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WO2017100140A2 - Appareil permettant une ablation efficace et la détection efficace de nerfs en lien avec la dénervation - Google Patents

Appareil permettant une ablation efficace et la détection efficace de nerfs en lien avec la dénervation Download PDF

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Publication number
WO2017100140A2
WO2017100140A2 PCT/US2016/065017 US2016065017W WO2017100140A2 WO 2017100140 A2 WO2017100140 A2 WO 2017100140A2 US 2016065017 W US2016065017 W US 2016065017W WO 2017100140 A2 WO2017100140 A2 WO 2017100140A2
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Prior art keywords
catheter
distal
ablation
electrode
needle
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Ceased
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PCT/US2016/065017
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WO2017100140A3 (fr
Inventor
David R. Fischell
Tim A. Fischell
Vartan Ghazarossian
Steven ALMANY
Michael Sasha John
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Ablative Solutions Inc
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Ablative Solutions Inc
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Priority claimed from US14/963,179 external-priority patent/US9949652B2/en
Application filed by Ablative Solutions Inc filed Critical Ablative Solutions Inc
Publication of WO2017100140A2 publication Critical patent/WO2017100140A2/fr
Publication of WO2017100140A3 publication Critical patent/WO2017100140A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6848—Needles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B18/1492—Probes or electrodes therefor having a flexible, catheter-like structure, e.g. for heart ablation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • A61N7/022—Localised ultrasound hyperthermia intracavitary
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/06—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating caused by chemical reaction, e.g. moxaburners
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00345—Vascular system
    • A61B2018/00404—Blood vessels other than those in or around the heart
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00434—Neural system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00505—Urinary tract
    • A61B2018/00511—Kidney
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00577—Ablation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B2018/1405—Electrodes having a specific shape
    • A61B2018/1425—Needle
    • A61B2018/143—Needle multiple needles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B2018/1475—Electrodes retractable in or deployable from a housing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0067—Catheters; Hollow probes characterised by the distal end, e.g. tips
    • A61M25/0082—Catheter tip comprising a tool
    • A61M25/0084—Catheter tip comprising a tool being one or more injection needles
    • A61M2025/0087—Multiple injection needles protruding laterally from the distal tip

Definitions

  • This invention relates in some aspects to the field of devices that monitor, stimulate, and/or ablate tissue and nerve fibers primarily in the adventitial and/or periadvential area surrounding a blood vessel.
  • the procedure is be performed in a catheterization laboratory or operative-type suite.
  • the benefit-risk, cost-benefit, and incremental cost effectiveness ratio, of this invasive procedure would all be enhanced if measures related to procedural success could be assessed during the procedure. Assessing the success, or sensing relevant data to guide the ablation procedure, during the surgery would allow the physician to perform additional ablation interventions and/or to adjust the technique as needed. This real-time assessment would be expected to improve efficacy and to reduce the need to bring the patient back for a second procedure at additional cost and risks to the patient.
  • the desired effect of renal sympathetic nerve ablation procedure is a lowering of blood pressure, with consequent reduction in the need for chronic antihypertensive drug treatment.
  • Radiofrequency-based methods transmit radiofrequency energy through the renal artery wall to ablate the renal nerves surrounding the blood vessel.
  • Chemical neurolysis uses small gauge needles that pass through the renal artery wall to inject a neurolytic agent directly into the adventitial and/or periadvential area surrounding the blood vessel, which is where the renal sympathetic nerves entering and leaving the kidney (i.e., afferent and efferent nerves) are located.
  • Recent technology for renal denervation includes energy delivery devices using radiofrequency or ultrasound energy, such as SimplicityTM (Medtronic), VessixTM. (Boston Scientific) EnligHTNTM (St. Jude Medical) and One Shot l i system from Covidien, all of which are RF ablation catheters.
  • SimplicityTM Medtronic
  • VessixTM. Boston Scientific
  • EnligHTNTM St. Jude Medical
  • One Shot l i system from Covidien all of which are RF ablation catheters.
  • the short-term complications and the long-term sequelae of applying RF energy from the inner lining (intima) of the renal artery to the outer wall of the artery are not well defined.
  • This type of energy applied within the renal artery, and with transmural renal artery injury, may lead to late stenosis, thrombosis, renal artery spasm, embolization of debris into the renal parenchyma, or other problems related to the thermal inj ry of the renal artery.
  • the Simplicity lM system for RF delivery applies energy to the intimal surface of the artery in a spiral pattern because intraluminal circumferential ablation would result in a higher risk for permanent arterial damage leading to renal artery stenosis or perforation.
  • the "burning" of the interior wall of the renal artery using RF ablation can be extremely painful during the procedure.
  • the long duration of the RF ablation renal denervation procedure requires sedation and, at times, high doses of morphine or other opiates, and anesthesia, close to the levels used for general anesthesia, to control the severe pain associated with repeated burning of the vessel wall and its associated pain fibers.
  • This device also does not allow for a precise, controlled and adjustable penetration depth (i.e. relative to the wall surface) of delivery of a neuroablative agent.
  • the physical constraints regarding the length that can be used thus limits the ability to inject agents to an adequate depth outside of the arterial wall, particularly in diseased renal arteries with thickened intima. All of these limitations could lead to incomplete denervation and treatment failure.
  • Another limitation of the Bullfrog® is that inflation of a balloon within the renal artery- can induce transient renal ischemia during the operation and possibly late vessel stenosis due to balloon injury of the intima and media of the artery, as well as causing endothelial cell denudation.
  • Jacobson and Davis in U.S. Pat. No. 6,302,870 disclose a catheter for medication injection into the interior wall of a blood vessel. While Jacobson includes the concept of multiple needles expanding outward, each with a hilt to limit penetration of the needle into the wall of the vessel, his design depends on rotation of the tube having the needle at its distal end to allow it to get into an outwardly curving shape.
  • the hilt design shown of a small disk attached a short distance proximal to the needle distal end has a fixed diameter which will increase the total diameter of the device by at least twice the diam eter of the hilt so that if the hilt is large enough in diameter to stop penetration of the needle, it will significantly add to the diameter of the device.
  • Jacobson appears to intend the drug to be injected into the vessel wail rather than injecting exterior to the vessel wail (at the targets nerve sites themselves) since the hilts, which limit penetration, are a relatively short fixed distance from the distal end of the needles. Longer penetration depths that are needed to provide the advantage of extending beyond the adventitia to the location of the sympathetic nerves outside of the renal artery would greatly increase the diameter of the Jacobson catheter thereby making insertion of the catheter tip problematic and needlestick injuries even more likely. There is also no mechanism that would provide for the adjustment of penetration depth which may be important if the clinician wishes to selectively target a specific layer in a vessel or penetrate all the way through to the volume of tissue outside of the adventitia in vessels that may have different wall thicknesses.
  • Jacobson does not envision use of the injection catheter for denervation. It is also of note that FIG. 3 of the Jacobson patent shows a sheath over expandable needles and does not disclose a guide wire. Further, the sheath has an open distal end. Both of these design limitations make advancement through the vascular system more difficult. Lastly, because of the hilts used by Jacobson, if the needles were withdrawn completely inside of the sheath they could get stuck inside the sheath and be difficult to push out during the intended deployment at the target area. The above listed limitations and complexity of the Jacobson system might increase the risk of surgical complications and inadequate, or incomplete, renal denervation.
  • McGuckin in U.S. Pat. No. 7,087,040 discloses a tumor tissue ablation catheter having three expandable tines for injection of fluid that exit a single needle. The tines expand outwardly to penetrate the tissue.
  • the McGuckin device has an open distal end that does not provide protection from inadvertent needle sticks from the sharpened tines.
  • the McGuckin device depends on the shaped tines to be of sufficient strength so that they can expand outwardly and penetrate the tissue. To achieve such strength, the tines would have to be so large in diameter that severe extravascular bleeding would likely often occur when the tines would be retracted back following fluid injection for a renal denervation application.
  • the limitation of the needle alone designs are that if small enough diameter needles are used to avoid unwanted surgical results such as blood loss following penetration through the vessel wall, then the needles may be too flimsy to reliably and uniformly expand to their desired positions.
  • the use of a cord or wire to connect the needles together in as shown in patent 9,056,185 helps some in the area.
  • the use of guide tubes as described in the Fischell US Patent No. 8,740,849 and patent application Ser. Nos. 13/294,439 and 13/342,521 greatly improves this support, but the unsupported guide tubes themselves depend on their own shape to ensure that they expand uniformly and properly center the distal portion of the catheter. Without predictable catheter centering and guide tube expansion it may be challenging to achieve accurate and reproducible needle penetration to a targeted depth.
  • perivascular space refers to the volume of tissue radially outside of (or deep to) the media of a vessel of the human body- such as an artery.
  • the present application discloses, in some embodiments, a Nerve Sensing Catheter (NSC) that senses perivascular renal sympathetic nerve activity (as an example although other types of extra-vascular nerve activity, including non-sympathetic nerves, may also be measured) and can be used complementary to a non-sensing renal denervation device whether it is a chemical device such as the PTAC of Fischell (e.g., US Patent Nos. 8,740,849 and 9,056, 185) or an energy delivery device such as SIMPLICITY®, or even when using external sources of ablation such as surgical intervention, or externally delivered energy such as focused ultrasound (such as the Surround SoundTM system of Kona Medical), etc.
  • a nerve Sensing Catheter that senses perivascular renal sympathetic nerve activity (as an example although other types of extra-vascular nerve activity, including non-sympathetic nerves, may also be measured) and can be used complementary to a non-sensing renal denervation device whether it is a chemical device
  • a perivascular Nerve Ablation and Sensing Catheter is capable of delivering an ablative fluid to produce circumferential damage in the tissue that is located within the vessel wall, (e.g. the media of an artery) in the outer layer of the vessel (e.g. in the adventitia of an artery) or beyond the outer layer of a vessel of a human body.
  • the PNASC also includes sensors for sensing the activity of nerves, such as the sympathetic nerves that lie outside of the external elastic lamina of the renal artery.
  • the integrated PNASC has the advantage of saving time at the cost of adding complexity to a device that was only designed to provide ablation.
  • the NSC requires a separate renal denervation device be used to provide ablation, but has a large potential market when used in combination with other, potentially less effective and less predictable renal denervation devices, such as those that ablate nerves using RF energy from intravascular sites.
  • PNASC embodiments also are disclosed that use, RF or ultrasonic energy to provide for perivascular nerve ablation, such as renal nerve ablation.
  • the nerve ablation procedure using perivascular injection of alcohol by the prior art catheters disclosed by Fischeil (e.g., the PTAC) or the PNASC disclosed herein, can be accomplished in a relatively short time as compared with RF ' ablation catheters, and in some embodiments also has the advantage of using only a single disposable catheter, with no additional, external, capital equipment. It will also, because of reduced pain levels and shorter procedural time, provide the advantages such as permitting:
  • Part of some embodiments of the present invention method for use of the PSNAC envisions that the pain associated with a chemical renal denervation procedure can be either largely reduced or completely eliminated by using ethanol as the ablative agent and also injecting the ethanol slowly over a period no shorter than at least 10 seconds and ideally longer than 30 seconds, which serves as a local analgesic at the site of the renal nerves prior to its effect as an ablative agent.
  • This provides the advantage of decreasing the use of general anesthesia, and its associated risks and disad vantages, by providing for analgesia in the region of ablation,
  • PNASC While the primary focus of use of PNASC is in the treatment of hypertension and congestive heart failure by renal denervation, the PNASC has the ability to sense nerve activity such as sympathetic nerve activity, and could also be used in conjunction with other renal denervation devices to enhance the effectiveness of the renal denervation or to provide additional denervation if the other device is not appropriately effective.
  • NSC and PNASC may be similar to the manually expandable PTAC designs shown in FIGS. 2 through 11 of Fischell et ai U.S. patent 8,740,849 incorporated herein by reference. Specifically, the NSC and PNASC would use the similar proximal control structures as well as the same guide tubes and radial and lateral support structures.
  • the injector tubes with distal injection needles of the PTAC of US Patent No. 8,740,849 are replaced by a solid sharpened wire that is electrically insulated except for its tip that forms an electrode.
  • the proximal end of each wire connects through conducting means to electronic equipment (e.g., connected to wires at the proximal end of the catheter) used to monitor nerve activity sensed by the electrodes and/or provide energy to the electrodes to ablate nerve tissue.
  • the PTAC structure shown in FIGS. 2-10 of U.S. Patent No. 8,740,849 would be modified to have the radiopaque wire inside the injector needles replaced by an electrode connected to a proximal insulated wire positioned within the distal end of the injection needle.
  • the electrode would be of gold or platinum or another radiopaque metal to provide radiopacity.
  • At least two configurations of this PNASC embodiment will be disclosed: one where the electrode lies completely within the lumen of the injection needle and a second embodiment where the electrode extends distal ly beyond the lumen of the injector tube and forms at least part of the sharpened needle.
  • these sensing electrodes could be advanced through the distal end of the injection needles, further into the perivascular space. It can also be preferred to coat the inside of the distal tip of the PNASC injection needles to prevent the needle tip from shorting to the inside of the metallic needle.
  • each of the proximal insulated wires then run through the injector tube lumen into the lumen of the inner tube and finally exit out of the catheter near the proximal end of the PNASC,
  • the wires can be attached directly or through a connector to an electronics module for any or all of the following: providing energy for nerve ablation,
  • the proximal exit for the wires may be though the side of the catheter or outward through the center of the injection port lumen where a Tuohy-Borst fitting would seal around the wires with the side port in the Tuohy-Borst used for infusion of the ablative fluid.
  • Sensing of the nerve activity may be done between pairs of electrodes located near or at the distal ends of the needles (PNASC) or wires (NSC) or between an active sensor located near or at the distal end of a needle/wire and a reference electrode.
  • the reference electrode could be any electrical reference used to reference voltage or current measurements from the distal electrodes embodiments including:
  • a reference electrode located on the body of the PNASC/NSC, including a ring located on the outside of the PNASC NSC, a portion of the distal nose of the PNASC/NSC, or an integrated guide wire:
  • an electrode placed on the body such as at a location over the location of the renal artery.
  • the preferred embodiment would measure activity between pairs of distal electrodes or would use the skin electrode (e.g., a standard ECG electrode) as this will allow a smaller diameter configuration of the internal lumen of the catheter.
  • skin electrode e.g., a standard ECG electrode
  • Embodiments of the PNASC can have injection ports such as side holes in the sensor/injector tube just proximal to the distal electrode or longitudinal holes through the electrode. These holes allow ablative fluid injected from a proximal injection port in the handle of the PNASC to effuse from the distal end of each needle
  • the PNASC similar to the PTAC of U.S. Patent No. 8,740,849 is a percutaneously introduced catheter with two or more injection needles configured for the delivery of ablative fluid.
  • the needles expand outwardly from the catheter and penetrate into or fully through the wall of the renal artery and into the perivascular space where the sympathetic nerves are located.
  • Another embodiment of the PNASC could have one or more expandable structures separate from the needles for fluid delivery. These structures could be configured to deliver a sharpened wire form ing a distal electrode through the arterial wall into the tissue beyond.
  • the control of the expansion of these sharpened wires can occur either by the same or separate mechanisms that expand and support the injection needles.
  • four guide tubes similar to those in the PTAC of U.S. Patent No. 8,740,849 could expand outwardly from the shaft of the PNASC catheter.
  • Four sharpened structures would then be advanced through the guide tubes through the renal artery wall and/or into the periadventitial space.
  • Two of the four structures could be injection needles for delivery of ablative fluid and two could be sharpened wires for providing energy based ablation and/or nerve activity sensing the effectiveness of the ablation.
  • the sensors are circumferential ⁇ offset from the injection needles.
  • the offset is about 90 degrees, and in a three-needle implementation, the offset is about 60 degrees. This type of "offset" configuration could be well suited for assessing ablation because the sensors are maximally separated from the injection needles that provide the therapy and so they are located where the effect of the injection would be least evident.
  • the nerves are appropriately damaged as reflected by sensed data that is sensed by sensors located at the points furthest from the point of fluid injection then the nerves everywhere else around the ring of ablation should be adequately ablated.
  • Configurations with more or less than 4 penetrating structures can also be envisioned.
  • Configurations with sensing electrodes offset longitudinally from the injection needles are also envisioned.
  • Embodiments where the 4 needles serve both as sensor and ablation elements (at different times) are also envisioned, and further the sensing or ablation can utilize bipolar montages where the anode and cathode are located on the same conduit tip, or monopolar montages where the energy travels between needles or where the return electrode is located elsewhere within/on the patient.
  • Embodiments where combinations of needle electrodes are activated for sensing and/or ablation in sequential order is also envisioned. Further, embodiments in which perivascular RF ablation is preceded or followed by injection of an ablative or analgesic agent will be disclosed- it may be an advantage to utilize RF ablation followed by chemical ablation since the two modalities of ablation may cover different regions of the target nerve pathways.
  • a PNASC integrated ablation and sensing system may also provide large advantages over other current technologies for applications other than renal denervation as the PNASC provides a highly efficient, and reproducible perivascular circumferential ablation of the muscle fibers and conductive tissue in the wall of the pulmonary veins near or at their ostium, into the left atrium of the heart, or in the pulmonary arteries in the case of nerve ablation to treat pulmonary arterial hypertension.
  • Such ablation could interrupt atrial fibrillation (AF) and other cardiac arrhythmias.
  • AF atrial fibrillation
  • nerve and/or cardiac myocyte electrical activity measurement could be an effective technique to provide immediate assessment of the success of an AF ablation procedure.
  • Other potential applications of this approach such as pulmonary artery nerve ablation, or others, may also become evident from the various teachings of this patent specification.
  • the NSC/PNASC of the present application can incorporate a small diameter catheter, which includes multiple expandable injector tubes having sharpened injection needles at or near their distal ends that are advanced through guide tubes designed to support and guide the needles into and/or through the inner layers of the target vessel. While this application concentrates on manually expandable versions of the NSC and PNASC, it is envisioned that similar electrodes could be used with structures similar to the self-expandable embodiments shown in U.S. Patent No. 8,740,849.
  • Some embodiments of the PNASC can also include any one, combinations, or all of the primary features of the self-expandable and balloon expandable embodiments of the Fischell et al U.S. Patent Nos. 8,740,849, 9,056, 185, 9, 179,962 and application Ser. Nos. 13/216,495, 13/294,439 and 13/342,521 including but not limited to:
  • Needle guiding elements/guide tubes to support the expandable injection needles.
  • Mechanical support structures to support the needle guiding elements,
  • Proximal handle for control of catheter activation including an injection port, Matched radii of curvature between the injector tubes and guide tubes,
  • Methods including injection of an anesthetic agent before the ablation.
  • the NSC PNASC devices would preferably have very small gauge needles (smaller than 25 gauge) to prevent unwanted surgical complications such as extravascular blood loss following penetration and removal through the arterial wall.
  • the PNASC which includes a distal opening in one or more needles to provide egress for the ablative fluid, would have a preferred embodiment with the distal needle being non- coring (cutting). With a cutting needle the injection egress/distal opening ports could be small injection holes (pores) cut into the sides of the injector tubes or distal needle, proximal to the cutting needle tip.
