US20060217771A1 - Potassium monitoring - Google Patents

Abstract

In general, the invention is directed to methods and devices for determining a potassium ion concentration in the extracellular fluid of a patient. A system includes an electrode deployed in or near a tissue, such as a skeletal muscle, of the patient. A pulse generator supplies one or more stimulations to the tissue, and a sensor, such as an accelerometer, detects the response of the tissue to the stimulations. A processor determines a concentration of potassium ions in the extracellular fluid as a function of the response.

Description

POTASSIUM MONITORING
• This application claims the benefit of U.S. provisional application Ser. No. 60/650,497, filed Feb. 7, 2005, the entire content of which is incorporated herein by reference.
• This application is related to U.S. patent application Ser. No. ______, attorney docket no. 1023-442US02/ P20657.01, filed Feb. 7, 2006, entitled “Ion Imbalance Detector,” the entire content of which is incorporated herein by reference.
TECHNICAL FIELD
• The invention relates to systems and methods associated with monitoring physiological conditions, and in particular, to systems and methods associated with monitoring concentrations of ions in extracellular fluid.
BACKGROUND
• The concentration of potassium ions, denoted [K⁺], in the extracellular fluid (ECF) of a patient is of clinical significance. Abnormal [K⁺] levels in the ECF can be a product of the pharmacological management of patients with heart failure. In general, [K⁺] in the intracellular fluid (ICF) of cardiac muscle or other tissue is high in comparison to [K⁺] in the ECF. When [K⁺] in the ECF becomes elevated, a reduced concentration gradient between ICF and ECF results. A reduction of the resting membrane potential is associated with the reduction in concentration gradient, often resulting in ectopic foci and arrhythmia.
• A reduction in concentration gradient further affects the magnitude and duration of the action potential. The change in membrane potential caused by an action potential, which is about 120 mV in healthy cardiac muscle, can be reduced substantially. In addition, the duration of the action potential, which is about 250 milliseconds in healthy cardiac tissue, can be diminished.
• [K⁺] can have additional clinical significance as well, and for some patients [K⁺] can be an important factor worth monitoring. For example, trauma patients, burn patients, diabetic patients with ketoacidosis, renal patients on dialysis, patients experiencing pulmonary edema, and cardiac arrest patients may have electrolyte fluctuations, particularly fluctuations of potassium ion concentrations. In addition, potassium ion retention accompanies the onset of some medical conditions, such as Addison's disease.
SUMMARY
• In general, the invention is directed to methods and devices for determining a concentration of potassium ion in extracellular fluid of a patient. A system includes electrodes, and at least one of the electrodes is deployed in or near a tissue of the patient. The tissue may be a skeletal muscle, such as the pectoral muscle. A pulse generator supplies one or more stimulations to the tissue, and a sensor detects the response of the tissue to the stimulations. A processor determines a concentration of potassium ion as a function of the response.
• As used herein, determining a concentration of potassium ions in extracellular fluid of the patient includes, but is not limited to, determining an absolute concentration, such as measuring or estimating a molarity. Determining a concentration of potassium ions can also include determining a relative concentration, such as a concentration with respect to a baseline. Furthermore, determining a concentration of potassium ions can include determining a change in concentration over time.
• The invention can be implemented as a stand-alone potassium monitoring system. The invention can also be implemented in conjunction with an implantable medical device such as a cardiac pacemaker, cardioverter-defibrillator, patient monitor, drug pump or neurostimulator. The invention can be implemented as an external system or a system having external and implantable elements.
• In one embodiment, the invention presents a system comprising a pulse generator configured to generate an electrical stimulation, an electrode configured to deliver the electrical stimulation to a tissue, such as a skeletal muscle, in a patient. The system further includes a sensor configured to detect at least one response of the tissue to the electrical stimulation, and a processor configured to determine a concentration of potassium ions in extracellular fluid of the patient as a function of the response. The processor can be configured to determine a concentration of potassium ions as a function of a sustained contraction of the tissue, for example, or a rippled contraction of the tissue, a rate of relaxation of the tissue, a pulse width of the response, the occurrence of summation in the response or the amplitude of the response. The system can be external, partially implantable or fully implantable.
• In another embodiment, the invention is directed to a method that includes delivering an electrical stimulation to a tissue in a patient, detecting a response of the tissue to the electrical stimulation, and determining a concentration of potassium ions in extracellular fluid of the patient as a function of the response. The method can further include delivering a therapy to the patient as a function of the response.
• In a further embodiment, the invention is directed to a method comprising delivering an electrical stimulation to a tissue in a patient, detecting at least one response of the tissue to the electrical stimulations and storing a relationship between a concentration of potassium ions in extracellular fluid of the patient and the response. This method is useful for calibrating a potassium monitoring system according to the invention.
• Additional embodiments of the invention include computer-readable media comprising instructions that cause a programmable processor to carry out any of the methods of the invention.
• The invention may result in one or more advantages. Compared to conventional techniques for detecting [K⁺], the invention offers convenience and supports long-term implantation. Tests that rely upon laboratory analysis of blood samples require that blood be drawn from the patient, and may not be available outside a hospital setting. Electrochemistry-based potassium sensors are implantable, but have not proven to be stable over long periods, and their performance degrades over time. Optical sensors for potassium typically call for periodic replacement of components, such as a disposable strip used for making measurements. By contrast, the invention can be implanted, can conveniently monitor potassium ion concentrations, and can remain reliable for extended periods of time.
• In addition, the invention can be implemented within an IMD that delivers therapy, such as a pacemaker or drug pump, or supports other monitoring functions. Many patients experiencing heart failure, for example, can benefit from the implantation of an IMD that can monitor [K⁺] and apply one or more pacing therapies. The invention can offer the further advantage of implementation with one or more external elements, which can be deployed without surgery.
• The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
BRIEF DESCRIPTION OF DRAWINGS
• FIG. 1A is a schematic illustration of a human heart in conjunction with an exemplary implantable medical device and an exemplary electrode element according to an embodiment of the invention.
