A cautious irreversible electroporation (IRE) protocol to avoid air bubble generation

Abstract

An irreversible electroporation (IRE) is provided that includes setting an initial IRE protocol for applying IRE pulses by electrodes of a catheter placed in contact with tissue in an organ. Upon determining that the initial IRE protocol is expected to cause bubbles in blood, a notification is issued to a user. In response to the notification, user input is received from the user that selects between the initial IRE protocol and an alternative protocol that is expected not to cause bubbles. Depending on the user input, the IRE pulses are applied in accordance with the initial IRE protocol or the alternative IRE protocol.

Description

Technical Field

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

[0002] Estimation of invasive ablation parameters and controlling ablation based on the estimation have been previously proposed in the patent literature. For example, U.S. Patent Application Publication No. 2013 / 0006228 describes an apparatus for localized delivery of energy and methods of using such apparatus, particularly for therapeutic treatment of biological tissue. The disclosed methods may involve positioning and deploying an energy delivery member at a target site, and delivering energy through the energy delivery member. In an embodiment, a 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 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 using real-time monitoring during an electroporation treatment protocol. A pulse generator generates a pre-treatment test signal having a frequency of at least 1 MHz before the treatment protocol and an intra-treatment test signal during the treatment protocol. A treatment control module determines an impedance value based on the pre-treatment test signal and the intra-treatment test signal, and determines the progress of electroporation and the end point of the treatment in real time based on the determined impedance value while the treatment is ongoing. Summary of the Invention

[0004] Embodiments of the present invention described below provide an irreversible electroporation (IRE) method that includes setting an initial IRE protocol for applying an IRE pulse via an electrode of a catheter placed in contact with tissue in an organ. Upon determining that the initial IRE protocol is expected to induce bubbles in blood, a user is notified. In response to the notification, user input is received from the user, the user input selecting between the initial IRE protocol and an alternative protocol that is not expected to induce bubbles. Depending on the user input, the IRE pulse is applied according to the initial IRE protocol or the alternative IRE protocol.

[0005] In some embodiments, receiving user input includes receiving an instruction to segment the sequence of IRE pulses of the initial IRE scheme into a given number of pulse trains with corresponding given pauses between the pulse trains.

[0006] In some embodiments, the initial IRE protocol and the alternative IRE protocol have the same total number of IRE pulses. In other embodiments, the alternative IRE protocol has a smaller number of IRE pulses than the initial IRE protocol.

[0007] According to another embodiment of the present invention, there is further provided an irreversible electroporation (IRE) system comprising a user interface and a processor. The user interface is configured to set an IRE protocol for applying IRE pulses through electrodes of a catheter placed in contact with tissue in an organ. The processor is configured to (i) notify a user upon determining that an initial IRE protocol is expected to cause bubbles in the blood; (ii) in response to the notification, receive user input via the user interface, the user input selecting between the initial IRE protocol and an alternative protocol that is not expected to cause bubbles; and (iii) apply the IRE pulse according to the initial IRE protocol or the alternative IRE protocol, depending on the user input. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The present invention will be more fully understood through the following detailed description of embodiments of the present invention in conjunction with the accompanying drawings, in which:

[0009] Figure 1 is a schematic illustration of a catheter-based irreversible electroporation (IRE) system according to an exemplary embodiment of the present invention; and

[0010] Figure 2 To schematically illustrate the use of an exemplary embodiment according to the present invention Figure 1 Flowchart of a method for applying irreversible electroporation (IRE) pulses using a system. DETAILED DESCRIPTION

[0011] Overview

[0012] 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 in order to treat arrhythmias. Cell damage occurs when the transmembrane potential exceeds a threshold, leading to cell death and, consequently, the development of tissue lesions. Therefore, of particular interest is the use of high-voltage bipolar electrical pulses (e.g., using a selected pair of electrodes in contact with the tissue) to generate high electric fields (e.g., above a certain threshold) to kill tissue cells between the electrodes.

