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Development of a Novel Autonomous Non-Invasive Absolute Intracranial Pressure Measurement Device Based on Ultrasound Doppler Technology

Final Report Summary - BRAINSAFE II (Development of a Novel Autonomous Non-Invasive Absolute Intracranial Pressure Measurement Device Based on Ultrasound Doppler Technology)

Executive Summary:
The primary aim of treatment and critical care for patients suffering of neurological diseases or brain injuries is to closely monitor the patient state and provide appropriate therapeutic intervention. A key component of such monitoring involves measurement of intracranial pressure (ICP). ICP is a central variable – a vital sign – in neurological diagnosing and monitoring because of its importance in intracranial dynamics, its direct effect on cerebral perfusion, and its correlation with prognosis and outcome in different groups of patients. However, current methods for direct measurement of ICP are highly invasive and carry risks of tissue damage and infection. The cost, complexity and risks involved mean that ICP is measured only in the most critically ill patients and not in the millions of neurological patients who are at mild to moderate risk. Thus, there’s a clear and compelling need for non-invasive ICP meter for routine clinical care.
Innovative non-invasive ultrasound based ICP measurement technology BrainSafe addresses this need and offers the World’s first non-invasive method for regularly measuring ICP accurately, precisely and reliably without the need for patient specific calibration. The BrainSafe II project continues on the development of the technology aiming to create fully automatic non-invasive ICP meter for routine clinical care – an autonomous, rapid, accurate and precise device for measurement of absolute (quantitative) ICP value without the need to calibrate the device for individual patient. The project achieved significant scientific and technological results including the development of enhanced ultrasound Doppler system, optimized signal processing algorithms, novel pressurization subsystem and automatic electromechanical ultrasonic transducer spatial positioning system. Fully integrated and automatic system for non-invasive ICP measurements by non-experts was created for the first time. The automatic operation of the device eliminates the need for highly qualified personnel which would otherwise create a bottleneck in the adoption and wide application of the device.
The impact of this technology will be highly significant across a wide spectrum of levels. The clinical impact will mean improvement in the diagnosis and treatment of neurosurgical and neurological diseases. Earlier, faster, easier to perform and more accurate diagnosis will save lives and prevent disability. The innovative technology will open up possibility for use in several settings where ICP monitoring would improve care, but it’s currently avoided because of complexity or highly invasive nature of available methods. A much greater number of patients than before will benefit from screening by this technological breakthrough because it will not be necessary to have highly trained personnel operating the device.
For the EU citizens, the impact lies in better treatment, prevented disability and enhanced quality of life of the patients, resulting in reduced care costs, and decreased loss of productive years.
For the European industry and decision makers project results give input for development and exploitation of products employing the innovative technologies developed in the project thereby increasing global competitiveness. The project has generated technological knowhow enabling differentiated, sustainable and competitive business growth for the European SME and its industrial partners. All the SMEs in the Brainsafe II consortium will enjoy a significant commercial benefit resulting from market expansion for ICP diagnostic devices driven by the adoption of Brainsafe II technology across the world neuro-diagnostic markets.
The BrainSafe II consortium partners contributed expert manpower and state of the art equipment, facilities and team competences required to achieve the main objectives of the project. The project was carried out by a consortium of field experts within ultrasonic techniques, signal processing, ergonomic hardware design and manufacturing ensuring coverage of all the key components for successful implementation of the project and supply chain capacities to exploit the results thereafter.

