Treatment of Cerebral Edema Using Ventricular Therapy

描述(由申请人提供)： 脑水肿可以说是重型颅脑损伤(TBI)最严重的并发症。中心假说是，增加脑脊液(CSF)的渗透压会将组织中的游离水转移到脑室，在那里可以将其清除，从而减少细胞肿胀、颅内压(ICP)和细胞死亡，最终改善大脑功能。方法：申请人提议进行一项用于减少脑水肿的创新导管的试验性人体研究。这种导管的初步临床应用将是严重的颅脑损伤，包括用减压性脑室渗透疗法(RVOT)导管取代标准的脑室外引流(EVD)导管，这种导管1)清除脑脊液中的游离水；2)如果需要控制颅内压，立即清除大量脑脊液；3)监测颅内压。清除游离水会增加脑脊液的渗透压，从理论上讲，这将导致间质脑水的清除，最大限度地减少脑水肿，改善营养交换和脑血流。对猪实验性颅脑损伤进行了对照研究，结果表明，脑脊液渗透压升高，颅内压降低，脑脊液乳酸等化学指标改善，细胞内水肿和细胞死亡减少。对照组采用EVD导管治疗。分析的变量一致表明，与EVD相比，RVOT产生了显著的改善或有利的趋势，支持了RVOT在最终改善大脑功能的同时减少细胞肿胀和细胞死亡的中心假设。具体目标：(I)将改进和测试RVOT系统设计，以优化临床研究和获得FDA调查设备豁免(IDE)批准的性能。(Ii)将进行一项多中心临床研究，以评估患者的安全性问题和RVOT在控制颅脑损伤患者的颅内压和细胞内水肿方面的有效性。这项针对三个地点的15名患者的初步研究有望证明RVOT导管与传统EVD导管的等效性，并提供临床数据，以支持旨在证明RVOT优于传统引流的关键研究的设计。国际比较方案将成为主要终点。研究结果将用于支持FDA 510(K)产品批准。意义：脑水肿是一种危及生命的疾病，在大量的脑外伤和严重中风患者中，常规治疗难以奏效。第二阶段目标的完成将使RVOT导管的关键人体研究成为可能。 公共卫生相关性： 2003年，超过120万美国创伤性脑损伤患者在医院急诊科接受治疗，29万人住院，5万多人死亡。脑水肿的二次损伤可能是导致三分之一的脑损伤死亡的原因。对这一问题缺乏创新的方法，目前可用于治疗这一危重疾病的疗法在有效性方面有限。

DESCRIPTION (provided by applicant): Cerebral edema is arguably the most serious complication of severe traumatic brain injury (TBI). The central HYPOTHESIS is that increasing osmolality of cerebrospinal fluid (CSF) will move free water out of tissue into the ventricles where it can be removed, thereby reducing cellular swelling, intracranial pressure (ICP), and cell death; ultimately improving cerebral function. Approach: The applicant proposes to undertake a pilot human study of an innovative catheter for the reduction of cerebral edema. The initial clinical application of this catheter will be severe TBI, and will involve replacing standard external ventricular drain (EVD) catheters with Reductive Ventricular Osmotherapy (RVOT) Catheters that 1) remove free water from CSF 2) remove bulk CSF acutely if needed to control ICP, and 3) monitor ICP. Removal of free water increases osmolality of the CSF, which will theoretically result in removal of interstitial brain water minimizing cerebral edema and improving nutrient exchange and Cerebral perfusion. A controlled study of experimental TBI in swine was performed, which demonstrated elevation of CSF osmolality, reduction in intracranial pressure (ICP), improvement in CSF chemistry variables such as lactate, and reduction in intracellular edema and cell death. Controls were treated with EVD catheters. The analyzed variables consistently indicated that RVOT produced either significant improvement or a favorable trend compared to EVD, supporting the central hypothesis that RVOT reduces cellular swelling and cell death while ultimately improving cerebral function. Specific Aims: (I) The RVOT System design will be refined and tested to optimize performance for clinical studies and for obtaining FDA Investigational Device Exemption (IDE) approval. (II) A multicenter clinical study will be conducted to assess patient safety issues and effectiveness of RVOT in controlling ICP and intracellular edema in TBI patients.This pilot study of 15 patients at three sites is expected to demonstrate RVOT Catheter equivalence with conventional EVD catheters and provide clinical data to support the design of a pivotal study intended to demonstrate RVOT superiority to conventional drainage. ICP will be the primary endpoint. Study results will be used to support a FDA 510(k) product approval. Significance: Cerebral edema is a life threatening condition that is refractory to conventional treatments in a significant population of TBI and severe stroke patients. Completion of Phase II aims will make pivotal human studies of RVOT catheters possible. PUBLIC HEALTH RELEVANCE: In 2003 over 1.2 million Americans with traumatic brain injury were treated at hospitals emergency departments, 290,000 were hospitalized, and over 50,000 died. Secondary insults from cerebral edema may be responsible for one-third of TBI deaths. Innovative approaches to this problem have been lacking and the current therapies available to treat this critical medical condition are limited in their effectiveness.