Patent Description:
Cardiac arrhythmias disrupt normal heart rhythm and reduce cardiac efficiency. These arrhythmias can be treated using pulsed field ablation (PFA) or radiofrequency (RF) ablation therapy. The delivery of ablation therapy involves the use of a reliable, powerful, and precisely controlled electrical energy source in the form of high voltage pulse generator. These pulses are delivered to perform reversible or irreversible electroporation via an ablation therapy delivery device of intended cardiac sites. Reversible electroporation is used to reversibly permeabilize cells to catalyze acceptance of genes or drugs, whereas irreversible electroporation is used to create permanent and lethal nanopores which can electrically isolate target areas of the myocardium and prevent arrhythmias, such as atrial fibrillation.

PFA deliveries are very low in total energy yet intense in power, but PFA energy delivered through its intended pathway from equipment (for example, an ablation therapy delivery device such as an ablation catheter or surgical ablation clamp) to the patient has incumbent constraints and design challenges for reliable, safe transmission. One of the most important issues for the design of ablation therapy delivery systems is the balance between delivering an effective amount of energy and keeping the delivery device as small as possible. For example, it may be desirable to apply the highest voltage that can be delivered reliably and safely through the greatest number of delivery device electrodes applying endocardial PFA therapy, but the size of the delivery device must be minimized to facilitate patient safety and physician ease of use. In addition, electrode surface areas and gaps between electrodes may both need to be minimized to achieve higher quality recordings of intracardiac electrograms, thereby increasing current density on each electrode. Therefore, PFA therapy transmission efficacy and optimality is traded off against reliability, safety, and operability where the latter constraints must be maintained at acceptable levels of patient risk.

An example of an efficacy/reliability tradeoff is the selection of catheter wire diameter. Both conductor and insulation thickness must be optimally chosen to reliably convey high current and insulate against voltage breakdown in the face of constraints. Although an increased number of wires and/or an increased diameter of each wire enhances current and voltage capability of the delivery device, such increases also demand greater lumen diameter(s) which, in turn, increases wire-lumen friction and wear. To reduce friction to an acceptable level when an increased number of wires and/or increased wire diameter are used, the diameter of the delivery device lumen and/or the diameter of an introducer device used to position the delivery device is also increased. However, the increased diameter increases the potential for post-procedure vasculature bleeding complications, which must be minimized.

Further, although quality and longevity of the delivery device are expected, there is always a risk that a particular delivery device will fail before its expected useful life. Therefore, the delivery device must be monitored to ensure that excessive amounts of energy are not delivered through a dysfunctional device, which could not only further damage the device, but could also harm the patient. Furthermore, it is important that the user (for example, a physician) is notified if the delivery device is not functional or if there is a danger of device failure before each energy delivery.

The diameter of the delivery device is largely dictated by the electrical requirements and, therefore, the size of one or more lumens within the elongate body or shaft of the delivery device. As noted above, there are restrictive size requirements placed on the delivery device to ensure patient safety. However, such constraints may severely limit on the size and quantity of the wires within one or more lumens of the elongate body of the delivery device. As a result, the energy delivery pathway is vulnerable to degradation and eventual failure. For example, when PFA energy is delivered through the delivery electrodes of the device, an arc, and possibly an arc-induced plasma, may occur when one or more of the delivery electrodes come into proximity with other metal objects within the patient, such as the delivery device's guide wire, an auxiliary diagnostic catheter, or an implanted stent. An arc occurs when current passes through a typically non-conductive medium, and plasma may be produced as a result (such as visible light). For example, an arc may occur through blood between an energy delivery electrode and tissue. As arc events create extremely high current (~ <NUM> amps), very small-gauge wires within the delivery device may overheat and fail. Onderdonk equation, a series of <NUM> biphasic, <NUM>-µs pulses at <NUM> amps per <NUM> gauge (<NUM> mil) conductor can cause a copper wire to rise <NUM> from <NUM> ambient temperature, resulting in a <NUM> temperature inside the delivery device, which can rapidly damage the device. While a properly designed device used in a routine cardiac ablation procedure can be expected to provide nominal performance, a single arc event can render a catheter defective, requiring that the catheter be explanted and replaced, a procedure that lengthens the operation's time and increases its cost. Additionally, current spikes, which may be caused by reasons such as insufficient electrode spacing, may also produce bubbles, barotrauma, heat, and other undesirable side effects. Therefore, a PFA system that can detect conditions conducive to arcing, as well as possessing the means of adjusting generator parameters and/or advising the physician to adjust their positioning and manipulation of the device to prevent such an occurrence, greatly increases patient safety and reduces complexity, time, and cost of a PFA procedure.

However, some currently known monitoring and safety systems are limited. Systems that include internal impedance measuring devices can resolve pathway failures in devices, interconnecting cables, and generator systems. Indeed, low-power impedance measurements are useful for determining the condition of the energy delivery pathway. However, since impedance measurements are typically made at very low levels of radio frequency (RF) energy, they are not useful in recognizing arcs or plasma, which only occur during application of very high energy capable of creating high electric fields. Arcs or plasma occurring in blood, outside the device, can lead to the formation of heat, barotrauma, and/or bubbles and embolic material that have the potential of causing cerebrovascular ischemic injury. An arc can also create a shockwave and subsequent cavitation, where pressures are exerted on vasculature causing permanent damage. Therefore, it is imperative that the PFA system recognize an arc in its early formation, so that the sourcing condition is terminated immediately, and the arc event is relegated to inconsequential thermal and mechanical energy.

High voltage electroporation waveform generators (such as PFA generators) will generate pulses <NUM> whose shape and characteristics are, for example, generally as shown in <FIG>. As a practical matter for pulsed field ablation, a tradeoff is made between shortening the rise time τr and/or the fall time τf (that is, the time it takes the waveform to rise from <NUM>% to <NUM>% or fall from <NUM>% to <NUM>% of the final amplitude, respectively) to reduce time spent at cellular sub-transmembrane potential and the propensity of short rise-fall times to cause overshoot and ringing. An example of a pulse <NUM> with severe overshoot and ringing is shown in <FIG>.

