The MAGIC trial: a pragmatic, multicentre, parallel, noninferiority, randomised trial of melatonin versus midazolam in the premedication of anxious children attending for elective surgery under general anaesthesia

Abstract

Background: Child anxiety before general anaesthesia and surgery is common. Midazolam is a commonly used premedication to address this. Melatonin is an alternative anxiolytic, however trials evaluating its efficacy in children have delivered conflicting results.

Methods: This multicentre, double-blind randomised trial was performed in 20 UK NHS Trusts. A sample size of 624 was required to declare noninferiority of melatonin. Anxious children, awaiting day case elective surgery under general anaesthesia, were randomly assigned 1:1 to midazolam or melatonin premedication (0.5 mg kg^-1, maximum 20 mg) 30 min before transfer to the operating room. The primary outcome was the modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF). Secondary outcomes included safety. Results are presented as n (%) and adjusted mean differences with 95% confidence intervals.

Results: The trial was stopped prematurely (n=110; 55 per group) because of recruitment futility. Participants had a median age of 7 (6-10) yr, and 57 (52%) were female. Intention-to-treat and per-protocol modified Yale Preoperative Anxiety Scale-Short Form analyses showed adjusted mean differences of 13.1 (3.7-22.4) and 12.9 (3.1-22.6), respectively, in favour of midazolam. The upper 95% confidence interval limits exceeded the predefined margin of 4.3 in both cases, whereas the lower 95% confidence interval excluded zero, indicating that melatonin was inferior to midazolam, with a difference considered to be clinically relevant. No serious adverse events were seen in either arm.

Conclusion: Melatonin was less effective than midazolam at reducing preoperative anxiety in children, although the early termination of the trial increases the likelihood of bias.

Clinical trial registration: ISRCTN registry: ISRCTN18296119.

Keywords: general anaesthesia; melatonin; midazolam; paediatric anxiety; perioperative care; premedication.

Fig 1

CONSORT flow diagram. mYPAS-SF, modified Yale Preoperative Anxiety Scale-Short Form; PI, principal investigator; RN, research nurse.

Fig 2

Boxplots of mYPAS-SF scores at each time point by treatment group. mYPAS-SF, modified Yale Preoperative Anxiety Scale-Short Form.

Fig 3

Adjusted mean difference in mYPAS-SF of melatonin compared with midazolam from the primary analysis models. (Mean [standard deviation]) mYPAS-SF scores and adjusted mean differences from the primary analysis model for each analysis population located in Supplementary Table S5 provided in Supplementary material (File 6). ITT, intention-to-treat; mYPAS-SF, modified Yale Preoperative Anxiety Scale-Short Form; NI, noninferiority; PP, per-protocol.

Fig 4

Mean post-surgery PAED and VSRS scores (with 95% CI) by treatment group. CI, confidence interval; PAED, Paediatric Anaesthesia Emergence Delirium scale; VSRS, Vancouver Sedation Recovery Scale.