WO2014091401A2

WO2014091401A2 - Dynamic denervation procedures and systems for the implementation thereof

Info

Publication number: WO2014091401A2
Application number: PCT/IB2013/060771
Authority: WO
Inventors: Boaz Behar
Original assignee: Perseus-Biomed Inc.
Priority date: 2012-12-10
Filing date: 2013-12-10
Publication date: 2014-06-19
Also published as: WO2014091401A3

Abstract

A method of controlling a denervation procedure for ablating a sympathetic nerve. The method comprises measuring a level of at least one biochemical indicator in the blood circulation of a patient undergoing a denervation procedure for ablating at least one sympathetic nerve and controlling the denervation procedure according to the level.

Description

DYNAMIC DENERVATION PROCEDURES AND SYSTEMS FOR THE

IMPLEMENTATION THEREOF

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to denervation procedures and, more particularly, but not exclusively, to dynamic denervation procedures and systems for the implementation thereof.

Increase of systemic tone is a primary medical concern in the world population. Multiple major disease conditions are clinically related to increase in systemic tone, for example hypertension, diabetes, severe sleep apnea, congestive heart failure, and others. Treatment of these diseases has been facilitated by multiple drugs, commonly used by doctors all over the world, including Alpha adrenoceptors, Beta adrenoceptor antagonists, Ganglionic blockers, and/or the like. Recently, a new form of treatment has emerged which shows promising results on the reduction of sympathetic tone, lowering of hypertension, increasing insulin uptake and more. This new form of treatment, called renal denervation (RDN), reduces sympathetic tone by denervating of afferent and efferent nerves leading to the kidneys. The renal denervation is an endovascular catheter- based procedure using radiofrequency ablation to reduce sympathetic drive. Other energy modalities for conducting renal denervation are also available, such as ultrasound, X-Ray radiation, microwave; so as other forms of denervating target nerves, such as the infusion of alcohol, nerve toxins, and alike. By applying radiofrequency pulses to the renal arteries, nerves are ablated. This causes reduction of renal sympathetic afferent and efferent activity.

Efficacy of the renal denervation process for the reduction of hypertension and for increasing insulin uptake has been shown, for example see "renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial", The Lancet, Volume 376, Issue 9756, Pages 1903 - 1909, 4 December 2010, digital object identifier (DOI): 10.1016/S0140- 6736(10)62039-9.

An exemplary device for treatment of sympathetic tone is described in: Uta C. Hoppe, MD et. al., "Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial", Journal of the American Society of Hypertension Volume 6, Issue 4 , Pages 270-276, July 2012. SUMMARY OF THE INVENTION

According to some embodiments of present invention, there is provided a method of controlling a denervation procedure for ablating a sympathetic nerve. The method comprises measuring a level of at least one biochemical indicator in the blood circulation of a patient undergoing a denervation procedure for ablating at least one sympathetic nerve, and controlling the denervation procedure according to the level.

Optionally, the measuring comprises: providing a nanosensor unit configured to detect the level; and contacting the nanosensor unit with a sample of the blood circulation during the denervation procedure to determine the level.

Optionally, the measuring is performed using a nanosensor unit having a nano wire-based field-effect transistors.

Optionally, the controlling comprises automatically forwarding instructions to an energy source performing the denervation procedure for adjusting the ablating of the at least one sympathetic nerve.

Optionally, the controlling comprises automatically forwarding instructions to a dispenser which dispenses a material for performing the denervation procedure for adjusting the denervation of the at least sympathetic nerve.

Optionally, the controlling comprises presenting on a display, during the denervation procedure, at least one visual indicator generated according to the level to facilitate a physician to adjust an energy source used for ablating of the at least one sympathetic nerve.

Optionally, the controlling comprises: presenting on a display, during the denervation procedure, at least one visual indicator generated according to the level to facilitate a physician to adjust a release of medical substance used for denervation of the at least one sympathetic nerve.

Optionally, the measuring comprises calculating a rate of change in the level during the denervation procedure; wherein the controlling is performed according to the rate of change. Optionally, the measuring comprises detecting an increase of the level above a threshold; wherein the controlling comprises halting a radiation of an energy used for ablating the at least one sympathetic nerve when the increase is identified.

Optionally, the measuring comprises detecting an increase of the level above a threshold; wherein the controlling comprises halting a radiation of an energy used for ablating the at least one sympathetic nerve when a predefined count of the identified increases occurs.

