Abstract:
A transdermal drug delivery device in communication with at least one IMD is externally mounted to deliver pain analgesics and/or threshold reduction medicants prior to or contemporaneous with a shock associated with a pacer, a defibrillator and similar therapy device. The drug delivery device includes an attachable strip with a storage for medicants and is epidermally mounted. The medicants are released into the bloodstream in response to an indication that the IMD is about to deliver a shock. The drug delivery device is adapted for use with various drugs. Further, the delivery of drugs could be controlled by the patient to provide a semi-automatic use and/or to terminate delay shock. The transdermal drug delivery device and the IMD include system status indicators to provide real-time operational data of the drug delivery device and the IMD individually and in combination. The drug delivery device is also implemented with a CHF monitor to treat CHF patients.

Description:
FIELD OF THE INVENTION  
         [0001]    The present invention generally relates to medical devices. Specifically, the invention relates to communication between an implanted medical device and an external drug delivery device in wireless data communication thereof. More specifically, the invention relates to a system that automatically delivers analgesic and/or threshold reduction medications prior to the application of cardiac shock or drug delivery for pulmonary hypertension, for example, using RV pressure. The release of the drug is coordinated between the implanted device and the external device via the wireless communication system. The invention also provides remote management of a patient wherein drug delivery data from the external device and therapy information from the implanted device are transferred to a remote location using various methods of data transfer to enable physicians and caregivers to remotely review and monitor the patient as needed. In one aspect of the present invention, the drug delivery dose and frequency of treatment are preferably controlled via parametric modifications and adjustments of the implanted medical device. In yet another embodiment, the external drug delivery device is directly programmed overriding communication signals that initiate and call for drug delivery from the implanted medical device.  
         BACKGROUND OF THE INVENTION  
         [0002]    Current practice of implanting both a therapeutic medical device such as a cardiac pacemaker, defibrillator, etc., in conjunction with implantable drug pumps is cumbersome and expensive to manage. Further, for example, with a defibrillator and an implanted drug delivery device, one would need to run a catheter to deliver the drug in addition to leads for the defibrillator. Most implanted drug delivery devices known in the art, do not deliver drugs directly into the bloodstream.  
           [0003]    The alleviation of cardioversion shock pain has been the subject of various patents in the prior art. Most of the pain-alleviating therapy, in conjunction with the delivery of cardioversion energy to the heart chamber is well known in the art. Further, the alleviation of pain through the operation of implantable drug dispensers for automatically, periodically, delivering a bolus of a pain-alleviating drug at the site in the body are also well known in the art. For example, U.S. Pat. Nos. 5,662,689 and 5,817,131 to Elsberry et al, disclose a methods and apparatus for alleviating cardioversion shock pain. The disclosures include an implantable cardioverter for providing cardioversion electrical energy to at least one chamber of a patient&#39;s heart in need of cardioversion and applying a pain alleviating therapy at an appropriate site in the patient&#39;s body prior to, or in conjunction with, the delivery of the cardioversion energy to the heart chamber to alleviate propagated pain perceived by the patient. The combined cardioversion and pain alleviating therapies are preferably realized in a single implantable, multi-programmable medical device or separate implantable cardioversion and pain control devices with means for communicating operating and status commands between the devices through the patient&#39;s body.  
           [0004]    U.S. Pat. No. 5,893,881 issued to Elsberry et al discloses a method and apparatus for alleviating cardioversion shock pain by delivering a bolus of analgesic. Specifically, the invention discloses an implantable cardioverter for providing cardioversion electrical energy to at least one chamber of a patient&#39;s heart in need of cardioversion and applying a pain alleviating therapy at an appropriate site in the patient&#39;s body prior to or in conjunction with the delivery of the cardioversion energy to the heart chamber to alleviate propagated pain perceived by the patient. The combined cardioversion and pain alleviating therapies are preferably realized in a single implantable, multiprogrammable medical device or separate implantable cardioversion and pain control devices with means for communicating operating and status commands between the devices through the patient&#39;s body.  
           [0005]    U.S. Pat. No. 5,087,243 to Avitall discloses a myocardial iontophoresis device. An implantable iontophoretic delivery system for use in applying medicinal materials rapidly to specific subcutaneous tissue sites of interest in conjunction with an implanted defibrillator is disclosed which uses a subcutaneously situated pouch for supplying medication in conjunction with a pair of defibrillator electrodes connected to a power source. One of the electrodes is located proximately with respect to the tissue of interest and is designed to dispense the medication of interest utilizing controlled electrical pulses. The pouch is connected with the administering electrode of the electrode system via pumping mechanism.  
           [0006]    U.S. Pat. No. 5,733,259 to Valcke et al discloses a method and apparatus for closed loop drug delivery. Specifically, a closed-loop drug delivery system uses patient response and rule based decision-making methods to achieve operator specified responses for diagnostic purposes. In the preferred embodiment, cardiac diagnosis is performed by pharmacologically stressing the heart by administration of an exercise simulating agent drug. In the preferred method, a protocol is defined, which preferably includes a target for a physiologic variable, such as heart rate, and a plan to achieve that target value. Preferably, the plan includes a specification of the desired rate of increase in that variable, such as the rate of increase in the heart rate per minute. The plan comprises the desired changes in the physiologic variable as a function of time.  
