Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal Encephalopathy (DICE trial)

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PROJECT SUMMARY Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal Encephalopathy (DICE trial) Hypoxia-ischemia encephalopathy (HIE, commonly called “birth asphyxia”) is a condition where the brain doesn’t get enough oxygen. HIE affects 2 out of every 1,000 babies. Despite early intervention using brain cooling, outcomes of death or major disability, such as cerebral palsy and mental retardation, still occurs in nearly 30% of these babies. No other therapies have been proven to further reduce brain injury for these high risk infants. Furthermore, additional brain injury may be caused by concomitant use of drugs such as morphine to treat pain and sedation in this population. Morphine use in animal models can increase neuronal apoptosis and negatively affect neurodevelopment. Developing adjunctive therapies that improve outcomes in infants with HIE is an urgent, unmet public health need. Dexmedetomidine is a potent α2-adrenergic receptor agonist that may be a better alternative to morphine for newborns with neonatal HIE treated with cooling. Dexmedetomidine provides sedation, analgesia, and prevents shivering but does not suppress breathing. Importantly, dexmedetomidine has been shown to protect the brain in animal models of brain injury. Recent clinical studies also suggest improved brain outcomes after dexmedetomidine administration in adult patients with brain injury. Even though there are limited data on dexmedetomidine safety and usefulness as well as pharmacokinetics (PK; drug levels in blood) in infants with HIE it has been increasingly administered in many centers. Our central hypothesis is that dexmedetomidine administered for sedation to full-term infants with HIE undergoing cooling will be safe (AIM 1) and will be associated with improved short and long-term outcomes (AIM 3). To test this hypothesis, we have designed a Phase II multicenter, randomized, safety and PK trial. Fifty infants (n=25 in each arm) with HIE and requiring sedation will be randomized to receive either dexmedetomidine (1 μg/kg for loading dose followed by 0.1 to 0.5 μg/kg/h continuous infusion) or morphine (0.02-0.03 mg/kg/dose intermittent dosing q 4 hours IV or as continuous infusion dose of 0.005- 0.01 mg/kg/hr). Two opportunistic PK samples (at time of routine laboratories) and a PRN PK sample any time there is an adverse event will be obtained for measurement of Dexmedetomidine plasma concentrations (AIM 2). Promising preliminary data show that dexmedetomidine may improve outcomes but optimal dosing, safety, and efficacy still need to be established. We propose to confirm dexmedetomidine optimal dosing by collecting opportunistic blood samples for PK data and determine safety of dexmedetomidine in this population in a phase II safety trial. These data will inform a larger phase III trial to assess the efficacy of this therapy in reducing the risk of long-term disabilities in infants with HIE who survive beyond the newborn period.