A PFA generator may use metal oxide varistors to limit or clamp a waveform's voltage before it reaches a damaging level. A limitation of varistors, however, is that their thresholds for minimum and maximum actuation cover a wide span, typically <NUM>% of their nominal rating. Thus, their actuation threshold can be either too low, such that the device begins to clamp at the intended level of therapy voltage and therefore limit the effectiveness of therapy, or too high, such that the arc occurs anyway. Varistors also add considerable capacitance to the waveform generator's source impedance, which distorts the therapy waveform and adds load reactance, which, in turn, encourages overshoot and ringing. Overshoot and ringing then imparts undesirable heat to the electroporated tissue. Last, a varistor can only clamp a voltage transient after it is produced and cannot apply a feedback to end the arc in its formation.

In some cases, the arc occurs due to an oscillation created by a waveform pulse with abnormally fast rise and fall times. As shown in <FIG>, the lower horizontal line on the left-hand side of the pulse <NUM> is the desired PFA therapy potential (voltage), but the ring (more formally referred to as an oscillation) exceeds the therapy amplitude by a factor of approximately <NUM>. An oscillation of this magnitude is likely related to an arc condition with commensurate heating of tissue, denaturing of blood proteins (forming embolic material), and possible damage to the delivery device and generator system.

In addition to potential device failure and size constraints associated with PFA systems, delivery of PFA energy to muscle tissue can also cause unintended muscle stimulation, which occurs when electrical charge builds up in the tissue. This unintended stimulation can be mitigated by using short, balanced, biphasic waveform pulses <NUM>, wherein any charge accumulation from the first positive phase 12A of the biphasic waveform <NUM> is quickly cancelled by a pulse of opposite polarity (that is, the negative phase 12B of the biphasic waveform <NUM>). For example, as shown in <FIG>, the integrated current <NUM> has a charge of zero. However, even a slight asymmetry between the phases 12A, 12B may lead to incomplete cancellation of the charge (for example, as shown in <FIG>).

One potential cause of asymmetry is the discharge of one or more capacitors of the PFA generator to power the delivery. PFA therapy can deliver an enormous amount of power over short periods of time (potentially dozens of kilowatts in pulses several microseconds long). A power supply capable of supplying that much power continually would be prohibitive, so energy is stored in a bank of capacitors before delivery. During delivery, current flows from the capacitor bank rather than from the power supply itself. Once a delivery is complete, the power supply can resume charging the capacitor bank. However, therapy voltage and delivery current will decrease as charge is depleted from the capacitor bank. Exaggerated, non-limiting examples of output current decrease are shown in <FIG>. In <FIG>, the peak voltage of each subsequent pulse <NUM> (or phase pulse 12A, 12B) is slightly less than the peak voltage of the pulse before, leading to a net imbalance of delivered charge. The amount of reduction depends on the electrical current delivered and capacitance of the capacitor bank: a higher current will more rapidly deplete the energy stored in the capacitor banks, while a capacitor bank having a higher capacitance will offer a larger amount of stored energy. Unless mitigated, this will lead to an imbalance of charge accumulating in the direction of the first pulse's polarity (positive or negative).

Another potential cause is mismatched rise and/or fall times between polarities. An exemplary ideal PFA pulses would be a perfectly rectangular pulse, with impossibly sharp rising and falling edges. Limitations imposed by real components, however, result in non-zero actual rise and fall times. As a non-limiting example, consider an H bridge circuit <NUM> constructed from n-type metal-oxide semiconductor (nMOS) with transistors <NUM>, such as metal-oxide-semiconductor field-effect transistors (MOSFETs) of insulated gate bipolar transistors (IGBTs), used to create biphasic PFA pulses (for example, transistors <NUM> are Q1, Q2, Q3, and Q4, as shown in <FIG>). In order to deliver a pulse, a low-voltage "positive pulse enable" signal is sent from a digital control circuit into a gate driver integrated circuit (IC), which, in turn, is connected to the gate of a transistor <NUM>. Voltage at the gate of the transistor <NUM> controls resistance between its drain and source, which creates the therapy pulse. However, the original digital signal is delayed slightly by the gate driver, the gate driver has a finite current capability which requires time to charge the transistor's parasitic gate capacitance, the drain-source resistance will reduce the total current delivered, and so on. These effects lead to wasted power in the PFA generator and reduced dwell time at the desired therapy voltage. Further, these effects may vary from component to component. If the components driving one polarity switch faster than those driving the other polarity, or if one polarity's transistor <NUM> has a significantly lower saturated drain-to-source resistance, charge will tend to accumulate in that polarity. For example, <FIG> shows the effect of mismatched rise times τr-positive and τr-negative between each half of the biphasic pulse (that is, between the positive phase pulse 12A and the negative phase pulse 12B), in which the negative phase takes longer to reach the nominal voltage and leads to a net positive charge. <CIT> relates to a system and method for ablating a tissue site by electroporation with real-time pulse monitoring.

Some embodiments advantageously provide methods and systems for monitoring and modifying pulsed field ablation (PFA) energy delivery to prevent patient safety risks and/or delivery device failure. In particular, some embodiments provide methods and systems for detecting and preventing arcs and arc-induced plasma, and their causal events, during delivery of pulsed field ablation energy, as well as methods and systems for identifying conditions leading to potential delivery device failure and correcting charge imbalance or asymmetry. Methods of treatment by therapy or surgery or in vivo diagnosis methods are not encompassed by the wording of the claims but are considered as useful for understanding the invention.

A method including using at least one detector that measures the rise-fall time of a pulse in its early formation is described herein. If the measured rise-fall time is too short, feedback can be provided to the PFA generator's output stage to temporarily disable the sourcing energy responsible for the oscillation, but then increase the PFA generator's H bridge circuit's rise-fall time, such that the arc, or condition causing an arc, is eliminated for subsequent delivery pulses. As a result, the arc never occurs.