           [0007]    U.S. Pat. No. 5,925,066 to Kroll et al discloses an atrial arrhythmia sensor with drug and electrical therapy control apparatus. The invention relates to an atrial arrhythmia sensor and drug-dispensing apparatus is disclosed. The apparatus comprises a multiphase, multistage intelligent system to monitor and treat atrial fibrillation. The apparatus includes atrial rate sensing means, cardiac pacing and antitachycardia pacing means, drug delivery means including a self-cleaning catheter line with multi-drug dispensing capability preferably operated using a dual pump arrangement and an iontophoretic device. The drug delivery system may also include a porous catheter to discharge drug into the atrium. The intelligent system includes a memory implemented logic (software) to continuously monitor the atrial rate and initiate a response of either cardiac pacing, antitachycardia pacing or drug dispensing based on preset cardiac activity parameters. The system also includes a medical history-recording feature.  
           [0008]    U.S. Pat. No. 5,527,344 to Arzbaecher et al discloses a pharmacological atrial defibrillator and method. In this invention, a method and an implantable apparatus for automatically delivering a defibrillating drug to a patient upon detection of the onset of atrial fibrillation are disclosed. Atrial activity of a heart is detected and monitored. A delivery time is continuously computed and a delivery signal is emitted as a function of the monitored level of the atrial activity. When the delivery signal is emitted, an infusion pump discharges a defibrillating drug into the bloodstream of the patient. The atrial activity is also continuously monitored for computing a pacing time at which a pacing signal is emitted as a second function of the monitored level of atrial activity. When the pacing signal is emitted a pacer paces the atrium of the heart.  
           [0009]    U.S. Pat. No. 5,135,480 to Bannon et al discloses a transdermal drug delivery device. More specifically, the invention relates to a transdermal device having a detachably mounted electrode with a first surface adapted for contact with human skin and through which a drug substance contained in the electrode passes to the skin under the influence of an iontophoretic or electro-osmotic force and a second surface which is electrically conducting, the electrode has a surface area in contact with the skin, in use, in the range 0.1 to 30 cm and a drug dissolved or dispersed in a hydrophilic medium at a concentration in the range 0.1 to 15% (w/v) based on the hydrophilic medium.  
           [0010]    U.S. Pat. No. 6,091,989 to Swerdlow et al discloses a method and apparatus for reduction of pain from electric shock therapies. The invention discloses a method and apparatus for pretreating a patient prior to a therapeutic painful stimulus, comprising the application of pain inhibiting stimuli to a patient prior to an application of the therapeutic painful stimulus. Applying pain-inhibiting stimuli comprises the steps of sensing a need for the therapeutic painful stimulus, preparing to deliver the pain inhibiting stimuli to the patient prior to applying the therapeutic painful stimulus, and delivering the pain inhibiting stimuli to the patient prior to applying the therapeutic painful stimulus. The method and apparatus are embodied in a fully automatic; fully implantable, single or dual chamber atrial or ventricular cardioverter-defibrillators. The pain inhibiting prepulse method is intended primarily for use in conscious patients but may also be used in sleeping patients.  
           [0011]    As can be seen from the prior art recited hereinabove, alleviation of cardioversion shock pain is an important consideration in cardiac therapy. However, there is a need for a closed loop controlled system to automatically deliver pain analgesics and/or threshold reduction medications prior to or contemporaneous with an atrial defibrillation shock or other drug delivery therapy that may be associated with discomfort or pain.  
         SUMMARY OF THE INVENTION  
         [0012]    The present invention generally relates to a drug delivery device in wireless communication with an implanted medical device that preferably provides drugs transdermally prior to the delivery of therapy by the implanted device. The system is preferably telemetry or wireless communication-enabled to exchange data with the implanted device to thereby identify preshock events so that shock attenuation drugs could be delivered prior to an atrial defibrillation shock. More specifically, an iontophoretic drug delivery device is externally mounted on a patient&#39;s body, and is interconnected by communication transmission channel with an implanted medical device in the patient. The external device and the implanted medical device are in a bi-directional data exchange using telemetry and equivalent wireless communication systems therebetween.  
           [0013]    Further, the external iontophoretic drug delivery device and the implanted medical device are independently accessible to a programmer or an Independent Remote Monitor (IRM) external device for interrogation and reprogramming of parameters as needed. Furthermore, through either the IRM or a programmer, data may be transmitted to a PC for review by physicians or caregivers. Similarly, the data may be transferred to a server, which may be accessible to a plurality of users of the data for analysis, follow-up or research and development purposes.  
           [0014]    Further, through media such as the Internet, intranet, extranet or World Wide Web, data from the server may be accessible by third parties, remotely to follow-up the patient and provide recommendations for adjustment or therapy as needed.  
           [0015]    One aspect of the invention relates to the provision of one or more therapy regimens to the body, including two or more discreet medical devices, at least one of which medical devices is implanted into the living body and the other externally mounted, and being in bi-directional data communication and exchange with the implanted device.  
           [0016]    Yet another aspect of the invention includes monitoring a condition of a living body on a continuous basis to provide a shock attenuation therapy before cardioversion electrical energy is applied to at least one chamber of a patient&#39;s heart. Continuous monitoring and communication between the external device and the internal device coordinates the delivery of drug from the external device before shock is delivered by the implatned medical device. In this aspect of the invention, the external device and the internal device communicate and identify preshock conditions that indicate the eminence of cardioversion.  
