Functional lumen imaging probe (FLIP) for adults with esophageal disorders

INTRODUCTION — The functional lumen imaging probe (FLIP) is an assessment tool for measuring the mechanical properties of the intestinal wall within a specific area of the upper gastrointestinal tract (eg, esophagus). FLIP utilizes high-resolution impedance planimetry during volume-controlled distension to measure esophageal cross-sectional area and distensibility (ie, cross-sectional area in relation to distension pressure). This measurement tool can be used to evaluate patients with esophageal dysphagia and to guide interventions such as achalasia therapy.

This review will discuss the technical aspects, data acquisition, and data analysis of FLIP for adult patients with esophageal disorders.

Other methods for evaluating patients with esophageal disorders are discussed separately:

●(See "High resolution manometry".)

●(See "Esophageal multichannel intraluminal impedance testing".)

●(See "Approach to the evaluation of dysphagia in adults".)

PATIENT SELECTION

Clinical applications — Clinical applications for FLIP studies in adults include:

●Evaluation of patients with dysphagia or suspected esophageal motility disorder in the absence of mechanical obstruction (ie, no history of esophageal stricture or large hiatal hernia) [1] (see "Approach to the evaluation of dysphagia in adults")

●Monitoring response to therapy in patients with eosinophilic esophagitis by assessing distensibility and diameter of the esophageal body [2,3] (see "Treatment of eosinophilic esophagitis (EoE)")

●Assessment of esophagogastric junction (EGJ) distensibility intraoperatively during surgical intervention (eg, fundoplication, laparoscopic Heller myotomy, peroral endoscopic myotomy) and postoperative assessment of recurrent symptoms [4-11]:

•(See "Surgical treatment of gastroesophageal reflux in adults".)

•(See "Peroral endoscopic myotomy (POEM)".)

•(See "Surgical myotomy for achalasia".)

Contraindications — FLIP studies are contraindicated when upper gastrointestinal endoscopy is contraindicated. The risk of performing upper endoscopy generally outweighs the benefits in the following conditions (see "Overview of upper gastrointestinal endoscopy (esophagogastroduodenoscopy)", section on 'Contraindications'):

●Patients who cannot tolerate moderate sedation, monitored anesthesia care, or general anesthesia (see "Anesthesia for gastrointestinal endoscopy in adults")

●Patients who are hemodynamically unstable

In addition, FLIP is contraindicated for patients with any of the following:

●Acute or incompletely healed esophageal perforation

●Active gastrointestinal bleeding (eg, bleeding esophageal varices)

STUDY DETAILS

Patient preparation — The preprocedure preparation for patients undergoing upper gastrointestinal endoscopy with FLIP is similar to that described for patients undergoing upper endoscopy alone (see "Overview of upper gastrointestinal endoscopy (esophagogastroduodenoscopy)", section on 'Patient preparation'):

●Anesthesia – The procedure is typically performed on an outpatient basis using moderate sedation or monitored anesthesia care. Anesthetic management for endoscopic procedures including preprocedure fasting is discussed separately. (See "Anesthesia for gastrointestinal endoscopy in adults" and "Gastrointestinal endoscopy in adults: Procedural sedation administered by endoscopists".)

Sedative and analgesics used for endoscopy (eg, midazolam and fentanyl) may affect esophageal contractility and sphincter function; however, motility patterns observed with FLIP correlate well with high-resolution esophageal manometry performed in the absence of such medications [12-15]. Thus, no adjustment to sedatives or analgesics is necessary.

●Medication adjustments – Atropine and other anticholinergic drugs (eg, glycopyrrolate) are avoided when FLIP is performed because such medications reduce distension-induced esophageal contractility [16].

Equipment — To perform a FLIP study, the following equipment is needed (figure 1 and table 1):

●EndoFLIP system – The EndoFLIP system (Medtronic, Inc.) is a commercially available system that consists of a console with an operator-controlled infusion pump, video display, and a flexible catheter with impedance sensors contained within a compliant cylindrical bag. The EndoFLIP setup is directed by system prompts and includes an automated three- to four-minute calibration cycle that also purges the catheter of air.