[0013] However, IRE pulses used to ablate tissue can also cause unwanted and / or undesirable effects that are potentially clinically harmful when the pulses are strong enough. For example, a 1 kV pulse voltage (one of two possible values) across a 100 Ω blood impedance instantaneously creates a local peak current of 10 A (i.e., 10 kW) in the blood. This voltage applied between electrodes to form a bipolar IRE pulse sequence can also be high enough to generate enough Joule heat that, if not dissipated quickly, can create bubbles in the blood. Some physicians can choose to accept some risk of bubble formation, but others can prefer not to, often due to the patient’s condition, such as a recent stroke.

[0014] Embodiments of the invention described below provide methods and systems for IRE. In some embodiments, various IRE ablation protocols (also referred to as “initial protocols”) are evaluated a priori to determine whether they can generate bubbles. The evaluation, performed in a laboratory, can also determine one or more alternative protocols to present to a user. If, during an ablation procedure, a physician (or other user) initially sets an IRE ablation protocol that can generate bubbles, the system notifies the physician, who then selects to use (hereinafter also referred to as “a user input of the selection of”) the “as-is” protocol or an adjusted, more cautious IRE ablation protocol that will not generate bubbles.

[0015] In some embodiments, determining that the selected protocol can generate bubbles means estimating or measuring the impedance between the electrodes in a given electrode pair and comparing the impedance to a threshold. If the estimated or measured impedance is below the threshold, the processor determines that the dissipated power in the blood between the electrode pair can generate bubbles.

[0016] In some embodiments, the more cautious IRE ablation protocol splits the IRE pulse sequence of the selected protocol into a pulse sequence comprising multiple pulse trains, with pauses between the pulse trains. The pauses allow the Joule heat generated by any pulse to dissipate sufficiently so that no bubbles are formed.

[0017] In some embodiments, to maintain clinical effectiveness, the more cautious IRE ablation protocol does not change the total energy dissipated. Instead, the protocol extends the pulse application time so as to allow the generated heat to diffuse more and reduce the maximum temperature caused by the heating. In addition, in the cautious IRE ablation protocol, the pulse peak voltage is typically not reduced, as this would affect the generated electroporation field. If the peak voltage is reduced at all, it must still remain above a predefined minimum level required for IRE ablation to be clinically effective.

[0018] In other embodiments, the physician (or other user) can modify any parameter of the cautious protocol from the user interface, and more specifically, the number of pulse trains and the minimum pause length. For example, the physician can split the IRE pulse sequence of the selected protocol into a pulse sequence comprising multiple pulse trains with pauses between the pulse trains. The pauses allow the Joule heat generated by any pulse to dissipate sufficiently so that bubbles are not formed. The user can also decide to reduce the total number of pulses to further reduce the cumulative (i.e., overall) electrical power delivered to the tissue.

[0019] In an embodiment, the system gates the pulse train to be applied synchronously with the beating of the heart, for example, to apply the pulse train during the refractory period of the tissue. Typically, the ventricular electrogram and the atrial electrogram are collected at the ventricular tissue location or the atrial tissue location by, for example, electrodes in contact with the tissue at the location catheter during electrophysiological mapping of the wall tissue portion of each corresponding cardiac chamber. The ventricular refractory period or the atrial refractory period is the duration of the pause in neural activity after activation at the tissue location (in the tissue of any of the above-mentioned cardiac chambers). The refractory period typically overlaps to a large extent with the QRST interval portion of the cardiac cycle, which is displayed in the ventricular electrogram and the atrial electrogram acquired at the location. The refractory period can be deliberately induced at the tissue portion of the heart, for example, by pacing the tissue at the tissue location using a pacing catheter.

[0020] According to the disclosed technology, cardiac IRE ablation can be performed using an expandable frame (e.g., a balloon or basket-like structure) mounted on the distal end of an ablation catheter. In an exemplary procedure, the expandable frame, provided with ablation electrodes, is navigated through the cardiovascular system and inserted into the heart to, for example, ablate the ostium of a pulmonary vein (PV).

[0021] By offering a more cautious approach as an alternative to the initial IRE approach, IRE ablation procedures (eg, in the ostium of a PV using an expandable frame catheter) may be made safer while maintaining clinical efficacy.

