Abstract:
An implantable medical device for treating breathing disorders such as central sleep apnea wherein stimulation is provided to the phrenic never through a transvenous lead system with the stimulation beginning after inspiration to extend the duration of a breath and to hold the diaphragm in a contracted condition.

Description:
CROSS-REFERENCE TO RELATED CASES 
     This case claims priority from and the benefit thereof and incorporates entirely: U.S. Provisional Application 60/737,808, filed Nov. 18, 2005, and entitled “System and Method to Modulate Phrenic Nerve to Prevent Sleep Apnea;” U.S. Provisional Application 60/743,062, filed Dec. 21, 2005, and entitled “System and Method to Modulate Phrenic Nerve to Prevent Sleep Apnea;” and U.S. Provisional Application 60/743,326, filed Feb. 21, 2006, and entitled “System and Method to Modulate Phrenic Nerve to Prevent Sleep Apnea.” 
    
    
     FIELD OF THE INVENTION 
     The present invention relates generally to implantable medical devices and more particularly to a device and method for controlling breathing and for treating Central Sleep Apnea. 
     BACKGROUND OF THE INVENTION 
     History 
     Sleep Disordered Breathing (SDB) and particularly Central Sleep Apnea (CSA) is a breathing disorder closely associated with Congestive Heart Failure (CHF). The heart function of patients with heart failure may be treated with various drugs, or implanted cardiac pacemaker devices. The breathing function of patients with heart failure may be treated with Continuous Positive Air Pressure (CPAP) devices or Nocturnal Nasal Oxygen. These respiratory therapies are especially useful during periods of rest or sleep. Recently, implanted devices to directly address respiration disturbances have been proposed. Some proposed therapeutic devices combine cardiac pacing therapies with phrenic nerve stimulation to control breathing. 
     Phrenic nerve pacing as a separate and stand alone therapy has been explored for paralyzed patients where it is an alternative to forced mechanical ventilation, and for patients with the most severe cases of central sleep apnea. For example, Ondine&#39;s Curse has been treated with phrenic nerve pacemakers since at least the 1970&#39;s. In either instance, typically, such phrenic nerve pacemakers place an electrode in contact with the phrenic nerve and they pace the patient&#39;s phrenic nerve at a constant rate. Such therapy does not permit natural breathing and it occurs without regard to neural respiratory drive. 
     Motivation for Therapy 
     SDB exists in two primary forms. The first is central sleep apnea (CSA) and the second is obstructive sleep apnea (OSA). In OSA the patient&#39;s neural breathing drive remains intact, but the pulmonary airways collapse during inspiration, which prevents air flow causing a form of apnea. Typically, such patients awake or are aroused as a result of the apnea event. The forced airflow of CPAP helps keep the airways open providing a useful therapy to the OSA patient. 
     CSA patients also exhibit apnea but from a different cause. These CSA patients have episodes of reduced neural breathing drive for several seconds before breathing drive returns. The loss of respiratory drive and apnea is due to a dysfunction in the patient&#39;s central respiratory control located in the brain. This dysfunction causes the patient&#39;s breathing pattern to oscillate between too rapid breathing called hyperventilation and periods of apnea (not breathing). Repeated bouts of rapid breathing followed by apnea are seen clinically and this form of disordered breathing is called Cheyne-Stokes breathing or CSR. Other patterns have been seen clinically as well including bouts of hyperventilation followed by hypopneas only. 
     In patients with CHF, prognosis is significantly worse when sleep apnea is present. A high apnea-hypopnea index (a measure of the number of breathing disturbances per hour) has been found to correlate to a poor prognosis for the patient. The swings between hyperventilation and apnea characterized by central sleep apnea have three main adverse consequences, namely: large swings in arterial blood gases (oxygen and carbon dioxide); arousals and shifts to light sleep; and large negative swings in intrathoracic pressure during hyperventilation. The large swings in blood gases lead to decreased oxygen flow to the heart, activation of the sympathetic nervous system, endothelial cell dysfunction, and pulmonary arteriolar vasoconstriction. Arousals contribute to increased sympathetic nervous activity, which has been shown to predict poor survival of patients with heart failure. Negative intrathoracic pressure, which occurs during the hyperventilation phase of central apnea, increases the after load and oxygen consumption of the left ventricle of the heart. It also causes more fluid to be retained in the patient&#39;s lungs. As a result of these effects the patient&#39;s condition deteriorates. 