  • a Huber type needle is an example of such a non- coring needle.
  • the PNASC would also preferably have at least 2 injector tubes with distal needles, but 3 to 8 tubes with distal needles may be more appropriate for some applications.
  • the number and spacing of needles may be set depending on the diameter of the vessel to be treated and the ability of the injected ablative fluid to spread within the perivascular space. For example, in a 5-7 mm. diameter renal artery, 3 needles should typically be utilized if ethanol is the ablative fluid.
  • a preferred embodiment of the PNASC would use ethanol as the ablative fluid because this fluid is agrophobic, hygroscopic, lipophilic, and spreads quickly in the perivascular space. Therefore, only 3 needles are typically needed to create approximately circumferential delivery of this ablative agent for a vessel of the size of a human renal artery. This allows the use of a smaller diameter and less expensive device than would be possible with 4 or more needles. It is also envisioned that use of ethanol or another alcohol plus another neurotoxic agent could also enhance the spread of the ablative agent in the perivascular space.
  • NSC and PNASC embodiments which include a fixed distal guide wire
  • a separate guide wire could be used with the catheter designed to be either an over-the-wire configuration where the guide wire lumen runs the entire length of the catheter or a rapid exchange configuration where the guide wire exits the catheter body at a proximal guide wire port positioned at least 10 cm proximal to the distal end of the catheter and runs outside of the catheter shaft, for its proximal section. It is also envisioned that one could use a soft and tapered distal tip, even without a distal guide wire, for some applications.
  • a fixed wire embodiment, or an embodiment with the soft tapered distal tip (without a guidewire), are preferred embodiments, as they would have the smallest distal diameter.
  • a tapered distal portion of the SNAC/PN ASC that eliminates any sharp change in diameter that could cause the catheter to snag during advancement into the vasculature of a human.
  • the wires leading to two or more of the distal needle/electrodes could be attached at the proximal end of the PN ASC to an electrical or RF source to deliver electric current or RF energy to perform tissue and/or nerve ablation.
  • This could provide an ideal configuration for RF energy based renal denervation since the electrodes deliver the energy outside of the medial layer of the renal artery, and the normal intimal and medial wail structures would be cooled by blood flow. This configuration should dramatically reduce the damage to the artery, and associated clinical complications, as compared with intraluminal RF ablation.
  • the electrical equipment may also include nerve activity sensing electronics.
  • the same electrodes used in a first mode to ablate nerves or other tissue are also used in a second mode to evaluate the electrical characteristics at the treatment site. For example, one could measure nerve activity to obtain baseline data, provide ablation treatment to the nerves with energy and subsequently confirm the efficacy of the ablation by one or more post-ablation nerve activity measurements. These measurements could then compare the difference between the pre-procedure and post-procedure sensed data to at least one defined therapy efficacy criterion.
  • a secondary ablation treatment followed by a secondary post-ablation nerve activity measurement would be done to again assess whether the nen/es are sufficiently ablated to meet at least one defined therapy efficacy criterion. This can obviously be continued until the one or more therapy criteria are met. Further, while accomplishing more than one ablation treatment the catheter can be moved distally or proximally along the vessel, or rotated, so that the ablation treatment is applied to a new region. This may be especially important in some embodiments when using electrical rather than chemical ablation since this type of ablation may be more localized in its effects.
  • the PNASC device could be operated according to an ablation protocol to provide one ablation substance.
  • more than one neuroablative substances can be injected sequentially or simultaneously according to the ablation protocol.
  • the ablation protocol can also define a sequence of injections configured to ablate the target nerves, in order to optimize permanent sympathetic nerve disruption in a segment of the renal artery (neurotmesis).
  • the anticipated neurotoxic agents that could be utilized to provide ablation include but are not limited to ethanol, phenol, glycerol, local anesthetics in relatively high concentration (e.g., lidocaine, or other agents such as bupivacaine, tetracaine, benzocaine, etc.), antiarrhythmic drags that have neurotoxicity, botulinum toxin, digoxin or other cardiac glycosides, guanethidine, heated fluids including heated saline, hypertonic saline, hypotonic fluids, potassium chloride, cooled or heated neuroablative substances such as those listed above.
  • the ablative substance used for the ablation treatment according to the ablation protocol can be hypertonic fluids such as hypertonic saline (extra salt) or hypotonic fluids such as distilled water. These could cause damage to the nerves and could be as effective as alcohol or specific neurotoxins. These can also be injected hot, or cold or at room temperature.
  • hypertonic fluids such as hypertonic saline (extra salt) or hypotonic fluids such as distilled water.
  • hypotonic saline or hypotonic saline with an injection volume of less than 1 mi eliminates one step in the use of the PNASC because small volumes of these fluids should not be harmful to the kidney.
  • this obviates the need to completely flush the ablative fluid from the PNASC with normal saline to prevent any of the ablative fluid getting into the renal artery during catheter withdrawal.
  • This system and method provides the advantage that there would be only one fluid injection step per artery instead of two as would occur if a more toxic ablative fluid were used during ablation.
  • the PNASC could be connected to a heated fluid source to deliver high temperature fluids to ablate or injure the target tissue or nerves.
  • the heated fluid could be normal saline, hypertonic fluid, hypotonic fluid alcohol, phenol, lidocaine, or some other combination of fluids.
  • Injection of hot or vaporized normal saline, hypertonic saline, hypotonic saline, ethanol, distilled water or other fluids via the needles could also be performed in order to achieve thermal ablation of target tissue or nerves at and around the needle injection sites.
  • the present disclosure also envisions use of anesthetic agents such as lidocaine before the ablation procedure begins in order to provide a local anesthetic/analgesic to reduce or eliminate the pain associated with the denervation procedure.
  • anesthetic agents such as lidocaine
  • the external equipment may include a display of one or more electrical characteristics of sensed nerve activity such as the peak voltage, average voltage, peak power, average power, one or more bands of power, absolute spectral power, normalized power, inter-burst interval, characteristics of a low-frequency band or a high frequency band, or the ratio between the two, relative spectral power, burst rate, burst duration, spike count, spike rate, correlation (either autocorrelation or correlation between data from 2 or more monopolar or differential sensed channels), correlation of time waveforms or one or more ranges of band-passed sensed activity, and/or coherence.
  • the measurements can be evaluated over a time interval and summary statistics can be provided.
  • Further measurements may be categorized, sorted, time-locked, correlated, normalized or otherwise evaluated in relation to measures such as blood pressure, a component of the cardiac cycle, heart rate, and/or other measures of the sympathetic and parasympathetic system.
  • measures such as blood pressure, a component of the cardiac cycle, heart rate, and/or other measures of the sympathetic and parasympathetic system.
  • the difference between measurements made before and after the provision of a renal denervation procedure can be used to assess the effectiveness of the procedure. Of these nerve measurements, the average voltage would be a preferred measurement.
  • the external equipment could also include a graphical display of the actual sensed signals (after signal conditioning such as amplification and filtering).
  • the electronic equipment can also allow a user to select and define at least one pair of electrodes that is being used to derive a signal that is displayed.
  • a switch control can be provided to enable a user to choose electrode-pair derivations such as 1 -2, 2-3 or 3-1, where each electrode is on a different conduit, would be desirable.
  • electrode-pair derivations such as 1 -2, 2-3 or 3-1, where each electrode is on a different conduit, would be desirable.
  • Other derivations where electrode 1 is referenced to an electrode located distal ly within a patient could also allow electrical activity to be localized to a more specific degree since the active electrode recording the activity would reflect nerve activity and the reference electrode would not.
  • Measurement may be made between two electrodes:
  • both PNASC and NSC devices of the present application normally include the control means in the proximal portion of the catheter that serves to limit the needle/wire penetration of the vessel wall which occurs distaliy. Accordingly, the PNASC and NSC would include one or more manual controllers, such as handles similar to those shown in FIG. 11 of US Patent No. 8,740,849. In an embodiment, these controllers would be used by the operator to cause first the expansion of the guide tubes and second, the advancement of the needles/electrodes.
  • US Patent No. 8,740,849 includes disclosure of a proximal section with separate ports for flushing of the catheter lumen and ablative fluid injection that may also be included in the embodiments disclosed in the present application which can have similar structures and controls in the proximal section.
  • conducting insulated wires provide conduction of electrical signals between distal electrodes/sensors and the external equipment attached to the wires near the proximal end of the catheter.
  • the insulated wires would typically run through the body of the catheter.
  • the PNASC can have radiopaque markers to show, during fluoroscopy, the extension of the needles through the artery wall into the periadventitial space.
  • the NSC also can have radiopaque markers on the sharpened wires to show under fluoroscopy the extension of the wires through the artery wail into the periadventitial space.
  • the sensor itself would likely be made of gold or platinum and serve as a radiopaque marker.
  • Another feature of the presently disclosed PNASC that ties into the PTAC disclosed by Fischeli in 8,740,849, is a design that reduces the internal volume of the injection lumens of the catheter (the "dead space"). It is anticipated that less than 0.5 ml of an ablative fluid such as ethanol will be needed to perform. Perivascular Renal Denervation (PVRD).
  • the dead space should be less than 0.5 ml and ideally less than 0.2 ml. With certain design features it is conceived that the dead space can be reduced to less than 0.1 ml. Having the insulted wires inside of the fluid injection lumen may further reduce the dead space volume.
  • Such features include using a small diameter ⁇ 0.5 mm ID hypotube for the inner tube used for fluid injection for the PNASC, and/or designing the proximal injection port and or injection manifold at the proximal end of the PNASC to have low volume by having small ⁇ 0.5 mm inner diameter and a short, ⁇ 2 cm length.
  • a wire attached to each distal sensor extends the entire length of the catheter and exits at or near the proximal end. In an embodiment this can occur with the wires exiting through a connector which permits electrical connection to an electronics module. While the preferred embodiment has the insulated wires running within the catheter body, it is also envisioned that the wires could be run outside of the catheter body.
  • the electronics module can include amplifiers for each sensor (or differential amplifiers for pairs of sensors), filters, analog-to-digital converters to digitize the signals and a central processing unit with memory (CPU) to process the signals and present measures related to nerve activity using a nerve activity visual display.
  • Nerve activity measurements can also be used to drive sonic transducers which provide auditory signals related to the nerve activity or the comparison of nerve activity to a treatment criterion. Auditory feedback and alarms may be provided based upon the measures and/or their assessment in relation to treatment or safety criteria such as thresholds.
  • the electronics module can be high level and allow sensed data from defined pairs of sensors to be displayed and actual measurements of nerve activity displayed. Alternatively, basic nerve activit 7 measurements can be reflected on a low level using a simple 5 LED display for each sensor,
  • a calibrate button can be used by a user in order to operate a calibration module and to normalize the sensed "nerve activity level" which occurs during or after ablation in relation to baseline measurements made during initial measurement of sympathetic nerve activity which occurred prior to ablation.
  • all 5 LEDs could be activated to show maximum activity.
  • the user could operate the electronics module to cause a post-therapy measurement to be obtained which can then be compared to the pre-therapy measurements.
  • the reduction in nerve activity between the pre-therapy measurement and the post-therapy measurement would be displayed by illumination of the new level as a normalized value (e.g., if 4 of the 5 LEDs were lit, then the normalized sensed activity would be in the 80% range (+/- 10%) of the baseline activity that occurred prior to ablation).
  • the therapy criteria might be defined as a reduction of the number of diodes that are lit, for example, 0, 1, or 2 out of 5. If the post denervation level is 40% of the normalized level for one of the sensors, then only 2 of the 5 LEDs would be lit showing a 60% drop in nerve activity.
  • An example of even simpler version would have a green, yellow and red LED for various sensors, wherein this example, green indicates normal nerve activity (e.g., in relation to the pre-abiation baseline), yellow indicates a partial reduction and red indicates a significant reduction.
  • the range used for normal does not need to be derived from a baseline sample for the patient can be a range defined as normal for the population (which can be a population norm value that is adjusted according to demographic variables such as gender and age and may also be adjusted according to physiological measurements of the patient such as blood pressure or according to medication taken by the patient).
  • a characteristic of the sound e.g. tone
  • a processor within the electronics can calculate an average measurement of the sensed activity over at least one specified measurement time interval.
  • the processor could then be configured to compare the post-ablation sensed activity over a similar, or different (e.g. shorter), duration of nerve activity measurement which occurs after ablation therapy.
  • the electronics of a sensing module can be configured to display a quantitative, numerical reduction value (e.g., "Nerve activity reduced by 64% compared to baseline nerve activity.")
  • the guide tubes are needle guiding elements for the advancement of the ultra-thin injection needles or sharpened wires that are advanced outwardly through the wall of the renal artery.
  • prior art such as Jacobson that describes curved needles that are advanced outwardly from a central catheter to penetrate the interior wall of a target vessel, have bare needles that are advanced on their own, and without structural support, from the distal end or the side of a catheter. Without additional guiding (support) during advancement, needles that are thin enough to not cause blood loss following withdrawal from the wall of the artery are generally too flimsy to reliably penetrate as desired into the vessel wall.
  • a key aspect of the small needle embodiments disclosed in the present application is the inclusion of needle guiding elements such as guide tubes that allow the ultra-thin injection needles to be reliably- advanced into the wall of a target vessel to the desired depth.
  • Such guiding elements need not be a tube or have a round cross-section.
  • the structure support can be realized by a half or partial tube, or they can be a structure with a slot that provides a guide for the advance-able needles.
  • a guiding structure could be any expandable structure such as a spring that expands outwardly and provides radial support and/or a guide for the needles.
  • expand and “expands” are intended to refer to motion of a structure from a first position relatively closer to a longitudinal axis of the catheter to at least a second position that is relatively farther away from the longitudinal axis, whether the motion is by expansion, deflection, pivoting, or oilier mechanism. It is desirable that the needle guiding elements expand outwardly from the central catheter.
  • the present disclosure like the PTAC of 8,740,849 includes the design of structures that provide radial ("backup") support for the needle guiding elements that provide resistance to the guiding elements backing away from the interior surface as the needles are advanced into the wall of the vessel.
  • PNASC Pulmonary Disease
  • COPD Chosteric Obstructive Pulmonary Disease
  • PTAC PTAC of Fischeil et al Ser. No. 13/752,062
  • a feature of the present application is to have a NSC that is percutaneously delivered with outwardly expandable sensors designed to penetrate into and/or through the renal artery wall into the periadvential space where the sensors can be used with associated external electronics to measure sympathetic nerve activity, including changes in the level of sympathetic nerve activity following a renal denervation procedure.
  • a NSC percutaneously delivered with outwardly expandable sensors designed to penetrate into and/or through the renal artery wall into the periadvential space where the sensors can be used with associated external electronics to measure sympathetic nerve activity, including changes in the level of sympathetic nerve activity following a renal denervation procedure.
  • Such an NSC could be used with any renal denervation system or device.
  • a feature of the presently disclosed PNASC is to have a percutaneously delivered catheter with expandable supported needle guiding elements through which injection needles are advanced for injection of an ablative fluid into or beyond the outer layers of the renal artery with sensing electrodes and associated external electronics to measure sympathetic nerve activity, including changes in the level of sympathetic nerve activit 7 following a renal denervation procedure,
  • Another aspect of the present application is to have an electronics module external to the PNASC or NSC which amplifies the signal from the distal sensors located in the perivascular space and provides a display of nerve activity to allow the user to identify the effectiveness of the nerve ablation procedure such as a renal denervation procedure.
  • Still another aspect of the present disclosure is to have embodiments with at least three guide tubes/needle guiding elements in the PNASC each having a radiopaque marker.
  • the guide tubes/needle guiding elements being manually expandable outwardly from within a set of tubular shafts which provide additional support and backup to stabilize each guide tube/needle guiding element against the interior wall of the target vessel. Expansion of the guide tubes/needle guiding elements is accomplished by manipulation of a mechanism in the proximal portion of the catheter.
  • NSC and PNASC of the present disclosure are to include one or more of the following radiopaque markers to assist in positioning, opening, closing and using the PNASC. These include the following:
  • Wires of radiopaque metals such as gold or platinum to conduct the signals from the distal sensors to the electronics module.
  • the distal fixed guide wire of the PNASC being radiopaque (e.g., using platinum wire);
  • a catheter for sensing the activity of nen/es outside of the mterior wall of a target vessel of the human body.
  • the catheter comprises a catheter body, having a central axis extending in a longitudinal direction and also having a central lumen.
  • At least two needle guiding elements are provided, and adapted to expand outwardly toward the interior wall of the target vessel.
  • At least two needles, each needle having a distal electrode are adapted to be advanced outwardly guided by the at least two needles guiding elements, to penetrate the interior wall of the target vessel and advance further into the tissue outside of the inside wall of the target vessel.
  • At least two wires are provided for conducting signals sensed by at least two electrodes, the wires connecting the electrodes to external equipment outside of the catheter.
  • each needle guiding element is a guide tube, having a lumen, for receiving a needle therethrough.
  • the catheter may include at least three needle guiding elements, three needles, and three insulated wires.
  • a catheter for sensing the electrical activity of extravascular tissue at a target site.
  • the catheter comprises an elongate flexible body, and at least one flexible extendable arm having a sharpened tissue penetrating tip carried by the body.
  • the extendable arm is movable between a first position in which the tip is positioned within the body and a second position in which the tip is displaced radially outwardly from the body to penetrate tissue and reach the target site.
  • An electrode is carried by the extendable arm, and an electrical conductor extends through the body and is in electrical communication with the electrode.
  • the catheter comprises three flexible extendable arms.
  • a needle support element in the form of a support tube or guide tube is provided for each flexible extendable arm.
  • the support tubes are movable between a first position within the body and a second position extending away from the body.
  • the flexible extendable arms are movable through the support tubes.
  • a dual purpose catheter for both disrupting and evaluating the electrical conductivity of a nerve.
  • the disruption function is provided by application of electrical voltages between at least one pair of electrodes. Such voltages can produce electroshock, electrocautery or RF ablation depending on the amplitude, duration, and frequency of the signal and the material and structure of the electrodes.
  • the dual purpose catheter comprises an elongate flexible body, and at least two tissue penetrating probes extendable laterally from the body.
  • a fluid effluent port is provided on each probe, each fluid effluent port in fluid communication with a fluid supply lumen extending through the body.
  • An electrode is carried by each probe, each electrode in electrical communication with a unique conductor extending through the body.
  • each tissue penetrating probe is movably advanceable through a tubular support.
  • a method of evaluating nerve ablation in a patient using a catheter system configured to provide sensing of nerve activity and electronics configured for sensing, evaluation, and display of measures derived from sensed data.
  • the method compri ses the steps of providing a catheter having an elongate flexible body with a proximal end, a distal end and a first electrode earned by the distal end.
  • the first electrode is movable between a retracted position within the catheter and an extended position for piercing a vessel wall.
  • the electrode communicates signals from the distal end along an electrically conductive conduit to a connector in the proximal end of the catheter which communicates with electronics to provide sensing.
  • the evaluation of sensed data includes a step wherein the distal end of the catheter is positioned at an intravascular site within the patient.
  • the first electrode is advanced into the wall of the vessel, and an electrical characteristic of one or more nerves is measured.
