Standardized ultrasound evaluation of carotid stenosis for clinical trials University of Washington Ultrasound Reading Center

Background

Repair of carotid artery stenoses (carotid revascularization) has been shown to be effective in reducing thechance of embolic stroke from carotid plaque ruptureand embolization to the brain [1]. Clinical trials of carotid artery revascularization methods such as carotidendarterectomy and carotid artery stenting are in progress to provide guidance to clinicians about the choiceof therapy.

Noninvasive ultrasonic duplex Doppler examinationhas been a standard method for the clinical evaluationof the carotid arteries for a third of a century [2,3]. Doppler velocity waveforms are gathered from the commonand internal carotid arteries to detect local elevatedblood velocity as a marker of arterial stenosis allowingcategorical classification of the right and left commonand internal carotid arteries into clinically useful categories. One often used classification scheme is: 1) nosignificant stenosis (< 50%DR), 2) moderate stenosis(50%-79%DR), 3) severe stenosis (80%-99%DR), and 4)occluded. The method and associated criteria for stenosis classification were developed in the decade prior to 1990 [3-10]. The reference standard for the classificationmethod is X-ray contrast angiography. Some publications use other angiographic categories with divisions at60%, 70% or other values.

A variety of Doppler velocity measurement methodsare used to classify arteries into the proper angiographiccategories. However, detailed publications demonstratethat although satisfactory sensitivities and specificitiescan be obtained by associating selected angiographicclassifications with particular Doppler measurements,the relationship between Doppler measurements andangiography is not a narrow monotonic line, [11] but amultivariate relationship. The additional variablesinclude: the presence of a moderate or severe contralateral stenosis [12-15], cerebral territory perfused [16],completeness of the circle of Willis [17-19], ipsilateralcollateral flow [20], vertebral flow [21] and method ofrevascularization [22].

Methods

All carotid ultrasound duplex Doppler examinations areperformed by field centers under IRB approval at thefield center institutions. A duplex Doppler UltrasoundProtocol Manual is provided to each participating ultrasound laboratory by the University of Washington Ultrasound Reading Center (UWURC). Anonymized imagesand worksheets from each examination are sent to theUWURC.

The protocol specifies that at least 16 ultrasound Bmode images with associated Doppler waveforms begathered from each patient: On each side the sonographer should acquire 3 images from the commoncarotid artery (CCA), 3 from the internal carotid artery(ICA), one from the external carotid artery (ECA) andone from the vertebral artery (VA) (Figure 1). Additionalimages and waveforms are required from locations distalto the stent (to detect post-stent stenosis) and distal toany stenosis (to document post-stenotic turbulence).

For each of the 16 or more spectral waveforms, systolic and diastolic velocities are measured and transcribedalong with the Doppler angles (from the associated Bmode images) to a standard worksheet. The worksheetis submitted with paper, film, photocopied or electronicversions of the images to the UWURC. Studies on videotape recordings are discouraged because of the excessivetime required for video processing.

At the UWURC, worksheet data (Figure 2A) are singlekeyed into the UWURC database. For each side of eachcase, a review form is printed (Figure 2B) including thekeyed worksheet data. During UWURC review, thereader verifies the anatomic location of each waveformfrom the B-mode image labels and anatomic features,determines whether a stent can be seen and verifies correct transcription of the data from the images (Figure 3)including proper location of the decimal points (someimages are marked in cm/s, others in m/s). The readeralso checks the Doppler angle alignment on the imageand the spectral velocity measurement cursors on thewaveform and checks for end acceleration velocity(EAV) (Figure 4). If the measurement cursors are absentor improperly placed, the reader marks and measuresthe velocities and indicates whether the Doppler

ultrasound beam was tilted toward the head (H) or foot(F). The reader also marks the preferred waveformsfrom the common (CCA) and internal (ICA) carotidarteries for use in computing the ratio and classificationof stenosis. Finally, the reader checks the computationof the ICA/CCA systolic velocity ratio and marks theclassification categories for CCA, ICA and ECA (external carotid artery). After completion of the case by thereader, each value is verified by a reviewer. The completed review form is then sent for double key entryinto the UWURC data base.