     In spite of advances in care and in knowledge there is a large unmet clinical need for patients with sleep disordered breathing especially those exhibiting central sleep apnea and congestive heart failure. 
     SUMMARY OF THE INVENTION 
     The device of the present invention can sense the patients breathing and it can distinguish inhalation or inspiration from exhalation or expiration. 
     The device can periodically stimulate the phrenic nerve as required. In some embodiments the stimulation may be invoked automatically in response to sensed physiologic conditions. In some embodiments the device can stop the delivery of therapy in response to sensed conditions. In some embodiments the device can be prescribed and dispensed and the therapy delivered without regard to the sensed conditions. As a result, the device may be used to detect and intervene in order to correct episodes of sleep disordered breathing or the device may intervene to prevent episodes of sleep disordered breathing from occurring. The methods that are taught here may be used alone to treat a patient or they may be incorporated into a cardiac stimulating device where the respiration therapy is merged with a cardiac therapy. The therapy and its integration with cardiac stimulation therapy and the architecture for carrying out the therapy are quite flexible and may be implemented in any of several forms. 
     Hardware implementation and partitioning for carrying out the methods of the invention are also flexible. For example the phrenic nerve stimulation may be carried out with a transvenous lead system lodged in one of the cardiophrenic vein a short distance from the heart. One or both phrenic nerves may be accessed with leads. Either one side or both (right and left) phrenic nerves may be stimulated. Alternatively the phrenic nerve may be accessed through a large vein such as the jugular or the superior vena cava. 
     Because of the variety of anatomy and branching of the smaller veins, all non-central veins proximate to the phrenic nerve, including the pericardiophrenic, are call “phrenic nerve”. For example, the left or right pericadiophrenic veins are suitable for left or right phrenic nerve stimulation because of their proximity to the phrenic nerves, relatively simple catheter access, relative distance and separation from the excitable heart tissue by non-excitable tissue such as the pericardial membrane. Preferred placement of a stimulation electrode can be characterized by: not triggering heartbeat when stimulation current is applied, trigging breath, minimum phrenic nerve stimulation current, and lack of stimulation of different muscle groups not involved in respiration. As an alternative, a stimulation electrode may be placed in the pericardial space on the heart, near the phrenic nerve but electrically isolated from the heart. 
     The lead and stimulation electrodes may also take any of several forms. Leads may contain anchoring devices to prevent slippage. Multiple stimulation electrodes may be placed along the length of a lead. Any pair of these electrodes may be used for bipolar stimulation. The stimulator may switch between different electrodes to achieve capture of the phrenic nerve at a minimum energy level without stimulating the heart. Any electrode may be used as a sensory electrode, even those engaged in intermittent stimulation. Monopolar stimulation may also be used. When the electrode is monopolar, the reference electrode is likely the stimulator case. Leads may be coated with medications such as, but not limited to, steroids. 
     Implementation of respiration detection and measurement may also take any of several forms. Transthoracic impedance measurement may be taken from electrodes implanted at locations in the body to measure or sense the change in lung volume associated with breathing. Alternatively one or more implanted pressure transducers in or near the pleural cavity may be used to track pressure changes associated with breathing. Alternatively, respiration sensing may be carried out by an airflow sensor, a respiratory belt, a temperature sensor, a humidity sensor, and/or a CO2 sensor. In conjunction, or in alternative, sensing electrodes may be used to sense events such as cardiac electrical activity, patient activity, patient metabolic state. Knowledge of breathing rates and patterns are useful in carrying out the invention but distinguishing reliably the inspiration phase from expiration phase is a breath is particularly important for timing the delivery of the stimulation. 
