US20090076409A1

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Publication number: US20090076409A1
Application number: US12/159,306
Authority: US
Inventors: Andrew Wu; Benjamin J. Clark; Erik Thai; Denise Zarins
Original assignee: Ardian Inc
Current assignee: Medtronic Ardian Luxembourg SARL
Priority date: 2006-06-28
Filing date: 2007-06-28
Publication date: 2009-03-19
Also published as: CN105056408B; ATE536147T1; US20080255642A1; WO2008003058A3; CN103222894A; CN101610735A; US20090062873A1; ATE494040T1; ES2361583T5; EP2218479A3; EP2092957B1; EP2037840A4; EP2037840B2; DE602007011813D1; ES2361583T3; PL2037840T3; EP2218479A2; CN105056408A; US9314644B2; EP2842604A1

Abstract

Methods and system are provided for thermally-induced renal neuromodulation. Thermally-induced renal neuromodulation may be achieved via direct and/or via indirect application of thermal energy to heat or cool neural fibers that contribute to renal function, or of vascular structures that feed or perfuse the neural fibers. In some embodiments, parameters of the neural fibers, of non-target tissue, or of the thermal energy delivery element, may be monitored via one or more sensors for controlling the thermally-induced neuromodulation. In some embodiments, protective elements may be provided to reduce a degree of thermal damage induced in the non-target tissues. In some embodiments, thermally-induced renal neuromodulation is achieved via delivery of a pulsed thermal therapy.

Description

REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of the following pending U.S. patent applications:

(a) U.S. Provisional Patent Application No. 60/880,340, filed on Jan. 12, 2007; and

(b) U.S. Provisional Patent Application No. 60/816,999, filed on Jun. 28, 2006.

The present application is a continuation-in-part application of each of the following co-pending U.S. patent applications:

(a) U.S. patent application Ser. No. 11/599,723, filed on Nov. 14, 2006;

(b) U.S. patent application Ser. No. 11/504,117, filed on Aug. 14, 2006; and

(c) U.S. patent application Ser. No. 11/189,563, filed on Jul. 25, 2005, which is a continuation-in-part application of U.S. patent application Nos. (a) Ser. No. 11/129,765, filed on May 13, 2005, and which claims the benefit of U.S. Provisional Patent Application Nos. 60/616,254, filed on Oct. 5, 2004, and 60/624,793, filed on Nov. 2, 2004; (b) Ser. No. 10/900,199 filed on Jul. 28, 2004, now U.S. Pat. No. 6,978,174, and (c) Ser. No. 10/408,665, filed on Apr. 8, 2003, now U.S. Pat. No. 7,162,303.

All of these applications are incorporated herein by reference in their entireties.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods and systems for neuromodulation. More particularly, the present invention relates to methods and systems for achieving renal neuromodulation via thermal heating and/or cooling.

BACKGROUND

Congestive heart failure (“CHF”) is a condition typically caused by a structural or functional disorder of the heart and can impair the ability of the heart to fill itself or pump a sufficient amount of blood throughout a body (e.g., kidneys). It has been established in animal models that a heart failure condition can cause abnormally high sympathetic activation of the kidneys, which leads to decreased removal of water from the body, decreased removal of sodium, and increased secretion of renin. Increased renin secretion leads to vasoconstriction of blood vessels supplying the kidneys, which causes decreased renal blood flow. As a result, the reaction of the kidneys to heart failure can perpetuate a downward spiral of the heart failure condition. In addition, the kidneys also play a significant role in the progression of Chronic Renal Failure (“CRF”), End-Stage Renal Disease (“ESRD”), hypertension (pathologically high blood pressure), and other renal or cardio-renal diseases.

Reduction of sympathetic renal nerve activity (e.g., via denervation), can reverse these processes. Ardian, Inc. has developed methods and systems for treating renal disorders by applying an electric field to neural fibers that contribute to renal function. See, for example, Ardian, Inc.'s co-owned and co-pending U.S. patent application Nos. (a) Ser. No. 11/129,765, filed on May 13, 2005, (b) Ser. No. 11/189,563, filed on Jul. 25, 2005, and (c) Ser. No. 11/363,867, filed Feb. 27, 2006, all of which are incorporated herein by reference in their entireties. An electric field can initiate renal neuromodulation via denervation caused by irreversible electroporation, electrofusion, apoptosis, necrosis, ablation, thermal alteration, alteration of gene expression or another suitable modality. The electric field can be delivered from an apparatus positioned intravascularly, extravascularly, intra-to-extravascularly, or a combination thereof. Additional methods and apparatus for achieving renal neuromodulation via localized drug delivery (e.g., by a drug pump or infusion catheter), the use of a stimulation electric field, and other modalities are described, for example, in co-owned U.S. Pat. Nos. 7,162,303 and 6,978,174, both of which are incorporated herein by reference in their entireties.

Although these applications provide promising methods and systems, several improvements for enhancing the implementation of these methods and systems would be desirable.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view illustrating human renal anatomy.

FIG. 2 is a schematic, isometric detail view illustrating the location of the renal nerves relative to the renal artery.

FIG. 3A is an isometric view of a system for controlling thermally-induced renal neuromodulation configured in accordance with one embodiment of the disclosure.

FIG. 3B is a schematic side view, partially in section, illustrating an embodiment of an extravascular system for thermally-induced renal neuromodulation.

FIGS. 4A and 4B are schematic diagrams illustrating several types of thermally-induced renal neuromodulation that may be achieved with the systems and methods described herein.

FIGS. 5A-5C are schematic side views, partially in section, illustrating an intravascular apparatus for thermally-induced renal neuromodulation configured in accordance with an embodiment of the disclosure.

FIGS. 6A and 6B are schematic side views, partially in section, illustrating another embodiment of an intravascular apparatus having one or more wall-contact electrodes.

FIGS. 7A and 7B are schematic side views, partially in section, illustrating still another embodiment of an intravascular apparatus having wall-contact electrodes.

FIGS. 8A and 8B are schematic side views, partially in section, illustrating yet another embodiment of an intravascular apparatus having multiple wall-contact electrodes.

FIGS. 9A-9F are schematic side views, partially in section, illustrating still further embodiments of intravascular systems including one or more wall-contact electrodes, as well as optional blood flow occlusion features and/or thermal fluid injection functions.

FIGS. 9G-9N are schematic side views, partially in section, illustrating embodiments of probes for thermally-induced renal neuromodulation.

FIG. 10 is a schematic side view, partially in section, illustrating an example of an intra-to-extravascular system for thermally-induced renal neuromodulation configured in accordance with an embodiment of the disclosure.

FIG. 11 is a schematic side view, partially in section, illustrating an embodiment of an apparatus configured for thermally-induced renal neuromodulation via application of thermal energy.

FIG. 12 is a schematic side view, partially in section, illustrating an embodiment of an apparatus for thermally-induced renal neuromodulation comprising a thermoelectric element suitable for application of thermal energy to target neural fibers.

FIG. 13 is a schematic side view, partially in section, illustrating another embodiment of an apparatus for thermally-induced renal neuromodulation comprising a thermoelectric element.

FIGS. 14A and 14B are schematic side views, partially in section, illustrating an embodiment of an apparatus for thermally-induced renal neuromodulation via high-intensity focused ultrasound.

FIG. 15 is a schematic side view, partially in section, illustrating an alternative embodiment of the apparatus ofFIGS. 14A and 14B.

FIG. 16 is a flow diagram illustrating a method for controlling an energy delivery process for thermally-induced renal neuromodulation.

FIG. 17 is a block diagram illustrating computing system software modules for controlling thermally-induced renal neuromodulation.

FIG. 18 is a block diagram illustrating a process module suitable to be used in the computer system ofFIG. 17.

FIG. 19 is a power vs. time diagram showing an example of a response to performing the method ofFIG. 16.

DETAILED DESCRIPTIONA. Overview

The present disclosure provides methods and systems for controlling renal neuromodulation via thermal heating and/or thermal cooling mechanisms. Many embodiments of such methods and systems may reduce renal sympathetic nerve activity. Thermally-induced neuromodulation may be achieved by heating or cooling structures associated with renal neural activity via an apparatus positioned proximate to target neural fibers. For example, such an apparatus can be positioned (a) within renal vasculature (i.e., positioned intravascularly), (b) extravascularly, (c) intra-to-extravascularly, or (d) a combination thereof. Thermally-induced neuromodulation can be achieved by applying thermal stress to neural structures through either heating or cooling for influencing or altering these structures. Additionally or alternatively, the thermal neuromodulation can be due to, at least in part, alteration of vascular structures such as arteries, arterioles, capillaries, or veins that perfuse the target neural fibers or surrounding tissue.

As used herein, thermal heating mechanisms for neuromodulation include both thermal ablation and non-ablative thermal alteration or damage (e.g., via sustained heating or resistive heating). Thermal heating mechanisms may include raising the temperature of target neural fibers above a desired threshold to achieve non-ablative thermal alteration, or above a higher temperature to achieve ablative thermal alteration. For example, the target temperature can be above body temperature (e.g., approximately 37° C.) but less than about 45° C. for non-ablative thermal alteration, or the target temperature can be about 45° C. or higher for the ablative thermal alteration.

As used herein, thermal cooling mechanisms for neuromodulation include non-freezing thermal slowing of nerve conduction and/or non-freezing thermal nerve alteration, as well as freezing thermal nerve alteration. Thermal cooling mechanisms may include reducing the temperature of target neural fibers below a desired threshold, for example, below the body temperature of about 37° C. (e.g., below about 20° C.) to achieve non-freezing thermal alteration. Thermal cooling mechanisms also may include reducing the temperature of the target neural fibers below about 0° C., e.g., to achieve freezing thermal alteration.

In addition to monitoring or controlling the temperature during thermal neuromodulation, the length of exposure to thermal stimuli may be specified to affect an extent or degree of efficacy of the thermal neuromodulation. In many embodiments, the length of exposure to thermal stimuli is longer than instantaneous exposure. For example, the duration of exposure can be as short as about 5 seconds, or could be longer, such as about 30 seconds, or even longer than 2 minutes. In certain specific embodiments, the length of exposure can be less than 10 minutes, but this should in no way be construed as the upper limit of the exposure period. In other embodiments, the exposure can be intermittent or continuous to achieve the desired result. Exposure times measured in hours, days, or longer may be utilized to achieve desired thermal neuromodulation.

When conducting neuromodulation via thermal mechanisms, the temperature thresholds discussed previously may be determined as a function of the duration of exposure to thermal stimuli. Additionally or alternatively, the length of exposure may be determined as a function of the desired temperature threshold. These and other parameters may be specified or calculated to achieve and control desired thermal neuromodulation.

In some embodiments, thermally-induced renal neuromodulation may be achieved by directly and/or indirectly applying thermal cooling or heating energy to the target neural fibers. For example, a chilled or heated fluid can be applied at least proximate to the target neural fiber, or heated or cooled elements (e.g., a thermoelectric element or a resistive heating element) can be placed in the vicinity of the neural fibers. In other embodiments, thermally-induced renal neuromodulation may be achieved via generation and/or application of the thermal energy to the target neural fibers, such as through application of a “thermal” energy field, including, electromagnetic energy, radiofrequency, ultrasound (including high-intensity focused ultrasound), microwave, light energy (including laser, infrared and near-infrared) etc., to the target neural fibers. For example, thermally-induced renal neuromodulation may be achieved via delivery of a pulsed or continuous thermal energy field to the target neural fibers. The energy field can be sufficient magnitude and/or duration to thermally induce the neuromodulation in the target fibers (e.g., to heat or thermally ablate or necrose the fibers). As described herein, additional and/or alternative methods and systems can also be used for thermally-induced renal neuromodulation.

