# Patent

## Title
Implantable neurostimulator-implemented method for managing tachyarrhythmic risk during sleep through vagus nerve stimulation

## Abstract

A patient suffering from congestive heart failure is at increased risk of cardiac arrhythmogenesis during sleep, particularly if experiencing central sleep apnea as a co-morbidity. Low intensity peripheral neurostimulation therapies that target imbalance of the autonomic nervous system have been shown to improve clinical outcomes. Thus, bi-directional autonomic regulation therapy is delivered to the cervical vagus nerve at an intensity that is insufficient to elicit pathological or acute physiological side effects and without the requirement of an enabling physiological feature or triggering physiological marker. The patient's physiology is monitored to identify periods of sleep. In one embodiment, upon sensing a condition indicative of tachyarrhythmia following a period of bradycardia, as naturally occurs during sleep, an enhanced “boost” dose of bi-directional neural stimulation intended to “break” the tachyarrhythmic condition is delivered. In a further embodiment, the boost dose is delivered upon sensing a physiological pattern indicative of Cheyne-Stokes respiration.

## Background
FIELD
This application relates in general to chronic cardiac dysfunction therapy and, in particular, to an implantable neurostimulator-implemented method for managing tachyarrhythmic risk during sleep through vagus nerve stimulation.
BACKGROUND
Congestive heart failure (CHF) is a chronic medical condition in which the heart is unable to pump sufficient blood to meet the body's needs. If left untreated, CHF can lead to cardiac arrhythmogenesis, progressively worsening cardiac function and eventually patient death. CHF patients are at increased risk of tachyarrhythmias, such as atrial fibrillation (AF), ventricular tachyarrhythmias (ventricular tachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter, particularly when the underlying morbidity is a form of coronary artery disease, cardiomyopathy, mitral valve prolapse, or other valvular heart disease.
Additionally, around one half of the patients suffering from CHF or stroke develop a type of central sleep apnea (CSA), known as Cheyne-Stokes respiration, which is a breathing disorder that can occur during sleep or wakefulness during which the patient alternates between episodes of apnea and rapid breathing. In contrast to obstructive sleep apnea (OSA), which is caused by a physical blockage of the airway, CSA is due to an imbalance of respiratory control by the brain, where the brain fails to transmit signals to breathing muscles, thereby causing breathing to temporarily stop. Cessation of breathing in CSA causes hypoxaemia as the percentage of oxygen in the blood drops below normal levels and hypercapnia as the concentration of carbon dioxide in the blood rises to higher than normal levels. In CSA, central respiratory drive is absent and the brain fails to respond to the changing levels of these respiratory gases, resulting in an elevated heart rate. A severe drop in blood oxygen level due to CSA can cause angina, trigger arrhythmias or even myocardial infarction.
Even without developing OSA, CHF patients face increased cardiac risks during sleep that stem from a circadian rhythm-driven interplay of the sympathetic and parasympathetic nervous systems, particularly during non-rapid eye movement (NREM) sleep, which occupies about 75% of a night's sleep. During NREM sleep, sympathetic activation is withdrawn, while parasympathetic neural activity predominates and causes natural decreases in heart rate, blood pressure, cardiac output, arterial baroreceptor set point, and systemic vascular resistance. As a result, during NREM sleep, all persons may experience sinus bradycardia or sinus pauses lasting up to two seconds, and transitory atrioventricular blockages. While these conditions are benign in healthy persons, the risk of developing pathological bradyarrhythmias during NREM sleep can be of particular concern in CHF patients. Moreover, the threat of bradyarrhythmias during sleep is exacerbated in CHF patients suffering from CSA, who additionally experience an increased incidence of nocturnal AF and VT and multiple tachyarrhythmic events. Further, sleep apneic induction of hypoxia can lead to bradyarrhythmia with profound effect, as sequela hyperventilation can potentially trigger tachyarrhythmia, which can degrade into VF and eventual patient death.
CSA can exacerbate CHF through hypoxaemic-increased heart rate and heightened arrhythmogenic risk. CHF, as well as other forms of chronic cardiac dysfunction (CCD), are generally accompanied by an autonomic imbalance of the sympathetic and parasympathetic nervous systems and pathologically characterized by an elevated neuroexitatory state and impaired arterial and cardiopulmonary baroreflex function with reduced vagal activity. CHF triggers compensatory activations of the sympathoadrenal (sympathetic) nervous system and the renin-angiotensin-aldosterone hormonal system, which initially helps to compensate for deteriorating heart-pumping function, yet, over time, can promote progressive left ventricular dysfunction and deleterious cardiac remodeling. Sympathoadrenal activation, particularly when co-occurring with a sleep apneic episode, increases the risk and severity of tachyarrhythmias due to neuronal action of the sympathetic nerve fibers in, on, or around the heart and through the release of epinephrine (adrenaline), which can worsen an already-elevated heart rate.
Therapeutic electrical stimulation of neural structures that directly address the cardiac autonomic nervous system imbalance and dysregulation underlying CCD through high intensity neural stimulation has been proposed. In one form, the cervical vagus nerve is stimulated to directly modulate cardiovascular regulatory function. Currently, vagus nerve stimulation (VNS) is only approved for the clinical treatment of drug-refractory epilepsy and depression, but has been proposed for therapeutic treatment of CHF. For instance, VNS has been demonstrated in canine studies as efficacious in simulated treatment of AF and heart failure, such as described in Zhang et al., “Therapeutic Effects of Selective Atrioventricular Node Vagal Stimulation in Atrial Fibrillation and Heart Failure,” J. Cardiovasc. Electrophysiol., Vol. 24, pp. 86-91 (January 2013), the disclosure of which is incorporated by reference.
Conventional VNS for cardiac therapy generally targets the efferent nerves of the parasympathetic nervous system, such as described in Sabbah et al., “Vagus Nerve Stimulation in Experimental Heart Failure,” Heart Fail. Rev., 16:171-178 (2011), the disclosure of which is incorporated by reference. Sabbah discusses canine studies using a VNS system manufactured by BioControl Medical Ltd., Yehud, Israel, that includes an electrical pulse generator, right ventricular endocardial sensing lead, and right vagus nerve cuff stimulation lead. The sensing lead enables closed loop synchronization to the cardiac cycle; stimulation is delivered only when heart rate increases beyond a preset threshold. An asymmetric tri-polar nerve cuff electrode provides cathodic induction of action potentials while simultaneously applying asymmetric anodal blocks that lead to preferential activation of vagal efferent fibers. Stimulation is provided at an intensity and impulse rate intended to measurably reduce basal heart rate by ten percent by preferential stimulation of efferent vagus nerve fibers leading to the heart while blocking afferent neural impulses to the brain. The degree of therapeutic effect on parasympathetic activation occurs through incidental recruitment of afferent parasympathetic nerve fibers in the vagus, as well as through recruitment of efferent fibers.
Other uses of electrical nerve stimulation for therapeutic treatment of cardiac and physiological conditions are described. For instance, U.S. Pat. No. 8,219,188, issued Jul. 10, 2012 to Craig discloses synchronization of vagus nerve stimulation with a physiological cycle, such as the cardiac or respiratory cycle, of a patient. Electrical stimulation is applied to the vagus nerve at a selected point in the physiological cycle correlated with increased afferent conduction, such as a point from about 10 msec to about 800 msec after an R-wave of the patient's ECG, optionally during inspiration by the patient; to increase heart rate variability, such as a point from about 10 msec to about 800 msec after an R-wave of the patient's ECG, optionally during expiration by the patient; not correlated with increased efferent conduction on the vagus nerve; to generate efferent electrical activity on the vagus nerve; or upon the detection of a symptom of a medical condition. In a further embodiment, conventional VNS is applied to the vagus nerve along with microburst electrical signals, which is a portion of a therapeutic electrical signal having a limited plurality of pulses, separated from one another by interpulse intervals, and a limited burst duration, separated from one another by interburst periods. Stimulation may be applied to generate efferent electrical activity on the nerve in a direction away from the central nervous system; through a “blocking” type of electrical signal, such that both afferent and efferent electrical activity on the nerve is prevented from traveling further; or wherein afferent fibers are stimulated while efferent fibers are not stimulated or are blocked, and vice versa. By applying a series of microbursts to the vagus nerve, enhanced vagal evoked potentials (eVEP) are produced in therapeutically significant areas of the brain, in contrast to conventional VNS alone, which fails to produce eVEP.
