肾脏高溶质清除重症感染患者万古霉素合适初始剂量的临床研究

Clinical study of vancomycin for appropriate dosing in severe infective patients with augmented renalclearance

目的探讨肾脏高溶质清除（ARC）对重症感染患者万古霉素治疗达标的影响，分析基于12 h肌酐清除率（12 h-CLCR）的万古霉素初始剂量。方法采用回顾性观察性研究方法，选择2013年2月至2017年12月南京大学医学院附属鼓楼医院重症医学科（ICU）收治的采用万古霉素抗感染经验性治疗或目标性治疗的重症感染患者。纳入患者均采用万古霉素间断滴注方式治疗，6～12 h给药1次，4个或5个治疗剂量后，于下一次给药前取血检测万古霉素初始血清谷浓度（Cmin），目标浓度为15～20 mg/L。检测患者尿肌酐（UCr），计算CLCR。根据万古霉素治疗前12 h-CLCR将入选患者分为ARC组和非ARC组，12 h-CLCR〉130 mL·min-1·1.73 m-2定义为ARC。监测患者基础肾功能，记录患者万古霉素初始剂量和血药浓度达标时剂量。12 h-CLCR与血药浓度达标时万古霉素剂量和万古霉素血药浓度的相关性采用Spearman相关分析；并根据不同12 h-CLCR进行剂量分层分析；采用受试者工作特征曲线（ROC）评估12 h-CLCR对血药浓度达标时万古霉素剂量的预测价值。结果共收集135例重症感染患者数据，排除万古霉素治疗时间〈72 h、慢性肾脏病5期、入ICU前即开始万古霉素治疗、数据资料不完整者，最终102例患者纳入分析，平均12 h-CLCR为（114.31±73.38） mL·min-1·1.73 m-2；ARC组（44例，占43.14%）12 h-CLCR明显高于非ARC组（58例，占56.86%）（mL·min-1·1.73 m-2：179.37±59.04比65.95±35.71，P〈0.01）。50.98%（52/102）的患者万古霉素Cmin达标，ARC组患者达标率明显低于非ARC组〔29.55%（13/44）比67.24%（39/58），P〈0.01〕，而且万古霉素Cmin明显低于非ARC组（mg/L：10.98±6.09比14.67±6.20，P〈0.01）。Spearman相关分析显示，12 h-CLCR与万古霉素Cmin呈显著负相关（n＝102，r＝-0.436，P〈0.001），与血药浓度达标时万古霉素剂量则呈显著正相关（n＝52，r＝0.275，P＝0.048）。ARC组患者较非ARC组患者需要更高的万古霉素剂量才能使血药浓度达标（mg·kg-1·d-1：42.47±13.17比31.53±14.43，P〈0.01）。根据12 h-CLCR将初始治疗达标患者分为〈40、40～70、71～100、101～130和〉130 mL·min-1·1.73 m-2 5个亚组进行分层分析显示，随着12 h-CLCR增加，初始血药浓度达标时万古霉素剂量也相应增加；ROC曲线分析显示，当12 h-CLCR≥69.83 mL·min-1·1.73 m-2时，血药浓度达标时万古霉素剂量大于常规剂量（30 mg·kg-1·d-1）。结论发生ARC的重症感染患者万古霉素血药浓度低，常常无法实现治疗目标；万古霉素初始剂量可以根据12 h-CLCR选择，12 h-CLCR越高，万古霉素所需剂量越大；当12 h-CLCR≥69.83 mL·min-1·1.73 m-2时，万古霉素使用剂量应高于常规剂量。

ObjectiveTo explore the impact of augmented renal clearance （ARC） on vancomycin pharmacokinetic target attainment in severe infective patients, and to analyze the initial dose of vancomycin based on the measured 12-hour urinary creatinine clearance （12 h-CLCR）.MethodsA retrospective observational study was conducted. The patients with severe infection, who receiving vancomycin empiric or targeted therapy, admitted to intensive care unit （ICU） of the Affiliated Drum Tower Hospital of Nanjing University Medical School from February 2013 to December 2017 were enrolled. All patients were treated with vancomycin intravenously by intermittent bolus every 6-12 hours. After four or five doses, blood samples were drawn before the next dosage for serum trough vancomycin concentration （Cmin）, and target concentration was defined between 15 mg/L and 20 mg/L. The urine creatinine （UCr） was measured, and CLCR was calculated. ARC was defined as 12 h-CLCR 〉 130 mL·min-1·1.73 m-2. According to 12 h-CLCR before treatment, the patients were divided into ARC group and non-ARC group. The basic renal function of the patients was monitored, and the dosage of vancomycin and the dosage of vancomycin when the blood concentration reached the target were recorded. The correlations between 12 h-CLCR and the dosage of vancomycin when the blood concentration reached the target as well as the blood concentration of vancomycin were analyzed by Spearman correlation analysis. Dosage stratification analysis was carried out according to different 12 h-CLCR. The predictive value of 12 h-CLCR for vancomycin dosage when the blood concentration reached the target was evaluated by using the receiver operator characteristic curve （ROC）.ResultsData was provided from a total of 135 patients with severe infection, in which 102 patients met the inclusion criteria. The patients with vancomycin treatment duration less than 72 hours, chronic kidney disease Ⅴ phase, vancomycin treatment before entering ICU and those with incomplete data were excluded. The mean 12 h-CLCR was （114.31±73.38） mL·min-1·1.73 m-2. The 12 h-CLCR in ARC group （n = 44, 43.14%） was significantly higher than that in non-ARC group （n = 58, 56.86%） （mL·min-1·1.73 m-2： 179.37±59.04 vs. 65.95±35.71, P 〈 0.01）. Target Cmin of vancomycin was achieved in 50.98% of patients （52/102）, the target rate in ARC group was significantly lower than that in non-ARC group [29.55% （13/44） vs. 67.24% （39/58）, P 〈 0.01], and the Cmin of vancomycin in ARC group was significantly lower than that in non-ARC group （mg/L： 10.98±6.09 vs. 14.67±6.20, P 〈 0.01）. Spearman correlation analysis showed that there was a significantly negative correlation between 12 h-CLCR and initial Cmin of vancomycin （n = 102, r = -0.436, P 〈 0.001）, but a positive correlation was found between 12 h-CLCR and vancomycin dosage when the blood concentration reached the target （n = 52, r = 0.275, P = 0.048）. The patients with ARC need higher dosage for blood concentration reaching the target than those without ARC （mg·kg-1·d-1： 42.47±13.17 vs. 31.53±14.43, P 〈 0.01）. According to 12 h-CLCR, the patients with initial treatment reaching the target were divided into five subgroups, 〈 40, 40-70, 71-100, 101-130 and 〉 130 mL·min-1·1.73 m-2. The results showed that as 12 h-CLCR increased, the attained dosage of vancomycin was also increased correspondingly. ROC curve analysis showed that when 12 h-CLCR≥69.83 mL·min-1·1.73 m-2, the attained dose of vancomycin when the blood concentration reached the target was greater than conventional dosage of 30 mg·kg-1·d-1.ConclusionsPatients with ARC have low concentrations of vancomycin and often fail to achieve therapeutic target. The initial dose of vancomycin can be selected according to 12 h-CLCR, the higher the 12 h-CLCR, the more the dosage of vancomycin is. When 12 h-CLCR is greater than or equal to 69.83 mL·min-1·1.73 m-2, the dosage of vancomycin should be higher than the conventional dosage.