METHOD AND APPARATUS FOR PULMONARY INTERVENTIONS

Abstract

Apparatus and methods for deactivating bronchial nerves extending along the secondary bronchial branches of a mammalian subject to treat asthma and related conditions. An ultrasonic transducer (11) is inserted into the bronchus as, for example, by advancing the distal end of a catheter (10) bearing the transducer into the secondary bronchial section to be treated. The ultrasonic transducer emits circumferential ultrasound so as to heat tissues throughout circular impact volume (13) as, for example, at least about 1 cm.sup.3 encompassing the bronchus to a temperature sufficient to inactivate nerve conduction but insufficient to cause rapid ablation or necrosis of the tissues. The treatment can be performed without locating or focusing on individual bronchial nerves.

The apparatus and methods utilized for lung tumor ablation.

Claims

1. A method for performing pulmonary interventions in a mammalian subject, comprising: providing an ultrasound catheter having an ultrasound transducer at a distal end; inserting the ultrasound catheter into a bronchial system of the mammalian subject so that the ultrasound transducer is disposed proximate to a treatment site; while the ultrasound transducer is disposed proximate to the treatment site, operating an actuator or control unit electrically connected to the ultrasound transducer, to energize the ultrasound transducer to emit a short pulse at a sub-therapeutic level; receiving via the ultrasound transducer an ultrasound echo from organic tissues of the mammalian subject in response to the short pulse, the ultrasound echo being a volume-integrated A-mode signal; operating the actuator or control unit to process the volume integrated A-mode signal, which represents an accumulated intensity of the circumferential ultrasound echoes; analyzing the volume integrated A-mode signal to determine locations of bronchial cartilage rings; and activating the ultrasound transducer to transmit ultrasound therapeutic waveform energy between adjacent ones of the bronchial cartilage rings.

2. The method of claim 1 wherein the inserting of the ultrasound catheter into the bronchial system of the mammalian subject includes inserting the ultrasound catheter into a secondary bronchus, and wherein ultrasound transducer is disposed inside a balloon attached to the distal end of the ultrasound catheter, further comprising moving the ultrasound transducer within the balloon to position the ultrasound transducer adjacent a space or gap between adjacent bronchial cartilage rings in the secondary bronchus prior to the activating of the ultrasound transducer to transmit the ultrasound therapeutic waveform energy.

3. The method of claim 2 wherein the ultrasound transducer includes multiple separately activatable cylindrical transducer elements, and wherein the activating of the ultrasound transducer includes energizing certain of the separately activatable transducer elements to direct the ultrasound therapeutic waveform energy between the adjacent bronchial cartilage rings.

4. The method of claim 1 wherein the inserting of the ultrasound catheter into the bronchial system of the mammalian subject includes inserting the ultrasound catheter into a secondary bronchus, and wherein the ultrasound transducer is disposed inside a micro porous balloon attached to the distal end of the ultrasound catheter, the micro porous balloon providing a fluid coupling to a wall of the secondary bronchus, further comprising moving the ultrasound catheter and therewith the ultrasound transducer to position same adjacent a space or gap between the adjacent cartilage rings of the secondary bronchus prior to the activating of the ultrasound transducer to transmit the ultrasound therapeutic waveform energy.

5. The method of claim 1 wherein the ultrasound transducer is disposed inside a balloon attached to the distal end of the ultrasound catheter, further comprising analyzing the volume integrated A-mode signal to detect presence of air pockets or trapped air between the balloon and surrounding tissue, the activating of the ultrasound transducer to transmit ultrasound therapeutic waveform energy being carried out only when analyzing of the volume integrated A-mode signal reveals an absence of air, thereby ensuring complete circumferential coupling.

6. The method of claim 1, further comprising operating the actuator or control unit to process the electrical signal to measure time delay of the ultrasound echo waveform relative to a time of emission of the short pulse to determine size of a bronchial section to be treated, wherein the activating of the ultrasound transducer to transmit ultrasound therapeutic waveform energy includes activating the ultrasound transducer at an acoustic power level in accordance with the determined size of the bronchial section and in accordance with efficiency of the ultrasound transducer.

7. The method of claim 1 applied for denervation wherein: the inserting of the ultrasound catheter into the bronchial system of the mammalian subject includes inserting the ultrasound catheter into a secondary bronchus; the inserting of the ultrasound transducer into the secondary bronchus includes positioning the ultrasound transducer at a sufficient distance from the esophagus of the mammalian subject in order to prevent peri esophageal vagus nerve or esophageal damage; and the activating of the ultrasound transducer includes transmitting an amount of ultrasound therapeutic waveform energy into an impact volume circumferentially surrounding the secondary bronchus, in an amount therapeutically effective to inactivate conduction of all bronchial nerves in the impact volume.

8. The method of claim 7 used to ablate bronchial nerves to prevent bronchial contractions from amplifying ARDS and to optimize utilization of the remaining healthy lung capacity of a COVID 19 damaged lung.

9. The method of claim 7 applied in patients who recovered from COVID 19 but suffer from persistent symptoms in particular dyspnea.

