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(Stroke. 1995;26:2293-2297.)
© 1995 American Heart Association, Inc.

Articles

Application of Transcranial Doppler Sonography to Evaluate Cerebral Hemodynamics in Carotid Artery Disease

Comparative Analysis of Different Hemodynamic Variables

Wolfgang H. Hartl, MD Heinrich Fürst, MD

From the Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilian University Munich (Germany).

Correspondence to Heinrich Fürst, MD, Chirurgische Klinik, Klinikum Grosshadern, Marchioninistrasse 15, D-81377 Munich, Germany.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Transcranial Doppler sonography in combination with manipulation of cerebral resistance vessels is widely used to screen patients with suspected intracranial hemodynamic disturbances. Maximal flow velocity (V_max), mean flow velocity (V_mean), cerebral pulsatility index (CP_i), and cerebral resistance index (CR_i) have all been used to describe cerebral hemodynamics. The present study examined CO₂ reactivity of the above hemodynamic variables with respect to its variability between different age groups and its capability to discriminate between normal and abnormal findings.

Methods Absolute and relative CO₂ reactivity of V_max, V_mean, CR_i, and CP_i were determined in both hemispheres in 30 young and 37 elderly control subjects and in 245 consecutive patients with strictly unilateral symptomatic (n=101) or asymptomatic (n=144) carotid artery disease (>80% stenosis or occlusion).

Results Hemispheric reactivities of V_mean, CR_i, and CP_i were significantly age dependent. Hemispheric V_max reactivity and interhemispheric differences of individual reactivities (except absolute CP_i reactivity) did not vary with age and could therefore be used to define normal values. Patient classification according to these values revealed different frequencies of subjects with pathological findings (3% for hemispheric V_max reactivity, 5% to 7% for interhemispheric differences of V_max or V_mean reactivity, 39% and 45% for interhemispheric differences of relative CR_i and CP_i reactivity, respectively).

Conclusions Hemispheric reactivities are less suitable to evaluate cerebral hemodynamics than interhemispheric differences, since most of the latter do not vary with age. However, interhemispheric differences vary with respect to their discriminatory power. Power is low for interhemispheric differences of V_max and V_mean reactivity, since the corresponding frequencies of abnormal findings do not differ from the 5% frequency expected in the reference population (reference range defined as mean±2 SD). With respect to the discriminatory power, interhemispheric differences of relative CR_i and CP_i reactivity may be superior to other parameters.

Key Words: carotid artery disease • hemodynamics • ultrasonics

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Treatment of patients with significant ipsilateral symptomatic ICA stenosis is no longer controversial.^{1 2} However, the value of carotid endarterectomy for managing patients with asymptomatic carotid artery disease remains in question.³ In theory, the patients who may profit from surgery are at risk of either thromboembolic stroke or stroke from a hemodynamic cause. For such patients, a variety of methods and variables are available for examining cerebrovascular hemodynamics.

In addition to measurement of cerebral blood volume, cerebral blood flow, and oxygen extraction fraction, it is possible to obtain flow velocities at the MCA by transcranial Doppler sonography. The method is widely used to screen patients with suspected intracranial hemodynamic disturbances because it does not require invasive, expensive, or time-consuming equipment. Usually, transcranial Doppler sonography is combined with manipulation of cerebral resistance vessels (by varying the arterial CO₂ concentration or by administering acetazolamide) to increase the sensitivity of the method.⁴

Thus far, there is no agreement as to which sonographic variable is the most appropriate to identify hemodynamic risk patients. V_max,^{5 6} V_mean ,^{4 7 8 9} CP_i,¹⁰ and CR_i¹¹ have all been used to describe cerebral hemodynamics. The situation is further complicated because either absolute^{5 7} or relative^{4 6 8 9 11} changes of the above variables were used to evaluate their reactivity to variations of cerebral vessel diameter. Finally, instead of hemispheric reactivities, some authors^{8 11} favor use of interhemispheric reactivity differences (side-to-side asymmetry) to study hemodynamics in patients with carotid artery disease.

