Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N7/02—Localised ultrasound hyperthermia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B17/00—Surgical instruments, devices or methods
  • A61B17/22—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for
  • A61B17/22004—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
  • A61B90/10—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges for stereotaxic surgery, e.g. frame-based stereotaxis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
  • A61B8/06—Measuring blood flow
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
  • A61B8/08—Clinical applications
  • A61B8/0808—Clinical applications for diagnosis of the brain
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
  • A61B8/48—Diagnostic techniques
  • A61B8/488—Diagnostic techniques involving Doppler signals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0004—Applications of ultrasound therapy
  • A61N2007/0021—Neural system treatment
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0052—Ultrasound therapy using the same transducer for therapy and imaging
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0078—Ultrasound therapy with multiple treatment transducers

Definitions

• the present technology relates generally to neurological treatments.
• several embodiments are directed to using ultrasound energy to enhance hematoma resolution (e.g., to prevent cerebral vasospasm or to reduce the severity of cerebral vasospasm) in extravascular thrombolytic treatment regimes with relatively low probability of causing additional cerebral hemorrhage, e.g., due to the types and/or doses of thrombolytic agents used in the regimes.
• Tested therapeutic agents intended to prevent cerebral vasospasm or to reduce the severity of cerebral vasospasm include certain calcium channel blockers, endothelin receptor antagonists, and antispasmodics. These agents have mostly either failed to cause improved outcomes or provided only short lived effects. Nimodipine (a calcium channel blocker) and papaverine (an antispasmodic) have shown some promise, but still have little or no potential for robust prevention of cerebral vasospasm. Tested therapeutic agents intended to reduce the ischemic effects of cerebral vasospasm include certain N-methyl D- aspartate receptor antagonists and free radical scavengers. To date, these agents have also failed to significantly improve outcomes.
• the Triple-H therapy which involves intravascularly administering a combination of drugs and fluid to induce hypervolemia, hypertension, and hemodilution, is currently the most widely used treatment. This approach is intended to increase blood flow through vasospastic vessels and thereby increase blood delivery to ischemic areas of the brain.
• Transluminal balloon angioplasty of major intracerebral arteries is also used in some cases with the same objective. Although useful, the Triple-H therapy and transluminal balloon angioplasty at best only partially reduce the ischemia associated with cerebral vasospasm. Their effect is often insufficient to prevent neurological impairment or even death.
• the Triple-H therapy can increase the rate of pulmonary edema, myocardial ischemia, hyponatremia, renal medullary washout, cerebral edema, and additional cerebral hemorrhage.
• Transluminal balloon angioplasty can increase the risk of surgically induced neurological damage, infection, and vessel stenosis.
• cerebral vasospasm directly (e.g., preventing cerebral vasospasm or reducing the severity of cerebral vasospasm) has much greater potential for improving outcomes than merely mitigating the corresponding ischemic effects. Furthermore, since cerebral vasospasm typically has a delayed onset and a relatively gradual clinical course after hemorrhage (e.g., following aneurysm rupture), in most cases, there is a window of opportunity to apply preventative therapies. An effective approach for preventing cerebral vasospasm or reducing the severity of cerebral vasospasm has the potential annually to save thousands of lives and to prevent thousands of cases of neurological impairment. Accordingly, for this reason and/or for other reasons not stated herein, there is a need for innovation with respect to devices, systems, and methods for treating subarachnoid hematoma, cerebral vasospasm, and/or other related conditions.
• Figure 1 is an inferior cranial view illustrating a patient having a subarachnoid hematoma.
• Figure 2 is a partially schematic perspective view illustrating a therapeutic system during treatment of a patient having a subarachnoid hematoma in accordance with an embodiment of the present technology.
• Figure 3 is an inferior cranial view of the patient shown in Figure 1 during sonothrombolysis using a commercially available headset in accordance with an embodiment of the present technology.
• Figures 4-6 are inferior cranial views of the patient shown in Figure 1 during sonothrombolysis using other headsets in accordance with embodiments of the present technology.
• Figure 7 is a partially schematic cross-sectional view illustrating delivery of ultrasound energy into a subarachnoid region in accordance with an embodiment of the present technology.
• Figure 8 is a partially schematic cross-sectional view illustrating resolution of a subarachnoid hematoma in accordance with an embodiment of the present technology.
