Nitrous oxide has a long history in anesthetic practice, dating as far back as 1844 when a dentist by the name of Horace Wells attended a demonstration of its use after seeing an advertisement which claimed, “Those who inhale the gas once, are always anxious to inhale the second time… No language can describe the delightful sensation produced.1” Wells himself later had one of his own teeth extracted under the anesthetic, experimented with its use on his patients and presented findings on its effects at Harvard University1. Following this time, the gas not only became widely used across the world, it did what later anesthetic agents, including ether and chloroform could not – remain central to modern anesthetic practice1.
However, with mounting worries about adverse effects from nitrous oxide use, utilization of the agent has steadily declined. For example, from 2009 to 2011, the number of surgical procedures using nitrous oxide declined from 33% to just 21% in the United States alone3.
That’s why in this article, we’ll discuss the controversy around nitrous oxide use, taking a look at both its potential adverse effects, as well as its clinical benefits to answer the question of whether or not nitrous oxide has a place in the practice of anesthesiology after more than 150 years of use.
Risks of Nitrous Oxide in Current Anesthetic Practice
Concerns about the use of nitrous oxide range from ones involving the gases’ environmental impact to health issues, since the agent has a number of known side effects1.
Stenqvist et al. explored the history of the anesthetic agent and came to the conclusion, which was partly based on the availability and effectiveness of modern drugs, that it should be retired from use. This was an opinion that was echoed by Eger and colleagues1.
Adverse effects that have led to a decline in nitrous oxide use include:
- Inhibition of methionine synthase
The rapid decline of nitrous oxide use of the past quarter century began with the discovery that irreversible inactivation of methionine synthase following nitrous oxide exposure may lead to immune suppression and adverse cardiovascular events2.
By oxidizing the cobalt atom and irreversibly inhibiting methionine synthase, the agent interferes with the metabolism of folate and vitamin B121. When this occurs, the production of methionine, which is necessary for DNA synthesis, is impaired1. This effect is considered time-exposure dependent, with two hours of exposure to the agent, linked to a 50% reduced activity of methionine synthase1.
The risk posed by nitrous oxide’s effect on methionine synthase is also potentially greater for the elderly or unwell patient1. As Myles et al. points out, unrecognized deficiency of vitamin B12 and folate is prevalent, particularly in the elderly1. With the nitrous oxide’s well-known effects on these vitamins, it may therefore pose a risk of megaloblastic anemia1.
The possible immunosuppression seen with the effect of nitrous oxide on methionine synthase may be compounded by the fact that the agent has additional effects on the immune system. Nitrous oxide is known to inhibit lymphocytic response and depress the chemotactic migration of monocytes and neutrophils more than other anesthetic agents1.
- Wound infection
The administration of nitrous oxide reduces oxygen concentrations, which may increase wound infection rates. Greif et al. compared the incidence of wound infection in patients undergoing colorectal surgery when given 80% oxygen (in nitrogen) or 30% oxygen (in nitrogen). They discovered a lower rate of infection (5%) for the higher oxygen group than for those receiving increased levels of nitrous oxide (11%)1.
- Myocardial ischemia
Because of its inactivation of methionine synthase, nitrous oxide also results in increased plasma concentration of homocysteine, an issue which lasts at least a week after surgery1,4. This is important to note since acute increases of homocysteine may cause hypercoagulability and endothelial dysfunction. Because of this, Myles et al. note that nitrous oxide may increase the risk of postoperative myocardial ischemia1.
This opinion is supported by, Badner et al. who compared patients who underwent anesthesia with or without nitrous oxide, finding that those who were given the agent experience significantly increased plasma homocysteine concentrations, as well as a higher incidence of myocardial ischemia (46% vs. 25%; P<0.05)1.
- Postoperative nausea and vomiting
Postoperative nausea and vomiting (PONV) can delay recovery and hospital discharge after surgery, and may increase patient dissatisfaction1. The ENIGMA trial of 2,050 adults undergoing major, non-cardiac surgery compared patients receiving nitrous-oxide based anesthesia to a nitrous oxide-free group. The results showed that those who were given nitrous oxide experienced higher rates of PONV, as well as fever, pulmonary atelectasis and infectious complications2.
However, a meta-analysis delved into the question of whether duration of exposure influenced the risk of PONV due to nitrous oxide, finding that patients who were exposed to the agent for less than an hour did not have an increased risk of PONV4.
Clinical Benefits of Nitrous Oxide in Anesthesia
Yet, despite the potentially adverse effects we discussed above, Myles et al. noted that most anesthesiologists consider nitrous oxide to have a very good safety profile, as it’s been used with millions of patients since 1844 and its side effects are well understood1.