When utilizing thermal heating mechanisms for thermal neuromodulation, protective cooling elements, such as conductive or convective cooling elements, optionally may be utilized to protect smooth muscle cells or other non-target tissue from undesired thermal effects during the thermally-induced renal neuromodulation. Likewise, when utilizing thermal cooling mechanisms, protective heating elements, such as conductive or convective heating elements, may be utilized to protect the non-target tissue. Non-target tissue additionally or alternatively may be protected by focusing the thermal heating or cooling energy on the target neural fibers so that the intensity of the thermal energy outside of the target zone is insufficient to induce undesired thermal effects in the non-target tissue. When thermal neuromodulation is achieved via thermal energy delivered intravascularly, the non-target tissue may be protected by utilizing blood flow as a conductive and/or convective heat sink that carries away excess thermal energy (hot or cold). For example, when blood flow is not blocked, the circulating blood may remove excess thermal energy from the non-target tissue during the procedure. The intravascularly-delivered thermal energy may heat or cool target neural fibers located proximate to the vessel to modulate the target neural fibers while blood flow within the vessel protects non-target tissue of the vessel wall from the thermal energy. For example, the thermal energy can target neural fibers within the adventitia to necrose or ablate the target fibers, and the blood flow can protect tissue in the vessel wall.

One drawback of using a continuous, intravascularly-delivered thermal energy therapy in the presence of blood flow to achieve-desired intravascularly-induced neuromodulation is that the feasible thermal magnitude (e.g., power) and/or duration of the therapy may be limited or insufficient. This can be caused by the limited heat capacity of the blood flowing through the blood vessel to remove excess thermal energy from the vessel wall to mitigate damage or necrosis to the non-target tissue. Pulsed RF electric fields or other types of pulsed thermal energy may facilitate greater thermal magnitude (e.g., higher power), longer total duration and/or better controlled intravascular renal neuromodulation therapy compared to a continuous thermal energy therapy. For example, a pulsed thermal therapy may allow for monitoring of effects of the therapy on target or non-target tissue during the interval between the pulses. This monitoring data optionally may be used in a feedback loop to better control therapy, e.g., to determine whether to continue or stop treatment, and it may facilitate controlled delivery of a higher power or longer duration therapy.

Furthermore, the time interval between delivery of thermal energy pulses may facilitate additional convective or other cooling of the non-target tissue of the vessel wall compared to applying an equivalent magnitude or duration of continuous thermal energy. This may occur because blood flow through the blood vessel may convectively cool (heat) the non-target tissue of the vessel wall.

When providing a pulsed thermal therapy, this difference in the heat transfer rate between the tissue of the blood vessel wall and the relatively remote target neural fibers may be utilized to ablate, necrose, or otherwise modulate the target neural fibers without undesirably affecting the non-target tissue. The pulsed thermal energy therapy may be applied with greater thermal magnitude and/or of longer total duration (i.e., the cumulative duration of all thermal energy pulses within the therapy) than a continuous thermal therapy. Heat transfer from the vessel wall to the blood (or vice versa) during the off-time or low-energy interval between the thermal energy pulses facilitates the greater magnitude with moderated damage to the non-target tissue. For example, increasing thermal magnitude (e.g., higher power) may result in an increased rate of heating and, accordingly, a more effective thermal neuromodulation (e.g., ability to affect nerves further away from the lumen wall).

In addition, or as an alternative, to utilizing the patient's blood as a heat sink to establish the difference in heat transfer rate, a thermal fluid (hot or cold) may be injected, infused, or otherwise delivered into the vessel to remove excess thermal energy and protect the non-target tissues. The thermal fluid may, for example, comprise a saline or other biocompatible fluid that is heated, chilled, or at a room temperature. The thermal fluid may, for example, be injected through the device or through a guide catheter at a location upstream from an energy delivery element, or at other locations relative to the tissue for which protection is sought. The thermal fluid may be injected in the presence of blood flow or with the flow temporarily occluded.

Occlusion of flow in combination with thermal fluid delivery may facilitate improved control over the heat transfer kinetics in the non-target tissues. For example, the normal variability in blood flow rate between patients, which would vary the heat transfer capacity of the blood flow, may be controlled for by transferring thermal energy between the vessel wall and a thermal fluid that is delivered at a controlled rate. Use of injected thermal fluids to remove excess thermal energy from non-target tissues to relatively protect the non-target tissues during therapeutic treatment of target tissues may be utilized in body lumens other than blood vessels.

In some embodiments, methods and apparatuses for real-time monitoring of an extent or degree of neuromodulation or denervation (e.g., an extent or degree of thermal alteration) in tissue innervated by the target neural fibers and/or of thermal damage in the non-target tissue may be provided. Likewise, real-time monitoring of the thermal energy delivery element may be provided. Such methods and apparatuses may, for example, comprise a thermocouple or other temperature sensor for measuring the temperature of the monitored tissue or of the thermal energy delivery element. Other parameters that can be measured include the power, total energy delivered, nerve activity or impedance. Monitoring data may be used for feedback control of the thermal therapy. For example, intravascularly-delivered thermal therapy may be monitored and controlled by acquiring temperature or impedance measurements along the wall of the vessel in the vicinity of the treatment zone, and/or by limiting the power or duration of the therapy.

To better understand the structures of several embodiments of devices described below, as well as the methods of using such devices for thermally-induced renal neuromodulation, a description of the renal anatomy in humans is provided.

B. Renal Anatomy Summary

As shown inFIG. 1, the human renal anatomy includes the kidneys K, which are supplied with oxygenated blood by the renal arteries RA. The renal arteries are connected to the heart via the abdominal aorta AA. Deoxygenated blood flows from the kidneys to the heart via the renal veins RV and the inferior vena cava IVC.

FIG. 2 illustrates a portion of the renal anatomy in greater detail. More specifically, the renal anatomy also includes renal nerves RN extending longitudinally along the lengthwise dimension L of renal artery RA. The renal nerves RN, for example, are generally within the adventitia of the artery. The renal artery RA has smooth muscle cells SMC that surround the arterial circumference and spiral around the angular axis θ of the artery. The smooth muscle cells of the renal artery accordingly have a lengthwise or longer dimension extending transverse (i.e., non-parallel) to the lengthwise dimension of the renal artery. The misalignment of the lengthwise dimensions of the renal nerves and the smooth muscle cells is defined as “cellular misalignment.”

C. Embodiments of Systems and Methods for Thermally-Induced Renal Neuromodulation

FIGS. 3A-19 illustrate examples of systems and methods for thermally-induced renal neuromodulation.FIG. 3A, for example, is an isometric view of asystem100 for controlling thermally-induced renal neuromodulation of apatient101 configured in accordance with an embodiment of the disclosure. Thesystem100 can include aprocessor114, afield generator110 electrically connected to theprocessor114, and aprobe104 operatively coupled to thefield generator110. In the illustrated embodiment, acable112 electrically connects theprobe104 to thefield generator110. In other embodiments, theprocessor114, theprobe104, and/or thefield generator110 can be connected wirelessly via, for example, radio frequency signals.

Theprocessor114 can be any general purpose, programmable digital computing device including, for example, a personal computer, a Programmable Logic Controller, a Distributed Control System, or other computing device. Theprocessor114 can include a central processing unit (CPU), random access memory (RAM), non-volatile secondary storage (e.g., a hard drive, a floppy drive, and a CD-ROM drive), and network interfaces (e.g., a wired or wireless Ethernet card and a digital and/or analog input/output card). Program code and data can be loaded into the RAM from the non-volatile secondary storage and provided to the CPU for execution. The CPU can generate results for display, output, transmit, or storage.

Thefield generator110 can generate electrical, radiofrequency, ultrasonic (including high intensity focused ultrasound), microwave, laser or other types of signals with desired parameters sufficient to thermally or otherwise induce renal neuromodulation in target neural fibers. For example, thefield generator110 can generate an electrical signal having a desired frequency, amplitude, and power level, and thecable112 can transmit the generated signal to theprobe104. Theprocessor114 is in communication with thefield generator110 to control the power output of thefield generator110 for providing the desired amount of energy to the target neural structures. In the illustrated embodiment, thefield generator110 is located external to thepatient101. In other embodiments, however, thefield generator110 may be positioned internally within the patient.

Theprobe104 can be a laparoscopic probe, a percutaneous probe, an intravascular catheter, or another suitable device configured for insertion in proximity to a track of a renal neural supply along and/or in the renal artery, renal vein, hilum, and/or Gerota's fascia under CT, radiographic, or another suitable guidance modality. Theprobe104 can include at least oneelectrode108 for delivery of a thermal energy field therapy and anelectrical connector106 coupled to thefield generator110 via thecable112 for delivering a thermal energy field to theelectrode108. In some embodiments, theprobe104 can include an integrated cable (not shown) for delivering a thermal energy field to theelectrode108, and theelectrical connector106 can be omitted. In the illustrated embodiment, theprobe104 is a percutaneous probe configured to be percutaneously advanced into proximity of, for example, an anatomical target102 (e.g., a renal artery or renal vein) of thepatient101 as described in more detail below with reference toFIG. 3B. In other embodiments, theprobe104 can be an implantable device.

The electrode(s)108 can be individual electrodes that are electrically independent of each other, a segmented electrode with commonly connected contacts, or a continuous electrode. A segmented electrode can, for example, be formed by providing a slotted tube fitted onto the electrode, or by electrically connecting a series of individual electrodes. Individual electrodes or groups ofelectrodes108 can be configured to provide a bipolar signal. Theelectrodes108 can be dynamically assignable to facilitate monopolar and/or bipolar energy delivery between any of the electrodes and/or between any of the electrodes and a remote electrode. The remote electrode may, for example, be attached externally to the patient's skin (e.g., to the patient's leg or flank).

Theprobe104 can also include at least one sensor (not shown) for measuring a physiological parameter of thepatient101. For example, theprobe104 can include a temperature sensor, an impedance sensor, an ultrasound sensor, and/or other types of sensors. The sensor can measure the physiological parameter (e.g., a temperature) and transmit the measured physiological parameter to theprocessor114 for processing.

Optionally, thesystem100 can also include aninput device118, anoutput device120, and/or acontrol panel122 operatively coupled to theprocessor114. Theinput device118 can include a keyboard, a mouse, a touch screen, a push button, a switch, a potentiometer, and any other devices suitable for accepting user input. Theoutput device120 can include a display screen, a printer, a medium reader, an audio device, and any other devices suitable for providing user feedback. Thecontrol panel122 can include indicator lights, numerical displays, and audio devices. In the embodiment shown inFIG. 3A, arack124 withwheels126 carries theprocessor114, thefield generator110, theinput device118, and theoutput device120 for portability. In another embodiment, the various components can be incorporated into a single enclosure (e.g., the field generator110) for portably mounting on, for example, an IV stand, an IV pole, an instrument stand, an infusion stand, and/or other supporting structures. In further embodiments, the various components can be fixedly installed.

In operation, an operator can place theprobe104 at least proximate to a wall of a body lumen of thepatient101, for example, the renal artery or renal vein, and then deliver energy to theprobe104 to achieve thermal renal neuromodulation as described in more detail below.FIGS. 4A and 4B, for example, illustrate the various types of thermal neuromodulation that may be achieved with the systems and methods described herein.FIGS. 4A and 4B are provided only for the sake of illustration and should in no way be construed as limiting.

FIG. 4A illustrates thermal neuromodulation due to heat exposure. As shown, exposure to heat in excess of a body temperature of about 37° C., but below a temperature of about 45° C., may induce thermal alteration via moderate heating of the target neural fibers or of vascular structures that perfuse the target fibers. In cases where vascular structures are affected, the target neural fibers are denied perfusion resulting in necrosis of the neural tissue. For example, this may induce non-ablative thermal alteration in the fibers or structures. Exposure to heat above a temperature of about 45° C., or above about 60° C., may induce thermal alteration via substantial heating of the fibers or structures. For example, such higher temperatures may thermally ablate the target neural fibers or the vascular structures. In some patients, it may be desirable to achieve temperatures that thermally ablate the target neural fibers or the vascular structures, but that are less than about 90° C., or less than about 85° C., or less than about 80° C., and/or less than about 75° C. Regardless of the type of heat exposure utilized to induce the thermal neuromodulation, a reduction in renal sympathetic nerve activity (“RSNA”) is expected.

