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

摘要/项目摘要 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。麻醉药产生的主要作用是 无意识和抗伤害性感觉通过作用于大脑和中枢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一种实践要求。不是的 令人惊讶的是，全身麻醉后的大脑功能障碍非常普遍，特别是在老年人中。 同样，可以在重症监护病房麻醉数周的COVID 19患者通常会留在 呼吸机支持终止后的严重脑功能障碍。多年的研究表明， 可以使用实时跟踪来可靠地跟踪接受全身麻醉的患者的昏迷程度 脑电(EEG)记录的处理。近年来，在以下方面取得了显著进展 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 闭合循环麻醉输送(CLAD)系统的开发，该系统可根据脑电实时确定 患者的昏迷程度，并准确控制麻醉剂的输注，以将水平维持在 合适的目标。联邦药品管理局(FDA)欣然承认这一显著的增强 到覆盖系统所能提供的病人护理。到目前为止，还没有系统被批准用于人类使用，因为 缺乏适当的动物模型来充分测试这些系统的可靠性和健壮性。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记录(EEG， 局部场电位和神经放电活动)，同时使用 计算机控制的注射器泵，当动物执行行为任务时，表征 不省人事。数据将通过结合药代动力学和药效学模型进行分析， 开发和测试实时CLAD系统的现代控制理论和统计信号处理方法。 这项研究项目的具体目标是开发和测试非人类灵长类动物模型，CLAD系统 用于使用麻醉剂：异丙酚、右旋美托咪定和异丙酚实时控制意识障碍 同时给予右美托咪定。广泛的长期目标是：建立一个非人类的 用于包层系统开发和测试的灵长类模型范例；并使包层系统的使用成为 麻醉学中智能脑状态监测和精确的秒至秒给药标准。这个 健康相关性影响的研究将为计算机辅助警示大脑状态提供新的范式 以及计算机辅助的麻醉剂剂量。这样的系统应该通过减少 通过促进麻醉相关脑功能障碍以及其他方面的显著减少 麻醉相关的疾病(疼痛控制不充分、低血压、恶心)通常由 每年有数以百万计的患者在手术室和重症监护病房接受麻醉护理。

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.