Emergence agitation, characterized by crying, excitation, and disorientation after general anesthesia, is a serious complication in pediatric patients, especially those undergoing tonsillectomy. It increases the risk of self-injury and necessitates additional care and medication, potentially leading to respiratory depression. While medications like midazolam, fentanyl, and propofol can be used, they carry the risk of respiratory depression. Melatonin, a sleep-regulating hormone, has shown promise in preventing emergence agitation without causing respiratory depression, but previous studies lacked definitive conclusions due to wide confidence intervals. Ramelteon, a melatonin receptor agonist with higher affinity than melatonin, was hypothesized to prevent emergence agitation in children, prompting this study.

A previous systematic review and meta-analysis suggested melatonin's potential to prevent emergence agitation in children, but the confidence intervals were wide, necessitating further research. Studies on ramelteon's effect on delirium in adults existed, but its effect on pediatric emergence agitation remained unexplored. This study aimed to fill that gap and provide more robust evidence on the efficacy of melatonin receptor agonists for preventing this common pediatric anesthesia complication.

This prospective, double-blind, parallel-group, placebo-controlled, randomized clinical trial enrolled 50 children (18-119 months old, ASA physical status 1 or 2) scheduled for tonsillectomy. Patients were randomly assigned to receive either 0.1 mg·kg⁻¹ of ramelteon or placebo (lactose syrup) before anesthesia induction. Anesthesia was induced using sevoflurane and nitrous oxide, with fentanyl administered intraoperatively. Postoperative assessments included the Paediatric Anaesthesia Emergence Delirium (PAED) score (every 5 minutes), Children’s Hospital Boston Ontario Pain Scale (CHEOPS) score, and incidence of postoperative vomiting (POV). The primary outcome was the incidence of emergence agitation (PAED score ≥10). Data were analyzed using appropriate statistical tests (unpaired t-test, Mann–Whitney U test, Fisher's exact test) for a modified intention-to-treat population.

Forty-eight patients completed the study. There was no statistically significant difference between the ramelteon and placebo groups in the incidence of emergence agitation (66.7% in both groups; risk ratio 1.0, 95% CI 0.67–1.49, P > 0.99). Secondary outcomes, including PAED scores, Aono’s scores, rescue drug use, POV incidence, CHEOPS scores, PAB scores, desaturation incidence, and time to recovery from anesthesia, also showed no significant between-group differences. Table 1 details patient characteristics, and Table 2 presents primary and secondary outcomes.

The study's findings refute the hypothesis that 0.1 mg·kg⁻¹ of ramelteon prevents emergence agitation in children undergoing tonsillectomy. The lack of benefit across all outcomes suggests that this dose is ineffective. While previous research suggested a dose-dependent effect of melatonin, the higher affinity of ramelteon for melatonin receptors did not translate to efficacy at this dose. The similar outcomes in both groups, including pain scores and POV incidence, further support the lack of efficacy of this dose. The absence of increased desaturation or respiratory depression is consistent with previous findings on melatonin.

This study demonstrates that 0.1 mg·kg⁻¹ ramelteon does not prevent emergence agitation or improve other postoperative outcomes in children undergoing tonsillectomy. Further research should explore the effects of higher ramelteon doses on emergence agitation in pediatric patients. The lack of a clinically significant difference between groups for secondary outcomes further reinforces the null result for the primary outcome.

The single-center design and focus solely on tonsillectomy limit the generalizability of the findings. The study only assessed one ramelteon dose, and higher doses might yield different results. The age range of the participants (18-110 months) might have introduced variability in responses. The high baseline rate of emergence agitation in the tonsillectomy population may have also influenced the results.