U.S. patent application number 11/599723 was filed with the patent office on 2007-06-14 for methods and apparatus for thermally-induced renal neuromodulation.
This patent application is currently assigned to Ardian, Inc.. Invention is credited to Mark Deem, Denise Demarais, Hanson III Gifford, Andrew Wu.
Application Number | 20070135875 11/599723 |
Document ID | / |
Family ID | 46326579 |
Filed Date | 2007-06-14 |
United States Patent
Application |
20070135875 |
Kind Code |
A1 |
Demarais; Denise ; et
al. |
June 14, 2007 |
Methods and apparatus for thermally-induced renal
neuromodulation
Abstract
Methods and apparatus 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.
Inventors: |
Demarais; Denise; (Los
Gatos, CA) ; Wu; Andrew; (Foster City, CA) ;
Gifford; Hanson III; (Woodside, CA) ; Deem; Mark;
(Mountain View, CA) |
Correspondence
Address: |
PERKINS COIE LLP;PATENT-SEA
P.O. BOX 1247
SEATTLE
WA
98111-1247
US
|
Assignee: |
Ardian, Inc.
Palo Alto
CA
|
Family ID: |
46326579 |
Appl. No.: |
11/599723 |
Filed: |
November 14, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10408665 |
Apr 8, 2003 |
7162303 |
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11599723 |
Nov 14, 2006 |
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11189563 |
Jul 25, 2005 |
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11599723 |
Nov 14, 2006 |
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11129765 |
May 13, 2005 |
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11189563 |
Jul 25, 2005 |
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11504117 |
Aug 14, 2006 |
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11599723 |
Nov 14, 2006 |
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60816999 |
Jun 28, 2006 |
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60370190 |
Apr 8, 2002 |
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60415575 |
Oct 3, 2002 |
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60442970 |
Jan 29, 2003 |
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60616254 |
Oct 5, 2004 |
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60624793 |
Nov 2, 2004 |
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Current U.S.
Class: |
607/96 |
Current CPC
Class: |
A61B 2018/00642
20130101; A61F 7/123 20130101; A61N 1/326 20130101; A61B 2018/00511
20130101; A61B 2018/00577 20130101; A61N 1/36007 20130101; A61N
5/045 20130101; A61M 5/1723 20130101; A61N 1/36117 20130101; A61B
2018/00404 20130101; A61N 1/28 20130101; A61N 7/02 20130101; A61B
18/1492 20130101; A61N 1/403 20130101; A61B 2018/00434 20130101;
A61N 1/32 20130101; A61N 2007/003 20130101; A61B 2018/00505
20130101; A61M 5/14276 20130101; A61N 1/36017 20130101; A61N
1/36114 20130101; A61N 1/3627 20130101; A61F 2007/126 20130101;
A61M 2210/1082 20130101 |
Class at
Publication: |
607/096 |
International
Class: |
A61F 7/00 20060101
A61F007/00 |
Claims
1. A method for thermally-induced renal neuromodulation, the method
comprising: positioning a thermal apparatus at least proximate to a
neural fiber that contributes to renal function; and delivering
pulsed energy via the thermal apparatus to modulate a function of
the neural fiber via thermal effects.
2. The method of claim 1, wherein positioning the thermal apparatus
further comprises delivering the device via an approach chosen from
the group consisting of intravascularly, extravascularly,
intra-to-extravascularly and combinations thereof.
3. The method of claim 1, wherein delivering the pulsed energy
further comprises directly applying pulsed thermal energy to the
neural fiber.
4. The method of claim 1, wherein delivering the pulsed energy
further comprises indirectly applying pulsed thermal energy to the
neural fiber.
5. The method of claim 1, wherein delivering the pulsed energy
further comprises delivering a pulsed thermal electric field to the
neural fiber via at least one electrode.
6. The method of claim 5, wherein positioning the thermal apparatus
further comprises intravascularly delivering the device, and
wherein delivering a pulsed thermal electric field to the neural
fiber via at least one electrode further comprises delivering the
pulsed thermal electric field via at least one wall-contact
electrode.
7. The method of claim 1 further comprising monitoring a parameter
of at least one of the neural fiber, a non-target tissue or the
apparatus during thermally-induced modulation of the function of
the neural fiber.
8. The method of claim 7 further comprising controlling the
delivery of the pulsed energy in response to the monitored
parameter.
9. The method of claim 1 further comprising actively protecting
non-target tissue during thermal modulation of the neural
fiber.
10. The method of claim 9, wherein actively protecting the
non-target tissue further comprises reducing a degree of thermal
damage induced in the non-target tissue.
11. The method of claim 9, wherein actively protecting the
non-target tissue further comprises delivering a thermal fluid to a
vicinity of the non-target tissue.
12. The method of claim 9, wherein actively protecting the
non-target tissue further comprises establishing a heat transfer
rate discrepancy between the non-target tissue and the neural
fiber.
13. The method of claim 1, wherein delivering the pulsed energy
further comprises delivering pulsed high intensity focused
ultrasound to the neural fiber.
14. The method of claim 1, wherein delivering the pulsed energy
further comprises heating the neural fiber via the pulsed thermal
energy.
15. The method of claim 1, wherein delivering the pulsed energy
further comprises cooling the neural fiber via the pulsed thermal
energy.
16. Apparatus for thermally-induced renal neuromodulation, the
apparatus comprising: a pulse generator configured to provide
pulsed thermal energy; a device configured for delivery within a
blood vessel to a vicinity of a neural fiber that contributes to
renal function; and a thermal modulation element supported by the
device, the thermal modulation element being configured to expand
from a first dimension to a second dimension, wherein the thermal
modulation element is configured to (a) contact a wall of the blood
vessel upon expansion of the thermal modulation element to the
second dimension within the blood vessel, and (b) transmit the
pulsed thermal energy relative to the neural fiber to thermally
induce modulation of a function of the neural fiber upon expansion
of the thermal modulation element to the second dimension within
the blood vessel.
17. The apparatus of claim 16, wherein the thermal modulation
element is configured to self-expand from the first dimension to
the second dimension.
18. The apparatus of claim 16, wherein the device further comprises
an expandable member that is at least proximate to the thermal
modulation element, the expandable member being configured to
expand the thermal modulation element from the first dimension to
the second dimension.
19. The apparatus of claim 16, wherein the thermal modulation
element is configured for direct application of the pulsed thermal
energy relative to the neural fiber.
