Energy modulated treatment modality for cryoablation

Abstract

A cryoablation ablation system includes a cryoablation apparatus for creating a lesion in target tissue and a console programmed and operable modulate the energy delivered from the catheter to the tissue based on computing real-time energy delivered from the catheter. The cryoablation is continued until the computed real-time energy delivered falls within an empirically-supported pre-computed energy window, at which time the cryoablation is halted.

Description

Attorney Docket No.: ADAG023PCTENERGY MODULATED TREATMENT MODALITY FOR CRYOABLATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This claims priority to provisional application number 63 / 684,384, filed August 18, 2024, and entitled “Energy Modulated Treatment Modality For Cryoablation”, the entirety of which is incorporated herein by reference for all purposes.BACKGROUND

[0002] 1. Field of the Invention

[0003] Embodiments of the invention relate to cryosurgery and more particularly to cryoablation systems and catheters for the treatment of heart disease.

[0004] 2. Description of the Related Art

[0005] Atrial flutter and atrial fibrillation are heart conditions in which the left or right atrium of the heart beat improperly. Atrial flutter is a condition when the atria beat very quickly, but still evenly. Atrial fibrillation (Afib) is a condition when the atria beat very quickly, but unevenly.

[0006] These conditions are often caused by aberrant electrical behavior of some portion of the atrial wall. Certain parts of the atria, or nearby structures such as the pulmonary veins, can misfire in their production or conduction of the electrical signals that control contraction of the heart, creating abnormal electrical signals that prompt the atria to contract between normal contractions caused by the normal cascade of electrical impulses. This can be caused by spots of ischemic tissue, referred to as ectopic foci, or by electrically active fibers in the pulmonary veins, for example.

[0007] Ventricular tachycardia (V-tach or VT) is a type of regular and fast heart rate that arises from improper electrical activity in the ventricles of the heart. In ventricular tachycardia, the abnormal electrical signals in the ventricles cause the heart to beat faster than normal, usually 100 or more beats a minute, out of sync with the upper chambers. When this happens, the heart may not be able to pump enough blood to the body and lungs because the chambers are beating so fast or out of sync with each other that the chambers do not have time to fill properly. Thus, V-tach may result in cardiac arrest and may turn into ventricular fibrillation.

[0008] Atrial fibrillation is one of the more prevalent types of heart conditions. Failing to treat atrial fibrillation can lead to a number of undesirable consequences including heart palpitations, shortness of breath, weakness and generally poor blood flow to the body.

[0009] Various techniques are available to treat atrial fibrillation. One technique to treatAttorney Docket No.: ADAG023PCTAF is pulmonary vein isolation (PVI). PVI is performed by creating lesions circumscribing the pulmonary veins. PVI serves to block the errant or abnormal electrical signals.

[0010] The lesions may be created by ablation. Ablation modalities include radio frequency (RF) ablation and cryoablation.

[0011] RF ablation is performed by applying radio frequency energy to the target tissue. RF ablation typically is performed by creating a number of focused spots over an area to form the lesion. Although the spots can be overlapped, RF ablation relies on a substantial amount of skill by the physician to form a complete continuous ring-shaped lesion without ablating non-target tissue.

[0012] Cryoablation is another methodology to create a lesion to carry out a PVI procedure. However, and regardless of whether the cryoablation is performed using a balloon or a shaped linear treatment implement, challenges arise relating to the amount of energy to apply to achieve optimal clinical efficacy without risking safety. Use of a cryoballoon has the additional disadvantage of blocking blood flow during the procedure.

[0013] Accordingly, a system and method that overcomes the above mentioned challenges is desirable.SUMMARY

[0014] A cryoablation system for creating a lesion in target tissue comprises a catheter and a cryoablation console.

[0015] In embodiments, the catheter comprises: a freezing portion; at least one cryogen delivery lumen; and at least one cryogen return lumen.

[0016] In embodiments, the cryoablation console is programmed and operable to: provide a predetermined value of a desired total energy (Qmin), wherein Qmin is determined based on an empirical dataset of multiple cryoablations of tissue; circulate a cryogen through the freezing portion using the at least one cryogen delivery lumen and return lumen; continuously compute real-time energy delivered (Qreal) based on elapsed time, temperature and pressure data generated from sensors in the flow path of the cryogen; and continue circulating the cryogen and delivery of energy at least until Qreal exceeds Qmin.

[0017] In embodiments, Qmin is determined according to statistical trend for which recorded total energy level in the empirical dataset achieved a target return fluid temperature of -160 C or lower in a majority of the cryoablations, and optionally, achieved a temperature variance of less than 1%, and in some embodiments, is at least 6 kJ.

[0018] In embodiments, the console is further operable to halt the ablation when theAttorney Docket No.: ADAG023PCT elapsed time exceeds a maximum time (Tmax), and optionally, wherein the Tmax ranges from 30-60 seconds, and, more preferably, ranges from 40-50 seconds.

[0019] In embodiments, the console is further operable to halt the circulation of the cryogen and delivery of energy when Qreal exceeds a pre-determined threshold maximum total energy delivered (Qmax), and in some embodiments, wherein the Qmax ranges from 7- 10 kJ and preferably is between 7-8 kJ.

[0020] In embodiments, the catheter further comprises a plurality of electrodes on an exterior surface of the freezing portion.

[0021] In embodiments, the system further comprising a tissue contact module operable to measure tissue contact information based on information detected by the plurality of electrodes.

[0022] In embodiments, the system further comprising a pulsed field ablation generator operably coupled to the plurality of electrodes to create a pulsed field of electricity to induce cell death in the target tissue.

[0023] In embodiments, the computed real-time total energy delivered is based on computing the enthalpy at the inlet and exit of the catheter, and computing power based on the computed enthalpy, and integrating power over the time elapsed.

[0024] In embodiments, Qmin is pre-determined based on clinical efficacy for PVI ablations.

[0025] In embodiments, the console is operable to allow a user to adjust the Qmin.

[0026] In embodiments, a cryoablation method for creating at least one lesion in a patient comprises: determining a value of a desired total energy (Qmin), wherein Qmin is determined based on an empirical dataset of multiple cryoablations of tissue; circulating a cryogen through the catheter; monitoring temperature and pressure along the flowpath to cause tissue ablation; continuously computing real-time total energy delivered from the catheter (Qreal); and continue circulating the cryogen and delivery of energy at least until Qreal exceeds Qmin.

[0027] In embodiments, the computing step comprises: computing the enthalpy at the flow inlet and flow exit of the catheter, and computing power based on the computed enthalpy, and integrating power over the time elapsed.

[0028] In embodiments, the empirical dataset comprises clinical or preclinical data of multiple ablations.

[0029] In embodiments, the empirical dataset comprises clinical data of PVI ablations.

[0030] In embodiments, Qmin is determined according to statistical trend for which recorded total energy level in the empirical dataset achieved a target return fluid temperatureAttorney Docket No.: ADAG023PCT of -160 C or lower in a majority of the cryoablations, and optionally, achieved a temperature variance of less than 1%, and in some embodiments, is at least 6 kJ.

[0031] In embodiments, the method further comprises performing halting when Qreal exceeds a pre-determined threshold maximum total energy delivered (Qmax), and optionally, wherein the Qmax ranges from 7-10 kJ and preferably is between 7-8 kJ.

[0032] In embodiments, the method further comprises performing halting when the elapsed time exceeds a maximum time (Tmax), and optionally, wherein the Tmax ranges from 30-60 seconds and, more preferably, from 40-50 seconds.

[0033] In embodiments, the method further comprises measuring tissue contact information based on information detected by a plurality of electrodes arranged on the cryoablation apparatus.

[0034] In embodiments, the method further comprises creating a pulsed field of electricity by a plurality of electrodes arranged on the cryoablation apparatus to induce cell death in the target tissue.

[0035] In embodiments, the method comprises adjusting or modifying the Qmin.

[0036] In embodiments, a method for modulating total energy delivered for cryoablation comprises one or more of the steps described herein.

[0037] In embodiments, a system operable to modulate total energy delivered for cryoablation comprises one or more of the components as described herein.

[0038] In embodiments, the cryogen is nitrogen.