  • the measuring step may include placing the first electrode and a second electrode into electrical communication with electronics including an instrument electrically coupled to the proximal end of the catheter to receive data from at least the first electrode through the proximal end.
  • the second electrode may ⁇ be carried by the catheter and can terminate in the proximal end of the catheter, or may be routed outside of the catheter or simply be in contact with the patient's skin.
  • a catheter system for energy based renal denervation from two or more electrodes that are placed more than 2mm deep to (radially outside of) the location of the pain nerves of the renal artery so as to ablate the sympathetic nerves that are radially outside of the arterial media while reducing the pain to the patient as compared with energy based denervation from inside of the renal artery.
  • Tire catheter system for sensing nerve activity in the volume of tissue just outside of the vessel within the human body.
  • Tire catheter system comprises electronic equipment designed to measure nerve activity, a first electrode, and a second electrode.
  • the first and second electrodes may be incorporated near the distal end of the catheter, the catheter including a mechanism to position the distal electrodes into the volume of tissue outside of the inside wall of a vessel of the human body.
  • the position of the electrode may be selected to be a location in the outer layer of the vessel wall, or a location in tissue that lies radially outside of the outer layer of the vessel (e.g. extravascular tissue).
  • Conductive wires are adapted to connect the first and second electrodes to the electronic equipment.
  • a method and systems for treatment of extravascular/perivascular tissue such as denervation of renal nerves, while minimizing or eliminating pain to the patient from the ablation portion of the procedure.
  • Pain associated with first generation RF renal denervation devices may be attributable to the nonspecific destruction of nerves associated with the vessel wall. Pain is believed to be associated with destruction of unmyelinated "C-fibers" which may am in or just outside of the media (smooth muscle layer) of the vessel or in or just outside of the external elastic lamina (outer skin of the media).
  • the sympathetic nerve fibers that affect blood pressure are predominantly the "efferent" nerves that transmit signals from the brain to the kidney and back.
  • intravascular energy delivery by ultrasound or RF will ablate tissue from the endothelium (the inside layer) of the artery all the way to the adventitia, thus damaging both unmyelinated "C-fibers" causing pain as well as a portion of the sympathetic nerve fibers, intravascular energy delivery may be limited in efficacy as it is limited in its ability to ablate the sympathetic nerves outside of the adventitia without causing irreparable damage to the artery.
  • locating the distal tip of the electrodes to locations in the adventitia or outside of the adventitia not only increases the effectiveness of ablative agents or energy that is delivered, but also locates the sensing electrodes in one or more locations that are near the relevant nerves in order to measure relevant nerve activity.
  • one aspect of the present invention provides a catheter for preferentially denervating efferent nerves while sparing unmyelinated C-fibers adjacent a target vessel.
  • the catheter comprises an elongate, flexible catheter body having a central axis extending in a longitudinal direction; at least two electrode guiding elements adapted to expand outwardly toward the interior wall of the target vessel; at least two electrodes, each electrode having a distal uninsulated electrode tip, the at least two electrodes adapted to be advanced outwardly, guided by the at least two electrode/needle guiding elements, to penetrate the interior wall of the target vessel and position the electrode tips beyond the external elastic lamina.
  • each electrode guiding element is a guide tube having a lumen.
  • Each electrode may be advanced outwardly coaxially through the lumen of a guide tube.
  • At least three electrode guiding elements and three electrodes may ⁇ be provided.
  • a catheter for localized RF ablation of extravascular tissue at a target site while sparing adjacent endothelium comprises an elongate, flexible body; at least one flexible extendable arrn having an electrically conductive tip carried by the body of the catheter, the extendable arm movable between a first position in which the electrically conductive tip is positioned within the body of the catheter and a second position in which the tip is displaced radially outwardly from the body to penetrate tissue of a target vessel and reach the target site, such that the electrically conductive tip is positioned completely beyond the endothelium of a target vessel.
  • the catheter will include at least three flexible extendable arms.
  • a support tube movable between a first position within the body and a second position extending away from the body may be provided the flexible extendable arrn extends through the support tube.
  • One method of some embodiments of the present invention comprises operating a catheter system designed for preferentially denervating efferent nerves while sparing unmyelinated C-fibers adjacent a target vessel to treat hypertension while minimizing procedure discomfort.
  • the method can comprise the steps of providing a catheter system having an elongate, flexible body with a proximal end, a distal end, and a first electrode carried by the distal end, the first electrode movable between a retracted position within the catheter and an extended position for piercing a vessel wall; positioning the distal end of the catheter at an intravascular site within the patient; advancing the first electrode into the vessel wall at a puncture site; and denervating tissue at a first depth deep to (outside of) the external elastic lamina to preferentially denervate efferent nerves while sparing unmyelinated C-fibers at a second depth near to or within the external elastic lamina, the second depth less than the first depth.
  • the method above can include using the electrodes to sense electrical activity primarily from the efferent nerves and this may occur both before and after ablation so that the sensed data may be evaluated to determine the efficacy of the ablation.
  • Another aspect of the method of minimizing pain during renal denervation comprises the steps of advancing a distal end of a catheter transiuminaliy to a site in a renal artery; advancing an ablation element from the catheter, through the media and into the adventitia; and ablating tissue within the adventitia while sparing the media.
  • the ablation element may dispense an ablative fluid delivered from an effluent fluid port.
  • the ablation element may comprise an energy delivery element including at least one of a: radiofrequency (RF), microwave, cryogenic, ultrasound, electrocauter ', or heating element.
  • RF radiofrequency
  • the ablative element e.g., conductive surface of an electrode; fluid from an effluent port
  • the catheter permits blood perfusion through the renal artery during the ablation and/or nerve activity sensing procedures.
  • perivascular energy based ablation will be more effective than intravascular is that it is less damaging to the media that will be cooled by the significant blood flow through the artery, while there is much less cooling in the perivascular space.
  • PNASC that can provide both RF ablation and medication deliver ⁇ ', is that an anesthetic such as Iidocaine could be injected before the RF ablation procedure to also provide minimal or no pain to the patient during nerve ablation.
  • sensor and electrode may be used interchangeably here to describe a conducting electrical contact which forms the distal end of the conduit 20
  • sharpened wire and needle may be used interchangeably to refer to a sharpened distal portion that penetrates the through a vessel or artery.
  • the catheter based system of the present disclosure can, in some embodiments, be varied, either by using hollow or solid conduits, and also by adjusting the equipment (e.g., to provide delivery of ablative or anesthetic fluid) and electronics (e.g., for proving sensing, stimulation, and or ablation) that are operated at the proximal end of the catheter.
  • the catheter system can serve as, in some embodiments, at least one of the following novel embodiments to provide advantages over the prior art:
  • a sensing catheter system that can provide sensing that is used to assess ablation provided by a treatment catheter configured to provide ablation such as by RF, ultrasound, or ablative fluid:
  • catheter system of (a) configured with hollow, rather than solid, conduits in order to provide local anesthetic such as Iidocaine:
  • a catheter system that can provide both sensing and ablation, wherein the ablation treatment is provide by RF, ablation fluid, or ultrasound;
  • a catheter system configured with hollow rather than solid conduits in order to provide local anesthetic such as Iidocaine and also energy based ablation by ultrasound or RF based ablation;
  • a catheter system of a to £ configured to provide at least one of sensing, stimulation, and ablation in a monopolar or bipolar fashion using at least one distal tip of a conduit;
  • a catheter system of a to f configured to provide at least one of sensing, stimulation, and ablation using conduits that pierce the inner wall to reside in the perivascular space outside of a renal artery of a patient:
  • a catheter system configured to provide ultrasonic stimulation using a stimulation element residing, at least in part, in the perivascular space outside of a renal artery of a patient.
  • Nerve Sensing Catheter 10 which utilizes solid conduits at the distal tip of the catheter;
  • Nerve Sensing Catheter NSC 100 which utilizes hollow conduits at the distal tip of the catheter;
  • Ultrasound Nerve Ablation catheter UNAC 600 also disclosed herein is a catheter for sensing the activity from nerves outside of the lumen of a target vessel of a human body.
  • the catheter can include a catheter body having a distal end for insertion into a patient, a proximal end for controlling the movement of at least one needle, and a central axis extending in a longitudinal direction.
  • the catheter can also include a connector configured to connect to external electronic equipment outside of a proximal end of the catheter.
  • Hie equipment can have a sensing subsystem configured for sensing local nerve activity within a patient, and can be configured to be connected to at least one additional electrode in electrical contact with the patient.
  • the catheter can also include at least one needle guiding element adapted to expand outwardly from the catheter body toward the interior wall of the target vessel.
  • the catheter can also include at least one needle, the needle having at least one distal electrode, the needle adapted to be advanced outwardly, guided by the at least one needle guiding element to penetrate and advance through the interior wall of the target vessel into the tissue outside of the vessel lumen.
  • the catheter can also include at least one wire for conducting electrical signals between the at least one electrode and the connector for communicating with said external electronic equipment.
  • conduit will mean a structure in a catheter that can be utilized to transmit electrical energy and/or fluid between a proximal end of the catheter and tissue within a human body.
  • injector tube with distal injection needle is used to specify a tube with a sharpened distal end that penetrates into tissue and is used to inject a fluid into that tissue.
  • a stmcture could also be called a hypodermic needle, an injection needle or simply a needle.
  • element and structure may be used interchangeably within the scope of this application.
  • Luer fitting may be used throughout this application to mean a tapered Luer fitting without a screw cap or a Luer Lock fitting that has a screw cap.
  • needle will be used throughout this disclosure to characterize a small diameter sharpened wire or tube designed to penetrate through the wall of a target vessel, its primary characteristic being a sharpened tip.
  • the distal portion of the sharpened wire as disclosed herein is also a needle.
  • ablative fluid, ablative solution and/or ablative substance will be used interchangeably to include a liquid, gel, suspension, or a gaseous substance delivered into a volume of tissue in a human body with the intention of damaging, killing or ablating nerves or tissue within that volume of tissue.
  • inside wall or interior surface applied to a blood vessel, vessel wall, artery or arterial wall mean the same thing which is the inside surface of the vessel wall, or the "intimal" surface of the vessel lumen.
  • injection egress is defined as the distal opening in a needle from which a fluid being injected will emerge. With respect to the injection needle, either injection egress or distal opening may be used here interchangeably.
  • FIG. 1 is a schematic view of the distal portion of an NSC which uses three expandable sharpened wires in its open position as it would be when manually expanded for measurement of the activity of nerves such as the sympathetic nerves outside of the renal artery.
  • FIG. 2 is a longitudinal cross-section of a distal postion of the NSC of FIG. 1 in its open position.
  • FIG. 3 is an enlargement of region S3 of the NSC of FIG. 2.
  • FIG. 4 is an enlargement of region S4 of the NSC of FIG. 2.
  • FIG. 5 is a longitudinal cross-section of the central portion of the NSC showing the three proximal hypotubes.
  • FIG. 6 is a schematic view of the distal portion of either the NSC or PNASC both of which use three expandable NITINOL tubes with distal electrodes that act as sensors for nerve activity. The view shows the NSC or PNASC in the open position following manual expansion,
  • FIG. 7 is a longitudinal cross-section of a distal portion of the NSC of FIG. 1 in its open position.
  • FIG. 8 is an enlargement of region S8 of the NSC of FIG. 2.
  • FIG. 9 is an enlargement of region S9 of FIG. 8.
  • FIG. 10 is a transverse cross section at 10-10 of FIG. 9.
  • FIG. 1 1 is an enlargement of region S I 1 of the NSC of FIG. 7,
  • FIG. 12 is a longitudinal cross section of another embodiment of the distal portion of the artery penetration portion of the NSC.
  • FIG. 13 shows a modification of the distal portion of FIG. 12 that modifies the NSC design into a PNASC design by the addition of side holes for fluid injection into the perivascular space.
  • FIG. 14 is a longitudinal cross section of yet another embodiment of the distal portion of the PNASC of FIG. 8 that would replace the embodiment of the distal needles shown in FIG. 9.
  • FIG. 15 is a longitudinal cross-section of the central portion of the NSC/PNASC showing the three proximal hypotubes.
  • FIG. 16 is a schematic view of the mechanisms at the proximal portion of the NSC/PNASC.
  • FIG. 17 is a longitudinal cross section of the PNASC configured for providing ultrasound-based nerve ablation.
  • FIG 18 is an enlargement of section S18 of FIG. 17.
  • FIG. 19 is an enlargement of section S19 of FIG. 17.
  • FIG . 20a is a schematic view of a method for using the PNASC.
  • FIG. 20b is a schematic view of an alternative method for using the PNASC.
  • FIG. 21 is a schematic view of the electronics that provide stimulation and/or sensing at the proximal portion of the NSC PNASC.
  • FIG. 22 shows the modules through that may be included in the program memory of the electronics.
  • FIG. 1 is a schematic view of the distal portion of a Nerve Sensing Catheter (NSC) 10 that is designed to sense electrical energy (currents or voltages) from extra-vascular tissue within a human body.
  • the NSC may also deliver electrical energy to tissue, for example, to provide for obtaining and assessing evoked activity.
  • the NSC 10 is shown in its open position, showing an inner tube 11, middle tube 12, outer tube 13, outer tube extension 14 having distal openings 15 through which the guide tubes 30 with radiopaque markers 36, distal tip 34 and outer layer 32 are advanced outwardly from the body of the NSC 10. Also shown is the tapered section 16 and fixed guide wire 40 with distal tip 42.
  • the NSC includes three conduits 20 with outer insulation 22, and sharpened wire 24, with 2 of the three guide tubes and conduits shown in their fully deployed positions (the third is not shown).
  • the sharpened wires 24 are made from or coated with a radiopaque material such as gold or platinum.
  • the conduits 20 am all the way to the proximal end of the NSC 10 where they interface with electronic equipment 500 that provides sensing (as shown in FIG . 21).
  • the distal tips 24 of the conduits 20 are shown here in the distal portion of the NSC 10.
  • the conduits 20 extend through the catheter body within the lumen of the inner tube 11.
  • the insulation 22 that insulates the conduits within the catheter body does not extend around the most distal portion of the conduit 20 since this portion terminates as a sharpened wire/needle 24 which will penetrate the vascular wall and act as an electrode for sensing nerve activity from a perivascular location.
  • conduits 20 of FIGS, 1-5 are realized as solid insulted wires, while the conduits of FIGs 6-1 1 are realized as hollow tubes, with the understanding that the two variations of the embodiments should not be considered limiting and may be realized approximately interchangeably, or both may be incorporated into various embodiments, to realize advantages disclosed herein without departing from the scope of the invention.
  • the openings 15 in the distal portion of the catheter support the guide tubes 30 as the guide tubes 30 are advanced outwardly in order to provide structural support during the subsequent deployment of the conduits 20, .
  • the NSC 10 of FIG. 1 has three guide tubes 30, it is envisioned that other embodiments could have as few as one or as many as eight guide tubes with an optimum, number typically being three or four in the case of renal denervation.
  • a larger diameter target vessel might suggest the use of as many as 4 to 8 guide tubes 30 and conduits 20.
  • the conduits 20 may be adapted to be hollow to also provide a passageway for fluid injection near the tip of the sharpened wires 24.
  • a modified version of the NSC is disclosed herein, that provides both nerve sensing and nerve ablation capabilities. This dual function catheter will be called a Perivascular Nerve Ablation and Sensing Catheter (PNASC).
  • PNASC Perivascular Nerve Ablation and Sensing Catheter
  • the modifications can include:
  • distal openings (or windows) 15 in the outer tube extension 14 where the guide tubes 30 exit are envisioned. These possible shapes include and oval or round shapes such as a racetrack design with curved (e.g., round) proximal and distal ends and straight sides in the axial direction. It is also envisioned that there could be a movable flap (not shown) covering each opening 15, or a slit that could be opened to make the outer surface of the NSC smooth for better delivery through a guiding catheter into the renal artery. Such a moveable flap could be operated under the control of the catheter handle in the proximal section of the catheter. The mechanical operation of the catheter can function so that the flaps are retracted prior to the guide tubes 30 being deployed. Alternatively the flaps may be made flexible and soft enough that these are simply pushed aside by the guide tubes 30 upon deployment.
  • the guide tubes 30 serve as needle (i.e., conduit) guiding elements that provide structural support for the ultra-thin conduits 20.
  • needle i.e., conduit
  • prior art such as Jacobson that describe curved needles that are advanced outwardly from a central catheter to penetrate the wall of a target vessel, have needles that are advanced on their own (naked) from, the distal end or side of a catheter.
  • needles/sharpened wires that are thin enough to essentially eliminate the risk of bleeding following penetration and withdrawal from the wall of the artery are generally too flimsy to reliably penetrate as desired into the vessel wall.
  • the NSC 10 of the present application preferably includes needle-guiding elements such as the guide tubes 30 that allow the ultra-thin conduits 20 to be reliably supported and advanced into the wall of a target vessel to the desired depth.
  • the guiding elements also serve to center the catheter within the vessel and to promote reliable, similar, and measured deployment of all three sharpened wire tips 24 through the vessel wall.
  • the three conduits 20, sensors 24 and guide tubes 30 are spaced uniformly around the circumference of the catheter 10 at approximately 120 degrees separation.
  • the uniform spacing improves the sensing performance of the NSC 10. It is also envisioned that the spacing might be non-uniform for example two might be 50 degrees while the third could be 155 degrees from either of the first two.
  • a catheter for sensing the activity from nerves outside of the lumen of a target vessel of a human body- can only include one conduit 20.
  • a portion of the body of the NSC 10 such as the outer tube extension 14 will typically be pushed against the inside wall of the artery diametrically opposed to the contact point where the needle guiding element/guide tube 30 expands outward to contact the wall of the artery.
  • FIG. 2 is a longitudinal cross-section of a distal portion of the NSC 10 as shown in FIG. 1.
  • the proximal portion of this figure shown on the left side shows the three concentric tubes, the outer tube 13, middle tube 12 and inner tube 11 which form the central portion of the NSC 10.
  • the outer tube 13 is attached at its distal end to the outer tube extension 14 which is in rum. attached to the tapered section 16.
  • the fixed guide wire 40 with core wire 42 and outer layer 44 extends past the distal end of the tapered section 16. It should be noted that only part of the length of the guide wire 40 is shown in FIG. 2, its full length is shown in FIG. 1. Enlargements of the sections S3 and S4 of FIG. 2 are shown in FIGS. 3 and 4 respectively.
  • FIG. 2 shows two of the three guide tubes 30 with outer layer 32, distal tip 34 and radiopaque marker 36 in their fully deployed positions as advanced through the openings 15 in the outer tube extension 14.
  • the interior surface of the outer tube extension 14 forms part of the tubular shaft 21 that lies within the outer tube extension 14 and which is preferably made from a stiff material such as a high durometer plastic or metal so that the shaft 21 will be relative rigid as the guide tubes 30 are advanced and retracted.
  • the conduit 20 comprising an insulated outer layer 22A and core wire 24 with the exposed shaipened distal tip portion 24.
  • the uninsulated distal portion of the core wire 24 forms the electrode 25 which acts as a sensor.
