Supplemental Oxygen for Pulmonary Embolism (SO-PE) - A Mechanistic Clinical Trial

背景：急性肺栓塞（PE）可引起肺动脉（PA）压力突然升高 和右心室功能障碍（RVD），其可导致循环衰竭和死亡。增加PA 压力和RVD由血栓的机械性阻塞引起，但也由肺动脉（PA）引起 血管收缩我们已经开发了一种有效的急性PE猪模型，并发现，在实验后， 通过RVD诱导PE，补充氧气可快速且可重复地将PA压力降低50%。 然而，尚不清楚补充氧气如何降低PA压力和RVD，也不知道是否 潜在的机制也适用于人类患者。我们假设氧气主要通过以下方式影响RVD： 缓解缺氧性肺血管收缩和降低PA压力，并且这一过程是代谢性的。 有动力。为了研究这一假设，我们设计了一个机械试验，在急性呼吸道疾病患者中补充氧气。 猪PE及其相关性研究环境：本研究将在马萨诸塞州General 医院急诊科（MGH艾德）、哈佛医学院（HMS）和奥胡斯大学，丹麦。 急性PE患者将由具有PE专业知识的经验丰富的临床研究人员入组MGH艾德 和床旁超声心动图在奥胡斯大学，一个经验丰富的心脏病专家团队， 麻醉师将在我们的PE伴RVD的猪模型上进行实验。代谢组学将是 由Metabolon进行，分析将在HMS进行。研究计划：在MGH艾德，我们将 在80例急性PE、RVD证据和无基线的人类受试者中进行随机、交叉试验 低氧血症。患者将被随机分配呼吸室内空气或通过面罩吸入60%的补充氧气。 治疗将在T=15、T=30、T=45分钟交替进行，然后维持180分钟。每次 在180分钟时，我们将：1）进行超声心动图检查并计算具体测量值， 确定辅助供氧改变PA压力和RV功能的机制，2） 血液进行不可知代谢组学分析，并测试我们的先验假设，即调节 二酰基甘油、三酰基甘油、PC缩醛磷脂、TCA循环中间体、酰基肉毒碱和分解 支链氨基酸的产物随着补充的氧气而变化。在奥胡斯大学， 用RVD诱导PE 24头。在我们的人体实验中，我们将测量PA压力，RV 功能和循环代谢物。我们还将评估肺灌注和心脏 使用双能量计算机断层扫描与补充供氧相关的代谢， 超极化MRI。与公共卫生的相关性：PE每年导致超过10万人死亡，是第三大死亡原因。 是美国心血管疾病死亡的常见原因。这个项目将破译潜在的分子和 肺栓塞时吸氧引起的病理变化。我们的研究设计是创新的，基于强大的 临床前数据，我们的研究结果可能会为未来的临床试验确定治疗目标。

Background: Acute pulmonary embolism (PE) can cause a sudden rise in pulmonary artery (PA) pressure and right ventricular dysfunction (RVD), which can lead to circulatory collapse and death. Increased PA pressure and RVD results from mechanical obstruction by thrombus, but also pulmonary artery (PA) vasoconstriction. We have developed a validated porcine model of acute PE and found that, after experimental induction of PE with RVD, supplemental oxygen rapidly and reproducibly reduces PA pressure by 50%. However, it is not known how supplemental oxygen reduces PA pressure and RVD, nor is it known whether the underlying mechanisms also apply to human patients. We hypothesize that oxygen affects RVD primarily by relieving hypoxic pulmonary vasoconstriction and reducing PA pressure, and that this process is metabolically driven. To study this hypothesis, we designed a mechanistic trial of supplemental oxygen in patients with acute PE and a correlated study of PE in pigs. Setting: This study will be performed in the Massachusetts General Hospital Emergency Department (MGH ED), Harvard Medical School (HMS), and Aarhus University, Denmark. Patients with acute PE will be enrolled in the MGH ED by experienced clinical researchers with expertise in PE and bedside echocardiography. At Aarhus University an experienced team of cardiologists and anesthesiologists will perform experiments on our porcine model of PE with RVD. Metabolomics will be performed by Metabolon and analyses will be performed at HMS. Research Plan: In the MGH ED, we will perform a randomized, crossover trial of 80 human subjects with acute PE, evidence of RVD, and no baseline hypoxemia. Patients will be randomized to breathe room air or 60% supplemental oxygen via facemask. Therapy will be alternated at T=15, T=30, T=45 minutes, and then maintained for 180 minutes. After each change and at 180 minutes, we will: 1) perform echocardiograms and calculate specific measurements to identify the mechanisms by which supplemental oxygen changes PA pressure and RV function and, 2) draw blood for agnostic metabolomic analyses and to test our a priori hypotheses that the regulation of diacylglycerols, triacylglycerols, PC plasmalogens, TCA-cycle intermediates, acyl carnitines, and breakdown products of branched-chain amino acids change with supplemental oxygen. At Aarhus University, we will experimentally induce PE with RVD in 24 pigs. As in our human experiment, we will measure PA pressure, RV function, and circulating metabolites. We will also assess changes in pulmonary perfusion and cardiac metabolism associated with supplemental oxygen using dual-energy computed tomography and hyperpolarized MRI. Relevance to Public Health: PE causes >100,000 annual deaths and is the third most common cause of cardiovascular mortality in the U.S.. This project will decipher the underlying molecular and pathogenic changes induced by supplemental oxygen in PE. Our study design is innovative, based on strong preclinical data, and our results may identify therapeutic targets for future clinical trials.