AGA Clinical Practice Update on the Personalized Approach to the Evaluation and Management of GERD: Expert Review

Background & AimsAs many as one-half of all patients with suspected gastroesophageal reflux disease (GERD) do not derive benefit from acid suppression. This review outlines a personalized diagnostic and therapeutic approach to GERD symptoms.MethodsThe Best Practice Advice statements presented here were developed from expert review of existing literature combined with extensive discussion and expert opinion to provide practical advice. Formal rating of the quality of evidence or strength of recommendations was not the intent of this clinical practice update.Best Practice Advice 1Clinicians should develop a care plan for investigation of symptoms suggestive of GERD, selection of therapy (with explanation of potential risks and benefits), and long-term management, including possible de-escalation, in a shared-decision making model with the patient.Best Practice Advice 2Clinicians should provide standardized educational material on GERD mechanisms, weight management, lifestyle and dietary behaviors, relaxation strategies, and awareness about the brain-gut axis relationship to patients with reflux symptoms.Best Practice Advice 3Clinicians should emphasize safety of proton pump inhibitors (PPIs) for the treatment of GERD.Best Practice Advice 4Clinicians should provide patients presenting with troublesome heartburn, regurgitation, and/or non-cardiac chest pain without alarm symptoms a 4- to 8-week trial of single-dose PPI therapy. With inadequate response, dosing can be increased to twice a day or switched to a more effective acid suppressive agent once a day. When there is adequate response, PPI should be tapered to the lowest effective dose.Best Practice Advice 5If PPI therapy is continued in a patient with unproven GERD, clinicians should evaluate the appropriateness and dosing within 12 months after initiation, and offer endoscopy with prolonged wireless reflux monitoring off PPI therapy to establish appropriateness of long-term PPI therapy.Best Practice Advice 6If troublesome heartburn, regurgitation, and/or non-cardiac chest pain do not respond adequately to a PPI trial or when alarm symptoms exist, clinicians should investigate with endoscopy and, in the absence of erosive reflux disease (Los Angeles B or greater) or long-segment (≥3 cm) Barrett’s esophagus, perform prolonged wireless pH monitoring off medication (96-hour preferred if available) to confirm and phenotype GERD or to rule out GERD.Best Practice Advice 7Complete endoscopic evaluation of GERD symptoms includes inspection for erosive esophagitis (graded according to the Los Angeles classification when present), diaphragmatic hiatus (Hill grade of flap valve), axial hiatus hernia length, and inspection for Barrett’s esophagus (graded according to the Prague classification and biopsied when present).Best Practice Advice 8Clinicians should perform upfront objective reflux testing off medication (rather than an empiric PPI trial) in patients with isolated extra-esophageal symptoms and suspicion for reflux etiology.Best Practice Advice 9In symptomatic patients with proven GERD, clinicians should consider ambulatory 24-hour pH-impedance monitoring on PPI as an option to determine the mechanism of persisting esophageal symptoms despite therapy (if adequate expertise exists for interpretation).Best Practice Advice 10Clinicians should personalize adjunctive pharmacotherapy to the GERD phenotype, in contrast to empiric use of these agents. Adjunctive agents include alginate antacids for breakthrough symptoms, nighttime H2 receptor antagonists for nocturnal symptoms, baclofen for regurgitation or belch predominant symptoms, and prokinetics for coexistent gastroparesis.Best Practice Advice 11Clinicians should provide pharmacologic neuromodulation, and/or referral to a behavioral therapist for hypnotherapy, cognitive behavioral therapy, diaphragmatic breathing, and relaxation strategies in patients with functional heartburn or reflux disease associated with esophageal hypervigilance reflux hypersensitivity and/or behavioral disorders.Best Practice Advice 12In patients with proven GERD, laparoscopic fundoplication and magnetic sphincter augmentation are effective surgical options, and transoral incisionless fundoplication is an effective endoscopic option in carefully selected patients.Best Practice Advice 13In patients with proven GERD, Roux-en-Y gastric bypass is an effective primary anti-reflux intervention in obese patients, and a salvage option in non-obese patients, whereas sleeve gastrectomy has potential to worsen GERD.Best Practice Advice 14Candidacy for invasive anti-reflux procedures includes confirmatory evidence of pathologic GERD, exclusion of achalasia, and assessment of esophageal peristaltic