WO2009054758A1

WO2009054758A1 - Methods and systems for drug titration

Info

Publication number: WO2009054758A1
Application number: PCT/SE2007/000947
Authority: WO
Inventors: Andreas Blomqvist; Nils HOLMSTRÖM
Original assignee: St. Jude Medical Ab
Priority date: 2007-10-26
Filing date: 2007-10-26
Publication date: 2009-04-30

Abstract

The present invention generally relates to medical systems including an implantable medical device and an external programmer device and, in particular, to a medical system including an implantable medical device and an external programmer device, an implantable medical device, a programmer device and methods for drug titration or verification of drug dosage administration. The system comprises an extracorporeal device and an implantable medical device. The implantable medical device including an impedance measuring circuit connectable to at least one medical lead being adapted to apply excitation current pulses between at least a first electrode and at least a second electrode during consecutive heart beats and to measure the resulting impedance. Moreover, the system comprises a determining unit adapted to obtain impedance signals, and determine at least one hemodynamic parameter reflecting the hemodynamic of the heart; and an evaluation unit adapted to evaluate the hemodynamic parameters and to identify changes in the hemodynamic, wherein a verification that a proper dose of a medication has been taken by the patient can be obtained.

Description

Methods and systems for drug titration

Technical Field

The present invention generally relates to medical systems including an implantable medical device and an external programmer device and, in particular, to a medical system including an implantable medical device and an external programmer device, an implantable medical device, a programmer device and methods for drug titration or verification of drug dosage administration.

Background of the invention Many different heart conditions are treated with drugs that inhibit the effects of the sympathetic nervous system, for example, Beta blockers, with a negative inotropic effect. These kinds of drugs are for instance given to patients with hypertension, irregular heart rhythms or congestive heart failure. These kind of drugs have been found to be generally effective when prescribed with the appropriate dosage, but there are however unpleasant side effects and it can be unpleasant for the patient or even hazardous or dangerous for the patient if a too large dose is taken. Such side effects inlcude diarrhea, bronchospams, dyspnea, cold extremities, exacerbation, decreased concentration, hallucinatios, insomnia, nightmares, depression, and/or alteratio of glucose and lipid metabilism. Thus, more or less severe or unpleasant side effects are associated with an over administration of such drugs. Therefore, a fear of over administrating the drug may arise, which, instead, can entail that a too low dose of the drug is taken, diminishing the effects of the treatment. It is often difficult for the physician to ensure that the appropriate dosage actually is administrated to or taken by the patient. Some patients fail to take the prescribed dosage, either intentionally (because they want to avoid perceived side effects of the drug) or unintentionally (because they simply forget to take the drug or run out of the drug). Furthermore, even if the prescribed dosage of the drug is properly taken, the patient may become immune to effects of the drug with time. In other cases, the efficiency of the drug may be affected by conflicts with other drugs. Accordingly, it may be necessary for the patient to frequently visit the physician so that the physician can evaluate the efficiency of the drug and, if necessary, change the dosage or prescribe a new of different drugs. Moreover, even with frequent office visits, dosage is applied at all times between office visits. Thus, the patient may not be receiving optimal drug therapy at all times.

US 2004/0267321 discloses an implantable cardiac stimulation device, such as a pacemaker or implantable cardioverter defibrillator, configured to automatically monitor the effects of antiarrhythmic drugs on cardiac electrical signals within a patient to verify the efficiency of the drugs taken. The device monitors IEGM signals, for example, shape, duration, relative spacing between P-waves, R-waves, etc. The measured cardiac electrical signals, i.e. obtained parameters of the IEGM signals, are compared with values representative of the effects of different classes of antiarrhythmic drugs.

However, there is still a need within the art for an improved device that is capable of capturing an early response of the cardiac function to a drug to obtain a swift verification of the dosage of the drug taken by the patient.

There is a further a need within the art of an improved device that is capable of capturing an accurate and reliable response of the cardiac function to a drug to obtain a accurate and reliable verification that an appropriate dosage of the drug has taken by the patient.

Background of the invention Thus, an object of the present invention is to provide an improved medical system, implantable medical device, external programmer device, and method that are capable of obtaining an early response of the cardiac function of a patient to a drug taken by the patient to deliver a swift verification that a proper dosage of the drug has been taken. Another object of the present invention is to provide an improved medical system, implantable medical device, external programmer device, and method that are capable of obtaining an accurate and reliable response of the cardiac function to a drug taken by the patient to obtain an accurate and reliable verification that an appropriate dosage of the drug has been taken by the patient or has been administred to the patient.

Another object of the present invention is to provide an improved medical system, implantable medical device, external programmer device, and method that are capable of obtaining an early and accurate response of the cardiac function to a drug taken by the patient and to obtain a swift and accurate verification that a prescribed dosage of the drug has been taken by the patient or has been administred to the patient. Yet another object of the present invention is to provide an improved medical system, implantable medical device, external programmer device, and method that reduce the risk for over-administration of drugs that inhibit the effects of the sympathetic nervous system including beta blockers, Amiodarone (a class III anti- arrhytmic drug that increases QT-duration and reduces contractility and heart rate), Sotalol (a combined beat-blocker and class III anti-arrhytmic drug), or Verapamil (a calcium-blocking drug that increases AV-delay and reduces contractility. It is often used in patients with hypertension and/or need for heart-rate reduction).

These and other objects of the present invention are achieved by means of medical system, implantable medical device, external programmer device, and method having the features defined in the independent claims. Preferable embodiments are characterized by the dependent claims.

