title: Effects of melatonin premedication to prevent emergence agitation after general anaesthesia in children: A systematic review and meta-analysis with trial sequential analysis.
abstract: BACKGROUND
  Emergence agitation is a common phenomenon in children recovering from general anaesthesia. An emergence agitation reaction increases the risk of injuring the surgical repair, the patient and the caregivers.
  
  
  OBJECTIVE
  The objective of this study is to examine the efficacy of melatonin premedication in emergence agitation prevention.
  
  
  METHODS
  A systematic review and meta-analysis of randomised controlled trials (RCTs) with trial sequential analysis (TSA) and meta-regression analysis.
  
  
  METHODS
  We searched MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science, clinicaltrials.gov and UMIN Clinical Trials Registry up to 4 April 2014.
  
  
  METHODS
  RCTs reporting effects of melatonin on the incidence of emergence agitation in children who underwent general anaesthesia were included.
  
  
  RESULTS
  Four studies (358 participants) were analysed. A conventional random-effects meta-analysis showed that compared with placebo, melatonin premedication may be effective in emergence agitation prevention [risk ratio 0.31, 95% confidence interval (CI) 0.16 to 0.60; I2 = 0%]. However, TSA corrected the 95% CI to 0.07 to 1.47 and showed that 22.5% of the required information size (RIS) was achieved. The effect of melatonin compared with that of midazolam was not statistically significant (risk ratio 0.48, 95% CI 0.15 to 1.52) with significant heterogeneity (I2 = 36.8%). TSA-adjusted 95% CI could not be calculated because of the small information size (4% of RIS). Meta-regression showed that, compared with midazolam, melatonin dose was significantly correlated with the effect (P = 0.024). The risk ratios (95% CI) of low and high-dose melatonin were 1.02 (0.39 to 2.65) and 0.22 (0.08 to 0.58), respectively. There was no effect of melatonin compared with dexmedetomidine (risk ratio 1.0, 95% CI 0.15 to 6.55). TSA-adjusted 95% CI could not be calculated (0.9% of RIS).
  
  
  CONCLUSIONS
  Compared with placebo, melatonin premedication may be effective in preventing emergence agitation in children (GRADE: low). This TSA suggests that further studies are required to confirm the results. Compared with midazolam, high-dose melatonin might have a significant effect in preventing emergence agitation (GRADE: very low). The study protocol was registered in the UMIN Clinical Trials Registry (registration number: UMIN000011841).
authors.affiliation: From the Department of Anaesthesiology, Kanagawa Children's Medical Centre (TM, NN), Department of Biostatistics and Epidemiology, Yokohama City University (MSO), and Department of Anaesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan (TG).
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mihara
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Nakamura
authors.forename: Koui
authors.initials: K
authors.lastname: Ka
authors.forename: Mari S
authors.initials: MS
authors.lastname: Oba
authors.forename: Takahisa
authors.initials: T
authors.lastname: Goto
mesh_terms: D000762:Anesthesia Recovery Period; D000768:Anesthesia, General / Q000009:adverse effects*; D002648:Child; D006801:Humans; D008550:Melatonin / Q000008:administration & dosage*; D011292:Premedication / Q000379:methods*; D011595:Psychomotor Agitation / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D016896:Treatment Outcome
chemical_list: D008550:Melatonin