Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism

Project: Research project

Description

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
StatusFinished
Effective start/end date9/1/136/30/16

Funding

  • National Institutes of Health: $1,183,140.00
  • National Institutes of Health: $1,144,254.00
  • National Institutes of Health: $1,196,673.00

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Pulmonary Embolism
Nitric Oxide
Heart Ventricles
Vascular Resistance
Arginase
Hemolysis
Thrombin
Arginine
Lung
Troponin T
Nitric Oxide Synthase Type III
Guanylate Cyclase
Nuclear Proteins
Vasoconstriction
Heme
Blood Vessels
Echocardiography
Rupture
Dilatation
Hemoglobins

ASJC

  • Medicine(all)