Abstract:
A heart monitoring system comprises a ventricular sensing stage sensing excitation or contraction of ventricular myocardium, an activity sensor unit determining a signal reflecting a patient&#39;s physical activity, a ventricular impedance or conductance measuring module, said modules comprising a current source unit adapted to provide a sub-threshold excitation current to the myocardium and comprising an impedance or conductance measurement unit for measuring the resulting voltage on said electrode at the myocardium, a signal generator module, a filter module, a memory, a control unit adapted to derive single measures |ΣZ| of magnitude of impedance or conductance change over a preset sample time interval, determine the variability TARVI in the impedance or conductance change, compare this variability and the activity sensor output signal with a threshold and recent history, determine if sleep disturbed breathing (SDB) is present, and log the SDB episode in the memory device.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority under 35 USC §119(e) to U.S. Provisional Patent Application 60/747,211 filed 15 May 2006, the entirety of which is incorporated by reference herein. 
    
    
     BACKGROUND OF THE INVENTION 
     The invention relates to a monitoring system for monitoring sleep disordered breathing (SDB). 
     Sleep disordered breathing (SDB) adversely affects the systemic circulation (hypertension), the pulmonary circulation (pulmonary hypertension) and the myocardium (systolic and diastolic heart failure). Continual management of the SDB disorder is part of the overall management strategy for cardiac disease. The SDB burden is an under observed disorder and rarely quantified, because apnea and hypopnea episodes occur at night and out of the clinical setting. 
     Therefore there is a need for an automatic monitor of the SDB burden that would permit the clinician to manage the SDB risk factor. 
     Known solutions monitor the intra-thoracic impedance as a proxy for successful ventilation, (respiratory frequency and tidal volume). The clinical impact of the proxy impedance measurement with respect to the patient&#39;s cardiovascular system is not measured and can only be inferred by using epidemiological clinical studies. 
     Three and four intra-thoracic electrode measurements contain thoracic information, e.g. breathing effort and minute ventilation, as well as heart specific information. 
     Intra-thoracic impedance measurements often cannot detect obstructive apnea, due to the persistence of thoracic and abdominal breathing effort. 
     SUMMARY OF THE INVENTION 
     It is an object of the invention to provide an automatic monitor of the SDB burden providing reliable information on SDB burden and that can be implemented without excessive effort. 
     According to the invention this object is achieved by a heart monitoring system for monitoring at least a ventricle of a heart. 
     The heart monitoring system comprises:
         a ventricular sensing stage connected or being connectable to an electrode for picking up electric potentials inside at least a ventricle of a heart, said sensing stage being adapted to sense an excitation or a contraction of ventricular myocardium,   an activity sensor unit inside a lead or the device which is capable of determining an activity signal reflecting a patient&#39;s physical activity,   a ventricular impedance or conductance measuring module connected or being connectable to an electrode measuring the resistance of at least a ventricle of a heart, said impedance or conductance measuring module comprising a current source unit adapted to provide a sub-threshold excitation current to the myocardium and comprising an impedance or conductance measurement unit adapted to measure the resulting voltage on said electrode at the myocardium,   a signal generator module connected to the current source unit and the voltage measurement unit to construct the intra-cardiac impedance or conductance signal reflecting the time course of the impedance or conductance measurement unit&#39;s output signal and its derivative,   a filter module to filter the intra-cardiac impedance signal,   a memory for storing a history of intra-cardiac impedance values, and   a control unit that is connected to said memory, said sensing stage, said activity sensor and to said impedance or conductance measuring module.       

     The control unit is adapted to
         derive single measures |ΣZ| of magnitude of impedance or conductance change over a preset sample time interval,   determine the Total Active Right Ventricular Impedance variability TARVI, in the impedance or conductance change over a small number, e.g. 8, of cardiac cycles,   compare the variability in the impedance or conductance change with a threshold and recent history,   compare the activity sensor output signal with a threshold and recent history data stored in said memory,   determine if sleep disturbed breathing (SDB) is present, and   log the SDB episode in the memory device.       

     In addition to measuring a proxy for minute ventilation according to the prior art, the monitoring system according to the invention measures one or more attributes of ventricular systolic and/or diastolic function, and differentiates obstructive apnea from successful ventilation. Successful and unsuccessful breathing effort influence right ventricular filling, thus permitting the correlation of all classes of SDB with cardiac function. Unexplained excess activation of the cardiovascular system associated with SDB is the source of the SDB burden. The device may report trends in the SDB burden during routine follow-up. Optionally the device may report the SDB burden, via remote monitoring, to a patient management service. 
     It has been found that
         the indirect effect of apnea on cardiac function can be used to detect central, mixed and obstructive apnea episodes with good sensitivities.   the apnea episode detection may be used to automatically intervene to reduce the net SDB burden.   the apnea episode rate may be used to trend the apnea burden upon the cardiovascular system.       

