Liu Ji Tong, Brown Caitlin S, Mara Kristin C, Riker Richard R, Rabinstein Alejandro A, Fraser Gilles L, May Teresa L, Armstrong Kaitlin J, Seder David B, Gagnon David J
Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA.
Department of Pharmacy, Mayo Clinic, Rochester, MN.
Crit Care Explor. 2023 Oct 18;5(10):e0987. doi: 10.1097/CCE.0000000000000987. eCollection 2023 Oct.
Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients.
We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations.
Retrospective cohort study.
Two academic medical centers.
Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022.
Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared.
Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, -13.6 to 14.2]) than the Nasreddine (-9.2 [-26.5 to 8.2]), Kodama (-9.7 [-30.0 to 10.7]), Conde Giner (-7.9 [-24.9 to 9.1]), and Parent (-9.9 [-30.7 to 11.0]) equations, and similar to Doré (-2.0 [-16.0 to 11.9]). The Doré and new equations had the highest therapeutic concordance rate (73%).
For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.
丙戊酸盐的蛋白结合在重症监护病房（ICU）患者中存在差异，会改变具有生物活性的游离丙戊酸盐浓度（VPAC）。只有少数实验室能检测游离VPAC，且其结果常与总VPAC不一致。现有的预测游离VPAC的公式要么未经验证，要么在ICU患者中不准确。
我们设计本研究以推导并验证一个使用ICU患者数据预测游离VPAC的新公式，并将其性能与已发表的公式进行比较。
回顾性队列研究。
两个学术医疗中心。
2014年至2018年入院的18岁以上且在ICU同时检测了游离和总VPAC的患者纳入推导队列，2019年至2022年入院的患者纳入验证队列。
采用多变量线性回归推导预测游离VPAC的公式。比较改良的布兰德 - 奥特曼图以及实测和预测的游离VPAC之间的治疗一致性率。
推导队列中的115例患者和验证队列中的147例患者在人口统计学、游离和总VPAC中位数以及丙戊酸盐游离分数方面相似。布兰德 - 奥特曼图显示新公式表现优于纳瑟丁公式（偏差为0.3[95%一致性界限，-13.6至14.2]）、儿玉公式（-9.2[-26.5至8.2]）、康德·吉纳公式（-7.9[-24.9至9.1]）和帕伦特公式（-9.9[-30.7至11.0]），与多雷公式（-2.0[-16.0至11.9]）相似。多雷公式和新公式的治疗一致性率最高（73%）。
对于存在蛋白结合改变风险的患者，如ICU患者，现有的预测游离VPAC的公式与实测的游离VPAC不一致。一个新公式偏差较小但不够精确。应进行外部验证以提高其精度和可推广性。在此之前，建议在危重症期间监测游离丙戊酸盐。