• FIGS. 1B through 1E are schematic illustrations of an implantable medical device with alternate embodiments of electrode elements.
• FIG. 1F is a schematic illustration of an exemplary external medical device and an exemplary electrode element according to an embodiment of the invention.
• FIG. 2 is a schematic illustration of an implantation of an exemplary implantable medical device and an exemplary electrode element proximate to skeletal muscle.
• FIG. 3 is a block diagram showing a system that can deliver one or more electrical stimuli to a tissue and determine a concentration of potassium ion in extracellular fluid as a function of the response to the stimuli.
• FIGS. 4A and 4B are timing diagrams illustrating stimuli and the responses of skeletal muscle thereto, according to various embodiments of the invention.
• FIG. 5 is a flow diagram illustrating a technique for calibrating a medical device to determine a concentration of potassium ion in extracellular fluid.
• FIG. 6 is a flow diagram illustrating a technique for monitoring potassium ion concentration in extracellular fluid.
• FIG. 7 is a schematic diagram of an experimental setup to test muscle contractions due to electrical stimuli.
• FIG. 8 is a graph of exemplary data showing muscle force in various solutions of potassium versus time.
• FIG. 9 is a graph of exemplary data showing contraction amplitude versus potassium concentration.
DETAILED DESCRIPTION
• FIG. 1A is a schematic illustration of an exemplary embodiment of asystem10 that includes an implantable medical device (IMD)12 in relationship to aheart14 of a patient.IMD12 is configured to be implanted in a human or animal body. As depicted inFIG. 1A,IMD12 comprises a multi-chamber pacemaker having cardioversion and defibrillation capabilities. Although it can be advantageous to implement the invention with a multi-chamber pacemaker, the invention is not limited to the particular IMD shown. Furthermore, as discussed below, the invention need not be implemented as an implantable medical device. The invention can be implemented as a stand-alone potassium monitoring system, or in conjunction with a different type of implantable or external device such as a patient monitor, drug pump, muscle stimulator or neurostimulator.
• Aright ventricular lead16 includes an elongated insulative lead body carrying one or more concentric coiled conductors separated from one another by tubular insulative sheaths. The distal end ofright ventricular lead16 is deployed in theright ventricle18 ofheart14. Located adjacent the distal end of the lead body are one or more pace/sense electrodes20, which are configured to deliver cardiac pacing and are further configured to sense depolarizations ofright ventricle18. Afixation mechanism22 such as tines or a screw-in element, anchors the distal end inright ventricle18. The distal end also includes anelongated coil electrode24 configured to apply cardioversion or defibrillation therapy. Each of the electrodes is coupled to one of the coiled conductors within the lead body. At the proximal end ofright ventricular lead16 is aconnector26, which couples the coiled conductors in the lead body toIMD12 via aconnector module28.
• A rightatrial lead30 includes an elongated insulative lead body carrying one or more concentric coiled conductors separated from one another by tubular insulative sheaths corresponding to the structure ofright ventricular lead16. Located adjacent the J-shaped distal end of rightatrial lead30 are one or more pace/sense electrodes32, which are configured to sense depolarizations of and deliver pacing stimulations toright atrium34. As shown inFIG. 1A, anelongated coil electrode36 is provided proximate to the distal end of rightatrial lead30, and is located inright atrium34 and thesuperior vena cava38. At the proximal end of the lead is aconnector40, which couples the coiled conductors in rightatrial lead30 toIMD12 viaconnector module28.
• Acoronary sinus lead42 includes an elongated insulative lead body deployed in the greatcardiac vein44. The lead body carries one or more coiled conductors coupled to one or more pace/sense electrodes46.Electrodes46 are configured to deliver ventricular pacing to leftventricle48 and are further configured to sense depolarizations ofleft ventricle48. Additional pace/sense electrodes (not shown) may be deployed oncoronary sinus lead42 that are configured to pace and sense depolarizations of theleft atrium50. At the proximal end ofcoronary sinus lead42 isconnector52, which couples the coiled conductors incoronary sinus lead42 toconnector module28.
• Anexemplary electrode element54A is coupled to the distal end of alead56. Lead56 carries one or more conductors separated from one another by insulative sheaths. Aconnector58 at the proximal end of the lead couples the conductors inlead56 toIMD12 viaconnector module28.
• In addition toconnector module28,IMD12 comprises ahousing60 formed from one or more materials, including conductive materials such as stainless steel or titanium.Housing60 may include insulation, such as a coating of parylene or silicone rubber, and in some variations, all or a portion ofhousing60 may be left uninsulated. The uninsulated portion ofhousing60 can serve as a subcutaneous electrode and a return current path for electrical stimulations applied via other electrodes.
• In the embodiment shown inFIG. 1A,electrode element54A includes twoelectrodes62A and62B. At least one ofelectrodes62A and62B is deployed in or near test tissue and delivers stimulation to the tissue, while the other provides a return current path. In the embodiment shown inFIG. 1A,electrodes62A and62B are button electrodes, but the invention encompasses other electrode types as well. The invention will be described in terms of stimulation of muscle cells, but the invention can encompass other test tissues as well. The test tissue can comprise a collection of autologous or non-autologous cells that are sensitive to [K⁺]. For example, the test tissue may be one of cardiac muscle, skeletal muscle, smooth muscle, nerve tissue, skin, or the like.
• As described below,IMD12 includes one or more implantable pulse generators (IPGs) (not shown inFIG. 1A) configured to generate stimuli to be delivered to one or more muscles of the patient viaelectrode element54A. As described below, skeletal muscle is generally the most desirable tissue, because it is usually readily accessible and response of skeletal muscle can be readily related to [K⁺]. Furthermore, it may be desirable to stimulate skeletal muscles that do not get much use and are less prone to fatigue. The invention encompasses embodiments in which stimulation and response of other kinds of tissue can be related to [K⁺], but muscle tissue, such as skeletal muscle tissue is the exemplary tissue described herein.
• Housing60 may include one or more sensors (not shown inFIG. 1A) configured to detect at least one response of the stimulated muscle to the electrical stimulation or stimulations. In some embodiments, the sensor may be deployed elsewhere, such as on the distal end oflead56. In general, the sensor detects the electromechanical response of the stimulated muscle. Examples of sensors will be described below.
• In general, the distance betweenelectrodes62A and62B can be a function of the pulse magnitude generated by an IPG, a target stimulation magnitude, and the kind of electrodes employed. For example, to deliver a stimulus with a field strength of 10 volts per centimeter (V/cm) usingIMD12, which is capable of producing 2 V pulses,electrodes62A and62B can be separated by two millimeters. The invention is not limited to any particular physical dimensions or stimulation magnitudes, however.