     The invention provides or allows for the following advantages over the prior art:
         A more specific, more timely, and more cost effect indication of the SDB severity.   Improved patient management.   Reduced frequency of hospitalisation and clinical visits.   Improved long-term heart failure morbidity.   Prolongation of life.   Improved quality of life.   Decreased cost of disease management.       

     Variations and preferred embodiments of the monitoring system include: 
     Intracardiac impedance measurements provide measures of cardiac systolic and diastolic function. Intra-cardiac impedance may be measured using one or many intra-cardiac electrodes. Unipolar intracardiac impedance measurements provide the simplest method for measuring cardiac systolic and diastolic function. Impedance measurements focused outside the heart provides a measure of successful respiratory action (minute ventilation), and accelerometer provides evidence of corporeal motion. 
     The information from these intra-cardiac and extra cardiac sensors plus other sensors can be integrated to create the index of SDB burden. In particular, the monitoring system may be adapted to identify sequences of SDB episodes and measure the sequence duration. Further, the monitoring system may be adapted to accumulate the daily total duration of SDB sequences, the SDB burden. A telemetry unit provides a communication channel to a central service center. 
     According to a preferred embodiment, the device incorporating the monitoring system provides a means for automatic intervention to reduce the SDB burden. In that respect, the monitoring system may be adapted to modify a heart rate to reduce the cardiac excitability. Alternatively, the monitoring system may be adapted to modify a cardiac afferent neural signal to the brain to further reduce the cardiac excitability. Preferably, the monitoring system is adapted to stimulate the inhibitory nerves targeting the heart to reduce the cardiac excitability. 
     The invention may be used as a stand-alone monitor of SDB, or it may be included as a component of other therapies including implanted cardiac devices: pacemakers, defibrillators, and ventricular assist devices. 
    
    
     
       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 a configuration for an exemplary Sleep Disturbed Breathing (SDB) monitor. 
         FIG. 2  is a schematic diagram of an exemplary configuration for the monitor. 
         FIG. 3  shows a three chamber bi-ventricular implantable cardioverter/defibrillator (ICD). 
         FIG. 4  is a schematic diagram of the device modules of the ICD of  FIG. 3 . 
         FIG. 5  is a signal processing diagram of the algorithmic processing of impedance data to determine the Sleep Disordered Breathing burden. 
     
    
    
