English:
[0007] 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 United States Patent Application Nos. (a) 11/129,765, filed on May 13, 2005, (b) 11/189,563, filed on July 25, 2005, and (c) 11/363,867, filed February 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 intravascular^, 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 United States Patent Nos. 7,162,303 and 6,978,174, both of which are incorporated herein by reference in their entireties.
[0008] Although these applications provide promising methods and systems, several improvements for enhancing the implementation of these methods and systems would be desirable.
[0009] Figure 1 is a schematic view illustrating human renal anatomy.
[0010] Figure 2 is a schematic, isometric detail view illustrating the location of the renal nerves relative to the renal artery.
[0011] Figure 3A is an isometric view of a system for controlling thermally-induced renal neuromodulation configured in accordance with one embodiment of the disclosure.
[0012] Figure 3B is a schematic side view, partially in section, illustrating an embodiment of an extravascular system for thermally-induced renal neuromodulation.
[0013] Figures 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.
[0014] Figures 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.
[0015] Figures 6A and 6B are schematic side views, partially in section, illustrating another embodiment of an intravascular apparatus having one or more wall-contact electrodes.
[0018] Figures 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.
[0019] Figures 9G-9N are schematic side views, partially in section, illustrating embodiments of probes for thermally-induced renal neuromodulation.
[0020] Figure 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.
[0021] Figure 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.
[0022] Figure 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.
[0023] Figure 13 is a schematic side view, partially in section, illustrating another embodiment of an apparatus for thermally-induced renal neuromodulation comprising a thermoelectric element.
[0024] Figures 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.
[0025] Figure 15 is a schematic side view, partially in section, illustrating an alternative embodiment of the apparatus of Figures 14A and 14B.
[0026] Figure 16 is a flow diagram illustrating a method for controlling an energy delivery process for thermally-induced renal neuromodulation.
[0029] Figure 19 is a power vs. time diagram showing an example of a response to performing the method of Figure 16.
[0033] 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.
[0035] 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.
[0038] 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.
[0042] 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.
[0044] As shown in Figure 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.
[0046] Figures 3A-19 illustrate examples of systems and methods for thermally- induced renal neuromodulation. Figure 3A, for example, is an isometric view of a system 100 for controlling thermally-induced renal neuromodulation of a patient 101 configured in accordance with an embodiment of the disclosure. The system 100 can include a processor 114, a field generator 110 electrically connected to the processor 114, and a probe 104 operatively coupled to the field generator 110. In the illustrated embodiment, a cable 112 electrically connects the probe 104 to the field generator 110. In other embodiments, the processor 114, the probe 104, and/or the field generator 110 can be connected wirelessly via, for example, radio frequency signals.
[0049] The probe 104 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. The probe 104 can include at least one electrode 108 for delivery of a thermal energy field therapy and an electrical connector 106 coupled to the field generator 110 via the cable 112 for delivering a thermal energy field to the electrode 108. In some embodiments, the probe 104 can include an integrated cable (not shown) for delivering a thermal energy field to the electrode 108, and the electrical connector 106 can be omitted. In the illustrated embodiment, the probe 104 is a percutaneous probe configured to be percutaneously advanced into proximity of, for example, an anatomical target 102 (e.g., a renal artery or renal vein) of the patient 101 as described in more detail below with reference to Figure 3B. In other embodiments, the probe 104 can be an implantable device.
[0050] 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 of electrodes 108 can be configured to provide a bipolar signal. The electrodes 108 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).
[0051] The probe 104 can also include at least one sensor (not shown) for measuring a physiological parameter of the patient 101. For example, the probe 104 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 the processor 114 for processing.
[0052] Optionally, the system 100 can also include an input device 118, an output device 120, and/or a control panel 122 operatively coupled to the processor 114. The input device 118 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. The output device 120 can include a display screen, a printer, a medium reader, an audio device, and any other devices suitable for providing user feedback. The control panel 122 can include indicator lights, numerical displays, and audio devices. In the embodiment shown in Figure 3A, a rack 124 with wheels 126 carries the processor 114, the field generator 110, the input device 118, and the output device 120 for portability. In another embodiment, the various components can be incorporated into a single enclosure (e.g., the field generator 110) 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.
[0053] In operation, an operator can place the probe 104 at least proximate to a wall of a body lumen of the patient 101 , for example, the renal artery or renal vein, and then deliver energy to the probe 104 to achieve thermal renal neuromodulation as described in more detail below. Figures 4A and 4B, for example, illustrate the various types of thermal neuromodulation that may be achieved with the systems and methods described herein. Figures 4A and 4B are provided only for the sake of illustration and should in no way be construed as limiting.
[0054] Figure 4A illustrates thermal neuromodulation due to heat exposure. As shown, exposure to heat in excess of a body temperature of about 370C, but below a temperature of about 450C, 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 600C, 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 900C, or less than about 85°C, or less than about 800C, and/or less than about 750C. Regardless of the type of heat exposure utilized to induce the thermal neuromodulation, a reduction in renal sympathetic nerve activity ("RSNA") is expected.
[0055] Referring to Figure 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.
[0056] Referring back to Figure 3A, the operator and/or the processor 114 can monitor and control the energy delivery process. As described above, the probe 104 can include sensors that measure physiological parameters of the patient 101. The probe 104 can transmit the measured parameters to the processor 114 via the cable 112 or wirelessly. The processor 114 can process and analyze the received parameters and display the parameters in appropriate units on the output device 120. The processor 114 can cause the system to sound an alarm if the received parameters exceed preset thresholds and signal any alarms using either the output device 120 and/or the control panel 122. The processor 114 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. The processor 114 can also store the received parameters and data patterns in a database for later retrieval. In addition, the processor 114 can modulate the power output of the field generator 110 based on the received parameters and/or input received from the operator via the input device 118 as described in more detail below with reference to Figures 16-19.
[0057] In Figure 3B, the probe 104 has been advanced through a percutaneous access site P into proximity with the renal artery RA. The probe 104 pierces the Gerota's fascia F of the patient 101 , and the electrodes 108 are advanced into position through the probe 104 and along the annular space between the artery 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. In Figure 3B, for example, the electrode(s) 108 comprise a bipolar electrode pair that can generate thermal energy field 109. 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, the probe 104 can be removed from the patient to conclude the procedure.
[0058] Figures 5A-9, 14, and 15 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 generator 110) even through the generator is not explicitly shown or described below.
[0059] Figures 5A and 5B, for example, are schematic side views illustrating an intravascular apparatus 300 for thermally-induced renal neuromodulation. The apparatus 300 can include a catheter 302 having an optional positioning element 304, shaft electrodes 306a and 306b disposed along the shaft of the catheter 302, and optional radiopaque markers 308 disposed along the shaft of the catheter 302 in the region of the positioning element 304. The positioning element 304 can be a balloon, an expandable wire basket, other mechanical expanders, or another suitable device for holding the electrodes 306a-b relative to the vessel and/or the nerves. 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 306a-b are electrically coupled to the field generator 110 (Figure 3A) for delivering energy to the target neural fibers. In other embodiments, one or more of the electrodes 306a-b can comprise Peltier electrodes for heating or cooling the target neural fibers to modulate the fibers.
[0060] The positioning element 304 optionally can position or otherwise drive the electrodes 306a-b into contact with the lumen wall. For example, when the positioning element 304 is an inflatable balloon as shown in Figure 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 electrodes 306a-b into or across the vessel wall for modulation of target neural fibers. The electrical insulation provided by the positioning element 304 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 No. 11/266,993, filed November 4, 2005, which is incorporated herein by reference in its entirety.
[0061] 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.
[0062] The positioning element 304 (or any other portion of the 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 (Figure 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 the apparatus 300. Alternatively, electrodes 306a and/or 306b can have one or more thermocouples built into them.
[0063] The electrodes 306a-b of the intravascular embodiment shown in Figures 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 electrodes 306a-b can also be configured to provide a bipolar signal, or the electrodes 306a-b can be used together or individually in conjunction with a separate patient ground pad for monopolar use. The electrodes 306a-b can be attached to the positioning element 304 such that they contact the wall of the artery upon expansion of the positioning elements 304. The electrodes 306a-b can, for example, be affixed to the inside surface, outside surface, or at least partially embedded within the wall of the positioning element 304. Figure 5C, described hereinafter, illustrates one example of wall-contact electrodes, while Figures 6-9 illustrate alternative wall-contact electrodes.
[0064] As shown in Figure 5A, the catheter 302 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 No. 11/451 ,728, filed July 12, 2006, which is incorporated herein by reference in its entirety.
[0065] Once the positioning element 304 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 electrodes 306a-b across 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.
[0066] In the embodiment shown in Figure 5A, the positioning element 304 is an inflatable balloon that can preferentially direct the energy field as discussed above. In the embodiment illustrated in Figure 5B, the positioning element 304 comprises an expandable wire basket that substantially centers the electrodes 306a-b within 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 in Figure 5B.
[0067] 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 in Figure 5B includes a positioning element 304 for centering the electrodes 306a-b without blocking flow, it should be understood that the positioning element 304 may be eliminated and/or that the electrodes 306a-b may be attached to the positioning element 304 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.
[0069] 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.
[0073] One or more sensors, such as the thermocouple 310 of Figure 5A, can be used to monitor the temperature(s) or other parameter(s) at the electrodes 306a-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.
[0076] Figures 6A and 6B are schematic side views illustrating another embodiment of an intravascular apparatus 500 having electrodes configured to contact the interior wall of a vessel. The apparatus 500 of Figures 6A and 6B differs from the apparatus 300 of Figures 5A and 5B in that the proximal electrode 306a of Figures 5A and 5B has been replaced with a wall-contact electrode 306a1. The wall-contact electrode 306a1 includes a proximal connector 312a that connects the electrode 306a1 to the shaft of the catheter 302 and is electrically coupled to the field generator (not shown). 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 the positioning element 304. The extensions 314a optionally may be selectively insulated such that only a selective portion of the extensions 314a (e.g., the distal tips of the extensions) are electrically active. The electrode 306a1 and or the connector 312a 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.
[0077] As shown in Figure 6A, 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 306a1. When positioned as desired at a treatment site, the electrode 306a1 may be expanded into contact with the vessel wall by expanding the positioning element 304 (as shown in Figure 6B). A thermal bipolar electric field then may be delivered across the vessel wall and between the electrodes 306a1 and 306b to induce thermal neuromodulation, as discussed previously. Alternatively 306a' or 306b could comprise a monopolar electrode, wherein the return electrode (not shown) is placed on an external surface of the patient. 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.
[0078] After terminating the electric field, the electrode 306a1 may be returned to a reduced profile and the apparatus 500 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 306a1 may be contracted by withdrawing the catheter 302 within the guide catheter 303. Alternatively, the electrode 306a1 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 304.
[0079] Although the electrode 306a1 shown in Figures 6A and 6B is expanded into contact with the vessel wall, it should be understood that the electrode 306a1 alternatively may be fabricated from a self-expanding material biased such that the electrode 306a' self-expands into contact with the vessel wall upon positioning of the electrode 306a1 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 306a1 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.
[0080] Figures 7A and 7B are schematic side views illustrating still another embodiment of an apparatus 600 for delivering a field using a wall-contact electrode 306a". Figure 7A shows the electrode 306a" in a reduced profile configuration, and Figure 7B shows the electrode 306a" in an expanded configuration in which the conductive portions of the electrode 306a" contact the vessel wall. As an alternative to the proximal connector 312a of the electrode 306a' of Figures 6A and 6B, the electrode 306a" of Figures 7A and 7B includes a distal connector 316a for coupling the electrode 306a" to the shaft of the catheter 302 on the distal side of the positioning element 304. The distal connector 316a enables the electrode 306a" to extend over the entirety of the positioning element 304 and can facilitate contraction of the electrode 306a" after thermal neuromodulation. For example, the electrode 306a" can be contracted by proximally retracting the guide catheter 303relative to the catheter 302 during or after contraction of the positioning element 304. Alternatively, the wires at the proximal end of the apparatus can be proximally retracted to contract the electrode 306a".