A second method includes using at least one detector that uses a precise, programmable threshold that suppresses the waveform if a voltage and/or amplitude threshold is reached and/or exceeded (see <FIG>). As the threshold is reached and/or exceeded, a pulse is sent from a detector (or detector-comparator) that is processed within a few nanoseconds and sent as a "kill" signal to the PFA generator's output H bridge circuit.

A third method includes applying a mask to a delivered waveform to ensure that the therapy waveform's timing and amplitude characteristics fit the prescribed therapy waveform's dosing prescription. The purpose of this fitting is to detect an anomalous pulse prior to a subsequent pulse capable of arcing. The predictive period may be one pulse, many pulses, or a few deliveries consisting of many pulses until the eventual arc or catheter damage occurs.

A fourth method includes applying information gained using one or all three prior methods, and making an adjustment to the PFA generator's output circuit electronics, slowing the rise-fall time and/or reducing the delivery voltage, or interlocking and ceasing delivery altogether, to eliminate the arc on a subsequent pulse delivery.

A fifth method including applying information gained using one or all of the first three methods, and generating an electronic message advising the operating physician of the recommended course of action to remedy an arc condition that may exist due to a damaged or improperly manipulated catheter.

In one embodiment, a method of modifying pulsed field ablation (PFA) energy delivery comprises: delivering a PFA pulse from a PFA generator; measuring a rise time and a fall time of the PFA pulse; calculating a voltage of an oscillatory pole in the PFA pulsed based at least in part on rise time and the fall time; and modifying at least one of the rise time and the fall time to reduce the voltage of the at least one oscillatory pole in the PFA pulse.

In one aspect of the embodiment, the PFA generator further includes processing circuitry having an H bridge circuit.

In one aspect of the embodiment, modifying the at least one of the rise time and the fall time including adjusting an input resistance in the H bridge circuit.

In one aspect of the embodiment, modifying at least one of the rise time and the fall time includes reducing the time in which the PFA pulse reaches <NUM>% of a final amplitude of the PFA pulse under heavily loaded conditions.

In one aspect of the embodiment, the at least one of the rise time and the fall time is modified to a time between <NUM> and <NUM>.

In one aspect of the embodiment, the method further comprises: measuring a pulse width of the PFA pulse; calculating a voltage of an oscillatory pole in the PFA pulse based at least in part on the pulse width; and modifying the pulse width to reduce the voltage of the at least one oscillatory pole in the PFA pulse.

In one aspect of the embodiment, the method further comprises ceasing delivery of the PFA pulse from the PFA generator when the calculated voltage of the oscillatory pole is greater than a threshold voltage.

In one embodiment, a method of modifying pulsed field ablation (PFA) energy delivery comprises: delivering at least one biphasic PFA pulse from a PFA generator, each of the at least one biphasic PFA pulse including a biphasic pair having a positive phase and a negative phase; and calculating a value of an integral of a current over the biphasic pair.

In one aspect of the embodiment, the method further comprises measuring a pulse width of the PFA pulse; and modifying the pulse width of the biphasic PFA pulse when the integral of the current has a non-zero value.

In one aspect of the embodiment, the method further comprises delivering a runt pulse in the biphasic PFA pulse and modifying the pulse width of the biphasic PFA pulse when the integral of the current has a non-zero value.

In one aspect of the embodiment, the runt pulse has an amplitude that is less than an amplitude of the positive phase of the biphasic pair.

In one aspect of the embodiment, the runt pulse has an amplitude that is less than an amplitude of the negative phase of the biphasic pair.

In one aspect of the embodiment, the runt pulse is delivered after the negative phase of the biphasic pair.

In one embodiment, a system for delivering pulsed field ablation (PFA) energy comprises: a delivery device including at least one energy delivery electrode; and a control unit in electrical communication with the delivery device, the control unit including a PFA generator. In this embodiment, the PFA generator has: an H bridge circuit, the H bridge circuit being configured to deliver PFA energy to the delivery device, the PFA energy including a plurality of pulses; a detector, the detector being in electrical communication with the H bridge circuit and configured to: measure a rise-fall time of each of the plurality of pulses; measure a pulse width of each of the plurality of pulses; determine a voltage of at least one pole occurring in at least one of the plurality of pulses; compare the determined voltage of the at least one pole to a threshold voltage; and at least one of: adjust at least one of the rise-fall time and the pulse width of at least one of the plurality of pulses by adjusting a voltage of the PFA energy produced by the H bridge circuit when the detector determines the determined voltage is greater than the threshold voltage; and prompt a use to lower an output level of the PFA generator.

In one aspect of the embodiment, the detector is an amplitude detector, the amplitude detector being configured to determine an amplitude of each of the plurality of pulses in a time domain.

In one aspect of the embodiment, the PFA generator further has a counter circuit in electrical communication with the amplitude detector.

In one aspect of the embodiment, the amplitude detector is configured to initiate a time count by a timer circuit, the rise-fall time being determined at least in part by the time count.

In one aspect of the embodiment, the PFA generator further has a spectrum detector, the spectrum detector being configured to determine the voltage of the at least one pole occurring in at least one of the plurality of pulses in the spectral domain.

In one aspect of the embodiment, the control unit being further configured to determine that a fault condition exists in the delivery device, the determination that a fault condition exists being based at least in part on a determined amplitude of at least one of the plurality of pulses.

In one aspect of the embodiment, the control unit is further configured to: determine an accumulated amount of charge delivered by the PFA generator; and when the determined accumulated amount of charge has a non-zero value, at least one of: adjust the pulse width of at least one of the plurality of pulses until the determined accumulated amount of charge has a zero value; and deliver at least one runt pulse until the determined accumulated amount of charge has a zero value.

A more complete understanding of embodiments described herein, and the attendant advantages and features thereof, will be more readily understood by reference to the following detailed description when considered in conjunction with the accompanying drawings wherein:.

