From the Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Department of Pediatrics, Division of Critical Care Medicine, CHU Sainte-Justine, Montreal, Quebec, Canada.
Anesth Analg. 2023 Jan 1;136(1):152-162. doi: 10.1213/ANE.0000000000005988. Epub 2022 Apr 21.
Atomized intranasal dexmedetomidine is an attractive option when sedation is required for pediatric patients as either premedication or the sole agent for noninvasive, nonpainful procedures. While intranasal dexmedetomidine is used frequently in this population, it is still unclear what dose and time of administration relative to the procedure will result in the optimal effect. Knowledge regarding the maximum concentration (C max ) and time to reach maximum concentration (T max ) of intranasally administered dexmedetomidine is the first step toward this. The risk of hemodynamic instability caused by increasing doses of dexmedetomidine necessitates a greater understanding of the pharmacokinetics in children.
Sixteen pediatric patients 2 to 6 years of age undergoing elective cardiac catheterization received 2 or 4 μg/kg dexmedetomidine intranasally. Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry with a validated assay. Descriptive noncompartmental analysis provided estimates of peak concentrations and time to reach peak concentrations. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Simulations were performed using the final model to assess dose concentrations with an alternative dosing regimen of 3 µg/kg.
A median peak plasma concentration of 413 pg/mL was achieved 91 minutes after 2 μg/kg dosing, and a median peak plasma concentration of 1000 pg/mL was achieved 54 minutes after 4 μg/kg dosing. A 1-compartment pharmacokinetic model adequately described the data. Three subjects in the 4 μg/kg dosing cohort achieved a dose-limiting toxicity (DLT), defined as a plasma dexmedetomidine concentration >1000 pg/mL. None of these subjects had any significant hemodynamic consequences. Simulations showed that no subjects would experience a level >1000 pg/mL when using a dose of 3 µg/kg.
Concentrations associated with adequate sedation can be achieved with intranasal dexmedetomidine doses of 2 to 4 µg/kg in children 2 to 6 years of age. However, 50% of our evaluable subjects in this cohort reached a plasma concentration >1000 pg/mL. Doses of 3 µg/kg may be optimal in this population, with simulated concentrations remaining below this previously established toxicity threshold. Further studies correlating concentrations with efficacy and adverse effects are needed.
在需要镇静的小儿患者中，雾化鼻内给予右美托咪定是一种很有吸引力的选择，可作为术前用药或用于非侵入性、无痛性操作的单一药物。尽管鼻内给予右美托咪定在该人群中经常使用，但相对于操作，何时给予何种剂量仍不清楚，才能达到最佳效果。了解鼻内给予右美托咪定的最大浓度（C max ）和达到最大浓度的时间（T max ）是实现这一目标的第一步。由于右美托咪定剂量的增加会导致血流动力学不稳定，因此需要更好地了解儿童的药代动力学。
16 名 2 至 6 岁择期行心导管术的小儿患者接受 2 或 4 μg/kg 的右美托咪定鼻内给药。采用经液相色谱-串联质谱法（LC-MS/MS）测定血浆浓度，该方法具有验证后的检测方法。通过非房室描述性分析提供了峰浓度和达到峰浓度时间的估计值。使用非线性混合效应模型建立了群体药代动力学模型。使用最终模型进行模拟，以评估替代 3 μg/kg 给药方案的剂量浓度。
2 μg/kg 剂量后 91 分钟达到中位血浆峰浓度 413 pg/mL，4 μg/kg 剂量后 54 分钟达到中位血浆峰浓度 1000 pg/mL。单室药代动力学模型可充分描述数据。4 μg/kg 剂量组中有 3 名受试者达到了剂量限制毒性（DLT），定义为血浆右美托咪定浓度>1000 pg/mL。这些受试者均无明显的血流动力学后果。模拟结果显示，使用 3 μg/kg 剂量时，没有受试者的血药浓度会超过 1000 pg/mL。
在 2 至 6 岁的儿童中，2 至 4 μg/kg 的鼻内右美托咪定剂量可达到足够的镇静作用相关浓度。然而，在该队列中，50%的可评估受试者达到了 1000 pg/mL 以上的血浆浓度。该人群中 3 μg/kg 的剂量可能是最佳选择，模拟浓度仍低于先前建立的毒性阈值。还需要进一步的研究来关联浓度与疗效和不良反应。
