication tightness and lower esophageal sphincter myotomy adequacy, and as an adjunct to a bougie for measuring the size of the gastric sleeve during a sleeve gastrectomy.
      • Su B.
      • Callahan Z.M.
      • Novak S.
      • et al.
      Using impedance planimetry (EndoFLIP) to evaluate myotomy and predict outcomes after surgery for achalasia.
      • Vosoughi K.
      • Ichkhanian Y.
      • Jacques J.
      • et al.
      Role of endoscopic functional luminal imaging probe in predicting the outcome of gastric peroral endoscopic pyloromyotomy (with video).
      • Conchillo J.M.
      • Straathof J.W.A.
      • Mujagic Z.
      • et al.
      Gastric peroral endoscopic pyloromyotomy for decompensated gastroparesis: comprehensive motility analysis in relation to treatment outcomes.
      Figure thumbnail gr1
      Figure 1Image of an EndoFLIP system. ©2020 Medtronic. All rights reserved. Used with the permission of Medtronic.

      Main components

      The FLIP system consists of a 240-cm-long, 3-mm-diameter catheter with a highly compliant balloon at the distal end that conforms to the esophageal lumen (Table 1). The balloon contains 16 paired impedance electrodes spaced at regular intervals and a single solid-state pressure transducer at the distal end (Fig. 1). The electrodes are variably spaced from 5 mm to 1 cm apart, depending on the specific catheter model. The balloon device for standard esophageal evaluation is 16 cm in length; an 8-cm balloon device is also available for evaluation of sphincter anatomy and function or sizing of anastomoses. Devices with a balloon length of 8 and 16 cm are commercially available. Excitation electrodes located on the proximal and distal ends of the balloon generate a constant low electrical current through a conductive fluid that is instilled into the balloon through an 80-mL syringe housed in and controlled by the EndoFLIP system. Voltage is measured by the paired sensors along the length of the balloon and based on the current and voltage; the electrical resistance of the fluid, or impedance, is calculated using Ohm’s law (V = I × R). When the constant of a defined fluid conductivity at a given temperature combined with the fixed distance between the electrodes is used, the CSA is derived from changes in impedance. The system also measures distensibility based on simultaneous measurement of pressure within the balloon by the solid-state transducer.
      Table 1Technical specifications of the EndoFLIP system
      DescriptionPart Number
      EndoFLIP Catheter, 25 mm, 80 mm measurement length, with Pressure, Nasal TipEF-325N
      EndoFLIP Catheter, 22 mm, 80 mm measurement length, with Pressure, Nasal TipEF-322N
      EsoFLIP Catheter, 30 mm, 80mm measurement lengthES-330
      EsoFLIP Catheter, 20 mm, 80mm measurement lengthES-320
      EndoFLIP Localization KitLK-103
      HD Image Box TEAC UnitDD-971
      EndoFLIP 1.0 SystemEF-100
      EndoFLIP 2.0 SystemEF-200
      The EndoFLIP system also includes a touchscreen interface that displays a real-time colorized geometric image of the evaluated esophageal segment, numerical estimated luminal diameter (Dest) measurements along the electrodes, and the current balloon pressure (Fig. 2). The user may also toggle between display of the minimum diameter and CSA or distensibility and compliance. The distensibility index (DI) is used to measure sphincter distensibility and is calculated by dividing the median narrowest CSA by the median intraballoon pressure at a set timeframe or distension volume. Because CSA and pressure measurements are dynamic and influenced by respiration and spontaneous esophageal contractions, various statistical solutions are used to control for these variations, including FLIP Analytics software (Medtronic Inc) and MATLAB (The MathWorks, Natick, Mass, USA).
      • Lin Z.
      • Nicodème F.
      • Boris L.
      • et al.
      Regional variation in distal esophagus distensibility assessed using the functional luminal imaging probe (FLIP).
      • Lin Z.
      • Kahrilas P.J.
      • Xiao Y.
      • et al.
      Functional luminal imaging probe topography: an improved method for characterizing esophageal distensibility in eosinophilic esophagitis.
      • Carlson D.A.
      • Lin Z.
      • Hirano I.
      • et al.
      Evaluation of esophageal distensibility in eosinophilic esophagitis: an update and comparison of functional lumen imaging probe analytic methods.
      Data may be stored on the EndoFLIP system or uploaded to an electronic medical record.
      Figure thumbnail gr2
      Figure 2Examples of functional luminal imaging probe planimetry. A, Normal contraction pattern with repetitive antegrade contractions and normal distensibility index. B, Absent esophageal body contractility with reduced distensibility index in achalasia (courtesy of Dr Diana Snyder, Mayo Clinic Arizona).
      The FLIP Topography module (available in EndoFLIP 2.0) is software that displays real-time diameter and distensibility estimates for each point along the measurement area. The data are expressed as a topographic plot with a color scale to display diameter values. A historical graph also displays diameter readings for a given period, allowing an assessment of diameter changes over time (Fig. 2A and B). The expression of diameter values in this fashion is analogous to data presentation with HRM. Thus, FLIP Topography enables evaluation of EGJ distensibility, along with assessment of esophageal body distensibility and contractile activity. The latter requires use of the 16-cm catheter to allow for a longer region of measurement in the esophageal body, and analysis based on FLIP topography, which relies on detection of distension-induced secondary peristalsis.
      • Savarino E.
      • di Pietro M.
      • Bredenoord A.J.
      • et al.
      Use of the functional lumen imaging probe in clinical esophagology.
      Impedance-guided esophageal dilation catheters, which use the data acquired during impedance planimetry, are also available (EsoFLIP, Medtronic). These are available in 2 sizes (6 -20 mm, 3-30 mm), with the former indicated for dilation of benign esophageal strictures and the latter indicated for dilation of the EGJ in the setting of achalasia.

      Technique

      The procedure is usually performed with concomitant endoscopy. After catheter calibration and data entry, the catheter is advanced into the esophagus transorally, generally with patient sedation. The EGJ is identified by the waist-like constriction visible on the real-time 3-dimensional display at balloon fill volumes of around 20 to 30 mL. Catheter position is then adjusted, either under direct endoscopic visualization or based on measurements, depending on the clinical indication (eg, placement within the esophageal body for evaluation of EoE). Of note, if endoscopic visualization is used, the endoscope should be removed before initiating FLIP analysis; presence of the endoscope has been shown to significantly affect measurements.
      • Bianca A.
      • Schindler V.
      • Schnurre L.
      • et al.
      Endoscope presence during endoluminal functional lumen imaging probe (FLIP) influences FLIP metrics in the evaluation of esophageal dysmotility.
      Once the catheter is positioned, volume-controlled distention of the balloon is performed. The balloon may be inflated to a particular pressure or volume; the rate of balloon inflation and maximal balloon inflation may also be configured. Stepwise volumetric distention performed at 5- to 10-mL increments may provide additional information, such as calculation of a distensibility plateau (DP),
      • Kwiatek M.A.
      • Hirano I.
      • Kahrilas P.J.
      • et al.
      Mechanical properties of the esophagus in eosinophilic esophagitis.
      and it enables evaluation of the esophageal body contractile pattern.
      • Carlson D.A.
      • Kahrilas P.J.
      • Lin Z.
      • et al.
      Evaluation of esophageal motility utilizing the functional lumen imaging probe.
      Sixteen sequential CSAs and a single intraballoon pressure measurement are made at a 10-Hz sampling rate, which may then be used to calculate an estimated luminal diameter (Dest) based on the assumption of a circular lumen (CSA = Πr2). Various procedural protocols have been published, and a standardized testing algorithm has been recently proposed by an international consensus.
      • Savarino E.
      • di Pietro M.
      • Bredenoord A.J.
      • et al.
      Use of the functional lumen imaging probe in clinical esophagology.

      Effectiveness and comparative data

      Asymptomatic healthy subjects

      Although the establishment of normative reference values in healthy individuals is critical to the appropriate interpretation of FLIP measurements in both research and clinical practice, the available data suggest a wide range of values. A systematic review of 5 studies including healthy subjects (n = 98) demonstrated a wide range of median EGJ distensibility (0.8-5.7 mm2/mm Hg) at 30- to 40-mL balloon fill volumes, with a minimum observed EGJ distensibility of 2.4 mm2/mm Hg at a 40-mL fill volume.
      • Chen J.W.
      • Rubenstein J.H.
      Esophagogastric junction distensibility assessed using the functional lumen imaging probe.
      A subsequent prospective study of 20 healthy volunteers demonstrated a median distensibility of 5.8 mm2/mm Hg (interquartile range, 4.9-6.7 mm2/mm Hg) and a minimum observed distensibility of 2.8 mm2/mm Hg.
      • Carlson D.A.
      • Kou W.
      • Lin Z.
      • et al.
      Normal values of esophageal distensibility and distension-induced contractility measured by functional luminal imaging probe panometry.
      The variability among studies may be explained by the use of differing FLIP protocols and balloon sizes and heterogeneity of patient populations.
      • Chen J.W.
      • Rubenstein J.H.
      Esophagogastric junction distensibility assessed using the functional lumen imaging probe.
      Furthermore, body mass index (BMI) may also influence distensibility and CSA measurements.
      • Tucker E.
      • Sweis R.
      • Anggiansah A.
      • et al.
      Measurement of esophago-gastric junction cross-sectional area and distensibility by an endolumenal functional lumen imaging probe for the diagnosis of gastro-esophageal reflux disease.

      Achalasia and EGJ outflow obstruction

      Achalasia is characterized by incomplete relaxation of the lower esophageal sphincter (LES) and abnormal esophageal peristalsis. Although HRM is integral to the diagnosis of achalasia, diagnostic uncertainty may persist in select cases of borderline pressure measurements or conflicting data.
      • Amaravadi R.
      • Levine M.S.
      • Rubesin S.E.
      • et al.
      Achalasia with complete relaxation of lower esophageal sphincter: radiographic-manometric correlation.
      ,
      • Mearin F.
      • Malagelada J.R.
      Complete lower esophageal sphincter relaxation observed in some achalasia patients is functionally inadequate.
      Furthermore, although not a frequent issue, some patients do not tolerate the HRM procedure. By measuring EGJ distensibility, FLIP may provide complementary information to HRM to aid in the diagnosis of achalasia, definition of achalasia subtypes, and prediction of response to therapy.
      Several studies have reported a characteristically low EGJ DI (EGJ-DI) in untreated patients with achalasia.
      • Carlson D.A.
      • Lin Z.
      • Kahrilas P.J.
      • et al.
      The functional lumen imaging probe detects esophageal contractility not observed with manometry in patients with achalasia.
      • Rohof W.O.
      • Hirsch D.P.
      • Kessing B.F.
      • et al.
      Efficacy of treatment for patients with achalasia depends on the distensibility of the esophagogastric junction.
      • Rieder E.
      • Swanström L.L.
      • Perretta S.
      • et al.
      Intraoperative assessment of esophagogastric junction distensibility during per oral endoscopic myotomy (POEM) for esophageal motility disorders.
      • Pandolfino J.E.
      • de Ruigh A.
      • Nicodème F.
      • et al.
      Distensibility of the esophagogastric junction assessed with the functional lumen imaging probe (FLIP™) in achalasia patients.
      A single-center study that included 30 patients with achalasia and 15 healthy controls demonstrated a significantly lower EGJ-DI in the achalasia group as compared to controls (0.7 ± 0.9 vs 6.3 ± 0.7 mm2/mm Hg; P < .001).
      • Rohof W.O.
      • Hirsch D.P.
      • Kessing B.F.
      • et al.
      Efficacy of treatment for patients with achalasia depends on the distensibility of the esophagogastric junction.
      EGJ distensibility also correlated with esophageal emptying on timed barium esophagogram (r = –0.72; P < .01) and symptoms (r = 0.61; P < .01) in the achalasia group. Another study evaluated 20 healthy volunteers and 54 patients with achalasia, 31 of whom were treated with pneumatic dilation (n = 17), Heller myotomy with partial fundoplication (n = 10), or peroral esophageal myotomy (n = 4). The EGJ-DI was significantly different between controls (8.2; 95% CI, 1.7-18.7 at 40 mL) and patients with achalasia before treatment. Furthermore, in the 31 treated patients, there was a significant difference in post-treatment EGJ-DI in the 17 patients with a good response (3.4; 95% CI, 2.2-4.9 at 40 mL) versus the 14 patients with a poor response (1.5; 95% CI, 0.6-2.8 at 40 mL; P < .001) as determined by Eckardt score. Significant correlations were also noted between EGJ-DI and integrated relaxation pressure (IRP) as measured by HRM.
      • Pandolfino J.E.
      • de Ruigh A.
      • Nicodème F.
      • et al.
      Distensibility of the esophagogastric junction assessed with the functional lumen imaging probe (FLIP™) in achalasia patients.
      FLIP may also aid the diagnostic evaluation of the subset of patients who demonstrate characteristic symptoms of achalasia but have normal LES relaxation on HRM, seen especially in patients with type I achalasia. A single-center study included 13 patients with typical symptoms of achalasia (Eckardt score of 5-7) with HRM demonstrating absent peristalsis, a low mean basal EGJ pressure of 10 (5.8-12.9) mm Hg, and a normal mean IRP of 9.3 (6.1-12) mm Hg.
      • Ponds F.A.
      • Bredenoord A.J.
      • Kessing B.F.
      • et al.
      Esophagogastric junction distensibility identifies achalasia subgroup with manometrically normal esophagogastric junction relaxation.
      FLIP demonstrated a significant reduction in EGJ distensibility, as compared with previously acquired data from healthy controls (n = 15) (0.8 [0.7-1.2] mm2/mm Hg vs 6.3 [3.8-8.7] mm2/mm Hg; P < .001). Treatment resulted in significant improvement in Eckardt score as well as the EGJ-DI.
      By simultaneously measuring esophageal contractility and EGJ function, FLIP also provides complementary information to HRM in the differentiation of achalasia subtypes. A study included 51 treatment-naïve patients with achalasia subclassified with HRM and 10 asymptomatic controls who underwent FLIP during endoscopy.
      • Carlson D.A.
      • Lin Z.
      • Kahrilas P.J.
      • et al.
      The functional lumen imaging probe detects esophageal contractility not observed with manometry in patients with achalasia.
      Contractility was observed in 27% of patients with type I achalasia, 65% of patients with type II, and 100% of patients with type III. In patients with type III achalasia, 8 of 10 demonstrated novel contractility (repetitive retrograde contractions), which was not observed in controls. The authors further noted that FLIP topography detected lumen-occluding and nonoccluding contractions as well as specific distention-related contractions that were not observed with HRM.
      A second study from the same center included 145 patients with dysphagia who underwent HRM and FLIP with topography performed during sedated endoscopy.
      • Carlson D.A.
      • Kahrilas P.J.
      • Lin Z.
      • et al.
      Evaluation of esophageal motility utilizing the functional lumen imaging probe.
      FLIP topography was abnormal in 95% of patients who were diagnosed with achalasia or who had EGJ outflow obstruction by HRM. Furthermore, FLIP topography detected abnormalities in 17 of 34 (50%) symptomatic patients with normal or ineffective esophageal motility on HRM. Thirteen of these patients demonstrated abnormal EGJ-DI, whereas the remaining 4 patients demonstrated repetitive retrograde contractions and normal EGJ DI.
      EGJ outflow obstruction (EGJOO) is a motility abnormality diagnosed by HRM characterized by impaired EGJ relaxation but with some preserved peristalsis such that criteria for achalasia are not met. According to the most recent Chicago classification (CC) of esophageal motility disorders version 4.0,
      • Yadlapati R.
      • Kahrilas P.J.
      • Fox M.R.
      • et al.
      Esophageal motility disorders on high-resolution manometry: Chicago classification version 4.0©.
      EGJOO diagnosed by HRM requires confirmation of true outflow obstruction through additional testing, which can be accomplished by FLIP showing a reduced EGJ-DI. A study of 34 patients with EGJOO showed that FLIP was useful for identifying patients who are most likely to benefit from achalasia-type therapy.
      • Triggs J.R.
      • Carlson D.A.
      • Beveridge C.
      • et al.
      Functional luminal imaging probe panometry identifies achalasia-type esophagogastric junction outflow obstruction.
      Similarly, a recent study showed POEM to be a highly successful treatment for EGJOO confirmed by FLIP.
      • Ichkhanian Y.
      • Sanaei O.
      • Canakis A.
      • et al.
      Esophageal peroral endoscopic myotomy (POEM) for treatment of esophagogastric junction outflow obstruction: results from the first prospective trial.