• Figure 9 is a partially schematic perspective view illustrating drainage of cerebrospinal fluid in accordance with an embodiment of the present technology.
• Cerebral vasospasm includes blood vessel spasm and associated contraction of smooth muscle in the media of blood vessel walls. The condition is known to occur in the region of a subarachnoid hematoma.
• Figure 1 is an inferior cranial view illustrating a patient 100 having a subarachnoid hematoma 102 at the basal cisterns 104 inferior to the temporal lobes 106 and anterior to the cerebellum 108.
• Several major cerebral and cerebellar arteries are at or near the basal cisterns 104. These arteries are the primary blood supply for the brain.
• cerebral ischemia following spasm of these arteries triggered by the subarachnoid hematoma 102 can rapidly lead to neurological impairment or death.
• the basal cisterns 104 are a common location for blood to collect following intracerebral hemorrhage, other locations are also possible. Cerebral vasospasm of arteries at these other locations can also have serious complications.
• Aneurysm rupture is the most common cause of subarachnoid hematoma leading to cerebral vasospasm, but other causes, such as trauma, tumor, or arteriovenous malformation, are also possible. Cerebral vasospasm does not occur in all cases of subarachnoid hematoma and, when it does occur, its onset is typically delayed. For example, it has been observed that cerebral vasospasm often occurs between the fourth and tenth day following aneurysmal subarachnoid hemorrhage. The clinical manifestation of cerebral vasospasm suggests that it may be associated with byproducts (e.g., vasoconstrictors or other vasoactive substances) of hematoma resolution.
• byproducts e.g., vasoconstrictors or other vasoactive substances
• At least some embodiments of the present technology can include facilitating the removal (e.g., the complete or partial evacuation or other resolution) of subarachnoid hematomas with reduced side effects relative to conventional therapies.
• a thrombolytic agent can be used in combination with therapeutic ultrasound energy. This combination, known generally as sonothrombolysis, has been shown to be effective in other applications. For example, sonothrombolysis has been shown to facilitate recanalization in the treatment of ischemic stroke. Solely by way of theory, the effect of ultrasound energy on the effect of thrombolytic agents is likely to be largely mechanical rather than chemical. For example, ultrasound energy may increase the binding of thrombolytic agents to binding sites within the structure of a hematoma by facilitating streaming and/or mixing of the thrombolytic agents into the structure. Other mechanisms are also possible.
• thrombolytic agents outside the vasculature has typically been discouraged or at least highly limited for neurological applications due to the possibility of causing or exacerbating cerebral hemorrhaging.
• Adding ultrasound energy to thrombolytic therapy can faciliate the use of less aggressive thrombolytic agents and/or lower dosages of thrombolytic agents.
• using ultrasound energy can allow the therapeutically effective treatment of subarachnoid hematoma with a type and/or dosage of a thrombolytic agent sufficiently low to cause only a minor or even a negligible or generally no increase in the clinical probability of causing or exacerbating additional cerebral hemorrhaging, e.g., rehemorrhaging from the origin of the hematoma.
• a thrombolytic agent can be introduced at a dosage sufficiently low to cause less than a 10% increase in the clinical probability of rehemorrhage, such as less than a 5% increase or less than a 2% increase.
• the use of ultrasound energy in combination with a thrombolytic agent can faciliate the use of control algorithms for further limiting the dosage of the thrombolytic agent over time during a treatment regime so that it remains at or near a minimum therapeutically effective dosage.
• FIG. 2 is a partially schematic perspective view of a therapeutic system 200 during treatment of a patient 202 having a subarachnoid hematoma (not shown) in accordance with an embodiment of the present technology.
• the system 200 can include a thrombolytic delivery module 204, an ultrasound module 206, a drainage module 208, and a control module 210.
• the thrombolytic delivery module 204 can include a metering device 212 and a catheter 214 configured to deliver a thrombolytic agent into a subarachnoid region 215 of the patient 202, e.g., via a ventriculostomy.
• the ultrasound module 206 can include a headset 216, a power supply 218, and a power cord 220 extending between the headset 216 and the power supply 218.
• the headset 216 can be configured for hands-free delivery of transcranial ultrasound energy to the subarachnoid region 215.
• the drainage module 208 can include a drain line 222, a cerebrospinal fluid drain 224, and a cerebrospinal fluid analyzer 226 between the drain line 222 and the cerebrospinal fluid drain 224.
