右美托咪定在婴幼儿体外循环中的药代动力学及其新型给药模式
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Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass
背景与目的
心脏病患儿体外循环（CPB）期间及术后，未按说明书输注右美托咪定呈增加趋势，尽管应用频繁，但CPB期间右美托咪定的最佳剂量尚未确定，预计与非CPB的剂量不同。本研究旨在阐明：（1）婴幼儿CPB对右美托咪定清除率 (CL)和分布容积 (V) 的影响；（2）了解患儿对右美托咪定的耐受性和镇静特征；（3）明确婴幼儿进行CPB时的初始推荐剂量。本研究假设与CPB前和CPB后相比，CPB期间右美托咪定的 CL减少、V增加。
方 法
本研究为非盲、单中心、安全的药代动力学(PK)试验，按照护理标准给予患儿（≤36月龄）连续输注右美托咪定。采用NONMEM程序建立标准非线性混合效应模型并分析右美托咪定PK数据 ，将模型评估的PK参数与下列病例中右美托咪定PK参数进行比较：泌尿外科、下腹部或整形手术麻醉前；心脏或颅面部低风险手术后；纤支镜检查或核磁共振成像过程中。本研究探讨CPB相关因素对PK的影响，并采用最终模型评估推荐剂量，以达到安全有效的血浆药物浓度(0.6 ng/mL)。本研究采用Wilcoxon秩和检验评估发生低血压或心动过缓的婴幼儿和不发生这些不良反应的婴幼儿之间右美托咪定剂量的差异性。
结 果
本试验收集了18例患儿的213份右美托咪定血浆样本。患儿中间年龄3.3个月（0.1–34.0月龄），CPB时间161分钟（63–394min）。本试验评估CPB期间的右美托咪定清除率为13.4 L/h/70 kg （95%CI：2.6–24.2 L/h/70 kg），而其余病例的右美托咪定清除率为42.1 L/h/70 kg (95%CI：38.7–45.8 L/h/70 kg)。没有特定的CPB相关因素对PK产生统计学意义的影响。矫正胎龄42周或92周的婴儿在CPB前给予0.7 µg/kg负荷剂量的右美托咪定并维持10min以上，随后经CPB分别持续输注0.2或0.25 µg/kg/h的右美托咪定，可维持目标浓度。本研究发现右美托咪定剂量与所选择的不良反应之间没有相关性（P＝0.13）。
结 论
与非CPB相比，婴幼儿CPB期间右美托咪定低清除率与CPB密切相关，可能影响清除率的CPB相关因素有待进一步研究。
原始文献摘要
Kanecia OZ，Huali W，Matthew L,et al.Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass[J].Anesth Analg,2018.
BACKGROUND: Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states.
METHODS: Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or
during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events.
RESULTS: We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1–34.0 months) and underwent CPB for 161 minutes (63–394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6–24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7–45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant
effect on PK. A loading dose of 0.7 µg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 µg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13).
CONCLUSIONS: CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL.
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