Functional lumen imaging probe (FLIP) Panometry characterizes esophageal motility in response to sustained esophageal distension using high-resolution impedance planimetry. Using impedance planimetry technology, FLIP measures luminal cross-sectional area and pressure within a volumetrically distended bag to assess esophagogastric junction (EGJ) opening and distensibility, as well as secondary peristalsis and esophageal motility.^1,2

While both high-resolution manometry (HRM) and FLIP can evaluate esophageal motility, they do so in different ways: FLIP assesses esophageal response to distension; HRM assesses esophageal response to swallow. Prior studies have compared assessments of esophageal motility between FLIP and HRM and demonstrated parallel findings between the 2 modalities.^3-7 In particular, FLIP has demonstrated utility in the evaluation of esophageal motility disorders, including achalasia, EGJ outflow obstruction, and eosinophilic esophagitis.^8-11 Overall, FLIP may represent a stand-alone tool for esophageal motility evaluation in some scenarios, while also complementing existing esophageal diagnostic tools like HRM in certain clinical contexts.^2,8,12,13

An important practical difference between HRM and FLIP is that HRM is performed on awake patients, whereas FLIP is generally performed on sedated patients during endoscopy or surgery. While previous studies comparing sedated FLIP with awake HRM have demonstrated similar esophageal motility findings, studies comparing manometry between chronic opioid users and non-users have suggested an emerging clinical entity termed opioid-induced esophageal dysfunction (OIED).^2,5,6,14-20 Manometric motility abnormalities observed among OIED included impaired lower esophageal sphincter (LES) relaxation, increased LES pressures, and spastic peristalsis; hence, increased rates of type III (spastic) achalasia, EGJ outflow obstruction, distal esophageal spasm, and hypercontractile esophagus.^13-19 Further, studies have demonstrated opioid dose-dependent effects and reversibility of HRM changes after discontinuing chronic opioid medications.^17-20

Despite evidence for OIED related to chronic opioids, the evidence for esophageal motility changes related to acute administration of opioids and benzodiazepines is variable. While some studies of acute opioid administration have aligned with changes observed in chronic opioid use (eg, decreased LES relaxation and increased LES pressure),^21-25 other studies of intravenous opioid administration during manometry in healthy adults have demonstrated a reduction in LES pressure with opioid administration.^26-28 Data are equivocal regarding the effects of benzodiazepines with decreased, increased, and unchanged LES pressure having been demonstrated on manometry with intravenous benzodiazepine administration in healthy humans in different studies.^29-31 While the FLIP Panometry motility evaluation generally correlates well with motility findings from awake esophageal manometry, the effects of conscious sedation on FLIP Panometry findings have not been directly examined. Hence, we aimed to clarify the impact of conscious sedation on FLIP esophageal motility metrics and classification in healthy, asymptomatic subjects. A secondary goal of this study was to investigate perceived esophageal sensation with progressive FLIP distension during awake FLIP in healthy, asymptomatic subjects.

Cohort Inclusion Criteria

A cohort of healthy, asymptomatic (ie, free of esophageal symptoms including dysphagia, heartburn, and chest pain) volunteers were enrolled. Potential subjects were excluded for previous diagnosis of esophageal disorders. Additional exclusion criteria included previous diagnosis of autoimmune or eating disorders, use of antacids or proton pump inhibitors, body mass index > 30 kg/m², or a history of tobacco use or alcohol abuse. The study protocol was approved by the Institutional Review Board (STU00096856). Informed consent was obtained from all subjects; subjects were paid for their participation. This cohort was previously described.³²

Study Protocol

A cross-over study design was utilized such that each subject underwent 2 FLIP studies: 1 with conscious sedation (with midazolam and fentanyl) during endoscopy and then 1 on a separate day while awake without sedation. For both studies, evaluation was completed after a minimum 6-hour fast. For the awake studies, subjects gargled viscous lidocaine, which was then spit out with instructions not to swallow the lidocaine. All subjects also completed HRM and 24-hour pH-impedance studies.

Functional Lumen Imaging Probe Study Protocol and Analysis

Performed as previously described.⁷ In both sedated and awake studies, subjects were placed in the left lateral decubitus position. With the endoscope withdrawn and after calibration to atmospheric pressure, the FLIP was placed trans-orally and positioned within the esophagus with 1-3 impedance sensors beyond the EGJ. This positioning was maintained throughout the FLIP study. Stepwise 10-mL FLIP distensions beginning with 30 mL and increasing to a target volume of 70 mL were then performed; each stepwise distension volume was maintained for 30 seconds to 60 seconds (Fig. 1).