  • a sensor may operate either in combination with either or both of the other two electrodes 25 at the ends of the other two conduits 20, for example, the first electrode/sensor 25 can be active and can be referenced to the second or third electrode 25 using a differential amplifier of the electronics.
  • the electronics may be used to select which combination of sensors is used during sensing or for stimulation to measure evoked nerve activity as well as whether other sensors (not shown) in other areas may be used to obtain sensed data.
  • the core wires 24 are ideally made from a memory metal such as NITINOL or a stiff springy material such as stainless steel or "L605" which is a cobalt chromium alloy. While L605 is a fairly radiopaque material, if NITINOL or stainless steel is used, the distal portion of the wire 24 should be coated, at least in part, in a radiopaque material such as gold, platinum or tantalum.
  • a sensor 25 may be referenced to a distally located electrode that is in electrical communication with the patient in order to provide monopolar sensing in relation to the renal nerve activity recorded from the distal tip sensor 25.
  • the advantage of the current invention is that one or more sensors can be used to measure nerve activity of the sympathetic nerves while located in the perivascular space outside of a renal artery of a patient after being deployed from an intravascular location.
  • nerve sensing is performed in a responsive method where one or more electrodes 25 may be used to provide both non- ablative electrical stimulation and also sensing in order to assess evoked, 'time-locked", or “synchronized” nerve activity, or to provide nerve stimulation in order to evoke a different type of change which may be assessed, for example, by a distally located sensor (e.g., a blood pressure or distally located ECG sensor).
  • a distally located sensor e.g., a blood pressure or distally located ECG sensor.
  • the catheter system is configured as a PNASC for electrical ablation, then the electrodes 25 can be configured to provide either bi-polar or monopolar electrical energy delivery.
  • the central buttress 19 shown in FIG. 2 supports the guide tubes 30 both as these are pushed distally and after they are fully deployed.
  • This central buttress 19 also provides radial support for the advanced guide tubes 30 that prevents the guide tubes 30 from backing away from the interior wall of the target vessel as the conduits 20 are advanced through the guide tubes 30 forward and the electrodes 24 arrive at their desired positions such as in the periadventitial space 2-10 mm beyond the interior wall of the target vessel .
  • Additional lateral support for the guide tubes 30 are provided by the sides of the openings 15 that, in combination with the central buttress 19, provide both radial and circumferential/lateral support.
  • the support can in some embodiments be advantageous both during guide tubes 30 advancement and their outward expansion as well as providing additional support during delivery of the injection needles of the conduits 20 through the interior wall of the target vessel.
  • the buttress may- comprise a deflection surface such as a curved or linear ramp, which may, in a curved embodiment, correspond to the curvature of the outer surface of the guide tubes 30.
  • another feature of the NSC 10 is that each conduit 20 is biased to have a central axis with the same, or nearly the same, radius of curvature as the central axis of its corresponding guide tube 30 when measured in an unconstrained state.
  • the length of the guide tubes 30 is preferably at least as Song as the distal curved portion of the conduits 20. This design constrains the curved portion of each conduit 20 within the lumen of the guide tube 30 so that the conduit 20 cannot twist or change position.
  • the plastic cylinder 17 attaches the inner tube 11 to the three conduits 20.
  • the inner tube I I and plastic cylinder 17 can slide along the longitudinal axis of the NSC 10 inside of the middle tube 12 which is shown with uniform diameter over its length including the portion coaxially outside of the plastic cylinder 17.
  • the middle tube 12 attached to the guide tube connectors 18 under the control of the catheters handle mechanisms to cause the advancement and retraction of the guide tubes 30.
  • the inner tube 11 attached to the plastic cylinder 17 under the control of the catheters handle mechanisms to cause the advancement and retraction of the conduits 20.
  • FIG. 3 is the enlargement of section S3 of the longitudinal cross- section of the NSC 10 as shown in FIG. 2.
  • FIG. 3 shows the details of the guide tubes 30 with interior layer 38, outer layer 36, distal end 34 and radiopaque marker 32.
  • Coaxially within the lumen of the guide tube 30 is the conduit 20 with insulated outer layer 22A and core wire 24 with needle tip 23.
  • the uninsulated distal portion of the conduit 20 which is the core wire 24 forms the electrode 25 for sensing nerve activity such as sympathetic nerve activity in the perivascular space outside of the renal artery.
  • the other two of the three conduits 20 also have their own respective insulated layers 22B (shown in cross section for a different injection needle) and 22C (not shown).
  • Radiopacity of the tip of each of the conduits 20 can in some embodiments be important so that it can clearly be seen that the needle tips 23 are situated in an intended location such as in the perivascular space. This can be accomplished by using a dense metal such as gold or platinum for the core wire 24 or by attaching a radiopaque marker at or near the tip 23 of the core wire 24. Plating the needle tip 23 with gold could also be effective.
  • the guide tubes 30 are advanced out of, and retracted back into, the tubular shaft 21 through distal openings 15. In one embodiment, the three guide tubes 30 are attached to each other near their proximal ends by the guide tube connector 18. FIG.
  • FIG. 3 also clearly shows how the guide tube 30, when advanced against the central buttress 19 is forced outwardly and is supported by the curved ramp 29 of the central buttress 19 as well as the sides of the opening 15 of the tubular shaft 21.
  • the central buttress 19 also has proximal fingers 27 that provide additional lateral support for the guide tubes 30.
  • the outer tube extension 14 connects at its distal end 14a to the tapered section 16 which in turn lies coaxial i around the guide wire 40 with core wire 42 and outer layer 44.
  • the penetration depth LI which is the distance from the distal end of the guide tube 34 to the distal end 23 of the core wire 24.
  • Mechanisms at the proximal section of the NSC 10 control the motion of the distal components of the NSC 10 including the guide tube 30 and the conduits 20.
  • the proximal section also includes the mechanisms to limit and/or adjust the penetration depth LI of the distal end 23 of the conduits 20.
  • the proximal section also includes mechanisms to adjust the deployment length of the guide tubes 30 similar to the mechanisms used to adjust or limit the depth of penetration of the conduits 20 beyond the distal end of the guide tubes 30.
  • the central buttress 19 and distal openings 15 can, as shown in FIG. 3, be separate components of the NSC 10 or they can be formed as a single molded or machined part as is shown in FIG. 17 of Fischell et al US Patent no. 8,740,849.
  • the distal tip 45 of the central buttress 19 provides the attachment to secure the buttress 19 to the tapered section 16.
  • the butiressl9, distal openings 15 and tapered section 16 could be a single molded or machined component.
  • the NSC 10 has the guide tubes 30 with a pre-formed curved shape
  • flexible naturally straight guide tubes are also envisioned where the buttress 19 forces the straight guide tubes to curve outwardly for extension through the interior wall of the target vessel.
  • the key function of the buttress 19 is the deflection surface such as ramp 29 that provides both radial and lateral support for the deployed guide tubes 30.
  • the curved ramp 29 of the buttress 19 supports and guides the outward motion of the guide tubes 30 as they exit though the distal openings 15 and also provides radial support for the guide tubes 30 and conduits 20, as they come into contact with (engage) and then pierce through the interior wall of the target vessel .
  • Additional lateral support is provided by the fingers 27 of the central buttress 19 and the sides of the tubular shaft 21 and sides of the openings 15. Such lateral support ensures that the guide tubes move radially outward without deflections in the circumferential (transverse to the longitudinal axis of the catheter) direction.
  • central buttress 19 shown in FIG. 3 is a plastic part
  • a radiopaque metal part such as stainless steel, or a coating
  • a plastic material that includes radiopaque filler such as tungsten
  • a radiopaque marker could be attached to a portion of the openings 15 or buttress 19 or outer tube extension 14 to show the likely spot where the guide tubes 30, and thus the conduits 20, would engage the interior wall of the target vessel.
  • the plastic cylinder 17 (shown in FIG. 2) can be a molded part or be epoxy or another resin that is injected to affix the conduit wires 20 together within the lumen of the inner tube 11.
  • any or all of the inner tube 11, middle tube 12 or outer tube 13 could also be a metal hypotube or a metal reinforced plastic tube.
  • the conduits 20 would typically be made of a springy or shape memory rnetal such as niiinoi or a denser metal such as the cobalt chromium alloy L605. It is also envisioned that to enhance radiopacity, the uninsulated distal ends 23 of the wires 24 could be plated in gold or other radiopaque material. Another way could be to have a gold cap attached to the distal end needle tip 23 of the core wire 24.
  • the insulated layers 22A, 22B and 22 C are of a plastic material or any insulating coating.
  • the guide tube 30 radiopaque marker 32 could be made of a radiopaque material such as gold, platinum or tantalum or an alloy of these or similar metals.
  • the core wire 42 of the fixed guide wire 40 would typically be stainless steel and the outer layer 44 would be wrapped platinum or platinum iridium wire.
  • the outer layer could also be a polymeric material. Any or certain portions of the outside of the NSC 10 could be lubricity coated to provide improved performance, in typical embodiments for renal nerve ablation, the conduits 20 should be smaller than 0.5 mm in diameter and preferably less than 0.3 mm in diameter to avoid any blood loss or leakage as the conduits 20 penetrate into the wall of the target vessel and are then removed.
  • FIG. 4 is the enlargement of section S4 of FIG. 2 showing the transition from the central portion of the NSC 10 to the distal portion of the NSC 10, including the outer tube 13, middle tube 12 and inner tube 11. Also shown is the connection between the outer tube 13 and the outer tube extension 14.
  • the guide tube connector 18 connects the three guide tubes 30 to the middle tube 12 that provides the impetus for advancement and retraction of the three guide tubes 30.
  • the motion of the middle tube 12 is produced by the motion of control mechanisms at the proximal end of the NSC 10.
  • the plastic cylinder 17 lies inside of the distal portion of the inner tube 1 1 and connects together the three conduits 20 with core wires 24 and insulated layers 22A, 22B and 22C (not shown), so that advancement and retraction of the inner tube 11 provides simultaneous advancement and retraction of the conduits 20. Also shown in FIG. 4 are the flushing spaces between the several tubes.
  • FIG. 4 also shows how the conduit 20 with insulating layer 22A extends from the distal end of the plastic cylinder 17 inside the distal end of the inner tube 1 1 and then enters the lumen of the inner layer 38 of the guide tube 30 at the proximal end of the guide tube 30.
  • the guide tubes 30 and guide tube connector 18 are attached coaxially within the distal section of the middle tube 12.
  • longitudinal motion of the middle tube 12 will cause longitudinal motion of the guide tube connector 18 and guide tubes 30 thus allowing the mechanism at the proximal section of the NSC 10 to advance and retract the guide tubes 30 with respect to the outer tube 13 and outer tube extension 14.
  • the penetration depth limitation advantage of the catheter system 10 could be realized in various manners. In one embodiment, this is accomplished using a mechanism that limits the forward motion of the distal end of the inner tube 1 1 with respect to the guide tube connector 18. For example, a ring or other structure situated between the distal end of the inner tube 1 1 or plastic cylinder 17 and the proximal end of the guide tube connector 18 would lim it the forward (towards distal end of the catheter) motion of the distal end of the inner tube 11 and thus limit penetration of the conduits 20 beyond the distal ends 34 of the guide tubes 30. Such an extension limiting structure could be unattached, or attached to at least one internal structure of the NSC 10 shown in FIG.
  • Such an extension limiting structure could also have a length adjustment such as screw threads that would allow it to be used by a user prior to, or after, insertion in a patient to adjust or calibrate the penetration depth L of the conduits 20 beyond the distal ends 34 of the guide tubes 30.
  • the structure of the NSC 10 shown in FIG. 4 is similar to that of FIG. 5 of Fischell et al patent no. 8,740,849. While 8,740,849 shows transverse cross sections for clarity they will not be shown here as they are nearly identical except that in the illustrated embodiments the injector tubes with a platinum core wire are now the conduits 20.
  • the insulated conduits 20 may be realized as either solid wires or hollow wires which allow fluid to be provided at the distal tips 23 such as to provide, for example, fluid-based ablation (when embodied as an PNASC), an ablative fluid, saline, or anesthetic fluid as part of the procedure.
  • the conduits 2.0 may be configured to provide fluid related to a sensing procedure.
  • FIGS. 8-11 of US Patent No. 8,740,849 also show a set of schematic views that illustrate how the PTAC 100 disclosed therein is used for perivascular renal denervation. The same schematic views are applicable in embodiments of the NSC 10 of the current invention with conduits 20 replacing the injector tubes with sharpened distal needles of the PTAC 100.
  • FIG. 5 illustrates longitudinal cross-sections of the three portions of the central section of the NSC 10 of FIGS. I through 4 representing its proximal, central and distal portions. At the proximal end of the proximal portion of the NSC 10 are three concentric metal hypotubes, an outer hypotube 82, middle hypotube 83 and inner hypotube 85.
  • the outer hypotube 82 of the NSC 10 attaches at its distal end to a proximal portion of the plastic outer tube 92 typically made from a relatively high durometer plastic, for example polyimide.
  • the proximal plastic tube 92 attaches at its distal end to the proximal end of the outer tube 13 also shown in FIGS. 1 through 4.
  • the outer tube 13 is typically made from a lower durometer/more flexible plastic than the proximal plastic tube 92.
  • the middle hypotube 83 is attached at its distal end to the middle tube 12.
  • the inner hypotube 85 is attached at its di stal end to the proximal end of the inner tube 11.
  • plastic cylinder 17 that connects the inner tube 11 to the conduits 20 as shown in FIG. 4.
  • the plastic cylinder 17 allows movement of the inner tube 85 that in turn moves the tube 11 to move all three conduits 20 in the proximal and distal directions
  • FIGS. 6 through 11 show an alternative embodiment of the NSC 100 which is different than that shown in figures 1, 2 and 3 in thai the conduits 120 are configured to be hollow while the conduits 20 of FIGS. 1 -5 were disclosed mainly as solid insulted wires.
  • the conduits 120 include a sensor tube 116. Inside the sensor tube 116 is an insulated wire 133 (of FIG. 7) that connects to a distal electrode 117.
  • the sensor cube 116 is in certain embodiments will be an electrode when it is connected to the electrical equipment at the proximal end of the PNASC .
  • FIGS. 6 -11 may be used for purely sensing nerve activity, non-ablative electrical stimulation of nerves and/or as a Perivascular Nerve Ablation and Sensing Catheter (PNASC). Ablation may occur using electrical (e.g. RF) or fluid ablation of nerves.
  • PNASC Perivascular Nerve Ablation and Sensing Catheter
  • Ablation may occur using electrical (e.g. RF) or fluid ablation of nerves.
  • the primary difference between the NSCs 10 and 100 is that the hollow metal sensor tubes 116 can act as a reference for the electrode rip 117 allowing bipolar sensing and stimulation to occur at each of the conduits 120.
  • FIG. 6 is a schematic view of the distal portion of a NSC 100 in its open position, showing an inner tube 105, middle tube 103, outer tube 102, outer tube extension 104 having distal openings 131 through which the guide tubes 115 with radiopaque markers 12,2 are advanced outwardly from the body of the NSC 100. Also shown is the tapered section 106 and fixed guide wire 110 with distal tip 109.
  • the conduits 120 with central wires 133 with insulation 134 of FIG. 7 and distal electrodes 117 carry the signals sensed by the electrodes to an electronics module for monitoring and measuring the activity of the sympathetic nerves, or providing current for electrical stimulation and/or nerve ablation.
  • the sensor tubes 116 with distal sharpened sensing needles 119 and sensing electrode 117 are shown in their fully deployed positions.
  • the sensor tubes 116 are ideally made from a memory metal such as NITINOL or a stiff springy material such as stainless steel or L605 a cobalt chromium alloy.
  • the openings 131 in the outer tube extension 104 support the sides of the guide tubes 115 as the guide tubes 1 15 are advanced outward against the wall of a vessel before the advancement of the conduits 120.
  • the NSC 100 of FIG. 6 has three guide tubes with the third tube hidden behind the catheter and not visible in this schematic view. Although the NSC 100 of FIG. 6 has three guide tubes 1 15, it is envisioned that other embodiments could have as few as one or as many as eight guide tubes with a typical number being three or four when provided for renal nerve ablation. A larger diameter target vessel might suggest the use of as many as 4 to 8 guide tubes 115 and sensor tubes 1 16. Hie primary structure of the NSC 100 is based on the design of the PTAC 100 of FIG.
  • the NSC 100 may be used to sense nerve activity instead of deliver ablative fluid into the peri-adventitial space.
  • the open position may be approximately that which places the sensors in the periadventitial space to allow measurement the activity, or used for energy or chemical based ablation of the sympathetic nerves outside of the renal artery.
  • Different shapes are envisioned for the distal openings (or windows) 131 in the outer tube extension 104 where the guide tubes 1 15 exit. These possible shapes include a racetrack design with curved (e.g., round) proximal and distal ends and straight sides in the axial direction, and oval or round shapes. It is also envisioned that there could be a movable flap covering the opening 131 or a slit that could be opened to make the outer surface of the PTAC smooth for better delivery into the renal artery.
  • the guide tubes 1 15 act as needle guiding elements for the ultra-thin conduits 120.
  • prior art such as Jacobson that has curved needles that are advanced outward without a guiding element from a central catheter to penetrate the wall of a target vessel. Without additional guiding and backup support during advancement, needles that are thin enough to essentially eliminate the risk of extravascular bleeding following penetration and withdrawal from the wail of the artery are generally too flimsy to reliably penetrate as desired into the vessel wall.
  • FIG. 7 is a longitudinal cross-section of a distal portion of the NSC 100 as shown in FIG. 6.
  • the proximal end of FIG. 7 shows the three concentric tubes, the outer tube 102, middle tube 103 and inner tube 105 which form the central portion of the NSC 100.
  • the outer tube 102 is attached to the outer tube extension 104 which is in turn attached to the tapered section 106.
  • the fixed guide wire 1 10 with core wire 1 1 1 and outer layer 113 extends distally from the distal end of the tapered section 106. It should be noted that only part of the length of the guide wire 110 is shown in FIG. 7, its full length is shown in FIG. 6. Enlargements of the sections S8 and S l l of FIG. 7 are shown in FIGS. 8 and 1 1 respectively.
  • the conduits 120 have outer sensor tubes 1 16, distal needles 1 19 and distal sensor electrodes 1 17.
  • FIG. 7 shows the guide tube 1 15 with radiopaque marker 122 in its fully advanced position placed through the opening 131 in the outer tube extension 104.
  • the interior surface of the outer tube extension 104 forms part of the tubular shaft 1 39 should be made from a stiff material such as a metal or high durometer plastic so that it will be relative rigid as the guide tubes 1 15 are advanced and retracted.
  • the central buttress 121 shown in FIG. 7 supports the guide tube 115 both as it is pushed distally, and after it is fully deployed. This central buttress 121 also provides radial support for the guide tubes 115 after they are advanced against the interior wall of the target vessel.
  • the guide tubes 1 15 prevents the guide tubes 1 15 from backing away from the interior wail of the target vessel as the conduits 120 are advanced through the guide tubes 115 penetrating the vessel wall then forward to their desired position such as 2-6 mm beyond the interior surface of the wall of the target vessel .
