WO2016138541A1

WO2016138541A1 - Esophageal distensibility testing using electrical impedance

Info

Publication number: WO2016138541A1
Application number: PCT/US2016/020138
Authority: WO
Inventors: Ravinder MITTAL; Ali ZIFAN
Original assignee: University of California Berkeley; University of California San Diego UCSD
Current assignee: University of California Berkeley; University of California San Diego UCSD
Priority date: 2015-02-27
Filing date: 2016-02-29
Publication date: 2016-09-01
Anticipated expiration: 2017-08-27

Abstract

Systems and methods are provided for estimating intraluminal esophageal distension/luminal cross sectional area (CSA) during peristalsis using multichannel intraluminal impedance (MII) measurement in real time. Impedance measurements are taken while the subject swallows bolus with two concentrations of saline of varying volumes (e.g., 5cc, 10cc, and 15cc) while lying down in the Trendelenburg position. The CSA at each electrode pair of the MII catheter is estimated by solving two algebraic Ohm's law equations resulting from the two saline solutions. The latter estimate may be refined using a correction factor calculated previously in vitro (using the same methodology) in glass test tubes of known CSA. A graphical user interface allows visualization and quantification of the bolus as it transverses the length of the esophagus in real time.

Description

TITLE

ESOPHAGEAL DISTENSIBILITY TESTING USING ELECTRICAL IMPEDANCE

STATEMENT OF GOVERNMENT INTEREST

[0001] This invention was made with government support under DK060733 awarded by the National Institutes of Health. The government has certain rights in the invention.

TECHNICAL FIELD

[0002] The subject application relates to esophageal distensibility testing.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims benefit of priority of US Provisional Patent Application Serial No. 62/126,246, filed February 27, 2015, entitled "Esophageal Distensibility Testing Using Electrical Impedance", owned by the assignee of the present application and herein incorporated by reference in its entirety.

BACKGROUND

[0004] Prior methods for testing esophageal distensibility include using esophageal ultrasound imaging (US) or using a functional luminal imaging probe (FLIP) which estimates distention using a balloon at one site in the gastrointestinal tract. For example, one methodology involves measuring volume change across the entire esophagus as a surrogate of cross-sectional area (CSA) change, by combining the volume of the bolus taken by the patient during a swallow with an impedance measurement taken at multiple electrode pair sites to solve a system of linear equations, to get the individual volume changes at each electrode pair site. In this methodology, the resistance of a geometrical system is calculated as Ri = L* p/CSA, where Ri denotes the resistance measured by the impedance system, p denotes the resistivity (Ω-m) of the conductor material, L the length of the conductor (m), and CS_^4 is the cross sectional area (m²).This measurement is combined with a formula relating the volume of a cylinder and its height, volume=CSA *height, to determine a proposed method of estimating, volume, volume = L*L* p/sum(Ri).

[0005] However, this methodology suffers from certain drawbacks. For example, assuming a cylindrical bolus shape in the esophagus is not always accurate, as literature in the art states that the bolus shape is often more like an American football (e.g., having thin tails). Thus any cylindrical approximation (especially for large electrode spacings of 2 cm, commonly used in impedance measuring systems) tends to overestimate the actual volume.

[0006] In addition, parallel impedance still persists in this methodology and the use of only one saline concentration does not eliminate effect of parallel impedance, i.e., leakage of current from the esophageal wall to the outside and impedance from the adjacent organs. As such, baseline impedance fluctuations can be high, even for intra-patient measurements, and the use of a single concentration saline can add substantial error to the volume estimations. Moreover, aside from respiration effects, other organs in proximity to the electric field produced by an electrode pair can affect the measurements.

[0007] Moreover, the posture of the patient can also affect the measurement, as air swallowed along with salinecan create inaccurate measurements. Particularly in the supine position, there is a mixture of air and saline with each swallow. In order to measure the cross sectional area of the esophagus requires homogeneity of the bolus around the electrodes. Air in the bolus can result in an exaggeration of the impedance values.

[0008] In addition, previous methodologies do not fully account for the variability of the bolus morphology with each swallow. A single or even a few impedance measurements may not fully account for this variability. As such, the prior methodology can suffer from substantial variability in the estimated measurements. Furthermore, in patients suffering from Achalasia (having lower esophageal relaxation problems), the previous method cannot be used since it is dependent on total bolus clearing. If the entire swallowed volume isnot cleared in a timely manner using the previous method, the method may fail.

[0009] This Background is provided to introduce a brief context for the Summary and Detailed Description that follow. This Background is not intended to be an aid in determining the scope of the claimed subject matter nor be viewed as limiting the claimed subject matter to implementations that solve any or all of the disadvantages or problems presented above.

SUMMARY

[0010] Systems and methods according to present principles solve one or more of the problems above, and relate to measuring intraluminal esophageal distention/luminal cross sectional area (CSA) during bolus transport using multichannel intraluminal impedance (Mil) measurements.

