Assessing Treatment Outcomes in Achalasia Using 4-Dimensional High-resolution Impedance Manometry

Abstract

Background/Aims

Assessment of treatment response of achalasia often involves multiple procedures. We aim to investigate innovative metrics based on 4-dimensional high-resolution impedance manometry (4D HRM) to assess treatment response in achalasia patients.

Methods

Patients with achalasia treated by pneumatic dilation or myotomy who underwent follow-up evaluations were included. All patients completed high-resolution impedance manometry before and after treatment. 4D HRM analysis based on developed python program measured clearance ratio, intrabolus pressure (IBP), maximum esophagogastric junction diameter, and distensibility index. Good treatment outcomes were defined as barium column height of < 5 cm at 5 minutes on timed barium esophagram (TBE) and Eckardt score ≤ 3.

Results

Fifty-three patients with achalasia were included: 40% type I, 51% type II, and 9% type III. Change of clearance ratio and IBP on 4D HRM had superior performance in predicting abnormal TBE at 5 minutes (area under the receiver operating characteristic [AUROC] curve, 95% confidence interval: 0.76, 0.59-0.93; 0.74, 0.57-0.92). The combination of clearance ratio (increase with a threshold of 0.1) and IBP (reduction with a threshold of 8.9 mmHg) had a high positive predictive value for normal TBE outcome (93%), and a modest negative predictive value for abnormal TBE outcome (73%). Receiver operating characteristics of metrics related to poor symptomatic outcome only yielded AUROCs (95% CI) of 0.82 (0.68-0.96) for esophageal hypervigilance and anxiety scale posttreatment.

Conclusions

IBP and clearance ratio help to identify abnormal barium retention in patients after treatment. 4D manometry can be an alternative or complementary approach to characterize and assess treatment response of Achalasia, in additional to TBE or functional lumen imaging probe.

Introduction

Achalasia is the most well-defined and characterized esophageal motility disorder. Impaired lower esophageal sphincter (LES) relaxation and absent peristalsis are crucial hallmarks of achalasia, leading to failure of bolus clearance. This ultimately results in esophageal dilatation and retention, consistent with obstructive symptoms. Treatments for achalasia emphasize mechanically disrupting the LES through balloon dilation or myotomy; however, continued or recurrent symptoms occur in approximately 30% of patients.¹ Timed barium esophagram (TBE) assesses bolus retention and is often recommended in the post-therapy assessment of treatment success.¹ Nevertheless, as TBE provides information on esophageal anatomy and emptying, it does not provide detailed insights into esophageal neuromuscular function. Studies have reported that discordance exists between TBE and patient-reported symptoms.^2,3

Esophageal high-resolution impedance manometry (HRIM) has the advantage of providing both high-resolution manometry (HRM) metrics and impedance-based bolus transit patterns simultaneously.^4,5 There has been an increased emphasis on the objective derivation of novel “pressure-flow” variables using different analysis paradigms based on the combined utility of intraluminal impedance and pressure topography.^6-8 For instance, the use of esophageal impedance integral ratio, complemented by TBE, led to an improvement in treatment outcome assessment.⁶

Recently, we developed a novel technique termed 4-dimensional high-resolution impedance manometry (4D HRM) that incorporated an estimation of luminal cross-sectional area (CSA) using impedance with other HRM parameters focused on time, space/axial length and pressure. This novel technique allows for the calculation of bolus volume, esophageal lumen diameter when bolus is present, and distensibility during esophageal bolus transit, and the feasibility of 4D HRM has been demonstrated in patient settings.^9,10 Importantly, we recently revealed that those novel 4D HRM metrics have the potential to complement standard HRM and provide additional information on the objective measurement of bolus volume, intrabolus pressure (IBP) and esophagogastric junction (EGJ) opening during bolus transit, which may potentially avoid the need to obtain further testing (eg, functional lumen imaging probe [FLIP] or TBE) in selected cases.^11,12 However, little is known about the application of this technique in treated achalasia patients. Thus, the aims of this study are to determine whether 4D HRM metrics are useful in evaluating treatment outcomes in patients with achalasia following intervention.

