Patent Application
20080287833
The present invention relates generally to ingestible capsules and, more particularly, to a process for evaluating a subject for gastroparesis with an ingested capsule passing through the digestive tract of the subject.
Ingestible capsules are well-known in the prior art. Such capsules are generally small pill-like devices that can be ingested or swallowed by a patient. It is known that such capsules may include one or more sensors for determining physiological parameters of the gastrointestinal tract, such as sensors for detecting temperature, pH, pressure and the like.
It is also known that certain physiological parameters may be associated with regions of the gastrointestinal tract. For example, a 1988 article entitled “Measurement of Gastrointestinal pH Profiles in Normal Ambulant Human Subjects” discloses pH measurements recorded by a capsule passing through the gastrointestinal tract. It is know that pH has been correlated with transitions from the stomach to the small bowel (gastric emptying).
Gastroparesis, also known as delayed gastric emptying, is a condition characterized by multiple symptoms, including nausea, vomiting, bloating, abdominal pain or discomfort and early satiety. Diagnosing gastroparesis is traditionally determined from a combination of symptom assessment and gastric emptying scintigraphy. Gastro duodenal manometry may also be performed to provide further evidence of the condition. Gastro duodenal manometry is an invasive, catheter-based system in which a manometry probe is inserted through a patient's nose or mouth into the GI Tract. The manometry probe usually has a suite of pressure sensors located at fixed positions along its length. These pressure sensors detect and send contraction amplitude and frequency data through connected wires to an external recording device. For placement of the probe, this technique is uncomfortable for the patient and requires the patient to be sedated and physically connected to the detector. Besides being highly uncomfortable, the manometry measurement system directly impacts the normal functioning of the patient, which may skew the manometry results.
An additional method of diagnosing gastroparesis is the use of gastric scintigraphy. This method requires a patient to ingest a meal which contains a known amount of a radioactive compound. Isotope imaging is then used to determine the amount of radioactive matter remaining in the stomach. Physicians take images at times consistent with local standards. In general, if at two hours more than 50% of the radioactive tracer is present, or more than 10% is present after 4 hours, the patient is diagnosed as gastroparetic. This method has numerous drawbacks, including requiring the use of radioactive material, requiring the patient to remain at the test site for at least four hours, a lack of standardization, and requiring patients to stop using certain medications resulting in changes in the patient's normal daily functioning.
Thus, there is need for a less invasive method for diagnosing gastroparesis.
With parenthetical reference to corresponding parts, portions or surfaces of the disclosed embodiment, merely for the purposes of illustration and not by way of limitation, the present invention provides an improved method for diagnosing gastroparesis comprising the steps of providing an ingestible capsule having a pH sensor and a pressure sensor, having a subject ingest the capsule, recording pH measurements from the pH sensor as a function of time as the capsule moves through at least a portion of the gastrointestinal tract of the subject, recording pressure measurements from the pressure sensor as a function of time as the capsule moves through at least a portion of the gastrointestinal tract of the subject, determining the capsules location at a position in the gastrointestinal tract, deriving a pressure pattern as a function of time and the pressure measurements, providing a reference pressure pattern, and analyzing the subject's pressure pattern relative to the reference pressure pattern to evaluate the subject with respect to gastroparesis.
The location may be the junction between the stomach and the small bowel of the subject. The pressure pattern may be the number of contractions relative to a baseline over a given time interval, the area under the curve of pressure measurements for a given time interval, or amplitude. The step of evaluating the subject may comprise diagnosing gastroparesis. The step of analyzing the pressure pattern may comprise the step of determining if the subject's pressure pattern is significantly diminished from or lower than the reference pressure pattern, wherein the reference pressure pattern is derived from a healthy control group. The subject's pressure pattern may be at least ten percent less than the reference pressure pattern. The subject time may be a period of time that the capsule resides in the stomach of the subject or a period of time extending from about one hour before the capsule is determined to be at the position to the time the capsule is determined to be at the position. The step of analyzing the subject's pressure pattern relative to the reference pressure pattern to evaluate the subject with respect to gastroparesis may comprise the step of comparing the subject's pressure pattern to the reference pressure pattern for three consecutive twenty minute intervals before and after the capsule is determined to be at the position.
The method may further comprise the steps of determining transit time between a first location and a second location, and evaluating the transit time relative to a reference transit time. The first location may be the point at which the capsule is ingested by the subject and the second location may be the junction between the stomach and the small bowel of the subject. The step of evaluating the transit time relative to a reference transit time may comprise the step of determining whether the transit time is greater than or less than the reference transit time, and the reference transit time may be about five hours.