Before describing in detail exemplary embodiments, it is noted that the embodiments reside primarily in combinations of apparatus components and processing steps related to delivering pulsed field ablation energy. Accordingly, the system and method components have been represented where appropriate by conventional symbols in the drawings, showing only those specific details that are pertinent to understanding the embodiments of the present disclosure so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having the benefit of the description herein.

The step response of a low order electrical pulse generator, such as a pulsed field ablation (PFA) generator <NUM>, is well characterized by its <NUM>% - <NUM>% rise-fall time. As shown in <FIG>, the rise time, tr, extends between <NUM>% and <NUM>% of the amplitude and the fall time, tf, extends between <NUM>% and <NUM>% of the amplitude. The rise time and the fall time are collectively referred to herein as "rise-fall time" (τ or τr/τr), unless one differs or is adjusted differently than the other. Given that the system follows a first order resistive-capacitive or Gaussian system, the output should settle smoothly to a steady-state value with minimal overshoot (typically less than <NUM>%) and no ringing. An example of a nominal PFA biphasic waveform <NUM> is shown in <FIG>.

Yet, as the rise-fall time τ of the pulse <NUM> decreases, the bandwidth of the pulse <NUM> increases, and additional in-band poles <NUM> are revealed that store, rather than dissipate, energy (for example, as shown in <FIG>, where the pulses are designated with reference number <NUM>, and <FIG>, where the pulses are designated with reference number <NUM>). The stored energy is then released and superimposed on the intended pulse, resulting in high, and possibly damaging, overshoot and ringing (for example, as shown in <FIG>). However, the method disclosed herein includes purposely adjusting the PFA waveform rise and/or fall times τr and τf to be as short as possible to minimize imparted energy in the form of heat, while avoiding rise-fall time that create waveform overshoot and ringing. For example, excessive ringing (such as four times the amplitude) and overshoot may be caused by a rise-fall time that is too fast, and can lead to damage to the delivery device, the waveform or pulse generator (which may also be referred to herein as the PFA generator), and electrical and mechanical components of the delivery device and PFA system, and can potentially cause the formation of coagulants, bubbles, and char, which may present an embolism risk to the patient. A pulse <NUM> from the same PFA generator as in <FIG> is shown in <FIG>, except where the pulse's rise time τr is lengthened to approximately <NUM> ns (from less than <NUM> ns in <FIG>) to eliminate ringing.

Referring now to <FIG>, an exemplary PFA system <NUM> is shown. The PFA system <NUM> may be used to treat endocardial surfaces, but it will be understood that the PFA system <NUM> may be used to treat other areas, including epicardial tissue, esophageal tissue, dermal tissue, tumors, or any other tissue that is treated with the application of PFA energy. In one embodiment, the PFA system <NUM> generally includes a delivery device <NUM> and a control unit <NUM>.

The delivery device <NUM> may have any suitable size, shape, or configuration, but includes at least one energy delivery electrode <NUM> for delivering an electrical current, and may further include one or more electrodes such as mapping electrodes and/or electrodes for measuring characteristics such as impedance (not shown). In the non-limiting example shown in <FIG>, the delivery device <NUM> includes an elongate body <NUM> with a distal portion <NUM> and a proximal portion <NUM>, one or more lumens within the elongate body (not shown), and a flexible, expandable distal array <NUM> coupled to the distal portion <NUM> of the elongate body <NUM> and bearing a plurality of energy delivery electrodes <NUM>. The plurality of energy delivery electrodes <NUM> are in electrical communication with the control unit <NUM>. The delivery device <NUM> includes a handle <NUM> with one or more actuators for, for example, electrically and/or mechanically communicating with one or more steering elements within the delivery device <NUM> for maneuvering the distal array <NUM> to a target treatment location within the patient's body. The delivery device <NUM> may also include one or more sensors <NUM> (for example, associated with each energy delivery electrode, within one or more lumens of the elongate body <NUM>, and/or at other locations in the delivery device <NUM> and/or control unit <NUM>), such as temperature sensors, pressure sensors, piezoelectric elements, strain gauges, and/or fiber Bragg sensors.

The term "control unit" may be used to generally refer to any system components that are not part of the delivery device <NUM>. The control unit <NUM> may be described to include components that are physically located within or integrated with the control unit <NUM> or are in communication with the control unit <NUM>. In one embodiment, the control unit <NUM> includes a pulse or waveform generator (referred to herein as a PFA generator <NUM>) that is in electrical communication with the energy delivery electrode(s) <NUM> of the delivery device <NUM> and configured to deliver pulsed field electrical energy for the treatment of tissue using pulsed field ablation (PFA). In some embodiments, the PFA generator <NUM> and the control unit <NUM> are the same component. The PFA generator <NUM> is configured to deliver high-frequency, non-ablative pulses for causing reversible and/or non-reversible electroporation in targeted tissue cells. For example, the PFA generator <NUM> may be configured to deliver ablative energy pulses in the range of approximately <NUM> microsecond to <NUM> microseconds in duration and at frequencies of approximately <NUM> to <NUM>. In one embodiment, the PFA generator <NUM> and/or control unit <NUM> is configured such that the user is able to modulate or adjust one or more characteristics of the pulses <NUM>, such as rise-fall time τ and/or pulse width T. Optionally, the PFA generator <NUM> may also be configured to deliver ablative energy (such as radiofrequency (RF) energy, laser energy, microwave energy, or the like) or the control unit <NUM> may include an additional energy generator for providing ablative energy).

In one embodiment, the control unit <NUM> also includes a user interface by which the user may select the energy delivery mode, monitor energy delivery parameters, adjust or stop energy delivery, select one or more energy delivery electrodes with which to deliver energy, or the like. For example, the user interface may include a foot pedal, mouse, joystick, one or more computers having one or more displays, buttons, knobs, touchpads, touchscreens, or other communication and/or input means <NUM>. Although the PFA generator <NUM> and/or control unit <NUM> may be able to operate in a completely automated manner, the PFA generator <NUM> and/or control unit <NUM> may be configured to allow the user to assume control over energy delivery and/or to select, initiate, or otherwise assist the semi-automatic operation of the PFA system <NUM>. Additionally, the PFA system <NUM> may optionally include one or more components such as a navigation system, mapping system, imaging system, delivery device electrode distribution system, remotes, or the like.

