CA2333363C - Method allowing cyclic pacing with average rate just above the intrinsic rate - Google Patents
Method allowing cyclic pacing with average rate just above the intrinsic rate Download PDFInfo
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- CA2333363C CA2333363C CA002333363A CA2333363A CA2333363C CA 2333363 C CA2333363 C CA 2333363C CA 002333363 A CA002333363 A CA 002333363A CA 2333363 A CA2333363 A CA 2333363A CA 2333363 C CA2333363 C CA 2333363C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
- A61N1/365—Heart stimulators controlled by a physiological parameter, e.g. heart potential
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
- A61N1/365—Heart stimulators controlled by a physiological parameter, e.g. heart potential
- A61N1/36592—Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by the heart rate variability
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
- A61N1/3621—Heart stimulators for treating or preventing abnormally high heart rate
- A61N1/3622—Heart stimulators for treating or preventing abnormally high heart rate comprising two or more electrodes co-operating with different heart regions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
- A61N1/365—Heart stimulators controlled by a physiological parameter, e.g. heart potential
- A61N1/368—Heart stimulators controlled by a physiological parameter, e.g. heart potential comprising more than one electrode co-operating with different heart regions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
- A61N1/37—Monitoring; Protecting
- A61N1/371—Capture, i.e. successful stimulation
- A61N1/3712—Auto-capture, i.e. automatic adjustment of the stimulation threshold
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
- A61N1/365—Heart stimulators controlled by a physiological parameter, e.g. heart potential
- A61N1/36514—Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by a physiological quantity other than heart potential, e.g. blood pressure
Abstract
Method and apparatus for cyclic ventricular pacing starting at a rate just above the intrinsic atrial firing rate (overdrive pacing), followed by relaxation to a rate just below the intrinsic atrial firing rate (ventricular escape). The method and apparatus can be applied to one or both ventricles, and can utilize one or more electrodes per ventricle . The electrode(s) can be applied to inner or outer ventricular surfaces. Relaxation protocols as a function of time can be linear, curvilinear to include exponential, or mixtures thereof. Furthermore, relaxation protocols can include one or more periods of time during which th e pacing rate is held constant. Typically, the average ventricular pacing rate using this invention will be slightly greater than the intrinsic atrial firing rate, though alternate embodiments that encompass average ventricular pacing rates that are equal to or slightly less than the intrinsic atrial firing rate are also envisioned. Application of this method and apparatus to a heart in need thereof will produce a heart with an optimally minimized energy output requirement.
Description
RATE
Field of the Invention 6 The present invention relates generally to pacemakers to control the beating of hearts.
7 In particular, the present invention relates to pacemakers used to pmmote, on a cyclic basis, 8 ventricular tracking of atrial firing by overdriving ventricular pacing at a rate slightly over the 9 intrinsic heart (atrial) rate, followed by gradual relaxation of the rate of ventricular stimulation to the point of decoupling of ventricular beating from atrial firing, especially in 11 conjunction with ventricular synchronizing techniques such as biventricular pacing, biphasic 12 pulsing, and/or multiple-site ventricular pacing.
13 Background of the Invention 14 A-V blocks, encountered frequently in cardiac patients, arise when electrical impulses flowing from the SA node along the conduction bundles are delayed when they reach the A-V
16 junction/A-V node. In some pathologies, if an A-V delay is sufficiently great, the ventricles I7 will beat at their own intrinsic and slower rate. With A-V blocks in other pathologies, the I8 ventricles can beat at a variable and/or intermittent rate, or ectopic foci can appear, potentially 19 leading to life threatening ventricular fibrillation.
A variety of strategies have been employed for pacemakers to overcome the adverse 21 physiological effects of A-V blocks. One such strategy is overdriving or overpacing, in 22 which the pacemaker stimulates the ventricles at a faster rate than the atrial beating rate. A
23 problem encountered with such strategies is that the atrial and ventricular beating can not be 24 coordinated for optimal pumping efficiency. Another problem is that such fast ventricular pacing rates fatigue the heart because physiological and biochemical functioning generally are 26 not optimized. Furthermore, such additional fatigue only imposes greater restraints on the 27 already limited life style of the typical cardiac patient. Thus, the patient with an already 28 weakened heart can be subjected to unnecessary overstimulation, and be stressed and further 29 weakened as a result of application of current pacemaking protocols.
1 Patented technologies relating to overdriving pacing with subsequent relaxation of the 2 pacing rate include U.S. Patent No. 5,626,620 to Kieval, et al., which discloses a pacemaker 3 stimulation protocol in which fusion and/or near fusion beats are detected by monitoring 4 changes in the characteristics of the evoked QRS. The protocol is adjustable to allow selection of an acceptable percentage of fusion beats. When an unacceptable fusion 6 percentage is measured, the A-V delay is automatically decreased to lead to a higher 7 ventricular beating rate from the pacemaker's synchronous pace pulses (ventricular 8 "capture"). Once ventricular capture is maintained for a predetermined time interval or 9 number of cycles without an unacceptable rate of fusion, the A-V interval is incrementally increased to produce a beating rate toward the rate at which fusion had previously occurred.
11 Upon again meeting an unacceptable fusion percentage, the A-V delay is automatically 12 decreased, and the cycle continues so as to approximate the longest A-V
interval (i.e., the 13 slowest ventricular beating rate) consistent with avoiding fusion.
14 U.S. Patent No. 5,527,347 to Shelton. et al. discloses a pacemaker ventricular stimulation protocol in which the A-V delay is slowly increased until fusion occurs, at which 16 point the A-V delay is decreased slightly. The cycle is then repeated.
Thus, the A-V delay is 17 cyclically maintained in a small range of about that corresponding to fusion, to slightly lower 18 values (i.e., higher ventricular beating rate).
I9 U.S. Patent No. 5,522,858 to van der Veen discloses a pacemaker stimulation protocol in which A-V delays are gradually decreased until ventricular tracking of atrial firing occurs.
21 In particular, the ventricles are stimulated after the atrial depolarization impulse reaches the 22 ventricles, but are not stimulated during the ventricular refractory period. The net effect is to 23 decrease the prolonged A-V delay period, and thus increase the ventricular beating rate. In 24 small increments, the A-V delay period then is further decreased until ventricular tracking is observed.
26 U.S. Patent No. 5,480,413 to Greenhut, et al. discloses a means for using a pacemaker 27 to correct ventricular beating rate instability in the presence of atrial 28 fibrillation/tachyarrhythmia. First, ventricular beating is decoupled from atrial beating by 29 gradually increasing the ventricular beating rate (dual or multichamber pacemakers are switched to a single chamber pacing mode) via appropriately spaced electrical stimulations.
31 Once a stabilized beating rate is achieved at the higher ventricular beating rate, then the rate 1 of ventricular stimulation is slowly decreased to the lowest rate that provides ventricular rate 2 stability, and held at this rate until the atrial tachyarrhythmia/fibrillation disappears. Dual or 3 mufti-chamber (atria and ventricles) pacemaking is then resumed.
4 U.S. Patent No. 5,441,522 to Schitller discloses a dual chamber pacemaker stimulation protocol in which the A-V interval is cycled between two values when retrograde 6 conduction from ventricular stimulation renders the atria refractory to the normally timed 7 stimulation by the pacemaker. When such a condition is sensed, the A-V
interval is 8 shortened to one value. Once a predetermined time or number of pulses has occurred, or once 9 a spontaneous ventricular reaction is sensed within the shortened A-V
interval, then the longer A-V interval is restored.
11 U.S. Patent No. 5,340,361 to Sholder discloses a ventricular stimulation protocol in 12 which the A-V interval is automatically adjusted to just less than that for the intrinsic (and 13 pathological) rhythm to produce a ventricular firing that is slightly in advance of the intrinsic 14 ventricular firing time. This invention overcomes the problem of abnormal A-V delay, which decreases cardiac efficiency due to non-optimal atrial-ventricular synchronization. The rates 16 of atriaI firing and ventricular firing are equal in this invention.
17 U.S. Patent No. 5,334,220 to holder discloses a ventricular stimulation protocol in 18 which the A-V interval is automatically adjusted to avoid ventricular stimulation at a time 19 that would result in fusion (at the cross-over point) with the endogenous ventricular stimulation. A final A-V value is selected by incrementally adjusting the A-V
interval until 21 the crossover point is reached with respect to the R wave. The final A-V
value that is set is 22 based on the determined cross-over point, adjusted by a small margin. Thus, this procedure 23 overdrives the intrinsic rhythm to ensure a suitably short A-V
interval/delay that, otherwise, 24 would impair cardiac pumping efficiency. When this procedure is invoked (automatically) too frequently, it is suspended for a predetermined period.
26 U.S. Patent No. 5,105,810 to Collins, et al. discloses a cyclic protocol for achieving 27 the minimum voltage for ventricular pacing for the purpose of extending the life of batteries 28 used in pacemakers. The protocol uses a series of bradycardia support pacing pulses at a 29 predetermined voltage, and ventricular pressure measurements are analyzed during the pulse train to determine if capture has occurred. If capture has occurred during the pulse train, 31 bradycardia support pacing pulses again are delivered once the stimulus voltage has been 1 decreased by a step. If capture is the result, then the decremental voltage stepping and 2 capture assessing is continued until capture is lost, at which point the voltage is incrementally 3 increased until capture occurs.