[0081] Figures 8A and 8B are schematic side views illustrating yet another embodiment of an apparatus 700 for thermally-induced neuromodulation. The apparatus 700 of Figures 8A and 8B includes the proximal electrode 306a1 of Figures 6A and 6B, and a distal wall-contact electrode 306b1. The apparatus 700 also includes proximal and distal positioning elements 304a and 304b, respectively, for expanding the proximal and distal wall-contact electrodes 306a1 and 306b', respectively, into contact with the vessel wall. The embodiment shown in Figure 8B includes only a single positioning element 304, but the distal wall-contact electrode 306b1 is proximal facing and positioned over the distal portion of the positioning element 304 to facilitate expansion of the distal electrode 306b1. In the embodiment illustrated in Figure 8B, the extensions of the proximal 306a1 and distal electrodes 306b1 optionally may be connected along non-conductive connectors 318 to facilitate collapse and retrieval of the electrodes post-treatment.
[0083] Figures 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 to Figures 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.
[0084] 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.
[0085] Figures 9A and 9B illustrate an apparatus 800 including a catheter 802 having a positioning element 804 that can be used to position the apparatus within the vessel and/or to occlude blood flow. The positioning element 804, for example, can be an inflatable balloon. The apparatus 800 can further include one or more active monopolar electrodes 810 located proximally from the positioning element 804 such that inflation of the positioning element 804 blocks blood flow downstream of the electrode assembly 806. The electrode assembly 806 includes multiple extensions 814, 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. The apparatus 800 can also include an infusion port 805 between the positioning element 804 and the electrode assembly 806.
[0086] As shown in Figure 9A, the catheter 802 can be advanced within the renal artery RA in a reduced profile delivery configuration. Referring to Figure 9B, once properly positioned at the treatment site, the electrode assembly 806 can be actively expanded, or it may self-expand by removing a sheath, the guide catheter 803, or another type of restraint from the electrode(s) 810. The expanded electrode assembly 806 contacts the vessel wall. The positioning element 804 can be expanded (before, during, or after expansion of the electrode assembly 806) to properly position the electrode assembly 806 within the vessel and/or to occlude blood flow within the renal artery RA downstream of the electrode assembly 806. 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 two electrodes 810. 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.
[0087] 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 through injection port 805 of the catheter 802 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.
[0089] Figure 9C is a schematic side view illustrating another embodiment of an apparatus 820 including wall-contact electrodes 810, flow occlusion, and thermal fluid injection. In the embodiment shown in Figure 9C, an 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. The occlusion element 804 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 the catheter 802. Figure 9D illustrates another embodiment of an apparatus 830 where occlusion element 804 is positioned proximal or upstream of the electrode assembly 806, and the infusate I is delivered at a position distal of the occlusion element 804 but proximal of the electrode assembly 806.
[0090] Figure 9E is a schematic side view illustrating yet another embodiment of an apparatus 840 with occlusion elements 804 (two are shown as occlusion elements 804a and 804b) positioned both proximal and distal of the electrode assembly 806. In addition to having a first injection port 805a, the catheter 803 includes an aspiration port 805b. Separate lumens can extend through the catheter for injection and aspiration of the infusate I via the injection ports 805a and 805b. 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 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.
[0091] Figure 9F illustrates still yet another embodiment of an apparatus 850 having a catheter 852 including a wall-contact electrode 856 that can 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 852 in the vicinity of the electrode 856. The elongated member 857 may be configured for self or mechanical expansion, or it may extend through a 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 857 may be advanced relative to the catheter 852 by the medical practitioner such that the member assumes the illustrated curved profile.
[0092] 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, the positioning element 804 may be expanded to facilitate positioning of the electrode 856 via the elongated member 857 and/or to block flow through the vessel. The positioning element 804 can be coupled to the guide or delivery catheter 803. lnfusate I optionally may be delivered through the catheter 852 as shown.
[0093] Figures 9G-9N are partially schematic side views illustrating an embodiment of a probe or catheter 900 including a shaped or self-expanding or mechanically-activated electrode suitable for use in the system 100 of Figures 3A and 3B. Figure 9G, for example, illustrates the probe or catheter 900 in a reduced profile configuration for delivery to the treatment site, and Figure 9H illustrates a portion of the probe 900 in an expanded or uncompressed state. Referring to Figures 9G and 9H together, the probe 900 can include a shaft 904, an electrode 906, an intermediate portion or section 908 between the shaft 904 and the electrode 906, and a guide catheter or sheath 910 (e.g., a 5 French guide catheter) covering and releasably carrying the shaft 904 and the intermediate portion 908. The intermediate portion 908 can rest within the sheath 910 in a compressed state (i.e., the curved or shaped region is substantially flattened or otherwise straightened by the inner wall of the sheath 910) during delivery to the treatment site (Figure 9G). When the sheath 910 is retracted, the intermediate portion 908 will expand to its unconstrained arched or curved shape (Figure 9H). The curved or shaped profile of the intermediate portion 908 facilitates contact between the electrode 906 and the corresponding vessel wall. This process is described in greater detail below with reference to Figure 9J.
[0095] Referring back to Figures 9G and 9H together, the shaft 904 can be a generally cylindrical tube constructed from one or more biocompatible materials (e.g., plastic, metals, alloys, and ceramics). The shaft 904 can also include a more flexible region or section 904a at a distal portion of the shaft 904 and configured to allow the probe 900 to flex or contort during use. For example, the flexible region 904a can allow the probe 900 to make the relatively sharp turn from the aorta to the renal artery during delivery of the electrode 906 to the treatment site. In one embodiment, the flexible region 904a can include a braided shaft without the support of a hypotube or other support structure which may be incorporated into the shaft 904. As shown in Figure 9H1 the flexible region 904a has a length Li of about 7 cm. In other embodiments, however, flexible region 904a can have a length Li of from about 2 cm to about 140 cm (the entire working length of the shaft 904 could be generally flexible). In still other embodiments, the shaft 904 and/or the flexible region 904a can have a different arrangement and/or configuration.
[0096] The probe 900 can have a working or effective length l_2 of from about 55 cm to about 140 cm. As used herein, "working length" and "effective length" are defined as the length of the probe 900 (e.g., the shaft 904, the intermediate portion 908, and the electrode 906) that will fit inside a patient's body. In configurations where a 55 cm guide catheter is used to facilitate delivery of the probe 900, 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 the probe 900, the working or effective length may be from about 95 cm to about 120 cm. In the illustrated embodiment, for example, the probe 900 has a working or effective length l_2 of about 108 cm and is configured for use with a sheath 910 having a length of about 90 cm. In other embodiments, however, the probe 900 can have a different working length L2 and/or be configured for use with a sheath having a different dimension and/or configuration.
[0099] One expected advantage of an embodiment where only impedance is measured is that only one wire is needed for the probe 900. If the probe 900 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 the probe 900 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 the probe 900 and increase the potential for a malfunction.
[00100] Although the illustrated electrode 906 includes the band 914, the electrode 906 can have other configurations. For example, the electrode 906 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.
[00101] Figure 9I is an exploded view of a portion of the probe 900 taken from the area 9I of Figure 9H. The intermediate portion 908 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 the electrode 906 and the corresponding vessel wall. In the illustrated embodiment, the intermediate portion 908 flexes or bends to locate the electrode 906 at a dimension Y from a longitudinal axis S of the shaft 904. 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 the shaft 904 was positioned adjacent to a wall of an artery having an 8 mm diameter, the intermediate section 908 would have enough flexure or arch for the electrode 906 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.
[00102] The intermediate portion 908 is also configured to locate the electrode 906 at a dimension X from a distal portion 904b of the shaft 904. The dimension X can vary based, at least in part, on the material of which the intermediate portion 908 is composed (e.g., stainless steel or nitinol) and the desired working or effective length for the probe 900. For example, the dimension X of the intermediate portion 908 should be configured and sized to provide sufficient wall contact pressure such that the electrode 906 can create the desired treatment effect.
[00103] 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 in Figures 9L to 9N, an electrode tip 985 of a probe 980 can be deflected or steered using an actuator wire 982. The actuator wire 982 can be pulled from a first position or position of no deflection 986, as shown in Figure 9L, to a second position of slight deflection 987, as shown in Figure 9M, to a third position of substantial deflection 988, as shown in Figure 9N. The variable deflection of the probe 980 can be particularly helpful, for example, when attempting to achieve wall contact in a curved vessel.
[00104] Referring back to Figure 9I, the shaft 904 has an outer diameter D of from approximately 0.014 inches to approximately 0.085 inches. The outer diameter D of the shaft 904 can vary based, at least in part, on the outer diameter of the electrode 906. In the illustrated embodiment, for example, the shaft 904 has an outer diameter D of about 0.040 inches, which corresponds to one particular configuration of the electrode 906.
[00105] The electrode 906 has an outer diameter E of from about 0.020 inches to about 0.085 inches. In the illustrated embodiment, for example, the electrode 906 has an outer diameter E of about 0.049 inches. These dimensions can vary, however, from a practical standpoint, the outer diameter E of the electrode 906 can be no bigger than the inner diameter of the sheath or guide catheter (e.g., the sheath 910) through which the electrode 906 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.
[00107] Figure 9J is a schematic side view of an embodiment of an intravascular apparatus 950 including the probe 900 with the shaped or self-expanding electrode 906. The electrode 906 can be delivered to a treatment site within the sheath 910, and then it can move to a preselected shape after it has been removed from the lumen of the sheath 910. For example, the electrode 906 can be removed from the sheath 910 by advancing the shaft 904 and/or retracting the shaft 904. The electrode 906 contacts the vessel wall for delivery of therapy. Optionally, the shaft 904 may be rotated to rotate the electrode 906 relative to the vessel wall and angularly reposition the electrode 906. The therapy can be delivered at a singular angular position or at multiple angular positions, lnfusate I optionally may be delivered through the sheath 910 as shown.
[00108] 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.
[00109] Additionally or alternatively, the apparatus 950 can include multiple angularly spaced electrodes 906 positioned within the vasculature, as shown in Figure 9K. In addition to angular spacing, the electrodes 906 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).
[00111] Figure 10 is a schematic side view illustrating an embodiment of an intra-to- extravascular ("ITEV") system 900 for thermally-induced renal neuromodulation. The ITEV system 900 includes 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 includes an equal number of proximal and distal electrode lumens and side ports. The ITEV system 900 also includes proximal needle electrodes 928 that can 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. Alternatively, the embodiment illustrated in Figure 10 can be configured with a single needle electrode configured for monopolar energy delivery.
[00112] The catheter 922 includes an optional expandable positioning element 930. The positioning element 930 can include, for example, 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 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 928 and 929 to desired depths within/external to the patient's vessel (e.g., to deliver all of the needle electrodes 928 and 929 to approximately the same depth). In the embodiment illustrated in Figure 10, the positioning element 930 is between the proximal side ports 924 and the distal side ports 926 and, accordingly, 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 can 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).
[00113] As shown in Figure 10, the catheter 922 may be advanced to a treatment site within the patient's vasculature over a guidewire (not shown) via the lumen 923. During intravascular delivery, the needle 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 928 and 929 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.
[00114] The proximal electrodes 928 can be connected to a field generator (not shown) as active electrodes, and the distal electrodes 929 can serve as return electrodes. In this manner, the proximal and distal electrodes 928 and 929 form bipolar electrode pairs that align the thermal energy field with a longitudinal axis or direction of the patient's vasculature. The distal electrodes 929 alternatively may comprise the active electrodes and the proximal electrodes 928 may comprise the return electrodes. Furthermore, the proximal electrodes 928 and/or the distal electrodes 929 may both comprise active and return electrodes. Further still, the proximal electrodes 928 and/or the distal electrodes 929 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.
