Use of transcranial Doppler sonography and acetazoalmide test to demonstrate changes in cerebrovascular reserve capacity following carotid endarterectomy

Eur J VascEndovasc Surg 11, 83-89 (1996)

Use of Transcranial Doppler Sonography and Acetazoalmide Test to Demonstrate Changes in Cerebrovascular Reserve Capacity Following Carotid Endarterectomy Phi Barz61, Erika V~r~s 2 and Mihbly BodosP Departments of 1Neurosurgery and 2Radiology, Albert Szent-Gy~rgyi Medical University, Szeged, Hungary. Objectives: To assess the effect of carotid endarterectomy on cerebrovascular reserve capacity. Methods: Cerebral blood flow velocity (CBFV) and cerebrovascular reserve capacity (CVRC) were measured by transcranial Doppler sonography (TCD) and acetazolamide test in 40 patients who underwent uncomplicated unilateral carotid endarterectomy (CEA). Indication for operation was limited to stenoses > 70% as documented by angiography and/ or Duplex scanning. The TCD studies were carried out 6 days (range 1-14 days) before and 8 days (range 5-12 days) after endarterectomy. Results: Before endarterectomy, resting CBFV values and CVRC in the 40 patients were significantly different between the operated (51 + 19 cm/s; 20 + 16%) and the non-operated (60 + 19 cm/s; 34 + 24%) hemisphere (p < O.O&p < 0.01). After CEA the overall increase of resting CBFV of the operated side was highly significant with preoperative CBFV values of 51 + 19cm/s and postoperative values of 62 + 15 cm/s (p < 0.01). Cerebrovascular reserve capacity after operation was increased on both sides significantly (non-operated side:from 34 + 24% to 43 +_19%, p < 0.05; operated side:from 20 + 16% to 51 + 18%, p < 0.001), and the preoperative asymmetry was no longer present. Conclusions: CEA has a beneficial effect on the cerebral circulation in most patients, even those who presented with asymptomatic carotid artery stenosis. Since CVRC has been assessed in the early postoperative period, our findings also suggest that cerebral vascular adaption occurs within 2 weeks after CEA. Key Words: Carotid endarterectomy (CEA); Transcranial Doppler sonography (TCD); Acetazolamide test; Cerebrovascular reserve capacity (CVRC).

Introduction

many authors have demonstrated the usefulness of these tests in assessing the cerebral perfusion reserve The recent publication of data from three clinical trials before CEA, s-ll only a few studies have measured the has confirmed the benefits of carotid endarterectomy changes in cerebral vasoreactivity following CEA. 12-17 (CEA) in symptomatic patients with high-grade Methods for detection of the cerebrovascular response carotid stenosis. 1-3 - Carotid endarterectomy, combined to acetazolamide or CO2 changes have included with optimal medical treatment can also reduce the regional cerebral blood flow techniques, and positron incidence of ipsilateral neurologic events in high risk emission tomography. However, compared with these male patients with asymptomatic carotid stenosis. 4 techniques, the development of transcranial Doppler Whether the effect of surgery depends on the sonography (TCD) provides a noninvasive, nonimprovement of the hemispheric perfusion pressure radioactive, and easily performable method of assessor the prevention of the thromboembolic mechanism ing vasoreactivity. Although TCD does not directly is still not clear. In patients with carotid disease the measure flow, there is a linear relationship between collateral circulation to the brain can be measured by cerebral blood flow and velocity in a particular artery determining the responsiveness of the cerebral circula- if the diameter of the vessel remains constantJ 8-22 In this report we compare the preoperative and tion to carbon dioxide or acetazolamide. Although early postoperative cerebral blood flow velocity (CBFV) and cerebrovascular reserve capacity (CVRC) Please address all correspondence to: P~I Barz6, Department of values measured by TCD and acetazolamide provocaNeurosurgery, Albert Szent-Gy6rgyi Medical University, 6701 tion in symptomatic and asymptomatic patients. To Szeged, P.O, Box:464, Hungary. 1078-5884/96/010083+ 07 $12.00/0 © 1996W. B. Saunders Company Ltd.

84

P. Barz6 .et aL

our knowledge, this has been carried out for the first time by this simple method.

