Upright Integrated Relaxation Pressure Facilitates Characterization of Esophagogastric Junction Outflow Obstruction

Abstract

Background & Aims:

Under the Chicago Classification of esophageal motility disorders, esophagogastric junction outflow obstruction (EGJOO) includes a varied clinical spectrum that results in diagnostic and management difficulties. We aimed to demonstrate that including upright swallows during high-resolution manometry (HRM) helps identify patients with clinically significant EGJOO.

Methods :

We performed a retrospective study of consecutive patients diagnosed with EGJOO on HRM from January 2015 through July 2017. HRM studies included 10 supine and 5 upright 5-ml liquid swallows. HRM values, esophagrams, and patient-reported outcomes were evaluated to identify factors associated with objective EGJOO (defined by esophagram) and symptomatic dysphagia (brief esophageal dysphagia questionnaire scores, >10).

Results:

Of the 1911 patients who had HRM during the study period, 16.2% (310) were diagnosed with EGJOO; 155 patients completed an esophagram and 227 completed the brief esophageal dysphagia questionnaire. Of these patients, 30.3% (47/155) had radiographic evidence of EGJOO and 52.4% (119/227) had symptomatic dysphagia. The median upright integrated relaxation pressure for patients with radiographic evidence of EGJOO or symptomatic dysphagia was higher than for patients without. An upright integrated relaxation pressure >12 mmHg identified patients with radiographic evidence of EGJOO with 97.9% sensitivity and 15.7% specificity; for symptomatic dysphagia these values were 88.2% and 23.1%, respectively.

Conclusion :

An upright integrated relaxation pressure of >12 mmHg identifies patients with clinically significant esophageal outflow obstruction or dysphagia with a high level of sensitivity. This simple manometric maneuver (upright swallows) should be added to the standard manometric protocol.

Introduction

High-resolution manometry in combination with the Chicago Classification v3.0 (CC) is used to clinically evaluate patients with non-obstructive dysphagia, non-cardiac chest pain and regurgitation¹. Achalasia and esophagogastric junction outflow obstruction (EGJOO) are at the top of the hierarchical scheme set forth in the CC and are at least inpart defined by an elevated integrated relaxation pressure (IRP) which is the mean pressure of the 4 seconds of maximal deglutitive relaxation used to approximate lower esophageal sphincter (LES) relaxation. Analysis as described in the CC is based on ten 5-mL swallows performed in the supine position and an elevated IRP is defined as a median pressure of greater than 15 mmHg (95 percentile)¹. Swallows performed in the upright position are not currently included in the CC but the IRP upper limit of normal for upright swallows ranges from 10–15 (95 percentile) in the literature^2–4. In addition to an elevated IRP, patients with achalasia have absent peristalsis in their esophageal body, whereas, patients with EGJOO have an elevated IRP but have sufficient peristalsis as to not meet the definition of achalasia. A significant body of work has focused on classifying and refining treatment strategies for achalasia; however, our understanding of EGJOO remains limited.

Several retrospective studies have shown the etiologies of EGJOO to be quite heterogeneous and include hiatal hernia, eosinophilic esophagitis, infiltrative disease, Schatzki’s rings, vascular compression, and achalasia in evolution. Furthermore, the interventions patients receive once this diagnosis has been made are equally heterogeneous including watchful waiting, pharmacologic therapy (calcium channel blockers, nitroglycerin, muscle relaxants, antispasmodics, and proton pump inhibitors), cancer treatment, botulinum toxin, pneumatic dilation, per-oral endoscopic myotomy and Heller myotomy^5–11. Unfortunately this heterogeneity leads to clinical confusion as patients and practictioners are left wondering who will improve with watchful waiting and who will need more aggressive therapy. Thus, the aim of this study was to investigate whether including upright swallows during HRM could help identify patients with clinically significant EGJOO and therefore identify the cohort who may most benefit from therapeutic intervention.