[0039] The description, objects and advantages of embodiments of the present invention will become apparent from the detailed description to follow, together with the accompanying drawings.Brief Description of the Drawings

[0040] The above-mentioned aspects, as well as other features, aspects and advantages of the present technology will now be described in connection with various embodiments, with reference to the accompanying drawings. The illustrated embodiments, however, are merely examples and are not intended to be limiting. Throughout the drawings, similar symbols typically identify similar components, unless context dictates otherwise. Note that the relative dimensions of the following figures may not be drawn to scale.

[0041] FIG. 1 is an illustration of a cryoablation catheter system including a catheter, cryoablation console, pulsed field ablation console, and EP Console according to an embodiment of the invention;Attorney Docket No.: ADAG023PCT

[0042] FIG. 2 is a block diagram of the system shown in FIG. 1;

[0043] FIG. 3 is an enlarged side view of the distal section of the catheter shown in FIG.1;

[0044] FIG. 4 is an enlarged cross sectional view of the catheter shown in FIG. 3 taken along line 4-4;

[0045] FIG. 5 depicts sample shapes for the stylet advanceable through the catheter shown in FIGS. 3-4, according to embodiments of the invention;

[0046] FIG. 6 is a schematic illustration of a cryogenic cooling system, according to embodiments of the invention;

[0047] FIG. 7 is a cryogen phase diagram corresponding to the system shown in FIG. 6 where the cryogen is N2, according to embodiments of the invention;

[0048] FIG. 8 is a flow diagram of a method for modulating total energy delivered during cryoablation, according to embodiments of the invention;

[0049] FIG. 9 is a flow diagram of a method for cryoablation including evaluating tissue contact and efficacy of ablation, according to embodiments of the invention;

[0050] FIG. 10 is an illustration of a heart 1, including the right atrium 2, the left atrium 3, the right ventricle 4, the left ventricle 5, the aorta 6 (accessed through the femoral artery), the superior vena cava 6a (accessed through the subclavian veins) and the inferior vena cava 6b (accessed through the femoral vein), and locations of various lesions 8, 9 according to an embodiment of the invention;

[0051] FIG. 11 is an illustration of an embodiment of endovascular catheterization to access the heart;

[0052] FIGS. 12-13 are illustrations of a procedure to place a distal section of a cryoablation catheter against the endocardial wall in the left atrium, circumscribing the left superior and inferior pulmonary vein entries, according to an embodiment of the invention;

[0053] FIG. 14 is an aggregated data histogram displaying distribution of the energy levels;

[0054] FIG. 15 is a histogram showing the energy distribution (vertical bars) and the cumulative integral percentage (solid line with square symbols) for a pre-clinical study where the dark vertical bold line indicates the mean value of 8.5 kJ;

[0055] FIGS. 16-17 show, respectively, a distribution of the outlet temperature of the cryogen at the end of a 30-second freeze cycle as a function of delivered energy, and the corresponding values of calculated temperature variance. Energy levels below 6.1 kJ result in temperatures significantly higher than the desired -160°C, indicating reduced therapeuticAttorney Docket No.: ADAG023PCT effectiveness;

[0056] FIGS. 18-19 show, respectively, the coefficient of determination (R2) for all clinical freezes demonstrates a high degree of linearity for t > 15s, and 15 < t < 20s;

[0057] FIGS. 20A-20B show, respectively, histograms depicting energy values for the predicted dataset and actual dataset;

[0058] FIG. 21 shows predicted percentage of the clinical freezes made with a tested cryoablation system that will result in clinically inferior ablation with Q < Qmin = 6.1kJ as a function of the ablation duration; and

[0059] FIG. 22 shows predicted percentage of ablations that will achieve the preset energy level Qmax before the previously established value of the ablation timeout 45s.DETAILED DESCRIPTION

[0060] It is to be understood that the embodiments of the invention described herein are not limited to particular variations set forth herein as various changes or modifications may be made to the embodiments of the invention described and equivalents may be substituted without departing from the spirit and scope of the embodiments of the invention. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the embodiments of the present invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process act(s) or step(s) to the objective(s), spirit or scope of the embodiments of the present invention. All such modifications are intended to be within the scope of the claims made herein.

[0061] Moreover, while methods may be depicted in the drawings or described in the specification in a particular order, such methods need not be performed in the particular order shown or in sequential order, and that all methods need not be performed, to achieve desirable results. Other methods that are not depicted or described can be incorporated in the example methods and processes. For example, one or more additional methods can be performed before, after, simultaneously, or between any of the described methods. Further, the methods may be rearranged or reordered in other implementations. Also, the separation of various system components in the implementations described above should not be understood as requiring such separation in all implementations, and it should be understood that the described components and systems can generally be integrated together in a single product orAttorney Docket No.: ADAG023PCT packaged into multiple products. Additionally, other implementations are within the scope of this disclosure.

[0062] Conditional language, such as “can,” “could,” “might,” or “may,” unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain embodiments include or do not include, certain features, elements, and / or steps. Thus, such conditional language is not generally intended to imply that features, elements, and / or steps are in any way required for one or more embodiments.

[0063] Conjunctive language such as the phrase “at least one of X, Y, and Z,” unless specifically stated otherwise, is otherwise understood with the context as used in general to convey that an item, term, etc. may be either X, Y, or Z. Thus, such conjunctive language is not generally intended to imply that certain embodiments require the presence of at least one of X, at least one of Y, and at least one of Z.

[0064] Reference to a singular item, includes the possibility that there are plural of the same items present. More specifically, as used herein and in the appended claims, the singular forms “a,” “an,” “said” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0065] It will be understood that when an element is referred to as being “connected” or “coupled” to another element, it can be directly connected or coupled to the other element or intervening elements may be present. In contrast, if an element is referred to as being "directly connected" or "directly coupled" to another element, there are no intervening elements present.

[0066] It will also be understood that, although the terms first, second, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. Thus, a first element could be termed a second element without departing from the teachings of the present invention.

[0067] Language of degree used herein, such as the terms “approximately,” “about,” “generally,” and “substantially,” represent a value, amount, or characteristic close to the stated value, amount, or characteristic that still performs a desired function or achieves a desired result. For example, the terms “approximately,” “about,” “generally,” and “substantially” may refer to an amount that is within less than or equal to 10% of, within lessAttorney Docket No.: ADAG023PCT than or equal to 5% of, within less than or equal to 1% of, within less than or equal to 0.1% of, and within less than or equal to 0.01% of the stated amount. If the stated amount is 0 (e.g., none, having no), the above recited ranges can be specific ranges, and not within a particular % of the value. Additionally, numeric ranges are inclusive of the numbers defining the range, and any individual value provided herein can serve as an endpoint for a range that includes other individual values provided herein. For example, a set of values such as 1, 2, 3, 8, 9, and 10 is also a disclosure of a range of numbers from 1-10, from 1-8, from 3-9, and so forth.

[0068] Some embodiments have been described in connection with the accompanying drawings. The figures are drawn to scale, but such scale should not be limiting, since dimensions and proportions other than what are shown are contemplated and are within the scope of the disclosed inventions. Distances, angles, etc. are merely illustrative and do not necessarily bear an exact relationship to actual dimensions and layout of the devices illustrated. Components can be added, removed, and / or rearranged. Further, the disclosure herein of any particular feature, aspect, method, property, characteristic, quality, attribute, element, or the like in connection with various embodiments can be used in all other embodiments set forth herein. Additionally, it will be recognized that any methods described herein may be practiced using any device suitable for performing the recited steps.

[0069] While a number of embodiments and variations thereof have been described in detail, other modifications and methods of using the same will be apparent to those of skill in the art. Accordingly, it should be understood that various applications, modifications, materials, and substitutions can be made of equivalents without departing from the unique and inventive disclosure herein or the scope of the claims.

[0070] All existing subject matter mentioned herein (e.g., publications, patents, patent applications and hardware) is incorporated by reference herein in its entirety except insofar as the subject matter may conflict with that of the present invention (in which case what is present herein shall prevail).

[0071] CRYOABLATION SYSTEM

[0072] FIG. 1 illustrates an ablation system 4000 in accordance with an embodiment of the invention. The system shown in FIG. 1 includes a cryoablation catheter 4008, a cryoablation console 4020, and optionally, a pulsed field ablation console 4030 and an EP console 4040.

