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

肺栓塞补充供氧 (SO-PE) - 机制临床试验

基本信息

批准号：
10633784
负责人：
CHRISTOPHER KABRHEL
金额：
$ 57.86万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633784
关键词：
Accident and Emergency department Acute Address Affect Air American Angiography Biometry Blinded Blood Blood coagulation Blood flow Blood specimen Branched-Chain Amino Acids Breathing Cardiac Output Cardiology Cardiopulmonary Cardiovascular system Carnitine Categories Catheters Cessation of life Chest Citric Acid Cycle Clinical Clinical Trials Collaborations Correlation Studies Cross-Over Trials Data Denmark Diagnosis Diglycerides Dilatation - action Echocardiography Embolism Emergency Department patient Enrollment Etiology Experimental Designs Experimental Models Failure Family suidae Fellowship Financial cost Future General Hospitals Heart Human Hypoxemia Hypoxia Image Incidence Knowledge Label Left ventricular structure Lung Magnetic Resonance Imaging Massachusetts Measurement Measures Mechanics Metabolic Metabolic Pathway Metabolism Methodology Molecular Myocardial Myocardial perfusion Obstruction Oxygen Pathogenicity Patients Perfusion Physiology Plasmalogens Positioning Attribute Process Public Health Publishing Pulmonary Embolism Pulmonary Hypertension Pulmonary artery structure Pyruvate Randomized Recording of previous events Regulation Reproducibility Research Research Design Research Personnel Right Ventricular Dysfunction Right ventricular structure Risk Series Shock Societies Syndrome Testing Thrombus Time Tissues Training Triglycerides United States Universities Up-Regulation Ventricular septum Work X-Ray Computed Tomography design experience experimental study face mask heart metabolism human subject improved innovation lung hypoxia medical schools metabolomics mortality multimodality participant enrollment phrases porcine model pre-clinical pulmonary arterial pressure pulmonary vasoconstriction recruit supplemental oxygen therapeutic target vasoconstriction

项目摘要

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.

背景：急性肺栓塞（PE）会导致肺动脉（PA）压力突然升高和右心室功能障碍（RVD），这可能导致循环崩溃和死亡。 PA增加压力和RVD是由血栓机械阻塞引起的，但也是肺动脉（PA）引起的血管收缩。我们已经开发了经过验证的急性PE猪模型，发现在实验之后用RVD，补充氧气诱导PE迅速诱导PE，可重复可将PA压力降低50％。但是，尚不清楚补充氧如何降低PA压力和RVD，也不知道是否知道是否知道潜在的机制也适用于人类患者。我们假设氧主要影响RVD 减轻低氧肺血管收缩并降低PA压力，并且该过程是代谢驱动。为了研究这一假设，我们设计了急性患者补充氧的机械试验 PE和PE中PE的相关研究。设置：这项研究将在马萨诸塞州一般进行哈佛医学院（HMS）和丹麦的Aarhus大学医院急诊科（MGH ED）。经验丰富的PE专业知识的经验丰富的临床研究人员将招募急性PE的患者和床头超声心动图。在奥尔胡斯大学，一支经验丰富的心脏病专家团队麻醉师将在我们使用RVD的PE猪模型上进行实验。代谢组学将是由Mepabolon执行和分析将在HMS上进行。研究计划：在MGH ED中，我们将对具有急性PE的80名人类受试者进行随机，交叉试验，RVD的证据，没有基线低氧血症。患者将随机呼吸房间空气，或通过面部面包释放60％的补充氧气。治疗将在t = 15，t = 30，t = 45分钟时交替，然后保持180分钟。每个之后更改，在180分钟时，我们将：1）执行超声心动图并计算特定的测量值确定补充氧改变PA压力和RV功能的机制，2）绘制不可知代谢组分析的血液，并检验我们先验的假设，即调节二酰基甘油，三酰基甘油，PC浆元，TCA循环中间体，酰基肉碱和分解分支链氨基酸的产物随补充氧气而变化。在奥尔胡斯大学，我们将实验性地诱导24头猪中的RVD诱导PE。与人类实验一样，我们将测量PA压力，RV 功能和循环代谢物。我们还将评估肺部灌注和心脏的变化使用双能计算机断层扫描与补充氧相关的代谢和超极化MRI。与公共卫生有关：PE造成> 100,000年死亡，是第三大死亡美国心血管死亡率的常见原因。该项目将破译潜在的分子和 PE中补充氧引起的致病变化。我们的研究设计具有创新性，基于强大临床前数据，我们的结果可能会确定未来临床试验的治疗靶标。