Posted March 22, 2017

Stephane Bibian, Ph.D., NeuroWave Systems, Inc.

Total Intravenous Anesthesia (TIVA) is a technique that has recently gained popularity in the U.S. Army and has been successfully utilized in both Iraq and Afghanistan in response to combat situations. The benefits of this intravenous anesthetic and analgesics delivery technology include flexibility for the anesthesia team, increased emergence time, lower incidence of post-operative nausea and vomiting, and reduced incidence of post-operative cognitive dysfunction. The TIVA equipment is also simple, with a small logistical footprint that makes it ideal for military care providers. One of the major hurdles complicating the use of this technology on the battlefield is controlling the depth of anesthesia, as true drug plasma concentration is difficult to directly measure. Dr. Stephane Bibian at NeuroWave Systems, Inc. has been developing a closed-loop TIVA system, AutoTIVA, that continuously adjusts infusion rates of Propofol, a sedative, and Remifentanil, an analgesic. The goal of this Small Business Innovation Research (SBIR) is to develop safe and effective means of delivering TIVA in combat casualty situations. AutoTIVA's closed-loop controlled infusion system provides an observable and quantifiable drug effect.

After completing SBIR Phase I proof-of-concept in 2011, Dr. Bibian went on to obtain SBIR Phase II funding with the goal of making major steps toward developing the hardware and software for an AutoTIVA prototype that adheres to U.S. Food and Drug Administration (FDA) and military standards. Although multiple technical challenges were encountered, Dr. Bibian's team persevered through four years of Phase II work in order to complete the AutoTIVA design, which is now fully compliant for Underwriters Laboratories listing as a medical device. There are four major components of the AutoTIVA delivery system: (1) a clinical-grade electroencephalography (EEG) acquisition system, (2) a Wavelet-based Anesthetic Value for Central Nervous System (WAVcns) index, (3) a robust control algorithm, and (4) a multi-drug infusion pump. The AutoTIVA EEG system shares similar hardware with a miniaturized version that is now market-ready. Notably, NeuroWave Systems recently filed a patent application for its AutoTIVA EEG system circuitry. In addition, other clinical studies supported by Neurowave have shown that the WAVcns index can be effectively utilized in closed-loop anesthesia delivery in both children¹ and adults. WAVcns quantifies the effect of the drug on the brain using wavelet analysis. This index works to measure of brain activity in real time, directly addressing the depth-of-anesthesia issue. Dr. Bibian also designed a control algorithm that demonstrates mathematical proof of stability in a large population to ensure patient safety, which is a key element for receiving FDA approval. The final component of the AutoTIVA system, the infusion pump for Propofol and Remifentanil, is currently being developed under a contract with the U.S. Navy.² This proprietary infusion technology will be integrated into the next generation of the AutoTIVA device, which will eliminate the risk of any regulatory issues surrounding third-party infusion pumps. The Navy pump has been found to exceed the performance standards of en-route care pumps and is now ready for manufacturing.

In addition to the technical development of AutoTIVA, the second major goal of this SBIR Phase II work was to gain insight on the regulatory path forward for commercializing and marketing the device. In October 2015, Dr. Bibian's research team was invited to participate and present their work on AutoTIVA at an FDA workshop on physiological closed-loop control systems. As a result, Dr. Bibian's team has been working with the FDA to propose a guidance document on physiological closed-loop systems, which will be made available this year. In the final year of the Phase II SBIR, the AutoTIVA hardware was developed and the software finalized. In 2016, Dr. Bibian's group submitted a proposal to continue this work under a Phase II enhancement program, which has now been funded. With these funds, they plan to further develop AutoTIVA by integrating the new Navy infusion pumps into the technology.

Dr. Bibian's efforts will continue toward providing the Armed Forces with an integrated compact solution for TIVA drug delivery. Currently known as the battlefield anesthetic of the future, TIVA is expected to become a much more widespread technology in the military. Additional information about can be found in Military Medicine (2015; 180: 96-103).

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¹ West N, Dumont GA, van Heusden K, et al. 2013. Robust closed-loop control of induction and maintenance of propofol anesthesia in children. Paediatr Anaesth 23(8):712-719.

² The infusion pump technology is being developed under contract with the Navy (N00014-14-C-0324). The project was funded in response to a Long Range Broad Agency Announcement (BAA) for Navy and Marine Corps Science and Technology. The period of performance on this award is 9/30/2014 through 6/30/2019

Publication:

Bibian S, Dumont GA, Black I. 2015. Closed-loop target-controlled infusion systems: stability and performance aspects. Mil Med 180: 96-103. doi: 10.7205/MILMED-D-14-00380.

Link:

Award Information: Deployable Closed-Loop Anesthesia System 2015 Presentation to the FDA: Closed Loop Total Intravenous Anesthesia (TIVA)

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