Semi-Solid and Solid Bolus Swallows in High-Resolution Oesophageal Manometry for the Detection of Motility Disorders

Background/Aims: High-resolution oesophageal manometry utilises water swallows to evaluate oesophageal function. However, small volumes of water are not representative of normal eating and as a result often produce normal manometry studies in patients with dysphagia. This study sets out to establish optimal diagnostic thresholds for semi-solid solid swallows and evaluate their ability to uncover motility abnormalities in patients with motility disorders. Method: Manometry was performed using ten 5-mL single water swallows followed by two semi-solid and two solid swallows in the upright position. Normative values for the adjunctive tests were obtained from patient controls while patients with major motility disorders were used to establish the optimal diagnostic thresholds. Diagnostic thresholds identified were prospectively tested in patients with normal water swallows but oesophagus related symptoms and in those with minor and major motility disorders. Results: Normal values for semi-solid and solid were determined in patient controls (n = 100). Development of diagnostic thresholds included 120 patients with major motility disorders. Optimal diagnostic thresholds identified for oesophagogastric junction dysfunction in semi-solid and solid swallows (IRP > 15.5 mmHg). Hypercontractilty and spasm used existing thresholds (>8000 mmHg-s-cm and < 4.5 s, respectively) but modified frequency of ≥50% of adjunctive swallows. Diagnostic thresholds were applied to symptomatic patients with normal water swallows (n = 70) identifying 12/70 (17%) to have abnormal adjunctive swallows. One of 30 patients (3%) with ineffective motility had abnormal adjunctive swallow and 12 patients with oesophageal spasm, oesophagogastric junction obstruction, and hypercontractility had abnormal adjunctive swallows that moved them up the motility disorder hierarchy. Conclusions: How to cite this paper: Zhou, J., Sykes, C. and Ho, V. (2018) Semi-Solid and Solid Bolus Swallows in High-Resolution Oesophageal Manometry for the Detection of Motility Disorders. Open Journal of Gastroenterology, 8, 1-16. https://doi.org/10.4236/ojgas.2018.81001 Received: December 15, 2017 Accepted: January 22, 2018 Published: January 25, 2018 Copyright © 2018 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/


Introduction
The development of high-resolution oesophageal manometry (HRM) has rapidly revolutionised the investigation of oesophageal motility disorders and has become the gold-standard of diagnosis. The HRM catheter consists of 36 solidstate pressure sensors and provides a topographical pressure map describing oesophageal contractility from the pharynx to the stomach. Despite its impressive capabilities, HRM can only detect pathophysiology that is present during the study. Therefore, the most challenging aspect of identifying oesophageal disorders is providing a diagnosis that is representative of all the pathologic oesophageal motor abnormalities experienced by the patient.
Standard operating procedure for HRM testing involves the patient seated in an supine position and performing ten 5-mL single water swallows (SWS) based on criteria described in Chicago Classification version 3.0 (CCv3.0) [1]. This approach is limited as water swallows provide only indirect evidence about the cause of symptoms when eating solids and sometimes symptoms are not triggered at all by water swallows alone [1]. This suggests that water swallows may not always be the optimum bolus type for patients with dysphagia to swallow during HRM. Although many physicians are fully aware of these limitations, the lack of standardisation for different types of swallowing tests prevents them from being used routinely in standard clinical practice.
The addition of semi-solid and solid swallows to HRM has been shown to increase sensitivity for clinically relevant dysmotility [2]. Normative HRM data for a variety of adjunctive tests have been reported in several studies involving swallow tests with semi-solids [3], solids [4], or a mixture of both [5]. The inclusion of adjunctive swallows more representative of normal eating behaviour attempts to trigger symptoms by "challenging" oesophageal function during HRM. However, unlike their water counterpart, semi-solid and solids bolus tests can be more difficult to interpret as they are not always transported through the oesophagus with a simple peristaltic contraction [2]. Complex pressure activity can occur, posing challenges for analysis which can impair inter-investigator agreement, decreasing specificity of clinical diagnosis [1]. Studies with different bolus types, apple sauce [3], marshmallow [2], pasty with smoothie [5], have all found the inclusion of novel non-liquid bolus swallows to increase diagnostic yield in patients with dysphagia. However, to date, there has not been a comprehensive evaluation of semi-solid and solid swallows in patients with major motility disorders to establish and evaluate diagnostic thresholds. This study aims to: Open Journal of Gastroenterology 1) Establish normal values and diagnostics thresholds for semi-solid and solid swallows; 2) Evaluate the ability of semi-solid and solid swallows to increase diagnostic yield by the identification of classifiable motility disorders unnoticed in water swallow.