Optionally, the measuring comprises detecting a decrease of the level below a threshold; wherein the controlling comprises halting a radiation of an energy used for ablating the at least one sympathetic nerve when the decrease is identified.

Optionally, the controlling comprises adjusting an intensity of a radiation of an energy used for ablating the at least one sympathetic nerve during the denervation procedure and according to the level.

Optionally, the controlling comprises adjusting an intensity of a HIFU transmitter used for ablating the at least one sympathetic nerve during the denervation procedure and according to the level.

Optionally, the controlling comprises adjusting a duration of a radiation of an energy used for ablating the at least one sympathetic nerve during the denervation procedure and according to the level.

Optionally, method further comprises measuring an additional real time medical parameter of the patient during the denervation procedure and controlling the denervation procedure according to a combination of the level and the real time medical parameter.

More optionally, the real time medical parameter is selected from a group consisting of: a current heart beat rate, a current respiratory state, a current body temperature, and a current oxygen saturation level.

Optionally, method further comprises measuring comprises adjusting the level according to a naturally occurring fluctuation pattern of a medical parameter of the patient.

Optionally, method further comprises adjusting the level according to a naturally occurring fluctuation pattern of a medical parameter of the patient. Optionally, the controlling comprises adjusting a depth of a radiation of an energy used for ablating the at least one sympathetic nerve in a target tissue during the denervation procedure and according to the level.

Optionally, the controlling comprises adjusting a position of treatment of a radiation of an energy used for ablating the at least one sympathetic nerve in a target tissue during the denervation procedure and according to the level.

Optionally, the denervation procedure comprises radiating the at least one sympathetic nerve with an ablating energy in a plurality of sequential iterations; wherein the measuring comprises measuring the level during each the sequential iteration; wherein the controlling comprises performing a certain of the plurality of sequential iterations according to a measurement of the level during a preceding iteration.

Optionally, the level is a hormone level.

More optionally, the hormone level is a member of a group consisting of: an Epinephrine level and Norepinephrine level.

Optionally, the controlling comprises automatically controlling a delivery of a focused acoustic energy ablating the sympathetic nerve during the denervation procedure.

Optionally, the controlling comprises detecting a reduction in the level during denervation procedure.

More optionally, the reduction is below a threshold level.

More optionally, the reduction is higher than a threshold reduction rate.

According to some embodiments of present invention, there is provided a system of instructing a denervation procedure. The system comprises a nanosensor unit which detects level of at least one biochemical indicator in a blood circulation of a patient undergoing a denervation procedure of at least one sympathetic nerve, during the denervation procedure and a controlling module which generates, according to the level and during the denervation procedure, instructions to at least one of: (a) automatically instruct an energy source directing an energy to ablate the at least one sympathetic nerve, and (b) present instructive indications during the denervation procedure so as to allow a physician to manually control the energy source during the denervation procedure. Optionally, the nanosensor unit comprises a plurality of sensors to measure the level in a plurality of locations in the blood circulation; wherein the instructions are generated according to a combination of measurements from the plurality of sensors during the denervation procedure.

More optionally, the plurality of locations includes a blood vessel supplying an organ and a blood vessel draining the same organ.

More optionally, wherein the organ is a kidney.

More optionally, wherein the kidney is treated in a renal denervation procedure. Optionally, the nanosensor unit comprises a plurality of nanowire-based field- effect transistors.

Optionally, the nanosensor unit is integrated into a catheter guided in a blood vessel to direct the energy source during the denervation procedure.

According to some embodiments of present invention, there is provided a postoperative system of monitoring a patient after a denervation procedure. The postoperative system comprises a nanosensor unit which monitors a level of at least one biochemical indicator in a blood circulation of a patient after a denervation procedure of at least one sympathetic nerve and a controlling module which generates, according to the level and during the denervation procedure, instructions to at least one of: (a) automatically instruct a drug dispensing unit, and (b) present indications of the level after the denervation procedure so as to allow a physician to select a postoperative treatment to the patient.

According to some embodiments of present invention, there is provided a preoperative system of monitoring a patient before a denervation procedure. The system comprises a nanosensor unit which measures a level of at least one biochemical indicator in a blood circulation of a patient before a denervation procedure of at least one sympathetic nerve and a controlling module which generates, according to the level and before the denervation procedure, instructions to at least one of: (a) automatically select reference values for operating an energy source directing an energy to ablate the at least one sympathetic nerve, and (b) present indications of the level before the denervation procedure so as to allow a physician to select a preoperative treatment to the patient.

Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

Implementation of the method and/or system of embodiments of the invention can involve performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of embodiments of the method and/or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware or by a combination thereof using an operating system.

For example, hardware for performing selected tasks according to embodiments of the invention could be implemented as a chip or a circuit. As software, selected tasks according to embodiments of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more tasks according to exemplary embodiments of method and/or system as described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes a volatile memory for storing instructions and/or data and/or a non- volatile storage, for example, a magnetic hard-disk and/or removable media, for storing instructions and/or data. Optionally, a network connection is provided as well. A display and/or a user input device such as a keyboard or mouse are optionally provided as well. BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

In the drawings: FIG. 1 is a flowchart of a method of controlling a denervation procedure for ablating sympathetic nerve(s) according to a level of biochemical indicator(s), according to some embodiments of the present invention;

FIG. 2 is a schematic illustration of a system of instructing a denervation procedure by controlling an energy source, according to some embodiments of the present invention; and

FIG. 3 is a schematic illustration of a system of instructing a denervation procedure by presenting a feedback to a physician during a denervation procedure, according to some embodiments of the present invention.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

According to some embodiments of the present invention, there are provided methods and systems wherein a denervation procedure for ablating sympathetic nerve(s) of a patient undergoing the denervation procedure is controlled, manually by a physician and/or automatically by a source energy, according to real time measurements of biochemical indicators in the blood circulation of the patient, for example hormones, such as Epinephrine and/or Norepinephrine levels and/or level changes, of blood level, or of spillover levels from an organ, such as the treated kidney, during the denervation procedure. Optionally, a feedback is presented to the physician during the denervation procedure, for example on a display, guiding the physician how to perform and/or whether to proceed with the denervation procedure. Optionally, instructions for automatically operating one or more energy sources during the denervation procedure, for example acoustic energy sources, are calculated based on the measured biochemical indicators.

According to some embodiments of the present invention, there are provided methods and/or systems for dynamic preoperative and/or postoperative processes which are adjusted according to blood measurements of current biochemical indicators taken from a patient which is about to be treated with a denervation procedure and/or has completed a denervation procedure for ablating sympathetic nerve(s). Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

Reference is now made to FIG. 1, which is a flowchart of a method 100 of controlling a denervation procedure for ablating sympathetic nerve(s) according to level(s) of one or more biochemical indicators, for example hormone level(s) measured during the denervation procedure, for instance Epinephrine level and/or Norepinephrine level, according to some embodiments of the present invention. Reference is also made to FIG. 2, which is a schematic illustration of a system 200 of instructing a denervation procedure, for example by implementing the method 100 depicted in FIG. 1, according to some embodiments of the present invention. The system 200, which is optionally based on a processor 204 for calculations, includes and/or connected via a sensor interface 206 to, one or more nanosensor units operated to detect a level of one or more biochemical indicators in a blood circulation of a patient 203 undergoing a denervation procedure of a sympathetic nerve during the denervation procedure, for brevity referred to herein a nanosensor unit 202, for example as described below. The measured biochemical indicators may be hormones and/or derivatives of chemical and/or biological substances of a treated renal and/or systemic tone such as epinephrine blood level, norepinephrine blood level, kidney and/or heart spillover or clearance of epinephrine and/or norepinephrine, or any calculation of any of the above (such as epinephrine spillover from the kidney minus norepinephrine spillover from the same kidney).

The nanosensor unit 202 optionally includes nanotube sensors, such as nanowire- based field-effect transistors, for measuring biochemical indicators in the blood circulation. These sensors enable a relatively precise measurement of concentration levels of biochemical indicators, for example hormones, such as Epinephrine and/or Norepinephrine, during the denervation procedure. Exemplary nanowire -based field- effect transistors are described in F. Patolsky, G. F. Zheng, C. M. Lieber, Anal. Chem. 2006, 78, 4260; E. Stern, A. Vacic, M. A. Reed, IEEE Trans. Electron Devices 2008, 55, 3119; c) Y. Cui, Q. Q. Wei, H. K. Park, C. M. Lieber, Science 2001, 293, 1289; F. Patolsky, G. F. Zheng, O. Hayden, M. Lakadamyali, X. W. Zhuang, C. M. Lieber, Proc. Natl. Acad. Sci. USA 2004, 101, 14017; G. F. Zheng, F. Patolsky, Y. Cui, W. U. Wang, C. M. Lieber, Nat. Biotechnol. 2005, 23, 1294; b) B. P. Timko, T. Cohen-Kami, G. Yu, Q. Qing, B. Tian, C. M. Lieber, Nano Lett. 2009, 9, 914; and c) Z. Li, Y. Chen, X. Li, T. I. Kamins, K. Nauka, R. S. Williams, Nano Lett. 2004, 4, 245, which are incorporated herein by reference. Control according to Epinephrine and Norepinephrine concentration levels and spillover from certain organs may be as defined in G J Hasking, "Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardio renal sympathetic nervous activity", DOI: 10.1161/01.CIR.73.4.615, Circulation. 1986;73:615-62, Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231, which is incorporated herein by reference.

