WO2024110311A1 - Renal nerve stimulation system to guide rf renal denervation - Google Patents
Renal nerve stimulation system to guide rf renal denervation Download PDFInfo
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- WO2024110311A1 WO2024110311A1 PCT/EP2023/082084 EP2023082084W WO2024110311A1 WO 2024110311 A1 WO2024110311 A1 WO 2024110311A1 EP 2023082084 W EP2023082084 W EP 2023082084W WO 2024110311 A1 WO2024110311 A1 WO 2024110311A1
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- therapy
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Definitions
- This disclosure relates to systems and methods enabling positioning a therapeutic device within luminal tissues to enhance ablation during a therapeutic procedure.
- the present disclosure is directed to methods and systems for denervating nerves in or around vascular tissue.
- a catheter can be configured to deliver neuromodulation (e.g., denervation) therapy to a target tissue site to modify the activity of nerves at or near the target tissue site.
- the nerves can be, for example, sympathetic or parasympathetic nerves.
- the sympathetic nervous system (SNS) is a primarily involuntary bodily control system typically associated with stress responses. Chronic over-activation of the SNS is a maladaptive response that can drive the progression of many disease states.
- excessive activation of the renal SNS has been identified experimentally and in humans as a likely contributor to the complex pathophysiology of arrhythmias, hypertension, states of volume overload (e.g., heart failure), and progressive renal disease.
- Percutaneous renal denervation is a minimally invasive procedure that can be used to treat hypertension and other diseases caused by over-activation of the SNS.
- a clinician delivers stimuli or energy, such as radiofrequency, ultrasound, cooling, or other energy to a treatment site to reduce activity of nerves surrounding a blood vessel.
- the stimuli or energy delivered to the treatment site may provide various therapeutic effects through alteration of sympathetic nerve activity.
- One aspect of the disclosure is directed to a method of performing a therapeutic procedure.
- the method includes navigating a therapeutic device to target tissue, the therapeutic device including a plurality of electrodes.
- the method also includes applying a first stimulation signal from the electrodes to a blood vessel wall.
- the method also includes observing a first physiological response to the first stimulation signal.
- the method also includes applying a therapy to the blood vessel wall.
- the method also includes applying a second stimulation signal from the electrodes to the blood vessel.
- the method also includes observing second physiological response to the second stimulation signal, where the second physiological response being different from the first physiological response by more than a first threshold value indicates a successful therapy.
- Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.
- Implementations of this aspect of the disclosure may include one or more of the following features.
- the method further including adjusting parameters of the first stimulation signal when the first physiological response is observed less than a second threshold value.
- the method further including applying the first stimulation signal with the adjusted parameters to the blood vessel wall, prior to applying the therapy to the blood vessel wall.
- the method further including adjusting parameters of the therapy if the second physiological response is different from the first physiological response by less than the first threshold.
- the method further including applying a therapy with the adjusted parameters to the blood vessel wall.
- Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions.
- One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.
- a further aspect of the disclosure is directed to a system for denervation of nerves of a blood vessel.
- the system includes a therapeutic device configured for navigation within a blood vessel of a patient.
- the system also includes a plurality of electrodes formed on a distal portion of the therapeutic device.
- the system also includes a senor configured to measure one or more physiological parameters of the patient at a location to which the therapeutic device has been navigated.
- the system also includes a stimulation and therapy source.
- the system also includes a computing device including a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of the plurality of electrodes, sense a first change in a physiological parameter as a result of the application of the first stimulation signal, determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes, generate a therapy for application the blood vessel wall, generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes, sense a second change in the physiological parameter as result of the application of the second stimulation signal, and determine whether the application of the therapy has denervated the nerve proximate the electrode based on the second sensed change of the physiological parameter.
- Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.
- Implementations of this aspect of the disclosure may include one or more of the following features.
- the system where the first stimulation signal and the therapy are a combined signal that is generated for an initial period of time.
- the determination of the first sensed change occurs after the initial period of time.
- Second stimulation signal and the therapy are a combined signal that is generated for a second period of time.
- the instructions when executed by the processor present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the one of the plurality of electrodes, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation.
- the instructions when executed by the processor determine that the first sensed change in the physiological parameter is indicative of a lack of a nerve proximate the one of the plurality of electrodes.
- the instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time.
- the instructions when executed by the processor sense a third change in a physiological parameter as a result of the application of the first stimulation signal with the adjusted parameters; and determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes.
- the instructions when executed by the processor determine that the nerves are deep and require additional time to complete the denervation.
- Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions.
- One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.
- Still a further aspect of the disclosure is directed to a method of assessing a denervation site.
- the method includes positioning a therapeutic device in a blood vessel such that a plurality of electrodes are in contact with a wall of the blood vessel.
- the method also includes applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes for a first duration.
- the method also includes sensing a physiological parameter of the blood vessel after the application of the multiplexed stimulation and therapy.
- the method also includes determining that a first change in the physiological parameter of the blood vessel exceeds a first threshold.
- the method also includes applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes for a second duration.
- the method also includes sensing a physiological parameter of the blood vessel after the application of the multiplexed stimulation and therapy.
- the method also includes determining whether a second change in the physiological parameter of the blood vessel exceeds a second threshold.
- the method also includes indicating to a user a successful denervation when the sensed physiological parameter after the second duration is different than after the first duration.
- Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.
- Implementations of this aspect of the disclosure may include one or more of the following features.
- the method further including determining if a power limit has been reached when the determined change in the physiological parameter after the second duration is less than the threshold.
- the method further including increasing the power of the therapy if the power limit has not been reached.
- the plurality of electrodes are arranged in a first unique series of pairs of electrodes and a second unique series of pairs and applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes includes: applying stimulation to a first pair of the first unique series of pairs for a first time; applying therapy to a first pair of the second unique series of pairs for the first time; switching to a second pair of the first unique series of pairs and applying stimulation to the second pair for a second time; switching to a second unique pair of the second unique series of pairs and applying therapy to the second pair for a second time; and repeating the switching of the first unique series of pairs and the second unique series of pairs for the first duration or the second duration.
- Applying the multiplexed stimulation signal and therapy includes: applying a stimulation signal between a first pair of the plurality of electrodes for a first time; applying a therapy via a second pair of the plurality of electrodes simultaneously with the stimulation signal for a first time; applying the stimulation signal between the second pair of the plurality of electrodes for a second time; applying a therapy via the second pair of the plurality of electrodes simultaneously with the stimulation signal for the second time; and switching between the first pair and the second pair for the application of the stimulation signal and application of therapy until completion of the first duration or the second duration.
- the sensed physiological parameter is one or more of systolic blood pressure, mean arterial blood pressure, blood vessel stiffness, or pulse wave velocity.
- the determined first change of the physiological parameter is a reduction in systolic blood pressure.
- the determined second change of the physiological parameter is a reduction in systolic blood pressure and the threshold is the systolic blood pressure at a conclusion of the first duration.
- the method further including determining that the first change of the physiological parameter is less than the threshold; and stopping the application of a therapy portion of the multiplexed stimulation signal and therapy.
- the method further including adjusting a stimulation signal and applying the adjusted stimulation signal to alternating pairs of electrodes.
- the method further including determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter in excess of a threshold; increasing a power of the therapy; and applying a multiplexed adjusted stimulation signal and increased power therapy for the second duration.
- the method further including determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter less than the threshold; and generating an indicator for display on a user interface that no nerves are detected at the position of the therapeutic device.
- Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions.
- One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.
- a further aspect of the disclosure is directed to a method of performing a therapeutic procedure.
- the method also includes navigating a therapeutic device to target tissue, the therapeutic device including a plurality of electrodes.
- the method also includes applying a first stimulation signal from a first pair electrodes to a blood vessel wall.
- the method also includes applying a therapy to the blood vessel wall employing all electrodes.
- the method also includes switching the stimulation signal to a second pair of electrodes.
- the method also includes applying a second stimulation from the second pair of electrodes to the blood vessel.
- the method also includes applying a therapy to the blood vessel wall employing all electrodes.
- the method also includes repeating the switching and applying of the stimulation signal to each successive pair of electrodes and application of a therapy using all electrodes until a first time period expires.
- the method also includes sensing a physiological parameter of the blood vessel after the expiration of the first time period.
- the method also includes determining that a first change in the physiological parameter of the blood vessel exceeds a first threshold.
- the method also includes repeating the switching and applying of the stimulation signal to each successive pair of electrodes and application of a therapy using all electrodes until a second time period expires.
- the method also includes determining whether a second change in the physiological parameter of the blood vessel exceeds a second threshold.
- the method also includes indicating to a user a successful denervation when the sensed physiological parameter after the second time period is different than after the first time period.
- Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.
- Implementations of this aspect of the disclosure may include one or more of the following features.
- the method further including determining that the first change of the physiological parameter is less than the threshold; and stopping the application of the therapy.
- the method further including adjusting a stimulation signal and repeating the switching and applying of the stimulation signal to each successive pair of electrodes and application of a therapy using all electrodes until a first time period expires.
- the method further including determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter less than the threshold; and generating an indicator for display on a user interface that no nerves are detected at a location of the therapeutic device.
- the method further including increasing a power of the therapy; and applying the adjusted stimulation signal and increased power therapy for the second time period.
- the method further including determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter in excess of a threshold.
- Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions.
- One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.
- a further aspect of the disclosure is directed to a system for denervation of nerves of a blood vessel.
- the system includes a stimulation and therapy source and a computing device with a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of a plurality of electrodes of a therapeutic device, sense a first change in a physiological parameter as a result of the application of the first stimulation signal, determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes, generate a therapy for application the blood vessel wall, generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes, sense a second change in the physiological parameter as result of the application of the second stimulation signal, determine whether the application of the therapy has denervated the nerve proximate the electrode based on the second sensed change of the physiological parameter, and output an indicator of the success of the application of the therapy.
- Implementations of this aspect of the disclosure may include one or more of the following features.
- the system where the first stimulation signal and the therapy are a combined signal that is generated for an initial period of time.
- the determination of the first sensed change occurs after the initial period of time.
- Second stimulation signal and the therapy are a combined signal that is generated for a second period of time.
- the instructions when executed by the processor present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the one of the plurality of electrodes, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation.
- the instructions when executed by the processor determine that the first sensed change in the physiological parameter and output an indicator of a lack of a nerve proximate the one of the plurality of electrodes.
- the instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time.
- the instructions when executed by the processor sense a third change in a physiological parameter as a result of the application of the first stimulation signal with the adjusted parameters; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; and output an indicator of the presence of a nerve proximate the one of the plurality of electrodes.
- Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions.
- One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.
- a therapeutic device including electrodes by applying a stimulation signal from the electrodes to a blood vessel wall, observing a physiological response to the stimulation signal, applying a therapy to the blood vessel wall, applying another stimulation signal from the electrodes to the blood vessel, and observing second physiological response to the second stimulation signal, wherein, when the second physiological response is different from the first physiological response by more than a threshold, the therapy is successful.
- FIG. l is a schematic diagram of a therapy system provided in accordance with the disclosure.
- FIG. 2 is a schematic view of a workstation of the therapy system of FIG. 1;
- FIG. 3 is a perspective view of a therapeutic device of the therapy system of FIG.
- FIG. 4A is a graphical representation of changes in physiological parameters experienced by a patient as a result of a pre-therapy application of stimulation in accordance with the disclosure
- FIG. 4B is a graphical representation of changes in physiological parameters experienced by the patient as a result of post-therapy application of stimulation in accordance with the disclosure
- FIG. 5A is a graphical representation of two methods of performing a diagnostic and therapeutic procedure in accordance with the disclosure
- FIG. 5B is a graphical representation of a combined stimulation signal and therapy in accordance with the disclosure
- FIG. 6 is a schematical representation of a feedback system in accordance with the disclosure.
- FIG. 7 is a representation of changes a user-interface may display as a result of performing one or more of the methods of the disclosure
- FIG. 8 is a method of applying stimulation and therapy in accordance with the disclosure.
- FIG. 9 is a method of applying stimulation and therapy in accordance with the disclosure.
- FIG. 10 is a method of applying stimulation and therapy in accordance with the disclosure.
- FIG. 11 is a representation of a portion of a therapeutic device in accordance with aspects of the disclosure.
- This disclosure is directed to therapeutic systems and methods for denervation or neuromodulation of nerves such as the sympathetic, or parasympathetic, nerves, and in particular, unmyelinated nerve fibers in and around blood vessels and other luminal tissues.
- this disclosure is directed to systems and methods that provide pre-procedure guidance as to proper placement of a therapy catheter and intraprocedural guidance on the effects of the therapy and post procedural analysis on overall efficacy of the therapy.
- FIG. 1 illustrates a guidance and therapy system provided in accordance with the present disclosure and generally identified by reference numeral 10.
- the guidance and therapy system 10 enables navigation of a therapeutic device 50 to a desired location within the patient’s anatomy (e.g., the patient’s renal artery), delivery of neurostimulation to tissue within the renal artery, observing a physiological response to the application of neurostimulation to the tissue, if necessary adjustment of a position of the therapeutic device within the renal artery based upon the physiological response, reapplication of the neurostimulation to the tissue at the adjusted position, application of denervation therapy to the tissue within the renal artery to denervate sympathetic nerves within the tissue, and delivery of neurostimulation to the denervated tissue observe the physiological response to the neurostimulation and assess the efficacy of the denervation therapy.
- the guidance and therapy system 10 includes a workstation 20, a therapeutic device 50 operably coupled to the workstation 20, and an imaging device 70, which may be operably coupled to the workstation 20.
- the patient “P” is shown lying on an operating table 12 with the therapeutic device 50 inserted through a portion of the patient’s femoral artery, although it is contemplated that the therapeutic device 50 may be inserted into any suitable portion of the patient’ s vascular network that is in fluid communication with a desired blood vessel for therapy.
- the therapy system 10 may employ any suitable number of therapeutic devices 50.
- the therapeutic devices 50 may employ the same or different therapy modalities may and be operably coupled to the workstation 20. Further, the therapeutic device 50 may employ a guidewire or a guide catheter 58 (FIG. 3) without departing from the scope of the disclosure.
- the workstation 20 includes a computer 22, a therapy source 24 (e.g., an RF generator, a microwave generator, an ultrasound generator, a cryogenic medium source, a chemical source, etc.) operably coupled to the computer 22, and a stimulation source 24a operably coupled to the computer 22.
- a therapy source 24 e.g., an RF generator, a microwave generator, an ultrasound generator, a cryogenic medium source, a chemical source, etc.
- a stimulation source 24a operably coupled to the computer 22.
- the stimulation source 24a may be integrated within the therapy source 24, and the therapy source 24 may generate both therapy and stimulation modalities.
- the computer is coupled to a display 26 that is configured to display one or more user interfaces 28.
- the computer 22 may be a desktop computer or a tower configuration with display 26 or may include a laptop computer or other computing device.
- the computer 22 includes a processor 30 which executes software stored in a memory 32.
- the memory 32 may store one or more applications 34 and/or algorithms 44 to be executed by the processor 30.
- a network interface 36 enables the workstation 20 to communicate with a variety of other devices and systems via the internet.
- the network interface 36 may connect the workstation 20 to the Internet via a wired or wireless connection. Additionally, or alternatively, the communication may be via an ad hoc Bluetooth® or wireless network enabling communication with a wide- area network (WAN) and/or a local area network (LAN).
- WAN wide- area network
- LAN local area network
- the network interface 36 may connect to the Internet via one or more gateways, routers, and network address translation (NAT) devices.
- the network interface 36 may communicate with a cloud storage system 38, in which further data, image data, and/or videos may be stored.
- the cloud storage system 38 may be remote from or on the premises of the hospital such as in a control or hospital information technology room. It is envisioned that the cloud storage system 38 could also serve as a host for more robust analysis of acquired images (e.g., fluoroscopic, computed tomography (CT), magnetic resonance imaging (MRI), cone-beam computed tomography (CBCT), etc.), data, etc. (e.g., additional or reinforcement data for analysis and/or comparison).
- CT computed tomography
- MRI magnetic resonance imaging
- CBCT cone-beam computed tomography
- An input module 40 receives inputs from an input device such as a keyboard, a mouse, voice commands, an energy source controller (e.g., a foot pedal or handheld remote-control device that enables the clinician to initiate, terminate, and optionally, adjust various operational characteristics of the therapy source 24 and/or stimulation source 24a, including, but not limited to, power delivery), amongst others.
- An output module 42 connects the processor 30 and the memory 32 to a variety of output devices such as the display 26.
- the display 26 may be a touchscreen display.
- the therapy source 24 generates and outputs one or more of RF energy (monopolar or bipolar), microwave energy, ultrasound energy, cryogenic medium, or chemical ablation medium via an automated control algorithm 44 stored on the memory 32 and/or under the control of a clinician.
- RF energy monopolar or bipolar
- microwave energy microwave energy
- ultrasound energy ultrasound energy
- cryogenic medium or chemical ablation medium
- chemical ablation medium a temperature of the tissue (e.g., increases or decreased the temperature) to achieve the desired denervation of the nerves.
- the therapy source 24 may be configured to produce a selected modality and magnitude of energy and/or therapy for delivery to the treatment site via the therapeutic device 50, as will be described in further detail hereinbelow.
- the therapy source 24 may monitor voltage and current applied to target tissue via the therapeutic device 50 and monitors the temperature of the target tissue or tissue proximate the target tissue, and/or a portion of the therapeutic device 50.
- the therapeutic device 50, or therapy source 24 may also measure and monitor the impedance of the tissue through which therapeutic or guidance energy is transmitted to provide in indication of the status of the tissue.
- the stimulation source 24a generates a stimulation signal, for example a biphasic waveform at an energy level that is less the therapeutic (i.e., denervation energy) generated by the therapy source 24 such that the stimulation generated by the stimulation source 24a does not denervate the target tissue.
- the stimulation source 24a generates a stimulation signal capable of effectuating a response from the nerves indicative of tissue that would be a candidate for denervation.
- Responses may include an increase in blood pressure, an increase in vessel stiffness, changes in pulse wave velocity, augmentation pressure, heart rate variability, etc., and combinations of these.
- the stimulation source 24a generates a biphasic waveform where a leading phase of each successive pulse of the biphasic waveform is switched or otherwise inverted.
- a biphasic waveform having an initial pulse with an anodal leading phase and a cathodal trailing phase is followed by a second pulse with a cathodal leading phase and an anodal trailing phase which will be followed by a third pulse returning to an anodal leading phase and a cathodal trailing phase, and so on.
- a biphasic waveform having an initial pulse with a cathodal leading phase and an anodal trailing phase may be followed by a second pulse with an anodal leading phase and a cathodal trailing phase which will be followed by a third pulse returning to a cathodal leading phase and an anodal trailing phase.
- the leading phase of each pulse of the biphasic waveform may be alternated for the duration of the application of neurostimulation to the target tissue.