High-Resolution Oesophageal Manometry
Patients with oesophagus related symptoms or reflux symptoms are referred to the Gastroenterology (GI) Motility Clinic, Camden Hospital (Sydney, NSW, Australia) for HRM (ManoSan ESO high resolution manometry system; Medtronic, Minneapolis, Minnesota, USA) assessment of oesophageal motility and function based on standard 5-mL SWS in accordance with the CCv3.0 [1], modified for use in the upright position [4]. Patients with reflux symptoms also undergo 24 hr ambulatory pH monitoring with Digitrapper system (Medtronic, Minneapolis, Minnesota, USA) [6]. Patients attending HRM studies as part of routine care were recruited between 2014 and 2017. "Patient controls" were individuals referred for investigation of reflux-associated symptom but with a normal HRM study based on CCv3.0 and normal 24-hour pH studies. Patients with dysphagia symptoms but normal SWS and 24-hour pH studies were not included in our "patient controls" and were analysisd as a separate group of normal HRM patients with dysphagia symptoms. Patients diagnosed with minor motility disorder (ineffective motility) and major motility disorders (oesophageal spasm, hypercontractiliy/jackhammer, oesophagogastric junction obstruction, and Type I-III achalasia) by CCv3.0 were categorised into their respective groups for analysis. Adjunctive tests conducted included two semi-solid bolus swallows with a tea spoon (3.5 mL) of custard (1.07 g•cm −3 ) or jelly (1.24 g•cm −3 ) as a lactose-free alternative, and two solid bolus swallows with a single unmasticated 1.2 cm 3 marshmallow (0.37 g•cm −3 ). For semi-solid and solid swallows, patients with motility disorders often needed to swallow more than once to clear the pharynex. The number of pharyngeal deglutinations prior to effective distal oesophageal contraction was recorded as "attempts". Following pharyngeal de-  [3]. We used 100 control studies and 120 abnormal studies (30 per disorder group) to establish thresholds.

Statistical Analysis
Optimal diagnostic thresholds for integrated relaxation pressure (IRP) during adjunctive tests were identified by "receiver operating characteristic" (ROC) analysis. Patient controls and patients with major motility disorders were used to establish diagnostic thresholds. Diagnosis based on CCv3.0 was the reference standard. Following the approach used by the Chicago Classification [7], diagnostic thresholds for IRP semi-solid and solid tests were refined using results in results from cases of EGJ dysfunction (achalasia and EGJ outlet obstruction) to define clinically relevant, abnormal EGJ function. CCv3.0 thresholds for hypercontractility (jackhammer) and oesophageal spasm, distal contractile integral (DCI > 8000 mmhg•cm•s) and distal latency (DL < 4.5 s) were used for adjunctive swallows with modified swallow frequencies (abnormality noted in ≥ 50% of adjunctive swallows).
Patient data are reported as either median (95% CI) or mean ± SD where appropriate. The statistical analysis first established normative values for adjunctive tests, reported as median (99% confidence intervals [CI]). Optimal diagnostic thresholds based on ROC findings were identified in the data set. An area under the ROC curve (AUC) 0.80 -0.90 defined "good" and >0.90 "excellent" accuracy for medical tests [8]. Sensitivity and specificity, positive and negative predictive values, likelihood ratios, and numbers need to diagnosis (NND) for these thresholds were prospectively assessed in patients with major, minor and normal HRM patients with oesophagus-associated symptoms. The established diagnostic thresholds were used to analysis patients with minor motility disorders and patients with oesophagus-related symptoms but classified as normal by CCv3.0. Inter-group differences were compared using Student's t-test (unpaired, two tailed) for quantitative variables. Pairwise differences were analysed with Wilcoxon signed rank test. Statistical analysis was performed using the statistical software SPSS 24.0 package (SPSS Inc., Chicago, Illinois, USA) for Windows.