●FLIP catheter device – The FLIP catheter-based device has a cylindrical, highly compliant bag at the distal end of the catheter in addition to multiple, evenly-spaced impedance planimetry electrodes and a pressure sensor within the bag. The catheter is available in two configurations [17] (see 'Analysis' below):

•16 cm catheter – The 16 cm catheter (EF-322) has 16 impedance sensors that are spaced 1 cm apart, and it measures esophagogastric junction (EGJ) metrics (eg, luminal cross-sectional area and EGJ-distensibility index [EGJ-DI]) in addition to contractile response to distension of the esophagus (ie, secondary peristalsis). The 16 cm catheter is commonly used for evaluating the esophagus and EGJ.

•8 cm catheter – The 8 cm catheter (EF-325) has 16 impedance sensors that are spaced 0.5 cm apart, and it measures EGJ metrics but does not readily assess the contractile response to distension.

Technique — Immediately prior to a FLIP study, upper endoscopy (esophagogastroduodenoscopy) is typically performed to evaluate the mucosa of the esophagus and stomach, confirm the absence of an obstructing esophageal or EGJ lesion, and estimate the distance from the incisor teeth to the EGJ [17]. Technical aspects of upper endoscopy are discussed separately. (See "Overview of upper gastrointestinal endoscopy (esophagogastroduodenoscopy)", section on 'Procedure'.)

Placing the catheter — The steps of FLIP catheter placement are summarized as follows [18]:

●Prepare the catheter (with empty FLIP bag) by calibrating it to atmospheric pressure and lubricating it with a water-based lubricant.

●With the patient in the left lateral decubitus position, introduce the catheter through the patient's mouth and advance it through the upper esophageal sphincter and into the esophagus.

●Position the catheter such that the FLIP bag traverses the EGJ as initially determined by the endoscopically measured distance from the incisor teeth to the EGJ. The EGJ appears as a narrowing (also referred to as the "waist") on the display monitor when the FLIP bag begins to be filled with fluid (figure 1). For the 16 cm catheter, the FLIP bag traverses the EGJ with the distal 1 to 2 cm positioned in the stomach. For the 8 cm catheter, the FLIP bag is centered as it traverses the EGJ (ie, EGJ waist in the middle).

●Maintain catheter positioning during the study with manual adjustments while observing the real-time display.

Protocol summary — The study protocol is summarized as follows [12,15] (see 'Analysis' below):

●Distend the FLIP bag by filling it incrementally with conductive fluid (commercially provided with FLIP catheters). FLIP fill volumes vary by catheter design:

•16 cm catheter – With the 16 cm catheter, fill with a baseline volume of 30 mL and then 40 mL to observe the catheter positioning relative to the waist at the EGJ. Following this, increase FLIP fill volume in 10 mL increments until 70 mL is reached. Observe each fill volume (ie, 50, 60, and 70 mL) for 60 seconds before proceeding.

•8 cm catheter – With the 8 cm catheter, fill with a baseline volume of 20 mL and increase FLIP fill volume in 10 mL increments until achieving a target volume of 50 mL. Observe each fill volume (ie, 30, 40, and 50 mL) for 30 seconds before proceeding.

●Record the following parameters: FLIP pressure, cross-sectional diameter at the EGJ and in the esophageal body, EGJ-DI, and for the 16 cm catheter only, contractile response (ie, secondary peristalsis) pattern.

●Empty the bag and remove the catheter.

Modifications to the study protocol may be required for some patients:

●Patients with narrow caliber esophagus – For patients with conditions associated with narrow caliber esophagus (eg, eosinophilic esophagitis), the protocol is adjusted to use lower maximum fill volumes (eg, 50 or 60 mL) if high FLIP pressures (ie, >60 mmHg) occur during filling and to use lower incremental fill volumes (eg, 5 mL).

Another protocol modification for patients with a suspected stricture or narrowing of the proximal esophagus is repositioning the device to study the proximal esophagus. This is done by partially emptying the FLIP to 30 or 40 mL and then withdrawing the catheter until the upper esophageal sphincter (UES) begins to appear at the proximal margin. The FLIP is then advanced back into the esophagus to 1 to 2 cm below the UES and incremental filling is repeated.

