Electrotherapeutic apparatus

0001The invention relates to an implantable electrotherapy device, such as a pacemaker, a defibrillator or the like. The electrotherapy device has an activity sensor for detecting physical activity and generating a corresponding activity level signal. A housing of the electrotherapy device is provided with an electrode line connection for connecting at least one electrode line to be placed intracardially. The housing itself or part of the housing can serve as a neutral electrode or reference electrode. The electrode line connection is used for connection to the electrode line, which has at least one measuring electrode for receiving an intracardiac impedance or conductivity signal. An impedance or conductivity measuring unit is arranged in the housing and is designed to generate a unipolar or bipolar impedance or conductivity profile signal. For this purpose, several impedance or conductivity values ​​or a corresponding impedance or conductivity curve are measured during at least one cardiac cycle. This is done either unipolar by measuring between a neutral electrode and a measuring electrode or between two measuring electrodes. In addition, an evaluation unit is arranged in the housing, which is used to evaluate the impedance or conductivity curve and to derive a contractility value from the impedance or conductivity curve. Electrotherapy devices that can determine the contractility of a heart offer the possibility of adapting a therapy delivered by the electrotherapy device to the respective contractility state of the heart of the patient.

0002Contractility describes an inotropic state of a heart. It affects the strength and speed of a myocardial contraction. Contractility is controlled by three mechanisms:<ul id="ul0001" list-style="none"><li>direct control by the autonomic nervous system (ANS),</li><li>the so-called Starling mechanism, and</li><li>the so-called bowditch effect (force-frequency coupling).</li></ul>

0003The main mechanism, the regulation of circulatory regulation by the autonomic nervous system, increases contractility and the heart rate when there is an increased metabolic need, for example during physical or physical exertion, in order to ensure an adequate blood supply.

0004In patients with chronic heart failure (HF), myocardial contractility decreases to a low level and interventricular synchronization deteriorates. This is accompanied by a low ejection fraction (EF), as well as a low quality of life and high mortality. HF is common in the population. HF patients are treated with various drugs that affect the inotropic state, for example beta-blockers to stabilize the heart rate, but also with positive inotropic drugs, for example glycosides, to increase contractility. More recently, HF patients have been treated with resynchronization therapy devices, for example 3-chamber pacemakers or defibrillators. The aim of such pacemaker therapy is to synchronize the two ventricles of a heart by means of biventricular stimulation in order to improve the timing of the heart chambers and thus the cardiac output (Cardiac Resynchronization Therapy, CRT).

0005Contractility is therefore an important variable to be observed, especially for HF patients. Such observation is important to    observe the patient's condition and alleviation or progression of the disease,    determine and monitor cardiac resynchronization therapy (CRT), and    observing drug treatment.

0006Contractility information can also be used to optimize pacemaker therapy or implantable cardioverter / defibrillator (ICD) therapy.

0007Although contractility is of great importance, it is difficult to measure in clinical practice. It is common to measure contractility using a maximum ventricular pressure gradient dp / dt_Max to be determined in the right ventricle or in the left ventricle. A left ventricular ejection fraction can also be determined using echocardiography. Examination of the right ventricle using echocardiography is very difficult for anatomical reasons, although information about the right ventricle is very important for a complete examination. Both approaches, pressure measurement and echocardiography are time consuming and expensive. Ventricular pressure measurement requires an invasive procedure. It requires a pressure catheter in one or both ventricles and can only be performed during an electrophysiological study or the implantation of a pacemaker or cardioverter / defibrillator.

0008Implants with which the contractility of a heart can be determined are, for example, in the <patcit id="pcit0001" dnum="US4674518A"><text>U.S. Patents 4,674,518</text></patcit> and <patcit id="pcit0002" dnum="US5417717A"><text>5,417,717</text></patcit> described. The change in the ventricular volume is measured there by means of the pressure gradient dP / dt and by means of impedance plethysmography.

0009In the <patcit id="pcit0003" dnum="EP1062974A"><text>European patent application 1 062 974</text></patcit> is a pacemaker of the type mentioned above. The control method described there for an electrotherapy device and the electrotherapy device disclosed thereby are to be further developed in order to expand the area of ​​application of the electrotherapy device.

