Bilirubin-induced Auditory Neuropathy in Preterms

描述（由申请人提供）：本K23奖研究计划的目标是确定胆红素诱导的高胆红素血症高危早产儿听神经病变（AN）的发生率和决定因素。1996年首次报道AN。它在功能上被定义为缺乏或异常的听觉脑干反应（ABR）和正常的耳声发射（OAE）反应。OAE反映了耳蜗功能，是目前许多新生儿重症监护病房（NICU）听力筛查的标准。耳蜗后、胆红素诱发的AN患儿被OAE检测漏诊。胆红素对听觉神经通路有特殊的偏爱，但对于高胆红素血症高危早产儿AN的患病率和决定因素的了解相对较少。根据目前的理论，未结合胆红素（unbinding bilirubin， UB）可以穿过完整的血脑屏障，造成神经元损伤。然而，UB水平的诊断效用尚未建立，也没有在新生儿重症监护病房婴儿中常规测量这些水平。我们将使用OAE、ABR和胆红素-白蛋白结合变量（包括UB）的实验室测试来检查早产儿胆红素诱导AN的风险是否增加：1)早期表现出与高胆红素血症相关的ABR异常变化的婴儿；2)与UB水平的关系比与血清总胆红素或胆红素：白蛋白摩尔比的关系更密切；3)存在窒息、败血症、缺氧、酸中毒、溶血等临床危险因素时增加。最终，这些发现将揭示早产儿黄疸相关发病率的程度，UB作为胆红素诱导AN的预测因子的有效性，以及胆红素诱导AN的临床危险因素的作用。关于UB水平的新知识将使婴儿处于AN风险中，这对于以下方面具有重要意义：1)开展介入性试验以预防胆红素诱导的AN， 2)确定需要评估AN的高危婴儿。

DESCRIPTION (provided by applicant): The goal of the research plan for this K23 award is to establish the incidence and determinants of bilirubin-induced auditory neuropathy (AN) in high-risk premature infants with hyperbilirubinemia. AN was first reported in 1996. It is functionally defined by an absent or abnormal auditory brainstem response (ABR) and a normal otoacoustic emission (OAE) response. The OAE reflects cochlear function and is the current standard of care in many Neonatal Intensive Care Units (NICU) for hearing screening. Infants with retrocochlear, bilirubin-induced AN are being missed by OAE measures. Bilirubin has specific predilection for the auditory neural pathway, but relatively little is known regarding the prevalence and determinants of AN in high-risk premature infants with hyperbilirubinemia. According to current theory, unbound bilirubin (UB) can cross the intact blood-brain barrier and cause neuronal damage. However, the diagnostic utility of UB levels has not been established nor are these levels routinely measured in NICU infants. We will use OAE, ABR, and laboratory tests for bilirubin-albumin binding variables, including UB, to examine whether the risk of bilirubin-induced AN in premature infants is: 1) increased in infants who, early on, demonstrate abnormal changes in ABR in association with hyperbilirubinemia; 2) more closely associated with UB levels than with estimates of total serum bilirubin or the bilirubin:albumin molar ratio; and 3) increased in the presence of clinical risk factors such as asphyxia, sepsis, hypoxia, acidosis, and hemolysis. Ultimately, these findings will reveal the magnitude of jaundice-related morbidity in premature infants, the usefulness of UB as a predictor of bilirubin-induced AN, and the role of clinical risk factors in bilirubin-induced AN. New knowledge of UB levels that place infants at risk for AN will be important for: 1) developing interventional trials to prevent bilirubin-induced AN and 2) identifying those at-risk infants who need evaluation for AN. n the training component of this award the candidate will acquire and refine basic skills for conducting high-quality patient-oriented research. Namely, he will gain intimate knowledge of epidemiology and biostatistics and experience with advanced clinical and laboratory methods. An outstanding set of mentors and consultants at the University of Maryland and the University of Pennsylvania offer the candidate a rich and vibrant research and training environment in which to advance his career goals and this promising and important new line of research.