10. The method of claim 7, wherein for an impact volume of approximately 1 cm.sup.3, the ultrasound therapeutic waveform energy is transmitted at an acoustic power level of approximately 10 to approximately 20 watts for approximately 10 to approximately 20 seconds to provide an absorbed dose of approximately 100 to approximately 400 joules throughout the impact volume.

11. The method of claim 7, wherein the ultrasound therapeutic waveform energy is transmitted so as to maintain the temperature of a bronchial wall section surrounding the ultrasound transducer below 65° C. while heating bronchial nerves in a circumferential impact volume about the bronchial wall section to above 42° C.

12. The method of claim 7, wherein the activating of the ultrasound transducer to transmit ultrasound therapeutic waveform energy is performed without determining locations of any specific bronchial nerves.

13. Apparatus for performing pulmonary interventions in a mammalian subject, comprising: an ultrasound transducer adapted for insertion through a bronchial system of the mammalian subject to a treatment site in a bronchus of the mammalian subject; and an actuator or control unit electrically connected to the ultrasound transducer, the actuator or control unit being configured to activate the ultrasound transducer to emit a short pulse at a sub-therapeutic level, the ultrasound transducer being operatively connected to control unit for receiving an electrically encoded volume-integrated A-mode signal or accumulated intensity of ultrasound echoes from organic tissues of the mammalian subject, the actuator or control unit being further configured to process the volume integrated A-mode signal.

14. The apparatus of claim 13 wherein the actuator or control unit is additionally configured to analyze the volume integrated A-mode signal to distinguish a relative minimum of the volume integrated A-mode signal with respect to degree of insertion of the ultrasound transducer in the bronchial system, thereby enabling positioning of the ultrasound transducer to transmit therapeutically effective focused ultrasound energy between adjacent bronchial cartilage rings into a treatment or impact volume.

15. The apparatus of claim 13 wherein the ultrasound transducer includes a longitudinal array of separately activatable cylindrical transducer elements and the actuator or control unit is configured to energize those separately activatable transducer elements to direct the ultrasound therapeutic waveform energy between the adjacent ones of the bronchial cartilage rings.

16. The apparatus of claim 13 wherein the actuator or control unit is configured to analyze the volume integrated A-mode signal to facilitate complete circumferential coupling.

17. The apparatus of claim 13 wherein the actuator or control unit is configured to measure the time delay of the volume integrated A-mode signal and therewith determine the size of a bronchial section, the actuator or control unit being also configured to control the ultrasound transducer to vary the amount of the therapeutically effective ultrasound energy in accordance with the determined size of the bronchial section taking into account catheter efficiency variations.

18. The apparatus of claim 13 wherein the actuator or control unit is configured to measure cooling fluid volume and pressure and to determine a point of rapid pressure increase without significant volume increase which corresponds with the lumen size of the treatment section and to adjust ultrasound energy accordingly taking into account catheter efficiency variations.

19. Apparatus for inactivating bronchial nerve conduction in a mammalian subject, comprising: an ultrasound transducer adapted for insertion into secondary bronchial sections of the mammalian subject and for emitting ultrasound energy; and an actuator or control unit electrically connected to the ultrasound transducer, the actuator or control unit being configured to control the ultrasound transducer to transmit ultrasound energy into an impact volume of at least approximately 1 cm.sup.3 at least partially surrounding the bronchial section, the ultrasound energy being in an amount effective to inactivate conduction of bronchial nerves throughout the impact volume.

20. The apparatus of claim 19, wherein the actuator or control unit is configured to control the ultrasound transducer to transmit ultrasound energy at an acoustic power level of approximately 10 to approximately 20 watts for approximately 10 to approximately 20 seconds to provide a dose of approximately 100 to approximately 400 joules in the impact volume.

21. The apparatus of claim 19 wherein the actuator or control unit is configured to control the ultrasound transducer to transmit ultrasound energy in a pulsed mode to cause mechanical stress on nerve fibers through cavitational effects.

22. The apparatus of claim 19, wherein the actuator or control unit is configured to control the transducer and cooling fluid circulation so as to maintain temperature of a section of bronchial wall of the bronchial section below 65° C. while achieving a temperature above 42° C. throughout the impact volume.

23. A method for treating a lung tumor in a mammalian subject, comprising: conducting an Electromagnetic Navigation Bronchoscopy (ENB) procedure on the mammalian subject; inserting a guidewire during the Electromagnetic Navigation Bronchoscopy (ENB) procedure into a bronchial tree of the mammalian subject so that a distal end of the guidewire is disposed at a treatment site in the lung tumor of the mammalian subject; advancing an ultrasound transducer over the guidewire and into the lung tumor; and thereafter actuating the transducer to transmit ultrasound energy into the lung tumor in a therapeutically effective amount to ablate tumor tissue.

24. The method of claim 23 wherein the inserting of the guidewire includes operating a 3D navigation system, further comprising performing an on-site pathological examination of the tumor tissue, the actuating of the ultrasound transducer to transmit ultrasound energy into the lung tumor being performed directly after the on site pathological examination reveals the tumor as malignant.

