Bronchial denervation using integrated A-mode signals

Abstract

The present invention relates to an apparatus and method for deactivating bronchial nerves extending along the bronchi of a mammalian subject for the treatment of asthma and related conditions. An ultrasound transducer (11) is inserted into the bronchi, for example, by advancing the distal end of a catheter (10) equipped with the transducer into the bronchial section to be treated. The ultrasound transducer is inserted into the bronchi, for example, within a distance of at least about 1 cm, encompassing the bronchi. 3 The focused ultrasound is emitted in a manner that heats tissue throughout a circular volume of influence (13) to a temperature sufficient to inactivate nerve conduction but insufficient to cause rapid tissue ablation or necrosis. Treatment can be performed without having to locate or focus on individual bronchial nerves.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to devices and related methods for the treatment of asthma and other pulmonary therapies. The present invention contemplates the use of a circumferentially focused ultrasound field. [Background technology]

[0002] Successful treatment of lung diseases such as asthma and COPD is important because these diseases are significant global health problems that reduce quality of life. Pharmacological therapies (bronchodilators, anti-inflammatory drugs, leukotriene modifiers) can be used to treat asthma, but they are not always successful and are very expensive. Asthma is a disease characterized by constriction and inflammation of the airways, which causes difficulty breathing. Wheezing, shortness of breath, and coughing are typical symptoms.

[0003] These symptoms are caused by increased mucus production, airway inflammation, and smooth muscle contraction, which leads to airway obstruction. This obstruction can be treated by scarring the bronchial wall. This remodeling of the bronchial wall stiffens the bronchi and reduces their contractility. Mechanical means and the application of heat have been proposed, as in U.S. Patent No. 6,279,949. Other methods focus on the destruction of peribronchial smooth muscle cells, as described in U.S. Patent Nos. 6,279,949 and 6,279,949. Other techniques involve applying RF energy to the bronchial wall, thereby directly widening the bronchi through an undisclosed process, as in U.S. Patent Nos. 6,279,949 and 6,279,949. In any case, the bronchial wall is damaged, and therefore the treatment must be performed in stages, as described in U.S. Patent No. 6,279,949. U.S. Patent No. 6,279,949 describes the application of thermal shock with an injectable agent.

[0004] U.S. Patent No. 6,269,949 (Patent Document 7) proposes inactivating nerve conduction around the bronchial tubes by mechanical action, i.e., puncturing, tearing, or cutting the nerve tissue. U.S. Patent No. 6,269,949 (Patent Document 8) describes ablation of nerve tissue by applying energy (RF, HIFU, microwave, radiation, or thermal energy) directly to the nerve percutaneously. However, it does not teach how to identify the nerve's location in order to focus the energy (i.e., HIFU) on the nerve. This is problematic because nerves are too small to be visualized with standard ultrasound, CT, or MRI imaging. Therefore, the focus of the energy field cannot be predicted and aligned with the target or nerve location. U.S. Patent No. 6,269,949 (Patent Document 9) teaches denervation by applying RF energy to the bronchial wall with a catheter placed inside the bronchial lumen. It is proposed to protect the bronchial wall by simultaneously cooling it. Because RF ablation is limited to the electrode contact area, this is, of course, a very time-consuming treatment. Therefore, to achieve a larger ablation area with a higher probability of affecting the nerve, multiple ablation areas must be stitched together. The cooling effect may significantly limit efficacy.

[0005] However, the prior art does not teach a method for selectively targeting primarily nerves without affecting the bronchial wall and surrounding tissue. There is a need for devices and methods for selectively ablating bronchial nerves without damaging the bronchial wall and surrounding tissue. If this could be achieved, treatment would be easier and faster to administer. Today's multiple treatments (see U.S. Patent No. 5,629,492 and the Alair System description, BSX) could be reduced to a single treatment, which would be much better tolerated by patients, especially those with COVID-19. Furthermore, by selectively targeting nerves rather than tissue, a single ablation of more proximal nerves (which transmit signals to distal bronchial segments) would have the same clinical effect as treating the bronchial tree from proximal to distal with greater energy delivery.

[0006] To illustrate the difficulty of denervating bronchi without causing other damage, the anatomy of the bronchial system and nerves will now be described. Shown in Figure 6 is an illustration of the bronchial tree. Figure 3 shows a cross section of a bronchus surrounded by smooth muscle (7) and nerves (6). Furthermore, Figure 5 shows the bronchus (B R These figures show longitudinal sections of the bronchial nerve (6) and its adjacent nerve (6). As can be seen from these two figures (3 and 5), the bronchial nerve (6) surrounds the bronchus. Different individuals have nerves (6) at different circumferential locations around the bronchus. Furthermore, nerves may be at different radial distances from the central axis of the bronchus where the energy emitter (11) is placed (Figure 3). It is impractical to locate bronchial nerves by reference to anatomical landmarks. Furthermore, it is difficult or impossible to locate individual bronchial nerves using conventional in vivo imaging techniques. Furthermore, when denervating the main bronchus, the cartilage rings are particularly an obstacle to ultrasound ablation. Patent Document 10 proposes mechanical means and overlapping ultrasound beams to mount an ultrasound source so that ultrasound energy is applied between or behind the cartilage rings. Apart from mechanical placement, no device or method is taught for ensuring optimal intercartilage placement. A device and method that easily ensures placement of an energy source between the cartilage rings is needed. It would be desirable to know whether the ultrasound treatment volume is actually located between the annulus or whether the ultrasound is being reflected by the annulus, and it would be desirable to enable full circumferential ultrasound transmission with diameter-dependent dose optimization.

[0007] The inability to locate and target bronchial nerves (6) makes it difficult to interrupt or terminate bronchial nerve activity using non-surgical techniques without causing damage to the bronchial wall or other side effects. For example, attempting to apply energy to bronchial nerves may cause bronchial stenosis or necrosis. Furthermore, the inability to target and locate bronchial nerves (6) makes it difficult to ensure that bronchial nerve activity has been interrupted sufficiently to achieve an acceptable therapeutic treatment.

[0008] Patent Document 9 proposes the use of a radiofrequency ("RF") emitter connected to a catheter inserted into the bronchial tree. The RF emitter is placed against the bronchial wall, and RF energy is emitted to heat bronchial nerves that happen to be in close proximity to the emitter to a temperature that reduces their activity. To treat all the nerves surrounding the bronchi, the RF emitter must be repositioned multiple times inside each bronchus. To protect the bronchial wall, this RF heating is combined with cooling, further complicating the procedure. The emitter may miss some bronchial nerves, resulting in incomplete treatment. Furthermore, the RF energy source (electrode) must be in contact with the bronchial wall to heat the surrounding tissue and nerves, which can cause damage or necrosis to the bronchial inner wall.

[0009] Patent Document 8 also proposes the use of high-intensity focused ultrasound (HIFU) to deactivate bronchial nerves. It is unclear how the high-intensity focused ultrasound (HIFU) field can be aligned with the target bronchial nerve. Current technology makes it difficult or impossible to visualize and target bronchial nerves, and aligning this high-intensity field with bronchial nerves is difficult or impossible because bronchial nerves can be located at different radial distances and circumferential positions from the central axis of the bronchus. This latter problem is exacerbated in patients with bronchi that vary greatly in shape and thickness. Furthermore, the focus can only encompass a small portion of each bronchial nerve along the length of the bronchus. Because nerves tend to regenerate, a small treatment area allows nerves to reconnect in a short period of time.