Turbulence or complicated oscillating flow is mostlikely to occur during temporal deceleration in the latephase of systole and during spatial deceleration just distal to a stenosis. This turbulence causes bruits or murmurs that can be heard with a stethoscope, and appearsas spectral broadening that can be visualized in thespectral waveform. Application of“angle correction”tothe Doppler frequency measurement based on the Doppler equation by measuring the Doppler angle betweenthe ultrasound beam and the artery axis is not appropriate for turbulent wavforms because the heading of the velocity vector is random or at least chaotic duringspectral broadening. Thus, some examiners differentiatePeak Systolic Velocity (PSV), which is measured duringspectral broadening, from End Acceleration Velocity(EAV), which is measured just before the onset of turbulence (Figure 4). Because the PSV is often greaterthan the EAV and there is no guidance in the literatureon which to choose, the UWURC enters both values onthe review form for later analysis to provide a basis forselecting one or the other.

Two classification methods are used by the UWURCto complete the review form: 1) the ICA/CCA ratio [23]and 2) the“Strandness Criteria”[24,25]. For the ICA/CCA ratio, the EAV is used for each value if available;otherwise, the PSV is used. If both velocities were measured with valid Doppler examination angles between 58and 61 degrees, then the ratio is calculated; otherwise,an estimate of the ratio is placed into one of 5 categories (less than 2.0, near 2.0, between 2.0 and 4.0, near4.0, greater than 4.0), or cannot classify. The ratio criterion 2.0 separates stenoses < 50% from those > 50% [26];the ratio criterion 4.0 defines the 70% stenosis boundary [23]. The“Strandness”velocity criteria separate stenosesat: 1) the 50% (ACAS) boundary with a PSV criterion of1.25 m/s [24,25] and at 2) the 80% (ACAS) stenosisboundary with an EDV criterion of 1.4 m/s [27](Figure 5). Because of the plethora of classificationmethods for both angiography and for duplex Doppler,with indistinguishable sensitivity and specificitymeasures, the UWURC refers to stenoses simply asmoderate or severe.

The vascular diagnostic community is divided into twogroups: 1) those that perform duplex Doppler examinations using a 60 degree Doppler angle between theultrasound beam and the vessel axis, and 2) those thatuse a convenient angle less than or equal to 60 degrees[28]. Both groups then apply a geometric adjustmentusing the Doppler equation (assuming velocity parallelto the artery axis) to compute the arterial velocity. However, normal arterial flow is not usually parallel to theartery axis [29], thus the assumption behind the Dopplerequation is not valid. Attempts to validate the Dopplerequation in normal carotid arteries (Figure 6) and stenotic arteries result in a systematic bias: 1) using largerDoppler examination angles result in higher velocityvalues and 2) the relationship is monotonic. To minimize the effect of different Doppler angles between visits, the UWURC has recommended that, wheneverpossible, carotid artery Doppler ultrasound measurements are acquired at a Doppler examination angle of60 degrees. The UWURC has accepted and evaluated allsubmitted ultrasound examination velocities, including those taken at Doppler examination angles other than60 degrees. For measurements with incorrect anglemeasurement alignment visible on the B-mode image(Figure 7), the UWURC remeasured the angle using aprotractor overlying the image [30] and entered theremeasured angle in the database so that the appropriategeometric correction could be applied (Figure 3B) beforeanalysis.

The resulting data form (Figure 2B) accommodates fivefinal numeric values for each of the 16 recommendedand 2 optional (additional distal ICA) measurements: 1)“Machine Set Angle”(MSA), 2)“Hand Measured Angle”(HMA), 3)“Peak Systolic Velocity”(PSV), 4)“End Acceleration Velocity”(EAV), 5)“End Diastolic Velocity”(EDV). There are also ten categorical values: 1) Waveform Missing, 2) Other Can’t Verify (when the anatomiclocation cannot be established), 3) Angle should be Protocol (when a Doppler angle other than 60 degrees isused but a 60 degree angle could have been used), 4)Variable Angle Alignment (when the Doppler samplevolume is located in a curve or other anatomic locationin which the angle could have been measured differently)5) ?PSV (when due to arrhythmia or to turbulence (spectral broadening) the systolic velocity value is uncertain,6) PSV remeasured (used as an interim variable for marking EAV on a prior version of the review form), 7) PSV orEAV (marks whether the examiner measured the PSV orEAV), 8) H or F (marks whether the Doppler cursor wasangled toward the head or the foot), 9) Velocity in Stent(provides an indication of stent location), 10) Ratio View (marks the CCA and ICA values used in computing thevelocity ratio).