20. The apparatus of claim 16, wherein the thermal modulation
element is configured for indirect application of the pulsed
thermal energy relative to the neural fiber.
21. The apparatus of claim 16, wherein the thermal modulation
element further comprises at least one electrode configured to
deliver a pulsed thermal electric field relative to the neural
fiber.
22. The apparatus of claim 16, wherein the apparatus further
comprises at least one sensor.
23. The apparatus of claim 22, wherein the sensor is configured to
monitor a physiological parameter of the neural fiber.
24. The apparatus of claim 22, wherein the sensor is configured to
monitor a physiological parameter of non-target tissue.
25. The apparatus of claim 22, wherein the sensor is configured to
monitor a parameter of the apparatus.
26. The apparatus of claim 22 further comprising a feedback control
in communication with the sensor.
27. The apparatus of claim 16, wherein the apparatus further
comprises a protective element configured to reduce a degree of
thermal damage induced in non-target tissue.
28. The apparatus of claim 16, wherein the thermal modulation
element further comprises at least one thermoelectric element
configured to deliver the pulsed thermal energy relative to the
neural fiber.
29. The apparatus of claim 16, wherein the thermal modulation
element further comprises a high intensity focused ultrasound
element.
30. The apparatus of claim 16, wherein the thermal modulation
element further comprises a thermal fluid.
31. The apparatus of claim 27, wherein the protective element
comprises an infusion element configured to infuse a thermal fluid
in a vicinity of the non-target tissue.
32. The apparatus of claim 16 further comprising an occlusion
element configured to temporarily occlude blood flow within the
blood vessel.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Provisional Application No. 60/816,999 filed on Jun. 28, 2006. The
present application is also a Continuation-In-Part application of
co-pending U.S. patent application Ser. No. 10/408,665, filed on
Apr. 8, 2003, which claims the benefit of U.S. Provisional
Application Nos. (a) 60/370,190, filed on Apr. 8, 2002, (b)
60/415,575, filed on Oct. 3, 2002, and (c) 60/442,970, filed on
Jan. 29, 2003. Furthermore, this application is a
Continuation-In-Part application of co-pending 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 Ser.
No. 11/129,765, filed on May 13, 2005, and which claims the benefit
of U.S. Provisional Application Nos. (a) 60/616,254, filed on Oct.
5, 2004, and (b) 60/624,793, filed on Nov. 2, 2004. Furtherstill,
this application is a Continuation-In-Part application of
co-pending U.S. patent application Ser. No. 11/504,117, filed on
Aug. 14, 2006.
[0002] All of these applications are incorporated herein by
reference in their entireties.
INCORPORATION BY REFERENCE
[0003] 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
[0004] The present invention relates to methods and apparatus for
neuromodulation. More particularly, the present invention relates
to methods and apparatus for achieving renal neuromodulation via
thermal heating and/or cooling mechanisms.
BACKGROUND
[0005] Heart Failure or Chronic Heart Failure ("CHF") is a
condition that occurs when the heart becomes damaged and reduces
blood flow to the organs of the body. If blood flow decreases
sufficiently, kidney function becomes altered, which results in
fluid retention, abnormal hormone secretions and increased
constriction of blood vessels. These results increase the workload
of the heart and further decrease the capacity of the heart to pump
blood through the kidneys and circulatory system.
[0006] It is believed that progressively decreasing perfusion of
the kidneys is a principal non-cardiac cause perpetuating the
downward spiral of CHF. Moreover, the fluid overload and associated
clinical symptoms resulting from these physiologic changes result
in additional hospital admissions, poor quality of life and
additional costs to the health care system.
[0007] In addition to their role in the progression of CHF, the
kidneys play a significant role in the progression of Renal Failure
or Chronic Renal Failure ("CRF"), Renal Disease or End-Stage Renal
Disease ("ESRD"), Hypertension (pathologically high blood pressure)
and other cardio-renal diseases. The functions of the kidneys can
be summarized under three broad categories: filtering blood and
excreting waste products generated by the body's metabolism;
regulating salt, water, electrolyte and acid-base balance; and
secreting hormones to maintain vital organ blood flow. Without
properly functioning kidneys, a patient will suffer water
retention, reduced urine flow and an accumulation of waste toxins
in the blood and body. These conditions result from reduced renal
function or renal failure (kidney failure) and are believed to
increase the workload of the heart. In a CHF patient, renal failure
will cause the heart to further deteriorate as fluids are retained
and blood toxins accumulate due to the poorly functioning
kidneys.
[0008] It has been established in animal models that the heart
failure condition results in abnormally high sympathetic activation
of the kidneys. An increase in renal sympathetic nerve activity
leads to decreased removal of water and sodium from the body, as
well as increased renin secretion. Increased renin secretion leads
to vasoconstriction of blood vessels supplying the kidneys, which
causes decreased renal blood flow. Reduction of sympathetic renal
nerve activity, e.g., via denervation, may reverse these
processes.
[0009] Applicants have described methods and apparatus for treating
renal disorders by applying a pulsed electric field, preferably
non-thermal, to neural fibers that contribute to renal function.
See, for example, Applicants' co-pending U.S. patent application
Ser. Nos. (a) 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. A pulsed electric field ("PEF") may
initiate renal denervation or other types of neuromodulation via
irreversible electroporation or other processes. The PEF may be
delivered from apparatus positioned intravascularly,
extravascularly, intra-to-extravascularly or a combination thereof.
Additional methods and apparatus for achieving renal
neuromodulation via localized drug delivery (such as by a drug pump
or infusion catheter) or use of a stimulation electric field are
described in co-owned and co-pending U.S. patent application Ser.
No. 10/408,665, filed Apr. 8, 2003, and U.S. Pat. No. 6,978,174,
both of which are incorporated herein by reference in their
entireties.
[0010] A potential challenge of using non-thermal PEF systems for
treating renal disorders is to selectively electroporate target
cells without affecting other cells. For example, it may be
desirable to irreversibly electroporate renal nerve cells that
travel along or in proximity to renal vasculature, but it may not
be desirable to damage the smooth muscle cells of which the
vasculature is composed. As a result, an overly aggressive course
of non-thermal PEF therapy may persistently injure the renal
vasculature, but an overly conservative course of non-thermal PEF
therapy may not achieve the desired renal neuromodulation.
