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Title: The influence of carotid endarterectomy on cerebral blood flow in significant carotid stenosis- perfusion computed tomography study.

Authors:

Aleksander Lukasiewicz1,4 MD, PhD, Roman Mindykowski2 MD, Zbigniew Serafin3 MD, PhD

1.  Department of Vascular Surgery, Regional Specialty Hospital, Grudziadz, Poland

2.  Department of General and Vascular Surgery, A. Jurasz 1st University Hospital , Bydgoszcz, Poland

3.  Department of Radiology and Diagnostic Imaging, Nicolaus Copernicus University, Collegium Medicum, Bydgoszcz, Poland

4.  Department of Tissue Engineering, Chair of Medical Biology, Nicolaus Copernicus University, Collegium Medicum, Bydgoszcz, Poland

Funding: none

Conflicts of interest: none

Acknowledgements: none

Corresponding author:

Aleksander Lukasiewicz, MD.

Department of Vascular Surgery, Regional Specialty Hospital

Rydgier 15-17 Str. 86-300 Grudziadz

Phone: +48 566414082

Fax:+ 48 566414109

e-mail:

Abstract

Aim: Carotid endarterectomy (CEA) is well recognized procedure in treatment of patients with significant symptomatic internal carotid artery (ICA) stenosis. Operation reconstitutes physiologic blood flow in the ICA. The influence of CEA on cerebral perfusion (CP) is not well established. Some data suggest increased CP after stenosis correction however evidence in post-endarterectomy patients is scarce. Our aim was to investigate the influence of CEA in patients with symptomatic carotid stenosis on CP parameters by means of perfusion computed tomography (PCT).

Methods: 34 patients with symptomatic severe carotid stenosis qualified for CEA were included. The baseline PCT of the brain according to standardized protocol was performed within 3 weeks prior to surgical procedure. The follow-up PCT was performed between 30th -60th day postop. The following perfusion parameters were analyzed: cerebral blood flow (CBF), cerebral blood volume (CBV), peak enhancement intensity (PEI) and time to peak (TTP). Pre- and postoperative average values of these parameters were compared.

Results: No death/stroke occurred in the investigated group. Mean preoperative total CBF was 66.2 ml/100 g/min and was not dependent on the degree of the carotid stenosis or the presence of contralateral carotid artery stenosis. Mean postoperative total CBF was significantly lower (61,8 ml/100g/min, P<.05). No significant changes in PEI, TTP and CBV were observed

Conclusions: PCT of the brain reveals that CEA in patients with symptomatic carotid stenosis decreased total CBF especially in the contralateral hemisphere.

Key words: carotid endarterectomy, brain perfusion, perfusion imaging, computed tomography

TEXT

Introduction

Ischemic stroke is the third leading cause of mortality and the leading cause of permanent disability in the USA [1]. Carotid artery disease is responsible for 20-30% of cerebral ischemic events. Guidelines on treatment of carotid artery stenosis recommend interventional treatment in patients with symptomatic carotid disease in most good risk patients [2].

Atherosclerotic lesion removal by means of either surgical or endovascular intervention leads to changes of the blood flow dynamics and may cause serious disturbances of cerebral perfusion with fatal consequences in early postprocedural course [3,4].

Brain blood flow is regulated by complex system of extra- and intracranial mechanisms. Baroreceptors of the carotid sinus and aortic arch as well as carotid body receptors are chief extracranial regulators, while baroreceptors of the intracerebral arteries, miogenic vascular response and chemoreceptors in brain tissue are potent intracerebral regulators. All are responsible for brain homeostasis and all are affected by carotid intervention [5].

Cerebral blood perfusion after carotid artery stenting (CAS) was thoroughly analyzed and changes in blood flow prior and after the procedure were found [3,6]. The influence of carotid endarterectomy in symptomatic carotid artery stenosis was not so extensively analyzed and cerebral perfusion following successful procedure is debatable.

Perfusion computed tomography (PCT) is a noninvasive measure allowing dynamic assessment of brain blood flow [7]. It yields many parameters utilized to describe brain hemodynamics: cerebral blood flow (CBF), peak enhancement intensity (PEI), time to peak (TTP), cerebral blood volume (CBV) [8]. These values help to describe blood flow and are important in recognition of cerebral perfusion disturbances [9].

This study was conducted to evaluate changes of cerebral blood flow parameters following carotid endarterectomy in patients with severe symptomatic carotid stenosis using PCT.

Materials and Methods

The study protocol and informed consent were approved by the Institutional Review Board in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. 34 patients with severe symptomatic carotid stenosis (over 70% using NASCET criteria) were prospectively enrolled after informed consent.

The clinical inclusion criteria were: transient ischemic attack (TIA) or ischemic stroke (IS) attributable to the lesion in the ICA. Only patients with Rankin score <=2 within 1-3 months prior to baseline visit were enrolled. Since the study protocol required intravenous contrast injection patients with creatinine level above 176.8 umol/l were excluded.