25. The method of claim 23, further comprising operating an ultrasound imaging system to monitor the treatment site, the ultrasound imaging system including an imaging and treatment catheter with a circular phased array transducer or an annular rotational transducer array, wherein the actuating of the ultrasound transducer includes controlling tumor tissue ablation in response to visual feedback from operating the ultrasound imaging system.

26. The method of claim 23 wherein the ultrasound transducer is disposed at a distal end of a treatment catheter, the advancing of the ultrasound transducer including advancing the treatment catheter over the guidewire, further comprising: exchanging the treatment catheter for a diagnostic imaging catheter over the guidewire, the treatment catheter and the diagnostic imaging catheter each being provided with length markings on a respective outer surface, thereby facilitating catheter exchange; imaging the treatment site including the lung tumor; and controlling an ablation process in response to the imaging of the treatment site.

27. The method of claim 23 wherein the actuating of the ultrasound transducer to ablate tumor tissue includes actuating the ultrasound transducer to emit circumferentially ultrasound energy effective to necrose tumor tissue through hyperthermia, entailing an application of ultrasonic acoustic power of approximately 25 W for approximately a minute to provide an absorbed dose of approximately 1500 Joules.

28. The method of claim 23 wherein the ultrasound transducer is disposed at a distal end of a treatment catheter, the advancing of the ultrasound transducer including advancing the treatment catheter over the guidewire, further comprising selecting the treatment catheter based on tumor size from among a plurality of catheters with different transducer lengths or as having subdivided transducer sections so the tumor cross section lays within a transducer near field zone.

29. The method of claim 23 wherein the actuating of the ultrasound transducer to ablate tumor tissue includes actuating the ultrasound transducer in a pulsed mode to damage tumor cells via cavitation and to permeabilize cell membranes to enable targeted drug delivery to the tumor tissue.

30. The method of claim 23 wherein the ultrasound transducer is disposed in a balloon containing cooling fluid, further comprising circulating the cooling fluid through the balloon combined with active cooling to widen the circumferential treatment zone to avoid over heating of proximal tumor tissue enabling in depth ablation.

Description

B.SUB.R .IEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 is partially an anatomical view of typical main bronchial trunks B.sub.L and B.sub.R and associated structures and partially a block diagram of a system for treatment of pulmonary conditions, in accordance with the present invention.

[0022] FIG. 2 is partially a side elevational view of a treatment catheter 10 advanced through a bronchoscope 5 into a bronchial branch and a bronchial sectional view, diagrammatically depicting an ultrasound treatment volume 13.

[0023] FIG. 3 is a schematic transverse cross sectional view through a tumor 15 with an ultrasound transducer 11 in the center surrounded by cooling fluid in a balloon 12.

[0024] FIGS. 4 is a partially anatomical view showing the ablation catheter 10 advanced through the left bronchus B.sub.L into a tumor 15 over a guide wire 14 placed during electromagnetic navigation bronchoscopy (ENB).

[0025] FIG. 5 is a schematic cross-sectional view of a rotational ablation/imaging catheter in accordance with the invention

[0026] FIG. 6 shows the length marking 204 on a catheter 10 advanced through an oral intubation device 202

[0027] FIG. 7A through 7C show balloon diameter determination through pressure P/volume V monitoring in 7A and ultrasound pinging in 7B with the corresponding screen shot of an ultrasound volumetric A mode signal in 7C

[0028] FIGS. 8A and 8B are graphs showing magnitudes of volume integrated A mode signals for complete (8A) and incomplete (8B) balloon-bronchus/tumor coupling.

[0029] FIGS. 9A and 9C are cross sectional views of a bronchus with an inserted ultrasound catheter with longitudinal position sensing and position optimization, showing the catheter and particularly an ultrasound transducer and balloon at different longitudinal positions in the bronchus, relative to cartilage rings thereof.

[0030] FIGS. 9B and 9D show volume integrated A mode signals for balloon positioning relative to cartilage rings

[0031] FIG. 10 shows a subdivided transducer to allow for electronic inter-cartilage positioning and transducer length adjustment L for varying the near field zone to adjust tumor treatment volumes.

DETAILED DESCRIPTION

[0032] Apparatus according to one embodiment of the invention is advanced through the working channel of a bronchoscope 5 in FIG. 2. Alternatively, an ultrasound catheter 10 can be advanced through a sheath or directly without any delivery instrument over a guide wire 14 which has been placed by electromagnetic navigation bronchoscopy (ENB). The sheath or ultrasound catheter 10, generally, may be in the form of an elongated tube having a proximal end, a distal end and a proximal-to-distal axis. As used in this disclosure with reference to elongated elements for insertion into the body, the term “distal” refers to the end which is inserted into the body first, i.e., the leading end during advancement of the element into the body, whereas the term “proximal” refers to the opposite end. The sheath or ultrasound catheter may be a steerable sheath or catheter. Thus, the sheath or catheter may include known elements such as one or more pull wires (not shown) extending between the proximal and distal ends of the sheath or catheter and connected to a steering control arranged so that actuation of the steering control by the operator flexes the distal end of the sheath or catheter in a direction transverse to the axis. The sheath or the ultrasound catheter 10 may be inserted into a tumor which has been traversed by a guide wire placed under a 3D guided trans bronchial biopsy procedure (ENB) as shown in FIG. 4. Catheter 10 has compliant balloon 12 mounted at the distal end. In its inflated condition (FIGS. 2 and 3), balloon 12 engages the tumor/bronchial wall and therewith allows for ultrasound to be conducted from transducer 11 into surrounding tumor/bronchial tissues 15 (FIGS. 4 and 3).

