Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model

Abstract

Background: The highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown.

Methods: Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 μg/kg and maintenance infusion at doses from 10 to 0.6 μg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling.

Results: All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 μg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 μg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia.

Conclusions: Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications.

Fig. 1

Dexmedetomidine plasma concentrations from nine piglets at varying infusion rates following hypoxic-ischaemic brain injury and co-administration with hypothermia. One additional piglet did not incur brain injury and did not undergo hypothermia. The safe sedative concentration in human neonates is 0.4–0.8 μg/ml; the dotted line is at 1 μg/ml. All piglets achieved dexmedetomidine concentrations above 1 μg/ml.

Fig. 2

Visual predictive check for the dexmedetomidine pharmacokinetic (PK) model. All plots show median and 90% intervals (solid and dashed lines). Left hand plot shows all prediction corrected observed concentrations. Right hand plot shows prediction corrected percentiles (10%, 50%, 90%) for observations (lines with symbols) and predictions (lines) with 95% confidence intervals for prediction percentiles (gray shaded areas).