The control unit <NUM> and/or PFA generator <NUM> may further include processing circuitry <NUM> programmed to receive, process, and/or communicate data received from the delivery device <NUM> and/or other components of the PFA system <NUM>. In one embodiment, the PFA generator <NUM> includes a power source <NUM> and processing circuitry <NUM> including an H bridge circuit, such as the H bridge circuit <NUM> shown in <FIG>. In one embodiment, the H bridge circuit <NUM> generates positive and negative pulses to create a biphasic waveform <NUM> that is then transmitted to the energy delivery electrodes <NUM> of the delivery device <NUM>. The energy delivery electrodes <NUM> then transmit the biphasic waveform (PFA energy) to the targeted tissue. The PFA generator <NUM> and/or the control unit <NUM> may also include processing circuitry <NUM> including one or more detectors, counters, or other circuits, such as those discussed below.

The PFA system <NUM> also includes at least one detector, which may be integrated with or external to the PFA generator <NUM>. In one embodiment, the rise-fall time τ is determined by the at least one detector using time domain. In this embodiment, the PFA system <NUM> includes an amplitude detector <NUM>, such as the amplitude detector <NUM> shown in <FIG>, that detects the <NUM>% and <NUM>% amplitude of a pulse <NUM> (such as a trapezoidal pulse) delivered by the PFA generator <NUM> and initiates a time count by a counter circuit <NUM> (for example, as shown in <FIG>) that determines the rise and/or fall time of the pulse <NUM>. The amplitude detector <NUM> and counter circuit <NUM> are together also configured to apply a correction signal based on the determined rise-fall time to change the input base or gate resistance of the H bridge circuit <NUM>. As the input base or gate resistance increases, the gate or base time constant of the RC circuit will increase, and the rise-fall time of the pulse will similarly increase. As will be shown, the effect of slowing rise-fall time will be to greatly attenuate or reduce undesirable overshoot and ringing. Additionally or alternatively, the amplitude detector <NUM> and counter circuit <NUM> are configured to apply a correction signal to adjust the pulse width T.

Additionally or alternatively, poles <NUM> are identified by the at least one spectrum analyzer <NUM> (for example, the spectrum analyzer <NUM> shown in <FIG>) using spectral domain. In this embodiment, the PFA system <NUM> includes a spectrum detector <NUM> having an analog-to-digital (A/D) converter <NUM> that applies a discrete or fast Fourier transform (FFT) <NUM> on the delivered current to identify oscillatory poles and/or excessively high side lobes <NUM> in the frequency spectrum of the pulse. For example, <FIG> shows a comparison of two trapezoidal pulses in the time domain, the trapezoidal pulses having different rise-fall times τ (<NUM> and <NUM>), but the same pulse width T (<NUM>). <FIG> shows a comparison between the two trapezoidal pulse spectrums (τ = <NUM>, or fast pulse 66A, and τ = <NUM>, or slow pulse 66B), and <FIG> shows a comparison between the two trapezoidal pulse spectrums of <FIG>.

Mathematically, a trapezoidal pulse may be expressed as the convolution of two dissimilar width square pulses: <MAT> <MAT> where A is the pulse amplitude, τ is the rise and fall time, and T is the pulse width. The Bode plot magnitude response for Equation (<NUM>) in the trapezoidal pulse frequency spectrum is show in <FIG>, where both amplitude and frequency are plotted on logarithmic axes. The first response breakpoint is proportional to the trapezoidal pulse width and occur at frequency <MAT>, or for a <NUM> wide pulse: f = <NUM>. The response then falls at -<NUM> dB/decade until the next breakpoint (which is proportional to the trapezoidal pulse's rise/fall time) at frequency <MAT>, or for a. <NUM> rise/fall time characteristic: f = <NUM>. After the second breakpoint, the response continues to diminish at -<NUM> dB/decade.

In the first method of reducing ringing, the rise-fall time τ (also referred to as τr/τf) is adjusted. Two time domain trapezoidal pulses <NUM> with different rise-fall times, τ, are shown in <FIG>. For the first time domain trapezoidal pulse 66A, τ = <NUM>. For the second time domain trapezoidal pulse 66B, τ = <NUM>. The pulse width for both is T = <NUM>. The frequency spectrums of the two pulses 66A, 66B are compared in <FIG>. It is noted that the second trapezoidal pulse 66B has a wider spectral width than the first trapezoidal pulse 66A. Further, the faster pulse 66A (that is, where τ = <NUM>) has a much greater propensity to ring or create large amplitude oscillations <NUM> than the slower pulse 66B (that is, where τ = <NUM>).

As shown in <FIG>, a typical PFA generator <NUM> will contain energy delivery pathway imperfections that will result in energy storage and subsequent transfer of large oscillations to energy delivery electrodes <NUM> of the delivery device <NUM>. These imperfections are referred to as "poles" <NUM>, and must have their oscillatory effect minimized to avoid causing an in vivo arc as well as avoid damage to the PFA system <NUM>. Next, it will be shown that the faster pulse 66A (that is, where τ = <NUM>) has a much greater propensity to ring or create large amplitude oscillations <NUM> than does the slower pulse 66B (that is, where τ = <NUM>).

As a modification to Equation (<NUM>) above, a transfer function expressing energy delivery electrode potential in time, but including two underdamped poles (that is, poles that are dampened incompletely to allow for some oscillations) will be: <MAT> where the two pole locations are: <MAT>.

As an example, consider a system where two poles, s<NUM>+/-, are located at: <MAT> The two systems otherwise remain different only by their rise-fall times, that is, τ = <NUM> versus τ = <NUM>.

