Ultrasound assisted thrombolysis for acute pulmonary embolism

超声辅助溶栓治疗急性肺栓塞

• 批准号: 8048492
• 负责人: AZITA SOLTANI
• 金额: $ 17.5万
• 依托单位: EKOS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048492
• 关键词: Acoustics; Activase; Acute; Alteplase; Anatomy; Animal Model; Anticoagulant therapy; Area; Arteries; Autologous; Blood Clot; Blood coagulation; Caliber; Canis familiaris; Catheters; Ceramics; Cessation of life; Characteristics; Clinical; Clinical Data; Coagulation Process; Complication; Cytolysis; Data; Deep Vein Thrombosis; Development; Dose; Drug Formulations; Drug Transport; Embolism; Evaluation; Excision; FDA approved; Failure; Fibrinolytic Agents; Frequencies; Goals; Guidelines; Health; Hemolysis; Hemorrhage; Hour; Human; In Vitro; Infusion procedures; Lesion; Life; Liquid substance; Longevity; Lung; Lytic; Malignant Neoplasms; Measurement; Mechanics; Modeling; Operative Surgical Procedures; Output; Patients; Performance; Perfusion; Peripheral; Pharmaceutical Preparations; Phase; Physicians; Procedures; Process; Property; Pulmonary Embolism; Pulmonary artery structure; Relative (related person); Reporting; Research; Risk; Site; Specific qualifier value; Speed; Sudden Death; System; Technology; Testing; Thromboembolism; Thrombolytic Therapy; Thrombosis; Thrombus; Time; Transducers; Trauma; Ultrasonic Transducer; Ultrasonics; Ultrasonography; United States; Vascular blood supply; Veins; Venous; Whole Blood; base; clinical efficacy; design; effective therapy; energy density; improved; in vivo; in vivo Model; local drug delivery; peripheral blood vessel; pre-clinical; premature; pressure; prevent; prototype; response; thrombolysis

DESCRIPTION (provided by applicant): EKOS endovascular technology facilitates ultrasound-assisted catheter directed thrombolytic [CDT] therapy. The EkoSonicTM system is well characterized for use in CDT therapy for enhancing drug transport into peripheral clots. The EKOS Endovascular system is FDA approved for delivery of physician specified fluids in peripheral and pulmonary vasculature. It has been used with various drugs, including rt-PA, for catheter-directed thrombolysis of Deep Vein Thrombosis (DVT) and Massive Acute Pulmonary Embolism (PE). Chamsuddin et al. (2008) treated 10 patients with 13 massive acute PE lesions with EKOS endovascular systems specifically designed for peripheral vasculature. The mean time of thrombolysis was 24.76 hours 1 8.44 (median, 24 hours) and mean dose of t-PA used was 0.88 mg/h 1 0.19 (13 lesions). No hemorrhagic complications were suffered by any subject. The average total dose of rt-PA used was 21.12mg, 78% less than the fixed 100mg dose of t-PA used in IV thrombolytic administration. Clinical efficacy of intra-arterially delivered ultrasound is determined by ultrasound transducer performance with respect to the target anatomy. Since pulmonary arteries are many times larger than peripheral arteries, we propose to adapt this technology for an effective treatment of massive PE. High power catheter transducers can produce effectual acoustic pressures across the massive pulmonary embolus. Current EKOS' catheter transducers have been designed and tested for power output, longevity, efficiency and efficacy with the intended application in peripheral blood vessels (~6 to 12mm diameter). Hence current transducers are constrained by a very low tolerance when driven at high powers resulting in premature brittle failures. For enhanced drug transport across the transverse cross section of the relatively large pulmonary arteries (~27 mm diameter), the catheter transducers need to have operational ability to be driven at higher acoustic pressures. The overall goal of this project is to develop high power transducers and demonstrate feasibility of ultrasound-assisted thrombolytic therapy using high power catheter transducers to enable improved thrombus removal in massive pulmonary embolism at significantly shortened therapy time in vivo. Lytic drug (rt-PA, Activase(R)) will be infused directly in the immediate clot volume surrounding the high power catheter transducers. Our specific aims are: v SPECIFIC AIM #1: Acoustic characterization of fabricated high power transducer prototypes. We will fabricate transducer prototypes by investigating piezoelectric ceramic fabrication processes to build robust transducers that will have the operational ability to withstand a high electrical input and generate higher acoustic pressures to enhance drug transport across the transverse cross section of the relatively large pulmonary arteries (~27 mm diameter). We will determine the acoustic characteristics of the prototype trasnducers and prevent any unanticipated cavitation activity at the target acoustic pressures via empirical measurements. v SPECIFIC AIM #2: Optimize blood clot formation and conduct bioefficacy and hemolysis evaluation in vitro. To ascertain comparability of in-vitro and in-vivo clots with clinical clots, two independent approaches will be taken to form stasis whole blood clots with similar mechanical and structural property as venous clots (Cortran et al., 1994). The clot formulations will be evaluated by comparing their microstructure, mechanical property and lysis response to reported clinical clot values. The transducer developed in Task 1 will be integrated with its drug infusion catheter and evaluated for efficacy in a well-characterized in-vitro human blood clot perfusion system using both aforementioned clot formulations. Additionally, the hemolytic effect of the acoustic field emitted by this high power transducer will be determined. v SPECIFIC AIM #3: Explore bioefficacy in an in-vivo model of pulmonary embolism using high power transducer incorporated catheter system prototypes. The high power transducer incorporated catheter system prototypes will be tested for bioefficacy in-vivo in a canine model of pulmonary embolism. An autologous clot, formed based on one of the clot formulation in Aim 2, will be formed in a canine pulmonary artery. rt-PA will be delivered into the clot systemically and ultrasound exposure will be administered using catheter systems with high power transducers. At the end of therapy, time to lysis determined angiographically will be used to determine bioefficacy.

