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

总结 我们的建议的目的是证明，恢复呼吸力学和 低剂量中枢α-2激动剂右美托咪定的代谢导致通气增加 并防止阿片类药物过量造成的致命后果。 阿片类药物过量导致的死亡是由直接和间接的 抑制延髓呼吸神经元。这种抑制作用与即刻和长期强直性脊柱炎有关。 吸气和呼气肌肉的收缩以及上气道阻力的增加， 呼吸运动持续数小时。阿片类药物诱导的肌肉“僵硬”是通过蓝斑神经元产生的 并且可以被中枢α-2激动剂抑制。我们的初步结果，在镇静剂和非- 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恢复胸部 室壁顺应性，并抑制芬太尼诱导的肌肉僵硬产生的高代谢，而 增加分钟通气量。 我们建议的目的是证明阿片类药物暴露后给予右美托咪定， 防止致命的后果。如果在啮齿类动物中证实了疗效，我们打算在非- 芬太尼过量的麻醉绵羊模型。这个模型将使我们能够确定 右美托咪定需要在没有镇静的情况下产生有益效果。静脉注射和 将检查鼻内右美托咪定。我们的目的是通过505（B）2途径获得FDA批准 非镇静剂量的右美托咪定作为阿片类药物过量的治疗。

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.