• the drain line 222 can be configured to drain cerebrospinal fluid including, without limitation, byproducts of hematoma resolution from a lumbar region 227 or another suitable region of the patient 202.
• the control module 210 can include a user interface 228 and a controller 229 operatively connected to the thrombolytic delivery module 204, the ultrasound module 206, and the drainage module 208.
• the thrombolytic delivery module 204 and the ultrasound module 206 can be included in a kit configured for treatment of subarachnoid hematoma.
• the kit can further include the drainage module 208 and/or the control module 210.
• the patient 202 can first be diagnosed as having or likely having a subarachnoid hematoma.
• a ventriculostomy can then be performed and the catheter 214 can be inserted through the ventriculostomy into a ventricular space (not shown) of the patient's brain 230.
• the method can further include delivering a thrombolytic agent from the metering device 212 to cerebrospinal fluid within the ventricular space via the catheter 214.
• the metering device 212 can include a pump, a valve, a timer, a power source, a reservoir, and/or other suitable features.
• the thrombolytic agent can diffuse extravascularly within the cerebrospinal fluid and eventually migrate to the subarachnoid region 215 including the subarachnoid hematoma.
• delivering the thrombolytic agent via a ventriculostomy can be useful to enhance contact between the thrombolytic agent and the subarachnoid hematoma and/or to faciliate flow of byproducts of hematoma resolution toward the drain line 222 along the path indicated by arrows 232.
• the thrombolytic agent can be introduced intracisternally, intrathecally proximate the spinal cord, or in another suitable manner other than via a ventriculostomy.
• the drainage module 208 can faciliate removing the byproducts of hematoma resolution.
• cerebrospinal fluid including the byproducts can be slowly drained from the patient 202 via the drain line 222 while delivering ultrasound energy to the subarachnoid region 215 using the headset 216.
• the drain line 222 shown in Figure 2 is connected to the lumbar region 227, other suitable locations for draining cerebrospinal fluid can also be used.
• the drain line 222 can be intrathecally connected to the patient 202 at a cervical region 234 closer to the subarachnoid region 215 than the lumbar region 227.
• the thrombolytic delivery module 204 and the ultrasound module 206 can be used without the drainage module 208.
• merely dispersing the byproducts of hematoma resolution through the cerebrospinal fluid can be sufficient to prevent cerebral vasospasm or to reduce the severity of cerebral vasospasm.
• the headset 216 Before or after beginning delivery of the thrombolytic agent, the headset 216 can be connected to the patient 202.
• the headset 216 can include one or more ultrasound transducers (not shown) and can be fitted to the patient 202 such that the transducers are positioned to direct therapeutic ultrasound energy to the subarachnoid region 215.
• the headset 216 can be configured for hands-free delivery of transcranial ultrasound energy to the subarachnoid region 215.
• treatment regimes in accordance with embodiments of the present technology can extend over many hours or days.
• hands-free delivery of transcranial ultrasound energy can be more practical and/or reliable than delivery of ultrasound energy using techniques that involve the continuous presence of a clinician.
• Connecting the headset 216 to the patient 202 can include applying an ultrasound gel to the patient 202 and then fitting the headset 216 snuggly so that it generally remains in position during the treatment.
• the headset 216 can be adjustable to conform to a variety of head sizes. The positioning of the headset 216 can be periodically monitored during the treatment to determine if shifting has occurred. After positioning, the headset 216 can be activated to deliver ultrasound energy to the subarachnoid region 215 so as to enhance the thrombolytic effect of the thrombolytic agent. Enhancing the thrombolytic effect of the thrombolytic agent can include, for example, increasing the rate of hematoma resolution by at least about 20%, at least about 50%, or at least about 100%.
• the headset 216 is shown in Figure 2 as a band, in other embodiments the headset 216 can have other suitable forms.
• the headset 216 can be a helmet or can have a form that is not fully circumferential. Additional details regarding the headset 216 are described below with reference to Figures 3-6.
• the control module 210 can be configured to automatically or manually control operation of all or a portion of the system 200.
• the controller 229 can be programmed to receive input from the ultrasound module 206 and/or the drainage module 208 and to control operation of one or more aspects of the system 200 in accordance with the input.
• the controller 229 can be programmed to receive a signal from the ultrasound module 206 and to control delivery of a thrombolytic agent from the metering device 212 to the subarachnoid region 215 in response to the signal, to control delivery of ultrasound energy from the headset 216 to the subarachnoid region 21 5 in response to the signal, or both.