• IMD12 also includes one or more IPGs configured to generate pacing stimuli to be delivered to one or more chambers ofheart14. The IPGs that stimulateheart14 may be, but need not be, the same IPG that generates muscle stimulations.IMD12 further includes one or more processors (not shown inFIG. 1A) that regulate the delivery of pacing pulses. The processor inIMD12 is configured to apply a variety of pacing modes, including therapies that may be beneficial for patients suffering from heart failure, such as cardiac potentiation therapy (CPT) or cardiac resynchronization therapy (CRT). CPT generally involves electrically stimulating one or more heart chambers to induce post-extrasystolic potentiation, and CRT involves delivering pacing pulses to one or both ventricles to synchronize ventricular contractions.
• FIG. 1B is a schematic illustration ofIMD12, with an alternate embodiment of anelectrode element54B. In the embodiment depicted inFIG. 1B,electrode element54B, likeelectrode element54A, is coupled to the distal end oflead56, which carries one or more conductors separated from one another by insulative sheaths and is coupled toconnector module28 viaconnector58.Electrode element54B includes twoelectrodes62C and62D, which deliver electrical stimulation to muscle, or other tissue sensitive to [K⁺], and provide a return current path.
• Electrode element54B resembles a pace/sense electrode, such as pace/sense electrode32 inFIG. 1A, in thatelectrode element54B includes atip electrode62C and aring electrode62D. Dimensions ofelectrode element54B may be comparable to those of conventional pace/sense electrodes. Although not shown inFIG. 1B, the distal end oflead56 may include one or more fixation mechanisms configured to prevent or reduce lead migration.
• FIG. 1C is a schematic illustration ofIMD12, with another alternate embodiment of anelectrode element54C. In the embodiment depicted inFIG. 1C,electrode element54C includes anelectrode62E deployed at the distal end oflead56, and anotherelectrode62F in the body ofhousing60.Housing electrode62F can be deployed at any site inhousing60.Lead electrode62E is configured to generate an intense electrical field at the site of stimulation. A point at the distal end oflead electrode62E causes the electric field to be more intense at the point, which can improve the likelihood of stimulation of muscle tissue or other tissue sensitive to [K⁺]. The distal end oflead56 may include one or more fixation mechanisms configured to prevent or reduce lead migration.
• FIG.1D is a schematic illustration ofIMD12, with an additional alternate embodiment of anelectrode element54D.Electrode element54D includes anelectrode62G deployed on a fixedmount64. In the embodiment depicted inFIG. 1D, fixedmount64 is coupled toconnector module28, but fixedmount64 may also be deployed elsewhere onIMD12.Exemplary electrode62G, likeelectrode62E inFIG. 1C, is configured to generate an intense electrical field at the site of stimulation. Anotherelectrode62H is deployed in the body ofhousing60.
• As discussed below, some implantations ifIMD12 may placeIMD12 in direct contact with muscle such as skeletal muscle. The embodiment depicted inFIG. 1D may be desirable in such implantations, aselectrodes62G and62H can be deployed without leads.
• FIG. 1E is a schematic illustration ofIMD12, with a further alternate embodiment of anelectrode element54E.Electrode element54E includes twoelectrodes621 and62J deployed inhousing60. In a variation of this embodiment,housing60 may include an array of three or more electrodes. As with the embodiment shown inFIG. 1D, the embodiment shown inFIG. 1E may be desirable in implantations in whichIMD12 is implanted in direct contact with muscle or other [K⁺] sensitive tissue.
• FIG. 1F is a schematic illustration of a further embodiment of the invention, in which one or more elements are external and are not configured to be implantable in a human or animal body. In the embodiment depicted inFIG. 1F, externalmedical device65 includes one or more IPGs (not shown inFIG. 1F) configured to generate stimuli to be delivered to one or more muscles of the patient viaelectrode element66. Examples of medical devices that can be configured to generate stimuli to be delivered to muscles via an electrode element are a Transcutaneous Electrical Nerve Stimulation (TENS) unit, an Electronic Muscle Stimulation (EMS) unit and an electro-acupuncture unit. The invention is not limited to such medical devices, however.Medical device65 orelectrode element66 may also include one or more sensors (not shown inFIG. 1F) configured to detect an electromechanical response of the stimulated muscle to the electrical stimulation or stimulations. In a variation, a sensor module distinct fromdevice65 orelectrode element66 may be deployed on the patient's skin to detect the electromechanical response.
• Electrode element66 is coupled tomedical device65 vialead67.Electrode element66 includes twoelectrodes68A and68B, which deliver electrical stimulation to muscle, or other tissue sensitive to [K⁺], and provide a return current path. In the example ofFIG. 1F,electrodes68A and68B are deployed externally withadhesive pads69A and69B, which adhere to the skin.Electrodes68A and68B may deliver an electrical stimulation to any of several tissues, especially skeletal muscles located beneath the skin. Although the embodiment shown inFIG. 1F is completely external with no implantable elements, the invention encompasses embodiments that have external and implantable elements.
• The invention is not limited to the particular embodiments depicted inFIGS. 1A through 1F. For purposes of discussing the invention and its operation, the description below will focus principally upon implantable embodiments, and in particular, the embodiment depicted inFIG. 1A. Further, as discussed above, the invention is not limited to stimulation of skeletal muscle tissue, or stimulation via leads or electrodes that are separate from the leads or electrodes used to deliver therapeutic stimulation. For example, in some embodiments, [K⁺] may be determined by detecting the response of cardiac muscle to the therapeutic pacing stimuli delivered toheart14. In this manner, [K⁺] may be determined directly in the organ of interest without the use of an additional stimulation pulse or stimulation lead.
• FIG. 2 is a schematic illustration of an exemplary implantation in apatient70 of the apparatus depicted in FIG1A.Right ventricular lead16, rightatrial lead30 andcoronary sinus lead42 are deployed inheart14 via access through a vein such as the subclavian vein (not shown).Electrode element54A and lead56, by contrast, do not enter the cardiovascular system in the illustrated embodiment.
• Rather,electrode element54A is deployed proximate to skeletal muscle. In the exemplary implantation depicted inFIG. 2,electrode element54A is deployed proximate to thesternal portion72 andclavicular portion74 of thePectoralis major. The invention also supports implantations in whichelectrode element54A is deployed proximate to other skeletal muscles or other tissue sensitive to [K⁺]. When asurgeon implants IMD12 in a pocket, such as a pocket proximate to thePectoralis majoraccording to a conventional implantation procedure, the surgeon can deployelectrode element54A proximate to a desired skeletal muscle.Electrode element54A may include a fixation mechanism such as a loop or Dacron mesh that allows the surgeon to anchorelectrode element54A in place with suture.
• As shown inFIG. 2,housing60 ofIMD12 is deployed in contact withpectoral muscles72 and74. A conventional implantation technique for some implantable devices, such as a pacemaker, provides for deployingIMD12 in direct contact with pectoral muscle. In such implantations, embodiments such as those depicted inFIGS. 1D and 1E may be feasible.
