Cautious irreversible-electroporation (IRE) protocol for avoiding bubble generation

Abstract

Irreversible electroporation (IRE) involves establishing an initial IRE protocol to apply IRE pulses by electrodes of a catheter placed in contact with tissue within an organ. A notification is issued to the user when it is determined that the initial IRE protocol is expected to cause bubbles in the blood. In response to the notification, user input is received from the user, which selects between the initial IRE protocol and an alternative protocol that is not expected to cause bubbles. Depending on the user input, IRE pulses are applied according to either the initial IRE protocol or the alternative IRE protocol.

Description

Technology Field

[0001] The present invention generally relates to invasive resection, and in particular to irreversible electroporation (IRE) of cardiac tissue. Background Technology

[0002] Estimation of invasive resection parameters and control of resection based on such estimation have been previously proposed in patent literature. For example, U.S. Patent Application Publication No. 2013 / 0006228 describes devices for localized delivery of energy, particularly for therapeutic treatment of biological tissue, and methods using such devices. The disclosed methods may include the steps of positioning and deploying energy delivery members at a target site, and delivering energy through the energy delivery members. 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 output 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 resecting a tissue area while monitoring in real time during an electroporation procedure. A pulse generator generates a pre-treatment test signal having a frequency of 1 MHz or higher before the procedure and intra-treatment test signals during the procedure. A treatment control module determines impedance values ​​from the pre-treatment test signal and the intra-treatment test signal, and determines the progress and end of the electroporation in real time based on the determined impedance values ​​while the procedure is in progress.

[0004] Embodiments of the present invention described below provide an irreversible electroporation (IRE) process comprising the step of establishing an initial IRE protocol for applying IRE pulses by electrodes of a catheter placed in contact with tissue within an organ. A notification is issued to the user when it is determined that the initial IRE protocol is expected to cause bubbles in the blood. In response to the notification, user input is received from the user, which selects between the initial IRE protocol and an alternative protocol that is not expected to cause bubbles. Depending on the user input, IRE pulses are applied according to the initial IRE protocol or the alternative IRE protocol.

[0005] In some embodiments, receiving user input includes receiving a sequence of IRE pulses of an initial IRE protocol divided into a given number of pulse trains, each having a given pause 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 fewer IRE pulses than the initial IRE protocol.

[0007] According to another embodiment of the present invention, an irreversible electroporation (IRE) system comprising a user interface and a processor is further provided. The user interface is configured to set IRE protocols for applying IRE pulses by electrodes of a catheter placed in contact with tissue within an organ. The processor is configured to (i) issue a notification to the user when it is determined that an initial IRE protocol is expected to cause bubbles in the blood, (ii) receive user input through the user interface to select between the initial IRE protocol and an alternative protocol that is not expected to cause bubbles in response to the notification, and (iii) apply IRE pulses according to the initial IRE protocol or the alternative IRE protocol according to the user input. Brief explanation of the drawing

[0008] The present invention will be more fully understood from the following detailed description of embodiments of the invention taken together with the drawings. FIG. 1 is a schematic illustration of a catheter-based irreversible electroporation (IRE) system according to an exemplary embodiment of the present invention. FIG. 2 is a flowchart schematically illustrating a method for applying irreversible electroporation (IRE) pulses using the system of FIG. 1 according to an exemplary embodiment of the present invention. Specific details for implementing the invention

[0009] survey

[0010] Irreversible electroporation (IRE), also known as pulsed field ablation (PFA), can be used as an invasive therapeutic modality to kill tissue cells by subjecting them to high-voltage pulses. Specifically, IRE pulses have potential applications for killing myocardial tissue cells to treat cardiac arrhythmias. Cell destruction occurs when the transmembrane potential exceeds a threshold, which leads to cell death and consequently the development of tissue lesions. Therefore, there is particular interest in killing tissue cells between electrodes by generating a high electric field (e.g., exceeding a predetermined threshold) using high-voltage bipolar electric pulses (e.g., using a selected pair of electrodes in contact with the tissue).

