Impedance-based irreversible electroporation (IRE)

Abstract

To provide an irreversible electroporation (IRE) method.SOLUTION: An irreversible electroporation (IRE) method includes selecting electrodes of a catheter placed in contact with tissue in an organ, for applying IRE pulses to between the selected electrodes. An impedance is measured between the selected electrodes. Based on the measured impedance, an IRE protocol is chosen that has parameters that meet a predefined safety criterion under the measured impedance. The IRE pulses are applied according to the chosen protocol.SELECTED DRAWING: Figure 1

Description

[Technical Field]

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

[0002] Estimating invasive ablation parameters and controlling ablation according to the estimates has previously been proposed in the patent literature. For example, U.S. Patent Application Publication No. 2013 / 0006228 describes an apparatus for localized delivery of energy and a method of using such an apparatus, particularly for therapeutic treatment of living tissue. The disclosed method may include positioning and disposing an energy delivery member within 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 depending on one or more selected parameters, which may include the frequency of the treatment signal, the power of the treatment signal, or the tissue impedance to the treatment signal.

[0003] As another example, U.S. Patent Application Publication No. 2016 / 0066977 describes a medical system for ablating a tissue site with real-time monitoring during an electroporation treatment procedure. A pulse generator generates a pre-treatment test signal having a frequency of at least 1 MHz before the treatment and an in-treatment test signal during the treatment. A treatment control module determines impedance values ​​from the pre-treatment test signal and the in-treatment test signal and determines electroporation and treatment endpoints in real time based on the determined impedance values ​​while the treatment is in progress. Summary of the Invention [Means for solving the problem]

[0004] Embodiments of the invention described herein provide an irreversible electroporation (IRE) method that includes selecting electrodes of a catheter positioned in contact with tissue within an organ to deliver an IRE pulse between the selected electrodes. Impedance is measured between the selected electrodes. Based on the measured impedance, an IRE protocol is selected having parameters that meet pre-defined safety criteria under the measured impedance. The IRE pulse is delivered according to the selected protocol.

[0005] In some embodiments, selecting an IRE protocol includes selecting a pulse width, a pulse repetition rate, and a number of IRE pulses.

[0006] In some embodiments, selecting the predetermined safety standard includes selecting an IRE protocol that has an impedance threshold lower than the measured impedance, thereby ensuring that the IRE pulse does not overheat the tissue.

[0007] In one embodiment, the impedance threshold for the selected protocol is derived by one of a calculation and a look-up table.

[0008] In another embodiment, the IRE method further includes establishing an IRE protocol that includes an impedance threshold. Impedance is measured between selected electrodes, and the measured impedance is compared to a given threshold. If the measured impedance is below the threshold, the IRE protocol is modified to have a new impedance threshold that is below the measured impedance. IRE is administered according to the modified protocol.

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

[0010] In some embodiments, modifying the IRE protocol includes maintaining the same stored electrical energy provided by the IRE.

[0011] According to another embodiment of the present invention, there is additionally provided an irreversible electroporation (IRE) system including an interface and a processor. The interface is configured to exchange signals with a catheter positioned in contact with tissue within an organ. The processor is configured to (i) select electrodes of the catheter for delivering IRE pulses between the selected electrodes, (ii) measure impedance between the selected electrodes, (iii) based on the measured impedance, select an IRE protocol having parameters that meet predetermined safety standards under the measured impedance, and (iv) deliver the IRE pulses according to the selected protocol. [Brief explanation of the drawings]

[0012] The present invention will be more fully understood from the following detailed description taken in conjunction with the drawings, in which: [Figure 1] 1 is a schematic, depiction of a catheter-based irreversible electroporation (IRE) system, in accordance with an exemplary embodiment of the present invention. [Figure 2] 2 is a flow diagram that schematically illustrates a method of administering an irreversible electroporation (IRE) pulse using the system of FIG. 1, in accordance with an exemplary embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0013] Overview Irreversible electroporation (IRE), also known as pulsed field ablation (PFA), can be used as an invasive treatment modality to kill tissue cells by exposing them to high-voltage pulses. Specifically, IRE pulses have potential use in killing myocardial tissue cells to treat cardiac arrhythmias. Cell destruction occurs when the transmembrane potential exceeds a threshold, resulting in cell death and thus the development of tissue lesions. Therefore, specifically, high-voltage bipolar electric pulses are used to generate a high electric field (e.g., using a selected pair of electrodes in contact with the tissue) to kill tissue cells between the electrodes.

