Impedance-based irreversible electroporation (IRE)

Abstract

The invention is entitled "Impedance-based irreversible electroporation (IRE)". An irreversible electroporation (IRE) method includes selecting electrodes of a catheter placed in contact with tissue in an organ for applying IRE pulses between the selected electrodes. Impedance is measured between the selected electrodes. Based on the measured impedance, an IRE protocol is selected having parameters that satisfy predefined safety criteria at the measured impedance. The IRE pulses are applied according to the selected protocol.

Description

Technical Field

[0001] The present invention relates generally to invasive ablation, and more specifically to irreversible electroporation (IRE) of cardiac tissue. Background Technology

[0002] Estimation of invasive ablation parameters and control of ablation based on such estimations have been previously disclosed in patent literature. For example, U.S. Patent Application Publication No. 2013 / 0006228 describes an apparatus for local energy delivery and a method of using such an apparatus, particularly for therapeutic treatment of biological tissues. The method disclosed in this invention may involve positioning and deploying an energy delivery member in a target site, and delivering energy through the energy delivery member. In one embodiment, the radio frequency (RF) duty cycle and / or pulse duration may be configured to vary in response to one or more selected parameters, which may include the frequency of the treatment signal, the power of the treatment signal, or the tissue impedance of the treatment signal.

[0003] For example, U.S. Patent Application Publication No. 2016 / 0066977 describes a medical system for ablating tissue sites through real-time monitoring during an electroporation procedure. A pulse generator generates a pre-treatment test signal at a frequency of at least 1 MHz before the treatment procedure and a treatment test signal during the procedure. A treatment control module determines an impedance value based on the pre-treatment and treatment test signals, and determines the progress of electroporation and the end point of treatment in real time based on the impedance value determined during treatment. Summary of the Invention

[0004] One embodiment of the invention described below provides an irreversible electroporation (IRE) method comprising selecting electrodes of a catheter positioned to contact tissue in an organ for applying an IRE pulse between the selected electrodes. Impedance is measured between the selected electrodes. Based on the measured impedance, an IRE protocol having parameters that meet predefined safety criteria at the measured impedance is selected. An IRE pulse is applied according to the selected protocol.

[0005] In some implementations, selecting the IRE protocol includes selecting the pulse width, pulse repetition rate, and number of IRE pulses.

[0006] In some implementations, selecting predefined safety criteria includes selecting an IRE protocol with an impedance threshold lower than the measured impedance, thereby ensuring that the IRE pulse will not overheat the tissue.

[0007] In one implementation, the impedance threshold of the selected protocol is derived by either calculation or lookup in a table.

[0008] In another embodiment, the IRE method further includes setting an IRE protocol that includes an impedance threshold. Impedance is measured between the selected electrodes, and the measured impedance is compared to a given threshold. If the measured impedance is below the threshold, the IRE protocol is changed to have a new impedance threshold lower than the measured impedance. IRE is then applied according to the changed protocol.

[0009] In one embodiment, setting the IRE protocol includes selecting a pulse width, a pulse repetition rate, and the number of IRE pulses, and changing the IRE protocol includes changing one or more of the pulse width, pulse repetition rate, and number of IRE pulses. In another embodiment, changing one or more of the pulse width, pulse repetition rate, and number of IRE pulses includes decreasing one of the pulse width and repetition rate, and increasing the number of pulses.

[0010] In some implementations, modifying the IRE protocol includes maintaining the same accumulated electrical energy applied by the IRE.

[0011] According to another embodiment of the invention, an irreversible electroporation system including an interface and a processor is also provided. The interface is configured to exchange signals with a catheter placed to contact tissue in an organ. The processor is configured to (i) select electrodes of the catheter for applying an IRE pulse between the selected electrodes, (ii) measure the impedance between the selected electrodes, (iii) select an IRE protocol with parameters that meet predefined safety criteria at the measured impedance based on the measured impedance, and (iv) apply an IRE pulse according to the selected protocol. Attached Figure Description

[0012] The invention will be more fully understood from the following detailed description of embodiments thereof, taken in conjunction with the accompanying drawings, wherein:

[0013] Figure 1 This is a schematic diagram of a catheter-based irreversible electroporation (IRE) system according to an exemplary embodiment of the present invention; and

[0014] Figure 2 To illustrate the use of exemplary embodiments of the present invention Figure 1 The flowchart shows a method for applying irreversible electroporation (IRE) pulses to a system. Detailed Implementation

[0015] Overview

[0016] Irreversible electroporation (IRE), also known as pulsed field ablation (PFA), can be used as an invasive treatment modality to kill tissue cells by subjecting them to high-voltage pulses. Specifically, IRE pulses can be used to kill myocardial tissue cells to treat arrhythmias. Cell damage occurs when the transmembrane potential exceeds a threshold, leading to cell death and thus the development of tissue lesions. Therefore, particular interest is placed on using high-voltage bipolar pulses (e.g., using a selected pair of electrodes in contact with the tissue) to generate a high electric field (e.g., above a certain threshold) to kill tissue cells between the electrodes.