[0010] For many years, ultrasound has been used to promote cell repair, stimulate bone cell growth, enhance drug delivery to specific tissues, and image internal body tissues. Additionally, high-intensity focused ultrasound has been used to heat and ablate tumors and tissues within the body. Tissue ablation has been performed almost exclusively with high-intensity focused ultrasound because the emitted ultrasound energy is concentrated at a specific location, allowing for precise, deep tissue necrosis without affecting surrounding tissue and intermediate structures through which the ultrasound energy must pass.

[0011] US Patent No. 5,949,999 describes the use of highly collimated ultrasound energy, rather than high-intensity focused ultrasound, to ablate tissue to form a scar ring within the pulmonary vein for blocking the transmission of electrical signals to the heart (pulmonary vein isolation). [Prior art documents] [Patent documents]

[0012] [Patent Document 1] U.S. Patent No. 8,267,094 [Patent Document 2] US Patent Application Publication No. 2012 / 0143099 [Patent Document 3] U.S. Patent No. 7,906,124 [Patent Document 4] U.S. Patent No. 7,740,017 [Patent Document 5] U.S. Patent No. 8,161,978 [Patent Document 6] European Patent No. 2405841 [Patent Document 7] US Patent Application Publication No. 2012 / 0203216 [Patent Document 8] US Patent Application Publication No. 2011 / 0000118 [Patent Document 9] U.S. Patent No. 8,088,127 [Patent Document 10] US Patent Application Publication No. 2016 / 220851 [Patent Document 11] U.S. Patent No. 6,117,101 Summary of the Invention [Means for solving the problem]

[0013] One aspect of the present invention is to provide an apparatus for inactivating bronchial nerve conduction in a human or non-human mammalian subject. The apparatus according to this aspect of the invention preferably includes an ultrasound transducer suitable for insertion into the bronchial system of the mammalian subject. The ultrasound transducer is desirably configured to deliver a ring of focused ultrasound energy (see Figures 8A-8C and 12). The apparatus according to this aspect of the invention also desirably includes an actuator electrically connected to the transducer. The actuator most preferably extends over an area of ​​at least about 1 cm encompassing the bronchus, such that circumferentially focused ultrasound energy is applied at therapeutic levels sufficient to inactivate bronchial nerve conduction throughout the entire volume of effect. 3 The ultrasound transducer is configured to control the ultrasound transducer to deliver focused ultrasound energy to a volume of influence of the cartilage. This energy level is approximately one-tenth of the energy level typically applied for tissue necrosis. As explained further below, such treatment levels are below the level required for tissue ablation. Utilizing focused instead of unfocused ultrasound further increases the safety margin, as areas outside the bronchi where nerves are located are exposed to higher energy levels than areas of the bronchial wall through which the ultrasound pressure waveform energy passes. The present invention further contemplates the use of a position sensor to ensure treatment between the cartilage.

[0014] The device further includes a catheter with a distal end and a proximal end, with the transducer attached to the catheter adjacent the distal end, configured and positioned within a compliant balloon that contacts the bronchial wall. The compliant balloon is filled with a circulating coolant that conducts ultrasonic energy from the transducer to the bronchial wall and surrounding tissue and nerves. The coolant also transports excess heat away from the transducer. Approximately half of the electrical energy supplied to the transducer is converted to heat, and the other half is converted to ultrasonic energy. To be clinically viable, the energy level and balloon diameter must be tailored to the bronchial diameter at the ablation site. If these parameters are not tailored (i.e., a constant energy setting for all bronchial diameters), there is a significant risk that the ultrasonic ablation will cause either too much damage or insufficient energy to adequately ablate and denervate the lung. Therefore, to be effective across a variety of bronchial diameters, the device must be able to adjust the ultrasonic output settings according to the diameter of the bronchial airway. Furthermore, if the inflated diameter of the balloon is not large enough for the balloon to contact the bronchus circumferentially, energy will not be delivered to the bronchial wall circumferentially and denervation will be incomplete. Therefore, the device of the present invention must also be able to detect whether the balloon / bronchus circumferential contact is complete or partial.

[0015] The transducer may be configured to transmit ultrasound energy in a 360° cylindrical fashion around the longitudinal transducer axis, and the catheter may be constructed and arranged to hold the transducer axis generally parallel to the axis of the bronchus. The focusing mechanism may be electronic, such as a phased array, or may include a fluid lens 12' (FIG. 8B) or a mechanical lens 322 (FIG. 8C). In the case of a fluid lens implemented by a balloon 12' of appropriate configuration as shown in FIG. 8B, the diameter of the focal ring can be varied by the balloon pressure, by pressure-changing the shape of the compliant balloon 12', thereby changing the lens effect. Of course, the electronic focusing method can also be adjusted based on the diameter of the bronchus (i.e., the balloon), which can be calculated from the balloon pressure as shown in FIG. 10A, or by ultrasound detection (see FIGS. 10B and 11).

[0016] Another form is a rotating single crystal or annular array transducer 11'' (as shown in FIG. 12) such as those used in mechanical IVUS systems (i.e., BSX). Therapeutic ultrasound pulses and / or complete rotations can be alternated with imaging pulses to produce a near-simultaneous imaging / treatment mode. When an annular array transducer 11'' such as that shown in FIG. 12 is utilized, very high resolution images can be obtained. For denervation applications, it is desirable to defocus the therapeutic annular array beam to some extent to avoid harmful energy densities in the focal region and ensure a sufficiently large treatment volume to maximize effectiveness.

[0017] The coupling / cooling fluid circulating system may measure fluid volume and pressure, thereby determining bronchial diameter. See FIG. 10A. When the balloon makes circumferential contact with the bronchial tube, the system detects a pressure increase without a significant volume increase, corresponding to the balloon / bronchial diameter. Based on this bronchial diameter, the overall ultrasound power can be automatically optimized for different diameters.

[0018] A further aspect of the present invention provides a method for inactivating bronchial nerve conduction in a mammalian subject. The method according to this aspect of the invention preferably comprises the steps of inserting an ultrasound transducer into a bronchus of the subject and inserting an ultrasound transducer into at least about 1 cm of the bronchus encompassing the bronchus. 3 and operating the transducer to deliver therapeutically effective ultrasound energy to a circular volume of influence of the bronchial tube. Desirably, the therapeutically effective ultrasound energy is applied in a manner that inactivates conduction of all nerves within the volume of influence. For example, operating the transducer may heat solid tissue within the volume of influence, including nerves within the volume of influence, to above 42°C while maintaining a bronchial wall temperature below 65°C.

[0019] Because the affected volume is relatively large and tissue throughout the affected volume preferably reaches a temperature sufficient to inactivate nerve conduction, preferred methods according to this aspect of the invention can be successfully performed without determining the actual location of, and without targeting or focusing on, bronchial nerves. Treatment can be performed without measuring tissue temperature. Furthermore, preferably, the treatment is performed without damaging the bronchial tubes.