[0011] Applicants have also described methods and apparatus for
monitoring changes in tissue impedance or conductivity in order to
determine the effects of pulsed electric field therapy. Such
changes in tissue can be used to determine an extent of
electroporation and/or its degree of irreversibility in target or
non-target tissue. See, for example, Applicant's co-pending U.S.
patent application Ser. No. 11/233,814, filed Sep. 23, 2005, which
is incorporated herein by reference in its entirety. However, in
some patients it may be difficult or impractical to achieve such
real-time monitoring when utilizing non-thermal pulsed electric
field neuromodulatory mechanisms. This can result in insufficient
neuromodulation to achieve a desired treatment outcome, and thus
re-intervention may be necessary to complete the treatment.
Conversely, an overly aggressive course of relatively unmonitored
or uncontrolled therapy may induce undesirable and/or persistent
damage in non-target tissue. Thus, it would be desirable to achieve
renal neuromodulation via more easily monitored and/or controlled
neuromodulatory mechanisms.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] Several embodiments of the present invention will be
apparent upon consideration of the following detailed description,
taken in conjunction with the accompanying drawings, in which like
reference characters refer to like parts throughout, and in
which:
[0013] FIG. 1 is a schematic view illustrating human renal
anatomy.
[0014] FIG. 2 is a schematic isometric detail view showing the
location of the renal nerves relative to the renal artery.
[0015] FIG. 3 is a schematic side view, partially in section,
illustrating an example of an extravascular method and apparatus
for thermal renal neuromodulation.
[0016] FIGS. 4A-4C are schematic side views, partially in section,
illustrating examples of intravascular methods and apparatus for
thermal renal neuromodulation.
[0017] FIGS. 5A and 5B are schematic side views, partially in
section, illustrating an alternative embodiment of the
intravascular methods and apparatus of FIGS. 4 comprising
wall-contact electrodes.
[0018] FIGS. 6A and 6B are schematic side views, partially in
section, illustrating an additional alternative embodiment of the
intravascular methods and apparatus of FIG. 4 comprising
alternative wall-contact electrodes.
[0019] FIGS. 7A and 7B are schematic side views, partially in
section, illustrating other alternative embodiments of the
intravascular methods and apparatus of FIG. 4 comprising multiple
wall-contact electrodes.
[0020] FIGS. 8A-8H are schematic side views, partially in section,
illustrating embodiments of the intravascular methods and apparatus
of FIG. 4 comprising one or more wall-contact electrodes, as well
as optional blood flow occlusion and thermal fluid injection.
[0021] FIG. 9 is a schematic side view, partially in section,
illustrating an example of an intra-to-extravascular method and
apparatus for thermal renal neuromodulation.
[0022] FIG. 10 is a schematic side view, partially in section, of
an alternative embodiment of the method and apparatus of FIG. 8
configured for thermal renal neuromodulation via direct application
of thermal energy.
[0023] FIG. 11 is a schematic side view, partially in section,
illustrating a method and apparatus for thermal renal
neuromodulation comprising a thermoelectric element suitable for
direct application of thermal energy to target neural fibers.
[0024] FIG. 12 is a schematic side view, partially in section,
illustrating another method and apparatus for thermal renal
neuromodulation comprising a thermoelectric element.
[0025] FIGS. 13A and 13B are schematic side views, partially in
section, illustrating a method and apparatus for thermal renal
neuromodulation via high-intensity focused ultrasound.
[0026] FIG. 14 is a schematic side view, partially in section,
illustrating an alternative embodiment of the apparatus and method
of FIGS. 13.
[0027] FIGS. 15A and 15B are schematic diagrams for classifying the
various types of thermal neuromodulation that may be achieved with
the apparatus and methods of the present invention.
DETAILED DESCRIPTION
A. Overview
[0028] The following describes several embodiments of methods and
apparatus for renal neuromodulation via thermal heating and/or
thermal cooling mechanisms. Many embodiments of such methods and
apparatus may reduce renal sympathetic nerve activity.
Thermally-induced (via heating and/or cooling) neuromodulation may
be achieved via apparatus positioned proximate target neural
fibers, such as being positioned (a) within renal vasculature
(i.e., positioned intravascularly), (b) extravascularly, (c)
intra-to-extravascularly, or (d) a combination thereof. Thermal
neuromodulation by heating or cooling may be caused by directly
effecting or otherwise altering the neural structures that are
subject to the thermal stress. Additionally or alternatively, the
thermal neuromodulation may at least in part be due to alteration
of arteries, arterioles, capillaries, or veins or other vascular
structures which perfuse the target neural fibers or surrounding
tissue. Furtherstill, the modulation may at least in part be caused
by electroporation of the target neural fibers or of surrounding
tissue.
[0029] As used herein, thermal heating mechanisms for
neuromodulation include both thermal ablation and non-ablative
thermal injury 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 injury, or above a higher temperature)
to achieve ablative thermal injury. For example, the target
temperature can be above body temperature (e.g., approximately
37.degree. C.) but less than about 45.degree. C. for non-ablative
thermal injury, or the target temperature can be about 45.degree.
C. or more for the ablative thermal injury.
[0030] As used herein, thermal cooling mechanisms for
neuromodulation include non-freezing thermal slowing of nerve
conduction and/or non-freezing thermal nerve injury, as well as
freezing thermal nerve injury. 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.degree. C. (e.g., below about 20.degree. C.) to achieve
non-freezing thermal injury. Thermal cooling mechanisms also may
include reducing the temperature of the target neural fibers below
about 0.degree. C., e.g., to achieve freezing thermal injury.
[0031] 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,
such as longer than 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. Exposure times measured
in hours, days or longer, may be utilized to achieve desired
thermal neuromodulation.
[0032] When conducting neuromodulation via thermal mechanisms, the
temperature threshold 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.
[0033] In some embodiments, thermally-induced renal neuromodulation
may be achieved by directly 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 indirect generation and/or
application of the thermal energy to the target neural fibers, such
as through application of a `thermal` electric field,
high-intensity focused ultrasound, laser irradiation, or other
suitable energy modalities to the target neural fibers. For
example, thermally-induced renal neuromodulation may be achieved
via delivery of a pulsed or continuous thermal electric field to
the target neural fibers, the electric field being of 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). Additional and alternative methods and apparatus may
be utilized to achieve thermally-induced renal neuromodulation, as
described hereinafter.
[0034] When utilizing thermal heating mechanisms for thermal
neuromodulation, protective cooling elements, such as 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 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 while the blood
flow protects tissue in the vessel wall.