  • the injection needles 119 at the distal ends of the conduits 120 might be advanced as deep as, for example, 10 mm beyond the interior surface of the target vessel.
  • Additional lateral support for the guide tubes 1 15 is provided by the sides of the openings 131 that in combination with the central buttress 121 provide radial and circumferential/lateral support both during guide tube 115 advancement and outward expansions, and as backup during deliver ⁇ ' of the needles 1 19 through the interior wall of the target vessel .
  • the buttress may comprise a deflection surface such as a curved or linear ramp, which may in a curved embodiment correspond to the radius of curvature of the distal surface of the guide tube 115.
  • the radius of curvature of the distal portion of the conduits 120 have a central axis with the same, or nearly the same, radius of curvature as the central axis of the guide tubes 115 and of the central axis of the distal portion of the tubular shaft 139 that is formed within the central buttress 121 when measured in an unconstrained state.
  • the length of the guide tubes 115 are preferably at least as long as the distal curved portion of the conduits 120 with distal needles 119. This would constrain the curved portion of each conduit 120 within the lumen of the guide tube 115 so that the conduit 120 cannot twist or change position.
  • the inner tube 105 attaches through the plastic manifold 125 to the outer sensor tubes 1 16 of the conduits 120, thus the lumens of the sensor tubes 1 16 are in fluid communication with the lumen of the inner tube.
  • the inner tube 105 and manifold 125 can slide along die longitudinal axis of the NSC 100 inside of the middle tube 103 which is shown with uniform diameter over its length including the portion coaxially outside of the manifold 125.
  • the manifold 125 is located within the lumen of the inner tube 105 in a portion of the tube 105 that is proximal to the distal end of the tube 105.
  • the inner tube 105 and manifold 125 are both located coaxially within the outer tube 102 of the NSC 100 at a position proximal to the outer tube extension 104 which is the distal end section of the outer body of the NSC 100.
  • the insulated wires 130 including a core wire 133 and insulation 134, as shown in FIG. 8, connect the sensor electrodes 117 to the proximal end of the NSC 100 where they exit near the proximal end as shown in FIG. 16.
  • the wires 130 may there be connected to the external electronics located outside of the proximal end of the NSC 100.
  • FIGS. 9, 10, 12, 13 and 14 Different example configurations of the sensor electrodes 117 envisioned are shown in FIGS. 9, 10, 12, 13 and 14, which illustrate some preferred embodiments.
  • FIG. 8 is the enlargement of section S8 of the longitudinal cross- section of the N SC 100 as shown in FIG. 7.
  • FIG. 8 shows the details of the guide tubes 115 with interior layer 123, outer layer 127, distal end 129 and radiopaque marker 122.
  • Coaxially within the lumen of the guide tube 115 is the conduit 120 with sensor tube 116, distal sensing needle 1 19, sensor electrode 117 and insulted wire 130 with core wire 133 and insulation 134.
  • Radiopacity of the distal end of the sensor tubes 116 with distal needles 1 19 can in some embodiments be important so that the operator can confirm under fluoroscopy that the needles 119 have properly deployed into the wall of the target vessel.
  • the present embodiment uses the electrode 117 which would typically be formed from a dense and highly conducting metal such as gold or platinum to provide this radiopacity. It is envisioned however, that other embodiments of the present disclosure may use coatings, plating or markers on the outside and/or inside of the sensor tube 116 and needle 119 or the sensor tube 116 with distal needle 119 could be made from a two layer clad material.
  • the guide tubes 1 15 are advanced and retracted through the tubular shaft. 139 with distal opening 131.
  • the three guide tubes 115 are attached to each other near their proximal ends by the guide tube connector 132.
  • FIG. 8 also clearly shows how the guide tube 1 15, when advanced against the central buttress 121 is forced outwardly and is supported by the curved ramp 144 of the central buttress 121 as well as the sides of the opening 131 of the tubular shaft 139.
  • the central buttress 121 also has proximal fingers 142 that provide additional lateral support for the guide tubes 1 15.
  • Tire outer tube extension 104 connects at its distal end to the tapered section 106 which in turn lies coaxially around the guide wire 110 (of FIG. 6) with core wire 111 and outer layer 113.
  • the penetration depth L2 which is the distance from the distal end 129 of the guide tube 1 15 to the distal tip of the sensor needle 119.
  • Mechanisms at the proximal end of the NSC 100 control both the motion of the distal components such as the sensor tubes 116 and guide tubes 1 15 as well as to limit and/or adjust the penetration depth L2 of the needles 1 19.
  • the central buttress 121 and distal openings 131 can, as shown in FIG. 8, be separate components of the NSC 100 or they can be formed as a single molded or machined part.
  • the distal tip 145 of the central buttress 121 provides the attachment to secure the buttress 121 to the tapered section 106.
  • 121, 131, and 106 could be a single molded or machined component.
  • the preferred embodiment of the NSC 100 has the guide tubes 115 with a pre-formed curved shape
  • flexible naturally straight guide tubes are also envisioned where the buttress 121 forces the straight guide tubes to curve outward against the interior wall of the target vessel.
  • the term '"central buttress " as used herein includes the, ramp 344 or other deflection surface that provides radial and some lateral support for the deployed guide tubes 115.
  • the curved ramp 144 of the buttress 121 supports and guides the outward motion of the guide tubes 115 as they exit though the distal openings 131 and also provide radial support for the guide tubes 1 15 and injection tubes, as they engage the interior wall of the target vessel. Additional lateral support is provided by the fingers 142 of the central buttress 121 as well as the tubular shaft 139 and the sides of the opening 131 .
  • a schematic view of such a central buttress is shown in FIG. 17 of Fischell et al US Patent No. 8,740,849.
  • a radiopaque metal part such as stainless steel
  • a plastic material that includes radiopaque filler such as tungsten
  • a radiopaque marker could be placed or attached to a portion of the openings 131 or buttress 121 or outer tube extension 104 to show the likely spot where the guide tubes 1 15 and thus the needles 119 would engage the interior wall of the target vessel.
  • the components of the NSC 100 are typically made from plastic materials such as polyamide, polyurethane, nylon or tecothane. These include the outer tube 102, middle tube 103 and inner tube 105, the outer tube extension 104, inner layer 127 and outer layer 123 of the guide tubes 1 15, the tapered section 106, the buttress 121, the guide tube connector 132 and the manifold 125.
  • the manifold 125 can be a molded part or be epoxy or another resin that is injected to glue the sensor tubes together within the lumen of the inner tube 105.
  • any or all of the inner tube 105, middle tube 103 or outer tube 102 could also be a metal hypotube or a metal reinforced plastic tube.
  • the sensor tubes 116 would typically be made of a springy or shape memory metal such as nitinol.
  • the guide tube radiopaque marker 122 would be made of a radiopaque material such as gold, platinum or tantalum or an alloy of these or similar metals. Any or certain portions of the outside of the NSC 100 could be lubricity coated to provide improved performance.
  • the sensor tubes 116 and needles 119 should typically be smaller than 0.5 mm in diameter and preferably less than 0.3 mm in diameter to avoid any blood loss or leakage as the needles penetrate into the wall of the target vessel and are then removed.
  • FIG. 9 is a longitudinal cross section showing an enlargement of section S9 of FIG . 8 detailing the distal portion of the conduit 120 with sharpened needle 119 at the distal end of the sensor tube 116.
  • Attached inside of the distal portion of the sensor tube 116 is the electrode 1 17 with insulation 139 that prevents the electrode 117 from coming into electrical contact with the metal sensor tube 116 in order to keep the two components from shorting out.
  • the insulationl39 may also be configured to extent over die outside of the distal portion of the sensor tube 116 to reduce the potential for shorting further. The configuration shown in FIG.
  • the electrodes 1 17 would allow the electrodes 1 17 to be used for sensing and/or stimulation as a dipole referenced to the sensor tube 116 or a monopole referenced to another of the 3 conduits or a separate reference on another portion of the catheter or within the body or on the skin of the patient.
  • the insulated wire 130 with core wire 133 and insulation 134 is attached to the electrode 117 as shown with a distal portion of the core wire 133 fixedly attached to the electrode 1 17. This can be done using any of a number of mechanical or other techniques including welding, brazing and crimping.
  • voltages sensed by the electrode 117 will be transmitted by the conduits 120 to the proximal end of the NSC 100 where external equipment 500 of FIG.
  • sensing evoked nerve activity can be accomplished by using two electrodes on different conduits (or an electrode 117 and sensor tube 116) for stimulation and the other electrode 117 on the third conduit for sensing (the sensing would typically occur after the stimulation is provided).
  • sensing, stimulation, or ablation can be provided using any of the electrodes 1 17 by selecting the circuitry of the electronics 500 that is attached to the sensor/stimulator at the proximal site of the catheter system.
  • One technique for manufacturing the sensing tip configuration of FIG. 9 is to adhesively attach a cylindrical electrode 117 with insulation inside the distal end of a cylindrical sensor tube 116. Allow the adhesive to fix and then cut or grind the distal end of the sensor tube 116 with electrode 117 until the shaspened shape seen in FIG. 9 is produced. Alternatively, one could assemble the parts already sharpened as seen in FIG. 9.
  • the electrode 117 could be substituted by a thermocouple or thermistor with the objective of using the NSC as a temperature sensor to know the periadventitiai temperature during an energy or cryo based ablation procedure. This temperature sensing could be used to guide the operation of a secondary- device or could be used to guide operation of the PNASC itself. It is also envisioned that a thermocouple or thermistor may be attached to the guide tubes 115 and could be used for measuring the temperature of the intimal tissue using the external electronic equipment 500 to ensure that the temperature from energy based ablation does not overheat the media and intima of the artery.
  • FIG. 10 is a transverse cross section of the distal portion of the sensor tube 116 at 10-10 of FIG. 9. Shown are the sensor tube 116, the insulation 139, electrode 117 and core wire 133.
  • FIG. 1 1 is the enlargement of section SI 1 of FIG. 7 showing a preferred embodiment of the transition from the central portion to the distal portion of the NSC 100 including the outer tube 102, middle tube 103 and inner tube 105 with lumen 137, Also shown is the connection between the outer tube 102 and the outer tube extension 104. While the manifold 125 in FIG. 1 1 shows the proximal end of the sensor tubes 1 16 at a position distal to the proximal end of the manifold 125, it may be preferable to manufacture the NSC 100 with the proximal end of the sensor tube 116 located at or proximal to the proximal end of the manifold 125.
  • the guide tube connector 132 connects the three guide tubes 15 to the middle tube 103 that provides the impetus for advancement and retraction of the three guide tubes 115 of which two are visible in this view.
  • the m otion of the middle tube 103 is produced by the motion of control mechanisms at the proximal end of the NSC 100.
  • the manifold 12,5 lies inside of the distal portion of the inner tube 105 and connects together the three sensor tubes 116 so that advancement and retraction of the inner tube 105 provides simultaneous advancement and retraction of the sensor tubes 1 16. Also shown in FIG. 11 are the flushing spaces between the several tubes.
  • each of these spaces 109 and 99 are to be flushed through with normal saline solution prior to insertion of the NSC 100 into the patient's body.
  • FIG. 11 also shows that the proximal end of the sensor tube 116 is in fluid communication with the lumen 137 of the inner tube 105. This can in some embodiments be important when the conduit distal portion includes an opening for delivering an ablative fluid to the perivascular tissue for chemical tissue ablation such as shown in FIG. 13 for the embodiment of a Perivascular Nerve Ablation and Sensing Catheter (PN ASC) 200 with openings in the distal portion of a conduit.
  • PN ASC Perivascular Nerve Ablation and Sensing Catheter
  • the embodiment of the PNASC 100 of FIGS, 6 through 1 1 when connected to appropriate external equipment 500 of FIG. 21 can provide electrical stimulation and sensing and may also, be used for energy based tissue ablation as a perivascular Nerve Ablation and Sensing Catheter (PNASC) when sufficient energy is delivered through the wires 130 and electrodes 1 17.
  • PNASC perivascular Nerve Ablation and Sensing Catheter
  • the wires 130 (for sensing/stimulation/ablation) with core wires 133 and outer insulation 134 run coaxially within the lumens of the sensor tubes 116 extend proximally from the proximal end of the sensor tube 1 16 within the lumen of the inner tube 105 all the way to the proximal end of the NSC 100 where they exit as the wires 361, 362 and 363 and terminate in the connector 360 of FIG. 16 that allows the wires 130 to connect to external electronics 500 shown in FIG. 21 for measurement of nerve activity and/or for providing stimulation signals to achieve stimulation and/or ablation.
  • the NSC would act as a monopolar device with each electrode referenced to another electrode or an independent reference electrode.
  • a single wire may conduct electricity to two or more electrodes 117 which have an electrical bridging means incorporated into the catheter design in order to decrease the number of wires 130 that are carried along the length of the catheter.
  • the same signal is provided to two or more electrodes 117 by a single wire 130.
  • a fourth reference wire could be added that can be bridged to the three sensor tubes 116 to act as the reference for the bipolar electrodes 117. It is still further envisioned that separate reference wires could be am to each of the three sensor tubes with six wires now ranning to the length of the catheter providing fully independent bipolar sensing from each of the three electrodes 117 referenced to their own sensor tube 116.
  • FIG. 1 1 also shows how the three sensor tubes 1 16 extend from the distal end of the inner tube 105 and manifold 125 and then enter the lumen of the inner layer 127 of the guide tube 1 15 at the proximal end of the guide tube 1 15,
  • the guide tubes 1 15 and guide tube connector 132 are attached coaxially within the distal section of the middle tube 103.
  • longitudinal motion of the middle tube 103 will cause longitudinal motion of the guide tube connector 132 and guide tubes 115 thus allowing the mechanism at the proximal section of the NSC 100 to advance and retract the guide tubes 115 with respect to the outer tube 102 and outer tube extension 1 4,
  • the penetration depth limitation could be realized by a limiting mechanism that limits the forward motion of the distal end of the inner tube 105 with respect to the guide tube connector 132.
  • a ring or other structure situated between the distal end of the inner tube 105 or manifold 125 and the proximal end of the guide tube connector 132 would limit the forward (distal) motion of the distal end of the inner tube 105 and thus limit penetration of the needles 1 19 beyond the distal ends 129 of the guide tubes 115.
  • Such a structure could be unattached, or attached to an internal structure of the NSC 100 shown in FIG.
  • Such a structure could also have a length adjustment such as screw threads that would allow it to be used to calibrate the penetration depth of the needles 119 beyond the distal ends 129 of the guide tubes 115.
  • FIG. 12 shows an alternative embodiment of the NSC 100 of FIGS. 7 and 8, labelled 100', with the distal portion of a conduit 150. Except for the conduit 150, the remainder of the NAC 100' is identical to the NSC 100 of FIGS. 6, 7, 8 and 11.
  • the electrode 154 with sharpened needle tip 159 is attached within the distal end of a cylindrical sensor tube 152 with insulation 159 to prevent electrical contact between the electrode 154 and the sensor tube 152.
  • the distal end of the electrode 154 can be pre -sharpened or it could be sharpened by cutting or grinding following attachment into the distal end of the sensor tube 152. This configuration has advantage over the tip of FIG.
  • FIG . 13 is an embodiment of the distal portion of the conduit 160 of the PNASC 200 integrated ablation and nerve sensing catheter. Except for the conduit 160, the remainder of the PNASC 200 is identical to the NSC 100 of FIGS. 6, 7, 8 and 11.
  • the tip 160 differs from the tip 150 of FIG. 12 in that side holes 165A and 165B have been placed into the sides of the sensor tube 162 to allow ablative fluid injected at the proximal end of the PNASC 200 to flow through the lumen 137 of the inner tube 105 of FIG.
  • the electrode 164 with needle tip 169 and insulation 159 are identical to that of the electrode 154 and insulation
  • Tire sensor wire 130 is also the same as in FIG. 12 with core wire 133 and insulation 134.
  • the conduits 120, 150 and 160 of the NSC 100 and PNASC 200 devices would preferably be very small gauge (smaller than 25 gauge) to prevent blood loss following penetration and removal through the vessel wall.
  • the PNASC 200 which includes a distal opening in one or more of the conduits 160 to provide egress for the ablative fluid, as shown in FIG. 13 typically has a non-coring (cutting) needle 169.
  • the PNASC 200 would also preferably have at least 2 conduits 160 with distal electrodes 164, but 3 to 8 tubes with distal needles may be more appropriate, depending on the diameter of the vessel to be treated and the ability of the injected ablative fluid to spread within the perivascular space. For example, in a 5-7 mm diameter renal artery, 3 conduits
  • a PNASC 200 integrated ablation and sensing system may provide large advantages over other current technologies for applications in addition to renal denervation.
  • the PNASC 200 can provide a highly efficient, and reproducible perivascular circumferential ablation of the muscle fibers and conductive tissue in the wail of the pulmonary veins near or at their ostium into the left atrium of the heart to treat atrial fibrillation (AF).
  • AF atrial fibrillation
  • this system could benefit denervation of the pulmonary arteries in the case of nerve ablation to treat pulmonary arterial hypertension.
  • operating the catheter system to obtain nerve and/or cardiac myocyte electrical activity measurements could be an effective technique to provide immediate assessment of the success of an AF ablation procedure during the actual procedure.
  • Other potential applications of this approach such as pulmonary artery nerve ablation, or others, may also become evident from the various teachings of this patent specification.
  • FIGS. 12 and 13 could also be adapted to deliver ultrasonic energy to with an ultrasonic transducer replacing the electrodes 154 and 164 with the voltage to activate the transducer provided between the core wire 133 and the electrodes 154 and 164 and the removal of the insulation layer 159.
  • FIG. 14 is another embodiment of the distal portion of the conduit 170 of the PNASC 400 which can both inject ablative fluid and sense nerve activity. Except for the distal portion of the conduit 170, the remainder of the PNASC 400 can be identical to the NSC 100 of FIGS. 6, 7, 8 and 11.
  • This embodiment uses a non-coring Huber type needle configuration with sharpened needle tip 189 with a turn, in the distal end of the sensor/injector tube 172 to prevent coring during penetration.
  • a radiopaque wire 171 with core wire 174 and insulation 178 connects proximally to external equipment replacing the wires 130 of FIGS. 7 through 11.
  • the distal portion of the wire 171 has the insulation removed to allow for the sensing of nerve voltages.
  • the core wire 174 would typically be made from gold or platinum, or an alloy of gold or platinum. It is also envisioned that only the distal portion of the wire 171 would be radiopaque with the more proximal portion being a standard wire material such as copper.
  • FIG. 15 is a the longitudinal cross-sections of three portions of the central section of the catheter 450 that can be integrated into the NSC 100, PNASC 200 and PNASC 400 of FIGS. 6 through 14.
  • At the proximal end of the proximal portion of the catheter 450 are three concentric metal hypotubes, an outer hypotube 82, middle hypotube 83 and inner hypotube 85. These are typically made from thin walled metallic tubing such as stainless steel, L605, cobalt chromium or nitinoi.
  • the outer hypotube 82 attaches at its distal end to a proximal plastic outer tube 92 typically made from a relatively high durometer plastic, for example poiyimide. As seen in the central cross- section of FIG.
