WO2010027993A2

WO2010027993A2 - Systems for stimulation of the cholinergic anti-inflammatory pathway via a superior vena cava lead

Info

Publication number: WO2010027993A2
Application number: PCT/US2009/055655
Authority: WO
Inventors: James William Broderick; Michael Allen Faltys
Original assignee: Setpoint Medical Corporation
Priority date: 2008-09-05
Filing date: 2009-09-02
Publication date: 2010-03-11
Also published as: WO2010027993A3

Abstract

Described herein are devices, systems and methods for stimulation of the cholinergic anti-inflammatory pathway (CAP). In particular the devices and systems described herein are for intravascular stimulation of the CAP via the right vagus nerve by stimulating through the superior vena cava with minimal cardiac side effects. The systems described herein typically include one or more electrode leads configured to stimulate the cholinergic anti-inflammatory pathway (e.g., the vagus nerve) from a position within the patient's superior vena cava (SVC). The lead may include one or more electrodes and an anchor for securing the lead. The system may also include an implantable therapy administrator ("ITA") to which the lead may be connected. The ITA may be configured as a controller for controlling the stimulation applied. These devices and/or systems may also be referred to as "immune system pacemakers".

Description

SYSTEMS FOR STIMULATION OF THE CHOLINERGIC ANTI-INFLAMMATORY PATHWAY VIA A SUPERIOR VENA CAVA LEAD

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to USSN 61/191,188 entitled SYSTEMS FOR

STIMULATION OF THE CHOLINERGIC ANTI-INFLAMMATORY PATHWAY VIA A SUPERIOR VENA CAVA LEAD filed September 5, 2008 and USSN 61/101,625 entitled SYSTEMS FOR STIMULATION OF THE CHOLINERGIC ANTI-INFLAMMATORY PATHWAY VIA A SUPERIOR VENA CAVA LEAD filed September 30, 2008.

INCORPORATION BY REFERENCE

[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

BACKGROUND OF THE INVENTION

[0003] Inflammation is a complex biological response to pathogens, cell damage, and/or biological irritants. Inflammation may help an organism remove injurious stimuli, and initiate the healing process for the tissue, and is normally tightly regulated by the body. However, inappropriate or unchecked inflammation can also lead to a variety of disease states, including diseases such as hay fever, atherosclerosis, arthritis (rheumatoid, bursitis, gouty arthritis, polymyalgia rheumatic, etc.), asthma, autoimmune diseases, chronic inflammation, chronic prostatitis, glomerulonephritis, nephritis, inflammatory bowel diseases, pelvic inflammatory disease, reperfusion injury, transplant rejection, vasculitis, myocarditis, colitis, etc. In autoimmune diseases, for example, the immune system inappropriately triggers an inflammatory response, causing damage to its own tissues.

[0004] Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.

[0005] The nervous system, and particularly the Vagus nerve, has been implicated as a modulator of inflammatory response. The Vagus nerve is part of an inflammatory reflex, which also includes the splenic nerve, the hepatic nerve and the trigeminal nerve. The efferent arm of the inflammatory reflex may be referred to as the cholinergic anti-inflammatory pathway. For example, Tracey et al., have previously reported that the nervous system regulates systemic inflammation through a Vagus nerve pathway. This pathway may involve the regulation of inflammatory cytokines and/or activation of granulocytes. Thus, it is believed that appropriate modulation of the Vagus nerve may help regulate inflammation.

[0006] Systems for stimulating one or more nerves of the cholinergic anti-inflammatory pathway ("CAP") may include one or more electrical leads which may be implanted acutely or chronically, and may be positioned sufficiently near or in contact with the Vagus nerve or other nerves of the cholinergic anti-inflammatory pathway. [0007] Currently available systems for stimulating nerves, including vagus nerve stimulators, are generally not appropriate for stimulation of the cholinergic anti-inflammatory pathway in order to regulate inflammation. For example, the configuration of the electrodes and particularly the configuration of the stimulators used with the electrodes used to control the level, duration and frequency of stimulation, are generally unfit for appropriately inhibiting or modulation the inflammatory response (e.g., without desensitizing the inflammatory reflex). [0008] Thus, there is a need for devices, systems and methods configured to appropriately modulate the cholinergic anti-inflammatory pathway without desensitizing the anti-inflammatory response of the cholinergic anti-inflammatory pathway. Described herein are devices, methods and systems which may address these needs.