Subjects and Methods

We studied 40 patients who underwent uncomplicated unilateral CEA. There were 29 men and 11 women, aged 40-72 years (mean age 57 years). All patients were evaluated by a neurologist before and after endarterectomy. Eighteen patients had experienced cerebral transient ischaemic attacks (TIA). One had suffered a stroke with subsequent TIA, and six patients had suffered a stroke only. Nine patients had developed a reversible neurologic deficit lasting more than 24 h (PRIND) and only six operations were performed for asymptomatic critical (~ 80%) internal carotid stenosis. The indication for operation was limited to stenoses > 70% as documented by angiography a n d / o r Duplex scanning. The angiography a n d / o r Duplex scan findings are shown in Table 1. The median time between the latest neurologic event and surgery was 12 weeks (range 8-19 weeks) for strokes and 5 weeks (range 1-14 weeks) for TIA and PRIND. Carotid endarterectomy was performed under normotension and hypocapnia (arterial carbon dioxide tension (paCO2) of 35-40 mmHg). General anaesthesia was induced b y a short acting barbiturate, supplemented by neuroleptoanalgaesia and maintained with concentrations of halothane ranging between 0.0 and 1.5 minimal alveolar concentration. During endarterectomy the nerve to the carotid sinus was blocked with 2-5 ml of 1% hdocaine. Intravenous heparinisation (3000-5000 units) was given before carotid occlusion and reversed with 25-50 mg protamine sulphate at the end of the operation. Endarterectomy was performed through a longitudinal arteriotomy. Care was taken to taper the distal intimal margins and, if in doubt, intimal flaps were sutured. Arteriotomies were dosed directly and patches were not used. Intraoperative monitoring consisted of continuous ECG, blood pressure and EEG recordings. The CBFV was measured using a 2 MHz rangegated pulsed wave Doppler instrument with on line spectrum analysis (TC2-64B, Eden Medical Electronics Inc., Uberlingen, Germany). Examinations were performed through the transtemporal bone window. Following identification of the middle cerebral artery (MCA) at sampling depths of 45-55 mm as reported by Aaslid et al.9 the probe was strapped to the patient's head in the position providing the best MCA blood flow velocity signal. Four patients were Eur J Vasc Endovasc Surg Vo111,January 1996

excluded from the study due to difficulties in obtaining a satisfactory Doppler signal. The TCD studies were carried out 6 days (range 1-14 days) before and 8 days (range 5-12 days) after endarterectomy. The CBFV was displayed continuously before and 20 min after the i.v. administration of lg acetazolamide (Lederle). Cerebrovascular reserve capacity was calculated as follows: CVRC (%) -

Vl-V 0 6O

Where V 1 = acetazolamide stimulated CBFV; V0 = rest CBFV; 60 c m / s is the mean value of healthy subjects measured in the MCA. The end tidal carbon dioxide concentration was not measured. Since previous studies 1°'19"~4 showed that only markedly diminished or exhausted acetazolamide reactivities indicate haemodynamic impairment, we distinguished between three categories of sufficient, diminished, and exhausted CVRC. In the case of sufficient acetazolamide reactivit)~ the MCA blood flow velocity increased by at least 20%, while a diminished CVRC was characterised by an increase in CBFV between 10-20%. Less than 10% increase or a decrease in CBFV meant an exhausted acetazolamide reactivity. 1°,19,24 The data are expressed as the mean + one standard deviation (S.D.). A one-way analysis of variance (ANOVA) was used for overall intergroup comparisons. Intragroup comparisons (before and after acetazolamide test) were evaluated using Student's t-test for paired data. A probability level of < 0.05 was considered to indicate significant differences.

Results

Findings before endarterectomy Before endarterectom)~ resting CBFV values in the 40 patients differed significantly between the operated (51+19 cm/s) and the nonoperated (60+19 cm/s) hemispheres (p < 0.05). Cerebrovascular reserve capacity values on the operated side were also significantly lower (20 + 16%) than on the contralateral side (34 + 24%; p < 0.01). On the basis of the acetazolamide response, the patients were classified into three (I-III) groups: group I, (12 patients) normal CVRC in both sides (changes in CBFV > 20%); group II, (19 patients) diminished or exhausted CVRC in one side (changes in CBFV < 20%) and normal in other side; group III, (9 patients) diminished or exhausted in both sides. Decrease of