The step of deriving a pressure pattern as a function of time and the pressure measurements may comprise the step of conditioning the recorded pressure measurements. The conditioning may comprise the step of normalizing the pressure measurements by applying a baseline compensation, and the baseline may be about 3 mmHg. The conditioning may comprise the steps of filtering out data points in the pressure measurements above an upper limit and filtering out data points in the pressure measurements below a lower limit, and the upper limit may about 200 mmHg and the lower limit may be about 9 mmHg.
The method may further comprise the steps of deriving a pH pattern as a function of time and the pH measurements and analyzing the pH pattern for the subject and the pressure pattern for the subject relative to a pH reference pattern and a pressure reference pattern to determine the capsule's location at a second position. The method may further comprise the steps of determining transit time between the first position and the second position, and evaluating the transit time relative to a reference transit time. The first position may be a junction between the stomach and the small bowel of the gastrointestinal tract of the subject and the second location may be a junction between the ileum and the caecum of the gastrointestinal tract of the subject. The first position may be the junction between the ileum and the caecum of the gastrointestinal tract of the subject and the second location may be the point at which the capsule is discharged from the gastrointestinal tract of the subject.
The method may further comprise the steps of deriving a second pressure pattern different from the first pressure pattern as a function of time and the pressure measurements, providing a second reference pressure pattern, and analyzing the second pressure pattern variations for the subject relative to the second reference in determining the capsule's location at the first position. The first pressure pattern may be frequency of contractions relative to a baseline over a given time interval and the second pressure pattern may be motility index. The method may further comprise the steps of deriving a second pressure pattern different from the first pressure pattern as a function of time and the pressure measurements, providing a second reference pressure pattern, and analyzing the second pressure pattern variations for the subject relative to the second reference in determining the capsule's location at the second position. The first pressure pattern may be frequency of contractions relative to a baseline over a given time interval and the second pressure pattern may be motility index. The step of determining the capsules location at a first location in the gastrointestinal tract may comprise the steps of providing a reference pH or a reference degree of change of pH and analyzing the pH measurements for the subject relative to the reference pH or a reference degree of change of pH. The step of evaluating the pressure pattern may comprise the step of determining if the subject's pressure pattern is substantially similar to the reference pressure pattern, wherein the reference pressure pattern is derived from a gastroparetic control group.
In another aspect, the invention provides a method of evaluating gastroparesis comprising the steps of providing an ingestible capsule having a pH sensor, having a subject ingest the capsule, recording pH measurements from the sensor as a function of time as the capsule moves through at least a portion of the gastrointestinal tract of the subject, determining the capsules position at a junction between the stomach and the small bowel of the subject as a function of the pH measurements, determining a transit time of the capsule between the time the capsule is ingested by the subject and the time the capsule is determined to be at the position, providing a reference transit time, and evaluating the transit time relative to the reference transit time.
The method may further comprise the step of having the subject ingest a low fat meal with ingestion of said capsule. The step of evaluating transit time relative to the reference transit time may comprise the step of determining whether the transit time is greater than or less than the reference transit time, and the reference transit time may be about 5 hours.
Accordingly, the general object is to provide a method for evaluating whether a subject has gastroparesis using an ingested capsule.
Another object is to provide a method of diagnosing gastroparesis with an ingested capsule.
Another object is to provide a method of evaluating a subject for gastroparesis based on pressure patterns derived from a capsule passing through the subject's gastrointestinal tract.
Another object is to provide a method for evaluating a subject for gastroparesis based on transit time of a capsule passing through one or more segments of the gastrointestinal tract.
Another object is to provide a method for diagnosing gastroparesis using transit times as determined by a pH sensor and/or a pressure sensor as a capsule passes through the gastrointestinal tract.
Another object is to provide a method of diagnosing gastroparesis in a non-invasive manner suitable for the office setting.
These and other objects and advantages will become apparent from the foregoing and ongoing written specification, the drawings, and the claims.
At the outset, it should be clearly understood that like reference numerals are intended to identify the same structural elements, portions or surfaces consistently throughout the several drawing figures, as such elements, portions or surfaces may be further described or explained by the entire written specification, of which this detailed description is an integral part. Unless otherwise indicated, the drawings are intended to be read (e.g., cross-hatching, arrangement of parts, proportion, degree, etc.) together with the specification, and are to be considered a portion of the entire written description of this invention. As used in the following description, the terms “horizontal”, “vertical”, “left”, “right”, “up” and “down”, as well as adjectival and adverbial derivatives thereof (e.g., “horizontally”, “rightwardly”, “upwardly”, etc.), simply refer to the orientation of the illustrated structure as the particular drawing figure faces the reader. Similarly, the terms “inwardly” and “outwardly” generally refer to the orientation of a surface relative to its axis of elongation, or axis of rotation, as appropriate.