[00115] When the electrodes 928 and 929 are connected to a field generator and positioned extravascularly (and with the positioning element 930 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 and 929 can be retracted within the proximal and distal lumens, and the positioning element 930 can be collapsed for retrieval. The ITEV system 900 can then be removed from the patient to complete the procedure. Additionally or alternatively, the system 900, or any system disclosed herein, may be repositioned to provide therapy at another treatment site, such as to provide bilateral renal neuromodulation.
[00117] Although Figures 3A-8B and 10 illustrate bipolar systems, it should be understood that monopolar systems alternatively may be utilized as shown in Figures 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.
[00118] The embodiments described above with reference to Figures 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 (see Figures 11 and 13), via a Peltier element (see Figure 12), etc. Thermally-induced renal neuromodulation additionally or alternatively may be achieved via application of high-intensity focused ultrasound to the target neural fibers (see Figures 14A, 14B, and 15). Additional and alternative methods and systems for thermally-induced renal neuromodulation may be used in accordance with the present disclosure.
[00119] Figure 11 , for example, is a schematic side view of an alternative embodiment of an apparatus 1000 for thermally-induced neuromodulation via application of thermal energy. In this embodiment, the electrodes 328 and 329 of Figure 10 have been replaced with infusion needles 1028 and 1029, respectively. A thermal fluid F may be delivered through the infusion needles 1028 and 1029 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 370C, 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 200C, or still further cooled below a freezing temperature of about 00C. As will be apparent, in addition to intra-to-extravascular delivery of a thermal fluid, the thermal fluid F may be delivered intravascular^ (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.
[00123] Figure 13 illustrates yet another embodiment of an apparatus 1200 utilizing the Peltier effect. The apparatus 1200 includes an implanted or external pump 1202 connected to a renal artery cuff 1204 via an inlet fluid conduit 1206a and an outlet fluid conduit 1206b. The inlet fluid conduit 1206a transfers fluid from the pump 1202 to the cuff 1204, while the outlet fluid conduit 1206b transfers fluid from the cuff 1204 to the pump 1202 to circulate the fluid through the cuff 1204. A reservoir of fluid may be located in the cuff 1204, the pump 1202, and/or in the fluid conduits 1206a and 1206b.
[00126] Figures 14A and 14B, for example, are schematic side views illustrating an embodiment of an ultrasonic apparatus 1300 including a catheter 1302, one or more ultrasound transducers 1304 positioned along the shaft of the catheter 1302, and an inflatable balloon 1306 around the transducers 1304. Figure 14A illustrates the apparatus 1300 in a reduced delivery and retrieval configuration, and Figure 14B illustrates the apparatus 1300 in an expanded deployed configuration. The ultrasound transducers 1304 are coupled to an ultrasound signal generator (not shown) via conductors 1307. The balloon 1306 can have an acoustically reflective portion 1308 for reflecting an ultrasound wave and an acoustically transmissive portion 1309 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 1304 may be attached directly to the balloon 1306.
[00127] 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 1306.
[00129] Figure 15 illustrates still another embodiment of an ultrasonic apparatus 1400 having a catheter 1402, a conductor 1403, and concave ultrasound transducers 1404. The concave ultrasound transducers 1404 direct the energy to a specific focal point P. As such, the concave transducers 1404 are self-focusing and eliminate the need for reflective portions on the balloon 1406 (e.g., the balloon may be acoustically transmissive at all points).
[00130] The systems described above with respect to Figures 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.
[00131] 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.
[00133] In one embodiment, for example, a controller can command a power generator (e.g., the field generator 110 of Figures 3A and 3B) in accordance with an algorithm comprising various power delivery profiles. Figure 16, for example, is a flow chart illustrating a method 1600 of controlling such power delivery processes. The method 1600 can be implemented as a conventional computer program for execution by the processor 114 of Figure 3A or another suitable device (e.g., the field generator 110). The method 1600 can also be implemented manually by an operator.
[00134] As illustrated in Figure 16, after treatment is initiated, the first stage 1602 of the method 1600 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. At stage 1604, the method 1600 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.
[00135] When it is determined that one or more parameters or multiple parameters in combination fall outside a predetermined parameter profile, then the method 1600 calls for an adjustment to the system's power output at stage 1606. 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 in Figure 16, treatment will continue until power delivery has been adjusted to a level of zero (stage 1608).
[00136] 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.
[00137] 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. Figure 17, for example, illustrates a functional diagram showing software modules 1620 suitable for use in the processor 114 of Figure 3A or another suitable device (e.g., the field generator 110) 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 of processor 114. 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 the processor 114 can include an input module 1622, a database module 1624, a process module 1626, an output module 1628, and a display module 1630. In another embodiment, the software modules 1620 can be presented for execution by the CPU of a network server in a distributed computing scheme.
[00138] In operation, the input module 1622 accepts operator input, such as process setpoint and control selections, and communicates the accepted information or selections to other components for further processing. The database module 1624 organizes records, including an operating parameter 1634, an operator activity 1636, and one or more alarms 1638, and the database module 1624 facilitates storing and retrieving of these records to and from a database 1632. 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, California.
[00139] The process module 1626 can process the sensor readings 1640 (e.g., from the sensors 310 in Figure 5A), check for alarms and interlocks, and generate control variables for controlling an energy delivery process of the field generator 110 (Figure 3A) based on the sensor readings 1640. The output module 1628 can generate output signals 1642 based on the control variables. For example, the output module 1628 can convert the generated control variables from the process module 1626 into output signals 1642 suitable for an energy output modulator. The display module 1630 can display, print, or download the sensor readings 1640 and the output signals 1642 via devices such as the output device 120 (Figure 3A) or a visual display on the face of the field generator 110. A suitable display module 1630 can be a video driver that enables the processor 114 to display the sensor readings 1640 on the output device 120.
[00140] Figure 18 is a block diagram showing an embodiment of the process module 1626 of Figure 17. The process module 1626 can further include a sensing module 1650, a calculation module 1652, an alarm module 1654, a power output module 1656, and an interlock module 1658 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.
[00141] The sensing module 1650 can receive and convert the sensor readings 1640 into parameters in desired units. For example, the sensing module 1650 can receive the sensor readings 1640 as electrical signals and convert the electrical signals into instant temperatures in Celsius. The sensing module 1650 can have routines including, for example, linear interpolation, logarithmic interpolation, data mapping, or other routines to associate the sensor readings 1640 to parameters in desired units.
[00145] The interlock module 1658 continuously monitors operating parameters received from the sensing module 1650 and/or the calculation module 1652, and the interlock module 1658 can control operation of the power output module 1656 when the monitored operating parameters exceed certain interlock threshold values. Depending on the interlock condition, the power output module 1656 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, the interlock module 1658 can cause the power output module 1656 to reduce the power output when the average temperature from the calculation module 1652 exceeds a preset value. Additionally or alternatively, the interlock module can cause the power output module 1656 to terminate its operation (i.e., having a zero output value) when the instant temperature from the sensing module 1650 exceeds another preset value. In several embodiments, the interlock module 1658 can optionally be configured to directly generate output signals 1642 to the other system components.
[00149] As illustrated in Figure 19, the first interlock condition occurs at time 0 (i.e., the time at which the operator has initiated treatment and the timer begins counting up from zero). In this case, the method 1600 continues at stage 1606 with the power output module 1656 commanding the field generator 110 to gradually adjust its power output to a first power level Px (e.g., 5 watts) over a first time period (0-ti) (e.g., 15 seconds). The power output module 470 can generate and transmit a power setpoint to the field generator 110 as the output signals 1642. In one embodiment, as illustrated in Figure 19, the power increase during the first time period is generally linear. As a result, the field generator 110 increases its power output at a generally constant rate of PJt1 . In other embodiments, the power increase can be non-linear (e.g., exponential or parabolic) with a variable rate of increase.
[00150] After the first time period expires (or after the power level at P1 has been achieved), the power output module 1656 can command the field generator 110 to maintain its current output power level at P1 , i.e., pause for a second time period (U - t2). An operator or preprogrammed routine can adjust the time period (U - 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 (U - t2) to compensate for the additional response delay. In other embodiments, the power output module 1656 may cause the field generator 110 to reduce the output level to less than P1 or momentarily terminate its output level during the second time period (U - t2) or any other time period (e.g., the first time period or subsequent time periods).
[00151] After the second time period expires, the calculation module 1652 can derive an average temperature at the end of the second time period, i.e., t2, based on the temperature from the sensing module 1650. The method 1600 can continue with a test to determine whether the calculated average temperature at fø exceeds a preset threshold (e.g., 65°C). If the average temperature exceeds the preset threshold, then the power output module 1656 can command the field generator 110 to maintain its current output power level for a desired total treatment time.
[00153] The method 1600 can continue with another test to determine whether the increased power level (P1 +AP) exceeds a maximum power level (e.g., 10 watts) for the field generator 110. 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, then power output module 1656 commands the field generator 110 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 the method 1600 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.
[00154] Optionally, the calculation module 1652 can calculate the number of cycles before the maximum power level is reached. For example, when a fixed AP is used, the calculation module 1652 can calculate the number of cycles according to the following formula:
[00156] The method 1600 can also optionally include a ramping process that allows the power level to be increased at a faster rate. For example, the method 1600 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 the power output module 1656 can command the field generator 110 to increase the power level P1 by an amount equal to ΔP x 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.
[00157] The method 1600 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.
[00158] During power delivery, the interlock module 1658 can continuously monitor one or more operating parameters received from the sensing module 1650 and/or the calculation module 1652. For example, this method can include a test to determine whether the calculated average temperature is greater than or equal to a preset threshold Tt (e.g., 70° C). If the average temperature does not exceed the preset threshold Tt, then the interlock module 1658 does not interrupt operation of the power output module 1656 and the current power output level is maintained for treatment.
[00159] On the other hand, if the average temperature (from the calculation module 1652) exceeds the preset threshold Tt, then the method can continue with stage 1606 in which the power level is reduced. During this power reduction stage, the power output module 1656 can command the field generator to immediately decrease power by P3 (e.g., 1 watt). After decreasing the power, the method can pause the power output module 1656 for a time period Tw (e.g., 3 seconds). After the time period Tw expires, the calculation module 1652 can again derive an average temperature based on the temperature from the sensing module 1650. The method can continue with another test at to determine whether the calculated average temperature still exceeds the preset threshold Tt. In some cases, this power reduction process may need to be repeated several times, decreasing power by P8 each 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.
[00160] 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, the interlock module 1658 can measure the slope of the impedance over a fixed period of time. If the measured slope does not exceed a preset threshold, then the interlock module 1658 does not adjust operation of the power output module 1656, and the method can continue with a sustained power level. However, if the measured slope is greater than a preset threshold Zs (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 Z5. An operator or preprogrammed routine can adjust the preset thresholds Tt and Z3 or the power reduction rate based on the patient's physiological characteristics and/or one or more desired treatment parameters.
[00162] 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.
[00163] If the measured impedance is greater than the minimum impedance value plus a preselected threshold value Zd (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 the power output module 1656 for a time period TW2 (e.g., 3 seconds). After the time period TW2 expires, the interlock module 1658 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.
[00164] One expected advantage of the methods 1600 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 to Figures 3A and 3B, the field generator 110 can deliver an electric field to the probe 104 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, the method 1600 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.
[00166] 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.
[00167] 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.