Participants
Demographic and clinical data for study groups are presented in Table 1

Semi-Solid and Solid Swallows in Patient Controls
HRM metrics for patient controls are presented in Table 2. The SWS HRM metrics, using 99% Cl, for all patients controls (n = 100) were within the standard normal ranges set by CCv3.0 [1]. There were no significant differences in the swallowing parameters between the two types of semi-solids (3.5 mL of custard n = 57 and jelly n = 43) and, therefore, these data were combined for the semisolid analysis. The semi-solid and solid swallows had elevated IRP compared to SWS (7.8 vs 5.2 mmHg p < 0.001; 7.2 vs 5.2 mmHg p < 0.01). Using 99% Cl, the upper limits of the adjunctive tests were above normal limits for SWS but in these patients the LES does appear to relax despite raised IRP. The UES relaxation Open Journal of Gastroenterology

Semi-Solid and Solid Swallows in Patients with Major Motility Disorders
Comparison of SWS and adjunctive test metrics in patients with major motility disorders are presented in Table 3. IRP in semi-solid and solid swallows were higher than SWS-IRP in all major motility disorders, except achalasia. Only

Development of Diagnostic Thresholds
Evaluation of diagnostic thresholds and ROC analysis for IRP in semi-solid and solid swallow are presented in Figure 1. Semi-solid and solid IRP analysis demonstrated "excellent" accuracy of for "all forms of" EGJ dysfunction (achalasia Open Journal of Gastroenterology     EGJ thickening noted by gastroscopy (n = 2, Figure 2)  Eosinophilic esophagitis diagnosed by gastroscopy (n = 1)  Trial of nitrates alleviated some symptoms (n = 2)  Negative gastroscopy (n = 2)  No follow-up available (n = 5)