Materials and Methods

Subjects

Patients were retrospectively identified from the Northwestern Esophageal Center motility laboratory registry, which includes English-speaking patients 18–85 years old evaluated with HRM between January 2015 and June 2017. The standard HRM protocol at Northwestern consists of 10 supine and 5 upright, 5ml liquid swallows. Patients were excluded if they had prior foregut surgery, an HRM diagnosis of achalasia (subtypes I, II or III) based on the Chicago Classification v3.0, an IRP < 15 mmHg or failed to complete upright swallows. The study protocol was approved by the Northwestern University Institutional Review Board. A waiver of informed consent was obtained for this retrospective analysis.

High resolution manometry

After a minimum 6-hour fast, HRM studies were completed using a 4.2-mm outer diameter solid-state assembly with 36 circumferential pressure sensors at 1-cm intervals and 18 impedance segments at 2-cm intervals (Medtronic Inc, Shoreview, MN). The HRM assembly was placed transnasally and positioned to record from the hypopharynx to the stomach with approximately three intragastric pressure sensors. The HRM protocol included a 5-minute baseline recording, 10 supine and 5 upright, 5-ml swallows using 50% saline for test swallows at 20–30 second intervals. These 15 swallows are part of the basic manometry protocol at Northwestern Esophageal Center and are obtained on every patient. All studies were analyzed using ManoView version 3.0 analysis software to measure basal EGJ pressure (EGJP) at end-expiration, the integrated relaxation pressure (IRP), distal contractile integral (DCI), and distal latency. Esophageal motility diagnoses were determined from the ten supine swallows according to the Chicago Classification v3.0, using a median IRP of 15 mmHg as the upper limit of normal¹. The upright IRP was derived as the median value from the five upright swallows; an “abnormal upright IRP” was considered as a median upright IRP > 12 mmHg, while a “normal upright IRP” was considered at a median upright IRP ≤ 12 mmHg. 12 mmHg was selected as a threshold based on previous studies of asymptomatic volunteers^2–4.

Esophagram

Timed barium esophagrams (TBEs) were performed in the upright position with radiograph images of the esophagus obtained at 1, 2, and 5 minutes after ingestion of 200-ml of low-density (45% weight to volume) barium sulfate. The height of the barium column was measured vertically from the EGJ. Patients without liquid barium retention or in whom timed images were not recorded, were assessed following ingestion of a 12.5 mm barium tablet for delay or impaction of tablet passage. Patients were categorized as having radiographic EGJOO (RAD-EGJOO) if they had liquid barium retention on TBE at 1 minute and/or 12.5 mm barium tablet delay or impaction. Given the lack of a true gold standard to identify EGJOO, patients with RAD-EGJOO and/or symptomatic dysphagia (defined as a BEDQ > 10) were considered to have clinically significant EGJOO.

Brief Esophageal Dysphagia Questionnaire (BEDQ)¹²

The BEDQ is a 10-item, validated self-report measure of esophageal dysphagia and food impactions. The scale has 8 items which assess the frequency and difficulty with swallowing solid foods, soft foods, and liquids on a 5-point Likert scale over the past 14 days. An additional 2 items measure how many instances of food impaction lasting more than 30 minutes or requiring an emergency department visit occurred in the past year. Patients were classified as having symptomatic dysphagia if their BEDQ score was >10. Patients also completed the GERDQ¹³.

Statistical analysis

Data were analyzed using SPSS v25. Comparisons using chi-squared analysis and the Student’s t-test were made among the groups. Multivariate logistic regression was performed to assess predictors for RAD-EGJOO and symptomatic dysphagia (BEDQ >10). Values are expressed as median (interquartile range [IQR]), unless otherwise specified. Analyses assumed a 5% level of statistical significance.

Results

Study subjects

1911 HRMs were performed at the Northwestern Esophageal Center between January 2015 and July 2017. Of those, 465 were performed on patients with prior foregut surgery, 970 had a supine median IRP of less than 15, 166 met criteria for a diagnosis of achalasia based on the Chicago Classification v3.0 (Type I N = 39, Type II N = 94, Type III N = 33), leaving 310 studies with EGJOO. Three of these studies did not complete upright swallows, leaving a final cohort of 307 HRMs with EGJOO (Figure 1).

