Patent Description:
Estimation of invasive ablation parameters and controlling the ablation according to the estimation has been previously proposed in the patent literature. For example, <CIT> describes devices for localized delivery of energy and methods of using such devices, particularly for therapeutic treatment of biological tissues. The disclosed methods may involve positioning and deploying the energy delivery members in a target site, and delivering energy through the energy delivery members. In an embodiment, radiofrequency (RF) duty cycle and/or pulse duration can be configured to vary responsive to one or more selected parameters, which can include frequency of the treatment signal, power for the treatment signal, or tissue impedance to the treatment signal.

As another example, <CIT> 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 <NUM> prior to the treatment procedure and intra-treatment test signals during the treatment procedure. A treatment control module determines impedance values from the pre-treatment test signal and intra-treatment test signals and determines the progress of electroporation and an end point of treatment in real-time based on the determined impedance values while the treatment progresses.

<CIT> discloses methods and devices for performing IRE procedures and mentions the problem of bubble formation around the electrodes.

The present invention relates to an irreversible electroporation system as defined in appended claim <NUM>. Embodiments of the invention are defined in the appended dependent claims.

Irreversible electroporation (IRE), also called Pulsed Field Ablation (PFA), may be used as an invasive therapeutic modality to kill tissue cells by subjecting them to high-voltage pulses. Specifically, IRE pulses have a potential use to kill myocardium tissue cells in order to treat cardiac arrhythmia. Cellular destruction occurs when the transmembrane potential exceeds a threshold, leading to cell death and thus the development of a tissue lesion. Therefore, of particular interest is the use of high-voltage bipolar electric pulses (e.g., using a selected pair of electrodes in contact with tissue) to generate high electric fields (e.g., above a certain threshold) to kill tissue cells between the electrodes.

However, the IRE pulses used to ablate tissue may, when the pulses are intense enough, also cause unwanted and/or undesirable effects of potential clinical hazard. For example, a pulse voltage of <NUM> kV across <NUM>Ω of blood impedance (both possible values) momentarily generates a local peak current of <NUM> A, i.e., <NUM> kW in the blood. This voltage, applied between the electrodes to form a sequence of bipolar IRE pulses, may also be high enough to generate enough Joule heating which may, if not quickly dissipated, generate gas bubbles in the blood. Some physicians may elect to accept risk of some bubble formation, although others may prefer not to, typically due to the state of the patient, e.g., a recent stroke.

Embodiments of the present invention that are described hereinafter provide systems for IRE. In some embodiments, various IRE ablation protocols (also called "initial protocols") are evaluated a-priori to determine if they may generate bubbles. The evaluations, performed in the laboratory, may also determine one or more alternative protocols to be proposed to a user. If, during an ablation procedure, the physician (or other user) initially sets an IRE ablation protocol that may generate bubbles, the system notifies the physician, who is then given the choice of using (also called hereinafter, "receiving a user input that selects") the protocol "as is," or an adapted, more cautious, IRE ablation protocol that does not generate bubbles.

In some embodiments, determining that a selected protocol may generate bubbles means estimating or measuring an impedance between the electrodes in a given electrode-pair and comparing that impedance to a threshold. If the estimated or measured impedance is below the threshold, then the processor determined that dissipated power in blood between the electrode-pair may generate bubbles.

In some embodiments, the more cautious IRE ablation protocol partitions the IRE pulse sequence of the selected protocol into a pulse sequence comprising multiple pulse trains with pauses between them. The pauses permit Joule heating from any pulse to dissipate sufficiently so that bubbles do not form.

In some embodiments, to maintain clinical effect, the more cautious IRE ablation protocol does not change the overall energy dissipated. Rather, the protocol spreads out pulse application time so as to permit more diffusion of generated heat and to lower a maximum temperature caused by the heating. Moreover, the pulse peak voltage is typically not reduced in the cautious IRE ablation protocol, since this affects the electroporation field generated. If the peak voltage is somewhat reduced, it still must be kept above a predefined minimum level required for the IRE ablation to be clinically effective.

In other embodiments, the physician (or other user) can modify, from a user interface, any of the parameters of the cautious protocol, and in particular the number of pulse trains and the minimal 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 them. The pauses permit Joule heating from any pulse to dissipate sufficiently so that bubbles do not form. The user may further decide to lower the total number of pulses, so as to further reduce the accumulative (i.e., overall) electrical power delivered to tissue.

