Phase II year
2019
(last award dollars: 2020)
Phase II Amount
$1,496,205
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 providers 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 drugs 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 drugs 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 patients 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 FDAs 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.
Public Health Relevance Statement: PROJECT NARRATIVE Total IntraVenous Anesthesia (TIVA) in children offers significant advantages in terms of outcomes in comparison to commonly used inhaled anesthesia. In order to make the practice of TIVA more accessible and safer, we have developed an anesthesia auto-pilot - TIVAPeds - which automatically and continuously adjusts the administration of TIVA to maintain the patient in an optimal anesthetic depth. This auto-pilot was successfully tested in the feasibility phase of this program, and we now plan to develop the final commercial platform based on the FDAs written recommendations and guidance as part of the Phase II work.
Project Terms: Accounting; Agitation; Anesthesia procedures; Anesthetics; Animal Model; Attention deficit hyperactivity disorder; base; Brain; Bronchial Spasm; Canada; care providers; Cavia; Child; Childhood; Clinical; Clinical Trials; Complex; Country; Delirium; design; Development; Devices; Dose; Drug Delivery Systems; Drug Kinetics; Drug Modelings; Event; experience; Exposure to; Feedback; Goals; Hematologic Agents; Human; human error; improved outcome; Incidence; Infusion procedures; Infusion Pumps; Inhalation Anesthesia; Inhalation Anesthetics; interpatient variability; Intravenous; Intravenous Anesthesia; Investigation; Language; Laryngismus; Lead; Learning; Learning Disabilities; Macaca mulatta; Manuals; Measures; medical specialties; Methodology; Methods; Modeling; Monitor; Mus; Nature; neurotoxic; Operative Surgical Procedures; Outcome; Output; pain score; Patients; Pediatric Hospitals; Penetration; Performance; Pharmaceutical Preparations; pharmacokinetics and pharmacodynamics; Pharmacology; Phase; Physiological; Plasma; Postoperative Nausea and Vomiting; Postoperative Pain; Postoperative Period; processing speed; programs; Propofol; prototype; Pump; Rattus; Recommendation; Regimen; remifentanil; Research; Retrospective Studies; Safety; standard of care; Stimulus; Stream; System; technological innovation; Technology; Testing; Time; Titrations; Training; United States Food and Drug Administration; uptake; Variant; Work; Workload