U.S. Pat. No. 6,600,954, issued Jul. 29, 2003 to Cohen et al. discloses a method and apparatus for selective control of nerve fiber activations for reducing pain sensations in the legs and arms. An electrode device is applied to a nerve bundle capable of generating, upon activation, unidirectional action potentials that propagate through both small diameter and large diameter sensory fibers in the nerve bundle, and away from the central nervous system.
U.S. Pat. No. 6,684,105, issued Jan. 27, 2004 to Cohen et al. discloses an apparatus for treatment of disorders by unidirectional nerve stimulation. An apparatus for treating a specific condition includes a set of one or more electrode devices that are applied to selected sites of the central or peripheral nervous system of the patient. For some applications, a signal is applied to a nerve, such as the vagus nerve, to stimulate efferent fibers and treat motility disorders, or to a portion of the vagus nerve innervating the stomach to produce a sensation of satiety or hunger. For other applications, a signal is applied to the vagus nerve to modulate electrical activity in the brain and rouse a comatose patient, or to treat epilepsy and involuntary movement disorders.
U.S. Pat. No. 7,123,961, issued Oct. 17, 2006 to Kroll et al. discloses stimulation of autonomic nerves. An autonomic nerve is stimulated to affect cardiac function using a stimulation device in electrical communication with the heart by way of three leads suitable for delivering multi-chamber stimulation and shock therapy. For arrhythmia detection, the device utilizes atrial and ventricular sensing circuits to sense cardiac signals to determine whether a rhythm is physiologic or pathologic. The timing intervals between sensed events are classified by comparing them to a predefined rate zone limit and other characteristics to determine the type of remedial therapy needed, which includes bradycardia pacing, anti-tachycardia pacing, cardioversion shocks (synchronized with an R-wave), or defibrillation shocks (delivered asynchronously).
U.S. Pat. No. 7,225,017, issued May 29, 2007 to Shelchuk discloses terminating ventricular tachycardia in connection with any stimulation device that is configured or configurable to stimulate nerves, or stimulate and shock a patient's heart. Parasympathetic stimulation is used to augment anti-tachycardia pacing, cardioversion, or defibrillation therapy. To sense atrial or ventricular cardiac signals and provide chamber pacing therapy, particularly on the left side of the heart, the stimulation device is coupled to a lead designed for placement in the coronary sinus or its tributary veins. Cardioversion stimulation is delivered to a parasympathetic pathway upon detecting a ventricular tachycardia. A stimulation pulse is delivered via the lead to electrodes positioned proximate to the parasympathetic pathway according to stimulation pulse parameters based at least in part on the probability of reinitiation of an arrhythmia.
U.S. Pat. No. 7,277,761, issued Oct. 2, 2007 to Shelchuk discloses vagal stimulation for improving cardiac function in heart failure patients. An autonomic nerve is stimulated to affect cardiac function by way of three leads suitable for delivering multi-chamber endocardial stimulation and shock therapy. When the stimulation device is intended to operate as an implantable cardioverter-defibrillator (ICD), the device detects the occurrence of an arrhythmia, and applies a therapy to the heart aimed at terminating the detected arrhythmia. Defibrillation shocks are generally of moderate to high energy level, delivered asynchronously, and pertaining exclusively to the treatment of fibrillation.
U.S. Pat. No. 7,295,881, issued Nov. 13, 2007 to Cohen et al. discloses nerve branch-specific action potential activation, inhibition and monitoring. Two preferably unidirectional electrode configurations flank a nerve junction from which a preselected nerve branch issues with respect to the brain. Selective nerve branch stimulation can be used in conjunction with nerve-branch specific stimulation to achieve selective stimulation of a specific range of fiber diameters, substantially restricted to a preselected nerve branch, including heart rate control, where activating only the vagal B nerve fibers in the heart, and not vagal A nerve fibers that innervate other muscles, can be desirous.
U.S. Pat. No. 7,778,703, issued Aug. 17, 2010 to Gross et al. discloses selective nerve fiber stimulation for treating heart conditions. An electrode device is coupled to a vagus nerve and a control unit applies stimulating and inhibiting currents to the vagus nerve, which are capable of respectively inducing action potentials in a therapeutic direction in first and second sets of nerve fibers in the vagus nerve and inhibiting action potentials in the therapeutic direction in the second set of nerve fibers only. The nerve fibers in the second set have larger diameters than the first set's nerve fibers. Typically, the system is configured to treat heart failure or heart arrhythmia, such as AF or tachycardia by slowing or stabilizing the heart rate, or reducing cardiac contractility.
U.S. Pat. No. 7,813,805, issued Oct. 12, 2010 to Farazi and U.S. Pat. No. 7,869,869, issued Jan. 11, 2011 to Farazi both disclose subcardiac threshold vagus nerve stimulation. A vagus nerve stimulator is configured to generate electrical pulses below a cardiac threshold, which are transmitted to a vagus nerve, so as to inhibit or reduce injury resulting from ischemia. For arrhythmia detection, a heart stimulator utilizes atrial and ventricular sensing circuits to sense cardiac signals to determine whether a rhythm is physiologic or pathologic. In low-energy cardioversion, an ICD device typically delivers a cardioversion stimulus synchronously with a QRS complex. If anti-tachycardia pacing or cardioversion fails to terminate a tachycardia, after a programmed time interval or if the tachycardia accelerates, the ICD device initiates defibrillation.
U.S. Patent App. Pub. No. 2010/0331908, filed Sep. 10, 2010 by Farazi discloses subcardiac threshold vagus nerve stimulation in which a vagal nerve stimulator generates electrical pulses below a cardiac threshold of the heart for treating an ischemia of the heart, or for reducing a defibrillation threshold of the heart. The cardiac threshold is a threshold for energy delivered to the heart above which there is a slowing of the heart rate or the conduction velocity. In operation, the vagal nerve stimulator generates the electrical pulses below the cardiac threshold, that is, subcardiac threshold electrical pulses, such that the beat rate of the heart is not affected. Although the function of the vagal nerve stimulator is to treat an ischemia, or to reduce a defibrillation threshold of the heart, in other embodiments, the vagal nerve stimulator may function to treat heart failure, reduce an inflammatory response during a medical procedure, stimulate the release of insulin for treating diabetes, suppress insulin resistance for treating diabetes, or treat an infarction of the heart.
U.S. Pat. No. 7,634,317, issued Dec. 15, 2009, to Ben-David et al. discloses techniques for applying, calibrating and controlling nerve fiber stimulation, which includes a vagal stimulation system comprising a multipolar electrode device that is applied to a portion of a vagus nerve (a left vagus nerve and/or right vagus nerve), which innervates a heart of a subject. Alternatively, the electrode device is applied to an epicardial fat pad, a pulmonary vein, a carotid artery, a carotid sinus, a coronary sinus, a vena cava vein, a right ventricle, or a jugular vein. The system is utilized for treating a heart condition such as heart failure and/or cardiac arrhythmia; the vagal stimulation system further comprises an implantable or external control unit, which typically communicates with electrode device over a set of leads. Typically, the control unit drives the electrode device to (i) apply signals to induce the propagation of efferent nerve impulses towards heart, and (ii) suppress artificially-induced afferent nerve impulses towards a brain of the subject, to minimize unintended side effects of the signal application; the efferent nerve pulses in vagus nerve are typically induced by the electrode device to regulate the heart rate of the subject.