SUMMARY OF THE INVENTION

[0009] Systems and devices for stimulation of a patient's cholinergic anti-inflammatory pathway may include an electrical lead that is configured to be implanted and secured so that the electrical contacts are positioned in a patient's vasculature (e.g., in the vena cava) in parallel with the subject's descending vagus nerve, and distally connected to an implantable therapy administrator. Method of implanting such devices typically include inserting the lead through the subclavian vein, positioning the electrical contacts on the lead in the superior vena cava, and connecting the device to a therapy administrator (controller) that is configured to stimulate the cholinergic anti-inflammatory pathway via stimulation of the descending vagus nerve specifically, so that other branches of the vagus nerve are not stimulated sufficiently to depress the heart rate or cause muscle twitch.

[0010] For example, described herein are methods of implanting a system for stimulation of a patient's cholinergic anti-inflammatory pathway, the method comprising: inserting an electrical lead through the patient's left brachiocephalic vein and into the superior vena cava; anchoring the electrical lead so that an electrical contact on the electrical lead is positioned within the superior vena cava approximately parallel to the vagus nerve; and connecting the electrical lead to an implantable therapy administrator configured to apply stimulation sufficient to activate the patient's cholinergic anti-inflammatory pathway. [0011] The step of anchoring may further comprises anchoring the distal end of the electrical lead within the patient's heart. In some variations, the step of anchoring further comprises withdrawing the portion of the lead having the electrical contact from the heart and into the superior vena cava while leaving the anchor within the heart. [0012] The method may also include monitoring EKG to determine when the electrical contact has been withdrawn from the heart. The method may be further extended by initiating Bradycardia through the vagus nerve by stimulating at a value greater than 2mA to assure vagus nerve stimulation

[0013] In general, the methods of implanting may also include the step of activating the patient's cholinergic anti-inflammatory pathway by applying a stimulus of less than 10 mA (e.g., less than 2 mA) from the electrical contact on the lead.

[0014] The stimulation may be triggered based on the EKG. In particular, the stimulation may be triggered during the refractory period of the heart, and especially the sinoatrial (SA) node or other pacemaking region of the heart (e.g., AV node, etc.). Applying stimulation during the refractory period may allow stimulation of the vagus nerve while avoiding undesirable cardiac effects. The entire stimulation period for the devices and systems described herein may be applied during this refractory period.

[0015] Also described herein are methods of implanting a system for stimulation of a patient's cholinergic anti-inflammatory pathway, the method comprising: inserting an electrical lead through a patient's left brachiocephalic vein, wherein the lead comprises an elongate flexible member having a plurality of electrical contact positioned proximal to the distal end and a lumen therethrough; engaging an anchor in the patient's heart by exposing an anchoring guidewire from the lumen of the lead near the distal end of the lead; withdrawing the lead from the patient's heart so that the plurality of electrical contacts are outside of the patient's heart and within the superior vena cava; and connecting the lead to a controller configured to apply stimulation sufficient to activate the patient's cholinergic anti-inflammatory pathway. [0016] The step of engaging the anchor may include engaging the anchoring guidewire in the patient's right atrial appendage, hi some variations, the step of engaging the anchor comprises engaging the anchoring guidewire in the patient's right ventricle. [0017] The step of partially withdrawing the lead may include monitoring the patient's EKG from the movable electrical contacts to determine when the right atrial/ventricular EKG has changed shape indicating that the lead has left the heart. The morphology of an EKG (e.g., intracardiac EKG) is characteristic based on the position of the electrode detecting the EKG relative to different regions of the heart, as is well known in the art. In some variations, the step of connecting the lead comprises connecting the lead to an implantable therapy administrator allowing the system to be adjusted and tested before the patient is closed.

[0018] The methods described herein may also include the step of implanting an implantable therapy administrator.

[0019] Also described herein are systems for activating a patient's cholinergic antiinflammatory pathway. For example, these systems may include: an elongate, flexible electrical lead including a plurality of electrical contacts positioned proximal to the distal end of the active lead, a proximal end adapted for connection to an implantable therapy administrator, an anchor configured to secure the electrical contacts within the superior vena cava; and an implantable therapy administrator configured to apply stimulation from the electrical contacts sufficient to activate the cholinergic anti-inflammatory reflex without slowing the heart rate or causing muscle twitch, wherein the implantable therapy administrator is further configured to limit the applied stimulation to less than 10 mA (e.g., less than 2 mA) for therapeutic purposes. In some variations, the anchor is an anchoring guidewire configured to extend from a lumen of the elongate flexible lead. [0020] Also described herein are systems for activating a patient's cholinergic anti- inflammatory pathway, the system including: an elongate, flexible electrical lead including a central lumen having an opening at the distal end and a plurality of electrical contacts positioned proximal to the distal end of the lead; an anchoring guidewire configured move within the central lumen of the lead, wherein the lead and the anchoring guide are configured so that the distal end of the anchoring guidewire may be anchored within the patient's heart, while the electrical contacts of the lead are positioned within the superior vena cava; and an implantable therapy administrator configured to apply stimulation from the electrical contacts sufficient to activate the cholinergic anti-inflammatory reflex without slowing the heart rate or causing muscle twitch, wherein the implantable therapy administrator is further configured to limit the applied stimulation to less than 10 mA (e.g., less than 2 mA). BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 shows a conventional cardiac pacemaker

