Patent Publication Number: US-2011066055-A1

Title: System and method for use with an implantable medical device for detecting stroke based on physiological and electrocardiac indices

Description:
FIELD OF THE INVENTION 
     The invention generally relates to implantable medical devices, such as pacemakers and implantable cardioverter/defibrillators (ICDs) and, in particular, to techniques for detecting and responding to stroke within patients in which such devices are implanted. 
     BACKGROUND OF THE INVENTION 
     A stroke is a sudden loss of brain function caused by a blockage of a blood vessel to the brain (ischemic stroke) or a rupture of a blood vessel to the brain (hemorrhagic stroke). Each year, more than 700,000 people in the U.S. suffer a new or recurrent stroke and the consequences can be devastating. Some victims are physically and mentally devastated and unable to move, speak, or eat normally. About 15% of those who have a stroke die in the hospital. The proportion is even higher among the elderly. 
     Although the consequences of a stroke do not appear to be reversible, early intervention (particularly within the first one to three hours) can significantly reduce morbidity and mortality. Moreover, the degree of long-term impairment as a result of stroke can typically be reduced through prompt intervention. Accordingly, it would be highly desirable to provide techniques for detecting the onset of a stroke within a patient and for promptly alerting family members, caregivers or emergency personnel, and it is to that end that the invention is generally directed. It would also be desirable to automatically deliver therapy in response to the stroke to mitigate harm. 
     As many patients at risk of stroke are candidates for implantable medical devices such as pacemakers and ICDs, it would be particularly desirable to equip such devices with the capability to detect and respond to stroke. This is especially important for patients known to suffer from atrial fibrillation (AF) as these patients are at particular risk of having a stroke. 
     SUMMARY OF THE INVENTION 
     In an exemplary embodiment, a method is provided for detecting a stroke event for use by an implantable medical device for implant within a patient. Electrocardiac and physiological signals are sensed within the patient. A plurality of indices is derived from the electrocardiac signals and the physiological signals based on parameters affected by stroke. A stroke event is then detected within the patient based on an examination of the plurality of indices. Warnings are generated, neurostimulation is delivered, pacing therapy is adjusted, medications are delivered and/or other device functions are controlled in response to the indication of the stroke. 
     In one particular example, the electrocardiac signals sensed by the device include intracardiac electrograms (IEGMs) obtained within various chambers of the heart. The physiological signals include arterial and systolic blood pressure signals. The following indices are derived from these signals: a heart rate variability index (HRV_Index); a heart rate turbulence index (HRT_Index); a baroreflex index (BRS_Index); a QT index (QT_Index); a respiration index (RESP_Index); and a circadian variability index (CV_Index). Also, time delta indices are generated for each index representative of a time rate of change of the index. 
     The device then generates a composite stroke index from the plurality of separate indices using, e.g., the following equation: 
     
       
         
           
             
               
                 Composite 
                  
                 
                     
                 
                  
                 Stroke 
                  
                 
                     
                 
                  
                 Index 
               
               = 
               
                 
                   
                     HRV_Index 
                     / 
                     HRVtime_Delta 
                   
                    
                   _Index 
                 
                 + 
                 
                   
                     HRT_Index 
                     / 
                     HRTtime_Delta 
                   
                    
                   _Index 
                 
                 + 
                 
                   
                     BRS_Index 
                     / 
                     BRStime_Delta 
                   
                    
                   _Index 
                 
                 + 
                 
                   
                     QT_Index 
                     / 
                     QTtime_Delta 
                   
                    
                   _Index 
                 
                 + 
                 
                   
                     RESP_Index 
                     / 
                     RESPtime_Delta 
                   
                    
                   _Index 
                 
                 + 
                 
                   
                     CV_Index 
                     / 
                     CVtime_Delta 
                   
                    
                   _Index 
                 
               
             
             , 
           
         
       
