This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Pyloric dysfunction is believed to play a major role in the pathophysiology in a subset of gastroparesis patients.1,2 With limited medical therapies for the treatment of gastroparesis, there has been growing enthusiasm for pyloric-directed therapies, especially with the advent of the gastric peroral endoscopic myotomy (G-POEM) of the pylorus.3 The G-POEM procedure has been shown to improve gastric emptying rates and has had modest clinical effectiveness for medically refractory gastroparesis patients in non-blinded studies with mid-term follow-up periods.4,5 Identifying the subset of gastroparesis patients with pyloric dysfunction who would optimally benefit from the G-POEM procedure remains a challenging task and is an area of ongoing research.
The functional lumen imaging probe (FLIP) has shown to be a useful diagnostic tool to assess sphincter characteristics, mostly of the lower esophageal sphincter (LES).6 Although originally designed to straddle the LES where the FLIP balloon is essentially straight, the FLIP device eventually was used to assess pyloric sphincter physiology in patients with gastroparesis.7-9 Non-blinded treatment studies have shown that gastroparesis patients with pyloric dysfunction (low pylorus distensibility on FLIP) can help predict clinical response to intra-pyloric botulinum toxin injection10 and the G-POEM procedure.11 However, current studies in the literature report high variability in pyloric sphincter measurements using existing FLIP devices.8,12 Some investigators have proposed that some of this variability may be in part due to phasic contractions of the pyloric sphincter.12 However, current FLIP models, EF-325N (8-cm balloon) and EF-322N (16-cm balloon), may be affected by the curved geometry of the duodenal bulb and sweep. Impedance planimetry technology estimates sphincter cross-sectional area (CSA) using Ohm’s law and the field gradient principle.13,14 However, these calculations require a relatively straight balloon configuration to be valid measurements.13,14 In our experience using the FLIP to assess the pyloric sphincter, the position of the FLIP balloon affects FLIP measurements. Standardization of catheter positioning is imperative in order to compare measurements across studies. Thus, we aim to investigate whether varying FLIP catheter positions affect pyloric FLIP measurements.
Patients undergoing endoscopic evaluation of chronic unexplained nausea and vomiting (CUNV) or gastroparesis with pyloric FLIP during upper endoscopy were prospectively enrolled in this study from June 2019 to October 2019. Patients with past pylorus therapies (pyloroplasty, G-POEM or botox injections within 6 months of the endoscopy) were excluded from this study. Study was approved by the University Institutional Review Board (IU IRB No. 1701721848) and listed on Clinical.Trials.gov (NCT04503785).
All FLIP studies were performed during upper endoscopy with intravenous propofol sedation by an anesthesiologist. Patients with endoscopic evidence of gastric bezoar, pylorus or post-bulbar obstruction, antral or pyloric channel ulcers were excluded from study. After the endoscope was withdrawn, the EndoFLIP EF-325N catheter (Medtronic, Inc, Shoreview, MN, USA) was inserted transorally into the stomach. The FLIP catheter has a distal tapered 13-cm balloon with 17 ring electrodes every 5 mm inside the balloon to provide 16 impedance-measurements over a 8-cm measuring length. The endoscope was reintroduced transorally next to the FLIP catheter. The endoscope and FLIP catheter were advanced together to the third part of the duodenum. With an assistant holding the FLIP catheter in place, the endoscope was withdrawn to the stomach with caution to leave the FLIP catheter in place. The FLIP catheter was advanced further to ensure there was no resistance, to avoid the catheter being kinked. If necessary, an endoscopic raptor grasping device was used to grasp the non-functioning distal tip of the FLIP catheter to advance the catheter.
The FLIP device was adjusted for 3 pre-defined balloon positions within the pylorus: (1) the proximal position, 75% of the FLIP balloon in the duodenum and 25% in the antrum (Fig. 1A); (2) the middle position, 50% in the duodenum and 50% in the antrum (Fig. 1B); and (3) the distal position, 25% in the duodenum and 75% in the antrum (Fig. 1C). The FLIP procedure was performed under direct visualization with the endoscope in the stomach. Starting at the proximal position, the narrowest CSA, intra-bag pressure and distensibility index (DI = CSA divided by P) were measured with 30-mL distension volume for at least 40 seconds. Procedures were repeated by pulling back to place the FLIP balloon in the middle position and then to the distal position. The FLIP catheter and balloon was then advanced back to the proximal position and the process was repeated at 40-mL and 50-mL distention volumes. Each position was confirmed by endoscopic visualization and by images on the FLIP monitor (Fig. 1D-F). In the first few cases, fluoroscopy was utilized in conjunction with pylorus FLIP to ensure the FLIP balloon was in the desired position within the duodenum.