Materials and Methods

Subjects

Adult patients with achalasia (aged 18-89 years) who followed treatment with pneumatic dilation (PD), laparoscopic Heller’s myotomy, or peroral endoscopic myotomy (POEM) between 2019 and 2022 were prospectively enrolled into an NIH funded study (P01 DK117824) at the Esophageal Center of Northwestern. Consecutive patients who completed HRIM both prior to and following interventions were included. Our standard practice is to obtain TBE, HRIM, endoscopy with FLIP, and patient-reported outcomes including the Eckardt score within a period of 6-12 months after intervention (or earlier if significant symptoms persist or recur). Patients with missing posttreatment TBE or Eckardt score were still included. If multiple interventions were performed, the most recent intervention was used for study classification purposes and follow-up interval. The achalasia subtype was defined by HRM prior to achalasia treatment according to Chicago classification version 4.0.¹³ No adverse events were reported during the performance of HRIM, TBE, or FLIP. The study protocol was approved by the Northwestern University Institutional Review Board (IRB No. STU00201372). Informed consent was obtained from all subjects.

High-resolution Impedance Manometry Protocol

The HRIM catheter utilized was a 4.2-mm outer diameter solid-state assembly with 36 circumferential pressure sensors at 1-cm interval, and 18 impedance segments at 2-cm intervals (Medtronic Inc, Shoreview, MN, USA). HRIM studies were performed after at least 6 hours of fasting. Transducers were calibrated at 0 mmHg to 300 mmHg using externally applied pressure. The assembly was placed transnasally and positioned to record from the hypopharynx to the stomach with about 3 intragastric pressure sensors. The HRIM protocol included 5 minutes of baseline recording, ten 5 mL liquid supine swallows and five 5 mL upright swallows using 50% of normal saline. It also included a rapid drink challenge where subjects were asked to drink 200 mL of liquid as rapidly as possible in an upright position. The rapid drink challenge integrated relaxation pressure (IRP) was measured using a 30-second measurement window from rapid drink challenge onset.

Four-dimensional High-resolution Impedance Manometry Analysis

For each HRIM study, the first 5 supine swallows with adequate impedance readings were analyzed to derive 4D HRM metrics. As previously detailed, data from each swallow in Manoview software (Medtronic Inc) were exported into a customized analysis software and landmarks were manually input.^9,10 This allowed delineation of the 4 phases of esophageal bolus transport: accommodation, compartmentalization, peristalsis/esophageal emptying, and ampullary emptying.¹⁴ See example cases of 4D analysis in Supplementary Figure 1. The nadir impedance was tracked by the analysis program during these phases of bolus transit and utilized to define bolus presence, as in Supplementary Figure 1. Intraluminal CSA and diameter were derived from impedance data based on bolus properties, and Ohm’s law, as previously described and detailed.⁹ Phase-specific calculations were output from along the nadir impedance line (IBP) and at the EGJ line (EGJ CSA/diameter and EGJ distensibility index [DI]) to illustrate phase-specific features of bolus transit and biomechanical properties of the EGJ.¹² The IBP was determined as the median value of all time points during the peristalsis/esophageal emptying phase (ie, phase 3). The maximum EGJ CSA/diameter and pressure at the maximum EGJ CSA/diameter were also measured during phase 3. The 4D HRM EGJ-DI was then calculated as the maximum EGJ CSA divided by pressure. For clearance ratio measurement, a detailed description was reported in our previous work.¹¹ Briefly, the time history of integrated bolus volume before, during, and after the 4-phase swallow illustrates maximal volume, and retention volume (Supplementary Fig. 1). The clearance ratio was 1.0 - retention volume divided by the maximal volume.

