Supplementary Material for: A Double-Blind Randomised Controlled Trial of Fish Oil-Based versus Soy-Based Lipid Preparations in the Treatment of Infants with Parenteral Nutrition-Associated Cholestasis

Background: Infants receiving prolonged parenteral nutrition (PN) are at risk of PN-associated cholestasis (PNAC). This can progress to hepatic failure and death if PN cannot be discontinued. Fish oil-based parenteral lipid preparation (FOLP) has been shown to be beneficial in case studies. Objectives: (1) To evaluate whether FOLP could halt or reverse the progression of PNAC compared with soy-based parenteral lipid preparation (SLP) and (2) to assess the effects of FOLP on liver function and physical growth. Methods: Design: double-blind randomised controlled trial. Setting: level III neonatal intensive care unit. Participants: infants with PNAC (plasma-conjugated bilirubin concentration ≥34 µmol/l or 2 mg/dl) expected to be PN-dependent for >2 weeks. Intervention: to receive either FOLP or SLP at 1.5 g/kg/day. Primary outcome measure: reversal of PNAC within 4 months after commencement of lipid treatment; secondary outcomes: rate of change of weekly liver function tests, infant growth parameters, blood lipid profile and episodes of late-onset sepsis. Results: A total of 9 infants were randomised to the FOLP group and 7 to the SLP group. There was no significant difference in reversal of PNAC at 4 months between groups. Rates of increase of plasma-conjugated bilirubin and alanine aminotransferase in the SLP group were significantly greater than the FOLP group (13.5 vs. 0.6 µmol/l per week and 9.1 vs. 1.1 IU/l per week, respectively, p = 0.03). Increased enteral nutrition was associated with significant improvement of PNAC in infants receiving FOLP compared with SLP (-8.5 vs. -1.6 µmol/l per 10% increase in enteral nutrition, respectively). The study was terminated prematurely. Conclusions: progression of PNAC in PN-dependent infants can be halted by replacing SLP with FOLP and reversed by increasing the proportion of enteral nutrition in infants receiving FOLP. Replacement of SLP with FOLP in PN-dependent infants who develop PNAC may be considered.

背景：接受长期肠外营养（parenteral nutrition, PN）的婴儿存在肠外营养相关胆汁淤积症（PN-associated cholestasis, PNAC）的发病风险。若无法停用肠外营养，该病可进展为肝衰竭甚至死亡。现有案例研究显示，鱼油基肠外脂质制剂（fish oil-based parenteral lipid preparation, FOLP）具有治疗获益。研究目标：（1）对比鱼油基肠外脂质制剂与大豆基肠外脂质制剂（soy-based parenteral lipid preparation, SLP），评估前者是否能够阻断或逆转肠外营养相关胆汁淤积症的病情进展；（2）评估鱼油基肠外脂质制剂对肝功能与体格生长的影响。研究方法：试验设计为双盲随机对照试验。研究场景为三级新生儿重症监护病房。研究对象为预计需依赖肠外营养超过2周的肠外营养相关胆汁淤积症患儿（血浆结合胆红素浓度≥34 µmol/l或2 mg/dl）。干预措施为受试者以1.5 g/kg/天的剂量接受鱼油基肠外脂质制剂或大豆基肠外脂质制剂治疗。主要结局指标为脂质治疗开始后4个月内肠外营养相关胆汁淤积症得到逆转；次要结局指标包括每周肝功能指标的变化速率、婴儿生长参数、血脂谱以及晚发型败血症（late-onset sepsis）发作情况。研究结果：共计9名婴儿被随机分配至FOLP组，7名分配至SLP组。两组患儿在治疗4个月后PNAC逆转率无显著差异。SLP组患儿的血浆结合胆红素与丙氨酸氨基转移酶（alanine aminotransferase）升高速率显著高于FOLP组（分别为每周13.5 vs. 0.6 µmol/l、每周9.1 vs. 1.1 IU/l，p = 0.03）。与SLP组相比，接受FOLP的患儿中，肠内营养摄入量增加与PNAC的显著改善相关（肠内营养每增加10%，血浆结合胆红素分别下降8.5 vs. 1.6 µmol/l）。本研究提前终止。研究结论：对于依赖肠外营养的婴儿，将SLP替换为FOLP可阻断PNAC的病情进展；而在接受FOLP的患儿中，提升肠内营养占比可逆转该病病情。对于发生PNAC的依赖肠外营养婴儿，可考虑将其大豆基肠外脂质制剂替换为鱼油基肠外脂质制剂。