In the present study, we examined the CO₂ reactivity of different variables that can all be evaluated with transcranial Doppler sonography, with respect to their variability among different age groups and capability to discriminate between normal and abnormal findings. Measurements were performed in a prospective series of patients with significant unilateral ICA disease.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients
Studies were performed in 245 consecutive subjects (66±1.0 years of age, mean±SEM) seeking treatment in our hospital. All patients had unilateral 80% to 99% stenosis or occlusion of the ICA. One hundred one patients were symptomatic in the territory of the carotid artery disease. They demonstrated either transient reversible neurological deficits or minor strokes that had occurred at least 12 weeks before the study. None of these patients were suffering from a major stroke. One hundred forty-four patients were completely asymptomatic. All patients were taking appropriate medication according to the individual underlying disease.

Extracranial and intracranial supra-aortic vessels were screened with transcranial Doppler sonography, duplex sonography, color-flow Doppler imaging, and continuous-wave Doppler sonography. Patients were included if aortic arch angiography revealed an ICA occlusion or if they presented with an ICA that had a lumen diameter reduction from 80% to 99%. The criterion for this finding was a high-grade to threadlike stenosis at the initial continuous-wave Doppler sonography. At the subsequent color-flow Doppler imaging and duplex sonography, the stenosis had to demonstrate a short segment of marked color fading (>8 kHz), severe poststenotic flow reversal and mixed turbulence, reduced prestenotic flow velocity in the common carotid artery, and a lumen narrowing on B-mode scan of >80%. The latter was calculated by measuring the residual luminal diameter and the original diameter at the site of the maximal stenosis and by dividing the difference by the original diameter. The original diameter was measured as the distance between estimated luminal edges of near and far wall intima. The combination of duplex sonography, color-flow Doppler imaging, and continuous-wave Doppler sonography is more than 95% accurate to diagnose an 80% to 99% ICA stenosis.^{12 13}

Exclusion criteria in our study included lumen diameter reduction of <80% at the extracranial ipsilateral ICA, lumen diameter reduction of >50% at the contralateral ICA, previous major stroke, tandem lesions of the ICA/MCA, subclavian steal syndrome, vertebral artery occlusion or stenosis, lumen diameter reduction of >50% at the common carotid artery, previous ipsilateral or contralateral carotid endarterectomy or extracranial/intracranial bypass, and uncontrolled atrial fibrillation (absolute arrhythmia).

Control Subjects
To define reference ranges, two control groups of young subjects (n=30, 25±2.1 years of age) and of elderly subjects (n=37, 65±3.5 years of age) were studied. Details on these control groups have been published.¹¹ Young control subjects were completely healthy. Elderly subjects were suffering from different degrees and manifestations of peripheral atherosclerosis at the lower extremities (La Fontaine stage IIa-b). Significant atherosclerotic changes of the extracranial and intracranial arteries were excluded by Doppler and duplex sonography. None of these subjects had severe congestive heart disease or presented with or ever had symptoms of cerebrovascular disease, as determined by careful neurological examination. No effort was made to control medication.

Measurements
Systolic and diastolic blood flow velocity of the MCA in both hemispheres was measured by transcranial Doppler sonography as described previously.¹¹ To evaluate the complete reactivity of blood flow velocity to changes in CO₂ concentrations, the arterial CO₂ content was changed from normocapnia (CO₂ concentration at rest) to hypercapnia and hypocapnia. To produce hypercapnia, the subjects were connected through a mouthpiece with a nonreturn valve to a tank containing 5% CO₂. Hypocapnia was achieved by having the patient hyperventilate. During the CO₂ manipulation, the end-expiratory CO₂ content (vol%) was recorded continuously by an infrared CO₂ analyzer (Engstrom Eliza, CO₂ Analysator). Mean end-tidal values were used to estimate arterial CO₂ content. Flow velocity in the MCA was recorded when a steady state was reached in end-tidal CO₂ and flow velocity.

