Abstinence and Drug Withdrawal: Innovative Translational Methods for Neonates

描述（由申请人提供）：胎儿药物暴露是一个全国性的问题。全国近5%的孕妇使未出生的孩子在子宫内接触药物（非法和处方药）。新生儿戒断综合征（NAS）是指由于停用药物而引起的多系统紊乱和神经行为失调，婴儿对这些药物已经产生耐受性和身体依赖性。研究和治疗NAS的新方法是必要的，因为尽管目前的干预措施，NAS婴儿往往需要长期住院和药物治疗的中枢，自主神经，血管和胃肠道不稳定，这也可能有助于不良的神经行为结果。越来越多的研究表明感觉刺激的重要性，特别是触觉刺激，以促进正常的大脑发育和功能的稳定性。有证据表明，不可感知的噪声样振动（随机共振）可以在不稳定的生物系统中引起稳定。这一建议的基本假设是，NAS在新生儿的特点是生理紊乱，反映药物戒断的严重程度和病理生理不稳定性，在药物戒断新生儿可以稳定随机，振动触觉刺激。40名NAS（阿片类药物暴露）新生儿将参加马萨诸塞州纪念医疗中心的一项严格的短期研究，以检查以下两个目标：目标1。通过密集测量量化NAS婴儿药物戒断生理信号的不稳定性。生理信号之间的变化和关系，例如，将使用非线性计算信号分析（点过程和小波）来量化呼吸、心跳和温度的不稳定性以及过度运动，以探索生理不稳定性是否可以指示NAS严重性并预测戒断症状的发作/消失。这些信息将有助于促进新生儿戒毒和药物戒断的药理学管理。目标2.检查随机振动触觉刺激对提高NAS婴儿生理稳定性和缓解药物戒断症状的有效性。受试者将作为自己的对照，以检验随机的振动触觉扰动冲击不稳定的神经回路并减少NAS易激性从皮层下（脑干）到皮层结构的进行性传播的假设，其特征是呼吸、心率、温度的过度变化和随后的运动高潮。将随机振动的条件（具有嵌入泡沫中的机械致动器的专门设计的床垫; 30- 60 Hz，RMS振幅0.1mm）与控制周期进行比较，以测试刺激是否：1）通过减少心跳的不稳定性来改善心肺控制（例如，心动过缓、心动过速）和呼吸，包括减少呼吸暂停、周期性呼吸和呼吸急促的发生; 2）抑制睡眠中断，如通过减少过度的身体运动来标记的;和3）缓解戒断症状，其通过改善NAS临床评估评分来索引。这项提案的结果将阐明随机振动触觉刺激是否有潜力作为NAS的辅助治疗，以改善NAS婴儿的心肺控制和减少睡眠中断（由过度运动引起）。未来一项更严格的前瞻性研究可能最终有助于阐明NAS的潜在机制，改善治疗干预措施，以减少标准护理的严重程度和停药时间，从而改善发病率，降低NAS婴儿的住院和医疗费用。

DESCRIPTION (provided by applicant): Fetal drug exposure is a nationwide problem. Nearly five percent of pregnant women nationwide expose their unborn child to drugs in utero (illicit and prescription). Neonatal Abstinence Syndrome (NAS) refers to multi- system disturbances and dysregulated neurobehaviors caused by discontinuation of drug/s to which an infant has developed tolerance and physical dependence. Novel approaches to study and treat NAS are needed because despite current interventions NAS infants often require prolonged hospitalization and pharmacological treatment for central, autonomic, vasomotor and gastrointestinal instabilities, which may contribute also to poor neurobehavioral outcomes. Growing research suggests the importance of sensory stimulation, particularly tactile stimulation for enhancing normal brain development and stability of function. There is evidence that unperceivable noise-like vibrations (stochastic resonance) can provoke stability in destabilized biological systems. The underlying hypothesis of this proposal is that NAS in newborns is characterized by physiological disturbances that reflect drug-withdrawal severity and that pathophysiological instabilities in drug-withdrawing neonates can be stabilized by stochastic, vibro-tactile stimuli. Forty NAS (opiate-exposed) neonates will participate in a rigorous, short-term study at UMass Memorial Healthcare to examine the following two aims: Aim 1. Quantify via intensive measurement the instabilities of physiological signals of drug withdrawal in NAS infants. Changes and relationships among physiological signals, e.g., instability of respiration, heart beat and temperature, and excessive movement, will be quantified using non-linear computational signal analyses (point process and wavelet) to explore whether physiological instabilities can index NAS severity and predict onset/offset of withdrawal symptoms. Such information would help facilitate pharmacological management of abstinence and drug withdrawal in neonates. Aim 2. Examine the efficacy of stochastic, vibro-tactile stimulation for enhancing physiological stability in NAS infants and alleviating the symptoms of drug withdrawal. Subjects will serve as their own control to test the hypothesis that stochastic, vibro-tactile perturbations impinge upon destabilized neural circuits and reduce the progressive spread of NAS irritability from subcortical (brainstem) to cortical structure, marked by excessive changes in respiration, heart rate, temperature and subsequent upsurge in movement. Conditions of stochastic vibration (specially designed mattress with mechanical actuators embedded in foam; 30-60Hz, RMS amplitude 0.1mm) will be compared to control periods to test whether stimulation: 1) Improves cardio-respiratory control by reducing instability of heart beat (e.g., bradycardia, tachycardia) and respiration, including decreasing incidents of apnea, periodic breathing and tachypnea; 2) Inhibits sleep disruption as marked by reduction of excessive body movements; and 3) Relieves withdrawal symptoms indexed by improved NAS clinical assessment scores. Findings from this proposal will elucidate whether stochastic, vibro-tactile stimulation has potential as an adjuvant treatment of NAS for improving cardio-respiratory control and reducing sleep disruption (indexed by excessive movement) in NAS infants. A more rigorous future prospective study may ultimately help elucidate underlying mechanisms involved in NAS, lead to improved therapeutic interventions for reducing severity and duration of drug withdrawal complementary to standard care, and thereby improve morbidity and reduce hospitalization and medical costs among NAS infants.