Finally, U.S. Pat. No. 7,885,709, issued Feb. 8, 2011 to Ben-David discloses nerve stimulation for treating disorders. An electrode device stimulates the vagus nerve, so as to modify heart rate variability, or to reduce heart rate, by suppressing the adrenergic (sympathetic) system. Typically, the system is configured to treat heart failure or heart arrhythmia. Therapeutic effects of reduction in heart rate variability include the narrowing of the heart rate range, thereby eliminating very slow heart rates and very fast heart rates. For this therapeutic application, the control unit is typically configured to reduce low-frequency heart rate variability, and to adjust the level of stimulation applied based on the circadian and activity cycles of the subject. Therapeutic effects also include maximizing the mechanical efficiency of the heart by maintaining relatively constant ventricular filling times and pressures.
Notwithstanding, a need remains for an approach to ameliorate cardiac arrhythmogenic risk in a patient suffering from some form of CCD during sleep or due to a sleep-related disorder, such as CSA.
SUMMARY
CHF causes compensatory activation of the sympathetic nervous system and decreased parasympathetic central outflow, which can have a long-term negative effect on cardiac performance. A patient suffering from CHF, as well as other forms of CCD, is at increased risk of cardiac arrhythmogenesis during sleep, particularly if experiencing CSA as a co-morbidity. Low intensity peripheral neurostimulation therapies that target the imbalance of the autonomic nervous system have been shown to improve clinical outcomes. Thus, bi-directional autonomic regulation therapy is delivered to the cervical vagus nerve at an intensity that is insufficient to elicit pathological or acute physiological side effects and without the requirement of an enabling physiological feature or triggering physiological marker. The patient's physiology is monitored to identify periods of sleep. In one embodiment, upon sensing a condition indicative of tachyarrhythmia following a period of bradycardia, as naturally occurs during sleep, an enhanced “boost” dose of bi-directional neural stimulation intended to “break” the tachyarrhythmic condition is delivered. In a further embodiment, the boost dose is delivered upon sensing a physiological pattern indicative of Cheyne-Stokes respiration.
One embodiment provides an implantable neurostimulator-implemented method for managing tachyarrhythmic risk during sleep through vagus nerve stimulation. An implantable neurostimulator, including a pulse generator configured to deliver electrical therapeutic stimulation in a manner that results in creation and propagation (simultaneously in both afferent and efferent directions) of action potentials within neuronal fibers of a patient's cervical vagus nerve, is provided. Operating modes of the pulse generator are stored in a recordable memory. A maintenance dose of the electrical therapeutic stimulation is parametrically defined and is tuned to restore cardiac autonomic balance through continuously-cycling, intermittent and periodic electrical pulses at an intensity that is insufficient to elicit pathological or acute physiological side effects and without requirement of an enabling physiological feature or triggering physiological marker. A boost dose of the electrical therapeutic stimulation is parametrically defined and is tuned to prevent initiation of or disrupt tachyarrhythmia through periodic electrical pulses delivered at higher intensity than the maintenance dose. The maintenance dose is therapeutically delivered to the vagus nerve independent of cardiac cycle via a pulse generator included in the implantable neurostimulator through at least a pair of helical electrodes electrically coupled to the pulse generator via a nerve stimulation therapy lead. The patient's physiological state while asleep is monitored via at least one sensor included in the implantable neurostimulator. Upon sensing a condition indicative of naturally-occurring bradycardia followed by a condition indicative of potential tachyarrhythmia, the boost dose is delivered to the vagus nerve via the pulse generator through the pair of helical electrodes.
A further embodiment provides an implantable neurostimulator-implemented method for managing tachyarrhythmic risk accompanying central sleep apnea through vagus nerve stimulation. An implantable neurostimulator, including a pulse generator configured to deliver electrical therapeutic stimulation in a manner that results in creation and propagation (simultaneously in both afferent and efferent directions) of action potentials within neuronal fibers including a patient's cervical vagus nerve, is provided. Operating modes of the pulse generator are stored in a recordable memory. A maintenance dose of the electrical therapeutic stimulation is parametrically defined and is tuned to restore cardiac autonomic balance through continuously-cycling, intermittent and periodic electrical pulses at an intensity that is insufficient to elicit pathological or acute physiological side effects and without requirement of an enabling physiological feature or triggering physiological marker. A boost dose of the electrical therapeutic stimulation is parametrically defined and is tuned to prevent initiation of or disrupt tachyarrhythmia through periodic electrical pulses delivered at higher intensity than the maintenance dose. The maintenance dose is therapeutically delivered to the vagus nerve independent of cardiac cycle via a pulse generator included in the implantable neurostimulator through at least a pair of helical electrodes electrically coupled to the pulse generator via a nerve stimulation therapy lead. The patient's physiological state is monitored via at least one sensor included in the implantable neurostimulator. Upon sensing a pattern indicative of Cheyne-Stokes respiration, the boost dose is delivered to the vagus nerve via the pulse generator through the pair of helical electrodes.
By improving autonomic balance and cardiovascular regulatory function, therapeutic VNS operates acutely to decrease heart rate, reflexively increase heart rate variability and coronary flow, reduce cardiac workload through vasodilation, and improve left ventricular relaxation without aggravating comorbid tachyarrhythmia or other cardiac arrhythmic conditions. Over the long term, low dosage VNS provides the chronic benefits of decreased negative cytokine production, increased baroreflex sensitivity, increased respiratory gas exchange efficiency, favorable gene expression, renin-angiotensin-aldosterone system down-regulation, and anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatory effects.
Still other embodiments of the present invention will become readily apparent to those skilled in the art from the following detailed description, wherein are described embodiments by way of illustrating the best mode contemplated for carrying out the invention. As will be realized, the invention is capable of other and different embodiments and its several details are capable of modifications in various obvious respects, all without departing from the spirit and the scope of the present invention. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not as restrictive.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front anatomical diagram showing, by way of example, placement of an implantable vagus stimulation device in a male patient, in accordance with one embodiment.
FIGS. 2A and 2B are diagrams respectively showing the implantable neurostimulator and the simulation therapy lead of FIG. 1.
FIG. 3 is a graph showing, by way of example, the relationship between the targeted therapeutic efficacy and the extent of potential side effects resulting from use of the implantable neurostimulator of FIG. 1.
FIG. 4 is a timing diagram showing, by way of example, a stimulation cycle and an inhibition cycle of VNS as provided by implantable neurostimulator of FIG. 1.
FIG. 5 is a flow diagram showing an implantable neurostimulator-implemented method for managing sleep disorder-related tachyarrhythmias through vagus nerve stimulation, in accordance with one embodiment.
FIG. 6 is a graph showing, by way of example, a Cheyne-Stokes respiration pattern.
FIG. 7 is a flow diagram showing a routine for delivering a boost dose in response to an occurrence of tachyarrhythmia for use with the method of FIG. 5.
FIG. 8 is a flow diagram showing a routine for storing operating modes for use with the method of FIG. 5.