Project Context and Objectives:
Traumatic brain injury (TBI) occurs when a sudden trauma causes damage to the brain. It is a major health problem and the most common cause of permanent disability in people under the age of 40 years. Annual costs from traumatic brain injury in Europe and the US exceed €100 billion. Intracranial pressure (ICP) measurement is an extremely important part of the neurosurgical assessment. Not only is raised Intracranial pressure (ICP) the commonest cause of death in neurosurgical patients, it is extremely common in patients suffering from head injury. In this latter group, 40% of patients who are admitted to hospital in an unconscious state have raised ICP, and in 50% of those who die, raised ICP is the main cause. Numerous investigations have shown that sustained intracranial hypertension is associated with a poor prognosis. The effective treatment of high ICP has been shown to decrease mortality. Even so, ICP must be measured before a diagnosis of raised ICP and effective treatment can be made.
Only invasive technologies for the diagnosis of Intracranial Pressure (ICP) for patients with Traumatic Brain Injury (TBI) are available today. Current procedures require neurosurgeons to place a catheter inside the patient’s skull that exposes the patients to the risk of infection, bleeding, and leak of fluids or loss of other body tissue, pain, and hyperthermia as well as risks related to anesthetics. Relative to these risks and complexity of the procedure, only 20% of all TBI patients get access to the diagnostics of Intracranial Pressure measurement. This results in over 1.3 million head injury patients in Europe annually being diagnosed without proper examination of the potential severity of their brain injuries. Early diagnosis of elevated intracranial pressure is also essential for the treatment of neurological patients. The lack of early diagnosis of increased ICP causes 100,000 new long-term disabilities and 400,000 deaths each year for this patient group. Furthermore, it is estimated that 25 million EU citizens suffer from chronic headaches and over 12 million have some form of dementia. Each year, between 3 and 4 million suffer head injuries (up to 25% of which require hospitalization), over 1 million suffer strokes and over 100,000 suffer various brain tumors. These citizens would greatly benefit from the ICP monitoring, but only if an easy to use non-invasive ICP monitoring is available.
Innovative non-invasive ultrasound based ICP measurement technology BrainSafe addresses this need and offers the World’s first non-invasive method for regularly measuring ICP accurately and reliably without the need for patient specific calibration. The BrainSafe II project is initiated by Vittamed with the goal to develop non-invasive ICP meter for routine clinical care.
The Brainsafe II project aims to develop an innovative prototype device for the autonomous, individual patient specific calibration free, non-invasive, rapid, accurate and precise measurement of absolute (quantitative) intracranial pressure value (aICP).
BrainSafe II device has to be designed in compliance to EU Council Directive 93/42/EEC concerning medical devices and international industrial standards of the basic safety and essential performance of ultrasonic diagnostic equipment:
EN ISO 14971:2012 Application of risk management to medical devices;
EN 60601-1:2012 Medical electrical equipment Part 1: General requirements for basic safety and essential performance;
EN 60601-1-2:2007 Medical electrical equipment Part 1-2: General requirements for basic safety and essential performance;
EN 60601-2-37:2008 Medical electrical equipment Part 2-37: Particular requirements for the basic safety and essential performance of ultrasonic medical diagnostic and monitoring equipment;
EN 62304:2006 Medical device software – Software life cycle processes;
EN ISO 10993-1:2009 Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.
The Brainsafe II device has to be designed in such a way that, when used under the conditions and for the purposes intended, it will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with its intended use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety.
The intended use of the BrainSafe device is obtaining the quantitative value of intracranial pressure in a non-invasive manner.
Main features of the new innovative device:
1. Measurement of absolute ICP (aICP) by a non-invasive and fully automatic process with target precision of SD = +/-2.5 mmHg within the 0-50mmHg pressure range - comparable to the nominal precision of existing invasive ICP monitors.
2. Fast measurements. Measurements can be performed shortly after the injury, and will not require surgical operations to collect data. After mounting and adjusting of the mechanical frame and the biomechanical pressure capsule, automatic measurements can begin. The biomechanical pressure capsule touches the closed eye lid and is comfortable and safe for the patient. Our target pressure determination is within nine minutes or less.
3. Accessible. The device will be physically small, facilitating a table-top to be used in any clinical setting. It will therefore be accessible to a much wider group of patients compared to invasive solutions.
4. Does not require expert knowledge to operate. The automatic operation of the device will eliminate the need for highly qualified sonographers which would otherwise create a bottleneck in the adoption and application of the device. The device will present fully processed data, providing the operator with the necessary information.
Several research and technological tasks have to be accomplished in the development process of the fully integrated and automatic non-invasive ICP measurements system, to be operated by non-experts. The ultrasonic trans-cranial Doppler technology (TCD) must be enhanced in terms of resolution and accuracy in collecting Ophthalmic Artery (OA) blood flow measurements to enable implementation of automatic OA location and tracking solutions and reduce non-invasive ICP absolute value snapshot measurement time. Reliable automatic location and focusing of ultrasonic beams in two depths of blood flow measurements in the Intracranial Ophthalmic Artery (IOA) and Extracranial Ophthalmic Artery (EOA) segments have to be developed in order to shorten ICP segment location time and to eliminate possible errors of non-experienced operators’ of non-invasive ICP system. Biomechanical pressurization system for ICP measurement has to be developed to work with the automatic system. Robotic hardware must be developed for fast automatic location of IOA and EOA segments using a robotic ultrasonic transducer actuation or electronic scanning and switching of two ultrasonic beams in the required way.
Three main development areas were identified for the realization of the BrainSafe II instrument:
1. Development of specialized Trans Orbital Doppler (TOD) and ultrasound transducer hardware for continuous measurements of blood flow in the Ophthalmic Artery (OA) in two-depths simultaneously (intra and extra cranially), and with a needed measurement depth resolution , with a required double Doppler signal/noise (S/N) ratio enhancement compared to current solutions.
2. Development of an algorithm and associated data processing software for the automatic location of intracranial and extracranial segments of the Ophthalmic Artery and Internal Carotid Artery.
3. Development of an electromechanically actuated drive system and pressurisation system as integrated parts of the device. The associated communication protocols and firmware have to be developed to automatically manipulate the ultrasonic transducer in order to precisely locate the required segments of OA before non-invasive ICP measurement and during non-invasive automatic ICP measurement process.
4. Integration of the ultrasound transducer, electromechanical actuators and control system to deliver a complete fully automated working system for performing an aICP non-invasive measurement by a non-highly skilled operator in 9 minutes or less.
In order to achieve these technological aims, the following set of specific project objectives are defined for the BRAINSAFE II project:

Specific technological objectives for the Ultrasonic Transcranial Doppler Hardware:

1. Develop an optimized multi-element ultrasonic transducer array for IOA and EOA segment location and OA blood flow measurements capable of measuring blood flows with the SD of random error less than 1.0 mm/s and to a needed depth resolution.
2. Improve the signal-to-noise (S/N) ratio of OA blood flow Doppler measurements by a factor of 2 or more compared to conventional ultrasonic techniques using enhanced digital signal processing architecture.
3. Develop optimized ultrasonic hardware architecture for simultaneous dual depth measurement of blood flow .
4. Implement the Doppler device in electronic hardware and establish a Data transfer protocol capable of controlling the as close to optimal as possible ultrasonic beam focusing on IOA and EOA segments of the ophthalmic artery.

Specific technological objectives for the Data processing Software and Control system:
1. Develop optimized signal processing procedures for optimized OA blood flow measurements, to reduce background noise whereby improve S/N ratio by factor two or more compared to current BrainSafe system’s prototype.
2. Develop intelligent filtering solutions of the Doppler frequency shift signal, and for the removal of Doppler artefacts.
3. Develop algorithms for automatic location for Internal Carotid Artery (ICA) blood flow, the EOA and IOA segment blood flows to within 0,3 mm spatial accuracy.
4. Development of control software and user interface (UI), including GUI and architecture for location of blood flows in ICA, IOA and EOA, and also for automatic tracking of IOA and EOA segments during the non-invasive ICP measurement process.

Specific technological objectives for the ICA and OA segment location and pressurization subsystems:
1. Develop the electromechanical actuator device to drive the positioning of the ultrasonic transducers in an automated and precise manner.
2. Development of reliable, precise and safe to the patient pressurisation system.
3. Development of the headframe with integrated ultrasonic beam directional control and automatic pressurisation systems.
Within the Brainsafe II project preclinical studies of the developed Brainsafe II device were performed on 20 healthy volunteers. The objectives of the studies were to ensure the correct functioning and operation of the Brainsafe II device and not the clinical verification of its efficiency for its intended application. Testing was only performed using volunteers once the device has been fully tested for electrical and mechanical safety.

Project Results:
A number of intellectual proprietary materials were generated during the duration of the BRAINSAFE II project, inclusive of patents and know-how. The RTD partners generated the following key results during the project:
• Result 1: New two depth ultrasound transducer array.
• Result 2: Algorithm to improve the signal/noise ratio.
• Result 3: Algorithm to auto-direct the electromechanical actuators.
• Result 4: Electromechanical actuation system.
• Result 5: Communications hardware and software.

