DEXmedetomidine Trial of Adjunct Treatment with Morphine (DEXTA): a masked, randomised placebo-controlled trial

Research question In ventilated preterm babies who need morphine infusion for analgesia (Population) do 120-hour infusions of dexmedetomidine (0.5microgram/kg/hour) plus morphine?(Intervention 1) OR 120-hour infusions of dexmedetomidine (0.25microgram/kg/hour) plus morphine?(Intervention 2) as compared to

120-hour infusions of placebo plus morphine (Comparator)

reduce the cumulative dose of morphine given over 120-hours from starting the dexmedetomidine or placebo infusion (Primary Outcome) Background

Pain in preterm babies is inadequately managed and under-researched. Morphine is frequently used for analgesia during ventilation as it is painful. However, evidence suggests that morphine may not provide adequate analgesia and may adversely prolong the need for ventilation and time to reach full milk feeds.

Additionally, babies given larger doses of morphine in early life have a higher risk of brain injury and poorer neurodevelopment and behavioural outcomes in later life. Despite this, due to lack of alternatives, morphine continues to be the most popular analgesic for ventilated babies.

Dexmedetomidine is an alpha-2 agonist that provides analgesia without sedation. It is an alternative to morphine in adult and paediatric intensive care. Some observational studies found that it can reduce the dose of morphine needed to provide analgesia in babies. It is not currently used in UK neonatal practice. There are no completed or ongoing randomised trials investigating its use in ventilated preterm babies.

Aims and objectives

Our primary aim is to determine if dexmedetomidine is efficacious in reducing the cumulative dose of morphine needed to provide analgesia, given over 120 hours from starting the dexmedetomidine or placebo infusion in ventilated preterm babies.?

We will also determine if it reduces pain, the total duration and additional doses of morphine, duration of ventilation and intensive care, time to reach full milk feeds, the risk of bronchopulmonary dysplasia, and preterm brain injury at 36 weeks’ post menstrual age and neurodevelopment at 2-years corrected age, without increasing the risk of bradycardia and hypotension.

Methods, including justification of study design

We propose a three-arm, multicentre, blinded, randomised, placebo-controlled efficacy trial, including 120 babies who are expected to be ventilated for at least 48 hours. Babies will receive dexmedetomidine (one of two infusion doses) or placebo with morphine infusion for 5 days. Total cumulative dose of morphine and other outcomes will be measured at the end of the 5-day infusion, at 36 weeks post menstrual age, and 2-years corrected age.

Timelines?for delivery Set-up: 9 months Recruitment: 10 to 27 months (10 sites) Primary and other short-term outcomes: month 40 Outcomes at 2-years corrected age: month 60 Anticipated impact and dissemination

If dexmedetomidine is efficacious in reducing the cumulative dose of morphine needed to provide analgesia in ventilated preterm babies, we will progress (if funded) to a larger pragmatic randomised controlled trial of dexmedetomidine vs. morphine to assess its effectiveness in improving long-term neurodevelopment of ventilated preterm babies.

We have co-developed this study with a national charity, Bliss, and other PPI partners. We will work with them to disseminate the results to the public. The results will be published in peer-reviewed scientific journals and presented at key neonatal conferences.