Ineffective esophageal motility (IEM) is a disorder of esophageal peristalsis on high-resolution esophageal manometry (HRM) characterized by ineffective swallows (weak and/or failed contractions, or large peristaltic breaks) and may be associated with impaired bolus transit, gastroesophageal reflux disease, and symptoms of dysphagia.^1,2 Previously seen in as many as 11.0-17.0% of healthy volunteers by prior classification, the latest iteration of the Chicago classification version 4.0 (CC v4.0) established more strict and clinically relevant criteria.^3-5 According to CC v4.0, ≥ 70% of swallows must be ineffective, or at least 50% of swallows failed (distal contraction integral [DCI] <100 mmHg·s·cm).²

Multiple rapid swallows (MRS) is a provocative test commonly performed during HRM to assess contraction reserve (CR), a finding of prognostic significance in IEM including patients undergoing surgical fundoplication.^6-11 The normal response during MRS is absence of contraction in the esophageal body during rapid swallows followed by a robust, augmented peristaltic sequence defined as CR.¹² CR is typically defined when the post-MRS DCI is higher than the mean single swallow DCI. Historically, MRS is performed with the patient supine and repeated up to 3 times. However, anecdotally MRS is difficult for some patients to tolerate in the supine position and the test is performed in the upright position at our institution.² Although the supine position isolates peristalsis by minimizing the effects of gravity on bolus transit, this position is not physiologic. Though 1 or 2 MRS sequences are usually performed in clinical practice, the test has decreased reproducibility in IEM and the optimal MRS sequences number is still debated.^13,14

This study aims to determine the prevalence of CR in patients with IEM and MRS performed in the upright position, and to assess the ideal number of MRS sequences.

Adult patients aged 18 and older who underwent HRM with MRS and met criteria for IEM by the CC v4.0 based on analysis of 10 supine, single swallows between September 2021 and October 2023 were included. The study was approved by our institution Institutional Review Board (IRB No. 22-009037). Data was abstracted from the electronic medical record including patient demographics and symptoms.

HRM studies were performed after a 6-hour fast period, employing a catheter equipped with 36 circumferential pressure sensors spaced at 1-cm intervals (Medtronic, Shoreview, MN, USA). The HRM catheter was placed transnasally with the tip in the stomach and followed by a 30 second baseline period to assess landmarks before both supine and upright single swallows. The HRM protocol consisted of ten 5-mL liquid swallows in supine position, followed by ten 5-mL liquid swallows in an upright (seated) position with a 30-second interval between each sequence. Each MRS sequence consisted of five 2 mL swallows at 2-3 second intervals. Manometry studies were classified as IEM according to the CC v4.0 and defined as ≥ 70% ineffective swallows (including weak, fragmented, or failed swallows) or at least 50% failed peristalsis.² HRM studies were reviewed individually by the study authors to obtain the individual and mean single swallow DCI values.

CR was considered as present if any post-MRS DCI ratio to the mean single swallow DCI exceeded 1, and if the mean post-MRS DCI (average DCI of the 3 post-MRS sequences) compared to the single swallow DCI was greater than 1.⁷ Incomplete inhibition during the MRS sequence was defined as esophageal body contractility ≥ 100 mmHg·s·cm during the 5 MRS and pan-esophageal pressurization as simultaneous pressurization extending from the upper to the lower esophageal sphincter with pressure greater than 30 mmHg utilizing the isobaric contour.² To assess the utility of 1 versus multiple MRS sequences in assessing contraction reserve, the pooled prevalence of CR was calculated after 2 and 3 MRS sequences. As single supine swallows are the gold standard to assess peristalsis on HRM, CR was defined by referencing the post-MRS DCI to single supine swallows. However, as some patients do not tolerate supine swallows, but only upright swallows, we also assessed CR comparing the post-MRS DCI to upright single swallows.

Finally, to assess the utility of 1 versus 3 MRS sequences in detecting CR in IEM, we reviewed studies at our institution where only 1 upright MRS sequence was performed and compared to another sister institution where 3 upright MRS sequences were performed. The HRM protocol at our institution was 10 upright swallows followed by a single MRS sequence. Adult (age ≥ 18 years) patients were identified who met criteria for IEM by application of CC v4.0 to this HRM protocol. These patients were compared to patients who similarly met criteria for IEM by application of CC v4.0 to 10 upright swallows with 3 MRS sequences. Paired groups were compared with the paired samples t test or McNemar’s test and unpaired groups were compared with the independent samples t test and chi-square (χ²) test.