           [0017]    Yet another aspect of the invention includes a remote communication system in which an external drug delivery device is monitored and actuated to respond to indications of events that would trigger therapy by an implanted medical device, which may result in the perception of pain by the patient. The external device may be remotely programmed to deliver drugs transdermally immediately before or contemporaneous with the therapy. Similarly, the communication system would allow a remote review and programming of the implanted device. Further, amounts of pain reducing drugs to be delivered may be remotely adjusted to complement changes in cardioversion therapy.  
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0018]    [0018]FIG. 1 represents externally mounted drug delivery in bi-directional communications with an implanted medical device.  
         [0019]    [0019]FIG. 2 shows an external programmer or a remote home device such as used to uplink and downlink data with both external drug delivery device and the implanted medical device.  
         [0020]    [0020]FIG. 3 represents one aspect of the remote communication and monitoring system of the present invention.  
         [0021]    [0021]FIG. 4 is a schematic block diagram of an automatic atrial cardioverter and pain alleviating system of the present invention employing the automatic remote delivery of pain alleviating drug therapy.  
         [0022]    [0022]FIG. 5 illustrates a representative drug delivery device.  
         [0023]    [0023]FIG. 6 depicts a drug delivery system schematic block diagram.  
         [0024]    [0024]FIG. 7 represents a high-level logic flow diagram of the present invention. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
       [0025]    [0025]FIG. 1 is an illustration of an implantable medical device, for instance, IMD adapted for use to communicate with an externally mounted drug delivery device. The IMD implanted in patient  10  includes IMD  12 . In accordance with conventional practice in the art, IMD  12  is housed within a hermetically sealed biologically inert outer casing which may itself be conductive so as to serve as an indifferent electrode in the IMD&#39;s pacing cardioversion/sensing circuit. One or more pacemaker leads collectively identified with reference number  14  are electrically coupled to IMD  10  in a conventional manner and extend into the patient&#39;s heart  16  via vein  18 . Disposed generally near the distal end of leads  14  are one or more exposed conductive electrodes for receiving electrical cardiac signals and/or for delivering electrical pacing and/or cardioversion/defibrillation stimuli to heart  16 . As will be appreciated by those of ordinary skill in the art, leads  14  may be implanted with its distal end situated in the atrium and/or ventricle of heart  16 .  
         [0026]    Although the present invention will be described herein in one embodiment, which includes an implanted medical device, those of ordinary skill in the art having the benefit of the present disclosure will appreciate that the present invention may be practiced in connection with numerous other types of implantable medical device systems. As to every element, it may be replaced by any one of infinite equivalent alternatives, only some of which are disclosed in this specification.  
         [0027]    As depicted in FIG. 1, external drug delivery device  20  is linked via telemetry transmission  21  to IMD  12 .  
         [0028]    [0028]FIG. 2 is a variation of FIG. 1 in which programmer  22  is shown in communication with implanted medical device  12  and external drug delivery system  20 . Specifically, programming unit  22  is in telemetry or wireless communication with implanted medical device  12  and external drug delivery device  20  via uplink and downlink communication channels  23  and  23 ′, respectively. Programmer  22  described herein with reference to FIG. 2 is disclosed in more detail in U.S. Pat. No. 5,345,362 issued to Thomas J. Winkler entitled “Portable Computer Apparatus with Articulating Display Panel” which patent is hereby incorporated herein by reference in its entirety. Similarly, other remote devices that enable programming of IMD  12  and drug delivery device  20  such as a home monitor disclosed in U.S. patent applications Ser. Nos. 09/776,265 and 60/190,272 entitled “Information Remote Monitor (IRM) Medical Device” and “Heart Failure Quick Look Summary for Patient Management Systems” respectively, which are hereby incorporated herein by reference in their entireties.  
         [0029]    [0029]FIG. 3 is another embodiment of the present invention wherein data is communicated using various medium to transfer information from IMD  12  and drug delivery device  20  via programmer, IRM or equivalent device  22 . As discussed hereinabove data from IMD  12  and drug delivery device  20  is uplinked to device  22  from which it may be directed to a PC  24  or server  26  using, for example, a modem, an ISDN line, fiber optic, cable, infrared, bluetooth-enabled or equivalent direct or wireless communication systems. Server  26  is also accessible directly to qualified users at station  28 . Further, server  26  may be accessible via Internet  30  to remote users  32 .  
         [0030]    With this exemplary communication network, caregivers, physicians and other qualified personnel may be able to access and review or reprogram the operations of IMD  12  and drug delivery device  20  remotely. For example, user  28  may use a LAN 1  or other secure lines to access server  26  from which either current or stored data relating to the operation of IMD  12  and drug delivery device  20  could be obtained for evaluation and adjustment, or remote patient monitoring. Similarly, remote users at station  32  may be able to access operational and finctional data of IMD  12  and drug delivery device  20  via Internet  30 .  
         [0031]    One of the significant aspects of the present invention is the use of a transdernally operable drug delivery device  20 . It is similar to the electrotransport drug delivery system disclosed in Design Patent No. 384,745 to Lattin et al. Further, a similar device is disclosed in U.S. Pat. No. 5,995,869 to Cormier et al. Additionally, electrotransport delivery device with voltage boosting circuit is disclosed in U.S. Pat. No. 6,035,234 to Riddle et al. And an electrotransport device and method of setting the output using the same drug delivery device is disclosed in U.S. Pat. No. 6,086,572 to Johnson et al. which patent applications are incorporated herein by reference in their entireties.  
