Hemodynamic and Metabolic Changes After Carotid Endarterectomy in Patients With High-Degree Carotid Artery Stenosis Akihiko Hino, MD,* Hiroshi Tenjin, MD,‡ Yoshiharu Horikawa, Masahito Fujimoto, MD,* and Yoshio Imahori, MD‡
In symptomatic stenosis of the internal carotid artery (ICA), the predominant mechanism of ischemic event is considered thromboembolic. Carotid endarterectomy (CEA) removes the embolic source and is accepted as the major benefit from the surgery. Even in high-degree stenosis, hemodynamic compromise as a causal factor for cerebral ischemia remains controversial, however. We used positron emission tomography (PET) to evaluate possible hemodynamic and/or metabolic changes caused by a severe ICA stenosis and the subsequent changes after CEA. Subjects consisted of 10 patients with recent transient ischemic attack and/or minor stroke whose carotid stenosis exceeded 80% (mean, 92%). We measured regional cerebral blood flow (CBF), oxygen extraction fraction (OEF), oxygen metabolic rate (CMRO2), and regional cerebral blood volume (CBV) before and after the CEA. In addition, we calculated CBF/CBV value as an indicator of tissue perfusion reserve. We compared these PET values to those of 15 age-matched normal controls. Significant reductions in CBF, CBF/CBV, and CMRO2 values were observed in the hemisphere not only ipsilateral, but also contralateral to the stenosis. In 4 patients, an increase in OEF and decrease in CBF/CBV were also detected. These variables significantly recovered after CEA. High-degree carotid stenosis in the tested range reduces cerebral hemodynamic and metabolic reserve and forms a vulnerable environment in the brain. Successful CEA benefits not only by removing embolic source, but also by improving hemodynamic status, which may be seen in even the contralateral hemisphere. Key Words: Carotid endarterectomy— carotid stenosis— cerebral blood flow— cerebral metabolism—tomography, emission computed. © 2005 by National Stroke Association
Two large international clinical trials have demonstrated that carotid endarterectomy (CEA) reduces stroke risk in recently symptomatic patients with severe stenosis
*From the Department of Neurosurgery, Saiseikai Shigaken Hospital, Shiga, Japan; †Department of Neurosurgery, Saisekai Suita Hospital, Osaka, Japan; and ‡Department of Neurosurgery, Nishijin Hospital and Kyoto Prefectural University of Medicine, Kyoto, Japan. Received February 9, 2005; revised May 19, 2005; accepted June 5, 2005 Address reprint requests to Akihiko Hino, MD, Department of Neurosurgery, Saiseikai Shigaken Hospital, Ohashi 2-4-1, Ritto, Shiga 520-3046, Japan. E-mail: [email protected]
1052-3057/$—see front matter © 2005 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2005.08.001
of the internal carotid artery (ICA).1-4 The predominant mechanism of the ischemic event is considered thromboembolic,2,5 and a high-degree stenosis is most likely to shed emboli. CEA certainly removes the atheromatous plaque, a possible source of cerebral emboli, and this is widely accepted as the major benefit of CEA. But the hemodynamic compromise as a causal factor for cerebral ischemia remains a matter of debate, and its improvement by CEA is considered hypothetical.5-7 Many studies have been conducted to evaluate hemodynamic and/or metabolic status in these patients, but the results are conflicting.7-26 We used positron emission tomography (PET) to assess the regional cerebral hemodynamics and metabolism in patients with severe symptomatic ICA stenosis before and after CEA.