According to one aspect of the present invention, there is provided a system comprising an extracorporeal device and an implantable medical device each including a communication unit. The implantable medical device is connectable to at least one medical lead including at least one electrode located within or at a heart of a patient, which implantable medical device includes an impedance measuring circuit connectable to the at least one medical lead being adapted to apply excitation current pulses between at least a first electrode and at least a second electrode during consecutive heart beats and to measure the resulting impedance in the tissue of the heart between the electrode to the excitation current pulses during the consecutive heart beats. The system further comprises a determining unit adapted to obtain impedance signals reflecting the measured impedance for consecutive heart beats, and determine at least one hemodynamic parameter reflecting the hemodynamic of the heart using the measured impedances; and an evaluation unit adapted to evaluate the hemodynamic parameters and to identify changes in the hemodynamics of the heart using the evaluation, wherein a verification that a proper dose of a medication has been taken by the patient can be obtained.

According to a second aspect of the present invention, there is provided an implantable medical device. The implantable medical device is connectable to at least one medical lead including at least one electrode located within or at a heart of a patient and includes a communication unit and an impedance measuring circuit connectable to the at least one medical lead being adapted to apply excitation current pulses between at least a first electrode and at least a second electrode during consecutive heart beats and to measure the resulting impedance in the tissue of the heart between the electrode to the excitation current pulses during the consecutive heart beats. The implantable medical device further comprises a determining unit adapted to obtain impedance signals reflecting the measured impedance for consecutive heart beats, and determine at least one hemodynamic parameter reflecting the hemodynamics of the heart using the measured impedances, and wherein the hemodynamic parameters are used to identify changes in the hemodynamic of the heart, wherein a verification that a proper dose of a medication has been taken by the patient can be obtained.

According to a further aspect of the present invention, there is provided a method for obtaining a verification that a proper dose of a medication has been taken by a patient. The methods includes the steps of applying excitation current pulses between at least a first electrode and at least a second electrode during consecutive heart beats, measuring the resulting impedance in the tissue of the heart between the electrodes to the excitation current pulses during the consecutive heart beats, obtaining impedance signals reflecting the measured impedance for consecutive heart beats, determining at least one hemodynamic parameter reflecting the hemodynamics of the heart using the measured impedances, and evaluating the hemodynamic parameters to identify changes in the hemodynamic of the heart using the evaluation, wherein the verification that a proper dose of a medication has been taken by the patient can be obtained. According to yet another aspect of the present invention, there is provided an extracorporeal device for use in a system according to the first aspect of the present invention.

The invention is based on the insight that hemodynamic parameters based on measured cardiogenic impedance provides a good and sensitive measure of the hemodynamics of a heart of a patient and of changes in the hemodynamics of the heart. Used in drug titration this entails that an early and accurate verification that a patient has taken a proper or appropriate dose of a drug can be achieved.

The present invention provides a number of advatages. For example, the risk for over-administration can be reduced or minimized, which, in turn, reduces or minimizes the risk for unpleasant side effects that can be unpleasant for the patient or even hazardous or dangerous for the patient if a too large dose is taken. Such side effects inlcude diarrhea, bronchospams, dyspnea, cold extremities, exacerbation, decreased concentration, hallucinatios, insomnia, nightmares, depression, and/or alteratio of glucose and lipid metabilism. Furthermore, the risk that a too low dose of the drug is taken diminishing the effects of the treatment can also be reduced or minimized. Furthermore, the present invention entails that the physician can be informed of whether the appropriate dosage actually is administrated to or taken by the patient. Some patients fail to take the prescribed dosage, either intentionally (because they want to avoid perceived side effects of the drug) or unintentionally (because they simply forget to take the drug or run out of the drug).

A further advantage of the present invention is that a drug dosage or medication can be adjusted to cope with changes over time. For example, even if the prescribed dosage of the drug is properly taken, the patient may become less sensitive to effects of the drug with time. In other cases, the efficiency of the drug may be affected by conflicts with other drugs. Due to the fact that the effects of the drug delivery is evaluated continuously or at regular intervals, i.e. the hemodynamic parameter is evaluated continuously or at regular intervals, the patient can be provided an optimal drug therapy at all times. Another advantage of the present invention is therefore that the frequency of office or clinic visits of a patient can be reduced or minimized.

According to an embodiment of the present invention, the evaluation unit is adapted to determine a trend over time of the at least one hemodynamic parameter to identify the change in the hemodynamic of the heart using the trend, wherein the verification that a proper dose of a medication has been taken by the patient can be obtained.

In a further embodiment, the evaluation unit is adapted to compare the at least one determined hemodynamic parameter with hemodynamic reference data to identify whether a change corresponding to a predetermined change has been achieved, wherein the predetermined change reflects a desired effect on the hemodynamics of the heart associated with the proper dose of the medication, and to verify that a proper dose of a medication has been taken by the patient if a change corresponding to the predetermined change is identified. This reference data may have been obtained during a calibration process at a clinic, i.e. a drug with a prescribed dose is administered to the patient and the resulting change is observed, for example, at the extracorporeal device by a physician and stored as reference data.

According to yet another embodiment, the desired effect of the medication is determined to have been achieved when the at least one determined hemodynamic parameter has decreased at least to a level corresponding to a predetermined level during a predetermined time.

In embodiments of the present invention, the at least one hemodynamic parameter is the contractility and a desired effect is determined to have been achieved when the contractility has decreased below a predetermined level. In another embodiment of the present invention, the at least one hemodynamic parameter includes a first impedance parameter P corresponding to the contractility (e.g. dφldt ) and a second impedance parameter Q corresponding to the stroke volume. A desired effect of a treatment with a beta-blocker may be that the mean value of P is reduced with about 30 % of an initial value, the mean value of Q remains above 80 % of an initial value and the left atrial pressure is above a predetermined level. In embodiments of the present invention, the extracorporeal device further comprises a display means adapted to display a trend of the hemodynamic parameter over time. The display means may be a monitor, a display (e.g. a LCD) or a screen. Thereby, a user can be visually informed of or is capable of monitor or study changes of the at least one hemodynamic parameter over time. In embodiments of the present invention, the effects of a drug taken by a patient are monitored or studied by a physician to determine whether an appropriate or proper dose of a medication has been taken or whether a desired effect of a prescribed dose has been achieved. This can, for example, be done at a clinic or when the patient is at home in which case the information related to the changes of the impedance and/or the hemodynamic parameter is transferred via a communication network to the clinic.