      Assessment of treatment

      A growing body of literature supports the role of FLIP in the real-time assessment of EGJ function during endoscopic or operative therapy for achalasia. Several case series have demonstrated an increase in EGJ-DI measured intraoperatively immediately after laparoscopic Heller myotomy (LHM) and POEM.
      • Teitelbaum E.N.
      • Boris L.
      • Arafat F.O.
      • et al.
      Comparison of esophagogastric junction distensibility changes during POEM and Heller myotomy using intraoperative FLIP.
      • Teitelbaum E.N.
      • Soper N.J.
      • Boris L.
      • et al.
      Predictors of intraoperative esophagogastric junction distensibility and physiologic improvement during heller myotomy and poem.
      • Teitelbaum E.N.
      • Soper N.J.
      • Pandolfino J.E.
      • et al.
      An extended proximal esophageal myotomy is necessary to normalize EGJ distensibility during Heller myotomy for achalasia, but not POEM.
      • Teitelbaum E.N.
      • Soper N.J.
      • Pandolfino J.E.
      • et al.
      Esophagogastric junction distensibility measurements during Heller myotomy and POEM for achalasia predict postoperative symptomatic outcomes.
      • Teitelbaum E.N.
      • Sternbach J.M.
      • El Khoury R.
      • et al.
      The effect of incremental distal gastric myotomy lengths on EGJ distensibility during POEM for achalasia.
      • Ngamruengphong S.
      • von Rahden B.H.A.
      • Filser J.
      • et al.
      Intraoperative measurement of esophagogastric junction cross-sectional area by impedance planimetry correlates with clinical outcomes of peroral endoscopic myotomy for achalasia: a multicenter study.
      • Familiari P.
      • Gigante G.
      • Marchese M.
      • et al.
      EndoFLIP system for the intraoperative evaluation of peroral endoscopic myotomy.
      • Ilczyszyn A.
      • Hamaoui K.
      • Cartwright J.
      • et al.
      Intraoperative distensibility measurement during laparoscopic Heller's myotomy for achalasia may reduce the myotomy length without compromising patient outcome.
      In addition, FLIP may be used to inform intraoperative treatment decisions and predict postprocedure outcomes.
      A multicenter retrospective study of 63 patients with achalasia treated with POEM examined the association of intraoperative FLIP measurements and short-term clinical outcomes (median follow-up of 122 days).
      • Ngamruengphong S.
      • von Rahden B.H.A.
      • Filser J.
      • et al.
      Intraoperative measurement of esophagogastric junction cross-sectional area by impedance planimetry correlates with clinical outcomes of peroral endoscopic myotomy for achalasia: a multicenter study.
      Patients were divided into 2 groups based on postprocedure Eckardt score (good response: <3, n = 50; or poor response: ≥3, n = 13). The intraoperative CSA after POEM was significantly higher in the good-response group (89.0 [78.5-106.7] mm2 vs 72.4 [48.8-80.0] mm2; P = .01). The final EGJ CSA was also significantly higher in those patients with postprocedure reflux esophagitis. EGJ-DI was lower in the poor-response group, although this did not reach statistical significance. However, 2 other studies (n = 56 and n = 52) evaluating the predictive value of intraoperative FLIP reported that the postmyotomy EGJ-DI was an independent predictor of response to treatment.
      • Teitelbaum E.N.
      • Soper N.J.
      • Pandolfino J.E.
      • et al.
      Esophagogastric junction distensibility measurements during Heller myotomy and POEM for achalasia predict postoperative symptomatic outcomes.
      ,
      • Yoo I.K.
      • Choi S.A.
      • Kim W.H.
      • et al.
      Assessment of clinical outcomes after peroral endoscopic myotomy via esophageal distensibility measurements with the endoluminal functional lumen imaging probe.
      Several studies have evaluated the role of intraprocedural FLIP during POEM and LHM to optimally guide the proximal and distal extent of myotomy, with variable results reported.
      As with preoperative and intraoperative measurements, change in EGJ distensibility after treatment may provide complementary information to HRM. A prospective study compared the utility of FLIP EGJ-DI measurement and HRM in assessing posttreatment outcomes in achalasia. A total of 79 patients treated with pneumatic dilation, LHM, or POEM underwent timed barium esophagogram, HRM, and FLIP.
      • Jain A.S.
      • Carlson D.A.
      • Triggs J.
      • et al.
      Esophagogastric junction distensibility on functional lumen imaging probe topography predicts treatment response in achalasia - anatomy matters!.
      The area under the curve for EGJ metrics in association with barium retention was as follows: DI, 0.90; maximal EGJ diameter, 0.76; IRP, 0.64; and basal EGJ pressure, 0.53. When a 5-minute barium column area of >5 cm was used as the reference standard, only FLIP metrics were associated with retention given normal anatomy. Lower EJG-DI (2.4 vs 5.2 mm2/mm Hg; P < .0001) and higher maximal EGJ diameter (13.1 vs 16.6 mm; P = .002) were associated with retention. Furthermore, 21 of 22 patients with retention had a low or borderline low DI (<2.8 mm2/mm Hg). Additional cohort studies have demonstrated a significant association with post-myotomy EGJ-DI and symptom response as measured by Eckardt scores, as well as associations between increased CSA with postmyotomy reflux.
      • Su B.
      • Callahan Z.M.
      • Novak S.
      • et al.
      Using impedance planimetry (EndoFLIP) to evaluate myotomy and predict outcomes after surgery for achalasia.
      ,
      • Rohof W.O.
      • Hirsch D.P.
      • Kessing B.F.
      • et al.
      Efficacy of treatment for patients with achalasia depends on the distensibility of the esophagogastric junction.

      GERD

      Diagnosis

      EGJ incompetence and/or the presence of a hiatal hernia may contribute to GERD.
      • Barham C.P.
      • Gotley D.C.
      • Mills A.
      • et al.
      Precipitating causes of acid reflux episodes in ambulant patients with gastro-oesophageal reflux disease.
      With the advent of FLIP, it has been hypothesized that increased EGJ distensibility may facilitate GERD diagnosis.
      • Pandolfino J.E.
      • Shi G.
      • Curry J.
      • et al.
      Esophagogastric junction distensibility: a factor contributing to sphincter incompetence.
      ,
      • Jenkinson A.D.
      • Scott S.M.
      • Yazaki E.
      • et al.
      Compliance measurement of lower esophageal sphincter and esophageal body in achalasia and gastroesophageal reflux disease.
      However, several case series evaluating FLIP in this context have demonstrated inconsistent results. An initial series of 20 patients with GERD without hiatal hernia and 20 healthy controls demonstrated a 2- to 3-fold increase in EGJ distensibility among patients with GERD, compared with controls.
      • Kwiatek M.A.
      • Pandolfino J.E.
      • Hirano I.
      • et al.
      Esophagogastric junction distensibility assessed with an endoscopic functional luminal imaging probe (EndoFLIP).
      However, a subsequent study including 18 patients with GERD and 21 healthy volunteers evaluated with FLIP followed by 48-hour wireless pH monitoring showed that EGJ metrics were similar between participants with and without pathologic acid exposure (CSA 98 mm2 vs 107 mm2; P = .789, distensibility; P = .704).
      • Tucker E.
      • Sweis R.
      • Anggiansah A.
      • et al.
      Measurement of esophago-gastric junction cross-sectional area and distensibility by an endolumenal functional lumen imaging probe for the diagnosis of gastro-esophageal reflux disease.
      There was a correlation between BMI and CSA (R2 = 0.2758; P = .001) and distensibility (R2 = 0.2005; P = .005). Interpretation of these results is difficult because of the differences in BMI between the 2 groups.
      The disparate findings of these studies imply that the association between GERD and esophageal function may be more complex than abnormalities in EGJ distensibility alone. A study of 25 patients who underwent ambulatory pH monitoring and FLIP during endoscopy examined the relationship between total percent acid exposure time (AET), symptoms as measured by a validated questionnaire (GERDQ), and response to esophageal distention.
      • Carlson D.A.
      • Kathpalia P.
      • Craft J.
      • et al.
      The relationship between esophageal acid exposure and the esophageal response to volumetric distention.
      A weak and insignificant correlation was found between AET and EGJ DI, GERDQ and AET, and GERDQ and EGJ-DI. Notably, AET was lower among patients with (6.1%, 3-7.8) than without (14.9%, 8.5-22.3) repetitive antegrade contractions induced with volumetric balloon distention (P = .009). This suggests that abnormal esophageal acid exposure may be associated with impaired esophageal clearance.
      FLIP has also been shown to accurately identify the presence and quantify the effect of a hiatus hernia. A study including 30 patients with hiatus hernia and Barrett’s esophagus and 14 healthy controls found the LES had a lower pressure (47.7 ± 13.0 vs 61.4 ± 19.2 mm Hg at 50-mL distension volume) in patients with hiatus hernia and was more distensible than the common EGJ in controls (P < .001).
      • Jain A.S.
      • Carlson D.A.
      • Triggs J.
      • et al.
      Esophagogastric junction distensibility on functional lumen imaging probe topography predicts treatment response in achalasia - anatomy matters!.
      ,
      • Lottrup C.
      • McMahon B.P.
      • Ejstrud P.
      • et al.
      Esophagogastric junction distensibility in hiatus hernia.
      In addition, in patients with hiatus hernia, the crural diaphragm had a lower pressure (eg, 29.6 ± 10.1 vs 47.7 ± 13.0 mm Hg at 50-mL distension volume) and was more distensible than the LES (P < .001).

      Treatment

      FLIP has been used to determine the impact of antireflux surgery on EGJ distensibility, although normative reference values have not been established. Several case series have demonstrated a significant reduction in distensibility immediately after intervention.
      • Perretta S.
      • McAnena O.
      • Botha A.
      • et al.
      Acta from the EndoFLIP® symposium.
      • Ilczyszyn A.
      • Botha A.J.
      Feasibility of esophagogastric junction distensibility measurement during Nissen fundoplication.
      • Kwiatek M.A.
      • Kahrilas P.J.
      • Soper N.J.
      • et al.
      Esophagogastric junction distensibility after fundoplication assessed with a novel functional luminal imaging probe.
      • DeHaan R.K.
      • Davila D.
      • Frelich M.J.
      • et al.
      Esophagogastric junction distensibility is greater following Toupet compared to Nissen fundoplication.
      Pooled results from 4 expert centers demonstrated a mean EGJ distensibility of 2.82 ± 2.82 mm2/mm Hg after crural repair (n = 45) and a mean final DI of 1.60 ± 1.13 after creation of the fundoplication (n = 57).
      • Perretta S.
      • McAnena O.
      • Botha A.
      • et al.
      Acta from the EndoFLIP® symposium.
      However, clinical outcomes were not reported in these studies.
      Reductions in EGJ-DI have also been reported in the early postprocedure period after transoral incisionless fundoplication in animal models and in small case reports and series.
      • Hoppo T.
      • McMahon B.P.
      • Witteman B.P.L.
      • et al.
      Functional lumen imaging probe to assess geometric changes in the esophagogastric junction following endolumenal fundoplication.
      • Rinsma N.F.
      • Smeets F.G.
      • Bruls D.W.
      • et al.
      Effect of transoral incisionless fundoplication on reflux mechanisms.
      • Haito Chavez Y.
      • Ngamruengphong S.
      • Bukhari M.
      • et al.
      Transoral incisionless endoscopic fundoplication guided by impedance planimetry to treat severe GERD symptoms after per-oral endoscopic myotomy.
      However, a series including 25 patients who underwent preoperative FLIP demonstrated no significant difference in EGJ-DI values at 6 months postprocedure.
      • Smeets F.G.M.
      • Keszthelyi D.
      • Bouvy N.D.
      • et al.
      Does measurement of esophagogastric junction distensibility by EndoFLIP predict therapyresponsiveness to endoluminal fundoplication in patients with gastroesophageal reflux disease?.
      Furthermore, although low preoperative distensibility was associated with reduced AET after transoral incisionless fundoplication, it did not correlate with clinical outcomes.

      Eosinophilic esophagitis

      Diagnosis

      EoE is associated with esophageal remodeling and fibrosis, resulting in a loss of compliance, development of symptomatic strictures, and recurrent food impactions.
      • Dellon E.S.
      • Liacouras C.A.
      Advances in clinical management of eosinophilic esophagitis.
      Disease severity and stenosis are evaluated during upper endoscopy with biopsy, although this approach may be limited by biopsy sampling error and underrecognition of strictures.
      • Dellon E.S.
      • Speck O.
      • Woodward K.
      • et al.
      Distribution and variability of esophageal eosinophilia in patients undergoing upper endoscopy.
      ,
      • Gentile N.
      • Katzka D.
      • Ravi K.
      • et al.
      Oesophageal narrowing is common and frequently under-appreciated at endoscopy in patients with oesophageal eosinophilia.
      FLIP allows for objective assessment of the CSA and biomechanical properties of the fibrotic esophageal body. Specifically, the DP, calculated as the maximum achievable CSA of the narrowest portion of the esophageal body during stepwise volumetric balloon distention, has emerged as a useful measure of disease severity in EoE. In a study of 33 patients with EoE and 15 healthy controls, the DP measured with FLIP was significantly lower in patients with EoE (median: CSA 267 mm2 vs 438 mm2; P < .01).
      • Kwiatek M.A.
      • Hirano I.
      • Kahrilas P.J.
      • et al.
      Mechanical properties of the esophagus in eosinophilic esophagitis.
      Mucosal eosinophil count, age, sex, and current proton pump inhibitor (PPI) treatment did not predict reduced distensibility of the esophagus (P < .20).
      A subsequent study evaluated 72 patients with EoE, 90% of whom reported dysphagia. Higher ring scores on a validated scoring system (EoE Endoscopic Reference Score) were associated with lower DP (rs = –0.46; P < .0001), whereas no association between eosinophil counts and ring severity or distensibility was noted. The authors suggest that decreased distensibility may be of use for food impaction risk stratification.
      • Chen J.W.
      • Pandolfino J.E.
      • Lin Z.
      • et al.
      Severity of endoscopically identified esophageal rings correlates with reduced esophageal distensibility in eosinophilic esophagitis.