[0020] Further aspects of the present invention provide probes that can be used in the methods and devices described above, as well as devices incorporating means for carrying out the steps of the methods described above. [Brief explanation of the drawings]

[0021] [Figure 1] 1 is a partial anatomical view of typical main bronchial trunks BL and BR and associated structures, and a partial block diagram of a system for treating pulmonary conditions according to the present invention. [Figure 2] 1 is a partial side view and cross-sectional view of the bronchus of a treatment catheter 10 advanced through a bronchoscope 5 into the right bronchus, illustrating the ultrasound treatment volume 13. FIG. [Figure 3]FIG. 1 is a schematic cross-sectional view of a bronchus with a central ultrasound transducer 11 surrounded by coolant within a compliant balloon. [Figure 4] 4A and 4B are partial side views and partial longitudinal cross-sections of a treatment device and a bronchus, respectively, showing the effect on power distribution of proper alignment in FIG. 4A compared to a non-centered, misaligned ultrasound transducer in FIG. 4B. [Figure 5] FIG. 1 is a lateral view of the right bronchus showing the adjacent nerves running parallel to the bronchus. [Figure 6] FIG. 1 is a schematic front view showing the entire bronchial tree. [Figure 7] 1 is a flow chart illustrating steps in treating a bronchus in accordance with the present invention. [Figure 8] 8A-8C are diagrams illustrating different focus adjustment mechanisms for an ultrasound catheter for use in a method according to the present invention. [Figure 9] 9A to 9E are diagrams illustrating various catheter delivery methods that do not use a bronchoscope. [Figure 10A] 1 is a graph of a pressure measurement technique for determining bronchial diameter. [Figure 10B] 1 is a schematic side view of an apparatus according to the present invention for use in determining bronchial diameter by ultrasound detection; [Figure 11] 1 is a schematic cross-sectional view of a non-circular bronchus and a graph illustrating ultrasonic detection in the bronchus according to the present invention. [Figure 12] 1 is a schematic cross-sectional view of a rotational treatment and imaging catheter according to the present invention; [Figure 13] Figures 13A and 13C are cross-sectional views of a main bronchus with an ultrasound catheter inserted with longitudinal position sensing and position optimization, showing the catheter, particularly the ultrasound transducer and balloon, at different longitudinal positions within the bronchus relative to its cartilaginous rings. Figures 13B and 13D are graphs showing the integrated A-mode ultrasound echo magnitude for the ultrasound catheter, transducer, and balloon positions shown in Figures 13A and 13C, respectively. [Figure 14] Figure 14A is a diagram of a portion of the left (301) and right (302) main bronchi of a human bronchial tree, showing an air-filled balloon (315) placed in the esophagus (303) to allow distance measurement of the aorta (304) and esophagus. Figure 14B is a graph of the integrated ultrasound echo signal intensity as a function of time after emission of an ultrasound pulse for the configuration of Figure 14A. [Figure 15] 15A and 15B are graphs showing the magnitude of the integrated A-mode signal for perfect (15A) and imperfect (15B) balloon-bronchus coupling. DETAILED DESCRIPTION OF THE INVENTION

[0022] An instrument according to one embodiment of the present invention (FIG. 2) is advanced through a working channel of a bronchoscope 5. Alternatively, the ultrasound catheter 10 can be advanced directly through a sheath or through an oral intubation device without a delivery instrument (FIG. 1). The sheath or ultrasound catheter 10 may be in the form of a generally elongated tube having a proximal end, a distal end, and an axis from the proximal end to the distal end. As used herein with respect to an elongated element for insertion into the body, the term "distal" refers to the end that is first inserted into the body, i.e., the tip during advancement of the element into the body, while 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, such that actuation of the steering control by an operator bends the distal end of the sheath or catheter laterally relative to the axis. The sheath or ultrasound catheter 10 is inserted into the left bronchus B via an oral intubation device 202, as shown for a directly delivered ultrasound catheter 10 in FIG. 9B. L or right bronchus B R(FIG. 1). One delivery technique (as shown in FIG. 9A) may include an optical fiber 203 within a steerable sheath or within the central lumen of the ultrasound catheter. After passing through the tracheal bifurcation visible through the optical fiber, one of the treatment areas is reached, and the optical fiber 203 is withdrawn from the sheath and replaced with an ultrasound treatment catheter 10 advanced to the optical fiber insertion length. Another delivery method relies on a length indicator 204 (FIG. 9B) on the ultrasound catheter 10 or sheath. Once a certain length of the sheath / catheter shaft (determined pre-procedure by CT, MRI, or scope) has been inserted, the treatment balloon 12 or distal sheath end has reached the target area, as shown in FIG. 9B. Yet another delivery variation is to measure the degree of bending of the distal catheter section with a strain gauge 206 (FIGS. 9C and 9D). The catheter 10 remains relatively straight as long as it is positioned within the trachea. As shown in FIG. 9D, the distal catheter section is inserted into the right bronchus B. R (or left bronchus B L ) a large bend will be measured. Another delivery method is to monitor the bronchial diameter either by inflation of the balloon 12 in FIG. 10B or by ultrasound measurement as shown in FIG. 11. The carina has been crossed when a significant decrease in diameter (approximately 50%) is measured, as shown in FIG.

[0023] The device includes a catheter 10 having a proximal end, a distal end, and an axis extending from the proximal end to the distal end, which preferably coincides with the axis of the bronchus in the state shown in FIG. 4A. Alignment with the axis of the bronchus provides a more uniform energy distribution throughout the cylindrical or annular treatment volume, as shown in FIG. 4A by the superimposed curves 208a, 208b of ultrasonic power as a function of radial distance or displacement from the transducer 11 within the balloon 12 at the distal end of the catheter 10. If misaligned, the energy level will vary significantly from side to side, as shown by the power curves 210a, 210b in FIG. 4B. This asymmetry in the applied ultrasonic power distribution will cause wall damage on one side (210a) and be ineffective at ablating nerves on the other side (210b). Central alignment results in a flatter portion of the 1 / R curve defining the energy distribution within the treatment volume, as shown in FIG. 4A.

[0024] Catheter 10 has a compliant balloon 12 attached to its distal end. In its inflated state (FIGS. 2 and 3), balloon 12 fits against the bronchial wall, thereby allowing ultrasound waves to pass from transducer 11 to the bronchial wall and surrounding tissue 7 (FIG. 3).

[0025] The ultrasound transducer 11 (FIG. 3) is mounted adjacent to the distal end of the catheter 10 within the balloon 12. The transducer 11 is preferably formed from a ceramic piezoelectric material, is tubular, and has a cylindrical outer surface that rotates about an axis from the proximal end to the distal end of the transducer 11. The transducer 11 typically has an axial length of about 2 to about 10 mm, preferably about 6 mm. The outer diameter of the transducer 11 is about 1.5 to 3 mm, preferably 2 mm. The transducer 11 also has a conductive coating (not shown) on its inner and outer surfaces. Therefore, the transducer may be physically attached to a metal support tube (not shown), which is then attached to the catheter 10. The coating is 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 that is electrically coupled to the ultrasound system. A lumen (not numbered) extends between the proximal and distal ends of the catheter 10, and a wire 110 extends from the transducer 11 through the lumen to the proximal end of the catheter 10.

