What is the next step in managing a patient with gastroesophageal reflux disease (GERD) that is not responding to proton pump inhibitor (PPI) therapy?

Management of GERD Not Responding to PPI Therapy

If GERD symptoms persist after an initial 4-8 week trial of once-daily PPI, escalate to twice-daily dosing (before breakfast and dinner) for 8-12 weeks before pursuing diagnostic workup. 1

Initial Optimization Steps

Before declaring treatment failure, verify proper PPI administration:

• Confirm the patient takes PPI 30-60 minutes before meals, not with or after food 1
• Assess medication adherence, as non-compliance is a common cause of apparent PPI failure 2, 3
• Consider switching to a more potent PPI less metabolized through CYP2C19 (rabeprazole, esomeprazole) or an extended-release formulation (dexlansoprazole) 1

Escalation to Twice-Daily PPI

• Increase to twice-daily PPI dosing for a full 8-12 weeks 1
• This represents the upper limit of empirical therapy; patients not responding to twice-daily PPI should be considered treatment failures 1
• Approximately 54% of patients who fail once-daily PPI will improve with twice-daily dosing for an additional 8 weeks 1

Diagnostic Workup for Treatment Failures

Patients failing twice-daily PPI therapy require objective testing to determine the cause of refractoriness. 1

Step 1: Upper Endoscopy with Biopsies (Grade B Recommendation)

• Perform endoscopy to evaluate for erosive esophagitis (Los Angeles B or greater), Barrett's esophagus (≥3 cm), peptic stricture, or alternative diagnoses 1
• Obtain at least 5 esophageal biopsies to evaluate for eosinophilic esophagitis, even if mucosa appears normal 1
• Target any areas of suspected metaplasia, dysplasia, or malignancy 1
• Note that Los Angeles A esophagitis can occur in healthy volunteers and does not confirm GERD 1

Step 2: Esophageal Manometry (if endoscopy is normal)

• Perform manometry to localize the lower esophageal sphincter for subsequent pH monitoring, evaluate peristaltic function, and diagnose major motor disorders 1
• High-resolution manometry has superior sensitivity for detecting atypical presentations of achalasia and distal esophageal spasm 1

Step 3: Ambulatory pH Monitoring (if manometry shows no major abnormality)

• Withhold PPI for 7 days (ideally 2-4 weeks) before testing 1
• Wireless pH monitoring (96-hour preferred) is superior to catheter-based studies due to extended recording period and better accuracy 1
• This objectively confirms or rules out pathologic GERD and distinguishes true GERD from functional disorders 1

Common Causes of PPI Refractoriness

Understanding why patients fail PPI helps guide management:

• True refractory GERD with ongoing acid reflux (inadequate acid suppression, nocturnal acid breakthrough, rapid PPI metabolism) 2, 3
• Non-acid or weakly acidic reflux (PPI reduces acid reflux episodes but increases non-acid reflux) 2, 3
• Functional disorders (functional heartburn, reflux hypersensitivity) that mimic GERD but are not acid-mediated 2, 3, 4
• Misdiagnosis (achalasia, eosinophilic esophagitis, other esophagitis types) 2, 3

Treatment Based on Diagnostic Findings

If Pathologic GERD is Confirmed:

• Continue twice-daily PPI as the lowest effective dose that controls symptoms 1
• Add adjunctive therapies for breakthrough symptoms:
  • Alginate-containing antacids for rapid symptom relief 1
  • Baclofen 10 mg three times daily for regurgitation or belch-predominant symptoms (inhibits transient lower esophageal sphincter relaxations) 5
• Consider anti-reflux surgery (laparoscopic fundoplication or magnetic sphincter augmentation) only if:
  • Objective GERD is confirmed on testing 1
  • Patient has some response to PPI therapy (lack of PPI response predicts surgical failure) 1
  • Shared decision-making confirms understanding of risks and benefits 1

If Functional Disorder is Diagnosed:

• Initiate neuromodulators (tricyclic antidepressants preferred) 4
• Provide cognitive-behavioral therapy or hypnotherapy 4
• Lifestyle modifications remain important 4

Critical Pitfalls to Avoid

• Do NOT empirically escalate beyond twice-daily PPI without objective confirmation of GERD 1
• Do NOT add H2-receptor antagonists to PPI therapy (no evidence of improved efficacy with this combination) 5
• Do NOT continue long-term PPI without establishing a definitive diagnosis in treatment failures 1
• Do NOT ignore alarm symptoms (dysphagia, bleeding, anemia, weight loss, recurrent vomiting) that warrant immediate endoscopy 1
• Do NOT perform pH monitoring while on PPI in initial evaluation (withhold for 7 days minimum) 1