[0014] However, if the electrical impedance between the selected electrodes is low, high voltage between the electrodes can also generate excessive Joule heating within the ablated tissue, which can cause unwanted effects such as steam popping and potentially clinical hazards. For example, a pulse voltage of 2 kV across 100 Ω (both possible values) will instantaneously generate 20 amps, or 40 kW, within the tissue, which can be dangerous.

[0015] The embodiments of the invention described below take into account the electrical impedance between the electrodes to protect against excessive Joule heating of tissue undergoing IRE. In one embodiment, an IRE ablation protocol, such as a default protocol, is first selected, which typically specifies the pulse shape (peak voltage and width), pulse repetition rate, and number of pulses.

[0016] A selected protocol can be viewed as having a particular impedance threshold, i.e., a threshold that the actual electrical impedance between the electrodes must exceed for ablation to be considered safe. The impedance threshold for a given protocol may be calculated by the processor, for example, based on the protocol parameters, or may be read from a predetermined relationship (e.g., from an empirically derived or pre-calculated relationship stored in a look-up table).

[0017] Some embodiments use the electrodes selected for IRE to measure the impedance between the electrodes, and if the measured impedance is above the impedance threshold, i.e., if Joule heating is within an acceptable range, the processor instructs the system to perform IRE using the initial protocol.

[0018] However, if the measured impedance falls below the impedance threshold and the selected protocol would cause excessive heating, the processor, or user, modifies the initial protocol. Modifications may include shortening the individual pulse duration, decreasing the pulse repetition rate, and / or increasing the number of pulses (to maintain the same cumulative clinical effect). The modified protocol has a different impedance threshold (e.g., a lower threshold) so that IRE can be performed because the same measured impedance now exceeds the new threshold.

[0019] Regarding ablation energy, to ablate at a given impedance, if the impedance is below a threshold, the protocol is adjusted to maintain as similar energy delivery as possible. Optimization involves modifying the pulse duration and / or number of pulses and / or number of bursts to maintain similar energy delivery for the same clinical and thermal effect. For low-impedance ablations, the total energy is nevertheless reduced by modifying the pulse duration and / or number of pulses, and the impedance threshold is adjusted accordingly to the maximum allowable value.

[0020] When modifying the protocol, the peak voltage of the IRE pulse is typically not reduced because this would affect the electroporation field generated. In some embodiments, the peak voltage may be reduced as long as it remains above the predetermined minimum level required for IRE to be clinically effective.

[0021] As noted above, to maintain clinical efficacy, protocol modifications typically do not change the overall energy dissipated (e.g., accumulated). Rather, changes in distribution during pulse application allow the heat generated to increase or decrease the maximum temperature induced by heating.

[0022] In another embodiment, a physician first inserts and positions a catheter at a target tissue location. The IRE ablation system then measures the impedance between the catheter's electrodes. Based on the measured impedance, the system or physician then selects an IRE protocol with parameters that meet a predetermined safety criterion under the measured impedance. Any suitable safety criterion can be used. For example, a safety criterion aimed at minimizing the risk of overheating tissue is provided, where the safety criterion is based on a minimum measured impedance. The system selects a protocol with an impedance threshold lower than the minimum measured impedance, resulting in a current lower than that which would cause tissue overheating. Therefore, such a protocol can be used safely because the expected Joule heating is within an acceptable range. In this embodiment, there is no need to initially select a protocol (e.g., to upload the protocol and then modify it based on the measured impedance).

[0023] The disclosed technology can be used with various types of IRE ablation procedures and various types of catheters. In one embodiment, cardiac IRE ablation is performed using an expandable frame (e.g., balloon or basket) attached to the distal end of an ablation catheter. The expandable frame, with ablation electrodes disposed thereon, is navigated through the cardiovascular system and inserted into the heart to, for example, ablate the ostia of the pulmonary veins (PV).

[0024] By making the above modifications to the IRE protocol, for example, IRE ablation of PV ostia using an expandable frame catheter can be performed more safely while maintaining its clinical efficacy.

[0025] System Description 1 is a schematic, pictorial illustration of a catheter-based irreversible electroporation (IRE) system 20, according to an embodiment of the present invention. System 20 includes a catheter 21, whose shaft 22 is inserted through a sheath 23 and through the cardiovascular system of a patient 28 into a heart 30. A physician 30 then navigates a distal end 22a of shaft 22 to a target location (inset 25) inside the patient's heart 26.