     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. 
       FIG. 1  shows an exemplary configuration for implementing the monitoring for SDB burden with an implantable medical device. 
     As shown in  FIG. 1 , the implementation of the SDB monitor with an implantable medical device  10  requires at least one ventricular electrode affixed to the right or left ventricular chamber, a method to measure at least the intrinsic ventricular activation, a method to measure the intra-cardiac impedance. 
     In the preferred embodiment as shown in  FIG. 1 , impedance is measured by injecting a current between a right ventricular tip electrode  18  and an electrically conducting case  42  of the implantable medical device  10 . The voltage difference is measured between the same two electrodes  18  and  42 . For geometric reasons, 75% or more of the impedance is due to the lead/myocardium interface and ventricular volume. There is a small component due to the intra-thoracic impedance (minute ventilation), which is removed by measuring the derivative of the impedance measurement signal. 
       FIG. 2  shows an arrangement usable for the monitor of  FIG. 1 . As shown in  FIG. 2 , the device contains modules to sense and pace a ventricular chamber of the heart. The device contains modules to perform the impedance measurement  70 : The device contains a module to inject the excitation current  72 , to measure the resulting voltage  74 , to determine the impedance  76  and evaluate the impedance change (derivative)  78 , and a memory device  56  to store the systolic and diastolic impedance measurements. The device contains a controller  54  to perform algorithmic data processing and to take the indicate actions. The device contains a module  58  to communicate the SDB burden via telemetry to the clinic. 
     In  FIG. 3  the implantable medical device is a three chamber biventricular pacemaker and cardioverter/defibrillator  10  that is connected to pacing/sensing leads placed in a heart. 
     As shown in  FIG. 3 , the preferred embodiment is to couple the disclosed technology with a implantable bi-ventricular defibrillator. 
     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 atria  26  of the heart  12 . 
     Lead  16  is a right ventricular electrode lead that has a pair of ventricular stimulation an 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. 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. Atrial cardioversion shock coil  40  is a coil electrode providing a relatively large geometric area when compared to the stimulation electrodes  18 ,  20 ,  22  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 IMD CASE. 
     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. 
     Referring to  FIG. 4  a simplified block diagram of a three chamber pacemaker or cardioverter/defibrillator  10  is illustrated. During operation of the pacemaker leads  14  and  16  are connected to respective output/input terminals of pacemaker  10  as indicated in  FIG. 3 , and referring to  FIG. 4 , they carry stimulating pulses to the tip electrodes  22  and  18  from an atrial stimulation pulse generator  52  and ventricular pulse generators  50  and  66 , respectively. Further, electrical signals from the atrium are carried from the electrode pair  18  and  20 , through the lead  14 , to the input terminal of an atrial channel sensing stage  52 ; and electrical signals from the ventricles are carried from the electrode pair  22 / 24  and electrode pair  32 / 34  through the leads  16  and  30  respectively, to the input terminals of the ventricular sensing stages  50  and  66 . 
     Controlling the dual chamber pacemaker  10  is a control unit CTRL  54  that is connected to atrial stimulation and sensing stages  52  and to ventricular stimulation and sensing stages  50  and  66 . Control unit CTRL  54  receives the output signals from the atrial sensing stage  52  and from the ventricular sensing stages  50  and  66 . The output signals of sensing stages  52 ,  50  and  66  are generated each time that a P-wave representing an intrinsic atrial event or an R-wave representing an intrinsic ventricular event, respectively, is sensed within the heart  12 . An As-signal is generated when the atrial sensing stage  52  detects a P-wave, and a Vs-signal is generated when the ventricular sensing stage  50  or  66  detect an R-wave. 
     Control unit CTRL  54  also generates trigger signals that are sent to the atrial stimulation pulse generator  52  and the ventricular stimulation pulse generators  50  and  66 , respectively. These trigger signals are generated each time that a stimulation pulse is to be generated by the respective pulse generator. The atrial trigger signal is referred to simply as the “A-pulse”, and the ventricular trigger signals are referred to as the “V-pulse”. 
     During the time that either an atrial stimulation pulse or ventricular stimulation pulse is being delivered to the heart, the corresponding sensing stages in  52 ,  50  and  66  are typically disabled by way of a blanking signal presented to these amplifiers from the control unit CTRL  54 , respectively. This blanking action prevents the sensing stages  52 ,  50  and  66  from becoming saturated from the relatively large stimulation pulses that are present at their input terminals during this time. This blanking action also helps prevent residual electrical signals present in the muscle tissue as a result of the pacer stimulation from being interpreted as P-waves or R-waves. 
     Furthermore, atrial sense events As recorded shortly after delivery of a ventricular stimulation pulses during a preset time interval called the post ventricular atrial refractory period (PVARP) are generally recorded as atrial refractory sense events Ars, but are ignored. 
     Control unit CTRL  54  comprises circuitry for timing ventricular and/or atrial stimulation pulses according to an adequate stimulation rate that can be adapted to a patient&#39;s hemody-namic need as pointed out below. 
     Still referring to  FIG. 4 , the pacer  10  includes a memory circuit MEM  56  that is coupled to the control unit CTRL  54  over a suitable data/address bus ADR. This memory circuit MEM  56  allows certain control parameters, used by the control unit CTRL  54  in controlling the operation of the pacemaker  10 , to be programmably stored and modified, as required, in order to customize the pacemaker&#39;s operation to suit the needs of a particular patient. Such data includes the basic timing intervals used during operation of the pacemaker  10  and AV delay values and hysteresis AV delay values in particular. 
     Further, data sensed during the operation of the pacemaker may be stored in the memory MEM  56  for later retrieval and analysis. 
