SEMWO 2011, Vilnius
Human brain in microgravity: how to monitor
non-invasively intracranial pressure, brain
compliance and cerebrovascular autoregulation
Arminas Ragauskas, Prof. DSc, FBC, FLSHD
EUROPOS SAJUNGA
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 - ICP
Critically important, non-invasive Critically important, non-invasive
ABP measurement available since ICP measurement still not available
after more that 100 years.
1896 (Scipione Riva-Rocci).
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...
... 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;
5
[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 inflight capability to monitor ICP non-invasively.
Currently only invasive ICP monitoring methods
available:
Ventricular catheter
Fiberoptic probe
Unsuccessful non-invasive ICP measurement
approaches
Impossibility to measure absolute ICP values and to solve the
individual patient calibration problem
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
aICP
aPe
?
Unique Vittamed solution
The eye artery (ophthalmic artery OA) is a unique vessel with
intracranial and extracranial segments - a natural scales for absolute
ICP measurement.
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
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
Non-invasive
Vittamed
Neurodiagnostics
Invasive
Position
Vittamed 205 offers improved performance over invasive ICP monitors
Long-term implantable
device
Camino
Bolt
fiberoptic
Neurovent-P
fiberoptic
Codman
fiberoptic
Ventricular
catheter
Low (not usable)
Accuracy
High (usable)
Vittamed Non-invasive prototypes
Non-invasive aICP meter
•
•
3M patients/year with Head
trauma;
10M patients/year with
neurological diseases.
Non-invasive cerebral autoregulation
monitor
•
•
•
Prognostic maker for
ICP;
Therapy selection for
TBI treatment;
Etc.
Non-invasive cerebral compliance
monitor
•
•
•
•
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
Clinical evidence
Prospective clinical studies: simultaneous “golden standard”
invasive/non-invasive aICP measurements, neurological patients
A)
Probability density function
Red line: normal distribution (CI=0.99)
A) Normal distribution (CI=0,99) of mean aICP in
the group of 81 neurological patients –
evidence of perfect randomization,
C)
Probability density function
Mean aICP, mmHg
25 mmHg
+4 mmHg
-4 mmHg
0
4
8
12
16
Mean aICP, mmHg
20
24
28
32
D)
NEUROLOGICAL
PATIENTS
TBI
PATIENTS
50,00
+4.0 mmHg
45,00
ERROR
CORRIDOR
-4.0 mmHg
Non-invasive aICP, mmHg
40,00
35,00
30,00
25,00
20,00
15,00
10,00
5,00
0,00
0,00
5,00
10,00 15,00 20,00 25,00 30,00 35,00 40,00 45,00 50,00
“Golden standard” ICP, mmHg
PHASE A
PHASE B
Red line: uniform distribution (CI=0.95)
7
6
5
4
3
2
1
0
-1
-2
-3
-4
-5
-6
-7
Δ, mmHg
Δ, mmHg
B)
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 D (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
40.0
ICP, mmHg
32.0
28.0
26.2
±1.9
24.0
±2.2
20.0
18
16.0
±2.6
12.0
4.0
±3.1
±2.5
8.0
4.2
9.8
4.3
Non-invasive absolute ICP value, mmHg
36.0
30.0
±1.9
26.2
25.0
±2.2
20.0
18.0
15.0
±3.6
±3.0
±2.6
10.6
10.0
9.6
9.8
5.0
ΣΔs=1.8
0.0
0.0
-5.0
Expected ICP value, mmHg
Number N of healthy
volunteers:
N=10
Tilting table position
angles:
N=16
Supine
HDT
HDT
nICPj
nICPj +10 mmHg
nICPj +20 mmHg
N=41
N=11
N=10
0°
[21.6°; 25.8°]
[32°; 40.5°]
0.0
20.0
15.0
5.0
10.0
Expected ICP value, mmHg
HDT
Supine
25.0
30.0
HDT
Number N of healthy
volunteers:
nICPj
nICPj +10 mmHg
nICPj +20 mmHg
N=41
N=11
N=10
Tilting table position
angles:
0°
[21.6°; 25.8°]
[32°; 40.5°]
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)
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.brainit.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 !