      Treatment

      FLIP has also been shown to predict the need for treatment and response to therapy in the setting of EoE. A prospective study including 70 patients with EoE followed for a mean of 9.2 months demonstrated that those patients with a history of food impactions had significantly lower DP scores than those with dysphagia alone.
      • Nicodème F.
      • Hirano I.
      • Chen J.
      • et al.
      Esophageal distensibility as a measure of disease severity in eosinophilic esophagitis.
      Additionally, a reduced DP (< 225 mm2) was associated with future food impaction and need for dilation during the follow-up period. Notably, DP was the only significant predictor of future impaction, compared with age, sex, treatment type (including none), and mean esophageal eosinophil density.
      A second study included 18 patients EoE who underwent medical and dietary FLIP performed at baseline endoscopy and after therapy without interval dilation. Follow-up testing occurred at a mean (range) of 14.6 (8-28) weeks. Significant improvement in DP (13.9 [12.2-19.2] to 16.8 mm [15.8-19.2]; P = .007) and was noted with treatment. Six of 8 (75%) patients with a DP increase of ≥2 mm achieved at least a 30% improvement in a validated patient-reported outcome measure (P = .077), suggesting a possible role for FLIP DP as an outcome measure in EoE management.

      Evaluation of esophageal motility with FLIP topography

      The incorporation of the FLIP topography module into standard FLIP protocols has provided novel data in evaluation of the function of the esophageal body. It has been recognized that distention of the esophageal lumen by the balloon induces a contractile response that results in diameter changes that can be graphically represented over a space-time continuum using the FLIP topography module. The interpretation of such data has been used to identify characteristic distention-mediated anterograde and retrograde contractions of the esophageal body, which may provide an assessment of motor function analogous to HRM.
      • Carlson D.A.
      • Lin Z.
      • Rogers M.C.
      • et al.
      Utilizing functional lumen imaging probe topography to evaluate esophageal contractility during volumetric distention: a pilot study.
      Normative data have been recorded in asymptomatic healthy subjects, and characteristic findings in various disease states such as achalasia have been described.
      • Carlson D.A.
      • Kahrilas P.J.
      • Lin Z.
      • et al.
      Evaluation of esophageal motility utilizing the functional lumen imaging probe.
      ,
      • Carlson D.A.
      • Kou W.
      • Lin Z.
      • et al.
      Normal values of esophageal distensibility and distension-induced contractility measured by functional luminal imaging probe panometry.
      Furthermore, normal real-time FLIP topography results obtained during endoscopy reliably identify patients without major motility disorders and correlate with HRM findings.
      • Baumann A.J.
      • Donnan E.N.
      • Triggs J.R.
      • et al.
      Normal functional luminal imaging probe panometry findings associate with lack of major esophageal motility disorder on high-resolution manometry.
      ,
      • Carlson D.A.
      • Gyawali C.P.
      • Kahrilas P.J.
      • et al.
      Esophageal motility classification can be established at the time of endoscopy: a study evaluating real-time functional luminal imaging probe panometry.
      Further studies are needed to determine how FLIP topography is best used in assessment algorithms as a complement to HRM, the role of real-time topography, and whether published results can be validated outside of expert centers.

      Other applications

      Limited data exist regarding additional applications of FLIP in esophageal diseases. Several series have explored the role of FLIP in the evaluation of upper esophageal sphincter (UES) function in healthy controls, in patients with upper esophageal strictures, and sleeve gastrectomy stenoses before and after treatment.
      • Yu J.X.
      • Baker J.R.
      • Watts L.
      • et al.
      Functional lumen imaging probe is useful for the quantification of gastric sleeve stenosis and prediction of response to endoscopic dilation: a pilot study.
      The role of FLIP has also been explored in patients undergoing gastric POEM.
      • Vosoughi K.
      • Ichkhanian Y.
      • Jacques J.
      • et al.
      Role of endoscopic functional luminal imaging probe in predicting the outcome of gastric peroral endoscopic pyloromyotomy (with video).
      ,
      • Hedberg H.M.
      • Carbray J.
      • Ujiki M.B.
      Initial experience with endoscopic pyloromyotomy, with description and video of technique.
      In a multicenter study of 37 patients, intraoperative postmyotomy CSA using 40-mL distention was shown to correlate with improvement in gastric emptying and clinical success.
      • Vosoughi K.
      • Ichkhanian Y.
      • Jacques J.
      • et al.
      Role of endoscopic functional luminal imaging probe in predicting the outcome of gastric peroral endoscopic pyloromyotomy (with video).

      High-resolution manometry

      Esophageal motor disorders characterize a heterogeneous group of conditions that may result in deglutitive dysfunction. These disorders primarily manifest as dysphagia or chest pain. Esophageal manometry involves functional assessment of esophageal pressure changes during awake swallows. Esophageal manometry systems convert intraluminal pressure differences in the esophagus to a tracing that can be recorded. These tracings correspond to a specific distance within the esophagus; hence, a pressure/time graph is created.
      • Gyawali C.P.
      • Patel A.
      Esophageal motor function: technical aspects of manometry.
      Our understanding of esophageal motor disorders has evolved substantially over the past 10 years, largely as a result of the transition from conventional line tracings derived from recordings in a handful of pressure sensors (usually 8) to esophageal pressure topography (EPT) plots derived from HRM catheters that incorporate a large number of pressure transducers (most often 36) closely spaced together. HRM catheters enable collection of more comprehensive pressure data during swallows. The EPT is what is used to view and analyze the output from the HRM catheters. The CC of esophageal motor disorders, currently in its fourth version, is an algorithmic scheme used to diagnose esophageal motility disorders.
      • Yadlapati R.
      • Kahrilas P.J.
      • Fox M.R.
      • et al.
      Esophageal motility disorders on high-resolution manometry: Chicago classification version 4.0©.
      ,
      • Kahrilas P.J.
      • Bredenoord A.J.
      • Fox M.
      • et al.
      The Chicago Classification of esophageal motility disorders, v3.0.
      • Pandolfino J.E.
      • Ghosh S.K.
      • Rice J.
      • et al.
      Classifying esophageal motility by pressure topography characteristics: a study of 400 patients and 75 controls.
      • Yadlapati R.
      • Pandolfino J.E.
      • Fox M.R.
      • et al.
      What is new in Chicago Classification version 4.0?.

      High-resolution esophageal manometry catheters

      HRM catheters are made by several manufacturers and use either water-perfused or solid-state pressure transducers. Although both systems can convert intraluminal pressures into electrical signals that are used to develop pressure topography plots, substantial differences do exist in catheter design and pressure measurement technique.
      • Bredenoord A.J.
      • Hebbard G.S.
      Technical aspects of clinical high-resolution manometry studies.
      Water perfusion systems are silicone catheters with channels along the length of the catheter. An external pump perfuses the system, and changes in intraluminal pressure are transmitted through the column of water to an external sensor. In general, water-perfused systems have the advantage of a lower cost and smaller, more durable catheter. They are also autoclavable and can be sterilized. These relative advantages are weighed against several disadvantages. Water-perfused systems require longer setup and are technically more challenging to use. For example, perfusion pressure and hydrostatic pressure must be corrected to obtain an accurate recording. Furthermore, because the sensor is external to the patient, position changes can result in artifact.
      • Gyawali C.P.
      • Patel A.
      Esophageal motor function: technical aspects of manometry.
      Solid-state catheters generally incorporate 36 pressure sensors along the length of the catheter. Compared to water-perfused systems, solid-state systems are easier to calibrate, and the output from the sensors is not affected by patient position, resulting in easier setup and use. Solid-state sensors can be affected by temperature, and as a result, a thermal correction is needed before analyzing EPTs obtained during HRM (this is very easily done through the available software analysis platforms). Because several sensors are embedded within the solid-state catheter, it is prone to damage; hence, longevity of the catheter is less than that of water-perfused systems. Furthermore, these catheters cannot be sterilized in an autoclave and thus require standard reprocessing.
      • Gyawali C.P.
      • Patel A.
      Esophageal motor function: technical aspects of manometry.
      ,
      • Bredenoord A.J.
      • Hebbard G.S.
      Technical aspects of clinical high-resolution manometry studies.

      Technique of HRM

      Regardless of catheter type, the technique of performing HRM is similar. Studies are performed in nonsedated patients, usually after 6 hours of fasting. The lubricated manometry catheter is advanced through the nares into the stomach, similar to standard nasogastric tube placement; topical anesthesia with lidocaine is used as necessary. Under real-time manometric guidance, the catheter position is adjusted such that placement allows for manometric visualization of the UES and LES, and at least 5 sensors are positioned in the stomach. Once appropriate positioning is achieved, the catheter is secured at the nose with adhesive tape.
      • Ghosh S.K.
      • Pandolfino J.E.
      • Zhang Q.
      • et al.
      Quantifying esophageal peristalsis with high-resolution manometry: a study of 75 asymptomatic volunteers.
      The study is performed with the patient in supine position. Standard manometric protocol involves a 5-minute period to assess basal LES pressures. This is followed by 10 wet swallows, each consisting of 5 mL of water. Although normative values have been developed with this protocol, seated or upright swallows are sometimes performed. Additional techniques including increasing bolus volume and altering bolus consistency (standardized test meals, solid swallows) have been suggested to improve the diagnosis of esophageal outflow obstruction syndromes.
      • Rogers B.D.
      • Gyawali C.P.
      Enhancing high-resolution esophageal manometry: use of ancillary techniques and maneuvers.
      It is important to note that peristaltic contractility and EGJ morphology are affected by positioning; as such, relative normative values obtained in the supine position may not be applicable to those values obtained in the seated or upright position.
      • Xiao Y.
      • Read A.
      • Nicodeme F.
      • et al.
      The effect of a sitting vs supine posture on normative esophageal pressure topography metrics and Chicago Classification diagnosis of esophageal motility disorders.
      In a study of 75 healthy volunteers, significant differences were noted in both esophageal contractility and EGJ relaxation when comparing supine and upright positioning.
      In addition to the standard wet swallows, maneuvers such as multiple rapid swallows (MRS) have been suggested in specific clinical situations to reveal subtle pathology or evaluate peristaltic reserve. The MRS technique involves five 2-mL swallows every 2 to 3 seconds while in the upright position to reveal peristaltic reserve in patients with absent or ineffective esophageal motility. In one study, this technique was better able to demonstrate peristaltic augmentation and reserve in healthy controls compared to patients with scleroderma. This technique can be especially helpful in patients with ineffective esophageal motility (IEM) who are being considered for antireflux surgery because an abnormal response to MRS has been shown to be associated with increased risk of postfundoplication dysphagia.
      • Carlson D.A.
      • Crowell M.D.
      • Kimmel J.N.
      • et al.
      Loss of peristaltic reserve, determined by multiple rapid swallows, is the most frequent esophageal motility abnormality in patients with systemic sclerosis.
      ,
      • Stoikes N.
      • Drapekin J.
      • Kushnir V.
      • et al.
      The value of multiple rapid swallows during preoperative esophageal manometry before laparoscopic antireflux surgery.
      Although most esophageal motility studies are performed in unsedated patients, there are circumstances when sedation is needed. The primary factor is inability to pass the manometry catheter into the stomach, as in the case of tortuous esophagus. In this circumstance, endoscopy can be used to guide the manometry catheter. The impact of sedation before esophageal motility testing is not well studied; however, a small report suggests midazolam had a statistically significant impact on esophageal body function and EGJ relaxation.
      • Marsh J.K.
      • Hoffman S.M.
      • Dmuchowski C.F.
      Effect of intravenous midazolam on esophageal motility testing in normal human volunteers.
      Whether these changes affect the ultimate diagnosis is not clear. Of note, when endoscopic guidance is required, solid-state manometry catheters cannot be grasped using a snare or other tool because it will damage the sensors. The gastroscope tip can be used to guide the manometry catheter into the gastric lumen.

      Interpretation of HRM

      Interpretation of HRM studies involves an assessment of EGJ morphology, esophageal contractility, and coordination of esophageal peristalsis to formulate a diagnosis. This process has been simplified by the CC of esophageal motor disorders. Now in its fourth iteration, CC has developed a systematic process and algorithm based on HRM metrics.
      • Yadlapati R.
      • Kahrilas P.J.
      • Fox M.R.
      • et al.
      Esophageal motility disorders on high-resolution manometry: Chicago classification version 4.0©.
      ,
      • Kahrilas P.J.
      • Bredenoord A.J.
      • Fox M.
      • et al.
      The Chicago Classification of esophageal motility disorders, v3.0.
      There are 3 primary components to interpretation of an HRM study: (1) assessment of EGJ physiology and morphology, (2) esophageal body contractile vigor, and (3) assessment of peristaltic coordination.

      EGJ

      HRM allows for assessment of EGJ morphology, resting pressure, and deglutitive relaxation. Regarding morphology, HRM allows visualization of both the LES and crural diaphragm. Although normally overlapping and indistinguishable, separation between the LES and contractile deceleration (CD) is diagnostic of a hiatal hernia (Fig. 3). EGJ morphology functions as a surrogate for reflux barrier function. Three subtypes of barrier function have been reported. LES/CD separation is measured as the distance between the intrinsic LES and respiratory pressure signals indicative of the CD. Although variability is expected, the CC has suggested a range be reported for the length of the study.
      • Kahrilas P.J.
      • Bredenoord A.J.
      • Fox M.
      • et al.
      The Chicago Classification of esophageal motility disorders, v3.0.
      Although metrics have been proposed to characterize and define impaired EGJ relaxation, the only validated metric is the IRP. The IRP is median value of the maximum relaxation over a cumulative 4-seconds during a 10-second window starting at UES relaxation. A normal value is <15 mm Hg, and values >15 mm Hg are indicative of impaired relaxation, which may be seen in achalasia or EGJ outflow obstruction.
      • Ghosh S.K.
      • Pandolfino J.E.
      • Zhang Q.
      • et al.
      Quantifying esophageal peristalsis with high-resolution manometry: a study of 75 asymptomatic volunteers.
      ,
      • Pandolfino J.E.
      • Ghosh S.K.
      • Zhang Q.
      • et al.
      Quantifying EGJ morphology and relaxation with high-resolution manometry: a study of 75 asymptomatic volunteers.
      Figure thumbnail gr3
      Figure 3Hiatus hernia identified by high-resolution esophageal manometry. A, Normal esophagogastric junction without hiatus hernia; the lower esophageal sphincter and diaphragm are at the same position. B, Hiatus hernia, with displacement of the lower esophageal sphincter to a few centimeters above the diaphragm.

