march 2009 tardis: tcd sub-study tardis investigator meeting, nottingham, uk alice king

March 2009

TARDIS: TCD sub-studyTARDIS: TCD sub-study

TARDIS Investigator Meeting, Nottingham, UKTARDIS Investigator Meeting, Nottingham, UK

Alice KingAlice King

March 2009TARDIS TCD sub-study

OverviewOverview• BackgroundBackground

• RationaleRationale

• ScheduleSchedule

• MethodMethod- Headset & trans-temporal set-upHeadset & trans-temporal set-up- Equipment & settingsEquipment & settings- ArtefactArtefact- Storage and analysisStorage and analysis

• Interested?Interested?

• QuestionsQuestions


TCD allows examination of:TCD allows examination of:• Intracranial circulation (arteries e.g. MCA, PCA, ACA, BASILAR)Intracranial circulation (arteries e.g. MCA, PCA, ACA, BASILAR)

MOVING RBCs reflect/scatter ultrasound backMOVING RBCs reflect/scatter ultrasound back↓↓

FREQUENCY shiftFREQUENCY shift↓↓

↑ ↑ Speed = ↑ ShiftSpeed = ↑ Shift ↓↓

128 pt128 pt F Fast ast FFourier ourier TTransformransform↓↓

3D pulsatile blood flow with cardiac cycle3D pulsatile blood flow with cardiac cycle

DIRECTION and VELOCITY (y axis)DIRECTION and VELOCITY (y axis)+ ve shift = Flow towards probe + ve shift = Flow towards probe

- ve shift = Flow away from probeve shift = Flow away from probe

TIME (TIME (xx axis)axis)Signal INTENSITY - colour spectrum (z axis)Signal INTENSITY - colour spectrum (z axis)

TTransransCCranial ranial DDoppleroppler

• Dynamic cerebrovascular patho-physiologyDynamic cerebrovascular patho-physiologye.g. Autoregulation, COe.g. Autoregulation, CO22 reactivity, cerebral vasospasm, intra-op monitoring & reactivity, cerebral vasospasm, intra-op monitoring & ES detectionES detection


Gaseous ES = bubbles (e.g. from cavitation, decompression or Gaseous ES = bubbles (e.g. from cavitation, decompression or surgery)surgery)

Solid ES = thrombi, platelet aggregates and particulate atheromaSolid ES = thrombi, platelet aggregates and particulate atheroma

↓↓

Acoustic impedance ES > surrounding bloodAcoustic impedance ES > surrounding blood

↓↓

scatter/reflect ultrasound waves @ interfacescatter/reflect ultrasound waves @ interface

EEmboli mboli BBlood lood RRatio (EBR)atio (EBR)

↓↓

Large ↑ in the received ultrasound intensityLarge ↑ in the received ultrasound intensity

↓↓

Visual FFT- high intensity, short duration, unidirectionalVisual FFT- high intensity, short duration, unidirectional

Acoustic - chirpAcoustic - chirp

Frequency focused in blood flow spectraFrequency focused in blood flow spectra

Micro Micro EEmbolic mbolic SSignal Detectionignal Detection

Human observer remains gold standard for ES detectionHuman observer remains gold standard for ES detection

Video of ES, observed in blood flow on Video of ES, observed in blood flow on FFast ast FFourier ourier TTransformransform


RationaleRationale• EMBOLIC stroke > EMBOLIC stroke > 50% ALL stroke50% ALL stroke

- Arise from: Heart OR Large arteries – carotid stenosisArise from: Heart OR Large arteries – carotid stenosis

• Risk recurrent stroke is HIGHRisk recurrent stroke is HIGH

• Secondary prevention Secondary prevention ANTI-THROMBOTICS ANTI-THROMBOTICS- Clinical trials evaluate regimens & novel therapiesClinical trials evaluate regimens & novel therapies