Figure 1.

High resolution manometry performed at the Northwestern Esophageal Center between January 2015 and July 2017.

Among this cohort, the median age (IQR) was 59 (47 – 68) years, 36.8% of the patients were male and the median BMI (IQR) was 26.2 (22.7 – 31.3) kg/m² (Table 1). The median (IQR) supine IRP was 20.3 (17.0 – 24.2) mmHg and was greater than the median (IQR) upright IRP, 17.8 (13.6 – 23.3) mmHg, via paired comparison; P < 0.001.

Table 1.

Baseline characteristics (median [IQR] unless otherwise stated).

	Total Population	Upright IRP > 12	Upright IRP ≤ 12
N=	307	258 (84.0%)	49 (16.0%)
Age (yrs)	59.0 (47.0 – 68.0)	61.0 (49.8 – 69.0)**	53.0 (38.5 – 63.0)**
Male	36.8%	36.8%	36.7%
BMI (kg/m2) (N=292)	26.2 (22.7 – 31.3)	26.3 (22.8 – 31.3)	26.0 (22.0 – 31.0)
Indication
Dysphagia	62.9%	65.9%**	46.9%**
Reflux	18.2%	18.6%**	16.3%**
Chest Pain	10.7%	10.5%**	12.2%**
Regurgitation	5.2%	2.3%**	20.4%**
Other	2.9%	2.7%**	4.1%**
Motility Pattern
Normal	58.6%	57.0%	67.3%
IEM	21.5%	21.7%	20.4%
Hypercontractile	19.9%	21.3%	12.2%
Basal LESP (mmHg)	25.0 (18.0 – 36.0)	27.0 (19.0 – 37.3)**	21.0 (14.5 – 28.0)**
Supine IRP (mmHg)	20.3 (17.0 – 24.2)	21.1 (17.7 – 25.8)**	16.7 (15.7 – 18.3)**
% normal pressurization pattern	60.9%	57.8%**	77.6%**
EGJ morphology
Type I	79.5%	77.1%*	91.8%*
Type II (mean LES-CD; cm)	5.9% (1.81)	7% (1.81)*	None
Type III (mean LES-CD; cm)	14.7% (4.75)	15.9% (4.80)*	8.2% (4.30)*
% with esophagram	50.5%	53.1%*	36.7%*
RAD-EGJOO	15.3% (47/155)	33.6% (46/137)*	2% (1/18)*
% completed GERDQ	73.0%	70.9%	83.7%
GERDQ ≥8	62.1% (139/224)	62.8% (115/183)	58.5%(24/41)
% completed BEDQ	73.9%	72.9%	79.6%
BEDQ >10	52.4% (119/227)	55.9%* (105/188)	35.9%* (14/39)

^*p-value < 0.05

^**p-value <0.005

274 of the 307 patients had a report of an upper endoscopy performed within one year available for review. 54 of these patients had hiatal hernias, 19 of which were larger than 3 cm. Manometry in these cases was most often performed as preoperative planning for hernia repair. 9 patients had Los Angeles grade A or B esophagitis and 1 patient had Los Angeles grade C esophagitis. 13 patients had esophageal strictures noted on endoscopy 8 of which were dilated prior to having manometry performed. One patient was found to have a malignant esophageal mass identified on endoscopy performed following manometry and 11 patients were noted to have esophageal diverticula. Overall, 32 (11.7%) patients had a significant abnormality identified on upper endoscopy (hiatal hernia greater than 3 cm, stricture, LA grade C esophagitis, or esophageal mass).