Furthermore, the extracorporeal device may comprise an alarm device adapted to deliver an alarm signal when the determined at least one hemodynamic parameter shows a deviation from predetermined levels including upper and/or lower limits. For example, the implantable medical device may comprise a monitoring unit adapted to monitor the at least one determined hemodynamic parameter, and send an alert signal when the at least one determined hemodynamic parameter has decreased below a predetermined lower level and/or increased at least to a predetermined upper level, wherein the signal is transferred to the extracorporeal device via the communications units. Thereby, a patient and/or a physician can be informed whether an appropriate or the proper dose of a prescribed drug has been taken, whether a desired effect of the dose has been achieved, or whether any changes over time has occurred, for example, the patient may have become less sensitive to effects of the drug with time or the efficiency of the drug may be affected by conflicts with other drugs. According to another embodiment, the implantable medical device further comprises an alarm device adapted to deliver an alarm signal upon receiving the alert signal from the monitoring unit, the alarm signal indicating for the patient that the at least one determined hemodynamic parameter has fallen below predetermined lower level and/or increased at least to the predetermined upper level. The alarm device may be a vibration unit adapted to vibrate upon receiving the alert signal from the monitoring unit.

According to embodiments, the at least one hemodynamic parameter comprises a contractility measure, and/or an impedance morphology in diastole or systole during a heart cycle and/or, a maximum impedance amplitude during a heart cycle.

In one embodiment of the present invention, the evaluation unit is adapted to identify the end of an isovolumetric contraction phase of the cycle of each heart beat using the measured impedances and to calculate a systolic slope substantially immediately after the identified end of the isovolumetric contraction phase, or wherein the determining unit is adapted to determine an ejection time of each heart beat using the measured impedances and to calculate a systolic slope based on the ejection time.

According to embodiments of the present invention, the implantable medical device further comprises a posture sensor adapted to sense a posture of the patient, and/or an activity sensor adapted to sense an activity of the patient, and/or a blood temperature sensor adapted to sense a temperature of blood of the patient, and/or wherein the at least one medical lead comprises a pressure sensor adapted to sense a left atrium pressure (which increases both in diastolic and systolic heart failure), a right atrium pressure (which increases both in diastolic and systolic heart failure), or a left ventricular tension. Left atrium pressure is closely related to pulmonary capillary pressure and development of pulmonary oedema. The evaluation circuit is adapted to obtain at least one sensor signal including patient posture signals indicating a posture of the patient, and/or activity level signals indicating an activity level of the patient, and/or blood temperature signals indicating a blood temperature of the patient, and/or pressure signals, and utilize the at least one sensor signal in the evaluation together with the impedance signals. Thereby, it is possible to obtain a more accurate and reliable verification that an appropriate dosage of the drug has been taken by the patient or has been administred to the patient. As the skilled person realizes, steps of the methods according to the present invention, as well as preferred embodiments thereof, are suitable to realize as computer program or as a computer readable medium.

Further objects and advantages of the present invention will be discussed below by means of exemplifying embodiments.

Brief description of the drawings

Exemplifying embodiments of the invention will be described below with reference to the accompanying drawings, in which: Fig. 1 is a simplified partly cutaway view illustrating an implantable stimulator including an electrode configuration according to the present invention,

Fig. 2 is an illustration in a block diagram form of a system according to one embodiment of the present invention including an implantable stimulator according to the embodiment shown in Fig. 1 , Fig. 3 is an illustration in a block diagram form of a system according to another embodiment of the present invention including an implantable stimulator according to the embodiment shown in Fig. 1 ,

Fig. 4 is a flow chart describing the principles of the present invention according to an embodiment, and Fig. 5 is a flow chart describing an embodiment of the method according to the present invention.

Description of exemplifying embodiments

The following is a description of exemplifying embodiments in accordance with the present invention. This description is not to be taken in limiting sense, but is made merely for the purposes of describing the general principles of the invention. Thus, even though particular types of implantable medical devices such as heart stimulators will be described, e.g. biventricular pacemakers, the invention is also applicable to other types of cardiac stimulators such as dual chamber stimulators, implantable cardioverter defibrillators (ICDs), etc.

In the following a number of different electrode configurations suitable for obtaining impedances reflecting the mechanical functioning of the heart will be discussed.

With reference first to Fig. 1 , there is shown a implantable medical device according to an embodiment of the present invention. A stimulation device 10 is in electrical communication with a patient's heart 1 by way of two leads 20 and 30 suitable for delivering multi-chamber stimulation, which leads 20 and 30 are connectable to the stimulator 10. The illustrated portions of the heart 1 include right atrium RA, the right ventricle RV, the left atrium LA, the left ventricle LV, cardiac walls 2, the ventricle septum 4, the valve plane 6, and the apex 8. In order to sense right ventricular and atrial cardiac signals and impedances and to provide stimulation therapy to the right ventricle RV, the stimulation device 10 is coupled to an implantable right ventricular lead 20 having a ventricular tip electrode 22, a ventricular annular or ring electrode 24, and a first valve plane electrode 26. The ring electrode 24 is arranged for sensing electrical activity, intrinsic or evoked, in the right ventricle RV. The right ventricular tip electrode 22 is arranged to be implanted in the endocardium of the right ventricle, e.g. near the apex 8 of the heart. Thereby, the tip electrode 22 becomes attached to cardiac wall. In this example, the tip electrode 22 is fixedly mounted in a distal header portion of the lead 20. Furthermore, the first valve plane electrode 26, which may a annular or ring electrode, is located substantially at the level of the valve plane 6.