Evaluation of Treatment Outcome

TBE was performed with the patient consuming 200 mL of low-density barium sulfate in the upright position, with images obtained at 1 minute and 5 minutes. A poor TBE outcome posttreatment was defined as a column height greater than 5 cm at 5 minutes.

Eckardt score was obtained at the time of HRIM. The scores were not available for all subjects because some patients chose not to complete the symptom questionnaires. The Eckardt score attributes a 0-3 Likert scale for assess the frequency/severity of dysphagia, chest pain, and regurgitation and the degree of weight loss, ranging from 0-12, with greater scores indicating greater symptom severity. A poor symptomatic outcome was defined as Eckardt score greater than 3.

Additional Clinical Evaluation

The FLIP study was conducted using 16-cm FLIP (EndoFLIP EF-322 N; Medtronic Inc) during sedated endoscopy, following previously established protocols.^15,16 Analysis of FLIP Panometry focused on the EGJ opening classification as previously described.^17,18 Briefly, EGJ opening was classified by applying the EGJ-DI at the 60 mL FLIP fill volume and the maximum EGJ diameter that was achieved during the 60 mL or 70 mL fill volume.

Esophageal hypervigilance and anxiety scale (EHAS) was reviewed pre or posttreatment when available. The EHAS is a 15-item scale assessing esophageal hypervigilance and symptom specific anxiety scored on a 0-4 Likert scale. The items are summed to yield a total EHAS score ranging from 0 to 60 (greater hypervigilance/anxiety).¹⁹

Statistical Methods

Results were expressed as n (%), mean (SD), or median (interquartile range [IQR]), depending on the variable type and data distribution. Groups were compared using the chi-square test for categorical variables and ANOVA/t tests or Kruskal-Wallis/Mann-Whitney U tests for continuous variables, based on data distribution. Correlations were assessed using Spearman’s rho. Receiver operating characteristic (ROC) curves were applied to assess the variable’s ability to predict abnormal treatment outcomes. Statistical significance was set at a two-tailed P-value of < 0.05. Post hoc comparisons, as appropriate, were adjusted using the Bonferroni correction to account for multiple comparisons. The analyses were conducted with IBM SPSS Statistics (version 29.0.1.0; IBM Corp., Armonk, NY, USA).

Results

Subjects

A total of 53 patients (mean age 50 years, 58% female) were included in the primary analysis: 40% type I achalasia, 51% type II achalasia, and 9% type III achalasia (Table 1). Follow-up was completed at a median interval of 10.2 months (IQR, 6.9-13.7) between HRIM and treatment: 72% POEM, 15% PD, and 13% laparoscopic Heller's myotomy. Two patients underwent 2 interventions (initially PD, followed by POEM). Forty-six patients (87%) completed posttreatment Eckardt score (median, 2; IQR, 1-3), 80% of whom had a good symptomatic outcome. Thirty-six patients (68%) underwent posttreatment TBE (median, 3.9 cm; IQR, 0.0-7.2 cm), 69% of whom had a good TBE outcome. Rates of both good TBE and symptomatic outcomes did not differ based on treatment modalities. Type II achalasia had superior treatment outcomes, as reflected by good TBE and symptomatic relief (Table 1).

Table 1.

