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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 我们建议在同情使用的基础上，为重度肠外营养相关胆汁淤积（结合胆红素6）患者提供omega-6主要脂质输注（Omegaven）。我们将在最长5个月的干预期间监测安全性参数。Omegaven将以1 gm/kg/天的剂量静脉输注，直至婴儿脱离肠外营养，持续时间不超过5个月。这是方案H-21344的延续。 I. 假设 由于本方案的同情使用性质，因此不适用。 二. 具体目标 为肠外营养（PN）相关胆汁淤积的危重婴儿提供一种机制，使其在没有令人满意的替代治疗的情况下接受Omegaven同情使用。 三. 背景和意义 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含有人类饮食中最基本形式的常量营养素构建模块（氨基酸和葡萄糖），通常与脂肪乳剂一起给药，以避免必需脂肪酸缺乏症，并提供非蛋白质热量的高热量来源。此外，PN含有必需的微量营养素（电解质、微量元素和维生素），可提供最佳营养方案。在20世纪60年代末PN发展之前，胃肠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）。今天，超过30，000名患者永久依赖肠外营养生存。然而，PN仍然与肝损伤相关，肝损伤的发生率不可预测，包括生化，即，血清转氨酶和碱性磷酸酶升高，以及组织学改变，如脂肪变性、脂肪性肝炎、肝硬化、胆汁淤积、纤维化和肝硬化（3，4）。这些异常可能随着PN给药持续时间的延长而加重，在儿科人群中更为常见。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、败血症和多次手术（5）。 虽然PN引起的肝损伤的病理学特征已被很好地描述，但这种并发症的病因、预防和治疗尚不清楚。存在多种假说来解释PN诱导的肝损伤的发病机制，包括肠道激素谱改变（6）、在没有肠内摄入的情况下细菌移位的倾向（7，8）、导致肝毒性胆汁酸清除率降低的肠道淤滞（8）以及PN溶液本身的直接缺陷或毒性成分导致葡萄糖热量摄取过多、脂质输注过多，或营养缺乏症，如必需脂肪酸缺乏症（9-11）。这些理论都没有得到一致的证实。目前认为PN相关肝毒性的病因是多因素的。这种疾病过程的可用治疗方案是有限的，最多取得了中等程度的成功。PN依赖患者的护理重点是逐渐增加肠内热量摄入，因为残余肠道适应允许PN中断（12）。事实上，实验和临床均表明，部分肠内营养在耐受时有助于防止PN相关肝损伤的发展（13-15）。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。 含omega-3脂肪酸脂肪乳剂的清除机制尚不清楚，但似乎在很大程度上不依赖于上述途径（17）。此外，omega-3脂肪酸溶液已被证明可减少新生脂肪生成（18），预防或减轻大鼠（19）和豚鼠中PN诱导的脂肪肝，并改善大鼠中高脂饮食诱导的脂肪肝的严重程度（20）。此外，ω-3脂肪酸可以干扰炎症的花生四烯酸途径（18，21）。它们可以取代组织脂肪酸池中的花生四烯酸，从而降低类花生酸合成酶和炎症的可用性（21）。

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).