0010This object is achieved by the features specified in claim 1.

0011The evaluation unit is preferably for evaluating the impedance or conductivity profile signal generated by the impedance or conductivity measurement unit and for generating and outputting a contractility difference signal as a function of the impedance or conductivity profile signal by forming a difference between two impedance or Conductivity curve signals are formed at different time periods in such a way that a respective contractility difference value of the contractility difference signal depends on an area that includes two impedance or conductivity curve signals detected at different time periods between them. The evaluation unit is also designed to assign an activity signal value to a respective contractility difference value determined in this way, which is valid for at least one of the periods in which the impedance or conductivity profile signals were recorded, which contributed to the formation of the respective contractility difference value.

0012The area enclosed by two impedance or conductivity curve signals recorded at different time periods can be an imaginary area that would result from a graphical representation of the impedance curves.

0013This area is already in the <patcit id="pcit0004" dnum="EP1062974A"><text>EP 1 062 974</text></patcit> described, but without assigning the periods of time shown there and without the corresponding automatic assignment of activity values. This assignment allows you to assign an existing or non-existent contractility difference to an existing or non-existent activity difference.

0014Instead of measuring the impedance curve, the curve of the reciprocal of the impedance, ie the curve of the conductivity, can also be measured, see <patcit id="pcit0005" dnum="EP1062974A"><text>EP 1 062 974</text></patcit>.

0015If similar as in the <patcit id="pcit0006" dnum="EP1062974A"><text>EP 1 062 974</text></patcit> described, a conductivity or impedance profile signal for a known activity signal (for example, recorded in the patient's resting state) is stored, and this stored impedance profile signal is regularly used to form a difference with another impedance profile signal, it is generally sufficient if the stored activity signal reflects the activity during the period, to which the further impedance curve signal was recorded.

0016However, provision is made to dispense with storing a reference impedance signal curve that has been predetermined once. Instead, a reference signal curve is to be formed from the outset in dependence on simultaneously recorded activity level signal values. This is preferably done by using only those impedance or conductivity signal curves for the formation of an averaged reference signal curve that are associated with activity level values ​​below a predetermined limit activity level value. The impedance or conductivity signal curves used in this way to form a reference signal curve are in any case first normalized with the respectively assigned activity level value before the impedance or conductivity signal curves standardized in this way are then averaged to form the reference signal curve. In addition to normalizing a contractility signal (calculated from the impedance curve) itself with the activity, the contractility difference signal (difference area between the current and reference impedance curve) can also be normalized with the activity level signal value difference. This generates a contractility difference signal standardized to the activity difference, which is a measure of the ability of the heart to increase contractility (measured as a result of the impedance curve) as the load increases (measured as physical activity).

0017The periods over which the impedance curve signals are to be recorded in each case preferably have the duration of at least a defined part of a cardiac cycle or an entire cardiac cycle or an integer number of a few cardiac cycles, that is to say not only 100 cardiac cycles but, for example, only 8 or 16 cardiac cycles.

0018The electrotherapy device is furthermore preferably designed to form a respective impedance profile signal by a unipolar impedance measurement, in which the measurement takes place between a neutral electrode arranged on the housing of the electrotherapy device and a measuring electrode in the heart.

0019The impedance or conductivity measuring unit preferably has an input amplifier with an automatic input gain control (ACG), so that the output signal of an impedance or conductivity sensor is in each case optimally adapted to a subsequent analog-digital converter. The impedance or conductivity measuring unit is designed to scale the respective amplified output signal of the input amplifier after its analog-digital conversion with the associated amplification factor.

0020An advantageous embodiment variant of an implantable electrotherapy device in the form of a pacemaker or defibrillator results if a therapy device control unit is provided in the housing of the therapy device, which is connected to the evaluation unit and has at least one therapy parameter such as uni- or biventricular stimulation, interventricular delay time, atrio-ventricular delay time depending on a respective contractility signal or a contractility difference signal. The therapy device control unit is preferably designed such that it automatically sets the respective therapy parameter in such a way that the contractility signal or the contractility difference signal indicates a maximum contractility.