Figure 1. Examples of endoscopic images of the 3 functional lumen imaging probe (FLIP) positions within the pylorus. (A) Proximal balloon position: 75% of balloon is in the duodenum and 25% in the antrum, (B) middle balloon position: 50% of balloon in the duodenum and 50% in the antrum, (C) distal balloon position: 25% of balloon in the duodenum and 75% in the antrum. Corresponding FLIP images of the 3 FLIP positions; (D) proximal balloon position, (E) middle balloon position, and (F) distal balloon position.
FLIP data was analyzed by 2 separate methods. One investigator analyzed the FLIP data for each subject using the FLIP Analytic software provided by the manufacturer. A stable measurement for the narrowest CSA, P, and DI was determined visually for the 30, 40, and 50-mL distension time-period for each FLIP position. Artifacts from respiration, vomiting, and technical issues were excluded from data analysis.
Another investigator analyzed the FLIP data using MATLAB (The Math Works, Natick, MA, USA). The FLIP text files were exported to MATLAB using a customized program. The program identified the pylorus by searching for the minimal diameter of the impedance planimetry channels. Pylorus-DI was calculated by dividing the minimum CSA by the P at a given time period. Median values for minimum CSA, P, and DI for the 30, 40, and 50-mL balloon fill volume time periods were calculated. The MATLAB analysis was conducted independently from the FLIP Analytic analysis.
Statistical comparisons to compare measurements conducted at different pyloric FLIP probe positions was conducted using independent and paired two-tailed student’s
Twenty-two patients (19 females, mean age 47 years) underwent endoscopic evaluation with pyloric FLIP measurements using this research protocol. Eighteen patients had a diagnosis of gastroparesis (6 diabetic, 7 idiopathic, 4 post-surgical, and 1 mixed connective tissue disorder) with delayed 4-hour gastric emptying and 4 patients presented with CUNV with normal 4-hour gastric emptying.
Endoscopic and corresponding FLIP images of the pylorus at the proximal, middle, and distal balloon positions are shown in Figures 1A-F. At the proximal balloon position, the FLIP image (Fig. 1D) could not identify if the balloon is straight or bent distal to the pylorus, which was beyond the view of the endoscopy (Fig. 1A). Representative fluoroscopic images conducted at the proximal and distal balloon positions are shown in Figure 2. At the proximal balloon position within the pylorus, the FLIP balloon was bent in the second part (descending) of duodenum (Fig. 2A). At the distal balloon position within the pylorus, the FLIP balloon was straight within the first part of duodenum (Fig. 2B).
Figure 2. Examples of fluoroscopic images at different functional lumen imaging probe (FLIP) balloon positions within the pylorus sphincter (identified by the hemoclip). Duodenum is to the left of the hemoclip on the images, and antrum is to the right of the hemoclip. (A) Proximal balloon position: FLIP balloon (identified by multiple impedance sensors) was bent within the second (descending) part of duodenum. (B) Distal balloon position: FLIP balloon was straight within the first part of duodenum.
Measurements from the FLIP Analytic software are provided in Table 1. At the proximal balloon position, where the FLIP balloon was bent in the second part of duodenum, intra-bag pressures were significantly higher in for all distension volumes compared to the middle and distal positions, where the FLIP balloon were less bent or straight. Pylorus CSA were also significantly higher at the proximal position with 30-mL and 40-mL distensions compared to the distal position values, while no difference was seen at the maximal 50-mL distension. The mean (SD) pylorus DI at 40-mL distension were 9.8 (4.6) and 13.1 (7.7) at the proximal and distal balloon positions, respectively (
Table 1 . Pylorus Functional Lumen Imaging Probe Metrics at Varying Balloon Positions Within the Pylorus in 22 Patients Using Functional Lumen Imaging Probe Analytic Software
| FLIP metric | Proximal position (75% of balloon in duodenum and 25% in antrum) | Middle position (50% of balloon in duodenum and 50% in antrum) | Distal position (25% of balloon in duodenum and 75% in antrum) |
|---|---|---|---|
| CSA (mm2) | |||
| 30 mL | 92.2 (31.3)a | 88.5 (28.9)a | 70.2 (26.3) |
| 40 mL | 130.1 (30.9)a | 137.9 (52.4)a | 115.0 (28.4) |
| 50 mL | 183.0 (34.8) | 190.2 (42.8) | 185.8 (38.0) |
| Pressure (mmHg) | |||
| 30 mL | 11.7 (4.6)a,b | 9.9 (3.9)a | 8.5 (3.8) |
| 40 mL | 15.2 (5.6)a,b | 11.6 (4.0)a | 10.6 (3.9) |
| 50 mL | 28.1 (5.8)a | 31.5 (44.5) | 21.1 (6.2) |
| DI [CSA/P] (mm2/mmHg) | |||
| 30 mL | 9.6 (6.0) | 11.4 (9.0) | 9.6 (6.1) |
| 40 mL | 9.8 (4.6)a,b | 13.9 (8.8) | 13.1 (7.7) |
| 50 mL | 6.7 (1.7)a,b | 9.4 (3.4) | 9.6 (3.7) |
a
b
CSA, cross-sectional area; DI, distensibility index; P, intra-bag pressure.