      Esophageal body function

      Peristaltic contractile vigor and coordination are 2 other key elements of HRM interpretation. For analysis and interpretation of HRM studies, contractile vigor is summarized by the distal contractile integral, a measure that incorporates contraction amplitude in mm Hg, duration of the contraction in seconds, and length of the contracting segment in centimeters.
      • Kahrilas P.J.
      • Bredenoord A.J.
      • Fox M.
      • et al.
      The Chicago Classification of esophageal motility disorders, v3.0.
      The upper limit of normal, based on evaluation of healthy controls, is 8000 mm Hg/s/cm.
      • Roman S.
      • Pandolfino J.E.
      • Chen J.
      • et al.
      Phenotypes and clinical context of hypercontractility in high-resolution esophageal pressure topography (EPT).
      Although initially developed to assess hypercontractility, absent or weak peristalsis can also be assessed. Values less than 450 mm Hg/s/cm are considered weak peristalsis, whereas values <100 mm HG/s/cm are considered failed peristalsis.
      • Xiao Y.
      • Kahrilas P.J.
      • Kwasny M.J.
      • et al.
      High-resolution manometry correlates of ineffective esophageal motility.
      In addition to contractile strength, peristaltic coordination can be assessed during analysis of HRM through calculation of the distal latency, measured as the time (in seconds) from onset of UES relaxation to the contractile deceleration point, the point of relative slowing of peristaltic propagation in the distal esophagus.
      • Pandolfino J.E.
      • Leslie E.
      • Luger D.
      • et al.
      The contractile deceleration point: an important physiologic landmark on oesophageal pressure topography.
      A reduced distal latency (<4.5 seconds) indicates premature contractions consistent with distal esophageal spasm.

      Effectiveness and comparative data

      Achalasia

      The primary utility of HRM in the evaluation of dysphagia is to assess for the presence of achalasia. Furthermore, the utility of HRM in subtyping achalasia has been found in several studies to reliably predict outcome to treatments targeted at the EGJ.
      • Rohof W.O.
      • Hirsch D.P.
      • Kessing B.F.
      • et al.
      Efficacy of treatment for patients with achalasia depends on the distensibility of the esophagogastric junction.
      ,
      • Pandolfino J.E.
      • Ghosh S.K.
      • Rice J.
      • et al.
      Classifying esophageal motility by pressure topography characteristics: a study of 400 patients and 75 controls.
      ,
      • Pratap N.
      • Kalapala R.
      • Darisetty S.
      • et al.
      Achalasia cardia subtyping by high-resolution manometry predicts the therapeutic outcome of pneumatic balloon dilatation.
      ,
      • Andolfi C.
      • Fisichella P.M.
      Meta-analysis of clinical outcome after treatment for achalasia based on manometric subtypes.
      These studies have confirmed that patients with type II achalasia have the most durable symptom improvement after treatments targeted to the LES, whereas patients with type III have the least durable symptom improvement.
      • Ou Y.H.
      • Nie X.M.
      • Li L.F.
      • et al.
      High-resolution manometric subtypes as a predictive factor for the treatment of achalasia: a meta-analysis and systematic review.
      A study that based treatment response on Eckardt scores <3 revealed a treatment success rate of 96% in type II achalasia compared to 81% and 66% in type 1 and III, respectively.
      • Rohof W.O.
      • Salvador R.
      • Annese V.
      • et al.
      Outcomes of treatment for achalasia depend on manometric subtype.
      In a meta-analysis of 21 studies evaluating achalasia subtype, pneumatic dilation appeared to have an acceptable clinical success compared to both POEM and LHM in type II achalasia. The clinical success of LHM was 81%, 92%, and 75% for types I, II, and III, respectively. The success of POEM was 95%, 97%, and 93% in types I, II, and III.
      • Andolfi C.
      • Fisichella P.M.
      Meta-analysis of clinical outcome after treatment for achalasia based on manometric subtypes.
      The 2020 ASGE guideline on achalasia management states that laparoscopic Heller myotomy, pneumatic dilation, and POEM are comparable treatment options for achalasia types I and II but suggest POEM as the preferred treatment for type III achalasia.
      • Khashab M.A.
      • Vela M.F.
      • Thosani N.
      • et al.
      ASGE guideline on the management of achalasia.
      HRM also has clinical utility in the evaluation of recurrent symptoms after treatment of achalasia; however, the use of HRM metrics appears to be more nuanced than in the treatment naive patient. Prior studies have shown that an EGJ pressure of <10 mm Hg after pneumatic dilation correlated with improved symptoms. In a study of 75 patients after treatment (pneumatic dilation, Heller myotomy, or POEM), IRP values were not statistically significant between symptomatic and asymptomatic patients (12 vs 14).
      • Carlson D.A.
      • Lin Z.
      • Kahrilas P.J.
      • et al.
      High-resolution impedance manometry metrics of the esophagogastric junction for the assessment of treatment response in achalasia.
      Furthermore, the sensitivity of elevated IRP was only 65% for symptomatic outcome after treatment of achalasia.

      GERD

      HRM is not needed to make a diagnosis of GERD, but it does provide insight into faulty antireflux physiology in patients with pathologic reflux. Specifically, it can provide insight into the EGJ barrier function. In one study, prolonged separation of the crural diaphragm from the LES, pathognomonic for a hiatal hernia, was associated with prolonged reflux events, both acidic and weakly acidic
      • Bredenoord A.J.
      • Weusten B.L.
      • Timmer R.
      • et al.
      Intermittent spatial separation of diaphragm and lower esophageal sphincter favors acidic and weakly acidic reflux.
      (Fig. 3). To this end, HRM has greater sensitivity and specificity compared to both endoscopy and radiography for the diagnosis of hiatal hernia, with one study revealing 92% sensitivity and 95% specificity.
      • Weijenborg P.W.
      • van Hoeij F.B.
      • Smout A.J.
      • et al.
      Accuracy of hiatal hernia detection with esophageal high-resolution manometry.
      EGJ pressures are intuitively associated with competence of the antireflux barrier. Recently, a new metric, the EGJ contractile integral, has been developed. This has been shown to correlate with the presence and severity of distal esophageal acid exposure.
      • Nicodeme F.
      • Pipa-Muniz M.
      • Khanna K.
      • et al.
      Quantifying esophagogastric junction contractility with a novel HRM topographic metric, the EGJ-Contractile Integral: normative values and preliminary evaluation in PPI non-responders.
      ,
      • Rengarajan A.
      • Bolkhir A.
      • Gor P.
      • et al.
      Esophagogastric junction and esophageal body contraction metrics on high-resolution manometry predict esophageal acid burden.
      Esophageal manometry testing is a prerequisite for antireflux surgery. In one study of 1081 patients evaluated for fundoplication, preoperative manometry provided clinically relevant information that changed the surgical approach in 7% owing to impaired peristalsis or undiagnosed achalasia.
      • Chan W.W.
      • Haroian L.R.
      • Gyawali C.P.
      Value of preoperative esophageal function studies before laparoscopic antireflux surgery.
      Furthermore, although exact values for ineffective esophageal clearance that are prohibitive to complete fundoplication do not exist, aperistalsis on preoperative manometry may lead some surgeons to opt for a partial fundoplication. Those patients with dysphagia and ineffective esophageal motility preoperatively are 3 times more likely to have postoperative dysphagia after fundoplication. Finally, abnormal response to MRS has been shown to be associated with increased risk of postfundoplication dysphagia.
      • Stoikes N.
      • Drapekin J.
      • Kushnir V.
      • et al.
      The value of multiple rapid swallows during preoperative esophageal manometry before laparoscopic antireflux surgery.

      Multichannel intraluminal impedance

      MII is a catheter-based technique that enables detection of intraluminal bolus movement in the esophagus and can be combined with pH measurement or manometry to respectively provide information about both acid and nonacid gastroesophageal reflux and bolus transit.
      • Wang A.
      • Pleskow D.K.
      • Banerjee S.
      • et al.
      Esophageal function testing.
      ,
      • Tutuian R.
      • Vela M.F.
      • Balaji N.S.
      • et al.
      Esophageal function testing with combined multichannel intraluminal impedance and manometry: multicenter study in healthy volunteers.
      ,
      • Hirano I.
      • Richter J.E.
      ACG practice guidelines: esophageal reflux testing.
      Because MII-pH detects all reflux regardless of acidity (acid or nonacid) or composition (liquid, gas, or mixed), it is considered the criterion standard for reflux monitoring.
      • Gyawali C.P.
      • Kahrilas P.J.
      • Savarino E.
      • et al.
      Modern diagnosis of GERD: the Lyon Consensus.
      The addition of impedance to HRM provides further information not only on bolus transit but also clearing velocity, correlation between LES relaxation and bolus transit, and esophageal bolus retention.
      • Gyawali C.P.
      • de Bortoli N.
      • Clarke J.
      • et al.
      Indications and interpretation of esophageal function testing.
      The catheters used for impedance measurement have multiple sets of impedance electrodes distributed through the length of the esophagus. The change in resistance (in Ohms) between the rings is measured to calculate the impedance. At baseline, current is conducted between the rings by ions on the mucosa; passage of a liquid bolus with increased ion conductivity decreases impedance, and conversely an air bolus with poor conductivity increases impedance. By measuring the direction of the impedance changes, bolus movement from proximal to distal or vice versa can be detected, and antegrade or retrograde flow of esophageal contents can be determined.
      Several MII systems are available commercially. Systems usually consist of a selection of single- or multiple-use catheters, data recorders, and dedicated computers and/or proprietary software for data analysis and reporting. Separate catheters are required for MII and pH or MII and HRM. Catheters are usually made of biocompatible polyurethane, are latex-free, and have radiopaque markers. MII-pH catheters have a diameter around 6F and have 6 impedance channels (made of tin-plated copper) and 1 to 2 (esophageal or esophageal and gastric) pH channels (made of antimony or an ion-sensitive field-effect transistor).
      • Wang A.
      • Pleskow D.K.
      • Banerjee S.
      • et al.
      Esophageal function testing.
      ,
      • Wenzl T.G.
      • Benninga M.A.
      • Loots C.M.
      • et al.
      Indications, methodology, and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol.
      Probes are available in varying lengths for pediatric and adult use. Separate probes that are designed to measure pharyngeal and esophageal pH and impedance are also available. The data recorder is usually a small, lightweight ambulatory device that is carried by patients and has multiple event buttons that are used by patients to document body position, meals, and specific symptoms. At the end of the test, data are downloaded from a memory card in the data recorder. Catheters are only compatible with the individual manufacturer’s data recorders. Patients are also usually given a diary with instructions to record body position, meals, and symptoms manually in addition to documenting them electronically on the recorder.
      MII high-resolution manometry requires the use of different catheters, which combine esophageal solid-state or water-perfused pressure sensors for esophageal motor function assessment, with impedance electrodes to evaluate bolus transit. These probes are usually 8F to 12F in diameter and have up to 36 pressure channels and 16 impedance channels.
      Both MII and pH or manometry also include a proprietary software program that is part of the system and is designed to perform automated analysis of the recording and patient-reported events and provide a reporting interface for review and creation of a customized final report that incorporates salient data. The automated analysis may facilitate but should not replace interpretation by a clinician, and manual review of the tracings is mandatory to avoid false-positive or false-negative results. The impedance with manometry system includes a dedicated computer system or software program that provides topographic pressure graphs and 3-dimensional representation of the measured manometry and bolus transit. These systems also integrate reporting based on the CC of esophageal dysmotility.
      • Kahrilas P.J.
      • Bredenoord A.J.
      • Fox M.
      • et al.
      The Chicago Classification of esophageal motility disorders, v3.0.

      Patient preparation, test procedure, analysis, and interpretation

      MII-HRM

      Patients are usually asked to fast for at least 4 to 6 hours before the procedure.
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
      Patients are instructed to take their regular medications. After catheter calibration and application of a topical anesthetic to the patient’s nose and/or posterior pharynx, the MII-HRM catheter is introduced intranasally and advanced so that the pressure sensors span a length extending from the hypopharynx through the esophagus and 3 to 5 cm into the stomach.
      • Carlson D.A.
      • Pandolfino J.E.
      High-resolution manometry in clinical practice.
      Correct catheter placement can be ascertained by visualization of both UES and EGJ on the EPT plot and further confirmed by recognizing the pressure inversion point (the point at which the inspiration-associated negative intrathoracic pressure inverts to positive intra-abdominal pressure).
      • Carlson D.A.
      • Pandolfino J.E.
      High-resolution manometry in clinical practice.
      ,
      • Conklin J.L.
      Evaluation of esophageal motor function with high-resolution manometry.
      After appropriate positioning of the catheter and an acclimatization period of 5 minutes, 10 liquid swallows of 5 mL each are given 30 seconds apart with the patient in supine position. Normal saline solution is preferred over water for liquid swallows because it has standard ionic concentration and provides more predictable impedance changes. Newer testing protocols
      • Yadlapati R.
      • Pandolfino J.E.
      • Fox M.R.
      • et al.
      What is new in Chicago Classification version 4.0?.
      call for the addition of five 5-mL swallows in upright position, along with provocative maneuvers such as administration of multiple rapid swallows, a rapid drink challenge, or solid bolus swallows.
      • Rogers B.D.
      • Gyawali C.P.
      Enhancing high-resolution esophageal manometry: use of ancillary techniques and maneuvers.
      During MII-HRM, manometric data is interpreted and reported using the CC as outlined, and MII measurements are used to assess whether bolus transit is normal.