4 U.S. Patent No. 4,503,857 to Boute. et al. discloses a ventricular pacing protocol in which either spontaneous bradycardia or tachycardia is altered first by ventricular capture, 6 followed by gradual increase or decrease, respectively, in the rate of pulse pacing until a 7 normal programmed pacing rate is reached.
8 As can be seen from earlier inventions, pacemakers utilize overdrive ventricular 9 pacing that adjusts the A-V interval/delay in a manner that avoids fusion, and that controls ventricular firing solely by the imposed pacing impulses. However, such protocols have not 1 I been optimally designed to minimize the energy expenditure of the already compromised 12 patient's heart. Generally, the above references are designed to change the stimulation rate by 13 adjustment of the A-V interval/delay in order to achieve a predetermined rate or a 14 physiological standard.
What is needed is a pacemaker with a ventricular firing protocol that minimizes the 16 energy of the heart used for contraction/pumping work. Furthermore, what is needed is a 17 pacemaker with a ventricular firing protocol in which the maximum overdrive pacing rate is 18 only slightly (i.e., only a few beats per minute -- ideally two or three beats per minute) 19 greater than the atrial firing rate at the commencement of the first cycle of the protocol. In addition, what is needed is a pacemaker for ventricular firing that uses a pacing protocol that 21 achieves re-synchronization/fusion, so as to produce the least amount of stress on a heart 22 which may already be in a weakened condition.
23 Lastly, an improved means for stimulating muscle tissue, wherein the contraction 24 elicited is enhanced and the damage to the tissue adjacent to the electrode is diminished, is also desired.
26 Enhanced myocardial function is obtained through the biphasic pacing of the present 27 invention. The combination of cathodal with anodal pulses of either a stimulating or 28 conditioning nature, preserves the improved conduction and contractility of anodal pacing 29 while eliminating the drawback of increased stimulation threshold. The result is a depolarization wave of increased propagation speed. This increased propagation speed 31 results in superior cardiac contraction leading to an improvement in blood flow. Improved 1 stimulation at a lower voltage level also results in reduction in power consumption and 2 increased life for pacemaker batteries.
4 Summary of the Invention It is therefore an object of the present invention to provide a pacemaker with a 6 ventricular firing protocol that minimizes the energy required for contraction and pumping of 7 the heart of a cardiac patient.
8 It is another object of the present invention to provide a pacemaker with a ventricular 9 firing protocol that uses ventricular overdrive pacing only to a minimal degree; i.e., overdrive pacing is just a few beats per minute greater than the intrinsic atrial firing rate.
11 It is a further object of the present invention to provide a pacemaker with a ventricular 12 f ring protocol with a pacing relaxation period in which the ventricular pacing rate is slowly 13 decreased to just slightly less (i.e., by only 1-2 beats per minute) than the intrinsic atrial firing 14 rate before commencement of the next cycle.
I S It is a further object of the present invention to directly adjust the ventricular pacing 16 cycle length, rather than the A-V delay.
17 It is a further object of the present invention to provide rate modulation in conjunction 18 with multiple-site ventricular pacing.
19 The present invention accomplishes the above objectives by providing a ventricular firing protocol that is initiated by synchronization with the QRS complex of the 21 electrocardiogram. The time from one QRS complex to the next constitutes a practical 22 definition of the length of a heart beat, thereby providing the control circuit with a ready, 23 strong reference point that serves as a timing mark for the timing of the firing trigger of the 24 first electrical impulse to the ventricle(s). In theory, a P wave with an appropriate time interval could work. However, the weak P wave could disappear in the presence of 26 conditions such as atrial fibrillation. This is particularly true in the case of pathological 27 hearts. Therefore, the QRS complex, because of its large amplitude, serves as the best 28 reference point available in the electrocardiogram. However, it is to be understood that the 29 practice of the initial phase of this invention amounts to indirect timing/coordination with respect to atrial firing and contraction, as this is required for optimal total cardiac functioning.
31 The ventricular firing protocol is activated upon detection of a QRS
complex, and is WO 99/61101 PCT/US99/113'75 1 set at an overdrive rate of only a few beats per minute (i.e., no more than 3-5 beats per 2 minute) greater than the intrinsic atrial firing rate. Next, the ventricular firing rate is slowly 3 decreased ("relaxed") to a rate just a few beats per minute (i.e., no more than 2-3 beats per 4 minute; ideally, only 1-2 beats per minute) below the intrinsic atrial firing rate, which leads to ventricular escape (i.e., atrial firing and contraction no longer coordinate perfectly with 6 ventricular firing and contraction).
7 In particular, the present invention relates to pacemakers used to pmmote, on a cyclic basis, 8 ventricular tracking of atrial firing by overdriving ventricular pacing at a rate slightly over the 9 intrinsic heart (atrial) rate, followed by gradual relaxation of the rate of ventricular stimulation to the point of decoupling of ventricular beating from atrial firing, especially in 11 conjunction with ventricular synchronizing techniques such as biventricular pacing, biphasic 12 pulsing, and/or multiple-site ventricular pacing.
13 Background of the Invention 14 A-V blocks, encountered frequently in cardiac patients, arise when electrical impulses flowing from the SA node along the conduction bundles are delayed when they reach the A-V
16 junction/A-V node. In some pathologies, if an A-V delay is sufficiently great, the ventricles I7 will beat at their own intrinsic and slower rate. With A-V blocks in other pathologies, the I8 ventricles can beat at a variable and/or intermittent rate, or ectopic foci can appear, potentially 19 leading to life threatening ventricular fibrillation.
A variety of strategies have been employed for pacemakers to overcome the adverse 21 physiological effects of A-V blocks. One such strategy is overdriving or overpacing, in 22 which the pacemaker stimulates the ventricles at a faster rate than the atrial beating rate. A
23 problem encountered with such strategies is that the atrial and ventricular beating can not be 24 coordinated for optimal pumping efficiency. Another problem is that such fast ventricular pacing rates fatigue the heart because physiological and biochemical functioning generally are 26 not optimized. Furthermore, such additional fatigue only imposes greater restraints on the 27 already limited life style of the typical cardiac patient. Thus, the patient with an already 28 weakened heart can be subjected to unnecessary overstimulation, and be stressed and further 29 weakened as a result of application of current pacemaking protocols.
1 Patented technologies relating to overdriving pacing with subsequent relaxation of the 2 pacing rate include U.S. Patent No. 5,626,620 to Kieval, et al., which discloses a pacemaker 3 stimulation protocol in which fusion and/or near fusion beats are detected by monitoring 4 changes in the characteristics of the evoked QRS. The protocol is adjustable to allow selection of an acceptable percentage of fusion beats. When an unacceptable fusion 6 percentage is measured, the A-V delay is automatically decreased to lead to a higher 7 ventricular beating rate from the pacemaker's synchronous pace pulses (ventricular 8 "capture"). Once ventricular capture is maintained for a predetermined time interval or 9 number of cycles without an unacceptable rate of fusion, the A-V interval is incrementally increased to produce a beating rate toward the rate at which fusion had previously occurred.
11 Upon again meeting an unacceptable fusion percentage, the A-V delay is automatically 12 decreased, and the cycle continues so as to approximate the longest A-V
interval (i.e., the 13 slowest ventricular beating rate) consistent with avoiding fusion.
14 U.S. Patent No. 5,527,347 to Shelton. et al. discloses a pacemaker ventricular stimulation protocol in which the A-V delay is slowly increased until fusion occurs, at which 16 point the A-V delay is decreased slightly. The cycle is then repeated.
Thus, the A-V delay is 17 cyclically maintained in a small range of about that corresponding to fusion, to slightly lower 18 values (i.e., higher ventricular beating rate).
I9 U.S. Patent No. 5,522,858 to van der Veen discloses a pacemaker stimulation protocol in which A-V delays are gradually decreased until ventricular tracking of atrial firing occurs.
21 In particular, the ventricles are stimulated after the atrial depolarization impulse reaches the 22 ventricles, but are not stimulated during the ventricular refractory period. The net effect is to 23 decrease the prolonged A-V delay period, and thus increase the ventricular beating rate. In 24 small increments, the A-V delay period then is further decreased until ventricular tracking is observed.
26 U.S. Patent No. 5,480,413 to Greenhut, et al. discloses a means for using a pacemaker 27 to correct ventricular beating rate instability in the presence of atrial 28 fibrillation/tachyarrhythmia. First, ventricular beating is decoupled from atrial beating by 29 gradually increasing the ventricular beating rate (dual or multichamber pacemakers are switched to a single chamber pacing mode) via appropriately spaced electrical stimulations.
31 Once a stabilized beating rate is achieved at the higher ventricular beating rate, then the rate 1 of ventricular stimulation is slowly decreased to the lowest rate that provides ventricular rate 2 stability, and held at this rate until the atrial tachyarrhythmia/fibrillation disappears. Dual or 3 mufti-chamber (atria and ventricles) pacemaking is then resumed.
4 U.S. Patent No. 5,441,522 to Schitller discloses a dual chamber pacemaker stimulation protocol in which the A-V interval is cycled between two values when retrograde 6 conduction from ventricular stimulation renders the atria refractory to the normally timed 7 stimulation by the pacemaker. When such a condition is sensed, the A-V
interval is 8 shortened to one value. Once a predetermined time or number of pulses has occurred, or once 9 a spontaneous ventricular reaction is sensed within the shortened A-V
interval, then the longer A-V interval is restored.