[0033] Ultrasound transducer 11 (FIG. 2) is mounted adjacent the distal end of catheter 10 within balloon 12. Transducer 11, which is desirably formed from a ceramic piezoelectric material, is of a tubular shape and has an exterior emitting surface in the form of a cylindrical surface of revolution about the proximal-to-distal axis of the transducer 11. The transducer 11 typically has an axial length of approximately 2 and approximately 10 mm, and preferably about 6 mm. As shown in FIG. 10 this length L can be varied electronically to adjust the near field zone to accommodate different treatment depths and therewith tumor volumes. Also, the axial position of the treatment volume can be varied electronically by selectively activating different sub elements 11′ to allow for inter cartilage positioning of the treatment volume for denervation in the secondary bronchi or treatment of tumors proximate to or surrounding cartilage covered bronchial sections. The outer diameter of the transducer 11 is approximately 1.5-3 mm in diameter, and preferably 2 mm. The transducer 11 also has electrically conductive coatings (not shown) on its interior and exterior surfaces. Thus, the transducer may be physically mounted to the catheter 10. The coatings are electrically connected to ground and signal wires. Wires 110 extend from the transducer 11 through a lumen in the catheter 10 to a connector 102 electrically coupled with the ultrasound control system. The lumen (not designated) extends between the proximal end and the distal end of catheter 10, while the wires 110 extend from the transducer 11, through the lumen, to the proximal end of the catheter 10.

[0034] Transducer 11 is arranged so that ultrasonic energy generated in the transducer is emitted principally from the exterior or outer surface (not separately designated). Thus, the transducer may include features arranged to reflect ultrasonic energy directed toward the interior of the transducer so that the reflected energy, travelling outwardly, reinforces the ultrasonic vibrations at the exterior surface. For example, transducer 11 may be configured with air backing to reflect energy at an interior surface of the transducer 11 and thereby redirected the energy outwardly to enhance the overall efficiency of the transducer.

[0035] Transducer 11 is also arranged to convert ultrasonic waves impinging on the exterior surface into electrical signals on wires 110. While A-mode signals integrated over the treatment volume cannot provide for spatial resolution like with a 2D imaging transducer, a conclusion about the bronchial lumen can be made based on the magnitude of the amplitude and distance (time) of the volume-integrated A-mode signal as shown in an oscilloscope screen shot in FIG. 7C. Stated another way, transducer 11 can act either as an ultrasonic emitter or an ultrasonic receiver. The receiving mode is of particular importance for an array type transducer as described in U.S. patent application Ser. No. 14/770,941, Publication No. 2016/0008636, because with an array type transducer 11 the received echoes can be electronically focused, using phased array processing, and high-resolution images can be achieved.

[0036] The transducer 11 is designed to operate, for example, at a frequency of approximately 1 MHz to approximately a few tens of MHz, and typically at approximately 10 MHz for denervation and 1 to 5 MHz for tumor ablation. The actual frequency of the transducer 11 typically varies somewhat depending on manufacturing tolerances. The optimum actuation frequency of the transducer may be encoded in a machine-readable or human-readable element (not shown) such as a digital memory, bar code or the like affixed to the catheter. Alternatively, the readable element may encode a serial number or other information identifying the individual catheter, so that the optimum actuation frequency may be retrieved from a central database accessible through a communication link such as the internet.

[0037] An ultrasound control system, also referred to herein as an actuator, is releasably connected to catheter 10 and transducer 11 through a plug connector 102 (FIG. 1). A control unit 104 and an ultrasonic signal or waveform generator 106 are arranged to vary or adjust the amplitude and timing of the electrical signals to control the power level and duration of the ultrasound-frequency signals emitted by transducer 11. An energization circuit 100 including control unit 104 and ultrasonic signal generator 106 also includes a detection subcircuit 108 arranged to detect electrical signals generated by transducer 11 and transmitted via wires 110 and communicate such signals to the control unit 104. More particularly, detection subcircuit 108 includes a receiver or echo signal extractor 112, a digitizer 114, an ultrasonic echo signal preprocessor 116, and an image analyzer 118 connected in series to one another. Ultrasonic signal generator 106 produces both therapeutic denervation or tumor ablation signals and outgoing diagnostic A mode signals. As discussed hereinafter, the outgoing diagnostic signals and the returning echo signals may be transmitted and picked up by transducer 11. A multiplexer or switching circuit 124 is operated by control unit 104 to switch to a receiving mode after diagnostic signals are emitted during a transmitting mode via a digital-to-analog converter 126 and a transmitter module 128.