• FIG. 3 is a block diagram illustrating components of anexemplary system10 such as the system depicted inFIG. 1A.Electrode element54A includeselectrodes62A and62B, which are configured to deliver one or more electrical stimulations to a muscle or other tissue sensitive to [K⁺]. In a typical embodiment, one ofelectrodes62A and62B introduces a stimulation fromIMD12 to a skeletal muscle, and the other ofelectrodes62A and62B provides the return current path.
• In the embodiment shown inFIG. 3,IMD12 includes asensor80 that detects the electromechanical response of the muscle to the stimulations delivered byelectrodes62A and62B.Sensor80 can detect the mechanical response, the electrical response, or both. Examples of mechanical responses are muscle tension, muscle strength, muscle density, muscle length and pressure generated by the muscle.Sensor80 can be deployed insidehousing60 ofIMD12 oroutside housing60. Sensors such as an optical sensor could be configured to respond to one or more of these mechanical responses. An accelerometer, which responds to muscle movement, is another example of a sensor that can detect a mechanical response. In some embodiments ofIMD12, an accelerometer may be provided insidehousing60 to detect patient activity or posture. Such an accelerometer could also detect a mechanical response of stimulated muscle. In an external implementation such as that depicted inFIG. 1F, an accelerometer may be disposed indevice65, inelectrode element66, or as a separate module deployed on the patient's skin. Further examples of sensors that can detect a mechanical response are a pressure sensor and a piezoelectric sensor.
• Sensor80 can also be configured to detect an electrical response. In some embodiments of the invention,electrodes62A and62B not only deliver electrical stimulations to the muscle, but also convey the electrical response tosensor80. An example of a sensor that detects an electrical response is an impedance sensor.
• Apulse generator82 inIMD12 generates the stimulations that are delivered to the skeletal muscle viaelectrodes62A and62B.Pulse generator82 may be, but need not be, the same component that generates pacing stimulations that are delivered toheart14.Pulse generator82 operates under the control ofprocessor84.Processor84 can be embodied in one or more forms, such as a microprocessor, digital signal processor, application specific integrated circuit or full custom integrated circuit. In addition to controllingpulse generator82,processor84 receives and analyzes signals detected viasensor80 that are indicative of the response of the muscle to the stimulations, and determines a concentration of potassium ions in extracellular fluid (ECF) of the patient as a function of the signals. As discussed in more detail below, [K⁺] in the ECF affects the response of the muscle or other tissue being monitored.
• As used herein, determining a concentration of potassium ions in ECF of the patient can include determining an absolute concentration, such as measuring or estimating the molarity of potassium ions. Determining a concentration of potassium ions can also include determining a relative concentration, such as a concentration with respect to a baseline. Furthermore, determining a concentration of potassium ions can include determining a change in concentration over time. In practice, monitoring a change in concentration over time has clear clinical advantages.
• Processor84 controls the scheduling of stimulations.Processor84 may be configured to deliver the stimulations and monitor [K⁺] when the patient is in bed, for example.Processor84 may also be configured to deliver the stimulations and monitor [K⁺] a predetermined number of times each day.
• Processor84 may further be configured to determine whether conditions are suitable for delivering stimulations and monitoring [K⁺]. For example, it may be desirable to monitor [K⁺] once a day when the patient is inactive, particularly when the patient's muscles or other tissues are relaxed and when there is less likelihood of extraneous motion that could affectsensor80. When the patient is physically active, the physical activity can interfere with the monitoring of [K⁺].Processor84 may receive a signal fromsensor80 or from another sensor that generates a signal as a function of patient activity, such as an accelerometer. On the basis of the signal,processor84 may determine whether the patient is too active or whether conditions are otherwise unsuitable for monitoring. Whenprocessor84 determines that conditions are unsuitable,processor84 may defer delivering stimulations and may reschedule the stimulations for a later time.
• In addition,processor84 may be programmed to deliver the stimulations and monitor [K⁺] in response to an event. An exemplary event that could trigger delivery of stimulations and monitoring of [K⁺] is an arrhythmia. WhenIMD12 is a pacemaker or other device configured to treat arrhythmia,IMD12 may apply therapy to treat the arrhythmia, then deliver the stimulations and monitor [K⁺], to determine whether potassium ion concentration might be contributing to the arrhythmia.Processor84 can further be configured to control delivery of pacing therapy toheart14. Another exemplary triggering event is the detection of a low level of physical activity indicative of the onset of rest or sleep.
• Alternatively,processor84 may be programmed to deliver the stimulations and monitor [K⁺] to predict an arrhythmia. In this manner,IMD12 may detect poor regulation of [K⁺] and allow a physician to modify patient medication or suggest alternative diets. Exemplary medications may include anti-arrhythmic drugs, potassium channel inhibitors, or diets that include potassium sources such as bananas. In some embodiments,IMD12 may notify the patient of unsafe [K⁺] with an audible sound or stimulation so that the patient may take precautions before the arrhythmia.
• In the embodiment depicted inFIG. 3,IMD12 includes amemory element86 configured to store information about potassium ion concentration.Memory element86 can store information such as the time when electrical stimulations were administered, the frequency of the stimulations, the muscle's response to the stimulations, and the determined potassium ion concentration.Memory element86 can also store a history of such monitoring, and can store information concerning the change in [K⁺] over time.
• Further,memory element86 may store instructions that cause a programmable processor, such asprocessor84, to carry out techniques for monitoring potassium ion concentration.Memory element86 may include but is not limited to read-only memory, random access memory, Flash memory, EPROM and a magnetic or optical storage medium, or any combination thereof.
• Whenprocessor84 determines that [K⁺] in ECF is elevated to the point that heart function may be adversely affected, or whenprocessor84 determines that [K⁺] in ECF is rising to a point of concern,processor84 may take action.Processor84 may, for example, send a notification via an input/output element88. Input/output element88 comprises one or more elements that relay the message to the patient, the patient's physician, or any other person or monitoring device. Input/output element88 can include, for example, a radio frequency (RF) transmitter, an inductive coil transmitter or an audible alarm. For example, input/output element88 may issue a warning topatient12 if the determination of [K⁺] is above or below a predetermined threshold.