[0026] The transducer 11 is configured so that ultrasonic energy generated by the transducer is primarily emitted from the exterior or outer surface (not separately labeled). Accordingly, the transducer may include features configured to reflect ultrasonic energy directed toward the interior of the transducer, such that the reflected outward energy enhances ultrasonic vibrations at the exterior surface. For example, the support tube and transducer 11 may be configured so that energy radiated from the interior surface of the transducer 11 is redirected outward, increasing the overall efficiency of the transducer. In this embodiment, ultrasonic energy generated by the transducer 11 is reflected off the interior mounting to enhance the ultrasonic energy propagating from the transducer 11, thereby ensuring that the ultrasonic energy is directed outward from the exterior surface of the transducer 11.

[0027] The transducer 11 is also configured to convert ultrasound waves impinging on the external surface into electrical signals on the wire 110. While the A-mode signal integrated over the treatment volume cannot provide the spatial resolution of an imaging transducer, conclusions about the bronchial lumen can be made based on the magnitude of the volume-integrated A-mode signal's amplitude and distance (time). If the reflecting structure is not perfectly circular, the width of the reflected signal is mathematically related, e.g., proportional, to the difference between the maximum bronchial diameter dmax and the minimum diameter dmin (see FIG. 11). In other words, the transducer 11 can function as either an ultrasound emitter or an ultrasound receiver. The receive mode is particularly important for array-type transducers, such as those described in U.S. Patent Application No. 14 / 770,941 and Publication No. 2016 / 0008636, because the array-type transducer 11 can electronically focus the received echoes using phased array processing to obtain high-resolution images.

[0028] The transducer 11 is designed to operate at a frequency ranging from about 1 MHz to about several tens of MHz, typically about 10 MHz. The actual frequency of the transducer 11 will typically vary somewhat depending on manufacturing tolerances. The optimal operating frequency of the transducer may be encoded in a machine-readable or human-readable element (not shown), such as a digital memory or barcode, affixed to the catheter. Alternatively, the readable element may encode a serial number or other information identifying the individual catheter, and the optimal operating frequency may be retrieved from a central database accessible over a communications link such as the Internet.

[0029] The ultrasound system, also referred to herein as an actuator, is removably connected to the catheter 10 and transducer 11 via a plug connector 102 (FIG. 1). A control unit 104 and an ultrasound signal generator or waveform generator 106 are configured to control the amplitude and timing of electrical signals to control the power level and duration of the ultrasound frequency signal emitted by the transducer 11. The energization circuit 100, including the control unit 104 and the ultrasound signal generator 106, also includes a detection subcircuit 108 configured to detect the electrical signals generated by the transducer 11 and transmitted via wires 110 and communicate the signals to the control unit 104. More specifically, the detection subcircuit 108 includes a receiver or echo signal extractor 112, a digitizer 114, an ultrasound echo signal preprocessor 116, and an image analyzer 118, connected in series. The ultrasound signal generator 106 generates both the therapeutic denervation signal and the transmitted diagnostic imaging signal. As described below, the transmitted imaging signals and the reflected echo signals may be transmitted and detected by a circular array 120 of transducer elements 122 operating as a phased array. Thus, the transducer 11 may include an axial array of the circular array 120 of transducer elements 122. A multiplexer or switching circuit 124 is operated by the control unit 104 to switch to a receive mode after the imaging signals are emitted during the transmit mode via a digital-to-analog converter 126 and a transmit module 128.

[0030] As shown in FIG. 1 , the circulator 212 is connected to a lumen (not shown) within the catheter 10, which in turn is connected to the balloon 12. The circulator 212 is configured to circulate a liquid, preferably an aqueous liquid, through the catheter 10 to the transducer 11 within the balloon 12. The circulator 212 may include elements such as a tank 214 for holding circulating coolant, a pump 216, and a refrigeration coil 218 to provide liquid to the interior space of the balloon 12 at a controlled temperature, preferably below body temperature. The control unit 104 interfaces with the circulator 212 to control the flow of liquid into and out of the balloon 12. For example, the control unit 104 may include a motor controller 220 coupled to a drive motor 222 associated with the pump 216 to control the operating speed of the pump. Such a motor controller 220 may be used, for example, when the pump 216 is a positive displacement pump, such as a peristaltic pump. Alternatively or additionally, the control unit 104 may operate structures, such as controllable valves 224, connected within the fluid circuit to vary the circuit's resistance to fluid flow.

[0031] The ultrasound system monitors the fluid flow through the catheter 10 to identify the bronchus B L or B R The catheter 10 may further include a pressure sensor 226 (FIG. 1) to determine the bronchial diameter as shown in FIG. 10A by detecting the point of pressure increase without a significant volume increase corresponding to the balloon reaching full inflation within the bronchial B. The corresponding diameter can be determined via a look-up table, for example, via a look-up table in a memory connected to the control unit 104 in which volume / pressure values ​​are associated with diameters. At least one pressure sensor 226 monitors the flow of fluid into the distal end of the catheter 10 to determine if there is an obstruction, and another pressure sensor 226 monitors for leaks within the catheter 10. While the balloon 12 is in an inflated state, the pressure sensors 226, 228 preferably detect the pressure of the compliant balloon against the bronchial B. L or B RMaintain the desired pressure in the balloon to occlude the

[0032] The ultrasound system 100 incorporates a reader 228 for reading a machine-readable element on the catheter 10 and communicating information from that element to the control unit or console 104. As mentioned above, the machine-readable element on the catheter 10 may contain 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 configured to operate the excitation source or frequency scanner 230 to measure the operating frequency of the transducer by energizing the transducer at a low power level while scanning excitation frequencies over a predetermined frequency range, e.g., 8.5 MHz to 10.5 MHz, and to monitor the response of the transducer 11 to such excitation to select the optimal operating frequency.

[0033] The ultrasound system can be similar to that disclosed in U.S. Patent Application No. 14 / 770,941, Publication No. 2016 / 0008636, the disclosure of which is incorporated herein by reference.

[0034] A method according to an embodiment of the present invention is shown in flowchart form in FIG. 7. After preparation of a human or non-human mammalian subject, such as a patient (tracheal access site preparation), and connection of the catheter 10 to an ultrasound system, the bronchoscope is advanced to the desired treatment site using visual guidance via a bronchoscope camera or fiber optics (steps 1202, 1204), after which the ultrasound catheter 10 is inserted into the working channel of the bronchoscope (step 1206). Alternatively, a steerable sheath, preferably one with ultrasound imaging capabilities as described in U.S. Patent Application No. 14 / 770,941, Publication No. 2016 / 0008636, can be used as the delivery channel for the treatment catheter. In another embodiment, the treatment catheter includes a steering or deflection mechanism and can be advanced directly to the treatment site, as shown in FIG. As described in U.S. Patent Application No. 14 / 770,941 and Publication No. 2016 / 0008636, when a catheter combines imaging and therapeutic functions, this delivery method allows for the fastest procedure time and is easily tolerated by the patient. In yet another embodiment, a guidewire 14 (FIG. 2) is delivered to the treatment site through the working channel of the bronchoscope, and the ultrasound treatment catheter is advanced over the wire after the bronchoscope is withdrawn. This technique allows for the use of very small and flexible bronchoscopes.

