Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
Intensive Care Unit, Department of Pediatrics and Pediatric Surgery, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
Clin Epigenetics. 2021 Jul 27;13(1):146. doi: 10.1186/s13148-021-01124-3.
The PEPaNIC multicenter randomized controlled trial (RCT) has shown that early administration of supplemental parenteral nutrition (early-PN) as compared with withholding PN for 1 week (late-PN) induced long-term internalizing, externalizing and total emotional/behavioral problems in critically ill children, as observed 4 years later. Early-PN was further shown to alter the methylation status of 37 CpG-sites in leukocyte DNA between admission and discharge from the pediatric intensive care unit (PICU). In a preplanned subanalysis of the PEPaNIC trial, we now investigated whether the altered methylation of these CpG-sites could statistically explain the negative impact of early-PN on emotion/behavior documented 4 years after PICU admission.
The combination of DNA methylation data and data on behavior 4 years after PICU admission was available for 403 of the 1440 patients (aged 0-17 years at PICU admission) who were included in the PEPaNIC RCT (192 early-PN and 211 late-PN patients). Mediation analyses with use of bootstrapped multivariable non-linear regression analyses adjusted for baseline risk factors revealed that the adverse alterations by early-PN in methylation of the 37 CpG-sites together statistically explained its harmful impact on internalizing, externalizing and total emotional/behavioral problems. When adding the methylation status of the 37 CpG-sites to the models, the explanatory power improved with a 1.710 to 1.851-fold increase, and the impact of the altered methylation status of the CpG-sites explained the impact of the randomization to early-PN versus late-PN.
Abnormal DNA methylation induced by the early use of PN in the PICU provides a biological basis for its long-term harmful effect on emotion/behavior of critically ill children 4 years after PICU admission. Trial Registration ClinicalTrials.gov NCT01536275, registered February 17, 2012, https://clinicaltrials.gov/ct2/show/NCT01536275 .
PEPaNIC 多中心随机对照试验（RCT）表明，与延迟至 ICU 后 1 周再给予肠外营养（延迟 PN）相比，早期给予补充肠外营养（早期 PN）可导致 ICU 后 4 年时危重症患儿出现长期的内化、外化和总体情绪/行为问题。早期 PN 还进一步改变了入住儿科 ICU（PICU）时与 PICU 出院时之间白细胞 DNA 中 37 个 CpG 位点的甲基化状态。在 PEPaNIC 试验的一项预先计划的亚分析中，我们现在研究了这些 CpG 位点的甲基化改变是否可以从统计学上解释早期 PN 对 ICU 后 4 年时记录的情绪/行为的负面影响。
PEPaNIC RCT 中纳入的 1440 例患者（入 ICU 时年龄 0-17 岁）中有 403 例患者（192 例接受早期 PN，211 例接受延迟 PN）可获得 ICU 后 4 年时的 DNA 甲基化数据和行为数据。使用 bootstrap 多变量非线性回归分析调整基线风险因素进行中介分析显示，早期 PN 导致的 37 个 CpG 位点的甲基化不良改变共同从统计学上解释了其对内化、外化和总体情绪/行为问题的有害影响。当将 37 个 CpG 位点的甲基化状态添加到模型中时，解释能力提高了 1.710 至 1.851 倍，并且 CpG 位点的甲基化改变的影响解释了早期 PN 与延迟 PN 随机分组的影响。
PICU 中早期使用 PN 引起的异常 DNA 甲基化为其在 ICU 后 4 年对危重症患儿情绪/行为的长期有害影响提供了生物学基础。
ClinicalTrials.gov NCT01536275，注册于 2012 年 2 月 17 日，https://clinicaltrials.gov/ct2/show/NCT01536275。
Zotero 插件