• Additionally, whether or not a determination that patient function may be adversely affected has been made, input/output element88 may transmit data stored bymemory element86, i.e. [K⁺] orsystem10 status data, to another computing device such as a notebook computer, hand held computer, physician programmer, personal computer, or network server. The data may be transmitted for analysis and/or storage. In the case of a network server, the data may be further forwarded to a hospital, clinic, manufacturer ofIMD12, or another location where the data may be analyzed or stored.
• Whenprocessor84 determines that [K⁺] in ECF is of concern,processor84 can also control the delivery of therapy via atherapy element90.Therapy element90 can include, for example, an implantable drug delivery device that delivers a drug to the patient. The drug may be a diuretic, for example. As the patient's body loses water due to increased urinary output, the patient's arterial blood pressure declines, reducing the workload ofheart14. In addition, increased urinary output enhances [K⁺] elimination.Therapy element90 can work in concert with input/output element88. For example,therapy element90 can administer a drug while input/output element88 can notify the patient that the patient should take an action, such as contacting his physician or controlling the potassium in his diet. In addition, input/output element88 may issue a warning topatient12 if the determination of [K⁺] is above or below a predetermined threshold.
• Therapy element90 can also encompass elements thatpace heart14 vialeads16,30 and42, or any combination thereof, as depicted inFIGS. 1A and 2. In general, however, pacing therapies would probably not be applied to address or control [K⁺]. Although pacing therapies such as cardiac resynchronization and bi-ventricular pacing may be of benefit to patients having heart failure, such pacing therapies would not ordinarily be administered in response to elevated [K⁺]. Some pacing therapies can cause [K⁺] to become even more elevated. Accordingly, although it is unlikely thatprocessor84 would apply pacing therapies to address elevated [K⁺],processor84 may monitor [K⁺] to determine whether such pacing therapies ought to be employed or discontinued. In other words,processor84 may monitor [K⁺] to determine whether pacing therapies are likely to be safe and effective.
• FIGS. 4A and 4B are timing diagrams that illustrates exemplary techniques by whichprocessor84 can determine a concentration of potassium ion in ECF as a function of the response of skeletal muscle to stimulations from an electrode element such aselectrode elements54A-E. Each stimulus may have an amplitude of about two to twenty volts, for example, and a pulse width of about 0.1 to 1.0 milliseconds.Stimulus line100 shows the timing of stimuli generated bypulse generator82 delivered to the skeletal muscle via electrodes such aselectrodes62A-62J.Response line104 depicts a response of skeletal muscle to the stimulations in an environment where [K⁺] is low relative to concentrations in ICF. In other words,response line104 depicts a response of skeletal muscle in a “normal” patient. By contrast,response line104 depicts a response of skeletal muscle in a patient having elevated [K⁺]. A patient having elevated [K⁺] is not normal and is at risk of heart failure.
• For purpose of illustration, the response is depicted as muscle tension. Other responses, such as muscle motion or muscle length, may also be evaluated, although the response waveforms may look different from those inFIGS. 4A and 4B. In addition, the response waveforms may look different from those inFIGS. 4A and 4B depending upon the muscle or other tissue being stimulated. For example, in embodiments that monitor the response of nervous tissue to the stimulation as a means for monitoring [K⁺], the response waveform may include one or more action potentials.
• Stimuli can be delivered in a range of frequencies, such as from about 10 Hz to about 150 Hz. A first set ofstimuli106 at a low frequency produces similar but distinct responses in normal [K⁺] and elevated [K⁺] environments.Contractions108 in a normal muscle andcontractions110 in a muscle in an environment of elevated [K⁺] are indicated by muscle tension as a function of time. In comparison to one another,contractions108 in a normal muscle have a longer duration and may also exhibit some summation. In the example ofFIG. 4A,contractions108 also exhibit a greater amplitude. In contrast,contractions110 in an elevated [K⁺] environment are of a smaller amplitude, a shorter duration and exhibit little or no summation.
• A second set ofstimuli112 at a higher frequency produces distinct responses in normal [K⁺] and elevated [K⁺] environments as well.Contractions114 in a normal muscle exhibit marked summation. The muscle approaches tetanus, but, as depicted inFIG. 4, the frequency of stimulation is too low to produce a sustained tetanic response. Instead,muscle contractions114 exhibit “ripples” or wavering, rather than the sustained contraction of tetanus. In contrast withcontractions114,contractions116 in an elevated [K⁺] exhibit little or no summation.
• A third set ofstimuli118 at an even higher frequency producescontractions120 in a normal muscle that show a tetanic response. In particular, muscle tension rises steadily to a maximum and levels off.Contractions122 in an elevated [K⁺] environment, by contrast, exhibit summation, but the rise in tension is rippled and tension is not sustained. In other words,stimuli118 produce asustained response120 in a normal [K⁺] environment, but produce arippled response122 in an elevated [K⁺] environment.
• The frequency of third set ofstimuli118 can be used to distinguish a normal [K⁺] environment from an elevated [K⁺] environment. The distinction can be achieved in a number of ways. For example, an analog or digital highpass filter may be employed to detect whether a ripple is present. Fourier or wavelet analysis may be used to detect the presence of high frequency components. Template matching or other morphological analysis may be performed. Other forms of analog or digital signal analysis may be used to detect the presence of a rippled response.
• A fourth set ofstimuli124 at an even higher frequency producescontractions126 in a normal muscle andcontractions128 in an elevated [K⁺] environment that are similar, in that both exhibit a tetanic response. Consequently, stimuli at this frequency would be less desirable for distinguishing a normal [K⁺] environment from an elevated [K⁺] environment.
• FIG. 4B shows additional distinction techniques. A set ofstimuli130 evokesresponses132,134 similar toresponses120,122 inFIG. 4A. InFIG. 4B, the quantity of interest is the decline of the response following cessation of stimulation, which indicates how fast the stimulated muscle relaxes. InFIG. 4B, the decline is indicated by angles α and β of lines tangent to the responses. In general, the response returns to resting more quickly in an elevated [K⁺] environment and more slowly in a normal [K⁺] environment, so angle β is generally larger and indicative of a greater slope than angle α. Another measurement of the decline of the response is the fall time, i.e., the time for the response to decrease from one value to another. Fall time can be determined by measuring the time it takes for the response to fall from its peak value to half its peak value, for example, or the time it takes for the response to fall from ninety percent of its peak value to ten percent of its peak value. The signal decays more quickly in elevated [K⁺] environment and more slowly in a normal [K⁺] environment, so the fall time in the elevated [K⁺] environment is smaller than the fall time in a normal [K⁺] environment.Processor84 may detect the rate of muscle relaxation with any analog or digital technique, such as taking a difference at discrete points, measuring the time between high and low values, or differentiating the response waveform.