[0035] Once the distal end of the catheter is in place within the main bronchus, as shown in Figures 2 and 3, the balloon 12 is inflated with a pump (steps 1210 and 1212 in Figure 7). In this state, the compliant balloon 12 fits into the bronchial wall, thus centering the transducer 11 within the bronchus, with the axis of the transducer 11 approximately coaxial with the axis of the bronchus. This not only provides a relatively uniform energy distribution circumferentially, but also maintains very high energy levels near the transducer, which is located within the cooling fluid and is harmless because the ultrasound does not interact with the fluid (see Figure 4). If these peak energy levels were located near the bronchial wall (1), damage would occur. These two situations are illustrated in Figures 4A and 4B. In Figure 4A, the ultrasound transducer 11 is properly centered and penetrates the bronchus B. L or B R The energy is distributed without causing damage to the bronchial wall. Another advantage of proper central alignment is that the treatment volume coincides with a relatively flat portion of the 1 / R curve, providing a nearly constant power level throughout the treatment volume. In Figure 4B, the transducer 11 is not centrally positioned, resulting in a non-uniform power distribution at the periphery. Also, the transducer 11 is positioned off-axis (due to a balloon diameter that is too small), exposing the bronchial wall to peak power levels that could cause wall damage.

[0036] During treatment (step 1214 of FIG. 7), the circulation system, including pump 216, coil 218, and valve 224 (FIG. 1), maintains a flow of cooled aqueous liquid into and out of balloon 12 to cool transducer 11. The cooled balloon 12 also cools bronchus B. L , B R The fluid flowing within balloon 12 may contain an x-ray contrast agent to aid in visualization of the balloon under fluoroscopy and confirmation of proper placement.

[0037] In another embodiment, the ultrasound system is L , BR The ultrasound system uses a transducer 11 to measure the size of the bronchi (see FIG. 6). A control unit 104 and an ultrasound source or ultrasound signal generator 106 operate the transducer 11 to "probe" the bronchi with low-power ultrasound pulses, as shown in FIG. 11. These pulses of ultrasound are reflected by the bronchial walls as echoes to the transducer 11. The transducer 11 converts the echoes into electrical echo-coded signals. The ultrasound system, and in particular the control unit 104 (which typically takes the form of a programmed general-purpose computer or hard-wired processor), then determines the location of the bronchi B by analyzing the echo signals. L or B R The ultrasound system determines the diameter of the bronchial tube. For example, the ultrasound system can determine the time delay between the actuation of the transducer 11 generating the "sound wave" and the return of the echo signal. The width of the return signal indicates the difference between the diameter dmax and the diameter dmin when the bronchial cross-section is elliptical rather than perfectly circular (see Figure 11). The ultrasound system uses the measured bronchial size to set the acoustic power output by the transducer 11 when applying therapeutic ultrasound energy in a later step. For example, the control panel or control unit 104 can use a lookup table that correlates a specific echo delay (and therefore bronchial diameter) with a specific power level. Generally, the larger the diameter, the more power is required. While the A-mode signal integrated over the treatment volume with a cylindrical, uniform transducer cannot provide spatial resolution, conclusions about reflectors can be made based on the magnitude of the volume-integrated A-mode signal's amplitude and distance (time). In other words, the presence of a balloon / tissue interface can be detected, but it cannot distinguish in the circumferential direction.

[0038] The volume-integrated echo also indicates the coupling between the balloon and the bronchial wall, as shown in Figures 15A and 15B. In the case of trapped air, the echo amplitude at the balloon / bronchial interface will be significantly larger than in the case of perfect circumferential coupling as shown in Figure 15A, as shown in Figure 15B. While this integrated A-mode signal does not provide spatial resolution, it is possible to clearly detect air pockets, i.e., trapped air, by analyzing the amplitude of the integrated A-mode signal at the balloon / bronchial interface and the corresponding time delay between the transmitted and received echoes, as shown in Figures 15A and 15B. Although the integrated A-mode signal over the treatment volume does not provide spatial resolution, conclusions about trapped air can be made based on the magnitude of the integrated A-mode signal amplitude and distance (time) (see Figures 15A and 15B). In other words, the presence of air at the balloon / tissue interface can be detected, but the circumferential location of the trapped air cannot be determined. If the balloon diameter is not properly adjusted to eliminate trapped air, energy will not be fully delivered to the surroundings, which will negatively affect the efficacy of the treatment.

[0039] The volume-integrated A-mode signal can also be analyzed to detect any air-filled spaces within the treatment volume, i.e., an air-filled esophagus 303, as shown in Figure 14A, with an air-filled balloon catheter 315 placed in the esophagus 303. The air-filled balloon 315 in proximity to the distal end of the transducer catheter 10 will be recorded as an artifact in the volume-integrated A-mode signal, as shown in the graph of Figure 14B. To avoid nerve damage around the esophagus, the treatment catheter 10 should be placed within the bronchus B until the esophageal signal or artifact disappears, in other words, until the esophagus is located outside the treatment volume. L or B RIn extreme cases, it may be necessary to advance the treatment volume distal to the first bifurcation so that two energy applications are performed on that particular left or right side instead of one. As an additional safety measure, the air in the esophageal balloon 315 can be replaced with circulating coolant after distance detection to further reduce the possibility of collateral damage to the esophagus. Otherwise, esophageal fistula and / or damage to the vagus nerve surrounding the esophagus may occur.

[0040] The volume-integrated A-mode signal can also be analyzed to optimize the placement of the energy source or transducer 11 so that the portion of ultrasound reflected by the cartilage rings CR is minimized and the ultrasound treatment volume is primarily located in the plane BC between the cartilage rings CR. FIG. 13A shows the catheter 10, transducer 11, and balloon 12 positioned within the cartilage ring CR, i.e., in the transverse plane of the cartilage ring. FIG. 13C shows the catheter 10, transducer 11, and balloon 12 positioned in the transverse plane BC between adjacent cartilage rings CR. Optimized placement can be achieved by analyzing the volume-integrated A-mode signal to minimize the circumferentially integrated cartilage echo Uc by moving the catheter 10, moving the transducer 11 within the balloon 12, or electronically selecting the transducer portion as shown in FIG. 8A. Directionally, the echo signal Uc occurs distal to the bronchial wall signal Ub. In other words, rather than positioning the ultrasonic energy source through a mechanical placement mechanism by forcing the source into a specific position relative to the cartilage rings as described in U.S. Patent No. 6,277,999, positioning is now controlled directly by detecting cartilage echoes and adjusting the longitudinal position of the ultrasound source transducer 11 to optimally deliver ultrasonic energy between the cartilage rings CR. The entire catheter can be moved longitudinally until the echo signal Uc is minimized, or the transducer within the balloon can be moved until the echo signal Uc is minimized. In another embodiment, multiple portions or groups of transducers are activated until the echo signal Uc is minimized, thereby achieving optimal positioning between the cartilage rings CR.