New two depth ultrasound transducer array. Development of specialized Trans cranial Doppler (TCD) and ultrasonic transducer (UT) hardware for continuous measurements of blood flow in the Ophthalmic Artery (OA) in two-depths simultaneously ( intra and extra cranially ), and with a needed measurement depth resolution, with a required double Doppler signal/noise (S/N) ratio enhancement compared to current solutions were the core developments of this technological result of the project.
The developed TOD subsystem with appropriate communication protocol and new software for data exchange with host computer has been developed according to the technical requirements. The developed TOD subsystem works automatically with limited interactivity of operator in adjustment mode, M mode, and two depth Doppler signal monitoring mode and automatic quantitative ICP measurement mode. The possibility to have robotic IOA and EOA (Intracranial and Extracranial segments of Ophthalmic Artery) location solution opened up possibilities for simplification of TCD hardware. The cost-effective BrainSafe II device was designed using single ultrasonic beam trans-orbital Doppler concept.
Ultrasonic Transducer (UT) array with specific beam spatial shape has been developed and tested. The UT is optimally focused for IOA and EOA blood flow velocity measurements with the best signal to noise ratio capable of measuring blood flows with the SD of random error less than 1.0 mm/s and with the OA blood flow measurement depth resolution of 1.0 mm or even less.
A possibility to use simplified ultrasonic transducer arrays instead of scanning multi element ultrasonic transducers in Brainsafe II prototype was identified after in-depth analysis of collected more than 100 patients’ ICP non-invasive measurements’ clinical data with Brainsafe I system. Initial testing results during the design process confirmed feasibility of this option. This opened up possibility to simplifying the whole Brainsafe II system in combination with electromechanical actuation of the UT positioning.
Two cost effective UT solutions were developed and tested with existing system. Acoustic intensity measurements have been performed in focused and unfocused modes of operation in the wet tank and using calibrated hydrophone. A microcontroller or FPGA based hardware and software for forming ultrasonic beam transmitted from transducer array was developed. This unit allows adjust beam shape to get best focusing to IOA and EOA and highest accuracy measurements.
Optimized UT arrays were initially tested with TOD subsystem and integrated with electromechanical actuation subsystem. The designed ultrasonic transducers are able to simultaneously insonate needed segments of the OA (IOA and EOA) with high resolution measurements of blood flow velocity at needed depths in order to perform non-invasive aICP measurement.
Algorithm to improve the signal/noise ratio. The novel clutter removal algorithm based on the Doppler signal Hankel-Singular Value Decomposition filtering and multi-depth signal analysis has been implemented and the codes for real-time Doppler signal processing prepared. The programming of the codes has been prepared in C++ language and compiled in mex files allowing running them from Matlab application.
The results show that the current implementation of the Hankel-SVD filter is able to effectively suppress clutter noise, i.e. the low-frequency and large-amplitude noise. The created Hankel-SVD filter can be easily modified to also suppress the high-frequency noise (the level of high-frequency noise suppression is determined by the user). In fact, in case of noise analysis based on singular values it is even beneficial to use high-frequency noise suppression because it reduces execution times.
Current implementation of the proposed Hankel-SVD filter using multi-depth signal analysis is able to process all necessary input signals in real time using modern computer. For example, benchmarking tests show that it takes approximately 1:5–3 seconds to process 10 seconds long input signals, which fulfills the real-time processing constraint.

Algorithm to auto-direct the electromechanical actuators. Follow after cloud (FAC) algorithm has been created for automatic location for Internal Carotid Artery (ICA), EOA and IOA needed segments' blood flows to within 0.3 mm spatial accuracy.
FAC algorithm has been preliminary tested in vivo on healthy volunteers in order to evaluate possibility to locate IOA and EOA needed segments fully automatically.
Preliminary tests show that up to six iterations (six changes of initial UT positions) are technically possible within expected two minute duration of correct IOA and EOA segments' location procedure.
The automatic signal detection and optimal UT position location algorithm is implemented after placement of ultrasonic transducer on patient’s closed eye lid in an initial position and establishing the acoustic contact between ultrasonic transducer and an eye lid. UT position is steered electromechanically through the all predetermined number of discrete spatial positions.