Referring toFIG. 4B, thermal cooling for neuromodulation includes non-freezing thermal slowing of nerve conduction and/or nerve alteration, as well as freezing thermal nerve alteration. Non-freezing thermal cooling may include reducing the temperature of the target neural fibers or of the vascular structures that feed the fibers to temperatures below the body temperature of about 37° C., or below about 20° C., but above the freezing temperature of about 0° C. This non-freezing thermal cooling may either slow nerve conduction or may cause neural alteration. Slowed nerve conduction may use continuous or intermittent cooling of the target neural fibers to sustain the desired thermal neuromodulation, while neural alteration may require only a discrete treatment to achieve sustained thermal neuromodulation. Thermal cooling for neuromodulation also may include freezing thermal nerve alteration by reducing the temperature of the target neural fibers or of the vascular structures that feed the fibers to temperatures below the freezing point of about 0° C. Regardless of the type of cold exposure utilized to induce the thermal neuromodulation (freezing or non-freezing), a reduction in RSNA is expected.

Referring back toFIG. 3A, the operator and/or theprocessor114 can monitor and control the energy delivery process. As described above, theprobe104 can include sensors that measure physiological parameters of thepatient101. Theprobe104 can transmit the measured parameters to theprocessor114 via thecable112 or wirelessly. Theprocessor114 can process and analyze the received parameters and display the parameters in appropriate units on theoutput device120. Theprocessor114 can cause the system to sound an alarm if the received parameters exceed preset thresholds and signal any alarms using either theoutput device120 and/or thecontrol panel122. Theprocessor114 can also analyze and process parameter measurement data, for either a single parameter or multiple parameters in combination, and can compare the data against stored, non-empirical data to identify any patterns that may warrant closer attention. Theprocessor114 can also store the received parameters and data patterns in a database for later retrieval. In addition, theprocessor114 can modulate the power output of thefield generator110 based on the received parameters and/or input received from the operator via theinput device118 as described in more detail below with reference toFIGS. 16-19.

InFIG. 3B, theprobe104 has been advanced through a percutaneous access site P into proximity with the renal artery RA. Theprobe104 pierces the Gerota's fascia F of thepatient101, and theelectrodes108 are advanced into position through theprobe104 and along the annular space between the artery arm and fascia. Once properly positioned, the target neural fibers can be heated via a pulsed or continuous electric field delivered across the electrode(s)108. InFIG. 3B, for example, the electrode(s)108 comprise a bipolar electrode pair that can generatethermal energy field109. Such heating can ablate or cause non-ablative thermal alteration to the target neural fibers to at least partially denervate the kidney innervated by the target neural fibers. The energy field also can induce reversible or irreversible electroporation in the target neural fibers which can compliment the thermal alteration induced in the neural fibers. After treatment, theprobe104 can be removed from the patient to conclude the procedure.

FIGS. 5A-9,14, and15 illustrate several embodiments of intravascular systems and associated methods for thermally-induced renal neuromodulation. It will be appreciated that the electrode(s) in each of the following embodiments can be connected to a generator (e.g., the field generator110) even through the generator is not explicitly shown or described below.

FIGS. 5A and 5B, for example, are schematic side views illustrating anintravascular apparatus300 for thermally-induced renal neuromodulation. Theapparatus300 can include acatheter302 having anoptional positioning element304,

shaft electrodes

306aand306bdisposed along the shaft of thecatheter302, and optionalradiopaque markers308 disposed along the shaft of thecatheter302 in the region of thepositioning element304. Thepositioning element304 can be a balloon, an expandable wire basket, other mechanical expanders, or another suitable device for holding the electrodes306a-brelative to the vessel and/or the nerves. The electrodes306a-bcan be arranged such that theelectrode306ais near a proximal end of thepositioning element304 and theelectrode306bis near the distal end of thepositioning element304. The electrodes306a-bare electrically coupled to the field generator110 (FIG. 3A) for delivering energy to the target neural fibers. In other embodiments, one or more of the electrodes306a-bcan comprise Peltier electrodes for heating or cooling the target neural fibers to modulate the fibers.

Thepositioning element304 optionally can position or otherwise drive the electrodes306a-binto contact with the lumen wall. For example, when thepositioning element304 is an inflatable balloon as shown inFIG. 5A, the balloon can serve as both a centering and/or expansion element for the expandable electrode element(s)306a-b, and as an impedance-altering electrical insulator for directing an energy field delivered via the electrodes306a-binto or across the vessel wall for modulation of target neural fibers. The electrical insulation provided by thepositioning element304 can reduce the magnitude of applied energy or other parameters of the energy field necessary to achieve the desired modulation of the target fibers, which can include partial or full denervation of tissue containing the target fibers. Applicants have previously described use of a suitable impedance-altering element in co-pending U.S. patent application Ser. No. 11/266,993, filed Nov. 4, 2005, which is incorporated herein by reference in its entirety.

Furthermore, thepositioning element304 optionally may be utilized as a cooling element and/or a heating element. For example, thepositioning element304 may be inflated with a chilled fluid that serves as a heat sink for removing heat from tissue that contacts the element. Conversely, thepositioning element304 optionally may be a heating element by inflating it with a warmed fluid that heats tissue in contact with the element. The thermal fluid optionally may be circulated and/or exchanged within thepositioning element304 to facilitate more efficient conductive and/or convective heat transfer. Thermal fluids also may be used to achieve thermal neuromodulation via thermal cooling or heating mechanisms, as described in greater detail herein below.

The positioning element304 (or any other portion of the apparatus300) additionally or alternatively may comprise one or more sensors for monitoring the process. In one embodiment, thepositioning element304 has a wall-contact thermocouple310 (FIG. 5A) for monitoring the temperature or other parameters of the target tissue, the non-target tissue, the electrodes, the positioning element and/or any other portion of theapparatus300. Alternatively,electrodes306aand/or306bcan have one or more thermocouples built into them.

The electrodes306a-bof the intravascular embodiment shown inFIGS. 5A and 5B can be individual electrodes (i.e., independent contacts), a segmented electrode with commonly connected contacts, or a single continuous electrode. Furthermore, the electrodes306a-bcan also be configured to provide a bipolar signal, or the electrodes306a-bcan be used together or individually in conjunction with a separate patient ground pad for monopolar use. The electrodes306a-bcan be attached to thepositioning element304 such that they contact the wall of the artery upon expansion of thepositioning elements304. The electrodes306a-bcan, for example, be affixed to the inside surface, outside surface, or at least partially embedded within the wall of thepositioning element304.FIG. 5C, described hereinafter, illustrates one example of wall-contact electrodes, whileFIGS. 6-9 illustrate alternative wall-contact electrodes.

As shown inFIG. 5A, thecatheter302 can be delivered to a treatment site within the renal artery RA as shown, or it may be delivered to a renal vein or to any other vessel in proximity to neural tissue contributing to renal function, in a low profile delivery configuration through a guide catheter or other device. Alternatively, catheters may be positioned in multiple vessels for thermal renal neuromodulation, e.g., within both the renal artery and the renal vein. Techniques for pulsed electric field renal neuromodulation in multiple vessels have been described previously, for example, in co-pending U.S. patent application Ser. No. 11/451,728, filed Jul. 12, 2006, which is incorporated herein by reference in its entirety.

Once thepositioning element304 is at a desired location within the renal vasculature, it can be expanded into contact with an interior wall of the vessel. A thermal energy field then may be delivered via the electrodes306a-bacross the wall of the artery. The field thermally modulates the activity along neural fibers that contribute to renal function via heating. In several embodiments, the thermal modulation at least partially denervates the kidney innervated by the neural fibers via heating. This may be achieved, for example, via thermal ablation or non-ablative alteration of the target neural fibers.

In the embodiment shown inFIG. 5A, thepositioning element304 is an inflatable balloon that can preferentially direct the energy field as discussed above. In the embodiment illustrated inFIG. 5B, thepositioning element304 comprises an expandable wire basket that substantially centers the electrodes306a-bwithin the vessel without blocking blood flow through the vessel. During delivery of the thermal energy field (or of other thermal energy), the blood can act as a heat sink for conductive and/or convective heat transfer to remove excess thermal energy from the non-target tissue. This protects the non-target tissue from undesired thermal effects. This effect may be enhanced when blood flow is not blocked during energy delivery, such as in the embodiment shown inFIG. 5B.

Using the patient's blood as a heat sink is expected to facilitate delivery of longer or greater magnitude thermal treatments with reduced risk of undesired effects to the non-target tissue, which may enhance the efficacy of the treatment at the target neural fibers. Although the embodiment shown inFIG. 5B includes apositioning element304 for centering the electrodes306a-bwithout blocking flow, it should be understood that thepositioning element304 may be eliminated and/or that the electrodes306a-bmay be attached to thepositioning element304 such that they are not centered in the vessel upon expansion of the centering element. In such embodiments, the patient's blood may still mitigate excess thermal heating or cooling to protect non-target tissues.

One drawback of using a continuous, intravascularly-delivered thermal energy therapy in the presence of blood flow to achieve desired intravascularly-induced neuromodulation is that the feasible thermal magnitude (e.g., power) and/or duration of the therapy may be limited or insufficient. This can occur because the capacity of the blood to remove heat is limited, and thus the blood flowing through the blood vessel may not remove enough excess thermal energy from the vessel wall to mitigate or avoid undesirable effect in the non-target tissue. Use of a pulsed thermal energy therapy, such as a pulsed thermal RF electric field, may facilitate greater thermal magnitude (e.g., higher power), longer total duration, and/or better controlled intravascular renal neuromodulation therapy compared to a continuous thermal energy therapy. For example, the effects of the therapy on target or non-target tissue may be monitored during the intervals between the pulses. This monitoring data optionally may be used in a feedback loop to better control the therapy, e.g., to determine whether to continue or stop treatment, and it may facilitate controlled delivery of a higher power or longer duration therapy.

Furthermore, the off-time or low-energy intervals between thermal energy pulses may facilitate additional convective or other cooling of the non-target tissue of the vessel wall compared to use of a continuous thermal therapy of equivalent magnitude or duration. This can occur because blood flow through the blood vessel can convectively cool (heat) the non-target tissue of the vessel wall faster than the target neural fibers positioned outside of the vessel wall.

When providing a pulsed thermal therapy, the difference in heat transfer rates between tissue of the blood vessel wall and the relatively remote target neural fibers may be utilized to ablate, necrose, or otherwise modulate the target neural fibers without producing undesirable effects in the non-target tissue. As a result, the pulsed thermal energy therapy may be applied with greater thermal magnitude and/or of longer total duration (i.e., the cumulative duration of all thermal energy pulses) compared to a continuous thermal therapy. The higher heat transfer rate at the vessel wall during the intervals between the thermal energy pulses facilitates the greater magnitude/longer duration delivery.

In addition or as an alternative to utilizing the patient's blood as a heat sink to create a difference in the heat transfer rate, a thermal fluid (hot or cold) may be injected, infused or otherwise delivered into the vessel to remove excess thermal energy and protect the non-target tissues. The thermal fluid may, for example, comprise saline or another biocompatible fluid that is heated, chilled or at room temperature. The thermal fluid may, for example, be injected through the device or through a guide catheter at a location upstream from an energy delivery element, or at other locations relative to the tissue for which protection is sought. The thermal fluid may be injected in the presence of blood flow or with the blood flow temporarily occluded.