[0041] In any method of generating and analyzing an integrated A-mode signal, insertion of the ultrasound transducer 11 into the bronchial tree can be performed by any of the methods described herein, such as (i) through a working channel of a bronchoscope under visual guidance, (ii) through a steerable sheath, (iii) using a steerable ultrasound catheter through an oral intubation device, (iv) under optical image guidance using an optical fiber inserted through the central lumen of a steerable ultrasound treatment catheter, or (v) directly through an oral intubation device without a sheath or bronchoscope using a steerable ultrasound catheter with a distance scale indicator to monitor the extent of insertion after performing a CT or MRI procedure to confirm the distance along the bronchial tree to the bronchial segment. The ultrasound transducer may be attached to the distal end of a catheter, and inserting the ultrasound transducer into the bronchial tree includes inserting the catheter such that the ultrasound transducer is positioned at a desired operating position determined at least in part by the bend radius of the distal catheter portion as monitored via a strain gauge. The desired catheter position may be determined in part by monitoring the diameter of the trachea and bronchial branches, as described herein.

[0042] The physician initiates treatment through a user interface (not shown). During treatment, the ultrasound system or actuator, specifically the control panel or unit 104 and the ultrasound signal source or generator 106, energizes the transducer 11 to deliver therapeutically effective ultrasound waves to the volume of effect 13 (FIG. 2). The ultrasound energy transmitted by the transducer 11 propagates generally radially outward, encompassing a full circle around the proximal-distal dimension of the transducer 11 or a full circle around the longitudinal axis of the transducer 11 and the axis of the bronchial segment being treated, i.e., a 360° arc.

[0043] The selected operating frequency, focal characteristics, placement, size, and shape of the ultrasound transducer 11 allow the entire bronchial segment and bronchial nerves to be located within the "focal region" of the transducer 11. Within this region, an outwardly extending, focused, omnidirectional (360°) cylindrical field of ultrasound is generated by the transducer 11, as shown in Figure 2. For a cylindrical transducer, the radial area of ​​the near-field region onto which the beam can be focused is given by the equation L 2 / λ, where L is the axial length of the transducer 11 and λ is the wavelength of the ultrasonic wave. 2 At distances from the surface of the transducer 11 greater than / λ, the beam begins to diverge axially to a significant extent. 2 At distances less than λ / λ, the beam does not diverge axially to a substantial extent (FIG. 2) and can be focused. As used herein, the term "focused" refers to a beam whose intensity increases in the direction of propagation of the beam away from the transducer 11. The volume of influence 13 is generally cylindrical and coaxial with the bronchial segment being treated (FIG. 2). The volume of influence extends from the exterior or outer surface of the balloon to a radius of influence where the intensity of the ultrasound energy is low enough to heat tissue to a temperature range that will cause neural deactivation.

[0044] As mentioned above, the length of the transducer 11 can vary between 2 mm and 10 mm, preferably 6 mm to provide a wide aperture that allows for focusing. The diameter of the transducer 11 can vary between 1.5 mm and 3.0 mm, preferably about 2.0 mm. The dose is selected so that the radius of the volume of influence (focal region) 13 is preferably less than 5 mm from the balloon surface, not only for its therapeutic effect but also to encompass all treated bronchial segments and adjacent bronchial nerves within an average radius of less than 5 mm from the balloon surface, without transmitting damaging ultrasound energy to associated structures, such as the esophagus 3 shown in FIG. 1 and the esophagus 303 shown in FIG. 14A.

[0045] Preferably, the power level is selected so that throughout the affected volume, solid tissue is heated to above about 42° C. for several seconds or more, but preferably all solid tissue, including the bronchial walls, remains well below 65° C. Thus, throughout the affected region, solid tissue (including all of the bronchial nerves) is brought to a temperature sufficient to inactivate nerve conduction, but below a temperature that would cause rapid necrosis of the tissue.

[0046] Research has shown that nerve deactivation occurs much faster and at much lower temperatures 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, pp. 1318-1325 (December 8, 2005), which is incorporated by reference. Because tissue necrosis typically occurs at temperatures above 65°C for approximately 10 seconds or longer, while nerve deactivation typically occurs at temperatures above 42°C for several seconds or longer, the dose of ultrasound energy is selected to maintain the temperature in the effect volume 13 between these temperatures for several seconds or longer. The dose of ultrasound energy is also desirably less than the dose required to cause substantial contraction of collagen within the effect volume. Therefore, operation of the transducer is advantageously advantageous in that it is possible to achieve a tissue necrosis that is more pronounced in the bronchial B L or B R The transducer 11 provides a therapeutic dose that inactivates nerves without damaging the bronchial lining. Additionally, the circulation of cooled liquid through the balloon 12 containing the transducer 11 may also help reduce heat transferred from the transducer 11 to the bronchial lining. Thus, the transferred therapeutic focused ultrasound energy does not damage the bronchial lining, providing a safe treatment.

[0047] To produce a therapeutic dose of ultrasonic energy, the acoustic power output of the transducer 11 is typically about 10 watts to about 100 watts, more typically about 20 watts to about 50 watts. The duration of power application is typically about 2 seconds to about 1 minute or more, more typically about 10 seconds to about 20 seconds. The optimal dose to be used in a particular system to achieve the desired temperature level may be determined by mathematical modeling or animal testing.

[0048] The volume of influence 13 of the focused ultrasound energy encompasses the entire bronchial segment being treated and the adjacent surrounding tissue, thus forming the bronchial B L or B R It encompasses all of the surrounding bronchial nerves. Therefore, the transducer 11 L , B R Placement at the bronchus may be indiscriminate to inactivate conduction in all surrounding bronchial nerves 6 (see FIGS. 3 and 5) surrounding the target bronchus. As used herein, "indiscriminate" and "indiscriminately" mean not targeting or placing at a specific bronchial nerve. When ablation is performed in the main bronchus, the location of the ultrasound source is optimized to be between the cartilage rings, as described above with reference to FIGS. 13A-13D.

[0049] Optionally, the physician then L , B R Treatment can then be resumed by repositioning the catheter 10 and transducer 11 along the other main bronchus (B 1 ) and retransmitting the therapeutically effective focused ultrasound energy. This provides more reliable treatment by deactivating bronchial nerves at additional locations along the length of the bronchial tree (FIG. 6). The repositioning and retransmission steps can optionally be performed multiple times. The physician then repositions the catheter 10 with the transducer 11 along the other main bronchus (B 1 ). L , B R ) and perform the overall treatment again on the side of that bronchus (see FIG. 6). After the treatment is completed, the catheter 10 is withdrawn from the subject's body.