11 U.S. Patent No. 5,340,361 to Sholder discloses a ventricular stimulation protocol in 12 which the A-V interval is automatically adjusted to just less than that for the intrinsic (and 13 pathological) rhythm to produce a ventricular firing that is slightly in advance of the intrinsic 14 ventricular firing time. This invention overcomes the problem of abnormal A-V delay, which decreases cardiac efficiency due to non-optimal atrial-ventricular synchronization. The rates 16 of atriaI firing and ventricular firing are equal in this invention.
17 U.S. Patent No. 5,334,220 to holder discloses a ventricular stimulation protocol in 18 which the A-V interval is automatically adjusted to avoid ventricular stimulation at a time 19 that would result in fusion (at the cross-over point) with the endogenous ventricular stimulation. A final A-V value is selected by incrementally adjusting the A-V
interval until 21 the crossover point is reached with respect to the R wave. The final A-V
value that is set is 22 based on the determined cross-over point, adjusted by a small margin. Thus, this procedure 23 overdrives the intrinsic rhythm to ensure a suitably short A-V
interval/delay that, otherwise, 24 would impair cardiac pumping efficiency. When this procedure is invoked (automatically) too frequently, it is suspended for a predetermined period.
26 U.S. Patent No. 5,105,810 to Collins, et al. discloses a cyclic protocol for achieving 27 the minimum voltage for ventricular pacing for the purpose of extending the life of batteries 28 used in pacemakers. The protocol uses a series of bradycardia support pacing pulses at a 29 predetermined voltage, and ventricular pressure measurements are analyzed during the pulse train to determine if capture has occurred. If capture has occurred during the pulse train, 31 bradycardia support pacing pulses again are delivered once the stimulus voltage has been 1 decreased by a step. If capture is the result, then the decremental voltage stepping and 2 capture assessing is continued until capture is lost, at which point the voltage is incrementally 3 increased until capture occurs.
4 U.S. Patent No. 4,503,857 to Boute. et al. discloses a ventricular pacing protocol in which either spontaneous bradycardia or tachycardia is altered first by ventricular capture, 6 followed by gradual increase or decrease, respectively, in the rate of pulse pacing until a 7 normal programmed pacing rate is reached.
8 As can be seen from earlier inventions, pacemakers utilize overdrive ventricular 9 pacing that adjusts the A-V interval/delay in a manner that avoids fusion, and that controls ventricular firing solely by the imposed pacing impulses. However, such protocols have not 1 I been optimally designed to minimize the energy expenditure of the already compromised 12 patient's heart. Generally, the above references are designed to change the stimulation rate by 13 adjustment of the A-V interval/delay in order to achieve a predetermined rate or a 14 physiological standard.
What is needed is a pacemaker with a ventricular firing protocol that minimizes the 16 energy of the heart used for contraction/pumping work. Furthermore, what is needed is a 17 pacemaker with a ventricular firing protocol in which the maximum overdrive pacing rate is 18 only slightly (i.e., only a few beats per minute -- ideally two or three beats per minute) 19 greater than the atrial firing rate at the commencement of the first cycle of the protocol. In addition, what is needed is a pacemaker for ventricular firing that uses a pacing protocol that 21 achieves re-synchronization/fusion, so as to produce the least amount of stress on a heart 22 which may already be in a weakened condition.
23 Lastly, an improved means for stimulating muscle tissue, wherein the contraction 24 elicited is enhanced and the damage to the tissue adjacent to the electrode is diminished, is also desired.
26 Enhanced myocardial function is obtained through the biphasic pacing of the present 27 invention. The combination of cathodal with anodal pulses of either a stimulating or 28 conditioning nature, preserves the improved conduction and contractility of anodal pacing 29 while eliminating the drawback of increased stimulation threshold. The result is a depolarization wave of increased propagation speed. This increased propagation speed 31 results in superior cardiac contraction leading to an improvement in blood flow. Improved 1 stimulation at a lower voltage level also results in reduction in power consumption and 2 increased life for pacemaker batteries.
4 Summary of the Invention It is therefore an object of the present invention to provide a pacemaker with a 6 ventricular firing protocol that minimizes the energy required for contraction and pumping of 7 the heart of a cardiac patient.
8 It is another object of the present invention to provide a pacemaker with a ventricular 9 firing protocol that uses ventricular overdrive pacing only to a minimal degree; i.e., overdrive pacing is just a few beats per minute greater than the intrinsic atrial firing rate.
11 It is a further object of the present invention to provide a pacemaker with a ventricular 12 f ring protocol with a pacing relaxation period in which the ventricular pacing rate is slowly 13 decreased to just slightly less (i.e., by only 1-2 beats per minute) than the intrinsic atrial firing 14 rate before commencement of the next cycle.
I S It is a further object of the present invention to directly adjust the ventricular pacing 16 cycle length, rather than the A-V delay.
17 It is a further object of the present invention to provide rate modulation in conjunction 18 with multiple-site ventricular pacing.
19 The present invention accomplishes the above objectives by providing a ventricular firing protocol that is initiated by synchronization with the QRS complex of the 21 electrocardiogram. The time from one QRS complex to the next constitutes a practical 22 definition of the length of a heart beat, thereby providing the control circuit with a ready, 23 strong reference point that serves as a timing mark for the timing of the firing trigger of the 24 first electrical impulse to the ventricle(s). In theory, a P wave with an appropriate time interval could work. However, the weak P wave could disappear in the presence of 26 conditions such as atrial fibrillation. This is particularly true in the case of pathological 27 hearts. Therefore, the QRS complex, because of its large amplitude, serves as the best 28 reference point available in the electrocardiogram. However, it is to be understood that the 29 practice of the initial phase of this invention amounts to indirect timing/coordination with respect to atrial firing and contraction, as this is required for optimal total cardiac functioning.
31 The ventricular firing protocol is activated upon detection of a QRS
complex, and is WO 99/61101 PCT/US99/113'75 1 set at an overdrive rate of only a few beats per minute (i.e., no more than 3-5 beats per 2 minute) greater than the intrinsic atrial firing rate. Next, the ventricular firing rate is slowly 3 decreased ("relaxed") to a rate just a few beats per minute (i.e., no more than 2-3 beats per 4 minute; ideally, only 1-2 beats per minute) below the intrinsic atrial firing rate, which leads to ventricular escape (i.e., atrial firing and contraction no longer coordinate perfectly with 6 ventricular firing and contraction).
7 Subsequently, a new cycle is commenced.
8 Thus, the present invention uses a stimulation rate that is continuously cycled from a 9 highest rate that is just barely above the intrinsic atrial firing rate, to a rate just barely below the intrinsic atrial firing rate. Such a stimulation protocol is expected a priori to provide a 11 good approximation of an optimal lowest energy requiring protocol.
Therefore, the limited 12 energy of the cardiac patient can be used wisely and optimally to the benefit of the already 13 compromised patient. In summary, this technique allows pacing at an average rate that is just 14 above the intrinsic heart rate so as to maximize inotropic pacing effects at minimal heart rates, and thereby conserve the precious energy of the patient's heart.
16 Additionally, the ventricular firing protocol of the present invention can be used in 17 conjunction with biphasic pacing. The method and apparatus relating to biphasic pacing 18 comprises a first and second stimulation phase, with each stimulation phase having a polarity, 19 amplitude, shape, and duration. In a preferred embodiment, the first and second phases have differing polarities. In one alternative embodiment, the two phases are of differing amplitude.
21 In a second alternative embodiment, the two phases are of differing duration. In a third 22 alternative embodiment, the first phase is in a chopped wave form. In a fourth alternative 23 embodiment, the amplitude of the first phase is ramped. In a fifth alternative embodiment the 24 first phase is administered over 200 milliseconds after completion of a cardiac beating/pumping cycle. In a preferred alternative embodiment, the first phase of stimulation 26 is an anodal pulse at maximum subthreshold amplitude for a long duration, and the second 27 phase of stimulation is a cathodal pulse of short duration and high amplitude. It is noted that 28 the aforementioned alternative embodiments can be combined in differing fashions. It is also 29 noted that these alternative embodiments are intended to be presented by way of example only, and are not limiting.
Another aspect of the invention provides an implantable cardiac stimulator to perform pacing of a heart, the heart having an intrinsic atrial firing rate, the cardiac stimulator comprising: plural electrodes adapted to applying pacing stimuli to the heart; and pulse generating circuitry connected to the plural electrodes and adapted to generate electrical pulses as pacing stimuli; wherein a series of pacing stimuli are applied to at least one ventricle having an initial pacing rate, the initial pacing rate being slightly greater than the intrinsic atrial firing rate, and wherein the pacing rate is decreased over time from the initial pacing rate to a minimum pacing rate that is slightly less than the intrinsic atrial firing rate.