Results are expressed in mean (SD).
The FLIP data set was analyzed using MATLAB software. A representative study showing diameter, volume, and pressure changes over time during the different balloon positions is shown in Figure 3. Phasic variations of pressure measurements were common with oscillations occurring every 3 to 4 seconds, most likely related to respiration. These phasic variations were less prominent at 50-mL distension compared to 30-mL distension. Results from the MATLAB analysis are provided in Table 2. Similar to the FLIP Analytic analysis, the intra-bag P measurements were significantly higher in the proximal balloon position when the balloon was bent, compared to the middle and distal balloon positions when the balloon was less bent or straight (Table 2). The narrowest CSA measurements were less affected by balloon position than P. The CSA at the maximal 50-mL distension was not affected by balloon position within the pylorus. The calculated DI values mirrored the results using the FLIP Analytic software. Pylorus DI were significantly lower when the FLIP balloon is placed at the proximal positions for the 40-mL and 50-mL distensions, but no DI differences were seen at 30-mL distension.
Table 2 . Pylorus Functional Lumen Imaging Probe Metrics at Varying Balloon Positions Within the Pylorus in 22 Patients Using MATLAB Software
| FLIP metric | Proximal position (75% of balloon in duodenum and 25% in antrum) | Middle position (50% of balloon in duodenum and 50% in antrum) | Distal position (25% of balloon in duodenum and 75% in antrum) |
|---|---|---|---|
| CSA (mm2) | |||
| 30 mL | 85.7 (31.7)a | 76.8 (29.7)a | 64.2 (34.5) |
| 40 mL | 131.7 (32.8)a | 125.7 (32.3)a | 113.4 (27.2) |
| 50 mL | 187.8 (32.5) | 190.4 (39.3) | 185.1 (40.3) |
| Pressure (mmHg) | |||
| 30 mL | 11.9 (4.7)a,b | 9.8 (3.9)a | 9.1 (3.9) |
| 40 mL | 15.0 (5.1)a,b | 12.1 (5.0) | 11.1 (4.3) |
| 50 mL | 28.0 (6.2)a,b | 22.7 (5.4)a | 21.3 (6.1) |
| DI [CSA/P] (mm2/mmHg) | |||
| 30 mL | 8.6 (5.4) | 8.8 (5.9) | 8.3 (5.7) |
| 40 mL | 9.8 (4.6)a,b | 12.1 (6.3) | 12.8 (7.4) |
| 50 mL | 7.0 (2.1)a,b | 9.0 (3.1) | 9.5 (3.7) |
a
b
CSA, cross-sectional area; DI, distensibility index; P, intra-bag pressure.
Results are expressed in mean (SD).
Figure 3. Example study with MATLAB software analysis. The top panel shows a representative planimetry plot showing diameter changes over time during the 3 different balloon positions at 30, 40, and 50 mL balloon inflation volumes. The bottom panel depicts volume and pressure changes over time. Note (in blue) the phasic pressure variations (oscillations every 3 seconds) throughout the study. The black line is a weighted pressure average which reduces phasic oscillations. Also note the distinct pressure decreases as the balloon position changes from the proximal position to the middle position, then to the distal position in each balloon volume inflation time period.
There was a strong positive correlation between FLIP Analytic data for measured CSA and
Pylorus FLIP measurements were further analyzed by grouping patients by normal gastric emptying and gastroparesis etiology at the 50-mL balloon fill volume. Results are displayed in Table 3. There was no significant difference between pylorus metrics in patients with normal gastric emptying compared to gastroparesis patients. In all subgroups, there was a trend of increased pressure in the proximal compared to middle and distal positions, with significant differences found only in the normal gastric emptying, idiopathic gastroparesis, and total gastroparesis groups. There appeared to be a consistent trend among all subgroups for the proximal position to have lower distensibility measurements than the middle and distal positions.
