Treatment of Cerebral Edema Using Ventricular Therapy

描述（由申请人提供）： 脑水肿可以说是严重创伤性脑损伤（TBI）最严重的并发症。中心假设是，增加脑脊液（CSF）的渗透压将使组织中的自由水进入脑室内，从而减少细胞肿胀、颅内压（ICP）和细胞死亡;最终改善脑功能。方法：申请方提议对用于减少脑水肿的创新导管进行初步人体研究。该导管的初始临床应用将是重度TBI，并将涉及用还原性脑室渗透治疗（RVOT）导管替换标准脑室体外引流（EVD）导管，该导管1）从CSF中清除游离水2）在需要时急性清除大量CSF以控制ICP，以及3）监测ICP。清除游离水可增加CSF的渗透压，这在理论上将导致间质脑水的清除，从而最大限度地减少脑水肿并改善营养交换和脑灌注。在猪中进行了实验性TBI的对照研究，其证明了CSF渗透压升高、颅内压（ICP）降低、CSF化学变量（如乳酸盐）改善以及细胞内水肿和细胞死亡减少。对照组使用EVD导管治疗。分析的变量一致表明，与EVD相比，RVOT产生了显著改善或有利趋势，支持RVOT减少细胞肿胀和细胞死亡同时最终改善脑功能的中心假设。具体目标：（I）将对RVOT系统设计进行完善和测试，以优化临床研究性能，并获得FDA试验用器械豁免（IDE）批准。(II)将进行一项多中心临床研究，以评估RVOT在控制TBI患者ICP和细胞内水肿方面的患者安全性问题和有效性。这项在三个研究中心对15名患者进行的初步研究预计将证明RVOT导管与传统EVD导管的等效性，并提供临床数据支持旨在证明RVOT优于传统引流的关键研究的设计。ICP将是主要终点。研究结果将用于支持FDA 510（k）产品批准。重要性：脑水肿是一种危及生命的疾病，在大量TBI和严重卒中患者中，常规治疗难以治愈。II期目标的完成将使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120万美国人在医院急诊室接受了创伤性脑损伤治疗，29万人住院，超过5万人死亡。脑水肿的二次损伤可能是三分之一的TBI死亡的原因。一直缺乏解决这一问题的创新方法，目前可用于治疗这一严重疾病的疗法的有效性有限。

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.