In an embodiment, the system gates the pulse trains to be applied synchronously with the beating of the heart, e.g., to be applied during a refractory period of the tissue. Ventricular and atrial electrograms at ventricular or atrial tissue locations are usually acquired by electrodes in contact with tissue at the location catheter, e.g., during electrophysiological mapping of wall tissue portions of each of the respective cardiac chambers. A ventricular or atrial refractory period is a duration of a pause in neural activity at the tissue location, after an activation occurred there (in tissue of either of the above cardiac chambers). A refractory period typically largely coincides with the QRST interval portion of a cardiac cycle demonstrated in a ventricular or an atrial electrogram taken at the location. A refractory period can be deliberately induced at a tissue portion of the heart, for example, using a pacing catheter to pace the tissue at the tissue location.

Cardiac IRE ablation, in accordance with the disclosed techniques, may be performed using an expandable frame (e.g., balloon or basket) fitted on a distal end of an ablation catheter. In an example procedure, the expandable frame, which is disposed with ablation electrodes, is navigated through the cardiovascular system and inserted into a heart to, for example, ablate an ostium of a pulmonary vein (PV).

By offering a more cautious protocol as an alternative to the initial IRE protocol, IRE ablation procedures, for example in an ostium of a PV using an expandable frame catheter, can be made safer, while maintaining clinical efficacy.

<FIG> is a schematic, pictorial illustration of a catheter-based irreversible electroporation (IRE) system <NUM>, in accordance with an embodiment of the present invention. System <NUM> comprises a catheter <NUM>, wherein a shaft <NUM> of the catheter is inserted by a physician <NUM> through the vascular system of a patient <NUM> through a sheath <NUM>. The physician <NUM> then navigates a distal end 22a of shaft <NUM> to a target location inside a heart <NUM> of the patient as illustrated in inset <NUM>.

Once distal end 22a of shaft <NUM> has reached the target location, physician <NUM> retracts sheath <NUM> and expands balloon <NUM>, typically by pumping saline into balloon <NUM>. Physician <NUM> then manipulates shaft <NUM> such that electrodes <NUM> disposed on the balloon <NUM> catheter engage an interior wall of a PV ostium <NUM> to apply high-voltage IRE pulses via electrodes <NUM> to ostium <NUM> tissue.

As seen in insets <NUM> and <NUM>, distal end 22a is fitted with an expandable balloon <NUM> comprising multiple equidistant smooth-edge IRE electrodes <NUM>. Due to the flattened shape of the distal portion of balloon <NUM>, the distance between adjacent electrodes <NUM> remains approximately constant even where electrodes <NUM> cover the distal portion. Balloon <NUM> configuration therefore allows more effective (e.g., with approximately uniform electric field strength) electroporation between adjacent electrodes <NUM> while the smooth edges of electrodes <NUM> minimize unwanted thermal effects.

Certain aspects of inflatable balloons are addressed, for example, in <CIT>, titled "Balloon Catheter with Force Sensor," and in <CIT>, titled, "Contact Force Spring with Mechanical Stops," which are both assigned to the assignee of the present patent application.

In the embodiment described herein, catheter <NUM> may be used for any suitable diagnostic and/or therapeutic purpose, such as electrophysiological sensing and/or the aforementioned IRE isolation of PV ostium <NUM> tissue in left atrium <NUM> of heart <NUM>.

The proximal end of catheter <NUM> is connected to a console <NUM> comprising an IRE pulse generator <NUM> configured to apply the IRE pulses between adjacent electrodes <NUM>. The electrodes are connected to IRE pulse generator <NUM> by electrical wiring running in shaft <NUM> of catheter <NUM>. A memory <NUM> of console <NUM> stores IRE protocols comprising IRE pulse parameters, such as peak bipolar voltage and pulse width.

Console <NUM> comprises a processor <NUM>, typically a general-purpose computer, with suitable front end and interface circuits <NUM> for receiving signals from catheter <NUM> and from external electrodes <NUM>, which are typically placed around the chest of patient <NUM>. For this purpose, processor <NUM> is connected to external electrodes <NUM> by wires running through a cable <NUM>.

During a procedure, system <NUM> can track the respective locations of electrodes <NUM> inside heart <NUM>, using the Active Current Location (ACL) method, provided by Biosense-Webster (Irvine California), which is described in <CIT>.