[0022] System Description

[0023] Figure 1 FIG2 is a schematic illustration of a catheter-based irreversible electroporation (IRE) system 20 according to an embodiment of the present invention. The system 20 includes a catheter 21, wherein a physician 30 inserts a shaft 22 of the catheter 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, as shown in inset 25.

[0024] Once the distal end 22a of the shaft 22 has reached the target location, the physician 30 typically retracts the sheath 23 by pumping saline into the balloon 40, and inflates the balloon 40. The physician 30 then manipulates the shaft 22 so that the electrodes 50 disposed on the balloon 40 catheter engage the inner wall of the PV ostium 51 to apply high voltage IRE pulses to the ostium 51 tissue via the electrodes 50.

[0025] As shown in inset 25 and inset 27, the distal end 22a is fitted with an inflatable balloon 40 that includes a plurality of equidistant, smooth-edged IRE electrodes 50. Due to the flat shape of the distal portion of the balloon 40, the distance between adjacent electrodes 50 remains approximately constant even in the case where the electrodes 50 cover the distal portion. Thus, the balloon 40 configuration allows for more effective electroporation between adjacent electrodes 50 (e.g., with approximately uniform electric field strength), while the smooth edges of the electrodes 50 minimize unwanted thermal effects.

[0026] Certain aspects of the inflatable balloon are addressed, for example, 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 Stops,” both of which are assigned to the assignee of the present patent application, and the disclosures of which are incorporated herein by reference.

[0027] In the embodiments described herein, the catheter 21 can be used for any suitable diagnostic and / or therapeutic purposes, such as electrophysiological sensing of the PV ostium 51 tissue in the left atrium 45 of the heart 26 and / or the IRE isolation described above.

[0028] The proximal end of the catheter 21 is connected to a console 24 that includes an IRE pulse generator 38 configured to apply IRE pulses between adjacent electrodes 50. The electrodes are connected to the IRE pulse generator 38 by electrical wires extending in the shaft 22 of the catheter 21. A memory 48 of the console 24 stores IRE protocols that include IRE pulse parameters such as peak bipolar voltage and pulse width.

[0029] 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 placed around the chest of the patient 26. To this end, the processor 41 is connected to the external electrodes 49 by electrical wires extending through a cable 39.

[0030] During the procedure, the system 20 can track the respective positions of the electrodes 50 within the heart 26 using the Active Current Localization (ACL) method provided by Biosense-Webster (Irvine California), which is described in U.S. Patent No. 8,456,182, the disclosure of which is incorporated herein by reference.

[0031] In some embodiments, in the event that the processor 41 informs the physician 30 of a bubble risk using the initially set IRE protocol, the physician 30 can select a more cautious protocol that divides (segments) the IRE pulse delivery 55 of the selected protocol into a plurality of pulse trains 57 with pauses 59 between the pulse trains, as shown in the inset 27. The pauses allow the Joule heat generated by any pulse to dissipate sufficiently so that no bubbles are formed.

[0032] In other embodiments, the physician 30 can modify any of the parameters of the cautious protocol from the user interface 47, and more specifically the number of pulse trains and the minimum pause length. For example, the user can decide to remove pulses in the sequence in order to reduce the total number of pulses to be applied. The user interface 47 can include any suitable type of input device, such as a keyboard, mouse, trackball, etc.

[0033] The processor 41 is generally programmed in software to perform the functions described herein. The software can be downloaded to the computer in electronic form, over a network, for example, or it can alternatively or additionally be supplied and / or stored on non-transitory tangible media, such as magnetic, optical or electronic memory.

[0034] In particular, the processor 41 runs a dedicated algorithm as disclosed herein comprising Figure 2 the dedicated algorithm enabling the processor 41 to perform the disclosed steps, as further described below. In particular, the processor 41 is configured to output IRE pulses from the IRE pulse generator 38 according to the treatment protocol commands uploaded by the processor 41 from the memory 48.