0021A data memory for the contractility signal and preferably additionally for the activity level signal is preferably provided in the housing. This data memory is also referred to below as a memory and allows both the conductivity or impedance signal curves required for the calculation of the contractility difference signal to be stored and also the curve of the respective contractility difference signal itself in order to be able to call it up telemetrically in a preferred embodiment variant.

0022The data memory preferably comprises a plurality of memory areas which are used for the separate storage of, for example, a reference signal curve and at least one current impedance or conductivity signal curve as well as a contractility signal curve or contractility difference signal curve and the assigned activity level signal curve. The storage areas mentioned here contain data on different time ranges: The data on the reference signal curve and on the impedance signal curve: typically relate to a period of less than one cardiac cycle, while the data on the contractility signal curve or the contractility difference signal curve and the activity level signal curve each relate to a period of up to several months.

0023The data memory is preferably connected to the therapy control unit. In addition, the data memory is preferably connected to the evaluation unit.

0024In a preferred embodiment variant, a data telemetry unit is arranged in the housing and is connected to the therapy control unit or the data memory or both.

0025The invention will now be explained in more detail using an exemplary embodiment with reference to the figures. Show from the figures<dl id="dl0001"><dt>Figure 1:</dt><dd>an implantable therapy device in the form of a pacemaker and an associated electrode line and a heart in a schematic representation;</dd><dt>Figure 2:</dt><dd>a simulated potential distribution for an arrangement according to <figref idref="f0001">Figure 1</figref>;</dd><dt>Figure 3:</dt><dd>Impedance waveform signals recorded with the arrangement <figref idref="f0001">Figure 1</figref> for an unloaded and a loaded state including the representation of a difference area; and</dd><dt>Figure 4:</dt><dd>a schematic block diagram of the implantable therapy device <figref idref="f0001">Figure 1</figref>.</dd></dl>

0026In the <figref idref="f0001">Figure 1</figref> The arrangement shown comprises a pacemaker 10 to which two electrode lines are connected, namely an atrial electrode line 12 and a ventricular electrode line 14. The ventricular electrode line 14 has a tip electrode 16, which is placed in the apex of a right ventricle 18 of a heart 20, shown schematically. The atrial electrode line 12 is bent in a J shape in the region of its distal end and has an atrial tip electrode 22 which is arranged in the right atrium 24 of the heart 20.

0027To record the impedance curve of interest here, the impedance between the ventricular tip electrode 16 and a neutral electrode formed by a housing 26 of the pacemaker 10 is measured. For this purpose, the neutral electrode 26 and the ventricular tip electrode 16 are arranged in and inside the housing 26<figref idref="f0003">Figure 4</figref> schematically shown input amplifier 34 connected. This input amplifier 34 has an automatic gain control, which causes an impedance signal measured between the neutral electrode 26 and the ventricular tip electrode 16 to be amplified with a variable gain factor. The automatic gain control (AGC) has the effect that the output signal of an impedance sensor is adapted as optimally as possible to a downstream analog-to-digital converter 36. Impedance sensor 32, filter with input amplifier 34 and analog-digital converter 36 are part of an impedance measuring unit 30, which delivers as output signal an impedance curve signal scaled with the respectively set amplification factor. This impedance curve signal can be a quasi-continuous signal or an impedance signal sampled at larger time intervals and sampled by means of a sample and hold circuit. The automatic gain control is used to optimally adapt the impedance sensor output signal to the AD converter.

0028An activity sensor 40 is also arranged in the interior of the housing 26 of the pacemaker 10, which is suitable for detecting a respective activity level of a patient and for generating a corresponding activity level signal. In a preferred embodiment, the activity sensor 40 is an accelerometer and accordingly measures the respective acceleration of the pacemaker 10.

0029An evaluation unit 38, likewise arranged in the housing 26, is connected downstream of the impedance unit 30 and the activity sensor 40.

0030In addition, an impedance history memory 42 is arranged in the housing 26 of the pacemaker 10, which is connected at least indirectly to the evaluation unit 38 and can be connected directly to the impedance measurement unit 30.

