Automated Intravenous Anesthesia Delivery to Improve Outcome in Children-TIVAPeds - 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.