[0011] In one aspect, the invention is directed towards a method for estimating intraluminal esophageal distension/luminal cross sectional area (CSA) during peristalsis using multichannel intraluminal impedance (Mil) measurements in real-time, the measurements performed by a Mil catheter having a plurality of electrode pairs, including: taking a first set of impedance measurements while a subject swallows a bolus having a first volume and a first concentration of saline solution, the first set corresponding to measurements taken at different electrode pairs of the Mil catheter; taking a second set of impedance measurements while a subject swallows a bolus having a second volume and a second concentration of saline solution, the second set corresponding to measurements taken at different electrode pairs of the Mil catheter, where the second concentration of saline solution is different than the first concentration; repeating the taking a first set and the taking a second set for respective third and fourth volumes of saline solution; and estimating a CSA at one or more points of the esophagus based on the

measurements taken at the electrode pairs.

[0012] Implementations of the invention may include one or more of the following. The first volume may be equal to the second volume, and the third volume equal to the fourth, and the first and second volumes may be unequal to the third and fourth. The estimating a CSA may include solving two algebraic equations in two unknowns, the two algebraic equations expressing Ohm's law, the two algebraic equations resulting from the first and second sets of measurements taken at different concentrations of saline solution. The method may further include refining the estimates of CSA using a correction factor. The correction factor may be calculated in vitro in glass test tubes of known CSA. The method may further include providing a visualization of the estimated CSA. The visualization may include distention of the esophagus in real-time as a bolus is ingested. The first volume, second volume, third volume, and fourth volume may all be different. The first and second concentrations of saline may be chosen to reduce or eliminate an effect of parallel impedances. The first and second concentrations of saline may be chosen to cause the impedance measurements to have a net effect of only measuring esophageal impedance. The estimated CSA may be directly proportional to the distance between electrode pairs. The estimated CSA may be inversely proportional to the difference between the first and second concentration of saline. The estimated CSA may be based on nadir impedance values. The method may further include displaying an indication on a user interface that the subject being measured should adopt the Trendlenburg position. The method may further include measuring a pressure in the esophagus, and calculating a value of esophageal compliance based on the estimated CSA and the measured pressure.

[0013] In another aspect, the invention is directed towards a non-transitory computer readable medium, including instructions for causing a computing environment to perform the above method.

[0014] In yet another aspect, the invention is directed towards a system for estimating intraluminal esophageal distension/luminal cross sectional area (CSA) during peristalsis using multichannel intraluminal impedance (Mil) measurements in real-time, including: a catheter configured to perform Mil measurements and having a plurality of electrode pairs; a monitoring system, the monitoring system configured to perform a method, the method including steps of: taking a first set of impedance measurements using the catheter while a subject swallows a bolus having a first volume and a first concentration of saline solution while in a Trendelenburg position, the first set corresponding to measurements taken at different electrode pairs of the Mil catheter; taking a second set of impedance measurements using the catheter while a subject swallows a bolus having a second volume and a second concentration of saline solution while in the Trendelenburg position, the second set corresponding to measurements taken at different electrode pairs of the catheter, and where the second concentration of saline solution is different than the first concentration; repeating the taking a first set and the taking a second set for respective third and fourth volumes of saline solution; and estimating a CSA at one or more points of the esophagus based on the measurements taken at the electrode pairs. [0015] Advantages of the invention may include, in certain embodiments, one or more of the following. Implementations can expand use of current technology, e.g., esophageal manometry along with Mil is routinely performed in the diagnosis of difficulty swallowing (dysphagia) and esophageal motility disorders, and systems and methods according to present principles can greatly expand Mil, currently used in GI function labs, to measure luminal distension during bolus transport, which is not currently nor measured in an optimized way. The disclosed method can potentially revolutionize esophageal motility testing by adding another powerful tool alongside manometry, in diagnosing various motility disorders. From the measured CSA and pressure, one can calculate various other parameters such as compliance of esophageal wall, pressure-CSA loops, as well as other parameters along the entire length of the esophagus. These parameters may be of significant value in diagnosing and treating various disorders of the esophagus that result in symptoms such as dysphagia, heartburn, chest pain and so on. Other advantages will be understood from the description that follows, including the figures and claims.

[0016] This Summary is provided to introduce a selection of concepts in a simplified form. The concepts are further described in the Detailed Description section. Elements or steps other than those described in this Summary are possible, and no element or step is necessarily required. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended for use as an aid in determining the scope of the claimed subject matter. The claimed subject matter is not limited to implementations that solve any or all disadvantages noted in any part of this disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Fig. 1 shows the effect of posture on the separation of liquid and air in the swallowed bolus. In Fig. 1(A), the subject is in the supine position where air and liquid surround the electrodes. In Fig. 1(B), the subject is in the Trendelenburg position where air, being lighter than liquid, is located in the caudal and liquid in the cranial part of the bolus. Lines around the electrodes represent where the electrical field is present, which includes the bolus, the

esophageal wall, and structures outside the esophagus. [0018] Fig. 2 illustrates (a) the relationship between saline concentration and conductance values measured in test tubes of different cross sectional area, and (b) estimation error between actual CSA of the tube and values estimated from the impedance method.

