CARDIAC OUTPUT CONTROLLER

Abstract: This invention is an apparatus for modifying cardiac output of the heart of a subject, including one or more sensors (29) which sense signals responsive to cardiac activity, and a stimulation probe (21) including one or more stimulation electrodes (23) which apply non-excitatory stimulation pulses to a cardiac muscle segment. Signal generation circuitry (22) is coupled to the one or more sensors, and the stimulation probe which circuitry receives the signals from the one or more sensors and generates the non-excitatory stimulation pulses responsive to the signals.

Description: CARDIAC OUTPUT CONTROLLER FIELD OF THE INVENTION The present invention relates generally to cardiac therapeutic devices, and specifically to invasive devices for enhancing performance of the heart. BACKGROUND OF THE INVENTION Cardiac insufficiency, characterized infer alia by a reduction in the cardiac output, is a common, well-known and well-documented heart malfunction It develops as a result of congenital defects or as an end-effect of many diseases Cardiac output, i e , the output of the heart per unit time, is the product of stroke volume and heart rate Hence, variations in cardiac output can be produced by changes in cardiac rate or stroke volume The stroke volume can be influenced, for example, by changing the strength of cardiac contraction, by changing the length of the cardiac muscle fibers, and by changing contractility of cardiac muscle independent of fiber length The heart rate and rhythm influence the cardiac output both directly and indirectly, since changes in the rate and rhythm also affect myocardial contractility The human body normally regulates the cardiac output in response to body needs by changing the heart rate, as during physical exercise, and/or by adapting the stroke volume. Under pathological conditions, however, some of the normal regulatory mechanisms may be damaged For example, heart tissue damaged due to myocardial infarct typically cannot sustain normal pumping function, leading to a reduction in stroke volume, and hence of cardiac output The body may react to such a reduction by increasing the heart rate, thus imposing long term strain on the heart muscles, leading in more severe cases to heart failure There is thus a need for devices and treatments that can regulate the cardiac output, so as to compensate for the deficiencies in the normal regulation mechanisms . In response to this need, modern cardiology has developed means to control various parameters associated with the heart's operation Pharmaceuticals, for example, may be used to influence the conduction velocity, excitability, contractility and duration of the refractory period of the heart tissue These pharmaceuticals are used to treat arrhythmia, enhance cardiac output and prevent fibrillation Pharmaceuticals are generally limited in effectiveness in that they affect both healthy and diseased segments of the heart, usually, with a relatively low precision. They frequently also have unwanted side-effects. A special kind of control can be achieved using implantable electronic devices, which provide excitatory electrical stimulation to the heart to control directly the heart rate and/or rhythm. For example, a pacemaker, an electronic devices which is typically implanted in the heart to support the heart's electrical excitation system or to bypass a blocked portion of the conduction system Another type of cardiac electronic device is a defibrillator, which senses fibrillation in the heart and applies a high voltage impulse to "reset" the heart While electronic pacemakers can control the heart rate, however, they are limited in their capacity to enhance cardiac output, and they are known to i educe stroke volume in at least some instances Defibrillators are useful in treating arrhythmia when it occurs (although they are painful to the patient and traumatic to the heart), but they provide no long-term amelioration of cardiac insufficiency Thus, none of the treatments known in the art allow effective, long-term regulation of cardiac output The electromechanical properties of the heart, as well as methods known in the art for influencing these properties, are more fully described in the "Background of the Invention" section of PCT patent application PCT/1L97/00012, which is assigned to the assignee of the present patent application and is incorporated herein by reference. SUMMARY OF THE INVENTION It is an object of the present invention to provide a device and method for regulation of hemodynamic parameters, and particularly for increasing the cardiac output by enhancing the heart's stroke volume In preferred embodiments of the present invention, a cardiac output controller comprises a non-excitatory stimulation probe, including one or more non-excitatory stimulation electrodes; at least one sensor, preferably a sensing electrode, and electronic control circuitry, coupled to the stimulation probe and sensor The stimulation electrodes and, preferably, the sensor are implanted in the heart of a subject Alternatively, a sensing electrode may be placed on a body surface The circuitry receives signals from the sensor, indicative of the heart's activity, and responsive thereto, drives the stimulation electrodes to provide non-excitatory electrical stimulation to the heart The term "non-excitatory electrical stimulation," in the context of the present patent application and in the claims, refers to electrical pulses that do not induce new activation potentials to propagate in cardiac muscle cells Rather, such pulses generally affect the response of the heart muscle to the action potentials, possibly by modulating cell contractility within selected segments of the cardiac muscle Specifically, as described in the above- mentioned PCT patent application PCT/IL97/00012 and incorporated herein by reference, the inventors have found that by applying non-excitatory electrical stimulation pulses of suitable strength, appropriately timed with respect to the heart's electrical activation, the contraction of the selected segments can be increased or decreased, thus increasing or decreasing the stroke volume of the heart This finding forms the basis for the present invention In preferred embodiments of the present invention, characteristics of the non-excitatory stimulation are adjusted so as to modify the heart's muscular activity, thus affecting the cardiac output, preferably by increasing the stroke volume, without directly affecting the heart rate. Preferably, the device is used to increase cardiac output substantially continuously for extended periods of time, most preferably to boost cardiac output during those portions of a day for which a patient needs increased blood supply Accordingly, the device is preferably not used at night, to allow the heart muscle to rest Alternatively, the device may be used to modify the heart's muscular activity in other ways. For example, in some conditions, such as HOCM (hypertrophic obstructive cardiomyopathy), the device may be operated to reduce cardiac output, so as to reduce the workload on the heart, or particularly to reduce cardiac muscle contraction in a hypertrophic region of the heart As another example, the device may be used to increase the heart's contraction efficiency, so that a given level of cardiac output is maintained at a reduced expenditure of energy Such uses of the device are described further in a PCT patent application entitled, "Apparatus and Method for Controlling the Contractility of Muscles," filed on even date (docket no 4424/WO/97), which is assigned to the assignee of the present patent application, and whose disclosure is incorporated herein by reference In any case, the effect of the device on cardiac output is preferably regulated by changing the timing of the non-excitatory stimulation pulse relative to the heart's activity, preferably relative to the heart's local electrical activity or ECG signals received by the sensing electrode, and/or by changing other pulse characteristics, such as