In some embodiments, in case physician <NUM> is informed by processor <NUM> of a risk of bubbles using an initially set IRE protocol, physician <NUM> may select a more cautious protocol that divides (partitions) the IRE pulse delivery <NUM> of the selected protocol into multiple pulse trains <NUM> with pauses <NUM> between the pulse trains as illustrated in inset <NUM>. The pauses permit Joule heating from any pulse to dissipate sufficiently so that bubbles do not form.

In other embodiments, physician <NUM> can modify, from a user interface <NUM>, any of the parameters of the cautious protocol, and in particular the number of pulse trains and the minimal pause length. For example, the user may decide to remove pulses in a sequence in order to reduce a total number of pulses to be applied. User interface <NUM> may comprise any suitable type of input device, e.g., a keyboard, a mouse, a trackball and the like.

Processor <NUM> is typically programmed in software to carry out the functions described herein. The software may be downloaded to the computer in electronic form, over a network, for example, or it may, alternatively or additionally, be provided and/or stored on non-transitory tangible media, such as magnetic, optical, or electronic memory.

In particular, processor <NUM> runs a dedicated algorithm as disclosed herein, including in <FIG>, which enables processor <NUM> to perform the disclosed steps, as further described below. In particular, processor <NUM> is configured to command IRE pulse generator <NUM> to output IRE pulses according to a treatment protocol that processor <NUM> uploads from memory <NUM>.

<FIG> is a flow chart that schematically illustrates a method for applying irreversible electroporation (IRE) pulses using system <NUM> of <FIG>. The algorithm, according to the presented embodiment, carries out a process that begins when physician <NUM> navigates balloon catheter <NUM> to a target tissue location in an organ of a patient, such as at PV ostium <NUM>, using, for example, electrode <NUM> as ACL sensing electrodes, at a balloon catheter navigation step <NUM>.

Next, at an IRE planning step <NUM>, processor <NUM> uploads a protocol initially set by physician <NUM>, with parameters of the IRE pulses to apply to tissue. An example of IRE ablation settings in an initial protocol that may be used for ablating cardiac tissue using the disclosed balloon <NUM> is given in Table I.

Next, at a notification step <NUM>, processor <NUM> provides a notification to physician <NUM> that the initial IRE protocol may generate bubbles in blood. In response, the physician may decide, at a protocol decision step <NUM>, to use the protocol as is (i.e., use the initial protocol). Alternatively, at a protocol replacement decision step <NUM>, the physician decides to change the protocol, for example, into an alternative protocol given in Table II.

As seen in Table II, in the more cautious protocol the sequence of pulses of Table I is divided into eight pulse trains of five pulses each, with a minimal pause of two seconds between pulse trains.

In an embodiment, physician <NUM> can modify, from user interface <NUM>, any of the parameters of Table II and, in particular, the number of pulse trains and the minimal pause between pulse trains. Alternatively, the parameters of the alternative protocol may be set automatically by processor <NUM>. In one such embodiment, processor <NUM> holds a respective alternative protocol for each initial protocol being supported. In another embodiment, processor <NUM> derives the parameters of the alternative protocol from the parameters of the initial protocol in accordance with some predefined rule or method.

Once an IRE protocol has been chosen (the initial protocol per step <NUM> or the alternative protocol per step <NUM>), processor <NUM> commands generator <NUM> to apply the IRE pulses to tissue, at an IRE treatment step <NUM>. The IRE pulses are applied between selected electrodes of balloon <NUM> to isolate an arrhythmia originating or propagating via ostium <NUM>.

Although the embodiments described herein mainly address cardiac applications, the methods and systems described herein can also be used in other medical applications, such as in neurology and otolaryngology.

Claim 1:
An irreversible electroporation (IRE) system (<NUM>), comprising:
a user interface (<NUM>) configured for setting IRE protocols for applying IRE pulses by electrodes (<NUM>) of a catheter (<NUM>) placed in contact with tissue in an organ; and
a processor (<NUM>), characterised in that the processor (<NUM>) is configured to:
issue a notification to a user upon determining that an initial IRE protocol is expected to cause bubbles in blood;
receive via the user interface, in response to the notification, user input that selects between the initial IRE protocol and an alternative protocol that is not expected to cause the bubbles; and
apply the IRE pulses according to the initial IRE protocol or the alternative IRE protocol, depending on the user input.