Address for Correspondence Julie Regan, School of Clinical Medicine, Trinity College Dublin, Ireland, Speech & Language Therapy Department, Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland. Tel: +353 1 4142776; fax: +353 1 4144857; e-mail: email@example.com
Background This paper aims to measure upper esophageal sphincter (UES) distensibility and extent and duration of UES opening during swallowing in healthy subjects using EndoFLIP®.
Methods Fourteen healthy subjects (20–50 years) were recruited. An EndoFLIP® probe was passed trans-orally and the probe balloon was positioned across the UES. Two 20-mL ramp distensions were completed and UES cross-sectional area (CSA) and intra-balloon pressure (IBP) were evaluated. At 12-mL balloon volume, subjects completed dry, 5- and 10-mL liquid swallows and extent (mm) and duration (s) of UES opening and minimum IBP (mmHg) were analyzed across swallows.
Key Results Thirteen subjects completed the study protocol. A significant change in UES CSA (P < .001) and IBP (P < .000) was observed during 20-mL distension. UES CSA increased up to 10-mL distension (P < .001), from which point IBP raised significantly (P = 0.004). There were significant changes in UES diameter (mm) (P < .000) and minimum IBP (mmHg) (P < .000) during swallowing events. Resting UES diameter (4.9 mm; IQR 0.02) and minimum IBP (18.8 mmHg; IQR 2.64) changed significantly during dry (9.6 mm; IQR 1.3: P < .001) (3.6 mmHg; IQR 4.1: P = 0.002); 5 mL (8.61 mm; IQR 2.7: P < .001) (4.8 mmHg; IQR 5.7: P < .001) and 10-mL swallows (8.3 mm; IQR 1.6: P < 0.001) (3 mmHg; 4.6: P < .001). Median duration of UES opening was 0.5 s across dry and liquid swallows (P = 0.91). Color contour plots of EndoFLIP® data capture novel information regarding pharyngo-esophageal events during swallowing.
Conclusions & Inferences Authors obtained three different types of quantitative data (CSA, IBP, and timing) regarding UES distensibility and UES opening patterns during swallowing in healthy adults using only one device (EndoFLIP®). This new measure of swallowing offers fresh information regarding UES dynamics which may ultimately improve patient care.
The upper esophageal sphincter (UES) is a muscular constriction separating the pharynx and the esophagus. It consists of inferior pharyngeal constrictor (IPC) muscles, the cricopharyngeus (CP), and the cervical esophagus (CE), which create a 2–4 cm high pressure zone.1 UES high resting tone prevents diversion of air into the esophagus during inspiration and protects the airway from any retrograde passage of material refluxed from the esophagus or stomach. During swallowing, the UES needs to open adequately to ensure material passes safely and efficiently from the pharynx into the esophagus. This begins with CP relaxation and is followed closely by anterior and superior hyo-laryngeal excursion to stretch open the UES. Pressure from the oncoming bolus further distends the UES lumen.2
Impaired UES opening is a feature of crico-pharyngeal dysphagia which frequently leads to tracheal aspiration and pharyngeal retention post swallow. It is commonly associated with neurological conditions (e.g., brainstem stroke, amyotrophic lateral sclerosis), myopathy (e.g., fibrosis), and structural abnormalities (e.g., Zenkers diverticulum, CP bar).3–7 Treatment depends on the underlying cause and can include compensatory postures (e.g., head turn), rehabilitation (e.g., Shaker head lifting exercises), pharmaceutical and surgical intervention (e.g., botulinum toxin or CP myotomy).8–11 Objective and reliable UES evaluation is critical to determine the presence and nature of UES dysfunction and to ensure that the safest and most effective dysphagia intervention is provided. Currently, videofluoroscopy and pharyngeal manometry are the most commonly employed UES evaluations. However, several limitations to these evaluations have been identified including unacceptable interrater reliability of UES opening measures and varying resting UES pressure ranges between 35 and 200 mmHg across studies.12–16
The functional lumen imaging probe (FLIP) is a novel distensibility tool based on the principles of impedance planimetry.17 A balloon at the distal end of a FLIP probe is positioned in an anatomical lumen and is distended by filling it with a conductive solution. Functional lumen imaging probe provides multiple CSA measures of the lumen and uses these to recreate a functional dynamic image of sphincter geometry. These CSA measures, alongside a measure of intra-balloon pressure, facilitate measurement of sphincter distensibility.18 Functional lumen imaging probe was originally designed to evaluate esopho–gastric junction (EGJ) compliance.19 It has since been employed to evaluate other anatomical sites including the sphincter of Oddi, the upper esophagus, and laparoscopic lumens.20–23
Until recently, the role of FLIP in UES evaluation had not been explored. Two studies have demonstrated safe insertion and distension of the FLIP balloon in the UES of healthy adults and patients with dysphagia both with and without videofluoroscopic guidance.24,25 The derivation of preliminary UES distensibility data and novel quantitative UES diameter and intra-balloon pressure measures by FLIP without fluoroscopy has also been reported.25 Based on these initial studies, authors hypothesize that FLIP may provide new information on UES opening characteristics during distension and may provide objective measures of UES opening during swallowing. The aims of this study were (i) to measure UES distensibility using FLIP in a group of healthy adults, and (ii) to quantify UES opening during dry and liquid swallowing events in this healthy group using FLIP.