  • the proximal plastic tube 92 attaches at its distal end to the proximal end of the outer tube 102 also shown in FIGS. 6 through 8.
  • the outer tube 102 is typically made from a lower durometer/more flexible plastic than the proximal plastic tube 92.
  • the middle hypotube 83 is attached at its distal end to the middle tube 103.
  • die inner hypotube 85 is attached at its distal end to the proximal end of the inner tube 105.
  • the manifold 125 that connects the inner tube 105 to the sensor tube 1 16 as also shown in FIG. 1 1.
  • the wires 130 with core wire 133 and insulation 134 exit the proximal end of the sensor tubes 1 16 and continue in the proximal direction through the inner tube 105 and then proximally to that through the lumen 133 of the inner hypotube 85.
  • the lumen 138 of the inner hypotube 85 is in fluid communication with the lumen 137 of the inner tube 105 which is in fluid communication with the lumens of the sensor tubes 1 16 of FIGS. 6-1 1, or the sensor tubes 152, 162 or 172 of FIGS. 12, 13 and 14 respectively.
  • the 162 and 172 being for the PNASC 200 and 400 where injection of an ablative fluid moves from the injection port 354 in the handle 300 of the catheter and through the inner hypotube 85 into the inner tube 105 through the tubes 162 or 172 and into the perivascular space through openings in the distal portions of the tubes 162 or 172.
  • the inner hypotube 85 runs longitudinally to the fluid port or connector at the proximal end of the catheter 450 to allow injection of fluids.
  • FIG. 15 is the preferred embodiment as it provides flexibility where needed near the distal end of the catheter with better control of the motion of the inner and middle tubes 105 and 103 as the metal hypotubes do not compress as they move longitudinally while plastic may.
  • FIG. 16 is a schematic view of one embodiment of the proximal portion (handle) 300 of the NSC 10, NSC 100 or PNASC 200 or PNASC 400.
  • the terms proximal portion 300 and handle 300 will be used interchangeably here.
  • the handle 300 includes the mechanisms for advancing and retracting the needle guiding elements/guide tubes 30/1 15 and sensor/injector tubes 22/1 16 with distal needles 24/1 19 during the procedure to position the electrodes 1 17, 154, 164 and 174 of the various embodiments of the NSC 10, 100, PNASC 200 and PNASC 400 within the pen vascular space .
  • the handle 300 will do the same to position the distal tips of the conduits 20 of the SNASC 10 of FIGS.
  • the handle 300 also has locking mechanisms activated by first and second control mechanisms such as press-able buttons 332 and 342. Specifically, button 332 when depressed unlocks the motion of the guide tube control cylinder 333 with respect to the outer tube control cylinder 335.
  • the outer tube cylinder 335 is attached to the outer hypotube 82 which is in turn connected to the tube 92 that connects to the outer tube 102 as seen in FIG. 15 or the outer tube 13 of FIG. 5.
  • the transition section 338 provides strain relief to avoid kinks at the connection between the outer tube control cylinder 335 and the outer hypotube 82.
  • the guide tube control cylinder 333 is attached to the middle hypotube 83 that in as shown in FIGS. 5 and 15, connects to the middle tube 12 of the NSC 10 of FIGS. 1-4 or the middle tube 103 of FIGS. 6-8 that in turn is connected to the guide tubes 30 of FIGS. 1-4 or guide tubes 115 of FIGS. 6 through 8.
  • the guide tube control mechanism 330 allows the user of the NSC/PNASC to control the distal and proximal motion of the guide tubes 30 or 115 with respect to the outer tube 82 and includes the button 332 and the guide tube control cylinder 333.
  • the needle control mechanism 340 allows the user of the NSC/PNASC to control the distal and proximal motion of the conduits 20 of the NSC 100 of FIGS. 1-5 or the conduits 120 of the NSC 100 of FIGS. 6- 8.
  • the needle control mechanism includes the button 342 and the needle control cylinder 345.
  • the button 342 when depressed, unlocks the motion of the needle control cylinder 345 with respect to the guide tube control cylinder 333.
  • the needle control cylinder is attached to the inner hypotube 85 of FIG. 15. Moving the needle control cylinder 343 with respect to the guide tube control cylinder 333 will move the inner hypotube 85 which in turn will cause the relative longitudinal motion of the inner tube 105 of FIGS. 6-8 with respect to the middle tube 103 of FIGS. 6 through 8 which causes the advancement and retraction of the sensor tubes 1 16 with distal needles 119 though the guide tubes 115.
  • This mechanism advances and retracts the conduits 120 with distal electrodes 117 of FIGS. 6-10, as well as the electrodes 154, 164 and 1 74 of the distal tips shown in FIGS. 12, 13 and 14. Similarly this mechanism would advance and retract the conduits 20 of FIGS. 1-5 by the controlling the relative motion of the inner tube 11 with respect to the middle tube 12.
  • the handle 300 shown in FIG, 16 has the flushing port 344.
  • Port 344 which would typically have a Luer fitting, is shown with a cap 346.
  • Port 344 is used to flush with sahne the annular spaces 139 and 59 as shown in FIG. 15 and in turn will flush the lumens 109 and 99 shown in FIGS. 1 1 and 15.
  • the injection port 354 which typically has an ablative fluid connector fitting is shown with cap 356.
  • port 354 allows injection of ablative fluid into the lumen 138 of the inner hypotube of FIG. 15 which then will flow into the inner tube 105 and then into the sensor tubes 162 of the conduit 160 of the PNASC 200 of FIG. 13 and the sensor tube 172 of the conduit 170 of the PNASC 400 of FIG . 14.
  • the tubes 162 and 172 have openings near or at their distal end to allow flow of the ablative fluid into the perivascular space.
  • FIG. 16 shows one flushing port 344, it envisioned that two or more flushing ports could be used to flush the internal spaces (other than the injection lumen) within the various embodiments of the NSC and PNASC. It is also envisioned that a single button and cylinder mechanism could replace the two buttons 332 and 342. If this is the case, then a telescoping mechanism, internal to the proximal portion of the handle 300 would, upon ad vancement of the single button, fi rst advance the guide tubes 115 then advance the conduits 120 with distal electrodes 117. Retraction of the single button would first retract the conduits 120 and then retract the guide tubes 1 15.
  • Wlnle a standard Luer or Luer lock fitting could be used for the ablative fluid connector fitting for the injection port 354, Fischeil et al. in U.S. Pat. No. 8,740,849 describes a non-standard fitting that would be advantageous for injection of the ablative fluid. Because of the ablative/toxic nature of the ablative fluid, having a nonstandard fitting for the port 354 would reduce the chance of accidentally injecting the ablative fluid into one of the other ports (e.g. 344) or into the standard Luer fitting in the ⁇ " adapter typically used with a renal guiding catheter.
  • non-standard fitting port 354 it would also prevent the operator from the potential error of injecting flushing solution or other agents contained in a conventional Luer lock syringe, through the lumen of the injection tubes. It would also be an advantage for the non-standard fitting port 354 to have a smaller lumen than a standard Luer fitting so as to minimize the catheter dead space/internal volume.
  • the handle 300 also includes a gap adjustment cylinder 348 that when rotated in one direction reduces the penetration depth LI of FIG. 3 or L2 shown in FIG. 8 which is the distance the needle tip 23 or needles 1 19 extend beyond the distal ends 34 and 129 of the guide tubes 30 and 115. Rotation in the other direction of the cylinder 348 will increase the penetration depth LI or L2. It is envisioned that the gap adjustment cylinder 348 could be accessible to the user of the handle 300 with markings on the handle 300 to indicate the distance that will be achieved. This has advantages for use with the NSC 100 which is a purely diagnostic catheter so that the depth of electrode placement can be set and then adjusted of more than one depth is desired.
  • a handle that uses a gap to limit needle penetration depth is disclosed in US Patent Nos, 8,740,849 and 9,056, 185, which are incorporated by reference in their entireties,
  • the gap adjustment cylinder 348 could be accessible only during assembly and testing of the handle 300 at the factory.
  • This fabrication method is designed to ensure a properly calibrated penetration depth L1/L2 that is preset in the factory during manufacturing and testing of each NSC 10/100 or PNASC 200/400.
  • This bil ty to calibrate the penetration depth L1/L2 is useful to achieving a good yield during manufacturing.
  • the distance L1/L2 can be dialed in exactly using the gap adjustment cylinder 348.
  • the NSC 10/100 or PNASC 200/400 would be labeled according to the penetration depth L 1/1,2.
  • the NSC 100 might be configured to have three different depths L2 of 3 mm, 4 mm and 5 mm.
  • a set screw or other mechanism could be included to lock the gap adjustment cylinder 348 at the desired penetration depth setting after calibration. While a gap adjustment cylinder 348 is shown here, it is envisioned that other mechanisms such as a sliding cylinder could also be used to adjust the depth L1/L2.
  • wires 130 of FIGS. 6 through 13 and the wires 171 of FIG. 14 exit through the side of the most distal portion of the handle 300 as seen in FIG. 16.
  • These three wires 130 are connected to an electrical connector 360 which in turns connects to the electronics 500 of FIG. 21 where the voltages between pairs of wires 130 can be measured, processed, and displayed as sensed data measurements.
  • the wires 130 may exit the proximal section of the handle 300 through the lumen of the fitting 354 where the cap 356 has been removed.
  • a primary function of the handle 300 is to operate the NSC 10/100 for measurement of the activity of the sympathetic nerves outside of the renal artery before, during and after a renal denervation procedure.
  • the handle 300 also allows for injection of an ablative fluid to be delivered to the perivascular space.
  • the electrical signals communicated with the distal end of the catheter are transmitted along the wires 361, 362, and 363 which exit the handle 300 to communicate with the external electronic equipment 500 that provides, for example, sensing.
  • the hypotubes communicate fluid from the injection port 344 toward the distal tip.
  • FIG. 17 shows an alternative embodiment a longitudinal cross-section of a distal portion of an Ultrasound Nerve Ablation catheter (UNAC) 600.
  • the primary structure of the UNAC 600 is similar to that of the NSC 100 of FIG. 7.
  • the proximal end of FIG. 17 shows the three concentric tubes, the outer tube 602, middle tube 603 and inner tube 605 which form the central portion of the UNAC 600.
  • the outer tube 602 is attached to the outer tube extension 604 which is in turn attached to the tapered section 606.
  • the fixed guide wire 610 with core wire 611 and outer layer 613 extends distaliy from the distal end of the tapered section 606. It should be noted that only part of the length of the guide wire 610 is shown in FIG. 17, its full length is similar to that shown for the guide wire 110 of the NSC 100 in FIG. 6. Enlargements of the sections S18 and S 19 of FIG. 17 are shown in FIGS. 18 and 19 respectively.
  • FIG. 17 shows the guide tube 615 with radiopaque marker 622 in its fully advanced position placed through the opening 631 in the outer tube extension 604.
  • the interior surface of the outer tube extension 604 forms part of the tubular shaft 639 and can in some cases be made from a stiff material such as a metal or high durometer plastic so that it will be relatively rigid as the guide tubes 615 are advanced and retracted.
  • the central portion of the UNAC can be constructed similar to that shown in the embodiment of the central portion of the NSC 100 of FIG. 15.
  • the UNAC 600 utilizes an ultrasound transducer 650 coupled by the coupler 625 to three distal wires 616 with sharpened needle distal tips 619.
  • vibration from the transducer 650 is conducted to through the wires 616 into the perivascular tissue near the tips 619 of the wires 616. With sufficient intensity the vibration will cause ablation of the perivascular tissue.
  • Perivascular deliver ⁇ ' of energy by ultrasound for renal denervation can be advantageous in some cases over intravascular delivery as the pain nerves are in the media of the renal artery and the nerves to be ablated are in the perivascular space.
  • the central buttress 621 shown in FIG. 17 supports the guide tube 615 both as it is pushed distally, and after it is fully deployed.
  • This central buttress 621 also provides radial support for the guide tubes 615 after they are advanced against the interior wall of the target vessel. This prevents the guide tubes 615 from backing away from the interior wall of the target vessel as the needles 619 are advanced through the guide tubes 615 penetrating the vessel wall then forward to their desired position 2-10 mm beyond the interior surface of the wall of the target vessel.
  • the buttress may comprise a deflection surface such as a curved or linear ramp, which may in a curved embodiment correspond to the radius of curvature of the distal surface of the guide tube 615.
  • the radius of curvature of the distal portion of the wires 616 have a central axis with the same, or nearly the same, radius of curvature as the central axis of the guide tubes 615 and of the central axis of the distal portion of the tubular shaft 639 that is formed within the central buttress 621 when measured in an unconstrained state.
  • the lengths of the guide tubes 615 are preferably at least as long as the distal cur ed portion of the wires 616 with distal needles 619. This would constrain the curved portion of each conduit 620 within the lumen of the guide tube 615 so that the wires 616 cannot twist or change position.
  • FIG. 17 the inner tube 605 attaches to the ultrasound transducer 650 that connects through the coupler 625 to the wires 616. This allows longitudinal movement of the inner tube 605 to advance and retract the wires 616 coaxiaily through the guide tubes 615.
  • the inner tube 605, ultrasound transducer 650 and coupler 625 can slide along the longitudinal axis of the NSC 600 inside of the middle tube 603.
  • Two insulated wires 630 provide power for the ultrasound transducer 650 from external e uipment (not shown) beyond the proximal end of the UN AC 600.
  • FIG. 18 is the enlargement of section S18 of the longitudinal cross- section of the UNAC 600 as shown in FIG. 17.
  • FIG. 18 is the enlargement of section S18 of the longitudinal cross- section of the UNAC 600 as shown in FIG. 17.
  • FIG. 18 shows the details of the ultrasound transducer 650 with connector pins 655 that connect through the wire connectors 635 to the inner conductors 633 of the wires 130.
  • FIG. 18 also shows in detail how the inner tube 605 attaches to the outside of the ultrasonic transducer 650 that is attached to the coupler 625 that transmits the ultrasonic energy to the wires 616. Also shown is the middle tube 603.
  • FIG. 19 is a longitudinal cross section showing an enlargement of section S19 of FIG. 17 of the UNAC 600, FIG. 19 shows the detail of the distal portion of the guide tube 615 with distal end 639 and the wire 616 with sharpened distal needle 619.
  • the guide tube 615 has radiopaque marker 622, outer layer 623 and inner layer 627.
  • the radiopaque marker 622 is a band made from a radiopaque metal such as gold, platinum or tantalum.
  • the guide tube 615 is similar in construction to the guide tube 115 of FIGS. 7 and 8.
  • the wire 616 should either be made from a radiopaque metal or its distal portion could be plated or coated with a radiopaque material. It is also envisioned that the wire 616 could be a thin tube with a radiopaque wire through the center.
  • FIG 20a shows an embodiment of a procedure to first assess the perivascular nerve activity prior to a renal denervation procedure, then perform a renal denervation procedure followed by a post denervation assessment of nerve activity.
  • the element numbers referenced in the 100s are shown in FIG. 8 and element number 82, and those in the 300s, are shown in FIG. 16.
  • the procedure using the NSC 100 of FIGS. 6-1 1 would include the following steps although not every step is essential and steps may be, excluded, simplified or modified as will be appreciated by those of skill in this art.
  • the distal portion element numbers will reference the NSC 100 of FIGs, 6 through 1 1 although they also apply to the other similar embodiments shown of the NSC 10 (FIGS. 1-5) and 100' (FIG. 12) as well as the PNASC 200 and 400 of FIGS. 13 and 14.
  • the procedure begins by preparing the NSC 100 for insertion into a human body by flushing the device in step 270 which would typically include flushing all of the internal volumes of the NSC 100 with normal saline or another fluid through the ports 344 and 354 of the handle 300 of FIG, 16.
  • step 272 Engage and position device within first renal artery in step 272 which by inserting the distal end of the NSC 100 through a previously placed guiding catheter with the guiding catheter distal end engaged into the ostium of the renal artery where it attaches to the aorta and positioning the distal portion of the NSC 100 as at the desired location in the renal artery.
  • step 274 Deploy sensors to target in step 274 which may include depressing the button 332 (of FIG. 16), and while holding the outer tube control cylinder 335 which is locked to the guide tube control cylinder 333, push the guide tube control cylinder 335 in the distal di rection advancing the guide tubes 115 until the distal end of the guide tubes 129 come into contact with the inside wall of the renal artery limiting the advance of the middle tube 103 of FIG. 8 and deploying the guide tubes 1 5 from inside the tubular shafts 120 and out through the openings 31.
  • the notch 331 will otherwise stop the distal motion of the guide tube control cylinder 333 when it engages the tube 344 at the maximum allowable diameter for the guide tubes 115.
  • step 274 releasing the button 332 winch relocks the relative motion of the outer tube control cylinder 335 with respect to the guide tube control cylinder 333.
  • step 274 depressing the button 342 that allows relative motion of the needle control cylinder 345 with respect to the guide tube control cylinder 333 and while holding the outer tube control cylinder 335 (which is now locked to the guide tube control cylinder 333) advance the needle control cylinder 345 with distal end 349 until the internal gap 347 is closed against the proximal end of the gap adjustment cylinder 348 inside the needle control cylinder 345 stopping the motion at the preset depth L2 for the needle tips 119 with respect to the distal ends 129 of the guide tubes 1 15.
  • step 274 releasing the button 342, which relocks the motion of the needle control cylinder 345 to the guide tube control cylinder 333.
  • IEL internal elastic lamina
  • step 276 Configuring sensing components and obtaining sensed data in step 276 which may include attaching the connector 360 to the external nerve activity measurement equipment 500 of FTG. 21 and measuring the amplitude or level of sympathetic nerve activity between at least one pair of electrodes 1 17 of FIGS. 6-8.
  • the nerve activity may be measured between individual electrodes 17 and a separate reference electrode with a conducting wire that is attached to the external equipment 500 of FIG, 21 and also to the patient.
  • a separate wire/electrode may be part of the NSC system .
  • a wire connected to the catheter surface or fixed guide wire 110 of FIG. 6 may be attached to the external electronic equipment 500.
  • the wire could communicate from the catheter body to the electronic equipment by way of the connector 360 of FIG. 16.
  • the separate reference wire with distal electrode could also be on the skin surface such as used for an electrocardiogram or percutaneously inserted into tissue within the patient.
  • the separate reference could be a wire attached to a skin surface electrode. The level of nerve activity can be noted manually by the user and or might be saved in memory of the external equipment 500.
  • step 278 Retract the sensors/electrodes in step 278 which by depressing the button 342 and while holding the outer tube control cylinder 335, pulling the needle control cylinder 345 back in the proximal direction until the needles 1 19 are fully retracted back into the guide tubes 115. It is envisioned that a click or stop would occur when the needle control cylinder 345 reaches the correct position so that the needles 119 are fully retracted. Then releasing the button 342 locking the motion of the injection needle control cylinder 345 to the guide tube control cylinder 333.
  • the measurement of nerve activity can include sensing at least one interval of nerve activity for a selected duration in order to obtain sensed data, processing the sensed data to obtain at least one baseline dataset which can include raw data, and/or at least one summar - statistic.