[0038] As depicted in FIG. 1, a circulation device 212 is connected to lumens (not shown) within catheter 10 which in turn are connected to balloon 12. The circulation device 212 is arranged to circulate a liquid, preferably an aqueous liquid, through the catheter 10 to the transducer 11 in the balloon 12. The circulation device 212 may include elements such as a tank 214 for holding the circulating coolant, pumps 216, a refrigerating coil 218, or the like for providing a supply of liquid to the interior space of the balloon 12 at a controlled temperature, desirably at or below body temperature. By lowering the coolant temperature the inner radius of the circumferential treatment volume can be increased in order to protect certain structures like the inner bronchial lining from harmful temperatures. The control unit 104 interfaces with the circulation device 212 to control the flow of fluid into and out of the balloon 12. For example, the control unit 104 may include motor control devices 220 linked to drive motors 222 associated with pumps 216 for controlling the speed of operation of the pumps. Such motor control devices 220 can be used, for example, where the pumps 216 are positive displacement pumps, such as peristaltic pumps. Alternatively, or additionally, the control unit 104 may operate structures such as controllable valves 224 connected in the fluid circuit for varying resistance of the circuit to fluid flow.

[0039] The ultrasound system may further include pressure sensors 226 (FIG. 1), to monitor the liquid flow through the catheter 10 and determine the bronchial diameter and/or circumferential tissue contact as shown in FIG. 7A by detecting the point of pressure increase P without significant volume increase V which corresponds with the balloon reaching full inflation inside the bronchus and making circumferential tissue contact. The corresponding diameter can be determined through a look-up table, for instance, in a memory connected to control unit 104, where volume and pressure values are related to balloon diameters. At least one pressure sensor 226 monitors the flow of the liquid to the distal end of catheter 10 to determine if there is a blockage while another pressure sensor 226 monitors leaks in the catheter 10. While the balloon 12 is in an inflated state, the pressure sensors 226 and 228 maintain a desired pressure in the balloon preferably so that the compliant balloon occludes the bronchus and makes circumferential tissue contact.

[0040] The ultrasound system 100 incorporates a reader 228 for reading a machine-readable element on catheter 10 and conveying the information from such element to the control unit or board 104. As discussed above, the machine-readable element on the catheter may include information such as the operating frequency and efficiency of the transducer 11 in a particular catheter 10, and the control unit 104 may use this information to set the appropriate frequency and power for exciting the transducer. Alternatively, the control unit 104 may be arranged to actuate an excitation source or frequency scanner 230 to measure the transducer operating frequency by energizing the transducer at a low power level while scanning the excitation frequency over a pre-determined range of frequencies for example 1 Mhz-11 Mhz and monitoring the response of the transducer 11 to such excitation and to select the optimal operating frequency.

[0041] The ultrasonic system may be similar to that disclosed in U.S. patent application Ser. No. 14/770,941, Publication No. 2016/0008636, the disclosure of which is incorporated by reference herein.

[0042] After preparation of a human or non-human mammalian subject such as a patient (preparation of the tracheal access site), and connection of the catheter 10 to the ultrasound system, the ultrasound catheter 10 is inserted into the working channel of the bronchoscope after the bronchoscope has been advanced to the desired treatment site under visual guidance through the bronchoscope camera or electromagnetic guidance. Alternatively, a steerable sheath, preferably with ultrasound imaging capability as described in U.S. patent application Ser. No. 14/770,941, Publication No. 2016/0008636, can be used as a delivery channel for the treatment catheter. In another embodiment the treatment catheter is equipped with a steering or deflection mechanism and can be advanced directly to the treatment site as shown in FIG. 1. If the catheter combines imaging and therapeutic capabilities as described in the U.S. patent application Ser. No. 14/770,941, Publication No. 2016/0008636, this delivery method enables the fastest procedure time and is easily tolerated by the patient. Yet another embodiment provides for a guide wire 14 (FIGS. 1-4) to be delivered through the working channel of the bronchoscope to the treatment site and the ultrasound treatment catheter to be advanced over the wire after the bronchoscope has been withdrawn. This technique will allow for very small, flexible bronchoscopes to be utilized.

[0043] Once the distal end of the catheter is in position within a secondary bronchial branch ora tumor, pumps bring balloon 12 to an inflated condition as depicted in FIGS. 1 and 2. In this condition, the compliant balloon 12 engages the bronchial wall or tumor, and thus centers transducer 11 within the bronchial branch or tumor, with the axis of the transducer 11 approximately coaxial with the axis of the bronchial branch or tumor. This not only provides for a relatively homogeneous energy distribution circumferentially, but also keeps the very high energy levels close to the transducer located inside the cooling fluid where they are harmless, since ultrasound does not interact with the cooling fluid. If these peak energy levels were allowed to be located close to the bronchial wall, injury would result. Another advantage of proper centering is that the treatment volume coincides with the relatively flat portion of the 1/R curve, providing an almost constant power level throughout the treatment volume.

[0044] During treatment, the circulation apparatus, including pump 216, coils 218, and valves 224 (FIG. 1), maintains a flow of cooled aqueous liquid into and out of balloon 12, so, as to cool the transducer 11 and to protect proximal structures like the inner bronchial lining in case of a denervation procedure. The cooled balloon 12 also tends to cool the interior surface of the tumor to prevent excessive ablation temperatures and therewith a blocking effect for distal treatment areas.