As a result of the poles <NUM> (which are shown as "Xs" in <FIG>), the τ = <NUM> rise-fall time system stimulates <NUM> oscillations (or ringing) that are approximately three times higher in voltage (<NUM> dB) than the DC steady-state value (main lobe at <NUM> dB). In contrast, the τ = <NUM> rise-fall time system causes oscillations that are approximately <NUM> times less (-<NUM> dB) than the DC steady-state value, or approximately <NUM> times less than the oscillations produced by the τ = <NUM> rise-fall time PFA system. Of note, the oscillatory poles 24B in the slow pulse 66B (τ = <NUM>) are dampened more effectively than the oscillatory poles 24A in the fast pulse 66A (τ = <NUM>). Therefore, by increasing pulse rise-fall time τ to an acceptable level, the ringing that produces embolic material and causes stroke may be reduced or eliminated. Increasing pulse rise-fall time τ in this manner also protects PFA equipment from damage.

A second method of reducing ringing includes of adjusting the pulse width parameter, T, to cause pole(s) <NUM> to occur at area(s) on the trapezoid pulse waveform <NUM> that are at minima between sidelobes, or null(s). In this case, the rise-fall time is left unchanged at τ = <NUM>, but the pulse width T is increased from <NUM> to <NUM>. <FIG> is a graphical comparison of two trapezoidal pulses 68A, 68B in the time domain, with both pulses having the same rise-fall time τ but different pulse widths T. One pulse 68A has a pulse width of T = <NUM> and the other pulse 68B has a pulse width of T = <NUM> µs. <FIG> shows a comparison of two pulse spectrums, each having a rise-fall time of τ = <NUM>, without poles where the spectral sidelobes are purposely misaligned. The first pulse 68A has a pulse width of T = <NUM> µs and the second pulse 68B has a pulse width of T = <NUM>. <FIG> then exploits this property and compares the effect of poles <NUM> located at: <MAT>.

<FIG> reveals that increasing pulse width to <NUM> in pulse 68B, but otherwise leaving the rise-fall time unchanged at τ = <NUM>, reduces the PFA system's <NUM> ringing amplitude substantially by a factor of <NUM> times (-<NUM> dB) compared to using a <NUM> PFA pulse width T, as in pulse 68A. That is, the poles 24A in pulse 68A, which has a smaller pulse width, are approximately six times greater than the poles 24B in pulse 68B, which has a greater pulse width.

Thus, two methods are discussed above for reducing PFA waveform oscillations: adjusting the rise-fall time τ and adjusting the pulse width T. However, a hybrid approach may be used where both the rise-fall time τ and the pulse width T are adjusted to reduce ringing. Adjusting the rise-fall time τ and the pulse width T has the same effect as removing energy from the poles.

As noted above, the H bridge circuit <NUM> may include MOSFETs <NUM> to create the PFA energy (pulses, such as biphasic pulses). However, insulated gate bipolar transistors (IGBTs) may be used in addition to or instead of MOSFETs <NUM> in the H bridge. The rise-fall time τ of high voltage, enhancement mode, MOSFETs or IGBTs in transition from reverse bias to saturation (pulse rising edge) depends primarily on total applied charge and the time rate of change of charge (or current) applied to the gate-emitter junction. To achieve a fully saturated condition, the MOSFET's or IGBT's gate charge requirement increases with increasing emitter-collector current, meaning that if the gate current is limited by a fixed resistance, the device's rise time τr will slow. The effect of this rise time variability is to increase the time in which the electroporation pulse achieves <NUM>% of final amplitude under heavily loaded conditions, such as when gradients between energy delivery electrodes are 1KV/cm or more. Conversely, if energy delivery electrodes <NUM> present a lightly loaded condition, the H bridge circuit's <NUM> collector current is reduced, as is the gate charge requirement. This results in an undesirably fast rise time τr with overshoot and ringing. To compensate for changes in loading such that the rise time τr and/or fall time τf is kept constant, an automatic system of applying fixed, external gate resistances is provided herein. A non-limiting example of a circuit <NUM> for a PFA system is shown in <FIG>.

The H bridge circuit <NUM> may be controlled by the addition of a switch that is operable automatically or semi-automatically to select various discrete values of resistance to add to the H bridge circuit's <NUM> intrinsic input resistance, which then form a first order low-pass pole with the H bridge circuit's <NUM> gate or base input capacitance. A formula for the calculation of a typical high voltage switching MOSFET <NUM> input resistance in the H bridge circuit <NUM> is given as: <MAT> where a charge of <NUM> nC is necessary to bias the MOSFET <NUM> for a collector current of <NUM> amps. For the same representative MOSFET <NUM>, the gate input capacitance is given as <NUM> nF, which for one time constant (<NUM>% of steady state) <MAT> Assuming <NUM> time constants, the resulting <NUM>% - <NUM>% rise time is <NUM> ns, which far exceeds the requirement for a PFA system <NUM>.

The rise-fall time (τ or τr/τf) of the pulses produced by the PFA generator <NUM> is maintained within a range of <NUM> < τr/τf < <NUM>. Within this range, the rise-fall time is slow enough to avoid poles causing undesired oscillations yet is fast enough to minimize the overall pulse width T needed to achieve electroporative effect. For example, the necessary gate current may be applied using, for example, the circuit shown in <FIG>. Given varying therapy load conditions (thus currents) that affect the rise/fall time, a master processor unit (MPU) initially provides a known, gate resistance selection via a digital serial word that is sent across a system of isolation gates terminated by a digitally controlled switch. The switch then selects the corresponding resistance (one for forward, the other for reverse bias) and the PFA generator <NUM> is then prepared for a PFA delivery. Once the first pulse is detected (for example, by the method shown in <FIG>) and evaluated for its rise-fall time, and that duration falls outside the desired <NUM> < τr/τf < <NUM> range, the MPU will send a digital serial word to select a lower-valued resistor pair to decrease, and a higher-valued resistance pair to increase rise time τr and/or fall time τf.