- the amplitude, frequency, pulse width, and/or duration of the stimulation can be selected and/or modified to ensure neurostimulation of the sympathetic nerves of the luminal tissue without damaging the luminal tissue or the nerves within or surrounding the luminal tissue or causing excess vasoconstriction about the therapeutic device (e.g., inhibiting the movement of the therapeutic device within the luminal tissue).
- a pulse duration may be modified to ensure that anodic stimulation of the tissue is maintained as at certain pulse durations regions of anodic stimulation may dissipate or otherwise disappear resulting in reduced stimulation effect.
- the stimulation source 24a generates biphasic waveforms having a frequency of between approximately 10 - 30Hz, a voltage of between approximately 5 - 30 V, a current of between approximately 2 - 500 mA, and a pulse width of between approximately 2 - 10 ms. It is envisioned that in embodiments where unmyelinated nerve fibers are targeted, the pulse width of the biphasic waveform may be between approximately 2-120 ms.
- the stimulation parameters are a constant current of 20mA for a blood vessel branches and 30 mA for main blood vessels, a pulse width of 5 mS, a frequency of approximately 20 Hz and a duration of between 10 and 60 seconds.
- the therapeutic device 50 includes an elongated shaft 52 having a handle (not shown) disposed on a proximal end portion of the elongated shaft 52.
- the therapeutic device 50 includes an energy delivery assembly 54 at which one or more therapy electrodes 56 are located.
- the elongated shaft 52 of the therapeutic device 50 is configured to be advanced within a portion of the patient’s vasculature, such as a femoral artery or other suitable portion of patient’s vascular network that is in fluid communication with the patient’s renal artery.
- the energy delivery assembly 54 is configured to be transformed from an initial, undeployed configuration having a generally linear profile, to a second, deployed or expanded configuration, where the energy delivery assembly 54 forms a generally spiral and/or helical configuration for delivering energy to a site for either or both application of a stimulation signal or therapeutic energy at the treatment site.
- application of therapeutic energy should be construed to include application of cryogenic cooling to the treatment site to achieve a thermally induced neuromodulation.
- the energy delivery assembly 54, and in particular, the individual electrodes 56 is pressed against or otherwise contacts the walls of the patient’s vasculature tissue.
- the energy delivery assembly 54 may be deployed in other configurations without departing from the scope of the present disclosure.
- the therapeutic device 50 may be configurable, for example, using one or more pull wires (not shown) to adjust the configuration to promote contact between the electrodes 56 and the wall of the renal artery.
- the therapeutic device 50 may be capable of being placed in one, two, three, four, or more different configurations depending upon the design needs of the therapeutic device 50 or the location at which therapy is to be applied.
- the elongated shaft 52 may be configured to be received within a portion of a guide catheter or guide sheath (such as a 6F guide catheter) 58 that is utilized to navigate the therapeutic device 50 to a desired location at which point if a guide catheter 58 is retracted to uncover the therapeutic device 50.
- a guide catheter or guide sheath such as a 6F guide catheter
- retraction of the guide catheter 58 may enable the energy delivery assembly 54 to transition from the first, undeployed configuration, to the second, deployed or expanded configuration.
- the elongated shaft 52 of the therapeutic device 50 may further include an aperture (not shown) at a distal end thereof and configured to slidably receive a guidewire over which the therapeutic device 50, either alone or in combination with the guide catheter 58, are advanced.
- the guidewire is utilized to guide the therapeutic device 50 to the target tissue using over-the-wire (OTW) or rapid exchange (RX) techniques, at which point the guide wire may be partially or fully removed from the therapeutic device 50, enabling the therapeutic device 50 to transition from the first, undeployed configuration, to the second, deployed or expanded configuration (FIG. 3).
- OW over-the-wire
- RX rapid exchange
- the therapeutic device 50 may be transition from the first, undeployed configuration to the second, deployed configuration automatically (e.g., via a shape memory alloy, etc.) or manually (e.g., via pull wires, guide wire manipulation, etc. that is controlled by the clinician).
- the energy delivery assembly 54 includes one or more electrodes 56 disposed on an outer surface thereof that are configured to contact a portion of the patient’s vascular tissue when the therapeutic device 50 is placed in the second, expanded configuration.
- the therapeutic device 50 includes four electrodes 56.
- the present disclosure is not so limited and the therapeutic device 50 may have more or fewer electrodes 56 without departing from the scope of the present disclosure.
- the electrodes 56 may be replaced with ultrasound transducers, microwave antennae, ports for delivery of cryoablation medium or chemical medium and other implements and/or ablation and denervation modalities without departing from the scope of the present disclosure.
- the electrodes 56 are disposed in spaced relation to one another along a length of the therapeutic device 50 forming the energy delivery assembly 54. As will be appreciated, these electrodes 56 are in communication with both the therapy source 24 and the stimulation source 24a. In one example the therapy source 24 produces, monopolar RF energy to denervate the sympathetic nerves of the relevant blood vessel.
- the electrodes 56 may delivery RF energy independently of one another (e.g., monopolar), simultaneously, selectively, sequentially, and/or between any desired combination of the electrodes 56 (e.g., bipolar).
- the therapy source 24 is also the stimulation source 24a and includes a diagnostic mode, where the therapy source 24 generates a stimulation signal having, for example, a biphasic waveform, and a denervation mode, where the therapy source 24 generates RF energy to denervate the nerves of the relevant blood vessel. It is contemplated that the therapy source 24 may be manually switched from a stimulation mode to a denervation mode and vice versa or may be automatically switched by an algorithm 44 stored on the memory 32 of the computing device. Alternatively, the electrodes 56 are in communication with a stand-alone stimulation source 24a to deliver a stimulation signal to the blood vessel in question.
- the stimulation signal (e.g., the biphasic waveform), is generated by the stimulation source 24a and communicated to the electrodes 56 causing stimulation of the sympathetic nerves as described herein.
- the stimulation signal is applied to the target tissue via a first of the electrodes 56 and received by a second of the electrodes 56 in a bipolar manner and during the cathodal phase of the biphasic pulse the neurostimulation is applied to the target tissue via the second of the electrodes 56 and received by the first of the electrodes 56 in a bipolar manner.
- the stimulation signal is applied by two or more of the electrodes 56 or received by two or more of the electrodes 56 in any suitable configuration, such as a proximal most electrode 56 and a distal most electrode 56, a proximal most electrode 56 and a next proximal most electrode 56 a proximal most electrode 56 and an electrode 56 disposed just proximal of the distal most electrode 56, etc.
- one or more algorithms 44 may be employed for the stimulation of the multiple electrodes 56.
- the electrodes 56 may connect in a bipolar fashion as follows. In a first anodal phase between a first electrode and a fourth, first cathodal phase between the fourth electrode and the first electrode. This may be followed by a second cathodal phase between the fourth electrode and the first electrode and a second anodal phase between the first electrode and the fourth electrode. This may be followed in a similar manner by different pairs of electrodes 56, for example between the first and third electrodes 56, the first and second electrodes 56.
- a similar pattern may be followed between second and fourth electrodes and the second and third electrodes.
- an anodal and cathodal phase need not be between the same pairs of electrodes.
- a first anodal phase may be between a first and a fourth electrode and be followed by a cathodal phase between the fourth and the second electrode.
- the first anodal phase may be between a first and a fourth electrode and followed by a cathodal phase between the fourth and first electrodes 56, as in the first example, however the second anodal phase may be between the second and the fourth electrodes followed by a second cathodal phase between the fourth and second electrodes.
- the firing order of the electrodes 56 is limited only by the number of electrodes 56 and the biphasic waveform.
- alternating the leading phase of each successive pulse of the biphasic waveform stimulates a greater number of nerves within the target tissue as compared to traditional bipolar or monopolar stimulation.
- an optimal placement of the electrodes 56 within the target tissue for denervation can be more readily identified to ensure effective renal denervation and an optimal outcome.
- the location and/or orientation of the electrodes 56 relative to the tissue wall can be altered between the application of stimulation signals to map or otherwise identify optimal nerve candidates for denervation.
- FIGS. 4A and 4B depict one aspect of the disclosure.
- a stimulation signal 102 is applied via the electrodes 56 to the target tissue.
- the duration of the stimulation signal is graphically depicted by trace 104.
- the first effect is an increase in heart rate as depicted by trace 106.
- the mean arterial pressure as depicted in trace 108, both during and following the application of the stimulation signal 102 elevates and remains elevated over the pre-stimulation mean arterial pressure.
- This change in either or both heart rate and mean arterial blood pressure is indicative of stimulation of the afferent nerves of the blood vessel in which the therapeutic device 50 is positioned (e.g., the renal and/or hepatic arteries).
- the clinician may determine that the location of the energy delivery assembly 54 is appropriate for application for therapy to achieve denervation and therapeutic energy may be applied to the target tissue at that location within the blood vessel.
- the stimulation signal 102 may again be applied as shown in trace 104.
- FIG. 5A schematically depicts the application of stimulation and therapy in accordance with two aspects of the disclosure.
- An initial stimulation signal 202 may be applied to target tissue for a period T and a change in a physiological parameter (here blood pressure) is observed, as shown in the graph 204. If no response or insufficient response to stimulation is observed the therapeutic device 50 may be moved within the blood vessel, as described elsewhere herein. Once sufficient change in the physiological parameter is observed, therapy may be applied for a predetermined period of time.
- the therapy may be for example a monopolar RF ablation energy 206. Following the application of the therapy 206, there are at least two alternatives, in a first alternative, similar to the methods described above with respect to FIGS.
- a second stimulation signal 208 may be applied and if it is determined that the change in physiological parameter (e.g., mean arterial blood pressure) is below a threshold, the procedure may end.
- the change in physiological parameter as a result of the stimulation 208 in excess of the threshold is indicative of an unsuccessful or incomplete denervation and further therapy 210 is applied.
- This process of stimulation 208 and therapy 210 may be repeated until, the change in a physiological parameter (e.g., mean arterial blood pressure) caused by the stimulation 208 falls below a threshold as depicted in graph 212.
- the change is physiological parameter can is shown in graph 204 as a result of stimulation and may be compared to a threshold and if the difference is greater than a threshold the denervation can be determined to be successful, and therapy ended.
- the magnitude of the therapy power e.g., alteration of one or more of current, voltage, and duration
- a ramp rate may be employed such that at specific intervals of application of therapy 210 a greater therapeutic power that the preceding interval may be employed until a desired outcome is achieved (e.g., a physiological response to stimulus below a desired threshold).
- a combination stimulation signal and therapy 214 may be applied by the therapeutic device 50.
- This combination may be applied for predetermined period of time and/or until a change in physiological parameter (e.g., decrease in mean arterial pressure) during the stimulation signal portion of the combination is observed.
- physiological parameter e.g., mean arterial pressure
- the therapy power e.g., alteration of one or more of current, voltage, and duration
- the observed decrease in the physiological parameter may be recorded as shown in graph 216 and a termination point for the application of the combination signals 212 may be for example an absolute change (e.g., pressure delta from that observed in 204 and in 214) or alternatively, the observed rate of change between successive stimulation signal portions of the combination 214.
- an absolute change e.g., pressure delta from that observed in 204 and in 214
- the observed rate of change between successive stimulation signal portions of the combination 214 may be recorded as shown in graph 216 and a termination point for the application of the combination signals 212 may be for example an absolute change (e.g., pressure delta from that observed in 204 and in 214) or alternatively, the observed rate of change between successive stimulation signal portions of the combination 214.
- an absolute change e.g., pressure delta from that observed in 204 and in 21
- the observed rate of change between successive stimulation signal portions of the combination 214 may be recorded as shown in graph 216 and a termination point for the application of the combination signals 212 may be for example an absolute change (e
- FIG. 5B depicts a graphical representation of the combined stimulation signal and ablation 214. As can be seen, there is a train of alternative times of application of stimulation and ablation. As will be described herein below, the combined signal can be applied for a period T1 after which assessments can be made on the efficacy of the ablation based on changes in physiological parameters (e.g., systolic blood pressure, MAP, and others).
- physiological parameters e.g., systolic blood pressure, MAP, and others.
- the electrodes 56 may be selectively employed for the application of stimulation while other electrodes 56 are employed for the application of therapy.
- the stimulation 208 may be applied via a first electrode 56 and therapy 210 may be applied by a second electrode 56.
- both the stimulation 208 and therapy 210 may be delivered by the same selected electrode 56.
- the combined signal 214 may be delivered selectively from a first electrode 56 for a first period of time, and then from a second electrode for a second period of time.
- Other permutations of the selective application of stimulation and therapy to combinations of electrodes 56 without departing from the scope of the disclosure.
- FIG. 6 depicts a schematic representation of a feedback system in accordance with this disclosure.
- a therapy source 24 and a stimulation source 24a apply energy and signals to electrodes 56 of the therapeutic device 50, as described above.
- the impedance of the tissue through which the energy is passed can be measured by the therapy source 24.
- energy e.g., RF or microwave energy
- the tissue here the blood vessel wall
- the impedance of the tissue will begin to increase as it is heated.
- each electrode 56 may incorporate a thermistor or other temperature sensor (not shown) to monitor the temperature of the electrodes 56.
- the electrodes 56 directly contact the inner wall of a blood vessel or other luminal tissues, thus as energy is passed through the electrodes 56, the electrodes themselves begin to heat.
- the thermistor, thermocouple or other temperature senor in communication with the electrode 56 generates a signal that is received by the therapy source 24. That signal is representative of the temperature of the electrode, if that temperature of any of the electrodes 56 exceeds a predetermined threshold, below that at which damage might occur to the blood vessel wall, the therapy source 24 stops outputting therapeutic energy to the electrode 56. As will be appreciated, the movement of blood through the blood vessel will quickly cool the electrode 56. Once the temperature of the electrodes 56 return below a predetermined threshold, the therapy source 24 may again begin applying therapy using one or more of the methods descried herein to achieve the desired denervation or neuromodulation of the nerves surrounding the blood vessel.
- a blood pressure module 62 employing a blood pressure sensor 60 located on the therapeutic device 50, catheter 58 or a separate component navigated proximate the target tissue. In either event, the blood pressure sensor 60 monitors the blood pressure in the blood vessel to which therapy is applied. That measured blood pressure may be used directly as the feedback parameter or may be converted to one or more different indicia including but not limited to pulse wave velocity, augmentation index (AIX) a measure of arterial stiffness, tricuspid regurgitation velocity (TR).
- AIX augmentation index
- TR tricuspid regurgitation velocity
- FIG. 7 depicts an example of the UI 28 as it might appear on a display 26 in accordance with the disclosure.
- each electrode may be labeled E1-E4.
- stimulation signals 202 are passed from each of the electrodes 56 and one or more physiological parameters may be monitored to see if the stimulation signals have elicited a nervous response.
- electrodes E2-E4 are associated with a nervous response and depict a green light, as will be described in greater detail below. Stimulation of these electrodes may be associated with a change in measured systolic blood pressure in the blood vessel of the patient in which the therapeutic device 50 has been placed.
- Electrode El however, has a red light associated with it, indicating via the UI 28 that the stimulation signal from that electrode resulted in no change in physiological parameter (e.g., systolic blood pressure).
- physiological parameter e.g., systolic blood pressure.
- the stimulation signals 202 are followed by a therapy 206, which may be passed from one or more of the electrodes E1-E4 to denervate the nerves enervating a blood vessel in which the therapeutic device 50 is placed.
- stimulation signals may again be passed through the electrodes, particularly E2-E4 which showed the physiological parameter change in the pre-procedural mapping phase.
- the indicators associated with electrodes E2 and E3 show a green light or other positive indicator alerting the user that the application of the therapy 206 has effectively changed the physiological response to the stimulation 202 associated with the post-procedural mapping application of stimulation signals 202.
- the pre-procedural change to systolic blood pressure from the stimulation 202 may have been an initial value, and the post-procedural mapping may be a much lower level (e.g., below some threshold), indicating that the application of the therapy was successful in ablating or denervating the nerves proximate electrodes El and E2.
- Electrode E4 has a yellow light or other indicator which may be interpreted that though some reduction in the physiological parameter has been achieved, it is not yet sufficient to be considered a successful ablation/denervation of the nerves proximate electrode E4.
- the indicator allows the user to understand the effectiveness of the therapy before deciding to apply more therapy or to move the therapeutic device.
- FIG. 8 depicts a flow chart showing a method 800 in accordance with the disclosure.
- the therapeutic device 50 is placed at a desired location within the patient (e.g., in a renal or hepatic artery). As part of the placement, the therapeutic device 50 may be advanced from the catheter 58 and the therapeutic device 50 allowed to expand such that the electrodes 56 are in contact with an inner wall of the artery.
- a pre-ablation stimulation is applied, for example a biphasic stimulation signal may be transmitted between any two of the electrodes 56.
- the stimulation signal may alternate the leading phase of the stimulation signal. Further, the stimulation signal may alternate between pairs of the electrodes 56 to stimulate the afferent nerves of the blood vessel.
- the current and duration parameters for the stimulation may be adjusted (e.g., increased) at step 812 and the method may proceed to the commencement of the ablation at step 810, an indicator may be generated alerting the user of the change, the indicator may be audible, tactile, visual (e.g., on the user interface) or combinations of these. This may be an option where a change in pressure is observed, but it is less than the threshold, indicating that the nerves being stimulated are further from the electrodes or surrounded by tissue that is mitigating the stimulation effect.
- the method may return to step 804 to determine, for application of a pre-ablation stimulation, after which the change in systolic blood pressure is again compared to a threshold at step 806. Still further, the method may return to step 802 where the position of the therapeutic device 50 is adjusted before applying pre ablation stimulation at step 804. These processes can be repeated as needed until the clinician is satisfied that the position and energy levels being applied at that position in the blood vessel of the patient achieves sufficient change in physiological parameter being monitored.
- a post ablation stimulation may be applied at step 814 and the physiological parameter is again measured at step 816. If the change in the physiological parameter is greater than a threshold, the method moves to step 818, where the power or duration of the ablation energy are adjusted, and the method returns to step 810, an indicator may be generated alerting the user of the change, the indicator may be audible, tactile, visual (e.g., on the user interface) or combinations of these. This may be repeated as necessary until the measured change in the physiological parameter is not greater than some threshold (i.e., less than the threshold). This indicates that the ablation was successful in denervating the nerves in the blood vessel at that location. At this point, the method may optionally end or return to step 802 for re-positioning of the therapeutic device 50 for denervation at another location following the same method 800. An indicator of a successful denervation may be generated to alert the user to the success.
- FIG. 9 depicts an alternative method 900 employing the combined stimulation and ablation techniques, as noted above with respect to FIG. 5.
- Method 900 is focused on providing guidance regarding placement and efficacy of the application of therapy at the placed location of the therapeutic device 50.