[0011] However, IRE pulses used for tissue ablation can also cause unwanted and / or undesirable effects of potential clinical risk when the pulses are sufficiently intense. For example, a pulse voltage of 1 kV across a blood impedance of 100 Ω (both possible values) instantaneously generates a local peak current of 10 A, or 10 kW, within the blood. This voltage, applied between electrodes to form a sequence of bipolar IRE pulses, can also be high enough to generate sufficient Joule heating, which, if not rapidly dissipated, can cause gas bubbles within the blood. While some physicians may choose to accept the risk of some bubble formation, others may prefer not to, typically due to the patient's condition, such as a recent stroke.

[0012] The embodiments of the present 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. Evaluations performed in a laboratory may also determine one or more alternative protocols to be proposed to the user. During the ablation procedure, if the physician (or other user) sets an IRE ablation protocol that can initially generate bubbles, the system notifies the physician, and the physician is given the option to use the protocol “as is” or to use an adapted, more prudent IRE ablation protocol that does not generate bubbles (also referred to as “receiving user input to select” below).

[0013] In some embodiments, determining that a selected protocol can generate bubbles means estimating or measuring the impedance between the electrodes of a given electrode-pair and comparing that impedance to a threshold. If the estimated or measured impedance is below the threshold, the processor determines that power dissipated in the blood between the electrode-pair can generate bubbles.

[0014] In some embodiments, a more prudent IRE ablation protocol divides the IRE pulse sequence of the selected protocol into a pulse sequence comprising a plurality of pulse trains having pauses between the pulse trains. The pauses ensure that Joule heating from any pulse is sufficiently dissipated so that bubbles do not form.

[0015] In some embodiments, to maintain clinical efficacy, a more prudent IRE ablation protocol does not alter the total energy dissipated. Rather, the protocol increases the pulse application time to allow the generated heat to diffuse more effectively and to lower the maximum temperature caused by heating. Additionally, the pulse peak voltage is typically not reduced in prudent IRE ablation protocols because it affects the generated electroporation field. If the peak voltage is reduced again, it must be maintained above a predefined minimum level required for IRE ablation to remain clinically effective.

[0016] In other embodiments, a physician (or other user) may change any of the parameters of a deliberate protocol from the user interface, in particular the number of pulse trains and the minimum pause length. For example, the physician may divide the IRE pulse sequence of the selected protocol into a pulse sequence comprising multiple pulse trains with pauses between the pulse trains. The pauses ensure that the Joule heating from any pulse is sufficiently dissipated so that bubbles do not form. The user may further decide to reduce the total number of pulses to further reduce the accumulated (i.e., total) power delivered to the tissue.

[0017] In one embodiment, the system controls pulse trains to be applied synchronously with the heartbeat, for example, during the tissue's refractory period. Ventricular and atrial electrograms at ventricular or atrial tissue locations are typically obtained by electrodes in contact with the tissue from a positional catheter, for example, during electrophysiological mapping of the respective wall tissue portions of each heart chamber. The ventricular or atrial refractory period is the duration of the temporary cessation of neural activity at the tissue location after activation occurs (in the tissue of any one of the heart chambers). The refractory period typically corresponds to the QRST interval portion of the heart cycle demonstrated in the ventricular or atrial electrogram taken at that location. For example, the refractory period can be intentionally induced in the tissue portion of the heart by applying a rhythm to the tissue at the tissue location using a rhythmic catheter.

[0018] Cardiac IRE ablation may be performed using an expandable frame (e.g., balloon or basket) fitted onto the distal end of an ablation catheter, according to the disclosed techniques. In an exemplary procedure, the expandable frame, on which the ablation electrodes are placed, is navigated through the cardiovascular system and inserted into the heart to ablate, for example, the opening of a pulmonary vein (PV).

[0019] By providing a more prudent protocol as an alternative to the initial IRE protocol, IRE ablation procedures can be performed more safely while maintaining clinical efficacy, for example, within the pores of the PV using an expandable frame catheter.

[0020] System Description

[0021] FIG. 1 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), and the shaft (22) of the catheter is inserted by a physician (30) through the vascular system of a patient (28) via a sheath (23). The physician (30) then navigates the distal end (22a) of the shaft (22) to a target location inside the patient's heart (26) as illustrated in illustration (25).