In order to sense left atrium and ventricular cardiac signals and impedances and to provide pacing therapy for the left ventricle LV, the stimulation device 10 is coupled to a "coronary sinus" lead 30 designed for placement via the coronary sinus in veins located distally thereof, so as to place a distal electrode adjacent to the left ventricle and an electrode adjacent to the right atrium RA. The coronary sinus lead 30 is designed to received ventricular cardiac signals from the cardiac stimulator 10 and to deliver left ventricular LV pacing therapy using at least a left ventricular tip electrode 32 to the heart 1. In the illustrated example, the LV lead 30 comprises an annular ring electrode 34 for sensing electrical activity related to the left ventricle LV of the heart. Moreover, a second valve plane electrode 36, which may a annular or ring electrode, is located substantially at the level of the valve plane 6 and measurement electrode 35, which may a annular or ring electrode, is located adjacent to the right atrium RA.

With reference to the configuration shown in Fig. 1 , a number of impedances vectors that can be used for impedance measurements will be described. For example, a quadropolar impedance measurement vector wherein the current is applied between the electrode 25 and the tip electrode 22 and the resulting impedance is measured between the electrode 26 and the ring electrode 24. A further alternative, is a quadropolar impedance measurement vector where the current is applied between the tip electrodes 22 and 32 of the right ventricle and left ventricle, respectively. The resulting impedance is measured between the ring electrodes 24 and 34 of the right ventricle and left ventricle, respectively. Yet another alternative, is an impedance measurement vector where the current is applied between the ring electrode 24 of the right ventricle and the tip electrode 22 of the right ventricle. The resulting impedance is measured between the same electrodes. As the skilled person realizes, there are a number of other conceivable measurement vectors that can be used to measure the impedance, for example, if a further medical lead is implanted in the right atrium, the current may be applied between a tip electrode of the right atrium lead and the tip electrode of the right ventricle lead and the resulting impedance can be measured between a ring electrode of the right atrium electrode and the ring electrode of the right ventricle electrode.

Turning now to Fig. 2, a medical system according to an embodiment of the present invention including a heart stimulator according to a first embodiment, which may be connected to medical leads as shown in Fig. 1 , is shown in a block diagram form. For illustrative purposes, reference is made to Fig. 1 for the elements of the leads that are intended for positioning in or at the heart. The medical system 110 comprises an implantable medical device 100, for example a heart stimulator of the type shown in Fig. 1 and an external or extracorporeal device 144.

The heart stimulator 100 is connected to a heart 1 order to sense heart signals and emit stimulation pulses to the heart 1. Electrodes located within and at the heart, for example, any one of the elctrode configurations illustrated in Figs. 1 and outside the heart, for example, an indifferent electrode 12 (which, in this instance, consists of the enclosure of the heart stimulator 100 but can also consist of a separate electrode located somewhere in the body) are connected to a pulse generator 126 in the heart stimulator 100. The electrodes located within and/or at the heart are connected to the stimulator 100 via leads, for example, the leads 20 and 30 shown in Fig. 1. A detector 128 is also connected to the electrodes in order to sense activity of the heart.

The pulse generator 126 and the detector 128 are controlled by a control unit 140 which regulates the stimulation pulses with respect to amplitude, duration and stimulation interval, the sensitivity of the detector 128 etc.

Furthermore, the heart stimulator 100 comprises an impedance measuring circuit 146 adapted to, during impedance measuring sessions, measure impedance signals between at least a first pair of electrodes. Further, the impedance measuring circuit 146 is adapted to, during the impedance measuring sessions, measure impedance signals between at least a second pair of electrodes. In connection to Fig. 1 , a number of different electrode configurations by which impedance signals reflecting the hemodynamics of the heart can be obtained are discussed. The impedance measuring circuit 146 comprises a current generating circuit 147 adapted to apply excitation current pulses between the respective electrode pairs and a voltage measuring circuit 148 adapted to measure the resulting voltage over the respective electrode pairs and to determine resulting impedance signals. Further, a memory circuit 154 is connected to the impedance measuring circuit 146 and the control unit 140, which memory circuit 154 may include a random access memory (RAM) and/or a non-volatile memory such as a read-only memory (ROM).

The heart stimulator 100 can, via a communication unit, for example, a telemetry unit 142, communicate with external devices 144, for example, an extracorporeal programmer, a home monitoring device, a patient worn device. A user of the external device 144, for example a physician is thereby capable to obtain information on identified conditions and also reprogram the different functions of the heart stimulator 100. Furthermore, the heart stimulator 100 is adapted to communicate, via the telemetry unit 142, with external devices 144, for example, an extracorporeal programmer, a home monitoring device, a patient worn device via a communication network, for example, a wireless communication network including at least one external radio communication network such as wireless LAN ("Local Area Network"), GSM ("Global System for Mobile communications"), or UMTS ("Universal Mobile Telecommunications System"). For a given communication method, a multitude of standard and/or proprietary communication protocols may be used. For example, and without limitation, wireless (e.g. radio frequency pulse coding, spread spectrum frequency hopping, time-hopping, etc.) and other communication protocols (e.g. SMTP, FTP, TCP/IP) may be used. Other proprietary methods and protocols may also be used. The notification may include at least the patient identity, the occurrence of a myocardial infarction and/or the location of the detected infarct within the heart. The communication unit may be adapted to communicate with the user equipment, e.g. mobile phone, a pager or a PDA ("Personal Digital Assistant"), which is adapted to receive the notification via, for example, Bluetooth and to transmit it via the communication network further on to the medical care institution. Alternatively, the communication unit may be adapted to communicate with a home monitoring unit located in the home of the patient via, for example, Bluetooth. The home monitoring unit may be adapted to communicate with the care institution via a telephone link, or via the communication network as described above. The external device 144 comprises a communication unit, for example, a telemetry unit 156, adapted to communicate with the implantable medical device 100. Moreover, the external device 144 comprises a determining unit or impedance signal processor 158 adapted to obtain impedance signals reflecting the measured impedance for consecutive heart beats. These signals can, for example, be transferred at regular intervals from the implantable medical device 100 or upon an inquiry signal received by the implantable medical device 100 sent from the external device 144 requesting the implantable medical device 100 to transfer impedance signals measured during a predetermined period of time. The determining unit 158 is adapted to determine at least one hemodynamic parameter reflecting the hemodynamics of the heart 1 using the measured impedances. For example, a contractility index or contractility measure, and/or an impedance morphology in diastole or systole during a heart cycle and/or, a maximum impedance amplitude during a heart cycle. In one embodiment, the contractility index is determined by calculating the systolic slope immediately after the isovolumetric contraction phase, i.e. during the early fast ejection. Furthermore, the external device 144 comprises an evaluation unit 160 adapted to evaluate the hemodynamic parameter and to identify changes in the hemodynamic of the heart 1 using the evaluation. According to one embodiment of the present invention, the identified changes are used to obtain a verification that a proper dose of a medication has been taken by a patient. In one embodiment, the external device 144 further comprises display means