In several embodiments, the occlusion of the blood flow in combination with thermal fluid delivery may facilitate good control over the heat transfer kinetics. For example, the normal variability in blood flow rate between patients, which would vary the heat transfer capacity of the blood flow, may be controlled for by transferring thermal energy between the vessel wall and a thermal fluid that is delivered at a controlled rate. Furthermore, this method of using an injected thermal fluid to remove excess thermal energy from non-target tissues in order to protect the non-target tissues during therapeutic treatment of target tissues may be utilized in body lumens other than blood vessels.

One or more sensors, such as thethermocouple310 ofFIG. 5A, can be used to monitor the temperature(s) or other parameter(s) at the electrodes306a-b, the wall of the vessel and/or at other desired locations along the apparatus or the patient's anatomy. The thermal neuromodulation may be controlled using the measured parameter(s) as feedback. This feedback may be used, for example, to maintain the parameter(s) below a desired threshold. For example, the parameter(s) may be maintained below a threshold that may cause undesired effects in the non-target tissues. With blood flowing through the vessel, more thermal energy may be carried away, which may allow for higher energy treatments than when blood flow is blocked in the vessel.

As discussed previously, when utilizing intravascular apparatus to achieve thermal neuromodulation, in addition or as an alternative to central positioning of the electrode(s) within a blood vessel, the electrode(s) optionally may be configured to contact an internal wall of the blood vessel. Wall-contact electrode(s) may facilitate more efficient transfer of a thermal energy field across the vessel wall to target neural fibers, as compared to centrally-positioned electrode(s). In some embodiments, the wall-contact electrode(s) may be delivered to the vessel treatment site in a reduced profile configuration, then expanded in vivo to a deployed configuration wherein the electrode(s) contact the vessel wall. In some embodiments, expansion of the electrode(s) is at least partially reversible to facilitate retrieval of the electrode(s) from the patient's vessel.

FIG. 5C, for example, is a schematic side view illustrating an embodiment of anapparatus400 having one or more wall-contact electrodes306c. One or more struts of the expandablebasket positioning element304 can include a conductive material that is insulated in regions other than along segments that contact the vessel wall and form electrode(s)306c. The electrode(s)306ccan be used in either a bipolar or a monopolar configuration. Furthermore, the electrode(s)306ccan include one or more sensors (not shown) for monitoring and/or controlling the effects of the thermal energy delivery. The sensors, for example, can be thermocouples, impedance sensors, temperature sensors, etc.

FIGS. 6A and 6B are schematic side views illustrating another embodiment of anintravascular apparatus500 having electrodes configured to contact the interior wall of a vessel. Theapparatus500 ofFIGS. 6A and 6B differs from theapparatus300 ofFIGS. 5A and 5B in that theproximal electrode306aofFIGS. 5A and 5B has been replaced with a wall-contact electrode306a′. The wall-contact electrode306a′ includes aproximal connector312athat connects theelectrode306a′ to the shaft of thecatheter302 and is electrically coupled to the field generator (not shown). Theapparatus500 also has a plurality ofextensions314athat extend from theproximal connector312aand at least partially extend over a surface of thepositioning element304. Theextensions314aoptionally may be selectively insulated such that only a selective portion of theextensions314a(e.g., the distal tips of the extensions) are electrically active. Theelectrode306a′ and or theconnector312aoptionally may be fabricated from a slotted tube, such as a stainless steel or shape-memory (e.g., NiTi) slotted tube. Furthermore, all or a portion of the electrode may be gold-plated to improve radiopacity and/or conductivity.

As shown inFIG. 6A, thecatheter302 may be delivered over a guidewire G to a treatment site within the patient's vessel with theelectrode306a′ positioned in a reduced profile configuration. Thecatheter302 optionally may be delivered through aguide catheter303 to facilitate such reduced profile delivery of the wall-contact electrode306a′. When positioned as desired at a treatment site, theelectrode306a′ may be expanded into contact with the vessel wall by expanding the positioning element304 (as shown inFIG. 6B). A thermal bipolar electric field then may be delivered across the vessel wall and between theelectrodes306a′ and306bto induce thermal neuromodulation, as discussed previously. Alternatively306a′ or306bcould comprise a monopolar electrode, wherein the return electrode (not shown) is placed on an external surface of the patient. Theoptional positioning element304 may alter impedance within the blood vessel and more efficiently route the electrical energy across the vessel wall to the target neural fibers.

After terminating the electric field, theelectrode306a′ may be returned to a reduced profile and theapparatus500 may be removed from the patient or repositioned in the vessel. For example, thepositioning element304 may be collapsed (e.g., deflated), and theelectrode306a′ may be contracted by withdrawing thecatheter302 within theguide catheter303. Alternatively, theelectrode306a′ may be fabricated from a shape-memory material biased to the collapsed configuration, such that the electrode self-collapses upon collapse of thepositioning element304.

Although theelectrode306a′ shown inFIGS. 6A and 6B is expanded into contact with the vessel wall, it should be understood that theelectrode306a′ alternatively may be fabricated from a self-expanding material biased such that theelectrode306a′ self-expands into contact with the vessel wall upon positioning of theelectrode306a′ distal of theguide catheter303. A self-expanding embodiment of theelectrode306a′ may obviate a need for thepositioning element304 and/or may facilitate maintenance of blood flow through the blood vessel during delivery of an electric field via the electrode. After delivery of the electric field, the self-expandingelectrode306a′ may be returned to a reduced profile to facilitate removal of theapparatus300 from the patient by withdrawing thecatheter302 within theguide catheter303.

FIGS. 8A and 8B are schematic side views illustrating yet another embodiment of anapparatus700 for thermally-induced neuromodulation. Theapparatus700 ofFIGS. 8A and 8B includes theproximal electrode306a′ ofFIGS. 6A and 6B, and a distal wall-contact electrode306b′. Theapparatus700 also includes proximal and

distal positioning elements

304aand304b, respectively, for expanding the proximal and distal wall-contact electrodes306a′ and306b′, respectively, into contact with the vessel wall. The embodiment shown inFIG. 8B includes only asingle positioning element304, but the distal wall-contact electrode306b′ is proximal facing and positioned over the distal portion of thepositioning element304 to facilitate expansion of thedistal electrode306b′. In the embodiment illustrated inFIG. 8B, the extensions of the proximal306a′ anddistal electrodes306b′ optionally may be connected alongnon-conductive connectors318 to facilitate collapse and retrieval of the electrodes post-treatment.

A bipolar electric field may be delivered between the proximal and distal wall-contact electrodes306a′ and306b′, or a monopolar electric field may be delivered between theproximal electrode306a′ and/ordistal electrode306b′ and an external ground. Having both the proximal anddistal electrodes306a′ and306b′ in contact with the wall of the vessel may facilitate more efficient energy transfer across the wall during delivery of a thermal energy field, as compared to having one or both of the proximal anddistal electrodes306a′ and306b′ centered within the vessel.

FIGS. 9A-9N are schematic side views illustrating additional embodiments of intravascular systems including one or more wall-contact electrodes, blood flow occlusion features, and/or thermal fluid injection functions. The embodiments described below with reference toFIGS. 9A-9N are described as monopolar devices, but it should be understood that any (or all) of the embodiments may be configured or operated as bipolar devices. Furthermore, although blood flow occlusion and thermal fluid injection are described in combination with wall-contact electrode(s), it should be understood that such occlusion and injection features may be provided in combination with electrode(s) that do not contact the vessel wall.

As discussed previously, in addition or as an alternative to utilizing the patient's blood as a heat sink to create different heat transfer rates between target neural fibers and non-target tissue of the wall of the vessel within which thermal energy is delivered, a thermal fluid (hot or cold) may be injected, infused or otherwise delivered into the vessel. The thermal fluid may further remove excess thermal energy and protect the non-target tissues. When delivering thermal therapy via heating, the thermal fluid may, for example, comprise chilled or room temperature saline (e.g., saline at a temperature lower than the temperature of the vessel wall during the therapy delivery). The thermal fluid may be injected through the device catheter or through a guide catheter at a location upstream from an energy delivery element, or at other locations relative to the tissue for which protection is sought. The thermal fluid may be injected in the presence of blood flow or with blood flow temporarily occluded. The occlusion of blood flow in combination with thermal fluid delivery may facilitate good control over the heat transfer kinetics along the non-target tissues, as well as injection of fluid from a downstream location.

FIGS. 9A and 9B illustrate anapparatus800 including acatheter802 having apositioning element804 that can be used to position the apparatus within the vessel and/or to occlude blood flow. Thepositioning element804, for example, can be an inflatable balloon. Theapparatus800 can further include one or more activemonopolar electrodes810 located proximally from thepositioning element804 such that inflation of thepositioning element804 blocks blood flow downstream of theelectrode assembly806. Theelectrode assembly806 includesmultiple extensions814, and it should be understood that any desired number of extensions may be provided, including a single extension. The monopolar electrode(s)810 are utilized in combination with a remote electrode, such as a ground pad, positioned external to the patient. Theapparatus800 can also include aninfusion port805 between thepositioning element804 and theelectrode assembly806.

As shown inFIG. 9A, thecatheter802 can be advanced within the renal artery RA in a reduced profile delivery configuration. Referring toFIG. 9B, once properly positioned at the treatment site, theelectrode assembly806 can be actively expanded, or it may self-expand by removing a sheath, theguide catheter803, or another type of restraint from the electrode(s)810. The expandedelectrode assembly806 contacts the vessel wall. Thepositioning element804 can be expanded (before, during, or after expansion of the electrode assembly806) to properly position theelectrode assembly806 within the vessel and/or to occlude blood flow within the renal artery RA downstream of theelectrode assembly806. A monopolar electric field may be delivered between the active electrode(s)810 and the external ground. Alternatively, a biopolar electric field can be generated between any twoelectrodes810. The electric field may, for example, comprise a pulsed or continuous RF electric field that thermally induces neuromodulation (e.g., necrosis or ablation) in the target neural fibers. The thermal therapy may be monitored and controlled, for example, via data collected with thermocouples, impedance sensors, or other sensors, which may be incorporated into electrode(s)810.

To increase the power that may be delivered or the duration of the thermal treatment without undesirably affecting non-target tissue, a thermal fluid infusate I can be injected throughinjection port805 of thecatheter802 to cool the non-target tissue. This is expected to mitigate undesired effects in the non-target tissue. The infusate I, for example, can include chilled saline that removes excess thermal energy from the wall of the vessel during thermal therapy.

Convective or other heat transfer between the non-target vessel wall tissue and the infusate I may facilitate cooling (or heating) of the vessel wall at a faster rate than cooling (or heating) occurs at the target neural fibers. This difference in the heat transfer rates between the wall of the vessel and the target neural fibers may be utilized to modulate the neural fibers. Furthermore, when utilizing a pulsed thermal therapy, the accelerated heat transfer at the wall relative to the neural fibers may allow for relatively higher energy or longer duration therapies (as compared to continuous thermal therapies). Also, the interval between pulses may be used to monitor and/or control effects of the therapy.

FIG. 9C is a schematic side view illustrating another embodiment of anapparatus820 including wall-contact electrodes810, flow occlusion, and thermal fluid injection. In the embodiment shown inFIG. 9C, anocclusion element804 is coupled to the guide wire G, which may comprise an inflation lumen, and the infusate I is delivered through a distal outlet of thecatheter802. Theocclusion element804 alternatively may be coupled to a separate catheter or sheath (not shown) rather than to the guide wire G. Also, the infusate I may, for example, be delivered through the guide wire lumen or through an additional lumen or annulus of thecatheter802.FIG. 9D illustrates another embodiment of anapparatus830 whereocclusion element804 is positioned proximal or upstream of theelectrode assembly806, and the infusate I is delivered at a position distal of theocclusion element804 but proximal of theelectrode assembly806.