• controller 229 can be programmed to receive a signal from the drainage module 208 and to control delivery of a thrombolytic agent from the metering device 212 to the subarachnoid region 215 in response to the signal, to control delivery of ultrasound energy from the headset 216 to the subarachnoid region 215 in response to the signal, or both.
• Controlling delivery of the thrombolytic agent can include, for example, controlling continuous or intermittent administration (e.g., the rate of administration) of the thrombolytic agent over time.
• Controlling delivery of the ultrasound energy can include, for example, controlling the frequency, intensity, duty cycle, waveform, pulse pattern, and/or other suitable parameters of the ultrasound energy over time.
• the ultrasound module 206 and/or the drainage module 208 can have diagnostic functionality for generating information that can be used by the controller 229 and/or displayed by the user interface 228.
• the headset 216 can be configured to ultrasonically detect blood-flow velocity in one or more arteries (e.g., the middle cerebral artery or an intracranial portion of the internal carotid artery) proximate (e.g., at or near) the subarachnoid hematoma and to transmit a corresponding signal to the controller 229.
• the headset 216 can include one or more transducers configured to receive ultrasound echoes that can be processed based on the Doppler effect to determine the blood- flow velocity.
• Blood-flow velocity can be a reliable indicator of the likely clinical course of cerebral vasospasm in the patient 202.
• the trajectory of increasing blood-flow velocity can indicate the likely peak severity of the cerebral vasospasm.
• the controller 229 can be programmed to cause a higher dosage of the thrombolytic agent to be introduced into the subarachnoid region 215, and when the ultrasound module 206 detects a slow increase in blood-flow velocity, the controller 229 can be programmed to cause a lower dosage of the thrombolytic agent to be introduced into the subarachnoid region 215. Details of diagnostic functionality and other potentially useful aspects of the headset 216 are described in detail in U.S. Patent No.
• the drainage module 208 can be configured to detect one or more indicators of resolution of the subarachnoid hematoma and to transmit a corresponding signal to the controller 229.
• Such indicators can include, for example, concentrations of byproducts of hematoma resolution (e.g., red blood cells) or other chemical markers within the cerebrospinal fluid corresponding to hematoma resolution.
• the cerebrospinal fluid analyzer 226 is a flow cytometer configured to detect these concentrations continuously or intermittently over time. Information from the cerebrospinal fluid analyzer 226 can indicate the rate of hematoma resolution.
• the controller 229 can be programmed to cause a lower dosage of the thrombolytic agent to be introduced into the subarachnoid region 215, and when the drainage module 208 detects slow resolution of the subarachnoid hematoma, the controller 229 can be programmed to cause a higher dosage of the thrombolytic agent to be introduced into the subarachnoid region 215.
• the controller 229 can be programmed to cause the ultrasound energy to be introduced into the subarachnoid region 215 at a different intensity, frequency, and/or other suitable parameter. The parameters of the ultrasound energy can be varied, for example, until the rate of resolution of the subarachnoid hematoma increases to a sufficient level.
• the diagnostic functionality of the ultrasound module 206 and the drainage module 208 can be eliminated in some embodiments.
• the controller 229 can be programmed to control operation of the system 200 according to predetermined treatment parameters, such as parameters of predetermined treatment regimes including dosages of the thrombolytic agent, frequencies of the ultrasound energy, intensities of the ultrasound energy, and/or other suitable parameters over time.
• the controller 229 can be programmed to receive these parameters directly from the user interface 228 and/or to calculate these parameters based on other data from the user interface 228.
• a user may input patient information (e.g., age, sex, weight, etc.) and condition information (e.g., elapsed time since aneurysmal rupture, approximate hematoma volume, etc.) and the controller 229 can use this information to determine parameters of the treatment based on programmed algorithms. For example, when the elapsed time since aneurysmal rupture is relatively long (e.g., greater than about 36 hours) and/or the approximate hematoma volume is relatively high (e.g., greater than about 15 mL), a more aggressive treatment regime can be used.
• patient information e.g., age, sex, weight, etc.
• condition information e.g., elapsed time since aneurysmal rupture, approximate hematoma volume, etc.