[0022] FIG. 2 A the anatomic relation of the heart and the vagus nerve, and FIG. 2B illustrates one variation of an immune system pacemaker implanted in relation to the anatomy illustrated in FIG. 2A.

[0023] FIG. 3 A is an anterior view of the anatomy of the heart and vessels, and FIG. 3 C illustrates one variation of an immune system pacemaker implanted in relation to the anatomy shown in FIG. 3A.

[0024] FIG. 3B is a posterior view of the anatomy of the vessels and right vagus nerve, and FIG. 3D illustrates one variation of an immune system pacemaker implanted in relation to the anatomy shown in FIG. 3B.

[0025] FIG. 4 illustrates one variation of an immune system pacemaker implanted in the superior vena cava.

[0026] FIGS. 5A-5D illustrate various configurations of implantable leads for use herein. [0027] FIGS. 6A and 6B illustrate the stimulation of the vagus nerve using a superior vena cava lead as described herein.

[0028] FIG. 7 illustrates one method of using an immune system pacemaker, as described herein.

[0029] FIG. 8 A and FIG. 8C illustrate the method of implanting an immune system pacemaker which is described in the flowchart of FIGS. 8B, 8D and 8E (Steps 1-8).

[0030] FIGS. 9A-9D illustrate another variation of a lead which may be used. FIG. 9 A shows a perspective view of a lead, and FIG. 9B shows a partial cut-away view of the lead.

FIGS. 9C and 9D show enlarged perspective views of two regions of the lead.

[0031] FIG. 10 illustrates another variation of a lead. [0032] FIG. 11 illustrates another variation of a lead.

[0033] FIG. 12 illustrates another variation of a lead.

DETAILED DESCRIPTION OF THE INVENTION

[0034] Described herein are devices, systems and methods for stimulation of the cholinergic anti-inflammatory pathway. In particular the devices and systems described herein are for intravascular stimulation of the CAP via the right vagus nerve by stimulating through the superior vena cava with minimal cardiac side effects. The systems described herein typically include one or more electrode leads configured to stimulate the cholinergic anti-inflammatory pathway (e.g., the vagus nerve) from a position within the patient's superior vena cava (SVC). The lead may include one or more electrodes and an anchor for securing the lead. The system may also include an implantable therapy administrator ("ITA") to which the lead may be connected. The ITA may be configured as a controller for controlling the stimulation applied. These devices and/or systems may also be referred to as "immune system pacemakers". [0035] In general, the systems and devices described herein may be implanted in a patient so that the electrode(s) of are positioned within the patient's superior vena cava for stimulation of the appropriate region of the cholinergic anti-inflammatory pathway. For example, FIG. 1 illustrates a conventional single-channel cardiac pacemaker. The immune systems pacemakers described herein may be positioned similarly in that the controller (ITA) portion may be implanted subcutaneously in the infraclavicular region, under the pectorial muscle, or inframammallarially, so that the electrode lead may connect to the ITA and pass through the cephalic, axillary, and/or left subclavian vein, and extend into the superior vena cava. The lead may be anchored distally. For example, the lead may be anchored by securing the distal end of the lead in either a right atrial appendage or within the right ventricle.

