McAdams Ryan M, McPherson Ronald J, Kapur Raj, Phillips Brian, Shen Danny D, Juul Sandra E
1] Department of Pediatrics, University of Washington, Seattle, Washington [2] Seattle Children's Hospital, Seattle, Washington.
Department of Pediatrics, University of Washington, Seattle, Washington.
Pediatr Res. 2015 Jun;77(6):772-8. doi: 10.1038/pr.2015.45. Epub 2015 Mar 9.
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.
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.
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.
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.
α2-肾上腺素能激动剂右美托咪定（DEX）越来越多地用于危重新生儿的长时间镇静，但目前尚无数据评估新生儿长期暴露于DEX的可能后果。我们评估了新生儿暴露于DEX后的药代动力学和组织学后果。
将DEX皮下注射给未受伤的新生Lewis大鼠，以提供急性（25μg/kg，×1次）或长期（25μg/kg，每日3次，×2或×4天）暴露。使用水冷毯模拟治疗性低温。使用红外温度计测量颅骨温度。通过液相色谱-质谱法测量血浆和匀浆脑干组织中的DEX浓度，进行药代动力学分析。评估皮质、小脑和脑干是否有炎症或损伤迹象。
无论是低温还是对照大鼠，新生儿长期暴露于DEX均与肾脏或脑部病理学或胶质细胞增生、巨噬细胞活化或凋亡指标无关。血浆和脑内DEX浓度密切相关。在脑内，DEX在15分钟内达到峰值，在冷却大鼠中，注射后30分钟内颅骨温度从32°C降至30°C。
新生大鼠长期接受DEX治疗与脑组织学异常无关。这些数据为将DEX与治疗性低温联合用于治疗近足月脑损伤提供了令人安心的初步结果。
