Treatment of Fentanyl Overdose-Induced Respiratory Failure by Low-Dose Dexmedetomidine

小剂量右美托咪定治疗芬太尼过量所致呼吸衰竭

基本信息

批准号：
10701905
负责人：
Philippe A Haouzi
金额：
$ 60.18万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10701905
关键词：
Abdomen Acceleration Acute Acute respiratory failure Adrenergic Agents Airway Resistance Animals Breathing Central Sleep Apnea Cessation of life Chest wall structure Depressed mood Dexmedetomidine Dose FDA approved Fatal Outcome Fentanyl Goals Hour Human Hypoventilation Hypoxemia Hypoxia Induced Heart Arrest Infusion procedures Injections Intention Intranasal Administration Intravenous Lead Life Mammals Mechanical ventilation Mediating Mental Depression Metabolism Modeling Movement Muscle Muscle Contraction Muscle Rigidity Neurons Opioid Opioid agonist Outcome Oxygen Consumption Pathway interactions Phase Pontine structure Positioning Attribute Rattus Respiratory Failure Respiratory Mechanics Respiratory System Rodent Sedation procedure Skeletal Muscle Stimulant Structure Survival Rate Tidal Volume Time Toxic effect Ventilatory Depression alpha 2 agonist awake dosage efficacy study fentanyl overdose improved intravenous administration intravenous injection locus ceruleus structure opioid exposure opioid mortality opioid overdose prevent respiratory restoration sedative sheep model ventilation

项目摘要

SUMMARY The objective of our proposal is to demonstrate that the restoration of respiratory mechanics and of the metabolism by low doses of the central alpha-2 agonist dexmedetomidine results in an increase in ventilation and prevents the fatal outcome of an opioid overdose. Death by opioid overdose is the consequence of an acute respiratory failure mediated by a direct and indirect inhibition of the medullary respiratory neurons. This inhibition is associated with immediate and prolonged tetanic contractions of the inspiratory and expiratory muscles and an increase in upper-airway resistance that impede respiratory movements for hours. Opioid-induced muscle “rigidity” is produced via neurons in the locus coeruleus and can be suppressed by central alpha-2 agonist agents. Our preliminary results, obtained in sedated and non- sedated rats, show that infusion of low doses of the central alpha-2 agonist dexmedetomidine restores chest wall compliance and suppresses the hypermetabolism produced by fentanyl-induced muscle rigidity, while increasing minute ventilation. The objective of our proposal is to demonstrate that administration of dexmedetomidine, after opioid exposure, prevents a fatal outcome. If efficacy is demonstrated in rodents, we intend to pursue efficacy studies in a non- anesthetized sheep model of fentanyl overdose. This model will allow us to establish the doses of dexmedetomidine needed to produce a beneficial effect without sedation. The effects of intravenous and intranasal dexmedetomidine will be examined. Our intention is to obtain, via 505(b)2 pathway, an FDA approval for non-sedative doses of dexmedetomidine as a treatment of opioid overdose.

概括我们提案的目的是证明呼吸力学和呼吸功能的恢复低剂量的中枢α-2激动剂右美托咪定的代谢导致通气量增加并防止阿片类药物过量的致命后果。阿片类药物过量导致的死亡是直接和间接介导的急性呼吸衰竭的结果抑制髓质呼吸神经元这种抑制与立即和长期的强直性痉挛有关。吸气和呼气肌肉的收缩以及上呼吸道阻力的增加阻碍了阿片类药物引起的肌肉“僵硬”是通过蓝斑神经元产生的长达数小时的呼吸运动。并且可以被中枢α-2激动剂药物抑制。我们在镇静剂和非镇静剂中获得的初步结果。镇静大鼠，显示输注低剂量的中枢 α-2 激动剂右美托咪定可以恢复胸部壁顺应性并抑制芬太尼引起的肌肉僵硬产生的代谢亢进，同时增加每分钟通气量。我们提案的目的是证明在阿片类药物暴露后给予右美托咪定，如果在啮齿类动物中证明了疗效，我们打算在非啮齿类动物中进行疗效研究。芬太尼过量的麻醉绵羊模型使我们能够确定芬太尼的剂量。右美托咪定需要在没有镇静作用的情况下产生有益的作用。我们的目的是通过 505(b)2 途径获得 FDA 批准。用于非镇静剂量的右美托咪定作为阿片类药物过量的治疗。