摘要
目的：探讨接受连续性肾脏替代治疗（CRRT）的危重患者在连续性静脉-静脉血液滤过（CVVH）模式下亚胺培南的体外清除效率，患者血浆中的药物浓度能否有效达到抗感染治疗水平，以及时间及抗凝措施对亚胺培南清除的影响。方法采用前瞻性观察性研究方法，选择2013年3月至2014年9月河北医科大学第四医院重症医学科收治的严重脓毒症合并急性肾损伤（AKI）重症感染的成人患者，且需要接受CRRT并以亚胺培南为主要抗菌药物治疗。所有患者接受亚胺培南0.5 g静脉滴注0.5 h，按随机数字表法分为间隔6 h或8 h给药组。对无禁忌者应用普通肝素抗凝，合并高出血风险者应用无抗凝策略。距首次给药24 h后，分别于输注亚胺培南0、0.25、0.5、0.75、1、2、5、6、8 h采集滤器后血标本和超滤液标本，应用液相色谱-串联质谱法（LC-MS/MS）测定标本中亚胺培南浓度。结果共入选25例患者，其中接受间隔6 h给药方案者13例，接受间隔8 h给药方案者12例；应用普通肝素抗凝者13例，无抗凝者12例。空白血浆及超滤液样品低、中、高3个浓度的日内和日间精密度、基质效应、回收率，以及不同条件下样品稳定性观察结果均显示良好，准确度误差控制在±15%范围内。应用Prismaflex血滤系统和AN69-M100血滤器，在CVVH模式下，置换液实际用量达到（31.63±1.48）mL·kg^-1·h^-1时，25例患者亚胺培南总清除率为（8.874±2.828）L/h，CRRT对体外亚胺培南总清除率为（2.211±0.539）L/h，占总清除率的（30.1±15.7）%。间隔6 h给药方案组血药浓度在4×最低抑菌浓度（MIC）为2、4、6、8μg/mL时，药物浓度维持时间能达到给药间隔时间40%以上；间隔8 h给药方案组血药浓度在4×MIC≥4μg/mL时，药物浓度维持时间占给药间隔时间的40%以下，与间隔6 h给药方案组比较差异有统计学意义〔4×MIC＝2μg/mL：（60.84±20.25）%比（94.01±12.46）%，t＝4.977，P＝0.001；4×MIC＝4μg/mL：（39.85±15.88）%比（68.74±9.57）%，t＝5.562，P＝0.000；4×MIC＝6μg/mL：（27.58±13.70）%比（53.97±8.36）%，t＝5.867，P＝0.000；4×MIC＝8μg/mL：（18.87±12.43）%比（43.48±7.83）%，t＝5.976， P＝0.000〕。无肝素抗凝组和普通肝素抗凝组亚胺培南筛选系数在短时间（6 h）内均无明显改变，说明血滤器对亚胺培南的清除不受抗凝因素的影响，经重复测量统计分析差异无统计学意义（F＝0.787，P＞0.05）。结论严重脓毒症合并AKI重症感染患者接受CRRT治疗时，在置换液实际用量为（31.63±1.48）mL·kg^-1·h^-1的CVVH模式下，亚胺培南体外清除效率增加，患者的血浆药物浓度会受到明显影响，为达到理想抗感染治疗效果需要调整给药方案；间隔给药时间的缩短可以提高患者血浆中亚胺培南的药物浓度；AN69-M100滤器对亚胺培南的清除在短时间内不受抗凝措施和时间因素的影响，不影响滤器对此药物的清除效率。
ObjectiveTo 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.Methods 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）.Results 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 8μg/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 4μg/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 = 2μg/mL： （60.84±20.25）%vs. （94.01±12.46）%,t = 4.977,P = 0.001; 4×MIC = 4μg/mL： （39.85±15.88）% vs. （68.74±9.57）%,t = 5.562, P = 0.000; 4×MIC = 6μg/mL： （27.58±13.70）% vs. （53.97±8.36）%,t = 5.867,P = 0.000; 4×MIC = 8μg/mL：（18.87±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）.ConclusionsThe 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.
出处
《中华危重病急救医学》
CAS
CSCD
北大核心
2015年第5期359-365,共7页
Chinese Critical Care Medicine
基金
河北省省级重大医学科研课题（zd2013034）
关键词
亚胺培南
血药浓度
最小抑菌浓度
清除
连续性肾脏替代治疗
感染
急性肾损伤
脓毒症
Imipenem
Plasma drug concentration
Minimal inhibitory concentration
Clearance
Continuous renal replacement therapy
Infection
Acute kidney injury
Sepsis
作者简介
通讯作者：胡振杰，Email：syicu@vip．sina．com