Electromechanical actuation system
The electromechanically actuated drive system and pressurisation system were developed as integrated parts of the Brainsafe II device. The associated communication protocols and firmware were developed to automatically manipulate the ultrasonic transducer in order to precisely locate the required segments of OA before non-invasive ICP measurement and during non-invasive automatic ICP measurement process.
A plastic goggle was developed as the base for installing UT probe, electromechanical robotic system and pressure chamber. It was designed with flexible belt fasteners to ensure stable and comfortable fixation of the whole head-mount system on patients head. The goggle is designed to be manufactured from rigid suitable for medical use materials. It remains in stable position during the pressure increase in the range Pe = [0;50] mmHg. Plastic goggle is designed to be easily mounted-uncounted on/from patients head with no problems to remove quickly if needed. The new goggles design features an internal lens bayonet for easy twist-on/twist off installation of pressure cuff. Electromechanical system was designed and created to be safe for the patient and the operator. Robotic system operates according to specifications, movement limits on all axis has been tested and approved. Overall system weight is acceptable, system feels comfortable on the head in any position. UT probe pressure on the closed eyelid is comfortable, due to UT holder spring action. Robotic system has the static base which mounts on the goggles. 6 linear actuators simultaneously move the mobile platform in 6 DOF (degrees of freedom) – in X Y Z axis and Θ Φ Ψ axis – Roll, Pitch and Yaw in accordance with the requirements. New UT mount was designed to accommodate 20mm thickness UT. The complete retraction of the UT tip from the eye ball allows possibility to potentially use 20mm UT with better acoustic characteristics. Electromechanical system mounts easily on the goggles together with the pressure cuff.
Designed pressure cuff is mounted on the goggles and consists of polycarbonate disc and thin film non-latex non-allergic elastic material. It is low weight, potentially disposable, easily installable in to the goggle with easy connection to the pressure tubes. The pressure cuff withstands pressures of 0-100mmHg. Automatic electromechanical system for UT positioning and eye pressure chamber for application of external pressure are integrated on the goggles and constitute the “Head-mount part”. All components can be easily assembled and work in synchrony. The design meets the technological and safety requirements.

Communication protocols to drive the electromechanical actuation subsystem which works in synchrony with ultrasonic subsystem and pressurization subsystem were created. Hardware and software solutions for communications of subsystems and separate subsystem components’ were created. The subsystems were integrated to work in synchrony in the fully integrated device.
The performed initial testing of fully integrated device and data analysis confirm that that the completely assembled Brainsafe II device complies with essential requirements. Functional tests demonstrated that all components of the system work well in synchrony and the integrated device is able to perform its intended purpose:
• It is possible to receive signals from IOA and EOA;
• Signal quality is sufficient to perform reliable measurement of ICP.
• The device functions in fully automatic manner in IOA and EOA location mode and ICP measurement mode.
• The device displays result of quantities ICP absolute value in mmHg
• User friendly interface for the user.
• Measurement data storage in local storage media.
• Head frame and headset safe and comfortable for the patient

Brainsafe II device is classified as class IIA (Rule 10) Medical Device (MD) in accordance with MDD 93/42/EEC: Active devices intended for diagnosis are in Class IIa if they are intended to allow direct diagnosis or monitoring of vital physiological processes.
The MD is designed in such a way that, when used under the conditions and for the purposes intended, it will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with its intended use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety.
The performed testing of medical device and data analysis confirm, that that the completely assembled Non-invasive intracranial pressure absolute value meter complies with essential EN 60601-1-1, EN 60601-1-2, EN 60601-2-37, EN 62304, EN 10993-1 standards’ requirements. It is safe to use Brainsafe II device on healthy volunteers.
The pre-clinical research was carried out in consideration of best practice guidelines for healthy volunteers based upon the ICH Good Clinical Practice Guide: Consolidated Guideline and the revised ENISO 14155 standard providing guidance on the conducting medical device clinical investigations to the required standards to meet global regulations. The device testing was performed in accordance with the principles of the Declaration of Helsinki.
The study protocol and methodology was prepared together with Lithuanian University of Health Sciences. An approval of Kaunas Regional biomedical research ethics committee was granted.
Preclinical study of the developed Brainsafe II device was performed on 20 healthy volunteers in order to test the correct functioning and operation of the Brainsafe II and to validate the automatic operation and functionality of the device.
It has been shown experimentally that novel BrainSafe II device and its subsystems operate according to technical specifications. The operation of the Brainsafe II device is stable and repeatable.

