The present invention relates generally to systems and methods for monitoring and evaluating organ function and, more particularly, to non-invasive apparatus and methods for monitoring and evaluating the function of transplanted organs, detecting organ failure, and providing an appropriate warning to the patient and/or physician in the event of actual or anticipated organ failure.
Organ failure, particularly kidney failure, can be disabling or fatal. Renal failure is often treated by dialysis. This provides a substitute for the kidney function, but there are disadvantages associated with it, including the time, expense, and lifestyle changes required. Accordingly, when a donated kidney is available, a transplant (allograft) from a living or cadaver donor is performed on the patient. Each year approximately 14,000 kidney transplants are performed in the United States alone. The average one-year survival rate is about 95%. The most common cause of death is infection, followed by acute rejection. The currently available apparatus and methods for monitoring a transplanted kidney or for assisting in kidney failure assessment are quite limited and, for the most part, require the patient to undergo extensive invasive procedures or repetitive visits to a hospital or other medical facility which can be expensive. Furthermore, such methods are not usually effective in identifying incipient rejection at an early stage.
Known methods for monitoring patients who receive a kidney or other organ transplant typically require an invasive biopsy of the organ. The patient is taken to a laboratory and one or more small pieces of the organ are sampled, which are then sent for pathological evaluation. This procedure is expensive, invasive, and can not identify incipient organ failure which begins in localized regions of the organ. Furthermore, in an already immune-compromised patient, the biopsy procedure itself may cause damage which could precipitate organ failure.
Medical practitioners have attempted to reduce the risks associated with biopsies by exploring alternative methods for predicting transplant rejection. For example, a method of rejection monitoring is disclosed in U.S. Pat. No. 5,246,008 to Mueller. As disclosed in Mueller, a rejection monitor (“RM”) is connected to a patient's organ using current and measuring electrodes in which each current electrode is annularly surrounded by a measuring electrode. This RM includes a miniaturized, battery-operated electronic measuring circuit for impedance measurement and a transmitter-receiver. An AC voltage is applied in a square-wave pulse to the tissue via the current electrodes. The impedance of the body tissue is then measured via the measuring electrodes.
As disclosed in Mueller, the impedance consists substantially of the ohmic resistance and a capacitive reactance. The ohmic resistance depends substantially on the extracellular space of the tissue, whereas the capacitive reactance depends substantially on the properties of the cell membrane. As a result of ischemia of the tissue during a rejection reaction, intracellular edema with simultaneous shrinkage of the extracellular space occurs, which results in changes to the ohmic resistance and capacitive reactance of the tissue. The change of the pulse form of the ac voltage is a measure of the impedance. If a square-pulse voltage is used as the ac voltage, the change of the pulse height corresponds to the ohmic resistance, whereas the change in the steepness of the leading edges of the square-wave pulses is a measure of the capacitive reactance.
While Mueller provides an alternative to invasive biopsy, the system and method described therein is not believed to be sensitive to incipient cell degradation which may begin at locations remote from the electrodes. Furthermore, Mueller requires individual placement of the electrodes on the surface of the organ.
These and other shortcomings in the prior art are addressed by the present invention, which according to one aspect provides a method for monitoring a patient's organ, including: (a) inputting an electrical signal into the organ at a first location; (b) receiving the electrical signal from the organ at a second location spaced-apart from the first location; and (c) comparing the received electrical signal to a reference electrical signal to determine whether the patient's organ is functioning properly.
According to another aspect of the invention, a method for monitoring a patient's organ includes: (a) measuring a first flow characteristic within a blood vessel which is connected to the organ; and (b) comparing the first flow characteristic to a reference flow characteristic to determine whether the patient's organ is functioning properly.
According to another aspect of the invention, a system for monitoring a patient's organ includes: (a) A sensor sock comprising a flexible body adapted to at least partially surround an organ, the sock carrying a plurality of spaced-apart electrodes; and (b) a sensor unit adapted to be implanted into the patient's body, the sensor unit connected to the electrodes and adapted to transmit and receive electrical signals from the electrodes.
According to another aspect of the invention, a system for monitoring a patient's organ includes: (a) At least one transducer adapted to be attached to a blood vessel connected to the organ, and to sense at least one characteristic of flow inside the blood vessel; and (b) a sensor unit adapted to be implanted into the patient's body, the sensor unit connected to the transducer and adapted to transmit and receive electrical signals from the transducer.