[0036] The goal of these immune system pacemakers is to reliably produce chronic, intravascular neurostimulation of the cholinergic anti-inflammatory pathway (CAP). The devices and systems described herein may be positioned by a doctor, surgeon, or the like (and particularly an interventional cardiologist). Because they have been adapted for implantation similar to a cardiac pacemaker (see FIG. 1 , above), the overall system may be familiar, although there are significant differences (particularly with respect to the configuration of the system and the placement of the electrodes), as described in greater detail below. [0037] In operation, the system is implanted into the patient by first inserting and calibrating and anchoring the electrical lead. Insertion and calibration of the electrodes and the electrode leads may be optimized during a trial or pre-implantation phase, during which feedback from the patient's immune response may be considered. This is also described in greater detail below. Once a lead has been positioned (and anchored), the lead may be connected to a controller (ITA) for chronic use. [0038] The devices and systems described herein take advantage of the fact that that the portion of the cholinergic anti-inflammatory pathway targeted for stimulation of some variations of these devices and systems is the region of the vagus nerve that is parallel to the superior vena cava, allowing stimulation from the SVC that is oriented correctly (or as desired). In addition, blood in the superior vena cava can be used to create a conduction pathway that radiates from the lead in the SVA to the vagus nerve. [0039] For example, FIG. 2A illustrates a typical patient anatomy with respect to the heart and vagus. In this variation it is apparent that a portion of the vagus nerve (cranial nerve X) extends parallel to the superior vena cava. This portion of the vagus nerve includes a region of the descending vagus nerve that extends toward the celiac ganglia, and includes branches descending to the spleen and liver. This region runs near the posterior aspect of the superior vena cava. Further, this region is believed to be inferior to region of the vagus nerve that impacts heart rate (the cardiac branches) in the area of the great vessels. The devices and systems described herein are configured specifically to stimulate the inflammatory reflex by acting on the nerves of the descending vagus nerve extending towards the celiac ganglia. [0040] FIG. 2B shows the same anatomical region of FIG. 2A, but with an dashed line

203 indicating one possible region into which an immune system pacemaker lead (and controller 205) could be implanted via the superior vena cava.

[0041] FIGS. 3A and 3B show alternative partial views of this anatomical region. For example, FIG. 3 A shows an anterior view of the heart and great vessels, including the superior vena cava, and FIG. 3B illustrates a posterior view of the great vessels and the right vagus nerve. FIGS. 3 C and 3D, respectively, illustrate (via lines 303, 305) one possible region for implantation of an immune system pacemaker including the lead 303 and controller 305. [0042] FIG. 4 illustrates one variation of an immune system pacemaker. In FIG. 4, the immune system pacemaker includes a multi-electrode lead and a controller. The lead includes a flexible elongate body, a distal anchor region, and a proximal sheath. The lead is configured so that the electrodes are located proximally along the lead from the distal (anchor) region so that they are within the superior vena cava, but not the heart, while the anchor region extends either to a right atrial appendage or to the right ventricle apex anchor point. The proximal portion of the lead is configured to connect to the implantable therapy administrator (controller or ITA). [0043] This system is configured so that the lead may be introduced through the sublavian vein and anchored in the right atrium or ventricle. The contacts (electrodes) may be aligned in parallel to the vagus nerve alongside the superior vena cava, and then positioned within the superior vena cava by retracting or advancing them outside of the right atrium. The controller (ITA) is configured so that it can be implanted in a subclavicular pocket, wherein it can provide stimulation energy to the lead and monitor cardiac activity or other sensor input.

Electrical Lead

[0044] The electrical leads may be multipolar electrical leads. For example, FIG. 4-5D illustrate one variation of a multipolar electrical lead having four active surfaces (electrodes). For example, in FIG. 5A shows a lead including a carrier 501 having four contacts (electrodes) 503 along the outer circumference, and a central lumen. An anchoring guide- wire 510 is held within the central lumen. The distal end of the guidewire may include an anchor structure, shown here as a curved region which may engage the tissue. Other anchor regions may include screws, tines, hooks, expanding members, or the like. The anchoring region may be movably positioned in the lumen of the sheath 501, so that the anchor can be withdrawn into the sheath 501 as the lead is inserted into the patient, e.g., FIG. 5B, and then extended from the lead to be anchored once the distal end of the lead is near the anchoring point, e.g., FIG. 5C. Furthermore, the electrode contacts 503 can be positioned appropriately within the superior vena cava after anchoring, as illustrated in FIG. 5D. For example, the electrodes may be monitored to detect an right atrial/ventricular EKG, and withdrawn from the heart into the superior vena cava until the right atrial/ventricular EKG indicates the electrode has left the heart. This may give an approximate indication of the placement. Direct visualization (e.g., using fluoroscopy) may also be used. [0045] Other configurations of electrical leads may also be used. In one variation, the electrical lead is configured as a linear array that is anchored or positioned directly against the posterior wall of the superior vena cava near the region of the descending vagus nerve of interest. For example, a preformed or stressed wire may be used to secure the lead against the vagus nerve in addition, or instead of, the distal anchor. [0046] Another variation of a lead which may be used is a basket electrode, or a fixed segmented basket electrode. For example, the lead may include a plurality of ribs that extend outwards; each rib (or a subset of ribs) may form a bipolar electrode pair. The ribs may also anchor (or help anchor) the device. Alternatively, in one variation, the lead is configured as a friction anchored helix. [0047] Although the figures illustrate multi-polar electrodes, monopolar electrodes may also be used. For example, in some variations, the lead includes monopolar wires. Multiple monopoles may be used, or a single monopolar contact may be used. [0048] The size and shapes of the contacts may also be varied depending on the embodiment desired. For example, in some variation the electrode contacts on the lead are relatively large, and may extend annularly around the lead (e.g., as ring electrodes). [0049] Similarly, any appropriate size and shape lead may be used. For example, the lead in this example has an outer diameter that is less than about 6F. [0050] In general, the leads described herein are MRI compatible. For example, the anchoring lead is typically conductive, in this case the anchor in the heart is isolated from any long conductive path to greatly reduce charge inducted by the dynamic RF field. Contacts may be low impedance and circumferential so to shunt charge though the plasma to remove excess charge concentration on a fixed tissue site during the procedure. Lead contacts may be tuned so that they do not resonate at appropriate range of RF fields used for imaging (e.g., 1.5 T at 57 MHz). Low impedance contacts combined with low NCAP (nicotinic cholinergic anti- inflammatory pathway) thresholds may remove the requirement for magnetic components in the implant since only low voltages will be required for stimulation.