Potential Impact:
Two most frequent causes of intracranial hypertension, traumatic brain injury (TBI) and stroke are worldwide epidemics with an estimated joint annual incidence between 400 - 600 cases per 100,000 inhabitants in the developed countries. Over 3 million people in EU and US suffer from TBI annually. Furthermore, about one third of TBI and nearly half of stroke survivors suffer from permanent functional disabilities whose degree depends on the extent and severity of damages to the brain tissue. The causes of TBI are strongly connected to various human activities (traffic, sports, violence, wars, substance use, etc.) and to various environmental causes (weather, earthquakes, storms, etc.), why they will remain a major health challenge also in future. Motor vehicle crashes account for 50% of all TBIs. Pre-hospital emergencies with TBI in remote areas (e.g. roads) have an even greater mortality rate that can be reduced significantly by early assessment of vital intracranial parameters.
The problem is very significant in all European countries with a slightly variable causative epidemiologic profile. In developed countries, TBI causes more loss of productive life years than cancer, stroke and HIV/AIDS combined. In developing countries the number of TBI is steeply rising especially because of the increasing traffic. In this context, road traffic injuries have been predicted to become the fourth most important health burden in the world during the next decades. In the US, the yearly costs from TBI have been calculated to more than 60 billion $, which in the European context corresponds to about 100 billion € per year. However, these figures do not include many significant indirect costs that are caused e.g. by the stress and lowered productivity of the relatives or by the influence of TBIs on premature aging and dementia.
Due to the size of the problem, technological advances in diagnostics and improved treatment can have a potentially tremendous effect on the costs produced by TBI and its squeals. Costs related to TBI are costs of care, but especially costs from loss of productive years, reduced quality of life, and death – not forgetting the considerable impact on the entire social vicinity of the injured ones. The potential economic impact of the BrainSafe II is pointing out by the fact that an improvement of 1 % in the outcome of TBI would mean yearly savings of 1 billion € in Europe.
Patients with neurological diseases such as hydrocephalus, brain tumor, chronic persistently elevated ICP e.g. idiopathic intracranial hypertension (IIH), meningitis and metabolic- toxic, septic encephalopathies could also benefit from innovative non-invasive Brainsafe II technology.
The impact of Brainsafe II technology will be highly significant across a wide spectrum of levels:
• Improved Diagnostics – faster, safer, earlier, accurate diagnostics enabling earlier interventions and accurate treatment. The sooner patients are treated following the injury the more likely they are to recover or their secondary injuries are minimized.
• Improved treatment – appropriate patient - specific therapeutic interventions based on reliable diagnostic and monitoring data will result reduction in deaths and prevented disability due to TBI and neurological diseases.
• Improved monitoring of chronic neurological diseases like Hydrocephalus or IIH will provide valuable information for shunt monitoring and disease management.
• More patients will be diagnosed or screened because it will not be necessary to have highly trained personnel operating the device.
• More settings - the innovative technology will open up possibility for use in several settings where ICP monitoring would improve care, but it’s currently avoided because of complexity or highly invasive nature of available methods.
• More applications – Non-invasive ICP measurement could be informative in a still broader range of diseases in which elevated or decreased ICP may be involved in specific pathophysiological pathways, possibly even in such common conditions as migraine and glaucoma.
• Prevented disability and improved quality of life for many patients (and their families). Better treatment, prevented disability and enhanced quality of life of the patient, resulting in decreased loss of productive years.
• Significant cost reductions – TBI is a huge cost burden for healthcare providers in all countries. The younger the patient the greater the lifetime cost of care.
• Commercial impact for the SMEs involves marketing the technology worldwide including future growth when the technology is developed for emergency ambulances and first-on-scene practitioners.