To confirm the degree of ICA stenosis carotid duplex ultrasound was performed twice, by two independent sonographists. Degree of significant (over 70%) ICA stenosis was defined using peak systolic velocity and peak systolic ICA/CCA ratio according to Oates and coll. [10]. Peak systolic velocity in the ICA lesion over 230 cm/s and peak systolic ICA/CCA velocity ratio over 4 were considered significant. If both duplex ultrasounds were not in concordance, computed tomography angiography using Mx8000 scanner (Philips Medical Systems, Cleveland, Ohio, USA) was performed and the degree of stenosis was assessed according to NASCET protocol.

There were 20 men and 14 women in the study. Demographic details and co-morbidities are presented in Table 1.

Image acquisition

pCT examinations were performed at two time points: within 3 weeks prior to surgery and within 30th to 60th postoperative day (mean 40 days). PCT examinations were performed on an Mx8000 scanner (Philips Medical Systems, Cleveland, Ohio, USA). In all perfusion examinations, a non-ionic iodinated contrast medium was used (Iomeron 400; Bracco Altana Pharma GmbH, Konstanz, Germany) at a concentration of 400 mg I/ml. The medium was injected as a 50-ml bolus at a flow rate of 5 ml/s, followed by a 40-ml saline chase. Acquisition was parallel to the orbitomeatal line, and was selected at the level of the basal ganglia, just above the circle of Willis. We used a collimation 4x5 mm (total coverage of 20 mm), with a cycle time of 1 s for 40 s, and a 0.75-s rotation time. After a delay of 5 s, a continuous scan was initiated with the following parameters: 120 kVp, 200 mAs. During a scan time of 40 s, a set of 40 images was acquired for each of four layers. A total number of 160 images were reconstructed chronologically based on a rate of 1 layer per second and a slab thickness of 5 mm. Scanning parameters were the same for pre- and post-treatment examinations. An effort was made to place the ROI’s during both CT’s exactly at the same position.

Perfusion measurements

Images were analyzed with the use of an MxView v. 5.02 workstation and standard scanner perfusion software (Functional CT; Philips Medical Systems, Cleveland, Ohio, USA). Analysis was performed by the same investigator: a radiology fellow, who had 4 years’ experience in CT perfusion measurement. For this purpose, two contrast-agent concentration curves were calculated for two regions of interest (ROI): arterial and venous. The arterial ROI was placed in the A2 segment of the anterior cerebral artery contralateral to the treated side, and the venous ROI was placed in the superior sagittal sinus or confluence of sinuses. The size of the ROI was established to fit margins of the contrasted vessel. The particular size and the location of the ROIs were chosen by the investigator. After the calculation of the curves, a line of symmetry was established between the anterior and posterior margin of the falx cerebri. Two symmetrical elliptical ROIs (40x80 mm, approx. 25 cm2) were then placed in the territory of the middle cerebral artery (MCA) (Figure 1). Specific values of cerebral perfusion were then calculated by the software using the maximum slope method. In the final result, the software presented qualitative maps of cerebral blood flow (CBF), cerebral blood volume (CBV), and time to peak (TTP), as well as absolute values of CBF, CBV, TTP, and PEI for the set ROIs. All measurements were performed thrice and the mean of these was further evaluated.

Surgical technique.

All surgical procedures were performed according to standardized protocol. All patients received preoperative antibiotic prophylaxis (cefuroxime 1.5g i.v.) and procedures were performed in local anesthesia using 1% lidocaine solution. 50 units/ kg of unfractionated heparin were administered at skin incision. Neurological status was constantly monitored. Carotid endarterectomy was performed using standard technique described elsewhere [11]. Shunts were considered only in cases of neurologic deficit occurring during clamping. The arteriotomy was closed either primarily or with a patch at operators discretion. Most patients were discharged on the second postoperative day (range 2-3). Control duplex ultrasound to evaluate ICA patency was performed at 1 month after surgery, prior completion PCT.

Statistics.

Distribution of evaluated cerebral blood flow parameters was assessed using Shapiro-Wilk test. If normal distribution was found paired Student t test was utilized to compare pre- and posttreatment mean parameter value. If this condition was not fulfilled nonparametric Wilcoxon pair test was utilized; P<.05 was considered significant. c2 test was utilized to evaluate relations between preoperative data and perfusion parameters.

Results

Operation course was uneventful in all cases. No significant complications were observed in early postoperative course except for the tendency to bradycardia and hypotension during the first 24 hours. Most patients with hypotension were successfully treated conservatively with adequate fluid therapy. Atropine or vasoconstrictors (dopamine) were required in only few cases. No hyperperfusion syndrome was observed. The follow-up ultrasound revealed neither significant residual stenosis nor early occlusion of ICA.