- EndpointsEndpoints- Stroke - 4% per annumStroke - 4% per annum

- 25% with new treatment25% with new treatment- SAMPLE SIZE 14178SAMPLE SIZE 14178

- Sensitive surrogate marker – present in 50%Sensitive surrogate marker – present in 50%- 30% with new treatment30% with new treatment- SAMPLE SIZE 242SAMPLE SIZE 242


ES are a surrogate markerES are a surrogate marker• Stroke/TIA outcome infrequentStroke/TIA outcome infrequent

• ES detected by TCD = Surrogate markerES detected by TCD = Surrogate marker- ES are more frequent in acute stroke/TIAES are more frequent in acute stroke/TIA- ES are predominantly asymptomaticES are predominantly asymptomatic- Predict riskPredict risk- In vivoIn vivo

TARDIS TCD sub-studyTARDIS TCD sub-study

1.1. BEFORE vs. AFTER treatmentBEFORE vs. AFTER treatment

2.2. DUAL vs.TRIPLE ANTI-PLATELETDUAL vs.TRIPLE ANTI-PLATELET- ES repeatedly shown to be attenuated by anti-thrombotic therapyES repeatedly shown to be attenuated by anti-thrombotic therapy- E.g. CARESS (symptomatic carotid stenosis)E.g. CARESS (symptomatic carotid stenosis)

A + C > A aloneA + C > A alone


ES are frequent in acute strokeES are frequent in acute stroke• ES have been consistently shown in acute ischaemic strokeES have been consistently shown in acute ischaemic stroke

- 9.3 - 71% patients9.3 - 71% patients

(Daffertshofer et al 1996, Babikian et al 1994, Babikian et al 1997, Del et al 1997, (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 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 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)2002, Goertler et al 2002, Serena et al 2000, Valton et al 1998 & Kaposzta et al 1999)

- Most frequentMost frequent- large artery strokelarge artery strokecardio-embolic strokecardio-embolic stroke


Carotid stroke in evolutionCarotid stroke in evolution


Carotid endarterectomy Carotid endarterectomy ES common in post-op periodES common in post-op period


Asymptomatic embolism is probably Asymptomatic embolism is probably much more commonmuch more common


ES predict risk stroke/TIA: acute stroke – 8 studies, n=737ES predict risk stroke/TIA: acute stroke – 8 studies, n=737S

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CARESS: Study DesignCARESS: Study Design

Randomised, double-blind, placebo-controlledRandomised, double-blind, placebo-controlled

>50% symptomatic carotid stenosis>50% symptomatic carotid stenosis

N = 230 screened; 110 MES positive N = 230 screened; 110 MES positive includedincluded

D0 D1 D7 ± 1

Clopidogrel

R ASA 75 mg o.d. to all patients from D1 to D7±1

Placebo

MES detection

D-1

MES detection MES detection

Clopidogrel 300 mg Clopidogrel 75 mg o.d.

Placebo Placebo o.d.

Screening

Markus et al Circulation 2005


Day 7 RRR 37.3% (9.7 - 56.5) p=0.011Day 7 RRR 37.3% (9.7 - 56.5) p=0.011

24 hr RRR 25.2% (-1.0 - 44.7%) p=0.07824 hr RRR 25.2% (-1.0 - 44.7%) p=0.078

CARESS:CARESS:Results - Primary EndpointResults - Primary Endpoint


Placebo and ASAPlacebo and ASA

(n=56)(n=56)

Clopidogrel and ASAClopidogrel and ASA(n=51)(n=51)

TIATIA

Ischaemic strokeIschaemic stroke

TIA / Isch strokeTIA / Isch stroke

IS / MI / CV DeathIS / MI / CV Death

88

44

1212

44

55

00

55

11

CARESS:CARESS:Recurrent cerebral ischaemic eventsRecurrent cerebral ischaemic events