[0035] 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.
[0036] 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.
Without being limited to theory, this may occur because blood flow
through the blood vessel may convectively cool (heat) the
non-target tissue of the vessel wall with which the blood contacts
faster than target neural fibers positioned outside of the
vessel.
[0037] 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/longer duration delivery with moderated damage to the
non-target tissue.
[0038] In addition or as an alternative to utilizing the patient's
blood as a heat sink to establish the difference in heat transfer
rates, 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 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 the flow temporarily occluded.
[0039] Occlusion of flow in combination with thermal fluid delivery
may facilitate good control over the heat transfer kinetics along
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.
[0040] In some embodiments, methods and apparatus for real-time
monitoring of an extent or degree of neuromodulation or denervation
(e.g., an extent or degree of thermal damage) 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 apparatus 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, 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.
[0041] 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
[0042] With reference to FIG. 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.
[0043] 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, 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 .theta.
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 Apparatus and Methods for Neuromodulation
[0044] FIGS. 3-14 illustrate examples of systems and methods for
thermally-induced renal neuromodulation. FIG. 3 shows one
embodiment of an extravascular apparatus 200 that includes one or
more electrodes configured to deliver a thermal electric field to
renal neural fibers for renal neuromodulation via heating. The
apparatus 200 of FIG. 3 is configured for temporary extravascular
placement; however, it should be understood that partially or
completely implantable extravascular apparatus additionally or
alternatively may be utilized. Applicants have previously described
extravascular pulsed electric field systems, for example, in
co-pending U.S. patent application Ser. No. 11/189,563, filed Jul.
25, 2005, which has been incorporated herein by reference in its
entirety.
[0045] The specific embodiment of the apparatus 200 shown in FIG. 3
comprises a laparoscopic or percutaneous system having a probe 210
configured for insertion in proximity to the track of the renal
neural supply along the renal artery, vein, hilum and/or within
Gerota's fascia under a suitable guidance system. The probe 210 can
have at least one electrode 212 for delivering a thermal electric
field therapy. The electrode(s) 212, for example, may be mounted on
a catheter and electrically coupled to a thermal electric field
generator 50 via wires 211. The electrode 212 can be passed through
the probe 210, or in an alternative embodiment the electrode 212
may be mounted to the probe 210. The probe 210 may have an
electrical connector to couple the electrode 212 to the field
generator 50.
[0046] The field generator 50 is located external to the patient.
The generator, as well as any of the electrode embodiments
described herein, may be utilized with any embodiment of the
present invention for delivery of a thermal electric field with
desired field parameters, e.g., parameters sufficient to thermally
or otherwise induce renal neuromodulation in target neural fibers
via heating and/or electroporation. It should be understood that
electrodes of embodiments described hereinafter may be electrically
connected to the generator even though the generator is not
explicitly shown or described with each embodiment. Furthermore,
the field generator optionally may be positioned internally within
the patient. Furtherstill, the field generator may additionally
comprise or may be substituted with an alternative thermal energy
generator, such as a thermoelectric generator for heating or
cooling (e.g., a Peltier device), or a thermal fluid injection
system for heating or cooling, etc.
[0047] The electrode(s) 212 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 may, 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 of
electrodes 212 may be configured to provide a bipolar signal. The
electrodes 212 may 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. Such a remote electrode may be attached externally to
the patient's skin, e.g., to the patient's leg or flank. In FIG. 3,
the electrodes 212 comprise a bipolar electrode pair. The probe 210
and the electrodes 212 may be similar to the standard needle or
trocar-type used clinically for RF nerve block. Alternatively, the
apparatus 200 may comprise a flexible and/or custom-designed probe
for the renal application described herein.
[0048] In FIG. 3, the probe 210 has been advanced through a
percutaneous access site P into proximity with a patient's renal
artery RA. The probe pierces the patient's Gerota's fascia F, and
the electrodes 212 are advanced into position through the probe and
along the annular space between the patient's artery and fascia.
Once properly positioned, the target neural fibers may be heated
via a pulsed or continuous electric field delivered across the
bipolar electrodes 212. Such heating may, for example, ablate or
cause non-ablative thermal injury to the target neural fibers to at
least partially denervate the kidney innervated by the target
neural fibers. The electric field also may induce reversible or
irreversible electroporation in the target neural fibers, which may
compliment the thermal injury induced in the neural fibers. After
treatment, the apparatus 200 may be removed from the patient to
conclude the procedure.
[0049] Referring now to FIGS. 4A and 4B, several embodiments of
intravascular systems for thermally-induced renal neuromodulation
are described. Applicants have previously described intravascular
pulsed electric field systems, for example, in co-pending U.S.
patent application Ser. No. 11/129,765, filed May 13, 2005, which
has been incorporated herein by reference in its entirety. In one
embodiment, an apparatus 300 comprises a catheter 302 having an
optional positioning element 304, shaft electrodes 306a and 306b
disposed along the shaft of the catheter, and optional radiopaque
markers 308 disposed along the shaft of the catheter in the region
of the positioning element 304. The positioning element 304 can be
a balloon, an expandable wire basket, other mechanical expander
that holds the electrodes 306a-b at a desired location relative to
the vessel. The electrodes 306a-b can be arranged such that the
electrode 306a is near a proximal end of the positioning element
304 and the electrode 306b is near the distal end of the
positioning element 304. The electrodes 306 are electrically
coupled to the field generator 50 (see FIG. 3) for delivery of a
thermal electric field for heating of target neural fibers. In an
alternative embodiment, one or more of the electrodes may comprise
Peltier electrodes for cooling the target neural fibers to modulate
the fibers.
[0050] The positioning element 304 optionally may center or
otherwise position the electrodes 306a and 306b within a vessel.
Additionally, as in FIG. 4A, the positioning element may comprise
an impedance-altering element that alters the impedance between
electrodes 306a and 306b during the therapy to direct the thermal
electric field across the vessel wall. This may reduce the level of
energy required to achieve desired renal neuromodulation and may
reduce a risk of undesirably affecting non-target tissue.
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. When the positioning element
304 comprises an inflatable balloon as in FIG. 4A, the balloon may
serve as both a centering element for the electrodes 306 and as an
impedance-altering electrical insulator for directing an electric
field delivered across the electrodes, e.g., for directing the
electric field into or across the vessel wall for modulation of
target neural fibers. Electrical insulation provided by the
positioning element 304 may reduce the magnitude of applied energy
or other parameters of the thermal electric field necessary to
achieve desired heating at the target fibers.
