Yu Bin, Liu Lixia, Xing Dong, Zhao Congcong, Hu Zhenjie
Department of Critical Care Medicine, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei, China. Corresponding author: Hu Zhenjie, Email:
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2015 May;27(5):359-65. doi: 10.3760/cma.j.issn.2095-4352.2015.05.008.
To investigate the extracorporeal clearance rate of imipenem in severe infection patients in the mode of continuous vena-venous hemofiltration (CVVH) during continuous renal replacement therapy (CRRT), in order to approach if the concentration of imipenem in plasma could achieve effective levels of anti-infection, and to explore the effect of time and anticoagulation measure on imipenem clearance during CRRT treatment.
A prospective observational study was conducted. All adult severe infection patients complicating acute kidney injury (AKI) in the Department of Critical Care Medicine of the Fourth Hospital of Hebei Medical University from March 2013 to September 2014, who were prescribed imipenem as part of their required medical care, and CRRT for treatment of AKI were enrolled. 0.5 g doses of imipenem was administered intravenously every 6 hours or 8 hours according to random number table, and infused over 0.5 hour. The unfractionated heparin was used for anticoagulation in the patients without contraindications, and no anticoagulation strategy was used in the patients with high risk of bleeding. At 24 hours after first time of administration, postfilter venous blood and ultrafiltrate samples were collected at 0, 0.25, 0.5, 0.75, 1, 2, 5, 6, and 8 hours after imipenem administration. The concentration of imipenem in above samples was determined with liquid chromatography-mass spectrometer/mass spectrometer (LC-MS/MS).
A total of 25 patients were enrolled. Thirteen patients received imipenem intravenously every 6 hours, and 12 patients, every 8 hours. The anticoagulation was conducted with heparin in 13 cases, and 12 cases without anticoagulation. The intra-day precision, inter-day precision, matrix effect, and recovery rate in low, medium, and high concentration of plasma and ultrafiltrate, and the stability of samples under different conditions showed a good result, the error of accuracy was controlled in the range of ±15%. With the application of Prismaflex blood filtration system and AN69-M100 filter, under the mode with CVVH, the total clearance rate of imipenem was (8.874±2.828) L/h when the actual dose of replacement fluid was (31.63±1.48) mL×kg⁻¹×h⁻¹, the total CRRT clearance rate of imipenem in vitro was (2.211±0.539) L/h, which accounting for (30.1±15.7)% of the total drug clearance. In 6 hours interval dosage regimen, the percentages of the time > 4× minimum inhibitory concentration (MIC) at specific 4×MIC of 2, 4, 6, and 8 μg/mL of imipenem were more than 40% of the dosing interval. But in the 8 hours interval dosage regimen, when the level was above the 4×MIC of 4 μg/mL, maintaining time would drop below 40% of the dosing interval, with significant differences compared with that in 6 hours interval dosage regimen [4×MIC = 2 μg/mL: (60.84±20.25)% vs. (94.01±12.46)%, t = 4.977, P = 0.001; 4×MIC = 4 μg/mL: (39.85±15.88)% vs. (68.74±9.57)%, t = 5.562, P = 0.000; 4×MIC = 6 g/mL: (27.58±13.70)% vs. (53.97±8.36)%, t = 5.867, P = 0.000; 4×MIC = 8 μg/mL: ( 8.87±12.43)% vs. (43.48±7.83)%, t = 5.976, P = 0.000]. No significant change in sieving coefficient of imipenem was found within a short time (6 hours), which indicated that there was no effect of anticoagulation on clearance of imipenem by AN69-M100 filter, and no statistical significance was found with repeated measure analysis (F = 0.186, P > 0.05 ).
The clearance rate of imipenem is increased significantly in vitro under the mode of CVVH with the actual dose of replacement fluid was (31.63±1.48) mL×kg⁻¹×h⁻¹ in severe infective patients with severe sepsis complicating AKI, affecting the level of plasma drug concentration, need to adjust the dosage regimen. When the time of the dosing interval was shortened, the concentration of imipenem in patients' plasma could be increased significantly. In a short period of time, the sieving coefficient of imipenem through AN69 filter is not affected by anticoagulation measures and time cleaning efficiency will not decline.
探讨连续性肾脏替代治疗（CRRT）中持续静脉-静脉血液滤过（CVVH）模式下，亚胺培南在重症感染患者中的体外清除率，以探讨血浆中亚胺培南浓度能否达到有效抗感染水平，并探索时间及抗凝措施对CRRT治疗中亚胺培南清除率的影响。
进行一项前瞻性观察性研究。选取2013年3月至2014年9月在河北医科大学第四医院重症医学科住院的所有合并急性肾损伤（AKI）的成年重症感染患者，这些患者接受亚胺培南治疗且因AKI接受CRRT治疗。根据随机数字表，每6小时或8小时静脉注射0.5 g亚胺培南，输注时间为0.5小时。无禁忌证的患者采用普通肝素抗凝，出血风险高的患者不采用抗凝策略。首次给药后24小时，在亚胺培南给药后0、0.25、0.5、0.75、1、2、5、6和8小时采集滤器后静脉血和超滤液样本。采用液相色谱-质谱联用仪（LC-MS/MS）测定上述样本中亚胺培南的浓度。
共纳入25例患者。13例患者每6小时静脉注射亚胺培南，12例患者每8小时静脉注射亚胺培南。13例采用肝素抗凝，12例未抗凝。血浆和超滤液低、中、高浓度的日内精密度、日间精密度、基质效应和回收率以及不同条件下样本的稳定性均良好，准确度误差控制在±15%范围内。应用Prismaflex血液滤过系统和AN69-M100滤器，在CVVH模式下，当置换液实际剂量为（31.63±1.48）mL×kg⁻¹×h⁻¹时，亚胺培南的总清除率为（8.874±2.828）L/h，亚胺培南在CRRT体外的总清除率为（2.211±0.539）L/h，占总药物清除率的（30.1±15.7）%。在6小时给药间隔方案中，亚胺培南在2、4、6和8 μg/mL的特定4倍最低抑菌浓度（MIC）下，>4×MIC的时间百分比超过给药间隔的40%。但在8小时给药间隔方案中，当水平高于4 μg/mL的4×MIC时，维持时间将降至给药间隔的40%以下，与6小时给药间隔方案相比有显著差异[4×MIC = 2 μg/mL：（60.84±20.25）%对（94.01±12.46）%，t = 4.977，P = 0.001；4×MIC = 4 μg/mL：（39.85±15.88）%对（68.74±9.57）%，t = 5.562，P = 0.000；4×MIC = 6 μg/mL：（2上±13.70）%对（53.97±8.36）%，t = 5.867，P = 0.000；4×MIC = 8 μg/mL：（8.87±12上）%对（43.48±7.83）%，t = 5.976，P = 0.000]。短时间（6小时）内亚胺培南的筛系数无明显变化，表明抗凝对AN69-M100滤器清除亚胺培南无影响，重复测量分析无统计学意义（F = 0.186，P>0.05）。
在合并AKI的严重脓毒症重症感染患者中，当置换液实际剂量为（31.63±1.48）mL×kg⁻¹×h⁻¹时，CVVH模式下亚胺培南的体外清除率显著增加，影响血浆药物浓度水平，需要调整给药方案。当给药间隔时间缩短时，患者血浆中亚胺培南浓度可显著升高。短时间内，亚胺培南通过AN69滤器的筛系数不受抗凝措施影响，时间清除效率不会下降。
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