[0045] In another embodiment, the ultrasound system uses transducer 11 to measure the size of the bronchus as shown in FIGS. 7B and 7C. The control unit 104 and ultrasound source or ultrasonic signal generator 106 actuate the transducer 11 to “ping” the bronchus with an ultrasound pulse or burst. The ultrasonic waves in this pulse are reflected by the bronchial wall onto transducer 11 as echoes. Transducer 11 converts the echoes to electrical echo-encoding signals as shown in FIG. 7C. The ultrasound system, particularly control unit 104 (which typically takes the form of a programmed general-purpose computer or a hardwired processor), then determines the diameter D of the bronchus by analyzing the echo signals. For example, the ultrasound system may determine the time delay between actuation of the transducer 11 to produce the “ping” and the return of echo signals. The width of the return signal represents the difference between diameter dmax and diameter dmin in case the bronchial section is not perfectly circular but oval shaped. The ultrasound system uses the measured bronchus size D to set the acoustic power to be delivered by transducer 11 during application of therapeutic ultrasonic energy for denervation or tumor ablation. For example, the control board or unit 104 may use a lookup table correlating a particular echo delay (and thus bronchial diameter D) with a particular power level. For tumor ablations the treatment diameters are known from preprocedural CT or MRI imaging or from catheter imaging. Generally, the larger the diameter, the more power should be used. While the integrated A-mode signals over the treatment volume by a cylindrical uniform transducer cannot provide for spatial resolution, a conclusion about reflectors can be made based on the magnitude of the amplitude and distance (time) of the volume-integrated A-mode signal. In other words, the presence of the balloon/tissue interface can be detected but cannot be differentiated circumferentially.

[0046] The volume integrated echo will also represent coupling of the balloon with the bronchial wall/tumor tissue as shown in FIGS. 8A and 8B. If air is trapped the echo amplitude of the balloon/bronchus interface will be significantly larger as shown in FIG. 8B than in case of complete circumferential coupling as shown in FIG. 8A. While spatial resolution is not provided by this volume integrated A-mode signal, air pockets, i.e., trapped air, can be clearly detected by analyzing the amplitude of the integrated A-mode signal at the balloon/tissue interface or the corresponding time delay between transmit and receive echo as shown in FIGS. 8A and 8B. While the integrated A-mode signals over the treatment volume cannot provide for spatial resolution, a conclusion about trapped air can be made based on the magnitude of the amplitude and distance (time) of the integrated A-mode signal, see FIGS. 8A and 8B. In other words, the presence of air at the balloon/tissue interface can be detected by analyzing the echo amplitude but the trapped air cannot be located circumferentially. If the balloon diameter is not adjusted properly to eliminate the trapped air, the energy will not be delivered completely circumferentially which will affect the efficacy of the procedure negatively.

[0047] For denervation procedures it is preferable to advance the treatment volume distal to the first bronchial bifurcation so that 2 (instead of 1) energy applications are administered on each side. This will simplify the procedure significantly since precautions such as esophageal cooling/location balloon and/or fluoroscopic imaging can be omitted if the procedure is performed in secondary versus main bronchi. In order to explain the difficulties associated with denervation in the main bronchi without causing other damage, the anatomy of the bronchial system and nerves will be described now. FIG. 1 illustrates in part the main bronchi B.sub.R and B.sub.L and the esophagus 3. As can be seen, esophagus 3 and the peri-esophageal left and right vagus nerves (not shown) are in close vicinity to the main bronchi B.sub.L and B.sub.R. Therefore, placement of treatment catheter 10 (here shown in the left main bronchus B.sub.L) has to ensure sufficient distance from esophagus 3 and periesophageal vagus nerves so that subsequent pulmonary therapy does not damage the esophagus or the vagus nerves. This can be assured by monitoring the distance of a marker balloon inside the esophagus from the ultrasound transducer by ultrasonic A mode measurements or by fluoroscopic imaging of marker and treatment balloons. Different individuals have different esophageal locations relative to the main bronchi B.sub.R and B.sub.L so that distance measurements either fluoroscopically or through ultrasound A mode analysis are required in every individual treated. Furthermore, when denervation is performed in the main bronchi (as shown in FIG. 1 for B.sub.L), tightly spaced cartilage rings will represent an obstacle in particular for ultrasound ablation. As shown in FIG. 4 the cartilage coverage is less dense in the secondary bronchi distal to the second bifurcation making this location much better suited for ultrasound denervation.