Table 3 . Pylorus Functional Lumen Imaging Probe Metrics of Various Patient Groups at 50 mL Balloon Fill Volume
| FLIP metric | Normal gastric emptying (n = 4) | Gastroparesis patients total (n = 18) | Diabetic gastroparesis (n = 6) | Post-surgical gastroparesis (n = 4) | Idiopathic gastroparesis (n = 7) | MCTD (n = 1) |
|---|---|---|---|---|---|---|
| CSA (mm2) | ||||||
| Proximal | 196.8 (61.1) | 179.6 (28.0) | 179.5 (22.3) | 152.3 (19.4) | 198.4 (25.0)a | 158 |
| Middle | 203.0 (79.8) | 187.4 (33.0) | 189.0 (36.1) | 165.8 (35.8) | 199.3 (29.6) | 181 |
| Distal | 190.0 (65.4) | 184.9 (31.9) | 194.2 (35.1) | 159.8 (25.9) | 193.1 (30.2) | 172 |
| Pressure (mmHg) | ||||||
| Proximal | 29.8 (6.2)b | 27.7 (5.9)b,c | 27.8 (3.9) | 26.9 (7.8) | 29.7 (5.0)b,c | 15.6 |
| Middle | 20.5 (3.3) | 22.4 (6.1) | 23.6 (5.3) | 21.7 (7.0) | 23.4 (5.6) | 10.6 |
| Distal | 20.0 (1.8) | 21.4 (6.9) | 23.5 (6.7) | 22.0 (8.4) | 20.8 (6.3) | 10.9 |
| DI [CSA/P] (mm2/mmHg) | ||||||
| Proximal | 6.8 (2.1) | 6.8 (1.7)b,c | 6.7 (1.7)c | 6.0 (1.7) | 6.8 (1.3)b,c | 10.1 |
| Middle | 9.9 (4.6) | 9.2 (3.2) | 8.9 (2.5) | 8.1 (2.5) | 9.0 (3.0) | 17.1 |
| Distal | 9.5 (3.3) | 9.7 (3.8) | 8.8 (2.4) | 8.4 (4.0) | 10.3 (4.5) | 15.8 |
a
b
c
MCTD, mixed connective tissue disease; CSA, cross-sectional area; DI, distensibility index; P, intra-bag pressure.
Results are expressed in mean (SD).
The present study shows that pylorus FLIP measurements are dependent on FLIP probe positioning through the pyloric channel. Our findings show that there are significant differences in CSA, intra-bag pressure, and DI measurements with different FLIP catheter positions. Specifically, P measurements were significantly higher when most of the FLIP balloon was distal to the pylorus and bent in the second part of duodenum compared to when most of the FLIP balloon was in the antrum. The calculated pyloric DI were significantly lower when the balloon was placed mostly in the duodenum compared to the stomach. Based on fluoroscopic images obtained of the different balloon positions, these findings may be the result of balloon deformation and changes in FLIP geometry when placed within the duodenum.
We independently reviewed the pylorus FLIP studies by using the FLIP Analytics software provided by the product manufacturer versus the MATLAB analysis. The visually obtained point measurements of pylorus CSA and P using the FLIP Analytics software were comparable to the median measurements over a given inflation volume obtained using MATLAB. However, small numerical differences were noted and may be attributable to phasic variations in pressure measurements. These variations could be from respiratory motion, as some oscillations occurred every 3 seconds to 4 seconds, or from pylorus contractions. Previous investigators have shown dynamic pylorus changes with contractions propagating from the antrum to the pylorus or isolated pyloric contractions.12 Fortunately, these phasic variations were less prominent at the higher balloon distension volumes. Since the current FLIP Analytics software only allows visual point measurements, capturing the pressure at the peak or trough of an oscillation can cause variability in measurements.