Materials and Methods
Subjects were recruited from a pool of healthy volunteers. Inclusion criteria were (i) no history of oro-pharyngeal or esophageal dysphagia, (ii) no history of gastrointestinal, neurological, or respiratory disease, and (iii) no history of head and neck cancer or ear, nose and throat conditions. Fourteen subjects (six males, eight females) with a mean age of 30 years (age range 20–50 years; SD = 11.02) met inclusion criteria. Written consent was obtained from subjects. Ethical approval was obtained from the Research Ethics Committee, University Hospitals Leuven, Belgium.
A commercially developed FLIP (EndoFLIP® system; Crospon Ltd., Galway, Ireland) was used. In brief, a polyurethane balloon with a maximum volume of 60 mL is mounted on the distal 14 cm of a probe (EF-325) (length 240 cm, diameter 25 mm) attached to the EndoFLIP® unit. This balloon assumes a 10 cm long cylindrical shape with maximum diameter of 2.5 cm when fully filled. The maximum balloon diameter is critical to prevent airway compromise during balloon distension. Along a 7.5 cm segment within the balloon, 17 ring electrodes are spaced 5 mm apart to obtain 16 CSA measurements using an impedance planimetry technique. This allows diameter and pressure changes above (i.e., pharynx) and below (i.e., upper esophagus) the UES to be captured and for UES opening to be observed despite its upward shift during swallowing. Excitation electrodes situated at either end of the 17 ring electrodes emit a constant low electrical current within the balloon. The probe also contains a solid-state pressure transducer to measure intra-balloon pressure. EndoFLIP is CE marked under the European device directive and has been approved for inflation in the esophagus. Fill volumes were limited to a maximum of 20 mL in this study in a balloon that can hold 60 mL. The EndoFLIP® system was also pressure limited. The upper limit was set at 80 mmHg based on pilot studies. If this set pressure limit is reached, the system will stop the inflation and the alarm will sound.
The EndoFLIP® system was positioned beside the subject who was seated upright on a chair within the clinic room (Neurogastroenterology & Motility Clinic, University Hospital Leuven). The equipment was powered on and both the syringe and a precalibrated probe were connected to the EndoFLIP® unit. An automated purge sequence initiated by the EndoFLIP® removed air from the balloon and calibrated the pressure measurement inside. Topical anesthesia (Lignocaine spray) was administered to the posterior pharyngeal wall and subjects were instructed to perform a dry swallow. The tip of the EndoFLIP® probe was lubricated and inserted orally by a member of the research team until the deflated balloon at the distal end of EndoFLIP® was judged to have passed into the proximal esophagus (30 cm marking on EndoFLIP® catheter). The subject was transferred to a bed and seated in a 90° angle upright position. The EndoFLIP® catheter was held outside of the subjects’ teeth by a researcher to minimize displacement during the evaluation.
When the subject became accustomed to the probe, the probe balloon within the esophagus was distended with 10 mL saline solution from the syringe using a touch screen function on the EndoFLIP® monitor. The inflated balloon was then slowly retracted until the hourglass shape of the UES could be visualized on the EndoFLIP® display (17–20 cm marking on EndoFLIP® catheter; Fig. 1). This confirmed the balloon position in the UES. While holding the catheter in place, the balloon was deflated.