[0022] When the distal end (22a) of the shaft (22) reaches the target position, the physician (30) retracts the sheath (23) and inflates the balloon (40) by pumping saline solution into the balloon (40). Then, the physician (30) manipulates the shaft (22) so that the electrodes (50) placed on the balloon (40) catheter engage with the inner wall of the PV pore (51) and apply high-voltage IRE pulses to the pore (51) tissue through the electrodes (50).

[0023] As shown in illustrations (25, 27), an inflatable balloon (40) comprising a plurality of equidistant smooth-edged IRE electrodes (50) is fitted to the distal end (22a). Due to the flattened shape of the distal portion of the balloon (40), the distance between adjacent electrodes (50) is maintained approximately constant over the area where the electrodes (50) cover the distal portion. Thus, the balloon (40) configuration allows for more effective electroporation between adjacent electrodes (50) (e.g., by approximately uniform electric field strength) while minimizing unwanted thermal effects caused by the smooth edges of the electrodes (50).

[0024] A specific aspect of an inflatable balloon is covered, for example, in U.S. Provisional Application No. 62 / 899,259 filed September 12, 2019, with the title of the invention “Balloon Catheter with Force Sensor,” and in U.S. Patent Application No. 16 / 726,605 filed December 24, 2019, with the title of the invention “Contact Force Spring with Mechanical Stops,” both of which are assigned to the assignee of this patent application and whose disclosures are incorporated herein by reference.

[0025] In the embodiments described herein, the catheter (21) may be used for any suitable diagnostic and / or therapeutic purposes, such as electrophysiological sensing of PV pore (51) tissue within the left atrium (45) of the heart (26) and / or separation of the aforementioned IRE.

[0026] The proximal end of the catheter (21) is connected to a console (24) containing an IRE pulse generator (38) configured to apply an IRE pulse between adjacent electrodes (50). The electrodes are connected to the IRE pulse generator (38) by electrical wiring extending within the shaft (22) of the catheter (21). A memory (48) of the console (24) stores an IRE protocol containing IRE pulse parameters such as peak bipolar voltage and pulse width.

[0027] The console (24) includes a processor (41), which is typically a general-purpose computer, having a suitable front end and interface circuitry (37) for receiving signals from a catheter (21) and from external electrodes (49) typically placed around the chest of a patient (26). For this purpose, the processor (41) is connected to the external electrodes (49) by wires extending through a cable (39).

[0028] During the procedure, the system (20) can track the respective locations of the electrodes (50) inside the heart (26) using the Active Current Location (ACL) method provided by Biosense-Webster (Irvine, California, USA), as described in U.S. Patent No. 8,456,182, the disclosure of which is incorporated herein by reference.

[0029] In some embodiments, when the physician (30) becomes aware of the risk of bubbles using the IRE protocol initially set by the processor (41), as illustrated in Insert 27, the physician (30) may select a more prudent protocol and divide (divide) the IRE pulse delivery (55) of the selected protocol into a number of pulse trains (57) having pauses (59) between the pulse trains. The pauses allow sufficient dissipation of Joule heating from any pulse so that bubbles do not form.

[0030] In other embodiments, the physician (30) may change any of the parameters of the careful protocol, in particular the number of pulse trains and the minimum pause length, from the user interface (47). For example, the user may decide to remove pulses in the sequence to reduce the total number of pulses to be applied. The user interface (47) may include any suitable type of input device, such as a keyboard, mouse, trackball, etc.

[0031] The processor (41) is typically programmed with software to perform the functions described herein. The software may be downloaded electronically to a computer, for example, over a network, or it may be provided and / or stored on a non-transitory tangible media such as magnetic, optical, or electronic memory, alternatively or additionally.

[0032] In particular, the processor (41) executes a dedicated algorithm as disclosed herein, included in FIG. 2, which enables the processor (41) to perform the disclosed steps as further described below. In particular, the processor (41) is configured to command the IRE pulse generator (38) to output an IRE pulse according to a treatment protocol that the processor (41) uploads from memory (48).