中文:
[0007]交感肾神经活性减少,(例如,经由去神经),可以逆转这些过程。阿迪安(Ardian)公司已经开发了通过将电场施加到促进肾功能的神经纤维而用于治疗肾疾病的方法和系统。见,例如,阿迪安(Ardian)公司的共同拥有和共同未决的美国专利申请号(a)2005年5月13日提交的11/129,765,(b)2005年7月25日提交的11/189,563,和(c)2006年2月27日提交的11/363,867,将其全部通过参考整体结合于本文。电场可以经由去神经引发肾神经调制,所述去神经由不可逆电穿孔、电融合、细胞凋亡、坏死、消融、热变、基因表达改变或另一种适合的模态所引起。可以从定位在血管内的、血管外的、血管内到血管外的装置或其组合而传送电场。例如在共同拥有的美国专利号7,162,303和6,978,174中描述了经由局部药物递送(例如,通过药物泵或输注导管),刺激电场的使用,及其它模态用于实现肾神经调制的另外的方法和装置,将所述美国专利都通过参考全部结合于此。
[0008]虽然这些应用提供有希望的方法和系统,但是数种用于增强这些方法和系统实施的改善将是合乎需要的。
[0009]图1是图解人肾解剖学的示意图。
[0010]图2是显示肾神经相对于肾动脉的位置的示意性等比例的详细视图。
[0011]图3A是根据所公开内容的一个实施方案配置的控制热诱导(thermal induce)的肾神经调制的系统的等比例视图。
[0012]图3B是示意性侧视图,部分地以截面方式,图解用于热诱导的肾神经调制的血管外系统的实施方案。
[0013]图4A和4B是图解几种类型的热诱导的肾神经调制的示意图,所述热诱导的肾神经调制可以用本文所描述的系统和方法实现。
[0014]图5A-5C是示意性侧视图,部分以截面方式,图解根据所公开内容的实施方案配置的热诱导的肾神经调制的血管内装置。
[0015]图6A和6B是示意性侧视图,部分以截面方式,图解具有一个或多个壁接触电极的血管内装置的另一个实施方案。
[0018]图9A-9F是示意性侧视图,部分以截面方式,图解包括一个或多个壁接触电极的血管内系统的更进一步的实施方案,以及任选的血流阻塞特征和/或传热流体(thermal fluid)注射功能。
[0019]图9G-9N是示意性侧视图,部分以截面方式,图解用于热诱导的肾神经调制的探针的实施方案。
[0020]图10是示意性侧视图,部分以截面方式,图解根据所公开内容的实施方案配置的热诱导的肾神经调制的血管内到血管外的系统的实施例。
[0021]图11是示意性侧视图,部分以截面方式,图解经由热能的施加用于热诱导的肾神经调制而配置的装置的实施方案。
[0022]图12是示意性侧视图,部分以截面方式,图解用于热诱导的肾神经调制的装置的实施方案,所述装置包括适于将热能施加到靶神经纤维的热电元件。
[0023]图13是示意性侧视图,部分以截面方式,图解用于热诱导的肾神经调制的装置的另一个实施方案,所述装置包括热电元件。
[0024]图14A和14B是示意性侧视图,部分以截面方式,图解经由高强度聚焦的超声波用于热诱导的肾神经调制的装置的实施方案。
[0025]图15是示意性侧视图,部分以截面方式,图解图14A和14B的装置的备选实施方案。
[0026]图16是图解用于控制热诱导的肾神经调制的能量递送过程的方法的流程图。
[0029]图19是功率随时间变化的图,其显示对执行图16的方法的响应的实施例。
[0033]除在热神经调制期间监控或控制温度之外,可以指定暴露于热刺激的时间长度(length)以影响热神经调制功效的范围或程度。在许多实施方案中,暴露于热刺激的时间长度长于瞬时暴露。例如,暴露延续时间可以短至约5秒钟,或可以更长,诸如约30秒,或乃至长于2分钟。在某些具体的实施方案中,所述暴露时间可以小于10分钟,但是这决不应当被理解为暴露时间的上限。在其它实施方案中,所述暴露可以是间歇的或连续的以实现所需结果。以小时、天或更长方式测量的暴露时间可以用于实现所需的热神经调制。
[0035]在一些实施方案中,热诱导的肾神经调制可以通过将传热冷却或加热的能量直接和/或间接施加到靶神经纤维而实现。例如,可以将冷却的或加热的流体至少邻近于靶神经纤维施用,或可以将加热的或冷却的元件(例如,热电元件或电阻加热元件)放在所述神经纤维附近。在其它实施方案中,热诱导的肾神经调制可以通过将热能产生和/或施加到靶神经纤维而实现,诸如通过将“热”能量场施加到所述靶神经纤维来实现,所述“热”能量场包括,电磁能、射频、超声波(包括高强度聚焦超声波)、微波、光能(包括激光、红外线和近红外线)等。例如,热诱导的肾神经调制可以通过将脉冲的或连续的热能场递送到靶神经纤维而实现。所述能量场可以是足够的幅度和/或持续时间以热诱导靶纤维中的神经调制(例如,加热纤维或热消融纤维或使所述纤维坏死)。如本文所描述,另外的和/或备选的方法和系统也可以用于热诱导肾神经调制。
[0038]而且,与施加同等级别或持续时间的连续热能相比,热能脉冲递送之间的时间间隔可以促进血管壁的非靶组织的另外的对流或其它的冷却。这可以发生,因为通过血管的血流可以对流冷却(加热)血管壁的非靶组织。
[0042]在一些实施方案中,可以提供用于实时监控被靶神经纤维支配的组织中神经调制或去神经和/或非靶组织中热损伤的范围或程度(例如,热变的范围或程度)的方法和装置。同样地,可以提供热能递送元件的实时监控。例如,这样的方法和装置可以包括用于测量受监控的组织的温度或热能递送元件温度的热电偶或其它温度传感器。可以测量的其它参数包括功率、递送的总能量、神经活性或阻抗。监控数据可以用于所述热治疗的反馈控制。例如,可以通过沿着治疗区域附近的血管壁获得温度或阻抗测量,和/或通过限制治疗的功率或持续时间,监控和控制血管内递送的热治疗。
[0044]如图1所示,人肾解剖学包括肾K,其通过肾动脉RA被供给氧合的血液。经由腹部的主动脉AA将肾动脉连接到心脏。脱氧的血液经由肾静脉RV和下腔静脉IVC从肾流到心脏。
[0046]图3A-19图解用于热诱导的肾神经调制的系统和方法的实施例。例如,图3A是根据所公开内容的实施方案配置的用于控制患者101的热诱导的肾神经调制的系统100的等比例视图。系统100可以包括处理器114,电连接到处理器114的场发生器110,和操作连接到所述场发生器110的探针104。在图解的实施方案中,电缆112将探针104电连接到场发生器110。在其它的实施方案中,处理器114,探针104,和/或场发生器110可以经由例如射频信号无线连接。
[0049]探针104可以是在CT、X射线照相的、或另一种适合的引导模式下的腹腔镜检查探针、经皮探针、血管内导管、或另一个适合的设备,其配置用于沿着肾动脉、肾静脉、脐点、和/或格罗塔筋膜和/或在肾动脉、肾静脉、脐点、和/或格罗塔筋膜中邻近于肾神经供应的轨迹插入。探针104可以包括至少一个用于递送热能场治疗的电极108和经由电缆112连接到场发生器110的电连接器106,用于将热能场递送到所述电极108。在一些实施方案中,探针104可以包括用于将热能场递送到电极108的集成电缆(未显示),并且电连接器106可以被省略。在图解的实施方案中,例如,探针104是配置成经皮推进到邻近患者101的解剖靶102(例如,肾动脉或肾静脉)的经皮探针,如下面对于图3B所更详细地描述。在其它实施方案中,所述探针104可以是可植入的设备。
[0050]电极108可以是相互电独立的单独电极,具有共同连接的接触的分段电极,或连续电极。例如,分段电极可以通过提供安装到所述电极上的有槽管或通过电连接一系列单独电极而形成。单独电极或电极的组108可以配置成提供双极信号。电极108可以是动态可分配的以促进任何电极之间和/或任何电极和远程电极之间的单极和/或双极能量递送。例如,远程电极可以外部连接到患者皮肤(例如,到患者的腿或胁腹)。
[0051]探针104还可以包括至少一个传感器(未显示),用于测量患者101的生理学参数。例如,探针104可以包括温度传感器、阻抗传感器、超声波传感器、和/或其它类型的传感器。所述传感器可以测量生理学参数(例如,温度)并且将测量的生理学参数传输到处理器114用于处理。
[0052]任意的,所述系统100还可以包括操作性地连接到处理器114的输入设备118,输出设备120,和/或控制面板122。输入设备118可以包括键盘、鼠标、触摸屏、按钮、开关、电势差计、和任何其它适于接收使用者输入的设备。所述输出设备120可以包括显示屏,打印机,介质阅读器,音频设备,和适于提供使用者反馈的任何其它设备。控制面板122可以包括指示器灯、数字显示器、和音频设备。在图3A中显示的实施方案中,具有轮126的支架(rack)124携带处理器114,场发生器110,输入设备118,和输出设备120用于便携性。在另一个实施方案中,多种部件(component)可以合并成单一封装(enclosure)(例如,场发生器110),例如,用于便携式安装在IV台、IV极、仪器台、输注台、和/或其它的支撑结构上。在另外的实施方案中,可以固定地安装多种部件。
[0053]在操作中,操作者可以将探针104至少邻近患者101的体腔(例如肾动脉或肾静脉)的壁放置,然后将能量递送到探针104以实现热肾神经调制,如下更详细地描述。例如,图4A和4B图解可以用这里所描述的系统和方法实现的多种类型的热神经调制。仅为了说明而提供图4A和4B,并且其决不应当被理解为限制性的。
[0054]图4A说明由于热暴露产生的热神经调制。如所示,暴露到超过约37°C的体温但是低于约45°C的温度的热可以通过中度加热靶神经纤维或用于灌注所述靶纤维的血管结构而诱导热变。在血管结构被影响的情况下,靶神经纤维排斥灌注,导致神经组织的坏死。例如,这可以在所述纤维或者结构中诱导非消融的热变。暴露到超过约45°C或超过约60°C的温度的热量中可以经由对所述纤维或结构的实质加热而诱导热变。例如,这样的更高温度可以热消融所述靶神经纤维或所述血管结构。在一些患者中,可以合乎需要的是实现热消融靶神经纤维或所述血管结构的温度,所述温度小于约90°C,或小于约85°C,或小于约80°C和/或小于约75°C。不考虑用于诱导热神经调制的热暴露的类型,预期肾交感神经活性(“RSNA”)的减少。
[0055]关于图4B,用于神经调制的传热冷却包括神经传导和/或神经改变的非冷冻热延缓,以及冷冻的热神经改变。非冷冻的传热冷却可以包括将所述靶神经纤维或供养所述纤维的血管结构的温度减少到约37°C体温以下或约20°C以下,但是超过约0°C的冷冻温度的温度。该非冷冻的传热冷却可以延缓神经传导或可以导致神经改变。减缓的神经传导可以使用连续或间歇冷却靶神经纤维以维持所需热神经调制,同时神经改变可能仅需要不连续的处理以实现持续的热神经调制。用于神经调制的传热冷却还可以包括冷冻的热神经改变,其通过将靶神经纤维或供养所述纤维的血管结构的温度减少到约0°C的冷冻点以下的温度。不考虑用于诱导热神经调制(冷冻的或非冷冻的)的冷暴露的类型,预期RSNA的减少。
[0056]仍参考图3A,操作者和/或处理器114可以监控和控制能量递送过程。如上所述,探针104可以包括测量患者101的生理学参数的传感器。探针104可以将测量参数经由电缆112或无线地传输到处理器114。处理器114可以处理和分析所接收的参数并且将所述参数显示在输出设备120的适当单元上。处理器114可以导致所述系统发出警报声,条件是所接收的参数超过预定阈值并且利用输出设备120和/或控制面板122发出任何警报信号。处理器114还可以分析和处理参数测量数据,用于或者单参数或组合方式的多参数,并且可以将所述数据与存储的非经验数据进行比较以识别可以准许更密切注意的任何模式。处理器114还可以在数据库中存储所接收的参数和数据模式用于随后的检索。另外,处理器114可以调制场发生器110的功率输出,这基于所接收的参数和/或经由输入设备118从操作者接收的输入进行,如下对于图16-19更详细地描述。