[0019] Fig. 3 illustrates (a) US B-mode delineations for swallowed bolus volumes of 5, 10 and 15cc's, (b) a boxplot showing the distribution of CSA across the three volumes, (c) the identity relation for two US duplicates measurements, (d) Bland-Altman plots for the pair-wise comparisons of two US CSA measurements, including mean differences (solid line) and 2SD limits (dashed lines).

[0020] Fig. 4 illustrates (a) impedance topographs of a sample lOcc swallow: (a) 0.1N, (b) 0.5N, (c) impedance tracing with swallows of 0.1N and 0.5N saline swallows, where lines represent mean value and the shaded area around them represents one standard deviation, and (d) zoomed version of (c) between the 6^th and 10^th second time period. Following the swallow, there is an increase in the impedance value, which represents passage of air over the electrode followed by a drop in impedance which reflects passage of the saline bolus over the electrodes. Nadir impedance values are lower with 0.5N compared to 0.1N saline.

[0021] Fig. 5 illustrates (a) a boxplot of nadir impedance values with swallowed boluses of two saline concentration swallows with (a) 5cc, (b) lOcc, and (c) 15cc in each of the five subjects (A denoting 0.1N and B denoting 0.5N saline concentrations).

[0022] Fig. 6 illustrates (a) a boxplot showing the distribution of CSA across the three volumes using the two injection method protocol and equation described below, (b) the identity relation of the proposed impedance method versus an intraluminal US method, (c) Bland-Altman plots for the pair-wise comparisons of US and estimated CSA using Ohm's law with two solutions, mean differences (solid line) and 2SD limits (dashed lines).

[0023] Fig. 7(A) illustrates an exemplary user interface of the GulletX™ visualization tool, and Fig. 7(B) illustrates a sequence of bolus transport visualizations during peristalsis in the supine position of a pairwise 5cc saline compound swallow. Pressure is overlaid on the mesh with different shades ranging from low to high pressure values.

[0024] Like reference numerals refer to like elements throughout. Elements are not to scale unless otherwise noted. DETAILED DESCRIPTION

[0025] Multiple intraluminal impedance (Mil) measurements, described by Silney, to monitor movements of swallowed contents in the esophagus, with peristalsis and movements of gastric contents into the esophagus with gastroesophageal reflux (GER), have been in use for more than 25 years. Mil recordings are routinely used in clinical settings to monitor esophageal bolus clearance with peristalsis and GER of various types (e.g., liquid and air reflux).

[0026] Original studies by Silny and Sifrim investigated the correlation between changes in impedance between two electrodes placed in the esophagus during swallow-induced peristalsis. They observed that the arrival of bolus head at the site of impedance electrodes coincided with the onset of a drop in impedance, and nadir impedance corresponded with the maximal or peak esophageal distension.

[0027] In a more recent study, the current investigators found that the impedance drop between a pair of electrodes located in the esophagus during peristalsis occurs in a two-step process: an initial large drop in impedance that occurs with the arrival of bolus on the two electrodes (onset of esophageal distension), and a small drop in impedance that correlates with the increase in the esophageal luminal CSA thereafter. Thus, the peak CSA coincides with the nadir impedance. It was further observed that the CSA estimated from the intraluminal US imaging technique correlates strongly with the inverse of impedance during the entire bolus- induced esophageal distension (having a Pearson correlation of r=-0.62 and r=0.74 for the inverse of impedance, p < 0.001).

[0028] However, a statistically-significant correlation does not mean that one can precisely measure the CSA from the impedance values, nor that the two methodologies (i.e., Mil & US) can be used interchangeably. In other words, r measures the strength of a relation between two variables, not the agreement between them. Moreover, the purpose of comparing two methods of measurement of a continuous biological variable is to uncover 'systematic differences' and not to point to 'similarities', taking into account potential sources of systematic disagreement between the methods of measurement, i.e., fixed and proportional bias.

[0029] According to Ohm's law, there is an inverse correlation between impedance and luminal CSA. However, there are two major difficulties when estimating luminal CSA directly from the intraluminal esophageal impedance measurement. First, the electric field between the electrodes might generally not be uniform. Second, the tissue and organs surrounding the bolus allow leakage of the injected electrical current (also known as parallel impedance). This may be seen in the illustrations of Figs. 1(A) and 1(B). Both of the above factors violate the assumptions of Ohm's law.

[0030] Kassab et al. proposed a strategy to estimate CSA of the blood vessels from impedance measurements, in which both of the above problems were addressed. They injected saline in the blood vessels to transiently replace blood to make the electrical field around the electrodes more uniform. Second, by the injection of two different saline concentrations, they used a revised Ohm's law equation to estimate the luminal CSA of the blood vessel. The two saline injection method eliminated the parallel impedance issue.

[0031] Systems and methods according to present principles measure maximal esophageal luminal CSA from Mil measurements. In this way, a relatively simple protocol and methodology can be used to accurately measure maximal luminal CSA from electrical impedance

measurements during peristalsis.

