Phase II, randomized controlled trial of brain tissue oxygen monitoring

描述（由申请人提供）：创伤性脑损伤（TBI）是导致死亡和残疾的主要原因。仅在美国，每年就有约140万人遭受创伤性脑损伤，其中5万人死亡，20多万人住院。创伤性脑损伤的急性治疗旨在防止继发性神经元损伤，这是由多种机制引起的，其中最突出的是组织缺血。近年来，直接连续监测脑组织氧分压（pBrO2）已成为可能。几项观察性研究表明，低pBrO2的发作是常见的，并且与不良预后相关，并且在临床实践中，医学干预在改善pBrO2方面是有效的。然而，由于没有进行随机对照试验来确定pBrO2监测是否能改善严重TBI后的预后，因此该技术迄今尚未在神经外科icu中广泛采用。拟议的研究将是第一个pBrO2监测的随机对照临床试验，旨在获得确定的III期研究所需的数据，例如旨在治疗pBrO2的生理操作的有效性，以及跨多个临床站点标准化复杂重症监护病房管理方案的可行性。严重TBI患者将接受ICP和pBrO2监测，并将随机分为基于ICP的治疗组（对照组）或基于ICP + pBrO2值的治疗组（治疗组）。182名参与者将在四个临床地点登记，分别是德克萨斯大学西南医学中心/帕克兰纪念医院、华盛顿大学/港景医学中心、迈阿密大学/杰克逊纪念医院和宾夕法尼亚大学/宾夕法尼亚大学医院。损伤后6个月评估功能结果。本研究有一个主要假设和几个次要假设：(1)基于pBrO2监测的治疗方案可减少组织缺氧。(2)。安全性假设：与pBrO2监测相关的不良事件很少（感染性、出血性或其他监测相关不良事件的发生率小于3%），pBrO2定向治疗不会导致肺部或全身并发症（如急性肺损伤/成人呼吸窘迫综合征（ALI/ARDS））的风险增加。(3)。可行性假设：可识别pBrO2降低的发作，并在4个临床站点建立可比较的治疗方案，并且不同临床站点的协议违规率将较低（<10%）且统一。(4)。Non-futility假说。格拉斯哥预后量表（Glasgow outcome scale）测量的良好预后的相对风险为2.0，与本II期研究的结果一致。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. The acute management of TBI is aimed at preventing secondary neuronal injury, which results from a variety of mechanisms, prominently among them tissue ischemia. Recently, it has become feasible to directly and continuously monitor the partial pressure of oxygen in brain tissue (pBrO2). Several observational studies indicate that episodes of low pBrO2 are common and are associated with a poor outcome, and that medical interventions are effective in improving pBrO2 in clinical practice. However, as there have been no randomized controlled trials carried out to determine whether pBrO2 monitoring results in improved outcome after severe TBI, use of this technology has not so far been widely adopted in neurosurgical ICUs. The proposed study will be the first randomized, controlled clinical trial of pBrO2 monitoring, and is designed to obtain data required for a definitive phase III study, such as efficacy of physiologic maneuvers aimed at treating pBrO2, and feasibility of standardizing a complex intensive care unit management protocol across multiple clinical sites. Patients with severe TBI will be to be monitored with ICP and pBrO2 monitoring, and will be randomized to therapy based on ICP along (control group) or therapy based on ICP in addition to pBrO2 values (treatment group). 182 participants will be enrolled at four clinical sites, the University of Texas Southwestern Medical Center/Parkland Memorial Hospital, the University of Washington/Harborview Medical Center, the University of Miami/Jackson Memorial Hospital, and the University of Pennsylvania/Hospital of the University of Pennsylvania. Functional outcome will be assessed at 6-months after injury. This study has one primary and several secondary hypotheses: (1) Treatment protocol based on pBrO2 monitoring results in reduction of tissue hypoxia. (2). Safety hypotheses: Adverse events associated with pBrO2 monitoring are rare (< 3% for combination of infectious, hemorrhagic, or other monitoring-related adverse events) and pBrO2 directed therapy does not result in increased risk of pulmonary or systemic complications (such as acute lung injury/Adult Respiratory Distress Syndrome (ALI/ARDS). (3). Feasibility hypotheses: Episodes of decreased pBrO2 can be identified and treatment protocol instituted comparably across 4 Clinical sites, and protocol violations will be low (<10% and uniform across different clinical sites. (4). Non-futility hypothesis. A relative risk of good outcome measured by the Glasgow Outcome Scale-Extended 6-months after injury of 2.0 is consistent with the results of this phase II study. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major cause of death and disability, with an estimated cost of 45 billion dollars a year in the United States alone. Every year, approximately 1.4 million sustain a TBI, of which 50,000 people die, and another 235,000 are hospitalized and survive the injury. As a result, 80,000-90,000 people experience permanent disability associated with TBI. This results in an enormous psychosocial burden on patients, their families, and society. This project is designed to determine whether a device designed to measure brain tissue oxygenation and thus detect brain ischemia while it is still potentially treatable shows promise in reducing the duration of brain ischemia, and to obtain information required to conduct a definitive clinical trial of efficacy.