Figure 1. Representative awake (A) and sedated (B) functional lumen imaging probe (FLIP) Panometry. Two FLIP Panometry studies from the same subject ([A] awake, [B] sedated with midazolam and fentanyl) with output including FLIP fill volume (top), diameter topography (center), and pressure (bottom) are displayed. The perception score by FLIP fill volume is also displayed for the awake study (A).

FLIP data were exported to a customized program (open source at http://www.wklytics.com/nmgi) to generate FLIP Panometry plots for analysis as previously described.^7,33,34 Areas of the FLIP study that were affected by dry catheter artifact were omitted from EGJ (diameter and distensibility index [DI]) and body distensibility plateau (DP) analysis.^7,33 Analysis metrics included the EGJ-DI, FLIP pressure at the 60 mL FLIP fill volume (measured at the time point of greatest EGJ opening), and the maximum EGJ diameter that was achieved during the 60 mL or 70 mL fill volumes.^7,34 The change in FLIP pressure associated with antegrade contractions (pressure peak––pressure nadir) was also measured at the 50 mL and 60 m: fill volumes. Normal EGJ opening was defined as having an EGJ-DI > 2.0 mm²/mmHg and a maximum EGJ diameter > 16 mm.³⁴ The DP was measured as the narrowest fixed diameter that was observed in response to increasing FLIP volume and pressure (after excluding esophageal contractions). Typically, this was represented by the esophageal body diameter at the 60 mL or 70 mL fill volume.³⁵

The contractile response pattern was assessed from the FLIP study involving the 50 mL, 60 mL, and 70 mL fill volumes as a whole.^7,33 A normal contractile response pattern was defined by the presence of repetitive antegrade contractions (RACs) meeting the RAC Rule of 6 seconds: ≥ 6 consecutive antegrade contractions of ≥ 6 cm in axial length occurring at 6 ± 3 antegrade contractions per minute with regular rate. A borderline contractile response was defined when there were distinct antegrade contractions of at least 6-cm axial length, but not meeting the RAC Rule of 6 seconds. Normal esophageal motility was characterized by normal EGJ opening and a normal or borderline contractile response as previously described.⁷

Esophageal Perception Assessment

During the awake FLIP study, subjects were asked to rate the sensation, discomfort, or pain in the chest as the FLIP bag was filled with each 10-mL stepwise volumetric distension (Fig. 1). Subjects were asked to distinguish discomfort from the presence of the catheter being present and the sensation of the FLIP being filled and to only rate the sensation related to the FLIP inflation. Subjects reported perception (by raising the number of fingers to indicate the score) as follows: 0, no sensation; 1, raised awareness; 2, mild (minimal) discomfort; 3, moderate (tolerable) discomfort; and 4, severe pain.^36,37 FLIP parameters at the time of the initial report for each perception score were recorded.

High-resolution Manometry and 24-hour pH-impedance Protocol and Analysis

HRM studies were completed after a 6-hour fast using a 4.2-mm outer diameter solid-state assembly with 36 circumferential pressure sensors at 1-cm intervals (Medtronic, Shoreview, MN, USA). The HRM assembly was placed trans-nasally and positioned to record from the hypopharynx to the stomach with approximately 3 intragastric pH sensors. After a 2-minute baseline recording, the HRM protocol was performed with ten, 5-mL liquid swallows in a supine position and then five, 5-mL liquid swallows. Studies were analyzed according to the Chicago classification version 4.0 (CC v4.0).³⁸

Twenty-four-hour ambulatory pH-impedance studies were performed with a catheter containing 2 antimony pH electrodes positioned at 5 cm above the EGJ and 10 cm below the EGJ (Sandhill Scientific, Inc, Highlands Ranch, CO, USA). pH-impedance studies were analyzed using dedicated software. The total acid exposure time was calculated as the percentage of time (after exclusion of meal periods) that the pH was < 4 in the distal esophagus when associated with reflux events detected with impedance.

Statistical Methods

Descriptive statistics for all continuous measures were presented either as mean and standard deviation (SD) or median and interquartile range (IQR) depending on data distribution. Categorical measures were summarized as percentages. Each FLIP distension protocol was analyzed as an independent observation. Intra-subject comparisons were made using paired T-test or Wilcoxon rank-sum test according to data type and distribution. A 2-tailed P-value < 0.05 was considered to meet statistical significance.