     
     The device compares the composite index against a threshold indicative of a stroke event. If stroke is indicated, the device can respond by generating both internal warning signals for alerting the patient and external warning signals (via bedside monitors or the like) for notifying family members, caregivers or emergency personal. In particular, the device can notify urgent care centers for immediate response. 
     If so equipped, the device can deliver neurostimulation to the patient in an effort to improve heart rate and blood pressure in response to the stroke. Such stimulation can include, e.g., spinal cord stimulation, baro-receptor stimulation and sympathetic nerve stimulation. Pacing can also be controlled in response to stroke. For example, rate smoothing or paired pacing can be activated. Any changes in pacing can be synchronized with real-time changes in blood pressure detected within the patient. Also, if equipped with an implantable drug dispensing system such as a drug infusion pump, medications can be delivered directly to the patient in response to the stroke. 
     In addition to controlling pacing and/or neurostimulation therapy in response to the onset of the acute stroke, such therapy can also be controlled to work in conjunction with physician-directed therapy for the patient. 
     The implantable device can also be used to track improvement in patient condition after the patient has had the stroke and is then undergoing treatment. 
     System and method examples of the invention are described herein below. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The above and further features, advantages and benefits of the invention will be apparent upon consideration of the descriptions herein taken in conjunction with the accompanying drawings, in which: 
         FIG. 1  illustrates pertinent components of an implantable medical system capable of detecting the onset of a stroke based on electrocardiac and physiological signals sensed within the patient; 
         FIG. 2  provides an overview of the method for detecting stroke performed by the system of  FIG. 1 , which exploits a set of indices derived from various electrocardiac and physiological signals sensed by the system of  FIG. 1 ; 
         FIG. 3  illustrates an exemplary embodiment of the general technique of  FIG. 2 , wherein a composite stroke index is derived from a combination of individual indices; 
         FIG. 4  summarizes the derivation of the heart rate variability (HRV_Index) for use with the technique of  FIG. 3 ; 
         FIG. 5  is a graph illustrating the power spectra of heart rate variability for a healthy patient, portions of which are exploited in the derivation of the HRV_Index of  FIG. 4 ; 
         FIG. 6  is a graph illustrating the power spectra of heart rate variability for a patient after a stroke, illustrating the effect of the stroke on heart rate variability, which is quantified by the HRV_Index of  FIG. 4 ; 
         FIG. 7  summarizes the derivation of the heart rate turbulence index (HRT_Index) for use with the technique of  FIG. 3 ; 
         FIG. 8  summarizes the derivation of the baroreflex index (BRS_Index) for use with the technique of  FIG. 3 ; 
         FIG. 9  summarizes the derivation of the QT index (QT_Index) for use with the technique of  FIG. 3 ; 
         FIG. 10  summarizes the derivation of the respiration index (RESP_Index) for use with the technique of  FIG. 3 ; 
         FIG. 11  summarizes the derivation of the circadian variability index (CV_Index) for use with the technique of  FIG. 3 ; 
         FIG. 12  is a graph illustrating circadian variations in high frequency components of heart rate variability for a healthy patient and a patient after a stroke, illustrating the effect of the stroke on the circadian variability, which is quantified by the CV_Index of  FIG. 11 ; 
         FIG. 13  summarizes the derivation of the composite stroke index for use with the technique of  FIG. 3 ; 
         FIG. 14  is a simplified, partly cutaway view, illustrating the pacer/ICD of  FIG. 1  along with at set of leads implanted into the heart of the patient; and 
         FIG. 15  is a functional block diagram of the pacer/ICD of  FIG. 14 , illustrating basic circuit elements that provide cardioversion, defibrillation and/or pacing stimulation in the heart and particularly illustrating components for detecting and responding to stroke using the techniques of  FIGS. 2-13 . 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The following description includes the best mode presently contemplated for practicing the invention. This description is not to be taken in a limiting sense but is made merely to describe general principles of the invention. The scope of the invention should be ascertained with reference to the issued claims. In the description of the invention that follows, like numerals or reference designators are used to refer to like parts or elements throughout. 
     Overview of Implantable Medical System 
       FIG. 1  illustrates an implantable medical system  8  capable of detecting a cerebral stroke within a patient based on indices derived from electrocardiac and physiological signals. To this end, medical system  8  includes a pacer/ICD  10  or other cardiac rhythm management (CRM) device capable of detecting electrocardiac signals via cardiac sensing/pacing leads  12  implanted within the heart of the patient. The leads may be equipped with blood pressure sensors, photo-plethysmography (PPG) sensors, or other physiological sensors. One such physiological sensor  13  is shown implanted in the RV. This is merely exemplary. Other sensors may be implanted at other locations, in or around the heart or elsewhere within the patient. Note that in  FIG. 1  only two exemplary leads are shown—an RV lead and an LV lead, in stylized form. A more complete set of leads is illustrated in  FIG. 14 . 
     Warning signals may be generated to warn of stroke using an internal warning device within the pacer/ICD, a bedside monitor  14 , or a hand-held personal advisory module (PAM), not separately shown. The internal warning device (not shown in  FIG. 1 ) may be a vibrating device or a “tickle” voltage device that, in either case, provides perceptible stimulation to the patient to alert the patient. The bedside monitor or PAM then alerts family members or caregivers of the stroke and may also forward warning signals or other suitable information via a centralized processing system  14  to the patient&#39;s primary care physician or, in some implementations, directly to emergency personnel. Such an alarm would enable the patient/family to recognize the stroke early, so that the patient can be taken to the emergency care immediately. The centralized system may include such systems as the HouseCall™ system or the Merlin@home/Merlin.Net/Merlin Mobile systems of St. Jude Medical. 
     In some examples, the implantable system may be equipped with a drug pump  16  capable of the delivering medications to patient tissues in response to the stroke. Implantable drug pumps for use in dispensing medications are discussed in U.S. Pat. No. 5,328,460 to Lord, et al., entitled “Implantable Medication Infusion Pump Including Self-Contained Acoustic Fault Detection Apparatus.” This patent also discusses implantable “tickle” warning devices that may be used to deliver warning signals to the patient. 
     Diagnostic information pertaining to the stroke may be stored within the pacer/ICD for transmission to the PAM, bedside monitor or to an external programmer (not shown in  FIG. 1 ) for review by a clinician. The clinician then prescribes any appropriate therapies. The clinician may also adjust the operation of the pacer/ICD to activate, deactivate or otherwise control any therapies that are automatically applied. 
     The pacer/ICD may also be programmed to activate, adjust or control any pacing therapies that might be appropriate in response to stroke, such as activating rate smoothing or paired pacing. Still further, if equipped with suitable neurostimulators (such as a spinal cord neurostimulator  18 ) neurostimulation can be selectively applied to nerves of the patient in response to stroke. Additionally, the pacer/ICD performs a wide variety of pacing and/or defibrillation functions such as delivering pacing is response to arrhythmias or generating and delivering shocks in response to ventricular fibrillation. 
       FIG. 2  broadly summarizes a general technique for detecting stroke that may be performed by the implantable system of  FIG. 1  or other suitably equipped systems. Beginning at step  100 , the pacer/ICD senses electrocardiac and physiological signals within the patient and, at step  102 , derives a plurality of indices from the electrocardiac and physiological signals based on parameters affected by stroke. As will be explained in greater detail, such indices may include a heart rate variability index, a heart rate turbulence index, a baroreflex index, etc. At step  104 , the pacer/ICD then detects a stroke event within the patient based on an examination of the plurality of indices. In one example, the indices are combined into a composite stroke index for comparison against a threshold indicative of a stroke event. At step  106 , the device generates warnings, delivers neurostimulation, adjusts pacing, delivers medications and/or controls other device functions in response to the stroke. 
     Hence,  FIGS. 1 and 2  provide an overview of an implantable system and method capable of detecting stroke within a patient and further capable of controlling pacing, delivering medications, control neurostimulation, delivering warnings, etc., in response to the stroke. Embodiments may be implemented that do not necessarily perform all of these functions. For example, embodiments may be implemented that provide only for generating warnings in response to stroke without necessarily delivering medications or controlling therapy. In addition, systems provided in accordance with the invention need not include all the components shown in  FIG. 1 , such as the bedside monitor, the implantable drug pump or the neuro-stimulator. No attempt is made herein to describe all possible combinations of components that may be provided in accordance with the general principles of the invention. Also, note that, the particular shape, size and locations of the implanted components shown in  FIG. 1  are merely illustrative and may not necessarily correspond to actual implant locations. In particular, preferred implant locations for the leads are more precisely illustrated in  FIG. 14 . 
     Exemplary Index-Based Stoke Detection Technique 
