Automated Intravenous Anesthesia Delivery to Improve Outcome in Children-TIVAPeds

自动静脉麻醉可改善儿童预后 - TIVAPeds

• 批准号: 10018930
• 负责人: Stephane Bibian
• 金额: $ 83.25万
• 依托单位: NEUROWAVE SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018930
• 关键词: Accounting; Agitation; Anesthesia procedures; Anesthetics; Animal Model; Attention deficit hyperactivity disorder; Brain; Bronchial Spasm; Canada; Cavia; Child; Childhood; Clinical; Clinical Trials; Complex; Country; Delirium; Development; Devices; Dose; Drug Delivery Systems; Drug Kinetics; Drug Modelings; Event; Exposure to; Feedback; Goals; Hematologic Agents; Human; Incidence; Infusion Pumps; Infusion procedures; Inhalation Anesthesia; Inhalation Anesthetics; Intravenous; Intravenous Anesthesia; Investigation; Language; Laryngismus; Lead; Learning; Learning Disabilities; Macaca mulatta; Manuals; Measures; Methodology; Methods; Modeling; Monitor; Mus; Nature; Operative Surgical Procedures; Outcome; Output; Patients; Pediatric Hospitals; Penetration; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Plasma; Postoperative Nausea and Vomiting; Postoperative Pain; Postoperative Period; Propofol; Pump; Rattus; Recommendation; Regimen; Research; Retrospective Studies; Stimulus; Stream; System; Technology; Testing; Time; Titrations; Training; United States Food and Drug Administration; Variant; Work; Workload; base; care providers; design; experience; human error; improved outcome; interpatient variability; medical specialties; neurotoxic; pain score; pharmacokinetics and pharmacodynamics; processing speed; programs; prototype; remifentanil; safety outcomes; standard of care; technological innovation; uptake