• It may be possible to observe the decline with a single stimulus.Stimulus136 evokesresponses138,140. In addition to monitoring fall time or slope as described above,processor84 may detect the pulse width or action potential duration of the response. Because the response returns to resting more quickly in an elevated [K⁺] environment than in a normal [K⁺] environment, the pulse width of the in an elevated [K⁺] environment is narrower than in a normal [K⁺] environment. The narrower pulse width is associated with the shorter refractory period in an elevated [K⁺] environment. Narrower pulse width in an elevated [K⁺] environment has been demonstrated with both cardiac muscle and skeletal muscle.
• A set ofstimuli142 illustrates another distinction technique. This process includes delivering pairs of stimuli separated by different time intervals. InFIG. 4B, the initial pair of stimuli is separated by a very short interval, and subsequent pairs are separated by larger intervals. In an elevated [K⁺] environment, the response will exhibit a two-peak ripple at a smaller interval than in a normal [K⁺] environment.Processor84 can detect the presence of the two-peak ripple using any signal processing technique, including techniques mentioned above.
• Another distinction technique is to “sweep” through a range of frequencies, as illustrated by set ofstimuli148. In a normal [K⁺] environment, theresponse150 exhibits more rapid summation and reaches a sustained response in a shorter time. In contrast, theresponse152 in an elevated [K⁺] environment is slower to exhibit summation and sustained response.Processor84 can detect the onset of rapid summation and sustained response any signal processing technique, including techniques mentioned above.
• The signals depicted inFIGS. 4A and 4B are for purposes of illustration and the invention is not limited to signals of this type. Instead of measuring tension, as depicted inFIGS. 4A and 4B,sensor80 could respond to muscle motion or muscle length, for example. In other embodiments, other signals may be measured in other tissue sensitive to [K⁺], such as action potentials in nerve tissue.
• AsFIG. 4A shows, it may be more difficult to distinguish whether [K⁺] is low or elevated when stimulations are applied at high frequencies. Further, the frequency at which a normal [K⁺] environment can be distinguished from an elevated [K⁺] environment may vary from patient to patient. Accordingly, a patient who has receivedIMD12 may undergo one or more tests to calibrate muscle response to [K⁺] or other tissue response to [K⁺].
• FIG. 5 illustrates an exemplary calibration procedure. AlthoughFIG. 5 illustrates an example embodiment related to monitoring muscle tissue, the illustrated technique may be applicable to calibration for monitoring of other [K⁺] sensitive tissues, such as nerve tissue.
• In a laboratory setting, while conditions are suitable for stimulating the muscle and observing the response,IMD12 delivers one or more electrical stimulations to the muscle of the patient via the electrodes (160). The stimulations may be delivered according to a particular parameter, such as a known frequency. For purposes of illustration, it is assumed that the stimulation parameter is a known frequency of stimulation, and that the initial known frequency is a low frequency. It is further assumed that the characteristic of interest is whether the muscle exhibits a sustained tissue response.
• IMD12 detects the response of the muscle to the stimulations (162) and performs signal analysis to determine whether stimulations at the known frequency produce a tissue response (164). If not, the frequency may be changed (166), e.g., increased, and the testing may be performed again (160). At some point, the patient will exhibit a rippled response, and at a higher frequency the patient will exhibit a sustained response.
• At substantially the same time, the patient has his ECF [K⁺] measured by conventional laboratory techniques. Data concerning [K⁺] are then correlated to data pertaining to the patient's response to stimulation at one or more frequencies. In one embodiment,IMD12 receives the data concerning measured [K⁺], andprocessor84 performs the correlation. In another embodiment, another processor performs the correlation, and the relationship is supplied toprocessor84 via input/output element88.
• IMD12 stores the relationship between a known [K⁺] and the patient's response (168). In this way, a baseline measurement of [K⁺] can be established for the patient. Future determinations of [K⁺] can be measured against the baseline. If, at later time, the patient exhibits a sustained response at lower frequency, then [K⁺] has declined in comparison to the baseline. Conversely, if the later patient exhibits a sustained response at higher frequency, then [K⁺] has increased with respect to the baseline.
• AlthoughFIG. 5 illustrates calibration by observing sustained response, calibration may also be performed using other responses. Other responses can include, for example, the rate of relaxation following cessation of stimulation, the pulse width of a response, the occurrence of summation in the response, the amplitude of a response, or any combination thereof.
• As part of the calibration,IMD12 may deliver stimuli at different amplitudes. By iterative experimentation,IMD12 can discover what amplitude of stimulation will produce a response.IMD12 may be programmed to adjust the amplitude of stimulation as appropriate.
• FIG. 6 is a flow diagram illustrating a technique for monitoring ECF potassium ion concentration and for delivering therapy in response to a determination of ECF potassium ion. concentration. When, for example,processor84 determines that it is time for a scheduled monitoring or whenprocessor84 detects a triggering event that can activate monitoring,processor84 initiates the monitoring process (170). Before actually conducting the monitoring, however,processor84 determines whether the conditions are suitable for monitoring (172). An illustrative situation in which conditions might not be suitable for monitoring is a situation in which the patient has a high level of physical activity. When a signal from an activity sensor indicates that the patient is physically active, it may be difficult to monitor [K⁺] accurately. Whenprocessor84 determines that conditions are not suitable for monitoring,processor84 can defer monitoring to a later time (174).
• IMD12 delivers one or more electrical stimulations to the tissue of the patient (176). The stimulations may include a set of stimulations delivered at a known frequency or a set of stimulations that sweep through a range of frequencies.IMD12 detects the response of the tissue to the stimulations (178). Although not depicted inFIG. 6, stimulations and detection (176,178) may be repeated. For example, a later set of stimulations may be repeated at a known frequency that is different from an earlier set of stimulations.
• On the basis of the detections,processor84 determines a concentration of potassium ions in ECF of the patient (180). As noted above, this determination can include determining an absolute concentration, determining a relative concentration or determining a change in concentration, or any combination thereof.
• On the basis of the determination of a concentration of potassium ions in ECF,processor84 further determines whether action should be taken. In the exampleFIG. 6, the action in question is whether therapy is indicated (182). When therapy is indicated,processor84controls therapy element90 to deliver therapy to the patient (184). The invention is not limited to instances in whichIMD12 takes action in the form of administration of therapy. Other kinds of action include transmitting a notification via input/output element88 or changing how often IMD12 monitors [K⁺].
