Throwback Thursday, April 1, 2021

Before we get to today’s Throwback Thursday article, I have some exciting news that ain’t no April Fools! At the beginning of March, I began collecting voluntary donations from PAAD readers, and I’m happy to announce that stunningly, in one month you have contributed $2,718! That entire amount has been donated to the SPA Patient Safety Education & Research Fund, and I will forward to them the names of all paid subscribers. (Substack, the provider of this subscription platform and processor of payments keeps 10%.)
And now, on to today’s Throwback Thursday…

Rowland AS, Baird DD, Weinberg CR, Shore DL, Shy CM, Wilcox AJ. Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med. 1992 Oct 1;327(14):993–7. doi: 10.1056/NEJM199210013271405. PMID: 1298226.

How many PAAD readers have ever read the package insert (i.e., “label”) for nitrous oxide? Don’t ponder that for too long because it was a trick question. There is none. That’s because nitrous was in use for many decades before the FDA ever existed. In 1844, Horace Wells, a discontented dentist, made a fool of himself on the stage of a ‘Grand Exhibition’ after inhaling nitrous oxide. That same evening, he observed that another participant had injured his leg while dancing on the stage and felt no pain until the effects of the nitrous oxide had worn off. When Wells later inhaled it and had his former student John Riggs remove a tooth, he exclaimed ‘It is the greatest discovery ever made! I didn’t feel it so much as the prick of a pin!’.

Here we are, 177 years later, and nitrous oxide is still a bit of a mystery. After all this time, its safety seems unimpeachable. But there are continuing controversies whether it should be part of our pediatric anesthesia armamentarium. Some of us love it, and some do not. Some, like myself, use it sparingly (e.g., only during induction to increase the speed of unconsciousness) and then turn it off. So, in today’s Throwback Thursday, I want to highlight the possible complications of N2O using a paper published in 1992 that caused quite a stir at that time.

In brief, Rowland et al. sent questionnaires to 7,000 female dental assistants, ages 18 to 39, and through follow-up telephone interviews, determined that women exposed to high levels of nitrous oxide were significantly less fertile than women who were unexposed or exposed to lower levels of N2O. It wasn’t a great epidemiological study, as demonstrated by the fact that the effect was evident in only 19 women with 5 or more hours of exposure per week, but it was still jarring for all anesthesia providers.

Nitrous oxide inactivates vitamin B12 and thus, inhibits the activity of methionine synthetase. This mechanism may have played a role in the decreased fertility of the dental assistants. But that property has also been implicated in causing complications in anesthetized children. Dr. Kirk Hogan, a passionate opponent of the use of N2O has stated:

“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…and 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. 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. One hour of nitrous oxide administration is sufficient to inactivate methionine synthase by oxidation of cobalt in its vitamin B12 cofactor. 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. Up to 25% of infants and children before the age of 10 yr are deficient in vitamin B12. 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.” (See the link above for all references)

I’ll add a few more examples of the hazards of N2O use: An 8-month-old male infant with unrecognized nutritional vitamin B12 deficiency underwent orchiopexy under general anesthesia that included N2O. Six days later, the infant presented with fever, progressive lethargy, athetoid movements, and bone marrow failure. The infant recovered after several days of vitamin B12 supplementation. The authors speculated that exposure to N2O exacerbated this infant’s condition, and precipitated the neurological deterioration and bone marrow failure.

A 4-month-old female developed neurological deterioration and severe metabolic acidosis 3 weeks following elective craniosynostosis repair under general anesthesia that included N2O. Subsequent investigation revealed a nutritional vitamin B12 deficiency (of unknown etiology) that gradually resolved following exogenous supplementation.

Lastly, a case report described the neurologic deterioration and death of a 3-month-old infant anesthetized twice with N2O prior to establishing a diagnosis of 5,10-methylenetetrahydrofolate reductase deficiency, a rare autosomal recessive disorder.

It is unlikely that the therapeutic margin of nitrous oxide will ever become small enough to preclude its use altogether, but convincing arguments for its continued inclusion in pediatric anesthesia are tough to find.

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Pediatric Anesthesia Article of the Day

Ron Litman, Pediatric anesthesiologist, Children’s Hospital of Philadelphia, Med Director, ISMP, Past Chair FDA AADPAC