CARESS:CARESS:MES rate and recurrent eventsMES rate and recurrent events

MES rate per hour MES rate per hour

BaselineBaseline

24 hr24 hr

YesYes

N = 17N = 17

21.6 (28.3)21.6 (28.3)

14.7 (20.3)14.7 (20.3)

No No

N = 85N = 85

8.4 (11.1)8.4 (11.1)

5.1 (8.9)5.1 (8.9)

pp

0.00170.0017

0.00260.0026

Stroke/TIA recurrence Stroke/TIA recurrence


RR

pp

TCD : MES /hrTCD : MES /hrBaselineBaselineDay 7Day 7

PLATELET AGGREGATIONPLATELET AGGREGATION% max intensity % max intensity

BaselineBaselineDay 7Day 7

-0.308-0.3080.3080.308

0.1190.1190.1900.190

0.0010.0010.0020.002

0.2960.2960.1040.104

CARESS:CARESS:Correlations with any recurrent TIA/strokeCorrelations with any recurrent TIA/stroke


ScheduleSchedule

Day 0Day 0

Day Day 3±13±1

Written Informed ConsentWritten Informed Consent

TCD – 60 MINUTESTCD – 60 MINUTES

BloodsBloods

RandomisationRandomisation

mRSmRSNIHSSNIHSS

TCD – 60 MINUTESTCD – 60 MINUTES

SafetySafety

TolerabilityTolerability

END of TCD sub-studyEND of TCD sub-study


MethodMethod

TimepointTimepointDay 0Day 0

Day Day 3±13±1Each patient acts as own control = Each patient acts as own control = confounding confounding

Time required for adequate plasma levelsTime required for adequate plasma levels

SystemSystem

EME/Nicolet Pioneer EME/Nicolet Pioneer or Companion e.g. or Companion e.g. Pioneer TC8080 & Pioneer TC8080 &

Companion IIICompanion III

Continuity of recordings & analysisContinuity of recordings & analysis

TransducerTransducer 2MHz Pulsed wave 2MHz Pulsed wave (PW)(PW)

Higher freq. absorbed by bone (absorption Higher freq. absorbed by bone (absorption freq.) freq.)

Lower freq. = Lower freq. = RAYLEIGH scattering = RAYLEIGH scattering = EBR = EBR = ES ES detectiondetection

V. low freq. = V. low freq. = blood SCATTER = blood SCATTER = ES detection ES detection

PW – control SAMPLE VOL & DEPTHPW – control SAMPLE VOL & DEPTH

VesselVessel IPSILATERAL middle IPSILATERAL middle cerebral artery (MCA)cerebral artery (MCA)

Easily identified & monitoredEasily identified & monitored

High flow due to large territoryHigh flow due to large territory

IPSILATERAL ischemia - IPSILATERAL ischemia - ES cf. CONTRALATERAL ES cf. CONTRALATERAL


Standard Standard recording recording protocolprotocol

Sample volume (SV) - Sample volume (SV) - 5mm5mm

V. large= V. large= EBR EBR

V. small = ES undetectedV. small = ES undetected

optimal SV =optimal SV =EBREBR

Sweep speed – 5.1sSweep speed – 5.1sAvoid gaps in continuous freq.Avoid gaps in continuous freq.

ES short duration (10-100ms)ES short duration (10-100ms)

No dB thresholdNo dB threshold Experienced observers at final analysisExperienced observers at final analysis

““Automatic HITS” OFFAutomatic HITS” OFF No evidenceNo evidence

RecordRecord Doppler digital audio Doppler digital audio signalsignal Allow playback for ANALYSIS on 128pt FFTAllow playback for ANALYSIS on 128pt FFT

LengthLength 60 minutes60 minutes Standardised – ES temporal variabilityStandardised – ES temporal variability

StorageStorage CD/DVDCD/DVD Back-up, blinding & archivingBack-up, blinding & archiving

AnalysisAnalysisTo SGUL, LONDON for To SGUL, LONDON for

central analysis by central analysis by experienced observersexperienced observers