Configuration of the ITA

[0051] In general, the ITA is the controller for the immune system pacemakers, and may be adapted for use in specific ways. In general, the ITA is configured so that the stimulation applied from the lead is appropriate to inhibit the cholinergic anti-inflammatory without desensitizing the cholinergic anti-inflammatory pathway. Further, the ITA controls the stimulation parameters so that stimulation does not adversely affect the heart. In some variations the ITA receives input from one or more sensors configured to monitor cardiac status. For example, the heart rate, heart rate variability, EKG, etc. These sensors may provide feedback for deciding upon and assessing the applied therapy, and they may also be used as part of a safety mechanism for shutting off stimulation and/or setting maximum stimulation values.

[0052] Although known cardiac rhythm management procedures and techniques may be used to guide implantation and operation of the immune system pacemaker devices and systems described herein, the differences from cardiac pacemakers are reflected in the configuration and operation of the systems. [0053] Furthermore, the inventors believe that the threshold for stimulation of the cholinergic anti-inflammatory pathway is much lower than the threshold required for excitation of the myocardium or of the parasympathetic cardiac control through the vagus nerve. Thus, the immune system pacemakers described herein may require between about 10 and 100 times (or greater) less than the threshold for stimulation of the vagus nerve to provoke cardiac effects such as the suppression or depression of heart rate. For example, the current applied may be less than between about 20 μ A to 200 μA against the vagus nerve, but from 200μA and 2 mA transvenously. Furthermore, the duration of stimulation, as well as the interval between burst of stimulation (or individual pulses of stimulation) may be on the order of hours or days, rather than second and milliseconds. Because of the relative infrequency of stimulation and the low power requirements (e.g., low current/voltage necessary), the ITA can be extremely lightweight, and long-lasting. For example, the required power may be substantially lower than other implantable devices, allowing longer-lasting batteries, or smaller implant size.

[0054] The short stimulation times may allow for significant current required for the relatively remote transvenous stimulation to be used that would be impossible for continuous stimulation applications. Furthermore, the electrical lead/electrodes are typically adapted by including a very large contact surface to allow low-impedance and low-complexity circuits for simulation.

[0055] In some variations the system applies stimulation based on coordination with the heart. For example, the system may be configured to apply stimulation during a refractory period of the hart. The refractory period may be sensed or estimated (e.g., from EKG input) to be the refractory period of the SA node, or other pacemaker region of the heart. Thus, as mentioned, the controller controlling stimulation may include input from sensor or the electrodes competent to sense EKG or other input. [0056] The controller/ITA may be configured as an open-loop or a closed-loop device, and may toggle between these operating modes. For example, the device may be configured to provide stimulation by following one or more pre-determined stimulation regimes. The selection of the stimulation protocol may be based on patient or doctor input, or based on feedback from the device. In some variations the stimulation protocol applied is responsive to one or more sensors (e.g., monitoring heart rate, immune response, etc.). Thus, the controller may include one or more inputs for sensing patient condition (e.g., cardiac condition, temperature, etc.). The controller may also include one or more inputs and/or outputs for communication with a doctor and/or patient. Thus, the device may receive instructions on the stimulation protocol, or may output status or historical reports to monitoring or control devices external to the patient. [0057] In operation, the systems and devices described herein are configured so that the electrical contacts of the lead are positioned in the superior vena cava sufficiently near the descending vagus nerve that stimulation from the electrodes at an appropriate strength, duration and frequency can modulate the inflammation via the cholinergic anti-inflammatory pathway. FIG. 6 shows an exemplary cross-section though a portion of the superior vena cava into which an electrical lead for an immune system pacemaker is passing.