Patient Characteristics

Patient characteristics	Total cohort (n = 53)	TBE outcome			Eckardt score outcome
		Good (n = 25)	Poor (n = 11)		Good (n = 37)	Poor (n = 9)
Age (yr)	50 (17)	47 (18)	51 (16)		50 (17)	58 (13)
Gender (female/male)	31/22	13/12	8/3		19/18	7/2
Achalasia subtypea,b
Type I	21 (40%)	6 (24%)	8 (73%)		13 (35%)	5 (56%)
Type II	27 (51%)	17 (68%)	3 (27%)		22 (60%)	1 (11%)
Type III	5 (9%)	2 (8%)	0 (0%)		2 (5%)	3 (33%)
Treatment modality
Pneumatic dilation	8 (15%)	3 (12%)	2 (18%)		6 (16%)	0 (0%)
Laparoscopic Heller’s myotomy	7 (13%)	3 (12%)	1 (9%)		5 (14%)	1 (11%)
Per-oral endoscopic myotomy	38 (72%)	19 (76%)	8 (73%)		26 (70%)	8 (89%)
Follow-up interval, months	10.2 (6.9-13.7)	8.3 (6.8-13)	7.7 (5.5-14.8)		10.2 (7-13.4)	7.3 (3.9-13.5)
Posttreatment HRIM EGJ parameters
Median supine IRP (mmHg)	14 (9-19.8)	14 (11.5-19.5)	17.5 (10-28.5)		14 (9-20.8)	13 (6.8-20.8)
Supine IRP < 15 mmHg	31 (59%)	14 (56%)	4 (36%)		21 (57%)	5 (56%)
Supine IRP > 15 mmHg	22 (41%)	11 (44%)	7 (64%)		16 (43%)	4 (44%)
Posttreatment FLIP EGJ parameters
EGJ-DI (mm2/mmHg)b	5.1 (3.7-6.7)	5 (3.5-6.2)	4.8 (3.1-7.5)		5 (3.7-6)	6.4 (4.9-7.9)
Maximum EGJ diameter (mm)	17 (15-19)	17 (14.5-19)	16 (12-19)		17 (15-19)	18 (16-18.5)
Normal EGJ opening	38 (72)	17 (68%)	7 (64%)		24 (65%)	9 (100%)
Borderline EGJ opening	13 (25)	8 (32%)	3 (27%)		12 (32%)	0 (0%)
Reduced EGJ opening	2 (4)	0 (0%)	1 (9%)		1 (3%)	0 (0%)

^aP < 0.05 compared with good timed barium esophagram (TBE) outcome.

^bP < 0.05 compared with good Eckardt score outcome.

HRIM, high-resolution impedance manometry; EGJ, esophagogastric junction; IRP, integrated relaxation pressure; EGJ-DI, esophagogastric junction distensibility index.

Values are displayed as mean (SD), n (%), or median (interquartile range).

On posttreatment HRIM, 57% of patients had IRP < 15 mmHg. All patients completed posttreatment FLIP. The majority of patients (72%) had a normal EGJ opening, followed by 25% with borderline EGJ opening and 4% with reduced EGJ opening. Rates of both good TBE and symptomatic outcomes did not differ in terms of those EGJ parameters (Table 1).

Four-dimensional High-resolution Impedance Manometry Metrics

All the 4D HRM metrics improved after treatment (all P < 0.001) (Supplementary Table 1). Type III achalasia had the highest IBP on 4D HRM pretreatment (P < 0.001). Posttreatment abnormal supine IRP (> 15 mmHg) was associated with higher IBP on 4D HRM pretreatment (P = 0.001). Three pretreatment 4D HRM metrics (ie, clearance ratio, EGJ-DI, and maximum EGJ diameter) did not differ with respect to achalasia subtype or treatment modality.

Patients with type I and II achalasia showed a significant increase in clearance ratio and EGJ-DI on 4D HRM from pretreatment to posttreatment. A significant reduction in IBP on 4D HRM was observed across achalasia subtypes except for type III, and the increase in maximum EGJ diameter on 4D HRM was significant only in type I. In terms of treatment modality, POEM demonstrated a strong ability to significantly improve all 4D HRM metrics (Supplementary Table 1).

There is a statistically significant improvement in clearance ratio and maximum EGJ diameter on 4D HRM in patients with normal IRP (ie, IRP < 15 mmHg) from pretreatment to posttreatment. Although 4D HRM EGJ-DI increased across posttreatment IRP classifications, patients with normal IRP showed a greater percent of increase (P < 0.001). Among the posttreatment EGJ classifications on FLIP, the normal EGJ opening group demonstrated significant improvement in all 4D HRM metrics from pretreatment to posttreatment (P < 0.001) (Supplementary Table 1).