       FIG. 3  illustrates an exemplary index-based stroke detection technique wherein stroke indices and time delta indices are exploited. Beginning at step  200 , the pacer/ICD senses, records and stores IEGMs from the right atrium (RA), right ventricle (RV), left ventricle (LV) and the left atrium (LA) of the patient. With a set of bipolar or multipolar leads, numerous sensing vectors can be exploited. For the purposes of this example, it is assumed that at least one IEGM is sensed and stored for each of the RA, LA, RV, and LV. 
     At step  202 , the pacer/ICD derives electrocardiac interval parameters from all four chambers, including RR interval, QT interval, QRS width and T-wave width. Other interval parameters that might also be derived include PP intervals, PR intervals, ST intervals and P-wave width. 
     At step  204 , the pacer/ICD derives morphological parameters from all IEGMs, including parameters representative of QRS morphology, P-wave morphology, and T-wave morphology. Specific morphological parameters can include the waveform amplitude, slope, integral, etc. 
     At step  206 , the pacer/ICD detects and records physiological sensor parameters such as arterial and systolic blood pressure, respiration rate and respiration depth. Systolic blood pressure can be detected using, e.g., a PPG sensor. PPG sensors are discussed in U.S. patent application Ser. No. 11/927,026, filed Oct., 29, 2007, entitled “Systems and Methods for Exploiting Venous Blood Oxygen Saturation in Combination with Hematocrit or other Sensor Parameters for use with an Implantable Medical Device.” Arterial blood pressure detection techniques are discussed in U.S. patent application Ser. No. 11/378,604, filed Mar. 16, 2006, of Kroll et al., entitled, “System and Method for Detecting Arterial Blood Pressure based on Aortic Electrical Resistance using an Implantable Medical Device.” Particularly effective techniques for integrating one or more physiological sensors into pacing/sensing leads are set forth in U.S. patent application Ser. No. 11 /623,663, filed Jan. 16, 2007, of Zou et al., entitled “Sensor/Lead Systems for use with Implantable Medical Devices.” 
     Respiration parameters can be detected using any of a variety of techniques. For example, IEGMs can be exploited. See, U.S. Pat. No. 7,361,146, to Bharmi, et al., entitled “System and Method for Detecting Abnormal Respiration via Respiratory Parameters derived from Intracardiac Electrogram Signals.” Also, impedance can be used to track respiration. See, e.g., U.S. Pat. No. 6,449,509 to Park, et al., entitled “Implantable Stimulation Device having Synchronous Sampling for a Respiration Sensor.” Respiration parameters can also be obtained from heart sounds. See, e.g., U.S. Pat. No. 6,064,910 to Andersson, et al., entitled “Respirator Rate/Respiration Depth Detector and Device for Monitoring Respiratory Activity Employing Same.” 
     At step  208 , the pacer/ICD then derives from the various parameters obtained at steps  202 - 206 : a Heart Rate Variability Index (HRV_Index); a Heart Rate Turbulence Index (HRT_Index); a Baroreflex Index (BRS_Index); a QT Index (QT_Index); a Respiration Index (RESP_Index); a Circadian Variability Index (CV_Index); and a Time Delta Index for each individual Index. Techniques for deriving these particular indices are discussed below with reference to  FIGS. 4-12 . It should be understood that, in some examples, not all of these indices are calculated. In other examples, additional or alternative indices can be used. 
     At step  210 , the pacer/ICD then generates a composite stroke index based on the various individual indices and their respective time deltas. This is described in greater detail below with reference to  FIG. 13 . At step  212 , the pacer/ICD compares the composite index against a threshold indicative of stroke event. If the index exceeds the threshold, a cerebral stroke is thereby detected. If stroke is detected, the pacer/ICD generates warnings, delivers neurostimulation, delivers smoothed or paired pacing, delivers medications, records diagnostics, etc. 
     It is particularly important to restore blood pressure and heart rate following a stroke. A combination of neurostimulator and cardiac pacing can prevent help hemodynamic compromise of the patient to reduce the impact to the patient by closely tying the pacing scheme to real-time pressure. Hence, in some examples, therapy is delivered in conjunction with (or synchronized with) real-time blood pressure changes. For example, if the blood pressure is particularly low, certain types of therapy might be delivered that would not otherwise be delivered if the blood pressure were normal. In this regard, a major concern during stroke is maintenance of blood pressure. It is recommended that the blood pressure should not be low (e.g. less than 120 mmHg), but not too high either (e.g. not greater than 180 mmHg.) Multiple thresholds of differing levels may be used to evaluate the severity of the stroke and, in some examples, the response by the pacer/ICD to the stroke depends on the level of severity. 
     As noted above, warnings may be relayed through external systems or networks to family members, caregivers, emergency personnel, etc. 
     Neurostimulation may be delivered via the spinal cord, baro-receptors or sympathetic nerves, depending upon the capabilities of the device. Spinal cord stimulation via an implantable lead is discussed, e.g., in U.S. Pat. No. 7,099,718, to Thacker, et al. Baro-receptor stimulation to control blood pressure is discussed in U.S. Pat. No. 6,050,952 to Hakki, et al. Techniques for stimulating sympathetic nerves are discussed in U.S. Pat. No. 6,937,896, to Kroll, entitled, “Sympathetic Nerve Stimulator and/or Pacemaker.” 
     Rate smoothed pacing is discussed in U.S. Pat. No. 6,636,766, Bornzin, et al., “System and Method for Preventing Sudden Heart Rate Drop using Implantable Cardiac Pacing Device.” Paired pacing is discussed in U.S. patent application Ser. No. 11/929,719, of Bornzin et al., filed Oct. 30, 2007, entitled “Systems and Methods for Paired/Coupled Pacing and Dynamic Overdrive/Underdrive Pacing.” 
     Insofar as delivery of medications are concerned, tPA tissue plasminogen activator or like compounds can be used to help restore blood flow to the brain immediately following are stroke. (Note that tPA tissue plasminogen activator is a thrombolytic agent, i.e. a compound for breaking down clots). After the stroke is completed, anticoagulants can be given to prevent subsequent stokes, particularly in patients known to have atrial fibrillation or a heart-valve disorder. Suitable versions of these or other compounds may be identified for dispensing via an implantable drug dispensing unit, drug infusion unit and/or drug pump under the control of the pacer/ICD. See, e.g., U.S. Pat. No. 7,235,530, to Blair, et al., entitled “Kallikrein Inhibitors and Anti-Thrombolytic Agents and Uses Thereof,” which discusses compounds suitable for delivery via a medication infusion pump. 
     If the device is equipped with an alternative or secondary stroke detection system, it might be desirable in some implementations to confirm the detection of stroke using the alternative system before therapy is delivered. See, for example, the aforementioned patent application of Park, which discusses the use of U-waves, notched T-waves, and changes in ST segment duration or QT duration to provide a preliminary indication of stroke. (As noted above, the system of Park uses an external questionnaire-based confirmation system wherein family members or other caregivers input answers to a questionnaire into an external system, which then confirms the stroke. As the present invention is directed to providing prompt detection of stroke by the pacer/ICD itself, a questionnaire is not used.) 
     Note also that, in addition to controlling pacing and/or neurostimulation therapy in response to the onset of the acute stroke, therapy can also be controlled to work in conjunction with physician-directed therapy for the patient. The pacer/ICD can also be equipped to detect and record diagnostic information and to monitor for improvement in patient condition after the patient has had stroke and is undergoing treatment. For example, changes in the composite stroke index may be periodically recorded as an indication of patient recovery. 
     Turning now to  FIGS. 4-12 , exemplary techniques for deriving the individual indices will now be described. 
       FIG. 4  summarizes derivation of the heart rate variability index. A cerebral infarction located particularly in the hemispheric level or in the medullary oblongata causes cardiovascular autonomic dysregulation manifesting itself as impaired heart rate variability. Heart rate variability parameters correlate with functional independence measures in ischemic stroke patients. The values of HRV stay significantly lower after the acute phase of the disease in patients who have suffered ischemic stroke compared to healthy persons of the same age. Moreover, impaired heart rate variability correlates with the severity of neurological deficits and disability. 
     Accordingly, at step  250 , the pacer/ICD analyzes the electrocardiac interval parameters detected at step  202  of  FIG. 3  to extract or derive: a set of recently detected RR intervals (RRI), such as the last 256RR intervals or the last 4 minutes worth of RR interval data; the standard-deviation of the set of RR intervals (SDNN); a very low frequency power component of the set of RR intervals (VLF_POWER); a low frequency power component of the set of RR intervals (LF_POWER); and a high frequency power component of the set of RR intervals (HF_POWER). To this end, a Fast-Fourier Transform or other suitable technique may be employed to derive power spectra from the RR interval data, resulting in a power spectral curve of the type shown in  FIGS. 5 and 6 . The area under the spectral curve from 0.005 to 0.4 Hz represents the total power of heart rate variability, the area from 0.15 to 0.4 Hz represents HF power, the area from 0.04 to 0.15 Hz represents LF power, and the area from 0.005 to 0.04 Hz represents VLF power. See, e.g., Korpelainen et al., “Abnormal Heart Rate Variability as a Manifestation of Autonomic Dysfunction in Hemispheric Brain Infarction” Stroke. 1996;27:2059-2063. 
     More specifically,  FIG. 5  illustrates the power spectra 254 of RR intervals observed in a healthy 61-year-old male control subject.  FIG. 6  illustrates the power spectra 256 for a 61-year-old male patient four days after a right hemisphere brain infarction (i.e. stroke). As can be seen, all but the lowest frequency components of heart rate variability are suppressed in the stroke patient, indicative of very little variability in heart rate. As such, an index representative of the distribution of spectral components of heart rate variability can be indicative of stroke. 
     At step  258 , the pacer/ICD calculates an HRV_Index from RRI, SDNN, VLF_POWER, LF_POWER AND HF_POWER by using an average or weighted average. In one example, the following equation is used to calculate the HRV_Index: 
     