[0058] In the example shown in FIG. 6A, the lead has been anchored at its distal end in the heart (e.g., in the right atrial appendage or alternatively in the right ventricle apex). This anchoring assures that the active contacts will not migrate into the heart, and ensure a stable position within the superior vena cava. The lead includes four contacts that have been positioned outside of the right atrium in the superior vena cava. These four electrodes allow selection of any of six bipolar pairs. Further, in some variations, the contacts may be ganged (e.g., functionally combined) to achieve a larger effective contact surface. The electrodes pairs are positioned in parallel to the right vagus, so that they are orthogonal to the vagus cardiac branches. [0059] FIG. 6B shows an approximate mapping of the electric field based on the arrangement of the electrode within the superior vena cava as shown in FIG. 6A. The field seen by the descending vagus nerve may be attenuated, but still sufficient to activate the cholinergic anti-inflammatory reflex. Exemplary protocols and methods of stimulating the cholinergic anti- inflammatory reflex may be found, for example, in US Patent no. 6,610,713, filed on May 15, 2001 and titled "INHIBITION OF INFLAMMATORY CYTOKINE PRODUCTION BY CHOLINERGIC AGONISTS AND VAGUS NERVE STIMULATION"; pending US Patent Application Serial No. 11/807,493, filed on February 26, 2003 and titled "INHIBITION OF INFLAMMATORY CYTOKINE PRODUCTION BY STIMULATION OF BRAIN MUSCARINIC RECEPTORS"; pending US Patent Application Serial No. 10/446,625, with a priority date of May 15, 2001 and titled "INHIBITION OF INFLAMMATORY CYTOKINE PRODUCTION BY CHOLINERGIC AGONISTS AND VAGUE NERVE STIMULATION"; and pending US Patent Application serial no. 11/318,075, filed on December 22, 2005 and titled "TREATING INFLAMMATORY DISORDERS BY ELECTRICAL VAGUS NERVE STIMULATION"; US Patent Application Serial No. 12/198,808, titled "DEVICES AND METHODS FOR INHIBITING GRANULOCYTE ACTIVATION BY NEURAL STIMULATION"; and US Provisional Patent Application Serial No. 60/982,681, titled "TRANSCUTANEOUS VAGUS NERVE STIMULATION REDUCES SERUM HIGH MOBILITY GROUP BOX 1 LEVELS AND IMPROVES SURVIVAL IN MURINE SEPSIS", herein incorporated by reference in their entirety.

[0060] FIG. 7 provides an overview of one method of inserting and operating an immune system pacemaker. In FIG. 7, the lead for the device may first be inserted as part of a trial period, which may be useful to determine the proper settings and configuration for the immune system pacemaker, or for short-term use. Thereafter, a chronic or long-term device may be implanted, as shown in steps 3-4. A blood sample may be taken prior to inserting the lead (e.g., 20 minutes prior) to get a baseline for inflammatory markers or other indicators of inflammation. During the trial period, the lead is then inserted (e.g., through the subclavian or IJ veins). Insertion may be performed with a stimulating catheter, or directly with the same lead that is appropriate for chronic use. The lead in this example is anchored with the contacts in the superior vena cava, parallel to the descending vagus. The lead may then be connected to the acute stimulator. The acute stimulator is typically an external (external to the patient) stimulator that can be used to stimulate the lead. The lead may initially be stimulated at levels that are below the threshold for side effects such as changes in heart rate morphology or muscle twitching. Stimulation may be performed in a ramp or test parameter to optimize stimulation and position of the electrodes. Blood may be drawn after 20 minutes, then one day after the procedure, and assayed for markers of the inflammatory response. Evaluation of the relevant biomarkers (e.g., cell-surface markers, such as the pro-inflammatory cytokines) may be performed.