162 adapted to display results from the evaluation unit 160, for example, a trend of the hemodynamic parameter over time. The display means 162 may be a monitor, a display (e.g. a LCD) or a screen. Thereby, a user can be visually informed of or is capable of monitor or study changes of the at least one hemodynamic parameter over time. In embodiments of the present invention, the effects of a drug taken by a patient are monitored or studied by a physician to determine whether an appropriate or proper dose of a medication has been taken or whether a desired effect of a prescribed dose has been achieved. This can, for example, be done at a clinic or when the patient is at home in which case the information related to the changes of the impedance and/or the hemodynamic parameter is transferred via a communication network to the clinic.

With reference to Fig. 3, another embodiment of the medical system according to the present invention will be discussed. The description of the function and design of units, parts, components etc. being like or similar to units, parts, components etc. describe above with reference to Fig. 1 or 2 will be omitted in the following. For illustrative purposes, reference is made to Fig. 1 for the elements of the leads that are intended for positioning in or at the heart. The medical system 210 comprises an implantable medical device 200, for example a heart stimulator of the type shown in Fig. 1 and an external or extracorporeal device 244.

The heart stimulator 200 is connected to a heart 1 order to sense heart signals and emit stimulation pulses to the heart 1. Electrodes located within and at the heart, for example, any one of the elctrode configurations illustrated in Figs. 1 and outside the heart, for example, an indifferent electrode 12 (which, in this instance, consists of the enclosure of the heart stimulator 200 but can also consist of a separate electrode located somewhere in the body) are connected to a pulse generator 126 in the heart stimulator 200. The electrodes located within and/or at the heart are connected to the stimulator 200 via leads, for example, the leads 20 and 30 shown in Fig. 1. A detector 128 is also connected to the electrodes in order to sense activity of the heart.

Furthermore, the heart stimulator 200 comprises an impedance measuring circuit 146 adapted to, during impedance measuring sessions, measure impedance signals between at least a first pair of electrodes. Further, the impedance measuring circuit 146 is adapted to, during the impedance measuring sessions, measure impedance signals between at least a second pair of electrodes. In connection to Fig. 1 , a number of different electrode configurations by which impedance signals reflecting the hemodynamics of the heart can be obtained are discussed. The impedance measuring circuit 146 comprises a current generating circuit 147 adapted to apply excitation current pulses between the respective electrode pairs and a voltage measuring circuit 148 adapted to measure the resulting voltage over the respective electrode pairs and determined resulting impedance signals. Further, a memory circuit 154 is connected to the impedance measuring circuit 146 and the control unit 140, which memory circuit 154 may include a random access memory (RAM) and/or a non-volatile memory such as a read-only memory (ROM).

The heart stimulator 200 can, via a communication unit, for example, a telemetry unit 142, communicate with external devices 244, for example, an extracorporeal programmer, a home monitoring device, a patient worn device. A user of the external device 244, for example a physician is thereby capable to obtain information on identified conditions and also reprogram the different functions of the heart stimulator 200. Furthermore, the heart stimulator 200 is adapted, as described above, to communicate, via the telemetry unit 142, with external devices 244, for example, an extracorporeal programmer, a home monitoring device, a patient worn device via a communication network, for example, a wireless communication network, as described above. Furthermore, the heart stimulator 200 comprises a determining unit or impedance signal processor 258 adapted to obtain impedance signals reflecting the measured impedance for consecutive heart beats. The determining unit 258 is adapted to determine at least one hemodynamic parameter reflecting the hemodynamics of the heart 1 using the measured impedances. For example, a contractility index or contractility measure, and/or an impedance morphology in diastole or systole during a heart cycle and/or, a maximum impedance amplitude during a heart cycle. In one embodiment, the contractility index is determined by calculating the systolic slope immediately after the isovolumetric contraction phase, i.e. during the early fast ejection. The hemodynamic parameter or parameters can, for example, be transferred at regular intervals from the implantable medical device 200 or upon an inquiry signal received by the implantable medical device 200 sent from the external device 244 requesting the implantable medical device 200 to transfer impedance signals measured during a predetermined period of time. The external device 244 comprises a communication unit, for example, a telemetry unit 256, adapted to communicate with the implantable medical device 200. Furthermore, the external device 244 comprises an evaluation unit 260 adapted to evaluate the hemodynamic parameter and to identify changes in the hemodynamic of the heart 1 using the evaluation. According to one embodiment of the present invention, the identified changes are used to obtain a verification that a proper dose of a medication has been taken by a patient.

