Anesthetic considerations in patients with mitochondrial defects

Abstract

Mitochondrial disease, once thought to be a rare clinical entity, is now recognized as an important cause of a wide range of neurologic, cardiac, muscle, and endocrine disorders . The incidence of disorders of the respiratory chain alone is estimated to be about 1 per 4-5000 live births, similar to that of more well-known neurologic diseases . High-energy requiring tissues are uniquely dependent on the energy delivered by mitochondria and therefore have the lowest threshold for displaying symptoms of mitochondrial disease. Thus, mitochondrial dysfunction most commonly affects function of the central nervous system, the heart and the muscular system . Mutations in mitochondrial proteins cause striking clinical features in those tissues types, including encephalopathies, seizures, cerebellar ataxias, cardiomyopathies, myopathies, as well as gastrointestinal and hepatic disease. Our knowledge of the contribution of mitochondria in causing disease or influencing aging is expanding rapidly . As diagnosis and treatment improve for children with mitochondrial diseases, it has become increasingly common for them to undergo surgeries for their long-term care. In addition, often a muscle biopsy or other tests needing anesthesia are required for diagnosis. Mitochondrial disease represents probably hundreds of different defects, both genetic and environmental in origin, and is thus difficult to characterize. The specter of possible delayed complications in patients caused by inhibition of metabolism by anesthetics, by remaining in a biochemically stressed state such as fasting/catabolism, or by prolonged exposure to pain is a constant worry to physicians caring for these patients. Here, we review the considerations when caring for a patient with mitochondrial disease.

Keywords: anesthetics, inhaled agents; anesthetics, intravenous agents; general anesthesia; mitochondrial disorders; muscle disorders; neurologic disease.

Figure 1. The Mitochondrial Respiratory Chain

Electron donor substrates (pyruvate, glutamate, malate, succinate) for the respiratory chain are transported across the mitochondrial membrane by their respective carriers. In the matrix, electrons from pyruvate, glutamate, and malate are transferred to NAD⁺ by substrate-specific dehydrogenases (boxes) and enter the respiratory chain via complex I. Succinate donates electrons specifically to complex II. Electrons from complex I and II are transferred to complex III by the common shuttle Coenzyme Q. The electrons reach oxygen, the terminal acceptor, via cytochrome c and complex IV. Electron transport down the respiratory chain (flat grey arrows) is linked to proton transfer to the intermembrane space by complexes I,-III, and –IV (flat dotted arrows). ATP synthetase (complex V) allows protons to reenter the matrix and uses the energy released in this process to phosphorylate ADP to ATP. The Coenzyme Q analog DHQ can be used to reduce complex III directly while electrons from ascorbate can be shuttled to cytochrome c by the redox carrier TMPD (Tetramethylphenylenediamine).