Nitrous oxide (N2O) has a long history of safe use, starting almost a century and a half ago in 1884. However, research shows nitrous oxide also carries some significant risks. When I was training, we used nitrous oxide on just about every anesthetic. It was easy to use and inexpensive. Nitrous minimally effected hemodynamics, therefore, it was useful in less stable patients when combined with an opioid. It helped speed induction through the second gas effect. Renal and liver insufficiency were of less concern because nitrous was not metabolized. It allowed use of lower concentrations of volatile agents, which at the time were quite myocardial depressant. It provided pain relief in amnesia in conscious sedation settings.
However, recent investigation reveals a lot more about the pharmacologic disadvantages of nitrous oxide (1, 2, 3). Note: the article updated from 4/8/2018.
Inhibition of Methionine Synthase
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).
In its inactive form, vitamin B12 cannot function as a co-factor for methionine synthase and methylmalonyl coA mutase. Inactivation of the B12 pathway therefore disrupts production of myelin proteins and DNA synthesis. It also leads to elevated levels of homocysteine, associated with vascular events and prolonged recovery. B12 deficiency causes anemia, neurologic, psychiatric, hematologic, cardiovascular, and gastrointestinal manifestations.
Inhibition of methionine synthase by nitrous is irreversible. Production to replace inactivated enzyme takes 2-7 days.
Duration of exposure is important. Ninety minutes of exposure to 50% nitrous is enough to halve function of the pathway, raising homocysteine levels.
Folate (B6) Reduction
Nitrous impairs hepatic uptake of folate analogs. Folate rises in the plasma and more is lost in the urine. Hepatic folate concentration falls to 25% within 10 days of N2O exposure. Inactivation of the B12 pathway impedes folate synthesis, leading to further deficiencies..
Suppression of the Immune System
N2O inhibits lymphocyte action and depresses the chemotactic migration of neutrophils and monocytes greater than other agents.
Increased Rate of Infection
Use of N2O requires delivery in a lower concentration of oxygen. Use of nitrous dilutes delivered oxygen. Lower oxygen levels are associated with an increased rate of infection. One study showed that during colorectal surgery, patients receiving 80% oxygen mixed with nitrogen had fewer infections (5%) than those receiving 30% oxygen mixed with nitrogen (11%).
Risk of Myocardial Ischemia
Nitrous oxide raises the plasma concentration of homocysteine due to inactivation of methionine synthase. Elevated homocysteine is associated with hypercoagulopathy and endothelial dysfunction. So far there is no direct proof in the literature of increased cardiac risk. Pretreatment with B6 does not change cardiac outcome — even those with mutated folate pathways.
CNS Risk
What about central nervous system (CNS) risk? Provision of B6 in the stroke literature shows it does help preservation and recovery in the acute stroke patient. Lower B6 levels may increase stroke risk. Elevated homocysteine levels are a risk factor for dementia and Alzheimer’s.
Longer term inhalation, such as addicts, causes a neuropathy and megaloblastic anemia similar to B12 deficiency. Long term exposure to low concentrations results in increases in spontaneous abortion rate and neuropathy, especially in dental personnel.
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 oxide dial.
Pre-Existing Vitamin Deficiencies Are Common
Ten to twenty percent of adults have unknown, pre-existing folate and B12 deficiencies. Exposing a patient with B12 deficiency to nitrous oxide would further deplete their B12 stores, perhaps predisposing them to injury.
Other Issues
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 participates in 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 discussion of greenhouse effects of nitrous and volatile anesthetic agents.
When Do I Avoid Nitrous
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, then turn it off. Use at the very end of a case can occasionally smooth the wakeup.
I avoid nitrous in the following patients.
- serial anesthetics over a short period (less than time frame for regeneration of methionine synthase)
- 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, consider the effects of waste anesthetic gases on health care personnel exposed during the anesthetic (8).
Summary
You can correctly infer from that list that I personally don’t use nitrous oxide much at all. 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).
We’ve used nitrous oxide safely for many years. However, nitrous oxide has some significant pharmacologic disadvantages. These include inhibition of methionine synthase, immune system suppression, increased risk of infection, myocardial ischemia, CNS risk, and worsening of pre-existing vitamin deficiencies.
Nitrous oxide has it’s uses. But consider use only in those patients with minimum risk of harm.
May The Force Be With You
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
- Use of anesthetic agents in neonates and young children. Mellon RD, Simone AF, Rappaport BA. Anesth Analg. 2007 Mar; 104(3):509-20.
- 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.
- Pinyavat T, Warner DO, Flick RP, et al. Summary of the update session on clinical neurotoxicity studies. J Neurosurg Anesthesiol 2016;28:356-360
- Baum V: When Nitrous Oxide Is No Laughing Matter. http://www2.pedsanesthesia.org/meetings/2007winter/pdfs/Baum-Friday3-9-07-1050am.pdf
- 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
- Ishizawa Y: General Anesthetic Gases and the Global Environment. Anesth Analg 2011;112:213–7
- 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
- Health Effects Associated With Exposure to Anesthetic Gas Nitrous Oxide 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.
- Zdravka Zafirova, Colin Sheehan, Leila Hosseinian. “Update on nitrous oxide and its use in anesthesia practice.” Best Practice & Research Clinical Anaesthesiology, Volume 32, Issue 2, 2018, Pages 113-123, ISSN 1521-6896,
- Chanarin I. The effects of nitrous oxide on cobalamins, folates, and on related events. Crit Rev Toxicol. 1982 Sep;10(3):179-213. doi: 10.3109/10408448209037455. PMID: 6127188.