FIG. 9E is a schematic side view illustrating yet another embodiment of an apparatus840 with occlusion elements804 (two are shown as

occlusion elements

804aand804b) positioned both proximal and distal of theelectrode assembly806. In addition to having afirst injection port805a, thecatheter803 includes anaspiration port805b. Separate lumens can extend through the catheter for injection and aspiration of the infusate I via the

injection ports

805aand805b. Providing both injection and aspiraton of the infusate facilitates good control over the flow dynamics of the infusate, and thereby the heat transfer kinetics of the infusate I. For example, providing aspiration and injection at the same rate can provide consistent heat transfer kinetics between the vessel and the electrode(s)806.

FIG. 9F illustrates still yet another embodiment of anapparatus850 having acatheter852 including a wall-contact electrode856 that can be moved into contact with the vessel wall via anelongated member857. In this embodiment, theelongated member857 is distally connected to thecatheter852 in the vicinity of theelectrode856. Theelongated member857 may be configured for self or mechanical expansion, or it may extend through aport805 of thecatheter852 and through a lumen of the catheter to a proximal location for manipulation by a medical practitioner. The proximal section of theelongated member857 may be advanced relative to thecatheter852 by the medical practitioner such that the member assumes the illustrated curved profile.

Upon expansion of the elongated member, thecatheter852 is deflected such that theelectrode856 coupled to the catheter shaft contacts the vessel wall. Optionally, thepositioning element804 may be expanded to facilitate positioning of theelectrode856 via theelongated member857 and/or to block flow through the vessel. Thepositioning element804 can be coupled to the guide ordelivery catheter803. Infusate I optionally may be delivered through thecatheter852 as shown.

FIGS. 9G-9N are partially schematic side views illustrating an embodiment of a probe orcatheter900 including a shaped or self-expanding or mechanically-activated electrode suitable for use in thesystem100 ofFIGS. 3A and 3B.FIG. 9G, for example, illustrates the probe orcatheter900 in a reduced profile configuration for delivery to the treatment site, andFIG. 9H illustrates a portion of theprobe900 in an expanded or uncompressed state. Referring toFIGS. 9G and 9H together, theprobe900 can include ashaft904, anelectrode906, an intermediate portion orsection908 between theshaft904 and theelectrode906, and a guide catheter or sheath910 (e.g., a 5 French guide catheter) covering and releasably carrying theshaft904 and theintermediate portion908. Theintermediate portion908 can rest within thesheath910 in a compressed state (i.e., the curved or shaped region is substantially flattened or otherwise straightened by the inner wall of the sheath910) during delivery to the treatment site (FIG. 9G). When thesheath910 is retracted, theintermediate portion908 will expand to its unconstrained arched or curved shape (FIG. 9H). The curved or shaped profile of theintermediate portion908 facilitates contact between theelectrode906 and the corresponding vessel wall. This process is described in greater detail below with reference toFIG. 9J.

As best seen in the reduced profiled configuration ofFIG. 9G, theshaft904 and theintermediate portion908 can optionally have an internal space912 (not shown), and theprobe900 can further include wires112 (identified individually as112aand112b) coupled to theintermediate portion908. Thewires112a-belectrically couple theelectrode906 to thefield generator110 and may be comprised of thermocouple wires. As discussed in more detail below, theelectrode906 can deliver an electric field supplied by thefield generator110 via thewires112 to the wall of the corresponding body lumen.

Referring back toFIGS. 9G and 9H together, theshaft904 can be a generally cylindrical tube constructed from one or more biocompatible materials (e.g., plastic, metals, alloys, and ceramics). Theshaft904 can also include a more flexible region orsection904aat a distal portion of theshaft904 and configured to allow theprobe900 to flex or contort during use. For example, theflexible region904acan allow theprobe900 to make the relatively sharp turn from the aorta to the renal artery during delivery of theelectrode906 to the treatment site. In one embodiment, theflexible region904acan include a braided shaft without the support of a hypotube or other support structure which may be incorporated into theshaft904. As shown inFIG. 9H, theflexible region904ahas a length L₁of about 7 cm. In other embodiments, however,flexible region904acan have a length L₁of from about 2 cm to about 140 cm (the entire working length of theshaft904 could be generally flexible). In still other embodiments, theshaft904 and/or theflexible region904acan have a different arrangement and/or configuration.

Theprobe900 can have a working or effective length L₂of from about 55 cm to about 140 cm. As used herein, “working length” and “effective length” are defined as the length of the probe900 (e.g., theshaft904, theintermediate portion908, and the electrode906) that will fit inside a patient's body. In configurations where a 55 cm guide catheter is used to facilitate delivery of theprobe900, the working or effective length may be from about 60 cm to about 80 cm. In configurations where a 90 cm guide catheter is used to facilitate delivery of theprobe900, the working or effective length may be from about 95 cm to about 120 cm. In the illustrated embodiment, for example, theprobe900 has a working or effective length L₂of about 108 cm and is configured for use with asheath910 having a length of about 90 cm. In other embodiments, however, theprobe900 can have a different working length L₂and/or be configured for use with a sheath having a different dimension and/or configuration.

Theelectrode906 includes aband914 constructed from a first metal (e.g., platinum or iridium) and asecond metal916 disposed inside theband914. Theband914 can be generally cylindrical or have another suitable shape. Thesecond metal916 can be the same as the first metal, or thesecond metal916 can be a different metal or metal alloy. The wires are electrically coupled to one another. For example, the wires can be electrically connected directly or connected via the first and/or second metal. Thus, theelectrode906 can deliver an electric field supplied from thefield generator110 via thewires112a-bto the wall of the body lumen. In an alternative embodiment, a single wire is used instead of a pair of wires.

Theelectrode906 can also measure temperature (via a thermocouple or thermistor, or other temperature sensing elements), impedance or another parameter while delivering the electric field to the tissue. For example, voltage and current of the supplied electric field can be measured, and a resistance or impedance can be calculated according to Ohm's law.

One expected advantage of an embodiment where only impedance is measured is that only one wire is needed for theprobe900. If theprobe900 includes a temperature sensor electrically connected to the electrode, then at least one more wire must be used. In this case, a total of two wires can be used to deliver energy, measure impedance and measure temperature. If theprobe900 includes a temperature sensor electrically independent from the electrode then at least one more wire must be used. Additionally, more than one temperature sensors may be used to make additional temperature measurements. The additional wires can add to the size and complexity of theprobe900 and increase the potential for a malfunction.

Although the illustratedelectrode906 includes theband914, theelectrode906 can have other configurations. For example, theelectrode906 can include a coil constructed from a first metal wrapped around a core constructed from a second metal. One expected advantage of having a coil is that the coil can reduce stress due to heat expansion when measuring temperature. In another embodiment, the electrode can be formed from a single metal or other conductor without the band.

FIG. 9I is an exploded view of a portion of theprobe900 taken from the area9I ofFIG. 9H. Theintermediate portion908 may be comprised of a solid wire, ribbon, cylindrical tube, or coil constructed from stainless steel, nitinol, plastic or another suitable material (or combinations thereof) that can bend or otherwise flex or be actively directed to facilitate contact between theelectrode906 and the corresponding vessel wall. In the illustrated embodiment, theintermediate portion908 flexes or bends to locate theelectrode906 at a dimension Y from a longitudinal axis S of theshaft904. The dimension Y can vary from about 2 mm to about 20 mm. In some configurations, the Y dimension can be from about 10 mm to about 20 mm. In the illustrated embodiment, for example, the dimension Y is about 16 mm. By way of example, the average diameter of a human renal artery is from about 3 mm to about 8 mm. Accordingly, if theshaft904 was positioned adjacent to a wall of an artery having an 8 mm diameter, theintermediate section908 would have enough flexure or arch for theelectrode906 to contact the opposite wall of the artery. In other embodiments, however, the dimension Y can have a different value and maybe oversized to facilitate contact in a straight or curved vessel.

Theintermediate portion908 is also configured to locate theelectrode906 at a dimension X from adistal portion904bof theshaft904. The dimension X can vary based, at least in part, on the material of which theintermediate portion908 is composed (e.g., stainless steel or nitinol) and the desired working or effective length for theprobe900. For example, the dimension X of theintermediate portion908 should be configured and sized to provide sufficient wall contact pressure such that theelectrode906 can create the desired treatment effect.

In alternative embodiments, a pull or push wire can be used to actively flex the intermediate portion to facilitate placement of the electrode. For example, as illustrated inFIGS. 9L to 9N, anelectrode tip985 of aprobe980 can be deflected or steered using anactuator wire982. Theactuator wire982 can be pulled from a first position or position of no deflection986, as shown inFIG. 9L, to a second position ofslight deflection987, as shown inFIG. 9M, to a third position ofsubstantial deflection988, as shown inFIG. 9N. The variable deflection of theprobe980 can be particularly helpful, for example, when attempting to achieve wall contact in a curved vessel.

Referring back toFIG. 9I, theshaft904 has an outer diameter D of from approximately 0.014 inches to approximately 0.085 inches. The outer diameter1) of theshaft904 can vary based, at least in part, on the outer diameter of theelectrode906. In the illustrated embodiment, for example, theshaft904 has an outer diameter D of about 0.040 inches, which corresponds to one particular configuration of theelectrode906.

Theelectrode906 has an outer diameter E of from about 0.020 inches to about 0.085 inches. In the illustrated embodiment, for example, theelectrode906 has an outer diameter E of about 0.049 inches. These dimensions can vary, however, from a practical standpoint, the outer diameter E of theelectrode906 can be no bigger than the inner diameter of the sheath or guide catheter (e.g., the sheath910) through which theelectrode906 is delivered. In one particular example, an 8 French guide catheter (which has an inner diameter of 0.091 inches) would likely be the largest catheter used to access the renal artery. Thus, an electrode used in this situation would have an outer diameter E at least approximately less than 0.085 inches.

In an alternative embodiment, the catheter can be configured such that the sheath does not cover the entire electrode, but is rather used only to substantially straighten the intermediate portion of the catheter to facilitate delivery to the treatment location. In such configurations, the distal end of the sheath will abut the proximal end of the electrode. Accordingly, it would not be necessary for the electrode size to be limited by the inner diameter of the sheath.

FIG. 9J is a schematic side view of an embodiment of anintravascular apparatus950 including theprobe900 with the shaped or self-expandingelectrode906. Theelectrode906 can be delivered to a treatment site within thesheath910, and then it can move to a preselected shape after it has been removed from the lumen of thesheath910. For example, theelectrode906 can be removed from thesheath910 by advancing theshaft904 and/or retracting theshaft904. Theelectrode906 contacts the vessel wall for delivery of therapy. Optionally, theshaft904 may be rotated to rotate theelectrode906 relative to the vessel wall and angularly reposition theelectrode906. The therapy can be delivered at a singular angular position or at multiple angular positions. Infusate I optionally may be delivered through thesheath910 as shown.

It should be understood that in any of the embodiments disclosed herein, a guide wire can be optionally employed to facilitate delivery and/or removal of the probe. In such embodiments, the probe may be additionally configured with structural enhancements (e.g., guide wire lumen) for accommodating the use of a guide wire.

Additionally or alternatively, theapparatus950 can include multiple angularly spacedelectrodes906 positioned within the vasculature, as shown inFIG. 9K. In addition to angular spacing, theelectrodes906 may be longitudinally spaced to facilitate treatment over a longitudinal segment of the vessel (e.g., to achieve a circumferential treatment along the longitudinal segment rather than along a cross-section).

In addition to extravascular and intravascular systems for thermally-induced renal neuromodulation, intra-to-extravascular systems may be provided. The intra-to-extravascular systems may, for example, have electrode(s) that are delivered to an intravascular position, and then at least partially passed through/across the vessel wall to an extravascular position prior to delivery of a thermal energy field. Intra-to-extravascular positioning of the electrode(s) may place the electrode(s) in closer proximity to target neural fibers for delivery of a thermal energy field, as compared to fully intravascular positioning of the electrode(s). Applicants have previously described intra-to-extravascular pulsed electric field systems, for example, in co-pending U.S. patent application Ser. No. 11/324,188, filed Dec. 29, 2005, which is incorporated herein by reference in its entirety.