- method 900 starts with positioning of the therapeutic device 50 at a desired location within the patient (e.g., in a renal or hepatic artery).
- the therapeutic device 50 may be advanced from the catheter 58 and the therapeutic device 50 allowed to expand such that the electrodes 56 are in contact with an inner wall of the artery.
- a combined stimulation signal and therapy (e.g., signal 214 in FIG. 5) may be applied to the blood vessel wall.
- the stimulation signal is switched to a therapy and then back to a stimulation signal.
- This repeated switching allows for the generation of a series of datapoints related to the physiological parameter being observed (e.g., systolic blood pressure via sensors 60 on the therapeutic device 50.
- a determination is made whether change in a physiological parameter (e.g., systolic blood pressure) is greater than a pre-determined threshold. If the determination is yes at step 908 the application of the combined stimulation signal and therapy 214 is continued until expiration of a second duration T2.
- a green light or other indicator may be displayed on a UI 28 and displayed to the user signaling a successful ablation has been achieved.
- the process may then optionally end or return to step 902 where the therapeutic device 50 may be repositioned to ablate another location within in the same blood vessel or another blood vessel.
- step 906 if the change in physiological parameter is less than a threshold at time Tl, then the therapy is stopped at step 916 and the stimulation signal parameters are adjusted.
- An indicator of the lack of stimulation may be generated alerting the user of the change, the indicator may be audible, tactile, visual (e.g., on the user interface) or combinations of these at step 917, the adjusted stimulation signal is applied for a duration Tl.
- the threshold may be the same or different than the threshold used in step 906.
- method 900 proceeds to step 920 where an indicator is displayed in the UI 28, for example a red light, indicating that no nerves have been located at that location. The method then returns to step 902 where the therapeutic device 50 is moved to another location and the process is started again.
- an indicator is displayed in the UI 28, for example a red light, indicating that no nerves have been located at that location. The method then returns to step 902 where the therapeutic device 50 is moved to another location and the process is started again.
- step 918 there was a change in physiological parameter greater than the threshold when stimulated with the adjusted stimulation signal, is an indicator that the nerves at that location are further from the blood vessel wall (e.g., deep within the tissue) at step 922.
- the procedure requires more additional application of energy by either increasing power, increasing ablation duration, changing frequency, or pulse duration, adding additional electrodes to the array or combinations thereof.
- An indicator may be generated, and for example displayed on the UI 28 regarding the required adjustment.
- the parameter may be adjusted at step 924 and the method returns to step 904, where the process repeats as described above.
- FIG. 10 depicts a further method 1000 utilizing a combined stimulation signal and therapy.
- Method 1000 starts like method 800 and 900 with the positioning of the therapeutic device 50 within a blood vessel in need of therapy (e.g., ablation, denervation).
- the combined stimulation signal and therapy 214 is applied to the blood vessel wall.
- a determination is made whether a change in a physiological parameter (e.g., systolic blood pressure, MAP, etc.) in excess of a threshold after a duration of time T1 is observed.
- a physiological parameter e.g., systolic blood pressure, MAP, etc.
- step 1010 the method proceeds to step 1012 and a signal, such as a green light may be displayed on the UI 28 signaling a successful ablation at that location.
- a signal such as a green light may be displayed on the UI 28 signaling a successful ablation at that location.
- the method 1000 may then end or may return to step 1002 where the therapeutic device 50 may be repositioned for a further ablation/denervation procedure.
- step 1010 If, however, at step 1010 the physiological parameter is not different than as measured at time Tl or has not moved in the correct direction (e.g., a reduction in systolic blood pressure) the method proceeds to step 1014 where a determination is made whether a power limit has been reached. If the power limit has been reached, then the method may proceed to step 1018 where an indicator such as a red light is displayed on UI 28 signaling to the user that insufficient ablation has been received at that location within the blood vessel. The method may then optionally end or return to step 1002 for repositioning of the therapeutic device 50 and further therapy.
- a power limit e.g., a red light
- step 1014 If at step 1014 the power limit has not been reached, the method proceeds to step 1016 where the power to be applied during the therapy portion of the combined stimulation signal and therapy is increased. The method then returns to step 1008 were the increased power combined stimulation signal and therapy is applied the blood vessel all until the expiration of time T2. The method continues as described herein above until either a successful ablation is achieved, or an unsuccessful ablation is achieved, and the power limit has been reached.
- step 1020 the application combined stimulation signal and therapy is stopped.
- the stimulation signal is adjusted (e.g., frequency, current, voltage, etc.) and is again applied by the therapeutic device 50 to the blood vessel wall for duration Tl.
- a determination is made whether a change in physiological parameter (e.g., a change in systolic blood pressure) is greater than a threshold.
- step 1024 the method proceeds to step 1016 where the power of the therapy is increased. Once increased, a combined stimulation signal and therapy having both the adjusted stimulation and the increased therapy power is applied to the blood vessel of the patient at step 1008. The method proceeds as described herein above until either a successful ablation/denervation is achieved, or the power limit is reached.
- step 1026 an indicator, such as a blue indicator may be displayed on the UI 28 alerting the user that there are no detectable nerves at that location and the method returns to step 1002 for repositioning of the therapeutic device 50.
- the described methods 800-1000 are exemplary and steps of the methods may be performed in different orders or eliminated without departing from the scope of the disclosure. Further, as is known to those of skill in the art other methods may be employed determine the locations of nerves for therapy, measure the physiological parameters, and apply the therapy to the nerves of the patient.
- FIG. 11 depicts a schematic representation of a distal portion of a therapeutic device 50 showing the electrodes 56. These electrodes 56 are individually labeled El through E4. Further aspects of the disclosure are described herein with respect to this arrangement of the electrodes 56. As noted above, methods 900 and 1000 describe application of a combined stimulation signal and therapy. While FIG. 5 includes one depiction of this signal, through the use of multiple electrodes 56, multiplexed signals may employ the electrodes 56 in different pairings and timings to provide more accurate determination of where nerves are located, more complete ablation or denervation of the nerves, and a more accurate determination of success of the procedures.
- a first pair (e.g., El and E2) may be used in a first phase as the stimulation electrodes and the stimulation signal passes between the two electrodes for a set duration.
- a second par (e.g., E3 and E4) are used for application of the therapy for the set duration.
- the therapy is monopolar RF, wherein the energy passes from the electrodes E3 and E4 to a pad placed on the patient.
- the duration may be for example 10 seconds.
- the pairs are switched and El and E2 become the therapy electrodes and E3 and E4 become the stimulation electrodes.
- This switching back and forth between which pairs are applying therapy and which are applying stimulation may be continued (e.g., switching every 10 seconds) until the end of a longer duration (e.g., 50 seconds).
- a longer duration e.g., 50 seconds.
- all of the electrodes 56 of the therapeutic device 50 are employed in both the stimulation and application of therapy to the nerves of the patient, enabling a larger area to receive therapy and, when the therapeutic device 50 is formed as depicted in FIG. 3, a substantially circumferential ablation about the diameter of the blood vessel may be formed substantially reducing the likelihood that nerves (e.g., sympathetic nerves) remain after application of the therapy.
- nerves e.g., sympathetic nerves
- the pairs of electrodes 56 remains constant and the form of the energy or signal is switched. However, in another form of multiplexing the pairs themselves may be continually changed.
- El and E2 may apply stimulation and E3 and E4 may apply the therapy.
- E2 and E3 apply stimulation and El and E4 apply therapy.
- the third phase may see E3 and E4 apply the stimulation and El and E2 the therapy.
- E2 and E4 apply the stimulation and El and E3 apply the therapy.
- These pairings may be made until all potential pairs of electrodes has been achieved. Each phase may last form 50 msec to 5 seconds. The pattern may then be repeated until an overall therapy duration is reached (e.g., 50 seconds).
- every pair of electrode applies stimulation providing greater insight the effect of that stimulation between each pair. Further a clearer picture of the effect of the therapy can be developed. Indeed, using the data generated and the methods 900 and 1000, a more granular determination of the effect of the ablation achieved by each electrode 56 can be assessed allowing for the indicators (e.g., red, green, blue lights) on the UI to be displayed not just for the overall procedure but for individual electrodes 56, providing greater insight into the efficacy of the procedure.
- the indicators e.g., red, green, blue lights
- Another example of a stimulation and therapy pattern includes the reversal of the polarity of electrodes 56 for the stimulation.
- pairs of electrodes may be employed (e.g., E 1 and E2 may be a stimulation pair).
- the combined stimulation signal and therapy (similar to 214 of FIG. 5) may be employed.
- stimulation signals are passed from El to E2.
- all four electrodes 56 are used for application of therapy for a duration (e.g., 10 seconds).
- a second stimulation phase may again pass stimulation signals from El to E2, and again be followed by application of therapy from all electrodes 56.
- the polarity of the stimulation signals may be reversed passing from E2 to El.
- the switching of polarities of the stimulation is not limited to just electrodes El and E2 but can be between any two pairs of electrodes.
- the stimulation pairs may be switched between El and E2, E3 and E4, E2 and E3, E2 and E4, El and E3, El and E4, and each pairing may include the application of a first polarity stimulation and a reverse polarity stimulation.
- each stimulation all of the electrodes may be used for application of the therapy. This process may repeat until a set duration of stimulation and therapy has been reached as described in connection with methods 800, 900, 1000.
- the stimulation signal 208 when applied in a non-combined stimulation signal and therapy may utilize a reversing electrode pairs polarity scheme.
- the stimulation signal may be applied from electrode E1-E4 for a first duration, and then applied in a reverse polarity fashion from E-4 to El for a second duration. As noted elsewhere reversing the polarity enhances the nervous response to the stimulation.
- Still a further implementation employs combination stimulations where two pairs of electrodes are employed simultaneously.
- E1-E2 apply a stimulation signal during a first period.
- Simultaneously electrodes E3 and E4 are also used to apply stimulation during this same period.
- stimulation is applied between electrodes El and E4 while simultaneously being applied between electrodes E2 and E3.
- stimulation may be applied between electrodes E2 and E4 while simultaneously being applied between El and E3.
- Each of these periods may be very short for example 1 to 25 msec, and the switching between electrode pairs may be undertaken until a duration of stimulation is reached.
- this process may be supplemented with the application of reverse polarity stimulation as described in other aspects herein.
- FIG. 12 depicts a reversing polarity stimulation method 1200.
- the method 1200 is an automated stimulation sequence whereby pairs of electrodes E1-E4 are utilized both in an initial polarity and a reverse polarity to determine which of the electrodes are in closer the proximity to the nerves and which electrodes should be utilized to effectively ablate/denervate nerves.
- stimulation a stimulation signal is passed between electrodes El and E4 at step 1204. This represents the longest path between two electrodes.
- a determination is made whether a physiological response (e.g., change in systolic blood pressure) above a threshold value is achieved.
- a physiological response e.g., change in systolic blood pressure
- step 1206 the method progresses to step 1208 where stimulation is applied between electrodes El and E2.
- step 1210 a determination is made whether a stimulation response is experienced above a threshold value If yes at step 1210 the method moves to step 1212 where stimulation is applied between electrodes El and E3.
- step 1214 a determination is made whether a stimulation response is experienced above a threshold value. If the answer is yes, there are nerves around El for ablation/denervation and then at step 1216 that information is stored in the memory 32 for use with one or more applications 34. If at step 1214 no stimulation response is experienced the method progresses to step 1218 where stimulation is applied between electrodes E3 and El .
- step 1210 If at step 1210 there is not a pressure response in excess of a threshold, the method progresses to step 1224 where stimulation is applied between electrodes E2 and El. At step 1225 a determination is made whether a stimulation response above a threshold value is experienced. If the answer is yes, there are nerves around E2 for ablation/denervation and then at step 1226 that information is stored in the memory 32 for use with one or more applications 34.
- step 1206 if no stimulation response above a threshold is experienced from the stimulation of El and E4, the method moves to step 1228 where a reverse polarity stimulation (as compared to step 1204) from E4 to El is applied. If at step 1230 a pressure response in excess of a threshold is detected to method proceeds to step 1232 where stimulation is applied from electrode E4 to E3. At step 1234 the determination is made whether the stimulation response is above a threshold value. If the answer is yes, there are nerves around E4 for ablation/denervation and then at step 1236 that information is stored in the memory 32 for use with one or more applications 34.
- step 1234 the method progresses to step 1238 where stimulation is applied between electrodes E3 and E4 (essentially reverse polarity from step 1232).
- step 1240 an inquiry is made whether a stimulation response greater than a threshold is observed in response to step 1238. If the answer is yes, there are nerves around E3 for ablation/denervation and then at step 1242 that information is stored in the memory 32 for use with one or more applications 34.
- step 1244 stimulation is applied between electrodes E2 and E4.
- step 1246 an inquiry is made whether the stimulation response is above a threshold value. If the answer is yes, there are nerves around E2 for ablation/denervation and then at step 1248 that information is stored in the memory 32 for use with one or more applications 34. If the answer to the inquiry at step 1246 is no, the method proceeds to step 1250 where stimulation is applied between electrodes E3 and E2.
- step 1252 an inquiry is made whether the stimulation response is above a threshold value. If the answer is yes, there are nerves around E3 for ablation/denervation and then at step 1254 that information is stored in the memory 32 for use with one or more applications 34.
- the method 1200 may be part of an application 34 stored in the memory 32.
- the results of the method 1200 may also be stored in the memory and displayed on the UI 28 or used by an application performing any of methods 800, 900, or 1000 to limit which of the electrodes are employed to ablate/denervate the nerves of the patient at any given location where the therapeutic device 50 is placed.
- Table 1 depicts a table illustrating the methodology of determining which electrodes 56 are proximate nerves and thus should be employed in a denervation procedure.
- the method 1300 is initiated at step 1302, following navigation of the therapeutic device 50 to an artery for denervation by applying stimulation to electrodes El and E2. If at step 1304 no response is observed, then there are no nerves located proximate either electrodes El or electrodes E2, and the method will move to step 1322 where an indication that no nerves are proximate El or E2 is stored in memory and the method moves to step 1323, described below. However, if a response is observed then as noted at step 1306 the method Either El or E2 or both are proximate a nerve. To get further information, at step 1308 stimulation is applied to electrode El .
- a response is observed at step 1310, that response indicates that electrode El is proximate a nerve and should be used for a denervation procedure. El will then be stored in the memory as an electrode to be used for the denervation procedure at step 1312. If no response is detected, then El will be indicated in the memory as an electrode that is not to receive energy for application of therapy at step 1314. Regardless of the outcome of the determination at step 1310, after stimulation to El, stimulation will be delivered to E2 at step 1316. Again, if a response is detected at step 1318, E2 will be stored in memory as an electrode for application of therapy at step 1320, if no response is detected, at step 1321 E2 will be indicated as an electrode that is not to receive energy during a therapy.
- step 1323 stimulation is applied to both E3 and E4. If no response is detected at step 1324 electrodes E3 and E4 will both be indicated in the memory as not to receive energy during therapy at step 1326 and the method ends. If a response is detected at step 1324 the method progresses to step 1328 where stimulation is applied to E3. If a response is detected at step 1330 an indication that E3 is to receive energy during therapy is saved in the memory at step 1332, of no response is detected, then an indication is stored in memory that E3 is not to receive energy during therapy is stored in memory at 1336. Regardless the method progresses to step 1338 where stimulation is applied to E4.
- an assessment is made of a portion of a blood vessel in which a therapeutic device 50 has been placed and the proximity of each of electrodes E1-E4 to a nerve for denervation. Because the response from stimulation from each individual electrode 56 and pairs of electrodes 56 along the therapeutic device are assessed and stored in memory, a determination can be made as to which of the electrodes E1-E4 to utilize to apply therapy. This results in more targeted application of therapy, ensures that the therapy is more likely to be effective, and eliminates unnecessary destruction of tissue of the blood vessel.
- This method 1300 may be utilized as part of any of the methods of stimulation and therapy described herein to ensure that when therapy is applied it is targeted to those portions of a blood vessel likely to benefit the patient and prevent the unnecessary application of therapy to other portions of the blood vessel.
- the method 1300 may be also employed separately from other to map the locations of the nerves or to assess the placement of the therapeutic device 50.
- the electrodes 56 E1-E4 which are identified as being proximate a nerve and an indication of such is stored in the memory 32.
- a method such as methods 800, 900, 1000 is undertaken, only those electrodes E1-E4 from which a response to stimulation applied therethrough was detected receive the stimulation and therapy.
- the stimulation signals employed in embodiments herein may have a multiphasic-pulsed waveform (e.g., biphasic, triphasic, etc.).
- the neurostimulation includes a biphasic waveform, with each pulse of the biphasic waveform having an anodal leading phase and a cathodal trailing phase or vice versa.
- the therapy system may be configured to alternate the leading phase of each pulse of the biphasic waveform during the application of the neurostimulation such that, for example, a first pulse includes an anodal leading phase and a cathodal trailing phase, a subsequent, second pulse includes a cathodal leading phase and an anodal trailing phase, and a subsequent, third pulse returns to an anodal leading phase and a cathodal trailing phase.
- the leading phase of each pulse of the biphasic waveform is alternated for the duration of the application of the neurostimulation.
- a neural response to the neurostimulation is enhanced as compared to continuous first phase biphasic waveforms and monophasic waveforms as is known in the art.
- the therapeutic devices 50 contemplated in this disclosure can apply one or more of a variety of therapeutic modalities.
- the therapeutic modalities considered within the scope of this disclosure include monopolar or bipolar radiofrequency, microwave, cryogenic, ultrasound, chemical, and other yet to be developed modalities. Any of these therapy modalities may be incorporated into a therapeutic device, such as a catheter, which is configured for navigation to a desired location within the patient.
- a catheter configured to delivery one or more of these therapeutic modalities may be percutaneously navigated, for example via the femoral artery, to reach the blood vessels of the aorta including the celiac artery, hepatic arteries, splanchnic arteries, mesenteric arteries, and others that are enervated with sympathetic nerves or are proximate one or more sympathetic nerve ganglia.
- Such a catheter may also be laparoscopically placed in one or more of the above-identified blood vessels, or another luminal tissue without departing from the scope of the present disclosure.
- the therapeutic device 50 described herein is configured to deliver stimulation to the blood vessel or other luminal tissue.
- the amplitude, frequency, pulse width, and/or duration of the stimulation can be selected and/or modified to ensure stimulation of the target nerves of the periluminal tissue (e.g., unmyelinated nerve fibers) without damaging the luminal tissue or the nerves within or surrounding the luminal tissue or causing excess vasoconstriction about the therapeutic device (e.g., inhibiting the movement of the therapeutic device within the luminal tissue).
- the therapeutic device 50 is coupled to a therapy source 24 and a stimulation source 24a, although it is envisioned that the therapy source 24 and the stimulation source 24a may be the same and capable of generating both therapy and stimulation.