[0032] In more detail, when an electric current passes through the length of the esophagus, the current experiences an opposition or impedance (Z) to its flow, which results in a loss of energy. This impedance is not only due to the segment of the esophagus lying in between the electrode pairs, but also due to the tissue/organs in proximity of the electric field, because of leakage of the current into the surrounding body. In general, the impedance will be complex, having two components: Z=R +jX, resistive (energy dissipating) and reactive (energy

conserving) parts, where the magnitude and phase of the response will often be frequency- dependent. At low frequencies, similar to those used in common Mil systems, current passes through the extracellular fluid (ECF) space, and does not penetrate the cell membrane, diminishing their capacitive effects (X_C

0, ω being the angular frequency and capacitance is denoted by C). Thus, impedance becomes equivalent to resistance. Similarly, the inverse of impedance (i.e., admittance or conductance) becomes equivalent to the inverse of resistance, namely conductance, denoted by G. Moreover, the resistance of a geometrical system is related to the conductor length, its cross sectional area, and its intrinsic properties, namely resistivity:

[0033] (1) R = Lx p/CSA where p denotes the resistivity (Ω-m) of the conductor material, L the length of the conductor (m), and CSA the cross sectional area (m²). Therefore, one can use Eq. (1) to calculate CSA provided all the other parameters in the former equation are known.

[0034] Esophageal electrical impedance (or equivalently resistance) can be obtained from

Mil measurements. However, based on the previous discussion, the total resistance will be a weighted sum of all the tissue/organs present in the electric field between the electrode pair, rather than solely the esophagus, causing inter-patient impedance value variability, especially differences in baseline. The technique introduced by Kassab et al. for coronary arteries removes the above restriction, by using two bolus injections of saline solutions with known electrical conductivities to transiently displace blood and to effectively minimize the hemodynamics- induced blood conductance alterations for analytical determination of vessel cross-sectional area (CSA) and the electric current leakage through the vessel wall and surrounding tissue (parallel conductance). Applying this technique and assuming the esophagus has a conductance denoted by G_eso, the conductance of surrounding tissue and organs isG_perim, and the measured conductance asG_meas,

[0035] (2)G_meas— G_eso + Gp_eri_m

[0036] At timet_!, using a 0. IN volume saline of known resistivityp_{0 Λ} Nsaiine, using Eq. (1) we obtain the following:

[0037] meas _ eso , pperim

(3)G£

[0039] Next, doing the same for time t₂ using the same formulation, inserting the same volume with a different concentration (i.e., 0.5N) of resistivity ₀.sNsaiine, [0040] (4) G_t ^meas = G_t ^eso + Gf^erim→ G_t ^eso = [(¾≤ )] + Gf^erim

² 2 -2 2 L \Lpo.SW J _t2 ²

[0041]

[0042] Solving equations (3) and (4), and assuming the surrounding tissue conductivity stays the same (£ P^erim = Q P^^rim _ ^ ^ esophageal luminal CSA may be obtained as:

( _rmeas _rmeas\

[0043] (5)CSA_eso = L -

(^σ0.5Ν^{- σ}0.ΐΝ)

[0044] with CSi4_eso denoting the CSA of the esophagus at a particular height between an electrode pair (with distance L between them), the conductivity (inverse of resistivity) of the saline solutions used.

[0045] The same process may be carried out in vitro in glass tubes of known diameters, and the CSA estimations calculated for each tube. Next, non -linear regression may be carried out to obtain the correction factor for each tube and for the CSAs in-between.

[0046] Finally, in-vivo, the use of Equation (5) combined with the correction factor, estimated in-vitro, produces the final CSA at any electrode pair site.

[0047] In order to expand the CSA estimation capability during the entire duration of bolus flow one needs to overcome an important hurdle, i.e., the difference in the 'duration' of bolus flow with swallows (0.1N and 0.5N) and peristalsis. The corresponding waveforms of several swallows must be temporally aligned for all the impedance channels along the length of the esophagus. To solve the above problem of temporally alignment, one may use dynamic time warping, which will align different swallows and adjust the difference in the duration of bolus flow in the esophagus with each swallow. See Myers CS, Rabiner LR, "A comparative study of several dynamic time-warping algorithms for connected word recognition", The Bell System Technical Journal. 1981 ;60(7): 10.

[0048]

[0049] Example Study

[0050] In vitro studies were conducted by placing a high resolution manometry impedance (HRMZ) catheter, equipped with multiple impedance (GIVEN, Los Angeles, CA) electrodes in plastic tubes of known diameters (ranging from 9.8mm to 50.1mm). The diameter of each tube was measured with a micrometer and the CSA measured with the volume of water divided by the length of the tube filled with water. Solutions of different saline concentrations, 0.1N, 0.2N, 0.3N, 0.4N and 0.5N were prepared by mixing 0.9% saline (1.0N) and deionized water. The GIVEN system of impedance measurement can accurately resolve impedance values of greater than 90 Ohms; therefore higher concentrations of saline, i.e., > IN were not tested because they yielded impedance values < 90 Ohms. Tubes were filled with different concentrations of saline that was heated to body temperature (37 ^°C). At least one pair of impedance electrodes was submersed in the saline solution to measure the impedance value for each saline concentration and for each tube size. Conductivity of all the saline concentrations solutions at body

temperature (37 ^°C) was measured using a conductivity meter, with two ranges: 2mS/ 20 mS, resolution: O.OOlmS/0.01 mS, and accuracy: ± (3% FS +ld) with automatic temperature compensation from Omega.