[0048] The volume integrated A-mode signal can also be analyzed to optimize positioning of the energy source or transducer 11 so that the portion of the ultrasound reflected by cartilage rings CR is minimized and the ultrasound treatment volume is positioned in a plane BC mainly between cartilage rings CR. FIG. 9A shows catheter 10, transducer 11 and balloon 12 positioned within a cartilage ring CR, that is, in a transverse plane of the cartilage ring. FIG. 9C depicts catheter 10, transducer 11 and balloon 12 positioned in a transverse plane BC between adjacent cartilage rings CR. Optimized positioning is obtained by analyzing the volume integrated A-mode signal and minimizing a circumferentially integrated cartilage echo Uc by moving the catheter 10, moving the transducer 11 inside the balloon 12 or by electronic selection of transducer sections 11′ as shown in FIG. 10. For orientation, echo signal Uc will occur distally to a bronchial wall signal Ub. In other words rather than positioning ultrasound energy sources through mechanical seating mechanisms by forcing the ultrasound source into certain positions relative to cartilage rings, as described in U.S. Patent Application Publication No. 2016/0220851, the positioning is here controlled directly by detecting cartilage echoes and adjusting the longitudinal position of ultrasound source transducer 11 to optimally deliver the ultrasound energy in between cartilage rings CR. The complete catheter 10 may be moved longitudinally until echo signal Uc is minimal or the transducer 11 inside the balloon 12 can be moved until echo signal Uc is minimal. In another embodiment transducer segments 11′ or groups thereof are activated until echo signal Uc is minimized and therewith an optimal positioning between cartilage rings CR has been obtained. This inter cartilage positioning is of particular importance and advantage when the treatment is being performed in secondary bronchi since the cartilage spacing is coarse with wider cartilage segments and gaps as in main bronchi. Also, for tumors surrounding proximal bronchial branches this inter cartilage positioning is critical.

[0049] The physician initiates the treatment through a user interface (not illustrated). In the treatment, the ultrasonic system or actuator, and particularly the control board or unit 104 and ultrasonic signal source or generator 106, energizes transducer 11 to deliver therapeutically effective ultrasonic waves to a generally toroidal impact zone or volume 13 (FIG. 2). The ultrasound energy transmitted by the transducer 11 propagates generally radially outwardly and away from the transducer 11 encompassing a full circle, or 360° of arc about the proximal-to-distal dimension or longitudinal axis of the transducer 11 and the axis of the bronchial section and/or tumor treated.

[0050] The selected operating frequency, focus-characteristic, placement, size, and the shape of the ultrasound transducer 11 allow the entire treatment zone to lie within the “ focal field” of the transducer 11. As shown in FIGS. 2 and 10, within this region an outwardly spreading, focused omni-directional (360°) cylindrical field of ultrasound waves is generated by the transducer 11. For a cylindrical transducer, the radial extent of the near field region, in which the beam can be focused, is defined by the expression L.sup.2/λ, where L is the axial length of the transducer 11 (see FIGS. 10) and λ is the wavelength of the ultrasound waves. At distances from the transducer 11 surface greater than L.sup.2/λ, the beam begins to spread axially to a substantial extent as shown in FIG. 10. However, for distances less than L.sup.2/λ, the beam does not spread axially to any substantial extent (FIGS. 2 and 10). The impact volume 13 is generally cylindrical and coaxial with the bronchial section and/or tumor treated (FIGS. 2 and 4). The impact volume extends from the balloon exterior or outer surface to an impact radius, where the intensity of the ultrasonic energy is too small to heat the tissue to the temperature range that will cause inactivation of nerves or tumor ablation.

[0051] As discussed above, the length of the transducer 11 may vary between 2 mm and 10 mm, but is preferably 6 mm, to provide a wide aperture to enable focusing. The diameter of the transducer 11 may vary between 1.5 mm and 3.0 mm, and is preferably about 2.0 mm.

[0052] The power level desirably is selected so that throughout the impact volume, solid tissues are heated to about 65° C. or more which requires sonication times of up to several minutes for tumor ablation and about 50C for denervation requiring 10 to 30 sec sonication durations. For denervation desirably all of the solid tissues within the treatment volume, including the wall of the bronchus remain well below 65° C. Thus, throughout the impact region, the solid tissues (including all of the bronchial nerves) are brought to a temperature sufficient to inactivate nerve conduction but below that which causes rapid necrosis of the tissues as in tumor ablations.

[0053] Research shows that nerve inactivation occurs at much lower temperatures and much faster than tissue necrosis. See Bunch, Jared. T. et al. “Mechanisms of Phrenic Nerve Injury During Radiofrequency Ablation at the Pulmonary Vein Orifice, Journal of Cardiovascular Electrophysiology, Volume 16, Issue 12, pg. 1318-1325 (Dec. 8, 2005), incorporated by reference herein. Since, necrosis of tissue typically occurs at temperatures of 65° C. or higher for approximately 10 sec or longer while inactivation of nerves typically occurs when the nerves are at temperatures of 42° C. or higher for several seconds or longer, the dosage of the ultrasound energy is chosen to keep the temperature in the impact volume 13 between those temperatures for several seconds or longer. Operation of the transducer within these treatment parameters thus provides a therapeutic dosage that inactivates nerves without causing damage to the secondary bronchi In addition, the circulation of cooled liquid through the balloon 12 containing the transducer 11 may also help reduce the heat being transferred from the transducer 11 to the inner layer of the bronchus. Hence, the transmitted therapeutic ultrasound energy does not damage the inner layer of the bronchus, providing a safe treatment in case of denervation.

[0054] In order to generate the therapeutic dosage of ultrasound energy for nerve inactivation , the acoustic power output of the transducer 11 typically is approximately 10 watts to approximately 100 watts, more typically approximately 10 to approximately 20 watts. The duration of power application typically is approximately 2 seconds to approximately a minute or more, more typically approximately 10 seconds to approximately 30 seconds. The dosage used for tumor ablation (necrosis) varies between 10 to 30 W for up to several minutes. The optimal dosage with a particular system to achieve the desired temperature levels may be determined by mathematical modeling or animal testing.

