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Diffuse-Optical Monitor of Cerebral Hemodynamics after rtPA Administration in Acute Ischemic Stroke

Final Report Summary - RTPAMON (Diffuse-Optical Monitor of Cerebral Hemodynamics after rtPA Administration in Acute Ischemic Stroke)

Ischemic stroke is the leading cause of morbidity and long term disability in Europe and United States and one of the leading causes of death. The intravenous recombinant tissue-type plasminogen activator (rtPA) is the premier drug indicated for treatment of acute ischemic stroke. Current guidelines (as of project submission in 2009) call for its administration within the first ∼three hours of the stroke onset (now being extended to 4.5 hours due to positive results of ECASS III study). However, despite its success, about 50% of patients treated with rtPA suffer morbidity and even death. It is during this initial emergency treatment phase that a multitude of monitors are deployed in order to monitor the reperfusion (or lack thereof) of the ischemic parenchyma before widespread necrosis takes place.
In this multidisciplinary project, I brought together biomedical physicists and clinical neurologists to develop a novel diffuse optical technology to continuously, non-invasively and at the bed-side mon- itor microvascular, local, cerebral blood oxygenation, cerebral blood volume and cerebral blood flow. Proposed technological developments will enable the use of this technology in a challenging environ- ment such as that of the emergency care of acute ischemic stroke. We have monitored hemodynamics in penumbral regions before, during and after rtPA administration. A particular issue of interest was the onset of recanalization and its sustainment. This pilot data is now being used to assess the value of these monitors to follow the effects of recanalization (or lack thereof) on local microvascular metabolism. If successful, in the long run, it may provide clinicians with the ability to individualize rtPA treatment and also to develop secondary interventions to improve the treatment outcome. This, in turn, should reduce socio-economic costs of stroke care and improve the overall health of Europeans.
By the end of the project, we have completed three generations of the proposed instrumentation. The feedback for the first generation device was that it was difficult to utilize it in the emergency room settings and the second-generation device was designed according to that feed-back. The second generation device has allowed us to carry out a set of initial studies some which have been published [1]. A third generation device has then been constructed within the framework of project that we have obtained that has led to the formation of a spin-off company, HemoPhotonics (Barcelona, Spain), to commercialize this technology for a variety of applications. On the algorithms side, we have developed a two software packages for advanced analysis and incorporated them into our arsenal of tools.
Within this project, three set of studies on humans were also conducted:

1. The first study was to establish the range of healthy cerebro-vascular reactivity (CVR) index in healthy volunteers and to compare the findings of diffuse optical measurements to those of the transcranial Doppler ultrasound. The study was published [2] and was presented in several international conferences [3–5].

2. The second study has extended this to explore the changes in CVR due to severe steno-occlusive internal carotid artery lesions in the same protocol and to compare them to the healthy popu- lation. We have found out significant differences in micro-vascular and macro-vascular response and anecdotal evidence for risk stratification based on this combination. This study was pub- lished in a peer-reviewed paper [6] and presented in numerous conferences including an invited talk [7].

3. As the second-generation device became available for use in the hospital, we have trained the collaborating neurologists in the use of the instrument that have successfully studied a group of patients during the initial emergency room management including several injections of rtPA. The initial results were published [1] and the more complete data set from ten patients is being analyzed.

Several secondary studies and projects have emerged from the knowledge gained through this project which are outlined separately.