What side effects can nitrous oxide have?

The most common side effect of nitrous oxide (N₂O) in children is vomiting (2–14% depending on the setting), while the overall rate of adverse events is 4–17% and serious adverse events are extremely rare (0.1–0.2%). The vast majority of side effects are minor and self-limiting. ^[1][2]

Rate and range of side effects: data from large registries

None of the large registries recorded a single case of aspiration, conversion to intubation or death. [1-3]

II. Minor side effects (self-limiting)

Vomiting is the most clinically relevant minor effect. Factors that increase the risk: ^[2][4][6]

• Concomitant use of opioids: OR 2.89 (95% CI 1.14–7.32); with N₂O + intranasal fentanyl, vomiting reaches 14% (RR 1.8 compared with N₂O alone) ^[2][4]
• Clear fluids less than 2 hours before the procedure: OR 4.16 (95% CI 1.61–10.76) ^[2]
• Procedure duration: over 15 min the risk of AEs rises 4.2-fold, over 30 min 4.9-fold compared with under 15 min ^[1]
• A higher fentanyl dose: each dose increase raises the risk of vomiting by 30% (RR 1.3) ^[6]

Other minor effects: nausea (1.6–4.4%), dizziness (rate not standardized, but mentioned as common), dysphoria or agitation (3.7% according to the meta-analysis by Poonai et al.) ^[8], euphoria and laughter (an expected pharmacological effect, not an AE), transient voice change, sweating or diaphoresis (0.4%). ^[5][7]

III. Serious side effects (rare)

Respiratory. Desaturation (SpO₂ <90%) is extremely rare with N₂O alone: the largest registry (n=7,802) recorded only 9 potentially serious events, all of which resolved without consequences. The most clinically relevant respiratory effect is a dose-dependent depression of the ventilatory response to hypoxemia, which is potentiated by other sedatives. Unintended deep sedation: with 70% N₂O by continuous flow, moderate or deep sedation was seen in 3% of children, and with 50% N₂O in 0%. ^[1][3][7]

Diffusion hypoxia

When N₂O is stopped abruptly, rapid diffusion of the gas from the blood into the alveoli dilutes alveolar oxygen, which can cause a transient drop in saturation. The classic study by Fink (1955) described a 5–10% drop in saturation within 10 minutes of stopping N₂O. However, the pediatric study by Dunn-Russell et al. showed that in healthy children breathing room air, SpO₂ fluctuations were under 1% and did not reach clinically significant levels. Nevertheless, standard practice is to give 100% O₂ for 3–5 minutes after stopping N₂O to prevent diffusion hypoxia. ^[9][10]

IV. Effect on vitamin B₁₂ and methionine synthase

N₂O irreversibly oxidizes the cobalt in vitamin B₁₂, inactivating methionine synthase. This leads to a rise in homocysteine and impaired DNA methylation. ^[11][12]

The pediatric study by Pichardo et al. (Anesthesiology, 2012, n=32 children) showed that N₂O exposure of 2 hours or more causes a statistically significant 25% increase in homocysteine (from 5.1 to 6.4 µM) after 24 hours, and in 21% of children with initially normal levels, homocysteine exceeded the age norm. The duration of exposure was a strong predictor of the increase (R²=0.696). ^[11]

Clinical relevance for short procedural sedation (5–15 min): with a single short exposure, inactivation of methionine synthase is minimal and clinically insignificant. The risk rises with long exposures (2 hours or more), frequent repeated exposures and pre-existing vitamin B₁₂ deficiency — in that case even a single exposure can trigger neurological complications. ^[12][13]

V. Effect of combination with other drugs

The systematic review by Poonai et al. (CJEM, 2023, 30 RCTs) showed that the rate of adverse events rises sharply when N₂O is combined with other sedatives: ^[8]

This highlights that the safety profile of N₂O worsens considerably when other sedatives or analgesics are added, and most serious adverse events in the literature are linked to combined regimens. ^[8]

VI. Factors that modify the risk of AEs

Summary

Nitrous oxide alone has an excellent safety profile in children: no life-threatening events have been described in any large registry. The main side effect is vomiting (2–6% with N₂O alone), and its risk is minimized by a short procedure (under 15 min), avoiding combination with opioids and fasting for at least 2 hours for clear fluids. Diffusion hypoxia is clinically insignificant in healthy children, but standard practice is to give 100% O₂ after stopping N₂O. The effect on vitamin B₁₂ with short single exposures is minimal, but with repeated or long sedations the risk of methionine synthase inactivation should be taken into account, especially in children with pre-existing B₁₂ deficiency. [1-3]^[7][11]