Another aspect of the invention provides an 25 implantable cardiac stimulator to perform pacing of a heart, the heart having a paced atrial firing rate, the cardiac stimulator comprising: plural electrodes adapted to applying pacing stimuli to the heart; and pulse generating circuitry connected to the plural electrodes and adapted to generate electrical pulses as pacing stimuli; wherein a series of pacing stimuli are applied to at least one ventricle having an initial pacing rate, the initial pacing rate being slightly greater than the paced atrial firing rate, and wherein the pacing rate is decreased over time from the initial pacing rate to a minimum pacing rate that is slightly less than the paced atrial firing rate.
6a 1 Brief Description of the Drawings 2 Figure I shows a cyclic saw tooth (linear decay) stimulation-relaxation protocol for 3 ventricular pacing.
4 Figure 2 shows a cyclic exponential decay stimulation-relaxation protocol for ventricular pacing.
6 Figure 3 is a schematic representation of leading anodal biphasic stimulation.
7 Figure 4 is a schematic representation of leading cathodal biphasic stimulation.
8 Figure S is a schematic representation of leading anodal stimulation of low level and 9 long duration, followed by cathodal stimulation.
Figure 6 is a schematic representation of leading anodal stimulation of ramped low 1 I level and long duration, followed by cathodal stimulation.
12 Figure 7 is a schematic representation of leading anodal stimulation of low level and 13 short duration administered in a series, followed by cathodal stimulation.
I4 Description of the Preferred Embodiments The fundamentals of the present invention can be understood with reference to 16 Figures 1 and 2, which depict two cyclic stimulation-relaxation protocols for ventricular 17 pacing, in which the maximum rate of ventricular overdrive pacing is followed by relaxation 18 to a rate just less than the intrinsic atrial firing rate (which corresponds to ventricular escape).
19 Figure 1 shows a cyclic saw tooth (linear decay) stimulation-relaxation protocol. Figure 2 shows a cyclic exponential decay stimulation-relaxation protocol.
21 Referring to Figure 1, a cyclic saw tooth stimulation-relaxation protocol for 22 ventricular pacing is depicted with time points 102,106, and 108 to illustrate initiation of 23 ventricular overdrive pacing at maximum pacing rate A, followed by linear decay/relaxation 24 of the rate of pacing to minimum pacing rate C. Each cycle has total time length 110.
Intrinsic atrial firing rate B is shown as a dashed reference line. Rate difference A-B is 26 greater than rate difference B-C in this example. During the course of linear relaxation of 27 the ventricular pacing rate, crossover point 104 is reached when the ventricular pacing rate 28 equals intrinsic atrial firing rate B. Thus, the period between time point 102 and crossover 29 point 104 represents linear ventricular overdrive pacing period 112, and the period between crossover point 104 and time point 106 represents linear ventricular escape period 114. It is 1 evident that linear ventricular overdrive pacing period 112 is a longer time period than linear 2 ventricular escape period 114. Therefore, the average ventricular firing rate for this protocol, 3 with the above given relative parameters, will always be slightly greater than intrinsic atrial 4 firing rate B.
Referring to Figure 2, a cyclic exponential decay stimulation-relaxation ventricular 6 pacing protocol is shown with ventricular overdrive pacing to maximum pacing rate A being 7 initiated at time points 202, 206 and 208, followed by exponential relaxation of the rate of 8 pacing to minimum pacing rate C. Each cycle has total time length 210. The time course of 9 the pacing rate during the relaxation phase will be proportional to the time course of the product obtained by multiplying maximum pacing rate A (or the quantity A minus a selected 11 "factor") by the proportionality el~T where ris the time constant. The selected "factor"
12 typically will have a value less than C. As in Figure 1, dashed line B
represents the reference 13 line of intrinsic atrial firing rate. Compared to Figure I, two parameters have been adjusted 14 in Figure 2. First, the relaxation of pacing rate is an exponential function of time instead of a linear function of time. Second, minimum ventricular pacing rate C is closer to intrinsic I6 atrial firing rate B.
17 As in Figure 1, the period between time point 202 and crossover point 204 represents 18 exponential ventricular overdrive pacing period 212, and the period between crossover point 19 204 and time point 206 represents exponential ventricular escape period 214. Rate difference A-B is the same in Figures 1 and 2, as are cycle lengths I10 and 210. This 21 combination of parameters produces a protocol in which exponential ventricular overdrive 22 pacing period 212 of Figure 2 is shorter than linear ventricular overdrive pacing period 112 of 23 Figure 1.
24 In the case of a curvilinear (including exponential) relaxation protocol with cycle length 210, comparison of ventricular overdrive pacing period 212 and ventricular escape 26 period 214 of Figure 2 reveals that their magnitudes effectively are controlled by variations in 27 two parameters: (A-B)/(B-C), and ventricular overdrive pacing period 212.
28 Referring again to Figure l, in the case of a linear relaxation protocol with cycle 29 length 110, comparison of linear ventricular overdrive pacing period 112 and linear ventricular escape period 114 reveals that their magnitudes are controlled by variation in 31 single parameter (A-B)/(B-C), or any mathematical equivalent, such as (I02-104)/(104-106).
2 It is anticipated that different relaxation protocols will be required for different 3 pathologies and different medical situations. In addition, a virtually infinite array of 4 relaxation protocols are possible in theory. Thus, the preferred embodiment of the present S invention contemplates any monotonic relaxation protocol, where "monotonic"
indicates a 6 unidirectional change in the applied ventricular pacing rate. Further, "unidirectional change"
7 is to be understood to refer to a change in ventricular pacing rate that is in the direction of 8 decreasing ventricular pacing rate, and to include periods of time in which there is no change 9 in ventricular pacing rate.
Therefore, the preferred embodiment of the present invention contemplates relaxation I 1 protocols beyond the two depicted in Figures 1 and 2, as long as the relaxation protocol 12 embodies unidirectional change in ventricular pacing rate as defined above.
Thus, the shapes 13 of the relaxation curves can generally be decreasing linear, decreasing curvilinear, decreasing 14 in an exponential fashion, include one or more periods at a constant pacing rate, or combinations of these. For example, with reference to Figure 1, one can imagine a protocol 16 in which, between time points 102 and 104, there is a small time segment over which the 17 voltage is constant, followed by linear relaxation at the same or a different rate of relaxation 18 (i.e., the same or a different slope) compared to the initial rate of relaxation. In one 19 embodiment, the same or different rate of relaxation that follows the brief period of constant voltage is maintained up to time point 106, which marks the end of one cycle and the 21 beginning of the next cycle.
22 Alternate embodiments encompass relaxation protocols in which ventricular pacing 23 rates are not monotonic; i.e., as the ventricular pacing rate is declining in a given cycle, time 24 periods in which the ventricular pacing rates are increased slightly can be included. Further alternative embodiments can include the use of combinations of different rates of relaxation 26 within a single cycle, for example, within time segment 102 -106, or 202 -206.
27 Typically, physiological data from one or more sensing electrodes (including 28 electrodes that perform both pacing and sensing) are used to determine whether an "action 29 criterion" has been met, in order to initiate a cyclic pacing protocol if the situation so demands. Such sensing may be directed to detecting such nonlimiting physiological 31 parameters as abnormal or unacceptably long A-V delays, whether atrial firing entrains both 1 left and right ventricles, length of the QRS complex, magnitude of the QRS
complex, heart 2 rate, arterial and/or venous blood pressure, ventricular fibrillation, atrial fibrillation, and 3 probability density function ("PDF"). At the end of such a cyclic pacing protocol, sensing 4 again is performed to determine if additional pacing is required.
Alternatively, sensing can be conducted concurrently with a cyclic pacing protocol.
6 The ventricular firing protocol is activated upon detection of a QRS
complex, and is 7 set at an overdrive rate of only a few beats per minute (i.e., no more than 3-5 beats per 8 minute) greater than the intrinsic atrial firing rate. Next, the ventricular firing rate is slowly 9 decreased ("relaxed") to a rate just a few beats per minute (i.e., no more than 2-3 beats per minute; ideally, only I-2 beats per minute) below the intrinsic atrial firing rate, which leads to 11 ventricular escape (i.e., atrial firing and contraction no longer coordinate perfectly with 12 ventricular firing and contraction). Heart rates could vary from about 40 to 120 beats per 13 minute, with these rates being largely determined by the intrinsic physiology of the heart.
14 Rates that vary greatly from this 40 to 120 beats per minute range would not be beneficial physiologically.
16 What is central to the present invention is that the ventricular pacing rates hover not I7 far from the intrinsic atrial firing rate so as to minimize the energy requirements of the 18 myocardium. Generally, practice of the present invention will result in an average ventricular 19 beating rate that is just slightly greater than the intrinsic atrial firing rate. However, it is anticipated that some pathological/medical conditions will minimize the cardiac energy 21 requirements with a relaxation protocol that results in an average ventricular beating rate that 22 is equal to, or just slightly less than, the intrinsic atrial firing rate;
and such relaxation 23 protocols are well within the scope of the present invention.
24 The application of cyclic ventricular pacing with any of the above range of relaxation protocols pertains not only to mono-ventricular pacing, but also to biventricular pacing, 26 and/or pacing from multiple sites. In the case of biventricualr pacing, right and left ventricles 27 can be cyclically paced either on the same or similar time protocol or independently of one 28 another. Furthermore, one pacing electrode or multiple pacing electrodes can be employed 29 per ventricle, and the pacing electrodes can be applied to the external surfaces of the ventricles and/or to the internal surfaces. Typically, internal pacing electrodes will be applied 31 via the vena cava and the right atrium to the right ventricle only;
however, multiple internal 1 pacing electrodes are also contemplated for the left ventricle.
2 Additional embodiments encompass the use of monophasic stimulation,.as well as 3 biphasic stimulation. Furthermore, the monophasic stimulation and the biphasic stimulation 4 . can be applied to either atria or ventricles. Monophasic stimulation can be.either cathodal or anodal, and is known to those skilled in the art. Biphasic cardiac stimulation is disclosed in United states Puteat No. 5871506 to lower.
Typically, a cyclic pacing/relaxation period will fall within the three to 30 second g range; however, longer periods also are contemplated, particularly for patients with more "diff cult" pathologies.
Figure 3 depicts biphasic electrical stimulation wherein a first stimulation phase, 11 comprising arodal stimulus 302, is administered having amplitude 304 and duration 306.
12 This first stimulation phase is immediately followed by a second stimulation phase .
13 comprising cathodal stimulation 308 of equal intensity and duration.
14 Figure 4 depicts biphasic electrical stimulation wherein a first stimulation phase, ~mPnsing cathodal stimulation 402 having amplitude 404 and duration 406, is administered.
!6 ~s fust stimulation phase is immediately followed by a second stimulation phase 1~ comprising anodal stimulation 408 of equal intensity and duration.
Figure 5 depicts a preferred embodiment of biphasic stimulation wherein a first .
19 stimulation phase, comprising low level, long duration anodal stimulation 502 having ~plitude 504 and duration 506, is administered. This first stimulation phase is immediately 21 followed by a second stimulation phase comprising cathodal stimulation 508 of conventional 22 intensity and duration. in differing alternative embodiments, anodal stimulation 502 is: 1 ) at 23 maximum subth.-eshold amplitude; 2) less than three volts; 3) of a duration of 24 approximately two to eight milliseconds; and/or 4) administered aver 200 milliseconds post h~ beat. Maximum subthreshold amplitude is understood to mean the maximum 26 stimulation amplitude that can be administered without eliciting a contraction. In differing 2? alternative embodiments, cathodal stimulation 508 is: 1 ) of a short duration; 2) 2g approximately 0.3 to 1.5 milliseconds; 3) of a high amplitude; 4) in the approximate range 29 of three to twenty volts; andlor S) of a duration less than 0.3 millisecond and at a voltage ester than tweaty volts. In a preferred embodiment, cathodal stimulation is about 0.8 1 millisecond. In the manner disclosed by these embodiments, as well as those alterations and 2 modifications which can become obvious upon the reading of this specification, a maximum 3 membrane potential without activation is achieved in the first phase of stimulation.
4 Figure 6 depicts an alternative preferred embodiment of biphasic stimulation wherein S a first stimulation phase, comprising anodal stimulation 602, is administered over period 604 6 with rising intensity level 606. The ramp of rising intensity level 606 can be linear or non-? linear, and the slope can vary. This anodal stimulation is immediately followed by a second 8 stimulation phase comprising cathodal stimulation 608 of conventional intensity and 9 duration. In alternative embodiments, anodal stimulation 602: (1) rises to a maximum subthreshold amplitude less than three volts; (2) is of a duration of approximately two to eight 11 milliseconds; and/or (3) is administered over 200 milliseconds post heart beat. In yet other 12 alternative embodiments, cathodal stimulation 608 is: (1) of a short duration; (2) 13 approximately 0.3 to 1.5 milliseconds; (3) of a high amplitude; (4) in the approximate range 14 of three to twenty volts; and/or (5) of a duration less than 0.3 milliseconds and at a voltage greater than twenty volts. In the manner disclosed by these embodiments, as well as those 16 alterations and modifications which can become obvious upon the reading of this 17 specification, a maximum membrane potential without activation is achieved in the first 18 phase of stimulation.
19 Figure 7 depicts biphasic electrical stimulation wherein a first stimulation phase, comprising series 702 of anodal pulses, is administered at amplitude 704. In one 21 embodiment, rest period 706 is of equal duration to stimulation period 708, and is 22 administered at baseline amplitude. In an alternative embodiment, rest period 706 is of a 23 differing duration than stimulation period 708, and is administered at baseline amplitude.
24 Rest period 706 occurs after each stimulation period 708, with the exception that a second stimulation phase. comprising cathodal stimulation 710 of conventional intensity and 26 duration, immediately follows the completion of series 702. In alternative embodiments: ( 1 ) 27 the total charge transferred through series 702 of anodal stimulation is at the maximum 28 subthreshold level; and/or (2) the first stimulation pulse of series 702 is administered over 29 200 milliseconds post heart beat. In yet other alternative embodiments, cathodal stimulation 710 is: ( 1 } of a short duration; (2} approximately 0.3 to 1.5 milliseconds;
(3) of a high 31 amplitude; (4) in the approximate range of three to twenty volts, andlor (5) of a duration less WO 99!61101 PCT/US99/11375 1 than 0.3 milliseconds and at a voltage greater than twenty volts.
2 The preferred practice of the present invention is directed to ventricular pacing where 3 the pacing rate skirts just above and below the intrinsic atria! pacing rate, and is timed (albeit 4 indirectly) relative to intrinsic atria! firing in order to achieve optimal coordinated cardiac function. However, situations can be anticipated in which ventricular pacing is effected 6 independently of intrinsic atria! firing.
7 Furthermore, when atria! rhythmicity is pathologic, the present invention can be 8 practiced with respect to the rhythmicity of pacemaker paced atria. In embodiments in which 9 atria are paced by extrinsic pacemakers, the clinical practitioner first sets the rate of atria!
pacing, which can be fixed, or can be variable to permit appropriate response to changes in 11 physical activity or other change which would require a change in heart rate, for example, an 12 increased heart rate during a period of fever. Second, the ventricular firing protocol is 13 selected according to the principles described and disclosed herein. It is to be emphasized 14 that selection of the ventricular firing protocol generally will be a decision that is made independently of the atria! beating pattern, whether the atria! beating pattern is set 16 intrinsically or extrinsically, for example, by a pacemaker. However, it is within the scope of 17 the present invention to apply the teachings herein to cases in which decisions regarding 18 extrinsically controlled atria! and ventricular beating protocols are considered in a linked, 19 integrated manner.
In addition. testing procedures can be applied to achieve optimal parameters for a 21 given patient with a particular constellation of pathologies. Thus, it is within the scope of the 22 present invention to test, and vary, alternative stimulation pulse waveforms, for example, 23 durations, amplitudes, and shapes of the various waveforms required to reach optimal 24 physiological parameters for a particular patient at a given time. Further, various measurable parameters may be used to assess the effects of changes in stimulus waveforms, for example, 26 the effects on pulse pressure, duration of the QRS complex, maximum fusion, and production 27 of a minimal intrinsic heart rate, to name but a few.
28 Having thus described the basic concept of the invention, it will be readily apparent to 29 those skilled in the art that the foregoing detailed disclosure is intended to be presented by way of example only, and is not limiting. Various alterations, improvements and 31 modifications will occur and are intended to those skilled in the art, but are not expressly stated herein. These modifications, alterations and improvements are intended to be 2 suggested hereby, and within the scope of the invention. Accordingly, the invention is limited only by the following claims and equivalents thereto.
Therefore, the limited 12 energy of the cardiac patient can be used wisely and optimally to the benefit of the already 13 compromised patient. In summary, this technique allows pacing at an average rate that is just 14 above the intrinsic heart rate so as to maximize inotropic pacing effects at minimal heart rates, and thereby conserve the precious energy of the patient's heart.
16 Additionally, the ventricular firing protocol of the present invention can be used in 17 conjunction with biphasic pacing. The method and apparatus relating to biphasic pacing 18 comprises a first and second stimulation phase, with each stimulation phase having a polarity, 19 amplitude, shape, and duration. In a preferred embodiment, the first and second phases have differing polarities. In one alternative embodiment, the two phases are of differing amplitude.
21 In a second alternative embodiment, the two phases are of differing duration. In a third 22 alternative embodiment, the first phase is in a chopped wave form. In a fourth alternative 23 embodiment, the amplitude of the first phase is ramped. In a fifth alternative embodiment the 24 first phase is administered over 200 milliseconds after completion of a cardiac beating/pumping cycle. In a preferred alternative embodiment, the first phase of stimulation 26 is an anodal pulse at maximum subthreshold amplitude for a long duration, and the second 27 phase of stimulation is a cathodal pulse of short duration and high amplitude. It is noted that 28 the aforementioned alternative embodiments can be combined in differing fashions. It is also 29 noted that these alternative embodiments are intended to be presented by way of example only, and are not limiting.
Another aspect of the invention provides an implantable cardiac stimulator to perform pacing of a heart, the heart having an intrinsic atrial firing rate, the cardiac stimulator comprising: plural electrodes adapted to applying pacing stimuli to the heart; and pulse generating circuitry connected to the plural electrodes and adapted to generate electrical pulses as pacing stimuli; wherein a series of pacing stimuli are applied to at least one ventricle having an initial pacing rate, the initial pacing rate being slightly greater than the intrinsic atrial firing rate, and wherein the pacing rate is decreased over time from the initial pacing rate to a minimum pacing rate that is slightly less than the intrinsic atrial firing rate.
Another aspect of the invention provides an 25 implantable cardiac stimulator to perform pacing of a heart, the heart having a paced atrial firing rate, the cardiac stimulator comprising: plural electrodes adapted to applying pacing stimuli to the heart; and pulse generating circuitry connected to the plural electrodes and adapted to generate electrical pulses as pacing stimuli; wherein a series of pacing stimuli are applied to at least one ventricle having an initial pacing rate, the initial pacing rate being slightly greater than the paced atrial firing rate, and wherein the pacing rate is decreased over time from the initial pacing rate to a minimum pacing rate that is slightly less than the paced atrial firing rate.
6a 1 Brief Description of the Drawings 2 Figure I shows a cyclic saw tooth (linear decay) stimulation-relaxation protocol for 3 ventricular pacing.
4 Figure 2 shows a cyclic exponential decay stimulation-relaxation protocol for ventricular pacing.
6 Figure 3 is a schematic representation of leading anodal biphasic stimulation.
7 Figure 4 is a schematic representation of leading cathodal biphasic stimulation.
8 Figure S is a schematic representation of leading anodal stimulation of low level and 9 long duration, followed by cathodal stimulation.
Figure 6 is a schematic representation of leading anodal stimulation of ramped low 1 I level and long duration, followed by cathodal stimulation.
12 Figure 7 is a schematic representation of leading anodal stimulation of low level and 13 short duration administered in a series, followed by cathodal stimulation.
I4 Description of the Preferred Embodiments The fundamentals of the present invention can be understood with reference to 16 Figures 1 and 2, which depict two cyclic stimulation-relaxation protocols for ventricular 17 pacing, in which the maximum rate of ventricular overdrive pacing is followed by relaxation 18 to a rate just less than the intrinsic atrial firing rate (which corresponds to ventricular escape).
19 Figure 1 shows a cyclic saw tooth (linear decay) stimulation-relaxation protocol. Figure 2 shows a cyclic exponential decay stimulation-relaxation protocol.
21 Referring to Figure 1, a cyclic saw tooth stimulation-relaxation protocol for 22 ventricular pacing is depicted with time points 102,106, and 108 to illustrate initiation of 23 ventricular overdrive pacing at maximum pacing rate A, followed by linear decay/relaxation 24 of the rate of pacing to minimum pacing rate C. Each cycle has total time length 110.
Intrinsic atrial firing rate B is shown as a dashed reference line. Rate difference A-B is 26 greater than rate difference B-C in this example. During the course of linear relaxation of 27 the ventricular pacing rate, crossover point 104 is reached when the ventricular pacing rate 28 equals intrinsic atrial firing rate B. Thus, the period between time point 102 and crossover 29 point 104 represents linear ventricular overdrive pacing period 112, and the period between crossover point 104 and time point 106 represents linear ventricular escape period 114. It is 1 evident that linear ventricular overdrive pacing period 112 is a longer time period than linear 2 ventricular escape period 114. Therefore, the average ventricular firing rate for this protocol, 3 with the above given relative parameters, will always be slightly greater than intrinsic atrial 4 firing rate B.
Referring to Figure 2, a cyclic exponential decay stimulation-relaxation ventricular 6 pacing protocol is shown with ventricular overdrive pacing to maximum pacing rate A being 7 initiated at time points 202, 206 and 208, followed by exponential relaxation of the rate of 8 pacing to minimum pacing rate C. Each cycle has total time length 210. The time course of 9 the pacing rate during the relaxation phase will be proportional to the time course of the product obtained by multiplying maximum pacing rate A (or the quantity A minus a selected 11 "factor") by the proportionality el~T where ris the time constant. The selected "factor"
12 typically will have a value less than C. As in Figure 1, dashed line B
represents the reference 13 line of intrinsic atrial firing rate. Compared to Figure I, two parameters have been adjusted 14 in Figure 2. First, the relaxation of pacing rate is an exponential function of time instead of a linear function of time. Second, minimum ventricular pacing rate C is closer to intrinsic I6 atrial firing rate B.
17 As in Figure 1, the period between time point 202 and crossover point 204 represents 18 exponential ventricular overdrive pacing period 212, and the period between crossover point 19 204 and time point 206 represents exponential ventricular escape period 214. Rate difference A-B is the same in Figures 1 and 2, as are cycle lengths I10 and 210. This 21 combination of parameters produces a protocol in which exponential ventricular overdrive 22 pacing period 212 of Figure 2 is shorter than linear ventricular overdrive pacing period 112 of 23 Figure 1.
24 In the case of a curvilinear (including exponential) relaxation protocol with cycle length 210, comparison of ventricular overdrive pacing period 212 and ventricular escape 26 period 214 of Figure 2 reveals that their magnitudes effectively are controlled by variations in 27 two parameters: (A-B)/(B-C), and ventricular overdrive pacing period 212.
28 Referring again to Figure l, in the case of a linear relaxation protocol with cycle 29 length 110, comparison of linear ventricular overdrive pacing period 112 and linear ventricular escape period 114 reveals that their magnitudes are controlled by variation in 31 single parameter (A-B)/(B-C), or any mathematical equivalent, such as (I02-104)/(104-106).
2 It is anticipated that different relaxation protocols will be required for different 3 pathologies and different medical situations. In addition, a virtually infinite array of 4 relaxation protocols are possible in theory. Thus, the preferred embodiment of the present S invention contemplates any monotonic relaxation protocol, where "monotonic"
indicates a 6 unidirectional change in the applied ventricular pacing rate. Further, "unidirectional change"
7 is to be understood to refer to a change in ventricular pacing rate that is in the direction of 8 decreasing ventricular pacing rate, and to include periods of time in which there is no change 9 in ventricular pacing rate.
Therefore, the preferred embodiment of the present invention contemplates relaxation I 1 protocols beyond the two depicted in Figures 1 and 2, as long as the relaxation protocol 12 embodies unidirectional change in ventricular pacing rate as defined above.
Thus, the shapes 13 of the relaxation curves can generally be decreasing linear, decreasing curvilinear, decreasing 14 in an exponential fashion, include one or more periods at a constant pacing rate, or combinations of these. For example, with reference to Figure 1, one can imagine a protocol 16 in which, between time points 102 and 104, there is a small time segment over which the 17 voltage is constant, followed by linear relaxation at the same or a different rate of relaxation 18 (i.e., the same or a different slope) compared to the initial rate of relaxation. In one 19 embodiment, the same or different rate of relaxation that follows the brief period of constant voltage is maintained up to time point 106, which marks the end of one cycle and the 21 beginning of the next cycle.
22 Alternate embodiments encompass relaxation protocols in which ventricular pacing 23 rates are not monotonic; i.e., as the ventricular pacing rate is declining in a given cycle, time 24 periods in which the ventricular pacing rates are increased slightly can be included. Further alternative embodiments can include the use of combinations of different rates of relaxation 26 within a single cycle, for example, within time segment 102 -106, or 202 -206.
27 Typically, physiological data from one or more sensing electrodes (including 28 electrodes that perform both pacing and sensing) are used to determine whether an "action 29 criterion" has been met, in order to initiate a cyclic pacing protocol if the situation so demands. Such sensing may be directed to detecting such nonlimiting physiological 31 parameters as abnormal or unacceptably long A-V delays, whether atrial firing entrains both 1 left and right ventricles, length of the QRS complex, magnitude of the QRS
complex, heart 2 rate, arterial and/or venous blood pressure, ventricular fibrillation, atrial fibrillation, and 3 probability density function ("PDF"). At the end of such a cyclic pacing protocol, sensing 4 again is performed to determine if additional pacing is required.
Alternatively, sensing can be conducted concurrently with a cyclic pacing protocol.
6 The ventricular firing protocol is activated upon detection of a QRS
complex, and is 7 set at an overdrive rate of only a few beats per minute (i.e., no more than 3-5 beats per 8 minute) greater than the intrinsic atrial firing rate. Next, the ventricular firing rate is slowly 9 decreased ("relaxed") to a rate just a few beats per minute (i.e., no more than 2-3 beats per minute; ideally, only I-2 beats per minute) below the intrinsic atrial firing rate, which leads to 11 ventricular escape (i.e., atrial firing and contraction no longer coordinate perfectly with 12 ventricular firing and contraction). Heart rates could vary from about 40 to 120 beats per 13 minute, with these rates being largely determined by the intrinsic physiology of the heart.
14 Rates that vary greatly from this 40 to 120 beats per minute range would not be beneficial physiologically.
16 What is central to the present invention is that the ventricular pacing rates hover not I7 far from the intrinsic atrial firing rate so as to minimize the energy requirements of the 18 myocardium. Generally, practice of the present invention will result in an average ventricular 19 beating rate that is just slightly greater than the intrinsic atrial firing rate. However, it is anticipated that some pathological/medical conditions will minimize the cardiac energy 21 requirements with a relaxation protocol that results in an average ventricular beating rate that 22 is equal to, or just slightly less than, the intrinsic atrial firing rate;
and such relaxation 23 protocols are well within the scope of the present invention.
24 The application of cyclic ventricular pacing with any of the above range of relaxation protocols pertains not only to mono-ventricular pacing, but also to biventricular pacing, 26 and/or pacing from multiple sites. In the case of biventricualr pacing, right and left ventricles 27 can be cyclically paced either on the same or similar time protocol or independently of one 28 another. Furthermore, one pacing electrode or multiple pacing electrodes can be employed 29 per ventricle, and the pacing electrodes can be applied to the external surfaces of the ventricles and/or to the internal surfaces. Typically, internal pacing electrodes will be applied 31 via the vena cava and the right atrium to the right ventricle only;
however, multiple internal 1 pacing electrodes are also contemplated for the left ventricle.
2 Additional embodiments encompass the use of monophasic stimulation,.as well as 3 biphasic stimulation. Furthermore, the monophasic stimulation and the biphasic stimulation 4 . can be applied to either atria or ventricles. Monophasic stimulation can be.either cathodal or anodal, and is known to those skilled in the art. Biphasic cardiac stimulation is disclosed in United states Puteat No. 5871506 to lower.
Typically, a cyclic pacing/relaxation period will fall within the three to 30 second g range; however, longer periods also are contemplated, particularly for patients with more "diff cult" pathologies.
Figure 3 depicts biphasic electrical stimulation wherein a first stimulation phase, 11 comprising arodal stimulus 302, is administered having amplitude 304 and duration 306.
12 This first stimulation phase is immediately followed by a second stimulation phase .
13 comprising cathodal stimulation 308 of equal intensity and duration.
14 Figure 4 depicts biphasic electrical stimulation wherein a first stimulation phase, ~mPnsing cathodal stimulation 402 having amplitude 404 and duration 406, is administered.
!6 ~s fust stimulation phase is immediately followed by a second stimulation phase 1~ comprising anodal stimulation 408 of equal intensity and duration.
Figure 5 depicts a preferred embodiment of biphasic stimulation wherein a first .
19 stimulation phase, comprising low level, long duration anodal stimulation 502 having ~plitude 504 and duration 506, is administered. This first stimulation phase is immediately 21 followed by a second stimulation phase comprising cathodal stimulation 508 of conventional 22 intensity and duration. in differing alternative embodiments, anodal stimulation 502 is: 1 ) at 23 maximum subth.-eshold amplitude; 2) less than three volts; 3) of a duration of 24 approximately two to eight milliseconds; and/or 4) administered aver 200 milliseconds post h~ beat. Maximum subthreshold amplitude is understood to mean the maximum 26 stimulation amplitude that can be administered without eliciting a contraction. In differing 2? alternative embodiments, cathodal stimulation 508 is: 1 ) of a short duration; 2) 2g approximately 0.3 to 1.5 milliseconds; 3) of a high amplitude; 4) in the approximate range 29 of three to twenty volts; andlor S) of a duration less than 0.3 millisecond and at a voltage ester than tweaty volts. In a preferred embodiment, cathodal stimulation is about 0.8 1 millisecond. In the manner disclosed by these embodiments, as well as those alterations and 2 modifications which can become obvious upon the reading of this specification, a maximum 3 membrane potential without activation is achieved in the first phase of stimulation.
4 Figure 6 depicts an alternative preferred embodiment of biphasic stimulation wherein S a first stimulation phase, comprising anodal stimulation 602, is administered over period 604 6 with rising intensity level 606. The ramp of rising intensity level 606 can be linear or non-? linear, and the slope can vary. This anodal stimulation is immediately followed by a second 8 stimulation phase comprising cathodal stimulation 608 of conventional intensity and 9 duration. In alternative embodiments, anodal stimulation 602: (1) rises to a maximum subthreshold amplitude less than three volts; (2) is of a duration of approximately two to eight 11 milliseconds; and/or (3) is administered over 200 milliseconds post heart beat. In yet other 12 alternative embodiments, cathodal stimulation 608 is: (1) of a short duration; (2) 13 approximately 0.3 to 1.5 milliseconds; (3) of a high amplitude; (4) in the approximate range 14 of three to twenty volts; and/or (5) of a duration less than 0.3 milliseconds and at a voltage greater than twenty volts. In the manner disclosed by these embodiments, as well as those 16 alterations and modifications which can become obvious upon the reading of this 17 specification, a maximum membrane potential without activation is achieved in the first 18 phase of stimulation.
19 Figure 7 depicts biphasic electrical stimulation wherein a first stimulation phase, comprising series 702 of anodal pulses, is administered at amplitude 704. In one 21 embodiment, rest period 706 is of equal duration to stimulation period 708, and is 22 administered at baseline amplitude. In an alternative embodiment, rest period 706 is of a 23 differing duration than stimulation period 708, and is administered at baseline amplitude.
24 Rest period 706 occurs after each stimulation period 708, with the exception that a second stimulation phase. comprising cathodal stimulation 710 of conventional intensity and 26 duration, immediately follows the completion of series 702. In alternative embodiments: ( 1 ) 27 the total charge transferred through series 702 of anodal stimulation is at the maximum 28 subthreshold level; and/or (2) the first stimulation pulse of series 702 is administered over 29 200 milliseconds post heart beat. In yet other alternative embodiments, cathodal stimulation 710 is: ( 1 } of a short duration; (2} approximately 0.3 to 1.5 milliseconds;
(3) of a high 31 amplitude; (4) in the approximate range of three to twenty volts, andlor (5) of a duration less WO 99!61101 PCT/US99/11375 1 than 0.3 milliseconds and at a voltage greater than twenty volts.
2 The preferred practice of the present invention is directed to ventricular pacing where 3 the pacing rate skirts just above and below the intrinsic atria! pacing rate, and is timed (albeit 4 indirectly) relative to intrinsic atria! firing in order to achieve optimal coordinated cardiac function. However, situations can be anticipated in which ventricular pacing is effected 6 independently of intrinsic atria! firing.
7 Furthermore, when atria! rhythmicity is pathologic, the present invention can be 8 practiced with respect to the rhythmicity of pacemaker paced atria. In embodiments in which 9 atria are paced by extrinsic pacemakers, the clinical practitioner first sets the rate of atria!
pacing, which can be fixed, or can be variable to permit appropriate response to changes in 11 physical activity or other change which would require a change in heart rate, for example, an 12 increased heart rate during a period of fever. Second, the ventricular firing protocol is 13 selected according to the principles described and disclosed herein. It is to be emphasized 14 that selection of the ventricular firing protocol generally will be a decision that is made independently of the atria! beating pattern, whether the atria! beating pattern is set 16 intrinsically or extrinsically, for example, by a pacemaker. However, it is within the scope of 17 the present invention to apply the teachings herein to cases in which decisions regarding 18 extrinsically controlled atria! and ventricular beating protocols are considered in a linked, 19 integrated manner.
In addition. testing procedures can be applied to achieve optimal parameters for a 21 given patient with a particular constellation of pathologies. Thus, it is within the scope of the 22 present invention to test, and vary, alternative stimulation pulse waveforms, for example, 23 durations, amplitudes, and shapes of the various waveforms required to reach optimal 24 physiological parameters for a particular patient at a given time. Further, various measurable parameters may be used to assess the effects of changes in stimulus waveforms, for example, 26 the effects on pulse pressure, duration of the QRS complex, maximum fusion, and production 27 of a minimal intrinsic heart rate, to name but a few.
28 Having thus described the basic concept of the invention, it will be readily apparent to 29 those skilled in the art that the foregoing detailed disclosure is intended to be presented by way of example only, and is not limiting. Various alterations, improvements and 31 modifications will occur and are intended to those skilled in the art, but are not expressly stated herein. These modifications, alterations and improvements are intended to be 2 suggested hereby, and within the scope of the invention. Accordingly, the invention is limited only by the following claims and equivalents thereto.
Claims (28)
1. An implantable cardiac stimulator to perform pacing of a heart, the heart having an intrinsic atrial firing rate, the cardiac stimulator comprising:
plural electrodes adapted to applying pacing stimuli to the heart; and pulse generating circuitry connected to the plural electrodes and adapted to generate electrical pulses as pacing stimuli;
wherein a series of pacing stimuli are applied to at least one ventricle having an initial pacing rate, the initial pacing rate being slightly greater than the intrinsic atrial firing rate, and wherein the pacing rate is decreased over time from the initial pacing rate to a minimum pacing rate that is slightly less than the intrinsic atrial firing rate.
plural electrodes adapted to applying pacing stimuli to the heart; and pulse generating circuitry connected to the plural electrodes and adapted to generate electrical pulses as pacing stimuli;
wherein a series of pacing stimuli are applied to at least one ventricle having an initial pacing rate, the initial pacing rate being slightly greater than the intrinsic atrial firing rate, and wherein the pacing rate is decreased over time from the initial pacing rate to a minimum pacing rate that is slightly less than the intrinsic atrial firing rate.
2. The cardiac stimulator to perform cardiac pacing according to claim 1, further comprising:
physiological parameter sensor to determine if additional cardiac pacing is needed.
physiological parameter sensor to determine if additional cardiac pacing is needed.
3. The cardiac stimulator to perform cardiac pacing according to claim 2, wherein the physiological parameters are selected from the group consisting of A-V
interval, atrial entrainment of left and right ventricles, length of QRS complex, magnitude of QRS complex, arterial blood pressure, venous blood pressure, heart rate, ventricular fibrillation, atrial fibrillation, and probability density function.
interval, atrial entrainment of left and right ventricles, length of QRS complex, magnitude of QRS complex, arterial blood pressure, venous blood pressure, heart rate, ventricular fibrillation, atrial fibrillation, and probability density function.
