High Intensity Ultrasonic Device for Mitigating Neonatal Perioperative Bleeding

 描述(申请人提供)：先天性心脏病(CHD)的范围从良性病变到危及生命的结构异常。良性病变无需介入即可治愈，严重的结构性病变需要复杂的儿科心脏手术。严重的先天性心脏病包括大血管转位、左/单心室发育不良和严重的主动脉狭窄。治疗这些病变所需的具体手术有所不同，但至少有两个重要的相似之处：1)它们需要手术增强大血管(主动脉和肺动脉)，2)病变的严重程度需要在新生儿期进行手术。对于患有严重先天性心脏病的儿童，重建主动脉弓通常需要横断大血管，显著增强(通常使用生物补片材料)，然后使用非常小口径的缝合线进行缝合修复，以确保修复的完整性。然而，由于修复的复杂性、新生儿弓的解剖结构以及体外循环期间所需的抗凝治疗，围手术期出血是一种重要且常见的并发症。临床上迫切需要一种有效的方法来影响此类患者的围手术期止血。这项建议满足了这一需求。高强度聚焦超声(HIFU)为治疗围手术期出血提供了一种新的方法。超声的主要临床应用是诊断成像；然而，治疗性超声领域正在迅速增长。HIFU等超声波的治疗方式与诊断超声的不同之处在于，超声换能器的设计使得超声能量集中在较小的区域。聚焦超声波可以在几秒钟内将目标组织加热到100摄氏度以上。这种快速加热已经在许多固体器官和血管出血模型中诱导止血。我们的主要研究目标是减轻手术重建的大血管围手术期出血的影响，从而降低与外科手术相关的围产儿发病率和死亡率。这一第二阶段方案的目的是在动物模型中建立可行性和所需参数，以便HIFU可以安全有效地用于减少围手术期出血。为了实现这一目标，我们将：(I)评估HIFU对手术重建的原位血管的完整性和强度的影响(急性动物研究)(特定目的1)；(Ii)改进临床手持HIFU系统，用于治疗新生儿围手术期出血 (Iii)设计和开发用于治疗设置、参数记录和设备自检的自动控制模块的用户界面和说明手册(特定AIM 3)；以及(Iv)进行一系列实验，以测试我们的临床设备在存活动物研究中的安全性和有效性(特定AIM 4)。

 DESCRIPTION (provided by applicant): Congenital Heart Disease (CHD) ranges from benign lesions to life-threatening structural abnormalities. While benign lesions may resolve without intervention, severe structural lesions require complex pediatric cardiac surgery. Severe congenital heart defects include transposition of the great vessels, hypoplastic left heart/single ventricle, and severe aortic stenosis. The specific operations required to treat these lesions differ, but have at least two important similarities: 1) they require surgical augmentation of the great vessels (aorta and pulmonary artery), and 2) the severity of the lesions require an operation in the neonatal period. The reconstruction of the aortic arch in children with severe congenital heart disease often requires transection of the great vessels, significant augmentation (often with a biological patch material), then suture repair using very small caliber sutures placed extremely close together to ensure repair integrity. However, due to the complex nature of the repair, the anatomy of the neonatal arch, and the anti-coagulation regimen that is required during the cardio-pulmonary bypass, perioperative bleeding is a significant, important and frequent complication. There is a critical, unmet clinical need for an effective method to effect perioperative hemostasis in such patients. This proposal addresses this need. High Intensity Focused Ultrasound (HIFU) provides a novel approach for treating perioperative bleeding. The primary clinical application of ultrasound is for diagnostic imaging; however, the field of therapeutic ultrasound is growing rapidly. Therapeutic modalities of ultrasound such as HIFU differ from diagnostic ultrasound in that the ultrasound transducer is designed such that the ultrasound energy focuses to a small region. Focusing the ultrasound can result in heating the target tissue to greater than 100o C within seconds. This rapid heating has induced hemostasis in numerous solid organ and vascular bleeding models. Our overarching research objective is to mitigate the effects of perioperative bleeding in surgically reconstructed great vessels, thus reducing the perinatal morbidity and mortality associated with surgical procedures. The objective of this Phase II proposal is to establish the feasibility and required parameters in an animal model such that HIFU can be used safely and effectively to mitigate perioperative bleeding. To accomplish this objective we will: (i) Evaluate the effect of HIFU on the integrity and strength of surgically reconstructed vasculature in situ (acute animal studies) (SPECIFIC AIM 1); (ii) refine the clinical hand-held HIFU system for treating neonatal perioperative bleeding (SPECIFIC AIM 2); (iii) design and development of a user interface and instruction manual for the automated control module for treatment setup, parameter logging, and device self-testing (SPECIFIC AIM 3); and (iv) perform a series of experiments to test the safety and efficacy of our clinical device in survival animal studies (SPECIFIC AIM 4).