[0057]在图3B中,探针104已经推进经过经皮进入位置P进入肾动脉RA附近。探针104刺穿患者101的格罗塔筋膜F,并且所述电极108通过探针104并且沿着动脉和筋膜之间的环形空间被推进到位。一旦适当定位,可以经由跨越电极108递送的脉冲的或连续的电场加热靶神经纤维。例如,在图3B中,电极108包含双极电极对,其可以产生热能场109。这样的加热可以对靶神经纤维消融或引起非消融的热变,以至少部分切除受靶神经纤维神经支配的肾的神经。能量场还可以在靶神经纤维中诱导可逆的或不可逆的电穿孔,其可以提供在神经纤维中诱导的热变。在处理以后,可以将探针104从患者除去以终止所述程序。
[0058]图5A-9,14,和15图解用于热诱导的肾神经调制的血管内系统和有关方法的数个实施方案。应当理解,在下列实施方案的每一个中的电极可以连接到发生器(例如,场发生器110),即使所述发生器未在下面明确显示或描述。
[0059]例如,图5A和5B是示意性侧视图,其图解用于热诱导的肾神经调制的血管内装置300。装置300可以包括具有任选的定位元件304的导管302、沿着导管302的轴配置的轴电极306a和306b、和任选的在定位元件304的区域中沿着导管302的轴配置的不透射线的标记物308。相对于所述血管和/或神经,定位元件304可以是气囊、可展开的金属线筐(wire basket)、其它机械展开器,或用于容纳电极306a-b的另一种适合的设备。可以这样安排电极306a-b,以便电极306a接近定位元件304的近端并且电极306b接近定位元件304的远端。电极306a-b电连接到场发生器110(图3A),用于将能量递送到靶神经纤维。在其它实施方案中,一个或多个电极306a-b可以包含帕尔贴(Peltier)电极用于加热或冷却靶神经纤维以调制所述纤维。
[0060]定位元件304可以任意定位或以另外方式驱动电极306a-b与所述腔壁进行接触。例如,当定位元件304是可臌胀的气囊时,如图5A所示,所述气囊可以充当可展开的电极元件306a-b的定中心的和/或展开元件,并且作为阻抗-改变电绝缘器用于引导递送的能量场经由电极306a-b进入或跨越所述血管壁,用于调制靶神经纤维。由定位元件304提供的电绝缘可以减少为实现所需靶纤维调制所必需的施加能量的级别或其它能量场参数,其可以包括部分或完全将含有靶纤维的组织去神经。申请人在前已经描述了2005年11月4日提交的共同未决美国专利申请号11/266,993中的适合的阻抗改变元件的用途,将其通过参考全部结合于此。
[0061]而且,定位元件304任选地可以用作冷却元件和/或加热元件。例如,定位元件304可以随着冷却流体膨胀,所述冷却流体用作用于从接触所述元件的组织去除热的散热装置。相反,定位元件304任选地可以是加热元件,通过用温热流体膨胀它,所述温热流体加热和所述元件接触的组织。传热流体任选地可以在定位元件304之内循环和/或交换以促进更有效的传导和/或对流的传热传递。传热流体还可以用于经由传热冷却或加热机制实现热神经调制,如下所更详细所描述。
[0062]另外或备选地,定位元件304(或装置300的任何其它部分)可以包含一个或多个用于监控所述过程的传感器。在一个实施方案中,定位元件304具有用于监控靶组织及非靶组织的温度或其它参数的壁接触热电偶310(图5A),电极,定位元件和/或装置300的任何其它部分。备选地,电极306a和/或306b可以具有一个或多个组合到它们中的热电偶。
[0063]图5A和5Bb中显示的血管内实施方案的电极306a-b可以是单独的电极(即,独立的接触),具有共同连接接触的分段电极,或单一连续电极。而且,电极306a-b还可以配置成提供双极信号,或电极306a-b可以一起使用或连同单独的患者接地垫独立地用于单极用途。电极306a-b可以附属于定位元件304,以便它们在定位元件304展开时接触动脉壁。例如,电极306a-b可以固定到内表面,外表面,或至少部分埋置在定位元件304的壁之内。描述在下文中的图5C,图解壁接触电极的一个实例,而图6-9图解备选的壁接触电极。
[0064]如图5A中所示,以通过引导导管或其它设备的低姿态(lowprofile)递送构造的方式,导管302可以被递送到如所示的肾动脉RA之内的治疗部位,或者可以将它递送到肾静脉或递送到接近于对肾功能起作用的神经组织的任何其它血管。备选地,导管可以定位在多个用于热肾神经调制的血管中,例如,在肾动脉和肾静脉两者之内。在多个血管中用于脉冲电场肾神经调制的技术之前已经描述过,例如,在2006年7月12日提交的共同未决美国专利申请号11/451,728,将其通过参考全部结合于此。
[0065]一旦定位元件304是在所述肾血管系统之内的所需位置,则它可以展开成与所述血管的内壁进行接触。然后可以将热能场经由电极306a-b跨越动脉壁递送。所述场沿着对肾功能起作用的神经纤维通过加热热调制所述活性。在数个实施方案中,所述热调制至少部分地将受所述神经纤维支配的肾经由加热去神经。例如,这可以通过靶神经纤维的热消融或非消融的改变而实现。
[0066]在图5A中所示的实施方案中,定位元件304是可臌胀的气囊,其可以优先定向如上所述的能量场。在图5B中图解的实施方案中,定位元件304包括可展开的金属线筐,其基本上将电极306a-b定中心在血管之内,而不阻塞经过所述血管的血流。在热能场(或其它热能的)的递送期间,血液可以作为传导的和/或对流的传热传递的散热装置,以从非靶组织除去过量热能。这保护非靶组织免受不希望的热效应。当在能量递送期间不阻塞血流时,诸如在图5B中显示的实施方案中,该效应可以增强。
[0067]利用患者的血液作为散热装置预计将促进更长时间或更大级别的热处理以减小递送到非靶组织的不希望的效应的风险,其可以增强在靶神经纤维的治疗功效。虽然图5B中显示的实施方案包括用于在不阻塞流动的情况下将电极306a-b定中心的定位元件304,应该理解所述定位元件304可以被除去和/或所述电极306a-b可以附着于定位元件304,以便它们在定中心元件展开时未处于血管中心。在这样的实施方案中,患者的血液仍然可以减轻过量的传热加热或冷却以保护非靶组织。
[0069]而且,与使用同等级别或持续时间的连续热治疗相比,热能脉冲之间的休止时间或低能量间隔可以促进血管壁的非靶组织的另外的对流的或其它冷却。这可以发生,因为经过血管的血流可以比定位在血管壁之外的靶神经纤维更快地对流冷却(加热)血管壁的非靶组织。
[0073]一个或多个传感器,诸如图5A的热电偶310,可用于监控在电极306a-b、血管壁和/或在沿着所述装置或患者解剖学的其它预定位置的温度或其它参数。可以使用测量的参数作为反馈控制热神经调制。例如,该反馈可以用于将所述参数保持在所需阈值以下。例如,所述参数可以保持在可能引起非靶组织中不希望的效果的阈值以下。在血液流经血管的情况下,更多的热能可以被带走,这可以允许比血流在血管中被阻塞时更高的能量治疗。
[0076]图6A和6B是示意性侧视图,其图解具有配置成接触血管内壁的电极的血管内装置500的另一个实施方案。图6A和6B的装置500不同于图5A和5B的装置300,因为图5A和5B的近端电极306a已经用壁接触电极306a′替换。壁接触电极306a′包括将电极306a′连接到导管302的轴的近端连接器312a并且电连接到场发生器(未显示)。装置500还具有多个延伸314a,其从近端连接器312a伸出,并且至少部分地在定位元件304的表面上展开。任选地,延伸314a可以是选择性绝缘的,以便仅延伸314a的选择部分(例如,所述延伸的远端尖端)是电活性的。任选地,电极306a′和/或连接器312a可以从有槽的管制造,诸如不锈钢或形状记忆(例如,NiTi)有槽管。而且,所述电极的全部或一部分可以是镀金的以改善不透射线性和/或电导率。
[0077]如图6A所示,在电极306a′以减小的外形构造定位的情况下,导管302可以经过导线G递送到在患者血管之内的治疗部位。任选地,导管302可以经过引导导管303递送以促进壁接触电极306a′的这种减小的外形递送。当依照要求定位在治疗部位时,通过展开所述定位元件304(如图6B中所示),电极306a′可以展开成与血管壁接触。然后可以跨越血管壁并且在电极306a′和306b之间递送热双极电场以诱导热神经调制,如上所述。备选地,306a’或306b可以包括单极电极,其中返回电极(未显示)放置在患者的外表面上。任选的定位元件304可以改变血管之内的阻抗并且更有效地给跨越血管壁的电能量定路线到靶神经纤维。
[0078]在终止电场以后,电极306a′可以返回到减小的外形并且装置500可以从患者除去或在血管中复位。例如,定位元件304可以折叠(例如,被放气),并且电极306a′可以通过在引导导管303之内收回导管302而收缩。备选地,电极306a′可以由倾向成为折叠构造的形状记忆材料制造,以便在定位元件304折叠时所述电极自折叠。
[0079]虽然图6A和6B中显示的电极306a′展开成与血管壁接触,但是应当理解电极306a′备选地可以由倾向于自展开的材料制造,以便在电极306a′定位在引导导管303远端时,电极306a′自展开成与血管壁接触。在通过所述电极递送电场期间,电极306a’的自展开实施方案可以避免需要定位元件304和/或可以促进经过血管的血流的维持。在电场递送以后,自展开的电极306a′可以返回到减小的外形以促进通过在引导导管303之内收回导管302而将装置300从患者除去。
[0080]图7A和7B是示意性侧视图,其图解使用壁接触电极306a′′用于递送场的装置600的另一个实施方案。图7A显示减小的外形构造形式的电极306a′′,并且图7B显示展开的构造形式的电极306a′′,其中电极306a′′的传导部分接触血管壁。作为图6A和6B的电极306a′的近端连接器312a的备选方案,图7A和7B的电极306a′′包括用于将电极306a′′连接到定位元件304的远侧上的导管302的轴的远端连接器316a。远端连接器316a使电极306a′′在整个定位元件304上展开并且可以在热神经调制以后促进电极306a′′的收缩。例如,在定位元件304的收缩期间或以后,可以通过相对于导管302邻近地缩回引导导管303而收缩电极306a′′。备选地,在所述装置近端的金属线可以邻近地缩回以收缩电极306a′′。
[0081]图8A和8B是示意性侧视图,其图解用于热诱导的神经调制的装置700的又一个实施方案。图8A和8B的装置700包括图6A和6B的近端电极306a′和远端壁接触电极306b′。装置700还分别包括近端和远端定位元件304a和304b,用于分别展开所述近端和远端的壁接触电极306a′和306b′,与所述血管壁进行接触。图8B中显示的实施方案仅包括单一定位元件304,但是远端壁接触电极306b′邻近面对并定位在定位元件304的远端部分上以促进远端电极306b′的展开。在图8B中图解的实施方案中,近端电极306a′和远端电极306b′的延伸任选地可以沿着非传导的连接器318连接以促进治疗后的电极的折叠和回收。
[0083]图9A-9N是图解血管内系统的另外实施方案的示意性侧视图,其包括一个或多个壁接触电极、血流阻塞特征、和/或传热流体注射功能。如下对于图9A-9N所述的实施方案被描述为单极设备,但是应当理解任何(或全部)实施方案可以作为双极设备配置或运行。而且,虽然血流阻塞和传热流体注射是与壁接触电极结合描述的,但是应当理解这样的阻塞和注射特征可以与不接触血管壁的电极结合的方式提供。
