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 N 2 O for distress and pain in children. Study design We included trials of N 2 O 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 N 2 O 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% N 2 O (delta:-16.5; 95%CI:-28.6 to -4.4; p = 0.008; three trials; I 2 = 0%) and 50% N 2 O plus eutectic mixture of local anesthetics (EMLA) (delta:-1.2; 95%CI:-2.1 to -0.3; p = 0.007; two trials; I 2 = 43%) were superior to EMLA. 50% N 2 O was not superior to EMLA (delta:-0.4; 95%CI:-1.2 to 0.3; p = 0.26; two trials; I 2 = 15%). For distress and pain during laceration repair, N 2 O 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), N 2 O 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), N 2 O was “favorable” versus oxygen. For distress and pain during urethral catheterization (one trial), N 2 O was “neutral” versus oral midazolam. For pain during intramuscular injection (one trial), N 2 O plus EMLA was “favorable” versus N 2 O and EMLA alone. Common adverse effects of N 2 O included nausea (4.4%), agitation (3.7%), and vomiting (3.6%) AEs were less frequent with N 2 O alone (278/1147 (24.2%)) versus N 2 O plus midazolam (48/52 (92.3%)) and N 2 O plus fentanyl (123/201 (61.2%)). Conclusions There is sufficient evidence to recommend N 2 O plus topical anesthetic for IV insertion and laceration repair. Adverse effects are greater when combined with other sedating agents.