After a brief habituation period (1–2 min), two ramp distensions to 20 mL were completed (rate 60 mL min−1). Subjects were requested not to swallow during distensions and the EndoFLIP® screen was monitored to ensure the balloon remained in position. Two distensions were completed to allow for an accommodation effect. The balloon was then reinflated with a 12 mL volume of conductive solution. 12-mL balloon volume was selected as it was well tolerated during pilot studies and yet sufficient a volume to observe an hourglass shape on the EndoFLIP® screen when positioned in the UES. Once a baseline measure of minimum UES diameter (mm) and intra-balloon pressure (mmHg) was recorded, subjects were asked to complete the following:
(a) two dry swallows
(b) two 5-mL liquid swallow delivered orally via a syringe
(c) two 10-mL liquid swallow delivered orally via a syringe.
A minimum 10-s time period between the performances of each swallow was enforced to easily identify events during data analysis. The time (in seconds) displayed on the EndoFLIP® device at the execution of each swallow was recorded. When the protocol was completed, 12 mL was deflated from the balloon and the probe was removed.
UES distensibility EndoFLIP® provides 16 measures of CSA (mm2) and a measure of intra-balloon pressure (mmHg) at a rate of 10 Hz during distensions. Data from the second 20-mL ramp distension were transferred from EndoFLIP® into an Excel document on a personal computer. Median CSA (mm2) and intra-balloon pressure (mmHg) measures and interquartile ranges (IQRs) were determined at 1, 5, 10, 15, and 20-mL balloon volumes across subjects.
Swallow events EndoFLIP® measures of diameter, intra-balloon pressure, and time were transferred into an Excel document. To determine change in UES opening during swallowing, three EndoFLIP® measures were selected for examination at rest and during second dry, 5- and 10-mL liquid swallow events. There were (i) extent of UES opening (mm), (ii) duration of UES opening (ms), and (iii) minimum intra-balloon pressure (mmHg). The derivation of each variable is described below.
1Extent of UES Opening (mm): EndoFLIP® provides 16 estimated diameter (mm) measurements (based on CSA) at a rate of 10 s−1 throughout the examination. The minimum of the 16 diameter measures at each time point was considered to be the narrow UES region (Fig. 1B). This minimum UES diameter measure was evaluated during swallow events to ascertain the extent of UES opening during swallowing. Of note, the minimal detectable diameter of the EndoFLIP® probe is 4.8 mm (or 18.1 mm2) because of its physical size.
2Duration of UES opening (ms): Sixteen diameter measures were provided by EndoFLIP® at a rate of 10 s−1. Duration of UES opening was defined as the time from which the narrowest diameter in the UES region sharply rises from its baseline during swallowing until its return to baseline diameter (Fig. 1B).
3Minimum intra-balloon pressure (mmHg): FLIP provided 10 measures of intra-balloon pressure (mmHg) per second (Fig. 1B). To examine change in intra-balloon pressure observed during swallow events, the minimum pressure measurement during swallowing was examined across swallows.
Data were entered into SPSS statistical software package (version 19j (IBM CORP, Armonk, NY, USA). Based on Shapiro–Wilk tests, all data were not normally distributed. Data were therefore expressed as medians (IQR) and non-parametric tests were employed. Kruskal–Wallis tests were used to determine a change in UES CSA and intra-balloon pressure across balloon volumes (1, 5, 10, 15, and 20 mL) during distensibility testing and to establish differences in UES diameter, minimum intra-balloon pressure and duration of UES opening at baseline and across dry, 5- and 10-mL liquid swallow events. Significance was set at P < .05. Where significance was found, multiple comparisons were made using the Wilcoxin rank sum test. Bonferroni correction was made and post hoc tests were significant at an adjusted alpha level of 0.0127 for distensibility testing and 0.008 for swallow events.
