SEMWO 2011, Vilnius Human brain in microgravity: how to monitor non-invasively intracranial pressure, brain compliance and cerebrovascular autoregulation.

SEMWO 2011, Vilnius

E U R O P O S S A JU N G A

Human brain in microgravity: how to monitor non-invasively intracranial pressure, brain

compliance and cerebrovascular autoregulationArminas Ragauskas, Prof. DSc, FBC, FLSHD

Unmet market needs:

• Unique break-trough Vittamed technologies solve critical and costly medical problems.

• Unmet medical market needs already confirmed by the US and EU medical communities.

• Market potential up to 7 billion EUR.

• New niche in global medical market with no competitors - high anticipated revenue and profits.

Why ICP is so important?

Arterial blood pressure (ABP) and Intracranial pressure (ICP) are both fundamental physiological parameters of intracraniospinal system with the same importance, because blood flow in brain is driven by CPP:

CPP = ABP - ICPCritically important, non-invasive ABP measurement available since 1896 (Scipione Riva-Rocci).

Critically important, non-invasive ICP measurement still not available after more that 100 years.

?Mass market High market potential

Clinical need of ICP measurement

• Head trauma – the first reason of death of population under 45 years 3 million cases per year in the US and EU.

Brain Trauma Foundation’s Guidelines recommend ICP absolute value monitoring as a main physiological parameter for traumatic brain injury patient treatment decision making.

• 10 million patients with neurological brain diseases which cause elevated ICP which is the reason of disability or death:

– Stroke; – Hydrocephalus;– Brain Tumors; – Idiopathic intracranial hypertension (IIH);– Meningitis;– Etc...

5

... and the risks mean too few patients get it• ICP monitoring has risks…

– Bleeding (up to 18%), device malposition (up to 9%) and infection (1%) 1

• … limiting use even in eligible cases… – A third of US patients2 and two-third of European patients3 who fulfil clinical

guideline criteria do not receive ICP monitoring– Only a third of children with severe head injury receive ICP monitoring4

• … current invasive devices are imperfect– Difficult to use with significant swelling

• Imprecise with significant brain swelling• Impossible or difficult to insert with advanced or diffuse brain swelling

– Inaccurate after a few days • Zero drift for fiberoptic devices

• ... invasive aICP measurement is risky and expensive– Hospitalization and high profile surgeons necessary;

[1] Anderson et al: J Neurosurg. 2004 Aug;101(1 Suppl):53-8 [2]Bulger et al: Crit Care Med: 2002: 30: 1870-6[3] Stocchetti et al: Intensive Care Med 2001: 26; 400-6 [4] Keenan et al: Pediatr Crit Care Med. 2005;6(5):611-2.

Space medicine needs

• Elevated ICP may contribute to space adaptation syndrome:

– According to Visual Impairment Intracranial Pressure (VIIP) summit (2011) the vision, physiological and anatomical changes are observed in long duration astronauts including elevated intracranial pressure, optic nerve sweling, eye ball flattening.

– Elevated ICP causes headache, nausea, and projectile vomiting, which are symptoms of space adaptation syndrome in microgravity.

– The impaired cerebral autoregulation for cosmonauts and sportsmen under physical load may have consequences leading to serious health problems.

NASA recognized the need to directly non-invasively measure ICP before and after flight in all long duration astronauts and is seeking to establish an in-flight capability to monitor ICP non-invasively.

Currently only invasive ICP monitoring methods available:

Ventricular catheterVentricular catheter

Fiberoptic probeFiberoptic probe

Unsuccessful non-invasive ICP measurement approaches

Impossibility to measure absolute ICP values and to solve the individual patient calibration problem

aICP aPe

General solution of the calibration problem

The only solution of noninvasive aICP meter's calibration problem is to eliminate need of calibration by direct comparison of aICP and extracranially applied pressure (aPe) by the natural physiological "scales”. The same principle as in aABP noninvasive measurement:

aABP aPe

?

The eye artery (ophthalmic artery OA) is a unique vessel with intracranial and extracranial segments - a natural scales for absolute ICP measurement.

Unique Vittamed solution

Intracranial segment of EA

Extracranial segment of EA

Dura mater crossing point

Vittamed non-invasive aICP measurement technology uses the OA as a natural scales for aICP measurement by applying controlled external pressure to the eye ball and using a two depth transcranial Doppler which measures blood flow parameters in both segments in order to find a balance point of such scales. Vittamed technology is protected by US, EU and National patents.

