title: Generation of purified nitric oxide from liquid N2O4 for the treatment of pulmonary hypertension in hypoxemic swine.
abstract: Inhaled nitric oxide (NO) selectively dilates pulmonary blood vessels, reduces pulmonary vascular resistance (PVR), and enhances ventilation-perfusion matching. However, existing modes of delivery for the treatment of chronic pulmonary hypertension are limited due to the bulk and heft of large tanks of compressed gas. We present a novel system for the generation of inhaled NO that is based on the initial heat-induced evaporation of liquid N2O4 into gas phase NO2 followed by the room temperature reduction to NO by an antioxidant, ascorbic acid cartridge just prior to inhalation. The biologic effects of NO generated from liquid N2O4 were compared with the effects of NO gas, on increased mean pulmonary artery pressure (mPAP) and PVR in a hypoxemic (FiO2 15%) swine model of pulmonary hypertension. We showed that NO concentration varied directly with the fixed cross sectional flow of the outflow aperture when studied at temperatures of 45, 47.5 and 50°C and was independent of the rate of heating. Liquid N2O4-sourced NO at 1, 5, and 20 ppm significantly reduced the elevated mPAP and PVR induced by experimental hypoxemia and was biologically indistinguishable from gas source NO in this model. These experiments show that it is feasible to generate highly purified NO gas from small volumes of liquid N2O4 at concentrations sufficient to lower mPAP and PVR in hypoxemic swine, and suggest that a miniaturized ambulatory system designed to generate biologically active NO from liquid N2O4 is achievable.
authors: Department of Anesthesiology, Pain Medicine, and Critical Care, Steward St. Elizabeth's Medical Center, Boston, MA, United States. Electronic address: Mark.Lovich@steward.org.
authors: Mark A
authors: MA
authors: Lovich
authors: GeNO LLC, Cocoa, FL, United States.
authors: David H
authors: DH
authors: Fine
authors: GeNO LLC, Cocoa, FL, United States.
authors: Ryan J
authors: RJ
authors: Denton
authors: Department of Anesthesiology, Pain Medicine, and Critical Care, Steward St. Elizabeth's Medical Center, Boston, MA, United States.
authors: Matt G
authors: MG
authors: Wakim
authors: Department of Anesthesiology, Pain Medicine, and Critical Care, Steward St. Elizabeth's Medical Center, Boston, MA, United States.
authors: Abraham E
authors: AE
authors: Wei
authors: Department of Anesthesiology, Pain Medicine, and Critical Care, Steward St. Elizabeth's Medical Center, Boston, MA, United States.
authors: Mikhail Y
authors: MY
authors: Maslov
authors: GeNO LLC, Cocoa, FL, United States.
authors: Lucas G
authors: LG
authors: Gamero
authors: GeNO LLC, Cocoa, FL, United States.
authors: Gregory B
authors: GB
authors: Vasquez
authors: GeNO LLC, Cocoa, FL, United States.
authors: Bryan J
authors: BJ
authors: Johnson
authors: GeNO LLC, Cocoa, FL, United States.
authors: Robert F
authors: RF
authors: Roscigno
authors: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, United States.
authors: Richard J
authors: RJ
authors: Gilbert
mesh_terms: D000818:Animals; D005740:Gases / Q000138:chemical synthesis / Q000302:isolation & purification / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000188:drug therapy*; D000860:Hypoxia / Q000150:complications*; D009569:Nitric Oxide / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000737:chemistry*; D010084:Oxidation-Reduction; D013552:Swine; D013696:Temperature
chemical_list: D005740:Gases; D009589:Nitrogen Oxides; D009569:Nitric Oxide; C015167:nitrogen tetroxide
keywords: Ambulatory therapy; Dinitrogen tetraoxide; Hypoxemic swine model; Nitric oxide; Pulmonary hypertension