     Any detection system used to trigger stimulation has a disadvantage of being susceptible to non-respiratory signals such as an artifact of motion, sudden arousal, or cough. The recognition of possible artifacts and comparison to stored breath history of normal breath patterns may be advantageous. If a given breathing pattern significantly differs from the template, then the breath may be rejected and stimulation deferred. Artifacts may be recognized and rejected by identification of: an unacceptably fast inhalation slope, an unacceptably high amplitude of tidal volume and/or the presence of a high frequency component in the respiratory signal spectrum. In all cases the stimulator logic may reject this “breath” and not apply a stimulation burst. It may also be useful to reject signals for some duration immediately following a stimulation pulse. This so-called “refractory period” may be measured as the duration of stimulation plus minimum time of expiration. In addition, an implantable stimulator may be equipped with an accelerometer. Acceleration signals may be used to reject a breath or several breaths and delay stimulation. After a normal pattern of breathing is restored, stimulation is resumed. 
     We consider that breathing has an inspiration phase followed by an expiration phase. Each breath is followed by a pause when the lungs are “still” before the next breath&#39;s inspiration. The device delivers phrenic nerve stimulation after the start of inspiration preferably toward the start of exhalation. The duration and magnitude of the stimulation is selected to “extend” the expiration phase or the respiratory pause of a naturally initiated breath. We note relatively little change in lung volume and little air exchange during the stimulation phase of the therapy. We have observed that prolongation of a natural breath, while keeping some air trapped in the lungs, delays the inspiration phase of next natural breath until the air trapped in the lungs is exhaled. For this reason our therapy has a tendency to lower the observed breathing rate. Typically the stimulation maintains activation of the diaphragm long enough to mimic a patient holding their breath by not letting the diaphragm relax. This mechanism of action controls the rate of breathing by increasing the effective duration of each breath. 
     Our experimental animal work has demonstrated the ability of the stimulation regime to down-regulate breathing rate (and minute ventilation) to a desired (preset) value while maintaining natural inspiration (i.e. by prolonging exhalation and extending the respiratory pause phases of the breath) without blocking the phrenic nerve. We believe that maintenance of natural inspiration is important since it allows prevention of airway collapse and retains certain capacity of the body to auto regulate rate of inspiration and depth of breathing. We also demonstrated that unilateral and transvenous stimulation is sufficient to carry out the invention and insures adequate levels of patient safety. In the process of prolonging the respiratory pause we “stilled” the lungs (no air movement occurred) while keeping one lung inflated. We believe that the mechanism of action for this observed effect is a physiologic feedback that prevents the respiration control center of the central nervous system from initiating the following breath. In other words we have invented a novel and practical therapy by substantially immobilizing at least one lung of the patient by maintaining the diaphragm in the contracted state by transvenous electrical stimulation of a phrenic nerve for the duration sufficient to substantially reduce breathing rate and alter the blood gas Composition of the patient. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       A preferred embodiment and best mode of the invention is illustrated in the attached drawings where identical reference numerals indicate identical structure throughout the figures and where multiple instances of a reference numeral in a figure show the identical structure at another location to improve the clarity of the figures, and where: 
         FIG. 1  is a schematic diagram; 
         FIG. 2  is a schematic diagram; 
         FIG. 3  is a schematic diagram; 
         FIG. 4  is a schematic diagram; 
         FIG. 5  is diagram showing experimentally derived physiologic data displayed in two panels A and B; 
         FIG. 6  is a schematic diagram showing physiologic data known in the prior art; 
         FIG. 7  is a schematic diagram showing physiologic data and device timing information; and 
         FIG. 8  is a schematic diagram showing physiologic data and device timing information. 