         [0032]    The present invention implements a highly adaptable communication link between the implanted device and the drug delivery device disclosed in the prior art. The communication system as indicated hereinabove without limitation could be telemetry or as substantially described in U.S. Pat. No. 5,683,432 and 5,843,139, or an equivalent medical device communication system such as the one disclosed in U.S. Pat. No. 4,987,897 to Funke which patent is herein incorporated by reference in its entirety. Accordingly, the present invention provides a closed-loop drug delivery system that operates in data communications with an implanted device to attenuate the impact of shock and other discomfort resulting from IMD therapy.  
         [0033]    Referring now to FIG. 4, a fully implantable atrial cardioverter system  12  embodying the present invention in association with a schematically illustrated human heart  16  in need of atrial fibrillation monitoring and potential cardioversion of the atria  216 ,  218  and an external programmer  22  are shown. The atrial cardioverter system  12  is capable of the sequential initiation of delivery of a pain alleviating analgesic at therapeutic levels followed by delivery of atrial cardioversion electrical energy pulses or shocks of sufficient amplitude and duration to effectively cardiovert the heart  16  in atrial fibrillation. The portions of the heart  16  illustrated in FIG. 4 are the right ventricle (RV)  212 , the left ventricle  214 , the right atrium (RA)  216 , the left atrium  218 , the SVC  220 , the CS  221  including the CS ostium or opening  224 , the left ventricular free wall  226  and the inferior vena cava  227 .  
         [0034]    The system  30  generally includes an enclosure  232 , for hermetically sealing the internal circuit elements, battery, telemetry antenna, a bipolar RV lead  234 , and a RA-CS lead  236 . The enclosure  232  and leads  234  and  236  are arranged to be implanted beneath the skin of a patient so as to render the atrial cardioverter system  30  fully implantable.  
         [0035]    The RV lead  234  preferably comprises an endocardial bipolar lead having electrodes  238  and  240  arranged for establishing electrical contact with the right ventricle  212  of the heart  16 . The electrodes  238  and  240  permit bipolar sensing of ventricular depolarizations or R-waves in the right ventricle  212 . As illustrated, the lead  234  is preferably fed through the SVC  220 , the right atrium  216 , and then into the right ventricle  212  to lodge the electrodes  238 ,  240  in the apex thereof as illustrated.  
         [0036]    The RA-CS lead  236  generally includes a tip or CS cardioverting electrode  244  and a proximal ring or RA cardioverting electrode  246  as shown in U.S. Pat. No. 5,165,403, for example. As illustrated, the RA-CS lead  236  is flexible and arranged to be passed down the superior vena cava  220 , into the right atrium  216 , into the coronary sinus ostium  224 . The CS electrode  244  is advanced into the coronary sinus channel  221  of the heart near the left side thereof so that the first or tip electrode  244  is within the coronary sinus channel  221  either within the coronary sinus  222  adjacent the left ventricle  214  and beneath the left atrium  218  or most preferably within the great cardiac vein  223  adjacent the left ventricle  214  and beneath the left atrium  218 . The electrodes  244  and  246  are spaced apart such that when the CS electrode  244  is positioned as described above, the RA electrode  246  is in the right atrium  216 . The CS electrode  244  together with the RA electrode  246  provides bipolar sensing of heart activity in the atria  216  and  218 .  
         [0037]    The CS electrode  244  and the RA electrode  246  also provide for the delivery of defibrillating electrical energy to the atria. Because the CS electrode  244  is located beneath the left atrium  218  near the left ventricle  214  and the RA electrode  246  is within the right atrium  216 , the cardioverting electrical energy, when applied between these electrodes will be substantially confined to the atria  216  and  218  of the heart  16 . As a result, the electrical energy applied to the right ventricle  212  and left ventricle  214  when the atria are cardioverted or defibrillated will be minimized. This greatly reduces the potential for ventricular fibrillation of the heart to be induced as a result of the application of cardioversion electrical energy of the atria of the heart.  
         [0038]    Further electrode systems and cardioversion pathways have been disclosed and are suitable for use in the practice of the present invention. One such atrial cardioversion electrode system is disclosed in the article “Safety and Feasibility of Transvenous Cardioversion in Atrial Tachycardia”, by Blanc et al., published in Cardiac Pacing, edited by Gomez, Future Pub. Co., 1985, pp 1526-1529. This electrode system employs a single lead with electrodes located in the right atrium and in the pulmonary artery. Delivery of atrial cardioversion shocks between an RV electrode and a subcutaneous electrode is disclosed in U.S. Pat. No. 5,292,338. Delivery of atrial defibrillation pulses between a coronary sinus electrode and a subcutaneous electrode is also disclosed in U.S. Pat. No. 5,314,430.  
         [0039]    A further suitable atrial cardioversion electrode system is disclosed in U.S. Pat. No. 5,549,642 incorporated herein by reference in its entirety. The electrode system disclosed therein includes an RA/SVC electrode (alone or optionally coupled to a subcutaneous electrode) and a CS electrode. The elongated RA/SVC electrode appears to provide atrial defibrillation thresholds in the range of about 1.0 Joule or less across a substantial portion of the patient population which represents a substantial improvement over the RA or SVC to CS/great vein electrode system employed in the above-referenced &#39;403 patent.  