• the controller 229 can use this information to determine parameters of the treatment based on programmed algorithms. For example, when the elapsed time since aneurysmal rupture is relatively long (e.g., greater than about 36 hours) and
• control module 210 can be eliminated and the thrombolytic delivery module 204, the ultrasound module 206, and/or the drainage module 208 can be operated independently under the supervision of one or more clinicians.
• the headset 216 shown in Figure 2 can be a commercially available headset, such as a commercially available headset indicated for the treatment of ischemic stroke in the basal cerebral arteries.
• a commercially available headset is the CLOTBUST ER available from Cerevast Therapeutics, Inc. (Redmond, WA).
• Figure 3 is an inferior cranial view of the patient 100 shown in Figure 1 during sonothrombolysis using a commercially available headset 300 in accordance with an embodiment of the present technology.
• the temporal lobes 106 and the cerebellum 108 are not shown to faciliate illustration.
• the headset 300 can include an anterior headframe member 302, a posterior headframe member 304, and a knob 306 that can be turned to draw portions of the posterior headframe member 304 into the anterior headframe member 302 and thereby tighten the headset 300 around the patient's head.
• the anterior headframe member 302 can be configured to contact the patient 100 at the brow
• the posterior headframe member 304 can be configured to contact the patient 100 at the back of the neck.
• the headset 300 can further include an anterior brace 308 that can faciliate positioning the headset 300.
• the headset 300 can include lateral transducer assemblies 312a, 312b proximate the patient's ears 313a, 313b, and a posterior transducer assembly 314 centered on the anterior headframe member 302. Power and control signals for the transducer assemblies 312a, 312b, 314 can be conveyed to the headset 300 via a cable 316.
• the headset 300 can be configured to operate the transducer assemblies 312a, 312b, 314 according to a variety of suitable patterns (e.g., patterns of frequency, intensity, duty cycle, wave form, or other suitable parameters). Details of these patterns and other potentially useful aspects of the headset 300 are described in detail in U.S. Patent Application Publication Nos.
• Ultrasound energy 318 is shown in Figure 3 emanating from only the transducer assemblies 312a, 314 and from the groups of transducers rather than from the individual transducers to faciliate illustration.
• the headset 300 can be configured to deliver the ultrasound energy 318 to the basal cisterns 104 while reducing exposure of the parenchyma of the brain (e.g., including the temporal lobes 106) to the ultrasound energy 318. This can be useful, for example, to reduce the level of sonothrombolysis outside the basal cisterns 104.
• the ultrasound energy 318 can be directed toward the basal cisterns 104 such that an intensity of the ultrasound energy at the basal cisterns 104 is greater (e.g., at least 50% greater or at least 100% greater) than an intensity of the ultrasound energy at an origin of the intracerebral hemorrhage.
• an intensity of the ultrasound energy at the basal cisterns 104 is greater (e.g., at least 50% greater or at least 100% greater) than an intensity of the ultrasound energy at an origin of the intracerebral hemorrhage.
• This can be useful in some cases to reduce the possibility of causing additional hemorrhage at the origin of the intracerebral hemorrhage.
• long-duration exposure to low-intensity ultrasound is generally considered to be safe for brain tissue, reducing such exposure can still be desirable to reduce the possibility of unknown side effects, particularly in cases in which the exposure is not therapeutically useful.
• the headset 300 can be configured for alignment with craniological landmarks so that the transducer assemblies 312a, 312b, 314 direct the ultrasound energy 318 into a central region 320 of the basal cisterns 104.
• the major cerebral and cerebellar arteries are primarily located in the central region 320, making it a relevant treatment region for ischemic stroke. Delivering the ultrasound energy 318 into the central region 320 can also be useful for sonothrombolysis of subarachnoid hematomas. As shown in Figure 3, however, the subarachnoid hematoma 102 can also extend into a peripheral region 322 of the basal cisterns 104.
• Sonothrombolysis of the subarachnoid hematoma 102 at both the central region 320 and the peripheral region 322 can increase the rate of resolution. In some cases, it can be more difficult for a thrombolytic agent to access portions of the subarachnoid hematoma 102 at the central region 320 than portions of the subarachnoid hematoma 102 at the peripheral region 322. The potential for sonothrombolysis, therefore, may be greater at the peripheral region 322 than at the central region 320.
• the exact positions of subarachnoid hematomas vary from patient to patient and may change over the course of therapy as the subarachnoid hematomas shrink.