the voltage, current, duration, polarity, waveform and frequency of the waveform Preferably, the device senses the heart's sinus rhythm and applies and synchronizes the stimulation pulse relative thereto, preferably with a delay before the onset of the stimulation pulse Additionally, the circuitry may analyze the signals, for example, to determine the QT interval, so as to adjust the stimulation pulses responsive thereto Alternatively, when the heart's rhythm is irregulai, due to ventricular premature beats (VPB's) or other cardiac an hythmias, the device pieferably identifies and analyzes the irregularity, using signal processing methods known in the ait, and adjusts or withholds the stimulation pulse accordingly In some preferred embodiments of the present invention the control circuitry is contained within a console external to the body, and the electrodes aie fed percutaneously into the subject's vascular system, for example, through the femoral artery and are implanted in the heart Such embodiments aie useful particularly in short-term theiapy to regulate and stabilize the subject's hemodynamics following an insult oi tiau a for open heart surgery or MI In alternative piefened embodiments of the piesent invention, the electronic control circuitry is contained within a miniaturized implantable case similai to pacemaker cases known in the art In some piefen ed embodiments of the pi esent invention, the non-excitatory stimulation electrodes have a large surface area in contact with the heart tissue, by comparison with intracardiac electrodes known in the ai t, such as pacing oi electi ophysiology electrodes Preferably, the stimulation electrodes compnse large-aiea caibon electrodes, most preferably vitreous carbon, or alternatively, pyro-caibon Both types of carbon materials are known for their compatibility with heart tissue, m-vivo dm ability and excellent electrical properties, including high electrical conductivity 1 hus the) allow a l elativ ely high electi ical current to be delivered to a relatively laige segment of the heart tissue without inducing electrical excitation Alternatively, the non-excitatoiy stimulation electi odes mas comprise large-area electrodes of other types known in the an such as platinum oi platinuin/iudium In other piefened embodiments of the pie ent invention, the stimulation electrodes are inserted into one of the blood vessels of the heart, preferably into the coronary sinus, or alternatively, into a coi onary ai tei) T hese pi efen ed embodiments are based on the inventors' experimental findings that caidiac output is most enhanced when the stimulation electrodes are placed in the heart adjacent to the blood vessels In one such preferred embodiment, the non-excitatory stimulation pi obe compi ises a carbon wne electrode, which is inserted into the coionai y sinus and passed thei ein to a position adiacent the left ventricle In some preferred embodiments of the pi esent invention the stimulation probe comprises a plurality of stimulation electiodes Pi eferably, the probe comprises a stimulation net, which includes a plurality of interconnected, individually- and/or collectively- addressable electrodes, covering a substantial segment of the heart wall. As described in the above- mentioned '012 PCT application, the inventors have found that the extent of change in cardiac output, especially in left ventricular stroke volume, may be controlled by varying the size of the segment of the heart to which a non-excitatory field is applied. Such size variation is most preferably achieved by varying the number of the electrodes within the net that are to which the non-excitatory stimulation pulse is applied simultaneously. In another preferred embodiment of this type, different stimulation pulses are applied to respective ones or groups of the plurality of stimulation electrodes. Preferably, the different stimulation pulses are applied to the respective electrodes with a predetermined delay between the different pulses. The delay may be varied so as to achieve a desired hemodynamic effect, for example, to maximize the increase in stroke volume. In still other such preferred embodiments, the positions of the plurality of stimulation electrodes and/or characteristics of the stimulation pulses applied thereto are optimized responsive to clinical characteristics of the heart. Preferably, before insertion of the electrodes, a map of the heart is produced, for example, an electrophysiological map, as described in U.S. Patent 5,568,809, or a phase-dependent geometrical map, as described in PCT Patent Application PCT/IL97/0001 1 , both of which are incorporated herein by reference. Preferably, the map includes information regarding the viability of the heart tissue, for example, based on local contractility or electrical activity. The non-excitatory stimulation electrodes are then positioned responsive to the map. Alternatively or additionally, at the time of implantation of the non-excitatory stimulation electrodes, their positions are varied and the results of the variation on hemodynamics are observed, in order to find optimal, fixed positions for the electrodes. A similar effect may be attained by implanting the net electrode, as described above, and variably addressing different ones or groups of electrodes in the net so as to optimize the hemodynamic effect. In alternative embodiments of the present invention, the non-excitatory stimulation probe comprises at least one hybrid electrode. The hybrid electrode preferably comprises a sensing core, preferably a platinum or p!atinum/iridium electrode, surrounded by an annular non-excitatory stimulation electrode, preferably comprising a carbon electrode, as described above. In still other embodiments of the present invention, a single electrode may serve as both the sensing electrode and as one of the one or more stimulation electrodes. In some preferred embodiments of the present invention at least one non-excitatory stimulation electrode and the sensing electrode are implanted in the same chamber of the heart, preferably in the left ventricle. Preferably, the non-excitatory stimulation electrode is fixed against the wall of the left ventricle, and the sensing electrode is fixed at the septum thereof. Alternatively, the stimulation and sensing electrodes may be implanted in different chambers of the heart, in either the ventricles or the atria. The delay between the heart activity signal sensed by the sensing electrode and the pulse applied to the stimulation electrode is preferably dependent on the relative postions of these electrodes In some preferred embodiments of the present invention, the non-excitatory stimulation electrodes comprise a bipolar electrode, and the non-excitatory stimulation pulse is provided to the heart tissue between the poles of the electrode. In other preferred embodiments, the non- excitatory stimulation pulse is provided between the one or more stimulation electrode and another electrode, for example, the sensing electrode. Alternatively, the pulse may be applied between the stimulation electrodes and the case of the control circuitry, in those embodiments of the present invention in which the case is implanted in the patient's body, as described above. In preferred embodiments of the present invention, the control circuitry applies to the stimulation electrodes a square wave stimulation pulse having current up to 50 mA, most preferably between 5 and 10 mA, for a duration that may be nearly as long as the beat-to-beat interval of the heart, most preferably between 30 and 80 msec Preferably, the stimulation pulse is followed by a pulse of opposite polarity, to prevent problems of electrode degradation and polarization. In some preferred embodiments of the present invention, an alternating waveform is superimposed on the square wave pulse The waveform is itself preferably a square wave or, alternatively a sinusoidal or a sawtooth wave, having a frequency up to 10 kHz and amplitude less than or comparable to that of the square wave pulse. The inventors