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新型超声指标

• 批准号: 10097438
• 负责人: Misun Hwang
• 金额: $ 66.12万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10097438
• 关键词: Academy; Affect; Animal Model; Assessment tool; Biological Markers; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Cerebral Ischemia; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrum; Child; Childhood; Clinical; Clinical Trials; Complex; Data; Data Analyses; Diagnosis; Dilatation - action; Disease; Engineering; Etiology; Evaluation; Extracorporeal Membrane Oxygenation; FDA approved; Family suidae; Future; Goals; Guidelines; Heart Arrest; Hemorrhage; Histologic; Histology; Hospitals; Hydrocephalus; Image; Infant; Injections; International; Intervention; Intracranial Hypertension; Intracranial Pressure; Investigational Drugs; Judgment; Label; Lead; Lesion; Liquid substance; Live Birth; Liver; Measures; Meningomyelocele; Methods; Microbubbles; Microcirculation; Microspheres; Modeling; Monitor; Neonatal; Neurologic Deficit; Neurological outcome; Non-Invasive Cancer Detection; Operative Surgical Procedures; Outcome; Patients; Perfusion; Population; Pre-Clinical Model; Protocols documentation; Publishing; Reference Standards; Risk; Safety; Shunt Device; Stenosis; Stroke; Surgical Management; Techniques; Testing; Time; Tissues; Traumatic Brain Injury; Ultrasonography; Validation; Velocimetries; Ventricular; Vesico-Ureteral Reflux; Work; base; brain health; clinical care; clinical translation; clinically translatable; contrast enhanced; experience; imaging approach; improved; in vivo; indexing; intraventricular hemorrhage; member; neonatal brain; neonatal care; neonate; novel; particle; pre-clinical; standard measure; tool

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.

新生儿脑积水颅内压和脑缺血的新型超声指标 项目概要 每 1000 名活产儿中就有 1-2 人患有新生儿脑积水，并导致高达 78% 的神经功能缺损 接受治疗的患者。病因广泛，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会导致脑脊液 (CSF) 异常积聚 在这种疾病中，导致脑室扩张和颅内压（ICP）升高。尽管 脑室分流术作为脑脊液改道的手术治疗，分流的决定是基于心室分流术 大小和临床判断不是 ICP 和大脑健康的敏感标志。因此，延误诊断 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。 由于出血和局部脑损伤的相关风险，插入侵入式 ICP 监测仪并不常规进行 脆弱的新生儿大脑缺血。为了解决临床护理方面的重大差距 新生儿脑积水，我们利用超声造影（CEUS）技术进行无创治疗 在完善的猪脑积水模型中检测 ICP 和脑缺血。超声造影用途 血管内注射平均大小为 2-3 µm 的微泡，用于评估组织灌注。随着 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）和 传统的灌注分析可以揭示脑微循环的潜在时空变化 量化评估 ICP 升高和脑缺血。请注意，CEUS 已获得 FDA 批准 截至 2016 年，该技术在美国的儿科应用中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超说明书的。为此，PI 目前带头实施第一个 FDA 监管的、 研究性新药 (IND) 批准的婴儿脑部 CEUS 临床试验并发表第一个 婴儿脑部超声造影成像指南；经验证的立即临床转化的潜力 因此，完成本提案后的方法具有重要意义。提案的中心假设 CEUS将成为颅内压和脑缺血的准确生物标志物。该项目的总体目标是 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 建立了婴儿猪脑积水模型，并 2) 评估优化的脑部 CEUS 的体内安全性 协议。我们的工作将为用于评估颅内病变的新型非侵入性工具的临床转化奠定基础 新生儿脑积水的压力和脑缺血，最终可以改善分流的指导 和长期神经系统结果。