Anesthetic effects in mitochondrial disease

描述（由申请人提供）：来自我们实验室的数据显示，特定的线粒体！突变可以改变动物模型对挥发性麻醉剂的反应。突变gas-1改变了线粒体电子传递链复合体I的单个亚基。这种突变使得秀丽隐杆线虫对挥发性麻醉剂非常敏感。我们现在已经表明，在秀丽隐杆线虫中，复合物I的活性与麻醉敏感性在广泛的活动范围内相关。在患有线粒体疾病的儿童中，已发表的报告引用了麻醉暴露期间和之后发生的严重的、无法解释的并发症。我们现在已经麻醉了35名来到手术室诊断或治疗线粒体疾病的儿童。鉴于有报道称，在麻醉暴露后，患有线粒体细胞病变的儿童预后不良，我们用单一挥发性麻醉剂非常缓慢地诱导这些儿童。其中7名儿童对七氟醚非常敏感。所有7名过敏儿童都有与线粒体复合体i功能下降相一致的缺陷。这是对一种可以深刻改变人类麻醉敏感性的特定生理缺陷的首次报道。我们假设患有复合物I特异性线粒体缺陷的儿童对挥发性麻醉剂过敏；基于这种超敏反应，他们可能面临更大的不良后果风险。本研究的具体目的是：1)前瞻性地确定线粒体缺陷儿童对挥发性麻醉剂七氟醚的敏感性，并将敏感性与潜在的线粒体疾病联系起来；2)确定七氟醚用于儿童线粒体疾病的相对安全性。这些转化研究对患者安全以及对挥发性麻醉药作用机制的理解具有重要意义。

DESCRIPTION (provided by applicant): Data from our laboratory shows that specific mitochondria! mutations can change the response of an animal model to volatile anesthetics. The mutation gas-1 alters a single subunit of complex I of the mitochondrial electron transport chain. This mutation makes the nematode C. elegans very hypersensitive to volatile anesthetics. We have now shown that complex I activity correlates with anesthetic sensitivity in C. elegans across a wide range of activities. In children with mitochondrial diseases, published reports have cited severe, unexplained complications occurring during and following anesthetic exposure. We have now anesthetized 35 children who have come to the operating room for diagnosis or treatment of putative mitochondrial disease. Given reports of bad outcomes in children with mitochondrial cytopathies following anesthetic exposure, we induced these children very slowly with a single volatile anesthetic. Seven of these children were very hypersensitive to sevoflurane. All 7 of the hypersensitive children had defects consistent with decreased function of mitochondrial complex I. This is the first report of a specific physiologic defect that can profoundly change anesthetic sensitivity in humans. We hypothesize that children with mitochondrial defects specific to complex I are hypersensitive to volatile anesthetics; they may be at greater risk for adverse outcomes based on this hypersensitivity. The specific aims of this study are to: 1) prospectively determine the sensitivity of children with mitochondrial defects to the volatile anesthetic sevoflurane, and correlate sensitivity with the underlying mitochondrial disorder; 2) establish the relative safety of sevoflurane for use in children with mitochondrial disease. These translational studies have important implications for patient safety as well as for the understanding the mechanism of action of volatile anesthetics. .