[0017] However, if the impedance between the selected electrodes is low, the high voltage between the electrodes can also generate excessive Joule heating, which can lead to potentially clinically dangerous and undesirable effects, such as vapor bursting in the ablated tissue. For example, a 2kV pulse voltage across 100Ω (two possible values) instantaneously generates 20 amperes, or 40kW, in the tissue, which can be dangerous.

[0018] The embodiments of the invention described below prevent excessive Joule heating of tissue undergoing IRE by taking into account the electrical impedance between electrodes. In one embodiment, initially, an IRE ablation protocol is selected, such as a default protocol, where this protocol typically specifies the pulse shape (peak voltage and width), pulse repetition rate, and number of pulses.

[0019] The selected protocol can be considered to have a specific impedance threshold, that is, a threshold that the actual resistance between the electrodes must exceed for ablation to be considered safe. The impedance threshold for a given protocol can be calculated, for example, by the processor based on protocol parameters, or read from a predetermined relation (e.g., empirically derived from a lookup table or a pre-calculated relation).

[0020] Some implementations use the electrodes selected for the IRE to measure the impedance between the electrodes. If the measured impedance is higher than an impedance threshold, meaning that the Joule heating is within acceptable limits, the processor instructs the system to perform the IRE using the initial protocol.

[0021] However, if the measured impedance is below an impedance threshold, the selected protocol may lead to overheating, in which case the processor or user may change the initial protocol. This change may involve shortening the length of a single pulse, reducing the repetition rate of the pulses, and / or increasing the number of pulses (to maintain the same cumulative clinical effect). The changed protocol has a different impedance threshold (e.g., a lower threshold) so that the same measured impedance is now above the new threshold, and IRE can be performed.

[0022] Regarding ablation energy, in order to perform ablation at a given impedance, if the impedance is below a threshold, the protocol is adjusted to maintain similar energy delivery as much as possible. Optimization involves modifying the pulse duration and / or the number of pulses and / or the number of pulse bursts to maintain similar energy delivery, thereby achieving the same clinical and thermal effects. For ablation with lower impedance, the total energy is still reduced by modifying the pulse duration and / or the number of pulses, and the impedance threshold is adjusted accordingly to the maximum permissible value.

[0023] When the protocol is changed, the peak voltage of the IRE pulse is typically not reduced because this affects the generated electroporation field. In some implementations, the peak voltage may be reduced, provided it remains above a predetermined minimum level required for the IRE to achieve clinical efficacy.

[0024] As stated above, to maintain clinical efficacy, changes to the protocol typically do not alter the total (e.g., cumulative) dissipated energy. Instead, these changes extend the duration of the applied pulse to allow for greater heat diffusion and reduce the peak temperature caused by heating.

[0025] In another implementation, the physician first inserts and places a catheter at the target tissue location. Next, the IRE ablation system measures the impedance between the electrodes of the catheter. The system or physician then selects an IRE protocol with parameters that meet predefined safety criteria at the measured impedance. Any suitable safety criterion can be used. For example, a safety criterion aimed at minimizing the risk of overheated tissue is provided, based on a minimum measured impedance, where the system selects a protocol with an impedance threshold below the minimum measured impedance, such that the resulting current will be below the current that would cause tissue overheating. Therefore, such a protocol can be used safely because Joule heating is expected to be within acceptable limits. In this implementation, there is no need for initial protocol selection (e.g., uploading the protocol and subsequently modifying it based on the measured impedance).

[0026] The techniques disclosed in this invention can be used in various types of IRE ablation procedures and can be used with various types of catheters. In one example, cardiac IRE ablation is performed using an expandable frame (e.g., a balloon or basket) fitted to the distal end of an ablation catheter. The expandable frame, equipped with ablation electrodes, is navigated through the cardiovascular system and inserted into the heart to, for example, ablate the opening of a pulmonary vein (PV).

[0027] By making the above changes to the IRE protocol, it is possible to make IRE ablation of pores such as PV using expandable frame catheters safer, while maintaining its clinical efficacy.