Subjects

Twelve healthy, asymptomatic adult volunteer subjects (mean [SD]: age 31 [7] years; 9 [75%] were female) were included (Table). Based on HRM/CC v4.0 classification, 11 subjects (92%) had normal esophageal motility; 1 (8%) had ineffective esophageal motility. On 24-hour pH impedance, all subjects had an acid exposure time < 6%; 10/12 (89%) were < 4%. Endoscopic examination was normal in all 12 subjects. During sedated endoscopy with FLIP, doses of sedative mediations were median (IQR) 9 (8.8-10) mg midazolam and 200 (200-200) μg fentanyl. No early or late complications occurred.

Table. Subject Characteristics

Subject characteristics
Age (yr)	30.6 (6.7)
Female	9 (75%)
BMI (kg/m2)	24.3 (2.6)
HRM, EGD, and 24-hr pH impedance summary
HRM-CC v4.0	11 (92%)
Normal motility	1 (8%)
Ineffective esophageal motility
HRM––IRP (mmHg)	11 (8-14)
Acid exposure time (%)	1.8 (0.6)
Normal upper endoscopy	12 (100%)
Fentanyl dose (mcg)	200 (200-200)
Midazolam dose (mg)	9 (8.8-10.0)

BMI, body mass index; HRM, high-resolution manometry; EGD, esophagogastroduodenoscopy; CC v4.0, Chicago classification version 4.0; IRP, integrated relaxation pressure.

Data are presented as mean (SD), n (%), or median (interquartile range [IQR]).

Classification of Esophageal Motility and Contractile Response

All 12 subjects in both sedated and awake FLIP Panometry studies were classified as having normal esophageal motility.

All 12 subjects had antegrade contractions in both the sedated and awake FLIP studies. A normal contractile response was observed in 11/12 (92%) sedated studies and 9/12 (75%) awake studies; P = 0.250. Borderline contractile response patterns were observed in the remaining studies (1 sedated, 3 awake). Stimulation of the gag reflex appeared to be related to disruption of the RAC pattern during awake studies.

Among subjects with normal contractile responses in both sedated and awake studies (n = 8), the RAC rate (ie, antegrade contractions per minute in a RAC pattern) was not different between sedated and awake FLIP studies (mean [SD]: 6.9 [1.5] vs 6.3 [1.6] antegrade contractions per minute, respectively; P = 0.180). Further, there were no differences between sedated and awake studies at the onset of RACs (ie, RAC triggering) for FLIP volume (mean [SD]: 41 [7] vs 39 [11] mL, respectively; P = 0.708) or FLIP pressure (mean [SD]: 22 [9] vs 19 [10] mmHg, respectively; P = 0.6175) (Supplementary Figure). The RAC pattern persisted to the completion of the FLIP study (ie, end of 70 mL fill volume) in 10/12 (83%) sedated studies and in 9/9 (100%) awake studies with RACs. The pressure changes associated with antegrade contractions also did not differ between sedated (median [IQR]: 50 mL, 22 [11-32] mmHg; 60 mL, 24 [14-30] mmHg) and awake (50 mL, 23 [16-33] mmHg; 60 mL, 20 [16-31] mmHg) FLIP studies; P-values 0.875-0.859.

Esophagogastric Junction and Esophageal Body Functional Lumen Imaging Probe Metrics

All 12 subjects in both sedated and awake FLIP Panometry studies were classified as having normal EGJ opening.

The EGJ-DI (60 mL) in the sedated FLIP studies (median [IQR]: 5.8 [5.2-6.9] mm²/mmHg) was lower than in awake FLIP studies (8.9 [7.7-9.4] mm²/mmHg; P = 0.025) (Fig. 2). This related to a lower FLIP pressure (60 mL) in the sedated FLIP studies than in the awake FLIP studies (P = 0.010), as the EGJ diameter at 60 mL did not differ between sedated and awake FLIP studies (P = 0.610) (Fig. 2). The median (IQR) difference between sedated FLIP and awake FLIP was 3.0 (1.3-3.6) mm²/mmHg for EGJ-DI and 13 (9-21) mmHg for pressure. Maximum EGJ diameter (P = 0.999) and esophageal body DP (P = 0.098) also did not differ between sedated and awake FLIP studies (Fig. 2).

Figure 2. Effects of midazolam and fentanyl on functional lumen imaging probe (FLIP) Panometry metrics. Each line represents a single subject for FLIP Panometry metrics of (A) esophagogastric junction distensibility index (EGJ-DI), (B) FLIP pressure at 60 mL, (C) esophagogastric junction (EGJ) diameter at 60 mL, (D) maximum EGJ diameter, and (E) distensibility plateau (DP) of the distal esophageal body. Median values for each metric and condition (sedated and awake) are represented by the dashed black line.

