Effect of Prone Position on Ventilator-Induced Lung Injury

项目摘要 急性肺损伤（ALI）的发病率最近估计为86.2/10万人年， 死亡率为38.5%。这些数字意味着美国每年有74，500人死于ALI， 这一数字与乳腺癌或艾滋病毒造成的死亡人数相当，220万个重症监护病房日， 3.6每年有1000万个住院日专门用于护理急性肺损伤患者。呼吸机诱导的肺损伤（VILI） 被认为是ALI发病率和死亡率的一个因素。尽管尚未得出结论，但来自 临床试验表明俯卧位可以提高ALI患者的存活率。一个可能的原因 改善是VILI减少。嗜中性粒细胞已被证明在糖尿病的发病机制中起着至关重要的作用。 VILI和我们最近证明，中性粒细胞代谢活化发生在VILI早期。那个女人 这项研究的长期目标是提高对VILI机制的理解， 为了达到这个目的，目前的拨款建议审查了总体假设 通过促进均匀的肺实质通气和潮气量分布， 定位导致由大的局部潮汐膨胀引起的中性粒细胞代谢活化的减少。 该假设将在生理学与人类相似的大型动物中进行检验（即，羊），在三个 具体目标。具体目标1检查俯卧位作为延迟发作的手段的有效性 并降低初始时VILl诱导的中性粒细胞活化的严重程度和地形异质性。 未受伤的肺通气，潮气量大。在具体目标2中，提供了一种良好表征的实验模型， 生理盐水肺灌洗导致表面活性物质耗竭和明显的不均匀通气损失的ALI， 用于研究俯卧位是否导致背肺区域中性粒细胞活化减少， 由于身体的位置， 变化在具体目标3中，使用潮气量的分级增加来检验以下假设： 体位允许比仰卧位更高的潮气量，而不会增加中性粒细胞活化， 受伤前的肺正电子发射和计算机断层扫描成像和先进的示踪剂动力学建模 将用于测量中性粒细胞的局部代谢活性、肺灌注和通气， vivo.这种综合的解剖学、生理学和分子影像学方法有望应用于 紧密结合的特定目标将提供对机制的新见解，通过该机制，俯卧定位可以 减弱VILI。方法学方法的直接临床适用性，肺动脉高压的相似性， 羊和人之间的生理学和使用一个良好的表征模型的ALI大大提高了 这个项目的翻译。因此，拟议的研究可能有助于确定 在危重病人的急救管理中使用俯卧位有很强的理由 与ALI，并可以被视为有利于患者的后续研究。

Project Summary 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.