[0061] Steps 3 and 4 of FIG. 7 also illustrate implantation of an immune system pacemaker. In step 3, the implantable lead is chronically implanted. As mentioned above, the same lead use for the trial phase or for acute use may be used (e.g., already implanted), or a separate 'chronic' lead may be used. The chronic lead may be anchored by any appropriate method, so that the electrode contacts are properly positioned within the superior vena cava. For example, an anchor at the distal end of the lead may be inserted into the right atrial appendage or the right atrium. Placement within the right atrium may be confirmed by EKG (e.g., using the electrodes on the lead); thereafter the portion of the lead including the electrical contacts may be withdrawn until the EKG indicates that the contacts (electrodes) are out of the atrium and in the superior vena cava. Positioning may be confirmed by stimulating at a high level to trigger chronotopy to indicate that the vagus is being stimulated. The electrical contacts of the lead may then be secured in position. For example, in variations in which the electrical contacts are part of the outer sleeve, the proximal end of this sleeve may be secured (e.g., sutured) or held outside of the subclavial region, e.g., using a suture collar. The position may be adjusted as necessary. Once the lead is positioned, the ITA may be implanted and connected. [0062] Implantation of the system (or components of the system) may be performed by an interventionalist, such as an interventional cardiologist, as indicated in step 5.

[0063] After implantation, the device may be allowed to stimulate as needed to modulate the cholinergic anti-inflammatory reflex. In some variations, as illustrated in step 6 of FIG. 7, the implanted system may also receive instructions or provide output to other devices, including a wireless therapy schedule programmer. Such a programmer may be used to modify or refine therapy using the device. For example, the applied stimulation protocol may be adjusted to optimize therapy. In some variations, the triggering or timing of therapy may be adjusted to control or respond to flare-ups of an inflammatory condition being treated. [0064] FIGS. 8A-8E describe another method of implanting an immune system pacemaker. Fig 8 A illustrates schematically the insertion of a lead similar to the lead shown in FIGS. 5A-5D. In step one (see FIG. 8B), the lead is inserted into the right atrium so that the tip of the lead is within the right atrial appendage. The location may be confirmed with fiuoroscope and/or right atrial EKG, as indicated in step 2. The lead in this example include a central lumen having an anchoring guidewire that is initially (in steps 1-2) retracted. In step 3, the anchor is extended from the lead either by withdrawing the outer sleeve of the lead to expose the anchor region of the guidewire, or by pushing the anchoring region from the lead. Once exposed, the anchor may engage the heart tissue.

[0065] As illustrated in FIG. 8C and described in FIGS. 8D, the outer sleeve of the lead, including the electrical contacts, can then be slid out of the atrium while monitoring EKG using the electrical contacts, as described above. In some variations, the position may then be confirmed by stimulating at a high level to evoke bradycardia, as indicated in step 5 of FIG. 8D.

Thereafter, the electrodes on the lead may be secured in position.

[0066] After the lead has been implanted, it may be first attached to a trail stimulator, as indicated in step 7 of FIG. 8E. The trail stimulator may allow further refinement of the position and/or stimulation protocol to optimize stimulation of the cholinergic anti-inflammatory pathway without stimulating the heart, causing muscle twitch, or other undesirable side-effects.

Thereafter, the lead may be directly attached to a chronic (implanted) stimulator, as described in step 8 of FIG. 8E.

[0067] FIGS. 9A-9D show another variation of an electrical lead that may be used. In FIG. 9 A, the bipolar lead is shown in a perspective view. The lead includes a style portion that includes a handle 15, which may be used to position and anchor the stylet 1. The stylet includes an anchor 5 at the distal end that may be anchored into the heart, as described above. An active lead 11 is slideable over the stylet 1, and includes a plurality of contacts 9 that are bonded on the lead 11. The active lead 11 also includes a suture cuff 13 that may be used to stabilize the lead outside of the vein. Proximal end of the lead includes a connector 14 that is shown as a yoke that connects connectors 10 to the lead 11. The yoke shown in a two-part bipolar embodiment having two connectors 10, however a single bipolar embodiment may be used, having only one connector.

[0068] FIG. 9B shows a partial cross-section through the distal end of the lead shown in FIG. 9 A when the stylet is not extended from the lead. The distal end of the stylet, including the anchor region 5 is within the distal end of the lead, and a cross-section through a portion of the contact region 9 is shown.

[0069] FIG. 9C shows an enlarged view of the specific variation of the connector region shown in FIG. 9 A, and FIG. 9D shows an enlarged view of the suture cuff that may be used. [0070] FIGS. 10- 12 illustrate alternative variations of the electrode leads that may be used. For example, FIG. 10 illustrates a lead including multiple fixed contacts along the length of the lead. In this variation, the lead is not positioned by moving it, but the optimal stimulation electrodes are determined by choosing the electrodes to stimulate with from along the length of the electrode. [0071] In FIG 11, the lead is shown as a lasso catheter/electrode variation, in which the distal region of the lead is curled, allowing it to be positioned around the vein (e.g., the SVC) to apply stimulation. This distal end may be anchored in the SVC. As illustrated, in this variation the optimal set of electrodes to stimulate the vagus nerve may be chosen based on the electrode(s) nearest the target nerve tract ("vn"). The electrode on the surface of the lead may be chosen to minimize the radial component and/or the orthogonal component relative to the vagus nerve.