DETAILED DESCRIPTION
The autonomic nervous systems of patients suffering from various forms of CCD, including CHF, and related cardiovascular diseases exhibit increased sympathetic and decreased parasympathetic central outflow. This imbalance is accompanied by a pronounced elevation of basal heart rate arising from chronic sympathetic hyperactivation along the neurocardiac axis, which is exacerbated by Cheyne-Stokes respiration, a type of CSA common to patients suffering from CHF or stroke, and during NREM sleep during which a period of naturally-occurring bradyarrhythmia can be followed by tachyarrhythmia as breathing stops, blood oxygen level decreases and blood carbon dioxide level increases.
Low intensity peripheral neurostimulation therapies that target the imbalance of the autonomic nervous system have been shown to improve clinical outcomes in patients treated for three to twelve months. Bi-directional autonomic regulation therapy results in simultaneous creation and propagation of efferent and afferent action potentials within the vagus nerve. In contrast to conventional approaches to VNS, the neurostimulation is delivered bi-directionally and at an intensity that is insufficient to elicit pathological or acute physiological side effects, such as acute cardiac arrhythmias, and without the requirement of an enabling physiological feature or triggering physiological marker, such as heart rate or heart rate variability (HRV), such as for purposes of timing stimulation delivery, to confirm therapeutic effect, or other ends. Here, upon continuously-cycling, intermittent and periodic low intensity stimulation of the cervical vagus nerve, action potentials propagate away from the stimulation site in two directions, efferently toward the heart to influence the intrinsic cardiac nervous system and the heart and afferently toward the brain to influence central elements of the nervous system.
The low intensity neurostimulation therapy works to directly restore autonomic balance by engaging both medullary and cardiovascular reflex control components of the autonomic nervous system. The therapy is delivered through an implantable vagus nerve stimulator with, in one embodiment, an integrated heart rate sensor, such as used to treat drug-refractory epilepsy and depression, which can be adapted for use in managing chronic cardiac dysfunction during episodes of Cheyne-Stokes respiration and NREM sleep through low intensity bi-directional vagal stimulation. FIG. 1 is a front anatomical diagram showing, by way of example, placement of an implantable vagus nerve stimulation (VNS) device 11 in a male patient 10, in accordance with one embodiment. The VNS provided through the stimulation device 11 operates under several mechanisms of action. These mechanisms include increasing parasympathetic outflow and inhibiting sympathetic effects by blocking norepinephrine release. More importantly, VNS triggers the release of acetylcholine (ACh) into the synaptic cleft, which has beneficial anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatory effects.
The implantable vagus stimulation device 11 includes at least three implanted components, an implantable neurostimulator 12, a therapy lead 13, and helical electrodes 14. The implantable vagus stimulation device 11 can be remotely accessed following implant through an external programmer by which the neurostimulator 12 can be remotely checked and programmed; an external magnet for basic patient control; and an electromagnetic controller that enables the patient 10 to exercise increased control over therapy titration, delivery and suspension. The neurostimulator 12 is preferably interrogated prior to implantation and throughout the therapeutic period with a healthcare provider-operable external programmer and programming wand (not shown) for checking proper operation, downloading recorded data, diagnosing problems, and programming operational parameters. Generally, use of the external programmer is restricted to healthcare providers, while more limited manual control is provided to the patient through “magnet mode.” In one embodiment, the external programmer executes application software specifically designed to interrogate the neurostimulator 12. Together, the implantable vagus stimulation device 11 and one or more of the external components form a VNS therapeutic delivery system.
The neurostimulator 12 is implanted in the patient's right or left pectoral region generally on the same side (ipsilateral) as the vagus nerve 15, 16 to be stimulated, although other neurostimulator-vagus nerve configurations, including contra-lateral and bi-lateral are possible. The helical electrodes 14 are generally implanted on the vagus nerve 15, 16 about halfway between the clavicle 19a-b and the mastoid process. The therapy lead 13 and helical electrodes 14 are implanted by first exposing the carotid sheath and chosen vagus nerve 15, 16 through a latero-cervical incision on the ipsilateral side of the patient's neck 18. The helical electrodes 14 are then placed onto the exposed nerve sheath and tethered. A subcutaneous tunnel is formed between the respective implantation sites of the neurostimulator 12 and helical electrodes 14, through which the therapy lead 13 is guided to the neurostimulator 12 and securely connected.
The stimulation device 11 bi-directionally (simultaneously in both afferent and efferent directions) stimulates the vagus nerve 15, 16 through multimodal application of continuously-cycling, intermittent and periodic electrical stimuli. The stimulation is selectively delivered or suspended in response to episodes of Cheyne-Stokes respiration, and during NREM sleep in response to arrhythmias. In a further embodiment, tachyarrhythmias during wakefulness can be managed through application of a boost dose of VNS upon the sensing of a condition indicative of tachyarrhythmias, such as described in commonly-assigned U.S. patent application, entitled “Implantable Neurostimulator-Implemented Method for Managing Tachyarrhythmias through Vagus Nerve Stimulation,” Ser. No. 13/673,766, filed on Nov. 9, 2012, pending, the disclosure of which is incorporated by reference. In a still further embodiment, bradycardia in VNS-titrated patients can be managed through suspension of on-going low-level VNS.
Both sympathetic and parasympathetic nerve fibers are stimulated, but at an intensity that is insufficient to elicit acute physiological or acute physiological side effects and without the requirement of an enabling physiological feature or triggering physiological marker. Cervical vagus nerve stimulation results in propagation of action potentials from the site of stimulation in a manner that results in creation and propagation (simultaneously in both afferent and efferent directions) of action potentials within neuronal fibers comprising the cervical vagus nerve to restore cardiac autonomic balance. Afferent action potentials propagate toward the parasympathetic nervous system's origin in the medulla in the nucleus ambiguus, nucleus tractus solitarius, and the dorsal motor nucleus, as well as towards the sympathetic nervous system's origin in the intermediolateral cell column of the spinal cord. Efferent action potentials propagate toward the heart 17 to activate the components of the heart's intrinsic nervous system. Either the left or right vagus nerve 15, 16 can be stimulated by the stimulation device 11. The right vagus nerve 16 has a moderately lower stimulation threshold than the left vagus nerve 15 for heart rate affects at the same parametric levels.
The VNS therapy is delivered autonomously to the patient's vagus nerve 15, 16 through three implanted components that include a neurostimulator 12, therapy lead 13, and helical electrodes 14. FIGS. 2A and 2B are diagrams respectively showing the implantable neurostimulator 12 and the simulation therapy lead 13 of FIG. 1. In one embodiment, the neurostimulator 12 can be adapted from a VNS Therapy AspireSR Model 105 or Model 106 pulse generator, manufactured and sold by Cyberonics, Inc., Houston, Tex., although other manufactures and types of single-pin receptacle implantable VNS neurostimulators with or without integrated leadless heart rate sensors could also be used. The stimulation therapy lead 13 and helical electrodes 14 are generally fabricated as a combined assembly and can be adapted from a Model 302 lead, PerenniaDURA Model 303 lead, or PerenniaFLEX Model 304 lead, also manufactured and sold by Cyberonics, Inc., in two sizes based on helical electrode inner diameter, although other manufactures and types of single-pin receptacle-compatible therapy leads and electrodes could also be used.
Referring first to FIG. 2A, the neurostimulator 12 provides programmed multimodal vagal stimulation. The neurostimulator 12 includes an electrical pulse generator that is tuned to restore autonomic balance by triggering action potentials that propagate bi-directionally (both afferently and efferently) within the vagus nerve 15, 16. The neurostimulator 12 is enclosed in a hermetically sealed housing 21 constructed of a biocompatible, implantation-safe material, such as titanium. The housing 21 contains electronic circuitry 22 powered by a primary battery 23, such as a lithium carbon monoflouride battery. The electronic circuitry 22 is implemented using complementary metal oxide semiconductor integrated circuits that include a microprocessor controller that executes a control program according to stored stimulation parameters and timing cycles; a voltage regulator that regulates system power; logic and control circuitry, including a recordable memory 29 within which the stimulation parameters are stored, that controls overall pulse generator function, receives and implements programming commands from the external programmer, or other external source, collects and stores telemetry information, processes sensory input, and controls scheduled and sensory-based therapy outputs; a transceiver that remotely communicates with the external programmer using radio frequency signals; an antenna, which receives programming instructions and transmits the telemetry information to the external programmer; and a reed switch 30 that provides remote access to the operation of the neurostimulator 12 using an external programmer, a simple patient magnet, or an electromagnetic controller. The recordable memory 29 can include both volatile (dynamic) and persistent (static) forms of memory, such as firmware within which the stimulation parameters and timing cycles can be stored. Other electronic circuitry and components are possible.
Externally, the neurostimulator 12 includes a header 24 to securely receive and connect to the therapy lead 13. In one embodiment, the header 24 encloses a receptacle 25 into which a single pin for the therapy lead 13 can be received, although two or more receptacles could also be provided, along with the requisite additional electronic circuitry 22. The header 24 internally includes a lead connector block (not shown) and a set of set screws 26.
In one embodiment, the housing 21 can also contain a heart rate sensor 31 that is electrically interfaced with the logic and control circuitry, which receives the patient's sensed heart rate or, alternatively, HRV, as sensory inputs. In a further embodiment, the heart rate sensor 31 is either external to or physically separate from the neurostimulator 12 proper, but is operatively coupled, either through physical wired connection or via wireless interface. The heart rate sensor 31 monitors heart rate or HRV using an ECG-type electrode. Through the electrode, the patient's heart beat can be sensed by detecting ventricular depolarization or similar physiology. In a further embodiment, a plurality of electrodes can be used to sense voltage differentials between electrode pairs, which can undergo signal processing for further cardiac physiological measures, for instance, detection of the P-wave, QRS complex, and T-wave. The heart rate sensor 31 provides the sensed heart rate or HRV to the control and logic circuitry as sensory inputs that can be used to monitor whether the patient 10 is asleep or awake and determine the presence of arrhythmias, especially VT.
In a further embodiment, the housing 21 contains a minute ventilation sensor 32 that is electrically interfaced with the logic and control circuitry, which receives the patient's respiratory dynamics as sensory inputs. In a further embodiment, the minute ventilation sensor 32 is either external to or physically separate from the neurostimulator 12 proper, but is operatively coupled, either through physical wired connection or via wireless interface. The minute ventilation sensor 32, such as described in U.S. Pat. No. 7,092,757, issued Aug. 15, 2006, to Larson et al., the disclosure of which is incorporated by reference, measures the patient's respiratory rate and tidal volume, and calculates the patient's minute ventilation volume. In a yet further embodiment, other forms of metabolic sensors could be used either in combination with or in lieu of the minute ventilation sensor 32 for identifying changes in the patient's physiology, such as temperature, respiratory rate, and the like. The minute ventilation sensor 32 provides the minute ventilation volume to the control and logic circuitry as sensory inputs that can be used to determine whether the patient is asleep, awake, or as an indication of physical activity level, hyperventilation, or hypoventilation.
In a still further embodiment, the housing 21 contains at least one accelerometer 33 that is electrically interfaced with the logic and control circuitry, which can receive the patient's physical movement, posture or orientation as sensory inputs. In a yet further embodiment, the accelerometer 33 is either external to or physically separate from the neurostimulator 12 proper, but is operatively coupled, either through physical wired connection or via wireless interface. In a still further embodiment, the minute ventilation sensor 32 may be combined into a blended sensor with at least one accelerometer 33.
The accelerometer 33 contains the circuitry and mechanical components necessary to measure acceleration, movement or orientation of the patient's body along at least two axes, and may include multiple uniaxial accelerometers, a dual axial accelerometer, or a triaxial accelerometer. By measuring the acceleration along multiple axes, the accelerometer 33 provides sensory inputs that can be used to determine the patient's posture or orientation and rate of movement, which are indicative of activity level and whether the patient has fallen asleep or awakened. In a further embodiment, the accelerometer 33 can determine the patient's activity level and posture, for example, upright versus recumbent, which can be used to determine sleep state. For instance, a low level of activity combined with either a reclined or prone posture would indicate that the patient is asleep. Also, the angle of the patient during sleep can be indicative of the severity of a heart failure condition. This angle during sleep could be used to adjust the intensity or duty cycle of the maintenance dose.
Specifically, the following approaches of combining activity level with posture could be used:

    
    
        If the posture angle of the patient 10 is less than about 45 degrees (relative to horizontal) and the patient's activity level is below a pre-defined threshold, then the patient can be considered to be asleep.
        Upon detection of sleep, the maintenance dose may be reduced or suspended to prevent nighttime bradycardia. This suspension may be applied in addition to a temporary suspension in response to detected bradycardia.
        Detection of sleep posture may be used to determine the severity of the patient's heart failure. A greater sleep posture angle (relative to horizontal) may be the result of orthopnea, which may indicative of a more severe heart failure condition. Such a detection could be used to increase the intensity of the daytime maintenance dose.
    
    


Referring next to FIG. 2B, the therapy lead 13 delivers an electrical signal from the neurostimulator 12 to the vagus nerve 15, 16 via the helical electrodes 14. On a proximal end, the therapy lead 13 has a lead connector 27 that transitions an insulated electrical lead body to a metal connector pin 28. During implantation, the connector pin 28 is guided through the receptacle 25 into the header 24 and securely fastened in place using the set screws 26 to electrically couple the therapy lead 13 to the neurostimulator 12. On a distal end, the therapy lead 13 terminates with the helical electrode 14. In one embodiment, the lead connector 27 is manufactured using silicone and the connector pin 28 is made of stainless steel, although other suitable materials could be used, as well. The insulated lead body 13 utilizes a silicone-insulated alloy conductor material.
Preferably, the helical electrodes 14 are placed over the cervical vagus nerve 15, 16 at the location below where the superior and inferior cardiac branches separate from the cervical vagus nerve. In alternative embodiments, the helical electrodes may be placed at a location above where one or both of the superior and inferior cardiac branches separate from the cervical vagus nerve. In one embodiment, the helical electrodes 14 are positioned around the patient's vagus nerve oriented with the end of the helical electrodes 14 facing the patient's head. In an alternate embodiment, the helical electrodes 14 are positioned around the patient's vagus nerve 15, 16 oriented with the end of the helical electrodes 14 facing the patient's heart 17. The polarity of the electrodes could be configured into a monopolar cathode, a proximal anode and a distal cathode, or a proximal cathode and a distal anode.
The triggering of CHF compensatory mechanisms, specifically, the chronic sympathetic hyperactivation accompanying a CCD condition, significantly increases the risk of tachyarrhythmias. Moreover, such risk is heightened when the patient is suffering from both CHF and CSA, where the co-occurrence of hypoxaemia and hypercapnia during apneic episodes increases heart rate and causes follow-on hyperventilation as the patient resumes breathing. Similar heightened risk to CHF patients is also presented by nocturnal occurrence of bradyarrhythmias followed by the potential for sequela tachyarrhythmic events. To counter these risks, the VNS is delivered as a multimodal set of therapeutic and event-based doses, which are system output behaviors that are pre-specified within the neurostimulator 12 through the stored stimulation parameters and timing cycles implemented in firmware programming and executed by the microprocessor controller. The selections of therapeutic dose and duty cycle are a tradeoff among competing medical considerations. FIG. 3 is a graph 40 showing, by way of example, the relationship between the targeted therapeutic efficacy 43 and the extent of potential side effects 44 resulting from use of the implantable neurostimulator 12 of FIG. 1. The x-axis represents the duty cycle 41. The y-axis represents relative quantified physiological response 42 to VNS therapy. The neurostimulation is delivered bi-directionally and at an intensity that is insufficient to elicit pathological or acute physiological side effects, such as acute cardiac arrhythmias, and without the requirement of an enabling physiological feature or triggering physiological marker, such as heart rate or HRV.
The duty cycle 41 is determined by dividing the stimulation ON time by the sum of the ON and OFF times of the neurostimulator 12 during a single ON-OFF cycle. In a further embodiment, the stimulation time can include ramp-up and ramp-down times respectively preceding and following the ON time during which the neurostimulator 12 delivers the VNS at full output current, such as further described infra with reference to FIG. 4. Ramp-up and ramp-down times may be necessary, for instance, when the stimulation frequency exceeds a minimum threshold. The physiological response 42 can be expressed quantitatively for a given duty cycle 41 as a function of the targeted therapeutic efficacy 43 and the extent of potential side effects 44. The maximum level (“max”) 46 of physiological response 42 signifies the highest point of targeted therapeutic efficacy 43 or potential side effects 44.
The therapeutic efficacy 43 represents the intended effectiveness of VNS in provoking a beneficial physiological response, which may be patient- or population-dependent. In contrast to conventional feedback-driven VNS approaches that require an enabling physiological feature to gauge stimuli delivery efficacy, the acute responses and chronic contributing factors need not be (and are likely not) directly observed contemporaneous to VNS delivery. Rather, the contributing factors could be clinically measured over time, such as in-clinic during patient follow up via ECG trace or other metric. As well, in on-going laboratory studies involving canines, increased heart beat regularity during VNS on time, as exhibited through decreased heart rate variability, has been creditably detected through 24-hour Holter monitoring during vagal neural stimulation at a constant continuously-cycling level below a subcardiac threshold, above which there is a slowing of heart rate, conduction velocity or other cardiac artifact.
The therapeutic efficacy 43 can be quantified by assigning values to the realized acute and chronic responses, which together contribute to and synergistically produce the beneficial physiological response. Acute responses include realized changes in HRV, increased coronary flow, reduction in cardiac workload through vasodilation, and improvement in left ventricular relaxation. Chronic factors include improved cardiovascular regulatory function, decreased negative cytokine production, increased baroreflex sensitivity, increased respiratory gas exchange efficiency, favorable gene expression, renin-angiotensin-aldosterone system down-regulation, anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatory effects. Still other acute responses and chronic factors are possible.
Beneficial physiological response is generally also considered to be patient dependent, whereby certain of the contributing factors may be more important for one patient as compared to other patients, and no single contributing factor is fully dispositive or conclusive of whether the physiological response is beneficial for any given patient. The contributing factors can be combined in any manner to quantify the relative level of therapeutic efficacy 43, including weighting particular factors more heavily than others, by tailoring the importance of each contributing factor on a patient-specific or population-specific manner, or applying statistical or numeric functions based directly on or derived from realized changes to the patient's physiology. For example, therapeutic goals of achieving an increase of HRV of 10% and decreased negative cytokine production of 3% may be desired for a particular patient with equal weight assigned to each of these goals. Maximum physiological response 46 occurs when these goals are substantially met.
Empirically, therapeutic efficacy 43 steeply increases beginning at around a 5% duty cycle (patient-dependent), as beneficial physiological response 42 is realized, and levels off in a plateau near the maximum level 46 of physiological response 42 at around a 30% duty cycle (patient-dependent), although some patients may require higher (or lower) duty cycles to show similar beneficial physiological response 42. Thereafter, therapeutic efficacy 43 begins decreasing at around a 50% duty cycle (patient-dependent) and continues in a plateau near a 25% physiological response (patient-dependent) through the maximum 100% duty cycle.
The physiological response and occurrence of side effects to different combinations of VNS parameters and timing cycles has been empirically evaluated in pre-clinical work on canines Like the therapeutic efficacy 43, side effects 44 may be patient- or population-dependent and can be quantified by assigning values to the realized acute and chronic side effects. For example, benign acute side effects, such as coughing, could be assigned a low value, while pathological side effects, like bradycardia, could be rated significantly higher to reflect level of severity. In the canine study, the only side effects that were observed were coughing and throat irritation, retching, and bradycardia and heart block during 4-6 weeks of gradual titration. Following titration, the only remaining side effect that was observed was bradycardia, which was observed in the following ranges:

    
    
        Right VNS: In an awake animal, bradycardia was typically observed beginning at approximately 1.25-1.5 mA at a pulse width of 500 μsec and approximately 1.5-1.75 mA at a pulse width 250 μsec, independent of stimulation frequency. However, the magnitude of the current-dependent bradycardia increased with stimulation frequency, with the highest level of bradycardia observed at 20 Hz, the lowest level observed at 10 Hz, and an intermediate level observed at 15 Hz. During sleep, bradycardia was observed at similar parameters as in an awake animal.
        Left VNS: In an awake animal, bradycardia was only observed at amplitudes greater than 2.5 mA, and primarily in the 3.0-3.5 mA range. Stimulation frequencies of 15 or 20 Hz were more likely to produce bradycardia at the lower end of that amplitude range, and a stimulation frequency of 10 Hz was more likely to produce bradycardia only at the upper end of the range. In some animals, no bradycardia was observed at any combination of parameters up to the maximum stimulation current of 3.5 mA. During sleep, bradycardia was observed at similar parameters to right VNS.
    
