Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats.
BACKGROUND
The α2-adrenergic agonist dexmedetomidine (DEX) is increasingly used for prolonged sedation of critically ill neonates, but there are currently no data evaluating possible consequences of prolonged neonatal DEX exposure. We evaluated the pharmacokinetics and histological consequences of neonatal DEX exposure.


METHODS
DEX was administered (s.c.) to naive (uninjured) neonatal Lewis rats to provide acute (25 µg/kg, ×1) or prolonged (25 µg/kg three times daily, ×2 or ×4 d) exposure. Therapeutic hypothermia was simulated using a water-cooled blanket. Cranial temperatures were measured using an infrared thermometer. DEX concentrations were measured by LC-MS in plasma and homogenized brainstem tissue for pharmacokinetic analysis. Cortex, cerebellum, and brainstem were evaluated for evidence of inflammation or injury.


RESULTS
Prolonged neonatal DEX exposure was not associated with renal or brain pathology or indices of gliosis, macrophage activation, or apoptosis in either hypothermic or control rats. Plasma and brain DEX concentrations were tightly correlated. DEX peaked within 15 min in brain and reduced cranial temperature from 32 to 30 °C within 30 min after injection in cooled rats.


CONCLUSIONS
Prolonged DEX treatment in neonatal rats was not associated with abnormal brain histology. These data provide reassuring preliminary results for using DEX with therapeutic hypothermia to treat near-term brain injury.
1] Department of Pediatrics, University of Washington, Seattle, Washington [2] Seattle Children's Hospital, Seattle, Washington.
Ryan M
RM
McAdams
Department of Pediatrics, University of Washington, Seattle, Washington.
Ronald J
RJ
McPherson
1] Seattle Children's Hospital, Seattle, Washington [2] Department of Pathology, University of Washington, Seattle, Washington.
Raj
R
Kapur
Department of Pharmaceutics, University of Washington, Seattle, Washington.
Brian
B
Phillips
Department of Pharmaceutics, University of Washington, Seattle, Washington.
Danny D
DD
Shen
1] Department of Pediatrics, University of Washington, Seattle, Washington [2] Seattle Children's Hospital, Seattle, Washington.
Sandra E
0000000268616229
SE
Juul
D058647:Adrenergic alpha-2 Receptor Agonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D002853:Chromatography, Liquid; D020927:Dexmedetomidine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D007035:Hypothermia / Q000503:physiopathology*; D013058:Mass Spectrometry; D051381:Rats; D011917:Rats, Inbred Lew
D058647:Adrenergic alpha-2 Receptor Agonists; D020927:Dexmedetomidine