COMPASSIONATE USE OF AN INTRAVENOUS FAT EMULSION COMPRISED OF FSIH OIL IN THE TR

在 TR 中善意地使用由 FSIH 油组成的静脉脂肪乳剂

• 批准号: 8356700
• 负责人: STEVEN A ABRAMS
• 金额: $ 2.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356700
• 关键词: Alkaline Phosphatase; Amino Acids; Arachidonic Acids; Attenuated; Bacterial Translocation; Bile Acids; Bilirubin; Biochemical; Calories; Caring; Cavia; Childhood; Cholestasis; Cirrhosis; Clinical Research; Complication; Critical Illness; Development; Diet; Disease; Dose; Electrolytes; Emulsions; Energy Intake; Enteral; Enteral Nutrition; Enzymes; Essential Fatty Acids; Etiology; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Funding; Glucose; Grant; Hepatic; Hepatotoxicity; Histologic; Hormonal; Human; Infant; Inflammation; Infusion procedures; Injury; Intake; Intervention; Intestines; Intravenous; Intravenous Fat Emulsions; Length; Lipids; Lipoidosis; Liver; Liver Failure; Low Birth Weight Infant; Macronutrients Nutrition; Malnutrition; Micronutrients; Monitor; National Center for Research Resources; Nature; Nutrient; Nutritional; Oils; Omega-3 Fatty Acids; Operative Surgical Procedures; Parenteral Nutrition; Pathogenesis; Pathway interactions; Patients; Population; Prevention; Principal Investigator; Process; Protocols documentation; Rattus; Refractory; Regimen; Research; Research Infrastructure; Residual state; Resources; Risk Factors; Safety; Secondary to; Sepsis; Serum; Severities; Small Intestines; Solutions; Source; Starvation; Steatohepatitis; Supplementation; Tissues; Trace Elements; Transaminases; Transplantation; United States National Institutes of Health; Vitamins; Weaning; alternative treatment; base; cost; gastrointestinal; lipid biosynthesis; liver transplantation; premature; prevent; success; theories; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT We propose to provide an omega-6 predominant lipid infusion (Omegaven) to patients with severe parenteral nutrition associated cholestasis (conjugated bilirubin 6) on a compassionate use basis. We will monitor for safety parameters during the maximum 5 months of intervention. The Omegaven will be intravenously infused at a dose of 1gm/kg/day until the infant is weaned from parenteral nutrition and for no longer than 5 months. This is a continuation of protocol H-21344. I. HYPOTHESIS Not applicable due to the compassionate use nature of this protocol. II. SPECIFIC AIMS To provide a mechanism for critically ill infants with parenteral nutrition (PN) associated cholestasis to receive Omegaven for compassionate use situations for which there are no satisfactory alternative treatments. III. 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 1960s, patients with insufficient gastrointestinal absorptive function commonly died of starvation and subsequent complications of malnutrition (1, 2). 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 (3, 4). 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 (5). 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 (6), the propensity for bacterial translocation in the absence of enteral intake (7, 8), intestinal stasis resulting in the reduced clearance of hepatotoxic bile acids (8), 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 (9-11). 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 (12). 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 (13-15). In severe cases of refractory hepatic failure, liver transplantation with or without accompanying small bowel transplantation remains the only treatment option. 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 (17). Furthermore, omega-3 fatty acid solutions have been shown to decrease de novo lipogenesis (18), prevent or attenuate PN-induced hepatosteatosis in rats (19) and guinea pigs and ameliorate the severity of high-fat diet-induced hepatosteatosis in rats (20). In addition, omega-3 fatty acids can interfere with the arachidonic acid pathway of inflammation (18, 21). They can displace arachidonic acid from tissue fatty acid pools, thereby reducing the availability for eicasanoid-synthesizing enzymes and inflammation (21).

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 抽象的 我们建议以富有同情心的使用基础，为患有严重肠胃外营养相关胆汁淤积的严重肠胃营养（共轭胆红素6）的患者提供omega-6主要的脂质输注（Omegaven）。我们将在干预最长5个月内监视安全参数。 omegaven将以1gm/kg/天的剂量静脉注入，直到婴儿从肠胃外营养中断奶并且不超过5个月。这是协议H-21344的延续。 I.假设 由于本协议的富有同情使用性质，不适用。 ii。 具体目标 为了提供一种伴有肠胃外营养（PN）相关胆汁淤积的重症婴儿的机制，以接受omegaven，以富有同情的使用情况，而没有令人满意的替代治疗方法。 iii。 背景和意义 肠胃外营养（PN）为无法吸收肠道长度或功能不足的足够的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（1，2）。如今，超过30,000名患者永久依赖肠胃外营养以生存。然而，PN继续与以不可预测的速度发生的肝损伤有关，包括生化，即血清氨基转移酶升高和碱性磷酸酶的升高，以及组织学改变，例如脂肪变性，例如脂肪变性，脂肪性肝炎，脂肪性肝炎，脂肪，胆汁疾病，纤维化和cirrhosis（3，3，3，3） 4）。这些异常可能随着PN给药的持续时间而恶化，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，败血症和多种手术程序（5）。 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。存在多种假设来解释PN诱导的肝损伤的发病机理，包括改变肠道激素特征（6），在没有肠内摄入的情况下细菌易位的倾向（7，8），肠道暂停，导致肝毒性胆汁酸清除降低。 （8）以及PN溶液本身的直接缺陷或有毒成分，导致葡萄糖卡路里摄取过多，脂质输注过多或营养缺乏（例如必需脂肪酸缺乏）（9-11）。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。随着残留的肠道适应允许停用PN，对PN依赖性患者的护理集中在逐渐增加肠热摄入量（12）。实际上，在实验和临床上都显示出部分肠内营养（耐受）有助于防止与PN相关的肝损伤的发展（13-15）。在严重的难治性肝衰竭的情况下，有或没有伴随小肠移植的肝移植仍然是唯一的治疗选择。 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（17）。此外，omega-3脂肪酸溶液已被证明可以降低从头脂肪生成（18），预防或减轻大鼠（19）和豚鼠的PN诱导的肝脏诱导的肝脏造成的，并改善了大鼠饮食诱导的大鼠肝病的严重程度（ 20）。另外，omega-3脂肪酸可能会干扰炎症的花生四烯酸途径（18，21）。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（21）。