• The results of the determination (180), and the delivery of therapy, if any, may be recorded in memory86 (186). Among other purposes, data stored in memory are useful for monitoring the change in [K⁺] over time and for documenting the response of the patient to therapy.
EXAMPLE 1
• FIG. 7 is a schematic diagram illustrating an experimental setup that was used to test muscle contractions due to electrical stimuli. As shown inFIG. 7, mouseskeletal muscle202 was held betweenclamps208 and210 in achamber190.Clamp210 was connected to a wall ofchamber190 by asupport structure206 whileclamp208 was connected to forcetransducer212.Force transducer212 was connected to supportstructure204, which was attached tochamber190.Chamber190 was contained withinbath188.Electrical stimulator192 provided electrical stimuli to muscle202 throughelectrodes198 and200.Electrodes198 and200 were coupled toelectrical stimulator192 bywires194 and196, respectively.
• In the experiment described inFIGS. 7-9,bath188 was set to37 degrees Celsius, andchamber190 was filled with potassium buffer that was controlled to provide varying concentrations of potassium ions to determine howmuscle202 contracts with electrical stimuli in the presence of differing potassium ion concentrations.Muscle202 was an isolated mouse skeletal muscle.Force transducer212 was a strain gauge. Biphasic electrical stimuli was delivered tomuscle202 viaelectrodes198 and200 in order to trigger isometric contractions in the muscle. A computing device monitors the measurements fromforce transducer212 in real-time or offline. The experimental setup described inFIG. 7 may be varied to determine contraction forces from other tissues or using other devices.
• FIG. 8 is a graph of experimental data showing muscle force in various solutions of potassium versus time.Graph214 showselectrical stimuli216 and218 in conjunction with measured forces ofmuscle202 ofFIG. 7.Broken line220 represents contractions when [K⁺] equals 2 millimoles (mM),solid line222 represents contractions when [K⁺] equals 4 mM, and dottedline224 represents contractions when [K⁺] equals 10 mM. Contraction force was highest when [K⁺] equaled 2 mM, which is a lower [K⁺] than the normal potassium ion concentrations for a mouse. A medium level of force was generated with electrical stimuli when [K⁺] equaled 4 mM, and the lowest levels of force was generated when [K⁺] equaled 10 mM. Normal [K⁺] of a mouse is approximately 4 mM.
• In the experiment, a burst electrical stimulation consisting of 5 pulses with a frequency of 50 Hz were applied tomuscle202. Pulses were biphasic with anodic and cathodic pulse durations of 1 millisecond (ms), and 18 ms of pause between each pulse.
• FIG. 9 is a graph of experimental data showing contraction amplitude versus potassium concentration.Graph226 displays contraction amplitudes in Volts according to three different electrical stimuli frequencies. Volts may be translated into force measurements by a calibration procedure.Solid line228 and included closed boxes are representative of 50 Hz stimulation,broken line230 and included open boxes are representative of 100 Hz stimulation, and dottedline232 and included closed circles are representative of 150 Hz stimulation.
• The [K⁺] was varied in the sequence of 4 mM, 10 mM, 4 mM, 2 mM, and 4 mM. The results showed that the amplitude of the force generated bymuscle202 may be determined by the [K⁺] when thestimulation frequency 50 Hz and 100 Hz. In addition, stimulation at 150 Hz may also be used to determine [K⁺] in skeletal muscle, but was less sensitive to [K⁺] than the other frequencies tested. Other frequencies not tested in the experiment ofFIGS. 7-9 may also be useful for electrical stimulation.
• In some embodiments, other tissues may be tested and may respond similarly as the mouse skeletal muscle. Other frequencies and [K⁺] may also be tested, while the exemplary conditions provided herein are only a small sample of [K⁺] that may be detected with electrical stimulation.
• The invention may produce one of more advantages. In comparison with conventional implantable potassium sensors such as electrochemistry-based potassium sensors or optically based sensors, the invention supports long-term implantation. Conventional potassium sensors have proven to be unstable over extended periods. Some sensors require a periodic replacement of a sensing element, and other sensors lose sensitivity when the body naturally encapsulates the implanted elements. Some sensors also can be rejected by the body of the patient.
• IMDs such as those described above, however, have proven to be well tolerated in the long term. Rejection rates are low. Further, the IMD can respond to encapsulation by increasing the voltage of stimulations to provoke a response.
• The stimulations need not be painful. In practice, the patient may very likely experience a tingle. The tingle may be uncomfortable, but it would probably not be painful as long as stimulations are adjusted to a voltage that provokes a response and is not excessive. Further, as discussed above, the stimulations may be therapeutic stimulation of, for example, cardiac muscle or nervous tissue, that would have otherwise been delivered to the patient whether or not [K⁺] was monitored. There may further be an element of convenience to the patient, as the patient may reduce the number of tests that rely upon blood samples.
• IMDs such as those described above can be implanted using conventional, well-established surgical techniques. In the case of an IMD that delivers pacing or other heart therapies, an electrode configured to deliver an electrical stimulation to a tissue may be deployed as part of conventional device implantation technique, with little or no additional incision or trauma to the patient. Many patients experiencing heart failure may benefit from the implantation of an IMD that combines pacing therapies and potassium monitoring capability.
• In addition, the invention supports embodiments that include one or more external elements, which may offer further advantages. A patient may receive the embodiment depicted inFIG. 1F, for example, without surgery. An external electrode element, such as that depicted inFIG. 1F, may be deployed at several sites on the body of the patient without surgery. An external electrode element may also be readily redeployed from one site to another.
• Various embodiments of the invention have been described, but the invention is not limited to these particular embodiments. Although the invention has been depicted in the context of a pacemaker having one or more leads configured to deliver pacing stimuli to a heart, the invention can also be implemented in conjunction with other implantable and external devices. The invention can be implemented with a neurostimulator that includes a lead configured to deliver a pacing stimulation to a nerve, or a drug pump that includes a pump configured to deliver a drug to the patient from a reservoir. The invention may also be implemented as a standalone potassium monitor.
• The invention may be embodied in a computer-readable medium with instructions that cause a programmable processor to carry out the techniques described above. A “computer-readable medium” includes but is not limited to read-only memory, Flash memory, EPROM and a magnetic or optical storage medium. The medium may comprise instructions for causing a programmable processor to control a pulse generator to deliver an electrical stimulation to a muscle in a patient, for example, or receive from a sensor a signal indicative of a response of the tissue to the electrical stimulations. These and other embodiments are within the scope of the following claims.