function. As many as one-half of all patients with suspected gastroesophageal reflux disease (GERD) do not derive benefit from acid suppression. This review outlines a personalized diagnostic and therapeutic approach to GERD symptoms. The Best Practice Advice statements presented here were developed from expert review of existing literature combined with extensive discussion and expert opinion to provide practical advice. Formal rating of the quality of evidence or strength of recommendations was not the intent of this clinical practice update. Clinicians should develop a care plan for investigation of symptoms suggestive of GERD, selection of therapy (with explanation of potential risks and benefits), and long-term management, including possible de-escalation, in a shared-decision making model with the patient. Clinicians should provide standardized educational material on GERD mechanisms, weight management, lifestyle and dietary behaviors, relaxation strategies, and awareness about the brain-gut axis relationship to patients with reflux symptoms. Clinicians should emphasize safety of proton pump inhibitors (PPIs) for the treatment of GERD. Clinicians should provide patients presenting with troublesome heartburn, regurgitation, and/or non-cardiac chest pain without alarm symptoms a 4- to 8-week trial of single-dose PPI therapy. With inadequate response, dosing can be increased to twice a day or switched to a more effective acid suppressive agent once a day. When there is adequate response, PPI should be tapered to the lowest effective dose. If PPI therapy is continued in a patient with unproven GERD, clinicians should evaluate the appropriateness and dosing within 12 months after initiation, and offer endoscopy with prolonged wireless reflux monitoring off PPI therapy to establish appropriateness of long-term PPI therapy. If troublesome heartburn, regurgitation, and/or non-cardiac chest pain do not respond adequately to a PPI trial or when alarm symptoms exist, clinicians should investigate with endoscopy and, in the absence of erosive reflux disease (Los Angeles B or greater) or long-segment (≥3 cm) Barrett’s esophagus, perform prolonged wireless pH monitoring off medication (96-hour preferred if available) to confirm and phenotype GERD or to rule out GERD. Complete endoscopic evaluation of GERD symptoms includes inspection for erosive esophagitis (graded according to the Los Angeles classification when present), diaphragmatic hiatus (Hill grade of flap valve), axial hiatus hernia length, and inspection for Barrett’s esophagus (graded according to the Prague classification and biopsied when present). Clinicians should perform upfront objective reflux testing off medication (rather than an empiric PPI trial) in patients with isolated extra-esophageal symptoms and suspicion for reflux etiology. In symptomatic patients with proven GERD, clinicians should consider ambulatory 24-hour pH-impedance monitoring on PPI as an option to determine the mechanism of persisting esophageal symptoms despite therapy (if adequate expertise exists for interpretation). Clinicians should personalize adjunctive pharmacotherapy to the GERD phenotype, in contrast to empiric use of these agents. Adjunctive agents include alginate antacids for breakthrough symptoms, nighttime H2 receptor antagonists for nocturnal symptoms, baclofen for regurgitation or belch predominant symptoms, and prokinetics for coexistent gastroparesis. Clinicians should provide pharmacologic neuromodulation, and/or referral to a behavioral therapist for hypnotherapy, cognitive behavioral therapy, diaphragmatic breathing, and relaxation strategies in patients with functional heartburn or reflux disease associated with esophageal hypervigilance reflux hypersensitivity and/or behavioral disorders. In patients with proven GERD, laparoscopic fundoplication and magnetic sphincter augmentation are effective surgical options, and transoral incisionless fundoplication is an effective endoscopic option in carefully selected patients. In patients with proven GERD, Roux-en-Y gastric bypass is an effective primary anti-reflux intervention in obese patients, and a salvage option in non-obese patients, whereas sleeve gastrectomy has potential to worsen GERD. Candidacy for invasive anti-reflux procedures includes confirmatory evidence of pathologic GERD, exclusion of achalasia, and assessment of esophageal peristaltic function. The prevalence of symptomatic gastro-esophageal reflux disease (GERD) is rising, with more than 30% of United States adults reporting at least weekly symptoms.1Delshad S.D. Almario C.V. Chey W.D. et al.Prevalence of gastroesophageal reflux disease and proton pump inhibitor-refractory symptoms.Gastroenterology. 