[0084]如上所述,另外地或备选地,利用患者的血液作为散热装置而在递送热能所在的血管壁的靶神经纤维和非靶组织之间产生不同的传热速率,可以将传热流体(热的或冷的)注入、输注或以其它方式递送到血管中。传热流体可以进一步地除去过量热能并且保护非靶组织。当通过加热递送热治疗时,例如,传热流体可以包括冷却的或室温的盐水(例如,盐水的温度低于在治疗递送期间的血管壁温度)。可以在能量递送元件上游的位置,或在相对于要保护的组织的其它位置,将传热流体注射经过所述设备导管或经过引导导管。传热流体可以在血流存在的情况下或在血流暂时阻塞的情况下注入。与传热流体递送结合的血流阻塞可以促进对于沿着非靶组织的传热动力学的良好控制,以及来自下游位置的流体注射。
[0085]图9A和9B图解装置800,其包括具有定位元件804的导管802,所述定位元件804可用于在血管内定位所述装置和/或阻塞血流。例如,定位元件804可以是可臌胀的气囊。装置800可以进一步包括一个或多个邻近定位元件804定位的活动的单极电极810,以便定位元件804的膨胀阻滞电极组件806下游的血流。电极组件806包括多个延伸814,并且应当理解可以提供任何所需数量的延伸,包括单一延伸。将单极电极810与远程电极组合使用,所述远程电极诸如定位在患者以外的接地垫。装置800还可以包括定位元件804和电极组件806之间的输注端口805。
[0086]如图9A中所示,导管802可以以减小的外形递送构造在肾动脉RA之内推进。关于图9B,一旦适当定位在治疗部位,则电极组件806可以活动地展开,或它可以通过从电极810去除鞘、引导导管803、或另一种类型的限制器而自展开。展开的电极组件806接触所述血管壁。定位元件804可以展开(在电极组件806的展开以前、期间或以后)以将电极组件806适当定位在血管之内和/或将血流阻塞在电极组件806下游的肾动脉RA之内。单极电场可以在活动的电极810和外部接地之间递送。备选地,双极电场可以在任何两个电极810之间产生。例如,电场可以包括脉冲的或连续的RF电场,其在靶神经纤维中热诱导神经调制(例如,坏死或消融)。例如,可以通过用可以结合到电极810中的热电偶、阻抗传感器、或其它传感器收集的数据监控和控制所述热治疗。
[0087]为了在没有不合需要地影响非靶组织的情况下增加可以被递送的功率或热治疗的持续时间,可以将传热流体输注物(infusate)I经过导管802的注射口805注入以冷却非靶组织。这预计减轻非靶组织中不希望的影响。例如,输注物I可以包括冷却的盐水,其在热治疗期间从血管壁除去过量热能。
[0089]图9C是图解装置820的另一个实施方案的示意性侧视图,所述装置820包括壁接触电极810、流动阻塞、和传热流体注射。在图9C中所示的实施方案中,阻塞元件804被连接到导线G,其可以包括膨胀腔,并且将输注物I经过导管802的远端出口递送。备选地,阻塞元件804可以连接到单独的导管或鞘(未显示)而不是连接到导线G。同样,例如,输注物I可以经过导线腔或经过导管802的另外的腔或环状空间递送。图9D图解装置830的另一个实施方案,其中阻塞元件804定位在电极组件806附近或上游,并且输注物I在远离阻塞元件804但接近电极组件806的位置递送。
[0090]图9E是示意性侧视图,其图解具有定位在电极组件806的近端和远端的阻塞元件804(两个显示为阻塞元件804a和804b)的装置840的又一个实施方案。除具有第一注射口805a之外,导管803包括吸入口805b。单独的腔可以经由注射口805a和805b延伸穿过用于输注物I的注射和吸入的导管。提供输注物的注射和吸入促进对于输注物的流动动力学的良好控制,并且因此促进输注物I的传热动力学特性。例如,以相同速率提供吸入和注射可以在血管和电极806之间提供一致的传热动力学特性。
[0091]图9F图解具有导管852的装置850的又一个实施方案,其包括可以经由延长构件857移动成与血管壁接触的壁接触电极856。在这个实施方案中,延长构件857在电极856附近远端连接到导管852。延长构件857可以配置成用于自身或机械展开,或它可以延伸通过导管852的端口805并且通过导管的腔延伸到邻近位置用于被医疗专业人员操作。延长构件857的邻近截面可以相对于导管852被医疗专业人员推进,以便构件呈现图解的弯曲外形。
[0092]在延长构件展开时,偏转导管852,以致连接到导管轴的电极856接触血管壁。任选地,定位元件804可以展开以促进经由延长构件857定位所述电极856和/或阻塞通过所述血管的流动。定位元件804可以连接到所述引导或递送导管803。如显示,任选地,可以通过导管852递送输注物I。
[0093]图9G-9N是图解探针或导管900的实施方案的部分示意性侧视图,所述探针或导管900包括适于用在图3A和3B的系统100中的成型的或自展开的或机械活动的电极。例如,图9G图解用于递送到治疗部位的减小的外形构造形式的探针或导管900,并且图9H图解处于展开的或未压缩状态的探针900的一部分。一起参考图9G和9H,探针900可以包括轴904、电极906、轴904和电极906之间的中间部分(portion)或段(section)908和覆盖并且可释放携带轴904和中间部分908的引导导管或鞘910(例如,5French引导导管)。在递送到治疗部位(图9G)期间,中间部分908可以以压缩状态(即,使弯曲或成型区域基本上是平的或另外被鞘910的内壁变直)搁在鞘910之内。当鞘910缩回时,中间部分908将展开到它的未压缩的拱形的或弯曲的形状(图9H)。中间部分908的弯曲或成型的外形促进电极906和相应的血管壁之间的接触。参考图9J在下面更详细地描述该过程。
[0095]一起参考回到图9G和9H,轴904一般可以是由一种或多种生物相容的材料(例如,塑料、金属、合金、和陶瓷)构造的圆柱状管。轴904还可以在轴904的远端部分包括更柔性的区域或段904a,并且配置成允许探针900在使用期间弯曲或扭曲。例如,在电极906递送到治疗部位期间,柔性的区域904a可以允许探针900从主动脉进行相对急剧的转向到肾动脉。在一个实施方案中,所述柔性的区域904a可以包括编织的轴,而没有海波管(hypotube)或其它可以结合到轴904中的支持结构的支持。如图9H中所示,柔性区域904a具有约7cm的长度L1。然而,在其它实施方案中,柔性的区域904a可以具有约2cm至约140cm的长度L1(所述轴904的整个工作长度一般可以是柔性的)。在其它的实施方案中,轴904和/或柔性的区域904a可以具有不同的排列和/或构造。
[0096]探针900可以具有约55cm至约140cm的工作长度或有效长度L2。如这里所用,′′工作长度′′和′′有效长度′′限定为在患者身体内部安装的探针900的长度(例如,轴904,中间部分908,和电极906)。在其中55cm引导导管用于促进探针900的递送的构造中,工作长度或有效长度可以是约60cm到约80cm。在其中90cm引导导管用于促进探针900的递送的构造中,工作长度或有效长度可以是约95cm到约120cm。例如,在图解的实施方案中,探针900具有约为108cm的工作长度或有效长度L2并且配置成与长度约为90cm的鞘910一起使用。然而,在其它的实施方案中,所述探针900可以具有不同的工作长度L2和/或配置成与具有不同尺寸和/或构造的鞘一起使用。
[0099]其中仅测量阻抗的实施方案的一个预期优点是对于探针900仅需要一个金属线。如果探针900包括电连接至所述电极的温度传感器,则必须使用至少一个更多的金属线。在该情况下,总共两个金属线可用于递送能量、测量阻抗和测量温度。如果探针900包括电学上独立于电极的温度传感器,则必须使用至少一个更多的金属线。另外,超过一个温度传感器可以用于进行另外的温度测量。另外的金属线可能增加探针900的尺寸和复杂度并且增加故障的可能性。
[00100]虽然图解的电极906包括带914,但是电极906可以具有其它的构造。例如,电极906可以包括由第一金属构造的线圈,其围绕由第二金属构造的核心。具有线圈的一个预期优点是线圈可以减少应力,原因在于当测量温度时的热膨胀。在另一个实施方案中,所述电极可以由单一金属或其它没有所述带的导体组成。
[00101]图9I是取自图9H的区域9I的探针900的一部分的放大视图。中间部分908可以包括由不锈钢、镍钛金属互化物、塑料或另一种适合的材料(或其组合)构造的实心金属线、条带、圆柱状管、或线圈,其可以屈曲(bends)或以其他方式弯曲或活动定向以促进电极906和相应的血管壁之间的接触。在图解的实施方案中,中间部分908弯曲或屈曲以将电极906定位在距离轴904的纵轴S尺寸Y处。尺寸Y可以从约2mm变化到约20mm。在一些构造中,Y尺寸可以是约10mm至约20mm。例如,在图解的实施方案中,尺寸Y是约16mm。例如,人肾动脉的平均直径是约3mm到约8mm。因此,如果轴904定位在具有8mm直径的动脉壁附近,中间段908对于电极906将具有足够的挠曲或拱形以接触所述动脉的相对壁。然而,在其它实施方案中,尺寸Y可以具有不同的值并且可以是特大的以促进在直的或弯曲的血管中的接触。
[00102]中间部分908还配置成将电极906定位在距离轴904的末端部分904b尺寸X处。至少部分地,尺寸X可以基于构成中间部分908的材料(例如,不锈钢或镍钛金属互化物)和探针900的所需工作长度或有效长度而改变。例如,中间部分908的尺寸X应该配置并且定尺寸成提供足够的壁接触压力,以致电极906可以产生所需的治疗效果。
[00103]在备选实施方案中,拉或推金属线可用于活动地弯曲中间部分以促进所述电极的放置。例如,如图9L至9N中所图解,探针980的电极尖端985可以利用致动器金属线982偏转或转向。致动器金属线982可以从如图9L中所示的第一位置或没有偏转的位置986,拉到如图9M所示的轻微偏转的第二位置987,拉到如图9N所示的实质偏转的第三位置988。当试图在弯曲的血管中实现壁接触时,例如,探针980的可变偏转可能是特别有帮助的。
[00104]回到参考图9I,轴904具有大约0.014英寸至大约0.085英寸的外径D。至少部分地,轴904的外径D可以基于电极906的外径而改变。例如,在图解的实施方案中,所述轴904具有约0.040英寸的外径D,其对应电极906的一个具体的构造。
[00105]电极906具有约0.020英寸至约0.085英寸的外径E。在所图解的实施方案中,例如,电极906具有约0.049英寸的外径E。然而,从实用的观点,这些尺寸可以改变,相比于递送电极906所通过的鞘或引导导管(例如,鞘910)的内径,电极906的外径E可以不是更大的。在一个具体实施例中,8French引导导管(其具有0.091英寸的内径)将类似地是用于接入肾动脉的最大导管。因而,在该情况下使用的电极将具有至少大约小于0.085英寸的外径E。
[00107]图9J是血管内装置950的实施方案的示意性侧视图,其包括具有成型的或自展开的电极906的探针900。可以将电极906递送到在鞘910之内的治疗部位,然后在已经将它从鞘910的腔除去以后,它可以移动到预先选择的形状。例如,可以通过推进轴904和/或缩回轴904而从鞘910除去电极906。电极906接触用于递送治疗的血管壁。任选地,轴904可以旋转成相对于血管壁旋转电极906并且有角度地再定位电极906。可以在单个有角度的位置或在多个有角度的位置递送所述治疗。任选地,可以通过如所示的鞘910递送输注物I。
