USE OF A NOVEL INTRAVENOUS FAT PREPARATION IN THE MANAGEMENT OF INFANTS

新型静脉脂肪制剂在婴儿管理中的应用

• 批准号: 7950652
• 负责人: STEVEN A ABRAMS
• 金额: $ 1.19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950652
• 关键词: Accounting; Alkaline Phosphatase; Amino Acids; Apolipoprotein E; Apolipoproteins; Arachidonic Acids; Attenuated; Bacterial Translocation; Bile Acids; Biochemical; Blood Circulation; Calories; Caring; Cavia; Cessation of life; Childhood; Cholestasis; Cholesterol; Chylomicrons; Cirrhosis; Clinical Research; Complication; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Diet; Disease; Dose; Electrolytes; Emulsions; Energy Intake; Enrollment; Enteral; Enteral Nutrition; Enterocytes; Enzymes; Essential Fatty Acids; Etiology; Fat emulsion; Fatty Acids; Fatty acid glycerol esters; Feeds; Fibrosis; Frequencies; Funding; Glucose; Grant; Growth; Head circumference; Hepatic; Hepatotoxicity; High Density Lipoproteins; Histologic; Hormonal; Human; Hypertriglyceridemia; Incidence; Infant; Inflammation; Infusion procedures; Injury; Institution; Intake; Intestines; Intravenous; Intravenous Fat Emulsions; Length; Lipids; Lipoidosis; Lipolysis; Liver; Liver Failure; Liver diseases; Low Birth Weight Infant; Low Density Lipoprotein Receptor; Macronutrients Nutrition; Malnutrition; Micelles; Micronutrients; Mucous Membrane; Nutrient; Nutritional; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Operative Surgical Procedures; Parenteral Nutrition; Pathogenesis; Pathway interactions; Patients; Placebos; Population; Portal Venous System; Preparation; Prevention; Process; Proteins; Rattus; Refractory; Research; Research Personnel; Residual state; Resolution; Resources; Rickets; Risk Factors; Role; Route; Safety; Secondary to; Sepsis; Serum; Severities; Small Intestines; Solutions; Source; Starvation; Steatohepatitis; Structure; Supplementation; Time; Tissues; Total Parenteral Nutrition; Trace Elements; Transaminases; Transplantation; Treatment Protocols; Triglycerides; United States National Institutes of Health; Vitamins; Weaning; Weight; abstracting; base; gastrointestinal; high risk; intravenous administration; lipid biosynthesis; lipoprotein lipase; liver transplantation; novel; nutrition; open label; particle; premature; prevent; research study; success; theories; total measurement Bilirubin; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT: We propose to determine the efficacy of a novel intravenous lipid preparation in the management of infants with cholestasis. In this study, we aim to determine if changing from an omega-6 predominant product to an omega-3 predominant product will decrease the severity of existing cholestasis related to the use of intravenous nutrition (total parenteral nutrition, TPN). Omegaven, an omega-3 fatty acid-based lipid emulsion, will be intravenously infused at a dose of 1gm/kg/day until the infant is weaned from parenteral nutrition and for no longer than three months. This is an open-label study with no placebo needed. At the end of three months, the condition of the infant is evaluated, and Omegaven therapy may continue for an additional two months if needed. If the infant develops hypertriglyceridemia, the condition will be treated, and therapy will continue if the infant receives a transplant. HYPOTHESIS: Changing from an omega-6 predominant product to an omega-3 predominant product will decrease the severity of existing cholestasis related to the use of total parental nutrition in infants. Objective: To determine the short-term safety and obtain preliminary data related to the short-term efficacy of a novel intravenous lipid preparation in the management of infants with cholestasis who have a high risk of death or needing transplant. Primary endpoints include: death or transplant, number of episodes of sepsis, total bilirubin 60 days after enrollment and frequency of essential fatty acid deficiency. Secondary endpoints include: time to