According to another aspect of the invention, a system for monitoring a patient's organ includes: (a) a sensor unit adapted to be implanted into the patient's body, and to register an electrical signal from the patient's organ; and (b) a local data unit in operable communication with the sensor unit, the local data unit configured to receive and store data from the sensor unit and to selectively transmit the received data over a communications path.
According to another aspect of the invention, a method of monitoring a transplanted organ includes: (a) during a first data collection session occurring at a reference time, injecting a predetermined electrical signal into a patient's organ; (b) during the first data collection session, registering a resulting electrical signal from the organ, the resulting electrical signal configured as a first series of waveforms; (c) generating from the first series of waveforms, a reference waveform representative of the average characteristics of the waveforms collected during the first data collection session; (d) during a subsequent data collection session occurring at a time subsequent to the reference time, injecting the predetermined electrical signal into the patient's organ; (e) during the subsequent data collection session, registering a resulting electrical signal from the organ, the electrical signal configured as a second series of waveforms; (f) generating from the second series of waveforms, a registered waveform representative of the average characteristics of the waveforms collected during the subsequent data collection session; and (g) comparing the registered waveform to the reference waveform to determine whether the organ is functioning properly.
According to another aspect of the invention, a method of monitoring a transplanted organ includes: (a) during a data collection session, injecting a predetermined electrical signal into a patient's organ, the electrical signal configured as a series of waveforms; (b) during the data collection session, registering a resulting electrical signal from a patient's organ, the electrical signal configured as a series of waveforms; (c) evaluating whether each of the waveforms is usable according to a predetermined standard; (d) discarding waveforms which are not usable; (e) storing the remaining waveforms in a database for evaluation; and (f) comparing the stored waveforms to a reference waveform to determine whether the organ is functioning properly.
According to another aspect of the invention, a method of processing data for monitoring a patient's organ includes: (a) during a data collection session, injecting an electrical signal into a patient's organ; (b) during the data collection session, registering a resulting electrical signal from the organ, the electrical signal configured as a series of waveforms, wherein each of said waveform includes at least one upslope element extending to a peak; (c) establishing a minimum slope value; (d) comparing the actual slope value of each portion of the upslope to the minimum slope value; and (e) designating any point within the waveform in which the actual slope value is less than the minimum slope value to be a peak.
The invention may be best understood by reference to the following description taken in conjunction with the accompanying drawing figures in which:
Referring to the drawings wherein identical reference numerals denote the same elements throughout the various views,
For example, nominal path “P1” extends from electrode 12A to a second electrode 12B, corresponding to a path originating near a north or upper pole “N” of the kidney K and terminating near a south or lower pole “S” thereof. Nominal path “P2” extends from the first electrode 12A to a third electrode 12C. Nominal path “P3” extends from the first electrode 12A to a fourth electrode 12D. Finally, nominal path “P4” extends from the first electrode 12A to a fifth electrode 12E. The illustrated paths P1-P4 presume the use of the first electrode 12A as an introduction point for an electrical signal; however any of the electrodes 12 may be used for this purpose. For example, a path P5 extends from the second electrode 12B to the third electrode 12C. This provides a multiplicity of paths even with a relatively small number of electrodes 12. Of course, the internal structure of the kidney K is not homogenous, and thus the actual conduction path between any two electrodes 12 will vary and may not be linear.
The number, type, and position of the electrodes 12 may be varied to suit a particular application. In this example, the paths P1-P4 pass through and correspond to arbitrarily-designated quadrants of the kidney K labeled I-IV. This provides adequate signal coverage for the entire kidney K. This also allows the isolation of specific areas of the kidney K by the use of individual electrodes or pairs of electrodes 12. For example, If a particular signal pattern is observed only at a single electrode 12B (in a multipolar mode, along path P6) but not at other electrodes 12, this would indicate a difference in the structure of the Kidney K at that location. If a signal pattern is observed only between electrodes 12B and 12C (in a unipolar mode, along path P5) but not between other electrode pairs, this would indicate a difference in the structure of the kidney K somewhere in quadrants I or II. The greater the number of electrodes 12 used, the more accurate the location data will be. This aspect of the network of electrodes 12 may also be used to track the progression of changes in condition over a series of spaced-out observations.