Each of these variables is designed either to documenta feature of the measurement or to provide the basis oftesting specific hypotheses in future publications. Forvalues marked“Waveform Missing”or“Can’t Verify”,the values may contain errors not detected by the reviewprocess because of missing or obscured images. Forinstance, if a study was submitted as a clinical report,with some velocity values reported as text, but noimages or waveforms were provided, the clinical valueswere entered on the Review Form but the correspondingreview form lines were marked“Waveform Missing”.

After the“Reader”checked all of the data on eachform against the source data, the“Reviewer”recheckedall of the data and each reader entry against the sourcedata. Disagreements between Reader and Reviewer wereadjudicated by committee to assure uniform reading andreviewing.

Data were compiled into a file and checked forimplausible values including: EDV > PSV, EAV > PSV,Angle > 90 degrees, PSV > 6 m/s, and missing values.Such values might pass undetected through the systemdue to decimal point errors, conversion from alpha tonumeric values, and clerical errors. For each case withimplausible values, a custom error form was printed(Figure 8) so that the source data could be retrieved, thecase re-read and all errors fixed.

All entries keyed into the database are logged to document the Reader, Reviewer, Adjudicator, and Keyer.

Results

Between 1999 and 2009, the UWURC evaluated 10,687duplex Doppler examinations comprised of 21,374 sides (Figure 9). 12 staff members were qualified to evaluateexamination images. 53% of the examinations were readby a single staff member; an additional 45% were readby 4 others. 64% of the examinations were reviewed bya single reviewer; an additional 30% were reviewed bytwo others. Fewer than 3% of the examination sidesrequired adjudication. In no case was the reader and thereviewer the same person; the signing adjudicator couldbe either reader or reviewer.

Although the majority of waveforms and images wereeasily interpreted and classified, in some images theselection of a correct measurement required discussion.In the case of an arrhythmia (Figure 10), the systolicvelocities following a long diastolic period have elevatedvalues compared to those following a short diastolic period, because increased ventricular filling during thelonger diastole elevates the ventricular ejection volume.This variation in systolic velocity causes uncertainty inthe measurement, and affects derived systolic ratiomeasurements. In such cases a ?PSV entry is made onthe review form. When possible, measurements within astudy are taken at each location from a systole followinga“normal”diastolic interval.

The correct classification of significant stenoses intomoderate or severe categories is most important forboth clinical management and for clinical trials surveillance. Sonographic errors, if undetected on evaluation,can result in misclassification. Figure 11 provides twoexamples of cases misclassified by the sonographeraccording to the protocol.

Flow reversal in the extracranial arterial system is unusual except in cases of severe stenosis, occlusion, steal oraortic regurgitation. Figure 12 shows examples of velocityreversal. The Doppler waveform“reversal”in figure 12Anear the carotid bifurcation could not be flow reversalbecause the arteries proximal and distal have normalforward waveforms. This is an example of the effect ofcomplicated flow, with velocity toward the transducer (at an angle of 60 degrees to the vessel axis) in onesampled portion of the carotid bulb during temporaldeceleration at the end of systole. This is often called“flow separation”. This waveform should not be interpreted as indicating net flow in the carotid artery directedfrom the head toward the heart. The measurement of netflow requires complete sampling of velocities perpendicular to a surface that transects the vessel, and then integrating [velocities*area] to compute instantaneous flow.Unilateral left vertebral systolic flow reversal (Figure 12B)may indicate a stenosis at the origin of the left subclavianartery resulting in subclavian steal [31].

The data have been compiled into a database that canbe configured for analysis by patient, side, treatmentside, and/or time point to allow longitudinal or crosssectional comparisons.

The accuracy of duplex Doppler ultrasound is oneof the most frequently discussed topics in carotidartery diagnosis. Carotid Doppler velocities are usedto classify arteries into stenotic categories. From asubgroup of pre-procedure studies, Doppler velocityvalues were plotted against angiographic measurements in a small subpopulation [32] (Figure 13) andcompared to literature values [11]. Within the rangeof values available in this clinical trial (blue triangles,Stenosis 42% DR to 98% DR), the relationship doesnot suggest that systolic velocity would provide goodsensitivity or specificity for the clinical classificationthreshold of 70% DR.

