Abstract:
The invention refers to a monitoring device for monitoring and analyzing physiological signals. The monitoring device comprises a transthoracic impedance measurement unit and an evaluation unit connected to the transthoracic impedance measurement unit. The transthoracic impedance measurement unit is adapted to conduct a transthoracic impedance measurement and to generate a transthoracic impedance signal representing a measured transthoracic impedance at consecutive points in time. The evaluation unit being configured to process the transthoracic impedance signal received from the transthoracic impedance measurement unit and to thus generate a respiration signal and to generate therefrom an evaluation signal reflecting at least a diurnal pattern of the respiration rate.

Description:
This application takes priority from U.S. Provisional Patent Application Ser. No. 61/073,044, filed 17 Jun. 2008, the specification of which is hereby incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     Field of the Invention 
     The present invention generally relates to implantable cardiac devices, including pacemakers, defibrillators and cardioverters, which monitor the cardiac status and stimulate cardiac tissue electrically to control the patient&#39;s heart rhythm. More particularly, the present invention relates to a method and apparatus for monitoring heart failure status by trending analysis of circadian pattern of respiration rate, resting heart rate, and heart rate variability. 
     BRIEF SUMMARY OF THE INVENTION 
     According to this invention, monitoring the heart failure status is accomplished by trending analysis of multiple physiological parameters of the patient, including at least the diurnal pattern of the respiration rate, which is measured by means of transthoracic impedance of the implantable cardiac device. 
     In a preferred embodiment, early detection of heart failure or decompensation is made when the implantable cardiac device detects an increase of the night respiration rate of the patient, and/or decrease of the daytime respiration rate of the patient, and/or decrease of the circadian variability of the respiration rate of the patient. Alternatively, heart failure monitoring is achieved by trending analysis of multiple physiological parameters, including but are not limited to, the respiration rate, the heart rate, and the heart rate variability. 
     No additional leads or sensors are required beyond those for known implantable cardiac devices. The impedance measurements can be made with customary pacing/defibrillation leads, including leads placed endocardially, epicardially, or thru the coronary sinus. The information can become part of a medical information system, which provides early warning for detecting decompensating ventricular function, response to therapeutic intervention or developing heart failure. 
     Present invention identifies underlying physiologic changes that are latent in typical measures (electrogram) associated with left ventricular failure or its resolution. Circadian variation of respiration rate (including night respiratory rate) provides a novel probe of autonomic nervous function, and is particularly useful for heart failure monitoring. 
     The details of the invention can be understood from the following drawings and the corresponding text descriptions. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The above and other aspects, features and advantages of the present invention will be more apparent from the following more particular description thereof, presented in conjunction with the following drawings wherein: 
         FIG. 1  shows an implantable medical device including a monitoring device connected to leads placed in a heart. 
         FIG. 2  is a schematic block diagram of one configuration of the device of  FIG. 1 . For simplicity, the atrial sensing and stimulation channels are omitted. 
         FIG. 3  shows two representative electrode configurations for intrathoracic impedance measurement. 
         FIG. 4  illustrates the circadian patterns of the respiration rate measured in a chronic animal study. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The following description is of the best mode presently contemplated for carrying out the invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of describing the general principles of the invention. The scope of the invention should be determined with reference to the claims. 
     In  FIG. 1  an implantable medical device, a three chamber biventricular pacemaker and cardioverter/defibrillator  10  that is connected to pacing/sensing leads placed in a heart  12  is illustrated. Implantable medical device  10  incorporates a monitoring device. 
     The implantable medical device  10  is electrically coupled to heart  12  by way of leads  14 ,  16  and  30 . 
     Lead  14  is a right atrial electrode lead that has a pair of right atrial electrodes  22  and  24  that are in contact with the right atrium  26  of the heart  12 . 
     Lead  16  is a right ventricular electrode lead that has a pair of ventricular stimulation and sensing electrodes  18  and  20  that are in contact with the right ventricle  28  of heart  12 . Further, a ventricular defibrillation shock coil  38  and an atrial defibrillation shock coil  40  are arranged on lead  16 . 
     Electrodes  22  and  18  are tip electrodes at the very distal end of leads  14  and  16 , respectively. Electrode  22  is a right atrial tip electrode RA Tip and electrode  18  is a right ventricular tip electrode RV Tip. Electrodes  24  and  20  are ring electrodes in close proximity but electrically isolated from the respective tip electrodes  22  and  18 . Electrode  24  forms a right atrial ring electrode RA Ring and electrode  20  forms a right ventricular ring electrode RV Ring. Ventricular defibrillation shock coil  38  and atrial defibrillation shock coil  40  are coil electrodes providing a relatively large surface area when compared to the electrodes  18 ,  22 ,  20  and  24 . 
