Testing the Reliability and Validity of Pupil Diameter in Opioid-exposed neonates

描述(由申请人提供)：瞳孔直径是阿片类药物对人类药效学影响的最常评估的客观指标之一。阿片类药物的瞳孔效应很容易在成人中通过摄影测量，是身体依赖和戒断的存在和程度的高度敏感的衡量标准。对瞳孔反应的测量通常与自我报告和观察者评估的效果一起收集，以提供阿片类药物效果的全面概况。在宫内接触阿片类药物的婴儿在出生时就对身体有依赖，并经常患有戒断(即新生儿禁欲综合征)，严重到需要药物治疗。观察者评级量表是评估药物治疗的必要性和有效性的唯一工具。 NAS在临床和研究环境中的应用以及这些工具的缺陷(例如，基本验证、较长的培训和管理时间)导致对NAS进行更敏感、更客观的测量的呼声越来越高。我们已经开发了一种方法来测量接触阿片类药物的新生儿的瞳孔直径。使用这一方案的试点数据(N=10)表明，新生儿的瞳孔对阿片类药物的反应与成人相同，并表明与观察员评定的量表相比，瞳孔直径可能是衡量NAS的更敏感的指标。因此，下一步是充分测试阿片类药物暴露的新生儿瞳孔直径的可靠性和有效性。两项研究 都是为了实现这一总体目标而提出的。第一项研究将在40名接触阿片类药物的新生儿中正式测试OU瞳孔摄影方案的可靠性。第二项研究将以大量关于阿片类药物的瞳孔影响的成人文献为指南，测试新生儿的瞳孔变化作为阿片类药物影响的指标的有效性。110名接触阿片类药物的新生儿和30名非接触阿片类药物的新生儿将为四项有效性分析提供数据。首先，将检查在分娩后前24小时收集的瞳孔直径测量，以确定它们是否区分接触阿片类药物的新生儿和未接触阿片类药物的新生儿，测试判别效度。其次，在接触阿片类药物的新生儿中，将检查在分娩后前24小时内瞳孔直径变化与观察者评定的NAS量表分数变化之间的相关性，以检验同时有效性。第三，阿片耐受性和 对需要药物治疗的阿片类药物暴露的新生儿(估计n=35)进行阿片类药物治疗后的瞳孔效应时程检验，以检验结构效度。第四项也是最后一项分析将通过测试分娩后前24小时内瞳孔直径的变化是否预测哪些新生儿继续接受药物治疗来检验预测有效性。总之，建立阿片类药物暴露新生儿瞳孔直径的可靠性和有效性，有可能在临床和研究环境中大幅改善对阿片类药物暴露新生儿的评估和治疗，减少发病率，缩短住院时间，并降低成本。

DESCRIPTION (provided by applicant): Pupil diameter is one of the most frequently assessed objective indices of the pharmacodynamic effects of opioids in humans. The pupillary effects of opioids are easily measured photographically in adults and are a highly sensitive measure of the presence and extent of physical dependence and withdrawal. Measures of pupillary response are often collected along with self-reported and observer-rated effects to provide a comprehensive profile of opioid effects. Infants exposed to opioids in utero are born physically dependent and often suffer from withdrawal (i.e., neonatal abstinence syndrome~ NAS) that is severe enough to require pharmacological treatment. Observer- rated scales are the only tools available to evaluate the need for and effectiveness of pharmacological treatment for NAS in both clinical and research settings and shortcomings of these instruments (e.g., rudimentary validation, long training and administration times) have led to calls for more sensitive, objective measures of NAS. We have developed a protocol to measure pupil diameter in opioid-exposed neonates. Pilot data (N=10) using this protocol indicate neonatal pupils respond to opioids in the same manner as adults and suggest that pupil diameter may be a more sensitive measure of NAS compared to observer-rated scales. Thus, the next step is to fully test the reliability and validity of pupil diameter in opioid-exposed neonates. Two studies are proposed to meet this overarching aim. The first study will formally test the reliability of ou pupil photography protocol in 40 opioid-exposed neonates. The second study will test the validity of pupillary changes in neonates as an index of opioid effects using the extensive adult literature on the pupillary effects of opioids as a guide. One-hundred ten opioid-exposed neonates and 30 non-exposed neonates will provide data for four analyses of validity. First, pupil diameter measurements collected over the first 24 hours after delivery will be examined to see if they discriminate between opioid-exposed and non-exposed neonates, testing discriminant validity. Second, among the opioid-exposed neonates, correlations between changes in pupil diameter and changes in observer-rated NAS scale scores over the first 24 hours after delivery will be examined, testing concurrent validity. Third, opioid tolerance and the time course of pupillary effects after opioid administration will be examined among the opioid-exposed neonates who require pharmacological treatment (estimated n= 35), testing construct validity. The fourth and final analysis will examine predictive validity by testing whether changes in pupil diameter in the first 24 hours after delivery predicts which neonates went on to receive pharmacological treatment. In sum, establishing the reliability and validit of pupil diameter in opioid-exposed neonates has potential to substantially improve assessment and treatment of opioid-exposed neonates in both clinical and research settings, reducing morbidity, shortening hospital stays, and decreasing costs.