●Patients undergoing an intraoperative study – Special considerations are needed when performing intraoperative FLIP studies because factors such as positive pressure ventilation, pneumoperitoneum, and patient position impact FLIP measurements; thus, standardization of these factors is important [6,19,20]. We agree with the following consensus-based modifications for intraoperative studies [21]:

•Use the 8 cm catheter with the primary focus on assessing FLIP pressure, EGJ diameter, and EGJ-DI during the 40 mL FLIP fill volume.

•Measure EGJ metrics with the patient in the reverse Trendelenburg position, with no pneumoperitoneum, and during end-expiration (ie, hold positive pressure ventilation). (See "Mechanical ventilation during anesthesia in adults".)

Postprocedure care — After the procedure, patients are recovered from anesthesia, and this is discussed separately. (See "Anesthesia for gastrointestinal endoscopy in adults", section on 'Post-anesthesia care'.)

Adverse events — Use of the FLIP is safe and has been associated with very low risk of complications. In a study including 687 FLIP procedures, no adverse events occurred [22]. According to the FLIP manufacturer's label, possible but uncommon adverse events include allergic reaction, anaphylaxis, bleeding, cardiopulmonary complications, dental trauma, infection, pain, perforation, pulmonary aspiration, and vasovagal response.

ANALYSIS

General principles — The primary FLIP measurements are esophagogastric junction (EGJ) distensibility and the contractile response of the esophagus to distension. These data and other catheter-acquired outputs are displayed in real time on the monitor [23] (see 'Technique' above):

●Luminal diameters – Impedance planimetry technology measures the luminal cross-sectional area (CSA) of the esophagus and EGJ opening at each impedance sensor. For display purposes, the CSA measurements are transformed to diameter (by assuming a circular lumen). For the FLIP 1.0 and FLIP 2.0 systems, the luminal diameter measurements are displayed as a cylinder. With the FLIP 2.0 system, a color-coded diameter topography plot is also displayed (figure 1).

●FLIP distension pressure and fill volume – The distension pressure is gradually increased by infusing conductive fluid into the FLIP device in a stepwise fashion (ie, volume-controlled distension).

●The EGJ distensibility index – The EGJ distensibility index (EGJ-DI) is defined as the CSA in mm² divided by FLIP distension pressure in mmHg. (See 'Esophagogastric junction' below.).

The dynamic color topography plots are displayed in association with the corresponding FLIP pressure. These topography plots are produced by interpolating the diameter values between adjacent impedance planimetry channels (similar to the pressure topography plots of high resolution manometry studies). (See "High resolution manometry".)

●Contractile response of the esophagus to distension. (See 'Esophageal contractility' below.)

The initial version of the FLIP system (FLIP 1.0) displays these variables in real time but does not allow for real-time motility interpretation.

A customized open-source software program has been developed for analysis of FLIP studies. This analysis tool is maintained by W.K. Analytics and the Esophageal Center of Northwestern Research Lab, and it has been utilized in clinical research studies [1,9,12,23-29]. This software program generates FLIP panometry plots and facilitates their systematic analysis using the FLIP output file (.txt) that can be captured by "archiving" FLIP data after completion of the study.

Esophagogastric junction

Measuring EGJ opening — EGJ distensibility is assessed with the following metrics [30]:

●EGJ-distensibility index – EGJ luminal distensibility (referred to as the EGJ-DI) is determined by dividing the EGJ CSA by the concurrent FLIP distension pressure and is reported in units of mm²/mmHg. By convention, EGJ-DI is obtained during the 60 mL fill volume with the 16 cm catheter or during the 40 mL fill volume with the 8 cm catheter. These volumes typically provide sufficient filling to distend the EGJ while also remaining within the high compliance range of the FLIP bag such that the bag itself does not influence the reading.

The normal median (and 5^th to 95^th percentile) values for EGJ-DI with the 16 cm catheter are 5.8 (3.2 to 8.4) mm²/mmHg, respectively [22].

●Maximum EGJ diameter – The maximum EGJ diameter is the largest EGJ diameter that is achieved during the study and is usually measured during the 60 to 70 mL fill volume with the 16 cm catheter or during 40 to 50 mL fill volumes with the 8 cm catheter.