Upright IRP

Sixteen percent of patients had normalization of their IRP in the upright position (Table 1). There was no statistical difference in sex or BMI between patients with an abnormal upright IRP compared to those with a normal upright IRP, however patients with an abnormal upright IRP were significantly older (Table 1). Patients with an abnormal upright IRP were also more likely to be referred for testing due to dysphagia as compared to those with a normal upright IRP; these patients were more likely to be referred with a primary indication of regurgitation. Although there was no difference in motility pattern (based on the Chicago Classification v3.0) between the two groups, patients with an abnormal upright IRP were more likely to have intrabolus pressurization or pan-pressurization (not meeting criteria for achalasia) (Table 1). Furthermore, patients with an abnormal upright IRP had significantly higher basal EGJP, median supine IRP, were more likely to have symptomatic dysphagia (BEDQ >10), and RAD-EGJOO (Table 1). There was no significant difference in GERDQ scores. Of note, patients with a normal upright IRP were less likely to undergo further workup with an esophagram which is likely in part due to fewer patients in this group being referred for dysphagia (Supplemental Table 1). Cases demonstrating clinical application of the upright IRP are described in Figure 2.

Figure 2.

Panel A shows a representative patient who presented with dysphagia as her primary complaint and was diagnosed with EGJOO per Chicago Classification v3.0. However, her upright swallows (middle panel) revealed a normal upright IRP, her esophagram demonstrated an open EGJ, and her EGD was unrevealing for the etiology of her symptoms. She was started on a proton pump inhibitor with resolution of her dysphagia on follow-up. Panels B and C are images from representative patients who presented with dysphagia and were found to have EGJOO on manometry and an abnormal upright IRP (middle panels). Both patients demonstrated intrabolus pressurization and the patient in panel B had jackhammer esophagus with greater than two supine test swallows with a distal contractile integral of greater than 8000 mmHg*s*cm. Esophagrams of both patients revealed RAD-EGJOO with the patient in panel B demonstrating 12.5 mm barium tablet impaction and the patient in panel C with persistent liquid barium retention at 5 minutes. Both patient underwent endoscopic ultrasound to assess for pseudoachalasia which was negative but revealed esophageal wall thickening. Functional luminal imaging probe analysis for both patients showed a distensibility index of < 2.8 mm²/mmHg, the lower limit of normal¹⁴, and the patients were treated with botulinum toxin with improvement in their dysphagia on follow-up.

Of the patients with a significant abnormality on upper endoscopy, 6 (18.8%) had a normal upright IRP. 5 of these patients had hiatal hernias ranging from 5 cm to 7 cm in both the supine and upright positions and one patient had a benign distal stricture that was dilated to 48 French with a bougie 2 months prior to manometry. Two patients with esophageal diverticula also had normalization of their IRP in the upright position.

RAD-EGJOO

31 of the 47 patients with RAD-EGJOO had liquid barium retention with the median (IQR) column height of 9.3 (3.2 – 13.1) cm at 1 minute and 3.4 (0.0 – 8.7) cm at 5 minutes. Of patients with RAD-EGJOO compared to those who did not, there was no statistical difference in age, sex, BMI or indication for testing (Table 2). There was a statistical difference in motility patterns among these groups, with patients having RAD-EGJOO demonstrating an increased prevalence of ineffective esophageal motility and hypercontractility (Table 2). These patients had a greater median upright IRP, were more likely to have an abnormal upright IRP, and either intra bolus pressurization or pan-pressurization (Table 2). Furthermore, multivariate logistic regression analysis revealed an indication of dysphagia and the median upright IRP as the only significant factors contributing to RAD-EGJOO in our model with odds ratios (95% CI, p-value) of 1.863 (1.063 – 3.263, 0.030) and 1.106 (1.030 – 1.187, 0.005), respectively (Table 3). This analysis also highlights that the standard tool used in manometric analysis, median supine IRP, has no predictive value in identifying patients with RAD-EGJOO based on the degree of elevation above 15 mmHg. Interestingly, the median upright IRP, but not an indication of dysphagia, remained a predictive factor for RAD-EGJOO using multivariate logistic regression analysis when patients with significant abnormality on upper endoscopy were excluded from the analysis (odds ratios [95% CI, p-value] of 1.098 [1.019 – 1.183, 0.014] and 2.832 [0.819 – 9.794, 0.100], respectively).

Table 2.

Characteristics of patients based on RAD-EGJOO and symptomatic dysphagia (median [IQR] unless otherwise stated).