2020; 158: 1250-1261.e2Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar,2Peery A.F. Crockett S.D. Barritt A.S. et al.Burden of gastrointestinal, liver, and pancreatic diseases in the United States.Gastroenterology. 2015; 149: 1731-1741.e3Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar Symptoms of GERD encompass heartburn or regurgitation (typical esophageal symptoms), non-cardiac chest pain (atypical esophageal symptom), and a myriad of extra-esophageal symptoms which include cough, dysphonia, sore throat, and globus.3Vakil N. van Zanten S.V. Kahrilas P. et al.The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus.Am J Gastroenterol. 2006; 101 (quiz: 1943): 1900-1920Crossref PubMed Scopus (2617) Google Scholar Further, symptoms can arise from coexisting or confounding pathophysiology such as mechanical defects, physiologic abnormalities, heightened nociception, and hypervigilance. Despite heterogeneous presentations and pathogeneses, patients with GERD have historically been managed in a similar catch-all fashion, often in the absence of objective abnormalities. Up to 50% of patients, however, do not derive adequate relief with empirical proton pump inhibitor (PPI) therapy.4Sigterman K.E. van Pinxteren B. Bonis P.A. et al.Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease.Cochrane Database Syst Rev. 2013; : CD002095PubMed Google Scholar, 5Kahrilas P.J. Boeckxstaens G. Smout A.J. Management of the patient with incomplete response to PPI therapy.Best Pract Res Clin Gastroenterol. 2013; 27: 401-414Crossref PubMed Scopus (44) Google Scholar, 6Dent J. Vakil N. Jones R. et al.Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond Study.Gut. 2010; 59: 714-721Crossref PubMed Scopus (212) Google Scholar Drivers of inadequate response include absence of pathologic GERD to begin with or symptom pathophysiology that is insufficiently targeted with acid suppression.7Bytzer P. Jones R. Vakil N. et al.Limited ability of the proton-pump inhibitor test to identify patients with gastroesophageal reflux disease.Clin Gastroenterol Hepatol. 2012; 10: 1360-1366Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar In recognition of this problem, the current care paradigm has shifted towards a personalized approach to the evaluation and management of GERD symptoms.8Yadlapati R. Pandolfino J.E. Personalized approach in the work-up and management of gastroesophageal reflux disease.Gastrointest Endosc Clin N Am. 2020; 30: 227-238Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar This Clinical Practice Update (CPU) provides best practice advice for a personalized diagnostic and therapeutic approach to GERD. This expert review was commissioned jointly by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee, the AGA Center for GI Innovation and Technology (CGIT), and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. The AGA CGIT Consensus Conferences bring together content experts, stakeholders (industry, regulatory, and payor), along with a patient advocate to discuss current needs and gaps in innovation relevant to the topic. This is an exhaustive, comprehensive didactic and discussion session created to provide a novel interactive environment to foster the AGA CGIT mission. The topic of this CPU was thoroughly discussed by expert faculty contributors selected by AGA CGIT, industry representatives and patient advocates at the conference organized and hosted by AGA CGIT. The content of this expert review was generated, discussed, and voted upon by the expert faculty contributors at a closed-door meeting during the AGA CGIT conference. All faculty contributors provided up-to-date declaration of conflicts of interest to ensure credibility of this document, and signed off on the final manuscript, which underwent internal peer review by the AGA Institute Clinical Practice Updates Committee as well as external peer review through standard procedures of Clinical Gastroenterology and Hepatology. Patients with GERD symptoms seek care from a spectrum of health care providers including primary care physicians, gastroenterologists, otolaryngologists, pulmonologists, and surgeons. Health care providers and patients alike have questions and concerns regarding treatment of choice, need for objective testing, concerns about GERD complications over time, and risks of long-term treatments. Consistent, standardized approaches across health care teams are essential to streamline GERD evaluation and management. Clinicians should develop a care plan for investigation of symptoms suggestive of GERD, selection of therapy (with explanation of potential risks and benefits), and long-term management, including possible de-escalation, in a shared decision making model with the patient (Best Practice Advice [BPA] 1). To develop a care plan, providers need to ascertain the likelihood of pathologic GERD and discern which mechanisms may be driving symptoms. Symptom characterization is an essential first step. Typical esophageal symptoms of heartburn and regurgitation are approximately 70% sensitive and specific for objective GERD, providing the rationale for first-line PPI trials with high therapeutic gain for symptom relief despite lack of prior objective testing.6Dent J. Vakil N. Jones R. et al.Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond Study.Gut. 2010; 59: 714-721Crossref PubMed Scopus (212) Google Scholar Conversely, an empiric PPI trial is not optimal for isolated extra-esophageal symptoms because mechanisms other than GERD frequently contribute to symptom generation, making likelihood of PPI non-response high.9Gyawali C.P. Carlson D.C. Chen J.W. et al.Esophageal physiologic testing: American College of Gastroenterology Clinical Guideline.Am J Gastroenterol. 2020; 115: 1412-1428Crossref PubMed Scopus (33) Google Scholar,10de Bortoli N. Nacci A. Savarino E. et al.How many cases of laryngopharyngeal reflux suspected by laryngoscopy are gastroesophageal reflux disease-related?.World J Gastroenterol. 2012; 18: 4363-4370Crossref PubMed Scopus (98) Google Scholar Additional clinical factors that can explain symptom generation include central obesity and/or a known hiatal hernia pointing to a mechanical etiology of gastro-esophageal reflux, anxiety, or stress-induced symptoms suggesting visceral hypersensitivity and/or hypervigilance, behavioral disorders including rumination and supragastric belching, or mixed connective tissue disorder raising suspicion for esophageal dysmotility and reduced refluxate clearance.11Patel D.A. Sharda R. Choksi Y.A. et al.Model to select on-therapy vs off-therapy tests for patients with refractory esophageal or extraesophageal symptoms.Gastroenterology. 2018; 155: 1729-1740.e1Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 12Guadagnoli L. Yadlapati R. Taft T. et al.Esophageal hypervigilance is prevalent across gastroesophageal reflux disease presentations.Neurogastroenterol Motil. 2021; e14081Crossref Scopus (9) Google Scholar, 13Sawada A. Guzman M. Nikaki K. et al.Identification of different phenotypes of esophageal reflux hypersensitivity and implications for treatment.Clin Gastroenterol Hepatol. 2021; 19: 690-698.e2Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar During the initial clinic visit, it is essential that clinicians provide standardized educational material on GERD mechanisms, weight management, lifestyle and dietary behaviors, relaxation strategies, and awareness about the brain-gut axis relationship to patients with reflux symptoms (BPA 2). Patient education should emphasize that gastro-esophageal reflux is a physiologic process, commonly mediated through transient lower esophageal sphincter relaxations and controlled by protective factors such as the anti-reflux barrier, effective esophageal peristalsis and salivation, and downstream gastric motility.14Sharma P. Yadlapati R. Pathophysiology and treatment options for gastroesophageal reflux disease: looking beyond acid.Ann N Y Acad Sci. 2021; 1486: 3-14Crossref PubMed Scopus (12) Google Scholar This discussion frames patient expectations in terms of response to acid suppression and potential need for adjunctive strategies. For instance, appreciating the role of the crural diaphragm may facilitate adherence to diaphragmatic breathing.15Ong A.M. Chua L.T. Khor C.J. et al.Diaphragmatic breathing reduces belching and proton pump inhibitor refractory gastroesophageal reflux symptoms.Clin Gastroenterol Hepatol. 2018; 16: 407-416.e2Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Further, understanding the intra-abdominal to intra-thoracic pressure gradient may improve acceptance of weight management and modified dietary/nighttime routines.16Jacobson B.C. Somers S.C. Fuchs C.S. et al.Body-mass index and symptoms of gastroesophageal reflux in women.N Engl J Med. 2006; 354: 2340-2348Crossref PubMed Scopus (429) Google Scholar, 17Yadlapati R. Pandolfino J.E. Alexeeva O. et al.The Reflux Improvement and Monitoring (TRIM) program is associated with symptom improvement and weight reduction for patients with obesity and gastroesophageal reflux disease.Am J Gastroenterol. 2018; 113: 23-30Crossref PubMed Scopus (7) Google Scholar, 18Lindam A. Ness-Jensen E. Jansson C. et al.Gastroesophageal reflux and sleep disturbances: a bidirectional association in a population-based cohort study: the HUNT Study.Sleep. 2016; 39: 1421-1427Crossref Scopus (17) Google Scholar, 19Ness-Jensen E. Lindam A. Lagergren J. et al.Weight loss and reduction in gastroesophageal reflux. A prospective population-based cohort study: the HUNT study.Am J Gastroenterol. 2013; 108: 376-382Crossref PubMed Scopus (69) Google Scholar For patients with a known hiatal hernia and/or symptom burden following meals or during sleep, reduction of supine GERD by elevating the head of the bed and avoiding meals within 3 hours of bedtime are useful.20Ness-Jensen E. Hveem K. El-Serag H. et al.Lifestyle intervention in gastroesophageal reflux disease.Clin Gastroenterol Hepatol. 