The EndoFLIP® probe was safely inserted and the narrowing of the UES was identified on the EndoFLIP® screen across all 14 subjects. Thirteen of 14 subjects completed 20-mL ramp distensions. One subject (subject 11) was unable to tolerate more than 16 mL in the inflated balloon in the UES for prolonged periods. The data from this subject were therefore omitted from distensibility data analysis. The second of two 20-mL ramp distensions was included in data analysis to allow for an accommodation effect. One subject (subject 13) did not reach a maximum of 20-mL balloon volume on their second distension (18 mL) and hence their first distension (20 mL) was selected for data analysis.
Across all subjects, the hourglass shape of the UES could be visualized on the EndoFLIP® screen during the ramp distension. A representative geometric profile of the UES on the EndoFLIP® screen which was observed across all subjects at 20-mL balloon volume is shown in Fig. 1. The minimum UES CSA increased significantly during the 20-mL ramp distension as the balloon volume increased [H(2) = 18.32, 4 d.f., P < .001; Fig. 3]. A nearly significant increase in median UES CSA was found between 1 m and 5-mL balloon volumes (median CSA 18.7 and 22.5 mm2, respectively; P = 0.028) and there was a significant increase in UES CSA between 5- and 10-mL balloon volumes (median CSA 22.5 and 23.8 mm2, respectively; P < .001). The UES then resisted any further increase in CSA during the distension, as no difference in median CSA was observed between 10 and 154 mL (P = 0.382) or between 15 and 20 mL (P = 0.382) (Fig. 2).
Intra-balloon pressure also increased significantly during the 20-mL ramp distension [H(2) = 27.36, 4 d.f., P < .000; Fig. 3]. No significant difference in median intra-balloon pressure was found between 1 and 5 mL (P = 0.463) or between 5 and 10 mL (P < .861). However, once balloon inflation caused the UES CSA to reach a plateau, a significant increase in intra-balloon pressure was detected between 10 and 15 mL (4 and 13.4 mmHg, respectively) (P = 0.004) and between 15 and 20 mL (13.4 and 36.9 mmHg, respectively; P = 0.003, Fig. 2).
Thirteen of 14 subjects completed the entire swallow events protocol with the distended EndoFLIP® balloon (12 mL) within the UES. One subject (subject 12) could not tolerate the distended balloon in the UES for the entire protocol and was omitted from swallow maneuvers data analysis. Data at rest and from 39 swallows (the second dry, 5- and 10-mL liquid swallows) within the subject group were analyzed to obtain group measures of UES diameter, minimum intra-balloon pressure and duration of UES opening across swallow events.
There was a statistically significant change in UES diameter across swallow events (P < .000). During dry swallowing, UES diameter increased from a baseline diameter measure of 4.9–9.6 mm (IQR 1.3; N = 13, P < .001). Resting median UES diameter increased from 4.9 to 8.61 mm (IQR 2.7) during five liquid swallows (P < .001). Diameter increased from 4.9 mm at baseline to 8.27 mm (IQR 1.6) during 10-mL liquid swallows (P < .001). A significant median difference was also observed in UES diameter between dry and 10-mL liquid swallows (P < .005). However, no significant difference in UES diameter was observed during dry and 5-mL swallows (P = 0.64) or between 5- and 10-mL liquid swallows (P = 0.46; Fig. 3).
No significant difference was evident in duration of UES opening across swallow events (N = 13, P = 0.91; Fig. 3). Median duration of UES opening remained at 0.5 s across subjects during dry swallowing (IQR 0.3), 5-mL liquid swallows (IQR 0.3), and 10-mL liquid swallowing (IQR 0.1; Fig. 3).
A statistically significant difference in minimum intra-balloon pressure was observed across swallow events (P < .000). Minimum intra-balloon pressure dropped from 18.8 mmHg at rest to 3.6 mmHg (IQR 4.1) during dry swallowing (P = 0.002). Minimum intra-balloon pressure dropped from 18.8 mmHg at baseline to 4.8 mmHg (IQR 5.5) during 5-mL swallows (P < 0.001; Fig. 3). Pressure dropped from 18.8 to 2.96 mmHg (IQR 4.6) during 10-mL liquid swallows (P < 0.001). There was no significant difference in minimum pressure between dry and 5-mL (P = 0.6) or 10-mL (P = 0.86) swallows or between 5- and 10-mL swallows (P = 0.35; Fig. 3).
Using OriginLab data analysis software (version 8.6), EndoFLIP® diameter, pressure, and time measurements are displayed in color contour plots at rest and during swallowing (Fig. 4).