[0051] Furthermore, the positioning element 304 optionally may be
utilized as a cooling element and/or a heating element. For
example, the positioning element 304 may be inflated with a chilled
fluid that serves as a heat sink for removing heat from tissue that
contacts the element. Conversely, the positioning element 304
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 the
positioning element 304 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 element 304 (or any other portion of apparatus 300)
additionally or alternatively may comprise one or more sensors for
monitoring the process. In one embodiment, the positioning element
304 has a wall-contact thermocouple 310 (FIG. 4A) 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 the apparatus 300.
[0052] The electrodes 306 can be individual electrodes (i.e.,
independent contacts), a segmented electrode with commonly
connected contacts, or a single continuous electrode. Furthermore,
the electrodes 306 may be configured to provide a bipolar signal,
or the electrodes 306 may be used together or individually in
conjunction with a separate patient ground pad for monopolar use.
As an alternative or in addition to placement of the electrodes 306
along the central shaft of the catheter 302, as in FIGS. 4A and 4B,
the electrodes 306 may be attached to the positioning element 304
such that they contact the wall of the renal artery RA. In such a
variation, the electrodes may, for example, be affixed to the
inside surface, outside surface or at least partially embedded
within the wall of the positioning element. FIG. 4C, described
hereinafter, illustrates one example of wall-contact electrodes,
while FIGS. 5-8 illustrate alternative examples of wall-contact
electrodes.
[0053] In use, the catheter 302 may be delivered to 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.
[0054] Once the positioning element 304 is at a desired location
within the renal vasculature, it may be expanded into contact with
an interior wall of the vessel. A thermal electric field then may
be delivered via the electrodes 306 across the wall of the artery.
The electric 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 damage
of the target neural fibers. The electric field also may induce
electroporation in the neural fibers.
[0055] In the embodiment of FIG. 4A, the positioning element 304
illustratively comprises an inflatable balloon, which may
preferentially direct the electric field as discussed. In the
embodiment of FIG. 4B, the positioning element comprises an
expandable wire basket that substantially centers the electrodes
306 within the vessel without blocking blood flow through the
vessel. During delivery of the thermal electric field (or of other
thermal energy), the blood may 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, as in the
embodiment of FIG. 4B.
[0056] 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 of FIG. 4B
illustratively comprises a positioning element for centering the
electrodes without blocking flow, it should be understood that the
positioning element may be eliminated and/or that the electrodes
may be attached to the positioning element 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.
[0057] 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 effects 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.
[0058] 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 may 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.
[0059] 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.
[0060] In addition or as an alternative to utilizing the patient's
blood as a heat sink to create a difference in the heat transfer
rates, 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 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 the blood flow temporarily occluded.
[0061] In several embodiments, the occlusion of the blood flow in
combination with thermal fluid delivery may facilitate good control
over the heat transfer kinetics along 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. 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.
[0062] One or more sensors, such as the thermocouple 310 of FIG.
4A, may be used to monitor the temperature(s) or other parameter(s)
at the electrodes 306, 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 longer or higher energy treatments than
when blood flow is blocked in the vessel.
[0063] As discussed, 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 electric 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.
[0064] FIG. 4C depicts an embodiment of an apparatus 400 having one
or more wall-contact electrodes 306. One or more of the struts of
the expandable basket positioning element 304 may comprise a
conductive material that is insulated in regions other than along
segments that contact the vessel wall and form electrode(s) 306.
The electrode(s) may be used in either a bipolar or a monopolar
configuration. Furthermore, the electrode(s) may comprise
sensor(s), e.g., impedance or temperature sensors, for monitoring
and/or controlling the effects of the thermal energy delivery. The
sensors, for example, can be thermocouples.
[0065] FIGS. 5A and 5B depict an alternative embodiment of
intravascular apparatus 500 having electrodes configured to contact
the interior wall of a vessel. The apparatus 500 of FIGS. 5A and 5B
is an alternative embodiment of the apparatus 300 of FIGS. 4A and
4B wherein the proximal electrode 306a of FIGS. 4A and 4B has been
replaced with a wall-contact electrode 306a'. The wall-contact
electrode 306a' comprises a proximal connector 312a that connects
the electrode to the shaft of the catheter 302 and is electrically
coupled to the pulse generator. The apparatus 500 also has a
plurality of extensions 314a that extend from the proximal
connector 312a and at least partially extend over a surface of
positioning element 304. The extensions 314a optionally may be
selectively insulated such that only a selective portion of the
extensions, e.g., the distal tips of the extensions, are
electrically active. The electrode 306a' optionally 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.
[0066] As seen in FIG. 5A, the catheter 302 may be delivered over a
guidewire G to a treatment site within the patient's vessel with
the electrode 306a' positioned in a reduced profile configuration.
The catheter 302 optionally may be delivered through a guide
catheter 303 to facilitate such reduced profile delivery of the
wall-contact electrode. When positioned as desired at a treatment
site, the electrode 306a' may be expanded into contact with the
vessel wall by expanding the positioning element 304 (shown in FIG.
5B). A thermal monopolar or bipolar electric field then may be
delivered across the vessel wall and between the electrodes 306a'
and 306b to induce thermal neuromodulation, as discussed
previously. The optional positioning element 304 may alter
impedance within the blood vessel and more efficiently route the
electrical energy across the vessel wall to the target neural
fibers.
[0067] After terminating the electric field, the electrode 306a'
may be returned to a reduced profile, and the apparatus 300 may be
removed from the patient or repositioned in the vessel. For
example, the positioning element 304 may be collapsed (e.g.,
deflated), and the electrode 306a' may be contracted by withdrawing
the catheter 302 within the guide catheter 303. Alternatively, the
electrode may be fabricated from a shape-memory material biased to
the collapsed configuration, such that the electrode self-collapses
upon collapse of the positioning element.
[0068] Although in FIGS. 5A and 5B the electrode 306a' is expanded
into contact with the vessel wall, it should be understood that the
electrode alternatively may be fabricated from a self-expanding
material biased such that the electrode self-expands into contact
with the vessel wall upon positioning of the electrode distal of
the guide catheter 303. A self-expanding embodiment of the
electrode 306a' may obviate a need for the positioning element 304
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-expanding electrode
306a' may be returned to a reduced profile to facilitate removal of
the apparatus 300 from the patient by withdrawing the catheter 302
within the guide catheter 303.