       
         
           
             HRV_Index 
             = 
             
               
                 a 
                 * 
                 R 
                  
                 
                     
                 
                  
                 R 
                  
                 
                     
                 
                  
                 
                   I 
                   / 
                   
                     mean 
                      
                     
                       ( 
                       
                         Heart 
                          
                         
                             
                         
                          
                         rate 
                       
                       ) 
                     
                   
                 
               
               + 
               
                 b 
                 * 
                 
                   SDNN 
                   / 
                   
                     mean 
                      
                     
                       ( 
                       
                         Heart 
                          
                         
                             
                         
                          
                         rate 
                       
                       ) 
                     
                   
                 
               
               + 
               
                 c 
                 * 
                 
                   
                     ( 
                     
                       VLF_POWER 
                       + 
                       LF_POWER 
                       + 
                       HF_POWER 
                     
                     ) 
                   
                   / 
                   
                     ( 
                     
                       3 
                       * 
                       Total 
                        
                       
                           
                       
                        
                       Power 
                     
                     ) 
                   
                 
               
             
           
         
       
     
     and where a=10%, b=20%, c=70%. 
       FIG. 7  summarizes derivation of the heart rate turbulence index. HRT is an autonomous baro-reflex that is weakened/eliminated with stroke. HRT consists of a short initial acceleration followed by a deceleration of the heart rate following a premature ventricular contraction. The premature ventricular contraction causes a brief disturbance of the arterial blood pressure (low amplitude of the premature beat, high amplitude of the ensuing normal beat). When the autonomic control system of the patient is intact, this fleeting change is registered immediately with an instantaneous response in the form of HRT. If the autonomic control system is impaired, this reaction is either weakened or entirely missing. 
     Accordingly, at step  260 , the pacer/ICD analyzes the IEGM signals detected at step  200  of  FIG. 3  to detect premature ventricular contractions (PVCs) using otherwise conventional techniques. Alternatively, PVCs can be generated by a premature RV paced beat. Then, at step  262 , the pacer/ICD examines arterial pressure signals (detected at step  206  of  FIG. 3 ) to detect HRT response to PVC, then quantifies the response as the HRT_Index. In one example, the following equation/procedure is used to calculate the HRT_Index: 
       HRT_Index=(Turbulence onset+Turbulence slope+Turbulence timing)/mean(heart rate). 
     That is, the quantification of HRT may be achieved via Turbulence onset and turbulence slope. Turbulence Onset (TO) is the percentage difference between the heart rate immediately following PVC and the heart rate immediately preceding PVC. It may be calculated using the equation: 
       TO=(( RR 1 +RR 2)−( RR -2 +RR -1))/( RR -2 +RR -1)*100
 
     where RR-2 and RR-1 are the first two normal intervals preceding the PVC and RR1 and RR2 are the first two normal intervals following the PVC. Initially, TO is determined for each individual PVC, followed by the determination of the average value of all individual measurements. Positive values for Turbulence Onset indicate deceleration; negative values indicate acceleration of the sinus rhythm. 
     The Turbulence Slope (TS) corresponds to the steepest slope of the linear regression line for each sequence of five consecutive normal intervals in the local tachogram. The Turbulence Slope calculations are based on the averaged tachogram and expressed in ms per RR interval. Turbulence timing (TT) may be determined by the beat number of the 5 RR interval sequence used in the TS calculation at which the largest slope occurs. 
     See, for example, Watanabe, et al. “Effects of ventricular premature stimulus coupling interval on blood pressure and heart rate turbulence.” Circulation. Jul. 16, 2002;106(3):325-30.  FIG. 8  summarizes the derivation of the baroreflex (BRS) index. BRS decreases during exercise and mental activity and peaks during sleep. BRS can be measured by a ratio between changes in RR interval and changes in systolic blood pressure in a mid-frequency band (0.07-0.14 Hz). Accordingly, at step  264 , the pacer/ICD analyzes the IEGM interval parameters (detected at step  202  of  FIG. 3 ) to detect changes in RR intervals over time and also analyzes physiological signals (detected at step  206  of  FIG. 3 ) to detect changes in systolic blood pressure over time within a mid-frequency spectral band (0.07-0.14 HZ) derived from the systolic pressure signals. At step  266 , the pacer/ICD then calculate the BRS_Index as a ratio of changes in RR intervals over time to changes in systolic blood pressure over time within the mid-frequency spectral band. 
     For example, changes in RR interval may be represented as ΔRR. Changes in systolic pressure within the mid-frequency spectral band may be represented as ΔP sys . 
       BRS_Index=(Δ RR/ΔP   sys )/(mean heart rate/mean systolic pressure)
 