A method is provided for evaluating a subject for gastroparesis using an ingestible capsule as a function of pressure readings, pH readings taken by the ingested capsule and/or transit time. A capsule 20 is ingested by a subject and readings from sensors on the capsule are taken as the capsule passes through the gastrointestinal tract of the subject. Data from the pressure sensor and pH sensor are collected and analyzed by comparison to one or more reference templates to evaluate the subject for gastroparesis.
As shown in
Capsule 20 includes a pressure sensor assembly 23 comprising a flexible sleeve 26 affixed to the shell of the capsule and defining a chamber 28 between the shell and the sleeve. A pressure sensor 29 is operatively arranged to sense pressure within chamber 28 and communicates with the chamber through a fluid port 30 at one end of the shell of the capsule. As shown, the pressure sleeve 26 of capsule 20 extends from a point below the middle of the capsule up over the top end of the capsule. Capsule 20 also includes a temperature sensor.
On the opposite end of capsule 20 to pressure sensor 23 is pH sensor 22. In the preferred embodiment, pH sensor 22 is a conventional ISFET type pH sensor. ISFET stands for ion-selective field effect transistor and the sensor is derived from MOSFET technology (metal oxide screen field effect transistor). A current between a source and a drain is controlled by a gate voltage. The gate is composed of a special chemical layer which is sensitive to free hydrogen ions (pH). Versions of this layer have been developed using aluminum oxide, silicon nitride and titanium oxide. Free hydrogen ions influence the voltage between the gate and the source. The effect on the drain current is based solely on electrostatic effects, so the hydrogen ions do not need to migrate through the pH sensitive layer. This allows equilibrium, and thus pH measurement, to be achieved in a matter of seconds. The sensor is an entirely solid state sensor, unlike glass bulb sensors which require a bulb filled with buffer solution. Only the gate surface is exposed to the sample.
In the preferred embodiment, the capsule transmits sensed data at about 434 MHz and measures 26.8 mm long by 11.7 mm in diameter. A portable data receiver worn by the subject receives and stores data transmitted by the capsule. Software performs data analysis and presents a graphical data display of pH, pressure and temperature readings for analysis. After activation and ingestion, the capsule senses and transmits data for at least 120 hours after activation. The pH, pressure and temperature data are transmitted from within the GI tract to the data receiver. In the preferred embodiment, the range and accuracy of the sensors are generally 0.5 to 9.0 pH units with an accuracy of ±0.5 pH units, 0 to 350 mmHg with an accuracy of 5 mmHg, or 10% above 100 mmHg, and 25° to 49° C. with an accuracy of ±1° C. The data receiver contains rechargeable batteries and when seated in a docking station allows for battery charging and data download. Data is downloaded from the data receiver through the docking station via USB connection to a Windows PC compatible laptop.
The pH readings from the ingested capsule are plotted against time, as shown in
Based on this determination, the capsules gastric emptying or residence time may be determined. Gastric emptying time (GET) of the capsule is the duration of time from the capsule's ingestion to the point at which the foregoing pH rise is determined.
In the preferred embodiment, pressure patterns derived from pressure measurements taken by the capsule during a period of time before and after the capsule has transitioned from the stomach to the small bowel are also used to evaluate the subject for gastroparesis, or delayed gastric emptying. As shown in
In the preferred embodiment, the pressure data from the subject is conditioned to distinguish real contraction data from artifacts or “noise” within the data set, as well as to discount physiologically improbable values. In the preferred embodiment, both concerns are addressed as part of a process which inspects each data value in the pressure measurement data set provided by the capsule. Because the conditioning utilizes constant minimum and maximum threshold values to determine and eliminate data spikes and artifacts, the input pressure data is baseline compensated. As mentioned above, the pressure data is then conditioned by filtering out those sets of data points or contractions whose peaks are above a predetermined threshold or limit. In the preferred embodiment, this threshold is about 200 mmHg. In addition, those contraction patterns whose peaks are less than a predetermined threshold or limit are also filtered out. In the preferred embodiment, this minimum threshold is about 9 mmHg. Thus, in the preferred embodiment the process considers a set of baseline compensated pressure measurements and begins evaluating each value in linear sequence from beginning to end. If a point is found to exceed the defined maximum, then the high value or spike is removed with its associated ascending and descending artifact values by traversing the data set both behind and ahead of the detected spike and zeroing the spike and any associated values, until either its termination or a new contraction is detected. The determination that an artifact has terminated is defined as any data point below a minimum pressure value. Contrarily, finding the next contraction from the high value is based on the detection of three consecutive ascending values, which is interpreted as an ascent in pressure, indicating the edge of a different contraction. Thus, in determining, for example, the area under the curve for a given time interval, a pressure point is included in the calculation only if its value is greater than or equal to the sum of the baseline pressure and the minimum threshold and is below the sum of the baseline pressure and the maximum threshold.