[0073] The catheter 4008 is shown having a handle 4010, a distal treatment section 4012, an elongate flexible umbilical cord 4024 and cryo-connector 4022 which may be plugged into the cryoablation console 4020 where indicated in FIG. 1.Attorney Docket No.: ADAG023PCT

[0074] The catheter 4008 also includes a stylet receptable 4016 and stylet 4018 advanceable into the stylet receptacle for causing the distal section 4012 to assume a predetermined shape as described herein. In the catheter shown in FIG. 1, the stylet 4018 is straight and the distal section 4012 is likewise straight.

[0075] Optionally, as shown in FIG. 1, the catheter 4008 can include a negative connector 4034 and positive connector 4036. The negative and positive connectors are electrically coupled by wires to a plurality of electrodes located in the distal section 4012 of the catheter, described further herein. An elongate flexible adapter cord 4032 is provided to join the negative and positive connectors of the catheter to the inputs 4028 of PFA console 4030. The PFA console may thus activate the electrodes on the catheter as described further herein. PFA may be performed to apply a pulsed electric field to the tissue to ablate the tissue as described in US Patent Publication No. 20220071681, filed September 29, 2021, entitled “ MULTIMODALITY ABLATION CATHETER HAVING A SHAPE MEMORY STYLET”, and incorporated herein by reference in its entirety for all purposes.

[0076] Optionally, the EP console 4040 and / or patient monitoring console 4042 are coupled to the PFA console through receptables 4046, 4048 respectively.

[0077] In the embodiment shown in FIG. 1 , the catheter negative and positive connectors 4034, 4036 are also compatible with the EP console 4040 such that the EP console may be directly connected to the catheter instead of connected to the PFA console as described above. The system is thus capable to perform cryoablation only, and entirely bypass the PFA console.

[0078] Although not shown in FIG. 1 , embodiments of the invention include one or more thermocouple connectors extending proximally from the handle. The thermocouple connectors are electrically connected to wires extending through the catheter and for detecting temperature, described herein.

[0079] FIG. 2 is a block diagram of the cryoablation system shown in FIG. 1. The cryoablation console 4020 may include or house a variety of components (not shown) such as, for example, a computer, display, generator, controller, tank, valve, pump, sensors, etc. The display 980 is shown in FIG. 1 positioned on top of cart for convenient user operation. Computer may include a controller, timer, or communicate with an external controller to drive components of the cryoablation systems such as a pump, valve or generator. Input devices such as a mouse and a keyboard may be provided to allow the user to input data and control the cryoablation devices.

[0080] In embodiments, the computer is configured or programmed to control cryogenAttorney Docket No.: ADAG023PCT flowrate, pressure, temperatures, and cryoenergy modulation as described herein. Target values and real time measurement may be sent to, and shown, on the display.

[0081] FIG. 3 shows an enlarged side view of the distal section 4012 of the catheter 4008. Although not required in all embodiments of the invention, the embodiment shown in FIG. 3 includes a plurality of ring-shaped electrode pairs (e.g., 4052a, b, 4054a, b, etc.). When present, the electrodes may be used for evaluating tissue contact, efficacy of the ablation, or pulsed field ablation.

[0082] Seven (7) pairs are shown in FIG. 3, however, the number of electrode pairs may vary and in embodiments may range from 2-50 pairs, and more preferably from 5-15 pairs, and in one preferred embodiment about 10 pairs. The electrode pairs are shown separated by a space (S) which may vary. In embodiments the space (S) ranges from 5-10 mm and more preferably about 7-9 mm, and in one embodiment, is about 8 m. Additionally, each electrode may have a width ranging from 0.5 to 2 mm, and thickness of 0.03 to 0.08 mm.

[0083] When implemented for pulsed field ablation, in embodiments, each electrode pair (e.g., 4052, 4054) is activated with alternating positive (+) and ground (-) electric potential in a sequential pattern as illustrated in FIG. 3.

[0084] Optionally, one or more irrigation ports 4062 are located along the distal section of the catheter. The irrigation port(s) may be located between the pairs of electrodes 4052, 4054 as shown, or located between the two electrodes (4052a, 4052b) forming the pair (not shown). Additionally, for a given axial location along the shaft, several irrigation ports may be distributed around the circumference of the outer jacket (e.g., at the 12, 3, 6, and 9 o’clock positions). Consequently, liquid may be emitted from the catheter radially in multiple directions to irrigate or cool the catheter when the electrodes are activated during a pulsed field ablation procedure. A slow drip is generally suitable for the procedures described herein.

[0085] FIG. 4 shows a cross section of the catheter 4008 shown in FIG. 3 taken along line 4-4. As can be seen in the cross-sectional view, the ablation shaft / sleeve 5030 includes a plurality of cryogen delivery tubes / lumens 5040 for transporting the cryogen to the flexible distal ablation portion 4012 and a plurality of cryogen return tubes / lumens 5042 for transporting the cryogen away from the flexible distal ablation portion.

[0086] Optionally, each of the tubes 5040, 5042 can have a tube-in-tube construction (i.e., multilayer) for containing leaks of the cryogen in which a thin gap between the inner and outer layers is filled with a thermally conducting liquid such as water. Examples of such multilayer delivery and return tubes is described in U.S. Patent No. 10,667,854, filed FebruaryAttorney Docket No.: ADAG023PCT29, 2016, and entitled “ ENDOVASCULAR NEAR CRITICAL FLUID BASED CRYOABLATION CATHETER AND RELATED METHODS”, the entirety of which is incorporated herein by reference for all purposes.

[0087] Also shown are a plurality of service tubes / lumens 5022, 5024, 5026 and a water line 4014. The service tubes may include catheter control wires for articulating the catheter, electrode wires, or any other elements that may be desired and fit within the service lumens. The water line 4014 may be used to irrigate the site or be used to flush the system. The plurality of multilayer cryogen delivery tubes / lumens 5040, the plurality of multilayer cryogen return tubes / lumens 5042, the water line, and the plurality of service tubes / lumens are arranged in a circular array around a hollow tube / lumen 5060 that is adapted to receive the stylet (not shown) therein. The hollow tube / lumen 5060 extends along the length of the ablation shaft / sleeve from the handle 4010 to at least the flexible distal ablation portion 4012.

[0088] While FIG. 4 depicts four (4) multilayer cryogen delivery tubes, four (4) multilayer cryogen return tubes and three (3) service tubes / lumens, the embodiments of the invention are not intended to be so limited and may include any number of multilayer cryogen delivery tubes, multilayer cryogen return tubes and service tubes / lumens depending on the desired ablating power of the catheter or the condition that the catheter will be used to treat. In some embodiments, cooling is provided by only one cryogen delivery tube and only one cryogen return tube extending through the catheter. Additionally, while FIG. 4 depicts a certain configuration of the multilayer cryogen delivery tubes, the multilayer cryogen return tubes and the service tubes / lumens, specifically that pairs of multilayer cryogen delivery tubes and multilayer cryogen return tubes are located adjacent to one another and separated with a service tubes / lumens, the embodiments of the invention are not intended to be so limited and may include any number of different configurations for the multilayer cryogen delivery tubes, the multilayer cryogen return tubes and the service channels / tubes.

[0089] In embodiments the service lumens 5022, 5024, 5026 carry multiple electrode wires to provide the positive and negative polarity of the electrode pairs described in FIG. 3. Wires may also be used to measure pressure and temperature or can be dedicated ECG electrodes for mapping and evaluating electrical signals arising from the tissue.

[0090] FIG. 4 also shows an outer jacket or cover 5030 that serves to provide thermal conductivity, prohibit electrical conductivity, prohibit expansion, and generally maintain the arrangement of the inner components. Exemplary materials for the cover include materials having a low coefficient of thermal expansion and high thermal conductivity such as thermoplastic elastomers (TPE) or thermoplastic urethanes (TPU). An example of a TPE isAttorney Docket No.: ADAG023PCT poly ether block amide (PEBA), which is also known under the tradename PEBAX® manufactured by Arkema (France). An example of a TPU is PELLETHANE® manufactured by Lubrizol (Wickliffe, Ohio).

[0091] In the embodiment shown in FIG. 4, the service lumens 4022, 4024, 4026, water line 4014, and cryoenergy elements 5040, 5042 are circumferentially arranged in an annular space formed by cover 5030 and inner tube 5052. Preferably, as described herein, the water line 4014 communicates water into space 5010 to provide thermal conductivity as well as prohibit air bubbles from forming. Alternatively, space 5010 may be filled with a thermally conductive media, fill or conductive liner. Examples of thermally conductive liners are described in US Patent Application No. 16 / 958,589, filed June 26, 2020, entitled “CRYO ABLATION ELEMENT WITH CONDUCTIVE LINER’’ incorporated herein by reference in its entirety.