• the ultrasound energy 318 can be delivered (e.g., generally evenly delivered) over a broader portion (e.g., generally all) of the basal cisterns 104 (or even to more distant subarachnoid regions) than would typically be contemplated for the treatment of ischemic stroke.
• Figures 4-6 are inferior cranial views of the patient 100 shown in Figure 1 during sonothrombolysis using other headsets in accordance with embodiments of the present technology. As in Figure 3, the temporal lobes 106 and the cerebellum 108 are not shown and the depiction of ultrasound energy is simplified in Figures 4-6 to faciliate illustration. As shown in Figure 4, a headset 400 configured in accordance with a particular embodiment can include lateral transducer assemblies 402a, 402b and a posterior transducer assembly 404 having convex shapes configured to broaden delivery of ultrasound energy 406 to the peripheral region 322.
• the shape characteristics of piezoelectric crystals (not shown) of individual transducers of the transducer assemblies 402a, 402b, 404 can selected to broaden delivery of the ultrasound energy 406 with or without the transducer assemblies 402a, 402b, 404 being convex.
• another headset 500 can include four lateral transducer assemblies 502a-d and two posterior transducer assemblies 504a, 504b positioned to deliver ultrasound energy 506 to both the central region 320 and the peripheral region 322 of the basal cisterns 104.
• the headset 500 can have other suitable numbers and arrangements of transducer assemblies.
• another headset 600 can include a curved transducer assembly 602 configured to extend generally continuously between temporal regions 604a, 604b of the patient 100.
• the curved transducer assembly 602 can include a plurality of individual transducers 606 (one labeled in Figure 6) distributed along its length.
• the curved transducer assembly 602 can be at least partially flexible and/or adjustable to better conform to patients of different sizes.
• the headset 600 can be well suited for delivering ultrasound energy 608 generally evenly though at least the posterior half of the peripheral region 322.
• FIGs 7-8 are partially schematic cross-sectional views and Figure 9 is a partially schematic perspective view illustrating aspects of sonothrombolysis in accordance with an embodiment of the present technology.
• a plurality of transducers 700 in a transducer assembly 702 can deliver ultrasound energy 704 transcranial ly to a subarachnoid space 706.
• the ultrasound energy 704 can travel through several anatomical layers including the skin 708, the skull 710, the dura mater 712, and the arachnoid 713.
• frequency, intensity, duty cycle, waveform, pulse pattern, and/or other suitable parameters of the ultrasound energy 704 can be selected manually or automatically (e.g., based on clinical factors).
• reducing the possibility of undesirable side effects e.g., additional cerebral hemorrhaging
• increasing the rate of hematoma resolution are often competing objectives that can be considered case- by-case before initiating a treatment regime and reconsidered intermittently or continuously during a treatment regime to inform the selection of appropriate parameters for the ultrasound energy 704.
• using lower intensities and/or higher frequencies can reduce the probability of undesirable side effects while using higher intensities and/or lower frequencies can increase the rate of hematoma resolution.
• Various different or additional effects and correlations are also possible.
• Ultrasound at lower frequencies typically penetrates more effectively through anatomical layers (e.g., the skin 708, the skull 710, the dura mater 712, and the arachnoid 713 shown in Figures 7-8) than ultrasound at higher frequencies.
• Ultrasound at lower frequencies can also be more disruptive and potentially damaging to small cerebral blood vessels than ultrasound at higher frequencies.
• the frequency of the ultrasound energy 704 can be selected to be relatively high (e.g., greater than about 3 MHz, greater than about 3.5 MHz, or greater than about 4 MHz).
• Suitable frequencies for the ultrasound energy 704 can include, for example, frequencies between about 0.5 and about 5 MHz, between about 1 and about 4 MHz, or within other suitable ranges.
• Suitable intensities for the ultrasound energy 704 can include, for example, intensities less than about 5 W/cm 2 , less than about 3.5 W/cm 2 , less than about 2 W/cm 2 , between about 0.1 and about 5 W/cm 2 , between about 0.2 and about 3.5 W/cm 2 , or within other suitable ranges.
• the ultrasound energy 704 can faciliate mixing between a thrombolytic agent 714 and coagulated blood 716 or otherwise enhance activity of the thrombolytic agent 714.
• the thrombolytic agent 714 and the coagulated blood 716 are shown schematically in Figure 7 distributed generally evenly throughout the subarachnoid space 706. More typically, different portions of the subarachnoid space 706 may have different concentrations of the thrombolytic agent 714 and the coagulated blood 716.
