Predicting Bilirubin-induced Auditory Toxicity in Infants with Severe Jaundice

预测严重黄疸婴儿胆红素引起的听觉毒性

• 批准号: 7667629
• 负责人: SANJIV B AMIN
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667629
• 关键词: Academy; Acidosis; Acoustics; Acute; Admission activity; Age; Albumins; American; Anxiety; Asphyxia; Athetoid cerebral palsy; Audiometry; Auditory; Auditory system; Bilirubin; Binding; Blinded; Central Auditory Processing Disorder; Chronic; Clinical; Country; Coupled; Data; Dental Enamel Hypoplasia; Diagnosis; Emotional Stress; Encephalopathies; Enrollment; Evaluation; Evoked Potentials, Auditory, Brain Stem; FDA approved; Follow-Up Studies; Foundations; Functional disorder; Future; Gestational Age; Goals; Gold; Guidelines; Hearing; Heme; Hemolysis; Hospitals; Hyperbilirubinemia; Icterus; Incidence; India; Infant; Institution; International; Intervention; Joints; Kernicterus; Laboratories; Language Delays; Literature; Measurement; Measures; Medical center; Methods; Monitor; Morbidity - disease rate; Neonatal Jaundice; Neuropathy; Outcome; Oxygenases; Patient Recruitments; Pediatric Hospitals; Pediatrics; Peroxidases; Phototherapy; Population Heterogeneity; Premature Infant; Prevalence; Principal Investigator; Prospective Studies; Protocols documentation; Psychological reinforcement; Public Health; Publishing; ROC Curve; Receiver Operating Characteristics; Recommendation; Regression Analysis; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Sampling; Saran; Sensitivity and Specificity; Sepsis; Serum; Specificity; Speech; Standardization; Temperature; Testing; Therapeutic Intervention; Time; Toxic effect; Transfusion; Tympanometry; Universities; Visual; Work; age group; base; cohort; cost; effective intervention; evidence base; experience; gaze palsy; hearing impairment; high risk; improved; inhibitor/antagonist; interest; mortality; neonate; neurotoxicity; prevent; public health relevance; relating to nervous system; total measurement Bilirubin

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.

描述（由申请方提供）：重度黄疸导致婴儿慢性核小体后脑病、感觉神经性听力损失（SNHL）和听神经病（AN）。美国儿科学会（AAP）关于预防胆红素诱导的神经毒性的治疗指南是基于血清总胆红素的测量，但该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灵敏度但低特异性，因此经常引发不必要的积极治疗。婴儿听力联合委员会（JCIH）建议 AAP指南建议对血清总胆红素水平达到需要换血的婴儿进行听力学评估，但该建议也缺乏证据。本研究将重点关注未结合胆红素，主要研究者及其同事已证明未结合胆红素比血清总胆红素更能预测早产儿的听觉功能障碍。拟定研究的目的是确定未结合胆红素作为重度黄疸晚期早产儿和足月儿（血清总胆红素水平= 20 mg/dl或需要进行换血的水平）中胆红素诱导的听觉毒性的更敏感和特异性预测因子的有效性。由于重度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，其中包括重度黄疸患病率较高的印度婴儿，以及测量美国可用的未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者，具有共同的兴趣和互补的作用，将合作招募100名胎龄≥ 34周的重度黄疸婴儿，为期两年。 每个参与中心将按照AAP干预指南和JCIH听觉评估建议提供临床和实验室数据。将由经验丰富的听力学家在三个不同的时间段（1）高胆红素血症时间，2）2个月矫正年龄和3）9个月矫正年龄，在每个中心进行听觉毒性评价，对未结合胆红素水平设盲。使用FDA批准的UB分析仪（罗切斯特），通过过氧化物酶法测量未结合胆红素。各中心之间严格的标准化和监测样本运输的协议已经到位。将进行回归分析，以评价未结合胆红素与听觉毒性之间的相关性强度。将使用受试者工作特征曲线比较未结合胆红素、胆红素：白蛋白比值和血清总胆红素对胆红素诱导的听觉毒性的灵敏度和特异性。本研究的结果将为后续研究奠定基础，以评估未结合胆红素预测慢性核后脑病的有用性，以及其他与听觉毒性相关的长期结局，如语言延迟和中枢听觉处理障碍。最终目标是减少：1）黄疸相关的发病率，2）不必要的住院和相关费用，3）不必要的交换输血和相关并发症，4）不必要的听觉评估，以及5）父母焦虑和情绪压力。 公共卫生相关性：严重新生儿黄疸和相关疾病是一个全球性的公共卫生问题。美国儿科学会的治疗指南和婴儿听力联合委员会对听力评估的建议缺乏证据，并基于血清总胆红素的测量，这对胆红素诱导的神经毒性的特异性较差。由经验丰富的研究者在印度和美国进行的这项临床项目将检查未结合胆红素作为重度黄疸婴儿不同人群听觉毒性预测因子的有效性。如果游离胆红素是一个比血清总胆红素更好的预测因子，它将大大提高识别严重黄疸的婴儿谁是神经毒性的风险，需要光疗或交换输血。这种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）黄疸相关的发病率和死亡率，2）介入治疗的住院，3）可能与并发症相关的不必要的换血，4）不必要且昂贵的听力评估，以及5）父母的焦虑和情绪压力。