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. . ? ? ?
| Morgan, P G; Higdon, R; Kolker, N et al. (2015) Comparison of proteomic and metabolomic profiles of mutants of the mitochondrial respiratory chain in Caenorhabditis elegans. Mitochondrion 20:95-102 |
| Niezgoda, Julie; Morgan, Phil G (2013) Anesthetic considerations in patients with mitochondrial defects. Paediatr Anaesth 23:785-93 |
| Yang, Yu-Ying; Gangoiti, Jon A; Sedensky, Margaret M et al. (2009) The effect of different ubiquinones on lifespan in Caenorhabditis elegans. Mech Ageing Dev 130:370-6 |
