In the U.S., an exponential increase in opioid-related overdose deaths has occurred over the last decade. The hallmark symptom of an opioid-related overdose is decreased respiration, which can result in permanent hypoxic brain injury within minutes. The purpose of the proposed research is to develop a community-deployable Automated External Respiration System (AERS) device that is capable of maintaining adequate respiration in individuals experiencing opioid-induced respiratory depression - via external stimulation of the phrenic nerve - until other medical interventions (e.g., naloxone) can be administered or the effects of the opioids dissipate naturally over time. The concept of the AERS device is modeled after Automated External Defibrillator devices (AEDs), which are now widely available in medical and public settings for use by both medically trained and untrained individuals. A prototype AERS device was developed under a previous Small Business Innovation Research grant awarded to Coridea and demonstrated to be safe and effective in sustaining breathing in a preclinical model of drug- induced respiratory depression. The proposed research seeks to qualify the prototype system for human use, demonstrate feasibility and safety in human volunteers in a hospital setting, and then develop a commercial system capable of community deployment. The current prototype will be further optimized in miniature pigs (Aim 1a), and then evaluated for safety using rigorous testing in pigs under fentanyl-induced respiratory depression with different levels of chest wall compliance to mimic fentanyl-induced “wooden chest syndrome,” and finally in the setting of naloxone reversal (Aim 1b). Results from Aims 1a and 1b will be used to support an IDE for testing the AERS device in a clinical model of opioid-induced respiratory depression in healthy volunteers without (Aim 2a) and with opioid use disorder (Aim 2b). A commercial-grade, AED-like device will then be designed (Aim 3a) and tested in a human factors study (Aim 3b). The data collected in Aims 1-3 will be submitted to the FDA for approval of a pivotal trial (designed in collaboration with the FDA), which will be supported by a future grant proposal. The AERS device is built on the successful concept for treating cardiovascular dysfunction and can potentially be used in combination with AEDs to treat multi- drug overdoses (e.g., stimulants + opioids), and may offer a critical tool for use by medical and lay persons to reduce the morbidity and mortality associated with opioid overdoses.

The United States is in the middle of a fatal and growing opioid overdose epidemic. In this grant we will develop and validate an automated external respiration system, like a “respiratory AED”, that can provide life-saving therapy for people suffering from opioid-induced hypoventilation and apnea. This system can be deployed in public spaces and we believe that this therapy will significantly reduce the mortality and morbidity associated with opioid overdoses.