[0028] System Description

[0029] Figure 1This is a schematic illustration of a catheter-based irreversible electroporation (IRE) system 20 according to an embodiment of the present invention. System 20 includes a catheter 21, wherein the shaft 22 of the catheter is inserted by a physician 30 through a sheath 23 into the vascular system of a patient 28. The physician 30 then navigates the distal end 22A of the shaft 22 to a target location within the patient's heart 26 (illustration 25).

[0030] Once the distal end 22a of the shaft 22 has reached the target position, the physician 30 typically retracts the sheath 23 by pumping saline into the balloon 40, thus inflating the balloon 40. The physician 30 then manipulates the shaft 22 such that the electrode 50 disposed on the balloon catheter 40 engages the inner wall of the PV port 51 to apply a high-pressure IRE pulse to the tissue of the PV port 51 via the electrode 50.

[0031] As shown in Figures 25 and 27, the distal end 22A is fitted with an inflatable balloon 40 comprising a plurality of smooth-edged and equidistantly spaced IRE electrodes 50. Due to the flattened shape of the distal portion of the balloon 40, the distance between adjacent electrodes 50 (such as the distance 55 between electrodes 50a and 50b) remains substantially constant even when the electrodes 50 cover the distal portion. Therefore, the configuration of the balloon 40 allows for more efficient electroporation (e.g., with a substantially uniform electric field strength) between adjacent electrodes 50, while the smooth edges of the electrodes 50 minimize undesirable thermal effects.

[0032] For example, specific aspects of inflatable balloons are addressed in U.S. Provisional Patent Application No. 62 / 899,259, filed September 12, 2019, entitled “Balloon Catheter with Force Sensor”, and U.S. Patent Application No. 16 / 726,605, filed December 24, 2019, entitled “Contact Force Spring with Mechanical Stop”, both of which are assigned to the assignee of this patent application, and the disclosures thereof are incorporated herein by reference.

[0033] In the embodiments described herein, catheter 21 may be used for any suitable diagnostic and / or therapeutic purpose, such as electrophysiological sensing of the PV port 51 tissue in the left atrium 45 of heart 26 and / or the aforementioned IRE isolation.

[0034] The proximal end of catheter 21 is connected to console 24, which includes an IRE pulse generator 38 configured to apply IRE pulses between adjacent electrodes 50. Electrodes are connected to the IRE pulse generator 38 via wires extending in the shaft 22 of catheter 21. A memory 48 of console 24 stores an IRE protocol including IRE pulse parameters, such as peak bipolar voltage and pulse width.

[0035] The console 24 includes a processor 41, typically a general-purpose computer, with suitable front-end and interface circuitry 37 for receiving signals from the catheter 21 and from external electrodes 49 typically positioned around the chest of the patient 26. For this purpose, the processor 41 is connected to the external electrodes 49 via wires extending through cable 39.

[0036] During the procedure, system 20 may use the active current location (ACL) method provided by Bisense-Webster (Irvine, California) to track the corresponding position of electrode 50 within heart 26, as described in U.S. Patent No. 8,456,182, the disclosure of which is incorporated herein by reference.

[0037] In some implementations, interface circuitry 37 is configured to measure the impedance between selected electrodes in electrode 50, such as the impedance between electrodes 50a and 50b, after balloon 40 is placed at the target tissue but before IRE is performed, and to provide the measured impedance to processor 41. The processor compares the impedance to a predetermined impedance threshold, and if the impedance is below the threshold, processor 41 or (by the system) alerts physician 30 to modify protocols, such as those described in Tables I and II below, to mitigate thermal hazards while maintaining the clinical efficacy of the IRE.

[0038] In other implementations, physician 30 may modify any parameter of the altered protocol from user interface 47.

[0039] Processor 41 is typically programmed in software to perform the functions described herein. This software may be downloaded to a computer electronically via a network, or alternatively or additionally set and / or stored on a non-transitory tangible medium, such as magnetic storage, optical storage, or electronic storage.

[0040] Specifically, processor 41 performs operations as disclosed herein, including Figure 2 A dedicated algorithm is used to enable processor 41 to perform the disclosed steps, as further described below. Specifically, processor 41 is configured to output IRE pulses to IRE pulse generator 38 according to treatment protocol commands uploaded by processor 41 from memory 48.