	No RAD-EGJOO	RAD-EGJOO	BEDQ ≤ 10	BEDQ > 10
N=	108 (69.7%)	47 (30.3%)	108 (47.6%)	119 (52.4%)
Age (yrs)	60.5 (47.0 – 70.5)	59.0 (51.0 – 72.0)	56.0 (46.0 – 67.8)	61.0 (47.0 – 68.0)
Male	32.4%	36.2%	42.6%	37.0%
BMI (kg/m2) (N=292)	26.3 (23.1 – 31.3)	26.0 (22.7 – 31.3)	25.1 (21.9 – 30.7)	27.1 (22.7 – 31.6)
Indication
Dysphagia	70.4%	87.2%	47.2%**	77.3%**
Reflux	15.7%	6.4%	26.9%**	9.2%**
Chest Pain	6.5%	2.1%	16.7%**	7.6%**
Regurgitation	5.6%	2.1%	7.4%**	4.2%**
Other	1.9%	2.1%	1.9%**	1.7%**
Motility Pattern
Normal	64.8%*	40.4%*	63.0%**	57.1%**
IEM	20.4%*	31.9%*	25.9%**	15.1%**
Hypercontractile	14.8%*	27.7%*	11.1%**	27.7%**
Basal EGJP (mmHg)	27.0 (19.3 – 37.5)	25.0 (19.0 – 42.0)	24.0 (18.0 – 33.0)*	28.0 (20.0 – 39.0)*
Supine IRP (mmHg)	20.8 (17.5 – 20.5)	22.4 (16.4 – 31.8)	19.8 (16.6 – 23.9)	20.8 (17.5 – 25.8)
Upright IRP (mmHg)	18.1 (14.5 – 23.2)**	22.4 (16.4 – 31.8)**	17.3 (12.7 – 21.9)*	18.4 (14.9 – 24.3)*
Upright IRP >12	84.3%*	97.9%*	76.9%*	88.2%*
% normal pressurization pattern	64.8%*	44.7%*	64.8%	54.6%
EGJ morphology
Type I	67.6%	76.6%	79.6%	84.9%
Type II (mean LES-CD; cm)	9.3% (1.84)	4.3% (1.65)	7.4% (1.88)	4.2% (1.86)
Type III (mean LES-CD; cm)	23.1% (4.68)	19.1% (4.91)	13.0% (4.84)	10.9% (4.95)
% with esophagram			44.4%	56.3%
RAD-EGJOO			20.8% (10/48)	35.8% (24/67)
% completed GERDQ	73.1%	66.0%	86.1%	81.5%
GERDQ ≥8	65.8% (52/79)	61.3% (19/31)	55.9% (52/93)	70.1% (68/97)
% completed BEDQ	75.0%	72.3%
BEDQ >10	53.1% (43/81)	70.6% (24/34)

^*p-value < 0.05

^**p-value <0.005

Table 3.

Predictors of RAD-EGJOO and symptomatic dysphagia.

	Multivariate Logistic Regression
	RAD-EGJOO			BEDQ > 10
	OR	CI 95%	p-value	OR	CI 95%	p-value
Age	1.000	0.974 – 1.026	0.994	0.996	0.976 – 1.016	0.674
Sex	0.994	0.637 – 1.551	0.979	0.861	0.633 – 1.171	0.341
BMI	0.966	0.910 – 1.025	0.253	1.035	0.985 – 1.087	0.171
Indication - dysphagia	1.863	1.063 – 3.263	0.030	1.889	1.379 – 2.588	<0.001
Motility Pattern	-	-	0.165	-	-	0.079
Normal	1	-	Reference	1	-	Reference
IEM	1.318	0.687 – 2.531	0.407	0.598	0.354 – 1.012	0.055
Hypercontractile	1.258	0.617 – 2.566	0.527	1.830	1.379 – 2.588	0.029
Median Supine IRP	0.987	0.900 – 1.082	0.777	1.047	0.976 – 1.123	0.198
Basal LESP	0.974	0.941 – 1.009	0.140	1.004	0.980 – 1.029	0.758
Median Upright IRP	1.106	1.030 – 1.187	0.005	1.010	0.962 – 1.061	0.688
% normal pressurization pattern	1.355	0.864 – 2.123	0.186	0.939	0.674 – 1.308	0.710