A third method of reducing ringing (for example, the method shown in <FIG>) includes applying a spectral mask <NUM> to a delivered waveform to ensure that the waveform's timing and amplitude characteristics fit the prescribed therapy waveform's dosing prescription. As shown in <FIG>, the spectral mask <NUM> consists of an upper boundary and a lower boundary, which contains a compliance region between the two boundaries. The upper boundary limits the trapezoidal pulse spectral amplitude such that if the width of the pulse is too narrow, and/or the rise/fall time is too short, the FFT results will exceed the upper boundary and the pulse width and/or rise/fall time will be increased to compensate the waveform such that on subsequent sampling the spectral response returns to the compliance region. If the spectral response of the pulse falls below the lower boundary, then the pulse width is too long and/or its rise/fall time is too slow such that either or both are shortened, and the spectral response returns inside the compliance region. An exemplary application of a spectral mask <NUM> applied to a first pulse spectrum 80A with a rise-fall time of τ = <NUM> and to a second pulse spectrum 80B with a rise-fall time of τ = <NUM> is shown in <FIG>. Oscillations and lobes falling outside the spectral mask <NUM> force a correction into the compliance region. Additionally, the application of the spectral mask <NUM> facilitates detection of an anomalous pulse before subsequent pulses are delivered that may cause arcing.

A fourth method of reducing ringing and preventing arcing incorporates the first, second, and/or third methods, and further includes adjusting the PFA generator's waveform control, increasing or decreasing the width of delivered pulses, and/or interlocking and ceasing pulse delivery altogether, to eliminate the arc on a subsequent pulse delivery. For example, delivery of the PFA energy may be terminated automatically, semi-automatically, or manually when a determined voltage of the pole(s) is greater than a threshold voltage.

A fifth method to reduce ringing and prevent arcing incorporates the first, second, third, and/or fourth methods. The synergism of combining these methods can be appreciated by spectral analysis of the therapy generator's trapezoidal waveform. As shown in <FIG>, the trapezoidal spectrum amplitude is constant over the frequency range: <MAT> After the first pole at <MAT>, the spectrum begins to decrease by -<NUM> dB/decade over the range: <MAT> For frequencies higher than the second pole located at <MAT>, the spectrum decreases at a steeper rate of -<NUM> dB/decade. Therefore, to reduce ringing near the main lobe in the spectral mask <NUM>, it will be more effective to lengthen the pulse width T such that <MAT>. For higher frequencies, while lengthening T will reduce ringing, a second order effect of -<NUM> dB/decade of attenuation (rather than just -<NUM> dB/decade) can be realized if the rise fall time, τ, is adjusted such that <MAT>.

<FIG> shows an overall closed-loop method of generating and sampling the therapy waveform, performing a FFT to decimate spectral content into bins, measuring and determining which bins comply with or fall outside of a desired spectral mask, and increasing or decreasing pulse width and/or pulse rise/fall time. This loop process continues to iterate until the spectral mask goals are met by implying that ringing and arcing are eliminated. If pulse width rise/fall adjustments are unable to correct the waveform, a permanent condition may exist that necessitates generating an electronic message or display to the user that recommends a course of action to remedy an arc condition that may exist due to a damaged or improperly manipulated delivery device <NUM>. For example, the control unit <NUM> and/or PFA generator <NUM> may display a visual warning and/or an audible alert to the user recommending the user stop energy delivery because the delivery device <NUM> is compromised. Additionally or alternatively, the control unit <NUM> and/or PFA generator <NUM> may display operating characteristics of the delivery device <NUM> in real time so the user can identify any impending failure. For example, if the control unit <NUM> and/or PFA generator <NUM> determines the delivery device <NUM> is likely to fail, this may be referred to as a fault condition existing in the delivery device <NUM>. A non-limiting example of such a display is shown in <FIG>. In the lower portion of the display, the response is approximately +<NUM> dB above nominal at <NUM>, which indicates small arc oscillations are occurring and the delivery device <NUM> is likely to fail on subsequent energy deliveries. Another non-limiting example of such a display is shown in <FIG>. On the first pulse, a late overshoot or "hump" is shown, which indicates the delivery device <NUM> is likely to fail on subsequent energy deliveries. In some embodiments, when the PFA generator <NUM> detects an overshoot, the amplitude detector <NUM> automatically terminates energy delivery after the pulse having the overshoot so delivery device <NUM> failure (for example, a short caused by excessively high current) will not occur. The waveform <NUM> of the biphasic pulse of <FIG>, with overshoots <NUM>, and subsequent delivery device <NUM> failure occurring on a later pulse delivery is shown in <FIG>. In one example, the PFA generator <NUM> (for example, a charge detector) identifies a biphasic pulse as unbalanced when the integral of current over the first biphasic pulse has a non-zero value, that is, when: <MAT>.

The presence of oscillations in a pulse may also be indicative of misplacement of the energy delivery electrodes <NUM> within the patient's body. For example, <FIG> shows an exemplary display showing a pulse with areas of low current amplitude and excessive energy at <NUM>, which may be caused by overextension of the distal array <NUM> (and at least one of the energy delivery electrodes <NUM>) of the delivery device <NUM> into the pulmonary vein when performing a pulmonary vein isolation procedure. Such positioning may increase load resistance, which causes oscillations. In one embodiment, when this occurrence is detected, the user can specify that the system may undergo closed-loop waveform pulse rise-fall and width adjustment, such as is shown in <FIG>, or the user can elect that the control unit <NUM> and/or PFA generator <NUM> provides an alert to adjust the position of the distal array <NUM> and energy delivery electrodes <NUM>. Additionally, the control unit <NUM> and/or PFA generator <NUM> may receive data from one or more sensors <NUM>, such as temperature sensors associated with or in communication with the energy delivery electrodes <NUM>. Temperature data may be displayed by the control unit <NUM> and/or PFA generator. If temperature sensors record an energy delivery electrode temperature greater than approximately <NUM>, the temperature at which soft thrombus (thermal coagulum formation on the energy delivery electrode(s)) occurs, the control unit <NUM> and/or the PFA generator <NUM> may delay or prevent energy delivery until the temperature of all energy delivery electrodes <NUM> falls below <NUM>.