The sensor unit 10, shown in more detail in
The controller 20 is connected to terminals 28 which are in turn connected to the leads 14. The controller 20 is capable of generating a voltage having a desired characteristic, such as AC, DC, or an arbitrary waveform, which is injected through a selected one of the electrodes 12. The controller 20 is able to receive or register the returned signal from one or more of the electrodes 12, and to output corresponding analog or digital data which allows calculation of the impedance between electrodes. The controller 20 may also include hardware, software, or a combination of the two operable to calculate impedance values directly. These functions may be done either on demand in response to an external command, or automatically at a programmed time interval. The impedance measurement or other signal aspect may then be transmitted to an external device through the antenna 26. The operation of the sensor unit 10 is explained more fully below.
The electrodes 12 may be physically connected to the kidney K in a number of ways. For example, a network of known screw-in or suture-in electrodes, such as the type used for conventional pacemaker lead connections, may be individually attached to the Kidney K. Alternatively, a mesh, net, sock, or other structure which holds several electrodes 12 in a desired configuration may be provided. For example,
The sensor sock 32 is shown applied over a kidney K in
In addition to, or as an alternative to the impedance measurements described above, the sensor unit 10 may be used to produce a selected electrical waveform, which is introduced through one or more of the electrodes 12. The selected waveform may be sinusoidal, square-wave, sawtooth, half-wave DC, or it may be an arbitrary waveform compounded from individual signal elements. The selected waveform may be introduced a single time during a session or as a repeating sequence. The selected waveform is modified in various ways depending upon its path through the kidney K, and is subsequently picked up by at least one of the electrodes 12. For example, if the electrode 12 is being used in a multipolar mode, the signal will be sensed by that same electrode 12. If the electrode 12 is being used in a unipolar mode, the signal will be sensed by another electrode 12. The modified waveform (in the form of an electrical signal) is then output by the sensor unit 10 to an external device for subsequent analysis.
Analysis software, for example running on either a local data unit or a data server (described below), is used to analyze the data received from the patient's kidney K in several ways. According to one procedure, each time data is received corresponding to the electrical signals received by the sensor unit 10, the analysis software digitally creates or generates a graphical representation of the modified waveform such as a graph, or chart (referred to herein as a “waveform”). An example of a waveform is illustrated in
Several techniques may be used to generate the waveforms or portions thereof so as to produce data which is “cleaner” than the raw digitized data, i.e. relatively free from effects of electrical noise or digitization errors, and easier to analyze.
For example, depending on the waveform selected, it may comprise a series of line segments or portions having a high slope or first derivative, such that peaks (and nadirs) occur as sharply delineated events (i.e. the curves are strongly convex). Accordingly, peak detection may be implemented by establishing a minimum slope value. To accomplish this, the entire waveform is evaluated, either by the analysis software or by separate pre-processing software, for the presence of any location where the slope is less than the minimum value. Each of these locations are identified as a peak. Suitable threshold values will depend upon the particular waveform that is selected.
Some selected waveforms may appear as deviations from a baseline or generally horizontal trace, which may or may not be equal to a zero electrical potential line. The value (i.e. voltage level) of the baseline affects other measurements such as baseline-to-peak amplitude and area under the curve (described in more detail below). The specific value of the baseline is calculated based on the specific equipment configuration.
In practical application, portions of the signal ahead and behind of the selected waveform shape will not match the established baseline, i.e. they will not be simple horizontal traces, but will rather exhibit many small deviations. This is depicted by arrow “D” of the exemplary waveform “W” in
One manner in which the hysteresis band intercept may be accurately located is to apply a linear slope calculation to the relevant portion of the waveform W. For example, using the peak detection method described above, the time tp at which the dominant peak occurs and the peak voltage Vp will be known. The slope dv/dt of the immediately preceding segment is then determined, by calculating a linear ratio using an appropriate dt (e.g. 1 ms if a 1-kHz sampling rate is being used). Once the slope is known, it may be extrapolated back to calculate the intercept time ti, for example using equation (1) below. The resulting time ti is taken to the be the “beginning” of the upslope. A similar procedure may be used to determine the intercept of other upslopes or downslopes within the waveform W.
t
i
=t
p−(vp−vu)(dv/dt)−1 (1)
In cases where a cyclic signal or repeating waveform is used, the reference waveform and the registered waveforms which are generated for comparison and analysis purposes may be representative of the average of many individual waveforms in the data population recorded during a period of data collection.