The sensitivity of the median upright IRP > 12 mmHg in identifying RAD-EGJOO was 97.9% with a negative predictive value (NPV) of 94.4%. The specificity was 15.7% with a positive predictive value (PPV) of 33.6% (Table 4 top panel). Of note, the one patient who did have RAD-EGJOO and a median upright IRP of ≤ 12 mmHg met criteria for jackhammer esophagus, had a small hernia and pan-esophageal pressurizations outside of test swallows (Supplemental Figure 1).

Table 4.

Test characteristics of median IRP for RAD-EGJOO (Top Panel) and symptomatic dysphagia (Lower Panel).

	RAD-EGJOO	No RAD-EGJOO
Upright IRP > 12	46	91
Upright IRP ≤ 12	1	17
	BEDQ > 10	BEDQ ≤ 10
Upright IRP > 12	105	83
Upright IRP ≤ 12	14	25

Symptomatic Dysphagia

52.4% of patients had a BEDQ of greater than 10 identifying them as having symptomatic dysphagia (Table 3). These patients were more likely to have hypercontractile motility patterns, higher basal EGJPs, higher median upright IRPs, and abnormal upright IRPs (Table 3). Notably, patients with symptomatic dysphagia did not have greater median suprine IRPs compared to those who did not. Multivariate logistic regression identified an indication of dysphagia and hypercontractile motility patterns as the only factors predictive of symptomatic dysphagia in our model (Table 3). When patients with a significantly abnormal upper endoscopy were exclude from this analysis, an indication of dysphagia but not hypercontractility persisted as a predictor of a BEDQ >10 (odds ratios [95% CI, p-value] of 3.561 [1.836 – 6.906, <0.001] and 1.948 [0.835 – 4.546, 0.123], respectively). The sensitivity and specificity of a median upright IRP of >12 mmHg for symptomatic dysphagia is 88.2% and 23.1%, respectively (Table 4 lower panel).

Twenty four pateints had both RAD-EGJOO and a BEDQ of >10. Of these patients, only one had a normal upright IRP. 91.7% of these patients were referred for a primary indication of dysphagia and the median (IQR) upright IRP was two times the upper limit of normal at 24.0 (16.7 – 36.2) mmHg (Supplemental Table 2).

Discussion

The heterogeneity of etiologies and treatment strategies for EGJOO is a major problem facing patients and practitioners; it is unclear which patients with this diagnosis will benefit from watchful waiting and which may require LES targeted therapy. To aid in this differentiation, this study assessed 1911 HRMs at a tertiary care esophageal referral center to determine whether adding upright swallows to the standard CC protocol could help define clinically significant EGJOO. 307 of the 1911 (16.0%) studies were classified as EGJOO and 16% of those had normalization of their IRP (≤12 mmHg) in the upright position (Figure 1). More importantly, our findings support that normalization of the IRP to a value below 12 mmHg essentially rules out evidence of obstruction on barium esophagram. This obviates the need for more aggressive LES targeted therapy (pneumatic dilation, per-oral endoscopic myotomy, or laparoscopic Heller myotomy) and likely the need for further costly diagnositic testing with endoscopic ultrasound or CT scans in this patient population. Unfortunately, in practice, some patients diagnosed with EGJOO based on the CC inappropriately undergo LES targeted therapy. Based on our findings, if all patients diagnosed with EGJOO underwent LES targeted therapy a conservative estimate of the number needed to harm would be 6.25. Therefore, an accurate diagnosis and understanding of EGJOO is critical for patients. Although some may benefit from these treatment options, this finding supports earlier works where large proportions ( 40 % to 72 %) of patients with the CC diagnosis of EGJOO had spontaneous resolution of their symptoms suggesting that they did not have clinically significant outflow obstruction^{5, 6, 8, 10}. These works together emphasize that characterizing and treating patients based solely on supine IRP is fraught with problems as this value, although used as a measure of LES relaxation, is actually measuring EGJ resistance which is the sum of pressure from the LES, crural diaphragm and intrabolus pressure and is therefore prone to artificial elevations. Furthermore, our data suggests that 12 mmHg as the upper limit of normal for the median upright IRP can be used as screening tool to help identify clinically significant EGJOO. In our population, a median upright IRP of greater than 12 mmHg had a sensitivity of 97.4% and a negative predictive value of 94.4% for identifying clinically significant EGJOO. This allows us to confidently identify a subset of patients without clinically signficant EGJOO who will not benefit from LES targeted therapy. Of note, the upright IRP value of 12 mmHg is inline with what has been previously published regarding normative values for median upright IRP and was chosen to maximize the sensitivity and negative predictive value^2–4. Interestingly, the one patient that did not have an elevated upright IRP in this study but had RAD-EGJOO (Supplemental Figure 1) had a small hiatal hernia, pan-pressurization on dry swallows and jackhammer esophagus. Taken together, even in the absence of an elevated upright IRP, these factors should signal to the provider that this patient may have difficulty with bolus flow and esophageal clearance prompting further workup and evalutation.

