For many years, the use of nitrous oxide in pediatric anesthesia has been a foundational practice, valued for its analgesic properties, rapid onset, and its ability to facilitate mask acceptance in children. However, the role of this agent in modern anesthesia, particularly as a carrier gas during mask induction with sevoflurane or other general anesthetics, is under scrutiny.
Traditional proponents of nitrous oxide emphasize its capacity to accelerate the rate of alveolar–capillary uptake of volatile agents through the concentration and second gas effects. However, studies have called this and other benefits into question. Along with the non-clinical challenges of nitrous oxide, such as wastage due to leaks through piping, practice is overall moving away from anesthesia induction with nitrous oxide, even in pediatric patients.
Research by Lee et al. found that the addition of nitrous oxide to a single-breath vital capacity induction with 8% sevoflurane significantly reduced the time to loss of consciousness, as defined by the loss of eyelash reflex, from a mean of 63.5 seconds to 53.6 seconds in pediatric patients. Furthermore, this investigation noted a significant reduction in excitatory movements, suggesting that nitrous oxide facilitates a smoother transition through the excitatory stage of anesthesia.
Conversely, other studies found no meaningful clinical speeding of induction when using high-concentration sevoflurane, noting that 8% sevoflurane alone is already highly efficient due to its low blood–gas solubility. In fact, Agnor et al. observed that induction with 8% sevoflurane in 100% oxygen was slightly faster than with nitrous oxide in their cohort, though the absolute differences were small.
Concerns have also been raised regarding pediatric physiology and oxygen reserves. Gordon et al. argue that the routine use of nitrous oxide precludes adequate preoxygenation, which is a basic tenet of anesthesia practice intended to maximize the time to desaturation in the event of an airway complication. Given that pediatric patients have higher oxygen consumption per kilogram and lower functional residual capacity than adults, they are predisposed to rapid hypoxemia during apnea.
A laryngospasm occurring in the presence of 70% nitrous oxide leads to much more rapid and profound desaturation than if the child had been preoxygenated with 100% oxygen. Beyond immediate clinical safety, the metabolic effects of nitrous oxide remain a point of concern. The agent permanently inactivates the cobalt atom of the enzyme methionine synthetase, thereby interfering with vitamin B12 and folate metabolism. This inhibition impairs the transformation of homocysteine to S-adenosylmethionine, which is essential for DNA synthesis.
While a short exposure may be inconsequential for many, it can precipitate severe neurological and hematological toxicity in vulnerable populations, such as those with preexisting B12 deficiency or metabolic defects like methylenetetrahydrofolate reductase deficiency. Additionally, animal studies have raised concerns regarding anesthesia-induced neuroapoptosis in the developing brain, leading the United States Food and Drug Administration to issue safety alerts for children under three years of age.
Environmental and occupational hazards further add to the debate over anesthesia induction with nitrous oxide. It is a potent greenhouse gas that causes ozone depletion and has a global warming potential 265 times greater than that of carbon dioxide. Occupational exposure remains a potential health hazard to healthcare staff as well. In light of these concerns, some experts suggest that the second gas effect is of questionable clinical relevance for low-solubility agents like sevoflurane and that evidence-based distraction techniques can effectively facilitate mask acceptance without the risks associated with nitrous oxide.
References
- Lee, S. Y., Cheng, S. L., Ng, S. B. & Lim, S. L. Single-breath vital capacity high concentration sevoflurane induction in children: with or without nitrous oxide? Br. J. Anaesth. 109, 784-790 (2012). https://doi.org/10.1093/bja/aes319
- Gordon, D. W., Chatterjee, D. & McGain, F. It’s time to stop using nitrous oxide for pediatric mask induction. Paediatr. Anaesth. 34, 104-107 (2024). https://doi.org/10.1111/pan.14778
- Gupta, N., Gupta, A. & Narayanan, V. M. R. Current status of nitrous oxide use in pediatric patients. World J. Clin. Pediatr. 11, 93-104 (2022). https://doi.org/10.5409/wjcp.v11.i2.93
- Agnor, R. C., Sikich, N. & Lerman, J. Single-breath vital capacity rapid inhalation induction in children: 8% sevoflurane versus 5% halothane. Anesthesiology 89, 379-384 (1998). https://doi.org/10.1097/00000542-199808000-00010
