Novel Ultrasound Indices of Intracranial Pressure and Brain Ischemia in Neonatal Hydrocephalus

新生儿脑积水颅内压和脑缺血的超声新指标 项目摘要 新生儿脑积水影响每1000名活产儿中的1-2名，并导致高达78%的神经功能障碍 治疗过的病人。各种病因，包括脑室出血、先天性导水管 狭窄、脊髓脊膜膨出和脑肿瘤会引起脑脊液的异常积聚。 在这种疾病中，导致脑室扩张和颅内压(ICP)升高。而当 脑室分流术是脑脊液分流的外科治疗方法，根据脑室的情况决定是否分流。 大小和临床判断不是颅内压和脑健康的敏感指标。因此，延误的诊断 颅内压升高和手术分流可能导致永久性脑损伤和长期的神经功能障碍。 由于出血和局部脑出血的相关风险，不常规地插入有创的颅内压监测仪 脆弱的新生儿脑缺血。为了提供一种解决方案，以解决在临床护理方面的重大缺口 对于新生儿脑积水，我们利用超声造影(CEUS)技术进行无创性治疗 在一种公认的猪脑积水模型中检测颅内压和脑缺血。CEU使用情况 血管内注射平均大小为2-3微米的微泡，以评估组织灌注量。与 结合使用新的粒子跟踪方法(所谓的粒子强度和/或跟踪速度计)和 传统的脑血流灌注分析中，脑微循环的潜在时空变化可以 量化以评估颅内压升高和脑缺血。请注意，CEU已被FDA批准用于 截至2016年，美国儿科应用于评估局灶性肝脏病变和膀胱输尿管反流，但其 在新生儿大脑中的应用是不符合标签的。为此，PI目前是FDA监管的第一个， 研究新药(IND)批准的临床试验应用于婴儿的脑CEU，并发表了第一个 婴儿脑CEU的成像指南；有效的临床立即翻译的可能性 因此，完成本提案后的方法具有重要意义。该提案的核心假设是 CEUS将成为颅内压和脑缺血的准确生物标志物。该计划的总体目标 因此，建议1)验证CEUS的颅内压和脑缺血指数 建立仔猪脑积水模型及2)评价优化的脑CEU的体内安全性 协议。我们的工作将为一种新的非侵入性颅内评估工具的临床翻译奠定基础 新生儿脑积水的压力和脑缺血，最终可以提高分流的指导 以及长期的神经学结果。

Novel Ultrasound Indices of Intracranial Pressure and Brain Ischemia in Neonatal Hydrocephalus Project Summary Neonatal hydrocephalus affects 1-2 of every 1000 live births and results in neurologic deficits in up to 78% treated patients. A wide spectrum of etiologies including intraventricular hemorrhage, congenital aqueduct stenosis, myelomeningocele, and brain tumors cause an abnormal accumulation of cerebral spinal fluid (CSF) in this disease, resulting in cerebral ventricular dilatation and elevated intracranial pressure (ICP). While ventricular shunting is used as surgical treatment for CSF diversion, the decision to shunt is based on ventricular size and clinical judgement which are not sensitive markers of ICP and brain health. Thus, delayed diagnosis of elevated ICP and surgical shunting can result in permanent brain damage and long-term neurologic deficits. Insertion of invasive ICP monitor is not routinely done due to the associated risk of bleeding and regional brain ischemia in the vulnerable neonatal brain. In order to provide a solution to a significant gap in clinical care of neonatal hydrocephalus, we utilize the contrast-enhanced ultrasound (CEUS) technique for noninvasive detection of ICP and brain ischemia in a well-established porcine model of hydrocephalus. CEUS uses intravascular injection of microbubbles of average 2-3 µm in size for assessment of tissue perfusion. With the combined use of the novel particle tracking method (so-called particle intensity and/or tracking velocimetry) and traditional perfusion analysis, the underlying spatial and temporal changes in cerebral microcirculation can be quantified for assessment of elevated ICP and brain ischemia. Note that CEUS has been FDA-approved for pediatric applications in the U.S. as of 2016 for evaluation of focal liver lesions and vesicoureteral reflux, but its application in neonatal brain is off-label. For this, the PI currently spearheads the first FDA regulated, Investigational New Drug (IND)-approved clinical trial applying brain CEUS in infants and published the first imaging guidelines on brain CEUS in infants; the potential for immediate clinical translation of the validated method following the completion of this proposal is therefore significant. The central hypothesis of the proposal is that CEUS will be an accurate biomarker of intracranial pressure and brain ischemia. The overall goal of the proposal is therefore to 1) validate CEUS indices of intracranial pressure and brain ischemia using an already established infant porcine model of hydrocephalus and to 2) assess in vivo safety of the optimized brain CEUS protocol. Our work will set the stage for clinical translation of a new noninvasive tool for assessment of intracranial pressure and brain ischemia in neonatal hydrocephalus, which can ultimately improve the guidance of shunting and long-term neurologic outcomes.