      MII-pH

      Patient preparation is similar to the MII-EM. Usually a 24-hour study is performed. An a priori decision is made whether to perform the procedure on or off PPI therapy. The catheter is calibrated with buffer solution as per manufacturer recommendations. The location of the LES is usually identified previously by manometry; endoscopic assessment of LES location is thought to be less reliable.
      • Kahrilas P.J.
      • Quigley E.M.
      Clinical esophageal pH recording: a technical review for practice guideline development.
      The probe is passed transnasally with the esophageal pH sensor positioned 5 cm above the proximal border of the LES, leaving the gastric pH channel (when present), 10 cm beyond the LES. Once the catheter is positioned at the desired level, it is secured in place by taping to the skin, ensuring there is no pressure on the catheter or the nostril. The patient is then advised to continue all daily activities and consume a regular diet, including foods and activities that typically induce symptoms. However, patients are advised to limit food to mealtimes and to avoid carbonated beverages between meals. Patients are also instructed to record diet, position (upright or supine), and specific symptoms using the electronic recorder and/or diary for subsequent symptom correlation with acid exposure.
      Once the study period is completed, patients return the recorder and the data are downloaded and analyzed using the proprietary software. For pH studies, AET is considered the primary outcome (Fig. 4); this measure is easily extracted from automated analysis and is predictive of response to medical or surgical therapy.
      • Gyawali C.P.
      • Kahrilas P.J.
      • Savarino E.
      • et al.
      Modern diagnosis of GERD: the Lyon Consensus.
      ,
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
      ,
      • Savarino E.
      • Bredenoord A.J.
      • Fox M.
      • et al.
      Expert consensus document: advances in the physiological assessment and diagnosis of GERD.
      An AET value of >6% is considered abnormal, whereas <4% is considered normal, and 4% to 6% is considered inconclusive.
      • Gyawali C.P.
      • Kahrilas P.J.
      • Savarino E.
      • et al.
      Modern diagnosis of GERD: the Lyon Consensus.
      Total, upright, and supine AET are reported separately. A composite score (DeMeester score) is also calculated and reported combining total, upright, and supine AET; total number of reflux episodes; number of reflux episodes >5 minutes long; and longest reflux episode.
      • Gyawali C.P.
      • de Bortoli N.
      • Clarke J.
      • et al.
      Indications and interpretation of esophageal function testing.
      For MII-pH studies, the number of reflux episodes (total, acid, and nonacid) is reported based on the impedance measurements.
      Figure thumbnail gr4
      Figure 4Example of an impedance-pH report detailing reflux-related data and symptom association (courtesy of Dr Michael Crowell, Mayo Clinic Arizona).
      Symptom reflux association is also an important part of the analysis. Symptom index (SI) and symptom association probability (SAP) are other measures that are complementary to each other. SI is defined as the percentage of symptom events that are related to reflux episodes; a cutoff of >50% is considered positive. SAP is a statistical parameter that assesses the relationship between symptom events and reflux episodes during the measurement; SAP >95% is considered positive.
      • Weusten B.L.
      • Roelofs J.M.
      • Akkermans L.M.
      • et al.
      The symptom-association probability: an improved method for symptom analysis of 24-hour esophageal pH data.
      SI and SAP are independent predictors of response to therapy.
      • Patel A.
      • Sayuk G.S.
      • Gyawali C.P.
      Parameters on esophageal pH-impedance monitoring that predict outcomes of patients with gastroesophageal reflux disease.
      An abnormal AET with a positive SI and SAP is considered the strongest evidence for GERD.
      • Gyawali C.P.
      • Kahrilas P.J.
      • Savarino E.
      • et al.
      Modern diagnosis of GERD: the Lyon Consensus.
      ,
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
      MII also enables calculation of other parameters that may be useful as markers of GERD, including reflux bolus exposure, baseline impedance, postreflux swallow-induced peristaltic waves, and mean nocturnal baseline impedance; these MII-derived measures are adjunctive parameters that are variably used and are currently being validated.
      • Gyawali C.P.
      • Kahrilas P.J.
      • Savarino E.
      • et al.
      Modern diagnosis of GERD: the Lyon Consensus.
      ,
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
      ,

      Ravi K, Geno DM, Vela MF, et al. Baseline impedance measured during high-resolution esophageal impedance manometry reliably discriminates GERD patients. Neurogastroenterol Motil. Epub 2016 Oct 24.

      Of note, the number of reflux episodes determined by impedance has been recently shown to predict the need for and response to surgical augmentation of the LES in patients with PPI-refractory regurgitation.
      • Rogers B.D.
      • Valdovinos L.R.
      • Crowell M.D.
      • et al.
      Number of reflux episodes on pH-impedance monitoring associates with improved symptom outcome and treatment satisfaction in gastro-oesophageal reflux disease (GERD) patients with regurgitation.
      Finally, a modified MII-HRM protocol that includes a test meal can provide objective documentation of rumination.
      • Halland M.
      • Pandolfino J.
      • Barba E.
      Diagnosis and treatment of rumination syndrome.

      Effectiveness and comparative data

      MII-pH

      Ambulatory pH testing off PPI is recommended in patients with persistent symptoms of GERD who have failed an empiric treatment trial with PPIs and do not have confirmatory evidence of GERD on upper endoscopy (grade C or D esophagitis, peptic stricture, or Barrett’s mucosa), patients with atypical symptoms, preoperative testing when antireflux surgery/transoral endoscopic fundoplication is being considered, or persistent symptoms despite antireflux surgery.
      • Gyawali C.P.
      • Kahrilas P.J.
      • Savarino E.
      • et al.
      Modern diagnosis of GERD: the Lyon Consensus.
      ,
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
      For confirmation or exclusion of GERD while off PPIs, pH testing alone is sufficient. Twenty-four-hour MII-pH monitoring is considered superior to pH monitoring alone because it detects the type of refluxate, direction, and the nature of the refluxate (acidic pH <4, weakly acidic pH 4-7, weakly alkaline >7, gaseous and re-reflux episodes). MII-pH is also useful for detection of supragastric belching and evaluation of atypical symptoms such as cough, and it may suggest rumination as a mechanism for regurgitation (the latter can be confirmed by MII-HRM, as mentioned).
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
      Pharyngeal reflux monitoring is available, but consensus statements note that there is limited data currently for routine clinical use of this test.
      • Gyawali C.P.
      • Kahrilas P.J.
      • Savarino E.
      • et al.
      Modern diagnosis of GERD: the Lyon Consensus.
      ,
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.

      Testing on antisecretory therapy

      The merits of performing testing while the patient is on or off antisecretory therapy remain to be conclusively established in prospective studies, but recommendations are provided in consensus statements. Testing off PPI therapy provides information on basal AET and a higher yield of symptom-reflux association. The Lyon consensus recommends testing off PPI therapy as a means of confirming or excluding GERD in patients with no prior positive pH testing, absence of either grade C or D esophagitis, or when testing is being done to evaluate patients for antireflux surgery.
      • Gyawali C.P.
      • Kahrilas P.J.
      • Savarino E.
      • et al.
      Modern diagnosis of GERD: the Lyon Consensus.
      The recommendations of the Porto consensus conference are also similar: Testing off PPI therapy is recommended when the question is whether the patient has GERD or when testing is being done before antireflux surgery. Testing off PPI is also recommended for absence of response or incomplete response to PPI therapy, atypical symptoms, and recurrent or persistent symptoms after antireflux surgery.
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
      Testing on PPI therapy is recommended when there is unequivocal evidence of GERD (prior positive pH study, higher grades of esophagitis, peptic stricture or Barrett’s esophagus >1 cm in length) but there is incomplete or absence of response to treatment. In these instances, impedance-pH testing is recommended over pH monitoring alone to identify patients with nonacid reflux. In a study of 168 patients who were symptomatic despite being on twice-daily PPI therapy, MII-pH testing on therapy was performed; 48% had a positive symptom index for at least 1 symptom, and among these 77% were associated with nonacid reflux.
      • Mainie I.
      • Tutuian R.
      • Shay S.
      • et al.
      Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring.
      In patients who had atypical symptoms (131, 43%), the majority (78%) had a negative symptom index; 25 (19%) had a positive symptom index for nonacid reflux. In another multicenter study of 150 patients with GERD-type symptoms where impedance and pH measurements were performed, a positive symptom association probability was noted in only 55%; for patients on PPI (n = 71), nonacid reflux accounted for nearly 17% of symptoms. These studies demonstrate the relatively high prevalence of symptoms secondary to nonacid reflux and the importance of performing impedance along with pH monitoring to evaluate symptoms refractory to PPI therapy. As mentioned earlier, number of reflux episodes measured by MII-pH has been recently shown to predict the need for and response to surgical augmentation of the LES in patients with PPI-refractory regurgitation.
      • Rogers B.D.
      • Valdovinos L.R.
      • Crowell M.D.
      • et al.
      Number of reflux episodes on pH-impedance monitoring associates with improved symptom outcome and treatment satisfaction in gastro-oesophageal reflux disease (GERD) patients with regurgitation.
      The performance of MII-pH testing on and off medications also provides information on GERD phenotypes and can help differentiate between GERD, reflux hypersensitivity, and alternate diagnoses such as rumination syndrome.

      Atypical symptoms

      Atypical symptoms such as cough are often attributed to GERD, and patients receive empiric PPI therapy. MII-pH testing may be a useful diagnostic modality to evaluate the association between cough and gastroesophageal reflux. In a multicenter study of 192 patients with chronic cough, 24-hour pH impedance pressure monitoring was performed with measurement of acid and weakly acid reflux.
      • Herregods T.V.K.
      • Pauwels A.
      • Jafari J.
      • et al.
      Ambulatory pH-impedance-pressure monitoring as a diagnostic tool for the reflux-cough syndrome.
      Only 25% of patients had reflux-induced cough; among them, acid reflux episodes accounted for only 22% of patients. Conversely, 24% of patients had cough-induced reflux. Also, patients with acid reflux-induced cough were significantly more likely to have typical reflux symptoms compared to patients without the diagnosis. In patients with chronic cough undergoing esophageal function testing, MII-pH is preferred compared to pH monitoring alone to detect symptoms triggered by weakly acid reflux. An acoustic cough detector or esophageal manometry (EM) testing can be beneficial to differentiate reflux-cough from cough-reflux sequences,
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
      but this is not routinely used in clinical practice.
      Belching is also a common symptom that is seen both in GERD and in other functional disorders such as supragastric belching, functional dyspepsia, and rumination syndrome.
      • Kessing B.F.
      • Bredenoord A.J.
      • Smout A.J.
      The pathophysiology, diagnosis and treatment of excessive belching symptoms.
      MII-pH is a reliable test to differentiate gastric belching episodes due to reflux from supragastric belching, a behavioral disorder that can be managed by cognitive behavioral therapy. As mentioned earlier, rumination can be confirmed by a modified MII-HRM protocol that includes a meal challenge.
      • Halland M.
      • Pandolfino J.
      • Barba E.
      Diagnosis and treatment of rumination syndrome.
      ,
      • Kessing B.F.
      • Bredenoord A.J.
      • Smout A.J.
      Objective manometric criteria for the rumination syndrome.

      Testing before antireflux surgery

      Esophageal function testing by manometry and pH off PPI are recommended before antireflux surgery, to rule out esophageal motility disorders, and to confirm the presence of GERD because symptoms alone are not a reliable indicator of GERD.
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
      ,
      • Jobe B.A.
      • Richter J.E.
      • Hoppo T.
      • et al.
      Preoperative diagnostic workup before antireflux surgery: an evidence and experience-based consensus of the Esophageal Diagnostic Advisory Panel.
      The benefit of adding MII to pH testing for preoperative assessment is not clear but may be considered in patients with atypical symptoms or laryngeal symptoms. In a retrospective study of 237 patients with extraesophageal reflux symptoms who underwent pH and impedance testing before fundoplication, heartburn and regurgitation symptoms and abnormal acid exposure were the only predictors of response; impedance parameters did not predict response to fundoplication.
      • Francis D.O.
      • Goutte M.
      • Slaughter J.C.
      • et al.
      Traditional reflux parameters and not impedance monitoring predict outcome after fundoplication in extraesophageal reflux.
      In a recent retrospective study of 71 patients who underwent MII-pH testing on PPI, 42 (59%) had GERD as defined by >48 reflux episodes. When these patients were tested off medications, 31% did not have GERD based on pH testing (abnormal Demeester score).
      • Ward M.A.
      • Dunst C.M.
      • Glasgow M.E.
      • et al.
      Can impedance-pH testing on medications reliably identify patients with GERD as defined by pathologic esophageal acid exposure off medications?.
      A recent randomized controlled trial that compared magnetic sphincter augmentation (MSA) and twice-daily PPI in patients with regurgitation refractory to once-daily PPI showed a significantly higher rate of response for MSA (89% vs 10%).
      • Bell R.
      • Lipham J.
      • Louie B.
      • et al.
      Laparoscopic magnetic sphincter augmentation versus double-dose proton pump inhibitors for management of moderate-to-severe regurgitation in GERD: a randomized controlled trial.
      Subsequent analysis of the MII-pH studies used in that trial revealed that the presence of >80 reflux episodes detected by MII-pH on PPI predicted satisfaction with MSA, and reduction of reflux episodes to <35 was associated with improvement of regurgitation after MSA.
      • Rogers B.D.
      • Valdovinos L.R.
      • Crowell M.D.
      • et al.
      Number of reflux episodes on pH-impedance monitoring associates with improved symptom outcome and treatment satisfaction in gastro-oesophageal reflux disease (GERD) patients with regurgitation.
      Therefore, 24-hour pH testing with or without MII off medications is recommended for preoperative evaluation before antireflux surgery.
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.

      MII-EM

      As with standard HRM, MII-EM is also used for the evaluation of dysphagia, odynophagia, chest pain, and regurgitation after a structural cause is excluded. Impedance adds assessment of whether bolus transit is complete or incomplete for each swallow, along with other measurements such as bolus clearance velocity and esophageal bolus retention, to the information obtained during conventional manometry. Normative data for MII-EM (conventional line tracing manometry rather than HRM) were established in which impedance changes correlated with radiographic bolus movement in 97% of swallows.
      • Tutuian R.
      • Vela M.F.
      • Balaji N.S.
      • et al.
      Esophageal function testing with combined multichannel intraluminal impedance and manometry: multicenter study in healthy volunteers.
      In a prospective study of MII-EM (also based on conventional manometry) in 350 patients with various esophageal manometric abnormalities, all patients with achalasia (n = 24) and scleroderma (n = 4) had abnormal bolus transit.
      • Tutuian R.
      • Castell D.O.
      Combined multichannel intraluminal impedance and manometry clarifies esophageal function abnormalities: study in 350 patients.
      Dysphagia was noted most often in patients with abnormal bolus transit. Of the patients with diffuse esophageal spasm and IEM, 55% and 51%, respectively, had normal bolus transit, and patients with isolated LES abnormalities (hypo- or hypertensive LES), nutcracker esophagus, or normal manometry almost always (>95%) had normal bolus transit. This study suggested a role for MII-EM in assessment of the functional abnormalities associated with manometric diagnoses noted on conventional manometry. In a subsequent study focusing on the IEM group of patients (n = 70), the authors noted that 33% had normal bolus transit for both liquid and viscous swallows, and manometrically normal contractions were almost always associated with normal bolus transit.
      • Tutuian R.
      • Castell D.O.
      Clarification of the esophageal function defect in patients with manometric ineffective esophageal motility: studies using combined impedance-manometry.
      Abnormalities in viscous impedance were further evaluated in a prospective study of 240 patients (129 with nonobstructive dysphagia [NOD], 111 GERD patient controls) with normal liquid manometry. Patients with NOD were more likely to have abnormal viscous impedance compared to the control group (29% vs 16%; P = .02), but a statistically significant difference was not noted in liquid impedance abnormalities.
      • Clayton S.B.
      • Rife C.
      • Kalbfleisch J.H.
      • et al.
      Viscous impedance is an important indicator of abnormal esophageal motility.
      In a study evaluating the role of MII-EM in patients with achalasia and scleroderma, compared with normal controls, it was noted that patients with achalasia had impaired bolus transit across all sites in the esophagus, and pressures were also similar.
      • Mainie I.
      • Tutuian R.
      • Patel A.
      • et al.
      Regional esophageal dysfunction in scleroderma and achalasia using multichannel intraluminal impedance and manometry.
      In contrast, in patients with scleroderma, bolus clearance rates and contraction amplitudes decreased from proximal to distal; in normal controls, the majority of swallows were associated with normal bolus transit. Several other studies have evaluated the role of MII-EM in patients with NOD and other esophageal motility abnormalities, establishing the additional advantage of evaluating bolus transit, specifically viscous bolus transit in the functional evaluation of the esophagus in these diseases.
      • Mainie I.
      • Tutuian R.
      • Patel A.
      • et al.
      Regional esophageal dysfunction in scleroderma and achalasia using multichannel intraluminal impedance and manometry.
      • Blonski W.
      • Hila A.
      • Vela M.F.
      • et al.
      An analysis of distal esophageal impedance in individuals with and without esophageal motility abnormalities.
      • Conchillo J.M.
      • Nguyen N.Q.
      • Samsom M.
      • et al.
      Multichannel intraluminal impedance monitoring in the evaluation of patients with non-obstructive Dysphagia.
      • Cho Y.K.
      • Choi M.G.
      • Park J.M.
      • et al.
      Evaluation of esophageal function in patients with esophageal motor abnormalities using multichannel intraluminal impedance esophageal manometry.
      • Blonski W.
      • Hila A.
      • Jain V.
      • et al.
      Impedance manometry with viscous test solution increases detection of esophageal function defects compared to liquid swallows.
      That said, whether the impedance findings in MII-EM or MII-HRM alter clinical management has not been clearly proven.