- an electrical generator may be configured to generate biphasic pulses to be supplied to the electrodes 56 of the therapeutic device 50 and the supply monopolar RF energy to the electrodes 56.
- the therapeutic device may be navigated within the vessels or luminal tissue in one configuration (e.g., a linear configuration) and once located at a desired location, deployed or otherwise actuated to achieve a second configuration
- the application of stimulation 202 may achieve one of a number of physiological responses including an increase in systolic blood pressure, increase in mean arterial blood pressure, an increase in vessel stiffness, an increase in pulse wave velocity, an increase in vessel stiffness, and others.
- the physiological responses to the application of neurostimulation can be monitored by a control algorithm 44 stored on the computer 22, with the location and results of the application of neurostimulation stored in the memory 32.
- the observed post therapy and intra-procedural physiological responses can be compared to the pre-procedural responses to assess the efficacy of the therapy, determine if more therapy is required, and when sufficient therapy has been applied to achieve the desired abl ati on/ denervati on .
- the therapeutic device 50 has been primarily described in connection with a shape memory construction where exit from a guide catheter 58 frees the shape memory alloy to achieve a desired spiral shape of the and place the electrodes 56 against the blood vessel walls.
- the present disclosure is not so limited and the therapeutic device 50 may be formed such that the electrodes are placed on a balloon or other mechanism to achieve the desired contact with the blood vessel walls without departing from the scope of the disclosure.
- the memory 32 may include any non-transitory computer-readable storage media for storing data and/or software including instructions that are executable by the processor 30 and which control the operation of the workstation 20 and, in some embodiments, may also control the operation of the therapeutic device 50.
- memory 32 may include one or more storage devices such as solid-state storage devices, e.g., flash memory chips.
- the memory 32 may include one or more mass storage devices connected to the processor 30 through a mass storage controller (not shown) and a communications bus (not shown).
- computer-readable media can be any available media that can be accessed by the processor 30. That is, computer readable storage media may include non-transitory, volatile, and non-volatile, removable, and non-removable media implemented in any method or technology for storage of information such as computer-readable instructions, data structures, program modules or other data.
- computer-readable storage media may include RAM, ROM, EPROM, EEPROM, flash memory or other solid-state memory technology, CD-ROM, DVD, Blu-Ray or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which may be used to store the desired information, and which may be accessed by the workstation 20.
- Example 1 A method of performing a therapeutic procedure, comprising: applying a first stimulation signal from electrodes of a therapeutic device to a blood vessel wall; observing a first physiological response to the first stimulation signal; applying a therapy to the blood vessel wall; applying a second stimulation signal from the electrodes to the blood vessel; observing second physiological response to the second stimulation signal; and outputting an indicator of a successful therapy when the second physiological response is different from the first physiological response by more than a first threshold value.
- Example 2 The method of Example 1, further comprising adjusting parameters of the first stimulation signal when the first physiological response is observed less than a second threshold value.
- Example 3 The method of Example 2, further comprising applying the first stimulation signal with the adjusted parameters to the blood vessel wall, prior to applying the therapy to the blood vessel wall.
- Example 4 The method of Example 1, further comprising adjusting parameters of the therapy if the second physiological response is different from the first physiological response by less than the first threshold.
- Example 5 The method of Example 4, further comprising applying a therapy with the adjusted parameters to the blood vessel wall.
- Example 6 A system for denervation of nerves of a blood vessel comprising: a therapeutic device configured for navigation within a blood vessel of a patient; a plurality of electrodes formed on a distal portion of the therapeutic device; a sensor configured to measure one or more physiological parameters of the patient at a location to which the therapeutic device has been navigated; a stimulation and therapy source; and a computing device including a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of the plurality of electrodes; sense a first change in a physiological parameter as a result of the application of the first stimulation signal; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; generate a therapy for application the blood vessel wall; generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes; sense a second change in the physiological parameter as result of the application of the second stimulation signal;
- Example 8 The system of Example 7, wherein the determination of the first sensed change occurs after the initial period of time.
- Example 9 The system of Example 8, wherein second stimulation signal and the therapy are a combined signal that is generated for a second period of time.
- Example 10 The system of Example 6, wherein the instructions when executed by the processor present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the one of the plurality of electrodes, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation.
- Example 11 The system of Example 6, wherein the instructions when executed by the processor determine that the first sensed change in the physiological parameter is indicative of a lack of a nerve proximate the one of the plurality of electrodes and output an indicator.
- Example 12 The system of Example 11, wherein the instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time.
- Example 13 The system of Example 6, wherein the instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time.
- Example 12 wherein the instructions when executed by the processor sense a third change in a physiological parameter as a result of the application of the first stimulation signal with the adjusted parameters; determine whether the third sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; and output an indicator of the presence of a nerve proximate the one of the plurality of electrodes.
- Example 14 The system of Example 13, wherein the instructions when executed by the processor determine that the nerves are deep and require additional time to complete the denervation and reapply the therapy.
- Example 15 A method of assessing a denervation site comprising: applying a multiplexed stimulation signal and therapy to alternating pairs of a plurality of electrodes of a therapeutic device to a wall of a blood vessel for a first duration; sensing a physiological parameter of the blood vessel after application of the multiplexed stimulation and therapy; determining that a first change in the physiological parameter of the blood vessel exceeds a first threshold; applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes for a second duration; sensing a physiological parameter of the blood vessel after the application of the multiplexed stimulation and therapy; determining whether a second change in the physiological parameter of the blood vessel exceeds a second threshold; and indicating to a user a successful denervation when the sensed physiological parameter after the second duration is different than after the first duration.
- Example 16 The method of Example 15, further comprising determining if a power limit has been reached when the determined change in the physiological parameter after the second duration is less than the threshold and increasing the power of the therapy if the power limit has not been reached.
- Example 17 The method of Example 16, further comprising ceasing application of the multiplexed stimulation signal an therapy if the power limit has been reached.
- Example 18 The method of Example 15, wherein applying the multiplexed stimulation signal and therapy comprises: applying a stimulation signal between a first pair of the plurality of electrodes for a first time; applying a therapy via a second pair of the plurality of electrodes simultaneously with the stimulation signal for a first time; applying the stimulation signal between the second pair of the plurality of electrodes for a second time; applying a therapy via the second pair of the plurality of electrodes simultaneously with the stimulation signal for the second time; and switching between the first pair and the second pair for application of the stimulation signal and application of therapy until completion of the first duration or the second duration.
- Example 19 The method of Example 16, wherein the plurality of electrodes are arranged in a first unique series of pairs of electrodes and a second unique series of pairs and applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes comprises: applying stimulation to a first pair of the first unique series of pairs for a first time; applying therapy to a first pair of the second unique series of pairs for the first time; switching to a second pair of the first unique series of pairs and applying stimulation to the second pair for a second time; switching to a second unique pair of the second unique series of pairs and applying therapy to the second pair for a second time; and repeating the switching of the first unique series of pairs and the second unique series of pairs for the first duration or the second duration.
- Example 20 The method of Example 15, wherein the sensed physiological parameter is one or more of systolic blood pressure, mean arterial blood pressure, blood vessel stiffness, or pulse wave velocity.
- Example 21 The method of Example 20, wherein the determined first change of the physiological parameter is a reduction in systolic blood pressure.
- Example 22 The method of Example 21, wherein the determined second change of the physiological parameter is a reduction in systolic blood pressure and the threshold is the systolic blood pressure at a conclusion of the first duration.
- Example 23 The method of Example 15, further comprising determining that the first change of the physiological parameter is less than the threshold; and stopping application of a therapy portion of the multiplexed stimulation signal and therapy.
- Example 24 The method of Example 23, further comprising adjusting a stimulation signal and applying the adjusted stimulation signal to alternating pairs of electrodes.
- Example 25 The method of Example 24, further comprising determining that application of the adjusted stimulation signal resulted in a change of the physiological parameter in excess of a threshold; increasing a power of the therapy; and applying a multiplexed adjusted stimulation signal and increased power therapy for the second duration.
- Example 26 The method of Example 24, further comprising determining that application of the adjusted stimulation signal resulted in a change of the physiological parameter less than the threshold; and generating an indicator for display on a user interface that no nerves are detected at a position of the therapeutic device.
- Example 27 A method of performing a therapeutic procedure, comprising: applying a first stimulation signal from a first pair electrodes of a therapeutic device to a blood vessel wall; applying a therapy to the blood vessel wall employing all electrodes; switching polarity of the stimulation signal between the first pair of electrodes; applying a second stimulation from the first pair of electrodes to the blood vessel; applying a therapy to the blood vessel wall employing all electrodes; switching to a second pair of electrodes; applying a second stimulation signal with the second pair of electrodes, applying of therapy with all electrodes, switching polarity of the second pair of electrodes, applying the second stimulation signal with the second pair of electrodes, and applying therapy with all the electrodes; switching to all subsequent pairs of electrodes and repeating application of stimulation with each subsequent pair of electrodes, application of therapy with all electrodes, switching polarity of each subsequent pair of electrodes, application of stimulation with each subsequent pair of electrodes and application of therapy with all electrodes sensing a physiological parameter of the blood vessel after expiration of a first time period; determining
- Example 28 The method of Example 27, further comprising determining that the first change of the physiological parameter is less than the threshold; and stopping the application of the therapy.
- Example 29 The method of Example 28, further comprising adjusting a stimulation signal and repeating the switching and applying of the stimulation signal to each successive pair of electrodes and application of a therapy using all electrodes until a first time period expires.
- Example 30 The method of Example 29, further comprising determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter less than the threshold; and generating an indicator for display on a user interface that no nerves are detected at a location of the therapeutic device.
- Example 31 The method of Example 29, further comprising determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter in excess of a threshold.
- Example 32 The method of Example 30, further comprising increasing a power of the therapy; and applying the adjusted stimulation signal and increased power therapy for the second time period.
- Example 33 A system for denervation of nerves of a blood vessel comprising: a stimulation and therapy source; and a computing device including a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of a plurality of electrodes of a therapeutic device; sense a first change in a physiological parameter as a result of the application of the first stimulation signal; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; generate a therapy for application the blood vessel wall; generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes; sense a second change in the physiological parameter as result of the application of the second stimulation signal; determine whether the application of the therapy has denervated the nerve proximate the electrode based on the second sensed change of the physiological parameter; and output an indicator of success of the application of the therapy.
- Example 34 The system of Example 33, wherein the first stimulation signal and the therapy are a combined signal that is generated for an initial period of time.
- Example 35 The system of Example 34, wherein the determination of the first sensed change occurs after the initial period of time.
- Example 36 The system of Example 35, wherein second stimulation signal and the therapy are a combined signal that is generated for a second period of time.
- Example 37 The system of Example 33, wherein the instructions when executed by the processor present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the one of the plurality of electrodes, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation.
- Example 38 The system of Example 33, wherein the instructions when executed by the processor determine that the first sensed change in the physiological parameter and output an indicator of a lack of a nerve proximate the one of the plurality of electrodes.
- Example 39 The system of Example 38, wherein the instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time.
- Example 40 Example 40.
- Example 39 wherein the instructions when executed by the processor sense a third change in a physiological parameter as a result of the application of the first stimulation signal with the adjusted parameters; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; and output an indicator of the presence of a nerve proximate the one of the plurality of electrodes.
- Example 41 The system of Example 40, wherein the instructions when executed by the processor determine that the nerves are deep and require additional time to complete the denervation and reapply the therapy.
- a system for denervation of nerves of a blood vessel comprising: a stimulation and therapy source; and a computing device including a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of the plurality of electrodes; sense a first change in a physiological parameter as a result of the application of the first stimulation signal; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; generate a therapy for application the blood vessel wall; generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes; sense a second change in the physiological parameter as result of the application of the second stimulation signal; determine whether the application of the therapy has denervated the nerve proximate the electrode based on the second sensed change of the physiological parameter; and output an indicator of success of the application of the therapy.
- a therapeutic device configured for navigation within a blood vessel of a patient; a plurality of electrodes formed on a distal portion of the therapeutic device; a sensor configured to measure one or more physiological parameters of the patient at a location to which the therapeutic device has been navigated;
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Abstract
Systems and methods of performing a therapeutic procedure employing a therapeutic device including electrodes by applying a stimulation signal from the electrodes to a blood vessel wall, observing a physiological response to the stimulation signal, applying a therapy to the blood vessel wall, applying another stimulation signal from the electrodes to the blood vessel, and observing second physiological response to the second stimulation signal. When the second physiological response is different from the first physiological response by more than a threshold the therapy is successful.
Description
RENAL NERVE STIMULATION SYSTEM TO GUIDE RF RENAL DENERVATION
[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63/427,620, filed November 23, 2022, the entire content of which is incorporated herein by reference.
Technical Field
[0002] This disclosure relates to systems and methods enabling positioning a therapeutic device within luminal tissues to enhance ablation during a therapeutic procedure. In particular aspects, the present disclosure is directed to methods and systems for denervating nerves in or around vascular tissue.
Background
[0003] Catheters have been proposed for use with various medical procedures. For example, a catheter can be configured to deliver neuromodulation (e.g., denervation) therapy to a target tissue site to modify the activity of nerves at or near the target tissue site. The nerves can be, for example, sympathetic or parasympathetic nerves. The sympathetic nervous system (SNS) is a primarily involuntary bodily control system typically associated with stress responses. Chronic over-activation of the SNS is a maladaptive response that can drive the progression of many disease states. For example, excessive activation of the renal SNS has been identified experimentally and in humans as a likely contributor to the complex pathophysiology of arrhythmias, hypertension, states of volume overload (e.g., heart failure), and progressive renal disease.
[0004] Percutaneous renal denervation is a minimally invasive procedure that can be used to treat hypertension and other diseases caused by over-activation of the SNS. During a renal denervation procedure, a clinician delivers stimuli or energy, such as radiofrequency, ultrasound, cooling, or other energy to a treatment site to reduce activity of nerves surrounding a blood vessel. The stimuli or energy delivered to the treatment site may provide various therapeutic effects through alteration of sympathetic nerve activity.
[0005] During current denervation procedures, it is not possible for a clinician to visualize the nerves prior to application of the therapy. Instead, denervation catheters are positioned to the best of the clinician’s abilities and several ablations performed. As a result, the clinicians have no indication the ablations they are performing are actually ablating any nerves. Further, there is no indication during the procedure that the ablation was successful. Accordingly, this
disclosure is directed to systems and methods of addressing these shortcomings of the current technologies.
SUMMARY
[0006] One aspect of the disclosure is directed to a method of performing a therapeutic procedure. The method includes navigating a therapeutic device to target tissue, the therapeutic device including a plurality of electrodes. The method also includes applying a first stimulation signal from the electrodes to a blood vessel wall. The method also includes observing a first physiological response to the first stimulation signal. The method also includes applying a therapy to the blood vessel wall. The method also includes applying a second stimulation signal from the electrodes to the blood vessel. The method also includes observing second physiological response to the second stimulation signal, where the second physiological response being different from the first physiological response by more than a first threshold value indicates a successful therapy. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.
[0007] Implementations of this aspect of the disclosure may include one or more of the following features. The method further including adjusting parameters of the first stimulation signal when the first physiological response is observed less than a second threshold value. The method further including applying the first stimulation signal with the adjusted parameters to the blood vessel wall, prior to applying the therapy to the blood vessel wall. The method further including adjusting parameters of the therapy if the second physiological response is different from the first physiological response by less than the first threshold. The method further including applying a therapy with the adjusted parameters to the blood vessel wall. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions. One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.
[0008] A further aspect of the disclosure is directed to a system for denervation of nerves of a blood vessel. The system includes a therapeutic device configured for navigation within a blood vessel of a patient. The system also includes a plurality of electrodes formed on a distal portion of the therapeutic device. The system also includes a senor configured to measure one
or more physiological parameters of the patient at a location to which the therapeutic device has been navigated. The system also includes a stimulation and therapy source. The system also includes a computing device including a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of the plurality of electrodes, sense a first change in a physiological parameter as a result of the application of the first stimulation signal, determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes, generate a therapy for application the blood vessel wall, generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes, sense a second change in the physiological parameter as result of the application of the second stimulation signal, and determine whether the application of the therapy has denervated the nerve proximate the electrode based on the second sensed change of the physiological parameter. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.
[0009] Implementations of this aspect of the disclosure may include one or more of the following features. The system where the first stimulation signal and the therapy are a combined signal that is generated for an initial period of time. The determination of the first sensed change occurs after the initial period of time. Second stimulation signal and the therapy are a combined signal that is generated for a second period of time. The instructions when executed by the processor present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the one of the plurality of electrodes, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation. The instructions when executed by the processor determine that the first sensed change in the physiological parameter is indicative of a lack of a nerve proximate the one of the plurality of electrodes. The instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time. The instructions when executed by the processor sense a third change in a physiological parameter as a result of the application of the first stimulation signal with the adjusted parameters; and determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes. The instructions when executed by the processor determine that the nerves are deep and require additional time to complete the denervation. Implementations of
the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions. One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.
[0010] Still a further aspect of the disclosure is directed to a method of assessing a denervation site. The method includes positioning a therapeutic device in a blood vessel such that a plurality of electrodes are in contact with a wall of the blood vessel. The method also includes applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes for a first duration. The method also includes sensing a physiological parameter of the blood vessel after the application of the multiplexed stimulation and therapy. The method also includes determining that a first change in the physiological parameter of the blood vessel exceeds a first threshold. The method also includes applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes for a second duration. The method also includes sensing a physiological parameter of the blood vessel after the application of the multiplexed stimulation and therapy. The method also includes determining whether a second change in the physiological parameter of the blood vessel exceeds a second threshold. The method also includes indicating to a user a successful denervation when the sensed physiological parameter after the second duration is different than after the first duration. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.
[0011] Implementations of this aspect of the disclosure may include one or more of the following features. The method further including determining if a power limit has been reached when the determined change in the physiological parameter after the second duration is less than the threshold. The method further including increasing the power of the therapy if the power limit has not been reached. The plurality of electrodes are arranged in a first unique series of pairs of electrodes and a second unique series of pairs and applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes includes: applying stimulation to a first pair of the first unique series of pairs for a first time; applying therapy to a first pair of the second unique series of pairs for the first time; switching to a second pair of the first unique series of pairs and applying stimulation to the second pair for a second time; switching to a second unique pair of the second unique series of pairs and applying therapy to
the second pair for a second time; and repeating the switching of the first unique series of pairs and the second unique series of pairs for the first duration or the second duration. Applying the multiplexed stimulation signal and therapy includes: applying a stimulation signal between a first pair of the plurality of electrodes for a first time; applying a therapy via a second pair of the plurality of electrodes simultaneously with the stimulation signal for a first time; applying the stimulation signal between the second pair of the plurality of electrodes for a second time; applying a therapy via the second pair of the plurality of electrodes simultaneously with the stimulation signal for the second time; and switching between the first pair and the second pair for the application of the stimulation signal and application of therapy until completion of the first duration or the second duration. The sensed physiological parameter is one or more of systolic blood pressure, mean arterial blood pressure, blood vessel stiffness, or pulse wave velocity. The determined first change of the physiological parameter is a reduction in systolic blood pressure. The determined second change of the physiological parameter is a reduction in systolic blood pressure and the threshold is the systolic blood pressure at a conclusion of the first duration. The method further including determining that the first change of the physiological parameter is less than the threshold; and stopping the application of a therapy portion of the multiplexed stimulation signal and therapy. The method further including adjusting a stimulation signal and applying the adjusted stimulation signal to alternating pairs of electrodes. The method further including determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter in excess of a threshold; increasing a power of the therapy; and applying a multiplexed adjusted stimulation signal and increased power therapy for the second duration. The method further including determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter less than the threshold; and generating an indicator for display on a user interface that no nerves are detected at the position of the therapeutic device. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions. One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.