full feeds, evidence of rickets and resolution (maximum alkaline phosphatase activity) and growth in weight, length and head circumference. SPECIFIC AIMS: We aim to determine the efficacy of a novel intravenous lipid preparation in the management of infants with cholestasis. The experiment will help us to determine if changing from an omega-6 predominant product to an omega-3 predominant product will decrease the severity of existing cholestasis related to the use of intravenous nutrition (total parenteral nutrition). BACKGROUND AND SIGNIFICANCE Parenteral nutrition (PN) provides intravenous nutritional supplementation for patients unable to absorb adequate enteral nutrients secondary to insufficient intestinal length or function. PN contains the macronutrient building blocks of the human diet in their most elemental forms (amino acids and dextrose) and is commonly administered with a lipid emulsion to avoid essential fatty acid deficiency and to provide a calorically dense source of non-protein calories. In addition, PN contains the essential micronutrients (electrolytes, trace elements, and vitamins) to provide an optimal nutritional regimen. Before the development of PN in the late 1960 s, patients with insufficient gastrointestinal absorptive function commonly died of starvation and subsequent complications of malnutrition. Today, more than 30,000 patients are permanently dependent on parenteral nutrition for survival. However, PN continues to be associated with hepatic injury that occurs at an unpredictable rate and includes both biochemical, i.e., elevated serum aminotransferase and alkaline phosphatase, and histologic alterations such as steatosis, steatohepatitis, lipidosis, cholestasis, fibrosis, and cirrhosis. These abnormalities, which may worsen with the duration of PN administration, is more prevalent in the pediatric population. Additional risk factors for this condition include prematurity, low birth weight, long-term use of PN, the lack of concomitant enteral intake, sepsis, and multiple operative procedures. Although the pathological features of PN-induced liver injury have been well described, the etiology, prevention, and treatment of this complication are not well understood. Multiple hypotheses exist to explain the pathogenesis of PN-induced liver injury including altered gut hormonal profiles, the propensity for bacterial translocation in the absence of enteral intake, intestinal stasis resulting in the reduced clearance of hepatotoxic bile acids, and direct deficiencies or toxic components of the PN solution itself resulting in excessive glucose calorie uptake, excessive lipid infusion, or nutritional deficiencies such as essential fatty acid deficiency. None of these theories has been confirmed consistently. The etiology of PN-associated hepatotoxicity is currently considered multifactorial. Available treatment options for this disease process are limited and have achieved moderate success at best. Care of the PN-dependent patient is focused on gradually increasing enteral caloric intake as the residual bowel adapts allowing PN to be discontinued. In fact, it has been shown both experimentally and clinically that partial enteral nutrition, when tolerated, helps to protect against the development of PN-associated liver injury. In severe cases of refractory hepatic failure, liver transplantation with or without accompanying small bowel transplantation remains the only treatment option. Role of Intravenous Fat Emulsion on PN Associated Liver Disease: Recent evidence demonstrates that lipids are metabolized differently depending on their route of administration. Enteral lipids are absorbed by the enterocyte in the small bowel mucosa in the form of a micelle and packaged into chylomicrons which are released into the portal venous system for ultimate uptake and disposal in the liver. Once in the bloodstream, these particles rapidly acquire apolipoproteins