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 平台设计用于2岁及以上儿童的全静脉麻醉（TIVA）。拟议 该平台集成了一个大脑监测器，其输出用于自动和连续地调节 异丙酚根据护理提供者的目标效果。我们相信这个装置将成为一个 促进TIVA在国内外儿科麻醉中更广泛渗透的技术，以及 最终会带来更安全的实践和更好的结果。 依据：与吸入麻醉相比，TIVA已被证明是一种上级麻醉方案， 关于术中事件和术后结局[1]。特别是， 喉痉挛/支气管痉挛、术后恶心呕吐（PONV）和苏醒期躁动是 大幅下降[2]。例如，丙泊酚和瑞芬太尼的TIVA与较低的 苏醒期谵妄（38.3% vs. 14.9%）和较低的术后疼痛评分[3]。此外，挥发性麻醉剂 在迄今为止测试的所有动物模型（大鼠、小鼠、豚鼠）的发育中的大脑中显示出神经毒性。 猪、小猪和恒河猴）[5，25]。最近的一项研究显示， 吸入麻醉的累积暴露与更差的全面/言语/操作智商和处理能力之间的关系 速度[27]。其他回顾性研究也得出了关于学习障碍的类似结论[28， 注意力缺陷/多动障碍[30]和语言/抽象推理缺陷[32]。 因此，在一些儿科麻醉部门，如BC儿童医院， （温哥华，不列颠哥伦比亚省，加拿大），TIVA的使用已成为护理标准[4]。这与 在美国的实践中，吸入麻醉仍然主要使用，主要是出于方便的原因， 训练实际上，当使用吸入麻醉剂时，潮气末挥发性麻醉剂浓度测量提供了 血浆中挥发性麻醉剂浓度的实时估计。复杂药代动力学 因此，效果对于临床医生是透明的，临床医生可以相应地调整他们的滴定。类似的方法 当使用静脉内药物时，这些药物不可用，这使得TIVA的实践更加困难和容易出错。 然而，在大多数国家，TIVA的使用在过去15年中稳步增加。这种增加 目标控制输注（TCI）泵的可用性使其成为可能。这些专业泵嵌入 用于计算输注曲线的药物模型，所述输注曲线被设计为快速达到稳态药物血液 血浆浓度，从而解释药物的吸收、分布和消除。然而，开放 这些泵的回路性质使其易于由于患者间的差异而导致剂量过多/不足， 尤其是在儿童中。由于担心这些药理学模型的不足， 美国药品监督管理局（FDA）拒绝批准TCI泵用于人类。TIVA的实践 因此，美国仍然完全手动。深入了解药物的药代动力学和动力学是 这是一个先决条件。因此，吸入麻醉的使用被认为是更方便和更安全的， 尽管TIVA更有益的安全性和结局特征，但缺乏经验的护理提供者的手。 拟议的系统- TIVAPeds -旨在通过提供麻醉护理来促进TIVA的实践 根据大脑活动的水平，为异丙酚的输送提供“自动驾驶仪”。过程中 在外科手术中，系统自动且连续地调节药物的施用以驱动和 基于来自患者他/她自己的直接生理反馈，将患者维持在期望的状态。 由于手术刺激强度的变化而引起的皮质状态的变化也被自动补偿。 技术创新的潜力是巨大的。TIVAPeds是一种使能技术， 使TIVA更容易和更安全地管理。基于药物效果的直接反馈，患者间 药理学变异性和复杂的药物药代动力学和药效学自动 有记录根据设计，TIVAPeds将提供与TIVA相同的有利安全性和结局特征， 而不需要陡峭的学习曲线、增加的工作量或给药中人为错误的可能性。 此外，我们预计这样的闭环系统将本质上更安全（始终保持警惕，并更快地对 患者状态的变化），并将使临床医生能够向患者提供最佳麻醉剂量， 改善成果。 这个为期24个月的第二阶段项目的具体目标是推进研究原型，这是临床上 作为第一阶段工作的一部分进行评估，成为一个产品级平台，准备进行监管临床试验。这个平台 将利用以前和当前的开发工作。根据FDA的意见，进一步的控制器设计和验证将 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，这些建议构成了研究计划的基础。的 本II期的目标是获得研究器械豁免，以便在美国启动临床试验。 商业机会是巨大的。TIVA有可能成为儿科治疗的标准 麻醉，提供了一个安全有效的支持技术，如TIVAPeds存在。使用TIVAPeds 是基于使用专有管理集提供经常性收入流。