[0051] Five healthy volunteers were recruited for this preliminary study (age = 45 ± 19 years). Subjects fasted and stopped smoking for at least 6 hours prior to the study

commencement. For the study a FIFIUS catheter probe (15 MHz, Boston Scientific instruments, Boston, MA, USA) was used. Concurrent HRM/MII and FIFIUS imaging was recorded by placing the probe via the nose into the esophagus and positioning the same at 7cm above the lower esophageal sphincter (LES). The saline solutions of 0.1N and 0.5N were warmed in a water bath set at body temperature (37°C) and their conductivities measured using a

conductometer. The HRMZ catheter and the FIFIUS catheter were taped together in such a manner that the US transducer was positioned in the middle of two adjacent pressure transducers and the corresponding two impedance electrodes of the HRMZ catheter. The nasal cavity and oropharynx were anesthetized using 1 % lidocaine gel and 1 % bezocaine spray and the catheter assembly was introduced via the nose into the esophagus and positioned with the US transducer located 7 cm above the LES.

[0052] Following placement of the probes, an accommodation period of 10 minutes was allowed. Subjects were positioned on a stretcher that could be tilted to a Trendelenburg position (head and upper torso tilted down and feet up (-15 or -22.5 degree). Data were acquired during 8- 10 swallows of 5, 10 and 15 ml of 0.1N saline each, followed by 8-10 swallows of 5, 10 and 15ml of 0.5 N saline. All swallows were spaced at least 45 seconds apart. The reason for recording swallows in the Trendelenburg position was based on the observation that this body position allows separation of swallowed air from the liquid in the esophagus and therefore creates a homogenous electric field around the electrode during passage of saline bolus, thus providing reproducible impedance values (see Figs. 1(A) and 1(B)). Furthermore, separation of air from the liquid markedly improved the US image of the esophagus, which is important for the measurement of the luminal CSA.

[0053] Swallows with each volume were repeated at least 8-10 times. The HRMZ and US recordings were synchronized manually using event markers on the video recorder and HRMZ recordings.

[0054] Regarding the ultrasound measurements, ManoView ESO 3.0, when used in conjunction with a ManoScan V A400 (set to capture a maximum frame rate of 30Hz), provided the tools to acquire and visualize video data using a DVI-VGA connection. The output from the ultrasound was fed into ManoView and synchronized video was recorded for the entire length of the recording. In parallel, US images were also recorded on a SVHS tape and subsequently digitized at video rates (30 images/s) using a video capture card (Pinnacle Express; Mountain View, CA, USA) interfaced to a personal computer using the Adobe Premiere 6.0 program (Adobe Systems; Mountain View, CA, USA) and captured in AVI format. For calculating the maximum CSA, the corresponding B-mode US image was selected. Esophageal mucosa and liquid interface was marked interactively using a custom built Matlab graphical user interface to calculate the esophageal luminal CSA. Data were analyzed only for those events in which US image quality was adequate to define the luminal edges.

[0055] For CSA measurement from the impedance measurement, the analyses were run under Matlab R2012a using an Intel Core i7, 3.00 GHZ processor with 16.00GB of RAM. All the recorded data were imported into Matlab. The nadir impedance values corresponding to each of the saline swallows at the recording site were automatically extracted from the impedance tracings. For each swallow, nadir impedance values falling outside the ±1.5><IQR were removed. For each saline concentration, the mean value of the nadir impedance values was obtained. For each volume, Equation (5) was then used to estimate the esophageal CSA at that particular volume. The CSA value was updated using the correction factor estimated from t ein-vitro study to calculate the final CSA estimate. [0056] A Bland-Altman analysis was used to assess the level of agreement between the CSA measured by the proposed two-concentration impedance technique and the intraluminal ultrasound image technique. A range of agreement was defined as mean bias ±2SD. In a Bland- Altman diagram, the differences between the two measurements of CSA against their means are plotted. The relation between the CSA measured by the ultrasound method (US) and the proposed impedance method was expressed by CSAMII = CSA s + β, where a and β are empirical constants that were determined with a linear least squares fit and corresponding correlation coefficient R². The root mean square (RMS) error and squared sum of errors (SSE) was used to assess the reliability of the technique.