         FIG. 9  is a schematic diagram showing physiologic data and signal artifact rejection. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       FIG. 1  is schematic diagram showing an implanted medical device (IMD)  101  implanted in a patient&#39;s chest for carrying out a therapeutic stimulation of respiration. The patient has lungs shown in bold outline and indicated at  102  overlying the heart  103 . The right phrenic nerve  104  passes from the head alongside the heart to innervate the diaphragm  106  at location  105 . 
     In this embodiment a transvenous lead  107  passes from the IMD  101  and passes through venous vasculature to enter the cardiophrenic vein  108  on the right side of the patient. The cardiophrenic vein  108  lies next to the phrenic nerve  104  along the heart. Electrical stimulation pulses supplied to the stimulation electrode  110  on lead  107  interact with the phrenic nerve to stimulate it and thus activate the diaphragm  106 . In the figure a series of concentric circles  112  indicate electrical stimulation of the phrenic nerve. In this embodiment the stimulation electrode  110  lies far enough away from the heart  103  to avoid stimulating the heart  103 . In this embodiment only one branch of the phrenic nerve  104  is stimulated and the other side of nerve is under normal physiologic control. 
     A respiration electrode  114  on lead  107  cooperates with an indifferent electrode on the can of the IMD  101  to source and sink low amplitude electrical pulses that are used to track changes in lung volume over time. This well known impedance plethysmography technique is used to derive the inspiration and expiration events of an individual breath and may be used to track breathing rate. This impedance measurement process is indicated in the diagram by the dotted line  116  radiating from the electrode site of respiration electrode  114  to the IMD  101 . Transvenous stimulation of the phrenic nerve from a single lead carrying an impedance measuring respiration electrode is a useful system since it permits minimally invasive implantation of the system. However other architectures, are permissible and desirable in some instances. 
       FIG. 2  is a schematic diagram showing alternative electrode and lead placements for use in carrying out the stimulation regime of the invention. In some patients it may be easier or more suitable to access the phrenic nerve in the neck in the jugular vein at electrode location  200 . In some instances it may be preferable to place electrodes in veins both near the right phrenic nerve as indicated by the deep location of a stimulation electrode  110  and in the left phrenic nerve at electrode location  202 . Other potential locations for the stimulation electrodes are the large vessel (SVC) above the heart indicated by electrode  203 . Unilateral stimulation is preferred but having multiple sites available may be used to reduce nerve fatigue. Non-venous placement is possible as well. For example, placement of a patch electrode in the pericardial space between the heart and within the pericardial sac is suitable as well, as indicated by electrode location  205 . In this embodiment the insulating patch  206  isolates spaced electrodes  207  and electrode  208  from the heart. The lead  204  connects this bipolar pair of electrodes to the IMD  101 . 
     Also seen in this figure is a pressure transducer  209  located in the pleural cavity and connected to the IMD  101  via a lead. The pressure transducer  209  tracks pressure changes associated with breathing and provides this data to the implanted device  101 . The pressure transducer is an alternative to the impedance measurement system for detecting respiration. Such intraplueral pressure signal transducers are known in the respiration monitoring field. 
       FIG. 3  shows a schematic diagram of a system for carrying out the invention. The system has art implanted portion  300  and an external programmer portion  301 . 
     The IMD  101  can provide stimulation pulses to the stimulation electrode  110 . A companion indifferent electrode  306  may be used to sink or source the stimulation current generated in analog circuits  303 . A portion of the exterior surface  302  of the IMD  101  may be used with respiration electrode  114  to form an impedance plethysmograph. In operation, logic  305  will command the issuance of a train of pulses to the respiration electrode  114  and measure the amplitude of the signal as a function of time in circuits  304 . This well known process can measure the respiration of the patient and find the inspiration phase and the expiration phase of a breath. Respiration data collected over minutes and hours can be logged, transmitted, and/or used to direct the therapy. 