In one embodiment, the external device 244 further comprises display means 262 adapted to display results from the evaluation unit 260, for example, a trend of the hemodynamic parameter over time. The display means 262 may be a monitor, a display (e.g. a LCD) or a screen. Thereby, a user can be visually informed of or is capable of monitor or study changes of the at least one hemodynamic parameter over time. In embodiments of the present invention, the effects of a drug taken by a patient are monitored or studied by a physician to determine whether an appropriate or proper dose of a medication has been taken or whether a desired effect of a prescribed dose has been achieved. This can, for example, be done at a clinic or when the patient is at home in which case the information related to the changes of the impedance and/or the hemodynamic parameter is transferred via a communication network to the clinic.

In yet another embodiment of the medical system according to the present invention, the evaluation unit is arranged in the implantable medical device. Hence, in this embodiment, the determined or calculated at least one hemodynamic parameter is transferred to the external or extracorporeal device for further use, for example, for display at the display unit.

Turning now to Fig. 4, the principles of the method for obtaining a verification that a proper dose of a medication has been taken by a patient according to present invention will be discussed. First, at step S300, the impedance measuring circuit 146 measures, during impedance measuring sessions, impedances between at least a first pair of electrodes of the at least one medical lead, including applying excitation current pulses between at least a first electrode and at least a second electrode during consecutive heart beats, and measuring the resulting impedance in the tissue of the heart between the electrode to the excitation current pulses during consecutive heart beats. The impedance measurement can be initiated upon receiving a request for an initiation of impedance measuring session by the control unit 140 or by the external device 144, 244. For example, a physician may initiate a measurement session at the clinic by means of the external programmer to verify that a patient is provided or prescribed with the proper or appropriate dose of a drug. Hence a drug according to the prescribed dose may be administered to the patient and the effect from the drug can be monitored on a display unit of the programmer as will be described hereinafter. Alternatively, the impedance measuring circuit 146 may be adapted to automatically initiate the impedance measuring sessions at regular intervals or the measurements can be performed on a continuous basis. This step, i.e. the impedance measurement, may be preceded by a check of the measuring conditions, for example, which posture the patient is in, the activity level, the blood temperature, the intra-cardiac pressure in left atrium (which increases both in diastolic and systolic heart failure), right atrium (which increases both in diastolic and systolic heart failure), or a left ventricular tension. The impedance measurement may also be synchronized with a measurement of any one, some or all of the posture the patient is in, the activity level, the blood temperature, the intra-cardiac pressure in left atrium (which increases both in diastolic and systolic heart failure), right atrium (which increases both in diastolic and systolic heart failure), or a left ventricular tension. Then, at step S310, impedance signals reflecting the measured impedance for consecutive heart beats are obtained by the determining unit 158, 258. This can be done continuously, at regular intervals, or upon request. Thereafter, at step S320, at least one hemodynamic parameter reflecting the hemodynamics of the heart is determined using the measured impedances, for example, a contractility index or contractility measure, and/or an impedance morphology in diastole or systole during a heart cycle and/or, a maximum impedance amplitude during a heart cycle. In one embodiment, the contractility index is determined by calculating the systolic slope immediately after the isovolumetric contraction phase, i.e. during the early fast ejection. Subsequently, at step S330, the hemodynamic parameters are evaluated in the evaluation unit 160 to identify changes in the hemodynamics of the heart, wherein the verification that a proper dose of a medication has been taken by the patient can be obtained.

This verification can be obtained by comparing the at least one determined hemodynamic parameter with hemodynamic reference data to identify whether a change corresponding to a predetermined change has been achieved, wherein the predetermined change reflects a desired effect on the hemodynamics of the heart associated with the proper dose of the medication. A verification that a proper dose of a medication has been taken by the patient can be delivered if a change corresponding to the predetermined change can be identified. The predetermined change reflecting the desired effect may be determined to have been achieved when the at least one determined hemodynamic parameter has decreased at least to a level corresponding to a predetermined level during a predetermined time.

Optionally, a calibration step may precede the impedance measurement step 300. This calibration step is, preferably, performed at a clinic wherein a patient takes a prescribed dosage of a drug and the effect of the drug is monitored in real-time by a physician, for example, on the display unit of the external device 144, 244. Alternatively, the drug may be administered to the patient until the desired effect has been achieved and thus the appropriate or proper dose can be determined without over administration. The results of this calibration process may be stored as reference data and may hence be used for drug titration or monitoring of drug administration in the implantable medical device.

With reference to Fig. 5, an embodiment of the method for obtaining a verification that a proper dose of a medication has been taken by a patient according to present invention will be discussed. First, at step S400, the impedance measuring circuit 146 measures, during impedance measuring sessions, impedances between at least a first pair of electrodes of the at least one medical lead, including applying excitation current pulses between at least a first electrode and at least a second electrode during consecutive heart beats, and measuring the resulting impedance in the tissue of the heart between the electrode to the excitation current pulses during consecutive heart beats. The impedance measurement are performed on a continuous basis, or upon receiving an initiation request from the patient and/or the physician. The measurements may also be automatically initiated synchronized with a point of time when the patient takes his or her medication. This step, i.e. the impedance measurement, may be preceded by a check of the measuring conditions, for example, which posture the patient is in, the activity level, the blood temperature, the intra-cardiac pressure in left atrium (which increases both in diastolic and systolic heart failure), right atrium (which increases both in diastolic and systolic heart failure), or a left ventricular tension. The impedance measurement may also be synchronized with a measurement of any one, some or all of the posture the patient is in, the activity level, the blood temperature, the intra-cardiac pressure in left atrium (which increases both in diastolic and systolic heart failure), right atrium (which increases both in diastolic and systolic heart failure), or a left ventricular tension.