[0026] Once the distal end 22a of the shaft 22 reaches the target location, the physician 30 retracts the sheath 23 and expands the balloon 40, typically by pumping saline into the balloon 40. The physician 30 then manipulates the shaft 22 so that an electrode 50 disposed on the balloon catheter 40 engages the inner wall of the PV opening 51 and applies a high-voltage IRE pulse via the electrode 50 to the opening 51 tissue.

[0027] As seen in insets 25 and 27, distal end 22a is fitted with an expandable balloon 40 comprising a plurality of smooth-edged and equidistant IRE electrodes 50. Due to the flattened shape of the distal portion of balloon 40, the distance between adjacent electrodes 50, such as distance 55 between electrodes 50a and 50b, remains substantially constant even when electrodes 50 cover the distal portion. Thus, the configuration of balloon 40 allows for more effective electroporation (e.g., with a substantially uniform field strength) between adjacent electrodes 50, while the smooth edges of electrodes 50 minimize undesirable thermal effects.

[0028] Certain aspects of inflatable balloons are addressed, for example, in U.S. Provisional Patent Application No. 62 / 899,259, entitled "Balloon Catheter with Force Sensor," filed September 12, 2019, and U.S. Patent Application No. 16 / 726,605, entitled "Contact Force Spring with Mechanical Stops," filed December 24, 2019, both of which are assigned to the assignee of the present patent application, the disclosures of which are incorporated herein by reference.

[0029] In the embodiments described herein, the catheter 21 may be used for any suitable diagnostic and / or therapeutic purpose, such as electrophysiological sensing of PV opening 51 tissue within the left atrium 45 of the heart 26 and / or the aforementioned IRE isolation.

[0030] The proximal end of catheter 21 is connected to console 24, which includes an IRE pulse generator 38 configured to deliver IRE pulses between adjacent electrodes 50. The electrodes are connected to IRE pulse generator 38 by electrical wires that run through shaft 22 of catheter 21. Memory 48 of console 24 stores an IRE protocol, including IRE pulse parameters such as peak bipolar voltage and pulse width.

[0031] Console 24 includes a processor 41, typically a general-purpose computer, with suitable front-end and interface circuitry 37 for receiving signals from catheter 21 and from external electrodes 49, typically placed around the chest of patient 26. To this end, processor 41 is connected to external electrodes 49 by wiring running within cable 39.

[0032] During the procedure, the system 20 can track the location of each of the electrodes 50 within the heart 26 using the Active Current Location (ACL) method provided by Biosense-Webster (Irvine California), which is described in U.S. Pat. No. 8,456,182, the disclosure of which is incorporated herein by reference.

[0033] In some embodiments, interface circuit 37 is configured to measure the impedance between selected electrodes 50, such as the impedance between electrodes 50a and 50b, after balloon 40 is positioned at the target tissue but before IRE is performed, and 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 alerts physician 30 (depending on the system) to modify the protocol, for example, as described in Tables I and II below, to mitigate thermal risks while maintaining the clinical effectiveness of IRE.

[0034] In other embodiments, the physician 30 can modify any of the parameters of the altered protocol from the user interface 47 .

[0035] The processor 41 is typically programmed in software to carry out the functions described herein, which software may be downloaded to a computer in electronic form, for example over a network, or alternatively or additionally may be provided and / or stored on a non-transitory tangible medium, such as magnetic, optical or electronic memory.

[0036] In particular, processor 41 executes the dedicated algorithms disclosed herein, which are included in Figure 2 and enable processor 41 to perform the steps of the present disclosure, as further described below. In particular, processor 41 is configured to instruct IRE pulse generator 38 to output IRE pulses according to a processing protocol that processor 41 uploads from memory 48.

[0037] Impedance-based IRE method 2 is a flow diagram that schematically illustrates a method for delivering an irreversible electroporation (IRE) pulse using system 20 of FIG. 1, in accordance with an embodiment of the present invention. The algorithm according to this embodiment executes a process that begins with IRE planning step 80, when a physician uses processor 41 to upload a protocol with parameters for an IRE pulse to be delivered to tissue. Example IRE ablation settings in an initial protocol that may be used to ablate cardiac tissue using the disclosed balloon 40 are shown in Table I.

