Inhaled nitrous oxide for painful procedures in children and youth: a systematic review and meta-analysis.

Objectives: The objective of this study was to synthesize indication-based evidence for N₂O for distress and pain in children.

Study design: We included trials of N₂O in participants 0-21 years, reporting distress or pain for emergency department procedures. The primary outcome was procedural distress. Where meta-analysis was not possible, we used Tricco et al.'s classification of "neutral" (p ≥ 0.05), "favorable," or "unfavorable" (p < 0.05, supporting N₂O or comparator, respectively). We used the Cochrane Collaboration's Risk of Bias tool and the Grading of Recommendations Assessment, Development, and Evaluation system to evaluate risk of bias and quality of evidence, respectively.

Results: We included 30 trials. For pain using the Visual Analog Scale (0-100 mm) during IV insertion, 70% N₂O (delta:-16.5; 95%CI:-28.6 to -4.4; p = 0.008; three trials; I² = 0%) and 50% N₂O plus eutectic mixture of local anesthetics (EMLA) (delta:-1.2; 95%CI:-2.1 to -0.3; p = 0.007; two trials; I² = 43%) were superior to EMLA. 50% N₂O was not superior to EMLA (delta:-0.4; 95%CI:-1.2 to 0.3; p = 0.26; two trials; I² = 15%). For distress and pain during laceration repair, N₂O was "favorable" versus each of SC lidocaine, oxygen, and oral midazolam but "neutral" versus IV ketamine (five trials). For distress and pain during fracture reduction (three trials), N₂O was "neutral" versus each of IM meperidine plus promethazine, regional anesthesia, and IV ketamine plus midazolam. For distress and pain during lumbar puncture (one trial), N₂O was "favorable" versus oxygen. For distress and pain during urethral catheterization (one trial), N₂O was "neutral" versus oral midazolam. For pain during intramuscular injection (one trial), N₂O plus EMLA was "favorable" versus N₂O and EMLA alone. Common adverse effects of N₂O included nausea (4.4%), agitation (3.7%), and vomiting (3.6%) AEs were less frequent with N₂O alone (278/1147 (24.2%)) versus N₂O plus midazolam (48/52 (92.3%)) and N₂O plus fentanyl (123/201 (61.2%)).

Conclusions: There is sufficient evidence to recommend N₂O plus topical anesthetic for IV insertion and laceration repair. Adverse effects are greater when combined with other sedating agents.