Correlations Between 4-Dimensional High-resolution Impedance Manometry, High-resolution Manometry, and Functional Lumen Imaging Probe

Maximum EGJ diameter and EGJ-DI on 4D HRM exhibited robust positive correlations among themselves (pretreatment, r = 0.741, P < 0.01; posttreatment, r = 0.850, P < 0.01) (Supplementary Table 2). Posttreatment, EGJ-DI and maximum EGJ diameter on 4D HRM were moderately correlated with EGJ-DI on FLIP (r = 0.461, P < 0.01; r = 0.407, P < 0.01; respectively) (Supplementary Table 2). There was a moderate correlation between 4D HRM EGJ-DI and supine IRP or RDC-IRP both pretreatment and posttreatment.

Four-dimensional High-resolution Impedance Manometry Metrics to Predict Abnormal Treatment Outcomes

The increase of 4D HRM clearance ratio from pretreatment to posttreatment exhibited a significant negative correlation with TBE height at 5 minutes posttreatment (r = −0.617, P < 0.01); the correlation between posttreatment clearance ratio and TBE height at 5 minutes was fair to moderate (r = −0.405, P < 0.05). However, the correlation between standard HRM (supine IRP and RDC-IRP) or FLIP (EGJ-DI and maximum EGJ diameter) metric posttreatment and posttreatment TBE height at 5 minutes were weak (Table 2). Among all the metrics, only the posttreatment EHAS score demonstrated a notable positive correlation (r = 0.697, P < 0.001) for the posttreatment Eckardt score (Table 2).

Table 2.

Correlation Between Variables and Treatment Outcomes, and Accuracy of Each Variable in Predicting Abnormal Treatment Outcome

Metrics	Abnormal TBE outcome			Abnormal Eckardt score outcome
	Spearman rank correlation coefficient	AUROCs (95% CI)		Spearman rank correlation coefficient	AUROCs (95% CI)
Posttreatment metrics
Supine IRP	0.187	0.59 (0.36-0.82)		0.099	0.54 (0.31-0.76)
RDC-IRP	0.194	0.72 (0.52-0.91)		0.081	0.51 (0.29-0.72)
FLIP EGJ-DI	0.090	0.52 (0.28-0.75)		0.153	0.72 (0.53-0.90)
FLIP maximum EGJ diameter	–0.165	0.56 (0.34-0.78)		0.188	0.60 (0.43-0.77)
4D HRM clearance ratio	–0.405a	0.62 (0.43-0.80)		0.149	0.61 (0.40-0.82)
4D HRM IBP	0.006	0.52 (0.33-0.72)		0.027	0.51 (0.30-0.72)
4D HRM maximum EGJ diameter	–0.088	0.59 (0.40-0.78)		0.094	0.55 (0.33-0.77)
4D HRM EGJ-DI	–0.140	0.56 (0.34-0.77)		0.086	0.57 (0.32-0.81)
Posttreatment EHAS	0.085	0.59 (0.37-0.81)		0.697b	0.82 (0.68-0.96)
Metrics changes
4D HRM clearance ratio	–0.617b	0.76 (0.59-0.93)		–0.107	0.51 (0.27-0.75)
4D HRM IBP	–0.255	0.74 (0.57-0.92)		0.093	0.56 (0.34-0.78)
4D HRM maximum EGJ diameter	0.173	0.66 (0.46-0.85)		0.212	0.61 (0.40-0.82)
4D HRM EGJ-DI	0.015	0.54 (0.34-0.74)		0.106	0.55 (0.30-0.79)
Supine IRP	0.189	0.57 (0.36-0.78)		–0.109	0.59 (0.37-0.80)
RDC-IRP	0.079	0.52 (0.32-0.72)		–0.265	0.71 (0.56-0.86)

^aCorrelation is significant at the 0.05 level.

^bCorrelation is significant at the 0.01 level.