[0038] [Table 1]

[0039] Next, the physician 30 inserts and navigates the balloon 40 catheter to a target tissue location within the patient's organ, such as the PV opening 51, using the electrode 50 as, for example, an ACL detection electrode, in a balloon catheter navigation step 82.

[0040] Next, in an impedance measurement step 84, processor 41 measures the impedance between the selected electrodes (eg, using interface circuitry 37).

[0041] In an impedance threshold determination step 86, the processor 41 outputs (eg, calculates or selects from a look-up table) the impedance threshold of the uploaded protocol.

[0042] In an impedance check step 88, processor 41 compares the measured impedance to an impedance threshold. If the measured impedance is below the impedance threshold of the protocol, in a protocol change step 90, the physician uses processor 41 to change the protocol, for example, to the protocol shown in Table II.

[0043] [Table 2]

[0044] As can be seen in Table II, the stored electrical energy is kept the same by increasing the number of pulses, while the pulse width and repetition rate are decreased.

[0045] In other words, taking the measured impedance into account, the protocol parameters, with the exception of voltage, are modified so that energy remains similar to the planned value. The impedance threshold, thus optimized, is adjusted below the measured impedance. As a result, the automatically adjusted impedance threshold for the modified protocol (e.g., in Table II) moves below the same measured impedance, and then, using the modified IRE pulse parameters, processor 41 commands generator 38 to deliver an IRE pulse to tissue in IRE therapy step 92. The IRE pulse is delivered between selected electrodes of balloon 40 to isolate arrhythmias originating or propagating through opening 51.

[0046] On the other hand, if the modified protocol results in a new impedance threshold that is still above the measured impedance, the process is repeated by returning to step 90 and further modifying the IRE protocol.

[0047] Although the embodiments described herein primarily address cardiac applications, the methods and systems described herein may also be used in other medical applications, such as liver or lung cancer ablation, neurology, and ear, nose, and throat.

[0048] It will therefore be understood that the above-described embodiments are cited by way of example, and that the present invention is not limited to what has been particularly shown and described above. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described in the foregoing specification, as well as variations and modifications thereof that would occur to one skilled in the art upon reading the foregoing description, but which are not disclosed in the prior art. Documents incorporated by reference into this patent application are to be deemed part of this application, except that if any term is defined in such incorporated document in a way that contradicts the definition given herein, either expressly or impliedly, then only the definition given herein shall be considered.

[0049] [Embodiment] (1) An irreversible electroporation (IRE) method comprising: selecting electrodes of a catheter positioned in contact with tissue within the organ to apply an IRE pulse between the selected electrodes; measuring impedance between the selected electrodes; selecting an IRE protocol based on the measured impedance, the IRE protocol having parameters that meet predetermined safety standards under the measured impedance; administering the IRE pulses according to the selected protocol; A method comprising: (2) The IRE method of embodiment 1, wherein selecting the IRE protocol includes selecting a pulse width, a pulse repetition rate, and the number of IRE pulses. (3) The IRE method of embodiment 1, wherein selecting the predetermined safety standard includes selecting an IRE protocol having an impedance threshold lower than the measured impedance, thereby ensuring that the IRE pulse does not overheat the tissue. (4) The IRE method of embodiment 3, wherein the impedance threshold of the selected protocol is derived by one of calculation and a lookup table. (5) establishing an IRE protocol including the impedance threshold; and measuring the impedance between the selected electrodes and comparing the measured impedance to the given threshold; If the measured impedance is below the threshold, modifying the IRE protocol to have a new impedance threshold below the measured impedance; administering the IRE according to the modified protocol; 4. The IRE method of embodiment 3, comprising:

[0050] (6) The IRE method of embodiment 5, wherein setting the IRE protocol includes selecting a pulse width, a pulse repetition rate, and a number of IRE pulses, and changing the IRE protocol includes changing one or more of the pulse width, the pulse repetition rate, and the number of IRE pulses. (7) The IRE method of embodiment 6, wherein changing one or more of the pulse width, the pulse repetition rate, and the number of IRE pulses includes decreasing one of the pulse width and the repetition rate and increasing the number of pulses. (8) The method of embodiment 5, wherein modifying the IRE protocol includes maintaining the same stored electrical energy provided by the IRE. (9) An irreversible electroporation (IRE) system, comprising: an interface configured to exchange signals with a catheter positioned in contact with tissue within the organ; a processor, the processor comprising: selecting electrodes of the catheter for applying an IRE pulse between the selected electrodes; measuring the impedance between the selected electrodes; selecting an IRE protocol based on the measured impedance, the IRE protocol having parameters that meet predetermined safety standards under the measured impedance; administering the IRE pulse according to the selected protocol The system is configured as follows: (10) The IRE system of embodiment 9, wherein the processor is configured to select the IRE protocol by selecting a pulse width, a pulse repetition rate, and the number of IRE pulses.