[0092] In embodiments, a solid thermally conductive liner surrounds the individual tubes. In some embodiments where the solid thermally conductive liner at least partially surrounds the exterior or outward facing side of the individual tubes (i.e., the side opposite the stylet tube 5060, discussed herein, a cover is not required and is omitted from the design.

[0093] The catheter shown in FIG. 4 also includes stylet lumen 5060. In embodiments, stylet lumen 5060 is defined by a polymer reinforced flexible member 5054 such as a metal braid having a nylon inner coating 5056 and a nylon exterior coating 5052

[0094] Although the catheter is sized to be advanced through an endovascular delivery catheter, its outer diameter may vary to some degree. In embodiments, the outer diameter of the catheter ranges from 2 to 5 mm.

[0095] EXAMPLES OF STYLETS

[0096] Depicted in FIG. 5 are sample shapes that can be pre-set into the distal portion 898 of the stylet 882. In some embodiments, the length of the distal portion 898 corresponds to at least a portion of the length of the flexible distal ablation portion 4012 of the ablation catheter 4008. Thus, when the stylet 882 is in place in the hollow tube / lumen 5060 of the ablation catheter 4008 and the flexible distal ablation portion 4012 is positioned at the ablation site within the patient, the distal portion 898 of the stylet 882 transforms into its pre-set shape causing the flexible distal ablation portion 4012 to transform to a corresponding shape for creating a ring-shaped lesion as depicted, for example, in FIG 13 described herein as described in, e.g., US Patent Publication No. 20190076179, entitled “ABLATION CATHETER HAVING A SHAPE MEMORY STYLET” and incorporated herein by reference in its entirety for all purposes.Attorney Docket No.: ADAG023PCT

[0097] SCHEMATIC DIAGRAM

[0098] FIG. 6 provides a schematic illustration of a structural arrangement for a cryogenic system according to one embodiment, and FIG. 7 provides a phase diagram that illustrates a thermodynamic path taken by the cryogen when the system of FIG. 6 is operated. The circled numerical identifiers in the two figures correspond so that a physical position is indicated in FIG. 6 where operating points identified along the thermodynamic path are achieved. The following description thus sometimes makes simultaneous reference to both the structural drawing of FIG. 6 and to the phase diagram of FIG. 7 in describing physical and thermodynamic aspects of the cooling flow.

[0099] For purposes of illustration, both FIGS. 6 and 7 make specific reference to a nitrogen cryogen, but this is not intended to be limiting. Embodiments of the invention may more generally be used with any suitable cryogen such as, for example, argon, neon, helium, hydrogen, and oxygen.

[0100] In FIG. 7, the liquid-gas phase line is identified with reference label 256 and the thermodynamic path followed by the cryogen is identified with reference label 258.

[0101] A cryogenic generator 246 is used to supply the cryogen at a pressure that exceeds the critical-point pressure Pc for the cryogen at its outlet, referenced in FIGS. 6 and 7 by label CD. The cooling cycle may generally begin at any point in the phase diagram having a pressure above or slightly below Pc, although it is advantageous for the pressure to be near the critical-point pressure Pc. The cooling efficiency of the process described herein is generally greater when the initial pressure is near the critical-point pressure Pc so that at higher pressures there may be increased energy requirements to achieve the desired flow. Thus, embodiments may sometimes incorporate various higher upper boundary pressure but generally begin near the critical point, such as between 0.8 and 1.2 times Pc, and in one embodiment at about 0.85 times Pc.

[0102] As used herein, the term “near critical” is meant to refer to near the liquid- vapor critical point. Use of this term is equivalent to “near a critical point” and it is the region where the liquid-vapor system is adequately close to the critical point, where the dynamic viscosity of the fluid is close to that of a normal gas and much less than that of the liquid; yet, at the same time its density is close to that of a normal liquid state. The thermal capacity of the near critical fluid is even greater than that of its liquid phase. The combination of gas-like viscosity, liquid-like density and very large thermal capacity makes it a very efficient cooling agent. Reference to a near critical point refers to the region where the liquid-vapor system is adequately close to the critical point so that the fluctuations of the liquid and vapor phases areAttorney Docket No.: ADAG023PCT large enough to create a large enhancement of the heat capacity over its background value. The near critical temperature is a temperature within ±10% of the critical point temperature. The near critical pressure is between 0.8 and 1.2 times the critical point pressure.

[0103] Referring again to FIG. 6, the cryogen is flowed through a tube, at least part of which is surrounded by a reservoir 240 of the cryogen in a liquid state, reducing its temperature without substantially changing its pressure. In FIG. 6, reservoir is shown as liquid N2, with a heat exchanger 242 provided within the reservoir 240 to extract heat from the flowing cryogen. Outside the reservoir 240, thermal insulation may be provided around the tube to prevent unwanted warming of the cryogen as it is flowed from the cryogen generator 246. At point ®, after being cooled by being brought into thermal contact with the liquid cryogen, the cryogen has a lower temperature but is at substantially the initial pressure. In some instances, there may be a pressure change, as is indicated in FIG. 7 in the form of a slight pressure decrease, provided that the pressure does not drop substantially below the critical-point pressure Pc, i.e. does not drop below the determined minimum pressure. In the example shown in FIG. 7, the temperature drop as a result of flowing through the liquid cryogen is about 50° C.

[0104] The cryogen is then provided to a device for use in cryogenic applications. In the exemplary embodiment shown in FIG. 6, the cryogen is provided to an inlet 236 of a catheter 224, such as may be used in medical cryogenic endovascular applications, but this is not a requirement.

[0105] Indeed, the form of the medical device may vary widely and include without limitation: instruments, appliances, catheters, devices, tools, apparatus’, and probes regardless of whether such probe is short and rigid, or long and flexible, and regardless of whether it is intended for open, minimal, non- invasive, manual or robotic surgeries.

[0106] In embodiments, the cryogen may be introduced through a proximal portion of a catheter, continue along a flexible intermediate section of the catheter, and into the distal treatment section of the catheter. As the cryogen is transported through the catheter, and across the cryoablation treatment region 228, between labels ® and ® in FIGS. 6 and 7, there may be a slight change in pressure and / or temperature of the cryogen as it moves through the interface with the device, e.g. cryoablation region 228 in FIG. 6. Such changes may typically show a slight increase in temperature and a slight decrease in pressure. Provided the cryogen pressure remains above the determined minimum pressure (and associated conditions), slight increases in temperature do not significantly affect performance because the cryogen simply moves back towards the critical point without encountering the liquid-gas phase line 256,Attorney Docket No.: ADAG023PCT thereby avoiding vapor lock.

[0107] In embodiments, sensors are incorporated in cryoablation region 228, the inlet 236, and the outlet 237 for measuring various properties such as, e.g., temperature and pressure.

[0108] Flow of the cryogen from the cryogen generator 246 through the catheter 224 or other device may be controlled in the illustrated embodiment with an assembly that includes a check valve 216, a flow impedance, and / or a flow controller. The catheter 224 itself may comprise a vacuum insulation 232 (e.g., a cover or jacket) along its length and may have a cold cryoablation region 228 that is used for the cryogenic applications. Unlike a Joule- Thomson probe, where the pressure of the working cryogen changes significantly at the probe tip, these embodiments of the invention provide relatively little change in pressure throughout the apparatus. Thus, at point ®, the temperature of the cryogen has increased approximately to ambient temperature, but the pressure remains elevated. By maintaining the pressure above or near the critical-point pressure Pc as the cryogen is transported through the catheter, vapor lock are avoided.

[0109] The cryogen pressure returns to ambient pressure at point ®. The cryogen may then be vented through vent 204 at substantially ambient conditions.

