BACKGROUND Dexmedetomidine (DEX) is increasingly used intraoperatively in infants undergoing cardiac surgery. This phase 1 multicentre study sought to: (i) determine the safety of DEX for cardiac surgery with cardiopulmonary bypass; (ii) determine the pharmacokinetics (PK) of DEX; (iii) create a PK model and dosing for steady-state DEX plasma levels; and (iv) validate the PK model and dosing. METHODS We included 122 neonates and infants (0-180 days) with D-transposition of the great arteries, ventricular septal defect, or tetralogy of Fallot. Dose escalation was used to generate NONMEM® PK modelling, and then validation was performed to achieve low (200-300 pg ml-1), medium (400-500 pg ml-1), and high (600-700 pg ml-1) DEX plasma concentrations. RESULTS Five of 122 subjects had adverse safety outcomes (4.1%; 95% confidence interval [CI], 1.8-9.2%). Two had junctional rhythm, two had second-/third-degree atrioventricular block, and one had hypotension. Clearance (CL) immediately postoperative and CL on CPB were reduced by approximately 50% and 95%, respectively, compared with pre-CPB CL. DEX clearance after CPB was 1240 ml min-1 70 kg-1. Age at 50% maximum clearance was approximately 2 days, and that at 90% maximum clearance was 18 days. Overall, 96.1% of measured DEX concentrations fell within the 5th-95th percentile prediction intervals in the PK model validation. Dosing strategies are recommended for steady-state DEX plasma levels ranging from 200 to 1000 pg ml-1. CONCLUSIONS When used with a careful dosing strategy, DEX results in low incidence and severity of adverse safety events in infants undergoing cardiac surgery with cardiopulmonary bypass. This validated PK model should assist clinicians in selecting appropriate dosing. The results of this phase 1 trial provide preliminary data for a phase 3 trial of DEX neuroprotection. CLINICAL TRIALS REGISTRATION NCT01915277.

中文翻译：

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右美托咪定推注和输注在婴儿心脏矫正手术中的 1 期多中心研究结果。

背景右美托咪定（DEX）越来越多地在接受心脏手术的婴儿的术中使用。这项 1 期多中心研究旨在：(i) 确定 DEX 用于体外循环心脏手术的安全性；(ii) 确定 DEX 的药代动力学 (PK)；(iii) 创建稳态 DEX 血浆水平的 PK 模型和剂量；(iv) 验证 PK 模型和剂量。方法 我们纳入了 122 名患有大动脉 D 型转位、室间隔缺损或法洛四联症的新生儿和婴儿（0-180 天）。使用剂量递增来生成 NONMEM® PK 模型，然后进行验证以实现低剂量 (200-300 pg ml-1)、中剂量 (400-500 pg ml-1) 和高剂量 (600-700 pg ml-1) ) DEX 血浆浓度。结果 122 名受试者中有 5 名出现不良安全结果（4.1%；95% 置信区间 [CI]，1.8-9.2%）。两人有交界性心律，两人有二度/三度房室传导阻滞，一人有低血压。与 CPB 前的 CL 相比，术后即刻的清除率 (CL) 和 CPB 时的 CL 分别减少约 50% 和 95%。CPB 后 DEX 清除率为 1240 ml min-1 70 kg-1。50%最大清除率时的年龄约为2天，90%最大清除率时的年龄为18天。总体而言，在 PK 模型验证中，96.1% 的测量 DEX 浓度落在第 5-95 个百分位预测区间内。建议采用稳态 DEX 血浆水平范围为 200 至 1000 pg ml-1 的给药策略。结论 当采用谨慎的剂量策略时，DEX 可以降低接受体外循环心脏手术的婴儿不良安全事件的发生率和严重程度。该经过验证的 PK 模型应有助于临床医生选择适当的剂量。该 1 期试验的结果为 DEX 神经保护的 3 期试验提供了初步数据。临床试验注册 NCT01915277。