The current study suggests that the FLIP device yields different measurements while undergoing balloon deformation within the duodenum. It is important to remember that impedance planimetry technology is based on the electric field gradient principle and Ohm’s law. According to the device manufacturer and prior impedance planimetry studies, the electric field gradient estimation of CSA is valid in instances where (1) the device sensors are in the center of the FLIP balloon, and (2) when the slope of the balloon edges is not significant.13,14 One possible explanation for the differences in CSA measurements seen in the current study is the result of balloon deformation that occurs when the probe is pushed too far into the duodenum. This causes distortion of the balloon geometry, causing the sensors to no longer remain in the center of the balloon. Additionally, with this deformation the balloon edge slope also changes. Together, these changes may affect estimations of the pyloric sphincter CSA using impedance planimetry. We also found that probe placement affects P measurements. We suspect that this may be the result of (1) deformation of the balloon in the duodenum causing a falsely elevated pressure, (2) increased peristalsis while the balloon is placed in this position, or (3) artificially elevated pressures resulting from continued effort to hold the balloon in the proximal balloon position. As DI measurements are calculated from CSA and P measurements, it is not surprising that we also saw differences in DI with varying probe positions. Balloon deformation is minimized when the FLIP balloon is positioned mostly in the antrum.
With growing evidence that pyloric FLIP measurements may identify patients with pyloric dysfunction who may optimally benefit from pyloric-directed therapies such as G-POEM, this study highlights the need for standardized pylorus FLIP protocols. Previous pylorus FLIP protocols emphasized obtaining measurements over 5-second intervals to avoid variation from antroduodenal peristalsis and obtaining ideal, distinctive balloon shapes of the pylorus.7,8,15 The current study further suggests that balloon positioning within the pylorus significantly affects pyloric FLIP measurements. Researchers have shown that gastroparesis patients with impaired pyloric DI may have short-term benefits from pyloric interventions such as botox injection and the G-POEM procedure.10,11 Jacques et al11 identified that patients with DI < 9.2 mm2/mmHg at 50-mL benefited from G-POEM procedures. Desprez et al10 showed benefit of intrapyloric botox in patients with DI < 10 mm2/mmHg at 40-mL. Our findings show that patients may have lower calculated DI if the FLIP balloon is bent in the second part of duodenum and may be mis-labeled as having stiff pyloric sphincters. A new pylorus-specific FLIP balloon is needed. Based on the data presented, the FLIP balloon should be shorter to position the pylorus in the middle of the balloon with half in the antrum and half in the straight first part of duodenum. The pylorus-specific balloon also needs a greater diameter compared to the current balloon designed for the LES.
This study had several limitations. In this study, the balloon catheter was repeatedly moved from proximal to middle to distal positions and sequentially increased from 30-mL to 50-mL balloon fill volumes. It is a possibility that serial dilation may alter the numerical values of subsequent measurements due to the FLIP balloon causing a “dilatation effect.” As a balloon dilates a sphincter, one may expect subsequent CSA measurements to increase, P to decrease, and DI to increase. While there did appear to be a P decrease and DI increase with the progression from proximal to middle to distal positions, the CSA remained the same or tended to decrease. This suggests that the differences seen in this study are likely not due to a pure dilatation effect. Additionally, there were only 22 subjects in our study, and the anatomy of the antrum and proximal duodenum can vary among individuals. Only patients with gastroparesis and idiopathic nausea and vomiting were included in this study. The effects on FLIP balloon positions may be less in healthy volunteers with normal pylorus distensibility. Furthermore, there are inherent issues with pylorus FLIP testing. A barostat is a computerized device that can add or withdraw air to keep the balloon pressure constant (independent variable), in order to measure the lumen volumes (dependent variable) at multiple stepped-up pressures. A compliance curve (volume vs pressure) can then be plotted to determine the luminal wall stiffness. In contrast, pressure and CSA measurements of FLIP testing are both dependent on distension volume inside the balloon and positioning of the balloon within the pylorus. It is not surprising that pressure and CSA measurements are variable at different FLIP balloon placements. The narrowest pylorus CSA measurement is estimated by 2 impedance sensors at only 5-mm apart. The geometry of the 13-cm tapered FLIP balloon affects the pressure but not the distensibility characteristics of the pylorus. If the pressure can be kept constant, the balloon position may not be an issue.
In conclusion, we show that varying pyloric FLIP positions within the pyloric channel causes significant distortion in the FLIP balloon geometry and affects CSA, P, and DI measurements of the pylorus. We believe that placing the FLIP device mostly in the antrum minimizes balloon deformation and produces valid pylorus FLIP measurements. Standardized pyloric FLIP protocols as well as balloon design adjustments are needed for the continued application of this technology to the pylorus. Future studies to optimize pylorus FLIP protocols are needed.
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Brandon Yim: data analysis, and writing of the manuscript; Robert M Siwiec and Mohammad Al-Haddad: writing of the manuscript; Lennon Gregor: data analysis; Thomas V Nowak: recruitment and writing of the manuscript; and John M Wo: study conceptualization, writing of the protocol, recruitment, and writing of the manuscript.
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