     When the therapy is invoked by being turned on by the programmer  301  or in response to high rate breathing above an intervention set point, the logic  305  commands the stimulation the phrenic nerve via the stimulation electrode  110  at a time after the beginning of the inspiration phase. Preferable the stimulation begins after the onset of exhalation. There is some flexibility in onset of stimulation. The shape of the stimulation pulses is under study and it may be beneficial to have the logic  305  command stimulation at higher amplitudes of energy levels as the stimulation progresses. It may also be desirable to have stimulation ramp up and ramp down during the therapy. It may prove desirable to stimulate episodically. The therapy may be best administered to every other breath or in a random pattern. The programmer may permit the patient to regulate the therapy as well. However in each case the stimulation of the diaphragm “stills” the diaphragm resulting in an amount of air trapped in at least one lung and extends the breath duration. 
     The duration of the stimulation is under the control of logic  305 . It is expected that the therapy will be dispensed with a fixed duration of pulses corresponding to breathing rate. It should be clear that other strategies for setting the duration of stimulation are within the scope of the invention. For example the breathing rate data can be used to set the stimulation duration to reduce breathing rate to a fraction of the observed rate. The therapy may also be invoked in response to detected high rate breathing or turned on at a fixed time of day. In a device where activity sensors are available the device may deliver therapy at times of relative inactivity (resting or sleeping). Activity sensors may also help in the detection and rejection of artifacts. An accelerometer, such as those used in cardiac pacing, would be an exemplary activity sensor. 
       FIG. 4  shows a schematic diagram of an alternate partitioning of the system. In this implementation, the respiration sensing is carried out outside the patient with sensor  404 , while the implanted portion  400  communicates in real time with an external controller  401  via coils  403  and  402 . This respiration sensor  404  may be a conventional respiration belt or thermistor based system. Real time breathing data is parsed in the controller  401  and control signal sent to the IPG  101  to drive stimulation of the phrenic nerve via lead  107 . This implementation simplifies IMD  101  portion for the system and may be useful for delivery of therapy to a resting or sleeping patient. 
       FIG. 5  is set forth as two panels. The data collected from an experimental animal (pig) is presented in the two panels and should be considered together. Panel  5 B plots airflow into and out of the animal against time, while panel  5 A plots volume against time. In the experiment the volume data was computed (integrated) from the airflow measurement. The two panels are two ways of looking at the same data collected at the same time. In each panel the dotted tracing  500  in  5 B and  502  in panel  5 A represent the normal or natural or not-stimulated and therefore underlying breathing pattern of the animal. In panel  5 A the inspiration phase of tracing  502  is seen as segment  514 . After tracing  502  peaks, the expiration phase begins as indicated by segment  516 . The figure shows that along trace  502 , the air that is inhaled is exhaled before 2 seconds has elapsed, as indicated by the dotted trace  502  returning to the zero volume level. 
     Trace  504  is associated with the unilateral delivery of stimulation  508  to a phrenic nerve. In the tracing the start of stimulation at time  518  is well after the start of inspiration and corresponds approximately to the reversal of airflow from inspiration to expiration as seen at time  518 . Very shortly after the stimulation begins the animal inhales more air seen by the “bump”  520  in the tracing  504  in panel  5 B. A small increment in the total volume corresponding to this bump is seen at the same time in panel  5 A. Of particular interest is the relatively flat tracing  522  corresponding to no significant change in lung volume during stimulation. Once stimulation terminates the lungs expel air as seen at volume change  524  in panel  5 A corresponding to outflow labeled  512  in panel  5 B. Only after the exhalation outflow  512  was complete did the sedated experimental animal initiate the next breath (not shown). Thus duration of breath was extended in this case from approximately 2 seconds to approximately 6 seconds resulting in the breathing rate reduction from 30 to 10 breaths per minute. The data support the assertion that adequate phrenic stimulation initiated after inspiration and during expiration can “prolong” or “hold” the breath and thus regulate or regularize breathing which it the value of the invention. 
