Transcutaneous Phrenic Nerve Stimulation for Treating Opioid Overdose

经皮膈神经刺激治疗阿片类药物过量

• 批准号: 10681111
• 负责人: SANDRA D COMER
• 金额: $ 92.73万
• 依托单位: CORIDEA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681111
• 关键词: Apnea; Applications Grants; Automated External Defibrillator; Award; Benzodiazepines; Blood gas; Breathing; Businesses; Cardiovascular system; Cause of Death; Cessation of life; Chest; Chest wall structure; Clinical; Clinical Trials; Cocaine; Collaborations; Commercial grade; Communities; Data; Detection; Devices; Diagnosis; Dose; Drug Modelings; Electric Stimulation; Electrodes; Electronics; Emergency response; Environment; Epidemic; Evolution; External Defibrillator; Family suidae; Fentanyl; Functional disorder; Future; Generations; Geometry; Goals; Grant; Home; Homeostasis; Hospitals; Human; Human Volunteers; Hypoventilation; Hypoxic Brain Damage; Illicit Drugs; Impedance Cardiography; Individual; Industrialization; Institutional Review Boards; Intervention; Investigation; Laboratories; Life; Marketing; Mechanics; Mediating; Medical; Methamphetamine; Modeling; Morbidity - disease rate; Muscle Rigidity; Naloxone; Neck; Opioid; Opioid Antagonist; Opioid Receptor; Outpatients; Overdose; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Physiological; Pre-Clinical Model; Preclinical Testing; Preparation; Process; Qualifying; Recording of previous events; Research; Research Project Grants; Respiration; Safety; Small Business Innovation Research Grant; Stimulant; Structure of phrenic nerve; Support System; Symptoms; System; Testing; Time; Training; United States; Update; Ventilatory Depression; Wooden Chest Syndrome; Work; combat; data submission; design; design verification; experience; fentanyl overdose; fentanyl use; healthy volunteer; human model; illicit opioid; innovation; models and simulation; mortality; non-opioid analgesic; noradrenergic; opioid epidemic; opioid overdose; opioid use disorder; opioid user; overdose death; porcine model; portability; pre-clinical; preclinical development; prototype; remifentanil; research clinical testing; respiratory; safety and feasibility; safety testing; synthetic opioid; tool; trial design; usability; ventilation

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.

在美国，与阿片类药物过量相关的死亡人数在过去十年里呈指数级增长。这个 阿片类药物过量的显著症状是呼吸减慢，这可能导致永久性低氧。 几分钟内就会造成脑损伤。拟议研究的目的是开发一个可部署的社区 自动体外呼吸系统(AERS)设备，能够在 经历阿片类药物引起的呼吸抑制的个人--通过外部刺激膈神经-- 直到可以进行其他药物干预(例如，纳洛酮)或阿片类药物的作用消失 当然，随着时间的推移。AERS设备的概念仿照自动体外除颤器设备 (AEDs)，目前在医疗和公共环境中广泛提供，供受过医学培训的和 未受过训练的人。 AERS原型设备是在之前的小企业创新研究资助下开发的 Coridea，并在临床前药物模型中证明了在维持呼吸方面安全有效- 引起呼吸抑制。这项拟议的研究试图使原型系统符合人类使用的要求， 在医院环境中展示人体志愿者的可行性和安全性，然后开发商业 能够进行社区部署的系统。目前的原型将在小型猪(AIM)上进一步优化 1a)，然后在芬太尼诱导的呼吸抑制下使用严格的猪测试来评估安全性 通过不同水平的胸壁顺应性来模拟芬太尼诱导的“木胸综合征”，并最终在 纳洛酮逆转的设定(目标1b)。AIMS 1a和1b的结果将用于支持IDE进行测试 AERS装置在无AIM的健康志愿者阿片类药物所致呼吸抑制的临床模型中的应用 )和阿片类药物使用障碍(目标2b)。然后将设计一种商业级的、类似AED的设备(目标3a) 并在人的因素研究中进行了测试(目标3b)。在AIMS 1-3中收集的数据将提交给FDA 批准一项关键试验(与FDA合作设计)，该试验将得到未来赠款的支持 求婚。 AERS设备建立在治疗心血管功能障碍的成功概念之上，并可能 与AEDs联合用于治疗多种药物过量(如兴奋剂+阿片类药物)，并可提供一种 降低阿片类药物相关发病率和死亡率的关键工具，供医务人员和非专业人员使用 吸毒过量。