Pre- and postoperative PCT was performed in all patients. Preoperative total CBF (tCBF) was 66.2 ml/100g/min (range 36.3-114.9) and significantly decreased after successful operation to 61.8 (39.9 – 116.5) ml/100g/min (P<0.05, Student’s t test). Considering hemispheres separately CBF decrease was more pronounced on the contralateral side (65.9 vs. 60.7 ml/100g/min, respectively, P<0.03 Student’s t test) than on the ipsilateral one (66.6 vs. 62.9 ml/100g/min, respectively, P=0.096 Student’s t test, Figure 2). Results for individual patients are presented in details in Table 2. PEI was also decreased after operation, however insignificantly (14.3 HU (range 8.4-21.3) vs. 13.9 (6.8-22.9), respectively, P=0.65, Student’s t test). TTP remained unchanged (10.8s (7.2-18.8) vs. 10.8s (8.0-13.7)). CBV was slightly decreased after operation, but the difference also was not significant (1.56 ml/100g (1-2.67) vs. 1.51ml/100g (0.68-2.7), P=0.63, Student’s t test). Considering sides separately, preoperative and postoperative CBV values were not different (ipsilateral 1.55 ml/100g vs. 1.52 ml/100g, P=0.71; contralateral 1.56 ml/100g vs. 1.51 ml/100g, P=0.57).

No relation between any preoperative factor and pre- and postoperative perfusion parameters was found.

Discussion

Cerebral blood flow depends on a complex regulatory system that involves extra- and intracranial mechanisms to maintain stable blood flow in the brain. It allows sufficient cerebral perfusion despite systemic pressure fluctuations or decreased arterial in-flow (as in significant arterial stenosis). On the other hand autoregulation protects the brain against overflow after therapeutic intervention in significant carotid stenosis [12]. Successful vascular treatment restores dynamic blood in-flow through the internal carotid artery and exposes the brain to excessive hyperemia [13]. Although cerebral autoregulation is very efficient, still 1-3% of patients suffer from postprocedural brain hyperperfusion syndrome. Fortunately, in most cases regulatory system activates measures to attenuate the danger. Bradycardia and decreased systemic arterial pressure occur soon after flow restoration in almost half of patients [14]. Then intracranial regulatory mechanisms are restored and cerebral blood flow stabilizes [15].

In this study we observed decreased total cerebral blood flow in the brain after carotid stenosis surgical treatment at mean 40th postoperative day. We believe that observed phenomenon is a manifestation of normalized cerebral blood flow regulation [16]. Prior intervention, mechanisms of brain blood flow regulation are constantly disturbed. Baroreceptors at the carotid bifurcation are especially affected. Tsekouras and colleges demonstrated diminished baroreceptors sensitivity in carotid atherosclerosis, especially if echoopaque plaques at carotid bifurcation were present [17]. Also vascular resistance in the whole brain is decreased and collateral flow is increased [18]. After CEA significant hemodynamic changes are frequently observed [19]. It was found that plaque removal restores some of baroreceptors function [20]. Though after CAS similar clinical observations were done, the mechanism involved is different and probably related to balloon dilatation of the carotid bulb. In fact after carotid stenting baroreceptors function is additionally disturbed due to rigid stent structure and its radial force. The baroreceptors activity decreases, a phenomenon that was described by Parker et coll. as receptor stunning [21]. This leads to actual overflow through patent arteries and triggers intracranial control factors. Such mechanism explains increased cerebral blood flow after carotid stenting at early and late postprocedural period [18, 22]. Such changes were also reported at early postoperative period after CAE but were less pronounced and resolved at long term observation. Sustained, increased cerebral blood flow after successful carotid stenting is, in our opinion, a sign of regulatory mechanism failure and insufficiency of intracranial regulatory mechanism [23, 24]. This leads to brain blood overflow and clinically manifests in 6-7 fold increase of intracranial hemorrhage incidence comparing to surgical treatment [25]

Our opinion is further supported by Reinhard and coll. who found differences between the CAS and CEA patients in the post-treatment CO2 reactivity [18]. In the CEA group the reactivity to CO2 was significantly lower than in the CAS patients. This indicates that the cerebral perfusion in CEA patients depends less on the intracranial mechanisms than do in patients after CAS.

We believe, this aspect of carotid stenosis treatment should be mentioned in the ongoing debate on equivalence of CEA and CAS, especially since these differences were already noticed previously [26].

We studied highly selected population of symptomatic patients with significant, over 70% ipsilateral carotid artery stenosis. All qualified patients suffered neurologic symptoms within 1-3 months time frame to avoid possible acute disturbances of blood flow related to recent brain ischemia. We are aware that current guidelines recommend fast-track carotid surgery after ischemic event but polish national healthcare provider regulations preclude such treatment in most patients due to limited vascular surgery services availability.