2016; 14: 175-182.e1-3Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar An introductory discussion about the brain-gut axis can also empower and encourage the patient to integrate stress-reducing activities such as mindfulness into their daily lives, and can open the door for future psychological interventions.21Aziz Q. Fass R. Gyawali C.P. et al.Functional esophageal disorders.Gastroenterology. 2016; 150: 1368-1379Abstract Full Text Full Text PDF Scopus (279) Google Scholar The supplemental document available with this update is a handout that can be provided to patients with suspected GERD (Supplemental Figure 1). Clinicians should provide patients presenting with troublesome heartburn, regurgitation, and/or non-cardiac chest pain without alarm symptoms a 4- to 8-week trial of single-dose PPI therapy (BPA 4). Any commercially available PPI can be used for the trial, the choice of which may be guided by payor coverage, out-of-pocket costs, and prior experiences with a particular PPI. Patients should be counseled to take the PPI 30 to 60 minutes prior to a meal. Education and literature emphasizing safety of PPIs for the treatment of GERD should be provided (BPA 3).22Moayyedi P. How to advise patients on the risk of chronic proton pump inhibitor therapy.Curr Opin Gastroenterol. 2020; 36: 317-322Crossref Scopus (3) Google Scholar Patient symptoms should be reassessed after a 4- to 8-week trial (Figure 1). With inadequate response, dosing can be increased to twice a day or switched to a more effective acid suppressive agent once a day (BPA 4). These can include PPIs that are more potent,23Graham D.Y. Tansel A. Interchangeable use of proton pump inhibitors based on relative potency.Clin Gastroenterol Hepatol. 2018; 16: 800-808.e7Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar less metabolized through the CYP2C19 pathway (eg, rabeprazole, esomeprazole), or available in an extended release formulation (eg, dexlansoprazole),24Lima J.J. Franciosi J.P. Pharmacogenomic testing: the case for CYP2C19 proton pump inhibitor gene-drug pairs.Pharmacogenomics. 2014; 15: 1405-1416Crossref PubMed Scopus (14) Google Scholar as well as potassium competitive acid blockers when available. Routine re-evaluation of treatment should be performed, and the PPI should be tapered to the lowest effective dose when there is adequate response (BPA 4) (Figure 1). Best practices surrounding PPI de-prescribing are further elaborated in a separate AGA CPU. Particular clinical scenarios warrant objective evaluation. If troublesome heartburn, regurgitation, and/or non-cardiac chest pain do not respond adequately to a PPI trial or if alarm symptoms exist, clinicians should investigate with endoscopy and, in the absence of erosive reflux disease (Los Angeles B or greater) or long-segment (≥3 cm) Barrett’s esophagus, perform prolonged wireless pH monitoring off medication (96-hour preferred if available) to confirm and phenotype or to rule out GERD (BPA 6). In addition, clinicians should perform upfront objective reflux testing (rather than an empiric PPI trial) in patients with isolated extra-esophageal symptoms and suspicion of reflux etiology (BPA 8). Another indication for objective testing may include patients with unproven GERD that have a symptom response to empiric PPI therapy, in order to establish the appropriateness of long-term PPI therapy (Figure 1). Thus, if PPI therapy is continued in a patient with unproven GERD, clinicians should evaluate the appropriateness and dosing within 12 months after initiation, and offer endoscopy with prolonged wireless reflux monitoring off PPI therapy to establish appropriate use of long-term PPI therapy (BPA 5). In this context, endoscopy with prolonged reflux monitoring is optimally performed after withholding PPI for 2 to 4 weeks whenever possible.25Yadlapati R. Masihi M. Gyawali C.P. et al.Ambulatory reflux monitoring guides proton pump inhibitor discontinuation in patients with gastroesophageal reflux symptoms: a clinical trial.Gastroenterology. 2021; 160: 174-182.e1Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar This is an important consideration in terms of shared decision-making as many patients want to understand why they may need chronic lifelong maintenance therapy. Complete endoscopic evaluation of GERD symptoms includes inspection for erosive esophagitis (graded according to the Los Angeles classification when present), diaphragmatic hiatus (Hill grade of flap valve), axial hiatus hernia length, and inspection for Barrett’s esophagus (with grading according to the Prague classification and biopsy when present) (BPA 7).26Xie C. Li Y. Zhang N. et al.Gastroesophageal flap valve reflected EGJ morphology and correlated to acid reflux.BMC Gastroenterol. 