[0033] Careful IRE protocol to prevent bubble formation

[0034] FIG. 2 is a flowchart schematically illustrating a method for applying irreversible electroporation (IRE) pulses using the system (20) of FIG. 1 according to one embodiment of the present invention. According to the presented embodiment, the algorithm performs a process that begins in the balloon catheter navigation step (80) when a physician (30) navigates the balloon catheter (40) to a target tissue location within a patient's organ, such as a PV pore (51), using electrodes (50), such as ACL sensing electrodes, for example.

[0035] Next, in the IRE planning step (82), the processor (41) uploads a protocol initially set with parameters for the IRE pulses to be applied to the tissue by the physician (30). An example of an IRE ablation setting in an initial protocol that can be used to ablate heart tissue using the disclosed balloon (40) is given in Table I.

[0036] [Table I]

[0037]

[0038] Next, in the notification step (84), the processor (41) provides the physician (30) with a notification that the initial IRE protocol may cause bubbles in the blood. In response, the physician may decide to use the protocol as is (i.e., use the initial protocol) in the protocol decision step (86). Alternatively, in the protocol replacement decision step (88), the physician decides to change the protocol to, for example, an alternative protocol given in Table II.

[0039] [Table II]

[0040]

[0041] As shown in Table II, in a more prudent protocol, the sequence of pulses in Table I is divided into eight pulse trains of five pulses each, with a minimum pause of 2 seconds between pulse trains.

[0042] In one embodiment, the physician (30) may change any of the parameters of Table II, in particular, the number of pulse trains and the minimum pause between pulse trains, from the user interface (47). Alternatively, the parameters of an alternative protocol may be automatically set by the processor (41). In such an embodiment, the processor (41) maintains an alternative protocol for each supported initial protocol. In another embodiment, the processor (41) derives the parameters of the alternative protocol from the parameters of the initial protocol according to some predefined rule or method.

[0043] When an IRE protocol is selected (an initial protocol according to step (86) or an alternative protocol according to step (88)), the processor (41) commands the generator (38) to apply IRE pulses to the tissue during the IRE treatment step (90). The IRE pulses are applied between the selected electrodes of the balloon (40) to isolate the arrhythmia originating or propagating through the small opening (51).

[0044] Although the embodiments described herein primarily deal with cardiac applications, the methods and systems described herein may also be used in other medical applications such as neurology and otolaryngology.

[0045] Accordingly, it will be recognized that the embodiments described above are referred to by way of example, and that the invention is not limited to what has been shown and described in detail above. Rather, the scope of the invention includes both combinations and sub-combinations of the various features described above, as well as variations and modifications thereof that come to mind to those skilled in the art upon reading the foregoing description and which are not disclosed in the prior art. The literature incorporated by reference in this patent application shall be considered an indispensable part of this application, except that in the event that any term is defined in such incorporated literature in a manner that conflicts with the definitions explicitly or implicitly made in this specification, only the definitions within this specification shall be considered.

Claims

Claim 1 delete Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 An irreversible electroporation (IRE) system comprising: a user interface configured to set IRE protocols for applying IRE pulses by electrodes of a catheter placed in contact with tissue within an organ; and a processor, wherein the processor issues a notification to the user when it is determined that an initial IRE protocol is expected to cause bubbles in the blood; and in response to the notification, receives a user input through the user interface to select between the initial IRE protocol and an alternative protocol not expected to cause bubbles; and, in accordance with the user input, is configured to apply IRE pulses according to the initial IRE protocol or the alternative IRE protocol. Claim 6 In paragraph 5, the processor is configured to receive, in the user input, a sequence of IRE pulses divided into a given number of pulse trains, each having a given pause between the pulse trains, in the irreversible electroporation (IRE) system. Claim 7 In paragraph 5, the initial IRE protocol and the alternative IRE protocol are an irreversible electroporation (IRE) system having the same total number of IRE pulses. Claim 8 In paragraph 5, the alternative IRE protocol is an irreversible electroporation (IRE) system having fewer pulses than the initial IRE protocol.

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