After an overnight fast, 104 subjects (66 healthy and 38 gastroparetic) swallowed the capsule after an Eggbeater meal. Pressure, temperature and pH data were recorded and downloaded into a computer for analysis. The gastric emptying time (GET) was measured as the difference between the time of ingestion to a sudden and sustained rise of pH to greater than 4, and at least 3 pH units above baseline, which was correlated to gastric emptying or the location at the transition between the stomach and small bowel. As described above, the number of gastric contractions and the area under the curve (AUC) of pressure for 20 minute intervals in the last 1 hour of GET were calculated. A two tailed unequal variance t-test was used for statistical analysis, and a p<0.05 was considered significant. Ninety-five percent confidence intervals (CI) were also calculated. Tables 1 and 2 below indicate that, with means and 95% CI, gastroparetics had less contractions and a lower AUC in the last one hour of GET.
Thus, in the preferred embodiment a subject is evaluated for gastroparesis by comparing data recorded by a capsule as it moves through the gastrointestinal tract of the subject with a reference template or model. While in the preferred embodiment the pressure patterns for the time intervals 40-60 minutes before gastric emptying and 20-40 minutes before gastric emptying are used for purposes of comparison with the reference pattern, it is contemplated that other time periods may be used. For example, gastric contractions for the subject and the reference may be compared during the time interval of 30-60 minutes before gastric emptying. Alternatively, the window may be as large as the entire gastric residence time. Gastroparetics also have a statistically significant lower number of gastric contractions over a baseline in this time period when compared to a healthy control group, with p values of less than 0.02. In a study of 21 healthy subjects and 16 gastroparetic subjects, the healthy subjects had an average number of contraction per minute, or frequency of contractions, of about 1.23 during this period, while gastroparetic subjects had an average number of contraction above a 9 mmHg baseline per minute of about 0.74 during the same time period, with a p value of about 0.013.
Also, while a decrease in pressure patterns (such as frequency of contractions or motility index) compared to a template derived from pressure readings from non-gastroparetic controls is used in the preferred embodiment to evaluate a subject for gastroparesis, it is contemplated that alternatively the template may be derived from a gastroparetic control group, and similarities, rather than differences, between pressure patterns of the subject and the reference template may be used to evaluate the subject for gastroparesis. Furthermore, as indicated in Tables 1 and 2, these pressure patterns may be used to distinguish between gastroparetic subgroups, such as idiopathic and diabetic.
In the preferred embodiment, transit time in the stomach is used to supplement the information available for evaluating a subject for gastroparesis. In an alternative embodiment, transit time of the capsule in the stomach may be used alone to evaluate gastroparesis. In this embodiment, the non-digestible capsule 20 is used to determine GET and evaluate a subject for gastroparesis. GET is determined with the capsule based on the duration of time from the capsules ingestion to the point at which the capsule indicates an abrupt pH increase greater than 3 pH units from a baseline pH to a pH greater than 4. In the preferred embodiment, if this time is determined to be greater than about 300 minutes after ingestion of a standardized 255 k cal low fat meal and the capsule, then the subject is evaluated as having a gastroparetic condition.