Calculations
Each examination yielded values of minimal diastolic and maximal systolic flow velocity (V_min, V_max) in the MCA in both hemispheres during hypercapnia and hypocapnia. Flow velocities were used to calculate the following variables: V_mean=(V_max+V_min)/2; (Gosling's index) CP_i=(V_max-V_min)/V_mean; and (Pourcelot's index) CR_i=(V_max-V_min)/V_max. Subsequently, we calculated the relative or the absolute reactivity of the above variables to changes in the arterial CO₂ content (values were normalized by referring them to one vol%CO₂ change) as follows: absolute V_max reactivity as RV_max=(V_max^hyper-V_max^hypo)/CO₂; relative V_max reactivity as R%V_max=RV_max/V_max^hypo_*100; absolute V_mean reactivity as RV_mean=(V_mean^hyper-V_mean^hypo)/CO₂; relative V_mean reactivity as R%V_mean=RV_mean/V_mean^hypo_*100; absolute CP_i reactivity as RCP_i=(CP_i^hypo-CP_i^hyper)/CO₂; relative CP_i reactivity as R%CP_i=RCP_i/CP_i^hypo_*100; absolute CR_i reactivity as RCR_i=(CR_i^hypo-CR_i^hyper)/CO₂; and relative CR_i reactivity as R%CR_i=RCR_i/CR_i^hypo_*100.

To calculate CP_i and CR_i reactivities, we subtracted values at hypercapnia from corresponding values at hypocapnia to avoid negative reactivities (hypocapnic CP_i and CR_i are larger than corresponding hypercapnic values). CO₂ indicates the difference between CO₂ concentration at hypercapnia and CO₂ concentrations at hypocapnia. Hyper indicates values at hypercapnia, hypo at hypocapnia.

To obtain reference ranges from young and elderly control subjects, we used the following procedure. A reference range was defined as mean value±2 SD¹⁴ because hemispheric reactivities of all variables and their corresponding interhemispheric differences were normally distributed. Two classes of reference range were calculated. Normal hemispheric values were derived from the mean of all measurements in the left and right hemispheres in each group (60 measurements in 30 young subjects, 74 measurements in 37 elderly subjects), since no difference could be detected between means of the left and right hemispheres.

To calculate normal side-to-side asymmetry, the right reactivity of each parameter was arbitrarily subtracted from the left reactivity in young and elderly control subjects. Then the sign of the side-to-side asymmetries was ignored to determine absolute values of side-to-side asymmetry. The reference range of absolute side-to-side asymmetry was defined as mean±2 SD. The next step was to calculate absolute side-to-side asymmetry in the patients by subtracting—arbitrarily again—the reactivity of the contralateral hemisphere from the reactivity of the ipsilateral hemisphere. This allowed us to refer side-to-side asymmetry in the patients to the hemisphere of ICA disease and not to the left or right hemisphere. Then the sign of side-to-side asymmetry was ignored, and patients could be classified according to the selected reference interval as those with normal absolute side-to-side asymmetry and those with abnormal absolute side-to-side asymmetry. Subsequently, patients with abnormal absolute side-to-side asymmetry were further analyzed by looking at the sign of the original side-to-side asymmetry and dividing them into those with abnormal negative and those with abnormal positive side-to-side asymmetry (referred to the ipsilateral hemisphere).

Statistics
The differences between the means of young and elderly subjects were compared by the unpaired t test. Because the means of 16 variables were compared, the Bonferroni method was applied, taking into account the multiplicity of comparisons. A significance level of P=.05/16=.0031 was used throughout the study.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Tables 1 and 2 give the mean±SD of the individual parameters and their corresponding side-to-side asymmetries for young and elderly control subjects. When we compared hemispheric means from young subjects with those from elderly subjects, only absolute and relative reactivity of V_max did not vary significantly between the two. All other parameters were markedly lower in the elderly subjects. Side-to-side asymmetries of the individual parameters varied less between the two control groups. Only side-to-side asymmetry of the absolute CP_i reactivity was significantly lower in the elderly subjects.

View this table: [in this window] [in a new window]   Table 1. Average Values of CO2 Reactivities of Different Hemodynamic Variables in Young and Elderly Control Subjects

View this table: [in this window] [in a new window]   Table 2. Average Values of Side-to-Side Asymmetries in Young and Elderly Control Subjects

Only age-independent variables were used to calculate reference values (mean±2 SD) for a subsequent patient classification. Thus, for hemispheric variables, reference values were only calculated for absolute and relative reactivity of V_max. To obtain reference values for V_max, data from young and elderly control subjects (Table 1) were combined. Normal ranges amounted to 0.012 to 0.212 m/s per vol%CO₂ for absolute V_max reactivity and to 0.5% to 33.3% per vol%CO₂ for relative V_max reactivity. Evaluation of 245 patients yielded only a few (1 [0.4%] with abnormal absolute V_max reactivity and 7 [2.9%] with abnormal relative V_max reactivity) who had an abnormal response in the hemisphere of carotid artery disease. Five of the patients who had an abnormal low relative V_max reactivity were symptomatic, and two were asymptomatic.