have found that in at least some cases, such a waveform enhances the hemodynamic effect of the non-excitatory stimulation pulse on the heart muscle. In some preferred embodiments of the present invention, the control circuitry also receives a sensor signal indicative of hemodynamic conditions, preferably indicative of the cardiac output, and adjusts the stimulation pulse responsive to the signal to achieve a desired cardiac output level. Alternatively or additionally, physiological sensors may be used to sense other hemodynamic parameters, such as blood pressure or blood oxygenation, so as to provide feedback signals to the control circuitry or to telemetry apparatus associated with the control circuitry. Sensors used for this purpose may thus include flow rate sensors, pressure sensors, temperature sensors, oxygen sensors, and other types of sensors known in the art. The control circuitry then adjusts the stimulation pulse so that the hemodynamic parameters are maintained within a desired range of values. Although preferred embodiments of the present invention are described for the most part with reference to sensing electrogram signals in the heart, so the cardiac output controller applies the non-excitatory stimulation pulse in response to and generally synchronized with the sinus rhythm, cardiac output controllers in accordance with the present invention may also be synchronized by other methods For example, as described above, the non-excitatory stimulation pulse may be synchronized relative to a body-surface ECG, and may also be synchronized and controlled relative to an arrhythmic heart beat Alternatively, the pulse may be externally synchronized, for example by an externally- applied trigger pulse or by a pacing pulse that is applied to the heart. These aspects of the present invention are further described in a PCT patent application filed on even date, entitled "Cardiac Output Enhanced Pacemaker" (docket no 2718 1 ), which is assigned to the assignee of the present application, and whose disclosure is incorporated herein by reference. Preferred embodiments of the present invention may also be used in conjunction with suitable drugs, as described in a PCT patent application entitled "Drug-Device Combination for Controlling the Contractility of Muscles" (docket no 4425/WO/97), and in conjunction with devices and methods for preventing cardiac fibrillation, as described in a PCT patent application entitled "Fencing of Cardiac Muscles" (docket no 4437/WO/97), both filed on even date and assigned to the assignee of the present application The disclosures of these applications are incorporated herein by reference. There is therefore provided, in accordance with a preferred embodiment of the present invention, apparatus for modifying cardiac output of the heart of a subject, including: one or more sensors, which sense signals responsive to cardiac activity; a stimulation probe including one or more stimulation electrodes, which apply non- excitatory stimulation pulses to a cardiac muscle segment, and signal generation circuitry, coupled to the one or more sensors and the stimulation probe, which circuitry receives the signals from the one or more sensors and generates the non- excitatory stimulation pulses, responsive to the signals. Preferably, the signal generation circuitry is contained in a unit external to the subject's body, or alternatively, in an implantable case Preferably, application of the stimulation pulses engenders an increase in the cardiac output, or alternatively, a decrease in the cardiac output Alternatively or additionally, application of the stimulation pulses increases an efficiency of contraction of the heart. Preferably, the one or more sensors include a intracardiac electrode, and the signal generation circuitry synchronizes the stimulation pulse to electrical activity of the heart Alternatively, the one or more sensoi s includes a body surface electrode, and the signal generation circuitry synchronizes the stimulation pulse to an ECG signal Preferably, the signal generation circuitry identifies an arrhythmia in the signals and controls the stimulation pulses responsive thereto Additionally or alternatively, the signal generation circuitry detects a QT interval in the signals and controls the stimulation pulses responsive thereto Preferably, the signal generation circuitry varies one or more parameters of the stimulation pulse, from the group of parameters including voltage, current, duration, timing delay, waveform and waveform fϊequencv A tei the non-excitatory stimulation pulse, the signal generation circuitry generates anothei pulse of opposite polarity to the stimulation pulse, which is applied to the cardiac muscle segment by the stimulation probe Preferably, the one or more stimulation electrodes apply the stimulation pulse to a heart segment having an area of at least 5 mm-, more preferably at least 1 cm-, and -most preferably at least 4 cm^ In a preferred embodiment of the invention, the signal generation circuitry varies the area of the heart segment to which the stimulation pulse is applied Pieferably, the stimulation probe includes a net of electrodes, which are addressable such that an extent of the segment to which the stimulation pulses is applied is contiυlled by addressing selected electrodes in the net Preferably, the circuitry applies multiple, different stimulation pulses, preferably a time sequence of pulses, to different ones of the electrodes in the net In another preferred embodiment of the invention, the stimulation probe includes a hybrid electrode, including the inti acardiac electi ode togclhci with at least one of the one or more stimulation electrodes. Preferably, the hybrid electrode includes a core section including the sensing electrode, enclosed within an annular section including the at least one stimulation electrode, wherein the annular section preferably includes a carbon material. In still another preferred embodiment, the one or more stimulation electrodes include an elongate electrode, which is inserted into a blood vessel of the heart Preferably, the one or more stimulation electrodes include vitreous carbon or, alternatively, pyrolitic carbon. In a preferred embodiment of the invention the one or more sensors include a hemodynamic sensor, which generates signals responsive to a hemodynamic parameter. Preferably, the hemodynamic sensor generates the signals responsive to blood flow. Alternatively or additionally, the hemodynamic sensor generates the signals responsive to blood oxygenation and/or temperature Preferably, the one or more sensors include an electrode, which senses cardiac electrical activity Preferably, the apparatus includes a telemetry device, which receives the signals from at least one of the one or more sensors and controls the signal generation circuitry to adjust the non-excitatory stimulation pulse. There is further provided, in accordance with a preferred embodiment of the present invention, a method for modifying cardiac output, including applying a stimulation probe including one or more stimulation electrodes to a subject's heart; receiving a signal from at least one sensor responsive to the subject's cardiac muscle activity; generating a non-excitatory stimulation pulse responsive to the signal and conveying the pulse to at least one of the one or more electrodes. Preferably, receiving the signal includes introducing a sensing electrode into the heart and receiving signals therefrom, and generating the stimulation pulse includes generating a pulse synchronized with electrical activity sensed by the sensing electrode Alternatively or additionally, receiving the signal includes applying an electrode to a body surface and receiving signals therefrom, and wherein generating the stimulation pulse includes generating a pulse synchronized with an ECG signal. Further alternatively or additionally, receiving the signal includes receiving signals from at least one of the one or more stimulation electrodes Preferably, generating the stimulation pulse includes