A study was conducted to assess the correlation between an ingestible capsule's GET and the gastric emptying scintigraphy (GES) technique presently used to measure gastric emptying time, and to determine whether the capsule could discriminate healthy subjects from gastroparetics. Eighty-six healthy subjects and 60 gastroparetics were studied simultaneously with the capsule and GES. After overnight fast, subjects swallowed the capsule and ingested a 99mTc-SC radio-labeled low fat (255 k cal) meal. Images were obtained at 30 minute intervals for 6 hours. GET was determined for each subject. Correlations between capsule GET and GES time to 50% emptying (T-50%) and time to 90% emptying (T-90%) were performed. Correlation between capsule GET and GES T-90% was 0.82±0.06, and correlation for capsule GET and GES T-50% was 0.66±0.15. The diagnostic accuracy, as assessed by ROC, between gastroparetics and healthy subjects was 0.83 for capsule GET and 0.85 for T-90% (not statistically different) and 0.77 for T-50%. The cutoff time for capsule GET that maximizes both sensitivity and specificity for diagnosis of gastroparesis was 300 min, giving 86% sensitivity and 92% specificity. Thus, this new capsule based method correlates with T-90% GES emptying and discriminates between healthy and gastroparetic subjects, offering an efficient, ambulatory alternative to scintigraphy.
A ROC curve was used to examine the diagnostic utility the two tests in discriminating healthy normals and patients with gastroparesis. The area under the curve (AUC), and its corresponding 95% bootstrap confidence interval, was used as the primary measure of diagnostic utility. The optimal sensitivity versus specificity cutoff for diagnosing gastroparesis versus normal was taken to be the upper leftmost point on the ROC curve. The gold standard scintigraphy diagnosis of gastroparesis was based on previous history of disease. An additional analysis was performed using a refined gold standard definition of disease, which combined history of the disease with scintigraphy confirmation from the day of the test.
The median and 95% confidence interval times for T-50% emptying and T-90% emptying measure by scintigraphy and the GET measured by the capsule in the 125 healthy subjects and patients with gastroparesis are shown in Table 3 below.
In the healthy subjects, the median T-50% was 89 min, T-90% was 154 minutes, and capsule GET was 215 minutes. In patients with gastroparesis, the median T-50% was 123 minutes, T-90% was 239 minutes, and capsule GET was 360 minutes. Measurements times of T-50%, T-90% and capsule GET from the healthy subjects compared the gastroparetic subjects were statistically different from each other (p<0.05).
Table 4 below summarizes the sensitivity and specificity of T-50% GES, T-90% GES, and capsule GET based on the optimal cut-points from the ROC curve with the corresponding AUC values (c statistic).
In the preferred embodiment, the optimal cutoff point for capsule GET to discriminate between healthy subjects and gastroparetic patients is 300 minutes as determined from the sensitivity and specificity of this analysis.
Transit time in the small bowel may also be used to supplement the information available for evaluating a subject for gastroparesis. A latter variation in pH, indicated at B in
As shown in
By basing location on both pH and pressure patterns, one can more accurately determine the movement of ingested capsule 20 from one segment of the gastrointestinal tract to a second segment of the gastrointestinal tract of a subject. In comparing patterns from a subject with the reference templates for both pH and pressure, if there is a correlation between a variation in pH B and a variation in frequency of contractions D and/or motility F, then a determination of the capsule's location may be more accurate.
The patterns indicate that the intraluminal environment of the gastrointestinal tract as it transitions from the small intestine into the colon changes. The caecum, as compared to the distal ileum, is a less contractile reservoir where colonic bacteria cause an acidic change in pH. Thus, in the preferred embodiment, capsule 20 is ingested by the subject and pH readings and pressure readings are taken and compared as indicated above. Certain pH reference values are known in the prior art, as shown in
Thus, readings from a subject may also be compared to reference templates to determine the location of the capsule, with a change in pH and a change in either frequency of contractions or motility index correlating with the variations in the template used to determine that location. By using patterns based on both pH and pressure, location is more accurate because changes in pH based on bacterial overgrowth or malignancies in the gastrointestinal tract are not assumed to be a transition from one segment to a second segment if they are not accompanied by a corresponding variation in either the frequency of contractions or motility index.
With the determination that the capsule has passed from the stomach to the small bowel and then through the ileo-caecal junction, transit time through the small bowel is ascertained. Transit time through the colon can then be determined as well, as the time from passage through the ileo-caecal junction to discharge of the capsule. These times may then be used as additional information in the evaluation of the subject for gastroparesis.
The present invention contemplates that many changes and modifications may be made. Therefore, while the presently-preferred form of the improved method has been shown and described, and a number of alternatives discussed, persons skilled in this art will readily appreciate that various additional changes and modifications may be made without departing from the spirit of the invention, as defined and differentiated by the following claims.
This application claims the benefit of U.S. Provisional Patent Application No. 60/930,451, filed May 16, 2007. The entire content of such application is incorporated by reference herein.
| Number | Date | Country | |
|---|---|---|---|
| 60930451 | May 2007 | US |