The innovative Brainsafe II technology will be regarded globally by clinicians as a breakthrough in clinical diagnostics. The aim of care for patients suffering from brain injury or neurological disease is to provide appropriate patient- specific therapeutic interventions based on reliable diagnostic and monitoring data. A key objective after traumatic brain injury is the prevention of secondary insults caused by swelling of injured brain tissue. Because the brain is encased by the rigid skull, tissue swelling leads to raised intracranial pressure, which in turn reduces blood flow, and can lead onto the risk of brain damage and death. Prevention and control of intracranial hypertension are therefore the fundamental goals in the management of patients with TBI or stroke, and ICP monitoring might serve as a basis for making therapeutic decisions as well as provide an objective measure of success of the applied treatment.
However the severity of injury may be missed in up to 80% of patients putting them at risk for long-term disabilities and death. This reflects the fact that no specific clinical features or CT scan finding can reliably predict intracranial pressure - it must be measured directly. Intracranial pressure is measured in millimeters of mercury (mmHg). ICP is normal below 14.7 mmHg critical threshold in adults in supine body position. ICP levels above 14.7 mmHg are generally considered abnormal in neurology. Critical ICP threshold of 20 mmHg is accepted by nonsensus in nurosurgical in tensive care.
Due to the risks of invasive techniques, ICP is usually monitored only in patients with severe head injuries, and only if there is clinical or other evidence that the brain is at-risk due to increased pressure. Consequently many patients with TBI or neurological conditions who might benefit from ICP monitoring do not receive it.
The Brainsafe II technology will allow improvements in the current management of intracranial hypertension (neurological and brain trauma patients) and the expansion of ICP diagnosing to a much wider groups of patients, conditions and clinical settings.
Mild and moderate TBI - The BrainSafe II technology will improve diagnosis and monitoring of the early non-symptomatic stages of TBI, in mild and moderate TBI, as well as for repetitive concussions, in which ICP is typically not monitored currently, but in which diagnosis and management remains a difficult challenge.
Stroke – the BrainSafe II technology can provide additional diagnostic information reducing the time to treatment and improving patient outcomes.
Hydrocephalus - the BrainSafe II technology would improve monitoring and programming of CSF shunts allowing to distinguish between benign conditions, such as the flu, and hydrocephalus caused by shunt failure.
Brain Tumor is a malignant mass pressing on the patient’s brain within the rigid skull. The pre-operative and post-operative monitoring of ICP would reduce the time to treatment and improving patient outcomes.
Chronic persistently elevated ICP - currently, increased ICP caused by Idiopathic intracranial hypertension IIH can only be diagnosed via an invasive spinal tap. The non-invasive ICP-technology is able to diagnosis IIH by measuring ICP faster, safer, and more cost effectively than an invasive spinal tap, reducing patient discomfort and improving patient outcomes.
Meningitis - One of the important component or complication of meningitis is the development of increased intracranial pressure (ICP). Non-invasive measurement of ICP would be certainly beneficial for meningitis diagnosis and treatment.
Metabolic Encephalopathy - is temporary or permanent damage to the brain. The most common cause is an illness or condition that affects the liver. Toxins build up in the bloodstream because the liver is not working normally, what can cause raised ICP.
Glaucoma - is one of the leading causes of irreversible blindness. Recent studies show that ICP is lower in glaucoma patients when compared with nonglaucomatous control subjects. It has been shown, that the relationship between Intra Ocular Pressure and ICP may play a fundamental role in the development of glaucoma.
The wide range of possible applications of Brainsafe II technology may expand even further due to non-invasive nature of the devices. Non-invasive ICP measurement could be informative in a still broader population in which elevated ICP may be involved in specific pathophysiological pathways, possibly even in such common conditions as migraine. The need of non-invasive ICP measurement technology is well recognized in variety of medical fields. Recently, it has become clear that head trauma can lead to a progressive neurodegeneration known as chronic traumatic encephalopathy and cumulative effects of exposure to high ICP also contribute to the development of dementia and Alzheimer's disease.
Non-invasive technologies open up possibility to find answers to questions which could not be answered with invasive technologies. The perfect example is the space adaptation syndrome where ICP can play an important role. Elevated ICP causes headache, nausea, and projectile vomiting, which are similar to symptoms of space adaptation syndrome for astronauts in microgravity. NASA recognized the need to directly measure ICP before and after flight in all long duration astronauts and the goal to establish an in-flight capability to directly measure ICP.
The unmet clinical needs open up a great market opportunity for SME’s. It is estimated, that commercial market potential of more than €1 billion in EU and US could result to significant increase of sales after launch of the device. The effect of the project on the SME consortium will be to increase significantly the commercial benefits in the supply of ultrasound based medical devices and sub assembly products. The project’s results will first be applied in the direct measurement of absolute ICP in which Vittamed is already active. There are no products currently in this market that can meet all the requirements of undertaking non-invasive measurements of intracranial pressure, despite strong demand from the medical sector. As a result, interest in the product is expected to be extremely high, once customers are aware that the product is on the market. The BrainSafe II product will offer a clear advantage over its competitors, as no product currently offers the ability to determine aICP non-invasively with clinically acceptable accuracy, precision and reliability.
The consortium recognizes that having the best technical product available on the market provides no guarantee of commercial success. In order to ensure that the market is widely aware of the new Brainsafe II device, a dedicated dissemination programme has been planned. Key innovation-related elements of this will include:
• Dissemination through high-profile routes:
o High-impact trade shows
o Peer-reviewed journals
• Presentation of results at relevant scientific congresses
• Investigation of possible alternative uses of the technology
• Identification of potential licensees
• Demonstration and support to potential end-users
The primary target audience is end-users of the technology, i.e. health care professionals in the field of neurosurgery, neurology, emergency medicine and intensive care. In order to more effectively reach target audiences and establish credibility for the results, development of a network of key opinion leaders in the above-mentioned domains is essential.
The secondary audience include various public sector healthcare development related institutes and agencies, patient organizations and administrators of healthcare system. Support from a wider group of stakeholders, including public sector, will be a pre-requisite for successful market adoption.
The public audience is important in raising awareness of the product and developing pressure from the community side to adopt state of the art diagnostic methods into routine clinical care.