[0012] Yet a further aspect of the disclosure is directed to a method of performing a therapeutic procedure. The method also includes navigating a therapeutic device to target tissue, the therapeutic device including a plurality of electrodes. The method also includes applying a
first stimulation signal from a first pair electrodes to a blood vessel wall. The method also includes applying a therapy to the blood vessel wall employing all electrodes. The method also includes switching the stimulation signal to a second pair of electrodes. The method also includes applying a second stimulation from the second pair of electrodes to the blood vessel. The method also includes applying a therapy to the blood vessel wall employing all electrodes. The method also includes repeating the switching and applying of the stimulation signal to each successive pair of electrodes and application of a therapy using all electrodes until a first time period expires. The method also includes sensing a physiological parameter of the blood vessel after the expiration of the first time period. The method also includes determining that a first change in the physiological parameter of the blood vessel exceeds a first threshold. The method also includes repeating the switching and applying of the stimulation signal to each successive pair of electrodes and application of a therapy using all electrodes until a second time period expires. The method also includes determining whether a second change in the physiological parameter of the blood vessel exceeds a second threshold. The method also includes indicating to a user a successful denervation when the sensed physiological parameter after the second time period is different than after the first time period. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.
[0013] Implementations of this aspect of the disclosure may include one or more of the following features. The method further including determining that the first change of the physiological parameter is less than the threshold; and stopping the application of the therapy. The method further including adjusting a stimulation signal and repeating the switching and applying of the stimulation signal to each successive pair of electrodes and application of a therapy using all electrodes until a first time period expires. The method further including determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter less than the threshold; and generating an indicator for display on a user interface that no nerves are detected at a location of the therapeutic device. The method further including increasing a power of the therapy; and applying the adjusted stimulation signal and increased power therapy for the second time period. The method further including determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter in excess of a threshold. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the
system that in operation causes or cause the system to perform the actions. One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.
[0014] Yet a further aspect of the disclosure is directed to a system for denervation of nerves of a blood vessel. The system includes a stimulation and therapy source and a computing device with a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of a plurality of electrodes of a therapeutic device, sense a first change in a physiological parameter as a result of the application of the first stimulation signal, determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes, generate a therapy for application the blood vessel wall, generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes, sense a second change in the physiological parameter as result of the application of the second stimulation signal, determine whether the application of the therapy has denervated the nerve proximate the electrode based on the second sensed change of the physiological parameter, and output an indicator of the success of the application of the therapy. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods and systems described herein.
[0015] Implementations of this aspect of the disclosure may include one or more of the following features. The system where the first stimulation signal and the therapy are a combined signal that is generated for an initial period of time. The determination of the first sensed change occurs after the initial period of time. Second stimulation signal and the therapy are a combined signal that is generated for a second period of time. The instructions when executed by the processor present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the one of the plurality of electrodes, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation. The instructions when executed by the processor determine that the first sensed change in the physiological parameter and output an indicator of a lack of a nerve proximate the one of the plurality of electrodes. The instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time. The instructions when executed by the processor sense a third change in a physiological parameter as a result of the application of the
first stimulation signal with the adjusted parameters; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; and output an indicator of the presence of a nerve proximate the one of the plurality of electrodes. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions. One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.
[0016] Further disclosed herein are systems and methods of performing a therapeutic procedure employing a therapeutic device including electrodes by applying a stimulation signal from the electrodes to a blood vessel wall, observing a physiological response to the stimulation signal, applying a therapy to the blood vessel wall, applying another stimulation signal from the electrodes to the blood vessel, and observing second physiological response to the second stimulation signal, wherein, when the second physiological response is different from the first physiological response by more than a threshold, the therapy is successful.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Various aspects and embodiments of the disclosure are described hereinbelow with references to the drawings, wherein:
[0018] FIG. l is a schematic diagram of a therapy system provided in accordance with the disclosure;
[0019] FIG. 2 is a schematic view of a workstation of the therapy system of FIG. 1;
[0020] FIG. 3 is a perspective view of a therapeutic device of the therapy system of FIG.
1 advanced within a portion of the patient’s anatomy and in a deployed condition in accordance with the disclosure;
[0021] FIG. 4A is a graphical representation of changes in physiological parameters experienced by a patient as a result of a pre-therapy application of stimulation in accordance with the disclosure;
[0022] FIG. 4B is a graphical representation of changes in physiological parameters experienced by the patient as a result of post-therapy application of stimulation in accordance with the disclosure;
[0023] FIG. 5A is a graphical representation of two methods of performing a diagnostic and therapeutic procedure in accordance with the disclosure;
[0024] FIG. 5B is a graphical representation of a combined stimulation signal and therapy in accordance with the disclosure;
[0025] FIG. 6 is a schematical representation of a feedback system in accordance with the disclosure;
[0026] FIG. 7 is a representation of changes a user-interface may display as a result of performing one or more of the methods of the disclosure;
[0027] FIG. 8 is a method of applying stimulation and therapy in accordance with the disclosure;
[0028] FIG. 9 is a method of applying stimulation and therapy in accordance with the disclosure;
[0029] FIG. 10 is a method of applying stimulation and therapy in accordance with the disclosure;
[0030] FIG. 11 is a representation of a portion of a therapeutic device in accordance with aspects of the disclosure;
[0031] FIG. 12 is a method of determining proximity of nerves to electrodes of the therapeutic device of FIG. 11 and which electrodes should be employed to apply therapy; and [0032] FIG. 13 is a further method of determining proximity of nerves to electrodes of the therapeutic device of FIG. 11 and which electrodes should be employed to apply therapy.
DETAILED DESCRIPTION
[0033] This disclosure is directed to therapeutic systems and methods for denervation or neuromodulation of nerves such as the sympathetic, or parasympathetic, nerves, and in particular, unmyelinated nerve fibers in and around blood vessels and other luminal tissues. In particular, this disclosure is directed to systems and methods that provide pre-procedure guidance as to proper placement of a therapy catheter and intraprocedural guidance on the effects of the therapy and post procedural analysis on overall efficacy of the therapy.
[0034] For ease of description, much of the following description focuses on implementations of electrical stimulation and RF denervation. Those having skill in the art will recognize that the methods and systems described herein may employ any of the therapy and/or neurostimulation modalities described herein. Similarly, the following description focuses on navigation to and application of neurostimulation and/or therapy to the renal artery to denervate sympathetic or, in certain embodiments, parasympathetic, nerves in, around, and proximate the renal arteries. However, the present disclosure is not so limited and can be employed for denervating nerves accessible via any blood vessel described herein (e.g., hepatic, mesenteric, splanchnic, etc., and combinations of each) of other luminal tissue (e.g., a bile duct).
[0035] Turning now to the drawings, FIG. 1 illustrates a guidance and therapy system provided in accordance with the present disclosure and generally identified by reference numeral 10. As will be described in further detail hereinbelow, the guidance and therapy system 10 enables navigation of a therapeutic device 50 to a desired location within the patient’s anatomy (e.g., the patient’s renal artery), delivery of neurostimulation to tissue within the renal artery, observing a physiological response to the application of neurostimulation to the tissue, if necessary adjustment of a position of the therapeutic device within the renal artery based upon the physiological response, reapplication of the neurostimulation to the tissue at the adjusted position, application of denervation therapy to the tissue within the renal artery to denervate sympathetic nerves within the tissue, and delivery of neurostimulation to the denervated tissue observe the physiological response to the neurostimulation and assess the efficacy of the denervation therapy.
[0036] The guidance and therapy system 10 includes a workstation 20, a therapeutic device 50 operably coupled to the workstation 20, and an imaging device 70, which may be operably coupled to the workstation 20. The patient “P” is shown lying on an operating table 12 with the therapeutic device 50 inserted through a portion of the patient’s femoral artery, although it is contemplated that the therapeutic device 50 may be inserted into any suitable portion of the patient’ s vascular network that is in fluid communication with a desired blood vessel for therapy. Although generally described as having one therapeutic device 50, it is envisioned that the therapy system 10 may employ any suitable number of therapeutic devices 50. The therapeutic devices 50 may employ the same or different therapy modalities may and be operably coupled to the workstation 20. Further, the therapeutic device 50 may employ a guidewire or a guide catheter 58 (FIG. 3) without departing from the scope of the disclosure.
[0037] Continuing with FIG. 1 and with additional reference to FIG. 2, the workstation 20 includes a computer 22, a therapy source 24 (e.g., an RF generator, a microwave generator, an ultrasound generator, a cryogenic medium source, a chemical source, etc.) operably coupled to the computer 22, and a stimulation source 24a operably coupled to the computer 22. Although generally described as being separate from the therapy source 24, it is envisioned that the stimulation source 24a may be integrated within the therapy source 24, and the therapy source 24 may generate both therapy and stimulation modalities.
[0038] The computer is coupled to a display 26 that is configured to display one or more user interfaces 28. The computer 22 may be a desktop computer or a tower configuration with display 26 or may include a laptop computer or other computing device. The computer 22 includes a processor 30 which executes software stored in a memory 32. The memory 32 may
store one or more applications 34 and/or algorithms 44 to be executed by the processor 30. A network interface 36 enables the workstation 20 to communicate with a variety of other devices and systems via the internet. The network interface 36 may connect the workstation 20 to the Internet via a wired or wireless connection. Additionally, or alternatively, the communication may be via an ad hoc Bluetooth® or wireless network enabling communication with a wide- area network (WAN) and/or a local area network (LAN). The network interface 36 may connect to the Internet via one or more gateways, routers, and network address translation (NAT) devices. The network interface 36 may communicate with a cloud storage system 38, in which further data, image data, and/or videos may be stored. The cloud storage system 38 may be remote from or on the premises of the hospital such as in a control or hospital information technology room. It is envisioned that the cloud storage system 38 could also serve as a host for more robust analysis of acquired images (e.g., fluoroscopic, computed tomography (CT), magnetic resonance imaging (MRI), cone-beam computed tomography (CBCT), etc.), data, etc. (e.g., additional or reinforcement data for analysis and/or comparison). An input module 40 receives inputs from an input device such as a keyboard, a mouse, voice commands, an energy source controller (e.g., a foot pedal or handheld remote-control device that enables the clinician to initiate, terminate, and optionally, adjust various operational characteristics of the therapy source 24 and/or stimulation source 24a, including, but not limited to, power delivery), amongst others. An output module 42 connects the processor 30 and the memory 32 to a variety of output devices such as the display 26. In embodiments, the display 26 may be a touchscreen display.
[0039] The therapy source 24 generates and outputs one or more of RF energy (monopolar or bipolar), microwave energy, ultrasound energy, cryogenic medium, or chemical ablation medium via an automated control algorithm 44 stored on the memory 32 and/or under the control of a clinician. As can be appreciated, the therapy generated or output by the therapy source 24 changes a temperature of the tissue (e.g., increases or decreased the temperature) to achieve the desired denervation of the nerves. The therapy source 24 may be configured to produce a selected modality and magnitude of energy and/or therapy for delivery to the treatment site via the therapeutic device 50, as will be described in further detail hereinbelow. The therapy source 24 may monitor voltage and current applied to target tissue via the therapeutic device 50 and monitors the temperature of the target tissue or tissue proximate the target tissue, and/or a portion of the therapeutic device 50. The therapeutic device 50, or therapy source 24 may also measure and monitor the impedance of the tissue through which therapeutic or guidance energy is transmitted to provide in indication of the status of the tissue.
[0040] The stimulation source 24a generates a stimulation signal, for example a biphasic waveform at an energy level that is less the therapeutic (i.e., denervation energy) generated by the therapy source 24 such that the stimulation generated by the stimulation source 24a does not denervate the target tissue. Rather, the stimulation source 24a generates a stimulation signal capable of effectuating a response from the nerves indicative of tissue that would be a candidate for denervation. Responses may include an increase in blood pressure, an increase in vessel stiffness, changes in pulse wave velocity, augmentation pressure, heart rate variability, etc., and combinations of these. In one example, the stimulation source 24a generates a biphasic waveform where a leading phase of each successive pulse of the biphasic waveform is switched or otherwise inverted. In this manner, a biphasic waveform having an initial pulse with an anodal leading phase and a cathodal trailing phase is followed by a second pulse with a cathodal leading phase and an anodal trailing phase which will be followed by a third pulse returning to an anodal leading phase and a cathodal trailing phase, and so on. Alternatively, a biphasic waveform having an initial pulse with a cathodal leading phase and an anodal trailing phase may be followed by a second pulse with an anodal leading phase and a cathodal trailing phase which will be followed by a third pulse returning to a cathodal leading phase and an anodal trailing phase. As can be appreciated, the leading phase of each pulse of the biphasic waveform may be alternated for the duration of the application of neurostimulation to the target tissue.
[0041] As noted above, the amplitude, frequency, pulse width, and/or duration of the stimulation can be selected and/or modified to ensure neurostimulation of the sympathetic nerves of the luminal tissue without damaging the luminal tissue or the nerves within or surrounding the luminal tissue or causing excess vasoconstriction about the therapeutic device (e.g., inhibiting the movement of the therapeutic device within the luminal tissue). A pulse duration (pulse width) may be modified to ensure that anodic stimulation of the tissue is maintained as at certain pulse durations regions of anodic stimulation may dissipate or otherwise disappear resulting in reduced stimulation effect. In one non-limiting embodiment, the stimulation source 24a generates biphasic waveforms having a frequency of between approximately 10 - 30Hz, a voltage of between approximately 5 - 30 V, a current of between approximately 2 - 500 mA, and a pulse width of between approximately 2 - 10 ms. It is envisioned that in embodiments where unmyelinated nerve fibers are targeted, the pulse width of the biphasic waveform may be between approximately 2-120 ms. In a further example, the stimulation parameters are a constant current of 20mA for a blood vessel branches and 30 mA for main blood vessels, a pulse width of 5 mS, a frequency of approximately 20 Hz and a duration of between 10 and 60 seconds.
[0042] FIG. 3 depicts one embodiment of a therapeutic device 50 in accordance with the disclosure. The therapeutic device 50 includes an elongated shaft 52 having a handle (not shown) disposed on a proximal end portion of the elongated shaft 52. The therapeutic device 50 includes an energy delivery assembly 54 at which one or more therapy electrodes 56 are located. The elongated shaft 52 of the therapeutic device 50 is configured to be advanced within a portion of the patient’s vasculature, such as a femoral artery or other suitable portion of patient’s vascular network that is in fluid communication with the patient’s renal artery. In embodiments, the energy delivery assembly 54 is configured to be transformed from an initial, undeployed configuration having a generally linear profile, to a second, deployed or expanded configuration, where the energy delivery assembly 54 forms a generally spiral and/or helical configuration for delivering energy to a site for either or both application of a stimulation signal or therapeutic energy at the treatment site. Those of skill in the art will recognize in the context of the instant application that application of therapeutic energy should be construed to include application of cryogenic cooling to the treatment site to achieve a thermally induced neuromodulation. In this manner, when in the second, expanded configuration, the energy delivery assembly 54, and in particular, the individual electrodes 56, is pressed against or otherwise contacts the walls of the patient’s vasculature tissue. Although generally described as transitioning to a spiral and/or helical configuration, it is envisioned that the energy delivery assembly 54 may be deployed in other configurations without departing from the scope of the present disclosure. Further, the therapeutic device 50 may be configurable, for example, using one or more pull wires (not shown) to adjust the configuration to promote contact between the electrodes 56 and the wall of the renal artery. As such, the therapeutic device 50 may be capable of being placed in one, two, three, four, or more different configurations depending upon the design needs of the therapeutic device 50 or the location at which therapy is to be applied.
[0043] As depicted in FIG. 3, the elongated shaft 52 may be configured to be received within a portion of a guide catheter or guide sheath (such as a 6F guide catheter) 58 that is utilized to navigate the therapeutic device 50 to a desired location at which point if a guide catheter 58 is retracted to uncover the therapeutic device 50. As noted hereinabove, retraction of the guide catheter 58 may enable the energy delivery assembly 54 to transition from the first, undeployed configuration, to the second, deployed or expanded configuration.
[0044] The elongated shaft 52 of the therapeutic device 50 may further include an aperture (not shown) at a distal end thereof and configured to slidably receive a guidewire over which the therapeutic device 50, either alone or in combination with the guide catheter 58, are advanced. In this manner, the guidewire is utilized to guide the therapeutic device 50 to the
target tissue using over-the-wire (OTW) or rapid exchange (RX) techniques, at which point the guide wire may be partially or fully removed from the therapeutic device 50, enabling the therapeutic device 50 to transition from the first, undeployed configuration, to the second, deployed or expanded configuration (FIG. 3). As noted elsewhere herein, the therapeutic device 50 may be transition from the first, undeployed configuration to the second, deployed configuration automatically (e.g., via a shape memory alloy, etc.) or manually (e.g., via pull wires, guide wire manipulation, etc. that is controlled by the clinician).
[0045] Continuing with FIG. 3, in embodiments where the therapeutic device 50 is an RF ablation catheter, the energy delivery assembly 54 includes one or more electrodes 56 disposed on an outer surface thereof that are configured to contact a portion of the patient’s vascular tissue when the therapeutic device 50 is placed in the second, expanded configuration. As shown herein, the therapeutic device 50 includes four electrodes 56. However, the present disclosure is not so limited and the therapeutic device 50 may have more or fewer electrodes 56 without departing from the scope of the present disclosure. One of skill in the art will recognize that the electrodes 56 may be replaced with ultrasound transducers, microwave antennae, ports for delivery of cryoablation medium or chemical medium and other implements and/or ablation and denervation modalities without departing from the scope of the present disclosure.