FIG. 10 is a schematic side view illustrating an embodiment of an intra-to-extravascular (‘ITEV’)system900 for thermally-induced renal neuromodulation. TheITEV system900 includes acatheter922 having (a) a plurality of proximal electrode lumens terminating atproximal side ports924, (b) a plurality of distal electrode lumens terminating atdistal side ports926, and (c) aguidewire lumen923. Thecatheter922 preferably includes an equal number of proximal and distal electrode lumens and side ports. TheITEV system900 also includesproximal needle electrodes928 that can be advanced through the proximal electrode lumens and theproximal side ports924, as well asdistal needle electrodes929 that may be advanced through the distal electrode lumens and thedistal side ports926. Alternatively, the embodiment illustrated inFIG. 10 can be configured with a single needle electrode configured for monopolar energy delivery.

Thecatheter922 includes an optionalexpandable positioning element930. Thepositioning element930 can include, for example, an inflatable balloon or an expandable basket or cage. In use, thepositioning element930 may be expanded prior to deployment of the

needle electrodes

928 and929 to position or center thecatheter922 within the patient's vessel (e.g., within renal artery RA). Centering thecatheter922 is expected to facilitate delivery of all

needle electrodes

928 and929 to desired depths within/external to the patients vessel (e.g., to deliver all of the

needle electrodes

928 and929 to approximately the same depth). In the embodiment illustrated inFIG. 10, thepositioning element930 is between theproximal side ports924 and thedistal side ports926 and, accordingly, thepositioning element930 is between the delivery positions of the proximal and distal electrodes. However, it should be understood that thepositioning element930 additionally or alternatively can be positioned at a different location or at multiple locations along the length of the catheter922 (e.g., at a location proximal of theside ports924 and/or at a location distal of the side ports926).

As shown inFIG. 10, thecatheter922 may be advanced to a treatment site within the patient's vasculature over a guidewire (not shown) via thelumen923. During intravascular delivery, the

needle electrodes

928 and929 may be positioned such that their non-insulated and sharpened distal regions are positioned within the proximal and distal lumens, respectively. Once at a treatment site, a medical practitioner may advance the

electrodes

928 and929 via their proximal regions that are located external to the patient. Such advancement causes the distal regions of the

electrodes

928 and929 to exit

side ports

924 and926, respectively, and pierce the wall of the patient's vasculature such that the electrodes are positioned extravascularly via an ITEV approach.

Theproximal electrodes928 can be connected to a field generator (not shown) as active electrodes, and thedistal electrodes929 can serve as return electrodes. In this manner, the proximal and

distal electrodes

928 and929 form bipolar electrode pairs that align the thermal energy field with a longitudinal axis or direction of the patient's vasculature. Thedistal electrodes929 alternatively may comprise the active electrodes and theproximal electrodes928 may comprise the return electrodes. Furthermore, theproximal electrodes928 and/or thedistal electrodes929 may both comprise active and return electrodes. Further still, theproximal electrodes928 and/or thedistal electrodes929 may be utilized in combination with an external ground for delivery of a monopolar thermal energy field. Any combination of active and distal electrodes may be utilized.

When the

electrodes

928 and929 are connected to a field generator and positioned extravascularly (and with thepositioning element930 optionally expanded) delivery of the thermal energy field can provide the desired renal neuromodulation via heating. After achievement of the desired thermally-induced renal neuromodulation, the

electrodes

928 and929 can be retracted within the proximal and distal lumens, and thepositioning element930 can be collapsed for retrieval. TheITEV system900 can then be removed from the patient to complete the procedure. Additionally or alternatively, thesystem900, or any system disclosed herein, may be repositioned to provide therapy at another treatment site, such as to provide bilateral renal neuromodulation.

Cooling elements, such as convective cooling elements, may be utilized to protect non-target tissues like smooth muscle cells from thermal alteration during thermally-induced renal neuromodulation via heat generation. Non-target tissues may be protected by focusing the thermal energy on the target neural fibers such that an intensity of the thermal energy is insufficient to induce thermal alteration in non-target tissues distant from the target neural fibers.

AlthoughFIGS. 3A-8B and10 illustrate bipolar systems, it should be understood that monopolar systems alternatively may be utilized as shown inFIGS. 9A-9N. For example, an active monopolar electrode may be positioned intravascularly, extravascularly, or intra-to-extravascularly in proximity to target neural fibers that contribute to renal function. A return electrode may be attached to the exterior of the patient or positioned in the patient apart from the active electrodes. Finally, a thermal energy field may be delivered between the in vivo monopolar electrode and the remote electrode to effectuate desired thermally-induced renal neuromodulation. Monopolar apparatus additionally may be utilized for bilateral renal neuromodulation.

The embodiments described above with reference toFIGS. 3A-10 are directed generally to methods and systems for thermally-induced renal neuromodulation via delivery of thermal energy fields that modulate the target neural fibers. However, it should be understood that alternative methods and systems for thermally-induced (via both heating and cooling) renal neuromodulation may be provided. For example, electric fields may be used to cool and modulate the neural fibers with thermoelectric or Peltier elements. Also, thermally-induced renal neuromodulation optionally may be achieved via resistive heating, via delivery of a heated or chilled fluid (seeFIGS. 11 and 13), via a Peltier element (seeFIG. 12), etc. Thermally-induced renal neuromodulation additionally or alternatively may be achieved via application of high-intensity focused ultrasound to the target neural fibers (seeFIGS. 14A,14B, and15). Additional and alternative methods and systems for thermally-induced renal neuromodulation may be used in accordance with the present disclosure.

FIG. 11, for example, is a schematic side view of an alternative embodiment of anapparatus1000 for thermally-induced neuromodulation via application of thermal energy. In this embodiment, the electrodes328 and329 ofFIG. 10 have been replaced with

infusion needles

1028 and1029, respectively. A thermal fluid F may be delivered through the infusion needles1028 and1029 to the target neural fibers. The thermal fluid F may be heated in order to raise the temperature of the target neural fibers above a desired threshold. For example, the temperature of the neural fibers can be raised above a body temperature of about 37° C., or above a temperature of about 45° C. Alternatively, the thermal fluid F may be chilled to reduce the temperature of the target neural fibers below a desired threshold. For example, the neural fibers can be cooled to below the body temperature of about 37° C., or further cooled below about 20° C., or still further cooled below a freezing temperature of about 0° C. As will be apparent, in addition to intra-to-extravascular delivery of a thermal fluid, the thermal fluid F may be delivered intravascularly (e.g., may inflate and/or be circulated through a balloon member), extravascularly (e.g., may be circulated through a vascular cuff), or a combination thereof.

In addition or as alternative to injection of a thermal fluid to the target neural fibers through

infusion needles

1028 and1029, an alternative neuromodulatory agent, such as a drug or medicament, may be injected to modulate, necrose or otherwise block or reduce transmission along the target neural fibers. Examples of alternative neuromodulatory agents include, but are not limited to, phenol and neurotoxins, such as botulinum toxin. Additional neuromodulatory agents, per se known, will be apparent to those of skill in the art.

FIG. 12 is a schematic side view illustrating still another embodiment of anapparatus1100 for thermal renal neuromodulation via application of thermal energy to the target neural fibers. Theapparatus1100 includes arenal artery cuff1102 having one or more integrated thermoelectric elements that are electrically coupled to an internal orexternal power supply1104. The thermoelectric element(s) utilize the well-known Peltier effect (i.e., the establishment of a thermal gradient induced by an electric voltage) to achieve thermal renal neuromodulation.

An electric current is passed from thepower supply1104 to the thermoelectric element of thecuff1102. The thermoelectric element can include two different metals (e.g., a p-type and an n-type semiconductor) that are connected to each other at two junctions. The current induces a thermal gradient between the two junctions, such that one junction cools while the other is heated. Reversal of the polarity of the voltage applied across the two junctions reverses the direction of the thermal gradient. Either the hot side or the cold side of the thermoelectric element faces radially inward in order to heat or cool, respectively, the target neural fibers that travel along the renal artery to achieve thermal renal neuromodulation. Optionally, the radially outward surface of the thermoelectric element may be insulated to reduce a risk of thermal alteration to the non-target tissues. Thecuff1102 may include one or more temperature sensors, such as thermocouples, for monitoring the temperature of the target neural fibers and/or of the non-target tissues, wherein the monitored data may be used as feedback to control the delivery of therapy.

FIG. 13 illustrates yet another embodiment of anapparatus1200 utilizing the Peltier effect. Theapparatus1200 includes an implanted orexternal pump1202 connected to arenal artery cuff1204 via aninlet fluid conduit1206aand anoutlet fluid conduit1206b. Theinlet fluid conduit1206atransfers fluid from thepump1202 to thecuff1204, while theoutlet fluid conduit1206btransfers fluid from thecuff1204 to thepump1202 to circulate the fluid through thecuff1204. A reservoir of fluid may be located in thecuff1204, thepump1202, and/or in the

fluid conduits

1206aand1206b.

Thepump1202 can further include one or more thermoelectric or other thermal elements in heat exchange contact with the fluid reservoir for cooling or heating the fluid that is transferred to thecuff1204 to thermally modulate the target neural fibers. Theapparatus1200 optionally may have controls for automatic or manual control of fluid heating or cooling, as well as fluid circulation within thecuff1204. Furthermore, theapparatus1200 may include a temperature and/or renal sympathetic neural activity monitoring or feedback control. Although theapparatus1200 ofFIG. 13 is shown unilaterally treating neural fibers innervating a single kidney, it should be understood that bilateral treatment of neural fibers innervating both kidneys alternatively may be provided.

Thermal renal neuromodulation alternatively may be achieved via pulsed or continuous high-intensity focused ultrasound. Furthermore, the ultrasound may be delivered over a full 360° (e.g. when delivered intravascularly) or over a radial segment of less than 360° (e.g., when delivered intravascularly, extravascularly, intra-to-extravascularly, or a combination thereof.

FIGS. 14A and 14B, for example, are schematic side views illustrating an embodiment of anultrasonic apparatus1300 including acatheter1302, one ormore ultrasound transducers1304 positioned along the shaft of thecatheter1302, and aninflatable balloon1306 around thetransducers1304.FIG. 14A illustrates theapparatus1300 in a reduced delivery and retrieval configuration, andFIG. 14B illustrates theapparatus1300 in an expanded deployed configuration. Theultrasound transducers1304 are coupled to an ultrasound signal generator (not shown) viaconductors1307. Theballoon1306 can have an acousticallyreflective portion1308 for reflecting an ultrasound wave and an acousticallytransmissive portion1309 through which the ultrasonic energy can pass. In this manner, the wave may be focused as shown at a focal point or radius P positioned a desired focal distance from the catheter shaft. In an alternative embodiment, thetransducers1304 may be attached directly to theballoon1306.

The focal distance may be specified or dynamically variable such that the ultrasonic wave is focused at a desired depth on target neural fibers outside of the vessel. For example, a family of catheter sizes may be provided to allow for a range of specified focal distances. A dynamically variable focal distance may be achieved, for example, via calibrated expansion of theballoon1306.

Focusing the ultrasound wave may produce a reverse thermal gradient that protects the non-target tissues and selectively affect the target neural fibers to achieve thermal renal neuromodulation via heating. As a result, the temperature at the vessel wall may be less than the temperature at the target tissue.

FIG. 15 illustrates still another embodiment of anultrasonic apparatus1400 having acatheter1402, a conductor1403, andconcave ultrasound transducers1404. Theconcave ultrasound transducers1404 direct the energy to a specific focal point P. As such, theconcave transducers1404 are self-focusing and eliminate the need for reflective portions on the balloon1406 (e.g., the balloon may be acoustically transmissive at all points).