TBE, timed barium esophagram; AUROCs, area under the receiver operating characteristics; IRP, integrated relaxation pressure; RDC-IRP, integrated relaxation pressure during rapid drink challenge; FLIP, functional lumen imaging probe; EGJ-DI, esophagogastric junction distensibility index; EGJ, esophagogastric junction; 4D HRM, 4-dimensional high-resolution impedance manometry; EHAS, esophageal hypervigilance and anxiety scale; IBP, intrabolus pressure.

TBE outcome groups differed in pretreatment 4D HRM IBP (P = 0.045), 4D HRM EGJ-DI (P = 0.016), and 4D HRM maximum EGJ diameter (P = 0.003) (Fig. 1 and Supplementary Fig. 2). Notably, good TBE outcome was associated with a greater posttreatment clearance ratio increase (P = 0.011) and IBP reduction (P = 0.022) (Fig. 1). There was no difference in all the 4D HRM metrics when comparing good versus poor symptomatic outcome. Among the HRM and FLIP EGJ metrics, a good TBE outcome was found to be associated with lower post-treatment RDC-IRP (P = 0.043).

Figure 1.

Individual patient pretreatment to posttreatment 4-dimensional high-resolution impedance manometry (4D HRM) clearance ratio, intrabolus pressure (IBP) change among treatment outcomes. The data below each panel display the median (interquartile range) of 4D HRM metrics from pretreatment to posttreatment. (A) Individual 4D HRM clearance ratio change pretreatment and posttreatment. (B) Individual 4D HRM IBP change pretreatment and posttreatment. (C) Changes of 4D HRM clearance ratio and IBP pretreatment and posttreatment. The box plot represents the interquartile range and whiskers represent the maximum and minimum values. Pairwise comparisons performed using Kruskal-Wallis test. TBE, timed barium esophagram.

The change of 4D HRM metrics outperformed other physiologic EGJ parameters from HRM and FLIP in predicting poor TBE outcome, with area under the receiver operating characteristics (AUROCs) of 0.76 (0.59-0.93) for changes in clearance ratio, and AUROCs of 0.74 (0.57-0.92) for changes in IBP (Table 2). The ideal cut-points to identify a poor TBE identified via the ROC curves was a 0.1 increase for clearance ratio (sensitivity, 60%; specificity, 73%; positive predictive value [PPV], 44%; negative predictive value [NPV] 83%), and 8.9 mmHg reduction for IBP (sensitivity, 56%; specificity, 91%; PPV, 48%; NPV 93%). In particular, the 93% NPV of a reduction in IBP > 8.9 mmHg correctly identified good TBE outcome in 14/15 patients, while the 1 patient left had a borderline reduced EGJ opening on FLIP (EGJ-DI 2.17 mm²/mm, maximum EGJ diameter 11 mm). Of the 21 patients with an IBP reduction < 8.9 mmHg, the incorporation of an increase in clearance ratio < 0.1 further increased PPV from 48% to 73% (44% when use clearance ratio alone), leaving 3 out of 11 patients with good TBE outcome not being identified. Among the remainder with discordant results (clearance ratio improvement > 0.1, and IBP reduction < 8.9 mmHg), 8/10 (80%) had good TBE outcomes (Table 3 and Fig. 2).

Table 3.

Performance of Changes in 4-Dimensional High-resolution Impedance Manometry Clearance Ratio and Intrabolus Pressure, Both Alone and in Combination, in Predicting Timed Barium Esophagram Outcome at 5 Minutes

Predictor	Good TBE outcome	Poor TBE outcome	Totals
Change-IBP alone
> 8.9 mmHg	14 (93%)a	1 (7%)	15 (100%)
< 8.9 mmHg	11 (52%)	10 (48%)b	21 (100%)
Totals	25 (69%)	11 (31%)	36
Change-Clearance ratio alone
> 0.1	15 (83%)a	3 (17%)	18 (100%)
< 0.1	10 (56%)	8 (44%)b	18 (100%)
Totals	25 (69%)	11 (31%)	36
Combination of both
IBP reduction < 8.9 mmHg and clearance ratio increase > 0.1	8 (80%)	2 (20%)	10 (100%)
IBP reduction < 8.9 mmHg and clearance ratio increase < 0.1	3 (27%)	8 (73%)b	11 (100%)
Totals	11 (52%)	10 (48%)	21

^aNegative predictive values for good timed barium esophagram (TBE) outcome.