[0046] As illustrated in the figures, the electrodes 56 are disposed in spaced relation to one another along a length of the therapeutic device 50 forming the energy delivery assembly 54. As will be appreciated, these electrodes 56 are in communication with both the therapy source 24 and the stimulation source 24a. In one example the therapy source 24 produces, monopolar RF energy to denervate the sympathetic nerves of the relevant blood vessel. The electrodes 56 may delivery RF energy independently of one another (e.g., monopolar), simultaneously, selectively, sequentially, and/or between any desired combination of the electrodes 56 (e.g., bipolar). It is envisioned in one embodiment that the therapy source 24 is also the stimulation source 24a and includes a diagnostic mode, where the therapy source 24 generates a stimulation signal having, for example, a biphasic waveform, and a denervation mode, where the therapy source 24 generates RF energy to denervate the nerves of the relevant blood vessel. It is contemplated that the therapy source 24 may be manually switched from a stimulation mode to a denervation mode and vice versa or may be automatically switched by an algorithm 44 stored on the memory 32 of the computing device. Alternatively, the electrodes 56 are in communication with a stand-alone stimulation source 24a to deliver a stimulation signal to the blood vessel in question. The stimulation signal (e.g., the biphasic waveform), is generated by
the stimulation source 24a and communicated to the electrodes 56 causing stimulation of the sympathetic nerves as described herein.
[0047] In at least one embodiment, during the anodal phase of the biphasic pulse, the stimulation signal is applied to the target tissue via a first of the electrodes 56 and received by a second of the electrodes 56 in a bipolar manner and during the cathodal phase of the biphasic pulse the neurostimulation is applied to the target tissue via the second of the electrodes 56 and received by the first of the electrodes 56 in a bipolar manner. It is envisioned that during the anodal phase or the cathodal phase of the bipolar pulse, the stimulation signal is applied by two or more of the electrodes 56 or received by two or more of the electrodes 56 in any suitable configuration, such as a proximal most electrode 56 and a distal most electrode 56, a proximal most electrode 56 and a next proximal most electrode 56 a proximal most electrode 56 and an electrode 56 disposed just proximal of the distal most electrode 56, etc.
[0048] Further, one or more algorithms 44 may be employed for the stimulation of the multiple electrodes 56. Where for example, if there are four electrodes, there may be a firing order for the electrodes 56 to apply the neurostimulation. In such an example the electrodes 56 may connect in a bipolar fashion as follows. In a first anodal phase between a first electrode and a fourth, first cathodal phase between the fourth electrode and the first electrode. This may be followed by a second cathodal phase between the fourth electrode and the first electrode and a second anodal phase between the first electrode and the fourth electrode. This may be followed in a similar manner by different pairs of electrodes 56, for example between the first and third electrodes 56, the first and second electrodes 56. A similar pattern may be followed between second and fourth electrodes and the second and third electrodes. Still further, an anodal and cathodal phase need not be between the same pairs of electrodes. For example, a first anodal phase may be between a first and a fourth electrode and be followed by a cathodal phase between the fourth and the second electrode. Alternatively, the first anodal phase may be between a first and a fourth electrode and followed by a cathodal phase between the fourth and first electrodes 56, as in the first example, however the second anodal phase may be between the second and the fourth electrodes followed by a second cathodal phase between the fourth and second electrodes. The firing order of the electrodes 56 is limited only by the number of electrodes 56 and the biphasic waveform.
[0049] During the application of the stimulation signal to the target tissue, alternating the leading phase of each successive pulse of the biphasic waveform stimulates a greater number of nerves within the target tissue as compared to traditional bipolar or monopolar stimulation. By stimulating a greater number of nerves within the target tissue, an optimal placement of the
electrodes 56 within the target tissue for denervation can be more readily identified to ensure effective renal denervation and an optimal outcome. The location and/or orientation of the electrodes 56 relative to the tissue wall can be altered between the application of stimulation signals to map or otherwise identify optimal nerve candidates for denervation.
[0050] FIGS. 4A and 4B depict one aspect of the disclosure. As depicted in FIG. 4A, a stimulation signal 102 is applied via the electrodes 56 to the target tissue. The duration of the stimulation signal is graphically depicted by trace 104. As a result of the stimulation signal 102, during its application two physiological effects are observed. The first effect is an increase in heart rate as depicted by trace 106. As can be seen, even before cessation of the stimulation signal 102, the heart rate begins to return to normal. Conversely, the mean arterial pressure, as depicted in trace 108, both during and following the application of the stimulation signal 102 elevates and remains elevated over the pre-stimulation mean arterial pressure. This change in either or both heart rate and mean arterial blood pressure is indicative of stimulation of the afferent nerves of the blood vessel in which the therapeutic device 50 is positioned (e.g., the renal and/or hepatic arteries). In instances where the change in heart rate or mean arterial pressure is in excess of a predetermined threshold the clinician may determine that the location of the energy delivery assembly 54 is appropriate for application for therapy to achieve denervation and therapeutic energy may be applied to the target tissue at that location within the blood vessel. In one aspect of the disclosure, as depicted in FIG. 4B following application of the therapeutic energy, the stimulation signal 102 may again be applied as shown in trace 104. As shown, despite the application of the stimulation signal 102, very little response is observed in either heat rate 106 or in mean arterial pressure 108 in FIG. 4B. The difference between the observed response to the stimulation signal 102 applied before therapy (FIG. 4A) and the observed response to the stimulation signal 102 applied after therapy (FIG. 4B) is indicative of a successful ablation or denervation of the afferent nerves (e.g., sympathetic, or parasympathetic nerves) proximate the placement of the therapeutic device 50 within the blood vessel. Thus, employing the systems and methods of this disclosure a clinician can navigate a therapeutic device 50 to a location within the patient P, apply a stimulation signal 102 to confirm that the therapeutic device 50 is placed proximate afferent nerves, apply a therapy to the afferent nerves, and apply stimulation a second time to confirm the successful denervation of the afferent nerves or to determine that further application of therapy is needed. As will be appreciated, this cycle may be repeated as needed to achieve a successful ablation.
[0051] FIG. 5A schematically depicts the application of stimulation and therapy in accordance with two aspects of the disclosure. An initial stimulation signal 202 may be applied
to target tissue for a period T and a change in a physiological parameter (here blood pressure) is observed, as shown in the graph 204. If no response or insufficient response to stimulation is observed the therapeutic device 50 may be moved within the blood vessel, as described elsewhere herein. Once sufficient change in the physiological parameter is observed, therapy may be applied for a predetermined period of time. In FIG. 5 A the therapy may be for example a monopolar RF ablation energy 206. Following the application of the therapy 206, there are at least two alternatives, in a first alternative, similar to the methods described above with respect to FIGS. 4A and 4B, a second stimulation signal 208 may be applied and if it is determined that the change in physiological parameter (e.g., mean arterial blood pressure) is below a threshold, the procedure may end. The change in physiological parameter as a result of the stimulation 208 in excess of the threshold is indicative of an unsuccessful or incomplete denervation and further therapy 210 is applied. This process of stimulation 208 and therapy 210 may be repeated until, the change in a physiological parameter (e.g., mean arterial blood pressure) caused by the stimulation 208 falls below a threshold as depicted in graph 212. Alternatively, the change is physiological parameter can is shown in graph 204 as a result of stimulation and may be compared to a threshold and if the difference is greater than a threshold the denervation can be determined to be successful, and therapy ended. As a further component of this aspect of the disclosure, the magnitude of the therapy power (e.g., alteration of one or more of current, voltage, and duration) may be changed at each successive application of therapy 210. Further, a ramp rate may be employed such that at specific intervals of application of therapy 210 a greater therapeutic power that the preceding interval may be employed until a desired outcome is achieved (e.g., a physiological response to stimulus below a desired threshold).
[0052] Alternatively, following the initial therapy a combination stimulation signal and therapy 214 may be applied by the therapeutic device 50. This combination may be applied for predetermined period of time and/or until a change in physiological parameter (e.g., decrease in mean arterial pressure) during the stimulation signal portion of the combination is observed. As will be appreciated, and consistent with other aspects described herein, if the physiological parameter (e.g., mean arterial pressure) increases, the therapy power (e.g., alteration of one or more of current, voltage, and duration) may be changed. The observed decrease in the physiological parameter, may be recorded as shown in graph 216 and a termination point for the application of the combination signals 212 may be for example an absolute change (e.g., pressure delta from that observed in 204 and in 214) or alternatively, the observed rate of change between successive stimulation signal portions of the combination 214. Though described
generally with respect to mean arterial blood pressure, other physiological parameter may also be observed and employed including pulse wave velocity, arterial stiffness, heart rate, and any combination of these parameters or other parameters without departing from the scope of the disclosure.
[0053] FIG. 5B depicts a graphical representation of the combined stimulation signal and ablation 214. As can be seen, there is a train of alternative times of application of stimulation and ablation. As will be described herein below, the combined signal can be applied for a period T1 after which assessments can be made on the efficacy of the ablation based on changes in physiological parameters (e.g., systolic blood pressure, MAP, and others).
[0054] Still further, the electrodes 56 may be selectively employed for the application of stimulation while other electrodes 56 are employed for the application of therapy. In this aspect, the stimulation 208 may be applied via a first electrode 56 and therapy 210 may be applied by a second electrode 56. Or both the stimulation 208 and therapy 210 may be delivered by the same selected electrode 56. Alternatively, the combined signal 214 may be delivered selectively from a first electrode 56 for a first period of time, and then from a second electrode for a second period of time. Other permutations of the selective application of stimulation and therapy to combinations of electrodes 56 without departing from the scope of the disclosure.
[0055] FIG. 6 depicts a schematic representation of a feedback system in accordance with this disclosure. As described elsewhere herein, a therapy source 24 and a stimulation source 24a apply energy and signals to electrodes 56 of the therapeutic device 50, as described above. As therapy is applied to the electrodes 56, and there with the target tissue in an effort to denervate the afferent nerves located therein the impedance of the tissue through which the energy is passed can be measured by the therapy source 24. As will be understood by those of skill in the art as energy (e.g., RF or microwave energy) is applied to the tissue, here the blood vessel wall, the impedance of the tissue will begin to increase as it is heated. However, it is desirable to prevent the tissue from exceeding a predetermined temperature at which permanent damage to the tissue of the blood vessel wall occurs. Fortunately, nervous tissue tends to be more susceptible to heat and denatures or allows for denervation at temperatures below that at which the surrounding tissue experiences permanent and irreversible damage. Thus, by motoring the impedance of the target tissue, the therapy source 24 can be controlled to prevent undesirable heating of the blood vessel. In a similar fashion, each electrode 56 may incorporate a thermistor or other temperature sensor (not shown) to monitor the temperature of the electrodes 56. As will be appreciated, the electrodes 56 directly contact the inner wall of a blood vessel or other luminal tissues, thus as energy is passed through the electrodes 56, the
electrodes themselves begin to heat. The thermistor, thermocouple or other temperature senor in communication with the electrode 56, generates a signal that is received by the therapy source 24. That signal is representative of the temperature of the electrode, if that temperature of any of the electrodes 56 exceeds a predetermined threshold, below that at which damage might occur to the blood vessel wall, the therapy source 24 stops outputting therapeutic energy to the electrode 56. As will be appreciated, the movement of blood through the blood vessel will quickly cool the electrode 56. Once the temperature of the electrodes 56 return below a predetermined threshold, the therapy source 24 may again begin applying therapy using one or more of the methods descried herein to achieve the desired denervation or neuromodulation of the nerves surrounding the blood vessel.
[0056] In addition to the above-described forms of feedback which are primarily, though not exclusively, employed to protect the patient and the tissues of the patient during the procedure, another form of feedback may be provided via a blood pressure module. A blood pressure module 62 employing a blood pressure sensor 60 located on the therapeutic device 50, catheter 58 or a separate component navigated proximate the target tissue. In either event, the blood pressure sensor 60 monitors the blood pressure in the blood vessel to which therapy is applied. That measured blood pressure may be used directly as the feedback parameter or may be converted to one or more different indicia including but not limited to pulse wave velocity, augmentation index (AIX) a measure of arterial stiffness, tricuspid regurgitation velocity (TR). As described above in connection with FIGS. 4A-5B, analysis of the blood pressure as a result of the application of stimulation from the stimulation source can be employed to determine whether greater therapy power is required, whether more therapy is required, whether therapy duration should be increased, and when therapy can be ceased.
[0057] FIG. 7 depicts an example of the UI 28 as it might appear on a display 26 in accordance with the disclosure. As explained in greater below, each electrode may be labeled E1-E4. In accordance with the disclosure in a pre-procedural mapping phase, stimulation signals 202 are passed from each of the electrodes 56 and one or more physiological parameters may be monitored to see if the stimulation signals have elicited a nervous response. As seen in FIG. 7 electrodes E2-E4 are associated with a nervous response and depict a green light, as will be described in greater detail below. Stimulation of these electrodes may be associated with a change in measured systolic blood pressure in the blood vessel of the patient in which the therapeutic device 50 has been placed. Electrode El, however, has a red light associated with it, indicating via the UI 28 that the stimulation signal from that electrode resulted in no change in physiological parameter (e.g., systolic blood pressure).
[0058] As shown graphically in FIG. 7, the stimulation signals 202 are followed by a therapy 206, which may be passed from one or more of the electrodes E1-E4 to denervate the nerves enervating a blood vessel in which the therapeutic device 50 is placed. Following the application of the therapy, in a post-procedural mapping phase, stimulation signals may again be passed through the electrodes, particularly E2-E4 which showed the physiological parameter change in the pre-procedural mapping phase. The indicators associated with electrodes E2 and E3 show a green light or other positive indicator alerting the user that the application of the therapy 206 has effectively changed the physiological response to the stimulation 202 associated with the post-procedural mapping application of stimulation signals 202. In one example, the pre-procedural change to systolic blood pressure from the stimulation 202 may have been an initial value, and the post-procedural mapping may be a much lower level (e.g., below some threshold), indicating that the application of the therapy was successful in ablating or denervating the nerves proximate electrodes El and E2. Electrode E4 has a yellow light or other indicator which may be interpreted that though some reduction in the physiological parameter has been achieved, it is not yet sufficient to be considered a successful ablation/denervation of the nerves proximate electrode E4. The indicator allows the user to understand the effectiveness of the therapy before deciding to apply more therapy or to move the therapeutic device. These and other aspects of the disclosure are described in greater detail below.
[0059] FIG. 8 depicts a flow chart showing a method 800 in accordance with the disclosure. At step 802, the therapeutic device 50 is placed at a desired location within the patient (e.g., in a renal or hepatic artery). As part of the placement, the therapeutic device 50 may be advanced from the catheter 58 and the therapeutic device 50 allowed to expand such that the electrodes 56 are in contact with an inner wall of the artery. At step 804 a pre-ablation stimulation is applied, for example a biphasic stimulation signal may be transmitted between any two of the electrodes 56. The stimulation signal may alternate the leading phase of the stimulation signal. Further, the stimulation signal may alternate between pairs of the electrodes 56 to stimulate the afferent nerves of the blood vessel. At step 806 a determination is made whether a change in physiological parameter, for example the systolic blood pressure observed in the blood vessel, is greater than a predetermined threshold. In one implementation this determination employs pressure sensor 60. If yes, the stimulation parameters are maintained at the nominal max current and duration settings at step 808 and the ablation is commenced at step 810.
[0060] If, however, no change in blood pressure, or an insufficient change in blood pressure is observed at step 806, there are multiple options. In a first option, the current and duration
parameters for the stimulation may be adjusted (e.g., increased) at step 812 and the method may proceed to the commencement of the ablation at step 810, an indicator may be generated alerting the user of the change, the indicator may be audible, tactile, visual (e.g., on the user interface) or combinations of these. This may be an option where a change in pressure is observed, but it is less than the threshold, indicating that the nerves being stimulated are further from the electrodes or surrounded by tissue that is mitigating the stimulation effect. Alternatively, rather than proceed to the commencement of the ablation at step 810, the method may return to step 804 to determine, for application of a pre-ablation stimulation, after which the change in systolic blood pressure is again compared to a threshold at step 806. Still further, the method may return to step 802 where the position of the therapeutic device 50 is adjusted before applying pre ablation stimulation at step 804. These processes can be repeated as needed until the clinician is satisfied that the position and energy levels being applied at that position in the blood vessel of the patient achieves sufficient change in physiological parameter being monitored.
[0061] Following an ablation at step 810, a post ablation stimulation may be applied at step 814 and the physiological parameter is again measured at step 816. If the change in the physiological parameter is greater than a threshold, the method moves to step 818, where the power or duration of the ablation energy are adjusted, and the method returns to step 810, an indicator may be generated alerting the user of the change, the indicator may be audible, tactile, visual (e.g., on the user interface) or combinations of these. This may be repeated as necessary until the measured change in the physiological parameter is not greater than some threshold (i.e., less than the threshold). This indicates that the ablation was successful in denervating the nerves in the blood vessel at that location. At this point, the method may optionally end or return to step 802 for re-positioning of the therapeutic device 50 for denervation at another location following the same method 800. An indicator of a successful denervation may be generated to alert the user to the success.
[0062] FIG. 9 depicts an alternative method 900 employing the combined stimulation and ablation techniques, as noted above with respect to FIG. 5. Method 900 is focused on providing guidance regarding placement and efficacy of the application of therapy at the placed location of the therapeutic device 50. As with method 800, method 900 starts with positioning of the therapeutic device 50 at a desired location within the patient (e.g., in a renal or hepatic artery). As part of the placement, the therapeutic device 50 may be advanced from the catheter 58 and the therapeutic device 50 allowed to expand such that the electrodes 56 are in contact with an inner wall of the artery. At step 904 a combined stimulation signal and therapy (e.g., signal 214 in FIG. 5) may be applied to the blood vessel wall. During the application of the combined
stimulation signal and therapy, at regular intervals the stimulation signal is switched to a therapy and then back to a stimulation signal. This repeated switching allows for the generation of a series of datapoints related to the physiological parameter being observed (e.g., systolic blood pressure via sensors 60 on the therapeutic device 50.
[0063] At step 906, following application of combined stimulation signal and therapy 214 for a duration Tl, a determination is made whether change in a physiological parameter (e.g., systolic blood pressure) is greater than a pre-determined threshold. If the determination is yes at step 908 the application of the combined stimulation signal and therapy 214 is continued until expiration of a second duration T2. At step 910 a determination is made whether the measured physiological parameter (e.g., systolic blood pressure) as measured at time T2 is different from when it was measured at time Tl. For example, where systolic blood pressure is measured, step 910 would assess whether the systolic blood pressure is less at time T2 than it was at time Tl. Other parameters may however be employed where the determination looks to see if the measurement of the physiological parameter is greater at time T2 than at Tl, without departing from the scope of the disclosure. If the answer at step 910 is yes, a green light or other indicator may be displayed on a UI 28 and displayed to the user signaling a successful ablation has been achieved. The process may then optionally end or return to step 902 where the therapeutic device 50 may be repositioned to ablate another location within in the same blood vessel or another blood vessel.