[0057] Fig.2(A) shows the relationship between different concentrations of saline and conductance for test tubes of different CSAs. Note that the relation between the conductance and the saline concentrations are nearly linear, especially for tube diameters smaller than the electrode spacing (20mm). Two concentrations of saline, 0.1N and 0.5N, were chosen for in-vivo human studies based on their least CSA approximation error using Eq. (5), and the fact that these provided the biggest difference (spread) in the impedance values for the same CSA. Fig. 2(B) shows that there is a difference in the impedance calculated CSA of the tube using the proposed method (using saline concentration of 0.1N and 0.5N) and the actual CSA of the tubes, especially for tube diameters larger than the Mil electrode spacing. A nonlinear regression analysis was used to determine the percent error and correction factor for each of the tubes and in-between (Fig. 2(B)).

[0058] Referring to Fig. 3(A), the B-mode US images with three different swallow volumes, 5cc, lOcc and 15cc, were marked and interactive software in Matlab used to measure the luminal CSA. Fig. 3(B) shows the esophageal CSAs measured from the marked B-mode US images for the three volumes. The US CSA measurements were carried out in duplicates to measure the repeatability of the markings. A linear least-squares fit of the relation between the two measurements was expressed as CSAus2 = l .OlCSAusi - 1.42 (n=15, R² = 0.9872), where CSAusi and CSAus2 were the two CSA measurements from the two US duplicate measurements, as seen in Fig. 3(C). The percent difference in the two measurements was plotted against the mean value, as shown in Fig. 3(D). The mean percent difference was nearly zero and the SD was found to be 7.7% of the mean of the two measurements (i.e., repeatability coefficient), with a sum of squared errors (SSE) of 4.7mm². [0059] Figs. 4(A)-4(D) shows sample impedance topographs of the two swallows with two different concentrations of saline for a lOcc volume. Each swallow resulted in an increase in impedance followed by drop in impedance and a resultant nadir impedance value. The latter was lower for the 0.5N swallow compared to the 0. IN saline swallow (See Figs. 4(B) and 4(C)).

[0060] Figs. 5(A)-5(C) show nadir impedance values with 0.5N and 0. IN saline with swallows of 5, 10 and 10 ml bolus volumes in each of the five subjects. Each data point represents the mean of 8-10 swallows in that subject. The impedance values were significantly lower for 0.5N compared to 0. IN for each bolus volume. An increase in bolus volumes resulted in lower nadir impedance values.

[0061] Fig. 6(A) shows the esophageal CSAs measured from the electrode pair on the catheter close to the US probe, which was calculated using nadir impedance values for the swallowed saline solutions of two concentrations and the equation discussed above. The CSA measured from the US images and the one measured from the proposed impedance methodology were almost identical (Fig. 6(B)).

[0062] Bland- Altman plots for the pair-wise comparisons of US measured and estimated CSA using the proposed impedance method using two saline solutions are shown in Figure 6(C). The relation between the two measurements was expressed as CSAus = 1.04CSAi_mp -2.73 (n=15, R² = 0.9824), where CSAus and CSAimp were the two CSA measurements from two US and the two saline injection method, respectively. The 95% limits of agreement ranged from -9.1 to 13mm². This result can be interpreted to represent that 95% of the CSA as measured by the two injection method system will be within approximately ±1 1 mm² of the US CSA measurements (approximately a+1.87 mm radius assuming a circular cross-section). The root mean square RMS of the two measurements was 4.79% of the mean US measured CSA, and SSE equal to 5.5mm².

[0063] To summarize the above: first, in-vitro (test tube) measurements show the expected relationship between impedance values and CSA. That is, using in-vitro measurements, it is possible to determine a correction factor to accurately calculate CSA of the tubes. Second, in- vivo measurements with US B-mode images show a linear increase in the luminal CSA with an increase in the swallowed bolus volume. Third, an in-vivo study also shows an expected linear relationship between the impedance values with two saline concentrations for different volumes of swallowed boluses. Fourth, and most significantly, the two saline concentration algorithm may be effectively employed to estimate the esophageal luminal CSA analytically.

[0064] Strong agreement is found between luminal CSA measured from the US images and the impedance methodology implemented by systems and methods according to present principles.

[0065] A slight positive systematic bias is found in the US measurements, although the same can be adjusted for, and is not surprising because the accuracy of ultrasound measurements is based on various assumptions. For example, an assumption is made of an ideal perpendicular angle of incidence of the ultrasound beam to the esophageal wall, and the same requires the probe position in the center of the lumen and parallel to the long axis of the esophagus.

Moreover, overestimation of the true CSA has been previously observed with different catheters and US systems. Inter/intra observer variability may also contribute to some variability when it comes to delineating the desired tissue/organs from the US B-mode images. Moreover, both transducer obliquity and lumen curvature (albeit small) can produce an elliptical image that overestimates the true dimensions. The latter is not the case with bio-electrical impedance measurements, as the same do not rely on the assumptions of US measurements.