The choice of Doppler angle is another frequently discussed question [33]: should the Doppler angle be 60degrees or the smallest angle possible, so long as it isless than 60 degrees? For a subgroup of patients with 1month and 12 month post-procedure studies, thechange in contralateral systolic and diastolic velocitieswas plotted versus the change in Doppler angle(Figure 14) in cases which used different Doppler anglesduring the two studies. The positive slope comparingpercent velocity change to angle difference is consistentwith the experiment shown in figure 6.

Discussion

The most objective and comprehensive survey of carotidartery examination methods is the 2002 Carotid Ultrasound Consensus Conference [28]. In 1997, the Universityof Washington Ultrasound Reading Center designed theultrasound protocol which complies with the recommendations later adopted by the consensus conference, withthree exceptions: 1) The UWURC recommends the consistent use of a Doppler examination angle of 60 degrees; theConsensus Conference reports disagreement, with somemembers recommending 60 degrees and some recommending < 60 degrees; 2) the UWURC Doppler diastolicvelocity criterion for severe stenosis is 1.4 m/s rather than1.0 m/s as recommended by the Consensus Conference;

and 3) the UWURC makes no recommendation about theevaluation of B-mode or color Doppler images, except forthe identification of the location of a stent at the Dopplersample location; the Consensus Conference recommendsthe evaluation of these images, but provides no quantitativemethod of reporting the evaluation.

The Consensus Conference explains“the ability ofDoppler ultrasound to ... estimate the degree of stenosis[has] been disappointing.”so“Doppler ultrasound cannotbe used to predict a single percentage of stenosis.”but“..criteria should be consistently applied.” “Published literature is replete with velocity thresholds..” “The panel suggested that ICA PSV and the presence of plaque on ...images ... should be used when diagnosing and gradingICA stenosis.” “The ICA PSV is easy to obtain, has goodreproducibility, and should be used in conjunction with

grayscale and color Doppler..” “Two additional parameters, ICA-to-CCA PSV ratio and ICA EDV are useful....“A summary of recommended criteria are included inTable 3.”of the consensus paper [28].

The UWURC agrees with all of the findings, but practices the following minor differences for the classification of severity of stenosis.

1. The UW classifications, established prior to 1990,were based on a lower boundary for severe stenosis of80% DR by angiography: (NLD-MLD)/NLD where MLDis minimum lumen diameter and NLD is the normallumen diameter of the carotid bulb (ACAS method).Subsequently, others have adopted a 70% lower boundary where NLD is the normal lumen diameter of theICA distal to the stenosis (NASCET method). Generallythe bulb diameter is 1.5 times the normal distal ICAdiameter, thus 70% NASCET stenosis = 80% ACASstenosis.

2. The consensus paper offers two criteria for the 70%stenosis: PSV = 2.3 m/s and EDV = 1.0 m/s. TheUWURC recommends EDV = 1.4 m/s. Because theUWURC includes the velocity values in the database,future analyses can elect to use any of these criteria.

There is also a philosophical difference between theconsensus document and the UWURC recommendations. While the consensus document recommends thatdiagnosis be based on a combination of observationsfrom the grayscale B-mode image, color Doppler andspectral Doppler, the exact method of combination isunclear and the use of multiple variables or observationscan lead to conflicting results. The two alternate methods used in the summary portion of the UWURC reviewform–one based on highest PSV(ICA) with EDV(ICA)and the other based on PSV(ICA)/PSV(CCA) ratio–will not necessarily agree, and should not be usedtogether, but rather, one method should be selected andused consistently.