Fifty-seven patients with IEM who underwent HRM with 10 upright swallows, 10 supine swallows, and 3 upright MRS sequences were included. The median age was 60 years old (range 19-79), 33 (63.5%) patients were female, and the indications for HRM were dysphagia (25, 43.9%), GERD (21, 36.8%), cough (4, 7.0%), globus (3, 5.3%), and other (4, 7.0%). When comparing esophageal peristalsis between the upright and supine sequences, there were more failed (median 4 vs 2, P = 0.005) and fewer weak (4 vs 5, P = 0.020) swallows in the upright compared to supine position (Table 1). The total number of ineffective swallows (defined as weak, absent, or fragmented swallows) did not differ between upright and supine positions (9 vs 9, P = 0.780). Both the DCI (221.8 vs 307.4, P = 0.003) and integrated relaxation pressure (4.7 vs 7.4 mmHg, P = 0.001) were lower in the upright compared to the supine position.

Table 1 . Findings on High-resolution Esophageal Manometry in 57 Patients With Ineffective Esophageal Motility (Based on Chicago Classification Version 4.0 Criteria Applied to 10 Supine Swallows) Who Underwent 3 Multiple Rapid Swallow Sequences

Single swallows	Upright	Supine	P-value
Peristalsis classification No. of swallows
Intact	1	1	0.590
Fragmented	0	0	0.140
Weak	4	5	0.022
Failed	4	2	0.005
DCI (mmHg·s·cm)	221.8	307.4	0.003
IRP (mmHg)	4.7	7.4	0.001
MRS sequence
Post-MRS DCI (mmHg·s·cm)
MRS 1	192		0.450
MRS 2	172
MRS 3	80
Mean post-MRS DCI (mmHg·s·cm)	241
Contraction reserve	Upright	Supine
MRS sequence No. 1	26 (45.6)	23 (40.4)	0.180
MRS sequence No. 2	29 (50.9)	22 (38.6)	0.008
MRS sequence No. 3	18 (31.6)	15 (26.3)	0.320
2 MRS sequencesa	37 (64.9)	31 (54.4)	0.013
3 MRS sequencesa	39 (68.4)	33 (57.9)	0.034
Mean post-MRS DCI	32 (56.1)	22 (38.6)	0.004

^aRepresents presence of contraction reserve after 2 and 3 multiple rapid swallows (MRS) sequences defined as any post-MRS distal contraction integral (DCI) > single swallow DCI.

IRP, integrated relaxation pressure.

Contraction reserve was assessed referencing the post-MRS DCI to single upright and supine swallows.

Data are presented as median or n (%).

When comparing the post-MRS DCI to the mean DCI of the single supine swallows, CR occurred during the first, second, and third MRS sequences in 23 (40.4%), 22 (38.6%), and 15 (26.3%) patients, respectively (Table 1). Using the mean post-MRS DCI, CR occurred in 22 (38.6%) patients. When defining CR as any post-MRS DCI exceed mean single supine swallow DCI, the combined occurrence rate of CR following 1, 2, and 3 MRS sequences was 23 (40.4%), 31 (54.4%), and 33 (57.9%) (Fig. 1). Although more patients had CR after 2 MRS sequences compared to 1 MRS sequence (P < 0.001), there was no difference between 2 and 3 MRS sequences (P = 0.160). There were no differences between the 3 MRS sequences and integrated relaxation pressure, pan-esophageal pressurization, or incomplete inhibition (Supplementary Table 1).

Figure 1. Contraction reserve (CR) assessed by the ratio of any post-multiple rapid swallows distal contraction integral (post-MRS DCI) > mean single supine swallow DCI (A) and any post-MRS DCI > mean single upright swallow DCI (B). *Statistical significance in pairwise comparison to 1 MRS sequence.

When comparing the post-MRS DCI to the average DCI of the single upright swallows, a greater number of patients had CR after 2 and 3 MRS sequences compared to 1 sequence, although there was no difference between 2 and 3 sequences (P = 0.160). Greater numbers of patients exhibited CR after 2 (37 vs 31, P = 0.013) and 3 MRS sequences (39 vs 33, P = 0.034) when referenced to single upright versus single supine swallows (Table 1). CR was more prevalent when comparing the mean post-MRS DCI referenced to single upright versus supine swallows (32 vs 22, P = 0.004).