      Testing before and after antireflux surgery

      Esophageal manometry is recommended before antireflux surgery to exclude achalasia and other esophageal motor abnormalities, which may predispose to postoperative dysphagia.
      • Jobe B.A.
      • Richter J.E.
      • Hoppo T.
      • et al.
      Preoperative diagnostic workup before antireflux surgery: an evidence and experience-based consensus of the Esophageal Diagnostic Advisory Panel.
      The role of MII-EM to identify manometric abnormalities and guide patient selection before fundoplication has been evaluated in several studies,
      • Montenovo M.
      • Tatum R.P.
      • Figueredo E.
      • et al.
      Does combined multichannel intraluminal esophageal impedance and manometry predict postoperative dysphagia after laparoscopic Nissen fundoplication?.
      • del Genio G.
      • Tolone S.
      • del Genio F.
      • et al.
      Prospective assessment of patient selection for antireflux surgery by combined multichannel intraluminal impedance pH monitoring.
      • Myers J.C.
      • Nguyen N.Q.
      • Jamieson G.G.
      • et al.
      Susceptibility to dysphagia after fundoplication revealed by novel automated impedance manometry analysis.
      but although there are no direct comparative studies evaluating these 2 modalities, there does not appear to be an additional benefit to MII-EM over conventional HRM in guiding patient selection. In a prospective study of 74 patients undergoing Nissen fundoplication who were evaluated with MII-EM preoperatively and at a median of 18 months postoperatively, neither MII-EM nor manometry predicted postoperative dysphagia, and preoperative dysphagia was the only predictor of postoperative dysphagia.
      • Montenovo M.
      • Tatum R.P.
      • Figueredo E.
      • et al.
      Does combined multichannel intraluminal esophageal impedance and manometry predict postoperative dysphagia after laparoscopic Nissen fundoplication?.
      However, in this study, 43% of patients self-reported preoperative dysphagia without any difference in pH, manometric, or MII-EM parameters between those with and without dysphagia. There was a significant improvement in the severity of dysphagia symptom score postoperatively (6.8 ± 2 to 2.6 ± 3.4; P < .01). The high prevalence of preoperative dysphagia and the improvement postoperatively suggest that this study population may not be comparable to the majority of patients undergoing fundoplication.
      In another study, novel metrics were derived on MII-EM data before and after fundoplication through an automated iterative process, and 3 of these variables were combined to create a dysphagia risk index (DRI); a DRI >14 was noted to be optimally predictive of postoperative dysphagia.
      • Conchillo J.M.
      • Nguyen N.Q.
      • Samsom M.
      • et al.
      Multichannel intraluminal impedance monitoring in the evaluation of patients with non-obstructive Dysphagia.
      ,
      • Myers J.C.
      • Nguyen N.Q.
      • Jamieson G.G.
      • et al.
      Susceptibility to dysphagia after fundoplication revealed by novel automated impedance manometry analysis.
      DRI was applied in the evaluation of 25 children who underwent fundoplication, and in addition to postoperative delayed gastric emptying, DRI values were significantly higher in patients who developed postoperative dysphagia compared to those who did not (56, 15-105 vs 2, 2-6; P = .016).
      • Myers J.C.
      • Nguyen N.Q.
      • Jamieson G.G.
      • et al.
      Susceptibility to dysphagia after fundoplication revealed by novel automated impedance manometry analysis.
      MII-EM has also been used to evaluate bolus transit and manometric abnormalities after fundoplication.
      • Del Genio G.
      • Tolone S.
      • Del Genio F.
      • et al.
      Impact of total fundoplication on esophageal transit: analysis by combined multichannel intraluminal impedance and manometry.
      ,
      • Yigit T.
      • Quiroga E.
      • Oelschlager B.
      Multichannel intraluminal impedance for the assessment of post-fundoplication dysphagia.
      In a prospective study of 25 patients, MII-EM was performed before and after laparoscopic Nissen fundoplication; postoperatively, an increase was noted in the LES pressure, but there was no significant difference in the number of complete esophageal bolus transits and transit time for liquid swallows.
      • Del Genio G.
      • Tolone S.
      • Del Genio F.
      • et al.
      Impact of total fundoplication on esophageal transit: analysis by combined multichannel intraluminal impedance and manometry.
      Transit time was more rapid for viscous swallows after surgery. The authors attribute the absence of postoperative manometric abnormalities to careful patient selection by preoperative evaluation of manometric abnormalities and surgical technique. In a separate study comparing Nissen with Toupet fundoplication, no differences were noted in MII parameters between the 2 operations.
      • Koch O.O.
      • Kaindlstorfer A.
      • Antoniou S.A.
      • et al.
      Comparison of results from a randomized trial 1 year after laparoscopic Nissen and Toupet fundoplications.

      Safety and Tolerability

      HRM and impedance monitoring are safe, and there are no reported serious adverse events. Epistaxis can occur with the transnasal catheter passage but is usually self-limited. Passage of transnasal catheters may be relatively contraindicated in patients on anticoagulants, recent gastric surgery, and previous nasopharyngeal surgeries or trauma.
      • Rodriguez S.A.
      • Banerjee S.
      • Desilets D.
      • et al.
      Ultrathin endoscopes.
      There are no reported data on the safety of the use of MII in patients with cardiac defibrillators or pacemakers, but the voltage generated is below the threshold for cardiac stimulation.
      • Vaezi M.F.
      • Shay S.S.
      New techniques in measuring nonacidic esophageal reflux.
      There have been no reported adverse events associated with FLIP.

      Ease of Use

      HRM

      Placement of a transnasal manometry catheter requires basic understanding of pharyngeal and esophageal anatomy. In most centers, this is performed by a trained technician or nurse. HRM usually takes 30 to 40 minutes to complete and requires a 6-hour fast before the procedure. Sufficient understanding of HRM and EPT plots is required to ensure proper placement of the catheter and a study without artifacts. Occasionally, patients may be intolerant to passage of a catheter and may require sedation with endoscopic placement. FLIP topography can be considered as a means to assess esophageal motor function in patients who do not tolerate manometry.

      EndoFLIP

      The FLIP is usually placed transorally during sedated endoscopy or in the operating room with the patient under general anesthesia for patients who are undergoing fundoplication or Heller myotomy. Transnasal placement of FLIP is problematic because of the size of the probe, as is a study in an awake patient because of discomfort. Direct visualization during endoscopy may be used to assist with catheter placement, although the endoscope must be removed before taking measurements. Familiarity with the proprietary software and published measurement algorithms is needed for appropriate positioning of the catheter across the EGJ and reliable data acquisition. If the FLIP topography module is used, the software must be installed on a computer with an ethernet cable connection to the FLIP system. Analysis of the data may be aided by commercially available software, although the relative dearth of normative data and standardized protocols requires an experienced operator for final interpretation.

      MII-pH

      Placement of a transnasal catheter may be associated with transient discomfort despite the use of lubricant or topical anesthetic. Some patients may not tolerate a transnasal catheter and may require wireless pH monitoring.
      • Roman S.
      • Gyawali C.P.
      • Savarino E.
      • et al.
      Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
      The presence of a transnasal catheter may also affect some daily activities and dietary patterns, but most patients are able to complete the examination. Facilities offering MII pH or MII-HRM should have a dedicated area where catheter placement and testing can be performed and should have access to workstations or computers with the required proprietary software programs for analysis and reporting. Analysis and interpretation of the data collected during either of these tests requires an experienced operator. Automated analysis and interpretation of the data by the software programs included with these systems is helpful, but manual review and evaluation of this information by an experienced provider is mandatory before final reporting to avoid falsely negative or falsely positive results, which may affect treatment decisions.

      Financial Considerations

      EndoFLIP

      FLIP requires both a capital investment in the hardware and software, as well as purchase of single-use catheters. The list price for the EndoFLIP System 1.0 is $25,962. The EndoFLIP System 2.0 includes the Topography Display Terminal, Topography Cart, and EndoFLIP System 1.0 and costs $81,000. The 16-cm (EF-322N) and 8-cm (EF 325N) single-use catheters cost $1973 each, whereas the Esoflip 20-mm dilation catheter (ES-320) and 30-mm dilation catheter (ES-330) cost $1550 and $1863, respectively.
      FLIP may be reported using the Current Procedure Terminology code 91040 (Esophageal balloon distension study, diagnostic, with provocation when performed). Of note, this code is not included in the Medicare Ambulatory Surgical Center fee schedule. When performed in outpatient hospital facilities, 91040-26 is appropriate.

      HRM

      Performing high-resolution manometry involves an investment in both equipment and trained personnel to help perform the examination. Capital and per-case expenditures are needed, in addition to indirect costs related to equipment upkeep, reprocessing, and software upgrades. As indicated previously, water-perfusion systems require less upfront capital cost, but require more highly trained staff to perform the examination. Water-perfusion systems can cost $25,000, with the cost of each catheter being $500. The water-perfusion catheter has less overall durability. The most common HRM system is the Manoscan system (Medtronic Inc,). The system retails for $70,000, with each catheter costing $12,000. Reprocessing of catheters is required and incurs indirect processing costs.

      MII-pH

      MII-pH testing requires a similar set-up as HRM with dedicated personnel and initial purchase and continued upkeep of catheters and recorder devices. A dedicated laptop or desktop computer with the proprietary software program is also required for analysis and reporting of the results. Commercially available MII-pH systems include the Digitrapper system (Medtronic Inc), the ZepHr impedance/pH monitoring system (Diversatek Healthcare, Milwaukee, Wisc, USA), and the Ohmega system (Laborie, Portsmouth, NH, USA).
      Esophageal MII-pH testing may be reported using the Current Procedure Terminology code 91038 (esophageal function test, gastroesophageal reflux test 91038 with nasal catheter intraluminal impedance electrode(s) placement, recording analysis and interpretation).

      Areas of Future Research

      EndoFLIP

      Impedance planimetry has ushered in a new era of esophageal function testing, providing novel information regarding the function of the esophageal body and sphincters of the GI tract. Despite a growing body of literature supporting its use in the evaluation and treatment of esophageal motility disorders, normative data remain lacking and expansion of this data pool is needed. The role of the FLIP topography module is also yet to be defined. Distention-mediated contractility may also represent a novel measure in distinguishing normal esophageal function from disease states and merits further investigation. Finally, investigations into the role of FLIP in evaluation of the pyloric and anal sphincters have been limited and further study is warranted.

      HRM

      High-resolution manometry has been the primary tool for diagnosing esophageal motor disorders. One limitation has been the “snapshot in time” assessment of esophageal physiology. The nature of the catheter has made prolonged ambulatory esophageal motility studies challenging owing to patient tolerance; however, 24-hour studies have been reported. These studies may be helpful in identifying intermittent physiologic events that result in symptom generation (ie, esophageal spasm). They can aid in the identification of meal- or sleep-associated events such as transient LES relaxations. The primary limitation is patient tolerance. Smaller catheters or a wireless system may be able to overcome this. The clinical usefulness of prolonged, ambulatory manometry has not been clearly proven.

      Reflux monitoring with MII-pH

      GERD is a complex disease with diverse phenotypic presentations. There are several novel techniques and methods being studied to diagnose and characterize GERD to guide treatment strategies. The optimal testing strategy (on or off antisecretory therapy) and the sequence of testing needs further prospective evaluation. The reliability and validity of newer metrics such as postreflux swallow-induced peristaltic waves, baseline impedance, mean nocturnal baseline impedance, and so on, should also be further investigated. The characterization of manometric abnormalities in GERD and incorporation of these measures into the diagnosis and treatment of GERD is an area of active study. Furthermore, the role of EM in evaluating pharyngeal motor function and supraglottic symptoms needs further study. MII-pH and EM testing also has an emerging role in patients undergoing lung transplantation and bariatric surgery.

      Summary

      In the past few years, there have been substantial developments in the understanding and assessment of esophageal function, some of this owing to the introduction of newer technologies, which have led to a paradigm shift in disease classification, understanding of pathophysiology, and treatment. Impedance planimetry using the EndoFLIP system has been studied extensively in achalasia to diagnose and guide treatment. It also has a role in eosinophilic esophagitis and several other applications. The availability of HRM has enabled a greater understanding of swallow physiology and the manometric correlates of pathology related to non-obstructive dysphagia. Furthermore, the development of clinically relevant phenotypes has not only provided a better understanding of clinical outcomes related to therapy but has further helped define subgroups who may benefit from one therapy over another. MII combined with pH or high-resolution manometry assesses bolus transit and several other measures, which provide a functional assessment of esophageal motility and enable identification of nonacid reflux. HRM and pH monitoring are recommended before antireflux surgery for optimal patient selection with regard to postoperative outcomes such as symptom resolution and dysphagia. Refinements in automated analysis of the vast amounts of data generated during these studies can help facilitate clinician analysis and reporting. Prospective, randomized studies are needed to further evaluate the role of these technologies in clinical practice.

      Acknowledgments

      The ASGE Technology committee is grateful to Dr Michael Crowell, Mayo Clinic Arizona, for providing guidance on this manuscript, as well as Drs Glenn Littenberg, Felix Leung, and Jenifer Lightdale for their review of this document.