     Lead  30  is a left ventricular electrode lead passing through the coronary sinus of heart  12  and having a left ventricular ring electrode LV Ring  32 , and a left ventricular tip electrode LV Tip  34 . Further, a left ventricular defibrillation shock coil  36  is arranged on lead  30 . 
     Implantable medical device  10  has a case  42  made from electrically conductive material such as titanium that can serve as a large surface electrode herein called “can”. 
     The plurality of electrodes  18 ,  20 ,  22 ,  24 ,  32 ,  34 ,  36 ,  38  and  40  connected to implantable medical device  10  together with case  42  allow for a number of different electrode configurations for measuring intrathoracic and intracardiac impedance. 
     A subset of configurations possible with the device in  FIG. 1 , are the preferred configurations illustrated conceptually in  FIG. 3 . 
       FIG. 2  illustrates a simplified block diagram of an implantable medical device, for example, the one shown as item  10  in  FIG. 1 . While  FIG. 1  shows a three chamber biventricular pacemaker and cardioverter/defibrillator, in  FIG. 2  no means for connecting atrial electrodes or shock electrodes and means for driving these electrodes are shown. However, such means may be provided as is known in the art. 
     During operation of the implantable medical device leads  16  and  30  (of  FIG. 1 ) are connected to respective output/input terminals RV RING, RV TIP, LV RING and LV TIP, items  20 ,  18 ,  32 , and  34 , respectively, of implantable medical device  10  as indicated in  FIG. 1 . For pacing the right and the left ventricle they carry stimulating pulses to the tip electrodes  18  and  34  from a right ventricular stimulation pulse generator RV STIM  50  and a left ventricular stimulation pulse generator LV STIM  52 , respectively. Further, electrical signals from the right ventricle are carried from the electrode pair  18  and  20 , through the lead  16 , to the input terminal of right ventricular sensing stage RV SENS  50 ; and electrical signals from the left ventricle are carried from the electrode pair  32  and  34 , through the lead  30 , to the input terminal of a left ventricular sensing stage LV SENS  52 . 
     Controlling the implantable medical device  10  is a control unit CTRL  54  that is connected to stimulation pulse generators/sensing stages RV STIM/RV SENS  50  and LV STIM/LV SENS  52 . 
     Control unit CTRL  54  receives the output signals from the right ventricular sensing stage RV SENS  50  and from the left ventricular sensing stage LV SENS  52 . The output signals of sensing stages RV SENS  50  and LV SENS  52  are generated each time an R wave representing an intrinsic ventricular event in the respective ventricle is sensed within the heart  12 . Thus, control unit is capable of detecting excitations of the myocardium indicating a ventricular contraction and to act as a heart rate detector for determination of a heart rate. 
     Control unit CTRL  54  also generates trigger signals that are sent to the right ventricular stimulation pulse generator RV STIM  50  and the left ventricular stimulation pulse generator LV STIM  52 , respectively. Control unit CTRL  54  comprises circuitry for timing ventricular stimulation pulses (atrial stimulation pulses are also possible but not shown in  FIG. 2 ) according to an adequate stimulation rate that can be adapted to a patient&#39;s hemodynamic need as pointed out below. 
     Still referring to  FIG. 2 , the implantable medical device  10  includes a memory circuit MEM  56  that is coupled to the control unit CTRL  54  over a suitable data/address bus. This memory circuit MEM  56  allows certain control parameters, used by the control unit CTRL  54  in controlling the operation of the implantable medical device  10 , to be programmable, stored and modified, as required, in order to customize the implantable medical device&#39;s operation to suit the needs of a particular patient. Such data includes basic timing intervals used during operation of the implantable medical device  10  for triggering of ventricular or atrial stimulation pulses. 
     Further, data sensed during the operation of the implantable medical device may be stored in the memory MEM  56  for later retrieval and analysis. 
     For impedance measurement, an impedance measurement unit  70  is provided. Impedance measurement unit  70  comprises a constant current source  72  and a voltage measurement unit  74  that are respectively connected or can be connected to electrodes for intracorporeal placement as shown in  FIG. 1 . In order to allow for a plurality of impedance measurement electrode configurations, preferably some means of switching is provided between the constant current source  72  and the electrode terminals of the implantable medical device  10 . In  FIG. 2  switches SW 1  and SW 2  are shown. 
     As an alternative to constant current source  72  a constant voltage source can be provided. Then, the measuring unit will be adapted to measure a current strength of a current fed through a body by said constant voltage source. 
