一种新的校正方程可避免危重症患者苯妥英治疗药物监测中出现高幅度误差。
A Novel Correction Equation Avoids High-Magnitude Errors in Interpreting Therapeutic Drug Monitoring of Phenytoin Among Critically Ill Patients.
机构信息
Department of Pharmacy, Massachusetts General Hospital.
Division of Neurocritical Care, Massachusetts General Hospital; and.
出版信息
Ther Drug Monit. 2020 Aug;42(4):617-625. doi: 10.1097/FTD.0000000000000739.
BACKGROUND
Phenytoin has a narrow therapeutic index and the potential of under-treatment or toxicity. Available equations are used to correct for the impact of hypoalbuminemia on unbound (free) phenytoin levels. The authors aimed to determine the accuracy of equations used to estimate free phenytoin in hospitalized patients and assess the impact of using additional clinical data.
METHODS
Concurrently measured total and free phenytoin levels in hospitalized patients (2014-2018) were retrospectively evaluated, excluding those from patients on renal replacement therapy and valproic acid. Differences between actual and estimated free phenytoin levels by the original (Original WTZ), Anderson-modified, and Kane-modified Winter-Tozer equations were assessed using Pearson correlations and Bland-Altman analysis. Thereafter, a population-derived formula was developed and validated in a testing cohort.
RESULTS
In the 4-year training cohort (n = 81), the Original WTZ equation had the smallest mean difference of all equations. A higher mean difference [-0.362 mcg/mL (95% CI -0.585 to -0.138) vs. -0.054 mcg/mL (95% CI -0.186 to 0.078)] was observed in intensive care unit (ICU) patients compared with non-ICU patients. A cross-validated multivariable model improved the accuracy of free phenytoin estimation in ICU and non-ICU patients, even in the separate testing cohort (n = 52) with respective mean differences of -0.322 mcg/mL (95% CI -0.545 to -0.098) and -0.025 mcg/mL (95% CI -0.379 to 0.329) and was superior to the Original WTZ [mean difference -0.858 mcg/mL (95% CI -1.069 to -0.647) vs. -0.106 mcg/mL (95% CI -0.362 to 0.151), respectively].
CONCLUSIONS
Free phenytoin levels in hospitalized patients cannot be accurately determined using available estimation equations, particularly in critically ill patients. Combining ICU status and other available clinical data can improve therapeutic drug monitoring and prevent high-magnitude errors, particularly when free phenytoin assays are not readily available.
背景
苯妥英的治疗指数较窄，有治疗不足或中毒的风险。现有的公式可用于校正低白蛋白血症对未结合（游离）苯妥英水平的影响。作者旨在确定用于估算住院患者游离苯妥英的公式的准确性，并评估使用额外临床数据的影响。
方法
回顾性评估 2014 年至 2018 年住院患者的总游离苯妥英浓度（同时测量），排除接受肾脏替代治疗和丙戊酸的患者。使用 Pearson 相关性和 Bland-Altman 分析评估原始（Original WTZ）、Anderson 修正和 Kane 修正 Winter-Tozer 公式实际与估计的游离苯妥英水平之间的差异。然后，在测试队列中开发并验证了一个基于人群的公式。
结果
在 4 年的训练队列（n=81）中，所有公式中 Original WTZ 方程的平均差异最小。与非 ICU 患者相比，ICU 患者的平均差异较大[-0.362 mcg/mL（95%CI-0.585 至-0.138）与-0.054 mcg/mL（95%CI-0.186 至 0.078）]。在 ICU 和非 ICU 患者中，经过交叉验证的多变量模型提高了游离苯妥英估计的准确性，即使在分别的测试队列（n=52）中，平均差异分别为-0.322 mcg/mL（95%CI-0.545 至-0.098）和-0.025 mcg/mL（95%CI-0.379 至 0.329），也优于 Original WTZ[平均差异-0.858 mcg/mL（95%CI-1.069 至-0.647）与-0.106 mcg/mL（95%CI-0.362 至 0.151）]。
结论
现有的估算方程不能准确确定住院患者的游离苯妥英水平，尤其是在危重症患者中。结合 ICU 状态和其他可用的临床数据可以改善治疗药物监测，防止出现高幅度误差，特别是当游离苯妥英检测不可用时。
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