[0110] Examples of cryoablation systems, their components, and various arrangements are described in the following commonly-assigned U.S. patents and U.S. patent applications: U.S. Patent Application No. 10 / 757,768, which issued as U.S. Patent No. 7,410,484, on Aug. 12, 2008 entitled “CRYOTHERAPY PROBE,” filed January 14, 2004 by Peter J. Littrup et al.; U.S. Patent Application No. 10 / 757,769, which issued as U.S. Patent No. 7,083,612 on August 1, 2006, entitled “CRYOTHERAPY SYSTEM,” filed January 14, 2004 by Peter J. Littrup et al.; U.S. Patent Application No. 10 / 952,531, which issued as U.S. Patent No. 7,273,479 on September 25, 2007 entitled “METHODS AND SYSTEMS FOR CRYOGENIC COOLING,” filed September 27, 2004 by Peter J. Littrup et al.; U.S. Patent Application No. 11 / 447,356, which issued as U.S. Patent No. 7,507,233 on March 24, 2009 entitled “CRYOTHERAPY SYSTEM,” filed June 6, 2006 by Peter Littrup et al.; U.S. Patent Application No. 11 / 846,226, which issued as U.S. Patent No. 7,921,657 on April 12, 2011 entitled “METHODS AND SYSTEMS FOR CRYOGENIC COOLING,” filed August 28, 2007 by Peter Littrup et al.; U.S. Patent Application No. 12 / 018,403, which issued as U.S. Patent No. 8,591,503 on November 26, 2013 entitled “CRYOTHERAPY PROBE,” filed January 23, 2008 by Peter Littrup et al.; U.S. Patent Application No. 13 / 046,274, which issued as U.S. Patent No. 8,387,402 on March 5, 2013 entitled “METHODS AND SYSTEMS FOR CRYOGENIC COOLING,” filed March 11, 2011 by Peter Littrup et al.; U.S. PatentAttorney Docket No.: ADAG023PCTApplication No. 14 / 087,947, which is pending entitled “CRYOTHERAPY PROBE,” filed November 22, 2013 by Peter Littrup el al.; U.S. Patent Application No. 12 / 744,001, which issued as U.S. Patent No. 8,740,891, on Jun. 3, 2014 entitled “FLEXIBLE MULTITUBULAR CRYOPROBE,” fded July 29, 2010 by Alexei Babkin et al.; U.S. Patent Application No. 12 / 744,033, which issued as U.S. Patent No. 8,740,892, on Jun. 3, 2014 entitled “EXPANDABLE MULTI-TUBULAR CRYOPROBE,” filed July 29, 2010 by Alexei Babkin et al. and U.S. Patent Application No. 14 / 915, 632, which issued as U.S. Patent No. 10,667,854, on June 2, 2020, entitled “ENDOVASCULAR NEAR CRITICAL FLUID BASED CRYOABLATION CATHETER AND RELATED METHODS,” filed Sept. 22, 2014 by Alexei Babkin, et al., the contents of each of the above-identified U.S. patents / applications are incorporated herein by reference in their entireties for all purposes.

[0111] MODULATING TOTAL ENERGY DELIVERED FOR CRYOABLATION

[0112] FIG. 8 is a flow chart illustrating a method 100 for modulating total energy delivered for cryoablation, according to embodiments of the invention.

[0113] Step 110 states to provide cryoablation energy model for computing total energy delivered by a cryoablation apparatus circulating a coolant therethrough.

[0114] For embodiments, a cryoablation energy model is derived from the nitrogen equation of state as discussed in, e.g., Span et al. ,"A Reference Equation of State for the Thermodynamic Properties of Nitrogen for Temperatures from 63.151 to 1000 K and Pressures to 2200 MPa," J. Phys. Chem. Ref. Data, 29(6): 1361- 1433, 2000, which is herein incorporated by reference in its entirety for all purposes. The corresponding values of cryogen enthalpy at the catheter inlet and outlet are then calculated. These values of enthalpy are then used to calculate the instantaneous power of the freezing cycle at any given point in time t during the freeze cycle:

[0115] VT(t) = [HIN(TIN(t), PIN (P)') — H ouriTouT (t),PouT(ty)]xPMASS (0

[0116] where:

[0117] TIN - Temperature of the cryogen at the catheter inlet.

[0118] TOUT - Temperature of the cryogen at the catheter outlet.

[0119] PIN - Cryogen pressure at the inlet.

[0120] POUT - Cryogen pressure at the outlet.

[0121] FMASS - Mass flow rate of the cryogen.

[0122] The aggregated value of energy (QIABL) is obtained by integrating this value of power over the elapsed time of the ablation IABI.:

[0123] Q(tABL) = fotABLW(t) dtAttorney Docket No.: ADAG023PCT

[0124] In embodiments, the above listed equation is provided as the cryoablation energy model.

[0125] Step 120 states to apply the cryoablation energy model to compute total energy delivered based on at least one historical empirical data set. This step is performed by obtaining a set of empirical data corresponding to multiple cryoablations of tissue, and preferably human cardiac tissue. For each cryoablation, the total energy delivered is computed using the model from step 110, and the duration of the freeze is recorded. Following the treatment, the physician evaluates the clinical efficacy of the treatment by performing, e.g., an electrogram analysis to detect changes from baseline heart health. For example, an amplitude reduction or complete signal disappearance in pulmonary vein potentials is indicative of success of the procedure. Frequency analysis and voltage maps can also be applied to evaluate the clinical efficacy of the treatment. This raw data (e.g., the measured amplitudes, frequencies, and voltages associated with the pulmonary veins to be isolated) is recorded. Additionally, the physician may make qualitative annotations about the treatment such as, e.g., whether there was any collateral damage or other adverse events. Preferably the assessment is performed immediately after the procedure (acute) as well as at 3, 6, and 1 months out from the procedure.

[0126] In embodiments, empirical data is generated by treating human patients in PVI procedures. In other embodiments, the empirical data is generated in animal studies including testing on dogs and pigs, by e.g. ablating the vena cava or pulmonary vessel orifices.

[0127] Step 130 states to evaluate the computed total energy delivered and the clinical effectiveness to determine a Qmin, Qmax, and Tmax; where Qmin is the minimum energy level below which the effectiveness of the treatment may be compromised; Qmax is the optimal energy level that maximizes therapeutic efficacy while maintaining safety; and Tmax is the longest allowable duration for a cryoablation cycle to ensure safety and effectiveness without unnecessarily prolonging the procedure. Each of these parameters are determined based on the empirical data from step 120.

[0128] In embodiments, Qmin is selected based on selecting a value that resulted in the catheter return lumen temperature achieving a target temperature within a pre-set maximum time duration, and a desired clinical efficacy immediately following the procedure. For example, in embodiments, Qmin is selected based on selecting a value that resulted in the catheter return lumen temperature achieving a target cooling temperature of -160 C or lower within 30 seconds, having less than 1% temperature variance, and a desired clinical efficacy immediately following the procedure (i.e., acute) and more preferably, at a follow up dateAttorney Docket No.: ADAG023PCT(e.g., 6 months). In embodiments directed to use of the catheter described above, and for the treatment of PVI, Qmin is established at about 6 kJ.

[0129] In embodiments, Qmax is set based on ensuring that a target number of ablations (e.g., 90% or more) are successfully completed before reaching the timeout threshold (e.g., tmax = 45 s), thereby maintaining a robust therapeutic value. This only eliminates about 10% of the potential treatment energies but reasonably strikes a balance between applying as many energy levels as possible that can achieve clinical efficacy and avoiding patient injury.Inventors also note that a substantial number of tested ablations (approximately 75 in the examples discussed herein) were conducted at even higher energy levels without reported safety events. In embodiments directed to use of the catheter described above, and for the treatment of PVI, Qmax is established at about 7.5 kJ.

[0130] In embodiments, and in view of the above energy threshold ranges (namely Qmin and Qmax), Tmax is selected to accommodate a target number of ablations (e.g., at least 90 and more preferably 95%) in the clinical cases. In embodiments directed to use of the catheter described above, and for the treatment of PVI, an exemplary range for Tmax is 30-60 seconds, and more preferably about 40-50 seconds, and in one embodiment, is established at about 45 seconds.

[0131] It is also to be understood, as described herein, the threshold values (e.g., Qmin, Qmax, and tmax) shall be dependent on the type of cryoablation catheter (e.g., flexible tube bundle, rigid flow manifold, expandable member, etc.) and the type of procedure performed (e.g., VT or PVI). For example, it may take only 30 seconds for the tissue at a depth of 3 mm to reach a temperature sufficient to induce necrosis using one catheter whereas it may take 60 seconds using another catheter with less efficient cooling power. Additionally, performing the VT procedure may require more energy to be delivered than a PVI procedure. The inventors thus state for preferred embodiments of the invention, multiple empirical datasets are obtained for each type of catheter design and each type of procedure performed.