2017; 17: 118Crossref PubMed Scopus (10) Google Scholar,27Poh C.H. Gasiorowska A. Navarro-Rodriguez T. et al.Upper GI tract findings in patients with heartburn in whom proton pump inhibitor treatment failed versus those not receiving antireflux treatment.Gastrointest Endosc. 2010; 71: 28-34Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar Confirmatory evidence of erosive reflux on endoscopy is found in a minority of patients. These findings include esophagitis (Los Angeles B or greater) and/or the presence of long-segment (≥3 cm) Barrett’s esophagus, with Los Angeles C or D esophagitis constituting severe erosive disease. However, up to 80% of symptomatic patients will not have objective reflux evidence on endoscopy.28Gyawali C.P. Kahrilas P.J. Savarino E. et al.Modern diagnosis of GERD: the Lyon Consensus.Gut. 2018; 67: 1351-1362Crossref PubMed Scopus (488) Google Scholar Of note, Los Angeles A esophagitis can be seen in healthy asymptomatic volunteers and is not considered evidence of erosive reflux disease (Figure 2). Ambulatory reflux monitoring is available in 2 configurations. Wireless pH monitoring (Bravo) uses a pH capsule introduced via a trans-oral catheter during sedated esophagogastroduodenoscopy that adheres to the distal esophagus (6-cm proximal to the endoscopically identified squamocolumnar junction) using a vacuum suction mechanism.29Roman 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: 1-15Crossref PubMed Scopus (182) Google Scholar Wireless pH monitoring measures acid exposure in the distal esophagus for up to 96 hours (based on recorder battery life) and assesses the relationship between patient reported symptoms and acid reflux episodes.30Hasak S. Yadlapati R. Altayar O. et al.Prolonged wireless pH monitoring in patients with persistent reflux symptoms despite proton pump inhibitor therapy.Clin Gastroenterol Hepatol. 2020; 18: 2912-2919Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Catheter-based pH monitoring uses a trans-nasal catheter placed without sedation, which measures acid exposure in the distal esophagus as well as reflux-symptom association for up to 24 hours. Ideally, catheter-based pH monitoring is combined with multiple pairs of intraluminal impedance electrodes to assess air and liquid movement along the esophagus irrespective of pH.29Roman 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: 1-15Crossref PubMed Scopus (182) Google Scholar Based on advantages in assessing acid exposure over a prolonged period of time to account for day-to-day variability, ease of placement during sedated upper endoscopy, and patient tolerance, wireless pH monitoring is the preferred ambulatory reflux monitoring method to objectively assess for GERD in a symptomatic patient.31Scarpulla G. Camilleri S. Galante P. et al.The impact of prolonged pH measurements on the diagnosis of gastroesophageal reflux disease: 4-day wireless pH studies.Am J Gastroenterol. 2007; 102: 2642-2647Crossref PubMed Scopus (61) Google Scholar,32Prakash C. Clouse R.E. Value of extended recording time with wireless pH monitoring in evaluating gastroesophageal reflux disease.Clin Gastroenterol Hepatol. 2005; 3: 329-334Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Outcome data from a recent prospective study demonstrated that normal acid exposure time (<4.0%) on all 4 days of a 96-hour wireless study had an odds ratio of 10.0 (95% confidence interval, 2.70–43.32) in predicting successful PPI withdrawal, and abnormal acid exposure time on ≥2 days had an odds ratio of 5.3 (95% confidence interval, 2.91–13.44) in predicting need for continuing PPI treatment.25Yadlapati R. Masihi M. Gyawali C.P. et al.Ambulatory reflux monitoring guides proton pump inhibitor discontinuation in patients with gastroesophageal reflux symptoms: a clinical trial.Gastroenterology. 2021; 160: 174-182.e1Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar If wireless pH monitoring is not available, 24-hour impedance-pH monitoring off PPI therapy can be utilized when expertise in frame-by-frame interpretation is available.9Gyawali C.P. Carlson D.C. Chen J.W. et al.Esophageal physiologic testing: American College of Gastroenterology Clinical Guideline.Am J Gastroenterol. 2020; 115: 1412-1428Crossref PubMed Scopus (33) Google Scholar,33Gyawali C.P. Rogers B. Frazzoni M. et al.Inter-reviewer variability in interpretation of pH-impedance studies: the Wingate Consensus.Clin Gastroenterol Hepatol. 2021; 19: 1976-1978.e1Abstract Full Text Full Text PDF Scopus (13) Google Scholar In particular, 24-hour impedance-pH monitoring off PPI may be preferred in the evaluation of extra-esophageal symptoms,34Zerbib F. Bredenoord A.J. Fass R. et al.ESNM/ANMS consensus paper: diagnosis and management of re