• central portions of the subarachnoid space 706 within the basal cisterns may have lower concentrations of the thrombolytic agent 714 and greater concentrations of the coagulated blood 716 than peripheral portions of the subarachnoid space 706.
• the thrombolytic agent 714 and resolution products 718 can migrate in the direction of arrows 720, 722 down the spinal canal 724 to a drain line 726 proximate a lumbar vertebra 728. From the drain line 726, the thrombolytic agent 714 and resolution products 71 8 can be collected in a collection bag 730.
• the ultrasound module 206 shown in Figure 2 can be an energy delivery module configured to deliver thermal energy, electromagnetic (e.g., radiofrequency) energy, or another suitable type of mechanical energy (e.g., vibration or acoustic streaming).
• electromagnetic e.g., radiofrequency
• mechanical energy e.g., vibration or acoustic streaming
• Suitable thrombolytic agents 714 can include, for example, tissue plasminogen activators (e.g., alteplase, retaplase, and tenecteplase), streptokinase, anistreplase, and urokinase among others.
• tissue plasminogen activators e.g., alteplase, retaplase, and tenecteplase
• streptokinase e.g., anistreplase, and urokinase among others.
• the type and/or dosage of the thrombolytic agent 714 can be selected based on the enhanced thrombolytic effect associated with use of the ultrasound energy 704.
• Therapeutically effective dosages can vary according to factors such as the type of the thrombolytic agent 714, the physical characteristics of the patient, and the severity of the condition.
• a tissue plasminogen activator can be administered via a ventriculostomy at a dosage of about 1 mg every 8 hours, with transcranial ultrasound applied for about 2 hours following each administration.
• the thrombolytic agent 714 can include a combination of multiple drugs or other agents (e.g., anticoagulants).
• a sonothrombolysis enhancing agent can be introduced extravascularly into the subarachnoid space 706 along with or separate from the thrombolytic agent 714.
• the sonothrombolysis enhancing agent can include, for example, echogenic microbubbles or other contrast-enhancing agents commercially available for use in diagnostic ultrasonography. Such particles are typically buoyant, which is of little or no consequence during intravascular use.
• sonothrombolysis enhancing particles can be selected to be generally non-buoyant so that, after they are introduced (e.g., via a ventriculostomy), they can sink within the cerebrospinal fluid and settle by gravity into the basal cisterns.
• This can be useful, for example, to enhance the selectivity of sonothrombolysis to an area including a subarachnoid hematoma with reduced possibility of sonothrombolysis within intraparenchymal portions of the brain and the associated possibility of additional intracerebral hemorrhaging.
• Sonothrombolysis in accordance with the present technology has significant potential for preventing cerebral vasospasm or reducing the severity of cerebral vasospasm or other complications of subarachnoid hematoma in patients.
• Analytical measures of cerebral vasospasm include, for example, blood-flow velocities in arteries (e.g., the middle cerebral artery and intracranial portions of the internal carotid artery) proximate the subarachnoid hematoma.
• Another useful measure can be the ratio of blood-flow velocity in the middle cerebral artery to blood-flow velocity in an extracranial portion of the internal carotid artery.
• sonothrombolysis in accordance with the present technology can maintain blood-flow velocity in generally all arteries proximate a subarachnoid hematoma at less than about 120 cm/sec (e.g., less than about 160 or about 200 cm/sec) for at least about 14 days after first administering a thrombolytic agent.
• a ratio of blood-flow velocity in the middle cerebral artery to blood-flow velocity in an extracranial portion of the internal carotid artery can be generally maintained at less than about 3 (e.g., less than about 4 or about 6) for at least about 14 days after first administering a thrombolytic agent. It is expected that embodiments of the present technology may achieve these and other results at a statistically significant greater rate of occurrence relative to control.
• a method of treating a human patient having a subarachnoid hematoma comprising:
• delivering the ultrasound energy to the subarachnoid region includes delivering the ultrasound energy to generally all of the basal cisterns.
• delivering the ultrasound energy includes delivering the ultrasound energy at a frequency greater than about 3.5 MHz.
• introducing the thrombolytic agent includes introducing the thrombolytic agent at a dosage sufficiently low to cause less than a 5% increase in the clinical probability of rehemorrhage.