Optionally, the nanosensor unit 202 detects current level and/or change in the level of one or more biochemical indicators, such as hormones, for example Epinephrine and/or Norepinephrine, during the denervation procedure. These biochemical indicators act as neurotransmitters and known to take part in sympathetic tone increase. Optionally, the nanotube sensors are designed to measure hormone concentration changes, for example Epinephrine and/or Norepinephrine level changes, in a resolution of 1: 10^A-15 moles (femtomolar) (Molar concentration). Optionally, an exemplary detected change that is indicative of an ablation is a reduction of Norepinephrine and/or Epinephrine levels during a treatment of the systemic tone at an average rate of at least about 30-37 femtomolar decrease per minute.

Optionally, the nanosensor unit 202 includes one or more sensors which are placed to measure biochemical indicators in a single or multiple points in the body. For example, a venous intravascular catheter, inserted through the groin of the patient in a femoral access catheterization procedure, and maneuvered into the left renal vein enables drawing blood flowing from the left kidney. Similarly, an intravascular catheter, inserted into the left renal artery enables drawing blood flowing into the kidney. Such catheters may perform other functions during the denervation procedure, for example ablation. Optionally, two catheters are used for measuring biochemical indicators, such as a hormone level, for example norepinephrine, in blood entering the kidney and in blood flowing out of the kidney. Subtraction of these biochemical indicators is indicative of hormone spillover by the kidney.

The system 200 further includes a controlling module 205 that instructs a medical treatment device 201, such as an energy source directing a focused acoustic energy to ablate a sympathetic nerve of the patient 203 and/or a drug dispensing device which dispenses a medical material according to the detected biochemical indicator level during the denervation procedure, for example as described below. Optionally, the energy source 201 may be an acoustic energy source, such as a high intensity focused ultrasound (HIFU) energy source. Optionally, the energy source 201 may be a thermal energy source. Optionally, the energy source 201 may be a light emitting source. Optionally, the energy source 201 may be any energy source that is activated to ablate a tissue innervated by neural matter located within or in proximity to a treatment site, for example a blood vessel, in an ablation process. Optionally, the energy source 201 is part of the system 200 and/or controlled by the system 200. The energy source may be an internal energy source that is positioned within a blood vessel of a patient, for example see the Symplicity™ RDN System of Medtronic™. Optionally, denervation is conducted using non energy modalities, such as injection of nerve effected material into the artery, such as alcohol, or nerve toxin.

In such embodiments, the energy source radiates with energy, such as acoustic energy, from a tip of a catheter that is guided toward a target tissue, either for guiding an external energy source and/or to deliver low-level radio frequency (RF) energy through the wall of the renal artery to achieve RDN. The catheter is guided to be placed in the vasculature adjacent to the target neural site using standard interventional catheter techniques. RF energy is then delivered through the catheter to the target nerves. In such embodiments, the nanosensor unit 202 may be placed on the catheter, for example on the tip thereof. Optionally, the catheter tube is used to draw blood from the catheter distal end, and thereby measure level of the biochemical substance. Optionally, a miniature sensor is connected to the distal end of a catheter, and continuously measures said biological substance.

Optionally, the energy source 201 is extra-body device that is guided during the

RDN process using an internal guiding device such a catheter; and/or optionally supported by ultrasound image guidance and/or a magnetic resonance imaging (MRI) guidance method. In such embodiments, similarly to the above, the energy source 201 may be placed on the internal guiding device, for example on the tip thereof.

Optionally, the drug dispensing device is a catheter that is set to inject an ablating material, such as radioisotope, to a target nerve.

Reference is now made, once again, to FIG. 1. First, as shown at 101, a denervation procedure for ablating one or more sympathetic nerves, for example RDN, is initiated, for example as known in the art. The denervation procedure is optionally performed using an energy source as defined above. Optionally, the denervation procedure is performed as described in U.S. Patent Application No. 13/519,604 and in International patent Application No IB2012/054524 and International patent Application No IB2012/054525, which are incorporated herein by reference.

