MELAtonin for Prevention of Postoperative Agitation and Emergence Delirium in Children (MELA-PAED)

MELAtonin for Prevention of Postoperative Agitation and Emergence Delirium in Children. The MELA-PAED Trial: a Randomized, Double-blind, Placebo-controlled Trial.

Sygehus Lillebaelt, University of Copenhagen, Copenhagen Trial Unit, Center for Clinical Intervention Research

Postoperative agitation and emergence delirium describe a spectrum of symptoms of early postoperative negative behavior, in which the child experiences a variety of behavioral disturbances including crying, thrashing, and disorientation during early awakening from anaesthesia. The symptoms are common with a reported incidence of approximately 25%. Some clinical trials have studied the effect of prophylactic oral melatonin for reducing the risk of emergence agitation in children, some finding a considerable dose-response effect. Melatonin has a low bio-availability of approximately 15 %. The safety of exogenous melatonin for pediatric patients has been studied with no apparent serious adverse effects, even at repeated short-term use of high doses of intravenous melatonin. The aim of this clinical trial is to investigate the prophylactic effects and safety of intravenous melatonin administered intraoperatively for prevention of postopreative agitation and emergence delirium in children after an elective surgical procedure. The study is designed as a randomised, double-blind, placebo-controlled clinical trial.

Participants receive melatonin solution for injection 1 mg/mL in a dosage of 0.15 mg/kg body weight as a single intravenous injection approximately 30 minutes before end of surgical procedure.

Participants receive isotonic sodium chloride (9mg/mL) intravenously once approximately 30 minutes before end of surgical procedure in a volume equivalent to the melatonin group for the same weight.

Participants will be assessed on Watcha scale repeatedly ever 15 min during their stay at the Post-Anesthetic Care Unit. The variable is dichotomous: any score >2= "Yes" and no score <=2 = "No"

The total amount of opioids administered for postoperative pain in the PACU will be evaluated as units of morphine equivalents per kg. No more than 35 % of the popu-lation is expected to receive postoperative opioids in a range of approximately 10-100 µg/kg.

We will use the International Conference on Harmonization of technical require-ments for registration of pharmaceuticals for human use-Good Clinical Practice (ICH-GCP) definition of a serious adverse event, which is any untoward medical occurrence that resulted in death, was life-threatening, re-quired hospitalization or prolonging of existing hospitalization and resulted in persistent or significant disability or jeopardized the participant.

The incidence of postoperative pain will be assessed in each group according to the FLACC scale, assessed every 15 minutes in PACU. Postoperative pain is defined as any FLACC score >3.

The incidence of PONV will be assessed dichotomously every 15 minutes in PACU. Outcome assessors will observe for vomiting. Nausea can be considered present if the participant refuses to eat and other causes are ruled out. There is no adequate PONV assessment tool available. PONV will be considered present if any assess-ment during PACU stay is "Yes".

Time from end of anesthesia to the time point at which the first dose of opioid is administered in PACU. Not all participants (expectedly up to approximately 35%) will receive opioids in PACU.

Dichotomous assessment of any administration in PACU of rescue medication specifically targeting EA according to treatment algorithm i.e., clonidine or propofol.

Time from end of anesthesia to the first time point at which the participant is awake. If the participant is not awake two hours after arrival in PACU, a wake-up at-tempt will be carried out.

Time from end of anesthesia to the first time point at which the participant eats/drinks. All participants are assumed to eat/drink during their PACU stay.

Time from end of anesthesia (defined as above) to the time point at which partici-pant fulfills local discharge criteria. Discharge criteria will be evaluated by the re-sponsible physician prior to final discharge from PACU either to the participant's ward or to their home.

The incidence of emergence delirium will be evaluated according to the PAED score assessed every 15 minutes during PACU stay. The end-point is defined dichotomously as any score ≥10. Due to feasibility concerns, this outcome will solely be evaluated in a sub-population of approximately 50% of the trial population (200 participants), specifically only thos enrolled at the Juliane Marie Center Site.

Assessed dichotomously counting day 0 as the day of discharge from hospital after the procedure. For the small group (expectedly <5 %) who will have had any read-missions within 30 days, the number of readmissions will be described.

Inclusion Criteria: Patients aged 1-6 years Elective surgical procedure of en axpected duration of at least 30 minutes in general anesthesia maintained with sevoflurane Exclusion Criteria: Any known allergy or contraindication to study treatment or excipåients Current daily medication with melatonin