Vittamed: world’s first accurate non-invasive absolute ICP value meter

• No calibration

• Accurate – Clinically tested: 0.16 mmHg

accuracy and +/- 2.3 mmHg precision

• Reliable– In vivo proven repeatability of

results

• Rapid and easy to use– Easy to fit, with minimal training

required – 8 ... 10 minutes measurement

time

• Safe– Single-use pressure cuff and head

frame – Transmitted ultrasonic power

levels match approved safety standards for ultrasound devices

• No calibration

• Accurate – Clinically tested: 0.16 mmHg

accuracy and +/- 2.3 mmHg precision

• Reliable– In vivo proven repeatability of

results

• Rapid and easy to use– Easy to fit, with minimal training

required – 8 ... 10 minutes measurement

time

• Safe– Single-use pressure cuff and head

frame – Transmitted ultrasonic power

levels match approved safety standards for ultrasound devices

Vittamed R&D, D&D supported by the US DoD and US Dept. of the Army grants, European Commission’s funded projects, including FP7 Brainsafe.

Vittamed ICP non-invasive meter / monitor offers best-in-class accuracy

Accuracy

Posi

tion

Inva

sive

Non

-inva

sive

Low (not usable) High (usable)

Ventricular catheter

Ventricular catheter

VittamedVittamed

Vittamed 205 offers improved performance over invasive ICP monitors

NeurodiagnosticsLong-term implantable

device

NeurodiagnosticsLong-term implantable

device

Neuro-vent-P

fiberoptic

Neuro-vent-P

fiberoptic

Camino Bolt

fiberoptic

Camino Bolt

fiberoptic

CodmanfiberopticCodman

fiberoptic

Non-invasive cerebral autoregulation monitor

Non-invasive cerebral compliance monitor

Non-invasive aICP meter

Vittamed Non-invasive prototypes

• 3M patients/year with Head trauma;

• 10M patients/year with neurological diseases.

• 3M patients/year with Head trauma;

• 10M patients/year with neurological diseases.

• Prognostic maker for ICP;

• Therapy selection for TBI treatment;

• Etc.

• Prognostic maker for ICP;

• Therapy selection for TBI treatment;

• Etc.

• Hydrocephalus shunt monitoring;

• Early detection of post-surgical bleeding;

• Tumor diagnostics;• Etc.

• Hydrocephalus shunt monitoring;

• Early detection of post-surgical bleeding;

• Tumor diagnostics;• Etc.

Next step – non-invasive ICP meter for routine clinical practice

• Simple and easy to use:– Just essential functions and parameters for

easy ICP measurement– User friendly, fool proof– Guidance for IOA and EOA location with UT

• Cost effective:– Components and architecture aligned with

serial manufacturing processes

• Safe and robust:– Certified with CE mark

• Accurate and precise:– Clinically validated

• Reliable:– Clinically tested in different settings

• Simple and easy to use:– Just essential functions and parameters for

easy ICP measurement– User friendly, fool proof– Guidance for IOA and EOA location with UT

• Cost effective:– Components and architecture aligned with

serial manufacturing processes

• Safe and robust:– Certified with CE mark

• Accurate and precise:– Clinically validated

• Reliable:– Clinically tested in different settings

Clinical evidence

Prospective clinical studies: simultaneous “golden standard” invasive/non-invasive aICP measurements, neurological patients

-7-6-5-4-3-2-101234567

0 4 8 12 16 20 24 28 32

Probability density functionMean aICP, mmHg

Mean aICP, mmHg

Δ, m

mH

g

25 mmHg

+4 mmHg

-4 mmHg

Δ, m

mH

g

Prob

abili

ty d

ensi

ty f

unct

ion

Red line: normal distribution (CI=0.99)

Red line: uniform

distribution (CI=0.95)

A)

B) C)

D)

0,00

5,00

10,00

15,00

20,00

25,00

30,00

35,00

40,00

45,00

50,00

0,00 5,00 10,00 15,00 20,00 25,00 30,00 35,00 40,00 45,00 50,00

NEUROLOGICAL PATIENTS

TBI PATIENTS

“Golden standard” ICP, mmHg

Non

-inv

asiv

e a

ICP

, mm

Hg

+4.0 mmHg

-4.0 mmHg

PHASE A PHASE B

ERRORCORRIDOR

A) Normal distribution (CI=0,99) of mean aICP in the group of 81 neurological patients – evidence of perfect randomization,