During the denervation procedure, as shown at 102, one or more biochemical indicator level(s) in the blood circulation of the patient undergoing the denervation procedure 203 are monitored. The biochemical indicator level(s) may be sampled iteratively, for example every second, minute, ten minutes, or any intermediate or longer periods.

As shown at 103, as long as the denervation procedure does not end, the one or more biochemical indicator level(s) are monitored. This allows, as shown at 104, to control dynamically the denervation procedure according to the biochemical indicator levelfs), for example a hormone level as long as the denervation procedure does not end 105 and/or to end the denervation procedure based on the biochemical indicator level(s).

Optionally, the dynamic control is achieved by automatically instructing the operation of the medical treatment device 201 in real time. These instructions are calculated based on the measured biochemical indicator level(s), a change to the biochemical indicator level(s), and/or an estimated denervation level that is calculated according to the measured biochemical indicator level(s). An ablation process may be automatically stopped, halted, and/or intensified according to current biochemical indicator level(s), for example by instructions generated by the controlling module 205. For example, a process may be halted or stopped when desired biochemical indicator level(s) are measured. The desired biochemical indicator level(s) may be set dynamically based on data indicative of a patient clinical history and/or current stage and/or medical information and/or patient data, such as age, gender, weight, body mass index (BMI), height, and the like. Optionally, the desired biochemical indicator level(s) are set dynamically according to pathology that is treated by the denervation procedure. Optionally, the desired level(s) are set dynamically according to initial measurements measured prior to treatment. Optionally, a count of desired level(s) is kept (such as, for example counting the times a certain biomedical indicator level is intensified due to hitting a nerve) and once enough times are met the procedure is stopped, or directed to another area.

Additionally or alternatively, a dynamic control is manually achieved by presenting to a physician a feedback indicative of the biochemical indicator level(s), a change to the biochemical indicator level(s), and/or an estimated denervation level that is calculated according to the measured biochemical indicator level(s). For example, FIG. 3 depicts a system 300 of instructing a denervation procedure that is similar to the system 200 depicted in FIG. 1; however, in this figure a controlling module is a feedback module 301 which generates instructions for presenting indications of the biochemical indicator level(s), a change to the biochemical indicator level(s), and/or an estimated denervation level that is calculated according to the measured biochemical indicator level(s) is depicted. The feedback module 301 optionally updates a presentation of a graphical user interface (GUI) that is presented to the physician and/or any other presentation unit, for example an array of light emitting diodes (LEDs) and/or the like. Optionally, the feedback module 301 indicates to the physician desired biochemical indicator level(s) for a certain patient, for example based on data indicative of her clinical history and/or current stage and/or medical information and/or patient data, such as age, gender, weight, BMI, height, and the like. In such a manner, the physician is presented with a goal and/or a current state. Optionally, the desired biochemical indicator level(s) are adjusted according to pathology that is treated by the denervation procedure. For example, the denervation procedure may be aimed at the reduction of systemic tone activity, for the treatment of hypertension, diabetes, sleep apnea, congestive heart failure, and/or alike. The desired biochemical indicator level(s) are optionally adjusted according the pathology.

The feedback may be displayed iteratively or continuously during the denervation procedure. In such a manner, the physician may decide how and/or if to proceed with an ablation procedure. Optionally, the presentation allows the physician to direct and/or position an ablation element during the denervation procedure, for example to aim the energy source accordingly. For example, the physician may detect when the energy source is oriented to ablate a target nerve, when a treatment failed, when a treatment has been completed, when an increase or a decrease of one or more ablation process parameters such as depth, number of ablation points, size of a treatment area, position of ablation area, power intensity, and/or the like is needed according to a detection of a certain change in biochemical indicator level(s).

In some embodiments of the present invention, the monitored biochemical indicator level(s) are Epinephrine level and/or Norepinephrine level. In such an embodiment, ablation of a sympathetic nerve by the medical treatment device 20 lis stopped and/or halted when Norepinephrine level decreases below a certain threshold or is higher than a certain rate, see Richard E. KATHOLI et. al., decrease in peripheral sympathetic nervous system activity following RDN or Unclipping in the One-Kidney One-Clip Goldblatt Hypertensive Rat, Volume 69 January 1982, pages 55- 62 of Clin. Invest. © The American Society for Clinical Investigation, Inc. and Michael Doumas, Stella Douma Renal sympathetic denervation in patients with treatment- resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial, Volume 376, Issue 9756, Pages 1903 - 1909, 4 December 2010 which are incorporated herein by reference.

