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1-2每1000活产婴儿和结果在高达78%的神经功能缺损 治疗的病人。多种病因，包括脑室内出血、先天性导水管 狭窄、脊髓脊膜膨出和脑肿瘤引起脑脊液（CSF）异常积聚 在这种疾病中，导致脑室扩张和颅内压（ICP）升高。而 脑室分流术用作CSF分流术的外科治疗，分流术的决定基于脑室分流术。 其不是ICP和脑健康的敏感标志。因此，延迟诊断 颅内压升高和手术分流可导致永久性脑损伤和长期神经功能缺损。 由于存在出血和局部脑出血的相关风险， 脆弱的新生儿大脑出现缺血为了提供一个解决方案，在临床护理的显着差距， 新生儿脑积水，我们利用超声造影（CEUS）技术， 在建立良好的脑积水猪模型中检测ICP和脑缺血。CEUS用途 血管内注射平均尺寸为2-3 µm的微泡，用于评估组织灌注。与 结合使用新颖的粒子跟踪方法（所谓的粒子强度和/或跟踪测速法）， 传统的灌注分析，脑微循环中的潜在空间和时间变化可以被 定量用于评估ICP升高和脑缺血。请注意，CEUS已获得FDA批准， 截至2016年，在美国的儿科应用中用于评价局灶性肝脏病变和膀胱输尿管反流，但其 在新生儿脑中的应用是标签外的。为此，PI目前带头第一个FDA监管， 研究性新药（IND）批准的在婴儿中应用脑CEUS的临床试验，并发表了第一个 婴儿脑CEUS成像指南;经验证的 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。的总体目标 因此，建议1）使用已经存在的方法验证颅内压和脑缺血的CEUS指数， 建立脑积水的幼猪模型，以及2）评估优化的脑CEUS的体内安全性 议定书我们的工作将为临床翻译一种新的非侵入性工具，用于评估颅内 新生儿脑积水中的压力和脑缺血，这最终可以改善分流的指导 和长期的神经学结果。

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.