[0055] The impact volume 13 of the ultrasound energy encompasses the entire bronchial section treated and closely surrounding tissues, and hence encompasses all of the bronchial nerves surrounding the secondary bronchi. Therefore, the placement in the bronchus of the transducer 11 may be indiscriminate in order to inactivate conduction of all the surrounding bronchial nerves. As used in this disclosure “indiscriminate” and “indiscriminately” mean without targeting, or locating on, any specific bronchial nerves. For nerve ablation performed in particular in the secondary bronchi or for ablation of tumors located in proximal lung sections, the ultrasound source position will be optimized to lay between cartilage rings as described above with reference to FIGS. 9A to 9D.

[0056] Numerous variations and combinations of the features discussed above can be utilized. For example, the ultrasound system may control the transducer 11 to transmit ultrasound energy in a pulsed function during application of therapeutic ultrasonic energy. The pulsed function causes the ultrasound transducer 11 to emit the ultrasound energy at a duty cycle of, for example, 50%. Pulse modulation of the ultrasound energy is helpful in limiting the tissue temperature while increasing treatment times which will result in a more homogenous or even temperature distribution throughout the treatment volume.

[0057] The pulsed therapeutic function can also be designed to cause electrophoresis and enhance drug delivery to treat a lung tumor by causing cavitation which produces pressure waves to permeabilize cell membranes. This way non thermal ultrasound energy is used for targeting or controlling drug release through 2 mechanisms: Causing cell membranes to become more permeable to drugs and to disrupt the structure of the drug carrier vehicle to release the drug. These cavitation effects are possibly also advantageous for nerve ablation and to stimulate new cell creation to replace diseased cells in COVID affected lung segments.

[0058] The pulsed therapeutic function can also be interleaved with a diagnostic imaging mode when the ultrasound transducer comprises an array of separately activatable transducer elements instead of a single unitary cylindrical transducer. This way diagnostic ultrasound imaging can be obtained essentially or quasi simultaneously with the therapeutic treatment, see U.S. patent application Ser. No. 14/770,941, Publication No. 2016/0008636.

[0059] In a further variant, the balloon 12 may be formed from a porous membrane or include holes, such that cooled liquid circulated within the balloon may escape or flow from the balloon 12 against the bronchial walls or tumor tissue to improve acoustic contact and enable axial catheter movement for inter-cartilage positioning.

[0060] Typically, catheter 10 is a disposable, single-use device. The catheter 10 or ultrasonic system may contain a safety device that inhibits the reuse of the catheter 10 after a single use. Such safety devices per se are known in the art.

[0061] In yet another variant, the catheter 10 itself may include a steering mechanism which allows the physician to directly steer the distal end of the catheter. In this case a bronchoscope or sheath may be omitted.

[0062] As depicted in FIG. 5, a rotating transducer 11″ as found in mechanical intravascular ultrasound (IVUS) system (e.g., of Boston Scientific, BSX) maybe utilized. Therapeutic ultrasound pulses may be interleaved with imaging pulses to generate quasi simultaneous imaging/therapy modes.

[0063] The system (FIG. 1) circulating the coupling/cooling fluid may be configured to measure the fluid volume V and pressure P and therewith determine the bronchial diameter (FIG. 7A). Based on the measured bronchial diameter, the overall ultrasound power can be automatically optimized for denervation procedures. For tumor ablation the dosage will be calculated based on pre procedural images.

[0064] The tumor application for the devices described above takes advantage of the energy 1/r dispersion characteristics (significant depth without undue near field damage) as long as a coupling balloon is utilized. Once a lung tumor has been diagnosed with CT or MRI a guidewire is typically inserted under 3-dimensional guidance (i.e. Super Dimensions) in order to perform a biopsy. These systems combine 3D imaging with the localization of guidewires during bronchoscopy. However, treatment is typically performed later, in separate follow-up procedures. In the same biopsy procedure the guidewire may be used to advance the above-described ultrasound treatment catheter into the tumor. Depending on lesion volume, the ultrasound dose is calculated and one or more lesions are generated. Preferably, the ablation is performed under image guidance. In particular the annular array configuration of FIG. 5 provides image guidance of highest resolution which allows differentiation of tumor and normal tissues. In FIG. 5 a three element rotating annular array transducer 11″ is shown. Another way to perform the tumor ablation, image guided, is to exchange treatment and imaging catheters over the guidewire. An IVUS imaging catheter may be advanced after withdrawal of the treatment catheter to monitor the tumor ablation progress and change back to the treatment catheter if the IVUS image shows non-ablated tumor regions. Catheter exchange is simplified with length markings 204 as shown in FIG. 6.

[0065] An additional application for the devices described above is reducing negative effects of ARDS caused by COVID 19 by optimizing utilization of the remaining healthy lung capacity by preventing or reducing bronchial contraction and mucus secretion through denervation at the secondary bronchi.

[0066] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims.