Autoregulation and Hemodynamics in Human Cerebrovascular Disease

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1 Autoregulation and Hemodynamics in Human Cerebrovascular Disease

William J. Powers

Normal cerebral hemodynamics and energy metabolism

Introduction

Energy in the brain is required for maintenance of membrane potentials, ionic transport, and the biosynthesis and transport of neurotransmitters and cellular elements. Energy for these functions is supplied via adenosine triphosphate (ATP) from metabolism of exogenous compounds with a high-energy content (primarily glucose) to simpler compounds with less energy content (lactate, CO2, and H2O). Since storage of substrates for energy metabolism in the brain is minimal, the brain is highly dependent on a continuous supply of oxygen and glucose from the blood for its functional and structural integrity. It is exquisitely sensitive to even brief disturbances in this supply.

Normal Values of CBF and CMR

Healthy young adults have an average whole-brain cerebral blood flow (CBF) of approximately 46 ml 100g−1 min−1, cerebral metabolic rate of oxygen (CMRO2) of 3.0 ml 100g−1 min−1 (134 μmol 100g−1 min−1), and cerebral metabolic rate of glucose (CMRglc) of 25 μmol 100g−1 min−1.1–4 The CMRO2/CMRglc molar ratio of 5.4 is lower than the value of 6.0 expected for complete glucose oxidation due to the production of a small amount of lactate by glycolysis that occurs even with abundant oxygen supply.1,3,5 CBF in gray matter (80 ml 100g−1 min−1) is approximately four times higher than in white matter (20 ml 100g−1 min−1).6 Under normal physiological conditions, regional CBF is closely matched to the resting regional metabolic rate of the tissue.7,8 Thus CMRO2 and CMRglc are also higher in gray matter than in white matter. Because of this relationship between regional flow and metabolism, the fraction of blood-borne glucose and oxygen extracted is relatively constant throughout the brain (Figure 1–1). The oxygen extraction fraction (OEF) is normally 30% to 40%, indicating that oxygen supply is two to three times greater than oxygen demand. The glucose extraction fraction (GEF) is normally about 10%.8,9

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Figure 1–1 Cerebral blood flow and metabolism in a 70-year-old female normal volunteer. Note that cerebral blood flow (top left), cerebral oxygen metabolism (top middle), and cerebral glucose metabolism (bottom right) all show higher values in cortical gray matter than in white matter, whereas oxygen extraction fraction (top right) and glucose extraction fraction (bottom left) are uniform.

(From Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular disease. Neuroimaging Clin N Am 2003;13:741–758; with permission.)

Many studies report that CBF declines from the third decade onward.10–13 The change in metabolic rate for oxygen and glucose with age is less clear, with several studies showing a decrease 10,12,14–16 and others showing no change.17–19 Studies that have corrected for brain atrophy show lesser or absent changes in CBF, CMRO2, and CMRglc in the remaining tissue with increasing age.15,20–22 Our own data corrected for brain atrophy from 23 normal subjects, ages 23 to 71 years, show no significant change in CBF or CMRO2, but a significant decline in CMRglc of 4% to 5% per decade.

Control of CBF

Cerebral perfusion pressure (CPP) is equal to the difference between the arterial pressure driving blood into the brain and the venous backpressure. Venous backpressure is negligible unless there is elevated intracranial pressure (ICP) or obstruction of venous outflow. Thus, under most circumstances, regional CPP (rCPP) is equal to the regional mean arterial pressure (rMAP). The rMAP will be equal to the systemic MAP when there is no arterial obstruction, but may be substantially lower in the setting of acute or chronic arterial stenosis or occlusion.

Regional CBF (rCBF) is regulated by rCPP and the regional cerebrovascular resistance (rCVR):

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Under conditions of constant rCPP, any changes in rCBF must occur as a result of changes in rCVR. CVR is affected by blood viscosity and vessel length but is primarily determined by vessel radius. Arterial resistance vessels (primarily arterioles) dilate and constrict in response to a variety of stimuli causing changes in rCVR that produce changes in rCBF.