[0064] Returning to step 906, if the change in physiological parameter is less than a threshold at time Tl, then the therapy is stopped at step 916 and the stimulation signal parameters are adjusted. An indicator of the lack of stimulation may be generated alerting the user of the change, the indicator may be audible, tactile, visual (e.g., on the user interface) or combinations of these at step 917, the adjusted stimulation signal is applied for a duration Tl. At step 918 a determination is made whether the change in physiological parameter is greater than the threshold, the threshold may be the same or different than the threshold used in step 906. If the change in the physiological parameter is less than the threshold then method 900 proceeds to step 920 where an indicator is displayed in the UI 28, for example a red light, indicating that no nerves have been located at that location. The method then returns to step 902 where the therapeutic device 50 is moved to another location and the process is started again.
[0065] However, if at step 918 there was a change in physiological parameter greater than the threshold when stimulated with the adjusted stimulation signal, is an indicator that the nerves at that location are further from the blood vessel wall (e.g., deep within the tissue) at
step 922. As such, to achieve the desired effects of the ablation on the nerve tissue, the procedure requires more additional application of energy by either increasing power, increasing ablation duration, changing frequency, or pulse duration, adding additional electrodes to the array or combinations thereof. An indicator may be generated, and for example displayed on the UI 28 regarding the required adjustment. The parameter may be adjusted at step 924 and the method returns to step 904, where the process repeats as described above.
[0066] FIG. 10 depicts a further method 1000 utilizing a combined stimulation signal and therapy. Method 1000 starts like method 800 and 900 with the positioning of the therapeutic device 50 within a blood vessel in need of therapy (e.g., ablation, denervation). At step 1004 the combined stimulation signal and therapy 214, for example as shown in FIG. 5, is applied to the blood vessel wall. At step 1006 a determination is made whether a change in a physiological parameter (e.g., systolic blood pressure, MAP, etc.) in excess of a threshold after a duration of time T1 is observed. If the determination at step 1006 is that the change in physiological parameter is in excess of the threshold, the method continues to step 1008 where the application of the combined stimulation signal and therapy is continued until the expiration of time T2. At the conclusion of time T2 a determination is made at step 1010 whether the measured physiological parameter (e.g., systolic blood pressure) at time T2 is different from when it was measured at time Tl. For example, where systolic blood pressure is measured, step 910 would assess whether the systolic blood pressure is less at time T2 than it was at time Tl. Other parameters may however be employed where the determination looks to see if the measurement of the physiological parameter is greater at time T2 than at Tl, without departing from the scope of the disclosure. If the answer at step 1010 is yes, the method proceeds to step 1012 and a signal, such as a green light may be displayed on the UI 28 signaling a successful ablation at that location. Optionally the method 1000 may then end or may return to step 1002 where the therapeutic device 50 may be repositioned for a further ablation/denervation procedure.
[0067] If, however, at step 1010 the physiological parameter is not different than as measured at time Tl or has not moved in the correct direction (e.g., a reduction in systolic blood pressure) the method proceeds to step 1014 where a determination is made whether a power limit has been reached. If the power limit has been reached, then the method may proceed to step 1018 where an indicator such as a red light is displayed on UI 28 signaling to the user that insufficient ablation has been received at that location within the blood vessel. The method may then optionally end or return to step 1002 for repositioning of the therapeutic device 50 and further therapy.
[0068] If at step 1014 the power limit has not been reached, the method proceeds to step 1016 where the power to be applied during the therapy portion of the combined stimulation signal and therapy is increased. The method then returns to step 1008 were the increased power combined stimulation signal and therapy is applied the blood vessel all until the expiration of time T2. The method continues as described herein above until either a successful ablation is achieved, or an unsuccessful ablation is achieved, and the power limit has been reached.
[0069] Returning back to step 1006, if following the application of the combined stimulation signal and therapy for time T1 has not resulted in a change in a physiological parameter (e.g., a change in systolic blood pressure) greater than a threshold the method proceeds to step 1020 where the application combined stimulation signal and therapy is stopped. At step 1022 the stimulation signal is adjusted (e.g., frequency, current, voltage, etc.) and is again applied by the therapeutic device 50 to the blood vessel wall for duration Tl. At step 1024 a determination is made whether a change in physiological parameter (e.g., a change in systolic blood pressure) is greater than a threshold. In some instances, this may be the same threshold as used at step 1006, though another threshold may be used without departing from the scope of the disclosure. If the determination of step 1024 is yes, the method proceeds to step 1016 where the power of the therapy is increased. Once increased, a combined stimulation signal and therapy having both the adjusted stimulation and the increased therapy power is applied to the blood vessel of the patient at step 1008. The method proceeds as described herein above until either a successful ablation/denervation is achieved, or the power limit is reached.
[0070] Where the answer to the inquiry at step 1024 is no, meaning that the both the original stimulation and the adjusted stimulation signal failed to cause a change in the physiological parameter greater than the threshold, the method proceeds to step 1026. In step 1026 an indicator, such as a blue indicator may be displayed on the UI 28 alerting the user that there are no detectable nerves at that location and the method returns to step 1002 for repositioning of the therapeutic device 50.
[0071] The described methods 800-1000 are exemplary and steps of the methods may be performed in different orders or eliminated without departing from the scope of the disclosure. Further, as is known to those of skill in the art other methods may be employed determine the locations of nerves for therapy, measure the physiological parameters, and apply the therapy to the nerves of the patient.
[0072] FIG. 11 depicts a schematic representation of a distal portion of a therapeutic device 50 showing the electrodes 56. These electrodes 56 are individually labeled El through E4. Further aspects of the disclosure are described herein with respect to this arrangement of the
electrodes 56. As noted above, methods 900 and 1000 describe application of a combined stimulation signal and therapy. While FIG. 5 includes one depiction of this signal, through the use of multiple electrodes 56, multiplexed signals may employ the electrodes 56 in different pairings and timings to provide more accurate determination of where nerves are located, more complete ablation or denervation of the nerves, and a more accurate determination of success of the procedures.
[0073] In accordance with one aspect of the disclosures two pairs of electrodes 56 are established. A first pair (e.g., El and E2) may be used in a first phase as the stimulation electrodes and the stimulation signal passes between the two electrodes for a set duration. During that same duration, a second par (e.g., E3 and E4) are used for application of the therapy for the set duration. In one example, the therapy is monopolar RF, wherein the energy passes from the electrodes E3 and E4 to a pad placed on the patient. The duration may be for example 10 seconds. At the end of the duration, the pairs are switched and El and E2 become the therapy electrodes and E3 and E4 become the stimulation electrodes. This switching back and forth between which pairs are applying therapy and which are applying stimulation may be continued (e.g., switching every 10 seconds) until the end of a longer duration (e.g., 50 seconds). In this manner, all of the electrodes 56 of the therapeutic device 50 are employed in both the stimulation and application of therapy to the nerves of the patient, enabling a larger area to receive therapy and, when the therapeutic device 50 is formed as depicted in FIG. 3, a substantially circumferential ablation about the diameter of the blood vessel may be formed substantially reducing the likelihood that nerves ( e.g., sympathetic nerves) remain after application of the therapy.
[0074] In the multiplexing arrangement above, the pairs of electrodes 56 remains constant and the form of the energy or signal is switched. However, in another form of multiplexing the pairs themselves may be continually changed. In this example, in a first phase El and E2 may apply stimulation and E3 and E4 may apply the therapy. In the second phase, E2 and E3 apply stimulation and El and E4 apply therapy. The third phase may see E3 and E4 apply the stimulation and El and E2 the therapy. Further in a fourth phase E2 and E4 apply the stimulation and El and E3 apply the therapy. These pairings may be made until all potential pairs of electrodes has been achieved. Each phase may last form 50 msec to 5 seconds. The pattern may then be repeated until an overall therapy duration is reached (e.g., 50 seconds). In this manner every pair of electrode applies stimulation providing greater insight the effect of that stimulation between each pair. Further a clearer picture of the effect of the therapy can be developed. Indeed, using the data generated and the methods 900 and 1000, a more granular
determination of the effect of the ablation achieved by each electrode 56 can be assessed allowing for the indicators (e.g., red, green, blue lights) on the UI to be displayed not just for the overall procedure but for individual electrodes 56, providing greater insight into the efficacy of the procedure.
[0075] Another example of a stimulation and therapy pattern includes the reversal of the polarity of electrodes 56 for the stimulation. Again, pairs of electrodes may be employed (e.g., E 1 and E2 may be a stimulation pair). In accordance with this aspect, the combined stimulation signal and therapy (similar to 214 of FIG. 5) may be employed. During a first stimulation phase stimulation signals are passed from El to E2. Then following stimulation all four electrodes 56 are used for application of therapy for a duration (e.g., 10 seconds). A second stimulation phase may again pass stimulation signals from El to E2, and again be followed by application of therapy from all electrodes 56. In a subsequent phase the polarity of the stimulation signals may be reversed passing from E2 to El. Therapy may be applied following this reversed stimulation signal and then be followed by another cycle of stimulation and ablation. The changing of the polarity of the stimulation signal has been observed to increase the likelihood of response to stimulation and therewith the determination of success or failure of the procedure. [0076] The switching of polarities of the stimulation is not limited to just electrodes El and E2 but can be between any two pairs of electrodes. Thus, the stimulation pairs may be switched between El and E2, E3 and E4, E2 and E3, E2 and E4, El and E3, El and E4, and each pairing may include the application of a first polarity stimulation and a reverse polarity stimulation. Between each stimulation all of the electrodes may be used for application of the therapy. This process may repeat until a set duration of stimulation and therapy has been reached as described in connection with methods 800, 900, 1000.
[0077] In a further implementation of the devices and systems of the disclosure, and particularly with reference to method 800, the stimulation signal 208 (FIG. 5) when applied in a non-combined stimulation signal and therapy may utilize a reversing electrode pairs polarity scheme. In one example, the stimulation signal may be applied from electrode E1-E4 for a first duration, and then applied in a reverse polarity fashion from E-4 to El for a second duration. As noted elsewhere reversing the polarity enhances the nervous response to the stimulation.
[0078] Still a further implementation employs combination stimulations where two pairs of electrodes are employed simultaneously. In this example, E1-E2 apply a stimulation signal during a first period. Simultaneously electrodes E3 and E4 are also used to apply stimulation during this same period. During a second period stimulation is applied between electrodes El and E4 while simultaneously being applied between electrodes E2 and E3. In a third period
stimulation may be applied between electrodes E2 and E4 while simultaneously being applied between El and E3. Each of these periods may be very short for example 1 to 25 msec, and the switching between electrode pairs may be undertaken until a duration of stimulation is reached. In some embodiments, this process may be supplemented with the application of reverse polarity stimulation as described in other aspects herein.
[0079] FIG. 12 depicts a reversing polarity stimulation method 1200. The method 1200 is an automated stimulation sequence whereby pairs of electrodes E1-E4 are utilized both in an initial polarity and a reverse polarity to determine which of the electrodes are in closer the proximity to the nerves and which electrodes should be utilized to effectively ablate/denervate nerves. Following initializing the system at step 1202, stimulation a stimulation signal is passed between electrodes El and E4 at step 1204. This represents the longest path between two electrodes. At step 1206 a determination is made whether a physiological response (e.g., change in systolic blood pressure) above a threshold value is achieved. If the answer at step 1206 is yes, the method progresses to step 1208 where stimulation is applied between electrodes El and E2. At step 1210 a determination is made whether a stimulation response is experienced above a threshold value If yes at step 1210 the method moves to step 1212 where stimulation is applied between electrodes El and E3. At step 1214 a determination is made whether a stimulation response is experienced above a threshold value. If the answer is yes, there are nerves around El for ablation/denervation and then at step 1216 that information is stored in the memory 32 for use with one or more applications 34. If at step 1214 no stimulation response is experienced the method progresses to step 1218 where stimulation is applied between electrodes E3 and El . At step 1220 a determination is made whether a pressure response above a threshold is experienced. If the answer is yes, there are nerves around E3 for ablation/denervation and then at step 1222 that information is stored in the memory 32 for use with one or more applications 34.
[0080] If at step 1210 there is not a pressure response in excess of a threshold, the method progresses to step 1224 where stimulation is applied between electrodes E2 and El. At step 1225 a determination is made whether a stimulation response above a threshold value is experienced. If the answer is yes, there are nerves around E2 for ablation/denervation and then at step 1226 that information is stored in the memory 32 for use with one or more applications 34.
[0081] Referring back to step 1206, if no stimulation response above a threshold is experienced from the stimulation of El and E4, the method moves to step 1228 where a reverse polarity stimulation (as compared to step 1204) from E4 to El is applied. If at step 1230 a
pressure response in excess of a threshold is detected to method proceeds to step 1232 where stimulation is applied from electrode E4 to E3. At step 1234 the determination is made whether the stimulation response is above a threshold value. If the answer is yes, there are nerves around E4 for ablation/denervation and then at step 1236 that information is stored in the memory 32 for use with one or more applications 34.
[0082] If the determination at step 1234 is no, then the method progresses to step 1238 where stimulation is applied between electrodes E3 and E4 (essentially reverse polarity from step 1232). At step 1240 an inquiry is made whether a stimulation response greater than a threshold is observed in response to step 1238. If the answer is yes, there are nerves around E3 for ablation/denervation and then at step 1242 that information is stored in the memory 32 for use with one or more applications 34.
[0083] Referring back to step 1230 if there is no stimulation response detected the method progresses to step 1244 where stimulation is applied between electrodes E2 and E4. At step 1246 an inquiry is made whether the stimulation response is above a threshold value. If the answer is yes, there are nerves around E2 for ablation/denervation and then at step 1248 that information is stored in the memory 32 for use with one or more applications 34. If the answer to the inquiry at step 1246 is no, the method proceeds to step 1250 where stimulation is applied between electrodes E3 and E2. At step 1252 an inquiry is made whether the stimulation response is above a threshold value. If the answer is yes, there are nerves around E3 for ablation/denervation and then at step 1254 that information is stored in the memory 32 for use with one or more applications 34.
[0084] As noted above, the method 1200 may be part of an application 34 stored in the memory 32. The results of the method 1200 may also be stored in the memory and displayed on the UI 28 or used by an application performing any of methods 800, 900, or 1000 to limit which of the electrodes are employed to ablate/denervate the nerves of the patient at any given location where the therapeutic device 50 is placed.
[0085] Table 1 depicts a table illustrating the methodology of determining which electrodes 56 are proximate nerves and thus should be employed in a denervation procedure.
Table 1
[0086] As depicted in FIG. 13, the method 1300 is initiated at step 1302, following navigation of the therapeutic device 50 to an artery for denervation by applying stimulation to electrodes El and E2. If at step 1304 no response is observed, then there are no nerves located proximate either electrodes El or electrodes E2, and the method will move to step 1322 where an indication that no nerves are proximate El or E2 is stored in memory and the method moves to step 1323, described below. However, if a response is observed then as noted at step 1306 the method Either El or E2 or both are proximate a nerve. To get further information, at step 1308 stimulation is applied to electrode El . If a response is observed at step 1310, that response indicates that electrode El is proximate a nerve and should be used for a denervation procedure. El will then be stored in the memory as an electrode to be used for the denervation procedure at step 1312. If no response is detected, then El will be indicated in the memory as an electrode that is not to receive energy for application of therapy at step 1314. Regardless of the outcome of the determination at step 1310, after stimulation to El, stimulation will be delivered to E2 at step 1316. Again, if a response is detected at step 1318, E2 will be stored in memory as an electrode for application of therapy at step 1320, if no response is detected, at step 1321 E2 will be indicated as an electrode that is not to receive energy during a therapy.
[0087] Once electrodes El and E2 are assessed, the method proceeds to step 1323 where stimulation is applied to both E3 and E4. If no response is detected at step 1324 electrodes E3
and E4 will both be indicated in the memory as not to receive energy during therapy at step 1326 and the method ends. If a response is detected at step 1324 the method progresses to step 1328 where stimulation is applied to E3. If a response is detected at step 1330 an indication that E3 is to receive energy during therapy is saved in the memory at step 1332, of no response is detected, then an indication is stored in memory that E3 is not to receive energy during therapy is stored in memory at 1336. Regardless the method progresses to step 1338 where stimulation is applied to E4. If a response is detected in response to the stimulation at step 1340 an indication is stored in the memory that E4 is to receive energy during therapy at step 1342, if no response is detected, then an indication is stored in memory that E4 is not to receive energy during therapy 1344, and regardless of the determination at step 1340 the method ends.
[0088] By following method 1300, an assessment is made of a portion of a blood vessel in which a therapeutic device 50 has been placed and the proximity of each of electrodes E1-E4 to a nerve for denervation. Because the response from stimulation from each individual electrode 56 and pairs of electrodes 56 along the therapeutic device are assessed and stored in memory, a determination can be made as to which of the electrodes E1-E4 to utilize to apply therapy. This results in more targeted application of therapy, ensures that the therapy is more likely to be effective, and eliminates unnecessary destruction of tissue of the blood vessel. This method 1300 may be utilized as part of any of the methods of stimulation and therapy described herein to ensure that when therapy is applied it is targeted to those portions of a blood vessel likely to benefit the patient and prevent the unnecessary application of therapy to other portions of the blood vessel. The method 1300 may be also employed separately from other to map the locations of the nerves or to assess the placement of the therapeutic device 50.
[0089] In accordance with method 1300, the electrodes 56 E1-E4 which are identified as being proximate a nerve and an indication of such is stored in the memory 32. As such, when a method such as methods 800, 900, 1000 is undertaken, only those electrodes E1-E4 from which a response to stimulation applied therethrough was detected receive the stimulation and therapy.
[0090] Those of skill in the art will recognize that the stimulation signals employed in embodiments herein may have a multiphasic-pulsed waveform (e.g., biphasic, triphasic, etc.). In one non-limiting embodiment, the neurostimulation includes a biphasic waveform, with each pulse of the biphasic waveform having an anodal leading phase and a cathodal trailing phase or vice versa. The therapy system may be configured to alternate the leading phase of each pulse of the biphasic waveform during the application of the neurostimulation such that, for example, a first pulse includes an anodal leading phase and a cathodal trailing phase, a subsequent, second
pulse includes a cathodal leading phase and an anodal trailing phase, and a subsequent, third pulse returns to an anodal leading phase and a cathodal trailing phase. The leading phase of each pulse of the biphasic waveform is alternated for the duration of the application of the neurostimulation. As a result, a neural response to the neurostimulation is enhanced as compared to continuous first phase biphasic waveforms and monophasic waveforms as is known in the art. This in turn increases the likelihood of stimulating neural tissue and decreases the amount of time required to identify suitable neural tissue for denervation therapy. Further application of neurostimulation promotes accurate determinations of the suitability of a location for receiving therapy since a greater amount of neural tissue is stimulated by the alternating biphasic waveform described herein.