0031The evaluation unit 38 is designed to form a contractility or contractility difference signal from two impedance curve signals recorded at different, but equally long time periods. For this purpose, the contractility difference signal is formed in such a way that it corresponds approximately to an area enclosed between two impedance curve signals (see<figref idref="f0002">Figure 3</figref>, Difference area DA). This contractility difference signal is preferably determined by first determining a reference zero instant for the two impedance curve signals, for example given by a respective R wave. The absolute value of the difference between the two impedance curve signals is then formed for a series of successive time intervals from the reference zero time and finally the sum of these absolute difference values ​​is formed over the different time intervals. This results in a contractility difference value which corresponds to the sum of the absolute values ​​of the area integrals of the areas enclosed by the two impedance curve signals.

0032As described above, a respective impedance curve is measured unipolar. How<figref idref="f0001">Figure 2</figref> shows, such an unipolar impedance curve measured in the apex of a heart chamber essentially reflects the curve of the local impedance around the measuring electrode (ventricular tip electrode).

0033The claimed device is based on the observation of ventricular contractility by means of an implanted pacemaker or cardioverter / defibrillator by means of intracardial impedance measurement. In the<figref idref="f0001">Figure 2</figref> The calculation of an electromagnetic field shown shows that an unipolar impedance value measured by means of a measuring electrode arranged in the tip of the heart chamber reflects changes in impedance in the vicinity of the measuring electrode.

0034The measured impedance signal changes during the contraction of the heart because blood and the myocardial tissue have different electrical conductivities. The time course of the unipolar measured impedance therefore reflects the contraction dynamics of the ventricular apex. It is known that the unipolar measured right ventricular impedance signal agrees well with the maximum of the pressure change in the right ventricle during a cardiac cycle.

0035The impedance measurement itself is known per se. A constant, pulsed current is fed between two electrodes and the resulting voltage is time-sampled, filtered, amplified and converted from analog to digital.

0036In principle, all available electrodes can be used as current-feeding electrodes and as voltage-measuring electrodes. This applies in particular to arrangements in which more electrodes are provided than in the case of<figref idref="f0001">Figure 1</figref> shown arrangement. The same electrodes can be used both for feeding the current and for measuring the voltage. At the in<figref idref="f0001">Figure 1</figref> In the preferred embodiment shown, the voltage is measured unipolar between the pacemaker housing 26 and the ventricular tip electrode 16 and the measuring current is also fed between these two electrodes. Instead of the right ventricular tip electrode, a left ventricular electrode, for example arranged in the coronary sinus or a lateral vein branching off from it, can also serve as the measuring electrode. The contractility signal already mentioned is derived from the impedance curve signal obtained in this way, preferably in the form of a contractility difference signal, which is obtained by comparing an impedance signal curve in the patient's idle state and an impedance signal curve in the patient's stressed state.

0037As already mentioned above, the contractility difference signal is preferably formed in such a way that it reflects the difference area which is enclosed by two impedance curve signals recorded at different times. Impedance curve signals for an idle state and a load state are in<figref idref="f0002">Figure 3</figref> shown. The differential area DA enclosed by these two impedance curve signals is also shown.

0038As already mentioned, the difference area is the absolute difference between the impedance curve signal for the patient's resting state and the impedance curve signal for the patient's load state. The differential area DA (differential area) can be used for two impedance curve signals, each with N samples, for each of which a load impedance value Z_bel (or acute impedance value Z_akut) and a Ruheimpedance value Z_Quiet (or reference impedance value Z_Ref) is calculated as follows:<maths id="math0001" num=""><math display="block"><mi mathvariant="italic">THERE</mi><mo>=</mo><mfrac><mn>1</mn><mi>N</mi></mfrac><munderover><mo>∑</mo><mrow><mi>i</mi><mo>=</mo><mn>1</mn></mrow><mi>N</mi></munderover><mfenced open="|" close="|" separators=""><msub><mi>Z.</mi><mi mathvariant="italic">acute</mi></msub><mfenced><mi>i</mi></mfenced><mo>-</mo><msub><mi>Z.</mi><mrow><mi>re</mi><mo>⁢</mo><mi>f</mi></mrow></msub><mfenced><mi>i</mi></mfenced></mfenced></math><img file="EP1586348B1_D0001.tif" /></maths>

0039The two impedance curve signals or their scanning indices i are related to a suitable reference zero point in time, for example the R wave in the associated electrocardiogram.