[0066] Even though the Mil technique to measure bolus clearance and GER has been in use for almost 25 years, measuring esophageal distension/luminal CSA from Mil measurements has not been attempted in the esophagus or for that matter anywhere in the gastrointestinal tract. Based on Ohm's law and the relationship between impedance and CSA, there have been two techniques that have measured the luminal CSA inside a balloon for determining biomechanical properties of the esophageal wall. These two techniques, impedance planimetry and functional luminal imaging probe (FLIP), have been used extensively by a number of investigators and the same provide accurate measurement of the luminal CSA of the balloon. In both of these techniques, the electrodes are placed inside a balloon and saline solution of known concentration is injected into the balloon to create a homogenous electrical field inside the balloon. The balloon material in these studies is made of an electrically non-conducting material that prevents leakage of current outside of the balloon into the tissue, which eliminates the parallel impedance issue. Therefore, Ohm's law assumptions to measure luminal CSA are satisfied in the impedance planimetry and FLIP techniques. On the other hand, when measuring impedance using electrodes placed inside the esophageal lumen, as is the case with the Mil technique, non-homogeneity of swallowed bolus (air and liquid) and leakage of current through the esophageal wall and structures outside (parallel impedance), such are more problematic with respect to Ohm's law when trying to measure the luminal CSA.

[0067] In more detail, with every liquid swallow, a small amount of air (normally lodged in the pharynx) is swallowed along with the saline bolus. Ultrafast CT imaging and impedance measurements clearly show presence of air in the esophagus with every swallow. The US imaging studies described in the Example above also confirmed the presence of air with swallowed boluses of saline. Air may travel ahead of liquids or may be mixed with the bolus, in which case the impedance value reflects those of the mixture of air and liquid, and not the impedance resulting only from the swallowed saline of known conductivity.

[0068] Usual esophageal manometry studies are conducted in the supine or lateral positions, and in these positions, the air and liquid may not necessarily be separate, and therefore the impedance value is quite variable. By placing the subject in the Trendelenburg position, the air, being lighter than liquid, is relocated in the caudal and liquid in the cranial part of the swallowed bolus (see again Fig. 1). Impedance recording clearly show a large increase in the impedance value (air) followed by a drop in impedance (saline bolus) and such as highly reproducible (see, e.g., Fig. 4). US images confirm the finding of air traversing ahead of liquid quite reproducibly in the Trendelenburg position, thus satisfying the first requirement of homogeneity of bolus in the Ohm's law equation.

[0069] Parallel impedance is another major problem in estimating luminal CSA of ventricles of the heart and blood vessels using impedance methodology. As Fig. 1 shows, with the Mil technique, the current flows through the saline bolus, the esophageal wall, as well as through structures surrounding the esophagus, and as noted such is termed parallel impedance. To eliminate parallel impedance from the Ohm's law equation, the impedance methodology described above is used in which two impedance values are measured using two concentrations of saline. The impedance-based CSA calculations are dependent only on two nadir impedance values with two concentrations of saline (and the conductivity of the two concentrations of saline). The latter are fixed values and can be easily measured in-vitro using an electrical conductometer. Using these four variables and the correction factor determined from the in-vitro tube measurements, the maximal CSA may be measured and the value from the impedance value is almost identical to the one measured from the B-mode US image analysis.

[0070] Another important factor that is important in measuring accurate impedance value is the instrumentation used. The above Example used the GIVEN system that has electrodes located every two centimeters. Generally, electrode spacing determines the depth of current penetration and depth sensitivity, with most of the current density lying near the electrodes and exponentially decaying moving away from them. Therefore, the proposed method will perform best for esophageal dilations less than the 2cm (electrode spacing), and will underestimate any larger bolus dimensions. Ideally, a tetra-polar system using a different current injection/pickup protocol may be employed to remove this obstacle.

[0071] Another important factor is the margin of error in impedance measurements. The GIVEN system can measure impedance values of > 90 Ohms with a possible margin of error of 3-5%. However, different systems may have different fidelities and different distances between the electrodes that need to be taken into the consideration when using the proposed methodology.

[0072] The clinical relevance of measuring luminal CSA/esophageal distension during routine clinical manometry studies is manifold. Using US imaging at two different locations in the esophagus, it has been found that the esophageal distension during swallow-induced bolus transport is an important marker of the inhibitory phase of peristaltic reflex. However, measuring esophageal distension with US image analysis is expensive (equipment and labor), and data analysis is arduous and time consuming. Furthermore, with only one US transducer, one can only measure distension at one location in the esophagus.

[0073] On the other hand, the impedance measurement afforded by systems and methods according to present principles is relatively inexpensive and can be performed at closely-spaced intervals over the entire length of the esophagus at the same time. Data shows that Mil measurements can detect changes in the esophageal CSA accurately and thus provide useful information on the inhibitory phase of peristaltic reflex.

[0074] As a specific potential use, studies by Sifrim et al. show that patients with spastic motor disorder of esophagus have impaired inhibitory innervation, as measured by impaired relaxation of the artificial high-pressure zone. However, those studies have only been performed in a limited number of patients since they are not practical. On the other hand, Mil measurements can be performed easily in the routine clinical setting along with the HRM.