Using the CC v4.0 criteria applied to single upright swallows, 101 patients with IEM and a single MRS sequence and 71 patients with IEM and 3 MRS sequences were included (Table 2). No differences were observed between the groups and age, sex, or indication for HRM. The group with 1 MRS sequence had a greater mean single swallow DCI, more intact and fragmented swallows, fewer weak swallows, and a greater mean post-MRS DCI compared to patients with 3 MRS sequences. The prevalence of CR was similar between patients with 1 and 3 MRS sequences after a single MRS sequence, but the prevalence was greater in patients after 2 and 3 sequences performed (Fig. 2). CR assessed by the mean post-MRS DCI was similar between the 2 groups. Findings of pan-esophageal pressurization or incomplete inhibition were rare during the MRS sequences (Supplementary Table 2).

Figure 2. Contraction reserve (CR) between patients with ineffective esophageal motility (IEM) applied by Chicago classification version 4.0 (CC v4.0) to 10 upright swallows and assessed with 1 and 3 upright multiple rapid swallows (MRS) sequences. Numbers above the bars represent percentages. *Significance in pairwise comparison to patients with 1 MRS sequence performed. DCI, distal contraction integral.

Table 2 . Findings on High-resolution Esophageal Manometry in Patients With Ineffective Esophageal Motility by Chicago Classification Version 4.0 Criteria Applied to 10 Upright Swallows

Characteristics	1 MRS sequence (n = 101)	3 MRS sequences (n = 71)	P-value
Age (yr)	55	52	0.11
Sex (female)	64 (63.4)	42 (63.6)	0.970
Presenting symptom
GERD	37 (36.6)	23 (32.4)	0.200
Dysphagia	29 (28.7)	32 (45.1)
Chest pain	3 (3.0)	3 (4.2)
Cough	9 (8.9)	5 (7.0)
Other	23 (22.8)	8 (11.3)
Single swallows
Peristalsis classification No. of swallows
Intact	2	1	0.005
Fragmented	0	0	0.048
Weak	3	4	0.035
Failed	5	4	0.820
DCI (mmHg·s·cm)	307.8	221.8	0.001
IRP	6.4	4.4	0.500
MRS sequence
Post-MRS DCI (mmHg·s·cm)	307.8	221.8	0.001
MRS 1	392	292	0.046
MRS 2		172
MRS 3		108
Contraction reserve
MRS sequence No. 1	56 (55.4)	39 (54.9)	0.950
MRS sequence No. 2		38 (53.5)
MRS sequence No. 3		30 (42.3)
2 MRS sequencesa		50 (70.4)b	0.047
3 MRS sequencesa		53 (74.6)b	0.010
Mean post-MRS DCI	56 (55.4)	45 (63.4)	0.300

^aRepresents presence of contraction reserve after 2 and 3 multiple rapid swallows (MRS) sequences defined as any post-MRS distal contraction integral (DCI) > single swallow DCI.

^bRepresents comparison to contraction reserve (CR) in group 1 (1 MRS sequence).

GERD, gastroesophageal reflux disease; IRP, integrated relaxation pressure.

Group 1 (101 patients) underwent one MRS sequence and group 2 (71 patients) underwent 3 MRS sequences. Individual swallows were classified by the Chicago classification version 4.0.

Data are presented as median or n (%).

The main findings from this study aimed to assess the prevalence of CR in patients with IEM by CC v4.0 who underwent 3 upright MRS sequences was that 58% had CR referenced to single supine swallows and that 2 MRS sequences were sufficient for assessment when calculated by any post-MRS DCI higher than mean single swallow DCI. The most relevant findings are that CR in patients with IEM was similar to prior studies assessing supine MRS sequences with an estimated prevalence between 62.0%-69.0%.^{5,7,8,12,13,15} In a study in which patients underwent 10 MRS sequences, 50/79 (63.3%) patients with IEM and 50/80 (62.5%) with normal motility had CR. Although this study was not a direct comparison between upright and supine MRS sequences, this suggests an upright MRS sequence, which in the clinical experience of the study authors is better tolerated, may be sufficient.