Journal of Stroke and Cerebrovascular Diseases, Vol. 14, No. 6 (November-December), 2005: pp 234-238
PET BEFORE AND AFTER CAROTID ENDARTERECTOMY
Table 1. Clinical and angiographic findings of the 10 patients with carotid artery stenosis Patient
1 2 3 4 5 6 7 8 9 10 Overall
62/M 48/M 64/F 58/M 69/M 73/M 61/M 63/M 74/M 62/M 63.4 ⫾ 7.5
96% 85% 96% 84% 88% 92% 95% 92% 98% 94% 92 ⫾ 4.8
R L R R R L L R R L
Ischemic events Hemispheric Hemispheric Hemispheric Hemispheric Hemispheric Hemispheric Hemispheric Hemispheric Hemispheric Hemispheric
and retinal TIA and retinal TIA TIA and minor stroke and retinal TIA TIA and minor stroke and retinal TIA and retinal TIA TIA and retinal TIA and retinal TIA
Patients and Methods This prospective and observational study was approved by the institutional review board of the Kyoto Prefectural University of Medicine, and all patients gave written informed consent. The subjects were 10 patients with cervical ICA stenosis, with a mean age of 62.4 (range, 48 –74) years. Clinical and angiographic manifestations of the patients are tabulated in Table 1. All had a minor nondisabling stroke and/or transient ischemic attack (TIA), in which carotid stenosis exceeded 80% according to the criteria of the North American Symptomatic Carotid Endarterectomy Trial.3 Patients who had stenosis of the contralateral ICA or stenosis of major cerebral arteries were excluded. All 10 patients in the study group had a recent history of hemispheric and/or retinal TIA in the previous 3 weeks. Preoperatively, PET scans were performed with a Headtome 3 PET scanner (Shimadzu, Kyoto, Japan) with an image resolution of 8 mm in full width at half maximum and a slice thickness of 11–13 mm. Regional cerebral blood flow (CBF), oxygen extraction fraction (OEF), and oxygen metabolic rate (CMRO2) were measured by an oxygen-15–labeled gas steady-state inhalation technique,22,23 and regional cerebral blood volume (CBV) was measured by a O-labeled carbon monoxide bolus inhalation technique,24 with correction for overestimation of OEF and CMRO2 by CBV.25 In addition, we calculated the CBF/CBV value as an indicator of tissue perfusion reserve26,27 and the value of cerebral tissue oxygen supply (CBF ⫻ CaO2 ⫽ total oxygen content of arterial blood).22,28,29 All patients underwent successful CEA at 3– 6 weeks after the last neurologic event, and none of them had retinal or hemispheric TIA after surgery for up to 3 years of follow-up. Intraoperatively, the stump pressure of ICA was measured as an indicator of collateral perfusion, and a temporary cross-cramp shunting was
Stump pressure (mm Hg) 40 42 30 48 52 25 30 30 20 30 34.7 ⫾ 3.3
Risk factors Hypertension, smoking Smoking Hypertension, diabetes
Smoking Hypertension, smoking Hypertension, diabetes Hypertension, emphysema Smoking
routinely used in each patient. We repeated the PET study a mean of 2 months (range, 62–134 days) after CEA. The mean PET values were calculated in each patient for the cortical territory of bilateral carotid arteries and compared with those of 15 age-matched normal controls by the use of nonparametric Mann– Whitney U-test. The PET values of the patients measured before and after CEA were compared using the paired Wilcoxon 2-sample rank test. Statistical differences were considered significant when P ⬍ .05. An individual PET value ⬎ 2 standard deviations of normal controls was considered significant.
Results The mean PET values of the patients, as well as those of the age-matched 15 normal controls, are given in Table 2 and shown in Figure 1. On the whole, significant reductions in mean CBF, CBF/CBV, CMRO2, and CBF ⫻ CaO2 values and an elevation of OEF were observed in the hemisphere of carotid stenosis (Table 2). Reductions in mean CBF, CMRO2, and CBF ⫻ CaO2 values were also observed in the contralateral hemisphere. The CBF, CBF/ CBV, and CBF ⫻ CaO2 values significantly increased after surgery in the hemisphere of stenosis (Fig 1). Assessment of the results in individual patients showed that the OEF was elevated (⬎ 52.2%) in the cortical territory of carotid stenosis in 4 cases and in the contralateral hemisphere in 3 cases, and that the CMRO2 was reduced (⬍ 2.59 mL/100mL/min) in both hemispheres in 5 cases before CEA (Fig 1). The OEF decreased and the CMRO2 increased after surgery in each case, although the CMRO2 value remained lower than that in the normal controls (Fig 1). Figure 2 shows a typical PET image before and after CEA.
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Table 2. Cortical PET values of the 10 patients before and after CEA
Side of stenosis Before After Contralateral side Before After Normal control
CBF ⫻ CaO2
31.8 ⫾ 9.3* 38.3 ⫾ 10.3
49.3 ⫾ 7.0* 44.0 ⫾ 6.7
2.63 ⫾ 0.74* 2.60 ⫾ 0.58*
4.2 ⫾ 0.6 3.9 ⫾ 0.6
5.5 ⫾ 1.8* 6.1 ⫾ 2.0*
7.6 ⫾ 2.2* 10.0 ⫾ 2.1
33.8 ⫾ 9.9* 40.0 ⫾ 9.3 42.0 ⫾ 3.7
48.1 ⫾ 7.3 43.6 ⫾ 6.7 43.6 ⫾ 4.3
2.66 ⫾ 0.72* 2.64 ⫾ 0.47* 3.31 ⫾ 0.36
3.9 ⫾ 0.6 3.7 ⫾ 0.4 4.4 ⫾ 0.4
5.7 ⫾ 1.7* 6.3 ⫾ 1.9* 7.7 ⫾ 0.9
8.7 ⫾ 2.4 10.7 ⫾ 2.3 9.9 ⫾ 1.0
CaO2, total oxygen content of arterial blood. *P ⬍ .05, significantly different from normal control values by the Mann–Whitney U-test.
