Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism

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栓扩张。急性PE还会引起血管收缩，从而增加肺血管阻力(PVR)。急性PE可刺激右心室(RV)的血流，使其紧邻肺血管系统，这依赖于NO的稳定产生来维持低PVR。这种加压的湍流会破坏红细胞，释放游离的Hb和血红素，清除一氧化氮(NO)，并进一步增加PVR。这引发了RV压力急剧升高的恶性循环，RV肌肉受到二次剪切损伤，释放蛋白质和核物质到RV血液中，在那里产生凝血酶。溶血还通过释放精氨酸酶-1来破坏肺内一氧化氮的生物合成，精氨酸酶-1耗尽内皮型一氧化氮合酶(ENOS)底物L-精氨酸。游离血红蛋白还会激活血小板，损害其线粒体的氧化代谢，这可能会导致其表面膜带负电荷，从而形成凝血酶。在PE患者中，超声心动图显示重度PE和右室功能不全患者精氨酸酶-1和腺苷脱氢酶显著升高，而L-精氨酸显著降低。在实验性PE中，如果激活鸟苷环化酶，PVR可以恢复正常，防止心内溶血。吸入NO提供了一种合理而安全的治疗方法，因为它减少了PVR，全身血管扩张最小，不良事件发生的可能性很低，正如我们的I期研究所证明的那样。在拟议的临床试验中，我们将随机选择中重度PE患者接受NO+O2或Sham(仅O2)治疗24小时。临床疗效将被定义为正常的右室大小、超声心动图上的收缩功能和血清肌钙蛋白T&lt；14pg/mL的生存能力。基础科学研究测试了两个翻译和机械问题。1.如果没有应答者有溶血的基线生物标志物证据，则升高血浆精氨酸酶-1和降低L-精氨酸，如果NO+O2治疗比假治疗更能使这些生物标志物恢复正常；以及2.如果NO+O2纠正与PE相关的血小板氧化代谢缺陷，并减少CFDNA/RNA的释放，与减少凝血时间和血栓弹性成像强度相一致。

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.