Automated Intravenous Anesthesia Delivery to Improve Outcome in Children-TIVAPeds

具体目标 该计划的总体目标是开发TIVAPeds，一种麻醉的自动驾驶药物输送装置 专为2岁及以上儿童实施全静脉麻醉(TIVA)而设计的平台。建议数 平台集成了一个大脑监视器，其输出用于自动和连续地调整 异丙酚根据护理提供者的靶向效应。我们相信，这一装置将成为一种使 促进TIVA在国内外儿科麻醉中更广泛渗透的技术，以及 最终将导致更安全的做法和更好的结果。 原理：与吸入麻醉相比，TIVA被证明是一种更好的麻醉方案 对术中事件和术后结果的影响[1]。尤其是，这一发病率 喉痉挛/支气管痉挛、术后恶心呕吐(PONV)和苏醒激越 显著减少[2]。例如，丙泊酚和瑞芬太尼联合TIVA与较低的 出现精神错乱(38.3%对14.9%)和较低的术后疼痛评分[3]。此外，挥发性麻醉剂 到目前为止，已被证明在所有动物模型的发育中对大鼠、小鼠、豚鼠的大脑具有神经毒性 猪、小猪和恒河猴)[5，25]。最近的一项研究表明，在统计上有显著的关联 吸入麻醉的累积暴露与较差的全面/言语/操作智商和加工能力之间的关系 速度[27]。其他关于学习障碍的回溯性研究也得出了类似的结论[28， 29]，注意力缺陷/多动障碍[30]，以及语言/抽象推理缺陷[32]。 因此，在一些儿科麻醉科，如BC儿童医院，这并不令人惊讶 (温哥华，卑诗省，加拿大)，TIVA的使用已成为护理的标准[4]。这形成了鲜明的对比。 在美国的做法，在那里仍然主要使用吸入麻醉，主要是出于方便和 训练。事实上，当使用吸入麻醉剂时，呼气末挥发性麻醉剂浓缩措施提供了 血浆中挥发性麻醉剂浓度的实时估计。复合药代动力学 因此，效果对临床医生是透明的，他们可以相应地调整他们的滴定。类似的方法 在使用静脉注射制剂时是不可用的，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。这一增长已经 靶控输液(TCI)泵的问世使之成为可能。这些特殊的泵嵌入了 药物模型，用于计算快速达到稳态药物血液的输液曲线 血药浓度，从而说明药物的摄取、分布和消除。然而，公开的 这些泵的循环性质使它们容易因患者之间的差异而过量/不足，这是 尤其是在儿童中。由于对这些药理模型不足的担忧，食品 美国药品监督管理局(FDA)拒绝批准TCI泵用于人类。TIVA在医院临床实践中的应用 因此，美国仍保持完全手工操作。对药物的药代动力学和动力学有深入的了解 因此，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的安全性和结果更有利，但仍由经验较少的护理人员提供帮助。 拟议的TIVAPeds系统旨在通过提供麻醉护理来促进TIVA的实践 根据大脑活动水平，为异丙酚提供“自动驾驶”。在…的过程中 手术后，系统会自动和持续地调整给药，以驱动和 根据患者本人的直接生理反馈，将患者保持在所需状态。 由于手术刺激强度的变化而引起的皮质状态的变化也会自动补偿。 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。根据药物效果的直接反馈，患者之间 药理变异性和复杂药物的药动学和药效学自动 算进去了。通过设计，TIVAPeds将提供与TIVA相同的有利安全性和结果概况， 不需要陡峭的学习曲线，增加的工作量，或在剂量方面可能出现的人为错误。 此外，我们预计这样的闭环系统本质上会更安全(始终保持警惕，反应更快 患者状态的改变)，并将使临床医生能够为他们的患者提供最佳麻醉剂量 改善了结果。 这个为期24个月的二期项目的具体目标是推进临床应用的研究原型。 作为第一阶段工作的一部分进行评估，成为准备进行监管临床试验的产品级平台。这个平台 将利用以前和当前的开发工作。根据FDA的输入，进一步的控制器设计和验证将 使用在第一阶段开发和验证的方法进行。FDA向我们提供了详细的 指导我们的发展和临床工作的建议，这些建议构成了研究计划的基础。这个 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。 商机是巨大的。TIVA有可能成为儿科护理的标准 麻醉，只要有像TIVAPeds这样安全有效的支持技术存在。TIVAPeds的使用 是基于使用专有的管理集来提供经常性收入流。

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.