Discussion Key findings of this study are that unilateral ICA stenosis of the tested range reduces hemodynamic and metabolic parameters: CBF, CBF/CBV, CMRO2, and CBF ⫻ CaO2 values. It is noteworthy that these changes in PET parameters were seen not only in the hemisphere
ipsilateral to the stenosis, but also in the contralateral hemisphere. CEA markedly improved the PET parameters. In 4 cases, a global increase in CBF/CBV values with a reduction in OEF was noted. The findings indicate that the long-lasting hemodynamic and metabolic compromise exists in those patients, and that it can be recovered by CEA. However, they do not necessarily support the
Figure 1. Cortical PET values of each patient before and after CEA. Bars represent mean ⫾ standard deviation of normal control values. *P ⬍ .05, significantly different from baseline (preoperative) values by Wilcoxon’s paired 2-sample rank test.
PET BEFORE AND AFTER CAROTID ENDARTERECTOMY
Figure 2. PET imaging of a 64-year-old woman with right carotid artery stenosis (96%). Preoperative images show marked reductions in CBF, CBF/CBV, and CMRO2 values and an increase in OEF in the right hemisphere. The PET variables recovered significantly after CEA.
classic theory that the hemodynamic compromise directly causes ischemic symptoms, because the current findings represent resting hemodynamics, not hemodynamics in TIA. We speculate that most strokes were attributed primarily to an embolic phenomenon, because most of our patients had amaurosis fugax,30 and Doppler ultrasonography performed in some patients detected embolization from a stenosed carotid artery. Nevertheless, our findings indicate that high-degree carotid stenosis in the tested range reduces cerebral hemodynamic and metabolic reserves and creates a vulnerable environment in the brain. We consider such patients at high risk not only for embolic stroke, but also for a sudden drop in blood pressure precipitated by antihypertensive medication.31-33 It is also known that cerebral hyperperfusion syndrome may occur in such patients after CEA.34 Successful CEA provides benefits not only by removing the embolic source, but also by improving hemodynamic status, which may be evident even in the contralateral hemisphere. Clinically, it has been suggested that CEA improves cognitive psychological function by increasing blood supply to the brain.35-37 In some patients in this study, family members reported such improvements af-
ter CEA, although the patients underwent no objective psychological tests. Our findings agree with some previous studies,8-17 but are in conflict with other reports.7,18-21 For example, Kluytmans et al.19 observed hemodynamic compromise only in cases of occlusion of the contralateral ICA in patients with ipsilateral ICA stenosis ⬎ 70% using dynamic susceptibility contrast magnetic resonance imaging (MRI). In contrast, our findings indicate that even unilateral ICA stenosis may bring about a global hemodynamic and/or metabolic compromise. Several factors may be responsible for the conflicting findings. First, the degree of stenosis may be involved. In this series, mean stenosis was 92%, and in 6 of 10 cases stenosis was ⬎95%. It is known that the severity of stenosis associates poorly with the decrease in cerebral perfusion.7 However, it has also been suggested that a tight stenosis of ⬎90% reduces cerebral flow, and hence decreases the prevalence of distal embolization.38,39 Second, there may have been differences in the collateral anastomosis. Although we cannot substantiate the amount of collateral flow in individual patients,7,20 it is possible that the collateral flow in our cases was poorer than those in the previous series, because the stump pressure of ICA during surgery was 34.7 ⫾ 3 mm Hg. Third, the modality of measurements should be considered; various technologies were used in previous studies, including transcranial Doppler sonography,8-12,18 single photon emission computed tomography,16,17,20 and MRI.13-15,19 However, because these techniques cannot necessarily provide quantitative and/or regional hemodynamic or metabolic information of the brain, comparisons with the patients and control subjects are difficult. Our results may be limited to a symptomatic, extremely high-degree stenosis of ICA. Nonetheless, they clearly indicate that high-degree carotid stenosis in the tested range reduces cerebral blood flow and tissue oxygen supply and exhausts the hemodynamic and oxygen metabolic reserve in the patient’s brain. Ischemic symptoms in those patients may be due primarily to embolism, but widespread hemodynamic and metabolic insufficiencies may create a vulnerable environment in the brain. Successful CEA provides benefits not only by removing the embolic source, but also by improving hemodynamic and metabolic insufficiencies, which sometimes are evident in even the contralateral hemisphere.
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