[0091] The therapeutic devices 50 contemplated in this disclosure can apply one or more of a variety of therapeutic modalities. For example, the therapeutic modalities considered within the scope of this disclosure include monopolar or bipolar radiofrequency, microwave, cryogenic, ultrasound, chemical, and other yet to be developed modalities. Any of these therapy modalities may be incorporated into a therapeutic device, such as a catheter, which is configured for navigation to a desired location within the patient. A catheter configured to delivery one or more of these therapeutic modalities may be percutaneously navigated, for example via the femoral artery, to reach the blood vessels of the aorta including the celiac artery, hepatic arteries, splanchnic arteries, mesenteric arteries, and others that are enervated with sympathetic nerves or are proximate one or more sympathetic nerve ganglia. Such a catheter may also be laparoscopically placed in one or more of the above-identified blood vessels, or another luminal tissue without departing from the scope of the present disclosure.
[0092] The therapeutic device 50 described herein is configured to deliver stimulation to the blood vessel or other luminal tissue. The amplitude, frequency, pulse width, and/or duration of the stimulation can be selected and/or modified to ensure stimulation of the target nerves of the periluminal tissue (e.g., unmyelinated nerve fibers) without damaging the luminal tissue or the nerves within or surrounding the luminal tissue or causing excess vasoconstriction about the therapeutic device (e.g., inhibiting the movement of the therapeutic device within the luminal tissue).
[0093] As noted above, the therapeutic device 50 is coupled to a therapy source 24 and a stimulation source 24a, although it is envisioned that the therapy source 24 and the stimulation source 24a may be the same and capable of generating both therapy and stimulation. For example, an electrical generator may be configured to generate biphasic pulses to be supplied
to the electrodes 56 of the therapeutic device 50 and the supply monopolar RF energy to the electrodes 56.
[0094] In accordance with aspects of the present disclosure, the therapeutic device may be navigated within the vessels or luminal tissue in one configuration (e.g., a linear configuration) and once located at a desired location, deployed or otherwise actuated to achieve a second configuration
[0095] In a further one aspect of the disclosure the application of stimulation 202 may achieve one of a number of physiological responses including an increase in systolic blood pressure, increase in mean arterial blood pressure, an increase in vessel stiffness, an increase in pulse wave velocity, an increase in vessel stiffness, and others.
[0096] As described hereinabove, it is envisioned that the physiological responses to the application of neurostimulation can be monitored by a control algorithm 44 stored on the computer 22, with the location and results of the application of neurostimulation stored in the memory 32. As noted, the observed post therapy and intra-procedural physiological responses can be compared to the pre-procedural responses to assess the efficacy of the therapy, determine if more therapy is required, and when sufficient therapy has been applied to achieve the desired abl ati on/ denervati on .
[0097] Heretofore, the therapeutic device 50 has been primarily described in connection with a shape memory construction where exit from a guide catheter 58 frees the shape memory alloy to achieve a desired spiral shape of the and place the electrodes 56 against the blood vessel walls. However, the present disclosure is not so limited and the therapeutic device 50 may be formed such that the electrodes are placed on a balloon or other mechanism to achieve the desired contact with the blood vessel walls without departing from the scope of the disclosure. [0098] Although described generally hereinabove, it is envisioned that the memory 32 may include any non-transitory computer-readable storage media for storing data and/or software including instructions that are executable by the processor 30 and which control the operation of the workstation 20 and, in some embodiments, may also control the operation of the therapeutic device 50. In an embodiment, memory 32 may include one or more storage devices such as solid-state storage devices, e.g., flash memory chips. Alternatively, or in addition to the one or more solid-state storage devices, the memory 32 may include one or more mass storage devices connected to the processor 30 through a mass storage controller (not shown) and a communications bus (not shown).
[0099] Although the description of computer-readable media contained herein refers to solid-state storage, it should be appreciated by those skilled in the art that computer-readable
storage media can be any available media that can be accessed by the processor 30. That is, computer readable storage media may include non-transitory, volatile, and non-volatile, removable, and non-removable media implemented in any method or technology for storage of information such as computer-readable instructions, data structures, program modules or other data. For example, computer-readable storage media may include RAM, ROM, EPROM, EEPROM, flash memory or other solid-state memory technology, CD-ROM, DVD, Blu-Ray or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which may be used to store the desired information, and which may be accessed by the workstation 20.
[00100] While several embodiments of the disclosure have been shown in the drawings, it is not intended that the disclosure be limited thereto, as it is intended that the disclosure be as broad in scope as the art will allow and that the specification be read likewise. Therefore, the above description should not be construed as limiting, but merely as exemplifications of embodiments. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
[00101] The following examples are a non-limiting list of examples in accordance with one or more techniques of this disclosure.
[00102] Example 1. A method of performing a therapeutic procedure, comprising: applying a first stimulation signal from electrodes of a therapeutic device to a blood vessel wall; observing a first physiological response to the first stimulation signal; applying a therapy to the blood vessel wall; applying a second stimulation signal from the electrodes to the blood vessel; observing second physiological response to the second stimulation signal; and outputting an indicator of a successful therapy when the second physiological response is different from the first physiological response by more than a first threshold value.
[00103] Example 2. The method of Example 1, further comprising adjusting parameters of the first stimulation signal when the first physiological response is observed less than a second threshold value.
[00104] Example 3. The method of Example 2, further comprising applying the first stimulation signal with the adjusted parameters to the blood vessel wall, prior to applying the therapy to the blood vessel wall.
[00105] Example 4. The method of Example 1, further comprising adjusting parameters of the therapy if the second physiological response is different from the first physiological response by less than the first threshold.
[00106] Example 5. The method of Example 4, further comprising applying a therapy with the adjusted parameters to the blood vessel wall.
[00107] Example 6. A system for denervation of nerves of a blood vessel comprising: a therapeutic device configured for navigation within a blood vessel of a patient; a plurality of electrodes formed on a distal portion of the therapeutic device; a sensor configured to measure one or more physiological parameters of the patient at a location to which the therapeutic device has been navigated; a stimulation and therapy source; and a computing device including a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of the plurality of electrodes; sense a first change in a physiological parameter as a result of the application of the first stimulation signal; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; generate a therapy for application the blood vessel wall; generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes; sense a second change in the physiological parameter as result of the application of the second stimulation signal; determine whether the application of the therapy has denervated the nerve proximate the electrode based on the second sensed change of the physiological parameter; and output an indicator of success of the application of the therapy. [00108] Example 7. The system of Example 6, wherein the first stimulation signal and the therapy are a combined signal that is generated for an initial period of time.
[00109] Example 8. The system of Example 7, wherein the determination of the first sensed change occurs after the initial period of time.
[00110] Example 9. The system of Example 8, wherein second stimulation signal and the therapy are a combined signal that is generated for a second period of time.
[00111] Example 10. The system of Example 6, wherein the instructions when executed by the processor present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the one of the plurality of electrodes, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation.
[00112] Example 11. The system of Example 6, wherein the instructions when executed by the processor determine that the first sensed change in the physiological parameter is indicative of a lack of a nerve proximate the one of the plurality of electrodes and output an indicator.
[00113] Example 12. The system of Example 11, wherein the instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time. [00114] Example 13. The system of Example 12, wherein the instructions when executed by the processor sense a third change in a physiological parameter as a result of the application of the first stimulation signal with the adjusted parameters; determine whether the third sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; and output an indicator of the presence of a nerve proximate the one of the plurality of electrodes.
[00115] Example 14. The system of Example 13, wherein the instructions when executed by the processor determine that the nerves are deep and require additional time to complete the denervation and reapply the therapy.
[00116] Example 15. A method of assessing a denervation site comprising: applying a multiplexed stimulation signal and therapy to alternating pairs of a plurality of electrodes of a therapeutic device to a wall of a blood vessel for a first duration; sensing a physiological parameter of the blood vessel after application of the multiplexed stimulation and therapy; determining that a first change in the physiological parameter of the blood vessel exceeds a first threshold; applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes for a second duration; sensing a physiological parameter of the blood vessel after the application of the multiplexed stimulation and therapy; determining whether a second change in the physiological parameter of the blood vessel exceeds a second threshold; and indicating to a user a successful denervation when the sensed physiological parameter after the second duration is different than after the first duration.
[00117] Example 16. The method of Example 15, further comprising determining if a power limit has been reached when the determined change in the physiological parameter after the second duration is less than the threshold and increasing the power of the therapy if the power limit has not been reached.
[00118] Example 17. The method of Example 16, further comprising ceasing application of the multiplexed stimulation signal an therapy if the power limit has been reached.
[00119] Example 18. The method of Example 15, wherein applying the multiplexed stimulation signal and therapy comprises: applying a stimulation signal between a first pair of the plurality of electrodes for a first time; applying a therapy via a second pair of the plurality of electrodes simultaneously with the stimulation signal for a first time; applying the stimulation signal between the second pair of the plurality of electrodes for a second time;
applying a therapy via the second pair of the plurality of electrodes simultaneously with the stimulation signal for the second time; and switching between the first pair and the second pair for application of the stimulation signal and application of therapy until completion of the first duration or the second duration.
[00120] Example 19. The method of Example 16, wherein the plurality of electrodes are arranged in a first unique series of pairs of electrodes and a second unique series of pairs and applying a multiplexed stimulation signal and therapy to alternating pairs of the plurality of electrodes comprises: applying stimulation to a first pair of the first unique series of pairs for a first time; applying therapy to a first pair of the second unique series of pairs for the first time; switching to a second pair of the first unique series of pairs and applying stimulation to the second pair for a second time; switching to a second unique pair of the second unique series of pairs and applying therapy to the second pair for a second time; and repeating the switching of the first unique series of pairs and the second unique series of pairs for the first duration or the second duration.
[00121] Example 20. The method of Example 15, wherein the sensed physiological parameter is one or more of systolic blood pressure, mean arterial blood pressure, blood vessel stiffness, or pulse wave velocity.
[00122] Example 21. The method of Example 20, wherein the determined first change of the physiological parameter is a reduction in systolic blood pressure.
[00123] Example 22. The method of Example 21, wherein the determined second change of the physiological parameter is a reduction in systolic blood pressure and the threshold is the systolic blood pressure at a conclusion of the first duration.
[00124] Example 23. The method of Example 15, further comprising determining that the first change of the physiological parameter is less than the threshold; and stopping application of a therapy portion of the multiplexed stimulation signal and therapy.
[00125] Example 24. The method of Example 23, further comprising adjusting a stimulation signal and applying the adjusted stimulation signal to alternating pairs of electrodes.
[00126] Example 25. The method of Example 24, further comprising determining that application of the adjusted stimulation signal resulted in a change of the physiological parameter in excess of a threshold; increasing a power of the therapy; and applying a multiplexed adjusted stimulation signal and increased power therapy for the second duration. [00127] Example 26. The method of Example 24, further comprising determining that application of the adjusted stimulation signal resulted in a change of the physiological
parameter less than the threshold; and generating an indicator for display on a user interface that no nerves are detected at a position of the therapeutic device.
[00128] Example 27. A method of performing a therapeutic procedure, comprising: applying a first stimulation signal from a first pair electrodes of a therapeutic device to a blood vessel wall; applying a therapy to the blood vessel wall employing all electrodes; switching polarity of the stimulation signal between the first pair of electrodes; applying a second stimulation from the first pair of electrodes to the blood vessel; applying a therapy to the blood vessel wall employing all electrodes; switching to a second pair of electrodes; applying a second stimulation signal with the second pair of electrodes, applying of therapy with all electrodes, switching polarity of the second pair of electrodes, applying the second stimulation signal with the second pair of electrodes, and applying therapy with all the electrodes; switching to all subsequent pairs of electrodes and repeating application of stimulation with each subsequent pair of electrodes, application of therapy with all electrodes, switching polarity of each subsequent pair of electrodes, application of stimulation with each subsequent pair of electrodes and application of therapy with all electrodes sensing a physiological parameter of the blood vessel after expiration of a first time period; determining that a first change in the physiological parameter of the blood vessel exceeds a first threshold; repeating the switching and applying of the stimulation signal to each pair of electrodes and application of a therapy using all electrodes until a second time period expires determining whether a second change in the physiological parameter of the blood vessel exceeds a second threshold; and indicating to a user a successful denervation when the sensed physiological parameter after the second time period is different than after the first time period.
[00129] Example 28. The method of Example 27, further comprising determining that the first change of the physiological parameter is less than the threshold; and stopping the application of the therapy.
[00130] Example 29. The method of Example 28, further comprising adjusting a stimulation signal and repeating the switching and applying of the stimulation signal to each successive pair of electrodes and application of a therapy using all electrodes until a first time period expires.
[00131] Example 30. The method of Example 29, further comprising determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter less than the threshold; and generating an indicator for display on a user interface that no nerves are detected at a location of the therapeutic device.
[00132] Example 31. The method of Example 29, further comprising determining that the application of the adjusted stimulation signal resulted in a change of the physiological parameter in excess of a threshold.
[00133] Example 32. The method of Example 30, further comprising increasing a power of the therapy; and applying the adjusted stimulation signal and increased power therapy for the second time period.
[00134] Example 33. A system for denervation of nerves of a blood vessel comprising: a stimulation and therapy source; and a computing device including a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of a plurality of electrodes of a therapeutic device; sense a first change in a physiological parameter as a result of the application of the first stimulation signal; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; generate a therapy for application the blood vessel wall; generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes; sense a second change in the physiological parameter as result of the application of the second stimulation signal; determine whether the application of the therapy has denervated the nerve proximate the electrode based on the second sensed change of the physiological parameter; and output an indicator of success of the application of the therapy.
[00135] Example 34. The system of Example 33, wherein the first stimulation signal and the therapy are a combined signal that is generated for an initial period of time.
[00136] Example 35. The system of Example 34, wherein the determination of the first sensed change occurs after the initial period of time.
[00137] Example 36. The system of Example 35, wherein second stimulation signal and the therapy are a combined signal that is generated for a second period of time.
[00138] Example 37. The system of Example 33, wherein the instructions when executed by the processor present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the one of the plurality of electrodes, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation.
[00139] Example 38. The system of Example 33, wherein the instructions when executed by the processor determine that the first sensed change in the physiological parameter and output an indicator of a lack of a nerve proximate the one of the plurality of electrodes.
[00140] Example 39. The system of Example 38, wherein the instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time. [00141] Example 40. The system of Example 39, wherein the instructions when executed by the processor sense a third change in a physiological parameter as a result of the application of the first stimulation signal with the adjusted parameters; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; and output an indicator of the presence of a nerve proximate the one of the plurality of electrodes.1
[00142] Example 41. The system of Example 40, wherein the instructions when executed by the processor determine that the nerves are deep and require additional time to complete the denervation and reapply the therapy.
[00143] Further disclosed herein is the subject-matter of the following clauses:
1. A system for denervation of nerves of a blood vessel comprising: a stimulation and therapy source; and a computing device including a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of the plurality of electrodes; sense a first change in a physiological parameter as a result of the application of the first stimulation signal; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; generate a therapy for application the blood vessel wall; generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes; sense a second change in the physiological parameter as result of the application of the second stimulation signal; determine whether the application of the therapy has denervated the nerve proximate the electrode based on the second sensed change of the physiological parameter; and output an indicator of success of the application of the therapy.
2. The system of clause 1, further comprising: a therapeutic device configured for navigation within a blood vessel of a patient; a plurality of electrodes formed on a distal portion of the therapeutic device; a sensor configured to measure one or more physiological parameters of the patient at a location to which the therapeutic device has been navigated;
3. The system of clause 1 or 2, wherein the first stimulation signal and the therapy are a combined signal that is generated for an initial period of time.
4. The system of clause 3, wherein the determination of the first sensed change occurs after the initial period of time.
5. The system of clause 4, wherein second stimulation signal and the therapy are a combined signal that is generated for a second period of time.
6. The system of any one of clauses 1 to 5, wherein the instructions when executed by the processor present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the one of the plurality of electrodes, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation.
7. The system of any one of clauses 1 to 6, wherein the instructions when executed by the processor determine that the first sensed change in the physiological parameter is indicative of a lack of a nerve proximate the one of the plurality of electrodes and output an indicator.
8. The system of clause 7, wherein the instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time.
9. The system of clause 8, wherein the instructions when executed by the processor sense a third change in a physiological parameter as a result of the application of the first stimulation signal with the adjusted parameters;
determine whether the third sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; and output an indicator of the presence of a nerve proximate the one of the plurality of electrodes.
10. The system of clause 9, wherein the instructions when executed by the processor determine that the nerves are deep and require additional time to complete the denervation and reapply the therapy.
Claims
1. A system for denervation of nerves of a blood vessel comprising: a stimulation and therapy source; and a computing device including a memory and a processor and storing thereon instructions that when executed: generate a first stimulation signal for application to a blood vessel wall via one of the plurality of electrodes; sense a first change in a physiological parameter as a result of the application of the first stimulation signal; determine whether the first sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; generate a therapy for application the blood vessel wall; generate a second stimulation signal for application to the blood vessel wall via the one of the plurality of electrodes; sense a second change in the physiological parameter as result of the application of the second stimulation signal; determine whether the application of the therapy has denervated the nerve proximate the electrode based on the second sensed change of the physiological parameter; and output an indicator of success of the application of the therapy.
2. The system of claim 1, further comprising: a therapeutic device configured for navigation within a blood vessel of a patient; a plurality of electrodes formed on a distal portion of the therapeutic device; a sensor configured to measure one or more physiological parameters of the patient at a location to which the therapeutic device has been navigated;
3. The system of claim 1 or 2, wherein the first stimulation signal and the therapy are a combined signal that is generated for an initial period of time.
4. The system of claim 3, wherein the determination of the first sensed change occurs after the initial period of time.
5. The system of claim 4, wherein second stimulation signal and the therapy are a combined signal that is generated for a second period of time.
6. The system of any one of claims 1 to 5, wherein the instructions when executed by the processor present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the one of the plurality of electrodes, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation.
7. The system of any one of claims 1 to 6, wherein the instructions when executed by the processor determine that the first sensed change in the physiological parameter is indicative of a lack of a nerve proximate the one of the plurality of electrodes and output an indicator.
8. The system of claim 7, wherein the instructions when executed by the processor stop the generation of therapy, adjust the parameters of the first stimulation signal, and apply the first stimulation with the adjusted parameters for a first period of time.
9. The system of claim 8, wherein the instructions when executed by the processor sense a third change in a physiological parameter as a result of the application of the first stimulation signal with the adjusted parameters; determine whether the third sensed change in the physiological parameter is indicative of a presence of a nerve proximate the one of the plurality of electrodes; and output an indicator of the presence of a nerve proximate the one of the plurality of electrodes.
10. The system of claim 9, wherein the instructions when executed by the processor determine that the nerves are deep and require additional time to complete the denervation and reapply the therapy.
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