[0035] Cautious IRE protocol for avoiding bubble generation

[0036] Figure 2 A flowchart of a method of applying irreversible electroporation (IRE) pulses using the system 20 of Figure 1 in accordance with embodiments of the present application. According to the presented embodiment, the algorithm performs a process that begins with: at a balloon catheter navigation step 80, the physician 30 navigates the balloon 40 catheter to a target tissue location in a patient’s organ (such as at the PV ostium 51) using, for example, the electrodes 50 as ACL sensing electrodes.

[0037] Next, at an IRE planning step 82, the processor 41 uploads a protocol initially set by the physician 30, which has parameters for the IRE pulses to be applied to the tissue. Table 1 shows an example of IRE ablation settings in an initial protocol that can be used to ablate cardiac tissue using the disclosed balloon 40.

[0038] parameter scope Preset IRE peak voltage 1000V Pulse width 0.5 milliseconds Repetition rate 1Hz Number of pulses 40

[0039] Table I: Initial Plan

[0040] Next, at a notification step 84, processor 41 notifies physician 30 that the initial IRE protocol may generate bubbles in the blood. In response, the physician may decide to use the protocol as is (i.e., use the initial protocol) at a protocol decision step 86. Alternatively, at a protocol replacement decision step 88, the physician may decide to change the protocol to an alternative protocol, such as that shown in Table II.

[0041]

[0042]

[0043] Table II: Cautious Options

[0044] As shown in Table II, in a more cautious approach, the pulse sequence of Table I is divided into eight pulse trains, each with five pulses, with a minimum pause of 2 seconds between pulse trains.

[0045] In an embodiment, physician 30 can modify any parameter of Table II from user interface 47, and in particular, the number of pulse trains and the minimum pause between pulse trains. Alternatively, the parameters of the alternative regimens can be automatically set by processor 41. In one such embodiment, processor 41 maintains a corresponding alternative regimen for each supported initial regimen. In another embodiment, processor 41 derives the parameters of the alternative regimens from the parameters of the initial regimen according to some predefined rules or methods.

[0046] Once an IRE protocol is selected (either according to the initial protocol at step 86 or according to the alternative protocol at step 88), processor 41 commands generator 38 to apply an IRE pulse to tissue at an IRE processing step 90. The IRE pulse is applied between selected electrodes of balloon 40 to isolate arrhythmias originating or propagating via ostia 51.

[0047] Although the embodiments described herein are primarily directed to cardiac applications, the methods and systems described herein may also be used in other medical applications, such as in neurology and otolaryngology.

[0048] It should therefore be understood that the embodiments described above are cited by way of example, and that the present invention is not limited to what is specifically shown and described above. On the contrary, the scope of the present invention includes combinations and subcombinations 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. The documents incorporated by reference into this patent application are considered an integral part of this application, except that if any term defined in these incorporated documents conflicts with a definition explicitly or implicitly given in this specification, only the definition in this specification shall be considered.

Claims

1. An irreversible electroporation (IRE) system comprising: a user interface configured for setting an irreversible electroporation (IRE) protocol for applying an irreversible electroporation (IRE) pulse through an electrode of a catheter placed in contact with tissue in an organ; and a processor configured to: Notifying the user when an initial irreversible electroporation (IRE) protocol is determined to be expected to induce bubbles in the blood; receiving, in response to the notification, user input via the user interface, the user input selecting between the initial irreversible electroporation (IRE) protocol and an alternative protocol not expected to induce the bubbles; as well as The irreversible electroporation (IRE) pulses are applied according to the initial irreversible electroporation (IRE) protocol or an alternative irreversible electroporation (IRE) protocol, depending on the user input.

2. The system of claim 1 , wherein the processor is configured to receive in the user input a division of the sequence of irreversible electroporation (IRE) pulses into a given number of pulse trains with corresponding given pauses between the pulse trains.

3. The system of claim 1, wherein the initial irreversible electroporation (IRE) protocol and the alternative irreversible electroporation (IRE) protocol have the same total number of the irreversible electroporation (IRE) pulses.

4. The system of claim 1, wherein the alternative irreversible electroporation (IRE) protocol has a smaller number of pulses than the initial irreversible electroporation (IRE) protocol.

Images