     Both, constant current source  72  and measuring unit  74 , are connected to an impedance value determination unit  76  that is adapted to determine an impedance value for each measuring current pulse delivered by the constant current source  72 . 
     Further, an impedance evaluation unit  78  is provided, that is connected to said impedance determination unit  76  and that is adapted to control said impedance determination unit and to evaluate a sequence of consecutive impedance values determined by said impedance measurement unit  70 . Impedance evaluation unit  78  is also connected to memory  56  for storing of impedance data. Impedance measurement unit  70  and impedance evaluation unit can be controlled by control unit CTRL  54 . 
     The impedance measurement unit  70  is adapted to determine at least transthoracic impedance values and preferably in addition intracardiac impedance values for same period of time, wherein the intracardiac impedance values are preferably sampled with a higher sampling rate than the transthoracic impedance values. 
     A telemetry circuit TEL  58  is further included in the implantable medical device  10 . This telemetry circuit TEL  58  is connected to the control unit CTRL  54  and memory MEM  56  by way of a suitable command/data bus. Telemetry circuit TEL  58  allows for wireless data exchange between the implantable medical device  10  and some remote programming or analyzing device, which can be part of a centralized service center serving multiple implantable medical devices. 
     Implantable medical device  10  usually comprises an activity sensor ACT  60  that is used for rate adaptation and can be of further use for evaluation of impedance values and therefore is connected to the impedance evaluation unit  78  via control unit CTRL  54 . In particular, an output signal by activity sensor  60  is used by impedance evaluation  78  to derive and recognize periods of physical activity and periods of rest. This information is used for further processing and trending of the information derived from the impedance signal. 
     Monitoring the heart failure status is accomplished by the impedance evaluation unit  78  by trending analysis of multiple physiological parameters of the patient, including at least the diurnal pattern of the respiration rate, which is measured by means of transthoracic impedance of the implantable cardiac device. 
     In one typical embodiment, early detection of heart failure decompensation is made when the implantable cardiac device detects an increase of the night respiration rate of the patient, and/or decrease of the daytime respiration rate of the patient, and/or decrease of the circadian variability of the respiration rate of the patient. Alternatively, heart failure monitoring is achieved by trending analysis of multiple physiological parameters, including but not limited to, the respiration rate, the heart rate, and the heart rate variability. 
     According to this invention, the implantable cardiac device continuously measures the transthoracic impedance signal to derive the patient&#39;s respiration rate. As is well known in the art, there are different means to measure the transthoracic impedance signal by choosing various electrode configurations for current injection and voltage measurement. Typically, the impedance vectors pass through the lung in order to detect the respiration activity.  FIG. 3  shows two representative tripolar configurations for such impedance measurement. 
     Further configurations and preferred details for impedance measurement are disclosed in US2008/0300504 incorporated herein by reference. 
     In the left panel of  FIG. 3 , the current is injected between the right ventricular ring and can, and the voltage is measured between the right ventricular tip and can. In the right panel of FIG.  3 , the current is injected between the left ventricular ring and can, and the voltage is measured between the left ventricular tip and can. 
     Impedance value determination unit  76  calculates the transthoracic impedance as the ratio between the measured voltage and the injected current. In a preferred embodiment, the impedance signal is measured with sampling frequency of at least 8 Hz. 
     Impedance evaluation unit  78  further processes the impedance signal to remove a high frequency cardiac component, e.g., by using a low-pass filter with corner frequency of 2.5 Hz, to thus obtain the low frequency respiratory component. Impedance evaluation unit  78  further determines the peak-to-peak interval of the resulting respiration component of the transthoracic impedance signal, or the respiration cycle length. Its inverse, or the number of respiration cycles within a predefined time interval (e.g., one minute), is the respiration rate. In an alternative embodiment the inflection at the end of expiration to begin inspiration is identified to determine the respiration cycle length. 
       FIG. 4  illustrates the circadian patterns of the respiration rate measured in a chronic animal study. In this study, 10 mature Yucatan minipigs were chronically instrumented with a biventricular pacemaker and a left ventricular pressure-measuring device. For each animal, after a recovery and stabilization period following device implantation, heart failure was inducted by using high rate right ventricular pacing at 240 ppm over 2-4 weeks. Hourly left ventricular pressure measurements and weekly echo data were used to monitor the development of heart failure. Hourly recording of right ventricular and left ventricular tripolar impedance (during intrinsic rhythm) was performed over the course of the study, including 2-4 weeks after cessation of high rate pacing (recovery period). Respiratory measurements of respiration rate, tidal amplitude, and minute ventilation were extracted hourly from the tripolar impedance measurements. 