As discussed above, biphasic pulse asymmetry during PFA energy delivery may lead to unintended muscle stimulation. Several methods are disclosed herein for correcting charge imbalance or asymmetry. In a first embodiment, a method of correcting charge imbalance includes adjusting the pulse width T of the biphasic pulse. Exemplary ideal PFA pulse pairs have the same pulse width since any difference between the pulse pairs leads to an accumulation of charge. Therefore, adjusting the pulse width can correct such an imbalance. For example, the PFA generator <NUM> may include a controller that has processing circuitry configured to reduce the pulse width of the overcharged polarity and/or lengthen the pulse width of the undercharged polarity. In the non-limiting example shown in <FIG>, the negative phase 12B has a slower rise-fall time τ than the positive phase 12A of the pulse <NUM>. To compensate for the resulting charge imbalance, the controller increases the pulse width T by a target amount to effectively balance charge delivery. The pulse width T of the negative phase 12B in <FIG> is increased to <NUM>, or <NUM> ns over the pulse width T of <NUM> shown in <FIG>, resulting in a net charge of zero or approximately zero.

In a second embodiment, the method includes controlling charge buildup by the delivery of lower-voltage "runt" pulses <NUM>. The voltage of these runt pulses <NUM> must be high enough to delivery sufficient balancing energy in a timely manner, yet must be low enough to avoid electroporative effects, both reversible and irreversible. For example, it is important to avoid causing irreversible electroporation with runt pulses so the dosing level of the PFA therapy remains constant. Likewise, although the effects of reversible electroporation are temporary, they may change a patient's electrocardiograms in ways that may mislead the physician. <FIG> shows an exemplary biphasic pulse <NUM> including a runt pulse <NUM> following the negative phase 12B. Inclusion of the runt pulse <NUM> results in a net charge of zero or approximately zero. Implementing runt pulse delivery requires a lower voltage power supply in addition to the high-voltage therapy power supply, and must include a way to switch between the two power supplies while avoiding interference between them. <FIG> shows an exemplary H bridge <NUM> with a high-voltage power source <NUM> for delivering therapy pulses and a lower-voltage power source <NUM> for delivering runt pulses <NUM>, and <FIG> shows a gate voltage applied to each transistor of the H bridge of <FIG>. During therapy, the "Therapy Enable" signal on the gate of Q5 allows it to conduct, providing high voltage from the high-voltage power source <NUM> to the H bridge <NUM> and, ultimately, to the patient. If charge balancing is needed, the "Therapy Enable" signal is de-asserted and the "Runt Enable" signal is asserted instead. This allows the H bridge <NUM> to deliver lower runt voltage to the patient to balance charge as described above.

The PFA generator's <NUM> controller may implement either an open-loop control scheme or a closed-loop control scheme. An open-loop control scheme determines how much influence to exert on the PFA system <NUM> without measuring the amount of charge delivered, whereas a closed-loop control scheme adjusts the PFA generator's <NUM> output based on the actual amount of charge delivered to the patient.

In an open-loop control scheme, the controller simply chooses how much to influence the charge and exerts that much control, such as through adjusting pulse width T or runt pulse delivery. The controller may also prompt and/or require the user to adjust the PFA generator's <NUM> output. Such a system may work best if the source of the charge imbalance is well characterized. For example, the effect of discharging a capacitor bank is well understood, and therefore is relatively easily compensated for by the controller. The charge imbalance resulting from each pulse may be calculated using the equations below, with the necessary runt pulse parameters to equalize the imbalance. Equation <NUM> represents the charge imbalance due to pulse pair number n: <MAT> and Equation <NUM> represents the runt pulse width Trunt needed to balance the charge due to pulse number n: <MAT> where ΔQn is the difference in charge resulting from pulse pair n, C is the capacitance in Farads of the capacitor bank, V<NUM> is the initial therapy voltage, n is the number of the pulse pair requiring the balance, T is the pulse width in seconds of each therapy pulse, R is the combined tissue and delivery device impedance, Trunt is the pulse width in seconds of the runt pulse needed to balance the charge, and Vrunt is the voltage of the runt pulse.

Equations <NUM> and <NUM> depend on the load impedance seen by the PFA system <NUM>, which value may be obtained prior to delivery by use of an impedance meter or during delivery by monitoring therapy current during the first pulse before the capacitor bank has discharged significantly. Alternatively, the PFA system <NUM> (for example, the controller of the PFA generator <NUM>) may simply estimate the impedance based on known values, such as delivery device <NUM> type and energy delivery electrode <NUM> selection.

In a closed-loop control scheme, the controller includes sensors or detectors that monitor the amount of charge delivered and/or an integral of that charge and provide feedback to the H bridge circuit <NUM>. The H bridge circuit <NUM> uses data received by the sensors to dynamically tune the amount of charge compensation provided, either automatically or semi-automatically (for example, at user initiation). An exemplary circuit <NUM> used to provide such feedback is shown in <FIG>. The circuit <NUM> of <FIG> dynamically monitors charge delivered to the patient and sends a digital pulse when the accumulated charge returns to zero after having first risen past a threshold value. The control unit <NUM> and/or PFA generator <NUM> can use this digital pulse as feedback to indicate when the runt pulse or pulse width adjustment has fully balanced the charge. In one embodiment, the circuit <NUM> sends a digital pulse within a predetermined time period before the charge returns to zero to account for delays while the controller reacts to the digital signal.

Claim 1:
A control unit (<NUM>) for modifying pulsed field ablation (PFA) energy delivery, the control unit being configured to:
deliver a PFA pulse from a PFA generator (<NUM>);
measure a rise time and a fall time (τ ) of the PFA pulse;
calculate a voltage of an oscillatory pole (<NUM>) in the PFA pulsed based at least in part on the rise time and the fall time; and
modify at least one of the rise time and the fall time to reduce the voltage of the at least one oscillatory pole in the PFA pulse.