  • the measurement of nerve activity- can also include at least one of displaying and storing at least one baseline value related to the baseline dataset.
  • the summar - statistic related to the baseline dataset can include values such as mean, median, and standard deviation of a measure; variance, peak amplitude, average amplitude, peak frequency, average frequency, burst duration, guard- bands, and other measures as disclosed herein.
  • step 284 remove the entire NSC 100 and guiding catheter from the body.
  • step 286 Perform a renal denervation in step 286 on one (unilateral) or both (bilateral) arteries using energy based devices such as the Simplicity (TM) catheter from Medtronic or the PTAC of Fischeli et al US patent No. 8,740,849 and then remove the treatment device from the body.
  • energy based devices such as the Simplicity (TM) catheter from Medtronic or the PTAC of Fischeli et al US patent No. 8,740,849 and then remove the treatment device from the body.
  • step 288 Assess the efficacy of the renal denervation in step 288, by reinserting the NSC 100 through the guiding catheter and repeat steps a2 through a9. Using the difference in nerve activity between before and after the renal denervation procedure, assess the effectiveness of the renal derivation for each artery.
  • step 288 may simply entail measurement and assessment of post-ablation nerve activity such as comparing the sensed nerve activity to an appropriate population normative threshold value or otherwise appropriate determined quantitative or qualitative treatment criterion to determine if the treatment criterion was met or failed to be met.
  • step 286 If the denervation was not sufficiently effective (treatment criterion was not met), repeat the denervation in step 286 by repeating steps alO and al las needed until sufficient loss of sympathetic nerve activity is seen.
  • step 290 Finish the renal denervation procedure in step 290 by standard methods at the end of a renal catheterization procedure.
  • the steps related to sensing nerve activity outside of the first artery can be replaced by steps which include stimulation of the nerves outside of the first artery as part of an assessment of the treatment in order to determine if the ablative treatment met a treatment criterion.
  • steps which include stimulation of the nerves outside of the first artery as part of an assessment of the treatment in order to determine if the ablative treatment met a treatment criterion.
  • a surgeon could measure the change in blood pressure resulting from, the stimulation in order to determine if the nerves were sufficiently ablated (where no evoked change in blood pressure, or other type of evoked response, m ight fail to be evoked when ablation was successful).
  • steps 270 to 280 can be followed by steps 286 to 290, whereby the first artery ablation therapy is assessed.
  • steps 286 to 290 can be followed by steps 286 to 290, whereby the second artery ablation therapy occurs and is then assessed.
  • the NSC 100 can be used to assess sympathetic nerve activity as a follow up diagnostic tool.
  • the NSC 100 can be used to assess w hether nerve activity is below? a threshold level of activity.
  • the threshold amount of activity can be defined based upon population normative criteria (with appropriate adjustment for gender, age, and medication) or the activity recorded at the beginning or end of the earlier procedure carried out on the patient and this comparison can determine whether repeat treatment is required.
  • the N SC 100 can be used as a screening device to screen candidate ablation patients and assess whether they are suitable or unsuitable renal denervation candidates.
  • the screening can occur before a renal denervation procedure to assess sympathetic nerve activity of a patient to determine if the patient is a good candidate for renal nerve ablation therapy.
  • the NSC 100 can be used to assess whether nerve activity is within some normal range (defined by looking at a lookup-table that corresponds to ranges of acti vity that have been found for patients who are successfully treated with ablation therapy) that has been found to indicate that ablation therapy may be successful.
  • the NSC 100 can be used as a screening device to screen candidate ablation locations.
  • nerve density may vary with respect to how far the catheter is positioned within the arterial vessel.
  • the nerve density /distribution may vary as a function of the circumference of the artery, which tends to get bigger as one moves proximally along the renal artery. Further the target nerves may be clumped on one side of the artery rather than surrounding it in a relatively balanced manner. If the baseline nerve sensing at a first candidate ablation location does not record sufficient activity then the NSC (after the distal needles are retracted) may be moved to a second candidate location, or rotated, and then the activity can be sensed again.
  • a comparison of the sensed data at the first candidate ablation location can be compared to that in the second candidate ablation location, and the surgeon can then use the result to determine the next step of the ablation procedure.
  • the NSC 100 may also be used to stimulate the sympathetic nerves outside of a renal artery and the evoked change, for example, a change in blood pressure or other cardiac-related measure can be an indication of the patient's suitability for a renal denervation procedure.
  • FIG. 20b shows the steps associated with the procedure using the PNASC 2,00 or 400 for the combination of renal denervation and subsequent assessment (e.g., via sympathetic nerve activity measurement with or without stimulation to time- lock a response from the patient) would include the following steps although not every step is essential and steps may be simplified or modified as will be appreciated by those of skill in this art:
  • step 470 Flush the device to remove air from the lumens in step 470 which may include flushing the injection lumen with ablative fluid or an anesthetic such as lidocaine through the port 354 shown in FIG. 16 leaving ablative or anesthetic fluid in the dead space within the PNASC 200 or 400. Also flush all of the internal volumes of the PNASC 200 OR 400 with normal saline through the ports 344.
  • ablative fluid or an anesthetic such as lidocaine
  • Step 472 Engage and position the device within the first renal artery, in Step 472, which can include inserting the PNASC 200 OR 400 through a previously placed guiding catheter, positioning the distal portion of the PNASC 200 OR 400 at the desired location in one patient's renal artery.
  • step 473 Deploy the needles into/through the vascular wall in step 473, which can include depressing the button 332 shown in FIG. 16, and while holding the outer tube control cylinder 335 which is locked to the guide tube control cylinder 333, push the guide tube control cylinder 335 in the distal direction advancing the guide tubes 115 of FIG. 8 until the distal end of the guide tubes 129 come into contact with the inside wall of the renal artery limiting the advance of the middle tube 103 of FIG. 8 and deploying the guide tubes 115 from inside the tubular shafts 120 and out through the openings 131.
  • the notch 331 will otherwise stop the distal motion of the guide tube control cylinder 333 when it engages the tube 344 at the maximum allowable diameter for the guide tubes 115. Release the button 332 which relocks the relative motion of the outer tube control cylinder 335 with respect to the guide tube control cylinder 333.
  • step 474 Configure the sensing components and obtain sensed data in step 474, which can include depressing the button 342 that allows relative motion of the injection needle control cylinder 345 with respect to the guide tube control cylinder 333 and while holding the outer tube control cylinder 335 (which is now locked to the guide tube control cylinder 333) advance the needle control cylinder 345 with distal end 349 until the penetration limiting mechanism stops the motion and the preset depth L2 of the needles 169 or 189 with respect to the distal ends 129 of the guide tubes 115.
  • the surgeon may increase or decrease the depth of the needles in order to position these in an improved position for providing nerve ablation.
  • the surgeon may retract the needles and move the catheter more distal or proximal or rotate the catheter before re-deploying the needles.
  • the sensed data can again be evaluated in order to determine if the second candidate ablation location offers any advantage over the first.
  • This step 476 may therefore have a subcomponent set of steps that are related to selecting a promising ablation location/depth prior to carrying out the ablation to provide renal denervation.
  • Electrodes are situated outside of the media of the artery, nerves can be ablated without harming the media of the artery as compared with intraluminal RF ablation where direct contact of the electrode(s) with the intima can seriously damage the media.
  • step 476 attach the connector 360 to the external nerve activity measurement equipment and measure the amplitude or level of sympathetic nerve activity between at least one pair of electrodes 164 of FIG. 13, or electrodes 174 of FIG. 14.
  • a common ground wire is included in the PNASC 200 or 400 or provided by a skin surface electrode then a measurement between a distal electrode and the common ground can be made.
  • the level of nerve activity should be noted by the user and or might be saved in memory of the external equipment.
  • step 480 perform renal denervation in step 480, such as performing a renal denervation procedure on the first artery using the PNASC 200 of 400. If it is a chemical renal denervation procedure then a syringe or manifold with syringes (not shown) can be attached to the port 354 of FIG. 16 and the desired volume of ablative fluid is injected.
  • a syringe or manifold with syringes can be attached to the port 354 of FIG. 16 and the desired volume of ablative fluid is injected.
  • the ablative agent which can be an ablative fluid, such as ethanol (ethyl alcohol), distilled water, hypertonic saline, hypotonic saline, phenol, glycerol, lidocaine, bupivacaine, tetracaine, benzocaine, guanethidine, botulinum toxin, glycosides or other appropriate neurotoxic fluid.
  • a typical injection would be 0.1 to 5 ml. This should produce a multiplicity of ablation zones (one for each injection needle 169 or 189) that will intersect to form, an ablative ring around the circumference of the target vessel.
  • the local anesthetic can be at injected at the primary site of injection of ablative fluid, distal or proximal to the primary site. There may be some advantages of injecting an anesthetic proximal to the ablation site.
  • an energy-based renal denervation procedure is to be used one may still wish to inject a local anaesthetic first. Then the PNASC 200 or 400 would be connected to an appropriate source of electrical energy and the energy based renal denervation procedure would be performed using a stimulation protocol that is designed to be sufficient to provide an approximately circumferential ablation.
  • proximal or distal anesthetic can also apply to prior art devices such as the PTAC of Fischell application Ser. No. 13/752,062. Contrast could be added to the injection either during a test injection before the neuroablative agent or during the therapeutic injection to allow x-ray visualization of the ablation zone.
  • ethanol as an ablative agent, a volume of less than 0.6 mi is sufficient for this infusion as it will not only completely fill the needed volume including the sympathetic nerves, but is small enough that if accidentally discharged into the renal artery, would not harm the patient's kidneys. Ideally, a volume of 0.1 ml to 0.3 ml of ethanol should be used.
  • the amount used could be the same for all renal arteries or it could vary depending on the diameter of the renal artery into which the ethanol is to be injected.
  • the agrophobic, hygroscopic and lipophilic nature of ethanol enhances the spread allowing such a small volume to be effective. It is desirable to fluoroscopically verify the deployment of the needles 169 or 189 of FIGS. 13-14 into the vessel wall of the target vessel before injecting the ablative agent or fluid. .
  • A19 Asses the ablation treatment in step 482, such as after waiting up to 30 minutes for the ablative fluid to affect the nerves or the heat from, the energy based denervation to dissipate, measuring the nerve activity across at least one interval after the selected post-ablation duration has occurred and compare the post-ablation sensed activity to a selected value (prior baseline activity of the patient, population normative threshold value, etc. as has been disclosed) in order to assess the difference in nerve activity between before and after the renal denervation procedure. The difference can be assessed in relation to at least one treatment criterion in order to determine the effectiveness of the renal derivation.
  • step 484 Based upon the sensed data failing to meet the treatment criterion (e.g., if insufficient decrement of nerve activity is seen) then repeat steps 8 and 9, and if the assessment meets the treatment criterion then the ablation was effective and move to step 484.
  • the treatment criterion e.g., if insufficient decrement of nerve activity is seen
  • step 484 the sensing/stimulation components (e.g., needles and guide tubes) are retracted into the device, such as by depressing the button 342 of FIG. 16 and while holding the outer tube control cylinder 335, pull the needle control cylinder 345 back in the proximal direction until the injection needles 169 or 189 are fully retracted back into the guide tubes 115. Release the button 342 locking the motion of the injection needle control cylinder 345 to the guide tube control cylinder 333.
  • the sensing/stimulation components e.g., needles and guide tubes
  • step 484 Retract the PNASC 200 OR 400 back into the guiding catheter 140.
  • step 485 If in step 485, both arteries have been treated, go to a21 and step 490 to finish the procedure. Otherwise, in step 488, move the guiding catheter 140 to the other renal artery and advance the PNASC 200 or 400 into position. Repeat steps 473 through 484 for the other renal artery.
  • step 490 finish the ablation procedure such as by removing the guiding catheter with the PNASC 200 OR 400 from the body.
  • Fischell et al U.S. patent No. 8,740,849 discloses multiple techniques for use of saline pre and intermediate flushing of the injection lumens of the PTAC 100 which can also be used here.
  • buttons 332 and 342 release the motion of control cylinders when depressed and lock when released, it is also envisioned that they could also be interlocked as follows:
  • the first interlock allows the injection needle control cylinder 345 to be unlocked only when the guide tube control cylinder 333 is in its most distal position where the outer tube 102 is pulled back and the guide tubes 115 are fully deployed.
  • the second interlock allows the guide tube control cylinder 333 to be unlocked only when the injection needle control cylinder 345 is in its most distal position where the needles 169 or 189 are retracted within the guide tubes 1 15.
  • interlocks can be applied to the NSC 10 or 100 of FIGS. 1- 12.
  • the interlocks can be advantageous in some embodiments when associated with the injection of a neurotoxic ablative fluid.
  • buttons 332 and 342 should make the use of the NSC 10 or 100 and the PNASC 200 or 400 reasonably simple and straight forward.
  • the operator basically presses button 332 and pushes the guide tube cylinder 333 forward causing the guide tubes 30 or 115 to expand outward, then presses button 342 and advances the needles 23, 119, 169 or 189 forward to penetrate the wall of the renal artery. Nerve activity measurements and/or injections are performed then the reverse procedure is done with button 342 depressed and the needles 23, 1 19, 169 or 189 retracted, then button 332 is depressed and the guide tube cylinder 333 is retracted in the proximal direction retracting the guide tubes 30 or 115 within the body of the catheter.
  • FIG. 16 While a push-button activated handle where sections are pushed and pulled in the longitudinal direction to cause guide tube and needle deployment is shown in FIG. 16, it is envisioned that other techniques such as rotational mechanisms for locking or longitudinal motion can also be used.
  • a stopcock attached to the port 354 could also be used such that when closed, it would prevent leakage of ablative fluid out of the needle distal openings of the PNASC 200 or 400.
  • the blood pressure within the arterial system would if anything force any fluid within the injection lumens of the PNASC 200 or 400 back out of port 354.
  • the NSC 100 and the PNASC 200 or 400 can be packaged with the guide tubes 30 or 115 and the sensor tube 20, 1 16, 152, 162 or 172 fully extended.
  • the reason for this is that the preferred embodiment of the guide tubes are made from plastic such as polyimide formed into a curve shape. Such a plastic material may lose its shape over extended periods of time if it were packaged retracted back into the tubular shaft. 21 or 120 which would straighten it. In this case, the device would be shipped in a protective packaging to ensure handlers do not receive needle sticks.
  • the guide tubes 30 or 1 15 could be coated with a brightly colored dye or formed from a material that is brightly colored in order to serve as a visual deterrent when the needles are in their deployed position.
  • FIGS. 1-16 inclusive can be applied to measure electrical activity outside of any vessel or duct of the human body and in the case of the PNASC 200 or 400, inject any fluid for any purpose including that of local drag delivery into a specified portion of a blood vessel or the volume of tissue just outside of a blood vessel, or into prostatic tissue via the prostatic urethra.
  • these devices could be used to assess electrical activity in the wall of the left atrium, outside of the Pulmonary vein, and ablate the tissue there to diagnose and treat atrial fibrillation. It could also be used to assess nerve activity around a pulmonary artery, to assist in the treatment of pulmonary hypertension.
  • FIG. 21 is a block diagram of the external electronics equipment 500 with power supply 522.
  • the connector 360 connects to the connector 560 of the electronics 500 providing electrical conductivity from the NSC/PNASC wires 361, 362 and 363 to the wires 561, 562 and 563 respectively of the electronics 500
  • the wires 561, 562 and 563 connect to each of the amplifiers (each of which may have high, low, notch filters, and/or band pass filters) of the 3 A-D converters 521 , 522, 523.
  • the amplifiers can be referenced to a common ground 511, 512 and 513 respectively.
  • the amplifiers can be differential.
  • wires 561 and 562 can be routed to differential inputs of a first amplifier (in one embodiment 563 can serve as ground or a separate wire attached to the subject can serve as com/ground).
  • 562 and 563 can be routed to the second amplifier, and 561 and 563 to the third amplifier.
  • a multiplexor may be used to route the different signals to different amplifiers.
  • the routing can occur in a user selected manner (e.g. by adjusting a controller that determines the electrode montage, or can be controlled according to a sensing protocol implemented by the processor 540,
  • amplification modules may be incorporated into the circuitry such as isolated amplifiers, and pre-amphfiers
  • the amplified signals from the amplifiers 511, 512 and 513 are converted to digital signals by the analog to digital converters 521, 522, and 523 respectively.
  • the digital signals from the analog to digital converters 52, 1 , 52,2 and 523 are stored in the circular First-In-First-Out Buffers 531, 532 and 533 respectively that are read by the Central Processing Unit (CPU) 540 with RAM 542 and program memory 545.
  • CPU Central Processing Unit
  • the amplification and signal processing can be achieved using commercially available bioamplifiers and data acquisition systems (e.g. a Model 15LT Bipolar Portable Physiodata Amplifier System operating in conjunction with a national instruments NI USB-6212 BNC multifunction data acquisition unit or AD Instalments Bio Amps operating with a Powerlab system for recording extracellular potentials) which feed into a computer that is operating as part of the electronics equipment.
  • the CPU is connected to a Visual display 520 and a sonic transducer or loudspeaker 547 and receives input from a button touchpad 550 or touch sensitive screen of the visual display.
  • the visual display 520 may be as simple as a set of LEDs or it can be a full graphic display such as an LCD screen of a laptop, tablet or smartphone.
  • the button touchpad can be a limited or custom set of buttons or a full numeric or alphanumeric (e.g. QWERTY) keyboard for obtaining user input.
  • a clock/timing circuit 549 provides timing for the electronics 500 including the analog to digital converters 521, 522 and 523, the FIFO buffers 531, 532 and 533 and the central processing unit (CPU) 540.
  • the electronics 500 can be connected to a computers), equipment, accessories and electronic systems through the wired Input/Output (I/O) port 570, for example an RS-232 serial port or USB 1, 2, or 3 type port.
  • the wired Input/Output (I/O) port 570 can also be used to obtain input from an amplifier that senses patient data from one or more electrodes or other sensor located outside of the patient (e.g., ECG or blood pressure meter).
  • a wireless I/O sub-system 575 is also connected to the CPU 540 allowing wireless communication to and from other electronics, computer systems, and wireless local area network of a hospital, for example a Bluetooth or W T i-Fi protocol wireless circuit may be used.
  • the RAM 542 includes the storage for baseline data 544 and "current" nerve activity sensed data 546 that are captured at points during the ablation procedure.
  • the data can include raw waveforms summary, and trend data.
  • the RAM 542 can also contain as well as program protocols (for providing stimulation, sensing, or ablation), parameter values, criterion used during the treatment, and other values for settings that are used during screening, processing sensed data, and assessment of sensed data as can occur for the detection of significant changes in nerve activity indicative of effective denervation.
  • the values of the RAM can be accessed by the stimulation subsystem 580 or the sensing subsystem which is realized, at least in part, by the combination of amplifiers, A-to-D converters, FIFO buffers, and CPU.
  • a Hard Disk (HD) or Solid State Disk (SSD) provides non-volatile data, storage for the electronics 500 including recorded nerve activity and pre-set programs for operation.
  • a stimulation sub-system 580 contains signal generators related to providing stimulation and/or ablation signals and is controlled by the CPU 540.