     A telemetry circuit TEL  58  is further included in the pacemaker  10 . This telemetry circuit TEL  46  is connected to the control unit CTRL  54  by way of a suitable command/data bus. Telemetry circuit TEL  58  allows for wireless data exchange between the pacemaker  10  and some remote programming or analyzing device which can be part of a centralized service provider serving multiple pacemakers. 
     The implantable medical device  10  in  FIG. 3  is referred to as a three chamber pacemaker/cardioverter/defibrillator because it interfaces with the right atrium  26 , the right ventricle  28  and the left ventricle of the heart  12 . Those portions of the pacemaker  10  that interface with the right atrium, e.g., the lead  14 , the P-wave sensing stage and the stimulation pulse generator  52  and corresponding portions of the control unit CTRL  54 , are commonly referred to as the atrial channel. Similarly, those portions of the pacemaker  10  that interface with the right ventricle  28 , e.g., the lead  16 , the R-wave sensing stage and, the right ventricular stimulation pulse generator  50 , and corresponding portions of the control unit CTRL  54 , are commonly referred to as the right ventricular channel. 
     In order to be able to detect periods of physical activity of a patient indicating that the patient is awake and in order to allow rate adaptive pacing in a DDDR or a DDIR mode, the pacemaker  10  further includes a physiological sensor ACT  60  that is connected to the control unit CTRL  40  of the pacemaker  10 . While this sensor ACT  60  is illustrated in  FIG. 2  as being included within the pacemaker  10 , it is to be understood that the sensor may also be external to the pacemaker  10 , yet still be implanted within or carried by the patient. A common type of sensor is an accelerometer, such as a piezoelectric crystal, mounted to the case of the pacemaker. Other types of physiologic sensors are also known, such as sensors that sense the oxygen content of blood, respiration rate, blood pH, intra-cardiac impedance changes, and the like. The type of sensor used is not critical to the present invention. Any sensor capable of sensing some physiological parameter relatable to physical activity of a patient can be used. Such sensors are commonly used with “rateresponsive” pacemakers in order to adjust the rate of the pacemaker in a manner that tracks the physiological needs of the patient. 
     The control unit CTRL  54  is adapted to determine an adequate heart rate or stimulation rate in any manner known as such. 
     For impedance measurement, an impedance determination unit  70  is provided. Impedance determination unit  70  comprises a constant current source  72  that is connected or can be connected to electrodes for intracorporal placement as shown in  FIG. 1  or  3 . 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 . The switch is not shown in  FIG. 4 . Rather, a particular impedance measurement configuration is shown as an example. 
     Similarly, an impedance measuring unit  74  for measuring a voltage corresponding to a current fed through a body by said constant current source is provided and can be connected to a number of electrodes, although a switch for switching between these configurations is not shown in  FIGS. 4 and 5 . 
     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 impedance measurement 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 . 
     According to the embodiment shown in  FIGS. 1 and 2 , the measuring unit  74  and the constant current source  72  are both connected to the right ventricular tip electrode  18  and the IMD case electrode  42  for feeding the constant current via these electrodes and measuring the resulting voltage drop over these electrodes. 
     The embodiment of  FIGS. 3 and 4  allows for further impedance measurement configurations. 
     Further, an impedance measuring control and evaluation unit  78  is provided, that is connected to said impedance measurement unit and that is adapted to evaluate a sequence of consecutive impedance values determined by said impedance measurement unit. Impedance measuring control and evaluation unit  78  comprises a signal generator module (not shown) to construct the intra-cardiac impedance or conductance signal reflecting the time course of the impedance measurement unit&#39;s output signal and its derivative. 
     Impedance measuring control and evaluation unit  78  further comprises a filter module (not shown) to filter the intra-cardiac impedance signal. Impedance measuring control and evaluation unit  78  comprises is connected to memory  56  and to telemetry unit  58  to allow for storing of impedance data and further evaluation by an external service center. 
       FIG. 5  shows the algorithmic data processing as performed by the control unit  54  using the output signal from impedance determination unit  70 . 
     The output signal from impedance determination unit  70  is an impedance signal containing predominately cardiac functional information, such as the closed-loop-stimulation differential area (CLS DA) measurement as disclosed in U.S. Pat. No. 6,405,085, or another intra-cardiac impedance measurement is selected for a primary signal source. 
     The control unit  54  comprises a signal selection multiplexer (not shown) that isolates the variability in this impedance signal for processing an impedance signal containing predominately cardiac functional information. The variability in this impedance signal is measured and band-pass filtered. The disturbance signal is used to detect a putative apnea event. The putative apnea event is qualified by secondary correlates including the absence of physical activity and the presence of similar events in the recent history. 
     The episode detection process performed by the control unit  54  is adaptive. The apnea event and its duration is logged in the memory  56  as part of the statistics on the SDB burden. The SDB burden is transmitted to the central service center via the telemetry unit  58 . The SDB burden is made available to the device for actions to reduce the cardiac component of the SDB burden. 
     Eight delta impedance measurements (impedance change measurements) are performed spanning a systole from ˜46 ms to ˜280 ms following a ventricular activation (ventricular event). Each impedance or conductance change measurement reflects cardiac dynamics. For the purpose of creating an apnea detector, it is sufficient to consider the total resistance or impedance change due to systole. From the eight impedance change measurements, an RV Systolic Impedance Change signal, RV_SIC, is generated by control unit  54 . RV_SIC is the sum of the absolute values of the eight measurements obtained during systole. One RV_SIC value is determined for each ventricular contraction. 
     