Esophageal Perception During Awake Functional Lumen Imaging Probe

During awake FLIP, 7/12 subjects (58%) perceived esophageal distension during the awake FLIP (a representative study with esophageal perception score data superimposed is displayed in Fig. 1). The greatest perception score was 1 (raised awareness) in 5 subjects, 2 (minimal discomfort) in 1 subject, and 3 (moderate [tolerable] discomfort). The median (IQR) thresholds for initial esophageal perception were 40 (35-60) mL FLIP fill volume, 22 (16-25) mmHg pressure, and 20.4 (19.9-21.3) mm maximum esophageal body diameter (Fig. 3). In the 2 subjects that reported perception scores > 1, increased perception score occurred with increasing FLIP fill volume, pressure, and esophageal body diameter (Fig. 3). Of the 7 subjects that perceived distension, 5/7 (71%) had antegrade contractions triggered prior to perception while 2/7 (29%) had antegrade contractions concurrent with reported perception at the initial fill volume of 30 mL.

Figure 3. Functional lumen imaging probe (FLIP) fill volume (A), pressure (B), and esophageal body diameter (C) with esophageal sensation perception score. Each marker and line represent a single subject (among the 7 subjects that reported esophageal sensation). Metrics were recorded at the fill volume or the first report of esophageal sensation (the subjects represented by only a marker reported a greatest score of 1––“raised awareness”). Median values (for score of 1) represented with thick black dashed line.

In this cross-over study of healthy, asymptomatic volunteers we evaluated the effects of conscious sedation (midazolam and fentanyl) on distension-mediated esophageal motility parameters on FLIP Panometry. The major findings were that FLIP studies performed with conscious sedation had lower EGJ-DI and higher FLIP pressure than with awake FLIP studies. However, these changes in metrics did not change the classification of EGJ opening or the FLIP Panometry motility classification, which was normal for all studies both under sedation and while awake. Thus, clinically significant changes were not observed. While FLIP accompanying the standard, sedated endoscopic evaluation for symptomatic patients provides a well tolerated method to assess esophageal motility (as well as providing an opportunity to act upon FLIP findings with endoscopic intervention, eg, dilation), if awake FLIP were to be utilized clinically, this study suggests that different normative thresholds and classification criteria than those developed from sedated FLIP may need to be applied.^2,34

The findings of the present study align with previous experimental studies that showed decreased LES relaxation and increased LES pressure on manometry after acute intravenous opioid administration during manometry in healthy adults (noting as well that this was not universally observed as reduction in LES pressure with opioid administration was also observed in other studies).^21-28 The association of chronic opioid use with esophageal motility disorders (ie, OIED), particularly spastic (type III) achalasia, has garnered attention regarding the potential effect of fentanyl use in sedation with FLIP.^16,20 However, acute morphine administration did not change deglutitive LES relaxation pressures on manometry in achalasia (though did cause a reduction in resting LES pressure).²⁷ While manometry and FLIP assess subtly different LES physiology (ie, deglutitive LES relaxation with swallows on manometry versus response to distension without swallows on FLIP), there is shared function as evidenced by a negative correlation between integrated relaxation pressure (IRP) on HRM and EGJ-DI on FLIP (ie lower EGJ-DI and higher IRP in achalasia; higher EGJ-DI and lower IRP in patients with normal motility).³⁴ Thus, the lower EGI-DI and higher FLIP pressure with the sedated FLIP (as compared with awake) may be related to opioid activity on inhibitory esophageal signaling (as hypothesized in previous studies).^21,22 However, other factors could also be involved such as increased vagal stimulation or deeper respiration in the awake studies, with either possibly related to discomfort or coping with the transoral catheter.

As variable effects of intravenous benzodiazepines on manometric LES pressure (ie, decreased, increased and unchanged) were observed in previous studies of healthy adults, we hypothesize that fentanyl could be a contributing factor to the observed increased LES tone, leading to lower EGJ-DI (ie, higher FLIP pressure at similar EGJ diameter) in the sedated FLIP studies.^29-31 Previous studies that examined the potential effects of performing HRM after conscious sedation with intravenous fentanyl and midazolam have shown relatively minor changes in esophageal motility diagnosis.^32,39 A retrospective study of opioid naïve patients completing HRM either on the same day after conscious sedation or before receiving conscious sedation showed no difference in HRM metrics or motility diagnosis except for greater mean distal contractile integral in the same day cohort.³⁹ The direct effects of sedative medications on FLIP Panometry motility findings are relatively unexplored, though 1 study suggested that inhaled anesthetic (sevofluorane) with general anesthesia may yield lower FLIP pressure than propofol-based anesthesia among patients undergoing peroral endoscopic myotomy. Hence, the present study provides a novel assessment of sedation effects during FLIP.⁴⁰