SPECIFIC AIMS The overall objective of this Program is to develop the TIVAPeds, an anesthesia ‘auto-pilot’ drug delivery platform designed to administer Total Intravenous Anesthesia (TIVA) in children 2-yrs and older. The proposed platform integrates a brain monitor whose output is used to automatically and continuously adjust the delivery of propofol based on the care provider’s targeted effect. We believe that this device will become an enabling technology facilitating the wider penetration of TIVA in pediatric anesthesia, both domestically and abroad, and will ultimately lead to a safer practice, and improved outcome. Rationale: TIVA has been shown to be a superior anesthesia regimen as compared to inhaled anesthesia with respect to intra-operative events and post-operative outcome [1]. In particular, the incidence of laryngospasms/bronchospasms, Post-Operative Nausea and Vomiting (PONV), and emergence agitation are significantly reduced [2]. For instance, TIVA with propofol and remifentanil was associated with a lower rate of emergence delirium (38.3% vs. 14.9%) and a lower postoperative pain score [3]. In addition, volatile anesthetics have been shown to be neurotoxic in the developing brain of all animal models tested to-date rats, mice, guinea pigs, piglets, and rhesus monkeys) [5, 25]. A recent study has shown a statistically significant association between cumulative exposure to inhaled anesthesia and worse full-scale/verbal/performance IQ and processing speed [27]. Other retrospective studies have reached similar conclusions with respect to learning disabilities [28, 29], development of attention-deficit/hyperactivity disorder [30], and deficits in language/abstract reasoning [32]. It is therefore not surprising that in some pediatric anesthesia departments, like the BC Children Hospital (Vancouver, BC, Canada), the use of TIVA has become the standard of care [4]. This comes in sharp contrast to the practice in the US, where inhaled anesthesia is still primarily used, mostly for reasons of convenience and training. Indeed, when using inhalation anesthetics, end-tidal volatile anesthetic concentration measures provide a real-time estimate of the volatile anesthetic concentration in the plasma blood. Complex pharmacokinetics effects are thus made transparent to the clinicians, who can adjust their titration accordingly. Similar methods are not available when using intravenous agents, which makes the practice of TIVA more difficult and error prone. Yet, in most countries, the use of TIVA has seen a steady increase over the last 15 years. This increase has been made possible by the availability of Target Controlled Infusion (TCI) pumps. These specialty pumps embed drug models that are used to calculate an infusion profile designed to quickly reach a steady-state drug blood plasma concentration, thereby accounting for the drug’s uptake, distribution, and elimination. However, the open loop nature of these pumps makes them prone to over/under-dosing due inter-patient variability, which is particularly large in children. Due to concerns over the inadequacy of these pharmacological models, the Food and Drug Administration (FDA) has declined to approve TCI pumps for human use. The practice of TIVA in the US remains therefore fully manual. Thorough understanding of drug’s pharmacokinetics and dynamics is therefore a pre-requisite. As a result, the use of inhaled anesthesia is regarded as more convenient and safer in the hands of less experienced care providers, despite the more beneficial safety and outcome profile of TIVA. The proposed system – TIVAPeds – intends to facilitate the practice of TIVA by providing anesthesia care providers with an ‘auto-pilot’ for the delivery of propofol, based on the level of brain activity. During the course of the surgery, the system automatically and continuously adjusts the administration of the drug to drive and maintain the patient into a desired state, based on direct physiological feedback from the patient him/herself. Changes in cortical state due to variations in the surgical stimuli intensity are also automatically compensated. The potential for technological innovation is substantial. The TIVAPeds is an enabling technology aimed at making TIVA easier and safer to administer. Based on a direct feedback of drug effect, inter-patient pharmacological variability and the complex drug pharmacokinetics and pharmacodynamics are automatically accounted for. By design, the TIVAPeds will provide the same favorable safety and outcome profile as TIVA, without the requirement of a steep learning curve, increased workload, or the potential for human errors in dosing. In addition, we expect such closed-loop system will be inherently safer (always vigilant and reacting faster to changes in the patient’s state) and will empower clinicians to deliver optimal anesthetic dose to their patients for improved outcomes. The Specific Aim of this 24-month Phase II project is to advance the research prototype, which was clinically evaluated as part of the Phase I work, into a product-level platform ready for regulatory clinical trials. This platform will leverage prior and current development work. Further controller design and verification, per FDA’s input, will be carried out using the methodology developed and validated in the Phase I. The FDA provided us with detailed recommendations to guide our development and clinical work, which form the basis of the research plan. The goal of this Phase II is to obtain an Investigational Device Exemption to initiate clinical trials in the US. The commercial opportunity is substantial. TIVA has the potential to becoming a standard of care in pediatric anesthesia, provided a safe and effective supporting technology like the TIVAPeds exists. The use of TIVAPeds is predicated on the use of proprietary administration sets providing a stream of recurring revenues.