         [0040]    Any of the above atrial cardioversion electrode systems and associated atrial and/or ventricular leads may be used in the practice of the present invention. However, even an approximately 1.0 joule cardioversion shock can be painful to a substantial portion of the population, particularly since atrial fibrillation episodes repeat frequently, requiring frequent cardioversion.  
         [0041]    Within the enclosure  232 , the system  30  includes a ventricular sense amplifier  250  coupled to the RV lead  234  to receive electrical signals in the ventricle across the bipolar electrode pair  238 ,  240  and an R-wave detector  252  to detect the R-waves therefrom. The ventricular sense amplifier  250  and the R-wave detector  252  form a first detecting means that senses R-waves in the electrogram transmitted to ventricular sense amplifier by the RV lead  234 . The R-wave detector  252  is of the type well known in the art, which provides an output pulse upon the occurrence of an R-wave being sensed during a cardiac cycle of the heart. The delivery of the atrial defibrillation shock or pulse is timed from the R-wave employing the ventricular timer  264  as described below.  
         [0042]    The lead and electrode systems in certain embodiments of the above-referenced &#39;338, &#39;403 and &#39;430 and &#39;642 patents include an RV defibrillation electrode positioned on an RV lead inserted into the right ventricle and a pair of ventricular sense electrodes. Alternatively, in the atrial cardioversion system depicted in FIG. 4, common ventricular pacing leads having bipolar screw-in ventricular electrodes of this type may be employed as pace/sense electrodes  238 ,  240 .  
         [0043]    An atrial sense amplifier  254  is coupled to the RA-CS lead  236  to receive electrical signals or P-waves across the right atrium  216 . The atrial sense amplifier  254  forms a second detecting means for detecting P-wave atrial activity of the heart picked up by the CS electrode  244  and RA electrode  246  of the RA-CS lead  236 . The P-wave output signal of the atrial sense amplifier  254  is coupled to an analog to digital converter  260  which converts the analog signal representative of the atrial activity of the heart to digital samples for further processing to determine if atrial fibrillation is present and if the atrial cardioversion shock is effective in converting the atria to a normal atrial rate.  
         [0044]    The enclosure  232  of the atrial cardioverter system  30  further include a microcomputer  262  that is preferably implemented in a manner disclosed in the above-referenced &#39;338 patent and further as described hereinafter with respect to the flow diagram of FIG. 7. The implementation of the microcomputer  262  in accordance with this embodiment of the present invention results in a plurality of functional stages and RAM/ROM  282  for storing operating algorithms and programmable parameters as well as accumulated operating data for subsequent telemetry out to the external programmer  22 .  
         [0045]    The circuitry includes the ventricular timer  264  for timing various intervals that recur in each QRST cycle as well as the R-wave synchronization time interval, an interval set stage  266  for selecting time intervals to be timed out in the ventricular timer  264 , a delay timer  265  for timing out further delay times set in interval set stage  266  for the delivery of the pain alleviating therapy, an optional patient warning device  267  and warning set register  263 , a cardioversion energy level set stage  269 , an atrial fibrillation detector  270 , a charge delivery control stage  272 , an analgesic delivery control stage  290 , and a computation stage  280 .  
         [0046]    The microcomputer  262  is arranged to operate in conjunction with RAM/ROM memory  282  which may be coupled to the microcomputer  262  by a multi-bit address bus and a bi-directional multiple-bit data bus. This permits the microcomputer  262  to address desired memory locations within the memory for executing write or read operations. During a write operation, the microcomputer  262  stores data, such as time intervals or operating parameters in the memory  282  at the addresses defined by multiple-bit data bus. During a read operation, the microcomputer  262  obtains data from the memory at the storage locations identified by the multiple-bit addresses provided over the address bus and receives the data from the memory  282  over the bi-directional data bus. Data related to the detections of atrial fibrillation and the deliveries of the therapies may be recorded in the RAM memory  282  for interrogation and telemetry out to the external programmer  22  in a manner well known in the art.  
         [0047]    Detection of atrial fibrillation may be accomplished in atrial fibrillation detector  270 , in conjunction with computation stage  280 , of microcomputer  262  from the digitized P-waves detected by atrial sense amplifier  254  using any of the various atrial fibrillation detection methodologies known to the art. Generally, atrial fibrillation may be detected in response to an extended series of high rate (e.g. 240 BPM or greater) atrial depolarizations or P-waves. If greater specificity for atrial fibrillation is desired, analysis of regularity of rate waveform morphology may also be employed.  
         [0048]    Termination of atrial fibrillation may be detected in response to a decrease in the rate of atrial depolarizations and/or an increase in their regularity.  
         [0049]    Appropriate detection methodologies are disclosed in the article “Automatic Tachycardia Recognition”, by Arzbaecher et al., published in PACE, Vol. 7, May-June 1984, part II, pages 541-547 and in PCT Application No. US92/02829, Publication No. WO 92/18198 by Adams et al., both incorporated herein by reference in their entireties. In the PCT application, careful synchronization of the high voltage atrial defibrillation pulse to the ventricles to avoid induction of ventricular tachycardia or fibrillation is also discussed.  