CBRC Following Carotid Endarterectomy

85

Table 1. Middle cerebral artery blood flow velocity and cerebrovascular reserve capacity (CVRC) before and after endarterectomy in 40 patients Middle cerebral artery blood flow velocity (cm / sec) and CVRC (%) Non-operated side Before EA Stenosis %

No. Group I 1/1 2/2 3/3 4/4 5/5 6/6 7/7 8/8 9/9 10/10 11/11 12/12 Group 13/1 14/2 15/3 16/4 17/5 18/6 19/7 20/8 21/9 22/10 23/11 24/12 25/13 26/14 27/15 28/16 29/17 30/18 31/19

30D;70S 75D 90D 90D 50D;95S 60D;80S 90D 90S 0D;80S 75D;90S 75D;80S 80D Mean±SD

Rest

Max.

After EA CVRC

cm / sec

62 52 86 78 64 90 56 66 40 48 38 72 63_+17

75S 46 50D;90NOVD 68 80S 70 90S 78 90S 54 90D 72 50D;90S 72 90D 46 90S 50 90D 40 75S 60 50D; 75S 56 0D;90S 36 85S 38 85S 46 90S 56 90D 80 50D;90S 72 50D;90S 128 Mean_+SD 61±21

Group III 32/1 0D;90S 44 33/2 80D 72 34/3 80D 50 35/4 50S;90D; OVD 54 36/5 95S 66 37/6 95D 40 38/7 0N 80D 24 39/8 0N 90D 48 40/9 90S 66 Mean_+SD 52±15 Group I-III Mean_+SD 60+19

%

118 90 130 100 94 120 82 118 56 64 58 86 93±25

Operated side

Rest

Max.

cm / sec

93 63 73 37 50 50 43 87 27 27 33 23 51±24

Before EA CVRC

Rest

%

Max.

CVRC

cm / sec

122 76 128 86 96 108 96 106 64 84 54 120 95_+23

73 60 86 43 40 60 60 62 90 50 64 86 53 60 92 50 90 122 57 46 62 50 48 64 33 26 46 40 50 78 33 42 58 57 46 60 50_+12 53_+16 75_+21

72 43 86 30 94 40 96 30 104 83 112 67 106 57 72 43 82 37 48 13 90 50 72 27 44 13 52 23 62 27 72 27 94 23 86 23 144 27 8 4 ± 2 4 36_+18

66 70 74 90 62 60 86 64 52 50 60 58 32 60 52 72 94 46 86 65_+16

114 90 100 110 100 86 104 76 72 60 86 78 52 100 98 104 108 64 138 92_+21

80 33 43 33 63 43 30 20 33 17 43 33 33 67 77 53 23 30 87 44±21

34 74 56 64 78 52 34 52 72 57±16

46 60 96 114 76 92 60 94 74 112 42 56 70 80 60 64 50 66 64_+17 82±22

23 30 27 57 63 23 17 7 27 30±18

81_+26 34_+24 6 4 + 1 6

90+22

Rest

%

78 50 82 56 64 78 62 76 44 60 34 86 64_+16

-17 3 10 17 20 20 17 7 10 10_+12

After EA Max.

CVRC

cm / sec

%

43 33 47 37 53 53 27 27 33 47 27 23 38±11

64 40 72 60 60 72 64 64 38 56 42 90 60±15

98 57 56 27 108 60 86 42 98 63 118 77 102 63 102 63 66 47 92 60 72 50 164 123 97_+28 61±23

42 44 32 70 72 66 66 48 35 60 56 48 70 38 36 40 20 34 122 53±23

52 20 52 13 36 7 82 20 80 13 76 17 72 10 36 -20 42 12 80 33 60 7 60 20 86 27 48 17 48 20 42 3 30 17 34 0 122 0 60±24 12±12

46 64 66 66 72 52 86 62 60 60 58 54 52 78 44 62 48 62 106 63±15

90 94 104 94 128 76 104 82 78 90 82 90 86 104 72 90 70 90 142 93±18

42 52 62 44 38 30 36 46 72 47±13

46 7 66 13 60 -3 56 20 34 -7 38 13 44 13 56 17 82 17 5 4 ± 1 5 10_+9

72 86 23 78 108 50 92 114 37 46 68 37 68 92 40 46 58 20 52 90 63 54 92 63 54 86 53 62_+16 88_+17 43±16