[0069] FIGS. 6A and 6B depict another embodiment of an apparatus
600 and methods for delivering a field using a wall-contact
electrode. As an alternative to the proximal connector 312a of the
electrode 306a' of FIGS. 5A and 5B, the electrode 306a'' of FIGS. 6
comprises a distal connector 316a for coupling the electrode to the
shaft of catheter 302 on the distal side of the positioning element
304. The distal connector enables the electrode to extend over the
entirety of the positioning element 304 and may facilitate
contraction of the electrode 306a'' after thermal neuromodulation.
For example, the electrode 306a'' can be contracted by proximally
retracting the proximal connector 312a relative to the catheter 302
during or after contraction of the positioning element 304. FIG. 6A
shows the electrode 306a'' in the reduced profile configuration,
and FIG. 6B shows the electrode in the expanded configuration in
which the conductive portions contact the vessel wall.
[0070] FIGS. 7A and 7B show additional alternative embodiments of
methods and an apparatus 700. In FIGS. 7A and 7B, the apparatus 700
comprises the proximal electrode 306a' of FIGS. 5A and 5B, and a
distal wall-contact electrode 306b'. The embodiment of FIG. 7A
comprises proximal and distal positioning elements 304a and 304b,
respectively, for expanding the proximal and distal wall-contact
electrodes 306a' and 306b', respectively, into contact with the
vessel wall. The embodiment of FIG. 7B comprises only a single
positioning element 304, but the distal wall-contact electrode
306b' is proximal facing and positioned over the distal portion of
the positioning element 304 to facilitate expansion of the distal
electrode 306b'. In the embodiment of FIG. 7B, the extensions of
the proximal and distal electrodes optionally may be connected
along non-conductive connectors 318 to facilitate collapse and
retrieval of the electrodes post-treatment.
[0071] A bipolar electric field may be delivered between the
proximal and distal wall-contact electrodes, or a monopolar
electric field may be delivered between the proximal and/or distal
electrode(s) and an external ground. Having both the proximal and
distal electrodes in contact with the wall of the vessel may
facilitate more efficient energy transfer across the wall during
delivery of a thermal electric field, as compared to having one or
both of the proximal and distal electrodes centered within the
vessel.
[0072] FIGS. 8A-8H illustrate additional embodiments of the
apparatus and methods that can comprise one or more wall-contact
electrodes, blood flow occlusion features, and thermal fluid
injection functions. The embodiments of FIGS. 8 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.
[0073] 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 RF therapy, 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.
[0074] FIGS. 8A and 8B show an embodiment of an apparatus 800 that
comprises the catheter 802 having an element 804, which may be used
to position the apparatus within the vessel and/or to occlude blood
flow. The element 304 element 804 can be an inflatable balloon. The
apparatus 800 can further have an active monopolar electrode 806
located proximally from the element 804 such that inflation of the
element 804 blocks blood flow downstream of the electrode 806. The
monopolar electrode 806 illustratively comprises multiple
extensions 814, and it should be understood that any desired number
of extensions may be provided, including a single extension. The
monopolar electrode is utilized in combination with a remote
electrode, such as a ground pad, positioned external to the
patient. The apparatus can also comprise an infusion port 805
between the element 804 and the monopolar electrode 806.
[0075] In FIG. 8A, the catheter 802 may be advanced within the
renal artery RA in a reduced profile delivery configuration. In
FIG. 8B, once properly positioned, the electrode 806 may be
actively expanded, or it may self-expand by removing a sheath, the
guide catheter or another type of restraint from the electrode. The
expanded electrode 806 contacts the vessel wall. The element 804
may be expanded before, during or after expansion of the electrode
to properly position the electrode within the vessel and/or to
occlude blood flow within the renal artery downstream of the
electrode. A monopolar electric field may be delivered between the
active electrode 806 and the external ground. 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
810, impedance sensors or other sensors.
[0076] 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 may be injected through
injection port 805 of the catheter 802 to cool (heat) the
non-target tissue. This is expected to mitigate undesired effects
in the non-target tissue. The infusate may, for example, comprise
chilled saline that removes excess thermal energy (hot or cold)
from the wall of the vessel during thermal RF therapy.
[0077] Convective or other heat transfer between the non-target
vessel wall tissue and the infusate I may facilitate cooling
(heating) of the vessel wall at a faster rate than cooling
(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 higher
heat transfer rate at the wall relative to the target neural fibers
may allow for relatively higher power or longer duration therapies
compared to continuous thermal therapies. Also, the interval
between pulses may be used to monitor and/or control effects of the
therapy.
[0078] FIG. 8C shows an embodiment of another apparatus 801 with
wall-contact electrodes, a flow occlusion feature, and a thermal
fluid injection function. In FIG. 8C, the occlusion element 804 is
coupled to the guide wire G, which may comprise an inflation lumen,
and the infusate I is delivered through a distal outlet of the
catheter 802. As will be apparent, the occlusion element
alternatively may be coupled to a separate catheter or sheath
rather than to the guide wire. Also, the infusate may, for example,
be delivered through the guide wire lumen or through an additional
lumen or annulus of the catheter 802. FIG. 8D illustrates another
embodiment of an apparatus 830 wherein the occlusion element 804 is
positioned proximal or upstream of the electrode(s) 806, and the
infusate I is delivered at a position distal of the occlusion
element but proximal of the electrode(s).
[0079] FIG. 8E is an embodiment of an apparatus 840 with occlusion
elements 804 positioned both proximal and distal of the
electrode(s) 806. In addition to having a first injection port
805a, the catheter 802 comprises an aspiration port 805b. Separate
lumens can extend through the catheter for injection and aspiration
of the infusate I via the ports 805. Providing both injection and
aspiration of the infusate facilitates good control over the flow
dynamics of the infusate, and thereby the heat transfer kinetics of
the infusate. For example, providing aspiration and injection at
the same rate may provide consistent heat transfer kinetics between
the vessel and the electrode(s).
[0080] FIG. 8F illustrates another embodiment of an apparatus 850
having a catheter 852 comprising a wall-contact electrode 856 that
may be moved into contact with the vessel wall via an elongated
member 857. In this embodiment, the elongated member 857 is
distally connected to the catheter in the vicinity of the electrode
856. The elongated member may be configured for self expansion, or
it may extend through port 805 of the catheter 852 and through a
lumen of the catheter to a proximal location for manipulation by a
medical practitioner. The proximal section of the elongated member
may be advanced relative to the catheter 852 by the medical
practitioner such that the member assumes the illustrated curved
profile.