^bPositive predictive values for poor TBE outcome.

IBP, intrabolus pressure.

Figure 2.

Outcome analysis tree for timed barium esophagram (TBE) outcomes. 4D HRM, 4-dimensional high-resolution impedance manometry; IBP, intrabolus pressure.

ROCs of metrics related to poor symptomatic outcome only yielded AUROCs (95% CI) of 0.82 (0.68-0.96) for EHAS posttreatment. Use of 13.5 as the cut-point for EHAS yielded a sensitivity of 100% and specificity of 54% to detect a poor symptomatic outcome (Table 2).

Discussion

The main findings of the study demonstrate that all 4D HRM metrics showed improvement among achalasia patients following LES-targeted treatment. The complementary use of 4D HRM clearance ratio and IBP had better utility than the standard HRM (supine IRP, RDC-IRP) or FLIP (EGJ-DI, maximum EGJ diameter) metrics in association with radiologic treatment outcome. This approach could potentially replace the need for TBE and FLIP if these technologies are not available or cost-prohibitive for use in follow up. Notably, this study is the first to report the application of 4D HRM metrics in treated achalasia patients. These results support the use of 4D HRM as a comprehensive evaluation of esophageal physiology related to bolus transport and underscore its value as a complementary HRIM tool for the follow-up of treated achalasia patients.

Despite recent advances in impedance techniques, the standard interpretation of impedance data along with its association with clinical relevance, is far from clear. Even in the recently updated Chicago classification version 4.0, the application of impedance data during HRIM is barely described.¹³ Bolus clearance on impedance has been reported to correlate well with retention on TBE in patients with achalasia following intervention;²⁰ however, the dichotomous qualitative evaluation often limits its implementation.^5,21 An automated approach had been explored to extract esophageal pressure flow metrics by tracking nadir impedance, and the novel variables demonstrated the ability to discriminate between subjects with and without symptoms of dysphagia; however, the small (15 patients) and heterogeneous (7 out of 15 with post-surgery symptoms) dysphagia population in this study complicates the interpretation.⁷ Although with similar concept, the innovative aspect of 4D HRM in our study is incorporating impedance planimetry as used in FLIP Panometry, to develop an analysis paradigm which focused on the vertically aligned pressure and geometry relationship along the esophagus and EGJ across four dimensions: luminal CSA, time, space (axial length) and pressure. This approach allows for the phase-specific calculation of novel 4D HRM metrics across the phases of bolus transit, delineated by esophageal pressure topography landmarks, which have the potential to provide a more detailed evaluation of esophageal physiology relative to bolus retention, EGJ opening and IBP during bolus transit.

Effective esophageal clearance is a carefully coordinated phenomenon, which depends on the generation of a sustained IBP sufficient to overcome EGJ resistance. Impaired esophageal clearance leads to bolus retention which is typically defined by TBE on esophagram. In treated achalasia patients, however, despite successful LES-targeted treatment, persistent bolus retention may be related to insufficient IBP and/or residual EGJ resistance. In our dataset, the increase in clearance ratio and reduction in IBP after treatment showed better performance compared to other standard EGJ metrics from HRM and FLIP, aligning with their anticipated role in esophageal emptying within this specific patient cohort. This finding may reflect a response, wherein patients still have retained elastic properties of the esophageal body, enabling them to decompress the esophagus if the EGJ is adequately treated. Interestingly, an IBP reduction > 8.9 mmHg had higher NPV for abnormal barium retention, while incorporating a clearance ratio increase > 0.1 further improved the diagnostic sensitivity, the combination of those 2 metrics identified 88% as positive among all patients with normal TBE outcome and 73% as negative among all patients with abnormal TBE outcome, serving as an alternative or complementary approach for the majority of our patients.