Reference ranges of side-to-side asymmetries were calculated on the basis of values obtained in the elderly control group. With respect to the side-to-side asymmetry of CP_i and CR_i reactivity, we only calculated a reference range for side-to-side asymmetries of relative reactivities, since side-to-side asymmetries of relative CP_i and CR_i reactivity varied less between control groups than asymmetries of absolute reactivities (side-to-side asymmetry of the absolute CP_i reactivity was significantly lower in the elderly subjects). Calculated reference ranges for each side-to-side asymmetry are given in Table 3. Patient classification according to the corresponding normal values allowed us to identify a small number of subjects with pathological findings (5% to 7%) when sonographic indexes of blood flow were used (Table 3). Thus, among 245 patients (101 symptomatic, 144 asymptomatic), we found 17 subjects (8 symptomatic, 9 asymptomatic) with an abnormal side-to-side asymmetry of absolute V_max reactivity and 16 subjects (8 symptomatic, 8 asymptomatic) who had an abnormal side-to-side asymmetry of relative V_max reactivity. When the side-to-side asymmetry of V_mean reactivity was used for patient classification, we identified 16 patients (7 symptomatic, 9 asymptomatic) who had an abnormal side-to-side asymmetry of absolute V_mean reactivity and 13 patients (6 symptomatic, 7 asymptomatic) who had an abnormal side-to-side asymmetry of relative V_mean reactivity (Figure). Most of the patients with abnormal side-to-side asymmetry of flow velocity reactivity were abnormal negative, meaning that the poststenotic reactivity was clearly smaller than the contralateral reactivity. The frequency of abnormal findings with respect to interhemispheric differences of flow velocity reactivity was slightly but not significantly higher in symptomatic than in asymptomatic subjects (7.1% versus 5.7%). Latter values represent mean values of all abnormal findings that were obtained with the different flow velocity parameters in symptomatic or asymptomatic subjects.

View this table: [in this window] [in a new window]   Table 3. Classification of 245 Patients With Strictly Unilateral Significant Carotid Artery Disease According to Normal Values

View larger version (30K): [in this window] [in a new window]   Figure 1. Bar graph shows frequency of abnormal hemodynamic findings in 245 patients (shaded bars) with strictly unilateral significant carotid artery disease. Rvmax indicates absolute reactivity of Vmax; R%vmax, relative reactivity of Vmax; Rvmean, absolute reactivity of Vmean; R%vmean, relative reactivity of Vmean; R%CPi, relative reactivity of CPi; and R%CRi, relative reactivity of CRi.

Indexes of vascular resistance and pulsatility allowed us to clearly identify more patients with abnormal findings. Among 245 patients, we found 110 patients (44.9%) who had an abnormal side-to-side asymmetry of relative CP_i reactivity and 96 patients (39.2%) who had an abnormal side-to-side asymmetry of relative CR_i reactivity (Figure). Of the 245 patients, 80 had a simultaneous abnormal side-to-side asymmetry of the relative resistance and the CP_i reactivity. In about half of the subjects with abnormal findings, ipsilateral reactivity was clearly lower than contralateral reactivity, whereas in the other half, the opposite phenomenon was observed. The percentage of patients with a simultaneous abnormal side-to-side asymmetry of relative resistance index and of CP_i was somewhat higher in the symptomatic group than in the asymptomatic group (37.6% versus 29.2%, not significant).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Cerebral hemodynamics are considered clearly abnormal if a significant ICA lesion (stenosis >80% of diameter or occlusion) is combined with functionally inadequate intracerebral collaterals (circle of Willis) and with an exhausted cerebral autoregulatory response. Abnormal intracerebral hemodynamics cannot be predicted from the status of extracranial arteries and have been associated with a significantly higher incidence of ischemic hemispheric events and perioperative complications.^{15 16 17} An ideal method recognizes patients who have such abnormal cerebral hemodynamics with high accuracy and is minimally invasive and expensive.