       
         
           
             RV_SIC 
             = 
             
               
                 ∑ 
                 
                   i 
                   = 
                   1 
                 
                 8 
               
               ⁢ 
               
                  
                 
                   Δ 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   
                     Z 
                     i 
                   
                 
                  
               
             
           
         
       
     
     Then, control unit  54  generates a Total Active Right Ventricular Impedance signal, TARVI. The Total Active Right Ventricular Impedance, is a measure of the variability in the systolic impedance change and thus, TARVI is a measure of the variability in the RV_SIC signal. For a specific TARVI measurement at time point, t n . TARVI is the standard deviation of:
         1) the previous 8 RV_SIC values,   2) the nth RV_SIC value, and   3) the subsequent 8 RV_SIC values.       

     The value of 8 is used for demonstrative purposes and does not limit the band for isolating the spectral power.
 
TARVI n   =std (RV_SIC n−8  . . . SR_SIC n+8 )
 
     The TARVI result is delayed by 8 cardiac cycles. To facilitate computation, the control unit  54  calculates the mean absolute deviation rather than the square root of the variance. The device also normalizes TARVI to a zero mean. The device detects a putative apnea episode by the positive going threshold crossing of the normalized TARVI. The device provides post detection blanking, that is, once an apnea event is detected further detection is paused for an apnea blanking period of (for example) 30 s. Approximately thirty seconds blanking between detected episodes is useful to avoid multiple detections for a single crossing. The threshold crossing is usually coincident with the end of an apnea event. The detection threshold is automatically adjusted. 
     In the preferred embodiment, a putative apnea episode is accepted if both of the following criteria are met:
         1) the absence of activity on the accelerometer circuit for a suitable resting period and   2) a prior putative apnea event has occurred within 2 minutes.       

     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 Definition of Apnea Detection Contingency Table 
               
             
          
           
               
                   
                 Apnea present 
                 Breathing present 
                 total 
               
               
                   
                   
               
             
          
           
               
                 Apnea 
                 true positive breathing detected 
                 False positive breathing 
                 Total 
               
               
                 detected 
                 and apnea was present 
                 detected but apnea was present 
                 apnea 
               
               
                 Breathing 
                 False negative breathing 
                 true negative breathing 
                 Total 
               
               
                 detected 
                 detected but apnea was present 
                 detected and apnea was 
                 breathing 
               
               
                   
                   
                 present 
               
               
                   
               
             
          
         
       
     
     Sensitivity:
         ΣTrue Positives/(ΣTrue Positives+ΣFalse Negatives)   A high sensitivity means if apnea is not detected, then the patient probably has a low Apnea/Hypopnea Index (AHI).       

     Specificity:
         ΣTrue Negatives/(ΣTrue Negatives+ΣFalse Positives)   A high specificity means if apnea is detected, then the patient probably has an elevated AHI.       

     In order to be able to treat SDB, a nerve stimulation stage (not shown) is provided with the IMD and is connected to control unit  54 . The nerve stimulation stage is adapted to generate electric stimulation pulses for nerve stimulation. It is connected to or can be connected to a nerve stimulation electrode for stimulation of, for example, inhibitory nerves targeting the heart. The control unit  54  is adapted to trigger the nerve stimulation stage upon detection of SDB to stimulate the inhibitory nerves targeting the heart to reduce the cardiac excitability. 
     Alternatively, control unit  54  may be adapted to modify the heart rate by stimulation of the heart in order to reduce the cardiac excitability. 
     Although an exemplary embodiment of the present invention has been shown and described, it should be apparent to those of ordinary skill that a number of changes and modifications to the invention may be made without departing from the spirit and scope of the invention. In particular, it is possible to chose other electrode configurations for impedance determination based on the electrode configurations available for a particular device. This invention can readily be adapted to a number of different kinds of implantable medical devices by following the present teachings. All such changes, modifications and alterations should therefore be recognized as falling within the scope of the present invention.