[00108]应当理解,在这里公开的任何实施方案中,导线可以任选地用于促进探针的递送和/或除去。在这样的实施方案中,所述探针可以在结构增强(例如,导线腔)的情况下另外配置用于适应导线的使用。
[00109]另外地或备选地,装置950可以包括多个有角度间隔的电极906,其定位在血管系统内,如图9K所示。除有角度的间距之外,电极906可以纵向间隔以促进在血管的纵向段上的治疗(例如,以实现沿着纵向段而不是沿着横截面的周围治疗)。
[00111]图10是示意性侧视图,其图解用于热诱导的肾神经调制的血管内到血管外的(“ITEV”)系统900的实施方案。ITEV系统900包括导管922,其具有(a)多个在近端侧孔924终止的近端电极腔,(b)多个在远端侧孔926终止的远端电极腔,和(c)导线腔923。导管922优选包括相等数量的近端和远端的电极腔和侧孔。ITEV系统900还包括可以通过近端电极腔和近端侧孔924推进的近端针式电极928,以及可以通过远端电极腔和远端侧孔926推进的远端针式电极929。备选地,图10中图解的实施方案可以用单一针式电极配置,其配置用于单极能量递送。
[00112]导管922包括任选的可展开的定位元件930。定位元件930可以包括,例如,可臌胀的气囊或可展开的筐或笼。在使用中,定位元件930可以展开,之后针式电极928和929展开以将导管922定位或定中心在患者的血管内(例如,在肾动脉RA内)。使导管922定中心预计促进全部针式电极928和929递送到在患者血管之内/患者血管以外的所需深度(例如,递送全部针式电极928和929到大约相同深度)。在图10中图解的实施方案中,定位元件930在近端侧孔924和远端侧孔926之间,并且因此,定位元件930在近端和远端电极的递送位置之间。然而,应该理解,另外地或备选地,定位元件930可以沿着导管922的长度定位在不同的位置或在多种位置(例如,在侧孔924的近端位置和/或在侧孔926的远端位置)。
[00113]如图10所示,导管922可以经过导线(未显示)经由腔923推进到在患者血管系统之内的治疗部位。在血管内递送期间,针式电极928和929可以这样定位,以致它们的非绝缘的和锐化的远端区域分别定位在近端腔和远端腔内。一旦处于治疗部位,则医疗专业人员可以将电极928和929经由它们位于患者以外的近端区域推进。这样的推进分别使电极928和929的远端区域分别地离开侧孔924和926,并且刺穿患者血管系统的壁以便电极经由ITEV方法在血管外定位。
[00114]近端电极928可以连接到场发生器(未显示)作为活动的电极,并且远端电极929可以充当返回电极。用这样的方式,近端和远端电极928和929形成将热能场与患者血管系统的纵轴或方向排列的双极电极对。备选地,远端电极929可以包括活动的电极并且近端电极928可以包括返回电极。而且,近端电极928和/或远端电极929可以都包括活动电极和返回电极。仍然进一步地,近端电极928和/或远端电极929可以与外部接地结合使用,用于递送单极热能场。可以使用活动电极和远端电极的任何组合。
[00115]当电极928和929连接到场发生器并且血管外定位时(并且在定位元件930任选展开的情况下),热能场的递送可以经由加热提供所需的肾神经调制。在实现所需的热诱导肾神经调制以后,电极928和929可以缩回在近端和远端腔之内,并且定位元件930可以折叠以回收。然后可以从患者除去ITEV系统900以完成所述程序。另外或备选地,系统900或在这里公开的任何系统可以重新定位以在另一个治疗部位提供治疗,诸如提供双侧肾神经调制。
[00117]虽然图3A-8B和10图解双极系统,但是应当理解,备选地,可以使用单极系统,如图9A-9N中所示。例如,活动的单极电极可以定位在血管内、血管外、或血管内到血管外,接近于促进肾功能的靶神经纤维。返回电极可以附着于患者的外部或远离活动电极定位在患者中。最终,热能场可以在体内单极电极和远程电极之间递送,以实现所需的热诱导的肾神经调制。另外地,单极装置可以用于双侧的肾神经调制。
[00118]以上参考图3A-10描述的实施方案一般涉及通过递送用于调制靶神经纤维的热能场的用于热诱导的肾神经调制的方法和系统。然而,应该理解,可以提供用于热诱导(通过加热和冷却两者)的肾神经调制的备选方法和系统。例如,电场可以用于用热电元件或帕尔贴元件冷却和调制神经纤维。同样,任选可以通过电阻加热,通过加热的或冷却的流体的递送(参见图11和13),通过帕尔贴元件(参见图12)等实现热诱导的肾神经调制。另外地或备选地,可以通过将高强度聚焦的超声波施加到靶神经纤维而实现热诱导的肾神经调制(参见图14A、14B、和15)。可以依照本发明公开内容使用另外的和备选的用于热诱导的肾神经调制的方法和系统。
[00119]例如,图11是通过施加热能用于热诱导的神经调制的装置1000的备选实施方案的示意性侧视图。在该实施方案中,图10的电极328和329已经分别用输注针1028和1029替换。可以将传热流体F通过输注针1028和1029递送到靶神经纤维。可以加热传热流体F以便将靶神经纤维的温度增加在所需阈值以上。例如,神经纤维的温度可以升高在约37°C的体温以上,或约45°C的温度以上。备选地,可以冷却传热流体F而将靶神经纤维的温度降低到所需阈值以下。例如,可以将神经纤维冷却以低于约37°C的体温,或进一步地冷却在约20°C以下,或更进一步地冷却在约0°C的冷冻温度以下。显而易见的是,除血管内到血管外递送传热流体之外,传热流体F可以以下列方式递送:血管内(例如,可以通过气囊构件膨胀和/或被循环),血管外(例如可以通过血管套循环),或其组合。
[00123]图13图解利用帕尔贴效应的装置1200的又一个实施方案。装置1200包括通过进口流体管道1206a和出口流体管道1206b连接到肾动脉套1204的植入的或外部的泵1202。进口流体管道1206a将流体从泵1202传递到套1204,而出口流体管道1206b将流体从套1204传递到泵1202以循环通过套1204的流体。流体储器可以位于套1204、泵1202、和/或流体管道1206a和1206b中。
[00126]例如,图14A和14B是图解超声波装置1300的实施方案的示意性侧视图,所述超声波装置1300包括导管1302,沿着导管1302的轴定位的一个或多个超声波能量转换器1304,和围绕能量转换器1304的可臌胀的气囊1306。图14A图解缩小的递送和回收构造形式的装置1300,并且图14B图解以张开的展开构造形式的装置1300。超声波能量转换器1304通过导体1307连接到超声波信号发生器(未显示)。气囊1306可以具有用于反射超声波的声学反射部分1308和超声波能量可以经过的声学透射部分1309。用这样的方式,所述波可以如所示聚焦在距离导管轴所需焦距定位的焦点或半径P处。在备选实施方案中,能量转换器1304可以直接附着到气囊1306。
[00127]焦点距离可以是特定的或动态可变的,以致超声波聚焦在血管之外的靶神经纤维上的所需深度。例如,可以提供一组导管尺寸以允许指定的焦距的范围。例如,动态可变的焦点距离可以通过气囊1306的校准展开而实现。
[00129]图15图解具有导管1402、导体1403、和凹的超声波能量转换器1404的超声波装置1400的又一个实施方案。凹的超声波能量转换器1404将能量定向到特定的焦点P。因而,凹的能量转换器1404是自聚焦的并且不需要气囊1406(例如,气囊可以在全部点上都是声学透射的)上的反射部分。
[00130]以上关于图3A-15描述的系统任选地可以用于量化热诱导的肾神经调制的功效、范围、或细胞选择性,以便监控和/或控制神经调制。如上所述,所述系统还可以包括一个或多个传感器,诸如热电偶或成像能量转换器,用于测量和监控下列一个或多个参数:(a)系统,(b)靶神经纤维,和/或(c)非靶组织。例如,温度升高或降低超过或低于某些阈值预期,将热消融、非消融性改变、冷冻、或以其它方式改变靶神经纤维而因此调制靶神经纤维。
[00131]应当理解,在本文公开的任何方法、装置、和系统可以被修改或配置用于调制神经纤维的冷却或冷冻治疗。例如,在本文公开的任何探针可以被修饰成在血管内、血管外或ITEV途径的情况下将冷冻治疗递送到靶神经纤维。
[00133]在一个实施方案中,例如,控制器可以根据包含多种功率递送特性的算法指挥功率发生器(例如,图3A和3B的场发生器110)。例如,图16是图解控制这样的功率递送过程的方法1600的流程图。方法1600可以实施为被图3A的处理器114或另一种适合的设备(例如,场发生器110)执行的常规计算机程序。方法1600还可以由操作者人工实施。
[00134]如图16中所图解,在启动治疗以后,方法1600的第一阶段1602包括监控某些操作参数(例如,温度、时间、阻抗、功率等)。虽然优选这些操作参数是连续监控的,但是备选地,可以定期监控它们。在阶段1604,方法1600包括针对预定参数模式校验所监控的参数以确定参数是否独立地或组合地属于由预定参数模式设定的范围。例如,温度可以被监控并且与预定温度值相比。备选地,温度和阻抗两者都可以被监控并且与温度和阻抗两者的预定参数模式相比。如果监控的参数属于由预定参数模式设定的范围,则在相同的设定继续治疗并且继续监控操作参数。
[00135]当确定一个或多个参数或多种组合参数不属于预定参数模式时,则方法1600要求在阶段1606对系统的功率输出进行调节。功率输出调节的方向(即,增加或减少)和程度可以通过利用监控参数的常规以及它们如何针对其它预定参数模式进行比较而确定。例如,如果监控温度和时间并且确定监控的温度和时间超过温度和时间的预定参数分布,则可以减小功率递送。备选地,如果一个或多个监控参数或多种组合形式的监控参数落在预定参数分布以外,则可以增加功率递送。如图16中所示,治疗将继续直到功率递送已经调整到零的水平为止(阶段1608)。
[00136]根据算法监控的操作参数可以包括温度、时间、阻抗和功率。离散的温度值可以用于触发能量递送的改变。例如,高的温度值(例如85°C)可以表明组织干燥,在所述情况下,算法可以减少或停止能量递送以防止不合需要的热效应到达靶组织或非靶组织。时间还可以用于防止不合需要的热变到达非靶组织。对于每次治疗,校验设定的时间(例如,2分钟)以避免不确定的能量递送。阻抗可以用于测量组织改变。阻抗显示治疗部位的电性质。如果将热感应的电场施加到治疗部位,则阻抗将随着组织细胞对于电流的电阻变小而降低。如果施加太多的能量,则可能在电极附近发生组织干燥或凝固坏死(coagulation),随着细胞失去持水和/或电极表面积降低(例如,通过凝固物的积累),所述电极将增加阻抗。因而,组织阻抗的增加可以指示或预示对于靶组织或非靶组织的不合需要的热变。另外,功率是控制治疗递送中有效的监控参数。功率是电压和电流的函数。算法可以定制电压和/或电流以实现所需功率。上述参数的微分(例如,变化率)还可以用于引起能量递送的改变。例如,可以监控温度的变化率,以致在检测到温度的突然升高的情况下减小功率输出。
[00137]为了实施上述控制算法,所述系统可以包括一个或多个计算系统硬件和/或软件模块。备选地,计算机硬件和软件可以用于促进任何能量递送过程或系统。例如,图17图解显示适于在图3A的处理器114或在另一个适合的设备(例如,场发生器110)中使用的执行对于调制肾神经的方法的软件模块1620的功能框图。每个分量可以是以常规编程语言写成源代码的计算机程序、步骤、或工艺,所述编程语言诸如C++编程语言,并且可以为处理器114的CPU的执行而提供。源代码和对象以及字符代码的多种实施可以存储在计算机可读的存储介质中,或以载波形式具体表现在传送介质上。处理器114的模块可以包括输入模块1622,数据库模块1624,处理模块1626,输出模块1628,和显示模块1630。在另一个实施方案中,可以提供软件模块1620用于通过分布式计算方案中的网络服务器的CPU执行。
