Intravenous oxygen for the treatment of cardiac arrest

Project Summary/Abstract Cardiac arrest affects ~700,000 patients annually in the US, with a survival rate between 10% and 30%, and survivors often suffering from neurologic injury. Despite advances in resuscitation, maintaining adequate oxygenation during early resuscitation remains a significant challenge, irrespective of the cause of cardiac arrest. In asphyxia cardiac arrest (ACA), severe hypoxemia is often refractory to conventional inventions such as mechanical ventilation. In out-of-hospital cardiac arrest (OHCA), where none-asphyxia cardiac cause is common, existing ventilation methods such as bag-valve-mask and advanced airway placement are often ineffective to insufflate the lung during early resuscitation. To address this problem, we have developed a new gas carrier that allows safe intravenous injection of oxygen (IVO2), based on pH-responsive polymeric microbubbles (PMBs). PMBs feature a thin polymer shell encasing an oxygen gas core (~5 µm), providing high oxygen content (50% vol/vol) and storage stability. Designed to dissolve immediately in physiological media via a pH trigger, PMBs deliver a high volume of oxygen without requiring a diffusion sink (e.g., hyperoxic blood), thereby minimizing risks of embolism or vascular obstruction. The dissolved PMB shells revert to soluble, excretable components, reducing long-term side effects. In a realistic swine model of ACA, we demonstrated that administering very small doses of oxygen via PMBs effectively alleviates severe hypoxemia and significantly improves neurologically intact survival. We propose IVO2 may be developed as a new oxygen therapy for early resuscitation of cardiac arrest. The project has 3 specific aims. In Aim-1, we will optimize the molecular structures of PMBs shell polymer to accelerate their clearance. Tissue deposition presents a main risk for material toxicity, this study will allow minimize long-term adverse effects of IVO2 gas carriers. In Aim-2, building on our preliminary data, we will further interrogate how dose and treatment timing may influence physiologic response and mitochondrial health in rodent ACA models. This knowledge is essential to understanding the therapeutic efficacy and limits of IVO2 as a transitional treatment for ACA. In Aim-3, we will investigate whether IVO2 can replace and outperform existing ventilation methods in the early resuscitation of a ventricular fibrillation OHCA swine model to improve neurologically intact survival. By replacing early ventilation efforts, IVO2 may rapidly restore normoxia in a more reliable way and offer various physiologic benefits e.g., reducing pulmonary vascular resistance, allowing care provides to focus on chemist compressions and medication provision. All these factors contribute to earlier ROCS and neurologically intact survival. If success, the proposed therapy may transform the current paradigm for the early cardiac arrest resuscitation.