43_+19 51_+19 63_+22 20_+16 6 2 + 1 5

93+21

73 50 63 47 80 40 30 33 30 50 40 60 57 43 47 47 37 47 60 49_+14

51+18

Patients are grouped according to preoperative CVRC findings: Group I, normal CVRC in both sides; Group II, diminished or exhausted CVRC in one side; Group III, diminished or exhausted CVRC in both sides. D: right internal carotid artery; L: left internal carotid artery; 0: occlusion; VD: right vertebral artery; VL: left vertebral artery; EA: endarterectomy.

CBFV after acetazolamide stimulation (steal phenom-

significantly lower

e n a ) w a s f o u n d i n o n e o f 19 i n g r o u p II, a n d t h r e e o f

12+12%),

nine

(51 _+24%; 36 + 18%; p < 0.05; p < 0.001).

in group

III. I n g r o u p s

I and

II C V R C

was

on the operated

compared

with

the

s i d e ( 3 8 + 11%;

nonoperated

side

Eur J Vasc Endovasc Surg Vol 11, January 1996

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P. Barz6 et aL

Findings after endarterectomy N o n e of the patients d e v e l o p e d postoperative neurologic complications, a n d there were no n e w TIA or strokes d u r i n g the 2 w e e k perioperative observation period. The overall increase of resting CBFV of the operated side was highly significant with p r e o p e r a t i v e CBFV values of 51 ___19 c m / s a n d postoperative values of 62_+ 15 c m / s (p < 0.001). Cerebrovascular reserve capacity after operation was significantly increased in b o t h sides ( n o n - o p e r a t e d side: f r o m 34+24% to 43 + 19%, p < 0.05; operated side: f r o m 20 + 16% to 51 + 18%, p < 0.01), a n d the p r e o p e r a t i v e a s y m m e t r y w a s no longer present. Patients in groups I a n d II s h o w e d significant changes in acetazolamide stimulated ipsilateral M C A flow (38+11%; 12+12% before, a n d 61+23%; 49 + 14% after endarterectomy, (p < 0.05; p < 0.001 respectively). H o w e v e r in these groups, p o s t o p e r a t i v e studies failed to s h o w a n y change of stimulated flow of the M C A in the n o n o p e r a t e d side (Figs. la, b a n d 2a, b). In g r o u p III p r e o p e r a t i v e CVRC w a s m a r k e d l y reduced in b o t h sides. Postoperative acetazolamide (a)

-

51%

I

40

~ 50%

38%

27%

20

(b)

~

20 0

After surgery

54%

18%

Dimished

23%

Exhausted

Before surgery

After surgery

Group II Operated side

I00

80

44%

36%

Co) 84%

20

65%

~ 6O

Group I Operated side

i00

m

so

~ 4O

Dimished Exhausted Before surgery

Group II Nonoperated side

100

75%

60

"~ 4o

Patients with carotid artery disease present with a

(a)

62%

6O

Discussion

Group I Nonoperated side

100 80

stimulated CBFV obtained in these nine patients d e m o n s t r a t e d m a r k e d l y i m p r o v e d vasoreactivity bilaterally in six cases, a n d slightly i m p r o v e d in one case. In two patients no change occurred in CVRC contralaterally. H o w e v e r the CVRC in the o p e r a t e d side n o r m a l i s e d after CEA in each case (Fig. 3a, b). In the six patients in w h i c h CEA w a s p e r f o r m e d for a s y m p t o m a t i c critical carotid stenosis (5,6,11,31,35,40) preoperative CBFV m e a s u r e m e n t d e m o n s t r a t e d normal CVRC in three cases (5,6,11) a n d decreased or abolished CVRC in the other three cases. Carotid e n d a r t e r e c t o m y resulted in bilaterally significant i m p r o v e m e n t in CVRC in three patients (nonoperated side: f r o m + 1 9 % to 57+30%; o p e r a t e d side: f r o m 12 + 11% to 50 + 12%; p < 0.001), h o w e v e r in the other three cases only a unilateral change (from 44 + 15% to 63 + 14%; p < 0.01) w a s observed.

