Neuromuscular blocker-induced asthma during anesthesia

麻醉期间神经肌肉阻滞剂诱发的哮喘

基本信息

批准号：
7038219
负责人：
CHARLES W EMALA
金额：
$ 31.93万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2007-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Rapacuronium, a new rapidly acting nondepolarizing neuromuscular blocking drug, was released for use in 1999. It was developed specifically to facilitate tracheal intubation during the induction of general anesthesia, but has been associated with life threatening bronchospasm. At least five patients have died and the drug was recently withdrawn from clinical use. The mechanism underlying this airway constriction is not currently known. Possible mechanisms include histamine release, cholinesterase inhibition, M3 muscarinic receptor agonism and M2 muscarinic receptor antagonism. It is extremely important that we understand the mechanism by which this drug induces airway constriction to prevent this from ever occurring again with newly introduced neuromuscular blocking agents. A safe and effective ultra-short acting nondepolarizing neuromuscular blocker is urgently needed for routine clinical use, and until one is found the search will continue. We hypothesize that neuromuscular blocking agents that have selective M2 antagonistic properties potentiate parasympathetic release of acetylcholine mediating bronchoconstriction. During intubation of the trachea, parasympathetic nerves release acetylcholine that act on M3 muscarinic receptors on airway smooth muscle to promote bronchoconstriction. Preliminary data generated from this proposal strongly suggest that the mechanism by which rapacuronium induced fatal bronchospasm is by selective inhibition of M2 muscarinic receptors. We will use in vivo and in vitro approaches to define the mechanism of neuromuscular blocking agent-induced potentiation of bronchoconstriction. Neuromuscular affinities for M2 and M3 muscarinic receptors will be defined by radioligand binding and functional assays (adenylyl cyclase and inositol phosphate assays). Neuromuscular blocking agents effects on acetyl cholinesterase activity will also be measured. The ability of neuromuscular blocking agents to enhance acetylcholine release from parasympathetic nerves will be measured using guinea pig trachea in organ baths. The ability of neuromuscular blocking agents to potentiate vagal nerve mediated bronchoconstriction or to increase airway pressure via histamine release will be measured in vivo using a well-characterized guinea pig model. This mechanism needs to be clearly characterized so that it can serve as a gold standard screen for new agents developed for clinical practice. It is imperative that the mechanism of neuromuscular blocking agents potential to induce bronchospasm be understood so that the millions of patients who undergo general anesthesia on a yearly basis are not subjected to unnecessary life threatening bronchospasm.

描述（由申请人提供）：雷帕库溴铵是一种新型速效非去极化神经肌肉阻滞药物，于 1999 年上市使用。它是专门为促进全身麻醉诱导期间的气管插管而开发的，但与危及生命的支气管痉挛有关。至少有五名患者死亡，该药物最近已退出临床使用。目前尚不清楚这种气道收缩的机制。可能的机制包括组胺释放、胆碱酯酶抑制、M3毒蕈碱受体激动和M2毒蕈碱受体拮抗作用。非常重要的是，我们了解这种药物引起气道收缩的机制，以防止新引入的神经肌肉阻滞剂再次发生这种情况。临床常规使用迫切需要一种安全有效的超短效非去极化神经肌肉阻滞剂，在找到一种药物之前，我们将继续寻找。我们假设具有选择性 M2 拮抗特性的神经肌肉阻滞剂可增强介导支气管收缩的乙酰胆碱的副交感神经释放。气管插管期间，副交感神经释放乙酰胆碱，作用于气道平滑肌上的 M3 毒蕈碱受体，促进支气管收缩。该提议产生的初步数据强烈表明，雷帕库溴铵诱导致命性支气管痉挛的机制是通过选择性抑制 M2 毒蕈碱受体。我们将使用体内和体外方法来定义神经肌肉阻滞剂诱导的支气管收缩增强的机制。 M2 和 M3 毒蕈碱受体的神经肌肉亲和力将通过放射性配体结合和功能测定（腺苷酸环化酶和磷酸肌醇测定）来确定。神经肌肉阻断剂对乙酰胆碱酯酶活性的影响也将被测量。将使用器官浴中的豚鼠气管来测量神经肌肉阻滞剂增强副交感神经乙酰胆碱释放的能力。将使用充分表征的豚鼠模型在体内测量神经肌肉阻滞剂增强迷走神经介导的支气管收缩或通过组胺释放增加气道压力的能力。这种机制需要得到明确的表征，以便它可以作为临床实践开发新药物的金标准筛选。必须了解神经肌肉阻滞剂可能诱发支气管痉挛的机制，以便每年数百万接受全身麻醉的患者不会遭受不必要的危及生命的支气管痉挛。