In this study, distensibility and opening patterns of the UES were evaluated for the first time in a group of 14 adult healthy subjects using EndoFLIP®. EndoFLIP® was well tolerated within the UES in this subject group (13 of 14 subjects), with tolerance and comfort levels similar to fiberoptic endoscopic evaluation of swallowing (FEES).26,27 The UES was identified across all subjects during the 20-mL ramp distension. Major findings included the significant increase in the CSA of the UES lumen during distensibility testing. Specifically, UES CSA distended up until 10-mL distension and then resisted further distension. This resistance was presumably due to the high resting UES tone within this healthy non-elderly subject group. From this point, intra-balloon pressure raised significantly.
This was the first study to analyze compliance of the UES lumen using EndoFLIP® in healthy adults. EndoFLIP® measurement of UES dynamics may contribute to our understanding of UES function and dysfunction and may, in the longer term, enhance diagnosis and hence the rehabilitative or surgical treatment of dysphagia. Further studies will determine if a distinction in UES distensibility is evident between non-elderly and elderly subjects or between healthy and clinical groups with known UES dysfunction (e.g., CP hypertonicity, CP fibrosis). The effects of different bolus consistencies on UES opening during swallowing as measured by FLIP need to be evaluated. Beyond an initial study to demonstrate this technique, no other studies have used EndoFLIP® to evaluate UES distensibility to date. In a separate study, work has begun to compare FLIP measures of UES opening to data from other UES diagnostic tools within the same subject group.
This study also sought to examine extent and duration of UES opening during dry and liquid swallow events using EndoFLIP®. This information is currently difficult to quantify reliably in clinical dysphagia practice.28 EndoFLIP® provided quantitative measures of the extent and duration of UES opening and intra-balloon pressure changes over time during dry and liquid swallowing events. Significant changes in UES diameter and minimum intra-balloon pressure during swallowing events were found. Extent of UES opening was quantitatively measured and ranged between 8.3 and 9.6 mm across dry, 5- and 10-mL liquid swallows in this study. Videofluoroscopy studies have found that extent of UES opening in healthy adults has ranged between 8 and 12 mm during swallowing6,29–31 (Fig. 5). Duration of UES opening was 0.5 s across bolus volumes in this study. Measures of duration of UES opening also closely matched duration measures in previous videofluoroscopy research6,29–31 (Fig. 5). Although measures of UES opening were similar to other techniques, EndoFLIP® data are not labor intensive to acquire and geometric changes in the UES during swallowing can be observed in real time on the portable EndoFLIP® device as a biofeedback tool without any need for fluoroscopy.
In this study, extent of UES opening was largest for dry swallowing compared with 5- and 10-mL liquid swallows. Intra-balloon pressure during swallowing did not decrease with increase bolus volume and duration of UES opening remained the same across dry, 5- and 10-mL liquid swallows. This lack of volume effect has also been reported in videofluoroscopy and pharyngeal manometry-impedance studies.32,33 However, as swallow events were not randomized within the study protocol, a lack of volume effect between dry and 10-mL liquid swallows may have been due to an accommodation or fatigue effect.
When diameter, pressure, and time data provided by EndoFLIP® are depicted in color contour plots, professionals are provided with an innovative graphic display of the extent and duration of UES opening on a time axis during swallowing. As detection electrodes within the probe balloon are spaced only 5 mm apart, EndoFLIP® can provide a rich profile of UES dynamics during swallowing and can represent the relationship between UES opening and intra-balloon pressure. Patterns regarding the sequence and duration of diameter and pressure changes were apparent across swallows in this healthy subject group and may, based on future studies, define whether bolus transport through the UES is normal or impaired. Future validation of EndoFLIP® data with measures from other physiological examinations may assist in determining if the various phases of UES opening (e.g., CP relaxation) are captured by EndoFLIP®. Data in this study suggest that other pharyngo-esophageal events such as the upward shift of the UES during swallowing secondary to hyo-laryngeal excursion have the potential to be quantified based on these plots. This information may, in clinical practice, determine efficacy of or candidacy for rehabilitation (e.g., Shaker exercises) or surgical interventions such as botulinum toxin injections or CP myotomy.9–11
Pharyngo-esophageal swallowing events observed in EndoFLIP® color contour plots do present similarly to spatiotemporal pressure events on high-resolution manometry (HRM).34 The important distinction, however, is that EndoFLIP® measures changes in the narrowing of a lumen during swallowing, whereas HRM measures of UES opening are based on pressure changes during swallowing. It is hoped that the development of new physiological gastrointestinal tests such as multi-channel intra-luminal impedance, high-resolution manometry, and EndoFLIP® may lead to better diagnostic precision and hence tailor clinical dysphagia intervention. The use of a balloon to study UES dynamics avoids the issue of pressure sensor displacement from the UES during swallowing as seen in traditional manometry.
