TARDIS: TCD sub-study
TARDIS Investigator Meeting, Nottingham, UK
Alice King
March 2009
Overview
• Background
• Rationale
• Schedule
• Method
- Headset & trans-temporal set-up
- Equipment & settings
- Artefact
- Storage and analysis
• Interested?
• Questions
TARDIS TCD sub-study
March 2009
TransCranial Doppler
TCD allows examination of:
• Intracranial circulation (arteries e.g. MCA, PCA, ACA, BASILAR)
MOVING RBCs reflect/scatter ultrasound back
↓
FREQUENCY shift
↓
↑ Speed = ↑ Shift
↓
128 pt Fast Fourier Transform
↓
3D pulsatile blood flow with cardiac cycle
DIRECTION and VELOCITY (y axis)
+ ve shift = Flow towards probe
-ve shift = Flow away from probe
TIME (x axis)
Signal INTENSITY - colour spectrum (z axis)
•
Dynamic cerebrovascular patho-physiology
e.g. Autoregulation, CO2 reactivity, cerebral vasospasm, intra-op monitoring & ES detection
TARDIS TCD sub-study
March 2009
Micro Embolic Signal Detection
Gaseous ES = bubbles (e.g. from cavitation, decompression or
surgery)
Solid ES = thrombi, platelet aggregates and particulate atheroma
↓
Acoustic impedance ES > surrounding blood
↓
scatter/reflect ultrasound waves @ interface
Emboli Blood Ratio (EBR)
↓
Large ↑ in the received ultrasound intensity
↓
Visual FFT- high intensity, short duration, unidirectional
Acoustic - chirp
Frequency focused in blood flow spectra
Video of ES, observed in blood flow on Fast
Fourier Transform
Human observer remains gold standard for ES detection
TARDIS TCD sub-study
March 2009
Rationale
• EMBOLIC stroke > 50% ALL stroke
- Arise from: Heart OR Large arteries – carotid stenosis
• Risk recurrent stroke is HIGH
• Secondary prevention  ANTI-THROMBOTICS
- Clinical trials evaluate regimens & novel therapies
- Endpoints
- Stroke - 4% per annum
-  25% with new treatment
- SAMPLE SIZE 14178
- Sensitive surrogate marker – present in 50%
-  30% with new treatment
- SAMPLE SIZE 242
TARDIS TCD sub-study
March 2009
ES are a surrogate marker
• Stroke/TIA outcome infrequent
• ES detected by TCD = Surrogate marker
- ES are more frequent in acute stroke/TIA
- ES are predominantly asymptomatic
- Predict risk
- In vivo
TARDIS TCD sub-study
1. BEFORE vs. AFTER treatment
2. DUAL vs.TRIPLE ANTI-PLATELET
- ES repeatedly shown to be attenuated by anti-thrombotic therapy
- E.g. CARESS (symptomatic carotid stenosis)
A + C > A alone
TARDIS TCD sub-study
March 2009
ES are frequent in acute stroke
• ES have been consistently shown in acute ischaemic stroke
- 9.3 - 71% patients
(Daffertshofer et al 1996, Babikian et al 1994, Babikian et al 1997, Del et al 1997,
Grosset et al 1994, Koennecke et al 1998, Forteza et al 1996, Tong et al 1995, Lund
et al 2000, Iguchi et al 2007, Droste et al 2000, Gao et al 2004, Ghandehari et al
2002, Goertler et al 2002, Serena et al 2000, Valton et al 1998 & Kaposzta et al
1999)
- Most frequent
- large artery stroke
- cardio-embolic stroke
TARDIS TCD sub-study
March 2009
Carotid stroke in evolution
TARDIS TCD sub-study
March 2009
Carotid stroke in evolution
TARDIS TCD sub-study
March 2009
Carotid stroke in evolution
TARDIS TCD sub-study
March 2009
Carotid stroke in evolution
TARDIS TCD sub-study
March 2009
Carotid stroke in evolution
TARDIS TCD sub-study
March 2009
Carotid endarterectomy
ES common in post-op period
TARDIS TCD sub-study
March 2009
Asymptomatic embolism is probably
much more common
TARDIS TCD sub-study
March 2009
Stroke ALONE
Stroke/TIA
ES predict risk stroke/TIA: acute stroke – 8 studies, n=737
TARDIS TCD sub-study
March 2009
CARESS: Study Design
Randomised, double-blind, placebo-controlled
>50% symptomatic carotid stenosis
N = 230 screened; 110 MES positive included
D-1
D0
D1
Clopidogrel 300 mg
D7 ± 1
Clopidogrel
75 mg o.d.
