Analgesic-Behavioral and Neurophysiological Correlates of Opioid-Sparing Spinal Anesthesia Compared to General Anesthesia in Human Infants

仅在美国，每年就有大约600万儿童接受麻醉。正在进行的阿片类药物流行迫使医学界审查如何使用阿片类药物来止痛。现在有证据表明，早期接触阿片类药物与对疼痛更敏感，对生理、认知、运动技能和行为的不良长期影响，对疼痛控制的更高阿片类药物要求，以及持续使用阿片类药物的风险更高有关。因此，节制阿片类药物的麻醉剂和止痛药方案正在被深入研究。特别是对婴儿来说，脊柱麻醉剂能够在不使用阿片类药物的情况下提供镇痛，同时进一步诱导镇静的大脑状态，不同于成年人需要联合使用传统的镇静-催眠药来钝化意识。这种临床观察背后的神经学基础还不完全清楚，我们已经开始收集试点数据，以帮助进一步澄清这些特性。我和我的导师团队现在已经在K23指导的以患者为导向的研究职业发展奖申请中处于有利地位，与非阿片类药物脊麻相比，我们将严格和可重复地研究早期阿片类药物暴露在大脑中的急性影响及其对发育的潜在长期影响。我从2016年开始收集麻醉脑电(EEG)数据集--到目前为止，样本规模包括143名受试者，中位年龄为7个月，而且还在继续增长。我们的初步数据表明，脊柱麻醉的一个特征似乎是睡眠纺锤体复合体，它类似于正常的生理睡眠，不同于使用阿片类药物的全身麻醉(GA)效果。我有一个独特的机会，通过额外的K23支持来解决早期麻醉对大脑影响方面的关键知识空白，以继续进行分析整个脑电数据集所需的受试者招募和有指导的研究培训活动。这项我们已经证明是可行的工作，将进一步有助于从根本上发现阿片类药物和非阿片类药物之间的止痛-行为和神经生理相关性，目的如下：(1)前瞻性量化100名受试者中婴儿脊麻的止痛-行为和神经生理相关性，(2)比较接受脊麻的婴儿与100名在正常生理睡眠中的同龄婴儿和200名接受全麻的类似手术婴儿的神经生理特性，以及(3)比较在脊椎(n=100)和全麻(n=200)下接受类似手术的婴儿的临床和行为结果。蒙特菲奥里·爱因斯坦的研究环境非同寻常，我的导师团队拥有专业知识，可以指导我对早期麻醉对大脑的影响进行严格评估。我的培训计划是专门为培养我在临床研究设计、数据科学、发育神经科学和神经数据分析方面的技能而设计的。到职业发展奖完成时，我将成功申请R01级资金，并将准备过渡到一名完全独立的临床医生兼调查员，致力于改善儿童的麻醉护理。

Each year, approximately 6 million children receive anesthesia in the United States alone. The ongoing opioid epidemic has forced the medical community to examine how it uses opioids for pain management. There is now evidence that early life exposure to opioids is associated with greater sensitivity to pain, adverse long-term effects on physiology, cognition, motors skills and behavior, higher opioid requirements for pain control, and higher risk of persistent opioid use. Accordingly, opioid-sparing anesthetic and analgesic regimens are being investigated intensely. For infants in particular, spinal anesthetics are able to provide analgesia without opioids while further inducing a sedated brain state, unlike adults who require co-administration of traditional sedative-hypnotic agents to blunt awareness. The neurological basis underlying this clinical observation is not fully understood and we have begun to collect pilot data to help further clarify these properties. My mentorship team and I are now well-positioned in this K23 Mentored Patient-Oriented Research Career Development Award application to rigorously and reproducibly investigate the acute effects of early opioid exposure in the brain and its potential long-term impact on development, with comparison to opioid-sparing spinal anesthesia. I began assembling an anesthesia electroencephalogram (EEG) dataset beginning in 2016 - with a sample size to date now consisting of 143 subjects with a median age of 7 months that continues to grow. Our preliminary data demonstrate that a hallmark of spinal anesthesia appears to be the sleep spindle complex, which resembles normal physiologic sleep that is distinct from general anesthetic (GA) effects that employ opioids. I have a unique opportunity to address critical gaps in knowledge of the effects of early anesthesia on the brain with additional K23-support to continue the subject recruitment and mentored research training activities necessary to analyze the entire EEG dataset. This work, which we have already demonstrated is feasible, will further contribute to fundamental discovery of the analgesic-behavioral and neurophysiological correlates of opioids vs. opioid-sparing alternatives, with the following aims: (1) prospective quantification of analgesic-behavioral and neurophysiological correlates of infant spinal anesthesia in 100 subjects, (2) comparison of neurophysiological properties of infants receiving spinal anesthesia compared to 100 infants of similar age in normal physiologic sleep and 200 infants undergoing similar surgeries receiving general anesthesia, and (3) comparison of clinical and behavioral outcomes between infants undergoing similar surgeries under spinal (n=100) versus general anesthesia (n=200). The research environment at Montefiore Einstein is exceptional and my team of mentors has the expertise to guide me in rigorous assessments of early anesthetic effects on the brain. My training plan is specifically designed to develop my skills in clinical study design, data science, developmental neuroscience, and neural data analysis. By the completion of the career development award, I will have successfully applied for R01-level funding and will be ready to transition to a fully independent clinician-investigator dedicated to improving anesthesia care in children.