Optionally, a RDN procedure is performed in a number of discrete steps which timed and/or adjusted according to the measurements of Epinephrine and Norepinephrine levels. Optionally, different regions are ablated sequentially, one at a time. Each region may be placed at a different depth in a target tissue, for example proximate three dimensional (3D) spaces, optionally overlapping, having centers which are few millimeters from one another. Additionally or alternatively, different intensities are transmitted sequentially, one at a time, for example in intensified energies. In such embodiments, after and/or during each step, biochemical indicator levels and/or level change(s) are measured to allow generating a feedback (e.g. presenting a feedback and/or forwarding instructions to the energy source) accordingly. For example, in an RDN procedure, Epinephrine and/or Norepinephrine levels are measured in the blood, either locally on the artery and/or vein of a treated kidney and/or in another place (i.e. level in the body). First, a base level is measured before a first treatment iteration and after in or after each step. If a substantial reduction is reached, treatment is halt and if there is no effect iteration is performed. In another example Epinephrine and/or Norepinephrine levels or respective spillover and/or clearance levels are measured during treatment of each step. As nerves are being provoked in this process, Epinephrine and/or Norepinephrine levels may increase momentarily. Therefore, an abrupt change in these levels may be considered to indicate hitting of nerves, whereas no change may be identified as a sign to redirect and/or adjust the transmission energy and/or frequency of an energy source.

The control 103 that is based on real time monitoring 102 allows avoiding and/or reducing the risk for over treatment by identifying when a continuous or iterative ablation process achieves a desired reduction in one or more biochemical indicator levels.

This dynamic control allows adjusting a denervation procedure wherein the actual damage to the nerve is not measured during the denervation procedure, for example when the evolution of the target tissue is not facilitated.

For example, the controlled process is a denervation procedure that is held by a RDN catheter, optionally single point RDN catheter activated to radiate a blood vessel, for example an artery, with ablating energy during a plurality of sequential iterations, each time from a different position. Optionally, the feedback module 301 assists the physician with determining how many points to ablate, for example by indicating to the physician when to stop the ablation process in the denervation procedure. Alternatively, the controlling module 205 automatically determines how many ablation points (iterations) to complete, for example instructing when to stop the ablation process in the denervation procedure. Alternatively, when the procedure is conducted by extracorporeal HIFU for example, a measurement of biochemical indicator level(s) is used to determine whether to increase, or decrease the size of the lesion created, and/or the depth from the artery wall.

As described above, the monitoring 102 is based on measurements of the nanosensor unit 202. Optionally, the measurements are processed to increase the accuracy of the measurements. For example, the measurements of the nanosensor unit 202 are processed for noise reduction, time averaging, gating of blood measurement according to heartbeat and/or respiration. Such processing facilitates a comparison between actual patient measurements and reference values which may be used for indicating measured biochemical indicator level(s), a change to the biochemical indicator level(s), and/or an estimated denervation level that is calculated according to the measured hormone level(s).

According to some embodiments of the present invention, the measurements and/or reference values, which are used for the monitoring 102, are dynamically correlated and/or synchronized with real time medical parameters. As used herein, a real time medical parameter means a current heart beat rate, a current respiratory state, a current body temperature, and/or a current oxygen saturation level. This adjustment takes into account naturally occurring fluctuations in the measurements that affect the readings of concentration levels though not derived from the denervation process. The naturally occurring fluctuations may be actually measured and/or provided as a reference pattern. This adjustment also allows ignoring spillover levels and clearance levels of these substances; for example, an electrocardiogram (ECG) signal monitored during treatment may be used to determine when blood from a catheter is sampled and/or when to read biochemical indicator levels, for example at the peak of a T wave of the ECG signal.

Optionally, the system 200/300 is integrated and/or connected to catheter laboratory equipment and used by an interventional cardiologist and/or radiologist during a RDN treatment.

Optionally, the system 200/300 is connected to a drug dispensing device, enabling control of drug levels dispensed to the patient 203 automatically according to the current biochemical indicator level(s) during the denervation procedure.