Clopidogrel
R
ASA 75 mg o.d. to all patients from D1 to D7±1
Screening
Placebo
Placebo
MES detection
Placebo o.d.
MES detection
MES detection
Markus et al Circulation 2005
TARDIS TCD sub-study
March 2009
% of subjects MES +ve
CARESS:
Results - Primary Endpoint
100
Plac + ASA
100 100
80
Clopid + ASA
76
72.5
56.8
60
45.5
40
20
0
Baseline
24 hr
Day 7
Day 7 RRR 37.3% (9.7 - 56.5) p=0.011
24 hr RRR 25.2% (-1.0 - 44.7%) p=0.078
TARDIS TCD sub-study
March 2009
CARESS:
Recurrent cerebral ischaemic events
Placebo and ASA
(n=56)
Clopidogrel and ASA
(n=51)
TIA
8
5
Ischaemic stroke
4
0
TIA / Isch stroke
12
5
IS / MI / CV Death
4
1
TARDIS TCD sub-study
March 2009
CARESS:
MES rate and recurrent events
Stroke/TIA recurrence
Yes
No
p
N = 17
N = 85
Baseline
21.6 (28.3)
8.4 (11.1)
0.0017
24 hr
14.7 (20.3)
5.1 (8.9)
0.0026
MES rate per hour
TARDIS TCD sub-study
March 2009
CARESS:
Correlations with any recurrent TIA/stroke
R
p
TCD : MES /hr
Baseline
Day 7
-0.308
0.308
0.001
0.002
PLATELET AGGREGATION
% max intensity
Baseline
Day 7
0.119
0.190
0.296
0.104
TARDIS TCD sub-study
March 2009
Schedule
Written Informed Consent

TCD – 60 MINUTES
Bloods
Day 0

Randomisation
mRS
NIHSS

TCD – 60 MINUTES
Day 3±1
Safety
Tolerability

END of TCD sub-study
TARDIS TCD sub-study
March 2009
Method
Timepoint
Day 0
Day 3±1
Each patient acts as own control =  confounding
Time required for adequate plasma levels
System
EME/Nicolet Pioneer
or Companion e.g.
Pioneer TC8080 &
Companion III
Continuity of recordings & analysis
Transducer
2MHz Pulsed wave
(PW)
Higher freq. absorbed by bone (absorption  freq.)
Lower freq. =  RAYLEIGH scattering =  EBR =  ES
detection
V. low freq. =  blood SCATTER =  ES detection
PW – control SAMPLE VOL & DEPTH
Vessel
IPSILATERAL middle
cerebral artery (MCA)
TARDIS TCD sub-study
Easily identified & monitored
High flow due to large territory
IPSILATERAL ischemia -  ES cf. CONTRALATERAL
March 2009
Method
Sample volume (SV) 5mm
V. large=  EBR
V. small = ES undetected
optimal SV =EBR
Sweep speed – 5.1s
Avoid gaps in continuous freq.
ES short duration (10-100ms)
No dB threshold
Experienced observers at final analysis
“Automatic HITS” OFF
No evidence
Record
Doppler digital audio
signal
Allow playback for ANALYSIS on 128pt FFT
Length
60 minutes
Standardised – ES temporal variability
Storage
CD/DVD
Back-up, blinding & archiving
Analysis
To SGUL, LONDON for
central analysis by
experienced observers
International consensus criteria, 7dB
threshold
Blinded to treatment and patient identity
Standard
recording
protocol
TARDIS TCD sub-study
March 2009
Method: Set-up
1.
2.
3.
4.
TCD machine ON
Enter patient TARDIS ID & day 0 or day 3
Monitoring mode
Securely attach headset
- Make sure patient is as comfortable as possible!