       FIG. 9  summarizes derivation of the QT index. Deep brain infarction can result in a significant dysfunction of the autonomic nervous system, manifesting itself as distorted dynamic behavior of the QT interval and with impaired functional performance. Accordingly, at step  268 , the pacer/ICD analyzes the IEGM interval parameters (detected at step  202  of  FIG. 3 ) to detect QT duration and QT dispersion and calculate daily mean values of these parameters. Then, at step  270 , the pacer/ICD quantifies the extent to which individual QT duration and QT dispersion values deviate from the daily mean values as QT_Index. In one example, the following equation is used to calculate the QT_Index: 
     
       
         
           
             QT_Index 
             = 
             
               QTVI 
               = 
               
                 
                   log 
                   10 
                 
                  
                 
                   [ 
                   
                     
                       
                         QT 
                         v 
                       
                       / 
                       
                         QT 
                         m 
                         2 
                       
                     
                     
                       
                         HR 
                         v 
                       
                       / 
                       
                         HR 
                         m 
                         2 
                       
                     
                   
                   ] 
                 
               
             
           
         
       
     
     Classically, QT dispersion is defined as the difference between the maximum and minimum QT interval of the 12 lead ECG. For the purposes of the present descriptions, QT dispersion refers to a measure of variance of QT intervals. QTVI can be measured using consecutive 256 beats and a running average can be maintained over 24 hours. It may be calculated as a logarithm of the ratio of normalized QT variance to heart rate variance. QT_Index is, in one example, the difference between the 24 hour-long term QTVI and the instantaneous (i.e. current) QTVI. See, e.g. Berger et al. “Beat-to-Beat QT Interval Variability: Novel Evidence for Repolarization Lability in Ischemic and Nonischemic Dilated Cardiomyopathy”, Circulation. 1997;96:1557-1565. 
       FIG. 10  summarizes derivation of the respiration index. A unilateral medullary infarction can result in an extremely rapid and shallow tachypnea due to the increase in respiratory drive. The heart rate response to normal breathing, the Valsalva maneuver and tilting are significantly impaired in both hemispheric and brain stem infarctions, due to hypofunction of the parasympatheric nervous system. Accordingly, at step  272 , the pacer/ICD analyzes IEGM and/or other signals (such as impedance signals or PPG signals) representative of respiration to detect respiration rate, respiration depth and heart response to respiration. At step  274 , the pacer/ICD then calculates RESP_Index as a function of respiration rate, respiration depth and heart response to respiration. In one example, the following equation/procedure is used to calculate the RESP_Index: 
     
       
         
           
             RESP_Index 
             = 
             
               
                 
                   ∑ 
                   
                     x 
                     = 
                     
                       1 
                        
                       
                         : 
                       
                        
                       20 
                     
                   
                   
                       
                   
                 
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                    
                   i 
                 
               
             
           
         
       
     
     where Te-i=Time Interval between inspiration and expiration, which may be calculated over 20 beats and averaged. TDe-i=Depth of respiration calculated as absolute difference between peak expiration and peak inspiration (which may be calculated over 20 beats and averaged.) Resp_lndex is expressed as the sum of the above two terms divided by the average interval between inspiration and expiration calculated over a 24 hour interval. 
       FIG. 11  summarizes derivation of the circadian variability (CV) index. Circadian fluctuation of heart rate variability is reversibly abolished in the acute phase of ischemic stroke and then it returns during the subsequent six months. The loss of the relative vagal nocturnal dominance may contribute to the incidence of cardiac arrhythmias and other cardiovascular complications after acute stroke. IEGM-based respiration rate and depth variation during a twenty-four hour period can be used to reflect the circadian rhythm variability. Additionally, the HRV high frequency component (discussed above) also reflects the circadian rhythm variability. A running average of twenty-four hour circadian rhythm variability template can be maintained and compared with the current HRV high frequency component, e.g. the HRV feature at 7:00 am is compared against the corresponding 7:00 am component from the template, and the correlation coefficient forms the CV_Index. As the patient condition improves, the CV index will change and can be used to monitor chronic recovery of the patient. 
     Accordingly, at step  276 , the pacer/ICD analyzes the electrocardiac interval parameters detected at step  202  of  FIG. 3  to extract or derive HRV parameters, which are recorded over a twenty-four hour period. At step  276 , the pacer/ICD also calculates a twenty-four hour running average and stores the average as a template. 
       FIG. 12  illustrates the circadian variation  278  in the high frequency component of heart rate variability (based on HRV means) in healthy control subjects (Hist(i)). In contrast, curve  280  illustrates the circadian variation in patients with acute brain infarction (C(i)). See, e.g., Korpelainen et al., “Circadian Rhythm of Heart Rate Variability Is Reversibly Abolished in Ischemic Stroke.” Stroke. 1997;28:2150-2154. As can be seen, there is relatively little circadian variation in the brain infarction patients. As such, an index representative of the circadian variation can be indicative of stroke. 
     At step  258 , the pacer/ICD compares the current HRV value for a given time (e.g. 7:00 am) against the corresponding portion of the stored template to generate a correlation coefficient for use as CV_Index. In one example, the following equation is used to calculate the CV_Index: 
       CV_Index=Absolute (Hist( i )− C ( i ))/Integral of Hist( i ) over 24 hour period.
 
     As shown in  FIG. 12 , a 24 hour circadian trend can be stored and continuously rebuilt. At any given point in time, the current circadian variable (e.g. HF power) can be compared with the circadian variable 24 hours before. For example, the circadian trend can be derived as a measurement of QTinterval instead of HF power such that the units are in milliseconds. The CV_index can then be calculated as a difference as shown in the equation above, divided by the integral of the circadian trend. 
       FIG. 13  summarizes derivation of the composite stroke index based on the various individual indices. At step  284 , the pacer/ICD calculates time delays for all individual indices representative of the time rates of change of the indices. In this regard, strokes develop abruptly, hence a measure of the time delay of occurrence of the changes in the various indices is a useful feature. The time delta may be represented as the amount of time it takes for the index to change from its current value to the threshold value. With the device monitoring continuously, the device thereby can record a time trend to determine this information. Hence, for each individual index, e.g. HRV index, if the index changes above a respective threshold (e.g. HRVindexThreshold), the time delta of the change will be recorded by the device as: HRVtime_delta_index. (Particular values for use as the respective thresholds can be determined in advance based on an analysis of the stroke indices for healthy patients as compared with indices for stroke patients.) The time delta index can be quantified as a graded measure from the TIMEdelta on a scale of 0 to 1, as shown in TABLE 1: 
     