0040Instead of a Ruheimpedance course with Ruheimpedance values ​​Z_Quiet and a load impedance curve with impedance values ​​Z_bl can also be any reference impedance curve as a reference signal with impedance values ​​Z_Ref and a respectively current impedance signal curve with impedance values ​​Z_acute be used.

0041The impedance is measured continuously, for example with every heartbeat. The current impedance curve is formed as a short-term average with a small time constant, for example a 15/16 recursive low-pass filter. The reference impedance curve is preferably an averaged Ruheimpedance signal curve that is formed only from those impedance signal curves that were recorded in the patient's idle state. This reference impedance curve is filtered with a long time constant, for example with a 255/256 recursive low-pass filter.

0042The output signal of the activity sensor, that is, the accelerometer, determines whether a patient is at rest or under stress. This accelerometer outputs an activity level signal that indicates whether a patient is resting or physically active. A motion flag Mflag (Motional Flag) can be derived from the activity level signal, which is set (Mflag = 1) when an output signal of the accelerometer exceeds a predetermined limit value. The movement flag Mflag is reset (Mflag = 0) when the output signal from the accelerometer falls below a predetermined second limit value. The first and second limit values ​​can be different, but also identical. The reference impedance curve signal is only formed when the movement flag is reset (Mflag = 0).

0043The Mflag is used to control the averaging of the reference impedance signal curve. It should not replace the activity level signal, since (for example for normalizing the contractility reference signal) the activity level signal should be able to reproduce several levels of the activity level.

0044If the first limit value is exceeded when the patient is under load and the Mflag is set (Mflag = 1), the generation of the reference impedance curve signal is interrupted. At the same time, an average difference area DA_avg calculated. This average difference area is determined for a predetermined, for example programmable observation period, for example 24 hours. At the beginning of each new observation period, a new average difference area DA_avg calculated.

0045In addition to calculating the average difference area DA_avg an average activity level signal can also be determined. Each average difference area (that is, each average contractility difference signal) can then be normalized with the associated activity level signal value.

0046Alternatively, the average difference area DA_avg (the average contractility difference signal value) can be calculated for different initial value ranges of the accelerometer. It is also possible to normalize a respective contractility difference signal value (the difference area) with an associated short-term averaged activity level signal value before the averaged difference area, that is to say the averaged contractility difference signal value, is formed. This standardization ensures that observation periods with different activity levels are comparable.

0047The impedance curve to be measured depends not only on the contraction dynamics influenced by the contractility, but also on the type of ventricular event, i.e. on whether the ventricular contraction is a natural contraction or a stimulated one. The impedance curve (and the contraction curve) can be different for stimulated and intrinsic, natural ventricular contractions. Therefore, the average difference area DA_avg in a preferred embodiment variant for the two different types of ventricular events - stimulated and intrinsically - calculated separately.

0048For this purpose, in the preferred embodiment variant, the evaluation unit and a therapy control unit 44, which controls, for example, the delivery of stimulation pulses, are at least indirectly connected to one another in such a way that the therapy control unit 44 sends a signal to the evaluation unit 38 when ventricular stimulation takes place. In a particularly preferred embodiment variant, this signal is a marker signal known per se for identifying ventricular stimulation.

0049The average difference area DA determined in this way_avg is an indicator of the average change in contractility during physical exertion of an individual patient. This value can be used for diagnostic and therapeutic purposes in the manner described below.

0050In principle, it is also possible to obtain a signal that characterizes contractility from the impedance signal in a different way, as is done, for example, in the prior art cited at the beginning (for example by impedance plethysmography or by forming the second derivative of the impedance signal). The distinction between a patient's state of rest and a state of stress as well as the averaging over a given period of time should also be made in these cases (determination of contractility from the impedance in a different way than via the difference surface), as described here.