[0081] Upon expansion of the elongated member, the catheter 852 is
deflected such that the electrode 856 coupled to the catheter shaft
contacts the vessel wall. Optionally, element 804 may be expanded
to facilitate positioning of the electrode via the elongated member
and/or to block flow through the vessel. The element 804 can be
coupled to the guide or delivery catheter 803. Infusate I
optionally may be delivered through the catheter 803 as shown.
[0082] FIG. 8G is an embodiment of an apparatus 860 comprising a
shaped or self-expanding electrode 866. The electrode 866 may be
delivered to a treatment site within catheter 803, and then it
moves to a preselected shape after it has been removed from the
lumen of the catheter 803. For example, the electrode 866 can be
removed from the catheter by advancing the catheter 802 and/or
retracting the catheter 803. The electrode 866 contacts the vessel
wall for delivery of therapy. Optionally, the catheter 802 may be
rotated to rotate the electrode relative to the vessel wall and
angularly reposition the electrode. The therapy may be delivered at
a singular angular position or at multiple angular positions.
Additionally or alternatively, multiple angularly spaced electrodes
866 may be positioned within the vasculature, as shown in FIG. 8H.
In addition to angular spacing, the electrodes 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.
[0083] 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 electric 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
electric 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.
[0084] FIG. 9 illustrates one embodiment of an
intra-to-extravascular ("ITEV") system for thermally-induced renal
neuromodulation is described. ITEV system 900 comprising a catheter
922 having (a) a plurality of proximal electrode lumens terminating
at proximal side ports 924, (b) a plurality of distal electrode
lumens terminating at distal side ports 926, and (c) a guidewire
lumen 923. The catheter 922 preferably comprises an equal number of
proximal and distal electrode lumens and side ports. The ITEV
system 900 also includes proximal needle electrodes 928 that may be
advanced through the proximal electrode lumens and the proximal
side ports 924, as well as distal needle electrodes 929 that may be
advanced through the distal electrode lumens and the distal side
ports 926.
[0085] The catheter 922 comprises an optional expandable
positioning element 930, which may comprise an inflatable balloon
or an expandable basket or cage. In use, the positioning element
930 may be expanded prior to deployment of the needle electrodes
928 and 929 in order to position or center the catheter 922 within
the patient's vessel (e.g., within renal artery RA). Centering the
catheter 922 is expected to facilitate delivery of all needle
electrodes to desired depths within/external to the patient's
vessel (e.g., to deliver all of the needle electrodes approximately
to the same depth). In FIG. 9, the illustrated positioning element
930 is between the proximal side ports 924 and the distal side
ports 926, and thus the positioning element 930 is between the
delivery positions of the proximal and distal electrodes. However,
it should be understood that the positioning element 930
additionally or alternatively may be positioned at a different
location or at multiple locations along the length of the catheter
922 (e.g., at a location proximal of the side ports 924 and/or at a
location distal of the side ports 926).
[0086] As illustrated in FIG. 9, the catheter 922 may be advanced
to a treatment site within the patient's vasculature over a
guidewire (not shown) via the lumen 323. During intravascular
delivery, the electrodes 928 and 929 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
via their proximal regions that are located external to the
patient. Such advancement causes the distal regions of the
electrodes 928 and 929 to exit side ports 924 and 926,
respectively, and pierce the wall of the patient's vasculature such
that the electrodes are positioned extravascularly via an ITEV
approach.
[0087] The proximal electrodes 928 can be connected to an electric
field generator 50 as active electrodes, and the distal electrodes
929 can serve as return electrodes. In this manner, the proximal
and distal electrodes form bipolar electrode pairs that align the
thermal electric field with a longitudinal axis or direction of the
patient's vasculature. As will be apparent, the distal electrodes
929 alternatively may comprise the active electrodes and the
proximal electrodes 928 may comprise the return electrodes.
Furthermore, the proximal and/or the distal electrodes may comprise
both active and return electrodes. Furtherstill, the proximal
and/or the distal electrodes may be utilized in combination with an
external ground for delivery of a monopolar thermal electric field.
Any combination of active and distal electrodes may be utilized, as
desired.
[0088] When the electrodes 928 and 929 are connected to an electric
field generator and positioned extravascularly, and with the
positioning element 930 optionally expanded, delivery of the
thermal electric field may proceed to achieve desired renal
neuromodulation via heating. The electric field also may induce
electroporation. After achievement of the thermally-induced renal
neuromodulation, the electrodes may be retracted within the
proximal and distal lumens, and the positioning element 930 may be
collapsed for retrieval. The ITEV system 900 then may be removed
from the patient to complete the procedure. Additionally or
alternatively, the system may be repositioned to provide therapy at
another treatment site, such as to provide bilateral renal
neuromodulation.
[0089] Cooling elements, such as convective cooling elements, may
be utilized to protect non-target tissues like smooth muscle cells
from thermal damage 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 damage in non-target tissues distant from the target neural
fibers.
[0090] Although FIGS. 3-7 and 9 illustratively show bipolar
apparatus, it should be understood that monopolar apparatus
alternatively may be utilized as in FIGS. 8A-8H. 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
electric 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.
[0091] The embodiments of FIGS. 3-9 illustratively describe methods
and apparatus for thermally-induced renal neuromodulation via
delivery of thermal electric fields that modulate the target neural
fibers. However, it should be understood that alternative methods
and apparatus 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 direct application
of thermal energy to the target neural fibers. Such direct thermal
energy may be generated and/or transferred in a variety of ways,
such as via resistive heating, via delivery of a heated or chilled
fluid (see FIGS. 10 and 12), via a Peltier element (see FIG. 11),
etc. Thermally-induced renal neuromodulation additionally or
alternatively may be achieved via application of high-intensity
focused ultrasound to the target neural fibers (see FIG. 13).
Additional and alternative methods and apparatus for
thermally-induced renal neuromodulation may be used in accordance
with the present invention.
