TARDIS:%20TCD%20sub-study

1
TARDIS TCD sub-study

• TARDIS Investigator Meeting, Nottingham, UK
• Alice King

2
Overview

• Background
• Rationale
• Schedule
• Method
• Headset trans-temporal set-up
• Equipment settings
• Artefact
• Storage and analysis
• Interested?
• Questions

3
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

4
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 gt surrounding
blood ? scatter/reflect ultrasound waves _at_
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
5
Rationale

• EMBOLIC stroke gt 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

6
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
• BEFORE vs. AFTER treatment
• DUAL vs.TRIPLE ANTI-PLATELET
• ES repeatedly shown to be attenuated by
  anti-thrombotic therapy
• E.g. CARESS (symptomatic carotid stenosis)
• A C gt A alone

7
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

8
Carotid stroke in evolution
9
Carotid stroke in evolution
10
Carotid stroke in evolution
11
Carotid stroke in evolution
12
Carotid stroke in evolution
13
Carotid endarterectomy ES common in post-op
period
14
Asymptomatic embolism is probably much more common
15
ES predict risk stroke/TIA acute stroke 8
studies, n737
16
CARESS Study Design

• Randomised, double-blind, placebo-controlled
• gt50 symptomatic carotid stenosis
• N 230 screened 110 MES positive included

Markus et al Circulation 2005
17
CARESS Results - Primary Endpoint
Day 7 RRR 37.3 (9.7 - 56.5) p0.011 24 hr RRR
25.2 (-1.0 - 44.7) p0.078
18
CARESSRecurrent cerebral ischaemic events
Clopidogrel and ASA (n51)
Placebo and ASA (n56)



TIA Ischaemic stroke TIA / Isch stroke IS / MI
/ CV Death
8 4 12 4
5 0 5 1



19
CARESS MES rate and recurrent events
20
CARESSCorrelations with any recurrent TIA/stroke
21
Schedule
Written Informed Consent ? TCD 60
MINUTES Bloods ? Randomisation mRS NIHSS ? TCD
60 MINUTES Safety Tolerability ? END of TCD
sub-study
Day 0
Day 31
22
Method
Timepoint Day 0 Day 31 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) Easily identified monitored High flow due to large territory IPSILATERAL ischemia - ? ES cf. CONTRALATERAL
23
Method
Standard recording protocol Sample volume (SV) - 5mm V. large ? EBR V. small ES undetected optimal SV ?EBR
Standard recording protocol Sweep speed 5.1s Avoid gaps in continuous freq. ES short duration (10-100ms)
Standard recording protocol No dB threshold Experienced observers at final analysis
Standard recording protocol 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
24
Method Set-up

• 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!
• 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

25
MCA territory (red)
Henry Gray (18211865).  Anatomy of the Human
Body.  1918. via http//bartleby.com
26
Trans-temporal identification of MCA
Vessel Depth Direction of blood flow Velocity Spatial orientation
MCA 30-60mm Optimal signal55mm 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
MCA/ACA bifurcation 55-65mm Bidirectional - MCA toward, ACA away See above Anterior/superior
27
Equipment and Settings

• To aid identification of MCA
• ?sample volume to 10mm ? GAIN
• WEAR STEREO HEADPHONES
• Use M-mode
• Optimal signal identified patient is as
  comfortable as possible

Setting checklist For OPTIMAL EBR for ES monitoring
Sample volume 5mm OR as low as reasonably achievable (ALARA)
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
28
Recording

• 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

29
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
20043573-78
30
Storage and analysis

• Archive the recordings onto CD/DVD
• 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)

31
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

32
Interested????

• More centres ? sample size ? power
• Contact TARDIS co-ordinating centre
• e.g. details of TCD machine (continuity and
  analysis)
• 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
• START RECRUITING

33
Thank-you
Prof. Hugh Markus Prof. Philip Bath Margaret
Adrian
34
Questions????
Alice King aking_at_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 [phone]