Dexmedetomidine use in Infants undergoing Cooling due to neonatal Encephalopathy (DICE trial): safety and pharmacokinetics.

BACKGROUND

Infants undergoing therapeutic hypothermia (TH) due to neonatal encephalopathy often require sedation and pain medication. Dexmedetomidine may be a good alternative to morphine as it provides both sedation and analgesia. However, the safety and pharmacokinetics (PK) of dexmedetomidine in this population are not well established.

METHODS

In this Phase II, multicenter, open-label, randomized, safety and PK trial, 48 infants undergoing TH for encephalopathy were randomized to receive dexmedetomidine (25) or morphine (23) using standardized doses. PK parameters of dexmedetomidine in this population were calculated using a nonlinear mixed effects modeling using NONMEM® 7.5 software.

RESULTS

There were no statistically significant differences between groups in baseline characteristics, hospitalization outcomes and adverse events. A total of 315 dexmedetomidine PK samples using a 1-compartment model with first-order elimination analysis were analyzed. Median clearance and volume of distribution were 0.51 L/kg/h and 0.25 L/kg. Weight, post-menstrual age, maximum liver enzymes, and encephalopathy severity influenced dexmedetomidine PK.

CONCLUSION

The incidence of adverse events and hospitalization outcomes in infants randomized to dexmedetomidine or morphine during hypothermia were similar. Using population PK to model dexmedetomidine, lower clearance and volume of distribution parameters were found in infants undergoing hypothermia compared to previously published parameters in non-cooled infants.

IMPACT: Infants undergoing therapeutic hypothermia for encephalopathy often require drugs to treat pain and for sedation in the intensive care unit. Dexmedetomidine may be a better alternative to opiates since it provides sedation, analgesia, and prevents shivering but does not suppress ventilation. In this randomized, unmasked, safety and PK trial we found no significant differences in short term hospital outcomes and incidence of adverse events in infants receiving dexmedetomidine when compared to infants receiving morphine. The pharmacokinetics of dexmedetomidine in this at-risk population was further established.