International consensus criteria, 7dB International consensus criteria, 7dB thresholdthreshold

Blinded to treatment and patient identityBlinded to treatment and patient identity

MethodMethod


Method: Set-upMethod: Set-up1.1. TCD machine ONTCD machine ON2.2. Enter patient TARDIS ID & day 0 or day 3Enter patient TARDIS ID & day 0 or day 33.3. Monitoring modeMonitoring mode4.4. SecurelySecurely attach headset attach headset

- Make sure patient is as comfortable as possible!Make sure patient is as comfortable as possible!5.5. Trans-temporal identification of the ipsilateral MIDDLE cerebral artery (MCA)Trans-temporal identification of the ipsilateral MIDDLE cerebral artery (MCA)

- Steps 4/5 interchangeable depending on personal preference BUTSteps 4/5 interchangeable depending on personal preference BUT

***************Take time to make sure the optimal signal is identified ******************************Take time to make sure the optimal signal is identified ***************


MCA territory (red)MCA territory (red)

Henry Gray (1821–1865). Anatomy of the Human Body. 1918. via http://bartleby.com


Trans-temporal identification of MCATrans-temporal identification of MCAVesselVessel DepthDepth Direction of Direction of

blood flowblood flowVelocityVelocity Spatial Spatial

orientationorientation

MCAMCA

30-60mm30-60mmOptimal Optimal

signal~55signal~55mmmm

Toward the Toward the probeprobe

60 60 ±12cm/s±12cm/s Anterior/superiorAnterior/superior

ACAACA 60-80mm60-80mm Away from the Away from the probeprobe

50 50 ±12cm/s±12cm/s Anterior/superiorAnterior/superior

PCAPCA 60-70mm60-70mm Toward the Toward the probeprobe

40 40 ±12cm/s±12cm/s Posterior/inferiorPosterior/inferior

MCA/ACA MCA/ACA bifurcationbifurcation 55-65mm55-65mm

Bidirectional - Bidirectional - MCA toward, MCA toward,

ACA awayACA away

See See aboveabove Anterior/superiorAnterior/superior


Equipment and SettingsEquipment and Settings• To aid To aid identificationidentification of MCA of MCA

- sample volume to 10mm & sample volume to 10mm & GAIN GAIN- WEAR STEREO HEADPHONESWEAR STEREO HEADPHONES- Use M-modeUse M-mode

6.6. Optimal signal identified & patient is as comfortable as possible…Optimal signal identified & patient is as comfortable as possible…

Setting checklistSetting checklist For OPTIMAL EBR for ES monitoringFor OPTIMAL EBR for ES monitoring

Sample volumeSample volume 5mm OR 5mm OR aas s llowow a ass r reasonably easonably aachievable (ALARA)chievable (ALARA)

Gain Gain so spectra BLACK BACKGROUNDso spectra BLACK BACKGROUND

Sweep speedSweep speed 5.1s5.1s

EnvelopesEnvelopes Off Off

ScaleScale cm/s +/- 100cm/scm/s +/- 100cm/s

Zero baselineZero baseline Adjusted - full MCA signal above the x axisAdjusted - full MCA signal above the x axis

ONLY MCA signal visibleONLY MCA signal visible & eliminate & eliminate BRANCHESBRANCHES by: by:adjusting adjusting angle of the probeangle of the probe or if necessary changing or if necessary changing depthdepth

Automatic emboli indicatorAutomatic emboli indicator OFFOFF

ModeMode SINGLE SINGLE channelchannel


RecordingRecording7.7. Start recording…Start recording…

• Single channel recoding (Settings menu)Single channel recoding (Settings menu)

• click click curve recording oncurve recording on- either by using either by using DopplerDoppler menu or menu or REC REC button and record for 1 hour EXACTLY button and record for 1 hour EXACTLY

NB: make sure curve recording and CONTINUOUS SOUNDTRACK are ONNB: make sure curve recording and CONTINUOUS SOUNDTRACK are ONthere should be a blue dot in top RHS next to speaker iconthere 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!Make a note of the settings used - this will help with the follow up!

