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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 摘要：我们打算确定一种新型静脉脂质制剂在治疗婴儿胆汁淤积方面的功效。在这项研究中，我们的目的是确定从以 omega-6 为主的产品改为以 omega-3 为主的产品是否会降低严重程度。与使用静脉营养（全肠外营养，TPN）相关的现有胆汁淤积，Omegaven，一种基于 omega-3 脂肪酸的脂肪乳剂，将通过静脉注射来解决。以 1 克/公斤/天的剂量输注，直至婴儿断奶，持续时间不超过三个月。这是一项开放标签研究，无需安慰剂。三个月后，根据婴儿的状况进行研究。进行评估，如果需要，Omegaven 治疗可能会再持续两个月。如果婴儿出现高甘油三酯血症，则病情将得到治疗，如果婴儿接受移植，治疗将继续。 假设： 从以 omega-6 为主的产品改为以 omega-3 为主的产品将减轻与婴儿使用全肠外营养相关的现有胆汁淤积的严重程度。 目的：确定新型静脉脂质制剂治疗高死亡风险或需要移植的胆汁淤积婴儿的短期安全性并获得与短期疗效相关的初步数据。 主要终点包括：死亡或移植、败血症发作次数、入组后 60 天的总胆红素以及必需脂肪酸缺乏的频率。 次要终点包括：完全进食的时间、佝偻病的证据和缓解（最大碱性磷酸酶活性）以及体重、身长和头围的增长。 具体目标：我们的目标是确定新型静脉脂质制剂在治疗婴儿胆汁淤积方面的功效。该实验将帮助我们确定从以 omega-6 为主的产品改为以 omega-3 为主的产品是否会降低严重程度。现有的胆汁淤积与使用静脉营养（全肠外营养）有关。 一、背景及意义 肠外营养 (PN) 为因肠道长度或功能不足而无法吸收足够肠内营养的患者提供静脉营养补充，PN 包含人类饮食中最基本形式的大量营养素（氨基酸和葡萄糖），并且通常施用。含有脂肪乳剂，以避免必需脂肪酸缺乏，并提供热量密集的非蛋白质热量来源。此外，PN 还含有必需的微量营养素（电解质、微量元素和维生素），以提供所需的能量。在 20 世纪 60 年代末出现 PN 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 名患者永久依赖肠外营养生存。与肝损伤有关，肝损伤以不可预测的速度发生，包括生化损伤，即血清转氨酶和碱性磷酸酶升高，脂肪变性、脂肪性肝炎、脂肪沉积、胆汁淤积、纤维化和肝硬化等组织学改变在儿科人群中更为常见，这些异常可能会随着 PN 给药的持续时间而恶化。体重、长期使用 PN、缺乏伴随的肠内摄入、脓毒症和多次手术程序。 尽管 PN 诱发的肝损伤的病理特征已得到很好的描述，但该并发症的病因、预防和治疗尚不清楚，但存在多种假说来解释 PN 诱发的肝损伤的发病机制，包括肠道激素分布、倾向。对于缺乏肠内摄入的细菌易位、肠停滞导致肝毒性胆汁酸清除减少以及PN溶液本身的直接缺乏或有毒成分导致葡萄糖热量摄取过多， PN 相关肝毒性的病因目前被认为是由多因素引起的，并且目前已取得了一定的成功。 PN 依赖患者的最佳护理重点是随着残余肠道的适应逐渐增加肠内热量摄入，从而停止 PN。事实上，实验和临床均已表明，当患者需要部分肠内营养时，应进行部分肠内营养。耐受性，有助于防止 PN 相关肝损伤的发生。在严重的难治性肝衰竭病例中，肝移植伴或不伴小肠移植仍然是唯一的治疗选择。 静脉注射脂肪乳对 PN 相关肝病的作用： 最近的证据表明，脂质的代谢方式不同，具体取决于其给药途径。肠内脂质被小粘膜中的肠上皮细胞以胶束的形式吸收，并包装成乳糜微粒，乳糜微粒被释放到门静脉系统中，最终被吸收和处理。一旦进入血液，这些颗粒就会迅速从循环的高密度脂蛋白中获取载脂蛋白，并随后被肝脏代谢。商业制造和静脉注射的脂肪乳剂，例如 Intralipid¿ ，模仿乳糜微粒的大小和结构，但其含量不同。与乳糜微粒相比，人造脂质颗粒主要含有必需脂肪酸和 omega-6 甘油三酯，并且不含胆固醇或蛋白质。最近的研究表明，这些 omega-6 脂肪。含酸乳剂依赖于脂蛋白脂肪酶、载脂蛋白E和低密度脂蛋白受体进行清除，并且代谢时脂肪分解较少事实上，它们似乎可以作为完整颗粒被肝脏以外的组织清除，这些因素可能是与静脉注射英脱利匹特相关的脂肪性肝炎发病率增加的原因。 。 含有 omega-3 脂肪酸的脂肪乳剂的清除机制尚不清楚，但似乎很大程度上独立于上述途径。此外，omega-3 脂肪酸溶液已被证明可以减少从头脂肪生成，预防或减弱 PN-。诱导大鼠和豚鼠肝脂肪变性，并改善高脂饮食诱导的大鼠肝脂肪变性的严重程度。此外，omega-3 脂肪酸还可干扰花生四烯酸。它们可以取代组织脂肪酸库中的花生四烯酸，从而减少类二十碳烷酸合成酶和炎症的可用性。