Effect of Prone Position on Ventilator-Induced Lung Injury

描述(申请人提供)：最近估计急性肺损伤(ALI)的发病率为每10万人年86.2例，死亡率为38.5%。这些数字表明，美国每年有74,500人死于ALI，这一数字与乳腺癌或艾滋病毒的死亡人数相当，有220万个重症监护病房日和360万个住院日专门用于ALI患者的护理。呼吸机相关性肺损伤(VILI)是ALI发病和死亡的重要原因之一。虽然还不是决定性的，但临床试验的数据表明俯卧位可能会改善ALI的存活率。这一改善的一个可能原因是VILI的减少。中性粒细胞已被证明在VILI的发病机制中起着关键作用，我们最近证实中性粒细胞代谢激活发生在VILI的早期。这项研究的广泛和长期目标是提高对VILI机制的了解，并开发预防或减少VILI的方法。为此，目前的拨款提案检验了最重要的假设，即通过促进肺内均匀的实质充气和潮气量分布，俯卧位导致由大的局部性潮汐扩张引起的中性粒细胞代谢激活减少。这一假设将在一种生理上与人类相似的大型动物(即绵羊)中进行检验，目的有三个。具体目的1检验俯卧位作为一种手段的有效性，以延迟VILI诱导的中性粒细胞激活的开始，并降低VILI诱导的中性粒细胞激活的严重性和地形图异质性。在特定的目的2中，我们使用了一个典型的ALI实验模型，在该模型中，盐水肺灌洗导致肺表面活性物质耗竭和明显不均匀的通气量损失，以研究俯卧位是否导致肺背区中性粒细胞活性降低，而由于体位的改变，肺背区有望重新获得通气性和更均匀的潮气扩张。在具体目标3中，潮气量的逐步增加被用来检验这样的假设，即俯卧位允许比仰卧位更大的潮气量，而不会增加损伤前肺中中性粒细胞的激活。将使用正电子发射和计算机断层成像以及先进的示踪剂动力学模型来测量体内中性粒细胞的局部代谢活动、肺灌流和充气。预计这种综合的解剖学、生理学和分子成像方法在紧密结合的特定靶点上的应用将为俯卧位可能减弱VILI的机制提供新的见解。方法学的直接临床适用性，羊和人在肺生理学上的相似之处，以及ALI良好特征模型的使用，大大加强了该项目的翻译方面。因此，拟议的研究可能有助于确定是否存在在ALI危重患者的呼吸机管理中使用俯卧位的强有力的理由，并可被视为有助于对患者进行后续研究。 公共卫生相关性：据估计，在美国，急性肺损伤(ALI)每年造成74,500人死亡，360万天住院。由于呼吸机相关性肺损伤(VILI)是ALI的致残率和致死率的重要因素，降低VILI的干预措施可以改善ALI患者的预后。在这项研究中，我们将测试通过俯卧位促进均匀的肺充气和潮气扩张是否会减少中性粒细胞代谢的激活，这是VILI发病机制中的一个早期和重要的事件。

DESCRIPTION (provided by applicant): The incidence of acute lung injury (ALI) has been recently estimated at 86.2 per 100,000 person-years and its mortality rate at 38.5%. These figures imply that 74,500 persons die from ALI each year in the United States, a figure comparable to the deaths from breast cancer or HIV, and that 2.2 million Intensive Care Unit days and 3.6 million hospital days are devoted to the care of patients with ALI. Ventilator-induced lung injury (VILI) has been identified as a contributor to the morbidity and mortality from ALI. Although not yet conclusive, data from clinical trials suggest that prone positioning may improve survival in ALI. A possible reason for this improvement is reduction of VILI. Neutrophils have been shown to play a crucial role in the pathogenesis of VILI and we recently demonstrated that neutrophil metabolic activation occurs early during VILI. The broad, long-term objective of this research is to improve the understanding of mechanisms of VILI and to develop means to prevent or reduce it. To this end, the present grant proposal examines the overarching hypothesis that, by promoting uniform parenchymal aeration and tidal volume distribution throughout the lung, prone positioning leads to a reduction of neutrophil metabolic activation caused by large localized tidal expansion. This hypothesis will be examined in a large animal with physiology similar to the human (i.e., sheep), in three specific aims. Specific aim 1 examines the effectiveness of the prone position as a means to delay the onset and decrease the severity and topographical heterogeneity of VILI-induced neutrophil activation in initially uninjured lungs ventilated with large tidal volume. In specific aim 2, a well-characterized experimental model of ALI in which saline lung lavage leads to surfactant depletion and markedly heterogeneous loss of aeration is used to investigate whether the prone position leads to decreased neutrophil activation in dorsal lung regions, which are expected to regain aeration and more uniform tidal expansion as a result of the body position change. In specific aim 3, a graded increase in tidal volume is used to test the hypothesis that the prone position allows for higher tidal volumes than the supine position without augmenting neutrophil activation in a pre-injured lung. Positron Emission and Computed Tomography imaging and advanced tracer kinetic modeling will be employed to measure regional metabolic activity of neutrophils, pulmonary perfusion and aeration in vivo. It is expected that application of this integrated anatomic, physiologic and molecular imaging approach to the tightly knit specific aims will provide novel insights into the mechanism by which prone positioning may attenuate VILI. The direct clinical applicability of the methodological approach, the similarities in pulmonary physiology between sheep and humans and the use of a well-characterized model of ALI greatly enhance the translational aspect of this project. Consequently, the proposed studies will likely contribute to establishing if a strong rationale exists for the use of prone positioning in the ventilatory management of critically ill patients with ALI, and can be viewed as conducive to subsequent studies in patients. PUBLIC HEALTH RELEVANCE: Acute lung injury (ALI) has been estimated to account for 74,500 deaths and 3.6 million hospital days per year in the United States. Because ventilator-induced lung injury (VILI) contributes to the morbidity and mortality from ALI, interventions that reduce VILI could improve the prognosis of patients with ALI. In this research, we will test whether promoting uniform lung inflation and tidal expansion by prone positioning reduces neutrophil metabolic activation, an early and important event in the pathogenesis of VILI.