         [0050]    In addition, in the context of devices which automatically detect the occurrence of atrial fibrillation, the patient may optionally be warned of the detection of atrial fibrillation to be ready for the delivery of the atrial cardioversion shock through operation of the warning device  267 . In this alternate variation of the embodiment of the invention, a warning may be provided to the patient of the diagnosis of atrial fibrillation and the commencement of delivery of the pain alleviation drug therapy. The warning may be effected in the manner described in U.S. Pat. No. 5,332,400 incorporated herein by reference in its entirety, but is preferably effected by energizing a piezoelectric crystal oscillator that oscillates at an audible frequency intense enough for the patient to hear it and take precautions, if necessary. The patient may also optionally be provided with a limited function programmer  22  for use in communicating a command to the microcomputer  262  to prevent delivery of the cardioversion shock until the patient feels the effects of the pain alleviation therapy, at which time the patient may employ the programmer  22  to enable delivery of the cardioversion shock, subject to re-verification of the presence of the atrial fibrillation.  
         [0051]    In this regard, the system  30  also includes the warning set register  263 , the delay timer  265 , and the warning device  267  that are utilized for generating the warning alarm for the patient when the atrial fibrillation detector  270  determines that the atria are in fibrillation. The warning device  267  may constitute an audible alarm sounding piezoelectric crystal oscillator for warning the patient that atrial fibrillation has been detected and that cardioverting electrical energy will be applied to the patient&#39;s atria.  
         [0052]    If a programmer  22  is provided, it may also optionally include a patient activated command signal to initiate the delivery of the pain alleviating and cardioversion therapies in response to symptomatic atrial fibrillation. In this context as well, the ability to use the programmer  22  to delay the delivery of the cardioversion pulse until the patient has felt the effects of the pain alleviating therapy is believed valuable.  
         [0053]    After the fibrillation detection warning is delivered to the patient, or after the patient requests cardioversion therapy by means of the programmer  22 , register  263  is set to indicate that the patient has received the fibrillation detection warning or has requested therapy. Immediately thereafter, the delay timer  265  starts timing the warning delay period and initiates communication to drug delivery system  20  via RF transmitter  292  and antenna  294 . The delay period defines a time interval from when the patient receives the warning or requests therapy to when the patient should first expect to receive the cardioverting electrical energy. The delay time is preferably programmable between one minute and twenty minutes to afford sufficient time to permit the pain alleviating therapy to take effect and for the patient to prepare for receiving the atrial cardioverting electrical energy. A second warning may optionally be given slightly before delivery of the cardioversion pulse, if desired. If the patient does not perceive the analgesic effect of the pain alleviating therapy during the warning delay, the patient may use the programmer  22  to reset the delay timer  265  to delay delivery of the cardioversion pulse until timer  265  expires. Alternatively, the programmer may instead allow the patient to delay delivery of the pulse until the patient perceives the analgesic effect, and allow delivery of the cardioversion therapy only following a patient initiated enable signal to the implanted device indicating that therapy may be delivered. As yet another alternative, the programmer may be employed to simply abort the therapy during the warning delay, which may be especially useful if therapy was initially requested by the patient, and the patient&#39;s symptoms have subsided.  
         [0054]    A warning system as described above, including apparatus specifically dedicated to providing the warning may not be necessary if the patient can independently feel the analgesic take effect.  
         [0055]    [0055]FIG. 5 illustrates a representative electrotransport delivery device that may be used in conjunction with the present invention. Device  20  comprises an upper housing  46 , a circuit board assembly  48 , a lower housing  56 , anode electrode  57 , cathode electrode  59 , anode reservoir  62 , cathode reservoir  64  and skin-compatible adhesive  67 . Upper housing  46  has lateral wings  45 , which assist in holding device  20  on a patient&#39;s skin. Upper housing  46  is preferably composed of an injection moldable elastomer (e.g., ethylene vinyl acetate). Printed circuit board assembly  48  comprises an integrated circuit  49  coupled to discrete components  52 , antenna  54  and battery  50 . Circuit board assembly  48  is attached to housing  46  by posts (not shown in FIG. 5) passing through openings  43   a  and  43   b , the ends of the posts being heated/melted in order to heat stake the circuit board assembly  48  to the housing  46 . Lower housing  56  is attached to the upper housing  46  by means of adhesive  67 , the upper surface  72  of adhesive  67  beings adhered to both lower housing  56  and upper housing  46  including the bottom surfaces of wings  45 .  
         [0056]    Shown (partially) on the underside of circuit board assembly  48  is a button cell battery  50 . Other types of batteries may also be employed to power device  20 .  
         [0057]    The device  20  is generally comprised of battery  50 , electronic circuitry  49 ,  52 ,  54 , electrodes  57 ,  59 , and hydrogel drug reservoirs  62 ,  64 , all of which are integrated into a self-contained unit. The outputs (not shown in FIG. 5) of the circuit board assembly  48  make electrical contact with the electrodes  59 , and  57  through openings  58 ,  58 ′ in the depressions  60 ,  60 ′ formed in lower housing  56 , by means of electrically conductive adhesive strips  66 ,  66 ′. Electrodes  57  and  59 , in turn, are in direct mechanical and electrical contact with the top sides  68 ,  68 ′ of drug reservoirs  62  and  64 . The bottom sides  70 ′,  70  of drug reservoirs  62 ,  64  contact the patient&#39;s skin through the openings  65 ′,  65  in adhesive  67 .  