Benefits the agent has to offer in modern anesthesiology include:
- Dose-reduction of other (potentially more harmful) anesthetics
The utilization of nitrous oxide allows anesthesiologists to rely on lower doses of other anesthetics (in the order of 30% - 60%), such as opioids and muscle relaxants, which may be both more expensive and more toxic1.
Compared to other anesthetics, nitrous oxide may offer a better safety profile, with reduced cardiovascular and respiratory depression and a lower risk of intraoperative hypotension. Zafirova et al. note that because of this, the use of nitrous oxide may aid in hemodynamic stabilization due to reduction in the vasodilatory and cardiodepressant impact of other anesthetics4. Additionally, nitrous oxide is not linked to issues of nephro- or hepatotoxicity or malignant hypothermia1.
- Reduced risk of awareness
Because consciousness is lost at approximately 70% end-tidal concentration of nitrous oxide, the agent is believed to protect against awareness when combined with other anesthetics1. This conclusion is supported by the work of Tramer et al., who reported a reduced risk of awareness in patients receiving nitrous oxide1.
- Reduced incidence of chronic postsurgical pain
Brown and Snyed note that since NMDA receptors are involved in the development of central and peripheral sensitization leading to chronic postsurgical pain, the NMDA antagonism of nitrous oxide may offer a significant benefit in the reduction of this pain, as well as opioid-induced hyperalgesia3. A sub-group analysis of the ENIGMA-I trial offers support for this conclusion, finding a significant reduction in the incidence of chronic pain with the use of nitrous oxide3,2.
- Lower risk of respiratory irritation
Nitrous oxide is slightly sweet smelling. This lack of pungent odor and airway irritation makes it a particularly useful agent in inhalation induction, especially in children1,3.
- Increased speed of onset
Nitrous oxide also enhances the speed of onset of other volatile anesthetic agents through the ‘second gas effect’. Because of nitrous oxide’s high lipid solubility, it moves quickly across the alveolus, concentrating the remaining gases and boosting the driving pressure of the other agents into the blood.
Additionally, increased ventilation occurs due to the loss of volume associated with the uptake of nitrous oxide, which is known as the ‘concentration effect’. Together, these two phenomenon explain why nitrous oxide increases the speed of onset of anesthesia1,4.
- Pain control and satisfaction with the birthing experience
An analysis of 58 studies by Likis et al. looked at patient satisfaction and pain control with the birthing experience4. Findings of some studies demonstrated that nitrous oxide was better or comparable to intravenous (IV) pain medications. Additionally, some results pointed to a higher level of satisfaction with the birthing experience when nitrous oxide was utilized.
The Safety and Efficacy of Nitrous Oxide
Given both its clinical benefits and possible side effects, it’s easy to understand why the debate over nitrous oxide use in anesthesia has continued. Yet, the safety profile of the agent has been extensively demonstrated, including in the pediatric population.
One study surveyed 1,019 patients 18 years and younger for whom nitrous oxide was used for procedures ranging from lumbar punctures and bone marrow aspirations to bladder catheterization and foreign body extraction. The safety and efficacy of nitrous oxide was demonstrated in their findings, including4:
- No significant adverse events
- Side effects absent in 62.8%
- Side effects that were present resolved in five minutes after discontinuation
A second randomized, double-blinded pediatric study comparing a 50:50 ratio of N2O:oxygen vs. placebo for cutaneous, muscle, or bone/joint procedures also demonstrated significantly lower pain scores in the nitrous oxide group. Those receiving the agent also required less rescue with propofol and sevoflurane4.
Finally, one retrospective analysis of nitrous oxide use outside the operating room is notable as researchers found of 1,634 administrations there was an absence of side effects in 93.5%, and a very low incidence of serious adverse events, such as airway obstruction or oxygen desaturation, of just 0.2%4.
Nitrous oxide is one of the earliest anesthetics in use, yet utilization of the agent has declined over the past decades due to concerns about potential adverse effects. However, with its demonstrated efficacy and safety profile, as well as research-backed clinical benefits, nitrous oxide not only retains its role as a versatile agent with anesthetic, analgesic and sedative capabilities, it will continue to take its place in anesthetic practice.
1: Myles, P S et al. “A review of the risks and benefits of nitrous oxide in current anaesthetic practice.” Anaesthesia and intensive care vol. 32,2 (2004): 165-72. doi:10.1177/0310057X0403200202
2: Chan, Chee Sam and Matthew Tak Vai Chan. “Use of nitrous oxide in contemporary anesthesia—an ongoing tug of war.” Canadian Journal of Anesthesia/Journal canadien d'anesthésie 68 (2021): 1597 - 1600.
3: SM Brown, FRCA, JR Sneyd, FRCA, “Nitrous oxide in modern anaesthetic practice.” BJA Education, Volume 16, Issue 3, March 2016, Pages 87–91, https://doi.org/10.1093/bjaceaccp/mkv019
4: 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, https://doi.org/10.1016/j.bpa.2018.06.003
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