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

• 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
• 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

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 以及右室功能障碍(RVD)，这可能导致循环衰竭和死亡。增加的PA 压力和RVD是由血栓造成的机械性阻塞引起的，但也是由肺动脉(PA)引起的 血管收缩。我们已经建立了一个经过验证的猪急性PE模型，并发现在实验后 用RVD、补充氧气快速、可重复地诱导PE，可使PA压降低50%。 然而，目前还不知道补充氧气如何降低动脉压和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途径影响RVD 缓解缺氧性肺血管收缩和降低PA压力，这一过程是代谢的 干劲十足。为了研究这一假设，我们设计了一项对急性冠脉综合征患者进行补充氧气的机械性试验。 PE和猪PE的相关性研究。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PE患者将由具有PE专业知识的有经验的临床研究人员参加MGH ED 和床边超声心动图。在奥胡斯大学，一支经验丰富的心脏病专家团队和 麻醉师将在我们的RVD猪PE模型上进行实验。代谢组学将是 由新陈代谢公司执行，分析将在HMS执行。研究计划：在MGH ED中，我们将 对80名患有急性PE、有RVD证据且无基线的受试者进行随机交叉试验 低氧血症。患者将被随机分成两组，分别通过口罩呼吸室内空气或补充60%氧气。 在T=15、T=30、T=45分钟时交替治疗，然后维持180分钟。在每个 改变，在180分钟，我们将：1)进行超声心动图并计算具体测量以 确定补充氧气改变PA压力和RV功能的机制，以及，2)绘制 对血液进行不可知性代谢分析，并检验我们的先验假设，即 二酰基甘油、三酰甘油、PC血浆原、TCA循环中间体、酰基肉碱和分解 支链氨基酸的产物随着氧气的补充而变化。在奥胡斯大学，我们将 用RVD诱导24头猪发生PE。就像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。我们还将评估肺血流灌注和心脏的变化。 应用双能计算机断层扫描和双能计算机体层摄影术研究补充氧气的代谢 超极化核磁共振。与公共健康相关：体育导致每年10万人死亡，位居第三 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 补氧对PE的致病作用。我们的书房设计是创新的，基于强大的 临床前数据，我们的结果可能为未来的临床试验确定治疗靶点。