Potential limitations to this study include the fact that only 10 diameter recordings are provided per second by EndoFLIP®. This may have limited measures of duration of UES opening as peak values may have been missed between measurements. However, a good range of values was apparent within the subject group. These values of UES opening duration were also in keeping with previous videofluoroscopy research.6,29,30 Otherwise, the minimum diameter measure provided by EndoFLIP® is 4.8 mm, which may be narrowing some UES diameter data ranges. Perhaps one of the most important issues to consider based on this study is the optimum EndoFLIP® balloon dimensions and volumes for UES evaluation. While the study protocol was adapted from EGJ studies for UES evaluation, the probe used in these studies is a standard version for use in other regions of the esophagus. These studies suggest that EndoFLIP® balloon length and positioning need to be carefully considered during future UES testing. Care had to be taken to ensure too much of the balloon was not positioned in the pharynx during testing. Otherwise, tolerance of the balloon decreased as subjects were very sensitive to the inflated balloon in the pharynx. Although a shorter probe balloon may address this issue to some extent, too short a balloon might prevent the UES opening from being captured due to its upward shift during swallowing. The effect of this can be seen most clearly on the color contour plots where the top end of the UES can disappear during swallowing as the UES opens. Refinement of balloon dimensions and positioning during the study protocol is of prime importance to ensure that critical information is not lost during data collection. Tolerance of the probe will continue to be monitored in future research with larger subject groups. FLIP also does not provide real information on the actual luminal shape in the UES region. However, from this and studies of other regions (i.e., EGJ), we know it is representative of function, particularly as it relates to the distension required to open the sphincter and representing that opening as a measure of multiple radial cross-sectional areas.
Future research should examine UES distensibility and opening patterns in elderly healthy adults and clinical groups with known UES dysfunction (e.g., CP hypertonicity) to determine the effect of aging and disease on UES compliance. It will be of interest to determine if those with electromyography (EMG)-confirmed disordered CP relaxation present differently during UES distensibility testing to those with pharyngeal phase involvement (i.e., poor hyo-laryngeal excursion or weak intra-bolus pressure). Validation of EndoFLIP® against a gold standard assessment will determine the sensitivity of EndoFLIP® in diagnosing aspects of dysphagia. The development of any additional outcomes measures based on diameter, intra-balloon pressure, and time data obtained from EndoFLIP® needs to be explored.
This study presented a new technique to measure UES distensibility and to quantify the extent and duration of UES opening during swallowing events. EndoFLIP® was well tolerated by subjects and it provided valuable objective information regarding UES compliance without need for fluoroscopy. It also provided novel quantitative measures of UES opening during swallowing events which are currently lacking in clinical practice. Results on the diameter and timing of UES opening during swallow match with current knowledge on UES physiology. However, FLIP data obtainable at the bedside without need for contrast material or radiation. Color contour plots representing EndoFLIP® diameter and pressure data on a time axis provide a novel objective approach to the analysis of UES dynamics during swallowing. EndoFLIP® may provide a role in evaluating UES opening during swallowing in patients with dysphagia before and after rehabilitation or surgery. Further research is currently underway to validate EndoFLIP® as a diagnostic tool in UES evaluation.
JR was funded by the Health Research Board, Ireland (Grant HPF/2009/39).
BM previously worked as a consultant for Crospon Ltd and is currently a minor shareholder in Crospon Ltd.
JR, MW, NR, & BM designed study; JR, MW, NR, JT, & BM collected data; JR analyzed data & wrote manuscript; MW, NR, & BM reviewed article.