Although 4D HRM utilizes impedance planimetry to calculate CSA and subsequently distensibility, similar to the measurements provided by FLIP panometry; only moderate correlations were observed between the posttreatment EGJ parameters from 4D HRM and those from FLIP in the current study. This discrepancy arises because the esophageal physiology manifested on 4D HRM differs from that of FLIP; the former associated with primary peristalsis initiated by small-volume swallows, whereas the latter involves secondary peristalsis triggered by larger-volume distention within the confined bag of the FLIP assembly. Our recently published study showed the 4D HRM EGJ opening metric had strong correlations with FLIP EGJ opening metrics across a spectrum of esophageal motility disorders, highlighting its potential role in defining EGJ obstruction in equivocal cases.¹² The weaker correlations observed in our study may stem from the different patient cohort, as the treatment heterogeneity among achalasia patients could be a key factor impacting the results.

Symptomatic assessment after treatment is complex and can be influenced by various factors. In our study, besides EHAS, we did not find any physiological metrics that correlated well with a poor Eckardt score after treatment, suggesting the significant role of hypervigilance and anxiety. However, the relatively small sample size (particularly of patients with poor symptomatic outcomes) in our dataset may limit these results. Additionally, Eckardt score is a non-validated patient-reported outcome with inherent limitations, which may not accurately reflect true symptom recurrence and burden. A multicenter study reported that only dysphagia and chest pain were the major residual symptoms post-POEM.²² Further work will focus on utilizing well selected patient-reported outcomes to validate the value of 4D HRM in treated achalasia cohort.

This study also has several limitations. First, the observational study design may have led to selection bias for higher risk patients, given that the inclusion criteria necessitated specific physiological testing for participants. Further, the relatively small sample size constrained the ability to make robust comparisons between subgroups. Additionally, although our findings suggest potential associations between clinical factors, such as achalasia subtype and treatment modality, and treatment outcomes, our study was not designed to assess these relationships due to the potential for selection and referral biases. Next, there are some technical issues regarding 4D HRM, intraluminal air may influence impedance-based estimates of luminal CSA, although adopting a Trendelenburg position has been proposed as a strategy to mitigate air artifact.⁸ In addition, similar to Endoflip, 4D HRM also assumes the esophageal wall is a straight tube with a circular cross section. This assumption may generate a relatively large error in cases with distorted esophageal anatomy such as a sigmoid-shaped esophagus. Also, it is noted that the luminal CSA should be interpreted as the area of liquid content within the lumen (i.e. excluding luminal opening due to air). Nonetheless, despite these limitations, the 4D HRM metrics demonstrated superior performance in detecting retention observed on TBE compared to other metrics derived from HRM and FLIP. In addition, further studies focusing on 4D assessment during RDC could provide more valuable insights into bolus transit physiology in the context of a large volume of liquid swallow.

In conclusion, this study demonstrated the utility of 4D HRM in providing a comprehensive evaluation of esophageal physiology in treated achalasia patients. An improvement in clearance ratio in line with a reduction in IBP on 4D HRM outperformed the traditional HRM and FLIP EGJ metrics and this approach demonstrated the best predictive ability to abnormal barium retention. These findings suggest 4D HRM could be an effective surrogate for TBE in assessing esophageal emptying in treated achalasia patients and may be better because it defines the biomechanics of fluid transport in the esophagus. Although further prospective studies are necessary to fully define the utility of these measures, it appears that application of the 4D HRM during the follow-up evaluation may add further insight into esophageal function, thereby enhancing patient management for achalasia.

Supplementary Materials

Note: To access the supplementary tables and figures 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/jnm24170.