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: 7784751
• 负责人: Guido Musch
• 金额: $ 43.29万
• 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/7784751
• 关键词: Accounting; Acute; 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; 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; 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）的发病率为86.2/100，000人-年，死亡率为38.5%。这些数字意味着，在美国每年有74，500人死于ALI，这一数字与乳腺癌或HIV的死亡人数相当，并且有220万个重症监护室日和360万个住院日专门用于护理ALI患者。呼吸机诱导的肺损伤（VILI）已被确定为ALI发病率和死亡率的贡献者。虽然还没有结论，但临床试验的数据表明俯卧位可能会提高ALI的生存率。这种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的发病机制中起着至关重要的作用，我们最近证明，中性粒细胞代谢活化发生在VILI的早期。这项研究的广泛的，长期的目标是提高VILI的机制的理解，并制定手段，以防止或减少it. To为此，目前的拨款建议审查的总体假设，即通过促进均匀的肺实质通气和潮气量分布在整个肺，倾向定位导致减少中性粒细胞代谢活化引起的大型本地化潮汐扩张。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检查了俯卧位作为延迟发作和降低最初未受伤的肺中大潮气量通气的VILI诱导的中性粒细胞活化的严重程度和地形异质性的手段的有效性。在具体目标2中，使用充分表征的ALI实验模型（其中盐水肺灌洗导致表面活性剂消耗和通气的显著不均匀损失）来研究俯卧位是否导致背侧肺区域中的中性粒细胞活化减少，背侧肺区域预期由于体位改变而重新获得通气和更均匀的潮气膨胀。在具体目标3中，潮气量的分级增加用于检验以下假设：俯卧位允许比仰卧位更高的潮气量，而不会增加预损伤肺中的中性粒细胞活化。将采用正电子发射和计算机断层扫描成像以及先进的示踪剂动力学建模来测量体内中性粒细胞的局部代谢活性、肺灌注和通气。预计将这种整合的解剖学、生理学和分子成像方法应用于紧密结合的特定目标将为俯卧位可能减弱VILI的机制提供新的见解。方法学方法的直接临床适用性、绵羊和人类之间肺生理学的相似性以及使用充分表征的ALI模型极大地增强了该项目的转化方面。因此，拟定的研究可能有助于确定在急性肺损伤重症患者的辅助治疗中使用俯卧位是否存在强有力的依据，并且可以被视为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）每年造成74，500人死亡和360万住院日。由于呼吸机诱导的肺损伤（VILI）是导致ALI发病率和死亡率的重要因素，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位促进均匀的肺充气和潮式扩张是否会减少中性粒细胞代谢活化，这是VILI发病机制中的早期和重要事件。