[0132] In embodiments, a machine learning model is trained to select Qmin, Qmax and Tmax based on the empirical data sets. An example of a suitable model is a supervised learning regression model or optionally, a deep learning neural network model where the inputs or features include total energy delivered, freeze duration, outlet temperature, flowrate, pressure inlet and pressure outlet, and quantitative and optionally qualitative clinical efficacy data at various time points after the procedure. The ML model can be trained with each new empirical dataset obtained to finetune optimal values for Qmin, Qmax, and Tmax for achieving clinical efficacy and safety.Attorney Docket No.: ADAG023PCT

[0133] Step 140 states to provide candidate or default total energy to be delivered for treatment (Qtx) to cryoablate a target tissue in a procedure. This step can be performed by the cryoablation console. A suggested Qtx and optionally Tmax are indicated or displayed to the physician where the value for Qtx is midway between the Qmax and Qmin, and Tmax is provided from the step 130.

[0134] Step 150 states to commence cryoenergy delivery to ablate the target tissue. This step is performed by the cryoablation console. The coolant, preferably liquid nitrogen (N2) is circulated through the catheter, freezing the tissue.

[0135] Step 160 states to continuously compute real-time total energy delivered based on temperature, pressure and flowrate data received from the sensors arranged with the flow path in the cryoablation apparatus and cryoablation console (e.g., the console 4020 shown in FIG. 1). In embodiments, the computation is performed using the cryoablation energy model described above.

[0136] It is also important to note that the calculated energy represents the total energy delivered to a catheter, without specifying the fraction of this energy that actually reaches the ablation target tissue. Therefore, this value primarily indicates the proper functionality of the ablation device. However, its clinical efficacy may vary, depending on the accuracy of the device's positioning and the quality of contact between the catheter and the tissue being treated. The inventors address this challenge, in embodiments, by providing a tissue contact verification step prior to commencing the cryoablation, discussed herein.

[0137] Step 170 states to continue cryoenergy delivery until real-time total energy delivery is between Qmin and Qmax, or until the ablation timer exceeds Tmax, whichever comes first. Once the real-time total energy exceeds Qmax or the timer exceeds Tmax, whichever comes first, the cryoablation console halts freezing.

[0138] APPLICATION

[0139] Embodiments of the invention have a wide range of diagnostic and therapeutic applications. A preferred application, in embodiments, is endovascular-based cardiac ablation and more particularly, the endovascular-based cardiac ablation treatment of atrial fibrillation.

[0140] FIG. 9 is a flow chart of an overview for performing a PVI procedure 300 to treat Afib in accordance with an embodiment of the invention.

[0141] Step 310 states to advance the catheter to the cavity in the heart. This step may be performed with reference to FIG. 11 to reach the left atrium with the distal treatment section of a catheter.

[0142] The procedure may be performed under conscious sedation, or general anestheticAttorney Docket No.: ADAG023PCT if desired.

[0143] A peripheral vein (such as the femoral vein FV) is punctured with a needle. The puncture wound is dilated with a dilator to a size sufficient to accommodate an introducer sheath, and an introducer sheath with at least one hemostatic valve is seated within the dilated puncture wound while maintaining relative hemostasis.

[0144] With the introducer sheath in place, the guiding catheter 10 or sheath is introduced through the hemostatic valve of the introducer sheath and is advanced along the peripheral vein, into the target heart region (e.g., the vena cavae, and into the right atrium 2). Fluoroscopic imaging can be used to guide the catheter to the selected site.

[0145] Once in the right atrium 2, the distal tip of the guiding catheter is positioned against the fossa ovalis in the intraatrial septal wall. A needle or trocar is then advanced distally through the guide catheter until it punctures the fossa ovalis. A separate dilator may also be advanced with the needle through the fossa ovalis to prepare an access port through the septum for seating the guiding catheter. The guiding catheter thereafter replaces the needle across the septum and is seated in the left atrium through the fossa ovalis, thereby providing access for devices through its own inner lumen and into the left atrium.

[0146] Placement of the above tools may be carried out with guidance from one or more of the following: fluoroscopy, intracardiac pressures, transesophageal echocardiography (TEE), and intracardiac echocardiography (ICE).

[0147] FIGS. 12-13 illustrate a method for deploying a ring-shaped catheter in the left atrium and around pulmonary vein entries for treating various heart conditions such as atrial fibrillation.

[0148] With reference first to FIG. 12, a cross sectional view of the heart includes the right atrium RA, left atrium LA, left superior pulmonary vein LSPV entry, and left inferior pulmonary vein L1PV entry. Guide catheter 2100 is shown extending through the septum and into the left atrium.

[0149] Though not shown, mapping catheters for use with an EP console may be positioned in the entry to the LSPV of the left atrium for monitoring electrical signals of the heart. The mapping catheters may be placed in other locations, such as, for example the coronary sinus (CS). Examples of mapping catheters include the WEBSTER® CS Bi- Directional Catheter and the LASSO® Catheter, both of which are manufactured by Biosense Webster Inc. (Diamond Bar, CA 91765, USA). Another example of mapping and cryotreatment system is described in US Patent Publication No. 2015 / 0018809 to Mihalik.

[0150] Optionally, an esophageal warming balloon may be placed in the esophagus toAttorney Docket No.: ADAG023PCT mitigate collateral damage arising from creating the lesions. An esophageal warming balloon prevents the cold temperatures from reaching the inner layer of cells of the esophagus, and can prevent formation of, e.g., an atrio-esophageal fistula. An example of a suitable esophageal warming balloon apparatus that may be used is described in commonly assigned U.S. Patent Application No. 15 / 028,927, entitled “ENDOESOPHAGEAL BALLOON CATHETER, SYSTEM, AND RELATED METHOD,” filed October 12, 2014 by Alexei Babkin, et al., the contents of which is incorporated herein by reference in its entirety for all purposes.

[0151] FIG. 13 illustrates a distal section of the cryoablation catheter 2116 advanced through the guide sheath 2100. The energy element 2118 is shown having a circular shape formed as disclosed and described herein and urged against the endocardium. As described herein the shape may be adjusted to make continuous contact with the tissue, and to form an elliptical or circular-shaped continuous lesion (such as lesion 8 shown in FIG. 10) which encloses all the left PV entries.

[0152] In embodiments the shape is modified by reducing the diameter of loop, articulating the intermediate section of the shaft, and rotating or steering the catheter distal section. Collectively, the steps of deployment, diameter control, steering and articulation can place the entire circumference of the loop in continuous contact with the endocardium tissue.

[0153] Although the loop is shown encircling two vein openings, in other embodiments, the apparatus is arranged and deployed to encircle only one vein opening.

[0154] With reference again to FIG. 9, step 320 states to verify contact. This step may be performed using, for example, electrodes mounted on the distal treatment section. Electrical activity (e.g., impedance) is monitored by a tissue contact verification module to detect a change from a baseline electrical value. By evaluating the electrical activity throughout the length of the treatment section, tissue contact can be evaluated for the entire length of the treatment element. The software and electronics for the tissue contact verification module may be implemented as a stand along system or in the cryoablation console, PFA console, or EP console. Additional description of a tissue contact verification is set forth in commonly assigned Patent Publication No. 20190125422, entitled “TISSUE CONTACT VERIFICATION SYSTEM”, filed June 13, 2018, and Patent Application No. 18 / 667,042, entitled “ CALIBRATION METHOD FOR CONTACT VERIFICATION SYSTEM”, filed May 17, 2024, the entire contents of which are incorporated herein by reference for all purposes. Additionally, tissue electrocardiograms (ECGs) may be displayed using an EP recording system.Attorney Docket No.: ADAG023PCT

[0155] If adequate contact is not verified, the process returns to step 310 to reposition the treatment section.

[0156] If adequate contact is verified, the process moves to step 330.

[0157] Step 330 states to ablate. This step is performed by flowing a cryogen through the distal treatment section to form a continuous elongate ring-shaped lesion (frozen tissue), enclosing all left pulmonary vein entries.

[0158] Step 340 states to verify or confirm tissue ablation or necrosis following freezing. This step may be performed by comparing pretreatment electrical activity of the heart with post treatment data, and evaluating, for example, whether there are persistent aberrant signals.