  • the stimulation sub-system 580 is connected to the wires 561, 562 and 563 that are in turn connected through the connectors 560 and 360 to the wires 361, 362 and 363.
  • the connections of wires from the stimulation sub-system to the wires 561,562,563 can include multiplexor circuitry and other electronics in order to isolate and/or protect the amplifiers 511,512,513 during the provision of stimulation and/or ablation. This allows the stimulation sub-system to provide electrical energy for energy based ablation. In one configuration, the stimulation sub-system 580 would deliver the electrical energy sequentially to pairs of wires.
  • the sub-system 580 would deliver energy between any individual pair of the three electrodes 117 of FIG. 7, two of the three electrodes to the third as a reference return electrode or any combination of the three electrodes to a common reference return electrode either using a skin surface electrode or a portion of the catheter such as the guide wire 110.
  • the electrical energy delivered to a patient may take different forms.
  • the stimulation sub-system 580 may generate RF energy as is now used by devices such as the Medtronic Simplicity device.
  • the stimulation sub-system 580 would provide the electrical energy to drive the ultrasound transducer 650.
  • the wired I/O port 570 and/or wireless I/O port 575 may allow for another stimulator (not shown) to be used under control of the CPU 540 with the electronics 500 used for sensing only.
  • the ports 570 and 575 also can be used to control an external pump that may be further configured to heat or cool a liquid such as saline, so that a temperature controlled liquid can be provided to the proximal section of the PNASC 200/400 of FIGS. 13 or 14 for chemical or heated or cooled fluid deliver ' for renal denervation.
  • the ports 570 and 575 can be connected to systems of sensors to record data related to, for example, ECG, heart rate, or blood pressure. This may be essential as time-locked nerve activity measurement may require synchronization with the heartbeat.
  • the electronics 500 would typically connect to the wires 361, 362 and 363 connected to distal PNASC electrodes for both stimulation and sensing at different moments in time. It is also envisioned that stimulation and sensing could occur simultaneously. For example, using wire 561 as a common, stimulation could be provided to wire 562 with sensing from wire 563. This would typically be a stimulation signal followed by sensing although it is envisioned that simultaneous stimulation and sensing would be possible.
  • FIG. 22 shows the modules 504 through 524 that may be included in the program memory 545 of the electronics 500.
  • the modules contain software, electronics, and/or firmware, for accomplishing the functions disclosed. Modules can share resources and be controlled by other modules or components.
  • the electronics system 500 includes a control module 502 for controlling the overall function of the electronics 500.
  • the stimulation module 504 provides control of the stimulation sub-system 580 for providing electrical stimulation and/or energy based ablation through the electrodes such as the electrodes 117 of FIG. 7 that are positioned beyond the interior wall of the renal artery for the renal denervation application. Hie stimulation module 504 control of the stimulation sub-system 580 of FIG .
  • stimulation signals which can include RF signals, pulses, or arbitrary waveforms for output including alternating current (AC) and/or direct current (DC) signals to be used by electrical, stored in the protocols and parameters module 506, Treatment protocols that are stored in the protocols magnetic, optical, sonic, ultrasonic or other types of stimulators that are provided within catheter device with which it is configured to operate.
  • stimulation signals can include RF signals, pulses, or arbitrary waveforms for output including alternating current (AC) and/or direct current (DC) signals to be used by electrical, stored in the protocols and parameters module 506, Treatment protocols that are stored in the protocols magnetic, optical, sonic, ultrasonic or other types of stimulators that are provided within catheter device with which it is configured to operate.
  • the sensing and assessment module 505 (which may also be termed a sensing subsystem) provides control for the measurement of nerve activity collected by the CPU 540 from signals coming through the amplifiers 511, 512 and 513, A to D converters 521, 522 and 523 (which can include analog or digital filtering, processing, additional amplification, isolation, and safety circuitry) and FIFO Buffers 531,532 and 533.
  • the sensing and assessment module 505 controls the comparison of current nerve activity stored in the RAM 542 (e.g., in the RAM portion 546) with reference values or data such as previously recorded baseline nerve activity (e.g., stored in RAM location 544).
  • the module 505 can determine if one or more selected treatment criteria have been met or not and therefore determine whether one of effective nerve ablation or ineffective nerve ablation has occurred.
  • the Control module 502 can operate both stimulation module 504 and sensing module 505 according to treatment protocols and parameters and parameters module 506 can include nerve stimulation protocols, sensing protocols, ablation protocols, and evaluation protocols that enable the electronics system 500 to allow a medical practitioner to responsively adjust the catheter system operation in relation to the evaluation of sensed data, doctor input, time intervals, detection of events, and other triggers that can cause the selection, provision, and adjustment of therapy.
  • the control module can operate in a semi-automatic or fully automatic closed-loop manner to adjust the ablation treatment provided based upon the assessment of sensed data..
  • the sensing and assessment module 505 can also be used to calculate various quantitative measurements that can be derived from sensed data.
  • the assessment of sensed data may also include allowing a user to retrieve and display at least one of raw, summary, and trend results of sensed data for a patient that were collected at different moments in time. Assessment of data and modification of the ablation treatment may occur in a closed loop manner in which the stimulation is adjusted in relation to an evaluation of sensed data. Additionally or alternatively such assessment may cause information (information about the sensed data) or status signals displayed on the visual display 52 of FIG. 21 to be presented to a user of the electronics system 500. Sensing circuitry and sensors can be configured to allow the catheter system to measure such aspects as temperature.
  • At least one thermocouple or other temperature sensor for measuring the temperature of the monitored tissue or of the RF energy delivery element can be provided at the distal tip of the catheter.
  • the catheter system can be configured to acquire temperature or impedance measurements inside of, along, within, or outside of the wall of the vessel that is in the vicinity of the treatment target area.
  • Nerve stimulation can include stimulation that is provided, for example, in order to assess evoked cardiac activit 7 or evoked activity of the sympathetic nerve that is triggered by stimulation or may include electrical nerve ablation such as RF ablation or electrocautery.
  • the stimulation protocol can determine which of one or more stimulators or sensors on the catheter are used for stimulating, ablation, and sensing.
  • the electronics system 500 can also simply provide stimulation, ablation, or sensing under the manual control of a doctor.
  • the control module 502 has access to the clock/timing sub-system 549 including a real time clock and a timer.
  • the protocols module 506 can include, for example, a subroutine for processing data as part of steps such as step 288 of FIG. 20a.
  • sensed data can be evaluated according to at least one treatment c riteri on, and if the criteri on is passed then the ablation procedure is finalized, and if the treatment criterion is not passed, then ablative stimulation is adjusted, repeated, or otherwise provided, as defined by the treatment protocol as per step 286 of FIG. 20a.
  • a characteristic of the sensed data is e valuated before and after treatment in order to determine if a reduction in the characteristic has occurred due to therapy.
  • the characteristic is the peak (or mean) amplitude or frequency of energy within at least one selected frequency range, and reflects the energy within a selected frequency band.
  • the energy may be assessed by providing at least one band-pass, low-pass, or high-pass filter implemented with digital signal processing and allows the CPU 540 of FIG. 21 to filter the sensed data prior to its measurement of nerve activity.
  • a ratio may be calculated related to energy in a first frequency range (spectral band) compared to energy in a second band.
  • the CPU 540 can perform spectral analysis on the data to derive frequency, time-frequency, or time-locked time-frequency results.
  • a signal characteristic can be measured for 2 or more electrodes and can assess inter-electrode coupling. For example, prior to ablation the sensed data sensed from 2 or more electrodes may be more largely correlated due to the nerve signals being transmitted along the renal artery. After successful ablation a decrease in the post-ablation correlation or coherence (for one or more frequency ranges) should decrease relative to the baseline correlation or coherence.
  • Successful ablation can be defined to have occurred when at least one characteristic of the sensed activity related to an absolute activity level, a relative activity level (e.g., compared to baseline), or activity differences between 2 or more electrodes (e.g. decrease in coherence or correlation) meets at least one defined treatment criterion.
  • the one or more characteristics of the sensed data can be displayed by the visual display 520 to the user, and a histor - of values for the characteristic(s) can be stored by the CPU 540 in the RAM 542 or permanently in the SSD/HD 590.
  • the display 520 may show a digital display of one or more electrical characteristics such as the peak voltage, average voltage, peak power and/or average power of sensed nerve activity.
  • the difference (or ratio) in measurements before and after the renal denervation procedure can be used to assess the effectiveness of the procedure. Of these average voltage would be a preferred measurement.
  • the display 520 could pro vide a graphical display of the actual sensed signals as well as means to select which pair of electrodes is being used to derive a bipolar signal that is displayed. For example, using the button touchpad 550, control can be provided to enable a user to choose electrodes pair derivations such as 1-2, 2-3 or 3-1 would be desirable. This would have electrode 1 corresponding to wire 561, electrode 2 to wire 562 and electrode 3 to wire 563.
  • Electrode 1 is referenced to an electrode located distally within a patient could also allow electrical activity to be localized to a more specific degree since the active electrode recording the activity would reflect nerve activity and the reference electrode would not.
  • a calibration module 509 allows a user in to normalize the signal level during initial measurement of sympathetic nerve activity and capture the baseline nerve activity signal and thus establish the baseline activity level stored in the RAM portion 544 of FIG 21.
  • the visual display 520 would include 5 LEDs that could be activated to show maximum activity at the time of calibration/baseline recording. Following the renal denervation procedure, the user could operate the electronics module to cause a post-therapy measurement to be obtained. Tire reduction in nerve activity between the pre-therapy measurement and the post-therapy measurement would be displayed by illumination of the new level compared to the normalized value.
  • the post denervation level is 40% of the normalized level for one of the sensors, then only 2 of the 5 LEDs would be lit showing a 60% drop in nerve activity.
  • An example of even simpler version would have the visual display 520 include a green, yellow and red LED for various sensors, wherein this example, green indicates normal nerve activity, yellow indicates a partial reduction and red indicates a significant reduction,
  • a more complex embodiment could use the baseline as a "control" level of activity and then calculate the average activity over a specified measurement time interval.
  • the measurement protocol stored in the module 506 could then be configured to compare the sensed activity over a similar duration of nerve activity measurement which occurs after ablation therapy.
  • the visual display 520 using an alphanumeric of full graphical display can be configured to display a quantitative, numerical reduction value (e.g., "Nerve activity reduced by 64% compared to baseline nerve activity,")
  • a sensed data characteristic can be related to a measured neurogram.
  • a neurogram may be obtained by analog means by sending the sensed neural activity through a band pass filter (e.g., band-width, 700-2,000 Hz) and then a resistance - capacitance integrating network (e.g., time constant, 0.1 second) to obtain a mean voltage waveform.
  • a digital signal processing equivalent to this can also be performed by the CPU 540 according to a digital signal processing protocol stored in the module 506.
  • the neurogram may be processed to represent the average envel ope of the response in order to measure amplitude, burst rate, and other measures as is well known.
  • the sensed data can reflect evoked activity recorded in response to an evoking stimulus such as electrical or pharmaceutical stimulation, or other evoking stimulus.
  • an evoking stimulus such as electrical or pharmaceutical stimulation, or other evoking stimulus.
  • the sensed data can also be evoked by a change in the patient's state.
  • the patient state can be adjusted by raising and lowering blood pressure as can occur by providing vasoactive drugs to the patient. Either the baseline or post- ablation activity, or both, may be taken with blood pressure being higher or lower than might otherwise occur in the patient, in the absence of such intervention.
  • re and post assessment of patients can be adjusted based upon patient characteristics. For example, patients can be divided into two groups based upon high or low basal microvolt levels of renal sympathetic nerve activity. Assessment for the two groups may then occur differently. For example, patients with high basal microvolt levels of activity may have their baseline taken without intervention, while a low basal microvolt level patient may be assessed after drug exposure to increase activity during at least one of the baseline or post-ablation period.
  • Peak burst height (or maximum voltage) which can reflect the number of active fibers in renal sympathetic nerve activit 7 ( SNA) or synchronized RSNA . This measure may reflect residual nerve activity better than any post-ablation changes in average rhythm/burst rate/frequency over time, or peak frequency of the nerve activity. Nonetheless both amplitude and frequency of the activity (e.g., bursts) may be used to assess post-ablation nerve activity change relative to the pre-ablation baseline or relative to a threshold which defines successful therapy. Peak duration is influenced by the firing synchrony and the dispersion of the mass discharge due to different conduction velocities of the multiple renal nerve fibers. Peak duration, or averaged peak duration, may also be used to assess post-ablation changes in nerve activity.
  • Other measures can also include: average voltage; bursts/mm; average burst count; average burst amplitude; assessment of cyclical signatures; integrated and/or rectified renal sympathetic nerve activity (SNA); "leaky” or resetting integrators to integrate over time or up to a defined threshold; amplitude at a spectral frequency range associated with nerve activity; and, time locked activity recorded in response to an evoking stimulus such as at least one a drag or external electrical stimulus or internal electrical stimulus such as the ECG signal or non-electrical stimulus such as oscillation of arterial pressure.
  • SNA rectified renal sympathetic nerve activity
  • Correlation measures of recorded sensed data can also be obtained. Correlation may be accomplished between two electrodes and may be further processed according to cardiac data sensed by sensors located external to the patient. For example, correlation may also be calculated to assess association between heart beats, heart rates, and bursting patterns.
  • the SSD HD 520 of FIG. 21 may be configured to store a historical record in order to summarize, track, and store the ablation treatment that was provided and sensed data that was obtained which may be especially helpful evaluating what occurred during therapy.
  • the input/output module 507 works in conjunction with the control module 520 for presenting information to a user (e.g. physician) through the visual display 520 and/or sonic transducer 547 of FIG. 21 and obtaining information/input from the user through the touchpad 550 or touch sensitive display, when provided.
  • the visual and sonic transducers can present the user with alarms or notification related to the provision of therapy (e.g., a timer can be shown on the screen or an audio-sound can be related to a measurement of sensed activity, such as presenting a pitch that varies with the amount of sensed nerve activity). While not shown in FIG.
  • the electronics system 500 may communicate in a wired or wireless manner with, or be realized within, a specialized device, smartphone, laptop, or tablet computer the specialized device containing a visual display and loudspeaker,.
  • the device 500 can also contain user interface module 524 which interacts with user controls 525 such as nobs, switches, etc. to allow a user to provide input, such as through a menu guided system, as well as adjust operation of the device by manually adjusting nobs related to the operation of the device.
  • Both the control module 502 and the waveform generator module 512 may be configured with safety hardware and software routines, including calibration routines to calibrate the apparatus 500 and to ensure proper functioning.
  • optical fibers may be used for signal conduction through the catlieter and for delivery of laser based ablation for the nerve fibers
  • a solid state laser instead of an electrode could be located at the distal portion of the catlieter to turn electrical energy into light for ablation.
  • Such a laser could also be located in place of the ultrasonic transducer 650 of FIGS. 17 and 18 that could then send optical signals for ablation through optical fibers that would replace the wires 616.
  • the sensing capabilities of the NSC and PNASC presented here may have, in some embodiments, an important additional method of use.
  • the level of sympathetic nerve activity seen in the perivascular space may be indicative of whether the patient's hypertension is sympathetically driven. This would allow the clinician to decide whether denervation should be performed as well as providing a baseline against which the post-denervation nerve activity can be compared. It could also facilitate the choice of denervate vs. medicate and if medication is to be chosen, which medication would be best for non -sympathetically driven hypertension.
  • actions such as “sensing nerve activity using a catheter” include '"instructing the sensing of nerve activity using a catheter.”
  • the ranges disclosed herein also encompass any and all overlap, sub-ranges, and combinations thereof.
  • the terms “approximately”, “about”, and “substantially” may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01 % of the stated amount.

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Abstract

L'invention concerne un cathéter intravasculaire pour l'ablation et/ou la détection d'une activité nerveuse comprenant une ou plusieurs aiguilles introduites à travers des tubes de guidage supportés (éléments de guidage d'aiguille) qui se déploient pour entrer en contact avec la surface intérieure de la paroi de l'artère rénale ou d'un autre vaisseau d'un corps humain permettant aux aiguilles d'être introduites à travers la paroi du vaisseau jusque dans le tissu extra-luminal comprenant les milieux, l'adventice et l'espace périadventitiel. Le cathéter comporte également des structures assurant un support radial et latéral aux tubes de guidage de façon à ce que ces derniers s'ouvrent de façon uniforme et conservent leur position contre la surface intérieure de la paroi du vaisseau quand les aiguilles pointues sont introduites et pénètrent dans la paroi du vaisseau. Des électrodes à proximité des extrémités distales des aiguilles permettent la détection de l'activité nerveuse avant et après une tentative de dénervation rénale. Selon un mode de réalisation associé, de l'énergie ablative ou un fluide ablatif est fourni(e) par les aiguilles dans l'adventice ou à proximité de l'adventice pour procéder à l'ablation de nerfs à l'extérieur des milieux tout en épargnant les nerfs situés dans les milieux.
PCT/US2016/065017 2015-12-08 2016-12-05 Appareil permettant une ablation efficace et la détection efficace de nerfs en lien avec la dénervation Ceased WO2017100140A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109091728A (zh) * 2017-08-01 2018-12-28 中国科学院深圳先进技术研究院 一种微量液体注射器及对薄壁组织进行注射的方法
WO2021073862A1 (fr) * 2019-10-14 2021-04-22 Koninklijke Philips N.V. Surveillance de dénervation rénale par ablation à l'aide d'une angiographie par perfusion
CN116687556A (zh) * 2023-08-02 2023-09-05 上海微创电生理医疗科技股份有限公司 穿刺组件、定位方法及三维显示方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130274673A1 (en) * 2011-08-24 2013-10-17 Ablative Solutions, Inc. Intravascular ablation catheter with enhanced fluoroscopic visibility
US9931046B2 (en) * 2013-10-25 2018-04-03 Ablative Solutions, Inc. Intravascular catheter with peri-vascular nerve activity sensors

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109091728A (zh) * 2017-08-01 2018-12-28 中国科学院深圳先进技术研究院 一种微量液体注射器及对薄壁组织进行注射的方法
WO2021073862A1 (fr) * 2019-10-14 2021-04-22 Koninklijke Philips N.V. Surveillance de dénervation rénale par ablation à l'aide d'une angiographie par perfusion
JP2022551532A (ja) * 2019-10-14 2022-12-09 コーニンクレッカ フィリップス エヌ ヴェ 灌流血管造影を使用した腎除神経アブレーションのモニタリング
US12171603B2 (en) 2019-10-14 2024-12-24 Koninklijke Philips N.V. Renal denervation ablation monitoring using perfusion angiography
JP7653981B2 (ja) 2019-10-14 2025-03-31 コーニンクレッカ フィリップス エヌ ヴェ 灌流血管造影を使用した腎除神経アブレーションのモニタリング
CN116687556A (zh) * 2023-08-02 2023-09-05 上海微创电生理医疗科技股份有限公司 穿刺组件、定位方法及三维显示方法
CN116687556B (zh) * 2023-08-02 2023-11-03 上海微创电生理医疗科技股份有限公司 穿刺组件、定位方法及三维显示方法

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