When I was training, we used nitrous oxide on just about every anesthetic. It was easy to use. It was inexpensive. It didn’t tend to effect hemodynamics so it was useful in less stable patients when combined with an opioid. It helped speed induction through the second gas effect. It was not metabolized so renal and liver insufficiency were of less concern.

However, with all of the more recent investigation into reasons for cognitive dysfunction or decline in infants and the elderly following anesthesia, a lot more is now known about the pharmacologic disadvantages of nitrous oxide (1, 2, 3).

Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B12, transferring it from the active Co(I) state to the inactive Co(II or III) state, inactivating it, somewhat analogous to the reduction of hemoglobin to methemoglobin (4).

Methionine is an essential amino acid that serves as a methyl donor (via its activated form S-adenosylmethionine) in hundreds of biologic reactions. The end product of methionine demethylation is homocysteine, whose remethylation is catalyzed by the vitamin B12 dependent enzyme methionine synthase (synthetase). Inhibition of methionine synthetase by nitrous is irreversible. New enzyme must be produced to replace that which has been inactivated, which can take 2-7 days.

Ninety minutes of exposure to 50% nitrous is enough to halve function of the folate pathway, raising homocysteine levels. Duration of exposure is important.
Elevated homocysteine is associated with vascular events and prolonged recovery.
So far there is no proof in the literature of increased cardiac risk.  Pretreatment with B6 does not change cardiac outcome — even those with mutated folate pathways

HOWEVER, what about CNS risk? Provision of B6 in the stroke literature shows it does help preservation and recovery in the acute stroke patient Elevated homocysteine levels are a risk factor for dementia and Alzheimer’s. Four hours of nitrous in elderly rats causes long lasting (2 wk) memory impairment. Obviously rats are not humans, however it does give one pause before turning that nitrous dial. ten to Twenty percent of adults have folate and B12 deficiency, perhaps predisposing them to injury.

What about some the other issues with nitrous oxide.

• Nitrous methylates DNA — which may mean that it can have an epigenetic effect to future offspring. That means that methylation of DNA eggs and sperm could potentially cause changes in genetic expression in our sons and daughters, conceived years after the parent’s (or the grandparent’s) anesthetic.
• N2O is an NMDA receptor antagonist
• DNA methylation is involved with long term memory storage. Could interference with this process this be the mechanism effecting memory in elderly rats (5)?
• N2O is a potent green house gas. It remains in the upper atmosphere about 114 years and promotes depletion of the  ozone layer (5,6,7). Click here for a prior discussion of greenhouse effects of nitrous and our other anesthetic agents.

There are times when limited use of nitrous can be useful. I still use it occasionally to speed mask induction of pediatric inhalational anesthetic in the uncooperative child, for instance. I then turn the nitrous off and switch to air/oxygen. I might turn it on at the very end of a case to smooth the wakeup.

My current practice is to avoid use of nitrous

• serial anesthetics over a short period (less than time frame for regeneration of methionine synthetase)
• really long cases
• patient  with known folate and B12 deficiency
• malnutrition
• first trimester pregnancy
• in vitro fertilization
• renal failure
• those with inborn errors of metabolism (or untested family members) homocytineuria, an autosomal recessive disease, is the second most common disease of amino acid metabolism. Associated with elevated homocysteine levels and impaired folate pathway
• patient with hypotonia
• megaloblastic anemias
• during anti-folate chemotherapy
• hypercoagulability or a prothrombotic state

I consider avoiding or limiting exposure to nitrous in:

• bone marrow harvesting
• L&D/C-section ( avoiding interference with neurogenesis)
• Advanced peripheral vascular disease CAD with at risk phenotypes
• Demyelinating conditions
• Stroke and CNS surgery
• Young children and infants during time of major synaptic formation except for short periods during induction and emergence

Finally, one must consider the effects of waste anesthetic gases on health care personnel exposed during the anesthetic (8).

You can correctly infer from that list that I personally don’t use nitrous much at all these days,. If I do it’s not for very long. While it is certainly true that research has not yet shown clear evidence one way or the other that any specific anesthetic causes neurotoxic effects in our patients. Research is ongoing in infants and in the elderly (9, 10).

Nitrous has it’s uses. But consider use only in those patients with minimum risk of harm.

Christine E. Whitten MD
author of Anyone Can Intubate: A Step By Step Guide, 5th Edition &
Pediatric Airway Management: A Step-by-Step Guide

      

Please click on the covers to see inside my books at amazon.com

References

1. Use of anesthetic agents in neonates and young children.Mellon RD, Simone AF, Rappaport BA. Anesth Analg. 2007 Mar; 104(3):509-20.
2. Bittner EA, Yue Y, Xie Z. Brief review: Anesthetic neurotoxicity in the elderly, cognitive dysfunction and Alzheimer’s disease. Canadian journal of anaesthesia = Journal canadien d’anesthesie. 2011;58(2):216-223. doi:10.1007/s12630-010-9418-x.
3. Pinyavat T, Warner DO, Flick RP, et al. Summary of the update session on clinical neurotoxicity studies. J Neurosurg Anesthesiol 2016;28:356-360https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077165/
4. Baum V: When Nitrous Oxide Is No Laughing Matter. http://www2.pedsanesthesia.org/meetings/2007winter/pdfs/Baum-Friday3-9-07-1050am.pdf
5. Jevtovic-Todorovic V, Beals J, Benshoff N, Olney JW. Prolonged exposure to inhalational anesthetic nitrous oxide kills neurons in adult rat brain. Neuroscience 2003;122:609-16
6. Ishizawa Y: General Anesthetic Gases and the Global Environment. Anesth Analg 2011;112:213–7
7. Sherman J ; Le C; Lamers, V; Eckelman, M: Life Cycle Greenhouse Gas Emissions of Anesthetic Drug. Anesthesia & Analgesia: May 2012 – Volume 114 – Issue 5 – p 1086–1090
8. Health Effects Associated With Exposure to Anesthetic Gas Nitrous Oxide-N₂O in Clinical Hospital – Shtip Personel.Eftimova B, Sholjakova M, Mirakovski D, Hadzi-Nikolova M. Open Access Maced J Med Sci. 2017 Oct 15; 5(6):800-804. Epub 2017 Oct 10.