[0159] If the ablation treatment is sufficient or within a threshold range, the treatment procedure may be deemed completed as indicated by step 350. If, on the other hand, the degree of ablation (or tissue necrosis) is not sufficient, the surgeon may return to step 310, and repeat the process as desired.

[0160] EXAMPLES

[0161] EXAMPLE 1 - ANALYSIS OF THE HUMAN CLINICAL DATA

[0162] Embodiments of the invention comprise generating datasets. In embodiments, empirical sets of data were obtained, analyzed, and applied according to embodiments of the invention.

[0163] A first clinical data set consisted of recordings from 40 procedures and a total of 823 individual ablations. Acute results were extracted from the procedure data sheets and compared with energy levels calculated from the corresponding console logs. In this cohort, six cryoablation consoles were utilized. Furthermore, a subset of patients reached a six-month follow-up, enabling additional validation of treatment efficacy.

[0164] For each individual ablation, the integral energy was calculated using the model described previously. The aggregated data set is illustrated in FIG. 14 as a histogram, which displays the distribution of the obtained energy levels alongside the cumulative integral percentage.

[0165] The data reveals significant variability in energy levels obtained from 30-second ablation durations, showcasing a mean value of 6.79 kJ and a standard deviation of 1.41 kJ. Notably, the variance (the squared deviation from the mean value) in energy levels reaches as high as 1.97 kJ.

[0166] An immediate comparison with the acute success rates of ablation procedures indicated that in three of the 39 clinical cases, the procedures failed due to the inability to isolate all pulmonary veins in the patients. These instances were characterized by recordedAttorney Docket No.: ADAG023PCT energy levels significantly below the overall mean, at 5.21, 5.72, and 6.07 kJ, respectively. Moreover, all three patients experienced a recurrence of Atrial Fibrillation within the six- month follow-up period. In contrast, patients treated with higher energy levels achieved acute success with complete veins isolation. Of the remaining 13 patients who reached the six- month follow-up, only one reported an AFib recurrence.

[0167] The inventors submit the evidence indicates energy levels below the mean are insufficient for achieving both acute and long-term procedural success. Consequently, the inventors state to maintain energy levels in each ablation well above 6.1 kJ, a threshold where acute success has been consistently observed. Levels falling below this threshold should be considered suboptimal (as indicated by the shaded gray area in FIG. 14) and thus clinically avoided.

[0168] FIG. 16 shows a distribution of the outlet temperature of the cryogen at the end of a 30-second freeze cycle as a function of delivered energy.

[0169] The data indicates that at lower energy levels, the cryogen's output temperature generally remains above the desired -160°C. This is indicative of suboptimal system performance and may suggest a reduced therapeutic efficacy of the treatment. The vertical line in the plot marks the previously introduced cutoff of 6.1 kJ, which aligns well with the observed scatter of outlet temperatures.

[0170] EXAMPLE 2 - ENERGY THRESHOLD SELECTION: ESTABLISHING THE SAFE UPPER ENERGY LIMIT

[0171] In embodiments of the invention, a second pre-clinical data set was generated and served to establish safe limits for cryoablation parameters near the esophageal area, where any temperature-based ablation is known to carry risks of serious adverse effects, such as atrial- esophageal fistula.

[0172] These pre-clinical studies were conducted using standard animal model protocol, and involved three animals (ovine) and a total of 50 ablations. The anatomical specificity of the ablation region (superior vena cava) allowed the catheter to deliver increased energy within the standard 30-second ablation duration. This enhancement was made possible by employing a straight linear stylet, known for facilitating the most efficient and unrestricted cryogen flow.

[0173] The analysis, utilizing the energy computation model described above, reveals the energy distributions and cumulative integral percentages, as illustrated in FIG. 15.

[0174] This result substantiates that the mean energy value of 8.5 kJ, as identified in these studies, should be recognized as the safe level, in line with the study's conclusions describedAttorney Docket No.: ADAG023PCT herein. Furthermore, since the pre-clinical study included a significant number of applications at even higher energy levels ( ~ 50%), encompassing "worst-case" scenarios with multiple applications and no observed chronic safety concerns, the derived value is confidently established as a conservative safety benchmark for energy levels throughout the heart, including the esophageal region.

[0175] RANGE OF ACCEPTABLE LEVELS OF ENERGY SELECTION

[0176] CLINICAL DATA ANALYSIS

[0177] This clinical data consisted of recordings from 39 procedures and a total of 809 individual ablations. Acute results were extracted from the procedure data sheets and compared with energy levels calculated from the corresponding console logs. In this cohort, six cryoablation consoles were utilized. Furthermore, a subset of patients reached a six-month follow-up, enabling additional validation of treatment efficacy.

[0178] For each individual ablation, the integral energy was calculated using the model described previously. The aggregated data set is illustrated in FIG. 14 as a histogram, which displays the distribution of the obtained energy levels alongside the cumulative integral percentage.

[0179] The data reveals significant variability in energy levels obtained from the 30- second ablation durations, showcasing a mean value of 6.79 kJ and a standard deviation of 1.41 kJ. Notably, the variance (the squared deviation from the mean value) in energy levels reaches as high as 1.97 kJ.

[0180] A detailed analysis of the console log files indicates that at lower energy levels, the cryogen's output temperature demonstrates significant variance and generally remains above the desired -160°C, as illustrated in FIG. 16-17. This is indicative of suboptimal system performance and may suggest reduced therapeutic efficacy of the treatment. The vertical line in the FIG. 16 plot marks the previously introduced cutoff of 6.1 kJ, which aligns well with the observed variance of outlet temperatures.

[0181] An immediate comparison with the acute success rates of ablation procedures indicates that in three of the 39 clinical cases, the procedures failed due to the inability to isolate all pulmonary veins in the patients. These instances were characterized by recorded energy levels significantly below the overall mean, at 5.21, 5.72, and 6.07 kJ, respectively. Moreover, all three patients experienced a recurrence of Atrial Fibrillation within the six- month follow-up period. In contrast, patients treated with higher energy levels achieved acute success with complete veins isolation. Of the remaining 13 patients who reached the six- month follow-up, only one reported an AFib recurrence.Attorney Docket No.: ADAG023PCT

[0182] In embodiments of the invention, this data is used to determine the Qmin, i.e., the minimum energy level below which the effectiveness of the treatment may be compromised. With reference to the above data, it indicates that energy levels below the mean are insufficient for achieving both acute and long-term procedural success. Consequently, inventors state to maintain energy levels in each ablation well above Qmin = 6.1 kJ, a threshold where acute success has been consistently observed. Levels falling below this threshold should be considered suboptimal (as indicated by the gray area in FIG. 14) and thus clinically avoided.

[0183] Conversely, higher energy levels are likely to enhance the efficacy of the procedure, assuming they do not introduce safety concerns. The inventors integrate this discovery with data from the pre-clinical safety study to set the energy delivery not to exceed 8.5 kJ, especially considering the risks associated with ablations near the esophageal region, as depicted in FIG. 14 (unshaded area). Notably, in the current data analysis, this upper energy level aligns with approximately the 10th percentile in the overall energy distribution among the reviewed patient cohort, indicating that a substantial number (approximately 75) of ablations were conducted at even higher energy levels without reported safety events. The inventors submit this evidence provides additional confidence in the safety of setting the energy threshold.

[0184] PREDICTABILITY OF THE ENERGY DELIVERY AND PRACTICAL IMPLEMENTATION

[0185] Based on reviewing the above discussed datasets, the inventors have identified common trends in energy delivery across all recorded clinical freezes. In all cases, the initial stage of a freeze, lasting from 5 to 12 seconds, displays variable transitional behavior that can differ from case to case, depending on the initial condition of the catheter and / or the cryoablation console. However, after 15 seconds into an ablation cycle, the system reaches a steady state where the relationship between delivered energy and time becomes a linear function, though the slope may vary from one freeze to another. The degree of linearity for times t > 15 seconds in each case can be quantified using the coefficient of determination, known as R2. This analysis consistently reveals a very high degree of linearity, with R2values very close to 1, as illustrated in Figure 18. This approach allows for early prediction of energy delivery using the subset of data obtained between 15 and 20 seconds of ablation (Figure 19). By utilizing the linear regression model derived from this interval, the results can be extrapolated to longer durations.