According to some embodiments of the present invention, a system, such as system 300, may be used as a postoperative monitoring device that continuously or iteratively biochemical indicator levels, such as Epinephrine level and/or Norepinephrine level, after a denervation procedure, for example a RDN procedure. In such embodiments, the energy source 201 is not part of the system 300. In such embodiments, the nanosensor unit 202 may be placed at the patient's bedside, measuring changes in its blood circulation. In such embodiments, the feedback module 301 is designed to instruct a presentation unit, such as a display, and/or an alert unit, for example a messing unit that transmits messages to designated personals, for example instant messaging (IM) messages, emails, and short message service (SMS), to present feedback such as alerts, notification, and/or current measurements. The presented feedback(s) are optionally generated when one or more rules are complied with, for example a measured level which exceeds a preset level, a measured rate of change which exceeds a preset rate, an identification of presence or absence of certain biochemical indicators. This allows medical staff to respond immediately to the denervation procedure, or to determine required action by medical staff. Optionally, a drug dispensing unit is automatically operated according to the measurement(s), facilitating a control on delivered drug(s).

According to some embodiments of the present invention, a system, such as system 300, may be used as a preoperative device that measures biochemical indicator levels, such as Epinephrine level and/or Norepinephrine level, before a denervation procedure, for example a RDN procedure. In such embodiments, the energy source 201 may not be part of the system 300. In such embodiments, the nanosensor unit 202 may be placed in a laboratory, measuring levels taken from blood samples. In such embodiments, the feedback module 301 is designed to instruct a presentation unit and/or an alert unit (i.e. as defined above), to present current measurements that can be used as reference values during a denervation procedure, for example a RDN procedure. Reference values may also be calculated and forwarded for operating the energy source accordingly. This allows medical staff to prepare to the denervation procedure and/or the calibration of a system, such as system 200 and/or an energy source, for example as defined above, accordingly.

It is expected that during the life of a patent maturing from this application many relevant systems and methods will be developed and the scope of the term a processor, a sensor, and an energy source is intended to include all such new technologies a priori. As used herein the term "about" refers to + 10 %.

The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to". This term encompasses the terms "consisting of" and "consisting essentially of".

The phrase "consisting essentially of" means that the composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method. As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

The word "exemplary" is used herein to mean "serving as an example, instance or illustration". Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and/or to exclude the incorporation of features from other embodiments.

The word "optionally" is used herein to mean "is provided in some embodiments and not provided in other embodiments". Any particular embodiment of the invention may include a plurality of "optional" features unless such features conflict.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

Claims

WHAT IS CLAIMED IS:

1. A method of controlling a denervation procedure for ablating a sympathetic nerve, comprising:

measuring a level of at least one biochemical indicator in the blood circulation of a patient undergoing a denervation procedure for ablating at least one sympathetic nerve; and

controlling said denervation procedure according to said level.

2. The method of claim 1, wherein said measuring comprises: providing a nanosensor unit configured to detect said level; and contacting said nanosensor unit with a sample of said blood circulation during said denervation procedure to determine said level.

3. The method of claim 1, wherein said measuring is performed using a nanosensor unit having a nano wire-based field-effect transistors.

4. The method of claim 1, wherein said controlling comprises automatically forwarding instructions to an energy source performing said denervation procedure for adjusting the ablating of said at least one sympathetic nerve.

5. The method of claim 1, wherein said controlling comprises automatically forwarding instructions to a dispenser which dispenses a material for performing said denervation procedure for adjusting the denervation of said at least sympathetic nerve.

6. The method of claim 1, wherein said controlling comprises:

presenting on a display, during said denervation procedure, at least one visual indicator generated according to said level to facilitate a physician to adjust an energy source used for ablating of said at least one sympathetic nerve.

7. The method of claim 1, wherein said controlling comprises: presenting on a display, during said denervation procedure, at least one visual indicator generated according to said level to facilitate a physician to adjust a release of medical substance used for denervation of said at least one sympathetic nerve.

8. The method of claim 1, wherein said measuring comprises calculating a rate of change in said level during said denervation procedure; wherein said controlling is performed according to said rate of change.

9. The method of claim 1, wherein said measuring comprises detecting an increase of said level above a threshold; wherein said controlling comprises halting a radiation of an energy used for ablating said at least one sympathetic nerve when said increase is identified.

10. The method of claim 1, wherein said measuring comprises detecting an increase of said level above a threshold; wherein said controlling comprises halting a radiation of an energy used for ablating said at least one sympathetic nerve when a predefined count of said identified increases occurs.

11. The method of claim 1, wherein said measuring comprises detecting a decrease of said level below a threshold; wherein said controlling comprises halting a radiation of an energy used for ablating said at least one sympathetic nerve when said decrease is identified.

12. The method of claim 1, wherein said controlling comprises adjusting an intensity of a radiation of an energy used for ablating said at least one sympathetic nerve during said denervation procedure and according to said level.