描述（由申请人提供）：EKOS血管内技术有助于超声辅助导管定向溶栓[CDT]治疗。EkoSonicTM系统在CDT治疗中用于增强药物转运到外周血凝块中的特性很好。EKOS血管内系统经FDA批准，可在外周和肺血管系统中输送医生指定的液体。它已与各种药物（包括rt-PA）一起用于深静脉血栓形成（DVT）和大面积急性肺栓塞（PE）的导管定向溶栓。Chamsuddin等人（2008）使用专为外周血管系统设计的EKOS血管内系统治疗了10例患者的13处大面积急性PE病变。平均溶栓时间为24.76小时± 18.44小时（中位数，24小时），平均t-PA剂量为0.88 mg/h ± 10.19（13处病变）。任何受试者均未发生出血并发症。rt-PA的平均总用量为21.12mg，比静脉溶栓时t-PA的固定用量100 mg减少78%。动脉内输送超声的临床功效取决于超声换能器相对于目标解剖结构的性能。由于肺动脉比外周动脉大许多倍，我们建议采用这种技术来有效治疗大面积PE。高功率导管换能器可以在巨大的肺栓塞上产生有效的声压。目前EKOS的导管传感器已设计并测试了预期应用于外周血管（直径约6至12 mm）的功率输出、寿命、效率和有效性。因此，当在高功率下驱动时，电流传感器受到非常低的公差的限制，导致过早的脆性失效。为了增强穿过相对较大的肺动脉（直径约27 mm）的横截面的药物输送，导管换能器需要具有在较高声压下驱动的操作能力。本项目的总体目标是开发高功率换能器，并证明使用高功率导管换能器进行超声辅助溶栓治疗的可行性，以在显著缩短体内治疗时间的情况下改善大面积肺栓塞的血栓清除。溶解药物（rt-PA，Activase（R））将直接输注到高功率导管传感器周围的即时血凝块体积中。我们的具体目标是：v具体目标#1：制造高功率换能器原型的声学特性。我们将通过研究压电陶瓷制造工艺来制造换能器原型，以构建坚固的换能器，该换能器将具有承受高电输入的操作能力，并产生更高的声压，以增强药物在相对较大的肺动脉（直径约27 mm）横截面上的转运。我们将确定原型传感器的声学特性，并通过经验测量防止目标声压下任何意外的气穴活动。v具体目标#2：优化血凝块形成并进行体外生物功效和溶血评价。为了确定体外和体内凝块与临床凝块的可比性，将采用两种独立的方法来形成具有与静脉凝块相似的机械和结构特性的淤滞全血凝块（Cortran等人，1994年）。将通过比较其微观结构、机械性能和溶解反应与报告的临床凝块值来评价凝块制剂。任务1中开发的换能器将与其药物输注导管集成，并使用上述两种凝块制剂在充分表征的体外人血凝块灌注系统中评价疗效。此外，将确定由该高功率换能器发射的声场的溶血效应。特定目标#3：使用高功率换能器结合导管系统原型在肺栓塞体内模型中探索生物功效。将在肺栓塞犬模型中对高功率换能器结合导管系统原型进行体内生物有效性试验。将在犬肺动脉中形成基于目标2中的一种凝块制剂形成的自体凝块。rt-PA将被全身输送到凝块中，超声暴露将使用带有高功率换能器的导管系统进行。在治疗结束时，血管造影确定的溶解时间将用于确定生物有效性。