具体目标 该计划的总体目标是开发 TIVAPeds，一种麻醉“自动驾驶”药物输送装置 旨在对 2 岁及以上儿童进行全静脉麻醉 (TIVA) 的平台。 平台集成了一个大脑监视器，其输出用于自动、连续地调整大脑的输送 我们相信该设备将成为一种基于护理人员的针对性效果的异丙酚。 技术促进 TIVA 在国内外儿科麻醉领域的更广泛渗透，以及 最终将带来更安全的实践和更好的结果。 理由：与吸入麻醉相比，TIVA 已被证明是一种更优越的麻醉方案。 关于术中事件和术后结果[1]。 喉痉挛/支气管痉挛、术后恶心和呕吐 (PONV) 以及苏醒期躁动 显着降低[2]，例如，异丙酚和瑞芬太尼的 TIVA 与较低的发生率相关。 苏醒性谵妄（38.3% vs. 14.9%）和较低的术后疼痛评分 [3]。 已被证明对迄今为止测试的所有动物模型的发育中的大脑具有神经毒性，包括大鼠、小鼠、几内亚 猪、仔猪和恒河猴）[5, 25] 最近的一项研究显示了统计学上的显着关联。 吸入麻醉的累积暴露与较差的全面/语言/表现智商和处理之间 其他回顾性研究在学习障碍方面也得出了类似的结论[28， [29]，注意力缺陷/多动障碍的发展[30]，以及语言/抽象推理的缺陷[32]。 因此，在一些儿科麻醉科，例如 BC 儿童医院，这并不奇怪。 （加拿大不列颠哥伦比亚省温哥华），TIVA 的使用已成为护理标准 [4]。 与美国的实践相比，美国仍然主要使用吸入麻醉，主要是出于方便和 事实上，当使用吸入麻醉剂时，呼气末挥发性麻醉剂浓度测量可以提供。 血浆中挥发性麻醉剂浓度的实时估计。复杂的药代动力学。 因此，效果对防御者来说是透明的，他们可以相应地调整他们的滴定方法。 使用静脉注射药物时不可用，这使得 TIVA 的实践更加困难且容易出错。 然而，在大多数国家，TIVA 的使用在过去 15 年中稳步增长。 这些嵌入的专用泵使目标控制输注 (TCI) 泵成为可能。 用于计算输注曲线的药物模型，旨在快速达到稳态药物血液 血浆，从而解释药物的摄取、分布和消除。然而，开放浓度。 这些泵的回路性质使得它们容易由于患者间的差异而出现剂量过量/剂量不足的情况，即 由于对这些药理学模型的不足的担忧，食物在儿童中尤其严重。 药物管理局 (FDA) 拒绝批准 TCI 泵用于人体。 因此，美国对药物的药代动力学和动力学的透彻理解仍然是完全手动的。 因此，吸入麻醉的使用被认为更方便、更安全。 尽管 TIVA 具有更有益的安全性和结果特征，但仍由经验不足的护理人员负责。 拟议的系统 – TIVAPeds – 旨在通过提供麻醉护理来促进 TIVA 的实践 根据治疗过程中的大脑活动水平，提供异丙酚输送的“自动驾驶仪”。 手术过程中，系统自动连续调整给药剂量以驱动和 根据患者本人的直接生理反馈，使患者保持在所需的状态。 由于手术刺激强度的变化而导致的皮质状态的变化也会被自动补偿。 TIVAPeds 是一项旨在实现技术创新的潜力巨大。 基于药物效果的直接反馈，使 TIVA 的给药更容易、更安全。 药理学变异性和复杂的药物药代动力学和药效学自动 根据设计，TIVAPeds 将提供与 TIVA 相同的良好安全性和结果特征， 无需陡峭的学习曲线、增加工作量或剂量中出现人为错误的可能性。 此外，我们预计这种闭环系统本质上会更安全（始终保持警惕并更快地做出反应） 患者状态的变化）并将能够为患者提供最佳的麻醉剂量 改善结果。 这个为期 24 个月的 II 期项目的具体目标是推进研究原型，该原型已在临床上 作为第一阶段工作的一部分，该平台已被评估为可用于监管临床试验的产品级平台。 将根据 FDA 的意见，利用之前和当前的开发工作进行进一步的控制器设计和验证。 使用第一阶段开发和验证的方法进行。FDA 向我们提供了详细的 指导我们的开发和临床工作的建议，构成研究计划的基础。 第二阶段的目标是获得研究设备豁免，以便在美国启动临床试验。 TIVA 的商业机会巨大，有可能成为儿科护理标准。 麻醉，前提是存在 TIVAPeds 等安全有效的支持技术 TIVAPeds 的使用。 是基于使用专有管理集提供经常性收入流。

项目成果

Optimizing Robust PID Control of Propofol Anesthesia for Children: Design and Clinical Evaluation.

优化儿童异丙酚麻醉的稳健 PID 控制：设计和临床评估。

• 发表时间: 2019-10
• 作者: van Heusden, Klaske;Soltesz, Kristian;Cooke, Erin;Brodie, Sonia;West, Nicholas;Gorges, Matthias;Ansermino, J Mark;Dumont, Guy A
• 通讯作者: Dumont, Guy A