Non-Human Primate Model for Developing Closed-Loop Anesthesia Delivery Systems

摘要/项目总结 持续监测生理状态（氧合、呼吸、循环）是所有人的标准做法 接受全身麻醉和镇静的患者。麻醉剂的主要作用是 通过作用于大脑和中枢神经系统中的分子靶点和神经回路， 神经系统然而，持续监测大脑功能并不是实践的要求。毫不 令人惊讶的是，全身麻醉后的脑功能障碍非常普遍，特别是在老年人中。 同样，COVID 19患者可以在重症监护室麻醉数周，通常会留下 在终止辅助治疗后出现严重的脑功能障碍。多年的研究表明， 接受全身麻醉的患者的无意识水平可以使用实时 处理脑电图（EEG）记录。近年来，在以下方面取得了巨大进展： 传感器、执行器、人工智能和控制理论算法。一个非常合理的解决方案是 开发闭环麻醉输送（CLAD）系统，该系统根据EEG以真实的时间确定 患者的无意识水平，并精确控制麻醉剂输注，以保持水平在 合适的目标。联邦药品管理局（FDA）欣然承认， 到CLAD系统可以提供的病人护理。到目前为止，还没有系统被批准用于人类使用， 缺乏适当的动物模型来充分测试这些系统的可靠性和稳健性。因此 该项目的研究设计将在非人类灵长类动物中进行神经生理学记录（EEG， 局部场电位和神经尖峰活动），同时使用 当动物执行行为任务以表征 昏迷将通过药代动力学和药效学建模相结合来分析数据， 现代控制理论和统计信号处理方法来开发和测试实时CLAD系统。 该研究项目的具体目标是在非人类灵长类动物模型CLAD系统中开发和测试 使用麻醉剂：丙泊酚、右美托咪定和丙泊酚实时控制无意识， 右美托咪定同时给药。广泛的长期目标是： 灵长类动物模型范式的开发和测试的CLAD系统，并利用CLAD系统， 智能大脑状态监测和精确的秒到秒的麻醉药物剂量的标准。的 这项研究的健康相关性影响将成为计算机辅助大脑状态警戒的新范式 和计算机辅助麻醉剂给药。这样的系统应该通过减少 提供者的错误，并通过促进麻醉相关的脑功能障碍以及其他 麻醉相关疾病（疼痛控制不足、低血压、恶心） 每年有数百万患者在手术室和重症监护室接受麻醉护理。

ABSTRACT/PROJECT SUMMARY Continuous monitoring of physiological state (oxygenation, breathing, circulation) is a standard practice for all patients receiving general anesthesia and sedation. Anesthetics produce their primary effects of unconsciousness and antinociception by acting on molecular targets and neural circuits in the brain and central nervous system. Nevertheless, continuous monitoring of brain function is not a practice requirement. It is no surprise that brain dysfunction following general anesthesia is highly prevalent, particularly among the elderly. Similarly, COVID 19 patients who can be anesthetized for weeks in the intensive care unit, are often left with profound brain dysfunction following termination of ventilatory support. Many years of research have shown that the level of unconsciousness of a patient receiving general anesthesia can be reliably tracked using real-time processing of electroencephalogram (EEG) recordings. In recent years, dramatic advances have been made in sensors, actuators, artificial intelligence and control theory algorithms. A highly plausible solution is the development of closed loop anesthesia delivery (CLAD) systems that determine in real time from the EEG the patient’s level of unconsciousness and precisely control an anesthetic infusion to maintain the level at an appropriate target. The Federal Drug Administration (FDA) readily acknowledges the significant enhancement to patient care that CLAD systems can provide. To date, no system has been approved for human use due to a lack of appropriate animal models to test adequately the reliability and robustness of these systems. Therefore the research design of this project will be to conduct in non-human primates neurophysiological recordings (EEG, local field potentials and neural spiking activity) while simultaneously administering anesthetics using a computer-controlled syringe pump as the animals execute a behavior task to characterize level of unconsciousness. The data will be analyzed by combining pharmacokinetics and pharmacodynamic modeling, modern control theory and statistical signal processing approaches to develop and test real-time CLAD systems. The specific aims of this research project are to develop and test in a non-human primate model, CLAD systems for real-time control of unconsciousness using the anesthetics: propofol, dexmedetomidine, and propofol and dexmedetomidine administered simultaneously. The broad long-term objectives are to: establish a non-human primate model paradigm for development and testing of CLAD systems; and make the use of CLAD systems a standard for intelligent brain state monitoring and precise second-to-second drug dosing in anesthesiology. The health relatedness impact of the research will be a new paradigm for computer-assisted vigilance of brain state and computer-assisted dosing of anesthetic agents. Such systems should enhance patient safety by reducing provider errors and by fostering significant decreases in anesthesia-associate brain dysfunction as well as other anesthesia-related morbidities (inadequate pain control, hypotension, nausea) commonly experienced by the millions of patients who each year receive anesthesia care in operating rooms and intensive care units.