Then, at step S410, impedance signals reflecting the measured impedance for consecutive heart beats are continuously obtained by the determining unit 158, 258. Thereafter, at step S420, at least one hemodynamic parameter reflecting the hemodynamics of the heart is determined using the measured impedances, for example, a contractility index or contractility measure, and/or an impedance morphology in diastole or systole during a heart cycle and/or, a maximum impedance amplitude during a heart cycle. In one embodiment, the contractility index is determined by calculating the systolic slope immediately after the isovolumetric contraction phase, i.e. during the early fast ejection. Subsequently, at step S430, the hemodynamic parameters are evaluated in the evaluation unit 160 to identify changes in the hemodynamics of the heart.

Then, at step S440, a check whether the desired effect resulting from the administrating of a dose of a drug or whether the appropriate dose of the drug has been taken by the patient is performed. This check can be done by comparing the at least one determined hemodynamic parameter with hemodynamic reference data to identify whether a change corresponding to a predetermined change has been achieved, wherein the predetermined change reflects a desired effect on the hemodynamics of the heart associated with the proper dose of the medication. If yes, a verification that a proper dose of a medication has been taken by the patient can be delivered at step S450, e.g. if a change corresponding to the predetermined change can be identified. The predetermined change reflecting the desired effect may be determined to have been achieved when the at least one determined hemodynamic parameter has decreased at least to a level corresponding to a predetermined level during a predetermined time. On the other hand, if no, an alert signal can, at step S460, be delivered to an alarm device of the implantable medical device and/or transferred to an alarm device of the extracorporeal device signal when the determined at least one hemodynamic parameter shows a deviation from predetermined levels including upper and/or lower limits. Thereby, a patient and/or a physician can be informed whether an appropriate or the proper dose of a prescribed drug has been taken, whether a desired effect of the dose has been achieved, or whether any changes over time has occurred, for example, the patient may have become immune to effects of the drug with time or the efficiency of the drug may be affected by conflicts with other drugs. Although an exemplary embodiment of the present invention has been shown and described, it will be apparent to those having ordinary skill in the art that a number of changes, modifications, or alterations to the inventions as described herein may be made. Thus, it is to be understood that the above description of the invention and the accompanying drawings is to be regarded as a non-limiting example thereof and that the scope of protection is defined by the appended patent claims.

Claims

1. A medical system (110; 210) comprising an extracorporeal device (144; 244) and an implantable medical device (10; 100; 200) each including a communication unit (142, 156), wherein said implantable medical device (10;

100; 200) is connectable to at least one medical lead (20, 30) comprising at least one electrode (22, 24, 25, 26, 32, 34, 35, 36) located within or at a heart (1) of a patient, said implantable medical device (10; 100; 200) comprising an impedance measuring circuit (146) connectable to said at least one medical lead (20, 30) being adapted to apply excitation current pulses between at least a first electrode and at least a second electrode during consecutive heart beats and to measure the resulting impedance in the tissue of the heart (1) between said electrode to the excitation current pulses during said consecutive heart beats, said system further comprising a determining unit (158; 258) adapted to obtain impedance signals reflecting the measured impedance for consecutive heart beats, and determine at least one hemodynamic parameter reflecting the hemodynamic of said heart using said measured impedances; and an evaluation unit (160) adapted to evaluate said hemodynamic parameters and to identify changes in said hemodynamic of said heart using said evaluation, wherein a verification that a proper dose of a medication has been taken by said patient can be obtained.

2. The system according to claim 1 , wherein said evaluation unit (160) is adapted to determine a trend over time of said at least one hemodynamic parameter to identify said change in said hemodynamic of said heart using said trend, wherein said verification that a proper dose of a medication has been taken by said patient can be obtained.

3. The system according to claim 1 or 2, wherein said evaluation unit (160) is adapted to compare said at least one determined hemodynamic parameter with hemodynamic reference data to identify whether a change corresponding to a predetermined change has been achieved, wherein said predetermined change reflects a desired effect on said hemodynamics of said heart associated with said proper dose of said medication, and to verify that a proper dose of a medication has been taken by said patient if a change corresponding to said predetermined change is identified.

4. The system according to claim 3, wherein said desired effect of said medication is determined to have been achieved when said at least one determined hemodynamic parameter has decreased at least to a level corresponding to a predetermined level during a predetermined time.

5. The system according to claim 1-4, wherein said extracorporeal device (144; 244) further comprises a display means (162) adapted to display a trend of said hemodynamic parameter over time.

6. The system according to claim 1-5, wherein said extracorporeal device (144; 244) comprises an alarm device adapted to deliver an alarm signal when said determined at least one hemodynamic parameter shows a deviation from predetermined levels including upper and/or lower limits.

7. The system according to claim 1-6, wherein said implantable medical device (10; 100; 200) further comprises a monitoring unit (149) adapted to monitor said at least one determined hemodynamic parameter, and send an alert signal when said at least one determined hemodynamic parameter has decreased below a predetermined lower level and/or increased at least to a predetermined upper level, wherein said signal is transferred to said extracorporeal device (144; 244) via said communication units (142, 156).

8. The system according to claim 7, wherein said implantable medical device (10; 100; 200) further comprises an alarm device adapted to deliver an alarm signal upon receiving said alert signal from said monitoring unit (149), said alarm signal indicating for said patient that said at least one determined hemodynamic parameter has fallen below predetermined lower level and/or increased at least to said predetermined upper level.

9. The system according to claim 1-8, wherein said at least one hemodynamic parameter comprises a contractility measure, and/or an impedance morphology in diastole or systole during a heart cycle and/or, a maximum impedance amplitude during a heart cycle, and/or maximum systolic or diastolic slope.