    


Comparable ranges of side effects in humans are expected.
In the absence of patient physiology of possible medical concern, such as acute cardiac arrhythmias, VNS is delivered in therapeutic doses that each use alternating cycles of stimuli application (ON) and stimuli inhibition (OFF) that are tuned to activate both afferent and efferent pathways. Stimulation results in parasympathetic activation and sympathetic inhibition, both through centrally-mediated pathways and through efferent activation of preganglionic neurons and local circuit neurons. FIG. 4 is a timing diagram showing, by way of example, a stimulation cycle and an inhibition cycle of VNS 60 as provided by implantable neurostimulator 12 of FIG. 1. The stimulation parameters enable the electrical stimulation pulse output by the neurostimulator 12 to be varied by both amplitude (output current 66) and duration (pulse width 64). The set of stimulation parameters and timing cycle used depends upon the operating mode of therapy desired, that is, maintenance, sleep, or boost, as further described below with reference to FIG. 8. The number of output pulses delivered per second determines the signal frequency 63. In one embodiment, a pulse width in the range of 100 to 250 μsec is used to deliver between 0.02 and 50 mA of output current at a signal frequency of about 20 Hz, although other therapeutic values could be used as appropriate.
In the simplest case, the stimulation time equals the time period during which the neurostimulator 12 is ON and delivering pulses of stimulation. The OFF time 65 equals the time period occurring in-between stimulation times 61 during which the neurostimulator 12 is OFF and inhibited from delivering stimulation. In one embodiment, the neurostimulator 12 implements either or both of a ramp-up time 67 and a ramp-down time 68 that respectively precede and follow the ON time 62 during which the neurostimulator 12 is ON and delivering pulses of stimulation at the full output current 66. The ramp-up time 67 and ramp-down time 68 are used when the stimulation frequency is at least 10 Hz, although other minimum thresholds could be used, and both ramp-up and ramp-down times 67, 68 last two seconds, although other time periods could also be used. The ramp-up time 67 and ramp-down time 68 allow the strength of the output current 66 of each output pulse to be gradually increased and decreased, thereby avoiding deleterious reflex behavior due to sudden delivery or inhibition of stimulation at a full-strength programmed level of intensity.
Cardiac arrhythmogenic risk in a patient suffering from some form of CCD during sleep or due to a sleep-related disorder, such as CSA, can be ameliorated through multimodal VNS therapy. FIG. 5 is a flow diagram showing an implantable neurostimulator-implemented method for managing sleep disorder-related tachyarrhythmias through vagus nerve stimulation 70, in accordance with one embodiment. The method 70 is implemented on the stimulation device 11, the operation of which is parametrically defined through stored stimulation parameters and timing cycles. The method 70 can be used for treatment of both CHF patients and for non-CHF patients suffering from other forms of CCD or related disorders.
In one embodiment, at least three operating modes are stored, which include a maintenance dose, a sleep dose, and an enhanced or “boost” dose. The maintenance dose delivers stimulation at an intensity that is insufficient to elicit pathological or acute physiological side effects and without the requirement of an enabling physiological feature or triggering physiological marker. Nevertheless, low intensity therapeutic VNS can ameliorate pathological tachyarrhythmias in some patients. Further, although VNS has been shown to decrease defibrillation threshold, VNS will not terminate VF in the absence of defibrillation. Rather, VNS prolongs ventricular action potential duration, and so may be effective in extinguishing VT. In addition, the effect of VNS on the AV node may be beneficial in patients with AF by slowing conduction to the ventricles and controlling ventricular rate.
An implantable neurostimulator 12, in combination with at least one physiological or metabolic sensor, such as an integrated heart rate sensor 31, minute ventilation sensor 32, accelerometer 33, blended sensor, or other type of sensing mechanism for measuring the patient's physiology, metabolism, or activity level, is provided (step 71). The neurostimulator 12 includes a pulse generator 11, a nerve stimulation therapy lead 13, and a pair of helical electrodes 14. In a further embodiment, electrodes may be implanted with no implanted neurostimulator or leads. Power may be provided to the electrodes from an external power source and neurostimulator through wireless RF or inductive coupling. Such an embodiment may result in less surgical time for implantation and decreased trauma to the patient.
The pulse generator stores a set of one or more operating modes (step 72) that parametrically define at least three operating modes of the stimulation, including a sleep dose, a maintenance dose delivered at a higher intensity than the sleep dose, and a boost dose delivered at a higher intensity than the maintenance dose, as further described infra with reference to FIG. 8. The neurostimulator 12 delivers therapeutic VNS under control of the electronic circuitry 22, as programmed by the stored stimulation parameters and timing cycles. Each parameter can be independently programmed to define the characteristics of the cycles of therapeutic stimulation and inhibition to ensure optimal stimulation for a patient 10. The programmable stimulation parameters include output current, signal frequency, pulse width, signal ON time, signal OFF time, magnet activation (for VNS specifically triggered by “magnet mode”), and reset parameters. Other programmable parameters are possible. In a further embodiment, sets or “profiles” of pre-selected stimulation parameters can be provided to physicians, which can be selected with the assistance of an external programmer and fine-tuned to a patient's physiological requirements prior to being programmed into the neurostimulator 12 following implant.
Ordinarily, the maintenance dose is therapeutically delivered to the patient while the patient is awake (step 73), absent other reasons to suspend delivery, such as onset of pathological bradycardia. Additionally, in some patients, the maintenance dose is delivered throughout periods of both wakefulness and sleep. An awake patient's physiological, metabolic or physical state, depending upon the form of sensor used, is regularly monitored to determine whether the patient 10 has fallen asleep (step 74). In one embodiment, heart rate (or HRV) is used to check the patient's physiology using the heart rate sensor 31. A normative heart rate during sleep is generally considered to fall between 60 to 70 beats per minute (bpm). While awake, the heart rate generally falls somewhere under 100 bpm, depending upon patient age, condition and physiology. When the heart rate sensor 31 is used, the normative heart rate of the patient 10 is monitored and recorded periodically to determine whether the patient 10 has fallen asleep.
In general, falling asleep is characterized by the gradual onset of decreased heart rate, blood pressure, cardiac output, arterial baroreceptor set point, systemic vascular resistance, and lower HRV, which, in combination with the heart rate sensor 31, can be detected by the neurostimulator 12, as well as by evaluation of rhythm stability or related rate and rhythm morphological indicators, such as conventionally used in cardiac rhythm management devices. If the heart rate of the patient 10 gradually declines below the mean normative heart rate level recorded while awake, for instance, a heart rate that gradually decreases over a seven-minute period and is then maintained for a non-transitory period of time, the patient 10 is considered to be asleep. In contrast, an abrupt onset of decreased heart rate could be indicative of a bradycardia and not sleep.
In a further embodiment, a minute ventilation sensor 32 can be used to sense sleeping. Minute ventilation is closely tied to heart rate (and HRV) during sleep, as ventilatory volume (tidal volume) and breathing frequency (respiratory rate) decrease synchronously, as does heart rate (and HRV), as the patient falls asleep, then settles into a regular pattern. Tidal volume at rest is measured by the minute ventilation sensor 32. In general, tidal volume at rest is around 0.5 L/min and can increase up to 3.0 L/min at a higher intensity level of exertion. Similarly, respiratory rate at rest is measured by the minute ventilation 32. In general, respiratory rate at rest is around 12 to 16 breathes/min and can increase 40 to 50 breathes/min during maximum levels of activity. A normative activity level while awake can be established, for instance, by taking means of the tidal volume and respiratory rate. If tidal volume and respiratory rate of the patient 10 respectively fall below the mean resting values of tidal volume and respiratory rate, the patient 10 can be considered to be asleep. In a still further embodiment, the heart rate sensor 31 can be used in combination with the minute ventilation sensor 32.
In a still further embodiment, an accelerometer 33 can be used to identify periods of sleep and wakefulness. A normative activity level while awake can be established, for instance, by sensory inputs that can be used to determine the patient's posture and rate of movement. If the patient assumes a recumbent posture and the rate of three-dimensional movement significantly decreases, the patient 10 can be considered to be asleep.
In a yet further embodiment, the neurostimulator 12 can use a multiple forms of sensory data in determining whether the patient 10 is asleep. For instance, the accelerometer 33 can be used in combination with the minute ventilation sensor 32 as a blended sensor, which can correlate patient activity level with respiratory response. Still other measures and indications of patient sleeping and wakefulness are possible. As well, the neurostimulator 12 can assign more weight to one type of sensory data over other types of sensory data. For example, more weight can be assigned to accelerometer 33 data, which would discount a rise in heart rate that occurs while the patient 10 remains recumbent and otherwise still. Other ways of preferentially weighting the data are possible.
If the physiological, metabolic or physical state indicates that the patient 10 has not fallen asleep (step 75), the delivery of the maintenance dose (step 73) normally continues and patient's state is checked periodically (step 74). If the monitored state is indicative of the patient 10 having fallen asleep (step 75), the delivery of the maintenance dose is ordinarily suspended (step 76) for two reasons. First, heart rate naturally decreases during sleep. Delivery of the maintenance dose can be cumulative to the body's natural nocturnal reduction in heart rate and needlessly depletes the neurostimulator's primary battery 23 or other onboard power source. Second, suspending the maintenance dose avoids potentially causing bradycardia by continuing therapy into a period of naturally decreased heart rate during which further reduction of heart rate is undesirable.
Following the suspension of the maintenance dose delivery (step 76), as applicable, a set of optional VNS therapeutic protocols can be followed. One set of protocols (steps 78-82) addresses bradyarrhythmia followed by tachyarrhythmia as occurring during NREM sleep, while a second set of protocols (steps 83-84) deals with CSA and, in particular, episodes of Cheyne-Stokes respiration. Still other sets of sleep- and non-sleep-related protocols are possible.
While asleep, the patient's normative physiology is periodically monitored (step 78). In one embodiment, VNS stimulation remains suspended throughout the period of sleep, absent a tachyarrhythmic episode, which ensures that VNS therapy, particularly delivery of the maintenance dose, will not contribute to or possibly cause bradyarrhythmias. In a further embodiment, a sleep dose of VNS is delivered in place of the maintenance dose (step 77). The sleep dose is parametrically defined as a lower intensity form of the maintenance dose, as further described infra with reference to FIG. 8, and is delivered during the patient's sleep, particularly during NREM sleep, to help further restoration of cardiac autonomic balance. The sleep dose is both preventative and precautionary. Even though heart rate (and HRV) naturally drops during sleep, heart rate (and HRV) could also therapeutically decrease in response to the sleep dose delivery.