The systems described above with respect toFIGS. 3A-15 optionally may be used to quantify the efficacy, extent, or cell selectivity of thermally-induced renal neuromodulation in order to monitor and/or control the neuromodulation. As discussed previously, the systems can further include one or more sensors, such as thermocouples or imaging transducers, for measuring and monitoring one or more parameters of (a) the system, (b) target neural fibers, and/or (c) non-target tissues. For example, a temperature rise or drop above or below certain thresholds is expected to thermally ablate, non-ablatively alter, freeze, or otherwise alter the target neural fibers to thereby modulate the target neural fibers.

It should be understood that any of the methods, apparatuses, and systems disclosed herein can be modified or configured for cooling or freezing treatments which modulate neural fibers. For example, any of the probes disclosed herein can be modified to deliver cryotherapy to the target neural fibers with either an intravascular, extravascular or ITEV approach.

D. Modules and Methods for Controlling Thermally-Induced Renal Neuromodulation

With the treatments disclosed herein for delivering therapy to target tissue, it may be beneficial for energy to be delivered to the target neural structures in a controlled manner. The controlled delivery of energy will allow the zone of thermal treatment to extend into the renal fascia while minimizing undesirable energy delivery or thermal effects to the vessel wall. A controlled delivery of energy may also result in a more consistent, predictable and efficient overall treatment. Accordingly, it may be beneficial to incorporate a controller or computer system having programmed instructions for delivering energy to tissue into the energy delivery system. Additionally, these programmed instructions may comprise an algorithm for automating the controlled delivery of energy. Alternatively, the delivery of energy to target tissue can be controlled manually by an operator or the physician administering treatment.

In one embodiment, for example, a controller can command a power generator (e.g., thefield generator110 ofFIGS. 3A and 3B) in accordance with an algorithm comprising various power delivery profiles.FIG. 16, for example, is a flow chart illustrating amethod1600 of controlling such power delivery processes. Themethod1600 can be implemented as a conventional computer program for execution by theprocessor114 ofFIG. 3A or another suitable device (e.g., the field generator110). Themethod1600 can also be implemented manually by an operator.

As illustrated inFIG. 16, after treatment is initiated, thefirst stage1602 of themethod1600 includes monitoring certain operating parameters (e.g., temperature, time, impedance, power, etc.). While it is preferred that these operating parameters are monitored continuously, they can alternatively be monitored periodically. Atstage1604, themethod1600 includes checking the monitored parameters against predetermined parameter profiles to determine whether the parameters individually or in combination fall within the ranges set by the predetermined parameter profiles. For example, temperature can be monitored and compared to a predetermined temperature value. Alternatively, both temperature and impedance can be monitored and compared to a predetermined parameter profile of both temperature and impedance. If the monitored parameters fall within the ranges set by the predetermined parameter profiles, then treatment is continued at the same settings and the operating parameters continue to be monitored.

When it is determined that one or more parameters or multiple parameters in combination fall outside a predetermined parameter profile, then themethod1600 calls for an adjustment to the system's power output atstage1606. The direction (i.e., increase or decrease) and degree of the power output adjustment can be determined by a routine utilizing the monitored parameters and how they compare against other predetermined parameter profiles. For example, if temperature and time are monitored and it is determined that the monitored temperature and time exceed a predetermined parameter profile of temperature and time, then power delivery may be reduced. Alternatively, if one or more monitored parameters or multiple monitored parameters in combination falls short of a predetermined parameter profile, then power delivery may be increased. As shown inFIG. 16, treatment will continue until power delivery has been adjusted to a level of zero (stage1608).

The operating parameters monitored in accordance with the algorithm may include temperature, time, impedance, and power. Discrete values in temperature may be used to trigger changes in energy delivery. For example, high values in temperature (e.g. 85° C.) could indicate tissue desiccation in which case the algorithm may decrease or stop the energy delivery to prevent undesirable thermal effects to target or non-target tissue. Time may also be used to prevent undesirable thermal alteration to non-target tissue. For each treatment, a set time (e.g., 2 minutes) is checked to prevent indefinite delivery of energy. Impedance may be used to measure tissue changes. Impedance indicates the electrical property of the treatment site. If a thermal inductive, electric field is applied to the treatment site the impedance will decrease as the tissue cells become less resistive to current flow. If too much energy is applied, tissue desiccation or coagulation may occur near the electrode which would increase the impedance as the cells lose water retention and/or the electrode surface area decreases (e.g., via the accumulation of coagulum). Thus, an increase in tissue impedance may be indicative or predictive of undesirable thermal alteration to target or non-target tissue. Additionally, power is an effective parameter to monitor in controlling the delivery of therapy. Power is a function of voltage and current. The algorithm may tailor the voltage and/or current to achieve a desired power. Derivatives of the aforementioned parameters (e.g., rates of change) can also be used to trigger change in energy delivery. For example, the rate of change in temperature could be monitored such that power output is reduced in the event that a sudden rise in temperature is detected.

To implement the aforementioned control algorithm, the system may include one or more computing system hardware and/or software modules. Alternatively, computer hardware and software can be utilized to facilitate any energy delivery process or system.FIG. 17, for example, illustrates a functional diagramshowing software modules1620 suitable for use in theprocessor114 ofFIG. 3A or another suitable device (e.g., the field generator110) to perform methods for modulating renal nerves. Each component can be a computer program, procedure, or process written as source code in a conventional programming language, such as the C++ programming language, and can be presented for execution by the CPU ofprocessor114. The various implementations of the source code and object and byte codes can be stored on a computer-readable storage medium or embodied on a transmission medium in a carrier wave. The modules of theprocessor114 can include aninput module1622, adatabase module1624, aprocess module1626, anoutput module1628, and adisplay module1630. In another embodiment, thesoftware modules1620 can be presented for execution by the CPU of a network server in a distributed computing scheme.

In operation, theinput module1622 accepts operator input, such as process setpoint and control selections, and communicates the accepted information or selections to other components for further processing. Thedatabase module1624 organizes records, including anoperating parameter1634, anoperator activity1636, and one ormore alarms1638, and thedatabase module1624 facilitates storing and retrieving of these records to and from adatabase1632. Any type of database organization can be utilized, including a flat file system, hierarchical database, relational database, or distributed database, such as those provided by Oracle Corporation of Redwood Shores, Calif.

Theprocess module1626 can process the sensor readings1640 (e.g., from thesensors310 inFIG. 5A), check for alarms and interlocks, and generate control variables for controlling an energy delivery process of the field generator110 (FIG. 3A) based on thesensor readings1640. Theoutput module1628 can generateoutput signals1642 based on the control variables. For example, theoutput module1628 can convert the generated control variables from theprocess module1626 intooutput signals1642 suitable for an energy output modulator. Thedisplay module1630 can display, print, or download thesensor readings1640 and theoutput signals1642 via devices such as the output device120 (FIG. 3A) or a visual display on the face of thefield generator110. Asuitable display module1630 can be a video driver that enables theprocessor114 to display thesensor readings1640 on theoutput device120.

FIG. 18 is a block diagram showing an embodiment of theprocess module1626 ofFIG. 17. Theprocess module1626 can further include asensing module1650, a calculation module1652, analarm module1654, apower output module1656, and aninterlock module1658 interconnected with each other. Each module can be a computer program, procedure, or routine written as source code in a conventional programming language, or one or more modules can be hardware modules.

Thesensing module1650 can receive and convert thesensor readings1640 into parameters in desired units. For example, thesensing module1650 can receive thesensor readings1640 as electrical signals and convert the electrical signals into instant temperatures in Celsius. Thesensing module1650 can have routines including, for example, linear interpolation, logarithmic interpolation, data mapping, or other routines to associate thesensor readings1640 to parameters in desired units.

The calculation module1652 can perform various types of calculation to facilitate operation of other modules. For example, the calculation module1652 can derive an average temperature based on the measured temperatures over a period of time according to the following formula:

T_{avg} = \frac{\sum T_{i}}{N}

where T_iis a measured temperature, T_avgis the average temperature, and N is the number of temperature records. Other averaging techniques, such as an exponential moving average can also be used. The calculation module466 can also derive a rate of change for the measured temperature according to the following formula:

\frac{\partial T}{\partial t} \approx \frac{T_{i + 1} - T_{i}}{Δ t}

where T_i+1is the temperature record number i+1, T_iis the previous temperature record, and Δt is the time difference between the two temperature records.

Thealarm module1654 can generate alarms based on output from the calculation module1652 and/or thesensing module1650. For example, thealarm module1654 can compare the average or instantaneous temperature calculated in the calculation module1652 to a preset threshold value (i.e., predetermined parameter profile). If the average or instantaneous temperature exceeds the threshold value, thealarm module1654 can issue an alarm by raising an alarm flag or another type of response. In response to the alarm flag, the output device120 (FIG. 3A) can issue a notification by displaying a flashing message, sounding a horn, turning on a warning light, and/or providing another indicator. In certain embodiments, thealarm module1654 can also include routines for implementing hysteresis. For example, thealarm module1654 can latch the alarm flag when the average or instantaneous temperature exceeds the threshold and deactivate the alarm only when the average or instantaneous temperature drops below the threshold by a certain amount.

Thepower output module1656 can generate theoutput signals1642 to the field generator110 (FIGS. 3A and 3B) for modulating power output of thefield generator110. In one embodiment, thepower output module1656 can generate theoutput signals1642 according to a preset power delivery profile. For example, the power delivery profile can include a maximum power level, a minimum power level, and a rate of increase over a certain period of time to ramp from the minimum power level to the maximum power level. In other embodiments, thepower output module1656 can generate theoutput signals1642 based on monitored operating parameter data or other output from thesensing module1650 and/or the calculation module1652. For example, thepower output module1656 can modify the rate of increase based on the average temperature calculated in the calculation module1652, or the instant temperature from thesensing module1650, as described below.

Theinterlock module1658 continuously monitors operating parameters received from thesensing module1650 and/or the calculation module1652, and theinterlock module1658 can control operation of thepower output module1656 when the monitored operating parameters exceed certain interlock threshold values. Depending on the interlock condition, thepower output module1656 can set a power setpoint above or below the current setpoint (i.e., increase or decrease power) or it can set a power setpoint of zero (i.e., terminate power delivery). For example, theinterlock module1658 can cause thepower output module1656 to reduce the power output when the average temperature from the calculation module1652 exceeds a preset value. Additionally or alternatively, the interlock module can cause thepower output module1656 to terminate its operation (i.e., having a zero output value) when the instant temperature from thesensing module1650 exceeds another preset value. In several embodiments, theinterlock module1658 can optionally be configured to directly generateoutput signals1642 to the other system components.

In certain embodiments, theprocess module1626 can include additional modules. For example, theprocess module1626 can include a configuration module for configuring any one of thesensing module1650, the calculation module1652, thealarm module1654, thepower output module1656, and/or theinterlock module1658.

Theprocess module1626 can also include control modules for controlling selected process parameters. For example, theprocess module1626 can include proportional-integral-derivative (PID) modules for maintaining a process parameter (e.g., the measured temperature) at a desired value. Theprocess module1626 can also include one or more PID modules that attempt to maintain one process parameter (e.g., temperature) unless limited by other process parameters (e.g., maximum power or impedance values). Theprocess module1626 can also include feed-forward modules in addition to the PID modules for improved control. For example, the feed-forward modules can calculate an expected power level based on the measured temperature, the heat conductance, and/or other parameters of the wall of the body lumen. The expected power level can then be combined with the output of the PID modules to compensate for any delayed response.