[0092] With reference now to FIG. 10, an alternative embodiment of
an apparatus 1000 and methods for thermally-induced neuromodulation
via direct application of thermal energy is described. In the
embodiment of FIG. 10, the electrodes 928 and 929 of FIG. 9 have
been replaced with infusion needles 1028 and 1029, respectively. A
thermal fluid F may be delivered through the needles to the target
neural fibers. The thermal fluid 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.degree. C., or above a
temperature of about 45.degree. C. Alternatively, the thermal fluid
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.degree. C.,
or further cooled below about 20.degree. C., or still further
cooled below a freezing temperature of about 0.degree. C. As will
be apparent, in addition to intra-to-extravascular delivery of a
thermal fluid, the thermal fluid 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.
[0093] In addition or as alternative to injection of a thermal
fluid to the target neural fibers through infusion needles 1028 and
1029, 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.
[0094] FIG. 11 shows another method and apparatus 1100 for thermal
renal neuromodulation via direct application of thermal energy to
the target neural fibers. The apparatus 1100 comprises renal artery
cuff 1102 having one or more integrated thermoelectric elements
that are electrically coupled to an internal or external power
supply 1104. The thermoelectric element utilizes the well-known
Peltier effect (i.e., the establishment of a thermal gradient
induced by an electric voltage) to achieve thermal renal
neuromodulation.
[0095] An electric current is passed from the power supply 1104 to
the thermoelectric element of the cuff 1102. The thermoelectric
element can comprise 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 damage to the non-target tissues. The cuff 1102 may
comprise one or more temperature sensors, such as thermocouples,
for monitoring the temperature of the target neural fibers and/or
of the non-target tissues.
[0096] FIG. 12 shows another method and apparatus 1200 utilizing
the Peltier effect. The apparatus 1200 comprises an implanted or
external pump 1202 connected to a renal artery cuff 1204 via inlet
fluid conduit 1206a and outlet fluid conduit 1206b. The inlet fluid
conduit transfers fluid from the pump to the cuff, while the outlet
fluid conduit transfers fluid from the cuff to the pump to
circulate fluid through the cuff. A reservoir of fluid may be
located in the cuff, the pump and/or in the fluid conduits.
[0097] The pump 1202 further comprises 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
the cuff to thermally modulate the target neural fibers. The
apparatus 1200 optionally may have controls for automatic or manual
control of fluid heating or cooling, as well as fluid circulation
within the cuff. Furthermore, the apparatus may comprise
temperature and/or renal sympathetic neural activity monitoring or
feedback control. Although the apparatus illustratively 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.
[0098] Thermal renal neuromodulation alternatively may be achieved
via pulsed or continuous high-intensity focused ultrasound. High
intensity focused ultrasound also may induce reversible or
irreversible electroporation in the target neural fibers.
Furthermore, the ultrasound may be delivered over a full
360.degree. (e.g. when delivered intravascularly) or over a radial
segment of less than 360.degree. (e.g., when delivered
intravascularly, extravascularly, intra-to-extravascularly, or a
combination thereof). FIGS. 13A and B illustrate an embodiment of
an ultrasonic apparatus 1300 comprising a catheter 1302, one or
more ultrasound transducers 1304 positioned along the shaft of the
catheter, and an inflatable balloon 1306 around the transducers
1304. The ultrasound transducers 1304 are coupled to an ultrasound
signal generator via conductors 1307. The balloon 1306 can have an
acoustically reflective portion 1308 for reflecting an ultrasound
wave and an acoustically transmissive portion 1309 the wave 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, the transducers may be attached directly to the
balloon.
[0099] 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 the balloon.
[0100] 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. 13A shows the apparatus 1300 in a reduced delivery and
retrieval configuration, and FIG. 13B shows the apparatus 1300 in
an expanded deployed configuration.
[0101] FIG. 14 shows an alternative embodiment of an ultrasonic
apparatus 1400 having a catheter 1402, a conductor 1403, and
concave ultrasound transducers 1401. The concave ultrasound
transducers 1404 direct the energy to a specific focal point P, and
as such the concave transducers 1404 eliminate the need of the
reflective portion of the balloon 366 (e.g., the balloon may be
acoustically transmissive at all points).
[0102] The apparatus described above with respect to FIGS. 3-14
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 apparatus may further comprise one or more sensors,
such as thermocouples or imaging transducers, for measuring and
monitoring one or more parameters of (a) the apparatus, (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 injure, freeze or
otherwise damage the target neural fibers to thereby modulate the
target neural fibers.
[0103] FIGS. 15A and 15B classify the various types of thermal
neuromodulation that may be achieved with the apparatus and methods
of the present invention. FIGS. 15A and 15B are provided only for
the sake of illustration and should in no way be construed as
limiting. FIG. 15A classifies thermal neuromodulation due to heat
exposure. As shown, exposure to heat in excess of a body
temperature of about 37.degree. C., but below a temperature of
about 45.degree. C., may induce thermal injury via moderate heating
of the target neural fibers or of vascular structures that perfuse
the target fibers. For example, this may induce non-ablative
thermal injury in the fibers or structures. Exposure to heat above
a temperature of about 45.degree. C., or above about 60.degree. C.,
may induce thermal injury 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.degree. C., or less
than about 85.degree. C., or less than about 80.degree. C., and/or
less than about 75.degree. C. Regardless of the type of heat
exposure utilized to induce the thermal neuromodulation, a
reduction in renal sympathetic nerve activity ("RSNA") is
expected.
[0104] As seen in FIG. 15B, thermal cooling for neuromodulation
includes non-freezing thermal slowing of nerve conduction and/or
nerve injury, as well as freezing thermal nerve injury.
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.degree. C., or below about 20.degree. C., but above the freezing
temperature of about 0.degree. C. This non-freezing thermal cooling
may either slow nerve conduction or may cause direct neural injury.
Slowed nerve conduction may use continuous or intermittent cooling
of the target neural fibers to sustain the desired thermal
neuromodulation, while direct neural injury may require only a
discrete treatment to achieve sustained thermal neuromodulation.
Thermal cooling for neuromodulation also may include freezing
thermal nerve injury 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.degree. C.
Regardless of the type of cold exposure utilized to induce the
thermal neuromodulation (freezing or non-freezing), a reduction in
renal sympathetic nerve activity ("RSNA") is expected.
[0105] 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
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.
[0106] Although preferred illustrative variations of the present
invention are described above, it will be apparent to those skilled
in the art that various changes and modifications may be made
thereto without departing from the invention. It is intended in the
appended claims to cover all such changes and modifications that
fall within the true spirit and scope of the invention.
* * * * *