Current status of nitrous oxide use in pediatric patients

Table 1 Advantages and disadvantages of nitrous oxide use for anesthesia

Advantages	Disadvantages
Analgesia	Low potency
Reduced awareness	Risk of diffusion hypoxia
Colorless and odorless	PONV [risk ratio 1.21 (CI: 1.04-1.40); P = 0.014]2
Inexpensive (Rs 50/patient)1	Ability to expand air filled cavities
Faster onset and emergence (elimination half-life 5 min)	Increases cuff pressure of ETT and LMA
Minimal metabolism (< 0.004%)	Hematological/neurological toxicity
Cardiorespiratory stability	Immune deficiency?
Prevents CPSP	Reproductive effects
Treatment-resistant refractory depression	Myocardial ischemia?
	Greenhouse gas
	Apoptosis in developing brains

¹Cost of nitrous oxide used in dentistry in Indian rupees per patient.

²Risk ratio for the overall effect of nitrous oxide on postoperative nausea/vomiting.

PONV: Postoperative nausea/vomiting; CPSP: Chronic postsurgical pain; ETT: Endotracheal tube; LMA: Laryngeal mask airway; CI: Confidence interval.

Table 2 Systemic effects of nitrous oxide

Respiratory system	Decreases tidal volume and respiratory rate
	Reduced ventilatory response to carbon dioxide and hypoxia
Central nervous system	Loss of awareness
	Analgesia
	Increased cerebral blood flow and intracranial pressure
	(Concentration > 70%)
Cardiovascular system	Sympathomimetic
	Direct myocardial depression
Hemodynamic effects	Combination with other inhalational agents reduce the incidence of hypotension when compared to administration of the agents alone

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.

Table 4 Summary of various trials on use of nitrous oxide for alleviation of procedural pain and sedation in children

Ref.	Main study objective	Setting/procedures	Number of children; Age	Findings
Babl et al[43], 2008	Depth of sedation and incidence of adverse effects with various N2O concentrations	Pediatric ER procedures	762; 1-17 yr	N2O in high concentration (70%) and continuous flow was found to be a safe agent for procedural sedation and analgesia in toddlers and older children
Babl et al[44], 2010	Sedation practices and the associated adverse events profile	Procedural sedation and analgesia from registry database at the largest Australian pediatric ER of a children’s hospital	2002; 1-17 yr	N2O was used in majority cases (81%), and incidence of serious adverse events was low. (desaturation, n = 2; seizures, n = 2, and chest pain, n = 1)
Brown et al[45], 2009	Evaluate the PediSedate (a N2O delivery system combined with an interactive video component) for reducing children’s behavioral distress	Children who received the PediSedate before invasive procedures	40; 3-9 yr	PediSedate is an effective system for procedural sedation in children
Ekbom et al[46], 2011	To find out whether oral midazolam or 50% N2O, or 10% N2O; along with lidocaine/prilocaine ointment is most effective in gaining IV access in obese or growth retarded children	Children and adolescents undergoing IV access at a Children’s Hospital in Stockholm, Sweden	90; 5-18yr	50% N2O resulted in an improved rate of IV access, a shorter procedure time, and a better experience for these children
Jimenez et al[47], 2012	Comparison of N2O and hematoma block with and without trans-mucosal fentanyl for sedation and analgesia in the reduction of radioulnar fractures.	Retrospective, observational study, in children with radioulnar fractures in a pediatric ER	81; 4-15 yr	The combination of all 3 agents in pediatric ER improved analgesia compared with only N2O and hematoma block combination
Lee et al[48], 2012	Comparison of the sedaoanalgesia profile of N2O vs IV ketamine	Prospective, randomized study at ER of a single academic center in children undergoing primary repair of a laceration wound	32; 3-10 yr	N2O was found preferable to ketamine because it provides a faster recovery, is safe, and maintains a suitable safe plane of sedation
Srinivasan et al[49], 2013	Determine the effectiveness and safety of procedural sedation performed using ketamine (0.5-1 mg/kg) or N2O (50%-70%).	Retrospective review and analysis of a quality improvement database for procedural sedations performed at St Louis Children’s Hospital undergoing sedation by pediatric hospitalists	8870; 7 mo to 4 yr	Combination of ketamine and N2O provides lowest rates of complications. Respiratory and cardiovascular events occurred more frequently with ketamine, whereas NV, sedation level not achieved, and procedure not completed were more frequent with N2O

N₂O: Nitrous oxide; ER: Emergency room; IV: Intravenous; NV: Nausea vomiting.