13. The method of claim 1, wherein said controlling comprises adjusting an intensity of a HIFU transmitter used for ablating said at least one sympathetic nerve during said denervation procedure and according to said level.

14. The method of claim 1, wherein said controlling comprises adjusting a duration of a radiation of an energy used for ablating said at least one sympathetic nerve during said denervation procedure and according to said level.

15. The method of claim 1, further comprising measuring an additional real time medical parameter of said patient during said denervation procedure and controlling said denervation procedure according to a combination of said level and said real time medical parameter.

16. The method of claim 15, wherein said real time medical parameter is selected from a group consisting of: a current heart beat rate, a current respiratory state, a current body temperature, and a current oxygen saturation level.

17. The method of claim 1, further comprising measuring comprises adjusting said level according to a naturally occurring fluctuation pattern of a medical parameter of said patient.

18. The method of claim 1, further comprising adjusting said level according to a naturally occurring fluctuation pattern of a medical parameter of said patient.

19. The method of claim 1, wherein said controlling comprises adjusting a depth of a radiation of an energy used for ablating said at least one sympathetic nerve in a target tissue during said denervation procedure and according to said level.

20. The method of claim 1, wherein said controlling comprises adjusting a position of treatment of a radiation of an energy used for ablating said at least one sympathetic nerve in a target tissue during said denervation procedure and according to said level.

21. The method of claim 1, wherein said denervation procedure comprises radiating said at least one sympathetic nerve with an ablating energy in a plurality of sequential iterations; wherein said measuring comprises measuring said level during each said sequential iteration; wherein said controlling comprises performing a certain of said plurality of sequential iterations according to a measurement of said level during a preceding iteration.

22. The method of claim 1, wherein said level is a hormone level.

23. The method of claim 22, wherein said hormone level is a member of a group consisting of: an Epinephrine level and Norepinephrine level.

24. The method of claim 1, wherein said controlling comprises automatically controlling a delivery of a focused acoustic energy ablating said sympathetic nerve during said denervation procedure.

25. The method of claim 1, wherein said controlling comprises detecting a reduction in said level during denervation procedure.

26. The method of claim 25, wherein said reduction is below a threshold level.

27. The method of claim 25, wherein said reduction is higher than a threshold reduction rate.

28. A computer readable medium comprising computer executable instructions adapted to perform the method of claim 1.

29. A system of instructing a denervation procedure, comprising: a nanosensor unit which detects level of at least one biochemical indicator in a blood circulation of a patient undergoing a denervation procedure of at least one sympathetic nerve, during said denervation procedure; and

a controlling module which generates, according to said level and during said denervation procedure, instructions to at least one of:

(a) automatically instruct an energy source directing an energy to ablate said at least one sympathetic nerve, and

(b) present instructive indications during said denervation procedure so as to allow a physician to manually control said energy source during said denervation procedure.

30. The system of claim 29, wherein said nanosensor unit comprises a plurality of sensors to measure said level in a plurality of locations in said blood circulation; wherein said instructions are generated according to a combination of measurements from said plurality of sensors during said denervation procedure.

31. The system of claim 30, wherein said plurality of locations includes a blood vessel supplying an organ and a blood vessel draining the same organ.

32. The system of claim 31, wherein said organ is a kidney.

33. The system of claim 32, wherein said kidney is treated in a renal denervation procedure.

34. The system of claim 29, wherein said nanosensor unit comprises a plurality of nanowire-based field-effect transistors.

35. The system of claim 29, wherein said nanosensor unit is integrated into a catheter guided in a blood vessel to direct said energy source during said denervation procedure.

36. A postoperative system of monitoring a patient after a denervation procedure, comprising:

a nanosensor unit which monitors a level of at least one biochemical indicator in a blood circulation of a patient after a denervation procedure of at least one sympathetic nerve; and

(a) automatically instruct a drug dispensing unit, and

(b) present indications of said level after said denervation procedure so as to allow a physician to select a postoperative treatment to said patient.

37. A preoperative system of monitoring a patient before a denervation procedure, comprising:

a nanosensor unit which measures a level of at least one biochemical indicator in a blood circulation of a patient before a denervation procedure of at least one sympathetic nerve; and

a controlling module which generates, according to said level and before said denervation procedure, instructions to at least one of:

(a) automatically select reference values for operating an energy source directing an energy to ablate said at least one sympathetic nerve, and

(b) present indications of said level before said denervation procedure so as to allow a physician to select a preoperative treatment to said patient.