文献学习1 | ECMO治疗的重症患者中，阿米卡星峰浓度不足的预测因素

BACKGROUND

• Little is known about the inpact of ECMO on PK, antibiotic administration is challenging.
  

• Available data are actually limited to animals, simulated ex-vivo, or small retrospective human studies.

• Amikacin has good bactericidal activity against pseudomonas aeruginosa and low resistance rate.

• Antibacterial effect of amikacin is determined by Cmax/MIC ( optimal antibacterial activity obtained with 8-10).

• Amikacin Cmax range should be 60-80mg/L.（法国指南推荐>60mg/L，中国药品说明书56-64mg/L）.

• An amikacin dose of 25 mg/kg TBW, only 67-72% of ICU patients have been found to achieve that objective.

PURPOSE

• To determine the frequency and identify factors predictive of insufficient amikacin Cmax in critically ill patients on ECMO.

• To analyze the probability of attaining the established PK target ( 68-80mg/L).

METHODS

• Prospectively included all consecutive patients from 2015-1 to 2016-2.

• Intravenous amikacin loading dose on VV or VA  ECMO.

• Only the first dose was studied.

• Exclusion criteria.

• Incorrect amikacin regimen (<23 or="">27mg/kg TBW ).

• Incorrect time of amikacin infusion( ±5 min ).

• Incorrect time ( ±5 min ) or absence of Cmax determination.

• Incorrect time of Cmin determination( ±1h ) were excluded if Cmax had been obtained correctly.

• Amikacin: 25mg/kg TBW, diluted in 50mL of 0.9% NaCl, infused over 30 min.

• Weight >120 kg, amaximum of 120 kg was the loading dose ( 5 ).

• Cmax 30min after infusion ended.
  

• Cmin 24 h after infusion ended.
  

•  Fluorescence-polarization immunoassay to determine amikacin concentrations, as a routine procedure available 24h/day, 7 days/week.

METHODS —data collection

• Demographic data.

• Simplified acute physiology score (SAPS) II.
  

•  Reason for ECMO.
  

• ECMO-membrane duration “the delay between membrane first use and the time of amikacin infusion”.
  

• Organ dysfunction an inclusion.
  

• SOFA score.
  

• Laboratory tests.
  

• Inotrope score  [DA+NE+E dose(γ/kg/min)]*100.
  

• 24-h fluid balance=intake-output over 24 h before infusion.
  

• Proteinemia and hematocrit changes = (X0h – X24h)/(X0h + X24h)/2.
  

• Renal function KDIGO classification, ARF = KDIGO ≥ 2.
  

• Infection sites and pathogens.

RESULTS

    39% recevied amikacin loading dose

• Infection sites: lung 77%, cannula 14%.
  

• Pathogens: P. aeruginosa, Enterobacter spp. , escherichia coli.

Factors predictive of Cmax<60 mg/L

• Univariable analyses selected: BMI, higher AST or/and ALT, lower proteinemia, lower HCT, positive 24-h fluid balance.

• Multivariable analyses: independently associated with a higher risk of Cmax < 60mg/L.

• BMI < 22 kg/m2(OR, 6.38; 95% CI, 1.79-22.77; p=0.043).

• 24-h fluid balance(OR, per 550-mL increment, 1.28; 95% CI, 1.05-1.65; p=0.041).

• 出入量和Cmax < 60mg/L风险呈线性相关。

• Probability reached > 60% when 24-h fluid balance exceeded 2000mL.

• 未发现Cmax < 60mg/L和ECMO种类、流量、膜持续时间相关。

Factors predictive of Cmax>80 mg/L

• Univariable analyses: higher BMI, ECMO flow, dialysis, higher HCT.

• 24-h fluid balance was forced into the logistic regression.

• Multivariable analyses: independently associated with a higher risk of Cmax > 80mg/L.

• BMI > 22 kg/m2(OR, 1.10; 95% CI, 1.03-1.18; p=0.0037).

Dosing Simulations

• 根据测量的Cmax和药物公斤体重剂量，根据文献，假设阿米卡星PK是线性的，以模拟其他药物剂量时的Cmax。

• 出入量正平衡患者增加amikacin剂量至30mg/kg，可能降低低峰浓度风险至28%。

• 当增加amikacin至30-35mg/kg，出入量正平衡，BMI无论是多少，42%患者可能达到靶峰浓度，23%患者可能amikacin峰浓度仍不足。

OUTCOME

• Mortality 54%。
  

• 11 survivors AKI，与非AKI患者相比Cmax无明显差。
  

• ICU mortality和不足的Cmax或过高的Cmin无明显相。
  

•  ICU mortality在Cmax<60，60-80，>80之间无明显差异（59%，52%，51%）。

DISCUSSION

• 146例重症患者，其中15%为ECMO患者。
  

• 33%患者Cmax不足60mg/L。
  

• 预测Cmax不足的独立危险因素：BMI<25kg/m2及24小时出入量正平衡。

• ECMO患者，膜肺、入量多、疾病严重都会引起Vd增加，但本研究与重症患者药物浓度不足比例相似。

• 46例ECMO患者的队列研究发现，与非ECMO的重症患者相比，阿米卡星Cmax不足的比例相当。

• 作者推测，重症患者因sepsis、低白蛋白血症、低胶体渗透压，血管内液体向组织间隙中转移增加，最终可增加药物的Vd。
  

• 低BMI是Cmax不足的预测因素，与既往报道一致。

• 高BMI与Cmax >80mg/L独立相关，高BMI患者使用实际体重剂量可能高估阿米卡星的Vd。

• 体重和阿米卡星的Vd相关性较差，因此调整肥胖患者的体重，譬如理想体重或调整体重，可能会有不同的结果。

LIMITATIONS

• 单中心，ECMO患者多，不能代表其他中心。

• ECMO患者是VV、VA混合，基础病及预后均不相同，若根据基础病做亚组分析应有意义，但本研究多因素分析在亚组中不能找到预测峰浓度不足的因素。

• 合并用药也可能对AKI造成影响。

• 剂量模拟基于阿米卡星线性PK，其中出入量正平衡、BMI低亚组患者少，仅有11人。

• 不能除外阿米卡星附着在ECMO膜上。

CONCLUSIONS

• 使用ECMO治疗的重症患者，当阿米卡星25mg/kg体重使用时，1/3患者药物峰浓度不足60mg/L。

• 在低体重及出入量正平衡的ECMO患者中，增加阿米卡星剂量至35mg/kg，可能达到足够的药物峰浓度，需进一步研究。

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