PET/CT-Guided Personalized Mechanical Ventilation to Minimize Ventilator-Induced Lung Injury

呼吸机诱导的肺损伤（VILI）是一种炎症过程， 例如，美国每年有1700万外科手术或751，000名败血症患者。我们的长期目标是 了解和推进检测和预防VILI的方法。肺过度劳损（=体积变化/初始 体积）被理解为VILI的基本机制。最近的数据显示， 机械通气受呼吸机设置的影响，并与肺力学密切相关 与整体肺应变（驱动压力）相关的测量。然而，知识是缺乏的影响， 与人类肺大小相当的肺中菌株空间分布的设置以及随后的 肺损伤在本项目的前一阶段，我们提出了基于计算机断层扫描（CT）的配准 方法显示目前的临床标准治疗策略不能防止局部肺的恶化 在仰卧动物和人肺中的应变和通气，伴有依赖性肺的进行性去募集， 通气良好的非依赖性肺的应变增加。我们挑战了当前的模式，因为我们发现当地 低于拟议的全球有害阈值。使用正电子发射断层扫描（PET），我们 表明局部18F-FDG摄取是嗜酸性炎症的标志物，并且它直接随着 局部肺应变和血容量的相互作用（更高的炎症介质暴露）在模型中， 保护性机械通气和内毒素血症。这暗示了两次打击机制的新概念 在常见的临床菌株中，作为局部VILI的主要因素。我们还发现应变的均匀分布 通气防止了机械恶化，这表明肺扩张均质化可以 保护你免受暴力。我们令人兴奋的试点成像数据表明，潮汐局部毛细血管关闭与目前的澄清 为在假定的保护性环境中内皮损伤提供了新的证据。我们假设 局部肺机械恶化，特征为应变和通气不均匀性增加， 目前的临床治疗策略导致肺血容量的变化， 损伤，并构成大的不均匀膨胀的肺中的炎症和早期VILI的基质。我们 将使用CT衍生的肺应变和通气， 确定最能指示呼气末正压（PEEP）的整体力学测量， 绵羊的均匀拉伸分布。我们将使用这些措施来个性化PEEP，并评估其 影响：（a）应变恶化，以及这种恶化与潮汐毛细血管关闭的空间关系， 临床相关的48小时绵羊研究中的内皮损伤和肺损伤;和（B）应变的局部分布 和通气的能力。在这个项目的最后，我们将测试一个可以翻译给人类的策略。 最大限度地减少VILI;确定整体呼吸力学、内皮和实质之间的关系 损伤以增强肺保护;以及建立成像方法以评估局部VILI。

Ventilator-induced lung injury (VILI) is an inflammatory process that threatens patients requiring ventilatory support such as the 17 million surgical or the 751,000 septic patients/year in the US. Our long-term goal is to understand and advance methods to detect and prevent VILI. Excessive lung strain (=change in volume/initial volume) is understood as a fundamental mechanism of VILI. Recent data show that clinical outcomes during mechanical ventilation are influenced by ventilator settings and importantly associated with a lung mechanics measure related to global lung strain (driving pressure). Yet, knowledge is scant on the effects of ventilatory settings on the spatial distribution of strains in lungs of size comparable to those of humans and on the ensuing lung injury. In the previous period of this project, we advanced Computed Tomography (CT)-based registration methods to show that a current clinical standard ventilatory strategy does not prevent deterioration of local lung strain and aeration in supine animal and human lungs, with progressive derecruitment of dependent lung and increased strain in the well-aerated nondependent lung. We challenged current paradigms as we found local strains lower than proposed global injurious thresholds. Using Positron Emission Tomography (PET), we showed that local 18F-FDG uptake is a marker of neutrophilic inflammation and that it changes directly with the interaction of local lung strain and blood volume (higher exposure to inflammatory mediators) in a model of protective mechanical ventilation and endotoxemia. This implied the novel concept of the two-hit mechanism as the main factor for local VILI at usual clinical strains. We also found that homogeneous distributions of strain and aeration prevented that mechanical deterioration, suggesting that lung expansion homogenization could protect from VILI. Our exciting pilot imaging data indicate tidal local capillary closure with current ventilatory settings providing novel evidence for endothelial injury in presumably protective settings. We hypothesize that regional lung mechanical deterioration characterized by an increase in strain and aeration heterogeneity with current clinical ventilatory strategies produces changes in pulmonary blood volume conducive to endothelial injury, and composes the substrate for inflammation and early VILI in large heterogeneously inflated lungs. We will test this hypothesis with respiratory-gated PET/CT by using CT-derived lung strains and aeration to ascertain global mechanics measures best indicative of the positive end-expiratory pressure (PEEP) leading to homogenous stretch distributions in sheep. We will use such measures to personalize PEEP and assess its effect on: (a) strain deterioration, and the spatial relation of this deterioration with tidal capillary closure, endothelial damage, and lung injury in clinically relevant 48h sheep studies; and (b) local distributions of strain and aeration in septic patients. At the end of this project, we will have tested a strategy translatable to humans to minimize VILI; ascertained relations between global respiratory mechanics, endothelial and parenchymal injury to enhance lung protection; and established imaging methods to assess local VILI.