Correspondence  |   June 2018
Nitrous Oxide and Decreased White Matter Integrity and Volume during Childhood
Author Notes
  • University of Wisconsin, Madison, Wisconsin.
  • (Accepted for publication March 9, 2018.)
    (Accepted for publication March 9, 2018.)×
Article Information
Correspondence   |   June 2018
Nitrous Oxide and Decreased White Matter Integrity and Volume during Childhood
Anesthesiology 6 2018, Vol.128, 1260-1261. doi:10.1097/ALN.0000000000002211
Anesthesiology 6 2018, Vol.128, 1260-1261. doi:10.1097/ALN.0000000000002211
To the Editor:
The article by Block et al.1  reports that 94% of teenagers with broadly distributed, decreased white matter integrity and volume on magnetic resonance imaging of their brains inhaled nitrous oxide for over an hour during surgery and anesthesia in their first year of life. A manuscript cited by Block et al. reports that 88% of children between the ages of 5 and 18 yr with lower gray matter density in the occipital cortex and cerebellum inhaled nitrous oxide during surgery and anesthesia before their fourth birthday.2  Nitrous oxide is the only inhalational anesthetic that causes demyelination, cerebral atrophy, and loss of developmental milestones in a susceptible child after use in clinical concentrations and durations.3  One hour of nitrous oxide administration is sufficient to inactivate methionine synthase by oxidation of cobalt in its vitamin B12 cofactor.4  Up to 20% of infants and children in North America express one or more alleles that impair the activity of enzymes in single carbon pathways in which methionine synthase is the pivotal participant.4  Up to 25% of infants and children before the age of 10 yr are deficient in vitamin B12 with levels less than 148 pmol/l.5  Accordingly, up to 5% of infants have both an inborn and an acquired deficiency of vitamin B12 at the time they are anesthetized with nitrous oxide. The incidence of both inborn and acquired deficiencies of vitamin B12 are far greater in children living in Latin America, Africa, and Asia.6  In children with all but extreme phenotypes, vitamin B12 deficiency may be asymptomatic and undiagnosed before surgery. Not surprisingly, use of nitrous oxide for anesthetic maintenance has declined markedly in the United States and Europe in recent years.7 
In view of their findings and the facts above, do Block et al. presently recommend use of nitrous oxide for anesthetic maintenance in infants having procedures lasting an hour or longer? If not, what is the relevance of the author’s findings to contemporary pediatric anesthesia practice in which anesthetic maintenance with nitrous oxide is diminished? Is it not timely to reassure parents that at least one inhaled anesthetic associated with white and gray matter damage in susceptible children is no longer in widespread use?
Competing Interests
The author declares no competing interests.
Kirk Hogan, M.D., J.D., University of Wisconsin, Madison, Wisconsin.
Block, RI, Magnotta, VA, Bayman, EO, Choi, JY, Thomas, JJ, Kimble, KK Are anesthesia and surgery during infancy associated with decreased white matter integrity and volume during childhood? Anesthesiology 2017; 127:788–99 [Article] [PubMed]
Backeljauw, B, Holland, SK, Altaye, M, Loepke, AW Cognition and brain structure following early childhood surgery with anesthesia. Pediatrics 2015; 136:e1–12 [Article] [PubMed]
Selzer, RR, Rosenblatt, DS, Laxova, R, Hogan, K Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med 2003; 349:45–50 [Article] [PubMed]
Sanders, RD, Weimann, J, Maze, M Biologic effects of nitrous oxide: A mechanistic and toxicologic review. Anesthesiology 2008; 109:707–22 [Article] [PubMed]
Monsen, AL, Refsum, H, Markestad, T, Ueland, PM Cobalamin status and its biochemical markers methylmalonic acid and homocysteine in different age groups from 4 days to 19 years. Clin Chem 2003; 49:2067–75 [Article] [PubMed]
Green, R, Allen, LH, Bjorke-Monsen, AL, Brito, A, Gueant, JL, Miller, JW, Molloy, AM, Stabler, S, Toh, BH, Ueland, PM, Yajnik, C Vitamin B12 deficiency. Nat Rev Dis Primers 2017; 3:1–19
Sessler, DI Nitrous oxide is an effective and safe anesthetic. Turk J Anaesthesiol Reanim 2017; 45:1–2 [Article] [PubMed]