[0050] Many variations and combinations of the above-described features can be utilized. For example, the ultrasound system can control the transducer 11 to deliver ultrasound energy in a pulsed manner during application of therapeutic ultrasound energy. Pulsed operation causes the ultrasound transducer 11 to emit ultrasound energy at, for example, a 50% duty cycle. Pulse modulation of ultrasound energy is useful for limiting tissue temperature while increasing treatment time, resulting in a more homogeneous or uniform temperature distribution throughout the treatment volume. If the ultrasound transducer consists of an array of separately operable transducer elements instead of a single cylindrical transducer, pulsed therapeutic operation can also be alternated with diagnostic imaging modes. This allows diagnostic ultrasound imaging to be obtained essentially or nearly simultaneously with treatment. See U.S. Patent Application No. 14 / 770,941, Publication No. 2016 / 0008636.

[0051] In a further variation, the steps of measuring bronchial size and adjusting the dose may be omitted. In this example, the transducer is simply operated at a preset power level sufficient for the average subject's bronchial diameter. In a further variation, the bronchial diameter can be measured by techniques other than operation of the transducer 11, such as, for example, radiography or magnetic resonance imaging, fiber optic imaging, or the use of a separate ultrasound imaging catheter. In this example, data from a separate measurement can be used to set the dose.

[0052] In further variations, the balloon 12 may be formed from a porous membrane or may include holes that allow the cooled liquid circulated within the balloon to leak or flow out of the balloon 12 against the bronchial wall to improve acoustic contact.

[0053] Typically, the catheter 10 is a disposable, single-use device. The catheter 10 or ultrasound system may include a safety device that inhibits reuse of the catheter 10 after a single use. Such safety devices are known in the art.

[0054] In yet another variation, the catheter 10 itself may include a steering mechanism that allows the physician to directly steer the distal end of the catheter, in which case a bronchoscope or sheath may be omitted.

[0055] In another variation, an ultrasound energy emitter unit at the distal end of a catheter containing an ultrasound transducer may be placed in an adjacent structure, such as the pulmonary artery or aorta (4 in FIG. 1 and 304 in FIG. 14A ), and the ultrasound transducer may include a reflecting or blocking structure to selectively direct ultrasound energy from the transducer toward the bronchial nerves only within a limited radial range. When this method is used, the ultrasound energy is propagated as a beam or portion emanating from the outer surface of the transducer, commonly known as a side-firing transducer configuration. For example, the ultrasound transducer may be operated with an ultrasound array and a structure that emits directed ultrasound energy under image guidance, similar to the disclosure in U.S. Patent Application No. 14 / 770,941, Publication No. 2016 / 0008636, incorporated herein by reference. In this variation, the route by which the catheter is introduced into the body and positioned near the bronchi is changed from the bronchial approach described above.

[0056] FIG. 8A illustrates a multi-element transducer 11 comprised of multiple circular transducer elements 11′ that can be operated individually or in combination. As described with reference to FIG. 1, each circular transducer element 11′ may take the form of a circular array 120 of multiple transducer elements 122 operating as a phased array. Thus, the transducer elements 11′ may constitute an axial array of circular arrays of transducer elements. In response to signals from the control unit 104, a multiplexer or switching circuit 124 (FIG. 1) may switch between receive and transmit during imaging mode operation to receive ultrasound echoes or reflected waveforms after imaging signals are emitted by a digital-to-analog converter 126 and a transmit module 128. During treatment mode operation, the control unit 104 causes the phased array of transducer elements 11′ (FIG. 8A) to focus ultrasound energy on an annular treatment region 320 containing nerves to be deactivated. The control unit 104 may again be a hardwired processor or a programmed general-purpose computer or microprocessor. Additionally, in response to signals from the control unit 104, the multiplexer or switching circuit 124 may switch between imaging and therapy modes.

[0057] As shown in Figure 8B, the compliant balloon 12 is configured to function as a fluid lens, whereby the diameter of the focal ring (see 320 in Figure 8A) can be varied with balloon pressure by pressure-changing the shape of the balloon 12, thereby changing the lens effect. Of course, the electronic focusing method of Figure 8A may be combined with the fluid lens balloon 12 of Figure 8B. The focal point may be adjusted to correspond to or match the diameter of the balloon 12, which can be calculated from the balloon pressure, or based on the bronchial diameter determined by ultrasound detection as described above with reference to Figures 10 and 11.

[0058] As shown in Figure 12, a rotating transducer 11'' may be incorporated into a mechanical intravascular ultrasound (IVUS) system (e.g., Boston Scientific, BSX). Therapeutic ultrasound pulses and / or full rotations may be alternated with imaging pulses to result in near-simultaneous imaging / treatment modes. A coupling / cooling fluid circulating system (Figure 1) may measure fluid volume and / or pressure, thereby determining bronchial diameter (Figure 10). Based on the measured bronchial diameter, overall ultrasound power can be automatically optimized.

[0059] A further application of the above-mentioned device, taking advantage of its energy-dispersing properties (great depth without excessive near-field damage, Figure 4A), is lung tumor ablation. Once a lung tumor is diagnosed by CT or MRI, a guidewire is typically inserted under three-dimensional guidance (i.e., Super Dimensions) to perform a biopsy. These systems combine 3D imaging with guidewire placement during bronchoscopy. However, treatment is typically performed later in a separate follow-up procedure. During the same biopsy procedure, the guidewire can be used to advance the ultrasound treatment catheter described above into the tumor. Depending on the lesion volume, a dose of ultrasound is calculated to deliver one or more lesions. Preferably, the ablation is performed under image guidance. In particular, the annular array configuration of Figure 12 provides the highest resolution image guidance, enabling differentiation between tumor and normal tissue. Figure 12 shows a three-element rotating annular array transducer 11''. Another method for performing tumor ablation under image guidance is to exchange the treatment catheter and imaging catheter over a guidewire. The IVUS imaging catheter may be advanced after withdrawal of the treatment catheter to monitor the progress of tumor ablation and returned to the treatment catheter if the IVUS images show an undisturbed tumor area.

[0060] A further application of the above-mentioned device is to reduce the adverse effects of ARDS caused by COVID-19 by optimizing the utilization of remaining healthy lung function by preventing or reducing bronchoconstriction and mucus secretion through denervation in the main bronchi.

[0061] 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 changes can be made to the illustrative embodiments and other arrangements can be contemplated without departing from the spirit and scope of the present invention as defined by the appended claims. [Explanation of symbols]

[0062] 5 Bronchoscope 10 Ultrasound catheter 11 Transducer 11' circular transducer element 11'' Rotating Transducer, Annular Array Transducer 12 Treatment balloon 13 Impact volume (focal area) 14 Guidewire 100 energized circuit 110 Wire 102 plug connector 104 Control Unit 106 Ultrasonic signal or waveform generators 108 Detection Subcircuit 112 Receiver or echo signal extractor 114 Digitizer 116 Ultrasonic echo signal preprocessor 118 Image analyzer 120 circular array 122 transducer elements 124 Multiplexer or switching circuit 126 Digital / Analog Converter 128 Transmit Module 202 Oral intubation device 203 Optical Fiber 204 Length Display 206 Strain Gauge 208a, 208b Superimposed curves of ultrasonic power 210a, 210b Power curves 212 Circulation device 214 Tank 216 Pump 218 Refrigeration Coil 220 Motor control device 224 Valve 226 Pressure Sensor 228 Leader 230 Excitation Source or Frequency Scanner 303 Esophagus 315 Air-filled balloon catheter B L Left bronchus B R Right bronchus BC Transverse section between cartilage rings CR cartilaginous ring dmax Maximum bronchial diameter dmin Minimum bronchial diameter MB carina Ub bronchial wall signal Uc integrated cartilage echo

