Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism

描述（由申请方提供）：目前急性肺栓塞（PE）的标准治疗侧重于抗凝治疗，以减少凝块扩展。急性PE还引起血管收缩，增加肺血管阻力（PVR）。急性PE搅动紧邻肺血管系统的右心室（RV）中的血流，这取决于NO的稳态产生以维持低PVR。这种加压的湍流使红细胞破裂，释放游离的Hb和血红素，从而增加一氧化氮（NO），并进一步增加PVR。这引发了RV压力急性升高的恶性循环，伴随RV肌肉的继发性剪切损伤，其将蛋白质和核物质释放到RV血液中，在那里产生凝血酶。溶血还通过释放一氧化氮合酶-1破坏肺NO的生物合成，该酶-1消耗内皮型一氧化氮合酶（eNOS）底物L-精氨酸。游离血红蛋白还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，我们发现在超声心动图上亚大块PE和RV功能障碍的患者中，精氨酸酶-1和ADMA显著增加，但L-精氨酸减少。在实验性PE中，如果鸟苷酸环化酶被刺激，PVR可以正常化，并且防止心内溶血。吸入NO提供了一个合理和安全的补救措施，因为它减少了PVR，全身血管扩张最小，不良事件的可能性低，正如我们的I期研究所证明的那样。在拟定的临床试验中，我们将中度至重度PE患者随机分配接受NO+O2或假手术（仅O2）24小时。临床疗效将被定义为正常RV大小、超声心动图上的收缩功能和血清肌钙蛋白T <14 pg/mL的活力。基础科学研究测试两个翻译和机械问题。1.如果NO应答者具有溶血的基线生物标志物证据，则增加血浆凝血酶-1和减少L-精氨酸，并且如果NO+O2治疗使这些生物标志物比假治疗更正常化;和2.如果NO+O2纠正与PE相关的有缺陷的血小板氧化代谢，并减少CF DNA/RNA的释放，同时减少凝血时间和血栓弹性描记术的强度。

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.