Background

Despite the surge in use of extracorporeal membrane oxygenation (ECMO) in the adult intensive care unit, little guidance is available on the appropriate dosing of antimicrobials in this setting. Ceftriaxone is an antimicrobial with a high affinity to plasma protein, a property identified in the literature as susceptible to sequestration into extracorporeal circuits and hypothesised to require dosage adjustments in this setting.

Objective

The aim of this study was to describe the pharmacokinetics of ceftriaxone and identify the best dosing regimen for critically ill adult patients receiving ECMO.

Methods

Serial blood samples were taken from patients receiving both ECMO and ceftriaxone. Total and unbound drug concentrations were measured in plasma by chromatographic assay and analysed using a population pharmacokinetic approach with Pmetrics^®. Dosing simulations were performed to identify the optimal dosing strategy: 60 and 100% of time with free (unbound) drug concentration exceeding the minimum inhibitory concentration (fT_>MIC).

Results

In total, 14 patients were enrolled, of which three were receiving renal replacement therapy (RRT). Total and unbound ceftriaxone was best described in a two-compartment model with total body weight, serum albumin concentrations, creatinine clearance (CrCL), and the presence of RRT included as significant predictors of pharmacokinetics. Patients not on RRT generated a mean renal clearance of 0.90 L/h, non-renal clearance of 0.33 L/h, and central volume of distribution of 7.94 L. Patients on RRT exhibited a mean total clearance of 1.18 L/h. ECMO variables were not significant predictors of ceftriaxone pharmacokinetics. Steady-state dosing simulations found that dosages of 1 g every 12 h and 2 g every 24 h achieved >90% probabilities of target attainment in patients with CrCL of 0 mL/min with RRT and 30 and 100 mL/min and various serum albumin concentrations (17 and 26 g/L).

Conclusions

Dosing recommendations for critically ill adult patients not on ECMO appear to be sufficient for patients on ECMO. Patients exhibiting augmented renal clearance (> 130 mL/min) or treatment of less susceptible pathogens may require higher doses, which requires further investigation.

中文翻译：

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接受体外膜氧合的危重患者中头孢曲松的群体药代动力学和剂量模拟（ASAP ECMO 研究）

背景

尽管成人重症监护病房中体外膜肺氧合 (ECMO) 的使用激增，但在这种情况下，关于抗菌药物适当剂量的指导却很少。头孢曲松是一种对血浆蛋白具有高亲和力的抗菌剂，文献中发现这种特性容易被隔离到体外循环中，并假设在这种情况下需要调整剂量。

客观的

本研究的目的是描述头孢曲松的药代动力学，并确定接受 ECMO 的危重成年患者的最佳给药方案。

方法

从接受 ECMO 和头孢曲松的患者身上采集连续血样。通过色谱分析测定血浆中的总药物浓度和未结合药物浓度，并使用Pmetrics®^的群体药代动力学方法进行分析。进行给药模拟以确定最佳给药策略：60% 和 100% 的时间游离（未结合）药物浓度超过最小抑制浓度 ( f T _>MIC )。

结果

总共 14 名患者入组，其中 3 名正在接受肾脏替代治疗 (RRT)。总重和未结合的头孢曲松在两室模型中得到最好的描述，其中总体重、血清白蛋白浓度、肌酐清除率 (CrCL) 和 RRT 的存在作为药代动力学的重要预测因子。未接受 RRT 的患者产生的平均肾脏清除率为 0.90 L/h，非肾脏清除率为 0.33 L/h，中心分布容积为 7.94 L。接受 RRT 的患者表现出平均总清除率为 1.18 L/h。ECMO 变量并不是头孢曲松药代动力学的显着预测因子。稳态给药模拟发现，对于 CrCL 为 0 mL/min、RRT、30 和 100 mL/min 以及各种血清白蛋白的患者，每 12 小时 1 g 和每 24 小时 2 g 的剂量达到目标的概率 >90%浓度（17 和 26 g/L）。

结论

针对未使用 ECMO 的危重成年患者的剂量建议似乎对于使用 ECMO 的患者来说是足够的。表现出肾清除率增强（> 130 mL/min）或治疗不太敏感病原体的患者可能需要更高的剂量，这需要进一步研究。