       FIG. 6  shows a bout  601  of rapid breathing  603  followed by or preceded by apnea  602  events. This waveform is a presentation of Cheyne-Stokes respiration (CSR) well known in the prior art. The corresponding tracing of blood gas  607  indicates that the rapid breathing drives off blood carbon dioxide (CO2) as indicated the slope of line  606 . CSR begins with the rise of CO2 as indicated by ramp line  605  which triggers the rapid breathing. The ventilation drives the CO2 too low resulting in a loss of respiratory drive and an apnea event  602 . During the apnea the level of CO2 rises as indicated by the slope of line  604 . Once a threshold is reached the cycle repeats. 
       FIG. 7  shows a schematic diagram showing the delivery of the inventive therapy in the context of a patient experiencing CSR respiration. The patient experiences several quick breaths  701  and then the device is turned on as indicated by the stimulation pulses  709 . The device looks for a natural inspiration and waits until about the turn from inspiration to expiration, then the burst  709  of stimulation is delivered to a phrenic nerve. As explained in connection with  FIG. 5  the stimulation delays breath  706 . This next breath is also a candidate for the therapy and stimulation burst  710  is delivered to the phrenic nerve delaying breath  707 . In a similar fashion the device intervenes in breaths  707  and  708 . It is expected that the lower rate breathing resulting from repeated application of the therapy will keep the CO2 level in a “normal” range  715  and prevent CSR. The therapy could also be invoked in response to a detected bout of CSR but this is not necessary and it is believed that keeping a patient out of CSR is the better therapy. 
     It may be noted that the stimulation waveforms vary in  FIG. 7  with stimulation  710  rising in amplitude while stimulation  711  decreases in amplitude. Note as well that stimulation  712  ramps up and then down during the therapy. It is expected that the best waveform may vary from patient to patient or may vary over time. Also seen in the figure is a refractory period typified by period  730  that may be implemented in the logic  302  to prevent the device from issuing the therapy too close in time to the last intervention. In general the refractory period effectively disables the deliver of therapy until the refractory period expires. This places an effective low rate on stimulated rate of breathing. The refractory may be fixed, programmable or adjusted based on sensed breathing rate. 
       FIG. 8  illustrates the concept of expiratory period stimulation to expand a native breath. Panel  800  shows the inspiratory period  801  of the native breath  805 , the peak native inspiration  803  and the extended expiratory period  814 . For comparison, trace  805  shows the expiration period of the same breath without stimulation. Panel  810  shows the native phrenic nerve excitation burst  811  that causes spontaneous inspiration  801 . Without additional stimulation, inspiration would be over, and expiration will begin shortly after the duration of the native excitation burst. The phrenic nerve electrode stimulation burst  809  begins approximately at the time with the natural excitation  811  stops. This time point also approximately coincides with the peak native inspiration  803 . The respiratory signal on panel  800  can be a transthoracic impedance signal. Point  802  marks the inspiratory turn. Preferably, stimulation may begin after a delay following the inspiratory turn point or after the peak inspiratory point. 
       FIG. 9  illustrates the rejection of an artifact caused by cough or motion during sleep. Respiratory signal  900  shows disturbed breath  902  caused by cough. This signal pattern can be recognized and rejected by identification of: an unacceptably fast inhalation slop, an unacceptably high amplitude, and/or the presence of a high frequency component in the respiratory signal spectrum. In all cases the stimulatory logic will reject this “breath” and not apply a stimulation burst  910 . The next breath may also be rejected to allow the system to come to a stead state by extending the “blanking period” window to the duration of two normal breaths. After the normal pattern of breathing is restored  903 , stimulation is resumed  911  and  912 . In addition, implantable stimulator may be equipped with an accelerometer. Acceleration trace  920  shows high acceleration (vibrations)  921  corresponding to the patient&#39;s cough or motion. The acceleration signal may be used to reject a breath or several breaths and delay stimulation.