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

摘要 我们建议的目标是证明呼吸力学的恢复和 低剂量中枢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。 阿片类药物过量死亡是急性呼吸衰竭的后果，由直接和间接的 延髓呼吸神经元的抑制。这种抑制与即刻和长期的破伤风有关。 吸气肌和呼气肌收缩，上呼吸道阻力增加，阻碍 几个小时的呼吸运动。阿片诱导的肌肉“强直”是通过蓝斑神经元产生的 并可被中枢α-2激动剂抑制。我们的初步结果，在镇静剂和非镇静剂中获得 小剂量注射中枢α-2激动剂右旋美托咪定可恢复大鼠的胸部功能 WALL顺应性和抑制芬太尼诱导的肌肉僵直所产生的高代谢，而 增加分钟通风量。 我们建议的目的是证明在阿片类药物暴露后给予右美托咪定， 防止了致命的后果。如果在啮齿类动物身上证明了有效性，我们打算在非 麻醉绵羊芬太尼过量给药模型。这个模型将使我们能够确定 右美托咪定需要在不镇静的情况下产生有益的效果。静脉注射和静脉注射的效果 将检查鼻腔内右美托咪定。我们的意图是通过505(B)2途径获得FDA的批准 对于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.