Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome

Background: Volatile anaesthetics are widely used in human medicine. Although generally safe, hypersensitivity and toxicity can occur in rare cases, such as in certain genetic disorders. Anaesthesia hypersensitivity is well-documented in a subset of mitochondrial diseases, but whether volatile anaesthetics are toxic in this setting has not been explored.Methods: We exposed Ndufs4(-/-) mice, a model of Leigh syndrome, to isoflurane (0.2-0.6%), oxygen 100%, or air. Cardiorespiratory function, weight, blood metabolites, and survival were assessed. We exposed post-symptom onset and pre-symptom onset animals and animals treated with the macrophage depleting drug PLX3397/pexidartinib to define the role of overt neuroinflammation in volatile anaesthetic toxicities.Results: Isoflurane induced hyperlactataemia, weight loss, and mortality in a concentration-and duration-dependent manner from 0.2% to 0.6% compared with carrier gas (O-2 100%) or mock (air) exposures (lifespan after 30-min exposures *P<0.05 for isoflurane 0.4% vs air or vs O2, **P<0.005 for isoflurane 0.6% vs air or O-2;60-min exposures **P<0.005 for isoflurane 0.2% vs air, *P<0.05 for isoflurane 0.2% vs O-2). Isoflurane toxicity was significantly reduced in Ndufs4(-/-) exposed before CNS disease onset, and the macrophage depleting drug pexidartinib attenuated sequelae of isoflurane toxicity (survival ***P=0.0008 isoflurane 0.4% vs pexidartinib plus isoflurane 0.4%). Finally, the laboratory animal standard of care of 100% O-2 as a carrier gas contributed significantly to weight loss and reduced survival, but not to metabolic changes, and increased acute mortality.Conclusions: Isoflurane is toxic in the Ndufs4(-/-) model of Leigh syndrome. Toxic effects are dependent on the status of underlying neurologic disease, largely prevented by the CSF1R inhibitor pexidartinib, and influenced by oxygen con-centration in the carrier gas.