Ultrasound assisted thrombolysis for acute pulmonary embolism

描述(由申请人提供)：EKOS血管内技术促进了超声辅助导管定向溶栓[CDT]治疗。EkoSonicTM系统的特点是用于CDT治疗，以增强药物向外周血栓的传输。EKOS血管内系统被FDA批准用于外周和肺血管系统中医生指定的液体的输送。它已与包括rt-PA在内的各种药物一起用于深静脉血栓(DVT)和大面积急性肺栓塞(PE)的导管定向溶栓治疗。张苏丁等人。(2008)使用专门为外周血管设计的EKOS血管内系统治疗了10名患者13个大面积急性PE病变。平均溶栓时间24.76h，中位时间18.44(中位数24h)，平均t-PA用量0.88 mg/h，共13个病灶。所有受试者均未出现出血性并发症。Rt-PA的平均总剂量为21.12 mg，比静脉溶栓中固定的100 mg的t-PA剂量少78%。动脉内注射超声的临床疗效取决于超声换能器相对于靶区解剖的性能。由于肺动脉比外周动脉大许多倍，我们建议采用这项技术来有效地治疗大量PE。高功率导管换能器可以在巨大的肺栓子上产生有效的声压。目前EKOS公司的导管换能器已经设计并测试了功率输出、寿命、效率和效果，预计将用于外周血管(直径约6至12 mm)。因此，电流传感器在高功率驱动时会受到非常低的容差的限制，从而导致过早的脆性故障。为了增强药物在相对较大的肺动脉横截面(直径约27 mm)上的传输，导管换能器需要具有在较高声压下驱动的操作能力。该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，从而在显著缩短体内治疗时间的情况下改善大面积肺血栓的清除。溶解药物(rt-PA、激活酶(R))将直接注入高功率导管换能器周围的即刻血块中。我们的具体目标是：V特定目标#1：制造的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，以建立坚固的换能器，这些换能器将具有承受高电气输入的操作能力，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)的横截面上的传输。我们将确定原型换能器的声学特性，并通过经验测量防止在目标声压下发生任何意外的空化活动。V特异性目标2：优化血液凝块的形成，并进行体外生物效果和溶血评价。为了确定体外和体内凝块与临床凝块的可比性，将采取两种独立的方法来形成具有类似于静脉凝块的机械和结构特性的淤积性全血凝块(Cortran等人，1994)。这些凝块配方将通过比较它们的微观结构、机械性能和溶解反应与报道的临床凝血值进行比较来进行评估。在任务1中开发的换能器将与其药物输注导管集成在一起，并使用上述两种凝块配方在具有良好特性的体外人体血液凝块灌流系统中评估其有效性。此外，还将确定该高功率换能器发出的声场的溶血效果。V特定目的#3：使用结合导管系统原型的高功率换能器，在肺栓塞的体内模型中探索生物有效性。这种包含导管系统原型的高功率换能器将在犬肺栓塞模型中进行体内生物功效测试。根据AIM 2中的一种凝块配方形成的自体凝块将在犬的肺动脉中形成。Rt-PA将被系统地输送到血栓中，超声照射将使用带有高功率换能器的导管系统进行管理。在治疗结束时，血管造影术确定的溶解时间将用于确定生物疗效。

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.