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）可导致肺动脉（PA）压力突然升高右心室功能障碍（RVD），可导致循环衰竭和死亡。增加PA 压力和 RVD 是由血栓机械性阻塞以及肺动脉 (PA) 造成的血管收缩。我们开发了一种经过验证的急性肺栓塞猪模型，并发现，经过实验通过 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，目前尚不清楚补充氧气如何降低 PA 压力和 RVD，也不知道是否会降低 PA 压力和 RVD。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并降低 PA 压力，并且该过程是代谢性的驱动的。为了研究这一假设，我们设计了一项针对急性呼吸衰竭患者补充氧气的机制试验。猪的PE和PE的相关研究。地点：这项研究将在马萨诸塞州综合医院进行医院急诊科 (MGH ED)、哈佛医学院 (HMS) 和丹麦奥胡斯大学。急性肺栓塞患者将由具有肺栓塞专业知识的经验丰富的临床研究人员纳入麻省总医院急诊室和床边超声心动图检查。奥胡斯大学拥有一支经验丰富的心脏病专家团队麻醉师将在我们的带有 RVD 的 PE 猪模型上进行实验。代谢组学将由 Metabolon 执行，分析将在 HMS 进行。研究计划：在 MGH ED，我们将对 80 名患有急性肺栓塞、有 RVD 证据且无基线的人类受试者进行一项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补充 60% 的氧气。治疗将在T=15、T=30、T=45分钟交替进行，然后维持180分钟。每次之后改变，并在 180 分钟时，我们将：1) 进行超声心动图并计算具体测量值确定补充供氧改变 PA 压力和 RV 功能的机制，2) 绘制血液用于不可知的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、酰基肉碱和分解支链氨基酸的产物会随着氧气的补充而发生变化。在奥胡斯大学，我们将在 24 头猪中通过 RVD 实验诱导 PE。与我们的人体实验一样，我们将测量 PA 压力、RV 功能和循环代谢物。我们还将评估肺灌注和心脏的变化使用双能计算机断层扫描与补充氧气相关的代谢和超极化 MRI。与公共卫生的相关性：PE 每年导致超过 100,000 人死亡，是第三大死亡原因美国心血管死亡的常见原因。该项目将破译潜在的分子和 PE 中补充氧气引起的致病变化。我们的研究设计是创新的，基于强大的临床前数据，我们的结果可能会确定未来临床试验的治疗靶点。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Management of high-risk pulmonary embolism in the emergency department: A narrative review.

急诊科高危肺栓塞的管理：叙述性回顾。

DOI：
发表时间：
2024-05
期刊：
影响因子：
0
作者：
Rouleau, Samuel G;Casey, Scott D;Kabrhel, Christopher;Vinson, David R;Long, Brit
通讯作者：
Long, Brit

Intermediate-Risk and High-Risk Pulmonary Embolism: Recognition and Management: Cardiology Clinics: Cardiac Emergencies.

中危和高危肺栓塞：识别和管理：心脏病诊所：心脏急症。

DOI：
发表时间：
2024-05
期刊：
影响因子：
2.4
作者：
Birrenkott, Drew A;Kabrhel, Christopher;Dudzinski, David M
通讯作者：
Dudzinski, David M

Addressing the rising trend of high-risk pulmonary embolism mortality: Clinical and research priorities.

应对高危肺栓塞死亡率上升的趋势：临床和研究重点。

DOI：
发表时间：
2024-03
期刊：
影响因子：
0
作者：
Casey, Scott D;Stubblefield, William B;Luijten, Dieuwke;Klok, Frederikus A;Westafer, Lauren M;Vinson, David R;Kabrhel, Christopher
通讯作者：
Kabrhel, Christopher