To better understand the methods described above with reference toFIG. 16, it may be helpful to discuss themethod1600 in view of a power delivery profile.FIG. 19, for example, is a graph of power versus time showing a typical response of performing an embodiment of themethod1600. Referring toFIGS. 16-19 together, one embodiment of themethod1600 includes a function in which theinterlock module1658 checks for interlock conditions (i.e., monitored operating parameters vs. predetermined parameter profiles), which corresponds to

stages

1602 and1604 ofFIG. 16. If any interlock condition exists, then atstage1606 theinterlock module1658 adjusts power output or delivery (e.g., increase/decrease power level or force output to zero). If it is determined that the power level is adjusted to zero atstage1608, the therapy is terminated. The interlock conditions can include those indicating an unsafe or undesired operating state, or those indicating incomplete energy delivery. For example, the following is a non-exhaustive list of events that can be the interlock conditions:

- (1) The measured temperature exceeds a maximum temperature threshold (e.g., about 70° to about 85° C.).
- (2) The average temperature derived from the measured temperature exceeds an average temperature threshold (e.g., about 65° C.).
- (3) The rate of change of the measured temperature exceeds a rate of change threshold.
- (4) The temperature rise over a period of time is below a minimum temperature change threshold while the field generator110 (FIG. 3A) has non-zero output. Poor contact between theelectrode108 and the wall can cause such a condition.
- (5) A measured impedance exceeds an impedance threshold (e.g., <20 Ohms, or >500 Ohms).
- (6) A measured impedance exceeds a relative threshold (e.g., impedance decreases from a starting or baseline value and then rises above this baseline value).

As illustrated inFIG. 19, the first interlock condition occurs at time0 (i.e., the time at which the operator has initiated treatment and the timer begins counting up from zero). In this case, themethod1600 continues atstage1606 with thepower output module1656 commanding thefield generator110 to gradually adjust its power output to a first power level P₁(e.g., 5 watts) over a first time period (0−t₁) (e.g., 15 seconds). The power output module470 can generate and transmit a power setpoint to thefield generator110 as the output signals1642. In one embodiment, as illustrated inFIG. 19, the power increase during the first time period is generally linear. As a result, thefield generator110 increases its power output at a generally constant rate of P₁/t₁. In other embodiments, the power increase can be non-linear (e.g., exponential or parabolic) with a variable rate of increase.

After the first time period expires (or after the power level at P₁has been achieved), thepower output module1656 can command thefield generator110 to maintain its current output power level at P₁, i.e., pause for a second time period (t₁-t₂). An operator or preprogrammed routine can adjust the time period (t₁-t₂) based on the patient's physiological characteristics. For example, if the patient's body lumen is slow in responding to temperature changes, then the operator or preprogrammed routine can increase the time period (t₁-t₂) to compensate for the additional response delay. In other embodiments, thepower output module1656 may cause thefield generator110 to reduce the output level to less than P₁or momentarily terminate its output level during the second time period (t₁-t₂) or any other time period (e.g., the first time period or subsequent time periods).

After the second time period expires, the calculation module1652 can derive an average temperature at the end of the second time period, i.e., t₂, based on the temperature from thesensing module1650. Themethod1600 can continue with a test to determine whether the calculated average temperature at t₂exceeds a preset threshold (e.g., 65° C.). If the average temperature exceeds the preset threshold, then thepower output module1656 can command thefield generator110 to maintain its current output power level for a desired total treatment time.

If the average temperature does not exceed the preset threshold, then themethod1600 can continue atstage1606 with the power level P_ibeing increased by an amount ΔP from P_i. In one embodiment, ΔP can be a predetermined fixed amount (e.g., 0.5 watts). In other embodiments, ΔP can be a variable amount. For example, the difference between the average temperature and a maximum temperature threshold can determine ΔP according to the following formula:

ΔP=k×(T_max−T_avg)

where k is a user-selected or predetermined constant, T_maxis the maximum temperature threshold, and T_avgis the average temperature.

Themethod1600 can continue with another test to determine whether the increased power level (P_i+ΔP) exceeds a maximum power level (e.g., 10 watts) for thefield generator110. An operator or preprogrammed routine can select the maximum power level to represent a safe or preferred operating mode and adjust the selected power level based on treatment conditions. If the maximum power level is exceeded, thenpower output module1656 commands thefield generator110 to maintain its current output power level until a desired total treatment time is reached. If the maximum power level is not exceeded, then the process returns to pausing, and the subsequent stages are repeated. Although the specific example of themethod1600 described above uses the measured temperature as a process parameter, other physiological parameters (e.g., impedance, resistivity, and/or capacitance) and non-physiological parameters (e.g., time, power, etc.) can be used instead of or in addition to the measured temperature.

Optionally, the calculation module1652 can calculate the number of cycles before the maximum power level is reached. For example, when a fixed ΔP is used, the calculation module1652 can calculate the number of cycles according to the following formula:

n = \frac{P_{\max} - P_{1}}{Δ P}

where P_maxis the maximum power level, and n is the number of cycles.

After the ramp up process terminates, thepower output module1656 can still command thefield generator110 to modify its power output level based on the calculated average temperature, the rate of change of the measured temperature, the rate of change in impedance, and/or other parameters. For example, as discussed below, thepower output module1656 can command thefield generator110 to discretely or continuously decrease its power output level when the measured temperature is increasing at a rate exceeding a rate of change threshold or when the measured instant temperature exceeds another preset threshold.

Themethod1600 can also optionally include a ramping process that allows the power level to be increased at a faster rate. For example, themethod1600 can include a test to check the average temperature and determine if it is below a preselected threshold (e.g., 50 C). If the average temperature is below the threshold, then thepower output module1656 can command thefield generator110 to increase the power level P_iby an amount equal to ΔP×F where F is a step factor (e.g., 2). The test can be repeated at the start of each ramp stage or at other selected points in the ramping process. The rapid ramping process is expected to allow the power output level to reach its desired treatment level more quickly. In another embodiment where a PID module is used to control power output, the PID module can be tuned to rapidly ramp up power when the measured temperature is far below a specified level (e.g., 65 C) but slow down the power ramping as the measured temperature approaches the specified level.

Themethod1600 can also optionally include a power reduction process to incrementally step down or ramp down the power level during treatment. The example described above specifically tailors the power output process to reduce the risk of overheating the walls of the patient's body lumen via temperature monitoring. In the case where the maximum power level is reached, the temperature and/or the measured impedance may continue to rise beyond a certain threshold. In many cases, exceeding such thresholds could be an indicator that an alarm threshold could be reached where power output would be terminated. The method described below, however, can be used to decrease power to prevent a premature termination of power delivery due to temperature and/or impedance reaching an alarm threshold.

During power delivery, theinterlock module1658 can continuously monitor one or more operating parameters received from thesensing module1650 and/or the calculation module1652. For example, this method can include a test to determine whether the calculated average temperature is greater than or equal to a preset threshold T_t(e.g., 70° C.). If the average temperature does not exceed the preset threshold T_t, then theinterlock module1658 does not interrupt operation of thepower output module1656 and the current power output level is maintained for treatment.

On the other hand, if the average temperature (from the calculation module1652) exceeds the preset threshold T_t, then the method can continue withstage1606 in which the power level is reduced. During this power reduction stage, thepower output module1656 can command the field generator to immediately decrease power by P_s(e.g., 1 watt). After decreasing the power, the method can pause thepower output module1656 for a time period T_w(e.g., 3 seconds). After the time period T_wexpires, the calculation module1652 can again derive an average temperature based on the temperature from thesensing module1650. The method can continue with another test at to determine whether the calculated average temperature still exceeds the preset threshold T_t. In some cases, this power reduction process may need to be repeated several times, decreasing power by P_seach time, until the average temperature does not exceed the preset threshold. If the average temperature does not exceed the threshold, the method can continue with a sustained power stage for the duration of the treatment time.

In another aspect of this embodiment, the method can include a test to determine whether an increase or rate of increase in impedance is too large. More specifically, theinterlock module1658 can measure the slope of the impedance over a fixed period of time. If the measured slope does not exceed a preset threshold, then theinterlock module1658 does not adjust operation of thepower output module1656, and the method can continue with a sustained power level. However, if the measured slope is greater than a preset threshold Z_s(e.g., 3 ohms per second), then the method can proceed to the power reduction described above. As mentioned above, the power reduction process may need to be repeated several times until the measured slope does not exceed the preset threshold Z_s. An operator or preprogrammed routine can adjust the preset thresholds T_tand Z_sor the power reduction rate based on the patient's physiological characteristics and/or one or more desired treatment parameters.

In yet another aspect of this embodiment, theinterlock module1658 can continuously monitor the impedance and, if at any point during treatment the impedance rises above a minimum impedance plus a preselected threshold, the power output can be decreased until the impedance value is within the desired range. If the impedance value does not change to be within the desired range or continues to rise above an alarm threshold, then power delivery can be terminated.

In further detail, this method can include a test to compare the measured impedance value with a preselected minimum impedance value. If the measured impedance value is less than the preselected minimum impedance value, the minimum value is updated to be equal to the measured value. These stages can be repeated any number of times as necessary during treatment. In effect, the method keeps track of the lowest impedance value measured by the system.

If the measured impedance is greater than the minimum impedance value plus a preselected threshold value Z_d(e.g., 20 ohms), then the method can continue to the power reduction process as described above. After decreasing the power, the method can pause thepower output module1656 for a time period T_w2(e.g., 3 seconds). After the time period T_w2expires, theinterlock module1658 can again monitor impedance and, if the measured impedance value is still greater than the minimum impedance value plus the threshold value, the method can repeat the power reduction process any number of times as necessary until the impedance condition does not occur, and then return to the sustained power stage.

One expected advantage of themethods1600 and the various embodiments described above is the reduced risk of undesirable treatment effects to target and non-target tissue (e.g., excessively damaging the wall of the body lumen). As described above with reference toFIGS. 3A and 3B, thefield generator110 can deliver an electric field to theprobe104 to apply energy to the wall of the body lumen and surrounding areas for effectuating neural modulation. However, many factors can contribute to a delayed response of the body lumen to the applied energy (as indicated by the measured temperature and/or impedance). For example, the latent heat of the body lumen, circulation around or within the body lumen, contact between a sensor and the wall of the body lumen, and other factors can cause the delayed temperature and/or impedance response to the applied energy. To compensate for this delay in response, themethod1600 may incorporate a delay period in which some parameters are not monitored for the duration of the delay period. As a result, adverse overheating of the body lumen can be mitigated or even eliminated. Furthermore, a power reduction process further helps reduce the risk of excessively damaging the body lumen wall, while also preventing premature termination of power delivery due to a parameter reaching an alarm threshold.

It is expected that thermally-induced renal neuromodulation, whether delivered extravascularly, intravascularly, intra-to-extravascularly or a combination thereof, may alleviate clinical symptoms of CHF, hypertension, renal disease, myocardial infarction, atrial fibrillation, contrast nephropathy and/or other renal or cardio-renal diseases for a period of months (potentially up to six months or more). This time period may be sufficient to allow the body to heal; for example, this period may reduce the risk of CHF onset after an acute myocardial infarction to thereby alleviate a need for subsequent re-treatment. Alternatively, as symptoms reoccur, or at regularly scheduled intervals, the patient may receive repeat therapy. Thermally-induced renal neuromodulation also may systemically reduce sympathetic tone.

While the therapies disclosed herein relate to modulating nerves that contribute to renal function via denervation, it should be understood that the methods, apparatuses, and systems disclosed herein can be configured and/or modified for therapeutic energy transfer with other locations within the body. For example, these inventions can be modified for the purposes of energy delivery within a body lumen (e.g., a peripheral blood vessel) to achieve denervation or some other therapeutic result.

From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but well-known structures and functions have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments of the invention. Where the context permits, singular or plural terms may also include the plural or singular term, respectively. Moreover, unless the word “or” is expressly limited to mean only a single item exclusive from the other items in reference to a list of two or more items, then the use of “or” in such a list is to be interpreted as including (a) any single item in the list, (b) all of the items in the list, or (c) any combination of the items in the list. Additionally, the term “comprising” is used throughout to mean including at least the recited feature(s) such that any greater number of the same feature and/or additional types of other features are not precluded. It will also be appreciated that specific embodiments have been described herein for purposes of illustration, but that various modifications may be made without deviating from the invention. Accordingly, the invention is not limited except as by the appended claims.