         [0058]    Device  20  optionally has a feature, which allows the patient to self-administer a dose of drug by electrotransport. Upon depression of push button switch  42 , the electronic circuitry on circuit board assembly  48  delivers a predetermined DC current to the electrode/reservoirs  57 ,  62  and  59 ,  64  for a delivery interval of predetermined length. The push button switch  42  is conveniently located on the top side of device  20  and is easily actuated through clothing. A double press of the push button switch  42  within a short time period, e.g., three seconds, is preferably used to activate the device for delivery of drug, thereby minimizing the likelihood of inadvertent activation of the device  20 . Preferably, the device transmits to the user a visual, tactile and/or audible confirmation of the onset of the drug delivery interval by means of LED  44  becoming lit, TENs-like stimulation via electrodes  57  and  59  and/or an audible sound signal from, e.g., a “beeper”. Drug is delivered through the patient&#39;s skin by electrotransport, e.g., on the arm or body, over the predetermined delivery interval.  
         [0059]    Anodic electrode  57  is preferably comprised of silver and cathodic electrode  59  is preferably comprised of silver chloride. Both reservoirs  62  and  64  are preferably comprised of polymeric gel materials. Electrodes  57 ,  59  and reservoirs  62 ,  64  are retained by lower housing  56 .  
         [0060]    A liquid drug solution or suspension is contained in at least one of the reservoirs  62  and  64 . Drug concentrations in the range of approximately 1×10 −4  M to 1.0 M or more can be used, with drug concentrations, in the lower portion of the range being preferred. Typically, the reservoir containing the drug will also contain the selected countersensitizing agent, in an amount and concentration effective to provide the flux necessary to reduce or prevent sensitization of the skin or mucosa.  
         [0061]    [0061]FIG. 6 shows a simplified schematic block diagram of drug delivery system  20  integrated circuit  49 . Microprocessor  72  under control of a program contained in RAM/ROM  74  (interconnected via bi-directional bus  79 ) receives commands from IMD  12  through receiver  78  and antenna  54 . Upon a command to initiate drug delivery, the microprocessor  72  initiates drug delivery through drug delivery control block  80 , which initiates iontophoretic drug delivery through two electrodes (not shown). Timer  77  times the length of time for drug delivery under control of intervals stored in RAM/ROM  74  previously programmed via programmer  22  (not shown in FIG. 6). Upon timer  77  time out, a signal is sent to IMD  12  from transmitter block  76  and antenna  54  using the same telemetry system described herein above.  
         [0062]    The infusion of various analgesic drugs or agents (or, simply “analgesics”) including opiates (i.e. morphine sulfate, hydromorphone) and non-opiates (i.e. alpha-2 adrenergic agonists and neuron specific calcium channel blocking agents) have demonstrated rapid and effective analgesia following administration. Dependent upon the specific analgesic administered, it is also reported that the onset of pain suppression occurs in a couple of minutes to one hour, and the duration of analgesia may range from 4-24 hours. The delay in analgesia onset is not problematic, since rapid cardioversion is not necessary for atrial fibrillation as opposed to ventricular fibrillation. Time to analgesia can be utilized by the system  30  to re-verify the continuation of atrial fibrillation, charge storage capacitors to deliver the cardioversion shock, and ensure ventricular sensing to allow cardioversion shock synchronization with the R-wave of the cardiac cycle.  
         [0063]    A first alternative embodiment of the invention may employ the drug delivery system  20  for delivery of a cardioversion or defibrillation threshold reducing agent such as D-salotol, Procainamide or Quinidine as an alternative to, or in conjunction with, delivery of the pain alleviating therapy discussed above. The reduction of defibrillation threshold in such case would provide the possibility of a reduced amplitude, less painful cardioversion pulse. The delivery of a threshold reducing agent thus can be employed as a pain alleviating therapy or as part of a pain alleviating therapy. In a more complex embodiment, two separate drug delivery systems might be employed to allow delivery of the threshold reducing agent alone or in conjunction with an analgesic.  
         [0064]    A second alternative embodiment of the invention may employ the drug delivery system  20  for delivery of diuretic and blood pressure regulating agents such as Thiazide diuretics (hydrochlorothiazide, chlorthalidone), usually adequate for mild heart failure, loop diuretics (furosemide, bumetanide, ethacrynic acid) reserved for severe volume overload or thiazide-resistant edema. Additionally, ACE inhibitors have been shown to prevent or slow the progression of heart failure in patients with symptomatic and asymptomatic left ventricular dysfunction. Currently, four agents are used for the treatment of CHF (Congestive Heart Failure): captopril, enalapril, lisinopril, and quinapril. The implementation of IMD  12  of this embodiment would use the Medtronic Chronicle™ CHF monitoring system such as described in U.S. Pat. Nos. 5,535,752 and 6,155,267, incorporated herein by reference in their entireties. The IMD  12 , as described in the &#39;267 patent, would monitor chronic data representative of at least one physiological parameter. The chronic data is monitored to detect changes in state of the at least one physiological parameter. Data associated with detected changes in state is stored within IMD  12 . The detection of changes in state of the at least one physiological parameter is performed by establishing a baseline (e.g., a center reference line and upper and lower control limits), and then determining if the chronic data being monitored satisfies predetermined, preprogrammed conditions (e.g., conditions based on the center reference line and the upper and lower control limits) indicative of a change in state of the at least one physiological parameter. If data occurs outside of these predetermined limits, the IMD  12  sends telemetry signals to drug delivery system  20  to initiate the delivery of the appropriate drug as described herein above.  