Claims

1. 1. A device for treating an adverse respiratory condition in a mammalian subject, comprising: an ultrasound transducer configured for insertion into the bronchial tree of a mammalian subject; an actuator or control unit electrically connected to the ultrasound transducer for energizing the ultrasound transducer to emit short sub-therapeutic pulses; the actuator or control unit is configured to receive a cumulative intensity of ultrasonic echoes in a circumferential direction from organic tissue via the ultrasonic transducer and process a volume-integrated A-mode signal; The actuator or control unit a) determining the diameters of the bronchi of said bronchial tree; b) detecting the coupling of the balloon containing the ultrasound transducer with the bronchial wall; c) detection of air-filled spaces in the treatment volume; and / or d) placing the ultrasound transducer adjacent to a space or gap between adjacent cartilage rings in the bronchus; and analyzing the volume-integrated A-mode signal to provide non-therapeutic functions, including one or more of: The actuator or control unit is further configured to operate the ultrasonic transducer to deliver ultrasonic therapeutic waveform energy to provide a therapeutic function. device.

2. 10. The device of claim 1, wherein the device further comprises a catheter, the ultrasound transducer being disposed at a distal end of the catheter, and the catheter being configured to allow a user to move the ultrasound transducer axially or longitudinally to provide the non-therapeutic function of positioning the ultrasound transducer adjacent to a space or gap between adjacent cartilage rings in the bronchi of the bronchial tree.

3. 2. The device of claim 1, wherein the ultrasound transducer includes a plurality of separately actuatable transducer elements, and the actuator or control unit is also configured to energize the plurality of separately actuatable transducer elements to direct the ultrasonic therapeutic waveform energy between adjacent cartilage rings in the bronchi of the bronchial tree.

4. 2. The device of claim 1, wherein the device includes the balloon containing the ultrasound transducer in a liquid, the actuator or control unit configured to analyze the volume-integrated A-mode signal to detect the presence of an air pocket or trapped air between the balloon and the bronchus based on echo amplitude, and the actuator or control unit configured to activate the ultrasound transducer to deliver ultrasound therapeutic waveform energy only when analysis of the volume-integrated A-mode signal reveals no air pocket or trapped air, thereby indicating no air between the balloon and the bronchus.

5. 2. The device of claim 1, wherein the actuator or control unit is configured to process the volume-integrated A-mode signal to measure a time delay of the waveform of the ultrasound echo relative to the emission time of the short pulse to determine a diameter of the bronchial portion to be treated, and the actuator or control unit is further configured to operate the ultrasound transducer to deliver ultrasound therapeutic waveform energy at an acoustic power level responsive to the determined size of the bronchial portion.

6. 6. The device of claim 1, wherein the actuator or control unit is further configured to operate the ultrasound transducer to deliver a therapeutically effective amount of ultrasound therapeutic waveform energy to a volume of influence circumferentially surrounding a bronchial portion of the bronchial tree, the therapeutically effective amount inactivating the conduction of all bronchial nerves within the volume of influence.

7. The actuator or control unit also has a ３ 10. The device of claim 1, configured to deliver the ultrasonic therapeutic waveform energy to a volume of effect of 100 to 1000 Joules, energizing the ultrasonic transducer to deliver the ultrasonic therapeutic waveform energy at an acoustic power level of 10 to 50 Watts for 10 to 20 seconds, and providing an absorbed dose throughout the volume of effect of 100 to 1000 Joules.

8. 10. The device of claim 1 or 7, wherein the actuator or control unit is configured to deliver the ultrasonic therapeutic waveform energy in a manner that maintains the temperature of the area surrounding the ultrasonic transducer below 65°C and above 42°C.

9. 10. The device of claim 1, further comprising a working channel, a steerable sheath, a catheter, and an oral intubation device, or a bronchoscope with an optical fiber insertable through a central lumen of a steerable ultrasound treatment catheter, wherein the ultrasound transducer is insertable through the working channel under visual guidance, through the steerable sheath, through the oral intubation device using a steerable ultrasound catheter, or directly through the oral intubation device without a sheath or bronchoscope under optical image guidance using the optical fiber through the central lumen of the steerable ultrasound treatment catheter, or after performing a CT or MRI procedure using a steerable catheter with a distance scale indicator for monitoring the degree of insertion.

10. 10. The device of claim 1, comprising a fluid-filled balloon configured for insertion into the esophagus of a mammal, wherein the actuator or control unit is configured to monitor the volume-integrated A-mode signal so that a catheter having the ultrasound transducer disposed at a distal end can be inserted distally beyond a first bifurcation in the bronchial tree until a signal caused by the fluid-filled balloon in the esophagus is no longer detected, thereby preventing nerve damage around the esophagus, and the device further comprises means for circulating a coolant through the fluid-filled balloon, thereby reducing nerve damage around the esophagus.

11. 10. The device of claim 1, wherein the ultrasound transducer is attached to a distal end of a catheter, the catheter including a strain gauge at the distal end, the catheter configured for insertion into the bronchial tree such that the ultrasound transducer is positioned at a desired operating position determined at least in part by a bend radius of the distal end monitored via the strain gauge.

12. 8. The device of claim 1, wherein the actuator or control unit is configured to determine the desired catheter position by monitoring the diameter of the trachea and bronchial branches.

13. 10. The device of claim 1, wherein the actuator or control unit is configured to analyze the volume-integrated A-mode signal to identify a relative minimum in the volume-integrated A-mode signal related to a degree of insertion of the ultrasound transducer in the bronchial tree to enable placement of the ultrasound transducer to deliver therapeutically effective focused ultrasound energy to a treatment or influence volume between cartilage rings in the bronchus.

14. 14. The device of claim 13, wherein the actuator or control unit is configured to measure a time delay of the volume-integrated A-mode signal to thereby determine a size of the bronchial portion, and the actuator or control unit is also configured to control the ultrasound transducer to vary the amount of therapeutically effective focused ultrasound energy according to the determined size of the bronchial portion.

15. 2. The device of claim 1, wherein the ultrasound transducer comprises a longitudinal array of separately operable transducer elements, and the actuator or control unit is configured to sequentially energize the separately operable transducer elements to direct the ultrasonic therapeutic waveform energy between adjacent cartilage rings in the bronchus.

16. The device of claim 1 , wherein the actuator or control unit is configured to analyze the volume-integrated A-mode signal to promote full-circumference coupling.

17. 10. The device of claim 1, wherein the ultrasound transducer is provided in a steerable ultrasound catheter with a distance scale indicator for monitoring the extent of insertion after performing a CT, MRI procedure to ascertain the distance along the bronchial tree to the bronchial segment.

18. The device of claim 1 , wherein the ultrasound transducer is mounted on a strain-gaged catheter.

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