generating a pulse having a predetermined delay relative to the signal In a prefen ed embodiment of the invention, applying the stimulation probe includes applying a probe including a plurality of stimulation eiecirodes, and generating and conveying the pulse includes generating a sequence of pulses and applying each pulse in the sequence to a different one of the plurality of stimulation electrodes Preferably, generating and conveying the stimulation pulse includes generating and conveying stimulation pulses selectively, based on a chai ctenstic of the signals received from the at least one sensoi Furthei preferably, generating and conveying the pulses includes generating and applying pulses at a rate dependent on the heart t ate, but not equal to the heart rate Alternatively oi additionally, generating and conveying the pulses includes detecting a cardiac arrhythmia and ad|ustιng the application of the pulses l esponsive thereto Further additionally ot alternatively, genei ating and conveying the pulses compnses detecting a QT interval in the signals and generating pulses responsive theieto Preferably, generating the non-excitatory stimulation pulse includes varying one or more parameters of the pulse, selected fi om the gi oup including the pulse voltage, current, duration, delay, waveform and waveform frequency Further preferably, the pulse includes a baseline pulse and a waveform, preferably a square wave, of substantially higher frequency than the baseline pulse superimposed thereon Preferably, after generating the non-excitatoi v stimulation pulse, another pulse of opposite polarity thereto is generated and conveyed to the electrodes In a preferred embodiment of the inv ention, applying the non-excitatory stimulation pulse includes varying the extent of a portion of the ai ea of the heart segment to which the stimulation pulse is applied, wheiein vaiymg the extent pi eferably includes selectively addressing a net of stimulation electrodes implanted in the heart In another piefen ed embodiment, applying the stimulation piobe includes inserting the one or more stimulation electiodes in multiple chambers of the heart In still another pi efen ed embodiment, implanting the stimulation probe includes inserting at least one of the one oi moie stimulation electi odes into a blood vessel of the heart, preferably into the coronary sinus In a preferred embodiment of the invention, l eceivmg the signal includes sensing a hemodynamic parametei , pi eferably sensing cardiac output whei ein generating the pulse preferably includes changing the pulse responsive to the signal to increase the cardiac output, or alternatively, to decrease the cardiac output. Alternatively or additionally, sensing the hemodynamic parameter includes sensing a pressure and/or a flow rate and/or oxygenation and/or a temperature In another preferred embodiment of the invention, generating and conveying the pulse includes generating and conveying pulses at selected times of day, preferably conveying pulses to increase cardiac output during the subject's waking hours. Preferably, generating and conveying the pulses includes generating and conveying pulses which increase the subject's cardiac output, or alternatively decrease the subject's cardiac output. Further alternatively or additionally, generating and conveying the pulses includes generating and conveying pulses which increase the efficiency of contraction of the heart. Preferably, conveying the pulses includes applying pulses to a heart segment having an area of at least 5 mm-, more preferably at least I cm-, and most preferably at least 4 cm^. The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings in which: BRIEF DESCRIPTION OF TH E DRAWINGS Fig. 1A is a schematic illustration showing a device for controlling cardiac output, in accordance with a preferred embodiment of the present invention; Fig. I B is a schematic illustration showing a miniaturized implantable device for controlling cardiac output, in accordance with an alternative preferred embodiment of the present invention, Fig. 2A is a schematic sectional illustration showing the heart of a patient, into which stimulation and sensing electrodes for use in conjunction with the device of Fig. 1 A are inserted, in accordance with a preferred embodiment of the present invention; Fig. 2B is a schematic illustration of a non-excitatory stimulation probe, in accordance with another preferred embodiment of the present invention. Fig. 3 is a schematic block diagram of control circuitry use in the devices depicted in Fig. 1A, in accordance with a preferred embodiment of the present invention; Fig. 4 is a flow chart illustrating a method of regulating cardiac output, in accordance with a preferred embodiment of the present invention, Fig 5 is a schematic illustiation showing a squai e w ave stimulation pulse applied by stimulation electrodes to the patient's heart, m accordance with a piefen ed embodiment of the present invention, Fig 6 is a schematic illustration of a stimulation electiode for use in conjunction with the devices of Figs 1A and IB, in accoidance with a preferred embodiment of the present invention, Fig 7 is a schematic illustiation of a hybud electiode foi use in conjunction with the devices of Figs 1 A and I B, in accordance with an alternative pi efen ed embodiment of the present invention, and Figs 8-32 are electionic schematic electi onic diagrams showing ciicuitry for use in the device of Fig 1 A, in accoi dance with a pi efen ed embodiment of the piesent invention DETAILED DESC RIPTION OF PREFERRED EM BODIM ENTS Fig 1 A schematically lllusti ates a dev ice 20 foi i cgulating car diac output, comprising a control unit 27, an implantable non-excitatoiy stimulation probe 21 , including at least one non- excitatory stimulation electrode 23, and an implantable sensing electi ode 29 Control unit 27 includes signal generation circuitry 22 (shown in Fig 3 below and described with reference thereto), as well as an optional display 24 and a control panel 26 When properly implanted in the heart, as dese bed below, sensing electiode 29 lecei es local electrogi am signals from the heart muscle and ti ansmits them to the signal gonei alion cii cuiti y 22 I he ciicuitiy generates a non-excitatory stimulation pulse t esponsiv to the elect! oyi m signal which pulse is applied by probe 21 to cardiac muscle tissue Contiol unit 27 optionally also includes an external trigger input 30 Device 20 may furthei include anothei physiological sensoi 1 , foi example, a flow sensor, for determining the effect of the stimulation pi ovided by the device on the cardiac output Fig IB schematically lllustiates device 20 in accoi dance with an alternative preferred embodiment of the pi esent invention, in which signal genei uon ciicuitiy 22 is contained in an implantable miniaturized electi onic conti ol cii cuiti y case 32, similar to implantable pacemaker cases known in the art Unlike control unit 27, case 32 does not include display 24 and control panel 26, but in othei lespects, the embodiment of Fig I B is functionally similar to that of Fig 1A 1 ? In the embodiment shown in Fig I B, stimulation electrode 23 is shown to be a relatively large area electrode, designed to provide stimulation an area of at least 5 mm- in the heart. Electrode 23 preferably comprises a low-resistance carbon material, preferably vitreous carbon, or alternatively, pyrolitic carbon Electrodes made of such materials are manufactured, for example, by Sorin Biomedica, of Saluggia, Italy, and by Goodfellow Cambridge Ltd., of London, England Both types of carbon materials are known for their compatibility with heart tissue, in-vivo durability and excellent electrical properties It will be understood, however, that other types of electrode materials made also be used, such as various types described in A Guide to Cardiac Pacemakers, Defihπllators and Related Products, by Morse, et al. (Droege Computing Services, Durham, North Carolina), which is incorporated herein by reference. Stimulation probe 21 may comprise more than a single stimulation electrode Sensing electrode 29 may comprise any suitable type of intracardiac electrode, known in the art Preferably, electrodes 23 and 29 are coated with an anticoagulant, such as heparin, preferably in a time-release form, or elute the anticoagulant into the heart tissue, to prevent clot formation on and around the electrodes Such electrodes may be produced in a manner similar to steroid-eluting electrodes known in the art, for example, the Medtronic CAPSURE model 4003 electrode, described in 777C Foundations of Cardiac Pacing, by Sutton and Bourgeois, p. 73, which is incorporated herein by reference Fig 2A is a schematic illustration showing electrodes 23 and 29 implanted in a subject's heart 38, in accordance with a preferred embodiment of the present invention Electrodes 23 and 29 are implanted in a chambei of the heart, pieferably both in left ventricle 34 Most preferably, non-excitatory stimulation electi ode 23 is implanted in contact with the wall of left ventricle 34, and sensing electrode 29 is implanted in septum 36, between the ventricles Electrodes 23 and 29 are connected by wπ es passing through aorta 39 to either control unit 27 outside the body or to implantable case 32, which is preferably implanted in the patient's chest When circuitry 22 detects an electrical activation pulse in the electrogram signal received from electrode 29, it generates a stimulation pulse, which is applied to electrode 23, preferably so as to increase the contraction of at least the segment of the wall of ventricle 34 with which electrode 23 is in contact, thus increasing the ventricular stroke volume Alternatively, stimulation electrode 29 and, optionally, sensing electrode 23 may be implanted surgically, preferably in the epicardium Fig. 2B is a schematic illustration showing an alternative preferred embodiment of the present invention, in which non-excitatory stimulation probe 21 comprises a wire electrode 33. The electrode, which preferably comprises carbon material, as described above, is connected by an insulated conductor 43 to circuitry 22. It is preferably implanted in one of the blood vessels of the heart Most preferably, electrode 33 is passed through the right atrium of the heart, into the coronary sinus, using techniques of catheterization known in the art, and is positioned therein adjacent to left ventricle 34. The electrode is then driven by circuitry 22 to deliver the non-excitatory stimulation pulses to the heart wall, as described herein. Fig 3 is a schematic block diagram of signal generation circuitry 22, in accordance with a preferred embodiment of the present invention Circuitry 22 comprises a stimulation section 100, a detection circuit 104 and a sensing unit 1 1 0 Unit 1 1 0 receives and conditions electrogram signals from sensing electrode 29 Detection circuit 1 04 senses a local activation wave in the electrogram, preferably by detecting a slope and voltage level corresponding to the rising edge of the wave, as is known in the art, and generates a trigger pulse responsive thereto. The trigger pulse is conveyed to stimulation section 100, which generates the stimulation pulses and applies these pulses to the electrodes of stimulation probe 2 1 Sensing unit 1 10 includes signal blanking unit 1 0 1 and signal blank logic 102 and a differential amplifier and signal conditioning circuit 103 The blanking operates to block the input to detection circuit 104 while the output of stimulation section 100 is active, to prevent the system from generating trigger pulses due to stimulation artifacts Stimulation section 100 comprises a trigger divider 105, which generates a modified trigger pulse in response to input trigger pulses from detection circuit 1 04 or alternatively from external trigger input 30 The trigger divider allows a user of device 20 to select whether the stimulation pulse will be applied at every heart beat or only once in a predetermined number of beats. Section 100 further includes signal generators 106 and 107, which generate voltage signals of predefined characteristics, as described below, in response to the modified trigger pulse, and constant current units (CCU) 108 and 109, which convert input voltage signals from the signal generators to output current pulses Two stimulation output channels are shown in Fig. 3, enabling different stimulation pulses to be applied to two or more different stimulation electrodes. It will be appreciated, however, that only one of the channels need be used or alternatively, that additional channels may be added to drive additional stimulation electrodes. Fig 4 is a flow chart, which summarizes a method for l egulation of cardiac output using device 20, according to a prefen ed embodiment of the pi esent invention Preferably, parameters of the stimulation pulse, such as its level, dui ation delay and waveform characteristics, as described below, are pieset by the usei Sensing electrode 29 senses electrogram signals, as descnbed above, and signal genei ation cii cuitiy 22 receives these signals and inputs them to detection circuit 104, which detects heart activity, preferably the sinus rhythm, and generates a tπggei pulse l esponsive thereto The trigger pulse drives stimulation section 100 to generate the stimulation pulse, which is applied to the heart by stimulation electrode 23 In an alternative pi efen ed embodiment, an external tngger coupled to input 30 is employed Optionally, physiological paiametei s i elated to the caidiac output ai e monitored in order to verify the efficacy of the stimulation Foi example, flow of blood through aorta 39 may be detected by flow sensoi 3 1 , as illustrated in Fig 2A Preferably, at least some of the parameters of the stimulation pulse, foi example, its amplitude and/or timing, are adjusted responsive to the monitoied pai metei so as to achieve a desir ed cardiac output level Such monitoring and adjustment ai e pi eferably ear ned out on-line, for example, by control unit 27 itself Altei nativelv. oi additionally, a sepai ate telemetr y unit (not shown in the figures) monitoi s the pai ameteis and is used to pi giam conti ol unit 27 to vaiy the parameters of the stimulation pulse accoi dmglv Fig 5 is a schematic illusti ation of a non-excitatoi y stimulation pulse 51 applied by stimulation electi ode 23 to cai diac tissue, in accoidance with a pi efen ed embodiment of the present invention In some piefened embodiments of the piesent inv ention the iegulation of cardiac output is achieved by vai ying certain character rstrcs of pulse 51 Non-excitatory stimulation energy is applied to stimulation electi ode 23 in the foi m of a baseline pulse 53 having a baseline amplitude, indicated bv an aπou 54 in Fig , ol piefeiably 5 to 10 A, optionally up to 50 mA The dur ation of pulse ] , indicated by an an ow 52, pieferably ianges between 30 and 80 ms, and optionally up to 500 ms Pulse 53 is piefeiably followed by another pulse of opposite polar ity (not shown in the figui e) to pi event pi oblems of tissue polarization and electiode degiadation, as descnbed in the above-i efei enced '012 PCT application and mentioned above Pi efer ablv, a wav efoi 58 having a fi equency of up to 10 kHz and amplitude, indicated by an anow 56 up to oi comparable to the baseline amplitude is superimposed on the baseline amplitude of pulse 53 Although wavefoi m 58 is shown here as a ι : square wave, any othei suitable wavefoi m may be used, foi example, a sinusoid or sawtooth wave Preferably, waveform 51 is tπggeied upon the detection of the using edge of the R- wave of the heart's electrical activity by detection circuit 104 Alternatively, signal generators 106 and 107 may be controlled to provide a delay, indicated by an arrow 50 in Fig 5, of between 1 and 500 msec between the tπggei input and the pulse genei ation The appropriate delay may depend on whether the trigger is provided by detection cncuit 104 or by external trigger 30, as well as on the r elative positions of sensing electi ode 29 and sensing electrode 23 The delay is adjusted based on the desired increase or decrease of cai diac output that is to be achieved, and the optimal delay will geneially vaiy from patient to patient Fig 6 is a schematic illustration showing an electi ode net 40, for use as part of stimulation piobe 21 , in accordance with a pi efen ed embodiment of the pi sent invention Net 40 compnses a pluiality of stimulation electiodes 35 pieteiablv. mlci connected by a conductor network 37 Electrodes 35 are pι efeι abl\ individually and/oi collectiv ely addi essable, and may operate in either a unipolai oi a bipolai mode Net 40 is pi efeiably large enough to cover a substantial segment of the heart wall, piefei bly at least I cm- and most piefeiably at least 4 2 cm 2 Each individual electiode 35 pieferably has an ai ea of at least 5 mm *" , and is separated from its neighbois pi efeiably by at least 1 cm In this pi efened embodiment cai diac output l egulation is pi efeiably achieved through variation of the stimulated aiea of a segment of the heart wall with which net 40 is in contact, as described in the '012 PCT patent application Pi efei ably the stimulated area is varied by changing the active aiea of net 40, ι e , vaiying the extent of the aiea of the net over which electrodes 35 are driven to deliver electric stimulation to the heart T he inv entors have found, for example, that when the non-excitatoiy stimulation is applied between pairs of electrodes, selected among a plurality of electiodes placed in the left \ enti icle, the l esiiltant enhancement of left-ventuculai pi essui c and cai diac output anes l esponsn e to the ι e!atιve positions of the electrodes in the pan and the distance between them Electi odes 35 m net 40 may thus be selectably addressed to optimize the hemodynamic r esults of the stimulation Moreover, electrodes 50 may also be used as sensing electi odes, to map cai diac electi ical activity over the segment of the heart wall, so that the stimulation may be applied l esponsive to the map Fig 7 schematically lllusti ates a In hi id electiode piobe 4 1 foi use with device 20, in accordance with an alternativ e pi efen ed embodiment of the present invention Probe 41 l υ comprises an annulai stimulation electi ode 32, pi efeiably a cai bon electiode, as described above, surrounding a smallei sensing electiode 42 at the centei of the piobe, preferably, a platinum or platinum/indium electrode, most pieferably bipolai It will be understood that the methods, stimulation wavefoims and contiol electtonics descnbed abov e in relation to electrode 23 may be applied using pi obe 41 , as well as any other suitable electrode configuration Probe 41 is advantageous in that it reduces the numbei of separate electrodes that need to be introduced into and implanted in the heart Figs 8-31 ai e electionic schematic diagi ams lllusti ating circuitiy for use in implementing the functions of circuitry 22, in accoidance with a pi efened embodiment of the present invention As shown in Figs 8A and 8B, the ciicuitiy includes an ECG processor 130, a first CCU section 140, and main control ciicuit 1 0, which togethei peiform the functions of circuitry 22, as show n in Fig 3 and descnbed w ith lefei ence theieto In addition, a second CCU section 142 is designed to pi ovide optionally, excitatoi y stimulation pulses, i e , to pace the heart This element is beyond the scope of the piesent in ention howe er, and is described in detail in the above-mentioned PCT patent application entitled Cai diac Output Enhanced Pacemaker," filed on even date and mcoi poi atcd herein by l efei ence Figs 9 thiough 3 1 aie cii cuit diagi ams showing details of the implementation of the elements of Figs 8 A and 8B These diagtams ai e consideied sufficient in and of themselves to enable one skilled in the art to piactice the piesent invention Various aspects of these diagrams are described hereinbelow Figs 9A, 9B and 9C lllusti te main conti ol cii cuit 1 50 which is based on a microcontroller MPU l piefeiably an 805 1 -type miciocontiollei , as is known in the art The microcontroller receiv es usei commands via a communications interface, for example, to program parameters of the stimulation pulses to be applied It controls other elements of circuitry 22 via a data bus, mai ed AD0-AD7 Figs 10A and 10B show details of ECG pi ocessoi 1 30, which l eceives electiical signals from the patient's body and piocesses them to genei ate tuggei pulses, as described above, for duving the non-excitatoi y stimulation ECG pi ocessoi 1 0 includes ECG amplifier 152, an ECG signal conditioning unit 154 an A/D conveitei I 56, and a detection contiollei 158 ECG amplifiei 152 is show n in detail m Fig I I , and compnses a difTei ential preamplifier and programmable gam amplifiei and blanking unit Signal conditioning unit 1 4, shown in Figs 12A and 12B, includes pi ogiammable high-pass low-pass and notch filteis, selectable by means of a clock generatoi, and also including an analog switch foi bypassing the notch filter A/D converter 156 is shown in Fig 1 Figs 1 -1 A and 14B illusti ate conti ollei 158, including another 8051 -type miciocontiollei MPU2, which analy7es the ECG signal and generates the trigger pulse Figs 15 A, 15B and 15C illustrate fust CCU section 140, which generates two channels of non-excitatory stimulation pulses CCU section 140 includes two control units 162 and 164, waveform generators 166 and 168, powei units 170 and 174, and a waveform selector 172 Figs 16A and 16B show details of wavefoi m geneiatoi 166, which dnves a first one of the two non-excitatory channels, while Figs I A and I 9B show wav efoi m genei atoi 168, which is substantially similar to generatoi 166 and dr ives the second channel Figs 17 A, 1 7B and 17C illustrate contiol unit 162, which leceives and scales the wav efoi m fi om geneiator 166 Fig 17C shows timing conti ol logic common to both contiol units 162 and 164 Figs 20A, 20B, 20C and 20D illusti ate conti ol unit 164 w hei ein Tigs 20A and 20B show waveform scaling circuitry similai to that in Figs 17A and 1 7B Figs 20C and 20D include circuitry for controlling the l elativ e delays of the pulses gcnei ated by the tw o stimulation channels Figs 18 and 21 show details of pow ei units 174 and 1 78, l espcctively, Fig 22 illustrates wave selector 176 Fig 23 shows second CCU section 142, including two CCU channels 180 and 182, for generating pacing pulses at predetermined rates and a lelative delay theiebetween, similar to pacemakers known in the ai t Figs 24 A, 24B and 24C show details of channel 180 Figs 25A and 25B show details of channel 1 82, w hich is sw itched bv. the same switch and counters as channel 180 (shown in Fig 24B ) Figs 26, 27A, 27B, 28, 29 A and 29B show details ol isolation cii cuiti y, which is used when circuitry 22 is to be urn while connected to external powei Fig 30 illustrates a battery charging circuit Figs 3 I and 32 show fi ont and teai panel connections, respectively Although in some of the pi efened embodiments descnbed above, as shown in Fig IB, for example, circuitry 22 is shown as being contained within an implantable case 32, the specific implementation of the ciicuitry exemplified by Figs 8-32 is bettei suited to be contained in an external, bedside case, for example, conti ol unit 27, show n in f ig 1 in accoi dance with the best mode of the invention as it is pi acticed at pi esent It will be undei stood that the circuitry of Figs 8-32 can be suitably alteied and miniatuiized to fit in an implantable case, using methods and electronic devices known in the ai t, particular ly such as are currently used in implantable pacemakers On the other hand, under some circumstances, non-excitatory stimulation and cardiac output regulation may be best accomplished using such an external, bedside case, when the cardiac output must be regulated temporarily, for example, during recovery from infarction or surgery It will be appreciated that the preferred embodiments described above are cited by way of example, and the full scope of the invention is limited only by the claims.

Claims: CLAIMS 1. Apparatus for modifying cardiac output of the heart of a subject, comprising: one or more sensors, which sense signals responsive to cardiac activity; a stimulation probe comprising one or more stimulation electrodes, which apply non- excitatory stimulation pulses to a cardiac muscle segment, and signal generation ciicuitiy, coupled to the one or more sensors and the stimulation probe, which circuitry receives the signals from the one or more sensors and generates the non- excitatory stimulation pulses, responsive to the signals. 2. Apparatus according to claim 1 , wherein the signal generation circuitry is contained in a unit external to the subject's body 3. Apparatus according to claim 1 , wherein the signal generation circuitry is contained in aa implantable case. 4. Apparatus according to claim I , wherein application of the stimulation pulses engenders an increase in the cardiac output 5. Apparatus according to claim I , wherein application of the stimulation pulses engenders a decrease in the cardiac output. 6. Apparatus according to claim 1 , wherein application of the stimulation pulses increases an efficiency of contraction of the heart 7. Apparatus according to any of the pi eceding claims, w hei ein the one or more sensors comprise a intracardiac electrode, and wherein the signal generation circuitry synchronizes the stimulation pulse to electrical activity of the heart 8. Apparatus according to any of claims 1 -6, wherein the one or more sensors comprises a body surface electrode, and wherein the signal generation circuitry synchronizes the stimulation pulse to an ECG signal 9. Apparatus according to any of claims 1 -6, wherein the signal generation circuitry identifies an arrhythmia in the signals and controls the stimulation pulses responsive thereto 10. Apparatus according to any of claims 1 -6, wherein the signal generation circuitry detects a QT interval in the signals and controls the stimulation pulses responsive thereto. 1 1. Apparatus according to any of claims 1 -6, wherein the signal generation circuitry varies one or more parameters of the stimulation pulse, from the group of parameters including voltage, current, duration, timing delay, waveform and waveform frequency 12. Apparatus according to any of claims 1 -6, wherein after the non-excitatory stimulation pulse, the signal generation circuitry generates another pulse of opposite polarity to the stimulation pulse, which is applied to the cardiac muscle segment by the stimulation probe. 13. Apparatus according to any of claims 1 -6, wherein the one or more stimulation electrodes apply the stimulation pulse to a heart segment having an area of at least 5 miti^. 14. Apparatus according to claim 13, wherein the one or more stimulation electrodes apply the stimulation pulse to a heart segment having an area of at least 1 cm^ 15. Apparatus according to claim 14, wherein the one or more stimulation electrodes apply the stimulation pulse to a heart segment having an area of at least 4 cm- 16. Apparatus according to claim 13, whei ein the signal generation circuitry varies the area of the heart segment to which the stimulation pulse is applied 17. Apparatus according to any of claims 1 -6, wherein the stimulation probe comprises a net of electrodes 18 Apparatus accoiding to claim 17 whei ein the electi odes in the net are addressable, such that an extent of the segment to which the stimulation pulses is applied is controlled by addressing selected electi odes in the net 19 Apparatus according to claim 17, whei ein the circuitry applies multiple, different stimulation pulses to different ones of the electrodes in the net 20 Apparatus accoi ding to claim 19 whei ein the multiple, differ ent stimulation pulses comprises a time sequence of pulses 21 Apparatus accoi ding to claim 7, whei ein the stimulation probe comprises a hybrid electrode, including the intracardiac electi ode togethei with at least one of the one or more stimulation electrodes 22 Apparatus accoi ding to claim 2 1 , w hei ein the hv bnd electi ode compnses a coi e section iinncclluuddiinngg tthhee sseennssiinngg electrode, enclosed within an annulai section including the at least one stimulation electiode 23 Apparatus accoiding to claim 22 whei ein the annular section comprises a carbon material 24 Apparatus according to an> of claims 1 -6, w heiein the one oi more stimulation electrodes compuse an elongate electiode, which is inserted into a blood vessel of the heart 25 Apparatus according to any of claims 1 -6, wherein the one oi more stimulation electrodes compuse vitieous carbon 26 Apparatus accoiding to any of claims 1 -6 w hei ein the one oi moi e stimulation electrodes compuse pyiohlic cai bon 27 Apparatus accoi ding to any of claims 1 -6, whei ein the one oi moi e sensors comprise a hemodynamic sensor, which generates signals l esponsiv e to a hemodynamic parameter 28. Apparatus according to claim 27, wherein the hemodynamic sensor generates the signals responsive to blood flow. 29. Apparatus according to claim 27, wherein the hemodynamic sensor generates the signals responsive to blood oxygenation. 30. Apparatus according to claim 27, wherein the hemodynamic sensor generates the signals responsive to a temperature 31. Apparatus according to claim 27, wherein the one or more sensors comprise an electrode, which senses cardiac electrical activity. 32. Apparatus according to any of claims 1 -6, and comprising a telemetry device, which receives the signals from at least one of the one or more sensors and controls the signal generation circuitry to adjust the non-excitatory stimulation pulse. 33. A method for modifying cardiac output, comprising: applying a stimulation probe comprising one or more stimulation electrodes to a subject's heart; receiving a signal from at least one sensor responsive to the subject's cardiac muscle activity; generating a non-excitatory stimulation pulse responsive to the signal and conveying the pulse to at least one of the one or more electrodes 34. A method according to claim 33, wherein receiving the signal comprises introducing a sensing electrode into the heart and receiving signals therefrom, and wherein generating the stimulation pulse comprises generating a pulse synchronized with electrical activity sensed by the sensing electrode 35 A method according to claim 33, wherein receiving the signal comprises applying an electrode to a body surface and receiving signals theiefiom, and wheiein generating the stimulation pulse compnses geneiating a pulse synchronized with an ECG signal 36 A method accoiding to claim 33, wheiein receiving the signal compnses receiving signals from at least one of the one or moie stimulation electiodes 37 A method accoiding to any of claims 33-36, wheiein geneiating the stimulation pulse compnses geneiating a pulse having a predetei mined delav lelative to the signal 38 A method accoiding to claim 3 "? wheiein applving the stimulation piobe comprises applying a probe compnsmg a pluiality of stimulation electiodes, and wheiein generating and conveying the pulse compnses generating a sequence of pulses and applying each pulse in the sequence to a different one of the pluiality of stimulation electiodes 39 A method accoiding to an \ of claims 33-36, wherein geneiating and conveying the stimulation pulse compnses genei ting and conveying stimulation pulses selectively, based on a characteristic of the signals received fiom th at least one sensoi 40 A method accoiding to claim 39, wheiein geneiating and conveying the pulses comprises geneiating and applving pulses at a late dependent on the heart ιate, but not equal to the heart rate 41 A method accoiding to claim , wheiein geneiating and conveying the pulses comprises detecting a caidiac aiihvthmia and adiusting the application of the pulses responsive thereto 42 A method according to claim 39, wheiein geneiating and conveying the pulses compnses detecting a QT interval in the signals and genei ting pulses lesponsive thereto 43 A method according to any of claims 33-36, wheiein genei ating the non-excitatory stimulation pulse compnses vaiying one oi moi e pai ametei s of the pulse, selected from the group including the pulse voltage, current, dur ation, delay, wavefoi and wavefoi m frequency 44 A method accoiding to any of claims 33-36, w heiein the pulse comprises a baseline pulse and a waveform of substantially highei fi equency than the baseline pulse superimposed thereon 45 A method accoi ding to claim 44 hei ein the w a efoi m compnses a squai e wave 46 A method accoiding to any of claims 33-36, and compr ising, after generating and conveying the non-excitatoiy stimulation pulse, genei ating and conveying anothei pulse of opposite polarity thei eto 47 A method accoiding to an of claims 33-36 w heiein applying the non-excitatory stimulation pulse compnses vai ying the extent of a portion ol the ai ea of the heart segment to which the stimulation pulse is applied 48 A method accoiding to claim 47, whei ein vaiying the extent compnses selectively addressing a net of stimulation electi odes implanted in the heart 49 A method accoi ding to any of claims 33-36 whei ein applying the stimulation probe compnses inserting the one oi moi e stimulation electi odes in multiple chamber s of the heart 50 A method accoiding to any of claims 33-36, w hei ein implanting the stimulation probe comprises inserting at least one of the one oi more stimulation electrodes into a blood vessel of the heart 51 A method accoiding to claim 50, wheiein inserting the at least one stimulation electrode comprises inserting the electiode into the coionaiy sinus 52 A method according to any of claims 33-36, wherein receiving the signal comprises sensing a hemodynamic parameter 53 A method according to claim 52, wherein sensing the hemodynamic parameter comprises sensing cardiac output, and wherein generating the pulse comprises changing the pulse responsive to the signal to increase the cardiac output 54 A method according to claim 52, wherein sensing the hemodynamic parameter comprises sensing cardiac output, and wherein generating the pulse comprises changing the pulse responsive to the signal to decrease the cardiac output 55. A method according to claim 52, wherein sensing the hemodynamic parameter comprises sensing a pressure 56 A method according to claim ^2, wherein sensing the hemodynamic parameter comprises sensing a flow rate 57 A method according to claim 52, wherein sensing the hemodynamic parameter comprises sensing oxygenation 58 A method according to claim 52, whei ein sensing the hemodynamic parameter comprises sensing a temperature 59 A method according to any of claims 33-36, wherein genei ating and conveying the pulse comprises generating and conveying pulses at selected times of day 60 A method according to claim ^> w hei ein generating and conveying the pulses at selected times of day comprises conveying pulses to inci ease cardiac output during the subject's waking hours 61 A method according to any of claims 33-36, wherein generating and conveying the pulses comprises generating and conveying pulses which increase the subject's cardiac output 62. A method according to any of claims 33-36, wherein generating and conveying the pulses comprises generating and conveying pulses which decrease the subject's cardiac output. 63. A method according to any of claims 33-36, wherein generating and conveying the pulses comprises generating and conveying pulses which increase the efficiency of contraction of the heart. 64. A method according to any of claims 33-36, wherein conveying the pulses comprises applying pulses to a heart segment having an area of at least 5 miii- 65. A method according to claim 64, w herein applying the pulses comprises applying pulses to a heart segment having an area of at least I cm- 66. A method according to claim 65, wherein applying the pulses comprises applying pulses to a heart segment having an area of at least 4 cm- ft -7

Inventors: BEN-HAIM SHLOMO, DARVISH NISSIM, FENSTER MAIER, MIKA YUVAL, BEN-HAIM, SHLOMO, DARVISH, NISSIM, FENSTER, MAIER, MIKA, YUVAL
Applicants: BEN HAIM SHLOMO, DARVISH NISSIM, FENSTER MAIER, MIKA YUVAL, NEW TECHNOLOGIES SA YSY LTD, BEN-HAIM, SHLOMO, DARVISH, NISSIM, FENSTER, MAIER, MIKA, YUVAL, NEW TECHNOLOGIES (SA-YSY) LTD.
Application year: 1997
Main classification: A61N1
IPC codes: A61B17, A61N1