The first set of protocols (steps 78-82) applies during NREM sleep. Throughout the period of sleep, the patient's normative physiology while sleeping is assessed for a presence of a condition indicative of sinus bradycardia or sinus pause (step 79). During NREM sleep, a decreased heart rate develops as sympathetic activation is naturally withdrawn, and, in response, benign sinus bradycardia and sinus pauses normally occur. However, patients suffering from CHF or other forms of CCD face an increased risk of experiencing bradyarrhythmia, with follow-on hyperventilation as the body reacts to decreased blood oxygen level. In turn, the hyperventilation can trigger tachyarrhythmic episodes. As an initial precaution, the optional delivery of the sleep dose, if applicable, is suspended (step 80). The patient's normative physiology is also evaluated for a presence of a condition indicative an onset of possible tachyarrhythmia (step 81). For instance, if heart rate significant increases, say, in excess of 180 bpm or more, the patient 10 may be suffering an onset of a tachyarrhythmia. If appropriate, a boost dose of therapeutic VNS is then delivered (step 82), as further described infra with reference to FIG. 7.
The second set of protocols (steps 83-84) deals with the type of CSA known as Cheyne-Stokes respiration, which is most commonly associated with CHF or stroke. FIG. 6 is a graph showing, by way of example, a Cheyne-Stokes respiration pattern 90. The x-axis represents time 91. The y-axis represents respiration amplitude 92. Cheyne-Stokes respiration is characterized by periodic episodes of central apnea 93 and hyperpnea 95, which is interleaved between gradual waxing 97 and waning 98 of tidal volume. The condition can occur at any time, both during sleep and when awake. During each apneic episode 93, breathing stops 94 entirely for about 30 seconds to two minutes, which causes an increase in blood carbon dioxide level. Thereafter, breathing gradually resumes with compensatory hyperventilation 96 followed by gradual cessation, which obversely causes a decrease in blood carbon dioxide level. The oscillation in blood carbon dioxide levels seems to prompt the cyclic swings between apnea and hyperventilation.
The definitive physiological affect of Cheyne-Stokes respiration on CCD is unsettled, yet the condition does appear to exacerbate the excessive sympathetic nervous system activity that accompanies CHF due to apnea-related hypoxia and arousals from sleep, and the characteristic hyperventilation and low blood oxygen levels occurring in Cheyne-Stokes respiration would seem to contribute to a presumptively increased risk of tachyarrhythmia. Referring back to FIG. 5, The patient's normative physiology is evaluated for periodic breathing patterns indicative of Cheyne-Stokes respiration (step 83), using, for instance, a minute ventilation sensor 32. If presented, a boost dose of therapeutic VNS is then delivered (step 84), as further described infra with reference to FIG. 7. Note that in distinction to the first set of protocols (steps 78-82), the second set of protocols (steps 83-84) focus primarily on respiratory response, and not necessarily heart rate (or HRV) as an indicator of therapeutic intervention.
In CHF patients, tachyarrhythmias are of grave concern due to the increased potential for AF, VT, VF, and atrial flutter. The boost dose is delivered at a higher intensity than the maintenance dose and is intended to “break” the tachyarrhythmic condition. FIG. 7 is a flow diagram showing a routine 100 for delivery a boost dose in response to an occurrence of tachyarrhythmia for use with the method 70 of FIG. 5. In addition to the potential of bradyarrhythmia followed by tachyarrhythmia as occurring during NREM sleep, both obstructive and central sleep apneas can also potentially trigger arrhythmias. OSA is caused by an occlusion of the upper airways, with the sequela hypoxia being capable of triggering bradyarrhythmias. The patient makes strenuous ventilatory efforts during an apneic episode, and a significant spike in peripheral sympathetic activity occurs as the hypoxia worsens. In a CHF patient, the sympathetic spike can trigger tachyarrhythmia upon resumption of respiration. Similarly, patients with CSA, which is caused by central ventilatory control defects, experience an increased heart rate (and HRV) during periods of hyperpnea that follow apneic episodes and are consequentially at increased risk of developing tachyarrhythmias upon resumption of respiration. Delivery of the boost dose is intended to respond to all of these conditions.
If a sleep dose was being delivered to the patient 10, the sleep dose is suspended (step 101). Delivery of the maintenance dose is resumed (step 102). Recall that the maintenance dose, even though delivered at an intensity that is insufficient to elicit pathological or acute physiological side effects and without the requirement of an enabling physiological feature or triggering physiological marker, works to directly restore autonomic balance by engaging both medullary and cardiovascular reflex control components of the autonomic nervous system, so resuming delivery of the maintenance dose as an initial response to the possible occurrence of tachyarrhythmia is appropriate.
Thereafter, the patient's normative physiology is periodically checked (step 103). If the potential tachyarrhythmic condition is responding to the VNS stimulation (step 104), the routine 100 ends with the delivery of the maintenance dose resumed. However, if the condition is not responding (step 104), the patient 10 may be suffering onset of a tachyarrhythmia and a higher intensity boost dose of VNS that is tuned to prevent initiation of or disrupt tachyarrhythmia is delivered (step 105), such as described in commonly-assigned U.S. patent application, entitled “Implantable Neurostimulator-Implemented Method for Managing Tachyarrhythmias through Vagus Nerve Stimulation,” cited supra. Non-responsiveness can occur due to continuing heart rate elevation, which can present as no appreciable change in heart rate (or HRV), insufficient heart rate (or HRV) decrease, or non-transitory increase in heart rate. More generally, the onset or presence of pathological tachyarrhythmia can be determined by heart rate or rhythm, as well as rhythm stability, onset characteristics, and similar rate and rhythm morphological indicators, as conventionally detected in cardiac rhythm management devices, such as described in K. Ellenbogen et al., “Clinical Cardiac Pacing and Defibrillation,” Ch. 3, pp. 68-126 (2d ed. 2000), the disclosure of which is incorporated by reference.
If the tachyarrhythmia is not responding to the boost dose delivery after multiple checks (step 106), the intensity of the boost dose is gradually increased (step 107). Depending upon the patient's heart response trajectory, the intensity of the boost dose can be progressively increased by the same or similar amount each cycle (step 105-107), or for life-threatening or paroxysmal arrhythmias, a stronger boost dose of significantly higher intensity can be used right away (step 105), due to the lack of time to progressively ramp up the intensity. In one embodiment, the stronger boost dose delivery maximizes the VNS stimulation by delivering the maximum intensity of stimulation that the neurostimulator 12 can produce, that is, at full output current or capacity.
In a still further embodiment, delivery of the boost dose, as well as the stronger boost dose, can be manually triggered, increased, decreased, or suspended by providing the neurostimulator 12 with a magnetically-actuated reed switch, which can be triggered by the patient 10 using an external magnet, electromagnetic controller, or similar device. In addition, the delivery of the sleep dose, boost dose, and the maintenance dose can also be manually triggered or swapped. For instance, the reed switch can be triggered by the patient 10 when the maintenance dose is tolerable, while the boost dose is intolerable. Other uses of the switch are possible.
The recordable memory 29 in the electronic circuitry 22 of the neurostimulator 12 (shown in FIG. 2A) stores the stimulation parameters that programmatically control the overall functionality of the pulse generator 11 in providing VNS therapy. FIG. 7 is a flow diagram showing a routine 90 for storing operating modes for use with the method 70 of FIG. 5. At least three operating modes are stored, which include a maintenance dose of VNS tuned to restore cardiac autonomic balance (step 101) through continuously-cycling, intermittent and periodic electrical pulses. The autonomic regulation therapy is provided in a low level maintenance dose independent of cardiac cycle to activate both parasympathetic afferent and efferent neuronal fibers in the vagus nerve. The neurostimulation in the maintenance dose is delivered bi-directionally and at an intensity that is insufficient to elicit pathological or acute physiological side effects and without the requirement of an enabling physiological feature or triggering physiological marker. In one embodiment, in the maintenance dose, a pulse width in the range of 250 to 500 μsec delivering between 0.02 and 1.0 mA of output current at a signal frequency in the range of 5 to 20 Hz, and a duty cycle of 5 to 30%, although other therapeutic values could be used as appropriate.
In contrast, conventional approaches to delivering VNS rely on pulse stimulation of an intensity that is sufficiently strong to “coerce” a behavioral modification of the subject's physiology, that is, directly producing a physiological effect, or the measurement of an enabling physiological feature, such as for purposes of timing stimulation delivery, to confirm therapeutic effect, or other ends. For instance, Sabbah et al., cited supra, discloses preferential stimulation of efferent vagus nerve fibers leading to the heart while blocking afferent neural impulses to the brain using unidirectional activation with an output current in the range of 1-2 mA required to elicit the potentially beneficial effect of vagal stimulation. They observe that a higher output current, while desirable to recruit a larger proportion of B-type nerve fibers, is not feasible due to side effects. Moreover, they caution that non-unidirectional vagal stimulation of lower threshold fibers could lead to uncontrolled effects arising from propagation of neural activation towards the cranium. Similarly, Craig, cited supra, Craig discloses synchronization of vagus nerve stimulation with a physiological cycle, such as the cardiac or respiratory cycle, of a patient. They suggest that the efficacy of the exogenous electrical signal may be improved if the pulses are triggered while the patient is performing paced breathing. Thus, as based on a correlation between respiration-related HRV, electrical stimulation is applied to the vagus nerve at a selected point in the physiological cycle correlated with increased afferent conduction (and not correlated with increased efferent conduction) on the vagus nerve.
In addition, a sleep dose, tuned to a lower intensity than the maintenance dose, is defined (step 102). In one embodiment, the sleep dose uses a pulse width in the range of 250 to 500 μsec delivering between 0.01 and 0.2 mA of output current at a signal frequency in the range of 5 to 20 Hz, and a duty cycle of 5 to 30%, although other therapeutic values could be used as appropriate.
Finally, a boost dose, tuned to prevent initiation of or disrupt tachyarrhythmia, is defined (step 103) through periodic electrical pulses delivered at higher intensity than both the maintenance and sleep doses. Different boost doses can be provided to respond to different tachyarrhythmic events. The boost dose settings are physician-programmable. In one embodiment, for a default boost dose, the stimulation parameters would be in the same range as the maintenance dose, but would be moderately higher, with a pulse width again in the range of 250 to 500 μsec delivering between 1.5 and 2.0 mA of output current at a signal frequency in the range of 5 to 20 Hz. The duty cycle may change significantly from nominally 10% to temporarily 50% or 100%, although other therapeutic values could be used as appropriate. For non-life-threatening or non-paroxysmal tachyarrhythmias, the intensity of the boost dose is progressively increased over time by increasing output current, duty cycle, or frequency, lengthening pulse width, or through a combination of the foregoing parameters. Discretely-defined boost doses, each using different parameters sets, may be delivered in the course of treating a single continuing tachyarrhythmic event, such as for life-threatening or paroxysmal arrhythmias that rapidly generate and require a significantly stronger boost dose with no ramp up time.
In a further embodiment, the suspension and resumption of the maintenance, sleep, and boost doses can be titrated as applicable to gradually withdraw or introduce their respective forms of VNS.
While the invention has been particularly shown and described as referenced to the embodiments thereof, those skilled in the art will understand that the foregoing and other changes in form and detail may be made therein without departing from the spirit and scope.

