Lack of improvement of impaired chemical clearance characterizes PPI-refractory reflux-related heartburn

Objective: Heartburn is the most specific symptom of reflux disease and is highly responsive to proton pump inhibitor (PPI) therapy. Some patients do not respond to PPIs, but mechanisms of refractoriness have not yet been fully elucidated. Impedance-pH monitoring, allowing comprehensive on-therapy assessment of reflux, represents a valuable test to investigate PPI refractoriness. Methods: Prospective multicenter study comparing endoscopy-negative patients with PPI-refractory and PPI-responsive heartburn. Reflux disease was demonstrated by off-PPI impedance-pH monitoring and mechanisms of refractoriness were studied with on-PPI impedance-pH monitoring. Assessment of impedance-pH tracings comprised conventional parameters, post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedance (MNBI). Results : Sixty-four patients entered the study, 32 with PPI-refractory and 32 with PPI-responsive heartburn. On PPI, median percentage gastric and esophageal acid exposure time and number of acid refluxes did not differ between the two groups; conversely, number of total and weakly acidic refluxes and percentage bolus exposure were significantly higher while PSPW index and MNBI were significantly lower in PPI-refractory cases. At multivariate logistic regression analysis, PSPW index was the sole independent risk factor for PPI refractoriness (OR 1.082, 95% CI 1.022-1.146, P = 0.007). Comparing off-and on-PPI parameters, median PSPW index did not change in PPI-refractory patients (24% vs. 26%, P = 0.327) but increased significantly in PPI-responsive cases (29% vs. 46%, P < 0.001). Conclusions: Lack of improvement of impaired chemical clearance is a major determinant of PPI refractoriness. Timely post-reflux salivary swallowing represents a key defensive mechanism and a potential target for future treatment modalities in PPI-refractory reflux-related heartburn.