[0072] FIG. 12 illustrates a variation including a single, large, fixed contact at the distal end of the stylet that is configured to be anchored (e.g., in the heart). One or more moving electrodes may be included on a slideable lead that may be movable (e.g., positionable) over the stylet.

[0073] In addition to the lead variations illustrated above, other lead types may also be used. For example, in some variations the distal end of the lead is not anchored. For example, the lead may be a floating lead that is configured to be placed in the heart and/or the SVC or other region. Any appropriate lead may be used.

[0074] While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

WHAT IS CLAIMED IS:

L A method of implanting a system for stimulation of a patient' s cholinergic antiinflammatory pathway, the method comprising: inserting an electrical lead through the patient's left brachiocephalic vein and into the superior vena cava; anchoring the electrical lead so that an electrical contact on the electrical lead is positioned within the superior vena cava parallel to the vagus nerve; and connecting the electrical lead to an implantable therapy administrator configured to apply stimulation sufficient to activate the patient's cholinergic antiinflammatory pathway.

2. The method of claim 1 , wherein the step of anchoring further comprises anchoring the distal end of the electrical lead within the patient's heart.

3. The method of claim 2, wherein the step of anchoring further comprises withdrawing the portion of the lead having the electrical contact from the heart and into the superior vena cava while leaving the anchor within the heart.

4. The method of claim 3, further comprising monitoring EKG to determine when the electrical contact has been withdrawn from the heart.

5. The method of claim 1 , further comprising activating the patient's cholinergic anti- inflammatory pathway by applying a stimulus of less than 2 mA from the electrical contact on the lead.

6. A method of implanting a system for stimulation of a patient's cholinergic anti- inflammatory pathway, the method comprising: inserting an electrical lead through a patient's left brachiocephalic vein, wherein the lead comprises an elongate flexible member having a plurality of electrical contact positioned proximal to the distal end and a lumen therethrough; engaging an anchor in the patient's heart by exposing an anchoring guidewire from the lumen of the lead near the distal end of the lead; withdrawing the lead from the patient's heart so that the plurality of electrical contacts are outside of the patient's heart and within the superior vena cava; and connecting the lead to a controller configured to apply stimulation sufficient to activate the patient's cholinergic anti-inflammatory pathway.

7. The method of claim 6, wherein the step of engaging the anchor comprises engaging the anchoring guidewire in the patient's right atrial appendage.

8. The method of claim 6, wherein the step of engaging the anchor comprises engaging the anchoring guidewire in the patient's right ventricle.

9. The method of claim 6, wherein the step of withdrawing the lead comprises monitoring the patient's EKG off of the electrical contacts to determine when the EKG can no longer be detected.

10. The method of claim 6, wherein the step of connecting the lead comprises connecting the lead to an implantable therapy administrator.

11. The method of claim 6 further comprising implanting an implantable therapy administrator.

12. The method of claim 6, further comprising activating the patient's cholinergic antiinflammatory pathway by applying a stimulus of less than 2 mA from the electrical contact on the lead.

13. A system for activating a patient's cholinergic anti-inflammatory pathway, the system comprising: an elongate, flexible electrical lead including a plurality of electrical contacts positioned proximal to the distal end of the lead; a proximal end adapted for connection to an implantable therapy administrator; an anchor configured to secure the electrical contacts within the superior vena cava; and an implantable therapy administrator configured to apply stimulation from the electrical contacts sufficient to activate the cholinergic anti-inflammatory reflex without slowing the heart rate or causing muscle twitch, wherein the implantable therapy administrator is further configured to limit the applied stimulation to less than 2 mA.

14. The system of claim 13, wherein the anchor comprises an anchoring guidewire configured to extend from a lumen of the elongate flexible lead.

15. A system for activating a patient's cholinergic anti-inflammatory pathway, the system comprising: an elongate, flexible electrical lead including a central lumen having an opening at the distal end; a plurality of electrical contacts positioned proximal to the distal end of the lead; an anchoring guidewire configured move within the central lumen of the lead, wherein the lead and the anchoring guide are configured so that the distal end of the anchoring guidewire may be anchored within the patient's heart, while the electrical contacts of the lead are positioned within the superior vena cava; and an implantable therapy administrator configured to apply stimulation from the electrical contacts sufficient to activate the cholinergic anti-inflammatory reflex without slowing the heart rate or causing muscle twitch, wherein the implantable therapy administrator is further configured to limit the applied stimulation to less than 2 mA.