Consistent with prior study, we also found that 2 MRS sequences optimized the detection of CR when calculated by any post-MRS DCI higher than mean single swallow DCI. After 1 single MRS sequence in which the prevalence of CR was 40.4%, this increased to 54.4% after 2 MRS sequences and 57.9% after 3 MRS sequences with no difference between 2 and 3 sequences. We conclude at least 2 sequences should be performed to limit false negatives. Again referencing Mauro et al,¹³ in which 10 MRS sequences were performed, 2 sequences were needed using the highest post-MRS DCI, and 3 sequences using the mean post-MRS DCI to accurately detect CR in patients with IEM. The authors discovered that false positives were more frequent using highest post-MRS DCI compared to mean post-MRS DCI (22.0% vs 9.0% respectively) and thus concluded at least 3 MRS sequences using the mean post-MRS DCI was ideal. We found a lower prevalence of CR (22 patients, 38.6%) using the mean post-MRS DCI. Practically, calculation of CR with the greatest post-MRS DCI is simpler than by the mean post-MRS DCI. We argue that the presence of CR by greatest post-MRS DCI, even if not meeting criteria by mean post-MRS DCI, likely has clinical relevance as physiologically the patient is able to generate an augmented post-MRS contraction. As previously outlined by Mauro et al,¹³ the mean post-MRS DCI may be more appropriate in patients with severe IEM as the presence of CR in only 1 of 3 MRS sequences may have less clinical relevance in patients with largely ineffective swallows and significant dysmotility.

This study found that the prevalence of CR was greater when referencing the post-MRS DCI to upright swallows. This was expected as the strength of swallows (DCI) in the upright compared to the supine position is well known to be reduced, likely related to the effect of gravity on esophageal peristalsis.^16-19 In this study, the single swallow DCI was significantly less in the upright compared to supine position, and thus more patients met criteria for CR after 2 and 3 MRS sequences using greatest post-MRS DCI and by using mean post-MRS DCI when referenced to upright single swallows. The relevance of a patient meeting criteria for CR referenced to upright single swallows, but not by supine single swallows, is unclear and caution should be entertained as this may represent a false positive finding until normative data for this reference is available. Referencing an upright MRS to single upright swallows seems sensible based on a uniform position, however not all institutions perform upright swallows let alone 10. Nevertheless, this study found that the prevalence of CR increased similarly after 2 and 3 MRS sequences when referenced to single supine or upright swallows.

A conclusive diagnosis of IEM is defined as ≥ 70% ineffective swallows or ≥ 50% failed peristalsis, with ineffective swallows defined as a weak contraction (DCI ≥ 100 and < 450 mmHg·s·cm), failed peristalsis (DCI < 100 mmHg·s·cm), or a fragmented swallow (break in peristalsis at the transition zone > 5 cm).² Previously, IEM was defined by the CC v3.0 as ≥ 50% ineffective swallows. However, as many as 11.0-17.0% of healthy volunteers met these criteria for IEM and subsequent study demonstrated that ≥ 70% ineffective swallows associated better with esophageal acid reflux burden and abnormal bolus transit.^4,5 Thus, more strict criteria for IEM were created in CC v4.0.^8,20,21 Absence of CR in patients with IEM previously demonstrated prognostic importance with post-fundoplication dysphagia, greater esophageal reflux burden, persistence of IEM post-fundoplication, and is commonly used to guide fundoplication type.^6-11 However, a more recent retrospective study of 220 patients with a single MRS sequence found that CR was not predictive of early or late post-operative dysphagia.²² Thus, the presence of CR has demonstrated clinical relevance but requires further study, and attempts to optimize detection of this motor characteristic, such as with multiple MRS sequences, is important.

The main limitations of this study are its retrospective nature and small sample size. Nevertheless, the sample size is similar to other studies assessing CR in IEM and provides novel information on the performance of an upright MRS sequence. Although this study did not assess a direct comparison between upright and supine MRS sequences, the prevalence of CR during upright MRS is similar to other studies with supine MRS and suggests upright MRS is comparable. Symptom scores were not available to compare symptoms with presence of CR and patients were not further stratified by the severity of IEM, although earlier studies on MRS assessed patients by less stringent criteria with the CC v3.0.

In conclusion, in this study of patients with IEM, 58.0% of patients had CR by upright MRS sequences and 2 MRS sequences appeared sufficient to evaluate CR. This study supports use of upright MRS to evaluate CR although further study directly comparing upright and supine MRS is warranted.

None.

None.

Tian Li, D Chamil Codipilly, Diana Snyder, Karthik Ravi, Maoyin Pang, and Andree H Koop contributed to the study conception and design, material preparation, and data collection and analysis. All author has participated in the preparation of the manuscript, and all authors read and approved the final manuscript.

Note: To access the supplementary tables mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm24097.