The preprocessed data is evaluated as follows, with reference to
Various techniques may be used to implement this step. For example, waveforms elements which are at the edges of a normal distribution (e.g. beyond a 2σ interval) in terms of one or more characteristics such as area, amplitude, or slew may be discarded and not used in the generation of the averaged waveform.
Another method for eliminating extraneous data is to test a defined point-to-point horizontal distance (e.g. peak-to-peak or baseline-to-baseline) of each waveform. If any one waveform has a point-to-point distance varying from the average point-to-point distance by more than a selected threshold value, for example plus or minus 5%, then that entire waveform would be discarded and not used in the generation of the averaged waveform.
As the data is initially tested, a counter is incremented (block 208) each time a waveform is discarded. A high value of this counter could indicate an equipment fault or human error in collecting the data. High values may also indicate extreme acute rejection. Accordingly, this counter serves as a gross check for allograft rejection. If the counter exceeds a predetermined standard at block 210, the process is stopped and an error flag is set for operator attention at block 212. The process is repeated until all of the waveforms in the data collection session have been evaluated.
Next, the remaining waveforms from the data collection session are used to construct a single average waveform. The initial waveform generated at the reference time, immediately or very shortly after transplantation, becomes the reference waveform described above. Each subsequent data collection session results in a new averaged registered waveform. For example, a data collection session may be conducted three times each day after transplantation, resulting in three new registered waveforms each day.
When creating a representative waveform, the “average” image may be created in two different ways. In a first exemplary technique, all of the non-discarded waveforms recorded are averaged together to generate a single average waveform.
In another exemplary technique, the individual elements described above are identified for each non-discarded waveform in the data population. Those individual elements are averaged together. Then the individually-averaged elements are assembled to form a composite waveform.
Various portions, features, or elements of the waveforms can be used as a basis for comparison between the reference waveform and the registered waveform in determining the presence or absence of rejection.
One element is area measurement, which is shown in
Another element is amplitude measurement. For example,
Another element is duration.
Another element is slew rate or slope.
The difference in one or more of the individual signal elements or measurements described above (e.g. area, amplitude, slew, or impedance) between the reference waveform and the registered waveform is measured and used to assess organ function. The waveforms may also compared by measuring the total area of discrepancy between the waveforms and determining a comparison percentage match, as shown in
Regardless of which elements are being compared, a match-percentage threshold may be established, based on correlation to clinical data, which would indicate acute heart rejection. If a waveform corresponding to an electrical signal received from the patient's organ does not correlate to the reference waveform, by an amount greater than or equal to the established match-percentage threshold, then rejection is present. Early detection of rejection advantageously permits prompt initiation of life saving therapy.
Alternatively, evaluation of the waveforms may be carried out based on a multivariable statistical analysis of shifts in the registered data. When the average registered waveforms are created, each new waveform, along with the values of all of its individual elements, becomes a member of a statistical population in a database. As rejection takes place, causing changes in the kidney K, it is expected that the individual waveform elements described above will change in different ways. For example, the R-wave upslope might increase while the peak-to-peak amplitude decreases. No one of these elements necessarily represents a simple rejection-specific parameter, rather the aggregate difference, or certain combinations of changes, represents allograft rejection. However, the aggregate effect of these changes can be correlated to the presence of rejection.
Under either of the methods described above, a scale of rejection can be created. The greater the deviation from a nominal condition (determined either statistically or in terms of a scalar measurement), the more likely actual rejection is taking place, or the greater the severity of rejection. Increasing numbers on a scale is indicative of greater deviation of the registered waveform data from the reference waveform. The numbers on the scale may be likened to “grades” of rejection.
It is also possible correlate the scale of rejection to clinical results (from biopsies, autopsies, etc.) and to established “grades” of allograft rejection.
The method described herein is able to detect very slight changes in the recorded data. As such, it is believed that changes in the kidney K measurable on the scale of rejection will be present even if no rejection is yet observable in a contemporaneous biopsy. This can occur because the method described herein is sensitive to changes throughout the structure of the kidney, while a biopsy may show negative results if it is not taken from a localized area that happens to site where rejection is just starting. The present method thus has the possibility of detecting rejection early enough so as to be “predictive” in nature when compared to biopsies. Early detection of rejection advantageously permits prompt initiation of life saving therapy. This early detection is especially important in immuno-compromised patients who are prone to rapid onset of acute rejection.