Despite the appeal of utilizing FLIP during sedated endoscopy (eg, well tolerated, convenient, ability to immediately act on FLIP findings), awake FLIP might be a consideration in an agreeable patient if endoscopic evaluation was already performed. Awake FLIP also offers the opportunity to gauge esophageal perception and potentially assess for esophageal hypersensitivity. Esophageal hypersensitivity is an important factor that may drive or amplify esophageal symptoms in patients with functional esophageal syndromes and/or in patients with other recognized esophageal disorders.^41-43 In patients with non-cardiac chest pain and unrevealing esophageal studies, typical chest pain was consistently reproduced by esophageal balloon distention using impedance planimetry (a predicate device of FLIP).^37,44

In our study, esophageal perception was scored in 58% of our healthy controls, with increased perception scores occurring with increased FLIP volume, pressure and esophageal diameter in 2 subject (17%). However, nearly half (42%) of subjects did not report esophageal sensation during awake FLIP. Antegrade contractions, including the RAC pattern, occurred among subjects without esophageal perceptions and/or prior to onset of esophageal perception among these subjects who were not swallowing, further supporting secondary peristalsis as the physiologic process of the RAC pattern. Awake FLIP was reasonably well tolerated aside for occasional stimulation of the gag reflex, which appeared to disrupt the potential for a continuous RAC pattern, though antegrade contractions (secondary peristalsis) were still observed in all awake FLIP Panometry studies.

While the study strengths include using cross-over study design among comprehensively evaluated healthy subjects to provide novel data, the study also has limitations. While the cross-over study design facilitated paired comparisons related to sedation, the sample size (n = 12) of awake FLIP may limit its external validity to serve as normative data for awake FLIP, including perception scores. Further, while study of healthy volunteers provides important data, this study may not directly translate to esophageal disease states, noting previous differing effects of acute morphine administration on achalasia patients compared to healthy volunteers.²⁷ Further, the study cohort was relatively young, thus whether there is an interaction between sedation effects and age across a greater range may warrant future investigation.⁴⁵ Additionally, the doses of fentanyl and midazolam were similar between subjects (and all received both medications), thus effects related to specific dose or medication cannot be completely discerned from this study, though it did reflect the real-world scenario of endoscopy with conscious sedation.

In summary, our study demonstrated that conscious sedation using midazolam and fentanyl did not change the motility classification with FLIP Panometry in healthy volunteers. However, modest changes in FLIP pressure and EGJ-DI were observed between sedated FLIP and awake FLIP, suggesting that if awake FLIP were to be utilized, different thresholds and criteria for esophageal motility classification warrant consideration. While awake FLIP could be a consideration with potential to assess esophageal perception (eg, objectively evaluate for esophageal hypersensitivity), FLIP Panometry at the time of sedation endoscopy offers a valid and well-tolerated method to evaluate esophageal function.

This work was supported by P01 DK117824 from the Public Health service (John E Pandolfino).

John E Pandolfino: Sandhill Scientific/Diversatek (consulting, speaking, and grant), Takeda (speaking), Astra Zeneca (speaking), Medtronic (speaking, consulting, patent, and license), Torax (speaking and consulting), and Ironwood (consulting); Peter J Kahrilas: Reckitt (consulting), Medtronic (license), and Phathom Pharmaceuticals (speaking); Dustin A Carlson: Medtronic (speaking, consulting, and license); Phathom Pharmaceuticals (consulting and speaking); Braintree (consulting); and Medpace (consulting). Other authors have no conflicts to disclose.

Matthew B Stanton contributed to drafting of the manuscript, data analysis, data interpretation, and approval of the final version; John E Pandolfino contributed to study concept and design, data interpretation, obtaining funding, editing the manuscript critically, and approval of the final version; Aditi Simlote contributed to drafting of the manuscript, data analysis, data interpretation, and approval of the final version; Peter J Kahrilas contributed to data interpretation, editing the manuscript critically, and approval of the final version; and Dustin A Carlson contributed to study concept and design, drafting of the manuscript, data analysis, data interpretation, and approval of the final version.

Note: To access the supplementary figure mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm24087.