         [0065]    A third alternative embodiment may utilize the drug delivery system  20  as the patient activator/programmer  22  by incorporating the features and function as described in U.S. Pat. No. 5,987,356 incorporated herein by reference in its entirety.  
         [0066]    [0066]FIG. 7 depicts a flow chart of an operation of the system shown in FIG. 4 in accordance with the present invention. At step S 100 , which continues at all times (except during the delivery of atrial cardioversion shock), atrial activity of the heart is sensed. At step  102 , the atrial fibrillation detection algorithm is invoked in atrial fibrillation detector  270 . If it is detected, then in step S 104 , the IMD  30  transmits a signal to the drug delivery system  20  via drug delivery control  290 , RF transmitter  292  and antenna  294 .to initiate delivery at S 105  of a programmed bolus of the pain alleviating drug from drug dispenser  20 .  
         [0067]    The charge delivery control  272  may be commanded to start charge up of the charge storage capacitors, but it is preferred to delay capacitor charge up until the end of the delay for the analgesic to take effect and commence capacitor charge up during the analgesic time course, that is, the time period that the analgesia effect is expected to continue. At S 107  the drug delivery device  20  transmits a confirmation of drug delivery completion back to the IMD  12 . Optional warning steps for the patients to show the status of the detection, drug delivery and cardioverter status may be included but are not shown in the flow chart of FIG. 7.  
         [0068]    A delay timer  265  is loaded and enabled to time out the delay for the analgesia effect to take place in steps S 106  and S 108 . During this delay, the continuation of the atrial fibrillation episode may be verified in steps S 100  and S 102  and the algorithm may optionally be halted at that point. However, since atrial fibrillation bouts reoccur and since the bolus of pain alleviating drug is already delivered, reconfirmation at the end of the delay times is sufficient to determine whether or not to deliver the cardioversion shock therapy.  
         [0069]    When the delay timer  265  times out in step S 108 , the delay timer  265  is reset for the analgesic time course and is started in step S 110 . The atrial fibrillation detection is re-verified in step S 112  during the analgesic time course. If it only re-verified after the analgesic time course times out, then it is necessary to repeat steps S 104 -S 114  until it is re-verified during an analgesic time course.  
         [0070]    Then, in step S 116 , a charge delivery control  272  is commanded to enable the storage capacitor charge circuit  274  to charge the high voltage output capacitors up to the cardioversion energy set in level stage  269 . The microcomputer  262  then sets a synchronization time interval in interval set stage  266  from an R-wave detected by R-wave detector  252 . The ventricular timer  264  then provides a blanking signal to the ventricular and atrial sense amplifiers  250  and  254 . Both operations may be performed in step S  118 . Re-verification of continued atrial fibrillation may also be performed between steps S 116  and S 118 .  
         [0071]    At the expiration of the synchronization time interval in ventricular timer  264 , a command is applied through the charge delivery control to operate a discharge circuit  276  to discharge the atrial cardioversion shock via electrodes  244  and  246 . After the atrial cardioversion shock is delivered, the atrial and ventricular sense amplifiers are again enabled, and the presence or absence of atrial fibrillation is again tested in step S 112 . If the episode is terminated, then the algorithm loops back to step S 100 .  
         [0072]    If the episode is not terminated, the steps of FIG. 7 may be repeated. After a certain number of attempts, the available therapies may be exhausted. Whether or not the therapies are successful, the patient will likely have been advised to contact the attending physician. The event history of the episodes and delivered therapies are recorded in RAM  282  for subsequent telemetry out and analysis by the physician in a manner well known in the art in order to assist in reprogramming therapies.  
         [0073]    Thus, the methodological sequence to provide the pain alleviating therapy to counter the pain induced by delivery of atrial cardioversion energy includes the initial detection of atrial fibrillation, optional warning to the patient, drug infusion therapy to produce analgesia, time out to allow analgesia to take effect and the charge storage capacitors to be charged, reverification of atrial fibrillation, delivery of the cardioversion energy, and verification that successful atrial defibrillation has taken place. Should successful atrial cardioversion not take place, the steps of FIG. 7, would be reinitiated, except that analgesic drug delivery would not be repeated unless the analgesic time course time had timed out in order to prevent drug overdose.  
         [0074]    Depending on the analgesic employed, it may also be desirable to include a further timer to inhibit delivery of a further analgesic bolus timed from the previous delivery for a further time delay to prevent drug overdose. Such a timer may take into account the cumulative amount of analgesic delivered over a set time period.  
         [0075]    In addition, it may be desireable to provide the patient with the option of using programmer  22  to temporarily program the delivery of an increased quantity of analgesic, if the desired analgesia effect is not achieved at the permanently programmed setting. A time and date record of such patient programmed increases may be kept in the system memory for review by the physician, and the repetitive use of the programmer may be inhibited.  
         [0076]    The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood, therefore, that other expedients known to those of skill in the art or disclosed herein may be employed without reporting from the invention or the scope of the appended claim. It is therefore to be understood within the scope of the appended claims; the invention may be practiced otherwise than is specifically described, without departing from the scope of the present invention.