Unbound fatty acids, Intralipid and Unbound Bilirubin in Preterm Infants

描述（由申请人提供）：新生儿黄疸发生在60-70%的新生儿中。严重的高胆红素血症可导致神经功能障碍和可能的死亡，早产儿特别容易发生这些并发症。目前的诊断技术测量总血清胆红素水平（TSB），这是用光疗治疗的指标。然而，认为游离未结合胆红素（Bf）水平比TSB更准确地确定胆红素神经毒性的风险。Bf水平可以通过与游离脂肪酸（FFA）竞争结合位点而升高。大多数FFA与白蛋白结合循环，只有一小部分游离在水相中（FFAu）。游离脂肪酸是重要的营养成分，因此在完全肠内喂养之前，大多数早产儿接受的是Intradherid，一种静脉注射脂肪酸乳剂。初步数据表明，FFAu在接受Intraperoid的早产儿中可能显著升高，最有可能是由于代谢和储存不成熟。这可能导致脂质相关并发症，包括继发于与胆红素竞争白蛋白结合位点的Bf升高。早产儿光疗的开始和持续时间的阈值尚未完全确定，导致基于TSB、出生体重和/或胎龄的方法相互冲突。因此，虽然Bf水平-循环中的胆红素的毒性隔室-可能会显着升高，在婴儿接受Intraperoid，目前的方法不包括直接测量Bf。最近，我们通过迭代突变和高通量筛选荧光标记的FFA结合蛋白的过程开发了FFAu和Bf特异性探针。我们证明了这些探针可以检测血浆中生理纳摩尔浓度的Bf和FFAu。拟定的研究将利用这种新的创新技术来研究以下假设：1）Intraperoid输注将增加早产儿的FFAu，从而增加Bf和Bf/TSB比值，2）在出生后第一周内接受光疗（基于TSB水平）的早产儿接受Intraperoid治疗时，Bf水平比未接受Intraperoid治疗的早产儿高至少20%。这些发现将支持TSB低估了Intralidid治疗婴儿的风险的观点，并且Bf可能是光疗需求的更好决定因素。然后将设计更大的研究，以测试基于Bf的直接测量在早产儿中管理高胆红素血症后的临床疗效和改善的结局。

DESCRIPTION (provided by applicant): Neonatal jaundice occurs in 60-70% of newborns. Severe hyperbilirubinemia can lead to neurological dysfunction and possibly death, and preterm infants are particularly susceptible to these complications. Current diagnostic techniques measure total serum levels of bilirubin (TSB), which are used as indicators for treatment with phototherapy. However, levels of free, unbound bilirubin (Bf) are thought to determine the risk of bilirubin neurotoxicity more accurately than TSB. Bf levels can be elevated by competition for binding sites with free fatty acids (FFA). Most FFA circulate bound to albumin, with only a small fraction present unbound in the aqueous phase (FFAu). FFA are an important element of nutrition, so prior to full enteral feeding most premature infants receive them as Intralipid, an intravenous fatty acid emulsion. Preliminary data suggest that FFAu can be markedly elevated in premature infants receiving Intralipid, most likely due to immature metabolism and storage. This may lead to lipid associated complications, including elevated Bf secondary to competition with bilirubin for albumin binding sites. The thresholds for initiation and duration of phototherap are not well established in preterm infants, leading to conflicting approaches based on TSB, birth weight and/or gestational age. Thus, although levels of Bf-the toxic compartment of circulating bilirubin-may be markedly elevated in infants receiving Intralipid, current approaches do not include direct measurement of Bf. Recently, we developed FFAu- and Bf-specific probes through a process of iterative mutations and high throughput screening of fluorescently labeled FFA binding proteins. We demonstrated that these probes can detect physiologic, nanomolar concentrations of Bf and FFAu in plasma. The proposed studies will utilize this new, innovative technology to investigate the hypothesis that 1) Intralipid infusion will increase FFAu and consequently Bf and the Bf/TSB ratio in preterm infants, and 2) premature infants treated with phototherapy during the first week of life (based on TSB levels) who are receiving Intralipid will have at least 20% higher levels of Bf than those not receiving Intralipid. Such findings would support the idea that TSB underestimates risk in Intralipid-treated infants, and that Bf may be a better determinant of the need for phototherapy. Larger studies will then be designed to test clinical efficacy and improved outcomes after managing hyperbilirubinemia in preterm infants based on direct measurements of Bf.