5. Trans-temporal identification of the ipsilateral MIDDLE cerebral artery (MCA)
- Steps 4/5 interchangeable depending on personal preference BUT
***************Take time to make sure the optimal signal is identified ***************
TARDIS TCD sub-study
March 2009
MCA territory (red)
Henry Gray (1821–1865). Anatomy of the Human Body. 1918. via http://bartleby.com
TARDIS TCD sub-study
March 2009
Trans-temporal identification of MCA
Vessel
Depth
Direction of
blood flow
Velocity
MCA
30-60mm
Optimal
signal~55
mm
Toward the
probe
60
±12cm/s
Anterior/superior
ACA
60-80mm
Away from the
probe
50
±12cm/s
Anterior/superior
PCA
60-70mm
Toward the
probe
40
±12cm/s
Posterior/inferior
55-65mm
Bidirectional MCA toward,
ACA away
See
above
Anterior/superior
MCA/ACA
bifurcation
TARDIS TCD sub-study
Spatial
orientation
March 2009
Equipment and Settings
• To aid identification of MCA
- sample volume to 10mm &  GAIN
- WEAR STEREO HEADPHONES
- Use M-mode
6. Optimal signal identified & patient is as comfortable as possible…
Setting checklist
For OPTIMAL EBR for ES monitoring
5mm OR as low as reasonably achievable (ALARA)
Sample volume
Gain
 so spectra BLACK BACKGROUND
Sweep speed
5.1s
Envelopes
Off
Scale
cm/s +/- 100cm/s
Zero baseline
Adjusted - full MCA signal above the x axis
ONLY MCA signal visible
 & eliminate BRANCHES by:
adjusting angle of the probe or if necessary changing depth
Automatic emboli indicator
OFF
Mode
SINGLE channel
TARDIS TCD sub-study
March 2009
Recording
7. Start recording…
• Single channel recoding (Settings menu)
• click curve recording on
- either by using Doppler menu or REC button and record for 1 hour EXACTLY
NB: make sure curve recording and CONTINUOUS SOUNDTRACK are ON
there should be a blue dot in top RHS next to speaker icon
• Make a note of the settings used - this will help with the follow up!
- Depth
- Spatial orientation
- Sample volume
TARDIS TCD sub-study
March 2009
Artefact
Examples:
Tapping/touch headset
Adjusting probe
Chewing
Talking
Laughing
Mackinnon AD, Aaslid R, Markus HS: Long-Term Ambulatory Monitoring for Cerebral Emboli Using Transcranial Doppler Ultrasound. Stroke 2004;35:73-78
TARDIS TCD sub-study
March 2009
Storage and analysis
8. Archive the recordings onto CD/DVD
9. Analysis
• Central analysis
- Centre for Clinical Neuroscience, SGUL, LONDON
- Blinded to treatment and patient identity
• Recordings will be immediately check upon receipt
- Feedback to centres
- Quality control
- Constructive criticism of any problems
• International consensus criteria, 7dB threshold
- 2 EXPERIENCED observers review (PI reviews each ES)
TARDIS TCD sub-study
March 2009
Summary
• ES detected by TCD
- surrogate marker in vivo
 anti-platelet efficacy & prediction of risk
 previously shown e.g. in large international CARESS study
• TCD non-invasive & painless
• Only two 60 min recordings
• Only for first 3 days
• Central analysis
• Support & feedback from experienced centre
TARDIS TCD sub-study
March 2009
Interested????
More centres =  sample size  power
1. Contact TARDIS co-ordinating centre
e.g. details of TCD machine (continuity and analysis)
2. Send 1 hour TCD test recording on CD/DVD to:
Alice King
Centre for Clinical Neuroscience
St George's University of London
Cranmer Terrace
London
SW17 ORE
WE WILL provide feedback:
- Quality control
- Constructive criticism
3. START RECRUITING
TARDIS TCD sub-study
March 2009
Thank-you
Prof. Hugh Markus
Prof. Philip Bath
Margaret Adrian
TARDIS TCD sub-study
March 2009
Questions????
Alice King
aking@sgul.ac.uk
Centre for Clinical Neuroscience
St George's University of London
Cranmer Terrace
London
SW17 ORE
Tel: 020 8725 2735 or 020 8725 0961
Fax: 020 8725 2950
TARDIS TCD sub-study
March 2009