[0051] (11) The IRE system of embodiment 9, wherein the processor is configured to select the predetermined safety standard by selecting an IRE protocol having an impedance threshold lower than the measured impedance, thereby ensuring that the IRE pulse does not overheat the tissue. (12) The IRE system of embodiment 11, wherein the processor is configured to derive the impedance threshold for the selected protocol by one of calculation and a lookup table. (13) The processor: setting an IRE protocol including the impedance threshold; measuring the impedance between the selected electrodes; comparing the measured impedance to the given threshold; If the measured impedance is below the threshold, modifying the IRE protocol to have a new impedance threshold below the measured impedance; Administer the IRE according to the modified protocol An IRE system as described in embodiment 11, configured as follows. (14) The system of embodiment 13, wherein the processor is configured to set the IRE protocol by selecting a pulse width, a pulse repetition rate, and the number of IRE pulses, and to modify the IRE protocol by changing one or more of the pulse width, the pulse repetition rate, and the number of IRE pulses. (15) The system of embodiment 14, wherein the processor is configured to decrease one of the pulse width and the repetition rate and increase the number of pulses.

[0052] (16) The system of embodiment 13, wherein the processor is configured to change the IRE protocol while maintaining the same stored electrical energy provided by the IRE.

Claims

1. 1. An irreversible electroporation (IRE) system comprising: an interface configured to exchange signals with a catheter positioned in contact with tissue within the organ; a memory configured to store first and second IRE protocols for delivering IRE pulses and first and second impedance thresholds; a processor, the processor comprising: selecting electrodes of the catheter for applying the IRE pulse between selected electrodes; measuring the impedance between the selected electrodes; selecting the first IRE protocol while the measured impedance is above the first impedance threshold; selecting the second IRE protocol based on the measured impedance being below the first impedance threshold; selecting the second IRE protocol while the measured impedance is above the second impedance threshold; Applying the IRE pulse according to the selected IRE protocol It is configured as follows: the first and second IRE protocols each have parameters that meet a predetermined safety standard under the measured impedance; each of the first IRE protocol and the second IRE protocol defines a pulse width of the IRE pulse, a pulse repetition rate of the IRE pulse, and a number of the IRE pulses; the product of the pulse width, the pulse repetition rate, and the number of pulses is constant in the first and second IRE protocols; The system, wherein the second impedance threshold is less than the first impedance threshold.

2. 10. The IRE system of claim 1, wherein the processor is configured to derive the first and second impedance thresholds for the selected IRE protocol by one of a calculation and a lookup table.

3. The IRE system of claim 1 , wherein the processor is configured to decrease one of the pulse width and the repetition rate and increase the number of pulses.

4. 1. A method of operating a system for performing irreversible electroporation (IRE), comprising: The system comprises: a memory configured to store first and second IRE protocols for delivering IRE pulses and first and second impedance thresholds; a processor, selecting electrodes of a catheter by the processor to apply the IRE pulse between the selected electrodes; the processor measuring impedance between the selected electrodes; the processor selecting the first IRE protocol while the measured impedance is above the first impedance threshold; the processor selecting the second IRE protocol based on the measured impedance being below the first impedance threshold; the processor selecting the second IRE protocol while the measured impedance is above the second impedance threshold; the processor applying the IRE pulses in accordance with the selected protocol; Including, the first and second IRE protocols each have parameters that meet a predetermined safety standard under the measured impedance; each of the first IRE protocol and the second IRE protocol defines a pulse width of the IRE pulse, a pulse repetition rate of the IRE pulse, and a number of the IRE pulses; the product of the pulse width, the pulse repetition rate, and the number of pulses is constant in the first and second IRE protocols; The method, wherein the second impedance threshold is less than the first impedance threshold.

5. The method of claim 4 , wherein the first and second impedance thresholds for the selected IRE protocol are derived by one of a calculation and a look-up table.

6. The method of claim 4 , wherein the processor decreases one of the pulse width and the repetition rate, and increases the number of pulses.

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