10. The system according to claim 9, wherein said evaluation unit (160) is adapted to identify the end of an isovolumetric contraction phase of the cycle of each heart beat using said measured impedances and to calculate a systolic slope substantially immediately after said identified end of said isovolumetric contraction phase, or wherein said determining unit (158; 258) is adapted to determine an ejection time of each heart beat using said measured impedances and to calculate a systolic slope based on said ejection time.

11. The system according to claim 1-10, wherein said extracorporeal device (144; 244) further comprises input means allowing a user to input hemodynamic reference data to said evaluation unit (160).

12. The system according to any one of preceding claims, wherein said implantable medical device (10; 100; 200) further comprises a posture sensor adapted to sense a posture of said patient, and/or an activity sensor adapted to sense an activity of said patient, and/or a blood temperature sensor adapted to sense a temperature of blood of said patient, and/or wherein said at least one medical lead comprises a pressure sensor adapted to sense a pressure in left atrium, a pressure in right atrium, or a left ventricular tension, wherein said evaluation circuit (160) is adapted to obtain at least one sensor signal including patient posture signals indicating a posture of said patient, and/or activity level signals indicating an activity level of said patient, and/or blood temperature signals indicating a blood temperature of said patient, and/or pressure signals, and utilize said at least one sensor signal in said evaluation together with said impedance signals.

13. An implantable medical device (10; 200) connectable to at least one medical lead (20, 30) including at least one electrode (22, 24, 25, 26, 32, 34, 35, 36) located within or at a heart (1) of a patient, including a communication unit (142) and an impedance measuring circuit (146) connectable to said at least one medical lead (20; 30) being adapted to apply excitation current pulses between at least a first electrode and at least a second electrode during consecutive heart beats and to measure the resulting impedance in the tissue of the heart (1) between said electrode to the excitation current pulses during said consecutive heart beats, said implantable medical device further comprising a determining unit (258) adapted to obtain impedance signals reflecting the measured impedance for consecutive heart beats, and determine at least one hemodynamic parameter reflecting the hemodynamic of said heart using said measured impedances , and wherein said hemodynamic parameters is used to identify changes in said hemodynamic of said heart, wherein a verification that a proper dose of a medication has been taken by said patient can be obtained.

14. The implantable medical device according to claim 13, further comprising an evaluation unit adapted to evaluate said hemodynamic parameters and to identify changes in said hemodynamics of said heart using said evaluation, wherein a verification that a proper dose of a medication has been taken by said patient can be obtained.

15. The implantable medical device according to claim 14, wherein said evaluation unit is adapted to perform steps in accordance with any one of claim 2-4, 9 or 10.

16. The implantable medical device according to claim 13-15, further comprising a monitoring unit (149) adapted to monitor said at least one determined hemodynamic parameter, and send an alert signal when said at least one determined hemodynamic parameter has decreased below a predetermined lower level and/or increased at least to a predetermined upper level, wherein said signal is transferred to said extracorporeal device via said communication units (142, 156).

17. The system according to claim 16, wherein said implantable medical device (10; 200) further comprises an alarm device adapted to deliver an alarm signal upon receiving said alert signal from said monitoring unit (149), said alarm signal indicating for said patient that said at least one determined hemodynamic parameter has fallen below predetermined lower level and/or increased at least to said predetermined upper level.

18. The implantable medical device according to any one of preceding claims 13-

17, wherein said implantable medical device (10; 200) further comprises a posture sensor adapted to sense a posture of said patient, and/or an activity sensor adapted to sense an activity of said patient, and/or a blood temperature sensor adapted to sense a temperature of blood of said patient, and/or wherein said at least one medical lead comprises a pressure sensor adapted to sense a pressure in left atrium, a pressure in right atrium, or a left ventricular tension, wherein said evaluation circuit is adapted to obtain at least one sensor signal including patient posture signals indicating a posture of said patient, and/or activity level signals indicating an activity level of said patient, and/or blood temperature signals indicating a blood temperature of said patient, and/or pressure signals, and utilize said at least one sensor signal in said evaluation together with said impedance signals.

19. The implantable medical device according to any one of preceding claims 13-

18, wherein said implantable medical device (10; 200) is adapted for use in a system according to any one of preceding claims 1-12.

20. An extracorporeal device in accordance with any one of preceding claims 1- 12.

21. A method for obtaining a verification that a proper dose of a medication has been taken by a patient including the steps of: applying (S300; S400) excitation current pulses between at least a first electrode and at least a second electrode during consecutive heart beats, measuring (S300; S400) the resulting impedance in the tissue of the heart between said electrode to the excitation current pulses during said consecutive heart beats, obtaining (S310; S410) impedance signals reflecting the measured impedance for consecutive heart beats, and determining (S320; S420) at least one hemodynamic parameter reflecting the hemodynamics of said heart using said measured impedances, and evaluating (S330; S430, S440) said hemodynamic parameters to identify changes in said hemodynamics of said heart using said evaluation, wherein said verification that a proper dose of a medication has been taken by said patient can be obtained.

22. The method according to claim 21 , further comprising the step of determining (S330; S430) a trend over time of said at least one hemodynamic parameter to identify said change in said hemodynamic of said heart using said trend, wherein said verification that a proper dose of a medication has been taken by said patient can be obtained.

23. The method according to claim 21 or 22, further comprising the steps of comparing (S440) said at least one determined hemodynamic parameter with hemodynamic reference data to identify whether a change corresponding to a predetermined change has been achieved, wherein said predetermined change reflects a desired effect on said hemodynamics of said heart associated with said proper dose of said medication, and verifying (S450) that a proper dose of a medication has been taken by said patient if a change corresponding to said predetermined change is identified.

24. The method according to claim 21-23, further comprising the steps of performing steps in the evaluation unit (160) according to claim 1-12, and/or the display means (162) according to claim 5, and/or the alarm device according to claim 6 or 8, and/or the monitoring unit (149) according to claim 7.