Predicting Bilirubin-induced Auditory Toxicity in Infants with Severe Jaundice

描述(申请人提供)：严重黄疸导致婴儿慢性核黄体后脑病、感觉神经性听力损失(SNHL)和听神经病(AN)。美国儿科学会(AAP)预防胆红素神经毒性的治疗指南是基于血清总胆红素的测量，但这一指标的实用性缺乏证据：它对胆红素诱导的神经毒性具有高敏感性但低特异性，因此经常引发不必要的积极治疗。婴儿听证联合委员会(JCIH)建议 根据AAP指南，对血清总胆红素水平符合AAP指南的交换输血的婴儿进行听力学评估，但该建议也缺乏证据。这项研究将重点放在游离胆红素上，首席研究员和他的同事们已经证明，与总血清胆红素相比，游离胆红素更能预测早产儿的听力障碍。这项拟议研究的目的是确定无结合胆红素作为晚期早产儿和足月儿严重黄疸(血清总胆红素水平=20 mg/dl或换血水平)时胆红素所致听力毒性的更敏感和更特异的预测指标。由于严重黄疸在美国的患病率较低，因此需要进行一项国际合作研究，其中包括来自印度的婴儿，那里的重度黄疸患病率很高，以及在美国可以获得的测量结合胆红素的技术专业知识。来自印度和美国学术机构的经验丰富的研究人员具有共同的兴趣和互补的角色，将在两年内合作招募100名患有严重黄疸的胎龄=34周的婴儿。 每个参与中心将提供临床和实验室数据，遵循AAP的干预指南和JCIH的听力评估建议。在三个不同的时间段，经验丰富的听力学专家将在每个中心进行听力毒性评估，以确定未结合胆红素水平：1)高胆红素血症时间；2)2个月校正年龄；3)9个月校正年龄。使用FDA批准的罗切斯特UB分析仪，用过氧化物酶方法测定未结合胆红素。各中心之间的严格标准化和监测样本运输的协议已经到位。将进行回归分析，以评估未结合胆红素与听觉毒性之间的关联强度。受试者操作特征曲线将用于比较未结合胆红素、胆红素/白蛋白比率和血清总胆红素对胆红素所致听觉毒性的敏感性和特异性。本研究的结果将为后续研究评估无结合胆红素在预测慢性核黄体后脑病以及与听力毒性相关的其他长期结局(如语言延迟和中枢听觉处理障碍)方面的有效性奠定基础。最终目标将是减少：1)与黄疸相关的发病率，2)不必要的入院及相关费用，3)不必要的交换输血及相关并发症，4)不必要的听觉评估，以及5)父母的焦虑和情绪压力。 与公共卫生相关：严重的新生儿黄疸及相关疾病是一个全球公共卫生问题。美国儿科学会治疗指南和婴儿听力联合委员会关于听力评估的建议缺乏证据，而且基于血清总胆红素的测量，而血清总胆红素对胆红素诱导的神经毒性的特异性较差。这项将由经验丰富的研究人员在印度和美国进行的临床项目将检验无结合胆红素作为患有严重黄疸的不同婴儿群体中听觉毒性的预测指标的有用性。如果结合胆红素是比总胆红素更好的预测指标，它将极大地提高对有神经毒性风险且需要光疗或换血的严重黄褐症婴儿的识别能力。这一改进的识别对全球公共卫生产生了影响，因为它将有助于减少：1)与黄疸相关的发病率和死亡率，2)住院接受干预治疗，3)可能与并发症有关的不必要的交换输血，4)不必要且昂贵的听觉评估，以及5)父母的焦虑和情绪压力。

DESCRIPTION (provided by applicant): Severe jaundice causes chronic post-kernicteric encephalopathy, sensori-neural hearing loss (SNHL), and auditory neuropathy (AN) in infants. The American Academy of Pediatrics (AAP) guidelines for treatment to prevent bilirubin-induced neurotoxicity are based on measures of total serum bilirubin, but the utility of this indicator lacks evidence: it has high sensitivity but low specificity for bilirubin-induced neurotoxicity, so it often triggers unwarranted aggressive treatment. The Joint Committee on Infant Hearing (JCIH) recommends audiological evaluations in infants with total serum bilirubin levels at which exchange transfusion is indicated by AAP guidelines, but this recommendation also lacks evidence. This study will focus on unbound bilirubin, which has been shown by the Principal Investigator and his colleagues to be a better predictor of auditory dysfunction in premature infants than total serum bilirubin. The goal of the proposed research is to establish the usefulness of unbound bilirubin as a more sensitive and specific predictor of bilirubin-induced auditory toxicity in late preterm and term infants with severe jaundice (total serum bilirubin level = 20 mg/dl or level at which exchange transfusion is indicated). Because the prevalence of severe jaundice is low in the USA, an international collaborative study is required, that includes infants from India, where the prevalence of severe jaundice is high, and technologic expertise to measure unbound bilirubin that is available in the USA. Experienced investigators from academic institutions in India and the USA with common interests and complementary roles will collaborate to enroll 100 infants = 34 weeks gestational age with severe jaundice over two year period. Each participating center will provide clinical and laboratory data, following AAP guidelines for intervention and JCIH recommendations for auditory evaluations. Evaluations for auditory toxicity will be performed at each center by experienced audiologists, blinded to unbound bilirubin levels, at three different time periods: 1) time of hyperbilirubinemia 2) 2 months corrected age and 3) 9 months corrected age. The unbound bilirubin will be measured by the peroxidase method using an FDA approved UB analyzer in Rochester. Rigorous standardization across centers and protocols to monitor sample transport are in place. Regression analysis will be performed to evaluate the strength of association between unbound bilirubin and auditory toxicity. Receiver operating characteristic curves will be used to compare sensitivity and specificity for bilirubin-induced auditory toxicity of unbound bilirubin, bilirubin:albumin ratio, and total serum bilirubin. The findings of this study will lay the foundation for follow-up studies to evaluate the usefulness of unbound bilirubin for predicting chronic postkernicteric encephalopathy, and other long-term outcomes related to auditory toxicity such as language delay and central auditory processing disorder. The ultimate goal will be to reduce: 1) jaundice related morbidity, 2) unnecessary hospital admissions and associated costs, 3) unnecessary exchange transfusions and associated complications, 4) unnecessary auditory evaluations, and 5) parental anxiety and emotional stress. PUBLIC HEALTH RELEVANCE: Severe neonatal jaundice and associated morbidities is a global public health problem. American Academy of Pediatrics guidelines for treatment and Joint Committee on Infant Hearing recommendations for auditory evaluations lack evidence and are based on measures of total serum bilirubin, which have poor specificity for bilirubin-induced neurotoxicity. This clinical project to be performed in India and USA by experienced investigators will examine the usefulness of unbound bilirubin as a predictor of auditory toxicity in a diverse population of infants with severe jaundice. If unbound bilirubin is a better predictor than total serum bilirubin, it will greatly improve identification of severely jaundiced infants who are at risk for neurotoxicity and in need of phototherapy or exchange transfusion. This improved identification has ramifications for public health globally as it will help decrease: 1) jaundice related morbidity and mortality, 2) hospital admissions for intervention therapy, 3) unnecessary exchange transfusions that may be associated with complications, 4) unnecessary and costly auditory evaluations, and 5) parental anxiety and emotional stress.