In another aspect of the invention, which may be used separately or in conjunction with the electrical signal monitoring method described above, rejection and function of a transplanted kidney or other organ may be determined by monitoring flow rates of blood into and out of the organ, or other flow characteristics.
The quality of the anastomoses 50 and 52, the status of the kidney K, or both may be determined by monitoring flow through the renal vessels.
The flow transducers 54 may be active or passive. In this example, they are active ultrasonic flow sensors of a known type which are capable of imparting a sound wave into a vessel and sensing the sound energy reflected by bubbles or particles suspended in the blood. Such sensors are capable of measuring the diameter of the vessel to which they are attached. This information, in conjunction with an observed or assumed average blood velocity, may be used to calculate a flow rate within the vessel. In
The sensor unit 110 may be substantially identical in construction to the sensor unit 10 described above, for example it may include a housing which contains a controller, energy source, transceiver, and antenna (not shown). The sensor unit 110 is capable of sending a signal to the flow transducer 54, which then inputs sound energy into the renal vessel. The sensor unit 110 is able to receive and optionally store the reflected signal returned from the flow transducer 54, either on demand in response to an external command, or automatically at a programmed time interval. The reflected signal may then be transmitted to an external receiver. The operation of the sensor unit 110 is explained more fully below. In a combined application, a single sensor unit 110 may be used to collect information both from electrodes 12 and flow transducers 54.
The flow transducers 54 may be employed in various ways to produce clinically useful information. For example, if a flow transducer 54 is placed on each side of the anastomosis 52, as shown in
Alternatively, using at least one flow transducer 54, as shown in
A local data unit 58 is used to receive, store, and optionally process data from the sensor unit 10. The local data unit 58 can include a computer, microprocessor, or central processing unit operating under software control, with associated data storage means such as flash memory, RAM, EEPROM, hard disk, floppy disks, CD or DVD-ROM, etc., and a transceiver or other data communication means (e.g. a TCP/IP network adapter or modem).
In use, the local data unit 58 is placed in communication with the sensor unit 10, for example using a relay unit 66 such as the illustrated handheld wand. The relay unit 66 includes an antenna, power source, data storage means, and transceiver compatible with the with that of the sensor unit 10 (such as an induction coil). In use, the relay unit 66 receives data from the sensor unit 10, for example by inductive coupling at short range. The data is then either stored for later transfer to the local data unit 58, or immediately transferred to the local data unit 58. The transfer occurs through a communications link 67 such as a cable, infrared transmitter, or wireless link (e.g. BLUETOOTH wireless protocol).
Optionally, communication between the sensor unit 10 and the data unit 58 may be through a radio frequency (RF) communications link 60 of a known type.
The local data unit 58 receives data from the sensor unit 10 and then transfers that data over a remote communications path 62 such as a wireless or wired packet-switched network (e.g. a local area network, a wide area network, or Internet), over telephone lines using a modem, or through satellite connection. The remote communications link may be encrypted for security purposes. The data is then received by a data server 64 at a remote location (see
Optionally, a physician interface unit 68 may be provided. This comprises a computer 70 (e.g. a laptop microcomputer) and a relay unit 72 similar to the relay unit 66 described above, or other suitable communications link compatible with the sensor unit 10. The physician interface unit 68 is programmed with software enabling it to receive data from the sensor unit 10 and display the data for review, for example to show graphically in real time the impedances, flow rates, or other data measured and transmitted by the sensor unit 10. It may also be programmed to calculate impedance values based on the received data and/or perform the data analysis described above. The physician interface unit 68 is also able to send instructions to the sensor unit 10 through the relay unit 72, for example to change the value of programmable parameters of the sensor unit 10 (such as a measurement interval), to interrogate the sensor unit 10 for the actual values of the programmable parameters, or to command the sensor unit 10 to transmit data.
The foregoing has described systems and methods for monitoring organs. While specific embodiments of the present invention have been described, it will be apparent to those skilled in the art that various modifications thereto can be made without departing from the spirit and scope of the invention. Accordingly, the foregoing description of the preferred embodiment of the invention and the best mode for practicing the invention are provided for the purpose of illustration only and not for the purpose of limitation, the invention being defined by the claims.