The normal median (and 5^th to 95^th percentile) values for maximum EGJ diameter with the 16 cm catheter are 20.4 (16.7 to 21.9) mm, respectively [22].

Published data that establish normal values with 8 cm FLIP catheter are limited. Thus, normal values that were established with the 16 cm catheter can be applied when using the 8 cm FLIP catheter [31].

There are several important considerations related to measuring EGJ metrics:

●Timing of EGJ measurement – EGJ opening is dynamic, especially during concurrent contractility of the esophagus, and for standardization, the EGJ-DI should be determined when the EGJ opening is greatest [17,32,33]. Thus, we avoid measuring EGJ-DI during distension-induced contractions of the lower esophageal sphincter (LES) or during contractions of the crural diaphragm related to respiration.

●Recognizing artifact – Artifact can occur when an occluding contraction on the catheter interrupts conductivity between its electrodes. This observation is termed "dry catheter artifact" and results in artifactually large diameter measurements at the EGJ and/or esophageal body. Data affected by dry catheter artifact should be excluded.

●Accounting for low FLIP pressures – For recordings with very low FLIP pressures (ie, <15 mmHg), such as with esophageal dilatation in achalasia, the EGJ-DI metric is invalid because a very low pressure results in a falsely high EGJ-DI (ie, CSA divided by pressure) even though reduced EGJ CSA was present. In addition, if the FLIP pressure is in the 15 to 30 mmHg range, the corresponding EGJ-DI values should be scrutinized (especially normal EGJ-DI values in patients with low pressures). In such instances, the EGJ diameter measurement is more useful for accurately defining EGJ opening.

Classifying EGJ opening — The magnitude of EGJ opening is classified as follows (figure 2) [30]:

●Normal EGJ opening – Normal EGJ opening is defined as EGJ-DI ≥2.0 mm²/mmHg and maximum EGJ diameter ≥16 mm.

●Reduced EGJ opening – Reduced EGJ opening is defined as EGJ-DI <2.0 mm²/mmHg and maximum EGJ diameter <12 mm.

Patients who do not fulfill criteria for either normal or reduced EGJ opening have borderline EGJ opening. For such patients, additional studies (eg, high resolution manometry, timed barium esophagram) are typically performed. (See "High resolution manometry".)

Esophageal contractility — Esophageal contractility that is evaluated with FLIP represents distension-induced contractility (ie, secondary peristalsis). Secondary peristalsis occurs in response to esophageal distension that is independent of swallows, and it plays an important physiologic role for clearing refluxed gastric contents or retained esophageal content. (See "Pathophysiology of reflux esophagitis", section on 'Impaired esophageal acid clearance'.)

During FLIP studies, secondary peristalsis may occur in a repetitive manner because the protocol involves sustained distension of the esophagus.

Secondary peristalsis differs from primary peristalsis that occurs with swallows. Primary peristalsis is evaluated with esophageal manometry, and this is discussed separately. (See "High resolution manometry".)

Normal contractile response — A normal contractile response of the esophagus to distension is characterized by repetitive antegrade contractions (RACs) with the following features (referred to as the "rule of 6's") (figure 3) [25,34]:

●≥6 consecutive antegrade contractions that are

●≥6 cm in axial length occurring at

●6±3 antegrade contractions per minute regular rate

Studies involving asymptomatic individuals suggest that a normal contractile response (defined by an RAC pattern with the rule-of-6's) was observed in most study participants, while few individuals (ie, approximately 10 percent) had a borderline contractile response (ie, antegrade contractions that were not repetitive) [15,35,36].

Borderline contractile response — Borderline contractile response is characterized by distinct antegrade contractions that measure at least 6 cm in axial length but do not meet criteria for RACs or criteria for a spastic-reactive pattern (figure 3). (See 'Normal contractile response' above.)

Abnormal contractile response — Contractile response patterns in the esophagus that are not observed in control populations include (figure 3) [32,35]:

●Spastic-reactive contractile response – Spastic-reactive contractile response (SRCR) is characterized by any of the following:

•Sustained occluding contractions – Sustained occluding contractions are non-propagating occluding contractions that occur in continuity with the EGJ and that persist for >10 seconds with an associated increase in FLIP pressure of >35 mmHg.

