The Risk of Acute Respiratory Distress Syndrome after Severe Isolated Traumatic B

描述(申请人提供)：在美国，每年有170万人遭受创伤性脑损伤(TBI)，其中52,000人死亡。超过20%的严重孤立性脑损伤患者将发展为急性呼吸窘迫综合征(ARDS)。脑外伤后ARDS的发展与更高的医疗费用和更差的神经预后相关(Holland，2004，Mascia 2008)。孤立性脑损伤患者的肺损伤机制目前知之甚少。这里提出的研究将利用全面的、前瞻性收集的数据和从大量孤立的脑外伤患者队列中收集的血浆样本。我将评估可能导致ARDS风险的患者特定因素和护理过程中的差异，并测试三种候选生物标记物在预测ARDS风险方面的有效性。有生物学上的合理性和来自小鼠和临床研究的数据支持这一假设，即更严重的头部损伤与ARDS有关。我们的研究小组最近报告了另一个患者特有的因素，暴露在香烟烟雾中，会增加创伤患者随后发生ARDS的风险(Calfee，2011)。在这里，我们建议测试以下假设：患者特有的因素，如头部损伤的严重程度(目标1a)和暴露于烟草烟雾(目标1b)，导致生物紊乱，从而导致孤立性脑损伤患者的ARDS。此外，我们假设炎症、内皮激活和血管通透性的血浆标记物将捕捉孤立性脑损伤中ARDS的致病途径。我们将检测三个潜在的生物标志物，白介素8(IL-8)、血管生成素2(Ang-2)和基质金属蛋白酶组织抑制因子-3(TIMP3)，并验证这些血浆蛋白的早期差异预测ARDS后续发展的假设(目标2)。除了研究到达急诊科时存在的因素外，我们还将确定导致ARDS风险的护理流程。2009年，Mascia et al.描述了一种两次打击致急性呼吸窘迫综合征(ARDS)的模型，在该模型中，TBI使肺内皮细胞更容易受到呼吸机所致的肺损伤。我们将测试这一假设，即任何暴露于高潮气量通气量(理想体重为10毫升/公斤)的环境与孤立脑损伤后ARDS风险增加相关(目标3)。我们还将评估暴露于高潮气量机械通气和ARDS的发展是否通过一条共同的途径进行调节，所测量的生物标记物IL-8、Ang-2和TIMP3发生变化。如果具有特殊临床特征和更严重的炎症和内皮损伤的患者患ARDS的风险更高，这里概述的研究将建立一种方法，在他们的病程早期识别这些高风险患者，并设计未来的干预措施，旨在改善严重孤立脑损伤患者的临床结果。从事这项工作将使我在以患者为导向的科学研究、临床数据分析和科学合作方面建立技能，这将为我的翻译研究职业生涯奠定基础。

DESCRIPTION (provided by applicant): Each year in the United States 1.7 million people sustain Traumatic Brain Injury (TBI) and 52,000 of these patients die. Over 20% of patients with severe, isolated TBI will develop Acute Respiratory Distress Syndrome (ARDS). The development of ARDS after TBI is associated with higher health care costs and worse neurological outcomes (Holland, 2004, Mascia 2008). Little is known about the mechanisms that cause lung injury in patients with isolated TBI. The studies proposed here will take advantage of comprehensive, prospectively collected data and plasma specimens collected from a large cohort of isolated TBI patients. I will evaluate patient specific factors and differences in processes of care that may contribute to the risk of developing ARDS, and to test the utility of three candidate biomarkers in predicting higher risk of ARDS. There is biologic plausibility and data from murine and clinical studies to support the hypothesis that more severe head injury is associated with ARDS. Our research group recently reported that another patient-specific factor, exposure to cigarette smoke, confers a higher risk of subsequent ARDS in trauma patients (Calfee, 2011). Here we propose to test the hypotheses that patient-specific factors, such as the severity of head injury (Aim 1a) and exposure to tobacco smoke (Aim 1b), contribute to the biological derangements that subsequently lead to ARDS in patients with isolated TBI. Furthermore, we hypothesize that plasma markers of inflammation, endothelial activation, and vascular permeability will capture causal pathways of ARDS in isolated TBI. We will measure three potential biomarkers, Interleukin-8 (IL-8), angiopoietin 2 (Ang-2), and tissue inhibitor of matrix metalloproteinase-3 (TIMP3) in plasma samples obtained just after injury and test the hypothesis that early differences in these plasma proteins predict the subsequent development of ARDS (Aim 2). In addition to studying factors that are present upon arrival to the emergency department, we will identify processes of care that contribute to the risk of ARDS. In 2009 Mascia et al. described a two-hit model for ARDS in TBI in which TBI primes the pulmonary endothelium to be more susceptible to ventilator induced lung injury. We will test the hypothesis that any exposure to high tidal volume ventilation (>10cc/kg of ideal body weight) is associated with increased risk of ARDS after isolated TBI (Aim 3). We will also evaluate if exposure to high tidal volume mechanical ventilation and development of ARDS is mediated through a common pathway with changes in measured biomarkers IL-8, Ang-2, and TIMP3. If patients with particular clinical characteristics and more severe inflammation and endothelial injury are at higher risk of ARDS, the studies outlined here will establish a means of identifying these high risk patients early in their course illness and designing future interventions aimed at improving clinical outcomes in patients with severe isolated TBI. Carrying out this work will allow me to build skills in patient-oriented science research, clinical data analysis, and scientific collaborations that will lay the foundation for a career in translational research.