## Claims

1. An implantable neurostimulator-implemented method for managing tachyarrhythmic risk accompanying central sleep apnea through vagus nerve stimulation, comprising the steps of:
providing an implantable neurostimulator comprising a pulse generator configured to deliver electrical therapeutic stimulation in a manner that results in creation and propagation (simultaneously in both afferent and efferent directions) of action potentials within neuronal fibers comprising a patient's cervical vagus nerve;
storing operating modes of the pulse generator in a recordable memory, comprising:
parametrically defining a maintenance dose of the electrical therapeutic stimulation tuned to restore cardiac autonomic balance through continuously-cycling, intermittent and periodic electrical pulses at an intensity that avoids acute physiological side effects and with an unchanging cycle not triggered by physiological markers; and
parametrically defining a boost dose of the electrical therapeutic stimulation tuned to prevent initiation of or disrupt tachyarrhythmia through periodic electrical pulses delivered at higher intensity than the maintenance dose;

therapeutically delivering the maintenance dose to the vagus nerve independent of cardiac cycle via a pulse generator comprised in the implantable neurostimulator through at least a pair of helical electrodes electrically coupled to the pulse generator via a nerve stimulation therapy lead; and
monitoring the patient's physiological state via at least one sensor comprised in the implantable neurostimulator, and upon sensing a pattern indicative of Cheyne-Stokes respiration, delivering the boost dose to the vagus nerve via the pulse generator through the pair of helical electrodes.

2. A method according to claim 1, further comprising the steps of:
monitoring the patient's physiological state while awake via at least one sensor comprised in the implantable neurostimulator; and
upon sensing that the patient is asleep, suspending the delivery of the maintenance dose.

3. A method according to claim 1, further comprising the steps of:
upon sensing the pattern indicative of Cheyne-Stokes respiration, initially resuming the delivery of the maintenance dose prior to the delivery of the boost dose.

4. A method according to claim 1, further comprising the steps of:
providing a minute ventilation sensor as the at least one sensor;
periodically sensing the patient's tidal volume and respiratory rate with the minute ventilation sensor; and
confirming that the pattern is indicative of Cheyne-Stokes respiration when the patient's tidal volume and respiratory rate gradually wax, peak and wane in a periodic pattern.

5. A method according to claim 1, further comprising the step of:
progressively intensifying the electrical therapeutic stimulation as specified in the operating mode of the boost dose as the condition indicative of tachyarrhythmia continues.

6. A method according to claim 5, further comprising the step of:
maximizing the intensity of the electrical therapeutic stimulation as specified in the operating mode when the condition indicative of tachyarrhythmia fails to respond to the intensified electrical therapeutic stimulation.

7. A non-transitory computer readable storage medium storing code for executing on an implantable neurostimulator to perform the method according to claim 1.

8. An implantable neurostimulator-implemented apparatus for managing tachyarrhythmic risk accompanying central sleep apnea through vagus nerve stimulation, comprising the steps of:
means for providing an implantable neurostimulator comprising a pulse generator configured to deliver electrical therapeutic stimulation in a manner that results in creation and propagation (simultaneously in both afferent and efferent directions) of action potentials within neuronal fibers comprising a patient's cervical vagus nerve;
means for storing operating modes of the pulse generator in a recordable memory, comprising:
means for parametrically defining a maintenance dose of the electrical therapeutic stimulation tuned to restore cardiac autonomic balance through continuously-cycling, intermittent and periodic electrical pulses at an intensity that avoids acute physiological side effects and with an unchanging cycle not triggered by physiological markers; and
means for parametrically defining a boost dose of the electrical therapeutic stimulation tuned to prevent initiation of or disrupt tachyarrhythmia through periodic electrical pulses delivered at higher intensity than the maintenance dose;

means for therapeutically delivering the maintenance dose to the vagus nerve independent of cardiac cycle via a pulse generator comprised in the implantable neurostimulator through at least a pair of helical electrodes electrically coupled to the pulse generator via a nerve stimulation therapy lead; and
means for monitoring the patient's physiological state via at least one sensor comprised in the implantable neurostimulator, and upon sensing a pattern indicative of Cheyne-Stokes respiration, delivering the boost dose to the vagus nerve via the pulse generator through the pair of helical electrodes.