      Supplementary data

      References

        • El-Serag H.B.
        • Sweet S.
        • Winchester C.C.
        • et al.
        Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review.
        Gut. 2014; 63: 871-880
        • Richter J.E.
        • Rubenstein J.H.
        Presentation and epidemiology of gastroesophageal reflux disease.
        Gastroenterology. 2018; 154: 267-276
        • Wang A.
        • Pleskow D.K.
        • Banerjee S.
        • et al.
        Esophageal function testing.
        Gastrointest Endosc. 2012; 76: 231-243
        • Chotiprashidi P.
        • Liu J.
        • Carpenter S.
        • et al.
        ASGE technology status evaluation report: wireless esophageal pH monitoring system.
        Gastrointest Endosc. 2005; 62: 485-487
        • Savarino E.
        • di Pietro M.
        • Bredenoord A.J.
        • et al.
        Use of the functional lumen imaging probe in clinical esophagology.
        Am J Gastroenterol. 2020; 115: 1786-1796
        • McMahon B.P.
        • Frøkjær J.B.
        • Drewes A.M.
        • et al.
        A new measurement of oesophago-gastric junction competence.
        Neurogastroenterol Motil. 2004; 16: 543-546
        • Su B.
        • Callahan Z.M.
        • Novak S.
        • et al.
        Using impedance planimetry (EndoFLIP) to evaluate myotomy and predict outcomes after surgery for achalasia.
        J Gastrointest Surg. 2020; 24: 964-971
        • Vosoughi K.
        • Ichkhanian Y.
        • Jacques J.
        • et al.
        Role of endoscopic functional luminal imaging probe in predicting the outcome of gastric peroral endoscopic pyloromyotomy (with video).
        Gastrointest Endosc. 2020; 91: 1289-1299
        • Conchillo J.M.
        • Straathof J.W.A.
        • Mujagic Z.
        • et al.
        Gastric peroral endoscopic pyloromyotomy for decompensated gastroparesis: comprehensive motility analysis in relation to treatment outcomes.
        Endosc Int Open. 2021; 9: E137-E144
        • Lin Z.
        • Nicodème F.
        • Boris L.
        • et al.
        Regional variation in distal esophagus distensibility assessed using the functional luminal imaging probe (FLIP).
        Neurogastroenterol Motil. 2013; 25: e765-e771
        • Lin Z.
        • Kahrilas P.J.
        • Xiao Y.
        • et al.
        Functional luminal imaging probe topography: an improved method for characterizing esophageal distensibility in eosinophilic esophagitis.
        Therap Adv Gastroenterol. 2013; 6: 97-107
        • Carlson D.A.
        • Lin Z.
        • Hirano I.
        • et al.
        Evaluation of esophageal distensibility in eosinophilic esophagitis: an update and comparison of functional lumen imaging probe analytic methods.
        Neurogastroenterol Motil. 2016; 28: 1844-1853
        • Bianca A.
        • Schindler V.
        • Schnurre L.
        • et al.
        Endoscope presence during endoluminal functional lumen imaging probe (FLIP) influences FLIP metrics in the evaluation of esophageal dysmotility.
        Neurogastroenterol Motil. 2020; 32e13823
        • Kwiatek M.A.
        • Hirano I.
        • Kahrilas P.J.
        • et al.
        Mechanical properties of the esophagus in eosinophilic esophagitis.
        Gastroenterology. 2011; 140: 82-90
        • Carlson D.A.
        • Kahrilas P.J.
        • Lin Z.
        • et al.
        Evaluation of esophageal motility utilizing the functional lumen imaging probe.
        Am J Gastroenterol. 2016; 111: 1726-1735
        • Chen J.W.
        • Rubenstein J.H.
        Esophagogastric junction distensibility assessed using the functional lumen imaging probe.
        World J Gastroenterol. 2017; 23: 1289-1297
        • Carlson D.A.
        • Kou W.
        • Lin Z.
        • et al.
        Normal values of esophageal distensibility and distension-induced contractility measured by functional luminal imaging probe panometry.
        Clin Gastroenterol Hepatol. 2019; 17: 674-681
        • Tucker E.
        • Sweis R.
        • Anggiansah A.
        • et al.
        Measurement of esophago-gastric junction cross-sectional area and distensibility by an endolumenal functional lumen imaging probe for the diagnosis of gastro-esophageal reflux disease.
        Neurogastroenterol Motil. 2013; 25: 904-910
        • Amaravadi R.
        • Levine M.S.
        • Rubesin S.E.
        • et al.
        Achalasia with complete relaxation of lower esophageal sphincter: radiographic-manometric correlation.
        Radiology. 2005; 235: 886-891
        • Mearin F.
        • Malagelada J.R.
        Complete lower esophageal sphincter relaxation observed in some achalasia patients is functionally inadequate.
        Am J Physiol Gastrointest Liver Physiol. 2000; 278: G376-G383
        • Carlson D.A.
        • Lin Z.
        • Kahrilas P.J.
        • et al.
        The functional lumen imaging probe detects esophageal contractility not observed with manometry in patients with achalasia.
        Gastroenterology. 2015; 149: 1742-1751
        • Rohof W.O.
        • Hirsch D.P.
        • Kessing B.F.
        • et al.
        Efficacy of treatment for patients with achalasia depends on the distensibility of the esophagogastric junction.
        Gastroenterology. 2012; 143: 328-335
        • Rieder E.
        • Swanström L.L.
        • Perretta S.
        • et al.
        Intraoperative assessment of esophagogastric junction distensibility during per oral endoscopic myotomy (POEM) for esophageal motility disorders.
        Surg Endosc. 2013; 27: 400-405
        • Pandolfino J.E.
        • de Ruigh A.
        • Nicodème F.
        • et al.
        Distensibility of the esophagogastric junction assessed with the functional lumen imaging probe (FLIP™) in achalasia patients.
        Neurogastroenterol Motil. 2013; 25: 496-501
        • Ponds F.A.
        • Bredenoord A.J.
        • Kessing B.F.
        • et al.
        Esophagogastric junction distensibility identifies achalasia subgroup with manometrically normal esophagogastric junction relaxation.
        Neurogastroenterol Motil. Epub. 2016 Jul 25;
        • Yadlapati R.
        • Kahrilas P.J.
        • Fox M.R.
        • et al.
        Esophageal motility disorders on high-resolution manometry: Chicago classification version 4.0©.
        Neurogastroenterol Motil. 2021; 33e14058
        • Triggs J.R.
        • Carlson D.A.
        • Beveridge C.
        • et al.
        Functional luminal imaging probe panometry identifies achalasia-type esophagogastric junction outflow obstruction.
        Clin Gastroenterol Hepatol. 2020; 18: 2209-2217
        • Ichkhanian Y.
        • Sanaei O.
        • Canakis A.
        • et al.
        Esophageal peroral endoscopic myotomy (POEM) for treatment of esophagogastric junction outflow obstruction: results from the first prospective trial.
        Endosc Int Open. 2020; 8: E1137-E1143
        • Teitelbaum E.N.
        • Boris L.
        • Arafat F.O.
        • et al.
        Comparison of esophagogastric junction distensibility changes during POEM and Heller myotomy using intraoperative FLIP.
        Surg Endosc. 2013; 27: 4547-4555
        • Teitelbaum E.N.
        • Soper N.J.
        • Boris L.
        • et al.
        Predictors of intraoperative esophagogastric junction distensibility and physiologic improvement during heller myotomy and poem.
        Surg Endosc. 2014; 28: 3359-3365
        • Teitelbaum E.N.
        • Soper N.J.
        • Pandolfino J.E.
        • et al.
        An extended proximal esophageal myotomy is necessary to normalize EGJ distensibility during Heller myotomy for achalasia, but not POEM.
        Surg Endosc. 2014; 28: 2840-2847
        • Teitelbaum E.N.
        • Soper N.J.
        • Pandolfino J.E.
        • et al.
        Esophagogastric junction distensibility measurements during Heller myotomy and POEM for achalasia predict postoperative symptomatic outcomes.
        Surg Endosc. 2015; 29: 522-528
        • Teitelbaum E.N.
        • Sternbach J.M.
        • El Khoury R.
        • et al.
        The effect of incremental distal gastric myotomy lengths on EGJ distensibility during POEM for achalasia.
        Surg Endosc. 2016; 30: 745-750
        • Ngamruengphong S.
        • von Rahden B.H.A.
        • Filser J.
        • et al.
        Intraoperative measurement of esophagogastric junction cross-sectional area by impedance planimetry correlates with clinical outcomes of peroral endoscopic myotomy for achalasia: a multicenter study.
        Surg Endosc. 2016; 30: 2886-2894
        • Familiari P.
        • Gigante G.
        • Marchese M.
        • et al.
        EndoFLIP system for the intraoperative evaluation of peroral endoscopic myotomy.
        United European Gastroenterol J. 2014; 2: 77-83
        • Ilczyszyn A.
        • Hamaoui K.
        • Cartwright J.
        • et al.
        Intraoperative distensibility measurement during laparoscopic Heller's myotomy for achalasia may reduce the myotomy length without compromising patient outcome.
        Dis Esophagus. 2016; 29: 455-462
        • Yoo I.K.
        • Choi S.A.
        • Kim W.H.
        • et al.
        Assessment of clinical outcomes after peroral endoscopic myotomy via esophageal distensibility measurements with the endoluminal functional lumen imaging probe.
        Gut Liver. 2019; 13: 32-39
        • Jain A.S.
        • Carlson D.A.
        • Triggs J.
        • et al.
        Esophagogastric junction distensibility on functional lumen imaging probe topography predicts treatment response in achalasia - anatomy matters!.
        Am J Gastroenterol. 2019; 114: 1455-1463
        • Barham C.P.
        • Gotley D.C.
        • Mills A.
        • et al.
        Precipitating causes of acid reflux episodes in ambulant patients with gastro-oesophageal reflux disease.
        Gut. 1995; 36: 505-510
        • Pandolfino J.E.
        • Shi G.
        • Curry J.
        • et al.
        Esophagogastric junction distensibility: a factor contributing to sphincter incompetence.
        Am J Physiol Gastrointest Liver Physiol. 2002; 282: G1052-G1058
        • Jenkinson A.D.
        • Scott S.M.
        • Yazaki E.
        • et al.
        Compliance measurement of lower esophageal sphincter and esophageal body in achalasia and gastroesophageal reflux disease.
        Dig Dis Sci. 2001; 46: 1937-1942
        • Kwiatek M.A.
        • Pandolfino J.E.
        • Hirano I.
        • et al.
        Esophagogastric junction distensibility assessed with an endoscopic functional luminal imaging probe (EndoFLIP).
        Gastrointest Endosc. 2010; 72: 272-278
        • Carlson D.A.
        • Kathpalia P.
        • Craft J.
        • et al.
        The relationship between esophageal acid exposure and the esophageal response to volumetric distention.
        Neurogastroenterol Motil. Epub. 2018 Nov 2;
        • Lottrup C.
        • McMahon B.P.
        • Ejstrud P.
        • et al.
        Esophagogastric junction distensibility in hiatus hernia.
        Dis Esophagus. 2016; 29: 463-471
        • Perretta S.
        • McAnena O.
        • Botha A.
        • et al.
        Acta from the EndoFLIP® symposium.
        Surg Innov. 2013; 20: 545-552
        • Ilczyszyn A.
        • Botha A.J.
        Feasibility of esophagogastric junction distensibility measurement during Nissen fundoplication.
        Dis Esophagus. 2014; 27: 637-644
        • Kwiatek M.A.
        • Kahrilas P.J.
        • Soper N.J.
        • et al.
        Esophagogastric junction distensibility after fundoplication assessed with a novel functional luminal imaging probe.
        J Gastrointest Surg. 2010; 14: 268-276
        • DeHaan R.K.
        • Davila D.
        • Frelich M.J.
        • et al.
        Esophagogastric junction distensibility is greater following Toupet compared to Nissen fundoplication.
        Surg Endosc. 2017; 31: 193-198
        • Hoppo T.
        • McMahon B.P.
        • Witteman B.P.L.
        • et al.
        Functional lumen imaging probe to assess geometric changes in the esophagogastric junction following endolumenal fundoplication.
        J Gastrointest Surg. 2011; 15: 1112-1120
        • Rinsma N.F.
        • Smeets F.G.
        • Bruls D.W.
        • et al.
        Effect of transoral incisionless fundoplication on reflux mechanisms.
        Surg Endosc. 2014; 28: 941-949
        • Haito Chavez Y.
        • Ngamruengphong S.
        • Bukhari M.
        • et al.
        Transoral incisionless endoscopic fundoplication guided by impedance planimetry to treat severe GERD symptoms after per-oral endoscopic myotomy.
        Gastrointest Endosc. 2017; 85: 254-255
        • Smeets F.G.M.
        • Keszthelyi D.
        • Bouvy N.D.
        • et al.
        Does measurement of esophagogastric junction distensibility by EndoFLIP predict therapyresponsiveness to endoluminal fundoplication in patients with gastroesophageal reflux disease?.
        Neurogastroenterol Motil. 2015; 21: 255-264
        • Dellon E.S.
        • Liacouras C.A.
        Advances in clinical management of eosinophilic esophagitis.
        Gastroenterology. 2014; 147: 1238-1254
        • Dellon E.S.
        • Speck O.
        • Woodward K.
        • et al.
        Distribution and variability of esophageal eosinophilia in patients undergoing upper endoscopy.
        Mod Pathol. 2015; 28: 383-390
        • Gentile N.
        • Katzka D.
        • Ravi K.
        • et al.
        Oesophageal narrowing is common and frequently under-appreciated at endoscopy in patients with oesophageal eosinophilia.
        Aliment Pharmacol Ther. 2014; 40: 1333-1340
        • Chen J.W.
        • Pandolfino J.E.
        • Lin Z.
        • et al.
        Severity of endoscopically identified esophageal rings correlates with reduced esophageal distensibility in eosinophilic esophagitis.
        Endoscopy. 2016; 48: 794-801
        • Nicodème F.
        • Hirano I.
        • Chen J.
        • et al.
        Esophageal distensibility as a measure of disease severity in eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2013; 11: 1101-11007.e1
        • Carlson D.A.
        • Lin Z.
        • Rogers M.C.
        • et al.
        Utilizing functional lumen imaging probe topography to evaluate esophageal contractility during volumetric distention: a pilot study.
        Neurogastroenterol Motil. 2015; 27: 981-989
        • Baumann A.J.
        • Donnan E.N.
        • Triggs J.R.
        • et al.
        Normal functional luminal imaging probe panometry findings associate with lack of major esophageal motility disorder on high-resolution manometry.
        Clin Gastroenterol Hepatol. 2021; 19: 259-268.e1
        • Carlson D.A.
        • Gyawali C.P.
        • Kahrilas P.J.
        • et al.
        Esophageal motility classification can be established at the time of endoscopy: a study evaluating real-time functional luminal imaging probe panometry.
        Gastrointest Endosc. 2019; 90: 915-923.e1
        • Yu J.X.
        • Baker J.R.
        • Watts L.
        • et al.
        Functional lumen imaging probe is useful for the quantification of gastric sleeve stenosis and prediction of response to endoscopic dilation: a pilot study.
        Obes Surg. 2020; 30: 786-789
        • Hedberg H.M.
        • Carbray J.
        • Ujiki M.B.
        Initial experience with endoscopic pyloromyotomy, with description and video of technique.
        J Gastrointest Surg. 2019; 23: 1706-1710
        • Gyawali C.P.
        • Patel A.
        Esophageal motor function: technical aspects of manometry.
        Gastrointest Endosc Clin N Am. 2014; 24: 527-543
        • Kahrilas P.J.
        • Bredenoord A.J.
        • Fox M.
        • et al.
        The Chicago Classification of esophageal motility disorders, v3.0.
        Neurogastroenterol Motil. 2015; 27: 160-174
        • Pandolfino J.E.
        • Ghosh S.K.
        • Rice J.
        • et al.
        Classifying esophageal motility by pressure topography characteristics: a study of 400 patients and 75 controls.
        Am J Gastroenterol. 2008; 103: 27-37
        • Yadlapati R.
        • Pandolfino J.E.
        • Fox M.R.
        • et al.
        What is new in Chicago Classification version 4.0?.
        Neurogastroenterol Motil. 2021; 33e14053
        • Bredenoord A.J.
        • Hebbard G.S.
        Technical aspects of clinical high-resolution manometry studies.
        Neurogastroenterol Motil. 2012; 24: 5-10
        • Ghosh S.K.
        • Pandolfino J.E.
        • Zhang Q.
        • et al.
        Quantifying esophageal peristalsis with high-resolution manometry: a study of 75 asymptomatic volunteers.
        Am J Physiol Gastrointest Liver Physiol. 2006; 290: G988-G997
        • Rogers B.D.
        • Gyawali C.P.
        Enhancing high-resolution esophageal manometry: use of ancillary techniques and maneuvers.
        Gastroenterol Clin North Am. 2020; 49: 411-426
        • Xiao Y.
        • Read A.
        • Nicodeme F.
        • et al.
        The effect of a sitting vs supine posture on normative esophageal pressure topography metrics and Chicago Classification diagnosis of esophageal motility disorders.
        Neurogastroenterol Motil. 2012; 24: e509-e516
        • Carlson D.A.
        • Crowell M.D.
        • Kimmel J.N.
        • et al.
        Loss of peristaltic reserve, determined by multiple rapid swallows, is the most frequent esophageal motility abnormality in patients with systemic sclerosis.
        Clin Gastroenterol Hepatol. 2016; 14: 1502-1506
        • Stoikes N.
        • Drapekin J.
        • Kushnir V.
        • et al.
        The value of multiple rapid swallows during preoperative esophageal manometry before laparoscopic antireflux surgery.
        Surg Endosc. 2012; 26: 3401-3407
        • Marsh J.K.
        • Hoffman S.M.
        • Dmuchowski C.F.
        Effect of intravenous midazolam on esophageal motility testing in normal human volunteers.
        Am J Gastroenterol. 1993; 88: 860-863
        • Pandolfino J.E.
        • Ghosh S.K.
        • Zhang Q.
        • et al.
        Quantifying EGJ morphology and relaxation with high-resolution manometry: a study of 75 asymptomatic volunteers.
        Am J Physiol Gastrointest Liver Physiol. 2006; 290: G1033-G1040
        • Roman S.
        • Pandolfino J.E.
        • Chen J.
        • et al.
        Phenotypes and clinical context of hypercontractility in high-resolution esophageal pressure topography (EPT).
        Am J Gastroenterol. 2012; 107: 37-45
        • Xiao Y.
        • Kahrilas P.J.
        • Kwasny M.J.
        • et al.
        High-resolution manometry correlates of ineffective esophageal motility.
        Am J Gastroenterol. 2012; 107: 1647-1654
        • Pandolfino J.E.
        • Leslie E.
        • Luger D.
        • et al.
        The contractile deceleration point: an important physiologic landmark on oesophageal pressure topography.
        Neurogastroenterol Motil. 2010; 22: 395-400
        • Pratap N.
        • Kalapala R.
        • Darisetty S.
        • et al.
        Achalasia cardia subtyping by high-resolution manometry predicts the therapeutic outcome of pneumatic balloon dilatation.
        J Neurogastroenterol Motil. 2011; 17: 48-53
        • Andolfi C.
        • Fisichella P.M.
        Meta-analysis of clinical outcome after treatment for achalasia based on manometric subtypes.
        Br J Surg. 2019; 106: 332-341
        • Ou Y.H.
        • Nie X.M.
        • Li L.F.
        • et al.
        High-resolution manometric subtypes as a predictive factor for the treatment of achalasia: a meta-analysis and systematic review.
        J Dig Dis. 2016; 17: 222-235
        • Rohof W.O.
        • Salvador R.
        • Annese V.
        • et al.
        Outcomes of treatment for achalasia depend on manometric subtype.
        Gastroenterology. 2013; 144: 718-725
        • Khashab M.A.
        • Vela M.F.
        • Thosani N.
        • et al.
        ASGE guideline on the management of achalasia.
        Gastrointest Endosc. 2020; 91: 213-227.e6
        • Carlson D.A.
        • Lin Z.
        • Kahrilas P.J.
        • et al.
        High-resolution impedance manometry metrics of the esophagogastric junction for the assessment of treatment response in achalasia.
        Am J Gastroenterol. 2016; 111: 1702-1710
        • Bredenoord A.J.
        • Weusten B.L.
        • Timmer R.
        • et al.
        Intermittent spatial separation of diaphragm and lower esophageal sphincter favors acidic and weakly acidic reflux.
        Gastroenterology. 2006; 130: 334-340
        • Weijenborg P.W.
        • van Hoeij F.B.
        • Smout A.J.
        • et al.
        Accuracy of hiatal hernia detection with esophageal high-resolution manometry.
        Neurogastroenterol Motil. 2015; 27: 293-299
        • Nicodeme F.
        • Pipa-Muniz M.
        • Khanna K.
        • et al.
        Quantifying esophagogastric junction contractility with a novel HRM topographic metric, the EGJ-Contractile Integral: normative values and preliminary evaluation in PPI non-responders.
        Neurogastroenterol Motil. 2014; 26: 353-360
        • Rengarajan A.
        • Bolkhir A.
        • Gor P.
        • et al.
        Esophagogastric junction and esophageal body contraction metrics on high-resolution manometry predict esophageal acid burden.
        Neurogastroenterol Motil. 2018; 30: e13267
        • Chan W.W.
        • Haroian L.R.
        • Gyawali C.P.
        Value of preoperative esophageal function studies before laparoscopic antireflux surgery.
        Surg Endosc. 2011; 25: 2943-2949
        • Tutuian R.
        • Vela M.F.
        • Balaji N.S.
        • et al.
        Esophageal function testing with combined multichannel intraluminal impedance and manometry: multicenter study in healthy volunteers.
        Clin Gastroenterol Hepatol. 2003; 1: 174-182
        • Hirano I.
        • Richter J.E.
        ACG practice guidelines: esophageal reflux testing.
        Am J Gastroenterol. 2007; 102: 668-685
        • Gyawali C.P.
        • Kahrilas P.J.
        • Savarino E.
        • et al.
        Modern diagnosis of GERD: the Lyon Consensus.
        Gut. 2018; 67: 1351-1362
        • Gyawali C.P.
        • de Bortoli N.
        • Clarke J.
        • et al.
        Indications and interpretation of esophageal function testing.
        Ann N Y Acad Sci. 2018; 1434: 239-253
        • Wenzl T.G.
        • Benninga M.A.
        • Loots C.M.
        • et al.
        Indications, methodology, and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol.
        J Pediatr Gastroenterol Nutr. 2012; 55: 230-234
        • Roman S.
        • Gyawali C.P.
        • Savarino E.
        • et al.
        Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group.
        Neurogastroenterol Motil. 2017; 29: 1-15
        • Carlson D.A.
        • Pandolfino J.E.
        High-resolution manometry in clinical practice.
        Gastroenterol Hepatol (N Y). 2015; 11: 374-384
        • Conklin J.L.
        Evaluation of esophageal motor function with high-resolution manometry.
        J Neurogastroenterol Motil. 2013; 19: 281-294
        • Kahrilas P.J.
        • Quigley E.M.
        Clinical esophageal pH recording: a technical review for practice guideline development.
        Gastroenterology. 1996; 110: 1982-1996
        • Savarino E.
        • Bredenoord A.J.
        • Fox M.
        • et al.
        Expert consensus document: advances in the physiological assessment and diagnosis of GERD.
        Nat Rev Gastroenterol Hepatol. 2017; 14: 665-676
        • Weusten B.L.
        • Roelofs J.M.
        • Akkermans L.M.
        • et al.
        The symptom-association probability: an improved method for symptom analysis of 24-hour esophageal pH data.
        Gastroenterology. 1994; 107: 1741-1745
        • Patel A.
        • Sayuk G.S.
        • Gyawali C.P.
        Parameters on esophageal pH-impedance monitoring that predict outcomes of patients with gastroesophageal reflux disease.
        Clin Gastroenterol Hepatol. 2015; 13: 884-891
      1. Ravi K, Geno DM, Vela MF, et al. Baseline impedance measured during high-resolution esophageal impedance manometry reliably discriminates GERD patients. Neurogastroenterol Motil. Epub 2016 Oct 24.

