Supplementary Material for: MR Spectroscopy Shows Long Propylene Glycol Half-Life in Neonatal Brain

Introduction: Neonatal propylene glycol (PG) clearance is low with long plasma half-life. We hypothesized that neonatal brain PG clearance is diminished and may be related to perinatal asphyxia, infection, or stroke, via different blood-brain barrier permeability. This study aimed to estimate cerebral PG half-life with a clearance model including PG measured with MR spectroscopy (MRS) in neonates that received phenobarbital as the only PG source and to evaluate whether PG clearance was related to intracerebral pathology, for example, perinatal asphyxia, infection, or stroke. Methods: In this retrospective cohort study, 45 neonates receiving any dose of phenobarbital underwent MRS (short echo time single-voxel MRS at 1.5 T). Cumulative phenobarbital/PG doses were calculated. MRS indications were perinatal asphyxia (n = 22), infection (n = 4), stroke (n = 10), metabolic disease (n = 4), and others (n = 5). Results: Medians (interquartile range) included gestational age 39.4 (3.1) weeks, birth weight 3,146 (1,340) g, and cumulative PG dose 700 (1,120) mg/kg. First-order kinetics with mono-exponential decay showed cerebral PG half-life of 40.7 h and volume of distribution of 1.6 L/kg. Zero-order kinetics showed a rate constant of 0.048 mM/h and a volume of distribution of 2.3 L/kg, but the fit had larger residuals than the first-order model. There were no differences in ΔPG (i.e., PG estimated with clearance model minus PG observed with MRS) in infants with perinatal asphyxia, infection, or stroke. Discussion/Conclusion: This study showed a long cerebral PG half-life of 40.7 h in neonates, unrelated to perinatal asphyxia, infection, or stroke. These findings should increase awareness of possible toxic PG concentrations in neonatal brain due to intravenous PG-containing drugs.

引言：新生儿丙二醇（propylene glycol, PG）清除率较低，血浆半衰期较长。本研究假设新生儿脑部丙二醇清除能力受损，且可能通过不同的血脑屏障（blood-brain barrier）通透性与围产期窒息、感染或脑卒中相关。本研究旨在通过对仅以苯巴比妥（phenobarbital）作为丙二醇唯一来源的新生儿进行磁共振波谱（MR spectroscopy, MRS）检测丙二醇水平，并结合清除模型估算脑部丙二醇的半衰期，同时评估丙二醇清除率是否与围产期窒息、感染或脑卒中等颅内病变相关。方法：本项回顾性队列研究（retrospective cohort study）中，45名接受任意剂量苯巴比妥治疗的新生儿接受了1.5T场强下的短回波时间（echo time）单体素磁共振波谱（single-voxel MRS）检测。研究人员计算了累积苯巴比妥/丙二醇给药剂量。本次磁共振波谱检测的适应证包括：围产期窒息（n=22）、感染（n=4）、脑卒中（n=10）、代谢性疾病（n=4）及其他病症（n=5）。结果：受试者的胎龄中位数（四分位距（interquartile range））为39.4（3.1）周，出生体重中位数为3146（1340）g，累积丙二醇给药剂量中位数为700（1120）mg/kg。采用单指数衰减（mono-exponential decay）的一级动力学（first-order kinetics）模型分析显示，脑部丙二醇半衰期为40.7小时，分布容积（volume of distribution）为1.6 L/kg。零级动力学（zero-order kinetics）模型的速率常数（rate constant）为0.048 mM/h，分布容积为2.3 L/kg，但该模型的拟合残差（residuals）大于一级动力学模型。在合并围产期窒息、感染或脑卒中的新生儿中，ΔPG（即通过清除模型估算的丙二醇浓度减去磁共振波谱实测的丙二醇浓度）无显著差异。讨论与结论：本研究显示新生儿脑部丙二醇半衰期长达40.7小时，且与围产期窒息、感染或脑卒中无关。上述研究结果应提高临床对静脉输注含丙二醇药物可能导致新生儿脑部丙二醇毒性浓度的警惕性。