The relationship between Doppler velocity and angiographic stenosis within the significant stenosis range ofinterventional trials is poor. The sensitivity and specificity of the test only improves when a large number ofcases with minimal or no stenosis are included in thetabulation. Perhaps we have been naïve in the quest fora linear relationship between Doppler velocity and stenotic diameter. Although each hemisphere of the braindoes demand a constant average blood supply,

independent of intelligence or occupation, a stenosis islikely to induce flow diversion to other potential collateral pathways (contralateral arteries or the ipsilateralexternal carotid or vertebral arteries), reducing thetrans-stenotic flow and velocity by an unpredictableamount. The pattern of the flow diversion might provideimportant information for the velocity stenosis relationship, and in addition might allow inferences aboutrecruited collaterals which might serve to reduce therisk of stroke below the chance predicted by the stenosisalone. Some sonographers do report the ratio ((ipsilateral CCA PSV)/(contralateral CCA PSV)) to support thediagnosis of ICA stenosis. However, a value less than 1.0which indicates stenosis also indicates intracranial collateralization, which might be protective against stroke.Thus, although carotid Doppler has been used clinicallyfor a third of a century, puzzles remain and opportunities to improve the method invite exploration.

The geometry of the Doppler equation predicts that theDoppler frequency shift will be zero if the Doppler angle isperpendicular (90 degrees). However, because of transittime spectral broadening, helical (laminar) flow and complicated turbulent or eddy flow, even at 90 degrees theenvelope of the Doppler frequency shift spectrum is notzero. This broadening affects all of the Dopplermeasurements except those made at a Doppler angle ofzero degrees. Unfortunately, a Doppler angle of zerodegrees is not possible in ultrasound examination of peripheral arteries and veins. As a result, all“angle corrected”Doppler velocity measurements monotonically increasewith Doppler angle from zero to 90 degrees. If the Dopplerfrequency in the Doppler equation is held constant, andthe Doppler angle is changed from 40 degrees to 60degrees, the computed Doppler velocity increases by 42%or 2.1% per degree. In Figure 6, the velocity value increasesby about 1.5% per degree between the 40 degree measurement and the 60 degree measurement in PSV and oneEDV, and in the other EDV measurement by 0.8%. Notethat in Figure 14, the best fit line for systolic velocity measurement increases by 1.8% per degree and the diastolicvelocity measurement increased by 1.27% per degree.These values are consistent with the values that can beestimated from the Figure 1 1.30 in Primozich [24] of 2%per degree. It remains to be determined whether the statistically significant dependence on angle is an important factor affecting surveillance precision.

Conclusions

Although angle adjusted Doppler velocity measurementscan be used to classify the severity of carotid stenosis and to monitor the changes in carotid stenosis overtime, these velocity values computed from the measurement of a vector component of the velocity vectoradjusted by geometric angle projection are not equal tothe velocity components parallel to the vessel axis whichcontributes to the volumetric flow along the artery. Theangle adjusted velocity values can only be used forempirical classification based on published standards,and for time to time comparisons of values within eachpatient. The classifications are only valid when theacquisition protocol is consistent with the standard.

The Ultrasound Reading Center analysis method forduplex Doppler carotid artery data was developed toaddress several research questions raised in the consensus document and elsewhere:

1. How much of a change in estimated ICA stenosisshould be considered significant?

2. What criteria should be used to assess patients afterICA revascularization?

3. Does the degree of contralateral stenosis affect theipsilateral diagnostic criteria?

A detailed analysis of the data in the future willaddress these questions and the results will bepublished.

Because the classification of stenosis into angiographiccategories by Doppler has limitations, using this categorical variable for surveillance of a revascularized arteryto measure durability can lead to erroneous results. Inthis case, if a stenosis changes from a“moderate stenosis(50%-79%DR)”to a“severe stenosis (80%-99%DR)”, thechange in classification might be due to an increase inEDV from 1.38 m/s to 1.42 m/s. Such a small change inmeasurement might not indicate a change in arterialmorphology. An alternative might be to require achange in classification from“no significant stenosis (<50%DR)”to“severe stenosis (80%-99%DR)”, whichwould be a change from PSV < 1.25 m/s to an EDV >1.4 m/s. Important progression of a stenosis might notbe detected if that were the criteria. If, however, thestandard deviation (SD) of the difference in PSV or EDVbetween visits is measured, then an increase in valuemore then 3 SD would provide a 99% confidence thatthe stenosis has become more severe. In the absence oftreatment, a decrease in value more than 3 SD would besurprising. However, in a trial of 1000 cases, that rareevent would be expected in 10 cases, due t measurementvariability rather than stenosis regression.