        • Rogers B.D.
        • Valdovinos L.R.
        • Crowell M.D.
        • et al.
        Number of reflux episodes on pH-impedance monitoring associates with improved symptom outcome and treatment satisfaction in gastro-oesophageal reflux disease (GERD) patients with regurgitation.
        Gut. 2021; 70: 450-455
        • Halland M.
        • Pandolfino J.
        • Barba E.
        Diagnosis and treatment of rumination syndrome.
        Clin Gastroenterol Hepatol. 2018; 16: 1549-1555
        • Mainie I.
        • Tutuian R.
        • Shay S.
        • et al.
        Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring.
        Gut. 2006; 55: 1398-1402
        • Herregods T.V.K.
        • Pauwels A.
        • Jafari J.
        • et al.
        Ambulatory pH-impedance-pressure monitoring as a diagnostic tool for the reflux-cough syndrome.
        Dis Esophagus. 2018; 31: 1-7
        • Kessing B.F.
        • Bredenoord A.J.
        • Smout A.J.
        The pathophysiology, diagnosis and treatment of excessive belching symptoms.
        Am J Gastroenterol. 2014; 109: 1196-1203
        • Kessing B.F.
        • Bredenoord A.J.
        • Smout A.J.
        Objective manometric criteria for the rumination syndrome.
        Am J Gastroenterol. 2014; 109: 52-59
        • Jobe B.A.
        • Richter J.E.
        • Hoppo T.
        • et al.
        Preoperative diagnostic workup before antireflux surgery: an evidence and experience-based consensus of the Esophageal Diagnostic Advisory Panel.
        J Am Coll Surg. 2013; 217: 586-597
        • Francis D.O.
        • Goutte M.
        • Slaughter J.C.
        • et al.
        Traditional reflux parameters and not impedance monitoring predict outcome after fundoplication in extraesophageal reflux.
        Laryngoscope. 2011; 121: 1902-1909
        • Ward M.A.
        • Dunst C.M.
        • Glasgow M.E.
        • et al.
        Can impedance-pH testing on medications reliably identify patients with GERD as defined by pathologic esophageal acid exposure off medications?.
        J Gastrointest Surg. 2019; 23: 1301-1308
        • Bell R.
        • Lipham J.
        • Louie B.
        • et al.
        Laparoscopic magnetic sphincter augmentation versus double-dose proton pump inhibitors for management of moderate-to-severe regurgitation in GERD: a randomized controlled trial.
        Gastrointest Endosc. 2019; 89: 14-22.e1
        • Tutuian R.
        • Castell D.O.
        Combined multichannel intraluminal impedance and manometry clarifies esophageal function abnormalities: study in 350 patients.
        Am J Gastroenterol. 2004; 99: 1011-1019
        • Tutuian R.
        • Castell D.O.
        Clarification of the esophageal function defect in patients with manometric ineffective esophageal motility: studies using combined impedance-manometry.
        Clin Gastroenterol Hepatol. 2004; 2: 230-236
        • Clayton S.B.
        • Rife C.
        • Kalbfleisch J.H.
        • et al.
        Viscous impedance is an important indicator of abnormal esophageal motility.
        Neurogastroenterol Motil. 2013; 25: 563-e455
        • Mainie I.
        • Tutuian R.
        • Patel A.
        • et al.
        Regional esophageal dysfunction in scleroderma and achalasia using multichannel intraluminal impedance and manometry.
        Dig Dis Sci. 2008; 53: 210-216
        • Blonski W.
        • Hila A.
        • Vela M.F.
        • et al.
        An analysis of distal esophageal impedance in individuals with and without esophageal motility abnormalities.
        J Clin Gastroenterol. 2008; 42: 776-781
        • Conchillo J.M.
        • Nguyen N.Q.
        • Samsom M.
        • et al.
        Multichannel intraluminal impedance monitoring in the evaluation of patients with non-obstructive Dysphagia.
        Am J Gastroenterol. 2005; 100: 2624-2632
        • Cho Y.K.
        • Choi M.G.
        • Park J.M.
        • et al.
        Evaluation of esophageal function in patients with esophageal motor abnormalities using multichannel intraluminal impedance esophageal manometry.
        World J Gastroenterol. 2006; 12: 6349-6354
        • Blonski W.
        • Hila A.
        • Jain V.
        • et al.
        Impedance manometry with viscous test solution increases detection of esophageal function defects compared to liquid swallows.
        Scand J Gastroenterol. 2007; 42: 917-922
        • Montenovo M.
        • Tatum R.P.
        • Figueredo E.
        • et al.
        Does combined multichannel intraluminal esophageal impedance and manometry predict postoperative dysphagia after laparoscopic Nissen fundoplication?.
        Dis Esophagus. 2009; 22: 656-663
        • del Genio G.
        • Tolone S.
        • del Genio F.
        • et al.
        Prospective assessment of patient selection for antireflux surgery by combined multichannel intraluminal impedance pH monitoring.
        J Gastrointest Surg. 2008; 12: 1491-1496
        • Myers J.C.
        • Nguyen N.Q.
        • Jamieson G.G.
        • et al.
        Susceptibility to dysphagia after fundoplication revealed by novel automated impedance manometry analysis.
        Neurogastroenterol Motil. 2012; 24: 812-e393
        • Del Genio G.
        • Tolone S.
        • Del Genio F.
        • et al.
        Impact of total fundoplication on esophageal transit: analysis by combined multichannel intraluminal impedance and manometry.
        J Clin Gastroenterol. 2012; 46: e1-e5
        • Yigit T.
        • Quiroga E.
        • Oelschlager B.
        Multichannel intraluminal impedance for the assessment of post-fundoplication dysphagia.
        Dis Esophagus. 2006; 19: 382-388
        • Koch O.O.
        • Kaindlstorfer A.
        • Antoniou S.A.
        • et al.
        Comparison of results from a randomized trial 1 year after laparoscopic Nissen and Toupet fundoplications.
        Surg Endosc. 2013; 27: 2383-2390
        • Rodriguez S.A.
        • Banerjee S.
        • Desilets D.
        • et al.
        Ultrathin endoscopes.
        Gastrointest Endosc. 2010; 71: 893-898
        • Vaezi M.F.
        • Shay S.S.
        New techniques in measuring nonacidic esophageal reflux.
        Semin Thorac Cardiovasc Surg. 2001; 13: 255-264