8O

49%

61%

38% 38% 27% Dimished Exhausted Before surgery After surgery

Fig. 1. Group I (12 patients), normal cerebrovascular reserve capacity before carotid endarterectomy in both sides. Cerebrovascular reserve capacity before and after carotid endarterectomy on the nonoperated (la) and the operated side (lb). In each figure, the mean is represented by a bold line and one standard deviation by the faint lines. Eur J Vasc Endovasc Surg Vol 11, January 1996

63%

60 49%

> 40 24% 2o

35% 1 2 % Dimished

0% Before surgery

Exhausted

After surgery

Fig. 2. Group II (19 patients), diminished or exhausted cerebrovascular reserve capacity in one side (changes in cerebral blood flow velocity <20%) and normal in the other side. Cerebrovascular reserve capacity before and after carotid endarterectomy on the nonoperated (2a) and the operated side (2b).

CBRC Following Carotid Endarterectomy

87

be performed without haste. Thus, we chose to use an acetazolamide stimulus in this study for practical reasons. Transcranial Doppler sonography permits measurement of CBFV within the basal cerebral arteries from outside the skull. Compared with regional cerebral blood flow techniques and positron emission tomography, TCD is noninvasive, inexpensive, relatively simple to perform and is very sensitive to time dependent CBF changes. When a comparison is made between the CO2 and acetazolamide tests, a close and linear correlation is found between CBF and CBFV changes. 18-2° It is now possible to use TCD to evaluate the clinical significance of a reduced perfusion reserve. 15-18 The purpose of this study was therefore to define the acetazolamide reactivity as measured by TCD in patients who underwent CEA to determine if revascularisation would alter the response. However in our study the calculation of CVRC was modified. The changes in CBFV were compared with the mean value of healthy subjects (60 cm/s). Before endarterectomy resting CBFV values in the 40 patients were significantly different between the operated and the non-operated hemisphere. After surgery the overall increase of rest CBFV of the operated side was significant and the preoperative asymmetry of the rest CBFV was no longer present. In (a) Group III group III a minor though significant increase in the I00 Nonoperated side contralateral hemispheric CBFV was also observed 80 within the first postoperative 12 days. These findings r~ are in accordance with those of Schroeder et al., Engel 60 48% ¢$ et al. and Araki et al., and might indicate an increase of o 40 blood flow through the middle cerebral artery, result30% 22% ing in a greater amount of brain tissue being fed by the N 20 Dimished artery5 as observed previouslyF '29"3° 10% Exhausted 12% Araki et al. demonstrated that in patients with -2% occlusive ICA disease the severity of haemodynamic Before surgery After surgery change is proportional to the degree of ICA stenosis. 3° In the present stud:~ however, half of the patients with uni- or bilateral high grade stenosis preoperatively (b) Group III 100 presented with normal or only moderately reduced Operated side CVRC. These data are also supported by the results of 80 Leisinger et al. who used acetazolamide CBF test before and after endarterectomy and who also failed 59% 60 to find a correlation. 31 43% ~ 4o However, in contrast to previous studies - - in 19% 27% which surgery significantly improved CVRC only in m 20 Dimished patients who had an abnormal side-to-side asymmetry 10% Exhausted in reactivity before surgery - - the most striking 1% observations was the postoperative increase of CVRC Before surgery After surgery in almost every case, even in asymptomatic patients Fig. 3. Group III (9 patients), diminished or exhausted cerand in patients with normal CVRC. ~'1624 There are a ebrovascular reserve capacity in both sides. Cerebrovascular reserve few possibilities that might explain this effect. Firstly, capacity before and after carotid endarterectomy on the nonthe normal (control) vasomotor reactivity as defined in operated (3a) and the operated side (3b).

variable cerebral haemodynamic status. Whether perfusion pressure is reduced under these circumstances depends on several factors. One of them is cerebral autoregulation (normal vasomotor reserve) which keeps brain perfusion constant despite a reduced cerebral perfusion pressure. In addition, arteriolar vasodilatation will be also modified by the presence and the degree of collaterals. Measurement of vasomotor reactivity helps to identify patients with reduced cerebral perfusion pressure and quantifies the haemodynamic significance of the extracranial large vessel stenosis. The CVRC may be determined by assessing vasoreactivity using a potent vasodilator stimulus such as CO2 or acetazolamide. Acetazolamide is a carbonic anhydrase inhibitor that temporally elevates cerebral blood flow (CBF) by 30--80% 23-26 and CBFV by 40%. 10'22"27 One gram is necessary to achieve a supramaximal dilatative effect on the cerebral resistance arteries and to completely exhaust the CVRC. 28 Cerebral blood flow or CBFV begins to increase after 2 min, reaching a maximum at 10 min after the dose. The increase at this point is stable for the next 20 min. During this period CBF and CBFV measurements can