[00138]操作中,输入模块1622接收操作者输入,诸如处理设定点和控制选择,并且将接收的信息或选择传达到其它元件用于进一步处理。数据库模块1624组织记录,所述记录包括操作参数1634、操作者活动1636、和一个或多个警报器1638,并且数据库模块1624便于将这些记录存储到数据库1632并从数据库1632检索。可以使用任何类型的数据库组织,包括平面文件系统,分层数据库,关系数据库,或分布式数据库,诸如由加利福尼亚红杉郡的奥乐克公司(Oracle Corporation)提供的那些。
[00139]处理模块1626可以处理传感器读数1640(例如,来自图5A中的传感器310),校验警报器和互锁,并且基于传感器读数1640,产生用于控制场发生器110(图3A)的能量递送过程的控制变量。根据控制变量,输出模块1628可以产生输出信号1642。例如,输出模块1628可以将产生的控制变量从过程模块1626转变成适用于能量输出调制器的输出信号1642。显示模块1630可以通过设备显示、打印、或下载传感器读数1640和输出信号1642,所述设备诸如输出设备120(图3A)或在场发生器110的面上的视觉显示器。适合的显示模块1630可以是视频驱动器,所述视频驱动器可以使处理器114在输出设备120上显示传感器读数1640。
[00140]图18是显示图17的处理模块1626的实施方案的框图。处理模块1626可以进一步地包括传感模块1650,计算模块1652,警报模块1654,功率输出模块1656,和相互互连的互锁模块1658。每个模块可以是计算机程序,步骤,或例行程序,将其写成常规编程语言形式的源代码,或一个或多个模块可以是硬件模块。
[00141]传感模块1650可以接收传感器读数1640并将其转变成所需单位的参数。例如,传感模块1650可以接收传感器读数1640作为电信号并且将所述电信号转变成摄氏度形式的瞬时温度。传感模块1650可以具有的例行程序包括,例如,线性内插法,对数内插法,数据映射,或其它例行程序以将传感器读数1640结合到所需单位的参数。
[00145]互锁模块1658连续监控来源于传感模块1650和/或计算模块1652的操作参数,并且当监控的操作参数超过某些互锁阈值时,互锁模块1658可以控制功率输出模块1656的操作。根据互锁状态,功率输出模块1656可以将功率设定点设定在当前设定点以上或以下(即,增加或降低功率),或它可以设定功率设定点为零(即,终止功率递送)。例如,当来自计算模块1652的平均温度超过预定值时,互锁模块1658可以使功率输出模块1656减少功率输出。另外地或备选地,当来自传感模块1650的即时温度超过另一个预定值时,互锁模块可以使功率输出模块1656终止它的操作(即,具有零输出值)。在数个实施方案中,互锁模块1658可以任选地配置成直接产生输出信号1642到其他系统元件。
[00149]如图19中所图解,第一互锁状态发生在0时刻(即,操作者已经对治疗进行初始化并且计时器开始从零计数的时刻)。在该情况下,方法1600在阶段1606继续,功率输出模块1656控制场发生器110以经过第一时段(0-t1)(例如,15秒)逐渐调节它的功率输出到第一功率水平P1(例如,5瓦)。功率输出模块470可以产生和传送功率设定点到场发生器110作为输出信号1642。在一个实施方案中,如图19中图解,在第一时段期间的功率增加一般是线性的。结果,场发生器110以基本恒定速率P1/t1增加它的功率输出。在其它实施方案中,功率增加可以是非线性的(例如,指数的或抛物线的),具有可变的增长率。
[00150]在第一时段届满以后(或在P1的功率水平已经实现以后),功率输出模块1656可以控制场发生器110以保持它的当前输出功率水平在P1,即,暂停第二时段(t1-t2)。操作者或预编程的例行程序可以根据患者的生理学特征调节所述时段(t1-t2)。例如,如果患者体腔响应于温度改变而减缓,则操作者或预编程的例行程序可以增加时段(t1-t2)以补偿另外的响应延迟。在其它实施方案中,功率输出模块1656可以使场发生器110在第二时段(t1-t2)或任何其它时段(例如,第一时段或随后的时段)期间将输出水平减少到小于P1或暂时终止它的输出水平。
[00151]在第二时段届满以后,计算模块1652可以根据来自传感模块1650的温度得出在第二时段结尾时的平均温度,即,t2。方法1600可以继续测试以确定在t2计算的平均温度是否超过预定阈值(例如,65°C)。如果平均温度超过预定阈值,则功率输出模块1656可以控制场发生器110以保持它的当前输出功率水平持续所需的总治疗时间。
[00153]方法1600可以继续另一个测试以确定增加的功率水平(Pi+ΔP)是否超过场发生器110的最大功率水平(例如,10瓦)。操作者或预先编程的例行程序可以选择最大功率水平以表示安全的或优选的操作方式并且根据治疗条件调节所选择的功率水平。如果超过最大功率水平,则功率输出模块1656控制场发生器110以保持它的当前输出功率水平直到达到所需的总治疗时间。如果不超过最大功率水平,则所述过程返回到暂停,并且重复随后的阶段。虽然上述方法1600的具体实施例使用测量的温度作为处理参数,但是代替测量温度或除测量温度之外,可以使用其它生理学参数(例如,阻抗、电阻率、和/或电容)和非生理学参数(例如,时间、功率等)。
[00154]任选地,计算模块1652可以计算在达到最大功率水平以前的循环数目。例如,当使用固定的ΔP时,计算模块1652可以根据下式计算循环数目:
[00156]方法1600还可以任选地包括倾斜的过程,其容许功率水平以更快变化率增加。例如,方法1600可以包括测试以检验平均温度并且确定它是否低于预选择的阈值(例如,50C)。如果平均温度低于阈值,则功率输出模块1656可以控制场发生器110以增加功率水平Pi达等于ΔPxF的量,其中F是步进因子(step factor)(例如,2)。可以在每个倾斜阶段开始时或在所述倾斜过程其它所选择的点重复所述测试。迅速倾斜过程预计允许功率输出水平更快地达到它的所需治疗水平。在另一个实施方案中,其中PID模块用于控制功率输出,当测量的温度远低于指定水平(例如,65C)时,可以调谐所述PID模块以快速向上倾斜功率,但是随着测量温度接近指定水平而减缓所述功率倾斜。
[00157]方法1600还可以任选地包括功率减少过程以逐渐地降低或向下倾斜治疗期间的功率水平。以上具体描述的实施例设计功率输出过程以通过温度监控减少使患者体腔壁过热的风险。在其中达到最大功率水平的情况下,温度和/或测量的阻抗可以继续升高超过某一阈值。在许多情况下,超过这样的阈值可以是可以达到警报阈值的指示器,其中功率输出将要终止。然而,如下所述的方法可用于降低功率以防止由于温度和/或阻抗达到警报阈值而导致的功率递送的过早终止。
[00158]在功率递送期间,互锁模块1658可以连续监控从传感模块1650和/或计算模块1652接受的一个或多个操作参数。例如,该方法可以包括确定计算的平均温度是否大于或等于预定的阈值Tt(例如,70°C)的测试。如果平均温度不超过预定阈值Tt,则互锁模块1658不中断功率输出模块1656的操作并且保持当前的功率输出水平用于治疗。
[00159]另一方面,如果平均温度(来自计算模块1652)超过预定阈值Tt,则所述方法可以继续阶段1606,其中功率水平是减小的。在该功率减少阶段期间,功率输出模块1656可以控制场发生器而将功率立即降低Ps(例如,1瓦)。在降低功率以后,所述方法可以暂停功率输出模块1656达时段Tw(例如,3秒)。在时段Tw届满以后,计算模块1652可以再次根据来自传感模块1650的温度得出平均温度。所述方法可以继续另一个测试以确定计算的平均温度是否还超过预定的阈值Tt。在一些情况下,该功率减少过程可能需要重复若干次,每次将功率降低Ps,直到平均温度不超过预定阈值。如果平均温度不超过阈值,则方法可以在持续的功率阶段的情况下继续达治疗时间的持续时间。
[00160]在该实施方案的另一个方面中,所述方法可以包括确定阻抗的增加或增长率是否太大的测试。更具体而言,互锁模块1658可以测量阻抗在固定时段内的斜率。如果测量的斜率不超过预定阈值,则互锁模块1658不调节功率输出模块1656的操作,并且所述方法可以在持续的功率水平继续。然而,如果测量的斜率大于预定阈值Zs(例如,3欧姆/秒),则所述方法可以进行使上述功率减少。如上所述,功率减少过程可能需要重复若干次直到测量斜率不超过预定阈值Zs。操作者或预编程的例行程序可以根据患者的生理学特征和/或一个或多个所需治疗参数调节预定阈值Tt和Zs或功率减少速率。
[00162]更具体地,该方法可以包括将测量的阻抗值与预先选择的最小阻抗值比较的测试。如果测量的阻抗值小于预先选择的最小阻抗值,则最小值被更新成等于测量值。在治疗期间,这些阶段可以根据需要重复许多次。实际上,所述方法保持对系统测量的最低阻抗值的跟踪。
[00163]如果测量的阻抗大于最小阻抗值加预先选择的阈值Zd(例如,20欧姆),则所述方法可以继续到如上所述的功率减少过程。在降低功率以后,所述方法可以暂停功率输出模块1656达时段Tw2(例如,3秒)。在时段Tw2届满以后,互锁模块1658可以再次监控阻抗,并且,如果测量的阻抗值还大于最小阻抗值加阈值,则所述方法可以根据需要将功率减少过程重复许多次直到阻抗条件不发生为止,然后返回到持续的功率阶段。
[00164]方法1600和上述多种实施方案的一个预期优点是对于靶和非靶组织的不合需要的治疗作用的风险(例如,过多破坏体腔壁)减小。如上参考图3A和3B所述,场发生器110可以将电场递送到探针104以将能量施加到体腔壁和周围区域用于实施神经调制。然而,许多因素可以有助于体腔对于施加能量的延迟响应(如测量的温度和/或阻抗所指示)。例如,体腔的潜在热、体腔周围或内部的循环、传感器和体腔壁之间的接触、及其它因素可以引起对于施加的能量的延迟的温度和/或阻抗响应。为了补偿响应中的这种延迟,方法1600可以结合延迟期,其中对于延迟期的持续时间不监控一些参数。结果,可以减轻乃至除去不利的体腔过热。而且,功率减少过程进一步帮助减少过度破坏体腔壁的风险,同时也防止由于参数达到警报阈值而引起的功率递送的过早终止。
[00166]虽然在这里公开的治疗涉及通过去神经支配调制对肾功能起作用的神经,但是应当理解可以这里配置本文公开的方法、装置、和系统和/或修改用于身体之内的其它位置的治疗能量传递。例如,可以修改这些发明用于在体腔之内的能量递送目的(例如外周血管)以实现去神经支配或一些其它的治疗结果。
[00167]从以上应当理解,本发明的具体实施方案已经为了说明而描述于此,但是熟知的结构和功能没有显示或详细地描述以避免不必要地使本发明实施方案的描述不清楚。在上下文准许的情况下,单数的或复数的术语还可以分别包括复数或单数的术语。而且,除非措辞“或”在关于两个或更多项目列表时特意限于仅指单个项目而排除其它项目,则在这样一种列表中的“或”的使用应当解释为包括(a)所述列表中任何单一项目,(b)所述列表中全部项目,或(c)所述列表中项目的任何组合。另外,在全文中使用术语“包括”的含义是包括至少所述的一个或多个特征,因此不排除任何更大数量的相同特征和/或另外类型的其它特征。还应当理解,具体的实施方案已经为了说明的目的而描述于此,但是在不背离本发明的情况下可以获得多种变体。因此,本发明仅受后附的权利要求限定。