0051The pacemaker 16 preferably comprises a therapy control unit 44, which is designed to set one or more stimulation parameters to be controlled by it, such as the stimulation mode - biventricular, right-ventricular, left-ventricular, etc. - an atrio-ventricular delay time or an interventricular delay time depending on the respective contractility signal that there is the greatest possible contractility. This optimization of the stimulation parameters by therapy control unit 44 is preferably carried out in a recursive manner in the manner of a regulation, in that an initially predetermined stimulation parameter (for example for the atrio-ventricular delay time or the interventricular delay time) is changed step by step and always that value of the control parameter as the starting point for the next one Change is used, for which the highest contractility has resulted. In this sense, the therapy control unit 44 accesses a memory 42 for the contractility signal, which in the preferred embodiment variant is determined by the course of the average difference area DA_avg given is.

0052This therapy control unit 44 can additionally be connected to the evaluation unit 38, as in the aforementioned manner, in such a way that the evaluation unit receives a marker signal when ventricular stimulation takes place.

0053In a further preferred embodiment variant, the memory 42 for the contractility signal has separate memory areas for the difference area DA_avg for both types of ventricular events and for the number of difference area values ​​that are used to form the respective average difference area DA_avg have contributed to. This memory is preferably connected to a telemetry unit 46, so that the values ​​stored in the memory 42 can be queried telemetrically by a doctor.

0054In addition to storage areas for the last-mentioned data relating to the contractility signal (the difference area), a further storage area is preferably provided for the associated activity level signal values. The data to be telemetrically queried by the doctor in this way can then be displayed graphically on a screen and support the diagnosis by the doctor.

0055With the help of the telemetric connection of the pacemaker 16 to an external device, the averaged contractility and activity level signals can also be transmitted regularly, for example daily, as part of a so-called home monitoring. In this case, the data transmitted to an external device are transmitted from this external device to a central service center in a manner known per se and can be correlated with data previously stored there.

0056In addition, the therapy control unit can be designed in such a way that it triggers data transmission on its own when a special event, for example an alarm state, is present. This particular event can be a detected arrhythmia, for example. It is also possible that the special event is a telemetrically received request from a doctor or the patient himself. In connection with the monitoring and evaluation of the contractility signal, a special event triggering a telemetric connection can also be a significant change in the contractility signal, that is to say in the preferred case the value of the difference area itself.

0057The observation of the contractility determined by means of an implanted electrotherapy device in the manner described above can be used for various diagnostic or therapeutic purposes. The diagnostic options include:<ul id="ul0002" list-style="dash"><li>general monitoring of patients with heart failure (HF patients) using the stored and telemetrically transmitted data</li><li>Monitoring of HF patients using the homonitoring data and the previously mentioned alarm functionality</li><li>Monitoring of medication, for example when medications with positive or negative inotropic effects are administered</li><li>Monitoring resynchronization therapy; and or</li><li>Observation of patients who show an increased risk of sudden changes in contractility, for example patients at risk of myocardial infarction or ischemia.</li></ul>

0058The therapeutic options are:<ul id="ul0003" list-style="dash"><li>Adaptation of the stimulation mode to detected changes in contractility, for example switching between right ventricular, left ventricular and biventricular stimulation, and</li><li>Adaptation of other stimulation or defibrillation parameters, for example such time parameters as the atrio-ventricular delay time already mentioned, the biventricular delay time but also the stimulation rate itself or additionally or alternatively</li><li>Adjustment or control of drug therapy by the doctor.</li></ul>

0059In addition, such a pacemaker can also be used as an acute sensor, for example during an electrophysiological examination if the patient has permanently implanted electrode lines. The response of the heart to a temporary application of a positively inotropic drug, such as dobutamine, or to a standardized exercise can also be tested. Different examinations on a patient can be compared with one another and the changes in the respective stress reaction can be evaluated. This application is used to diagnose heart failure, to regularly monitor the deterioration or improvement of heart defects and to test general contractility.