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

M. Ezzati, K. Broad, G. Kawano, S. Faulkner, J. Hassell, B. Fleiss, P. Gressens, I. Fierens, J. Rostami, M. Maze, J. W. Sleigh, B. Anderson, R. D. Sanders, N. J. Robertson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

Background 
The highly selective 2-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 degrees C). Dexmedetomidine was administered with a loading dose of 1g/kg and maintenance infusion at doses from 10 to 0.6g/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 (0.4-0.8g/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 1g/l. Dexmedetomidine clearance was 0.126l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5 degrees 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.

Original languageEnglish
Pages (from-to)733-742
Number of pages10
JournalACTA ANAESTHESIOLOGICA SCANDINAVICA
Volume58
Issue number6
DOIs
Publication statusPublished - Jul 2014

Keywords

  • HYPOXIC-ISCHEMIC ENCEPHALOPATHY
  • EXCITOTOXIC BRAIN-INJURY
  • MODERATE HYPOTHERMIA
  • ALPHA(2A)-ADRENOCEPTOR SUBTYPE
  • ALPHA(2)-ADRENOCEPTOR AGONISTS
  • CHILDREN
  • RATS
  • DISPOSITION
  • CLONIDINE
  • SEDATION

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