B) Bland and Altman plot of paired data of simultaneous non-invasive aICP value and invasive “golden standard” ICP measurements (81 neurological patients, 91 pairs of data),

C) Close to uniform distribution of (CI=0,99), D) Regression graph of phases A and B of

prospective randomized and blinded comparative clinical study of non-invasive versus “golden standard” invasive ICP measurements,

Conclusion: Mean systematic error (accuracy or bias) of non-invasive absolute ICP value meter is 0.16 mmHg and standard deviation of the random error (precision) SD = 2.28 mmHg, CI > 0.95.

Brainsafe: Healthy volunteer study in 5 body possitions

Healthy volunteer study results

Healthy volunteer study in 5 body positions: bars show mean non-invasively measured ICP absolute values and SD in mmHg in vertical body position (green bar), sitting body position (yellow bar), supine body position (brown bar) and two HDT positions (orange and red bars)

0.0

4.0

8.0

12.0

16.0

20.0

24.0

28.0

32.0

36.0

40.0

ICP

, mm

Hg

4.2

±2.5

4.3

±3.1

±2.6

9.8

±2.2

18

±1.926.2

SupinenICPj

HDTnICPj +10 mmHg

HDTnICPj +20 mmHg

N=41 N=11 N=10

Tilting table position angles: [21.6°; 25.8°] [32°; 40.5°]0°

Number N of healthy volunteers:

Expected ICP value, mmHg

N=10 N=16

0.0

5.0

10.0

15.0

20.0

25.0

30.0

Non

-inva

sive

abs

olut

e IC

P v

alue

, mm

Hg

±2.6

9.8

±2.2

18.0

±1.9

26.2

SupinenICPj

HDTnICPj +10 mmHg

HDTnICPj +20 mmHg

N=41 N=11 N=10

Tilting table position angles: [21.6°; 25.8°] [32°; 40.5°]0°

Number N of healthy volunteers:

-5.0 0.0 5.0 10.0 15.0 20.0 25.0 30.0

±3.0

9.610.6

±3.6

ΣΔs=1.8

Expected ICP value, mmHg

Clinical projects - EC FP7 TBI Care – FP7-ICT-2009-6 project: Evidence based Diagnostic and

Treatment Planning Solution for Traumatic Brain Injuries – total budget 4.2M EUR. 2011 - 2013.

- NASA - Research and Technology Development to Support Crew Health and Performance in Space Exploration Missions – 100% funded. Application together with Harvard Medical School.

- NASA - Research and Technology Development to Support Crew Health and Performance in Space Exploration Missions – 100% funded. Application together with Baylor Medical School.

- Planned – Joint Lithuania – Switzerland R&D project for clinical testing. Partners from Kaunas, Vilnius, Zurich, Bern. The call to be announced in October 2011.

- Expected - New FP7 project applications together with EU BrainIT (www.brain-it.eu) centers.

More settings:• Emergency Rooms and Trauma Centers

– Over 2000 trauma centers in US and EU;– have highest patient turnover volume in the hospital;– early adopters of technology designed to improve the efficiency of care;– 3M TBI patients visits/year;

• Intensive Care Units and Operating Rooms– Over 50k target ICU beds and operating rooms in EU and US;– fastest growing segment of healthcare spending;

• Neurology clinics– Over 2000 target neurology clinics in US and EU;– Market of long term ICP monitoring and diagnosing for chronic diseases has

the largest growth potential because these patients need repeated measurements throughout life;

• Military• Other settings:

– ambulances, battle field hospitals;– Sports medicine;– Aero-cosmic medicine;– Research institutions;

More conditions:

• Mild traumatic brain injury:– 1,75 million cases per year in US – growing epidemics;

• Stroke – 500k patients in US every year;

• Hydrocephalus – 8 Million patients in US; Up to 80% of CSF shunts block within 2 years

of insertion; • Brain Tumor

– 100k patients in US every year; • Brain Surgery

– 100k patients in US every year;• Chronic persistently elevated ICP

– 0.9 to 1 cases per 100,000 per year;• Meningitis

– 0.9 to 1.5 cases per 100,000 per year;• Other conditions with risks of intracranial hypertension;

THANK YOU !

THANK YOU !