• the subarachnoid hematoma is the result of an intracerebral hemorrhage; and delivering the ultrasound energy includes directing the ultrasound energy toward the subarachnoid region such that an intensity of the ultrasound energy at the subarachnoid region is greater than an intensity of the ultrasound energy at an origin of the intracerebral hemorrhage.
• introducing the thrombolytic agent includes introducing the thrombolytic agent via a ventriculostomy.
• introducing the thrombolytic agent includes introducing the thrombolytic agent intracisternally.
• introducing the thrombolytic agent includes introducing the thrombolytic agent intrathecally proximate the spinal cord. 1 1 .
• the method of example 1 further comprising draining cerebrospinal fluid from the patient.
• draining cerebrospinal fluid from the patient includes draining cerebrospinal fluid from the patient while delivering the ultrasound energy to the subarachnoid region.
• the sonothrombolysis enhancing agent includes non-buoyant particles; and introducing the sonothrombolysis enhancing agent includes introducing the sonothrombolysis enhancing agent via a ventriculostomy.
• example 17 The method of example 1 , further comprising preventing cerebral vasospasm or reducing the severity of cerebral vasospasm in the patient.
• preventing cerebral vasospasm or reducing the severity of cerebral vasospasm in the patient includes maintaining blood-flow velocity in generally all arteries proximate the subarachnoid hematoma at less than about 120 cm/sec for at least about 14 days after introducing the thrombolytic agent.
• preventing cerebral vasospasm or reducing the severity of cerebral vasospasm in the patient includes maintaining blood-flow velocity in generally all arteries proximate the subarachnoid hematoma at less than about 200 cm/sec for at least about 14 days after introducing the thrombolytic agent.
• a system for treating a human patient having a subarachnoid hematoma comprising:
• a thrombolytic delivery module including a metering device
• an ultrasound module including a headset configured for hands-free delivery of transcranial ultrasound energy to a subarachnoid region including the subarachnoid hematoma and hands-free detection of blood-flow velocity in one or more arteries proximate the subarachnoid hematoma; and a control module including a controller operably connected to the thrombolytic delivery module and the ultrasound module, the controller configured to receive a signal from the ultrasound module corresponding to the blood-flow velocity and to control delivery of a thrombolytic agent from the metering device to the subarachnoid region in response to the signal, to control delivery of ultrasound energy from the headset to the subarachnoid region in response to the signal, or both.
• thrombolytic delivery module further includes a catheter configured to deliver the thrombolytic agent into the subarachnoid region via a ventriculostomy.
• a system for treating a human patient having a subarachnoid hematoma comprising:
• a thrombolytic delivery module including a metering device
• an ultrasound module including a headset configured for hands-free delivery of transcranial ultrasound energy to a subarachnoid region including the subarachnoid hematoma;
• a drainage module including—
• cerebrospinal fluid analyzer configured for detection of one or more indicators of resolution of the subarachnoid hematoma; and a control module including a controller, wherein the controller is—
• the controller is programmed to receive a signal from the drainage module corresponding to the one or more indicators of resolution of the subarachnoid hematoma and to control delivery of a thrombolytic agent from the metering device to the subarachnoid region in response to the signal,
• the controller operably connected to the ultrasound module and the drainage module, and the controller is programmed to receive a signal from the drainage module corresponding to the one or more indicators of resolution of the subarachnoid hematoma and to control delivery of ultrasound energy from the headset to the subarachnoid region in response to the signal, or (3) both (l ) and (2).
• the controller is operably connected to the thrombolytic delivery module and the ultrasound module;
• the headset is configured for hands-free detection of blood-flow velocity; and the controller is programmed to receive a signal from the ultrasound module corresponding to the blood-flow velocity and to control delivery of the thrombolytic agent from the metering device to the subarachnoid region in response to the signal, to control delivery of ultrasound energy from the headset to the subarachnoid region in response to the signal, or both.
• Certain aspects of the present technology may take the form of computer- executable instructions, including routines executed by a controller or other data processor.
• a controller or other data processor configured in accordance with the present technology can be specifically programmed, configured, or constructed to perform one or more of these computer-executable instructions.
• some aspects of the present technology may take the form of data stored or distributed on computer-readable media, including magnetic or optically readable or removable computer discs as well as media distributed electronically over networks. Accordingly, data structures and transmissions of data particular to aspects of the present technology are encompassed within the scope of the present technology.
• the present technology also encompasses methods of both programming computer-readable media to perform particular steps and executing the steps.

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