[0041] Impedance-based IRE method

[0042] Figure 2 To illustrate the use of embodiments of the present invention Figure 1A flowchart of a method for applying an irreversible electroporation (IRE) pulse using system 20 is provided. According to the presented implementation, the algorithm executes a process beginning with IRE planning step 80, at which point the physician uses processor 41 to upload a protocol containing parameters for the IRE pulse to be applied to the tissue. Examples of IRE ablation settings in the initial protocol that can be used to ablate cardiac tissue using the disclosed balloon 40 are given in Table I:

[0043] parameter value Preset IRE peak voltage 1000V Pulse width 1 millisecond Repetition rate 2Hz Number of pulses 10

[0044] Table I – Initial Protocol

[0045] Next, at balloon catheter navigation step 82, physician 30 uses, for example, electrode 50 as ACL sensing electrode to insert balloon 40 catheter and navigate to the target tissue location in the patient's organ, such as at PV port 51.

[0046] Next, at impedance measurement step 84, processor 41 measures the impedance between the selected electrodes (e.g., using interface circuit 37).

[0047] At impedance threshold determination step 86, processor 41 outputs (e.g., calculated or selected from a lookup table) the impedance threshold of the uploaded protocol.

[0048] At impedance testing step 88, processor 41 compares the measured impedance with an impedance threshold. If the measured impedance is lower than the protocol's impedance threshold, then in protocol change step 90, the physician uses processor 41 to change the protocol to, for example, one given in Table II:

[0049] parameter scope Preset IRE peak voltage 1000V Pulse width 0.5 milliseconds Repetition rate 1Hz Number of pulses 40

[0050] Table II – Changes to the Protocol

[0051] As shown in Table II, when the pulse width and repetition rate decrease, the accumulated electrical energy can be kept the same by increasing the number of pulses.

[0052] In other words, given the measured impedance, protocol parameters other than voltage are modified so that the energy will remain similar to the planned value. The impedance threshold is adjusted to be lower than the measured impedance because it is optimized in this way. Thus, the impedance threshold automatically adjusted for the changed protocol (e.g., the protocol in Table II) is moved below the same measured impedance, and then, at IRE processing step 92, the processor 41 commands the generator 38 to apply an IRE pulse to the tissue using the changed IRE pulse parameters. The IRE pulse is applied between the selected electrodes of the balloon 40 to isolate arrhythmias generated or propagating via the port 51.

[0053] On the other hand, if the changed protocol produces a new impedance threshold that is still higher than the measured impedance, the process is repeated by returning to step 90 and further changing the IRE protocol.

[0054] While the implementation methods described herein primarily relate to cardiac applications, the methods and systems described herein can also be used in other medical applications, such as ablation of liver or lung cancer, as well as in neurology and otolaryngology.

[0055] Therefore, it should be understood that the embodiments described above are cited by way of example, and the invention is not limited to what is specifically shown and described above. Rather, the scope of the invention includes combinations and sub-combinations of the various features described above, as well as variations and modifications thereof, which will occur to those skilled in the art upon reading the above description and which are not disclosed in the prior art. Documents incorporated herein by reference are considered an integral part of this application, except that if any terminology defined in such incorporated documents conflicts with the definitions expressly or implicitly given in this specification, only the definitions in this specification shall be considered.

Claims

1. An irreversible electroporation (IRE) system, the irreversible electroporation system comprising: An interface configured to exchange signals with a catheter placed in contact with tissue in an organ; and Processor, the processor being configured to: Select an irreversible electroporation (IRE) protocol that includes an impedance threshold, wherein the processor is configured to derive the impedance threshold of the irreversible electroporation (IRE) protocol by either calculation or lookup in a table; The electrodes of the catheter are selected for applying irreversible electroporation (IRE) pulses between the selected electrodes; Measure the impedance between the selected electrodes; The measured impedance is compared with the impedance threshold. If the measured impedance is lower than the impedance threshold, the irreversible electroporation (IRE) protocol is changed to have a new impedance threshold lower than the measured impedance, while maintaining the same accumulated electrical energy applied by the irreversible electroporation (IRE). as well as The irreversible electroporation (IRE) pulse is applied according to the modified protocol. The impedance threshold mentioned above is the threshold that the actual electrical resistance between the electrodes must exceed for ablation to be considered safe.

2. The irreversible electroporation (IRE) system of claim 1, wherein the processor is configured to set the irreversible electroporation (IRE) protocol by selecting a pulse width, a pulse repetition rate, and the number of the irreversible electroporation (IRE) pulses, and to change the irreversible electroporation (IRE) protocol by changing one or more of the pulse width, the pulse repetition rate, and the number of the irreversible electroporation (IRE) pulses.

3. The irreversible electroporation (IRE) system of claim 2, wherein the processor is configured to reduce one of the pulse width and repetition rate, and increase the number of pulses.

Images