A continuous supply of oxygen gas is required to maintain cellular structure and function. Even brief deficits in oxygenation, as occurs in patients with lung injury or airway problems, can cause the heart to stop beating, a disorder known as cardiac arrest. More than 200,000 patients per year in the US suffer from cardiac arrest in the hospital setting (i.e. in-hospital cardiac arrest, IHCA). Among those, approximately ~40-60% are thought to be precipitated by hypoxia (i.e. asphyxial cardiac arrest, or ACA), with a mortality rate between 70 and 95%, and neurologic injury is common in survivors. In these patients, the rapid restoration of oxygen delivery to the brain, heart, and other vital organs is paramount to intact survival. Delays of a few minutes can be the difference between recovering back to health and permanent neurologic impairment. In the most critically ill patients, underlying lung disease (for example) makes restoration of normal oxygen levels difficult. To address this problem, we have developed a way to administer oxygen gas intravenously. The key to this technology is that the oxygen gas is encapsulated within gas-filled microparticles small enough to pass through the circulation without causing obstruction. The particle shell is composed of a biocompatible material, modified dextran acetate succinate (DAS), which is stable for months in storage but releases gas immediately upon contact with the pH of blood. In rodents with cardiac arrest provoked by hypoxemia (i.e. ACA), the intravenous administration of oxygenated DAS (DAS-Ox) microparticles immediately restored oxygen levels to near-normal. When normal ventilation was restored, all treated animals exhibited return of spontaneous circulation (ROSC); all control animals died. We hypothesize that the early restoration of normal oxygen tension using injections of intravenous oxygen will sustain myocardial and cerebral energy production in asphyxial cardiac arrest, which will achieve early ROSC and improve neurologically intact survival. This project has 3 specific aims.
In Aim I, we will optimize the oxygen carrying capacity of DAS-Ox MPs in order to minimize the volume of administration and mass of DAS polymer required to meaningfully supplement the oxygen consumption of large animals. We will vary manufacturing parameters and chemical composition of the shell within a design of experiments construct, examining shell thickness, particle size, dispersibility, and rheology as endpoints.
In Aim II, we will infuse optimized microparticles in swine to screen for pulmonary vascular obstruction, rigorously examining for endothelial injury, interference with blood components, organ injury, and describing biodistribution, redesigning the particle shell as needed.
In Aim III, we will test whether the administration of intravenous oxygen in a swine model of asphyxial cardiac arrest improves neurologically intact survival. If successful, this work would create a paradigm-changing technology enabling the rapid reversal of hypoxemia and representing a powerful new therapy for the treatment of asphyxial cardiac arrest.
The goal of this project is to establish a new treatment for asphyxial cardiac arrest through the intravenous administration of oxygen gas packaged into hollow core microparticles. Following injection, these microparticles circulate in the bloodstream during CPR (as do all resuscitative medications), restoring oxygenation of the blood to normal and providing substrate for vital organs to respire. In this grant, we will optimize the oxygen carrying capacity of these microparticles, test their safety in swine, and then examine their ability to improve neurologically intact survival in a swine model of asphyxial cardiac arrest.
