Effect of Prone Position on Ventilator-Induced Lung Injury

俯卧位对呼吸机所致肺损伤的影响

• 批准号: 8321539
• 负责人: Guido Musch
• 金额: $ 43.77万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321539
• 关键词: Accounting; Acute Lung Injury; Anatomy; Animal Model; Animals; Applications Grants; Attenuated; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cessation of life; Clinical Trials; Critical Illness; Data; Deoxyglucose; Dorsal; Economic Inflation; Effectiveness; Emission-Computed Tomography; Environmental air flow; Event; Experimental Models; Functional Imaging; HIV; Heterogeneity; Histologic; Human; Hypoxemia; Image; Impairment; Incidence; Injury; Intensive Care Units; Intervention; Kinetics; Length of Stay; Lung; Measures; Mechanical ventilation; Mechanics; Metabolic; Metabolic Activation; Modeling; Morbidity - disease rate; Neutrophil Activation; Outcome; Pathogenesis; Patient Care; Patients; Perfusion; Persons; Physiological; Physiology; Play; Positron; Positron-Emission Tomography; Prone Position; Relative (related person); Research; Role; Saline; Severities; Sheep; Supine Position; Testing; Tidal Volume; Tracer; United States; Ventilator-induced lung injury; base; body position; clinical application; glucose uptake; improved; in vivo; injured; insight; lung injury; malignant breast neoplasm; molecular imaging; mortality; neutrophil; novel; outcome forecast; prevent; protective effect; public health relevance; surfactant; uptake

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.

描述（由申请人提供）：最近估计急性肺损伤（ALI）的发生率为每100,000人年86.2，其死亡率为38.5％。这些数字表明，在美国，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相当，而220万个重症监护病房和360万医院的医院时间专门用于ALI患者的护理。呼吸机诱导的肺损伤（VILI）已被确定为导致ALI发病率和死亡率的贡献者。尽管尚未确定，但临床试验的数据表明，俯卧定位可以提高ALI的生存。这种改善的可能原因是Vili的减少。中性粒细胞已被证明在VILI的发病机理中起着至关重要的作用，我们最近证明了中性粒细胞代谢激活发生在VILI期间。这项研究的广泛，长期的目标是提高对VILI机制的理解，并发展手段以防止或减少它。为此，目前的赠款提案研究了总体假设，即通过促进整个肺部均匀的实质曝气和潮汐体积分布，俯卧的定位会导致中性粒细胞代谢激活的减少。该假设将在类似于人类（即绵羊）的生理学的大动物中进行研究，以三个特定的目的。具体目标1研究了俯卧位的有效性，以此作为延迟发作并降低Vili诱导的中性粒细胞激活的严重程度和地形异质性的一种手段。在特定的目标2中，ALI的特征化实验模型，其中盐水肺灌洗会导致表面活性剂的耗竭，并明显地使用充气丧失，以研究易于下降的位置是否会导致背肺区域的中性粒细胞激活降低，预计会导致膨胀和更均匀的Tidal tidal tidal tidal tidal the Chands Chands Chands Chands Chands Change Chands Change。在特定的目标3中，使用潮汐体积的分级增加来检验以下假设：俯卧位可以比仰卧位更高的潮汐体积，而无需增强肺中的嗜中性粒细胞激活。正电子发射和计算机断层扫描成像和先进的示踪动力学建模将用于测量中性粒细胞的区域代谢活性，体内肺灌注和曝气。可以预期，这种综合的解剖，生理和分子成像方法在紧密编织的特定目的中的应用将提供对俯卧定位可能减轻Vili的机制的新见解。方法论方法的直接临床适用性，绵羊和人类肺部生理的相似性以及使用良好的ALI模型的使用极大地增强了该项目的转化方面。因此，拟议的研究可能有助于确定是否存在强大的理由，用于在患有ALI的重症患者的通风管理中使用易于定位，并且可以看作是有利于患者的后续研究。 公共卫生相关性：据估计，在美国，急性肺损伤（ALI）估计每年占74,500例死亡和360万例医院。由于呼吸机诱导的肺损伤（VILI）导致了ALI的发病率和死亡率，因此减少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定位来促进均匀的肺通胀和潮汐扩张是否会减少中性粒细胞代谢激活，这是VILI发病机理中的早期和重要事件。