柳叶刀：早期补充肠外营养的蛋白质越少越好？
前情提要
大型随机对照研究表明，成人和儿科重症监护室（PICU）患者早期补充肠外营养是有害的，能量（葡萄糖或脂肪）过多、蛋白质（氨基酸）过少是可能的原因。
2017年5月15日，英国《柳叶刀·呼吸医学》在线发表比利时荷语天主教鲁汶大学医院、荷兰鹿特丹伊拉斯谟大学医学中心索菲亚儿童医院、加拿大阿尔伯塔大学斯托雷儿童医院的研究报告，发现在儿科重症早期对比推迟肠外营养（PEPaNIC）随机研究中，氨基酸过多、葡萄糖或脂肪过少与早期补充肠外营养所致危害有相关性。
该研究的通讯作者，就是已在《新英格兰医学杂志》等国际顶级学术期刊发表过多项此类大样本随机对照研究的比利时天主教鲁汶大学医院细胞与分子医学系教授、重症医学实验室主任：格瑞特·范登堡（此姓又译：范登博格或大家熟知的凡登白）。
原随机对照研究（PEPaNIC）有7519例0～17岁儿童患者可被评定，排除其中6079例患者，其余1440例儿童于2012年6月18日～2015年7月27日被再次随机分组，723例接受早期补充肠外营养（定义为PICU收治24h内）、717例推迟肠外营养（定义为PICU收治1周后肠内营养不足时）。在这次再随机分组观察研究中，PICU收治前7天内输入的葡萄糖、脂肪、氨基酸剂量，按已公布临床指南相应年龄和体重参考剂量的百分比表示。使用多变量Cox比例风险模型，分析前7天宏量营养素每天平均剂量与PICU获得性感染率、早期撤呼吸机率、早期出监护室率的独立相关性，同步分析三种营养元素，并校正基线风险因素。
结果发现，随着氨基酸剂量的增加：
获得性新感染率升高（第1～5天氨基酸剂量每增加10%的校正风险比：1.043～1.134，P≤0.029）
早期撤呼吸机率降低（第3～7天氨基酸剂量每增加10%的校正风险比：0.950～0.975，P≤0.045）
早期出监护室率降低（第1～7天氨基酸剂量每增加10%的校正风险比：0.943～0.972，P≤0.030）
此外，氨基酸剂量低也存在有害风险。
相比之下：
第1～3天葡萄糖增加与获得性新感染率降低独立相关（校正风险比：0.870～0.913，P≤0.036）
第4～7天脂肪量增加与早期出监护室率升高独立相关（校正风险比：1.027～1.050，P≤0.043）
因此，这些相关性表明，早期给予氨基酸（而非葡萄糖或脂肪）或可解释重症儿童早期补充肠外营养所致危害。
对此，新加坡妇女儿童医院营养科和儿科重症监护室、新加坡国立大学杜克医学院的专家发表同期评论：重症儿童的蛋白质供给越少越好？
Lancet Respir Med. 2017 May 15. [Epub ahead of print]
Effect of early supplemental parenteral nutrition in the paediatric ICU: a preplanned observational study of post-randomisation treatments in the PEPaNIC trial.
Vanhorebeek I, Verbruggen S, Casaer MP, Gunst J, Wouters PJ, Hanot J, Guerra GG, Vlasselaers D, Joosten K, Van den Berghe G.
KU Leuven University Hospital, Leuven, Belgium; Erasmus MC, Sophia Children's Hospital, Rotterdam, Netherlands; University of Alberta, Stollery Children's Hospital, Edmonton, Canada.
BACKGROUND: Large randomised controlled trials have shown that early supplemental parenteral nutrition in patients admitted to adult and paediatric intensive care units (PICUs) is harmful. Overdosing of energy with too little protein was suggested as a potential reason for this. This study analysed which macronutrient was associated with harm caused by early supplemental parenteral nutrition in the Paediatric Early versus Late Parenteral Nutrition In Critical Illness (PEPaNIC) randomised trial.
METHODS: Patients in the initial randomised controlled trial were randomly assigned to receive suppplemental parenteral nutrition (PN) within 24 h of PICU admission (early PN) or to receive such PN after 1 week (late PN) when enteral nutrition was insufficient. In this post-randomisation, observational study, doses of glucose, lipids, and aminoacids administered during the first 7 days of PICU stay were expressed as % of reference doses from published clinical guidelines for age and weight. Independent associations between average macronutrient doses up to each of the first 7 days and likelihood of acquiring an infection in the PICU, of earlier live weaning from mechanical ventilation, and of earlier live PICU discharge were investigated using multivariable Cox proportional hazard analyses. The three macronutrients were included in the analysis simultaneously and baseline risk factors were adjusted for.
FINDINGS: From June 18, 2012, to July 27, 2015, 7519 children aged between newborn and 17 years were assessed for eligibility. 6079 patients were excluded, and 1440 children were randomly assigned to receive either early PN (n=723) or late PN (n=717). With increasing doses of aminoacids, the likelihood of acquiring a new infection was higher (adjusted hazard ratios [HRs] per 10% increase between 1.043-1.134 for days 1-5, p≤0.029), while the likelihood of earlier live weaning from mechanical ventilation was lower (HRs 0.950-0.975 days 3-7, p≤0.045), and the likelihood of earlier live PICU discharge was lower (HRs 0.943-0.972 days 1-7, p≤0.030). By contrast, more glucose during the first 3 days of PICU stay was independently associated with fewer infections (HRs 0.870-0.913, p≤0.036), whereas more lipids was independently associated with earlier PICU discharge (HRs 1.027-1.050, p≤0.043 days 4-7). Risk of harm with aminoacids was also shown for low doses.
INTERPRETATION: These associations suggest that early administration of aminoacids, but not glucose or lipids, could explain harm caused by early supplemental parenteral nutrition in critically ill children.
FUNDING: Flemish Agency for Innovation through Science and Technology; UZLeuven Clinical Research Fund; Research Foundation Flanders; Methusalem Programme Flemish Government; European Research Council; Fonds-NutsOhra; Erasmus-MC Research Grant; Erasmus Trustfonds.
PMID: 28522351
PII: S2213-2600(17)30186-8
DOI: 10.1016/S2213-2600(17)30186-8
Lancet Respir Med. 2017 May 15. [Epub ahead of print]
Protein provision in the critically ill child: is less more?
Ong C, Lee JH.
KK Women's and Children's Hospital, Singapore; Duke-NUS School of Medicine, Singapore.
The results of this analysis open more questions for paediatric critical care teams in an area that lacks robust data. The results suggest that high provision of aminoacids in the first few days of critical illness is potentially harmful, but is the effect the same throughout the course of paediatric critical illness? A stratified analysis of the PEPaNIC data according to early and late parenteral nutrition group could potentially address this issue. The authors did perform such an analysis and reported that provision of aminoacid did not reveal any benefit. Optimal timing of protein supplementation remains an important area on which to focus research efforts.
Many considerations remain with regard to optimal nutrition support in the critically ill child, including optimal route and doses of macronutrient supplementation, timing of such supplementation, and to whom this supplementation should be provided. This study reminds us of the complexity of nutrient metabolism and requirements in the critically ill child, and how much we still do not know. Further high-quality randomised controlled trials, supplemented with newer study approaches such as comparative effectiveness research strategies and adaptive trial designs are needed to inform nutritional practice recommendations in the PICU.
PMID: 28522350
DOI: 10.1016/S2213-2600(17)30175-3