       
         
           
               
               
               
             
               
                   
                 TABLE I 
               
               
                   
                   
               
               
                   
                 Time 
                 Time Delta index 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 0-10 sec 
                 0.1 
               
               
                   
                 10 sec-100 sec 
                 .2 
               
               
                   
                 100 sec-150 sec 
                 .3 
               
               
                   
                 150 sec-200 sec 
                 .4 
               
               
                   
                 200 sec-250 sec 
                 .5 
               
               
                   
                 250 sec-300 sec 
                 .6 
               
               
                   
                 300 sec-1 day 
                 .7 
               
               
                   
                 1 day-3 days 
                 .8 
               
               
                   
                 3 days-1 week 
                 .9 
               
               
                   
                 1 week-1 month 
                 1.0 
               
               
                   
                   
               
            
           
         
       
     
     At step  286 , the pacer/ICD then calculates the composite stroke index as: 
     
       
         
           
             
               Composite 
                
               
                   
               
                
               Stroke 
                
               
                   
               
                
               Index 
             
             = 
             
               
                 
                   HRV_Index 
                   / 
                   HRVtime_Delta 
                 
                  
                 _Index 
               
               + 
               
                 
                   HRT_Index 
                   / 
                   HRTtime_Delta 
                 
                  
                 _Index 
               
               + 
               
                 
                   BRS_Index 
                   / 
                   BRStime_Delta 
                 
                  
                 _Index 
               
               + 
               
                 
                   QT_Index 
                   / 
                   QTtime_Delta 
                 
                  
                 _Index 
               
               + 
               
                 
                   RESP_Index 
                   / 
                   RESPtime_Delta 
                 
                  
                 _Index 
               
               + 
               
                 
                   CV_Index 
                   / 
                   CVtime_Delta 
                 
                  
                 
                   _Index 
                   . 
                 
               
             
           
         
       
     
