Ultrasound assisted thrombolysis for acute pulmonary embolism

超声辅助溶栓治疗急性肺栓塞

• 批准号: 8212346
• 负责人: Curtis Genstler
• 金额: $ 21万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212346
• 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]疗法。 Ekosonictm系统的特征是用于CDT治疗，以增强药物转运为外围凝块。 Ekos血管内系统已批准用于外围和肺脉管系统中指定的液体。它已与包括RT-PA在内的各种药物一起用于导管导向深静脉血栓形成（DVT）和大量急性急性肺栓塞（PE）的溶栓。 Chamsuddin等。 （2008年）用EKOS内血管内系统治疗了10例患有13例大规模急性PE病变的患者，专门为外围脉管系统设计。溶栓的平均时间为24.76小时1 8.44（中值，24小时），使用的T-PA的平均剂量为0.88 mg/h 1 0.19（13个病变）。任何受试者均未遭受出血并发症。所使用的RT-PA的平均总剂量为21.12mg，比静脉溶栓剂使用中使用的100mg剂量的T-PA少78％。动脉内传递的超声检查的临床功效取决于目标解剖结构的超声传感器性能。由于肺动脉比周围动脉大很多倍，因此我们建议适应该技术以有效治疗大规模PE。高功率导管换能器可以在整个巨大的肺栓塞上产生有效的声压。当前的EKOS导管换能器已被设计和测试，以实现外围血管（直径约为6至12mm）的预定应用，以实现功率输出，寿命，效率和功效。因此，当以高功率驱动导致过早易碎失败时，当前的传感器受到非常低的公差的约束。为了增强跨越相对较大的肺动脉（直径约27毫米）的横截面的药物转运，导管传感器需要具有在较高声学压力下驱动的操作能力。该项目的总体目标是开发高功率传感器，并使用高功率导管传感器证明超声辅助溶栓疗法的可行性，以在体内明显缩短治疗时间的大规模肺栓塞中改善血栓清除。裂解药物（RT-PA，活化酶（R））将直接注入高功率导管传感器周围的立即凝块体积中。我们的特定目的是：V具体目标＃1：制造的高功率传感器原型的声学表征。我们将通过研究压电陶瓷制造工艺来制造换能器原型，以构建可靠的换能器，该过程将具有承受高电输入并产生较高声音压力的操作能力，以增强跨肺动物相对较大的肺动脉横截面（直径约27 mm）的横截面。我们将通过经验测量值确定原型缠绕器原型的声学特征，并防止目标声压力的任何意外的气蚀活性。 v特定的目标＃2：优化血块形成并在体外进行生物效能和溶血评估。为了确定具有临床凝结物的体外和体内凝块的可比性，将采用两种独立的方法来形成与静脉凝块相似的机械和结构特性的静止全血凝块（Cortran等，1994）。凝块制剂将通过将其微结构，机械性能和裂解反应与报道的临床凝块值进行比较。任务1中开发的换能器将与其药物输注导管集成，并在使用两个上述凝块配方的良好表征的体外人体血液凝块灌注系统中评估功效。此外，将确定该高功率传感器发出的声场的溶血效应。 v特定的目标＃3：使用高功率传感器掺入导管系统原型的肺栓塞体内模型中探索生物效能。高功率传感器掺入导管系统原型将在肺栓塞犬模型中测试体内生物效能感。基于AIM 2中的凝块制剂之一形成的自体凝块将在犬肺动脉中形成。 RT-PA将系统地传递到凝块中，并使用具有高功率传感器的导管系统进行超声曝光。在治疗结束时，在血管造影上确定裂解时间将用于确定生物效能。