The primary market is the complete ICP measurement in neurology departments and ICU at the hospitals. The market of non-invasive ICP measurement as such does not currently exist due to the lack of suitable products. It is a part of the total ICP monitoring market that is differentiated by the purpose of its use - either as diagnostics or for patient monitoring. The estimated global market of ICP monitoring is €247 million annually with a growth rate of 8% in Europe. The relative growth rate for this market is centered on the increase in ICP assessment practices that is signified by 9-10% aggregated annual rate.
ICP monitoring is a niche market of the total critical care patient monitoring products that is further divided into segments of invasive and non-invasive ICP assessment, where no commercialized non-invasive instruments are presently on the market.
The secondary market is the individual complete non-invasive ICP measurement in primary care departments (emergency rooms, emergency wards and accident, and emergency). There are 6,000 primary care departments in Europe that currently do not possess ICP monitoring equipment. This market segment has a potential of €100 million when easy and quick non-invasive diagnostics tools for intracranial pressure are introduced.
The long-term markets of portable non-invasive ICP measurement equipment are ambulances and pediatric departments that currently do not possess any equipment for this particular examination. Ambulances will be able to use the BrainSafe II instrument for post impact diagnosis of TBI patients in order to optimize the allocation of “level I” and “level II” trauma patients and assign a proper treatment early after the actual traumatic impact. Pediatric departments’ personnel will be able to use the instrument for diagnosis of TBI patients in the age group of 0-14 years that is currently a very limited practice due to invasiveness of existing methods. In the long-term, the potential within these two markets will constitute an additional €200 million.
The successful achievement of the BrainsafeII project objectives forms the basis for commercialization of developed BrainSafe II non-invasive ICP meter. The consortium now aims to bringing this breakthrough technology to routine clinical care.

List of Websites:
http://www.fp7brainsafe.com/
PROJECT COORDINATOR
Edvardas Satkauskas
UAB Vittamed
Tel: +370 614 62045
Email: edvardas[at]vittamed.lt
Web: http://www.vittamed.lt

TECHNICAL MANAGER
Prof. Arminas Ragauskas
Kaunas University of Technology
Tel: +370 37300003
Email: telematics[at]ktu.lt
Web: http://www.ktu.lt