- DepthDepth- Spatial orientationSpatial orientation- Sample volumeSample volume


ArtefactArtefactExamples:Examples:

Tapping/touch headsetTapping/touch headset

Adjusting probeAdjusting probe

ChewingChewing

TalkingTalking

LaughingLaughing

Mackinnon AD, Aaslid R, Markus HS: Long-Term Ambulatory Monitoring for Cerebral Emboli Using Transcranial Doppler Ultrasound. Mackinnon AD, Aaslid R, Markus HS: Long-Term Ambulatory Monitoring for Cerebral Emboli Using Transcranial Doppler Ultrasound. Stroke Stroke 2004;35:73-782004;35:73-78


Storage and analysisStorage and analysis8.8. Archive the recordings onto CD/DVDArchive the recordings onto CD/DVD

9.9. AnalysisAnalysis• Central analysisCentral analysis

- Centre for Clinical Neuroscience, SGUL, LONDONCentre for Clinical Neuroscience, SGUL, LONDON- Blinded to treatment and patient identityBlinded to treatment and patient identity

• Recordings will be immediately check upon receiptRecordings will be immediately check upon receipt- Feedback to centresFeedback to centres

- Quality controlQuality control- Constructive criticism of any problemsConstructive criticism of any problems

• International consensus criteria, 7dB thresholdInternational consensus criteria, 7dB threshold- 2 EXPERIENCED observers review (PI reviews each ES)2 EXPERIENCED observers review (PI reviews each ES)


SummarySummary• ES detected by TCDES detected by TCD

- surrogate marker surrogate marker in vivoin vivo anti-platelet efficacy & prediction of riskanti-platelet efficacy & prediction of risk previously shown e.g. in large international CARESS studypreviously shown e.g. in large international CARESS study

• TCD non-invasive & painlessTCD non-invasive & painless

• Only two 60 min recordingsOnly two 60 min recordings

• Only for first 3 daysOnly for first 3 days

• Central analysisCentral analysis

• Support & feedback from experienced centreSupport & feedback from experienced centre


Interested????Interested????More centres = More centres = sample size sample size power power

1.1. Contact TARDIS co-ordinating centreContact TARDIS co-ordinating centree.g. details of TCD machine (continuity and analysis)e.g. details of TCD machine (continuity and analysis)

2.2. Send 1 hour TCD test recording on CD/DVD to:Send 1 hour TCD test recording on CD/DVD to:Alice KingAlice KingCentre for Clinical NeuroscienceCentre for Clinical NeuroscienceSt George's University of LondonSt George's University of LondonCranmer TerraceCranmer TerraceLondonLondonSW17 ORESW17 ORE

WE WILL provide feedback:WE WILL provide feedback:- Quality controlQuality control- Constructive criticismConstructive criticism

3.3. START RECRUITINGSTART RECRUITING


Thank-youThank-you

Prof. Hugh MarkusProf. Hugh Markus

Prof. Philip BathProf. Philip Bath

Margaret AdrianMargaret Adrian


Questions????Questions????

Alice KingAlice King

[email protected]

Centre for Clinical NeuroscienceCentre for Clinical Neuroscience

St George's University of LondonSt George's University of London

Cranmer TerraceCranmer Terrace

LondonLondon

SW17 ORESW17 ORE

Tel: 020 8725 2735 or 020 8725 0961Tel: 020 8725 2735 or 020 8725 0961

Fax: 020 8725 2950Fax: 020 8725 2950

mailto:[email protected]

march 2009 tardis: tcd sub-study tardis investigator meeting, nottingham, uk alice king

Documents

babikian et

kaposzta et

koennecke et

valton et

forteza et

serena et

tong et

goertler et