4. The cardiac stimulator to perform cardiac pacing according to claim 1, wherein applying the pacing stimuli and decreasing the pacing rate is repeated in a cyclic pattern.
5. The cardiac stimulator to perform cardiac pacing according to claim 1, wherein a protocol for decreasing the pacing rate over time is selected from the group consisting of: linear, curvilinear, exponential, and combinations thereof.
6. The cardiac stimulator to perform cardiac pacing according to claim 5, wherein the protocol for decreasing the pacing rate includes one or more periods of time in which the pacing rate is held constant.
7. The cardiac stimulator to perform cardiac pacing according to claim 1, wherein a protocol for decreasing the pacing rate includes one or more periods of time in which the pacing rate is held constant.
8. The cardiac stimulator to perform cardiac pacing according to claim 1, wherein the initial pacing rate minus the intrinsic atrial firing rate is greater than the intrinsic atrial firing rate minus the minimum pacing rate.
9. The cardiac stimulator to perform cardiac pacing according to claim 1, wherein the initial pacing rate minus the intrinsic atrial firing rate is equal to the intrinsic atrial firing rate minus the minimum pacing rate.
10. The cardiac stimulator to perform cardiac pacing according to claim 1, wherein the initial pacing rate minus the intrinsic atrial firing rate is less than the intrinsic atrial firing rate minus the minimum pacing rate.
11. The cardiac stimulator to perform cardiac pacing according to claim 1, wherein the pacing stimuli are selected from the group consisting of: monophasic stimulation and biphasic stimulation.
12. The cardiac stimulator to perform cardiac pacing according to claim 11, wherein the monophasic stimulation is selected from the group consisting of: cathodal stimulation and anodal stimulation.
13. The cardiac stimulator to perform cardiac pacing according to claim 11, wherein the biphasic stimulation comprises an anodal stimulation phase followed by a cathodal stimulation phase.
14. The cardiac stimulator to perform cardiac pacing according to claim 13, wherein the anodal stimulation phase has a magnitude equal to or less than a maximum subthreshold amplitude; and has an approximate shape selected from the group consisting of:
square wave, increasing ramp, and series of short duration square waves.
square wave, increasing ramp, and series of short duration square waves.
15. The cardiac stimulator to perform cardiac pacing according to claim 1, wherein the pacing stimuli are applied via multiple electrodes to at least one ventricle.
16. An implantable cardiac stimulator to perform pacing of a heart, the heart having a paced atrial firing rate, the cardiac stimulator comprising:
plural electrodes adapted to applying pacing stimuli to the heart; and pulse generating circuitry connected to the plural electrodes and adapted to generate electrical pulses as pacing stimuli;
wherein a series of pacing stimuli are applied to at least one ventricle having an initial pacing rate, the initial pacing rate being slightly greater than the paced atrial firing rate, and wherein the pacing rate is decreased over time from the initial pacing rate to a minimum pacing rate that is slightly less than the paced atrial firing rate.
plural electrodes adapted to applying pacing stimuli to the heart; and pulse generating circuitry connected to the plural electrodes and adapted to generate electrical pulses as pacing stimuli;
wherein a series of pacing stimuli are applied to at least one ventricle having an initial pacing rate, the initial pacing rate being slightly greater than the paced atrial firing rate, and wherein the pacing rate is decreased over time from the initial pacing rate to a minimum pacing rate that is slightly less than the paced atrial firing rate.
17. The cardiac stimulator to perform cardiac pacing according to claim 16, wherein applying the pacing stimuli and decreasing the pacing rate is repeated in a cyclic pattern.
18. The cardiac stimulator to perform cardiac pacing according to claim 16, wherein a protocol for decreasing the initial ventricular pacing rate aver time is selected from the group consisting of: linear, curvilinear, exponential, and combinations thereof.
19. The cardiac stimulator to perform cardiac pacing according to claim 18, wherein the protocol for decreasing the initial pacing rate includes one or more periods of time in which the pacing rate is held constant.
20. The cardiac stimulator to perform cardiac pacing according to claim 16, wherein a protocol for decreasing the pacing rate includes one ar more periods of time in which the pacing rate is held constant.
21. The cardiac stimulator to perform cardiac pacing according to claim 16, wherein the initial ventricular pacing rate minus the paced atrial firing rate is greater than the paced atrial firing rate minus the minimum ventricular pacing rate.
22. The cardiac stimulator to perform cardiac pacing according to claim 16, wherein the initial ventricular pacing rate minus the paced atrial firing rate is equal to the paced atrial firing rate minus the minimum ventricular pacing rate.
23. The cardiac stimulator so perform cardiac pacing according to claim 16, wherein the initial ventricular pacing rate minus the paced atrial bring rate is less than the paced atrial firing rate minus the minimum ventricular pacing rate.
24. The cardiac stimulator to perform cardiac pacing according to claim 16, wherein the pacing stimuli are selected from the group consisting of: monophasic stimulation and biphasic stimulation.
25. The cardiac stimulator to perform cardiac pacing according to claim 24, wherein the monophasic stimulation is selected from the group consisting of: cathodal stimulation and anodal stimulation.
26. The cardiac stimulator to perform cardiac pacing according to claim 24, wherein the biphasic stimulation comprises an anodal stimulation phase followed by a cathodal stimulation phase.
27. The cardiac stimulator to perform cardiac pacing according to claim 26, wherein the anodal stimulation phase has a magnitude equal to or less than a maximum subthreshold ;amplitude, and has an approximate shape selected from the group consisting of: square wave, increasing ramp, and series of short duration square waves.
28. The cardiac stimulator to perform cardiac pacing according to claim 16, wherein the bracing stimuli are applied via multiple electrodes to at least one;
ventricle.
ventricle.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/084,571 US6141586A (en) | 1996-08-19 | 1998-05-26 | Method and apparatus to allow cyclic pacing at an average rate just above the intrinsic heart rate so as to maximize inotropic pacing effects at minimal heart rates |
| US09/084,571 | 1998-05-26 | ||
| PCT/US1999/011375 WO1999061101A1 (en) | 1998-05-26 | 1999-05-21 | Method allowing cyclic pacing with average rate just above the intrinsic rate |
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| CA2333363A1 CA2333363A1 (en) | 1999-12-02 |
| CA2333363C true CA2333363C (en) | 2004-05-04 |
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|---|---|---|---|
| CA002333363A Expired - Fee Related CA2333363C (en) | 1998-05-26 | 1999-05-21 | Method allowing cyclic pacing with average rate just above the intrinsic rate |
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| UA (1) | UA49994C2 (en) |
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-
1998
- 1998-05-26 US US09/084,571 patent/US6141586A/en not_active Expired - Lifetime
-
1999
- 1999-05-21 CN CNB99806596XA patent/CN1235651C/en not_active Expired - Fee Related
- 1999-05-21 NZ NZ508495A patent/NZ508495A/en unknown
- 1999-05-21 ID IDW20002442A patent/ID27797A/en unknown
- 1999-05-21 GE GEAP19995685A patent/GEP20033047B/en unknown
- 1999-05-21 WO PCT/US1999/011375 patent/WO1999061101A1/en active IP Right Grant
- 1999-05-21 UA UA2000127489A patent/UA49994C2/en unknown
- 1999-05-21 SK SK1801-2000A patent/SK286403B6/en unknown
- 1999-05-21 CN CNA2005101200542A patent/CN1803219A/en active Pending
- 1999-05-21 IL IL139780A patent/IL139780A/en not_active IP Right Cessation
- 1999-05-21 ES ES99925765T patent/ES2245106T3/en not_active Expired - Lifetime
- 1999-05-21 JP JP2000550556A patent/JP2002516162A/en active Pending
- 1999-05-21 PL PL99344392A patent/PL193754B1/en not_active IP Right Cessation
- 1999-05-21 HU HU0102153A patent/HUP0102153A3/en unknown
- 1999-05-21 DK DK99925765T patent/DK1079894T3/en active
- 1999-05-21 EA EA200001225A patent/EA003572B1/en not_active IP Right Cessation
- 1999-05-21 TR TR2000/03358T patent/TR200003358T2/en unknown
- 1999-05-21 CA CA002333363A patent/CA2333363C/en not_active Expired - Fee Related
- 1999-05-21 AU AU41984/99A patent/AU755994B2/en not_active Ceased
- 1999-05-21 EP EP99925765A patent/EP1079894B1/en not_active Expired - Lifetime
- 1999-05-21 BR BR9910702-3A patent/BR9910702A/en not_active Application Discontinuation
- 1999-05-21 KR KR10-2000-7013231A patent/KR100423964B1/en not_active IP Right Cessation
- 1999-05-21 CZ CZ20004238A patent/CZ298479B6/en not_active IP Right Cessation
- 1999-05-21 AT AT99925765T patent/ATE299736T1/en not_active IP Right Cessation
- 1999-05-21 DE DE69926232T patent/DE69926232T2/en not_active Expired - Lifetime
-
2000
- 2000-11-24 NO NO20005959A patent/NO20005959L/en not_active Application Discontinuation
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2005
- 2005-03-22 JP JP2005082143A patent/JP2005230566A/en not_active Abandoned
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