     As already explained, this composite stroke index is compared against a threshold indicative of stroke to detect a stroke event. (The particular value for use as the composite threshold can be determined in advance based on an analysis of composite stroke indices for healthy patients as compared with indices for stroke patients. The threshold value is then programmed into the pacer/ICD.) The composite index may be used, not only to detect stroke, but to also monitor patient recovery following the stroke. For example, the pacer/ICD can periodically record the stroke index for use a diagnostic tool in evaluating recovery. 
     As can be appreciated, the particular combination of indices listed at step  286  is only exemplary. Other composite indices can be derived using more or fewer individual indices. In some cases, only a single index might be used (such as only the HRV index and its respective time delta), rather than a composite index. 
     What have been described are various techniques for detecting stoke within a patient. A detailed description of an exemplary pacer/ICD for implementing these techniques will now be provided. However, principles of invention may be implemented within other pacer/ICD implementations or within other implantable devices such as stand-alone stroke monitoring devices, CRT devices or CRT-D devices. 
     Furthermore, although examples described herein involve processing of data by the implanted device itself to detect stroke, some operations might be performed using an external device, such as a bedside monitor, device programmer, computer server or other external system. For example, recorded data could be transmitted to an external device, which then processes the data to detect stroke. Processing by the implanted device itself is preferred as that allows the device to promptly detect stroke and to issue immediate warnings, deliver therapy, etc. 
     Exemplary Pacer/ICD 
       FIG. 14  provides a simplified block diagram of the pacer/ICD, which is a dual-chamber stimulation device capable of treating both fast and slow arrhythmias with stimulation therapy, including cardioversion, defibrillation, and pacing stimulation, as well as capable of performing the stroke detection functions described above. To provide atrial chamber pacing stimulation and sensing, pacer/ICD  10  is shown in electrical communication with a heart  312  by way of a left atrial lead  320  having an atrial tip electrode  322  and an atrial ring electrode  323  implanted in the atrial appendage. Pacer/ICD  10  is also in electrical communication with the heart by way of a right ventricular lead  330  having, in this embodiment, a ventricular tip electrode  332 , a right ventricular ring electrode  334 , a right ventricular (RV) coil electrode  336 , and a superior vena cava (SVC) coil electrode  338 . Typically, the right ventricular lead  330  is transvenously inserted into the heart so as to place the RV coil electrode  336  in the right ventricular apex, and the SVC coil electrode  338  in the superior vena cava. Accordingly, the right ventricular lead is capable of receiving cardiac signals, and delivering stimulation in the form of pacing and shock therapy to the right ventricle. 
     To sense left atrial and ventricular cardiac signals and to provide left chamber pacing therapy, pacer/ICD  10  is coupled to a “coronary sinus” lead  324  designed for placement in the “coronary sinus region” via the coronary sinus os for positioning a distal electrode adjacent to the left ventricle and/or additional electrode(s) adjacent to the left atrium. As used herein, the phrase “coronary sinus region” refers to the vasculature of the left ventricle, including any portion of the coronary sinus, great cardiac vein, left marginal vein, left posterior ventricular vein, middle cardiac vein, and/or small cardiac vein or any other cardiac vein accessible by the coronary sinus. Accordingly, an exemplary coronary sinus lead  324  is designed to receive atrial and ventricular cardiac signals and to deliver left ventricular pacing therapy using at least a left ventricular tip electrode  326 , left atrial pacing therapy using at least a left atrial ring electrode  327 , and shocking therapy using at least a left atrial coil electrode  328 . With this configuration, biventricular pacing can be performed. Although only three leads are shown in  FIG. 14 , it should also be understood that additional stimulation leads (with one or more pacing, sensing and/or shocking electrodes) may be used in order to efficiently and effectively provide pacing stimulation to the left side of the heart or atrial cardioversion and/or defibrillation. 
     The leads may be provided with one or more physiological sensors, such as sensor  13  shown attached to lead  330  in the RV. 
     A simplified block diagram of internal components of pacer/ICD  10  is shown in  FIG. 15 . While a particular pacer/ICD is shown, this is for illustration purposes only, and one of skill in the art could readily duplicate, eliminate or disable the appropriate circuitry in any desired combination to provide a device capable of treating the appropriate chamber(s) with cardioversion, defibrillation and pacing stimulation as well as providing for the aforementioned stroke monitoring functions. 
     The housing  340  for pacer/ICD  10 , shown schematically in  FIG. 15 , is often referred to as the “can”, “case” or “case electrode” and may be programmably selected to act as the return electrode for all “unipolar” modes. The housing  340  may further be used as a return electrode alone or in combination with one or more of the coil electrodes,  328 ,  336  and  338 , for shocking purposes. The housing  340  further includes a connector (not shown) having a plurality of terminals,  342 ,  343 ,  344 ,  346 ,  348 ,  352 ,  354 ,  356  and  358  (shown schematically and, for convenience, the names of the electrodes to which they are connected are shown next to the terminals). As such, to achieve right atrial sensing and pacing, the connector includes at least a right atrial tip terminal (A R  TIP)  342  adapted for connection to the atrial tip electrode  322  and a right atrial ring (A R  RING) electrode  343  adapted for connection to right atrial ring electrode  323 . To achieve left chamber sensing, pacing and shocking, the connector includes at least a left ventricular tip terminal (V L  TIP)  344 , a left atrial ring terminal (A L  RING)  346 , and a left atrial shocking terminal (A L  COIL)  348 , which are adapted for connection to the left ventricular ring electrode  326 , the left atrial tip electrode  327 , and the left atrial coil electrode  328 , respectively. To support right chamber sensing, pacing and shocking, the connector further includes a right ventricular tip terminal (V R  TIP)  352 , a right ventricular ring terminal (V R  RING)  354 , a right ventricular shocking terminal (R V  COIL)  356 , and an SVC shocking terminal (SVC COIL) 358, which are adapted for connection to the right ventricular tip electrode  332 , right ventricular ring electrode  334 , the RV coil electrode  336 , and the SVC coil electrode  338 , respectively. 
     At the core of pacer/ICD  10  is a programmable microcontroller  360 , which controls the various modes of stimulation therapy. As is well known in the art, the microcontroller  360  (also referred to herein as a control unit) typically includes a microprocessor, or equivalent control circuitry, designed specifically for controlling the delivery of stimulation therapy and may further include RAM or ROM memory, logic and timing circuitry, state machine circuitry, and I/O circuitry. Typically, the microcontroller  360  includes the ability to process or monitor input signals (data) as controlled by a program code stored in a designated block of memory. The details of the design and operation of the microcontroller  360  are not critical to the invention. Rather, any suitable microcontroller  360  may be used that carries out the functions described herein. The use of microprocessor-based control circuits for performing timing and data analysis functions are well known in the art. 
     As shown in  FIG. 15 , an atrial pulse generator  370  and a ventricular/impedance pulse generator  372  generate pacing stimulation pulses for delivery by the right atrial lead  320 , the right ventricular lead  330 , and/or the coronary sinus lead  324  via an electrode configuration switch  374 . It is understood that in order to provide stimulation therapy in each of the four chambers of the heart, the atrial and ventricular pulse generators,  370  and  372 , may include dedicated, independent pulse generators, multiplexed pulse generators or shared pulse generators. The pulse generators,  370  and  372 , are controlled by the microcontroller  360  via appropriate control signals,  376  and  378 , respectively, to trigger or inhibit the stimulation pulses. 
     The microcontroller  360  further includes timing control circuitry (not separately shown) used to control the timing of such stimulation pulses (e.g., pacing rate, atrio-ventricular (AV) delay, atrial interconduction (A-A) delay, or ventricular interconduction (V-V) delay, etc.) as well as to keep track of the timing of refractory periods, blanking intervals, noise detection windows, evoked response windows, alert intervals, marker channel timing, etc., which is well known in the art. Switch  374  includes a plurality of switches for connecting the desired electrodes to the appropriate I/O circuits, thereby providing complete electrode programmability. Accordingly, the switch  374 , in response to a control signal  380  from the microcontroller  360 , determines the polarity of the stimulation pulses (e.g., unipolar, bipolar, combipolar, etc.) by selectively closing the appropriate combination of switches (not shown) as is known in the art. 
     Atrial sensing circuits  382  and ventricular sensing circuits  384  may also be selectively coupled to the right atrial lead  320 , coronary sinus lead  324 , and the right ventricular lead  330 , through the switch  374  for detecting the presence of cardiac activity in each of the four chambers of the heart. Accordingly, the atrial (ATR. SENSE) and ventricular (VTR. SENSE) sensing circuits,  382  and  384 , may include dedicated sense amplifiers, multiplexed amplifiers or shared amplifiers. The switch  374  determines the “sensing polarity” of the cardiac signal by selectively closing the appropriate switches, as is also known in the art. In this way, the clinician may program the sensing polarity independent of the stimulation polarity. Each sensing circuit,  382  and  384 , preferably employs one or more low power, precision amplifiers with programmable gain and/or automatic gain control, bandpass filtering, and a threshold detection circuit, as known in the art, to selectively sense the cardiac signal of interest. The automatic gain control enables pacer/ICD  10  to deal effectively with the difficult problem of sensing the low amplitude signal characteristics of atrial or ventricular fibrillation. The outputs of the atrial and ventricular sensing circuits,  382  and  384 , are connected to the microcontroller  360  which, in turn, are able to trigger or inhibit the atrial and ventricular pulse generators,  370  and  372 , respectively, in a demand fashion in response to the absence or presence of cardiac activity in the appropriate chambers of the heart. 