     Still refer to  FIG. 4 . In all panels, the x-axis is the hour of the day, and the y-axis is the respiration rate (unit: cycles/minute) measured by the implantable cardiac device. The plotted respiration rate data are averaged over 10 subjects. The left panels show the respiration rate derived from the right ventricular tripolar impedance data obtained using the configuration shown in the left panel of  FIG. 3 , and the right panels show the respiration rate derived from the left ventricular impedance data obtained using the configuration shown in the right panel of  FIG. 3 . 
     The top panels show the 24-hour respiration rate during the baseline period (BL) (before heart failure induction). The respiration rate shows clear circadian variation that increases during the daytime whereas it decreases during the night time. The middle panels show the 24-hour respiration rate during the period with confirmed heart failure (HF) status. Clearly, the circadian variation of the respiration rate is dramatically reduced, evidenced by decreased respiration rate in the daytime and elevated respiration rate in the night time. The bottom panels show the 24-hour respiration rate during the recovery period (REC) (after stopping high rate pacing). Evidently, the circadian pattern of the respiration rate also recovered to some extent, although not to the baseline level (prior to heart failure induction). 
     It is believed by the inventors that the patient&#39;s respiration rate contains important diagnostic information on heart failure status, which is independent from other physiological parameters such as heart rate and heart rate variability. Normal function of the physiological system requires balance of the autonomic nervous system (ANS). However, in heart failure patients the sympathetic tone is increased whereas the parasympathetic tone is suppressed. Consequently, this results in increase of resting respiration rate, increase in resting heart rate, and decrease of the hear rate variability. 
     According to this invention, the night respiration rate is a reasonable measure of the resting respiration rate, thus elevation of the night respiration rate is a strong indicator of worsening heart failure. The nighttime respiration is less subject to the interference of a conscious subject and environmental stimuli, and thus reflects more autonomic driven respiration. It is also believed by the inventors that the daytime respiration rate also contains prognostic information on patient&#39;s heart failure status, because reduced daytime respiration rate likely reflects decreased daytime activity level, which is associated with worsening heart failure. Consequently, the damped circadian variation of the respiration rate (reduced difference between daytime and night time respiration rates) is also a strong indicator of worsening heart failure. 
     In a preferred embodiment, a pacemaker, implantable cardioverter/defibrillator (ICD), or cardiac resynchronization therapy (CRT) device with configurable impedance circuits is used to measure the tripolar intrathoracic impedance signal as illustrated in  FIG. 3 . 
     Methods for monitoring heart failure status by processing a transthoracic impedance signal are illustrated hereinafter. These methods can be carried out by the impedance evaluation unit  78  or by other means including a remote service center. 
     Then, from the transthoracic impedance signal, the cardiac component is separated from the respiration component. In a predefined time interval e.g. hourly, the respiration cycle length and/or the respiration rate is measured from the respiration component. Measured values (time interval, respiration cycle length and/or respiration rate) are stored in memory  56  for further processing. 
     The processing (to be carried out by the impedance evaluation unit  78 ) comprises: 
     calculation of overall statistics of the measured respiration rate, e.g. moving average within the past x-hours. 
     Calculation of separate day and night statistics of the measured respiration rate with user-programmable daytime and night time settings, e.g. daytime between 10 am and 5 pm, and night time between 1 am and 5 am. 
     Data may be transmitted routinely (daily) and as necessary (alert) via telemetry unit  58  to one or all of a remote server, data base and expert system using well known data transmission technologies for further processing e.g. for heart failure assessment. 
     Change from a baseline state of heart function to a worsening state, will be characterized by an increase of the night respiration rate, and/or decrease of the day-time respiration rate, and/or decrease of the circadian variability of the respiration rate of the patient. Alert for worsening heart failure is generated when the increase or decrease of the above parameters crosses a predefined threshold value or percentage as compared to the baseline. 
     Alternatively, a composite score (CS) is constructed from multiple physiological parameters. For example, define CS=a*rRR+b/dRR+c*rHR+d/HRV, where CS is the composite score, a, b, c, and d are predefined non-positive coefficients (weighting factors), rRR is the resting (night) respiration rate, dRR is the difference between day and night respiration rates (or alternatively, an index of 24-hour respiration rate variability), rHR is the resting (night) heart rate, and heart rate variability (HRV) is an index of 24-hour heart rate variability as known in the art. Worsening heart failure is indicated by increase of rRR, increase of rHR, decrease of dRR, and decrease of heart rate variability (HRV). Thus, early detection of heart failure decompensation is made when CS is increased above a predefined threshold. It should be understood that other definitions of CS can also be made based on the same concept.