Eur J Vasc Endovasc Surg Vol 11, January 1996

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P. Barz6 et al.

previous studies (an increase in CBFV of > 20%) might have been underestimated. SecondlN within a few days after surgery the resistance vessels are "overconstricted" due to the improved cerebral autoregulation that prevents cerebral hyperperfusion. This second explanation is supported by the results of Jorgensen and Schroeder who have found cerebral hyperperfusion to be manifest especially from the 2nd to the 4th postoperative day.32 In group III preoperative CVRC was markedly reduced on both sides even in patients with normal ICA on the contralateral side. This interesting observation suggests that unilateral carotid stenosis may have a hemodynamically significant effect on the contralateral side. Furthermore the severity of carotid atherosclerosis does not closely correlate with the impairment of CVRC. Postoperative acetazolamide stimulated CBFV obtained in this group demonstrated markedly improved vasoreactivity bilaterally in six cases, and a slight improvement in one case. For these seven the improved reactivity in the contralateral hemisphere may result from an intracerebral steal or from a reversal of intracerebral steal depending on the atheromatous changes of the contralateral internal carotid artery. Similar results have been published by Cirkit et al., Markus et al. and Widder et al. who reported an improvement in cerebral haemodynamics on the other hemisphere, 15'3B'34 although all these patients had occlusion or subtotal ICA stenosis on the nonoperated side. Therefore, we believe that endarterectomy of a high grade stenosis may improve haemodynamics on the contralateral side and the surgical removal of the stenosis seems to be the method of choice for restoring cerebral haemodynamics. Changes in cerebral vasoreactivity following CEA have been assessed in a few studies, 11-~4'34-37but most of the postoperative measurements were performed 1 to 6 months after surgery. Our findings demonstrated normalized CVRC following carotid endarterectomy in the early postoperative period. This is in agreement with Blohme et al. who observed an increase in velocity and pulsatility index of the middle cerebral artery waveform as soon as 3 days after surgery.B8 It is important to discuss the data of six patients in our study who underwent CEA for an asymptomatic carotid artery stenosis. Five patients had normal resting values whereas three of them had diminished or exhausted CVRC. Carotid endarterectomy resulted in bilaterally significant improvement in three patients and unilateral (operated side) increase in CVRC in the other three cases. It is clear that the numbers of asymptomatic patients in this series are too small to draw a firm conclusion. However, the results of our study agree with a study of five patients by Sullivan et Eur J Vasc Endovasc Surg Vol 11, January 1996

al. and 22 patients by Gratzl et aI. who observed postoperative improvement of CBF after endarterectomy.13'39 These findings suggest that ICA stenosis may impair cerebral haemodynamics more often than suspected from the clinical history alone and acetazolamide TCD may help to reveal which patients with asymptomatic critical carotid artery stenosis would benefit from CEA. Currently, it is our policy to perform CEA in asymptomatic patients with bilateral high grade ICA stenosis a n d / o r abnormal CVRC. In conclusion we consider that CEA has a beneficial effect on the cerebral circulation in most patients including those with an asymptomatic carotid artery stenosis. Since CVRC has been assessed in the early postoperative period, our findings also suggest that cerebral vascular adaption occurs within 2 weeks after CEA. Considering the clinical appliction of our findings, it would seem useful to monitor CVRC to evaluate both the prognosis (patency of CEA) and most appropriate treatment (neuroprotectant drugs, intraoperative shunt) during and after CEA.

Acknowledgement The authors would like to express their gratitude to Dr R. Bullock of the Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, for reviewing the manuscript prior to submission. This study has been supported by a grant from the Hungarian Scientific Research Foundation (OTKA).

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CBRC Following Carotid Endarterectomy

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Accepted 25 April 1995

Eur J Vasc Endovasc Surg Vol 11, January 1996