     For arrhythmia detection, pacer/ICD  10  utilizes the atrial and ventricular sensing circuits,  382  and  384 , to sense cardiac signals to determine whether a rhythm is physiologic or pathologic. As used in this section, “sensing” is reserved for the noting of an electrical signal, and “detection” is the processing of these sensed signals and noting the presence of an arrhythmia. The timing intervals between sensed events (e.g., P-waves, R-waves, and depolarization signals associated with fibrillation which are sometimes referred to as “F-waves” or “Fib-waves”) are then classified by the microcontroller  360  by comparing them to a predefined rate zone limit (i.e., bradycardia, normal, atrial tachycardia, atrial fibrillation, low rate VT, high rate VT, and fibrillation rate zones) and various other characteristics (e.g., sudden onset, stability, physiologic sensors, and morphology, etc.) in order to determine the type of remedial therapy that is needed (e.g., bradycardia pacing, antitachycardia pacing, cardioversion shocks or defibrillation shocks). 
     Cardiac signals are also applied to the inputs of an analog-to-digital (A/D) data acquisition system  390 . The data acquisition system  390  is configured to acquire intracardiac electrogram signals, convert the raw analog data into a digital signal, and store the digital signals for later processing and/or telemetric transmission to an external device  402 . The data acquisition system  390  is coupled to the right atrial lead  320 , the coronary sinus lead  324 , and the right ventricular lead  330  through the switch  374  to sample cardiac signals across any pair of desired electrodes. The microcontroller  360  is further coupled to a memory  394  by a suitable data/address bus  396 , wherein the programmable operating parameters used by the microcontroller  360  are stored and modified, as required, in order to customize the operation of pacer/ICD  10  to suit the needs of a particular patient. Such operating parameters define, for example, the aforementioned thresholds as well as pacing pulse amplitude or magnitude, pulse duration, electrode polarity, rate, sensitivity, automatic features, arrhythmia detection criteria, and the amplitude, waveshape and vector of each shocking pulse to be delivered to the patient&#39;s heart within each respective tier of therapy. Other pacing parameters include base rate, rest rate and circadian base rate. 
     Advantageously, the operating parameters of the implantable pacer/ICD  10  may be non-invasively programmed into the memory  394  through a telemetry circuit  400  in telemetric communication with the external device  402 , such as a programmer, transtelephonic transceiver or a diagnostic system analyzer. The telemetry circuit  400  is activated by the microcontroller by a control signal  406 . The telemetry circuit  400  advantageously allows intracardiac electrograms and status information relating to the operation of pacer/ICD  10  (as contained in the microcontroller  360  or memory  394 ) to be sent to the external device  402  through an established communication link  404 . Pacer/ICD  10  further includes an accelerometer or other physiologic sensor  408 , commonly referred to as a “rate-responsive” sensor because it is typically used to adjust pacing stimulation rate according to the exercise state of the patient. However, the physiological sensor  408  may further be used to detect changes in cardiac output, changes in the physiological condition of the heart, or diurnal changes in activity (e.g., detecting sleep and wake states) and to detect arousal from sleep. 
     Accordingly, the microcontroller  360  responds by adjusting the various pacing parameters (such as rate, AV Delay, V-V Delay, etc.) at which the atrial and ventricular pulse generators,  370  and  372 , generate stimulation pulses. While shown as being included within pacer/ICD  10 , it is to be understood that the physiologic sensor  408  may also be external to pacer/ICD  10 , yet still be implanted within or carried by the patient. A common type of rate responsive sensor is an activity sensor incorporating an accelerometer or a piezoelectric crystal, which is mounted within the housing  340  of pacer/ICD  10 . Other types of physiologic sensors are also known, for example, sensors that sense the oxygen content of blood, respiration rate and/or minute ventilation, pH of blood, ventricular gradient, etc. 
     The pacer/ICD additionally includes a battery  410 , which provides operating power to all of the circuits shown in  FIG. 15 . The battery  410  may vary depending on the capabilities of pacer/ICD  10 . If the system only provides low voltage therapy, a lithium iodine or lithium copper fluoride cell may be utilized. For pacer/ICD  10 , which employs shocking therapy, the battery  410  must be capable of operating at low current drains for long periods, and then be capable of providing high-current pulses (for capacitor charging) when the patient requires a shock pulse. The battery  410  should also have a predictable discharge characteristic so that elective replacement time can be detected. Accordingly, pacer/ICD  10  is preferably capable of high voltage therapy and appropriate batteries. 
     As further shown in  FIG. 15 , pacer/ICD  10  is shown as having an impedance measuring circuit  412  which is enabled by the microcontroller  360  via a control signal  414 . Uses for an impedance measuring circuit include, but are not limited to, lead impedance surveillance during the acute and chronic phases for proper lead positioning or dislodgement; detecting operable electrodes and automatically switching to an operable pair if dislodgement occurs; measuring respiration or minute ventilation; measuring thoracic impedance for determining shock thresholds; detecting when the device has been implanted; measuring stroke volume; and detecting the opening of heart valves, etc. The impedance measuring circuit  412  is advantageously coupled to the switch  374  so that any desired electrode may be used. 
     In the case where pacer/ICD  10  is intended to operate as an implantable cardioverter/defibrillator (ICD) device, it detects the occurrence of an arrhythmia, and automatically applies an appropriate electrical shock therapy to the heart aimed at terminating the detected arrhythmia. To this end, the microcontroller  360  further controls a shocking circuit  416  by way of a control signal  418 . The shocking circuit  416  generates shocking pulses of low (up to 0.5 joules), moderate (0.5-10 joules) or high energy (11 to 40 joules), as controlled by the microcontroller  360 . Such shocking pulses are applied to the heart of the patient through at least two shocking electrodes, and as shown in this embodiment, selected from the left atrial coil electrode  328 , the RV coil electrode  336 , and/or the SVC coil electrode  338 . The housing  340  may act as an active electrode in combination with the RV electrode  336 , or as part of a split electrical vector using the SVC coil electrode  338  or the left atrial coil electrode  328  (i.e., using the RV electrode as a common electrode). Cardioversion shocks are generally considered to be of low to moderate energy level (so as to minimize pain felt by the patient), and/or synchronized with an R-wave and/or pertaining to the treatment of tachycardia. Defibrillation shocks are generally of moderate to high energy level (i.e., corresponding to thresholds in the range of 11-40 joules), delivered asynchronously (since R-waves may be too disorganized), and pertaining exclusively to the treatment of fibrillation. Accordingly, the microcontroller  360  is capable of controlling the synchronous or asynchronous delivery of the shocking pulses. 
     Microcontroller  360  also includes various components directed to detecting and responding to stroke. In particular, the microcontroller includes a multiple parameter stroke index generation unit  401  operative to derive a plurality of indices from electrocardiac signals (sensed by the leads) and from physiological signals (sensed by physiologic sensors  413 ) based on parameters affected by stroke. A composite stroke index generation unit  403  is operative to derive a composite stroke index from the plurality of indices, as discussed above. A composite index-based stroke detector  405  is operative to detect a stroke event within the patient based on the composite stroke index, as already described. Collectively, the composite stroke index generation unit and the composite index-based stroke detector provide an index-based stroke detector operative to derive a plurality of indices from electrocardiac signals and physiological signals based on parameters affected by stroke. 
     A stroke therapy/diagnostics controller  407  is operative to initiate, adjust or otherwise control therapy in response to stroke, as well as record stroke diagnostics. The stroke therapy controller can control one more neuro-stimulation systems  418 : including spinal cord, baro-receptor, sympathetic nerve stimulators. The stroke therapy controller can also control the aforementioned drug pump  16 . Still further, the microcontroller includes a paired pacing and smoothed pacing controller  409  operative to initiate, adjust or otherwise control paired pacing and smoothed pacing in response to stroke. Warning signals may be relayed to the patient via internal warning device  411  or via bedside monitor  14  or programmer  402 . 
     Note that, for simplicity and clarity, some of the components external the pacer/ICD (such as the neuro-stimulators, the drug pump and the physiological sensors) are shown functionally connected to the microcontroller via phantom lines. In practice, additional electrical connection terminals (not shown) may be needed to connect these components to the pacer/ICD. 
     Note also that, depending upon the implementation, the various components of the microcontroller may be implemented as separate software modules or the modules may be combined to permit a single module to perform multiple functions. In addition, although shown as being components of the microcontroller, some or all of these components may be implemented separately from the microcontroller. 
     The principles of the invention may be exploiting using other implantable systems or in accordance with other techniques. Thus, while the invention has been described with reference to particular exemplary embodiments, modifications can be made thereto without departing from scope of the invention. Note also that the term “including” as used herein is intended to be inclusive, i.e. “including but not limited to.”