Similar to prior studies, patients in the EGJOO cohort were more likely to present with a chief complaint of dysphagia (Table 1)^{5, 7–9}. However, those who had normalization of their IRP in the upright position had a significant increase in regurgitation as their chief complaint compared to those with an elevated IRP. Patients with IRP normalization in the upright position also had significantly lower basal EGJPs, lower supine IRPs, higher rates of normal pressurization patterns (no IBP or pan-pressurization not meeting criteria for achalasia), and were less likely to have large hiatal hernias further supporting the fact that these patients are less likely to have clinically significant EGJOO (Table 1).

One of the main difficulties in attempting to refine the EGJOO diagnosis is that there is currently no gold standard to identify which patients need LES targeted intervention, which may improve with medicines, and which need no therapy at all. In this study we used RAD-EGJOO and symptomatic dysphagia as our standards. Although not perfect, these metrics represent the best approximation we have to help differentiate patients. There is likely selection bias in our patient population (who completed esophagrams, and who completed questionnaires) due to the fact that we are a tertiary care referral center. These factors likely increased the prevalence of clinically significant EGJOO in our patient population and, potentially, the fraction that normalized their IRP in the upright position. We minimized this bias as best we could by obtaining upright swallows on all patients undergoing HRM during the study period as part of our standard protocol. We also acknowledge that this is a retrospective, primarily cross-sectional study lacking long-term follow-up. Future prospective studies are needed to more thoroughly characterize the clinical utility of this tool. Furthermore, 32 of the patients were identified to have significant abnormalities on EGD and 6 of these had normalization of their IRP in the upright position. However, removing these patients from the analysis did not change the overall finding that approximately 16% (43/275) of patients had normalization of their IRP in the upright position. The upright IRP also remained the only predictor of RAD-EGJOO using multivariate logistic regression in this population.

In conclusion, the etiology and therefore treatment strategy for EGJOO remains heterogeneous. A substanstial patient population improves without therapy while others require aggressive LES targeted therapy. This work demonstrates a novel tool, the addition of 5 upright swallows to the CC protocol, that can help identify patients without clinically significant outflow obstruction. This addition can be used as a screening tool, with a NPV of 94.4%, and patients who normalize in the upright position should therefore not be considered for LES targeted therapy. This is supported by the fact that patients who normalize were more likely to have normal peristaltic patterns and were less likely to present with dysphagia. Treating patients based solely on a single manometric parameter, typically the supine IRP, is fraught with problems. We support a more global assessment in patients diagnosed with EGJOO which includes an assessment of upright swallows, intrabolus pressurization, hiatal hernia, and peristaltic abnormalities including jackhammer. Furthermore, adjunct testing including an esophagram and functional luminal imaging probe (FLIP) can also be useful in ultimately determing who can be treated conservatively and who needs LES targeted therapy.

Abbreviations:

EGJOO

HRM

CC

IRP

LES

EGJP

DCI

TBE

BEDQ

GERDQ

IQR