Esophagus functions as a tubular conduit for the bolus transport from the pharynx to the stomach. Patients with esophageal motor dysfunction may present with a variety of symptoms, including dysphagia, chest pain, heartburn, and regurgitation.¹ Currently, esophageal high-resolution manometry (HRM) remains the gold standard for the evaluation of esophageal function and diagnosis of esophageal motility disorders. Among the various esophageal motility abnormalities, esophageal hypo-contractile disorders, such as absent contractility and ineffective esophageal motility (IEM), may impair esophageal clearance and increase the mucosal exposure to noxious refluxates, and thus have been implicated as a major pathogenetic factor of gastroesophageal reflux disease.² The diagnosis of IEM keeps changing and evolving over the past decades, covering both conventional manometry and HRM periods. The earlier iteration of Chicago classification version 3.0 (CC v3.0) defines IEM as ≥ 50% ineffective (weak or failed) peristalsis with normal integrated relaxation pressure on HRM.³ Nevertheless, several limitations have emerged with CC v3.0 diagnostic criteria for IEM in clinical practice, such as inadequate discrimination of abnormal bolus transit and abnormal esophageal reflux burden.⁴ Moreover, up to 11-17% of healthy volunteers fulfill the IEM criteria in previous studies based on CC v3.0.⁴ Accordingly, the IEM criteria has been largely modified in the latest iteration CC v4.0, and become more stringent requiring > 70% ineffective (failed, weak, or fragmented) swallows or ≥ 50% failed peristalsis.⁵

Several provocative tests have been performed during HRM to better characterize IEM, including multiple rapid swallows (MRS), rapid drink challenge, and solid swallows. Among them, MRS with 5 consecutive 2-mL swallows at 2-3 second intervals could be the most commonly used and studied maneuver to assess the augmentation of smooth muscle contraction after repetitive swallows, also known as the contraction reserve. Contraction reserve is considered as present if the ratio of post-MRS distal contractile integral (DCI) to the mean single-swallow DCI greater than 1. Previous studies have demonstrated the presence of contraction reserve on MRS is inversely correlated with acid exposure time in patients with non-erosive reflux disease,⁶ and may be used to predict postoperative dysphagia or IEM progression following anti-reflux surgery.^7,8 Furthermore, in CC v4.0, for those with inconclusive IEM (50-70% of ineffective swallows), absence of contraction reserve on MRS could be used as supplementary evidence to support the diagnosis of IEM.⁴ Nonetheless, most of the earlier studies exploring the clinical utilities of MRS in patients with IEM came from observational case series, cohort studies, or case-control studies, limiting the scientific robustness for clinical applications.

In this issue of the Journal of Neurogastroenterology and Motility, Li et al⁹ conducted an interesting and practical study to assess the prevalence of contraction reserve in 57 patients with IEM as determined by CC v4.0, and MRS was performed in upright position based on the pre-established HRM protocol. Two different reference metrics (mean single-swallow DCI in supine or upright position) and different sequences or numbers of MRS have been used to determine the presence of contraction reserve. The authors have shown that the prevalence of contraction reserve as detected by upright MRS in patients with IEM was similar compared with prior studies utilizing supine MRS sequences (62-69%). In addition, more patients had contraction reserve after 2 MRS sequences compared to only one MRS sequence, and the difference of contraction reserve between 2 and 3 MRS sequences was nonsignificant. The authors concluded that 2 upright MRS sequences would be adequate to assess the presence of contraction reserve for patients with IEM. In another separate analysis, the prevalence of contraction reserve after a single MRS sequence was similar between two respective groups of patients with IEM (about 50%), but the prevalence was greater in patients who underwent 2 and 3 MRS sequences (about 70%). However, it should be noted that patients with one MRS sequence had a greater mean single-swallow DCI and a greater mean post-MRS DCI compared to patients with 3 MRS sequences.

This study has highlighted the importance of an ideal protocol of MRS for our daily practice. The results have provided a practical alternative testing for physicians evaluating patients with IEM who could not tolerate MRS in traditional supine position. Nevertheless, the study results need to be interpreted with caution. In addition to the inherent limitations of a retrospective study design and a relatively small sample size, the study subjects with IEM were rather heterogeneous with various presenting symptoms, suggesting different underlying pathophysiology or etiologies. Patient tolerability and success rates of different MRS sequences were also not specified. Moreover, there were no direct comparisons between the supine and upright MRS for the diagnostic yield. Finally, the clinical relevance of the contraction reserve detected on upright MRS, such as symptom correlation or outcome prediction, was not determined.

Normal esophageal peristalsis is the collaboration of circular and longitudinal muscle contraction under the delicate control of various cholinergic and nitrergic neurons. However, it should be emphasized that the current definition and calculation of contraction reserve are not absolute. Absence of contraction reserve could be observed in up to 20% of healthy volunteers after a single MRS.¹⁰ Therefore, despite that CC v4.0 has clearly defined the protocol of MRS for clinical practitioners, several important patient factors and technical factors still need to be explored and clarified. What would be the optimal times of MRS sequence and volume of each MRS swallows? Supine or upright position or both? Which metrics should be used for the calculation? The greatest post-MRS DCI or the mean post-MRS DCI? What would be the best ratio of post-MRS DCI to mean single-swallow DCI? How about the correlation between MRS and bolus transit as shown on high-resolution impedance manometry? Any alternative testing for patients who could not tolerate MRS? How to apply the results of MRS to direct further treatment plans? To answer these questions, more prospective, well-designed studies incorporating validated symptom questionnaires and outcome measures for pharmacological treatment (eg, prokinetic agent or proton pump inhibitor) or anti-reflux procedures (eg, fundoplication or endoscopic intervention) are warranted. The best MRS protocol and interpretation is yet to come but could be eagerly anticipated!

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