Claims (36)

1. A system comprising:

a pulse generator configured to generate an electrical stimulation;

an electrode configured to deliver the electrical stimulation to a tissue in a patient;

a sensor configured to detect a response of the tissue to the electrical stimulation; and

a processor configured to determine a concentration of potassium ions in extracellular fluid of the patient as a function of the response.

2. The system ofclaim 1, wherein the tissue is at least one of skeletal muscle, smooth muscle, cardiac muscle, nerve tissue, or skin.

3. The system ofclaim 1, wherein the processor is further configured to determine a concentration of potassium ions in the extracellular fluid of the patient by at least one of determining an absolute concentration of potassium ions in the extracellular fluid, determining a relative concentration of potassium ions in the extracellular fluid or determining a change in concentration of potassium ions in the extracellular fluid over time.

4. The system ofclaim 1, wherein the pulse generator is further configured to generate a set of electrical stimulations.

5. The system ofclaim 4, wherein the pulse generator is configured to generate a set of electrical stimulations at a known frequency.

6. The system ofclaim 4, wherein the processor is further configured to control the timing of the set of electrical stimulations generated by the pulse generator.

7. The system ofclaim 1, wherein the processor is further configured to determine a concentration of potassium ions in the extracellular fluid as a function of at least one of a sustained contraction of the tissue, a rippled contraction of the tissue, a rate of relaxation of the tissue, a pulse width of the response, the occurrence of summation in the response or the amplitude of the response.

8. The system ofclaim 1, wherein the electrode is a first electrode, the system further comprising a housing and a second electrode in the housing.

9. The system ofclaim 1, wherein the sensor comprises at least one of an optical sensor, an accelerometer, a pressure sensor, a piezoelectric sensor or an impedance sensor.

10. The system ofclaim 1, wherein the processor is further configured to control delivery of pacing therapy to a heart of the patient.

11. The system ofclaim 1, further comprising a lead configured to couple the electrode to the pulse generator.

12. The system ofclaim 1, wherein the system further comprises at least one of a lead configured to deliver a pacing stimulation to a heart, a lead configured to deliver a pacing stimulation to a nerve, or a pump configured to deliver a drug from a reservoir.

13. The system ofclaim 1, wherein at least one of the pulse generator, electrode, sensor and processor is configured to be implanted in a human or animal body.

14. The system ofclaim 1, wherein the processor monitors the concentration of potassium ions to predict an arrhythmia.

15. A method comprising:

delivering an electrical stimulation to a tissue in a patient;

detecting a response of the tissue to the electrical stimulation; and

determining a concentration of potassium ions in extracellular fluid of the patient as a function of the response.

16. The method ofclaim 15, wherein the tissue is at least one of skeletal muscle, smooth muscle, cardiac muscle, nerve tissue, and skin.

17. The method ofclaim 15, wherein determining the concentration of potassium ions in the extracellular fluid of the patient comprises least one of determining an absolute concentration of potassium ions in the extracellular fluid, determining a relative concentration of potassium ions in the extracellular fluid or determining a change in concentration of potassium ions in the extracellular fluid over time.

18. The method ofclaim 15, wherein determining the concentration of potassium ions in the extracellular fluid of the patient comprises least one of detecting a sustained contraction of the tissue, detecting a rippled contraction of the tissue, detecting a rate of relaxation of the tissue, detecting a pulse width of the response, detecting the occurrence of summation in the response or detecting the amplitude of the response.

19. The method ofclaim 15, further comprising delivering a therapy to the patient as a function of the response.

20. The method ofclaim 15, wherein the electrical stimulation is a first electrical stimulation and the response is a first response, the method further comprising:

delivering a second electrical stimulation to the tissue;

detecting a second response of the tissue to the second electrical stimulation; and

determining a change in concentration of potassium ions in the extracellular fluid of the patient as a function of the first and second responses.

21. The method ofclaim 15, further comprising:

detecting a triggering event; and

delivering the electrical stimulation in response to the triggering event.

22. The method ofclaim 15, further comprising:

determining whether conditions are suitable for determining the concentration of potassium ions; and

delivering the electrical stimulation when the conditions are suitable.

23. The method ofclaim 15, further comprising monitoring the concentration of potassium ions to predict an arrhythmia.

24. The method ofclaim 15, further comprising at least one of recording information relating to the determination, or issuing a warning to at least one of the patient or a caregiver based upon the determination.

25. The method ofclaim 15, further comprising transmitting information relating to the determination to another device.

26. A computer-readable medium comprising instructions that cause a programmable processor to:

control a pulse generator to deliver an electrical stimulation to a tissue in a patient;

receive from a sensor a signal indicative of a response of the tissue to the electrical stimulations; and

determine a concentration of potassium ions in extracellular fluid of the patient as a function of the response.

27. The medium ofclaim 26, wherein the tissue is at least one of skeletal muscle, smooth muscle, cardiac muscle, nerve tissue, or skin.

28. The medium ofclaim 26, the instructions further causing the processor to determine the concentration of potassium ions in the extracellular fluid by determining a change in concentration of potassium ions in the extracellular fluid over time.

29. The medium ofclaim 26, the instructions further causing the processor to determine the concentration of potassium ions in the extracellular fluid by at least one of detecting a sustained contraction of the tissue, detecting a rippled contraction of the tissue detecting a rate of relaxation of the muscle, detecting a pulse width of the response, detecting the occurrence of summation in the response or detecting the amplitude of the response.

30. The medium ofclaim 26, the instructions further causing the processor to control delivery of a therapy to the patient as a function of the response.

31. The medium ofclaim 26, further comprising instructions that cause the programmable processor to monitor the concentration of potassium ions to predict an arrhythmia.

32. A method comprising:

delivering an electrical stimulation to a tissue in a patient;

detecting a response of the tissue to the electrical stimulations; and

storing a relationship between a concentration of potassium ions in extracellular fluid of the patient and the response.

33. The method ofclaim 32, wherein the electrical stimulation is a first electrical stimulation and the response is a first response, the method further comprising:

delivering a second electrical stimulation to the tissue;

detecting a second response of the tissue to the second electrical stimulation; and

determining a concentration of potassium ions in the extracellular fluid of the patient as a function of the first and second responses.

34. The method ofclaim 33, wherein determining the concentration of potassium ions in the extracellular fluid of the patient comprises determining a change in concentration of potassium ions in the extracellular fluid over time.

35. A computer-readable medium comprising instructions that cause a programmable processor to:

control a pulse generator to deliver an electrical stimulation to a tissue in a patient;

receive from a sensor a signal indicative of a response of the tissue to the electrical stimulations; and

store a relationship between a concentration of potassium ions in extracellular fluid of the patient and the response.

36. The medium ofclaim 35, wherein the instructions further cause the processor to:

receive data concerning a measured concentration of potassium ions in the extracellular fluid; and

correlate the measured concentration with the response.

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