Effect of Prone Position on Ventilator-Induced Lung Injury

描述（由申请人提供）：急性肺损伤（ALI）的发病率最近估计为每10万人年86.2人，死亡率为38.5%。这些数字意味着，美国每年有74,500人死于急性呼吸道感染，这一数字与乳腺癌或艾滋病毒的死亡人数相当，并且有220万重症监护室日和360万住院日专门用于护理急性呼吸道感染患者。呼吸机诱导的肺损伤（VILI）已被确定为ALI发病率和死亡率的一个因素。虽然尚无定论，但来自临床试验的数据表明，俯卧位可能提高ALI患者的生存率。这种改进的一个可能原因是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激活发生在VILI早期。本研究的广泛、长期目标是提高对VILI机制的理解，并开发预防或减少VILI的方法。为此，本拨款提案检验了一个总体假设，即通过促进均匀的实质通气和整个肺的潮汐容量分布，俯卧位导致中性粒细胞代谢激活减少，这是由大面积的局部潮汐扩张引起的。这一假设将在一种生理上与人类相似的大型动物（即羊）中进行检验，有三个具体目的。具体目的1检验俯卧位作为延迟发作和降低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的有效性，在初始未损伤的大潮气量通气的肺部。在具体目标2中，我们使用了一个特征良好的ALI实验模型，其中生理盐水肺灌洗导致表面活性剂耗竭和明显不均匀的通气损失，以研究俯卧位是否会导致肺背区中性粒细胞激活减少，而肺背区有望因体位变化而恢复通气和更均匀的潮扩张。在特定目的3中，潮汐量的逐步增加被用来检验俯卧位比仰卧位允许更高的潮汐量而不增加损伤前肺部中性粒细胞激活的假设。将采用正电子发射、计算机断层成像和先进的示踪动力学建模来测量体内中性粒细胞的区域代谢活性、肺灌注和通气。这种综合解剖学、生理学和分子成像方法在紧密结合的特定目标中的应用，有望为俯卧位可能减轻VILI的机制提供新的见解。方法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具有良好特征的ALI模型大大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在急性呼吸道感染危重患者的通气管理中使用俯卧位是否存在强有力的理由，并可被视为有利于后续患者研究。

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.