We found that, with the exception of V_max, all other hemispheric parameters (V_mean, CP_i, and CR_i) demonstrated a significant difference between young and elderly control subjects. Age-dependency can be explained by arteriosclerosis-induced reduction in vascular elasticity and loss of endothelial cells,^{18 19} resulting in reduced CO₂ response with increasing age. This age-related fall in CO₂ response mainly affects the reactivity of diastolic flow velocity, which largely reflects (according to the theory of vascular impedance) changes in peripheral resistance and wave reflection.^{11 20} Consequently, parameters that include diastolic flow velocity (reactivity of V_mean, CP_i, and CR_i) were much more sensitive to variations in age or extent of arteriosclerosis than was the reactivity of V_max.

However, reactivity of V_max does not appear to be ideal with respect to patient classification. Classification by reference ranges only identified one patient (0.4%; analysis of absolute reactivity) or seven patients (2.9%; analysis of relative reactivity) who presented with abnormal intracerebral hemodynamics. This low frequency of abnormal findings would not differ from the frequency of abnormal findings (5%) that might be discovered in subjects without significant carotid artery disease, and it detracts from the value of V_max to diagnose patients with carotid artery disease.

High variability of hemispheric CO₂ reactivities presumably resulted because a variety of variables (hematocrit level, myocardial contractility, MCA diameter, medication) were not controlled, and these variables determine the absolute magnitude of V_max and of its CO₂ reactivity to a large extent.^{21 22 23 24} On the other hand, control of these interfering variables in a reference population can only be achieved with major effort and would also have to be adjusted to the complex individual profile of these variables in the patient to be examined.

Our findings in control subjects suggest that, in patients with strictly unilateral carotid artery disease, age-independent side-to-side asymmetry of a parameter might be more suitable for classification of subjects by intracerebral hemodynamic status than would hemispheric reactivities. However, when reactivities of relative or absolute V_max or V_mean were used, only 5% to 7% of the subjects demonstrated abnormal findings. Due to this low frequency, interpretation of abnormal findings remains uncertain. Therefore, the discriminatory power of flow velocity reactivities including their side-to-side asymmetries appears low when variable CO₂ concentrations are used.

Another uncertainty in the interpretation of flow velocity reactivities relates to the physiological meaning of these parameters. Several studies have tried to validate reactivity of V_mean against reactivity of cerebral blood flow (measured by single-photon emission CT). Some claimed that flow reactivities correlated with absolute⁷ but also with relative⁸ velocity reactivity; others found that they correlated neither with absolute⁹ nor with relative^{9 25 26} velocity reactivity. Therefore, it is unclear which variable best reflects cerebral blood flow reactivity and what CO₂-stimulated velocity changes mean. In this context, one has to keep in mind that the concept of V_mean (steady flow following Poiseuille's law), which is derived from measurements in pulsatile flow, does not accurately describe the steady components of pulsatile flow. Thus, in elastic vessels, nonlinear terms arising from the interaction between mean and pulsatile components of flow may introduce an error of more than 10%.²⁷

It appears that interpretation of hemodynamic findings obtained by transcranial Doppler sonography at different CO₂ concentrations is facilitated when side-to-side asymmetries of vascular impedance indexes (resistance and pulsatility) are analyzed. Use of the latter parameters allowed identification of a significant number of patients with abnormal findings (39% and 45%, respectively). Among these patients, we could identify abnormal hemodynamics in the affected hemisphere in about half of the cases and in the contralateral hemisphere in the other half. In a previous study, we showed that abnormal impedance indexes are exclusively the result of the carotid artery disease, since they return to normal after carotid endarterectomy.^{28 29} Thus, the method appears quite insensitive to interfering variables and might therefore be the method of choice to evaluate cerebral hemodynamics, if the diameter of peripheral cerebral vessels is manipulated by CO₂ and if the lesion is strictly unilateral. Indexes of cerebral blood flow (V_mean), which are mostly used in combination with acetazolamide, seem to be subject to detracting interferences when used in combination with variable CO₂ concentrations.

	Selected Abbreviations and Acronyms

 

CPi = cerebral pulsatility index CRi = cerebral resistance index ICA = internal carotid artery MCA = middle cerebral artery Vmax = maximal blood flow velocity Vmean = mean blood flow velocity Vmin = minimal blood flow velocity

Received April 5, 1995; revision received September 11, 1995; accepted September 11, 1995.

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