Research examinations are exploratory, designed toanswer a variety of questions. Usually, only a portion ofthe data gathered in a research protocol is found to berelevant to the questions finally addressed. In contrast,clinical examinations should be designed to efficientlydetermine whether each patient has a specific treatablecondition and whether treatment is likely to improvetheir quality of life. To refine advice on clinical examination methods, the UWURC will compare pairs ofDoppler velocity measurements acquired under theresearch protocol to address the following questions infuture publications:

1) Are three velocity measurements in the CCA necessary to:

a. identify CCA disease?

b. provide a reference denominator for ICA/CCAratio calculation?

2) Are measurements in the ECA and VA importantto the clinical evaluation?

3) Do contralateral velocities decrease when an ipsilateral stenosis is treated suggesting that:

a. intracranial cross-collaterals are present?

b. ipsilateral intra-stenotic velocities might bereduced due to collateral flow?

4) Are particular velocity values or ratios predictive ofcomplications during revascularization?

The first two questions relate to potentially simplifyingthe clinical examination by omitting superfluous measurements. The third question addresses a cofactor inthe correlation between Doppler velocities and angiographic arterial diameter measurements. The fourthquestion suggests that additional inferences might bederived from a complete clinical examination includingmodulating the predicted risk of stroke.

Of course clinical carotid examination should bedivided into two examinations: 1) screening examinations with a high sensitivity and acceptable specificityfor internal carotid artery stenosis which can be carriedout in a non-specialist primary care setting, and 2) diagnostic examinations with high specificity for severe carotid stenosis with“vulnerable”plaque to assure that highrisk patients are directed to appropriate treatment.

When carotid examinations according to protocolhave not been available, the UWURC has accepted datafrom“clinical examinations”to complete time points inthe data set. The minimum data included in the studieshave been single velocity measurements from the ICAand CCA on the evaluated side. Demonstration of a single end diastolic carotid velocity exceeding 1.4 m/s isuniversally accepted as proof of carotid stenotic disease,but verifying a non-stenotic carotid bifurcation requiresmore documentation.

Abbreviations

ACAS: Asymptomatic Carotid Atherosclerosis Study; CCA: Common CarotidArtery; DR: Angiographic stenotic Diameter Reduction; EAV: End AccelerationVelocity; ECA: External Carotid Artery; EDV: End Diastolic Velocity; F: Doppler beam directed toward the feet, normal flow“toward”transducer; H: Dopplerbeam directed toward the head, normal flow“away”from transducer; HMA:Hand Measured Angle by the UWURC from the B-mode image; ICA: InternalCarotid Artery; MSA: Machine Set Angle of the sonographer selectedDoppler cursor; NASCET: North American Symptomatic CarotidEndarterectomy Trial; PSV: Peak Systolic Velocity; UWURC: University ofWashington Ultrasound Reading Center; VA: Vertebral Artery.

Abbreviations prefixes

D: Distal; L: Left; M: Middle; P: Proximal; R: Right; ? Value uncertain due toarrhythmia.

Acknowledgements

We would like to thank Abbott Vascular, Boston Scientific, Guidant,Medtronic, NIH-NINDS R01 NS 38384 (CREST) and private donations forsupport of this work.

Authors’contributions

KWB Principal Investigator designed methods, reviewed studies, analyzeddata and wrote the text. ROB provided data management and analysis. DFLprovided data analysis. JFP designed UWURC methods and reviewed studies.PMS provided data analysis. ETS read a majority of the UWURC studies. REZClinical Director of the UWURC, provided clinical oversight for the center,analysis and publication. All authors have read and approved the finalmanuscript.

Authors’information

Kirk W. Beach, Ph.D., M.D. Emeritus Professor of Surgery and Bioengineering.

Robert O. Bergelin, M.S., Director of Departmental Computing

Daniel F. Leotta, Ph.D., Research Engineer, Applied Physics Laboratory

Jean F. Primozich, B.S., R.V.T., Lead Vascular Technologist

P. Max Sevareid, M.P.H., Project Manager

Edward T. Stutzman, B.S., R.V.T, Vascular Technologist

R Eugene Zierler, M.D., R.V.T., Professor of Vascular Surgery

Department of Surgery

University of Washington,

Seattle, WA 98195

[email protected]

Competing interests

The authors declare that they have no competing interests.

Received: 13 August 2010 Accepted: 7 September 2010Published: 7 September 2010