Future studies may be foreseen using the Mil technique that can easily investigate if lack of or impaired esophageal distension during peristalsis is the cause of unexplained dysphagia (also known as functional dysphagia).

[0075] Along these lines, Omari et al have observed an inverse correlation between the diameter of upper esophageal sphincter and nadir impedance in patients with swallowing disorders related to poor opening of the upper esophageal sphincter. Meyers and Omari have also developed a computer algorithm to predict patients undergoing fundoplication who may develop dysphagia following surgery. Nadir impedance value during swallow-induced bolus transport in the esophagus is an important variable in their algorithm and the same is a marker of esophageal distension/luminal CSA. Using methodology afforded by systems and methods according to present principles, it will be possible to measure esophageal distension along the entire length of the esophagus accurately and it is foreseen that esophageal distension measurements using the proposed methodology along with HRM will become a routine part of the esophageal function testing.

[0076] Since impedance measurements can be made simultaneously at multiple sites in the esophagus, a particularly unique aspect of the above methodology is that luminal CSA is measured at multiple sites in the esophagus at the same time. Once the two concentration saline swallow protocol is carried out during routine esophageal HRM/MII testing, a graphical user interface allows visualization of the bolus as it transverses the length of the esophagus. A snapshot of the interface (using GulletX), alongside a sample swallow for a lOcc swallow using the proposed method, is shown in Fig.7.

Claims

1. A method for estimating intraluminal esophageal distension/luminal cross sectional area (CSA) during peristalsis using multichannel intraluminal impedance (Mil) measurements in realtime, the measurements performed by a Mil catheter having a plurality of electrode pairs, comprising: a. taking a first set of impedance measurements while a subject swallows a bolus having a first volume and a first concentration of saline solution, the first set

corresponding to measurements taken at different electrode pairs of the Mil catheter; b. taking a second set of impedance measurements while a subject swallows a bolus having a second volume and a second concentration of saline solution, the second set corresponding to measurements taken at different electrode pairs of the Mil catheter, wherein the second concentration of saline solution is different than the first

concentration; c. repeating the taking a first set and the taking a second set for respective third and fourth volumes of saline solution; and d. estimating a CSA at one or more points of the esophagus based on the

measurements taken at the electrode pairs.

2. The method of claim 1, wherein the first volume is equal to the second volume, and wherein the third volume is equal to the fourth volume, and where the first and second volumes are not equal to the third and fourth volumes.

3. The method of claim 1, wherein the estimating a CSA includes solving two algebraic equations intwo unknowns, the two algebraic equations expressing Ohm's law, the two algebraic equations resulting from the first and second sets of measurements taken at different

concentrations of saline solution.

4. The method of claim 1, further comprising refining the estimates of CSA using a correction factor.

5. The method of claim 4, wherein the correction factor is calculated in vitro in glass test tubes of known CSA.

6. The method of claim 1, further comprising providing a visualization of the estimated CSA.

7. The method of claim 6, wherein the visualization indicates distention of the esophagus in real-time as a bolus is ingested.

8. The method of claim 1 , wherein the first volume, second volume, third volume, and fourth volume are all different.

9. The method of claim 1 , wherein the first and second concentrations of saline are chosen to reduce or eliminate an effect of parallel impedances.

10. The method of claim 1 , wherein the first and second concentrations of saline are chosen to cause the impedance measurements to have a net effect of only measuring esophageal impedance.

11. The method of claim 1 , wherein the estimated CSA is directly proportional to the distance between electrode pairs.

12. The method of claim 1 , wherein the estimated CSA is inversely proportional to the difference between the first and second concentration of saline.

13. The method of claim 1 , wherein the estimated CSA are based on nadir impedance values.

14. The method of claim 1 , further comprising displaying an indication on a user interface that the subject being measured should adopt the Trendelenburg position.

15. The method of claim 1 , further comprising measuring a pressure in the esophagus, and calculating a value of esophageal compliance based on the estimated CSA and the measured pressure.

16. A non-transitory computer readable medium, comprising instructions for causing a computing environment to perform the method of claim 1.

17. A system for estimating intraluminal esophageal distension/luminal cross sectional area (CSA) during peristalsis using multichannel intraluminal impedance (Mil) measurements in realtime, comprising: a. a catheter configured to perform Mil measurements and having a plurality of

electrode pairs; b. a monitoring system, the monitoring system configured to perform a method, the method comprising steps of: taking a first set of impedance measurements using the catheter while a subject swallows a bolus having a first volume and a first concentration of saline solution while ina Trendelenburg position, the first set corresponding to measurements taken at different electrode pairs of the Mil catheter; taking a second set of impedance measurements using the catheter while a subject swallows a bolus having a second volume and a second concentration of saline solution while in the Trendelenburg position, the second set corresponding to measurements taken at different electrode pairs of the catheter, and wherein the second concentration of saline solution is different than the first concentration; repeating the taking a first set and the taking a second set for respective third and fourth volumes of saline solution; and estimating a CSA at one or more points of the esophagus based on the

measurements taken at the electrode pairs.