•Sustained lower esophageal sphincter contractions – Sustained lower esophageal sphincter contractions (sLESC) are transient reductions in LES diameter that meet the following criteria:

-Not associated with respiration or crural contractions

-Independent of antegrade contractions

-Duration >5 seconds

-Associated with an increase in FLIP pressure

•Repetitive retrograde contractions – Repetitive retrograde contractions (RRCs) are characterized by ≥6 retrograde contractions occurring at a rate of >9 contractions per minute.

Patients with an SRCR typically require additional diagnostic evaluation with high resolution manometry to establish a diagnosis. SRCRs are associated with spastic or hypercontractile esophageal motility disorders (ie, type III achalasia or distal esophageal spasm) but FLIP may not differentiate among these disorders on its own [25,26]. (See "Achalasia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic evaluation' and "Distal esophageal spasm and hypercontractile esophagus", section on 'Diagnosis'.)

In addition, SRCR patterns have been associated with mechanical issues such as hiatal hernia or surgical changes (eg, fundoplication), and in some patients, SRCRs may reflect a reactive response rather than a primary motility disorder [27,37,38].

●Impaired/disordered contractile response – An impaired or disordered contractile response pattern is characterized by sporadic contractions without distinct antegrade contractions or SRCR pattern.

●Absent contractile response – Absent contractile response is characterized by no contractile activity.

Other metrics — Distensibility plateau (DP) is a measure of distensibility of the esophageal body [39]. The DP reflects the smallest esophageal diameter that is observed above the EGJ in response to increasing FLIP volume after excluding diameter reductions attributed to contractions.

Normal DP in asymptomatic volunteers is ≥18 mm [15]. For patients with eosinophilic esophagitis, DP <17 mm was associated with clinically significant dysphagia (ie, risk for food impaction or requirement for endoscopic dilation) [2].

APPROACH TO CLASSIFYING FLIP METRICS — For patients with a suspected esophageal motility disorder (ie, dysphagia in the absence of mechanical obstruction) who undergo FLIP study, measurements of the EGJ opening and contractile response can be applied to classify esophageal motility as a possible esophageal disorder (eg, achalasia) or no major motility disorder. The approach to classifying FLIP metrics is outlined in the figure (figure 4).

FLIP assessment is often a complementary tool, and correlation of FLIP with other clinical data (eg, high resolution manometry) may help establish a diagnosis [18]. (See 'Correlating FLIP with other clinical data' below.)

CORRELATING FLIP WITH OTHER CLINICAL DATA — Evaluating the esophagogastric junction (EGJ) opening and esophageal contractility with FLIP provides data to inform the diagnostic evaluation in patients with suspected esophageal motility disorders (figure 4). FLIP panometry results are routinely correlated with other clinical findings including patient symptoms, direct endoscopic visualization, high resolution manometry, and timed barium esophagram. Most patients with suspected esophageal motility disorders undergo complementary studies as part of the diagnostic evaluation. (See "Achalasia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic evaluation'.)

FLIP assessment may be particularly useful when the diagnosis is uncertain despite endoscopy and high resolution manometry.

FLIP assessment has been compared with other established diagnostic tests:

●High resolution manometry – FLIP metrics and high resolution manometry findings are often consistent in patients with suspected esophageal dysmotility. Data suggest that a normal FLIP panometry study in symptomatic patients was associated with the absence of a major motility disorder on high resolution manometry [28,32,40,41]. In an analysis of 539 adults who completed FLIP and high resolution manometry studies, 156 patients (29 percent) had normal motility on FLIP panometry (ie, normal EGJ opening and normal or borderline contractile response). In this subgroup, 149 patients (95 percent) did not have a major motility disorder detected by high resolution manometry [26]. In another subgroup of 202 patients with reduced EGJ opening and absent or impaired contractile response on FLIP study, 185 patients (92 percent) had achalasia or EGJ outflow obstruction on high resolution manometry [26].  

Although FLIP metrics and high resolution manometry findings may be correlated to some extent, it is important to recognize differences between the diagnostic studies. FLIP measures the opening mechanics of the EGJ and the contractile response to distension (ie, secondary peristalsis), while high resolution manometry measures pressure from EGJ contraction or relaxation during esophageal primary peristalsis with liquid swallows. Previous studies that used manometry to compare primary peristalsis and secondary peristalsis demonstrated that the two forms of peristalsis can differ within the same subject [40-42]. (See 'Esophageal contractility' above.)