from circulating high-density lipoproteins and can subsequently be metabolized by the liver. The emulsified particles of commercially made and intravenously administered lipid emulsions, such as Intralipid¿, mimic the size and structure of chylomicrons, but differ in their content. In contrast to chylomicrons, artificial lipid particles primarily contain essential fatty acids and omega-6 triglycerides and are devoid of cholesterol or protein. Recent studies suggest that these omega-6 fatty acid-containing emulsions are dependent on lipoprotein lipase, apolipoprotein E, and low-density lipoprotein receptors for clearance, and are metabolized with less lipolysis and release of essential fatty acids than are chylomicrons. In fact, it appears that they may be cleared as whole particles by tissues other than the liver. These factors may account for the increased incidence of steatohepatitis associated with the intravenous administration of Intralipid¿. The mechanism of clearance of omega-3 fatty acid containing lipid emulsions is unknown, but appears to be largely independent of the pathways identified above. Furthermore, omega-3 fatty acid solutions have been shown to decrease de novo lipogenesis, prevent or attenuate PN-induced hepatosteatosis in rats and guinea pigs and ameliorate the severity of high-fat diet-induced hepatosteatosis in rats. In addition, omega-3 fatty acids can interfere with the arachidonic acid pathway of inflammation. They can displace arachidonic acid from tissue fatty acid pools, thereby reducing the availability for eicasanoid-synthesizing enzymes and inflammation.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 摘要：我们建议确定一种新型静脉脂质制剂在胆汁淤积婴儿治疗中的有效性。在这项研究中，我们旨在确定是否从omega-6主要产物转变为omega-3主要产物将降低与使用静脉营养（总父母营养，TPN）有关的现有胆汁淤积的严重程度。 Omegaven是一种欧米茄3脂肪酸的脂质乳液，将以1gm/kg/day的剂量静脉注入，直到婴儿从父母的营养中断奶并且不超过三个月。这是一项不需要安慰剂的开放标签研究。在三个月结束时，评估了婴儿的状况，如果需要，omegaven疗法可能会持续两个月。如果婴儿发展出高甘油三酸酯血症，则将治疗该疾病，如果婴儿接受移植，则将继续治疗。 假设： 从omega-6主要产物转变为omega-3的主要产物将减少与婴儿总父母营养有关的现有胆汁淤积的严重程度。 目的：确定短期安全性并获得与新型静脉脂质制剂在管理胆汁淤积患者管理高死亡风险或需要移植的婴儿中的短期有效性有关的初步数据。 主要终点包括：死亡或移植，败血症的发作数量，入学后60天的总胆红素和必需脂肪酸缺乏频率。 次要终点包括：完整饲料的时间，风险和分辨率的证据（最大的酒精磷酸酶活性）以及体重，长度和头部循环的增长。 具体目的：我们旨在确定新型静脉脂质制剂在胆汁淤积婴儿治疗中的有效性。该实验将帮助我们确定从omega-6主要产物变为omega-3主要产物是否会降低与使用静脉营养相关的现有胆汁淤积的严重程度（总肠胃外营养）。 背景和意义 肠胃外营养（PN）为无法吸收其长度或功能不足的足够肠内营养的患者提供静脉营养补充。 PN包含人类饮食中最元素的形式（氨基酸和葡萄糖）的大型营养素构建区，通常用脂质乳液给药，以避免必要的脂肪酸缺乏症，并提供非蛋白质卡路里的热量致密来源。此外，PN含有必需的微量营养素（电解质，微量元素和维生素），以提供最佳的营养方案。在1960年代后期PN发展之前，胃肠道吸收功能不足的患者通常死于饥饿和随后的营养不良并发症。如今，超过30,000名患者永久依赖于父母的营养来生存。然而，PN继续与以不可预测的速率发生的肝损伤有关，包括生化，即血清氨基转移酶和酒精磷酸酶升高，以及组织学改变，例如脂肪变性，脂肪性肝炎，脂肪性肝炎，脂肪性疾病，脂肪症，胆汁疾病，纤维化，纤维化和cirrhsosis。这些异常在PN给药持续时间内可能很糟糕，在小儿人群中更为普遍。这种情况的其他风险因素包括早产，低出生体重，长期使用PN，缺乏伴随的肠内摄入量，败血症和多种操作程序。 尽管已经很好地描述了PN诱导的肝损伤的病理特征，但对这种并发症的病因，预防和治疗尚未得到充分了解。 Multiple hypotheses exist to explain the pathogenesis of PN-induced liver injury including altered gut hormonal profiles, the promise for bacteria translocation in the absence of enteral intake, intestinal stasis resulting in the reduced clearance of hepatotoxic bile acids, and direct deficiencies or toxic components of the PN solution itself resulting in excess glucose calorie uptake, excessive lipid infusion,或营养缺乏，例如必需脂肪酸缺乏。这些理论均未得到一致确认。当前认为与PN相关的肝毒性的病因被认为是多因素。此疾病过程的可用治疗选择是有限的，并且充其量至多取得了适度的成功。对PN依赖性患者的护理实际上逐渐地着重于实验和临床上表明，部分肠内营养在耐受性时有助于防止与PN相关的肝损伤的发展。在严重的难治性肝衰竭的情况下，有或没有参与小肠移植的肝移植仍然是唯一的治疗选择。 静脉脂肪乳液对PN相关肝病的作用： 最近的证据表明，脂质根据其给药途径而被不同的代谢。肠脂质被肠肠细胞以胶束的形式吸收在小肠粘膜中，并包装成酪蛋白，这些乳清细胞被释放到门户静脉系统中，以最终吸收和处置肝脏。进入血液后，这些颗粒从循环的高密度脂蛋白中迅速获取载脂蛋白，随后可以通过肝脏代谢。商业制造和静脉内施用的脂质乳液的乳化颗粒，例如内脂质，模仿乳糜微粒的大小和结构，但其含量不同。与乳糜微粒相反，人造脂质颗粒主要含有必需的脂肪酸和omega-6甘油三酸酯，并且没有胆固醇或蛋白质。最近的研究表明，这些含脂肪酸乳酸的乳液取决于脂蛋白脂肪酶，载脂蛋白E和低密度脂蛋白受体的清除率，并且与胆小性相比，脂解和必需脂肪酸的释放较少。实际上，似乎可以通过肝脏以外的组织将它们清除为整个颗粒。这些因素可能是与静脉内静脉内给药有关的脂肪性肝炎的发生率增加。 含有脂质乳液的omega-3脂肪酸清除的机理尚不清楚，但似乎在很大程度上与上述途径无关。此外，已经证明omega-3脂肪酸溶液可降低从头脂肪生成，预防或减轻大鼠和豚鼠的PN诱导的肝脏造成的肝脏造成的肝脏造成的肝脏造成的肝脏造成的肝脏造成的肝脏造成的肝脏造成的，并改善了大脂饮食诱导的大鼠肝运动的严重程度。另外，omega-3脂肪酸会干扰炎症的花生四烯酸途径。它们可以从组织脂肪酸池中置换蛛网膜酸，从而降低二十烷酸合成酶和炎症的可用性。