Discussion
The use of water swallows does not always provide enough simulation on oeso-  [3] and solid [4] swallows, these studies consisted of relatively small numbers of healthy individuals, 41 and 23 respectively. The pressure records for semi-solid and solid boluses are more complex and exaggerated than water swallows and would require a large number of normal and diseased studies to characterise. We analysed 220 patient controls and major motility disorder cases to establish diagnostic thresholds for semi-solid and solid swallows. The adjunctive test thresholds were able to identify classifiable pathology not detected in patients with relatively normal water swallow or minor motility disorders. Our choice of custard or jelly for semi-solid and marshmallow for solid swallows provide a known and normalised swallow consistency that can be reliably repeated for the evaluation of multiple patients. Previous studies using similar materials, apple sauce and marshmallow, have also found increased frequency of abnormal contractions in subjects with dysphagia compared to water swallows [2].
In our patient controls, an increase in bolus viscosity correlated with an increase in IRP. Past authors analysing similar bolus material have suggested this could be due to increased friction between the bolus and luminal wall [4] [9].
Unlike water swallows, we noted that semi-solid and solid boluses often require more than a single swallow to clear but had lower peristaltic amplitudes. This is consistent with studies using other non-liquid bolus swallows [3] [4]. The difference in UES relaxation pressures between adjunctive swallows and SWS are due to two factors; bolus viscosity and volume. Small volumes of viscus boluses lead to a conscious effort to swallow from the participant, generating a higher pharyngeal driving force compared to water, which in turn causes a more relaxed UES. Previous studies report similar increases in UES relaxation with increased bolus viscosity and reduced bolus size, measured by water-perfused manometry [14] and more recently solid-state manometry [15].
A recent study justified the use of "patient controls" as part of the control group because they found no significant difference between the patient controls and healthy asymptomatic volunteers (IRP 20.1 ± 9.1 vs 16.3 ± 8.1; P ≥ 0.05) and Open Journal of Gastroenterology proposed that the inclusion of "patient controls" ensured that reference values were more representative of the patient population [8]. However, unlike the study by Ang et al., we excluded patients with dysphagia symptoms but normal HRM and 24-hour pH studies from our "patient controls" and were analysed these as separate groups.
Semi-solid and solid swallow values were characterised in patients with major oesophageal motility disorders. We noticed semi-solid and solid swallows triggered more profound oesophageal pathophysiology compared with water, such as higher IRP in EGJ dysfunction patients and shorter DL in patients with spasm. These observations are in line with other research that found more frequent oesophageal symptoms and abnormal pathology experienced by patients swallowing non-liquid boluses [3]. Pan-oesophageal pressurisation was more frequently observed in major motility studies during adjunctive tests compared to SWS. The diagnostic significance of pan-oesophageal pressurisation, occurring in the context of EGJ outflow obstruction or achalasia is the consequence of a distinct motor pattern characterised by contraction of both sphincters and the intervening oesophageal longitudinal muscle, but without lumen-obliteration contraction of the circular muscle in the inter-sphincteric span [16]. In contrast, intrabolus pressurisation, recorded from within a compartment trapped between the contractile front to the LES, does not imply necessary downstream obstruction [17] and is of less diagnostic significance. In patients with spasm and type III achalasia, we observed shorter distal latencies and increased peristaltic velocity with semi-solid and solid bolus compared to water. The shorter distal latencies of adjunctive swallows may suggest abnormalities in peristaltic timing and deglutitive inhibition are exaggerated with viscous bolus types. Although clinically interesting, the differences in distal latencies between swallow types were not statistically significant. Literature is mixed on non-liquid peristaltic velocities Basseri et al. [3] found higher velocity with apple sauce in healthy controls while Sweis et al. [4] found lower velocity with bread.
Diagnostic thresholds for semi-solid and solid swallows were established by ROC analysis (Figure 1). water swallows and correctly predicted the progression of the disease.
In patients with major motility disorders, adjunctive tests can provide additional information to assist with choosing the best course of treatment. In one of the patients diagnosed with oesophageal spasm, impaired LES relaxation was also suspected but the SWS IRP was just within normal limits ( Figure 4). Adjunctive tests further suggested type III achalasia which instigated additional diagnostic tests (barium swallow and gastroscopy) before the patient to undergo peroral endoscopic myotomy (POEM). Additional insight into the mechanism of diseases provided by semi-solid or solid swallows can help expedite diagnosis to enable early clinical intervention.
In our patient group, adjunctive tests are most effective in the diagnosis of Figure 2. A 54-year-old woman with dysphagia to solids. Manometry at isobaric contour 20 mmHg with single water swallows (SWS) show integrated relaxation pressure (IRP) within normal limit (12.7 mmHg). However, in semi-solid swallow, IRP increased to 16.1 mmHg and intrabolus pressure 18.9 mmHg was elevated. Solid swallow IRP was higher at 20.2 mmHg. These findings reveal impaired oesophagogastric junction (EGJ) relaxation and/or opening, the diagnosis was functional or structural EGJ outflow obstruction with endoscopic examination of EGJ recommended. Figure 3. A 61-year-old woman suffered from dysphagia and reflux symptoms. Endoscopy was normal. Barium swallow showed impaired bolus transport. Single water swallows (SWS) revealed ineffective motility (>50% failed swallows and <450 mmHg-cm-s) but integrated relaxation pressure (IRP) was normal (11.8 mmHg). During semi-solid swallow the IRP was impaired (21.1 mmHg) and oesophageal pressurisation was noted, similarly in solid swallows. Over a period of 1.5 years the patient experienced more frequent and severe symptoms. On repeat manometry, all swallows show impaired IRP and pan-oesophageal pressurisation, pathological of Type II achalasia.  A limitation of our study is the absence of a validation set to test our diagnostic thresholds. In addition, the HRM data was collected at a tertiary care centre in which a number of patients were referred for HRM by outside gastroenterologists, we were therefore only able to follow up on approximately half of the patients and assess their progression or response to treatment. It would have been helpful to record and quantify patient perception and symptoms during HRM to correlate with the physiological changes during adjunctive tests. This would determine the value of semi-solid and solid swallows in replicating patient symptoms during manometry. From this study we noted emphasised manometric abnormalities during adjunctive swallow compared to water counter-parts. If this translates to symptoms would be of significant interest. Ang et al., 2017 [12] found an 80% association between reported oesophageal symptoms and manometric abnormalities during standard test meals. They also describe that symptoms are more likely to occur after the first minute of the meal. This may suggest that we would have detected a weaker symptom association, had this been measured. This study also does not address the issue of a standardised bolus for solid and semi-solid swallows. This means that the normative data set is specific to the food substances/volumes used here, but may not be applicable to other protocols. However, our result using two different semi-solids, custard and jelly, suggests that identical volumes of different semi-solids produce relatively similar HRM metrics. Further research is required to determine the HRM metrics for different foods types. Zhang et al., 2013 highlights the need for a standardised protocol [19]. In keeping with our finding, Hollentstein et al., 2014 [13] found that results from rice standard meal and soft pasty were almost identical. Open Journal of Gastroenterology This perhaps suggests that the bolus properties do not affect the manometric outcomes.

Conclusion
In summary, semi-solid and solid swallows increase the identification of classifiable motility disorders when water swallows fail to identify an abnormality in patients presenting with dysphagia. Viscous bolus types provide challenges to the oesophagus akin to ingestion of meals that can increase the yield of pathologic findings compared to water swallows. The additional information can help reclassify a previously unnoticed diagnosis and assist in better disease intervention. With few barriers to implement these alternative swallowing tests, we recommend they be introduced as a useful compliment to the standard SWS in routine clinical studies.