Thus, a direct comparison of FLIP with high resolution manometry is not always possible, and this is a limiting factor in establishing the diagnostic accuracy of FLIP with regard to predicting manometrically defined esophageal motility disorders.

●Barium esophagram – Data suggest that abnormal EGJ opening on FLIP was associated with esophageal retention on barium studies (eg, barium column height >5 cm at one minute or impaction of a barium tablet). In a study of 329 patients who completed timed barium esophagram and FLIP, the sensitivity and specificity of barium esophagram for EGJ distensibility index of 2.0 mm²/mmHg on FLIP were 81 and 76 percent, respectively, and sensitivity and specificity of barium esophagram for a maximum EGJ diameter of 12 mm were 74 and 90 percent, respectively [43]. When classifying EGJ opening using these metrics, reduced EGJ opening was found in 71 percent of patients with an abnormal barium study and in 10 percent of patients with a normal barium study. Conversely, normal EGJ opening was found in 9 percent of patients with abnormal barium study and in 60 percent of patients with normal barium study.  

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dysphagia".)

SUMMARY AND RECOMMENDATIONS

●General principles – The functional luminal imaging probe (FLIP) is an assessment tool that uses impedance planimetry to measure luminal dimension along the length of the esophagus (ie, cross-sectional area) and to measure esophageal distensibility. Assessing esophageal motility with FLIP is based on measuring metrics for esophagogastric junction (EGJ) opening and distension-induced esophageal contractility. FLIP studies are performed during upper endoscopy with sedation or intraoperatively. (See 'Introduction' above.)

●Clinical applications – Clinical applications for FLIP studies in adults include:

•Evaluating patients with dysphagia but without evidence of mechanical obstruction on upper endoscopy (see "Approach to the evaluation of dysphagia in adults")

•Monitoring response to therapy in patients with eosinophilic esophagitis by assessing distensibility and diameter of the esophageal body (see "Treatment of eosinophilic esophagitis (EoE)")

•Intraoperative assessment of EGJ distensibility related to surgical intervention (eg, fundoplication) and postoperative assessment of recurrent symptoms (see "Surgical treatment of gastroesophageal reflux in adults")

●Equipment – The EndoFLIP system consists of a console with an operator-controlled infusion pump, video display, and a FLIP catheter-based device (figure 1). The FLIP catheter has a cylindrical, highly compliant bag at its distal end in addition to multiple, evenly spaced impedance planimetry electrodes and a pressure sensor within the bag (table 1). (See 'Study details' above.)

●Adverse events – The FLIP study has been associated with a very low risk for adverse events. According to the manufacturer's label, possible but uncommon adverse events include allergic reaction, anaphylaxis, bleeding, cardiopulmonary complications, dental trauma, infection, pain, perforation, pulmonary aspiration, and vasovagal response. (See 'Adverse events' above.)

●Analysis – FLIP evaluates esophageal motility with the following metrics (see 'Analysis' above):

•EGJ opening – EGJ opening is measured with the EGJ distensibility index and EGJ diameter (figure 2)

•Esophageal contractility – Contractile response of the esophagus to FLIP distension is measured and classified as normal or abnormal (eg, spastic-reactive, impaired/disordered, absent) (figure 3)

●Classifying FLIP metrics – For patients with dysphagia in the absence of mechanical obstruction who undergo FLIP study, measurements of the EGJ opening and contractile response can be classified as a possible esophageal disorder (eg, achalasia) or no major motility disorder. The approach to classifying FLIP metrics is outlined in the figure (figure 4). (See 'Approach to classifying FLIP metrics' above.)

●Correlating FLIP results with other clinical data – FLIP assessment is a complementary tool, and results are routinely correlated with clinical findings including patient symptoms, direct endoscopic visualization, high resolution manometry, and barium esophagram. Most patients with dysphagia and suspected esophageal motility disorders undergo complementary diagnostic studies to establish a diagnosis. (See 'Correlating FLIP with other clinical data' above and "Approach to the evaluation of dysphagia in adults".)