Current status of nitrous oxide use in pediatric patients

Table 3 Summary of results of the key clinical trials and systematic reviews in relation to use of nitrous oxide as a component of anesthesia

Trial	Ref.	Main findings
ENIGMA Trial	Myles et al[26], 2007	Increased rates of major complications (OR: 0.71; 95%CI: 0.56-0.89; P = 0.003) myocardial infarction, stroke, pneumonia, pulmonary embolism, wound infection, severe PONV (OR: 0.40; 95%CI: 0.31-0.51; P < 0.001), and death.
ENIGMA II Trial	Myles et al[27], 2014	Risk of death at 1 year, cardiovascular complications (combined RR for death and cardiovascular complications was 0.96, 95%CI: 0.83-1.12; P = 0.64) or surgical-site infection in the nitrous oxide group not increased (P = 0.61). Risk of PONV was reduced by one third in the patients not exposed to nitrous oxide (P < 0.0001), but the absolute risk reduction was only 4%.
A large retrospective analysis of registries	Turan et al[28], 2013	Patients receiving nitrous oxide had 40% lower risk of pulmonary complication (OR: 95% Bonferroni-adjusted CI: 0.59, 0.44-0.78) and death (OR: 97.5%CI: 0.67, 0.46-0.97; P = 0.02), while cardiovascular complications were comparable.
Cochrane review on complications with use of nitrous oxide	Sun et al[29], 2015	Nitrous oxide increased the incidence of pulmonary atelectasis (OR: 1.57, 95%CI: 1.18-2.10, P = 0.002) but had no effects on the rates of in-hospital mortality, pneumonia, myocardial infarction, stroke, venous thromboembolism, wound infection, or length of hospital stay.
Cochrane review on accidental awareness with use of nitrous oxide	Hounsome et al[30], 2016	Despite the inclusion of 3520 participants, only three awareness events were reported by two studies. In one study the event was due to technical failure. Due to the low quality of evidence, the authors could not determine whether the use of nitrous oxide in general anesthesia increases, decreases, or has no effect on the risk of accidental awareness.

ENIGMA: Evaluation of Nitrous oxide In a Gas Mixture for Anesthesia; PONV: Postoperative nausea and vomiting; OR: Odds ratio; CI: Confidence interval; RR: Risk ratio.