[0186] To evaluate the quality of such early predictions, two datasets were compared: oneAttorney Docket No.: ADAG023PCT containing predicted values obtained by extrapolating data from the 15 < t < 20s subset, and the second containing actual data recorded at the end of the 30s ablation cycle. The histograms depicting energy values for real and computed cases are presented in Figures 20A, 20B, respectively.

[0187] The datasets analyzed were found to be statistically similar, as evidenced by the Wilcoxon signed-rank test, which yielded a p-value of 0.4317. This result indicates that there is no significant difference between the datasets, as the p-value substantially exceeds the commonly used significance threshold of 0.05.

[0188] TREATMENT TIMEOUT DETERMINATION

[0189] It is desirable to establish a timeout value or tmax. By tmax, it is meant the longest allowable duration for a cryoablation cycle to ensure safety and effectiveness without unnecessarily prolonging the procedure.

[0190] A timeout during treatment is important when the desired energy level cannot be delivered within a prolonged period, indicative of suboptimal system performance. We thus wish to establish a timeout duration that does not unnecessarily prolong treatment, yet is sufficient to prevent a high rejection rate of treatments that still hold therapeutic value, even if they do not reach the desired upper energy limit.

[0191] Considering the previously established therapeutically justified energy threshold, Qmin = 6.1 kJ, an extrapolation of the real clinical data illustrates the percentage of freezes where Q < Qcut (namely Qmin) as a function of ablation time, as shown in Figure 21.

[0192] This rejected fraction exhibits a very rapid (exponential) decline as the ablation time exceeds 45 seconds, with only incremental (linear) changes observed at longer durations. Consequently, it appears unreasonable to extend the timeout period beyond this point.Therefore, in embodiments of the invention, the timeout duration is set to about tmax = 45 seconds, which would accommodate ~ 95% of the ablations performed in clinical cases.

[0193] DETERMINATION OF THE OPTIMAL VALUE OF DELIVERED ENERGY

[0194] A similar approach can be used to determine the optimal maximum energy level to be delivered in each treatment. By the desirable maximum energy threshold, Qmax, it is meant the optimal energy level that maximizes therapeutic efficacy while maintaining safety.

[0195] Figure 22 depicts the predicted percentage of ablations that will achieve the preset energy level Qmax before reaching the 45-second timeout, as a function of Qmax.

[0196] The analysis of the predicted outcomes at tmax = 45 s timeout (Figure 22) demonstrates a pronounced dependence of the number of successful ablations on the preset energy level. This underscores the importance of setting the preset energy to the highest yetAttorney Docket No.: ADAG023PCT safe level to maximize therapeutic efficacy while minimizing incomplete energy delivery cases. Balancing these factors, in embodiments, the inventors establish the preset energy at Qmax = 7.5 kJ. This setting is expected to ensure that approximately 90% of ablations are successfully completed before reaching the timeout threshold, thereby maintaining a robust therapeutic value.

[0197] PREFERRED EMBODIMENTS

[0198] Based on the above empirical datasets, embodiments of the invention provide a system and method that determine a plurality of threshold schemes that significantly enhance the performance and safety of cryo-based energy delivery for the treatment of heart tissue. Exemplary threshold values for embodiments of the invention for treating PVI using the catheter described herein are:

[0199] Low Energy Threshold (Qmin) = 6.1kJ: This threshold ensures that the energy delivered is above a minimum level deemed necessary for effective treatment.

[0200] Maximum Freeze Time Threshold (tmax) = 45s: This threshold has been set to prevent unnecessarily prolonged treatments while ensuring optimal therapeutic effectiveness.

[0201] Desirable Energy Threshold (Qmax) = 7.5 kJ: This threshold represents an ideal energy delivery level that balances maximal therapeutic benefit with patient safety.

[0202] The establishment of these thresholds server to optimize control of cryoenergy. By recognizing and integrating these scientifically-derived empirically-based limits into the invention, treatment protocols are optimized to ensure clinical effectiveness and safety.

[0203] Alternative embodiments

[0204] Embodiments of the invention may be configured and operate using different types of cryogens or coolants to circulate through the tissue treatment region of the apparatus. Additionally, the phase of the cryogen fluid may vary, and is not required to be at near critical pressure and temperature unless recited in any appended claims.

[0205] Many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims the invention may be practiced otherwise than as specifically described.

Claims

Attorney Docket No.: ADAG023PCTCLAIMS1. A cryoablation system for creating a lesion in target tissue, the system comprising: a catheter, said catheter comprising: a freezing portion; at least one cryogen delivery lumen; at least one cryogen return lumen; and a cryoablation console programmed and operable to: provide a predetermined value of a desired total energy (Qmin), wherein Qmin is determined based on an empirical dataset of multiple cryoablations of tissue; circulate a cryogen through the freezing portion using the at least one cryogen delivery lumen and return lumen; continuously compute real-time energy delivered (Qreal) based on elapsed time, temperature and pressure data generated from sensors in the flow path of the cryogen; and continue circulating the cryogen and delivery of energy at least until Qreal exceeds Qmin.

2. The system of claim 1 , wherein Qmin is determined according to statistical trend for which recorded total energy level in the empirical dataset achieved a target return fluid temperature of -160 C or lower in a majority of the cryoablations, and in some embodiments, achieved a temperature variance of less than 1%.

3. The system of claim 1, wherein the console is further operable to halt the ablation when the elapsed time exceeds a pre-determined maximum time (Tmax), and optionally, wherein the Tmax ranges from 30-60 seconds.

4. The system of claim 1 , wherein the console is further operable to halt the circulation of the cryogen and delivery of energy when Qreal exceeds a pre-determined threshold maximum total energy delivered (Qmax).

5. The system of claim 1, wherein the catheter further comprises a plurality of electrodes on an exterior surface of the freezing portion.Attorney Docket No.: ADAG023PCT6. The system of claim 5, further comprising a tissue contact module operable to measure tissue contact information based on information detected by the plurality of electrodes.

7. The system of claim 5, further comprising a pulsed field ablation generator operably coupled to the plurality of electrodes to create a pulsed field of electricity to induce cell death in the target tissue.

8. The system of claim 1, wherein the computed real-time total energy delivered is based on computing the enthalpy at the inlet and exit of the catheter, and computing power based on the computed enthalpy, and integrating power over the time elapsed.

9. The system of claim 1 , wherein Qmin is pre-determined based on clinical efficacy for PVI ablations.

10. The system of claim 1, wherein the console is operable to allow a user to adjust the Qmin.

11. A cryoablation method for creating at least one lesion in a patient, the method comprising: determining a value of a desired total energy (Qmin), wherein Qmin is determined based on an empirical dataset of multiple cryoablations of tissue; circulating a cryogen though the catheter; monitoring temperature and pressure along the flowpath to cause tissue ablation; continuously computing real-time total energy delivered from the catheter (Qreal); and continue circulating the cryogen and delivery of energy at least until Qreal exceeds Qmin.

12. The method of claim 11, wherein the computing step comprises: computing the enthalpy at the flow inlet and flow exit of the catheter, and computing power based on the computed enthalpy, and integrating power over the time elapsed.Attorney Docket No.: ADAG023PCT13. The method of claim 11, wherein the empirical dataset comprises clinical or preclinical data of multiple ablations.

14. The method of claim 13, wherein the empirical dataset comprises clinical data of PVI ablations.

15. The method of claim 11, wherein Qmin is determined according to statistical trend for which recorded total energy level in the empirical dataset achieved a target return fluid temperature of -160 C or lower in a majority of the cryoablations, and in some embodiments achieved a temperature variance of less than 1%.

16. The method of claim 1 1 , further comprising performing halting when Qreal exceeds a pre-computed threshold maximum total energy delivered (Qmax).

17. The method of claim 11, further comprising performing halting when the elapsed time exceeds a pre-determined maximum time (Tmax), and in some embodiments,, wherein the Tmax ranges from 30-60 seconds.

18. The method of claim 1 1 , further comprising measuring tissue contact information based on information detected by a plurality of electrodes arranged on the cryoablation apparatus.

19. The method of claim 11, further comprising creating a pulsed field of electricity by a plurality of electrodes arranged on the cryoablation apparatus to induce cell death in the target tissue.

20. The method of claim 11, comprising adjusting or modifying the Qmin.

21. A method for evaluating a dataset as described herein to determine Qmin, Qmax and Tmax.

22. A method for modulating total energy delivered for cryoablation as described herein.

23. A system operable to modulate total energy delivered for cryoablation as described herein.

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