Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism

吸入一氧化氮治疗急性肺栓塞的随机试验

• 批准号: 8725221
• 负责人: ALAN E JONES
• 金额: $ 119.67万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725221
• 关键词: Acute; Adverse event; Anabolism; Anticoagulation; Area; Arginine; Attenuated; Basic Science; Biological Markers; Blood; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Caliber; Cannulas; Cell Respiration; Charge; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Consent; DNA; Devices; Diastole; Double-Blind Method; Dyspnea; Echocardiography; Electrocardiogram; Eligibility Determination; Enrollment; Erythrocytes; Exclusion; Exercise; Fibrinogen; Functional disorder; Funding; Future; Generations; Genetic; Goals; Guanylate Cyclase; Heme; Hemoglobin; Hemolysis; Heparin; Hospitals; Hour; Human; Individual; Injury; Kinetics; Leukocytes; Lung; Mediating; Membrane; Methodology; Methods; Mitochondria; Monitor; Muscle; Natriuretic Peptides; Necrosis; Nitric Oxide; Nose; Nuclear Proteins; Patients; Perception; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Placebos; Plasma; Production; Protocols documentation; Publishing; Pulmonary Embolism; Pulmonary Vascular Resistance; Quality of life; RNA; Randomized; Resistance; Right ventricular structure; Rupture; Safety; Sample Size; Serious Adverse Event; Serum; Severities; Solutions; Surface; Symptoms; Testing; Thrombelastography; Thrombin; Time; Troponin; Troponin T; Viscosity; Work; arginase; blood rheology; clinical efficacy; design; heart function; heme oxygenase-1; human NOS3 protein; improved; inhaled nitric oxide; instrument; minimal risk; mortality; patient oriented; phase 1 study; pressure; prevent; randomized trial; response; screening; standard care; success; vasoconstriction

DESCRIPTION (provided by applicant): Current standard treatment for acute pulmonary embolism (PE) focuses on anticoagulation to reduce clot extension. Acute PE also causes vasoconstriction that increases pulmonary vascular resistance (PVR). Acute PE agitates blood flow in the right ventricle (RV) immediately proximal to the pulmonary vasculature, which depends upon a steady state production of NO to maintain low PVR. This pressurized turbulence ruptures red cells, releasing free Hb and heme, which scavenge nitric oxide (NO), and further increasing the PVR. This initiates a vicious cycle of acutely elevated RV pressures, with secondary shear injury to the RV muscle, which releases proteins and nuclear material into the RV blood where it generates thrombin. Hemolysis also disrupts lung NO biosynthesis through the release of arginase-1, which depletes the endothelial nitric oxide synthase (eNOS) substrate, L-arginine. Free hemoglobin also activates platelets and damages their mitochondrial oxidative metabolism, which may cause their surface membrane to become negatively charged and allow thrombin formation. In humans with PE, we found a significant increase in arginase-1 and ADMA, but decreased L-arginine in the patients with submassive PE and RV dysfunction on echocardiography. In experimental PE, if guanylate cyclase is stimulated, the PVR can be normalized, and intracardiac hemolysis prevented. Inhaled NO offers a logical and safe remedy because it reduces PVR with minimal systemic vascular dilation and low likelihood of adverse events, as demonstrated in our phase I study. In the proposed clinical trial, we will randomize patients with moderate to severe PE to receive NO+O2 or sham (O2 only) for 24 hours. Clinical efficacy will be defined as normal RV size, systolic function on echocardiogram and viability by serum troponin T <14 pg/mL. The basic science study tests two translational and mechanistic questions. 1. If NO responders have baseline biomarker evidence of hemolysis, increased plasma arginase-1 and decreased L-arginine and if NO+O2 treatment normalizes these biomarkers more than sham treatment; and 2. if NO+O2 corrects defective platelet oxidative metabolism associated with PE, and reduces release of CF DNA/RNA coincident with reduced clotting time and strength on thromboelastography.

描述（由申请人提供）：目前急性肺栓塞（PE）的标准治疗侧重于抗凝以减少血块扩展。急性PE还会引起血管收缩，增加肺血管阻力（PVR）。急性PE刺激右心室（RV）靠近肺血管的血流，而右心室的血流依赖于NO的稳定生成来维持低PVR。这种高压湍流破坏红细胞，释放游离Hb和血红素，清除一氧化氮（NO），并进一步增加PVR。这引发了右心室压力急剧升高的恶性循环，右心室肌肉继发性剪切损伤，释放蛋白质和核物质到右心室血液中，并在那里产生凝血酶。溶血还通过释放精氨酸酶-1破坏肺NO的生物合成，从而消耗内皮型一氧化氮合酶（eNOS）底物l -精氨酸。游离血红蛋白也会激活血小板并破坏其线粒体氧化代谢，这可能导致其表面膜带负电荷并允许凝血酶形成。在PE患者中，超声心动图发现精氨酸酶-1和ADMA显著升高，但在PE亚肿块和RV功能障碍患者中，l -精氨酸降低。在实验性PE中，如果刺激鸟苷酸环化酶，可以使PVR正常化，并防止心内溶血。吸入NO提供了一种合乎逻辑且安全的治疗方法，因为它可以减少PVR，同时最小化全身血管扩张和低不良事件的可能性，正如我们的I期研究所证明的那样。在拟议的临床试验中，我们将随机分配中度至重度PE患者接受NO+O2或假手术（仅O2） 24小时。临床疗效以左室大小正常、超声心动图收缩期功能正常、血清肌钙蛋白T <14 pg/mL生存能力为标准。基础科学研究测试了两个转化性和机械性问题。1. 如果NO应答者有溶血、血浆精氨酸酶-1升高和l -精氨酸降低的基线生物标志物证据，并且如果NO+O2治疗比假治疗更能使这些生物标志物正常化；和2。如果NO+O2纠正与PE相关的血小板氧化代谢缺陷，并减少CF DNA/RNA的释放，同时减少血栓弹性成像上的凝血时间和强度。