Characterizing Pediatric Anesthesia Risks
Understanding and reducing neurotoxicity after pediatric exposure to volatile anesthetics
Anesthetics are invaluable clinical tools. However, some patients – including children with certain rare mitochondrial disorders – have an elevated risk of long-term neurological damage after exposure to volatile anesthetics. Children and babies must be given general anesthesia in emergency situations, so understanding what causes anesthetic-induced neurotoxicity and how to prevent it is critical to their medical care.
Effects on metabolism
Drs. Sedensky, Morgan, and Johnson found that anesthetics such as isoflurane, halothane, and sevoflurane alter metabolism. Within 15 minutes of exposure, neonatal mice show sustained depletion of blood ketone levels. Ketones are small molecules such as acetone that result from fatty acid oxidation. Ketones are important for normal brain function, particularly in infants and children.
The team’s work demonstrates that mitochondrial defects increase sensitivity to volatile anesthetics and risks of permanent neurological damage. Children with mitochondrial diseases are reported to be susceptible to lasting effects from volatile anesthetic exposure, including cognitive and behavioral consequences. Ndufs4 knockout mice are the premier model for the human mitochondrial disease Leigh syndrome. Ndufs4 knockout mice, which have a specific defect in the mitochondrial electron transport chain, are hypersensitive to volatile anesthetics. Even short exposure to extremely low doses of volatile anesthetics results in lasting damage in these mice.
Involvement of rapamycin and mTOR
In Ndufs4 knockout mice, Drs. Sedensky, Morgan, Johnson and colleagues found that rapamycin extends survival and attenuates disease progression. Rapamycin had, however, no impact on anesthesia sensitivity, demonstrating that the CNS lesions in this disease are mechanistically separable from the anesthesia sensitivity. Recent work by Drs. Johnson, Morgan, and Sedensky has identified PKA as a key mediator of some of the metabolic effects of anesthesia. Ongoing work is focused on defining the role of PKA and complex I function itself in the damage resulting from anesthesia exposure in mitochondrial disease patients.
As Drs. Sedensky, Morgan, and Johnson study how volatile anesthetics affect metabolic flux and nutrient sensing, they are interested in finding ways to reduce the risks of anesthetic-induced neurotoxicity. Examples may include supplementation with ketones or screens to find other drugs that target the PKA pathway.
Stage of Development
- Pre-clinical in vivo
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Hsieh VC, Niezgoda J, Sedensky MM, Hoppel CL, Morgan PG. Anesthetic hypersensitivity in a case-controlled series of patients with mitochondrial disease. Anesth Analg. 2021; in press.
- Stokes J, Freed A, Bornstein R, Su KN, Snell J, Pan A…Morgan PG, Sedensky MM, et al. Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics. Elife. 2021;13;10:e65400.
- Woods CB, Spencer KA, Jung S, Worstman HM, Ramirez JM, Morgan PG, Sedensky MM. Mitochondrial Function and Anesthetic Sensitivity in the Mouse Spinal Cord. Anesthesiology 2021;134(6):901-914.
- Johnson SC, Kayser EB, Bornstein R, Stokes J, Bitto A, Park KY, Pan A, Sun G, Raftery D, Kaeberlein M, Sedensky MM, Morgan PG. Regional metabolic signatures in the Ndufs4(KO) mouse brain 1 implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease. Molec Gen Metab. 2020;130(2):118-132.
- Stokes J, Freed A, Bornstein R, Su KN, Snell J, Pan A, Sun GX, Park KY, Jung S, Worstman H, Johnson BM, Morgan PG, Sedensky MM, Johnson SC. Mechanisms underlying neonate specific metabolic effects of volatile anesthetics. eLife. 2021; 0:e65400.
- Johnson SC, Pan A, Sun GS, Freed A, Stokes JC, Bornstein R, Witkowski M, Li L, Ford JF, Howard CRA, Sedensky MM, Morgan PG. Relevance of experimental paradigms of anesthesia induced neurotoxicity in the mouse. PLoS ONE. 2019;14(3): e0213543.
- Johnson SC, Pan A, Li L, Sedensky M, Morgan, P. Neurotoxicity of anesthetics: Mechanisms and meaning from mouse intervention studies. Neurotoxicol Teratol. 2019;71:22-31.
- Gentry K, Steele L, Sedensky M, Morgan P. Early developmental exposure to volatile anesthetics causes behavioral defects in Caenorhabditis elegans. Anesth Analg. 2013;116(1):185-189.