When there is a primary reduction in the metabolic demand of brain cells, such as that caused by hypothermia or barbiturates, arterial resistance vessels constrict to produce a comparable decline in CBF and thus little or no change in OEF or GEF.23–25 With normal physiological increases in neuronal activity, vessels dilate, producing an increase in regional CBF that is accompanied by an increase in regional CMRglc of similar magnitude, but with little or no increase in regional CMRO2.26–28 Acute changes in arterial pCO2 cause proportional changes in CBF. The mechanism for the change in CBF is a change in CVR produced by vasodilation with increased pCO2 and vasoconstriction with decreased pCO2.29 With prolonged hyperventilation, CBF returns toward normal values over a period of several hours.30 The effects of changes in arterial pO2 on the cerebral circulation show a threshold effect, different from the proportional changes seen with changes in pCO2. CBF does not increase until arterial pO2 is below about 30 to 50 mm Hg.31,32 A significant reduction in hemoglobin saturation and hence in arterial oxygen content (CaO2) does not occur until arterial pO2 falls to about 50 to 60 mm Hg, indicating that it is primarily CaO2 and not pO2 that determines CBF.31,33,34 Reductions in CaO2 due to anemia cause vasodilation and compensatory increases in CBF, whereas the increase in CaO2 with polycythemia is associated with a decrease in CBF.34 Acute changes in CaO2 produce less of an increase in CBF than do chronic changes.35,36 Hematocrit is an important determinant of viscosity, and thus viscosity and CaO2 often vary together. It is unlikely that viscosity is an important determinant of CBF under most circumstances, however. Increases in blood viscosity induce compensatory vasodilation to maintain cerebral oxygen delivery (CBF x CaO2).37–39 When pre-existing vasodilation impairs the ability of vessels to dilate further to changes in viscosity, this compensatory mechanism may be exhausted.40 Thus increases in CBF brought about by hemodilution, if they are simply reciprocal responses to changes in arterial oxygen content, will not increase cerebral oxygen delivery and may even decrease it.41

In contrast to the relationship of CBF to oxygen supply and demand, the balance between glucose supply and demand has little effect on CBF. Severe reductions in blood glucose down to 1.1 to 2.2 mmol/L produced modest but significant increases in CBF of 12% to 23%.42–46 This CBF response to severe hypoglycemia likely does not represent a compensatory mechanism to maintain glucose delivery to the brain since a blood glucose level of 2 mmol/L is well below the level at which brain dysfunction and counter-regulatory hormone response occur.47 Furthermore, increases in CBF do not increase blood:brain glucose transport.48,49

All of these responses of the cerebral vasculature occur at normal CPP. When CPP changes, a different set of cerebrovascular and brain metabolic responses occur.

Response of CBF to Changes in Cerebral Perfusion Pressure

Changes in CPP over a wide range have little effect on CBF.50 When CPP decreases, vasodilation of the small arteries or arterioles reduces CVR. When CPP increases, vasoconstriction of the small arteries or arterioles increases CVR.51,52 This compensatory mechanism is known as autoregulation.50 In most studies, the limits of autoregulation in normal normotensive subjects are from approximately 70 to 150 mm Hg.50,53 Strandgaard determined that the lower limit of autoregulation was 25 mm Hg below the resting BP in normotensive subjects.54 A contrasting viewpoint has been offered by Schmidt et al., who proposed a new computer method for assessing the lower limit of autoregulation.55 In this study, the lower limit in normotensive volunteers was only 85 mm Hg (11 mm Hg higher than that calculated from the conventional method) and at times was virtually identical to the baseline blood pressure. Within the limits of autoregulation, a 10% decrease in mean arterial pressure produces only a slight (2% to 7%) decrease in regional CBF.56,57 When CPP is reduced below the lower limit of autoregulation, more marked reductions in CBF occur. When the cerebral blood vessels are already dilated in response to some other stimulus, they are less able to dilate in response to reduced CPP. Therefore, the autoregulatory response is attenuated or lost in the setting of pre-existing hypercapnia, anemia, or hypoxemia.58,59

Chronic hypertension shifts both the lower and upper limits of autoregulation to higher levels. The average value of the lower limit of autoregulation in 13 poorly controlled hypertensive patients, ages 49 to 64, (113 ± 17 mm Hg) and 9 well-controlled hypertensives, ages 42 to 66, (96 ± 17 mm Hg) was elevated compared to 10 normotensive controls, ages 41 to 81 (73 ± 9 mm Hg).54 For all three groups combined, the lower limit of autoregulation was 70% to 80% of the resting MAP (r = 0.80). In another study, the lower limit was 88% to 89% of resting MAP (r = 0.81) for 19 normotensive and hypertensive subjects.55 Prolonged effective antihypertensive treatment may lead to a re-adaptation of autoregulation towards normal in some cases, but there are almost no data on this subject.54 Because of this upward shift of the lower limit, acute reductions in MAP or CPP that would be safe in normotensive subjects may precipitate cerebral ischemia in patients with chronic hypertension.60

These observations of the effect of changes in CPP on CBF were made by changing MAP or ICP over minutes, then measuring CBF at the new stable pressure. Recently, these responses have been termed “static cerebral autoregulation” to differentiate them from measurements of cerebral blood flow velocity with Doppler in response to more rapid and less marked fluctuations in MAP or ICP, termed “dynamic cerebral autoregulation.”61 The relationship between static and dynamic autoregulation is not clear. Abnormalities of dynamic cerebral autoregulation may be associated with normal or abnormal static autoregulation.62,63

When CPP falls below the autoregulatory limit and the maximum compensatory vasodilatory capacity of the cerebral circulation has been exceeded, CBF will decline markedly with further reductions in CPP. A progressive increase in OEF occurs as CBF falls and oxygen metabolism is maintained (Figure 1–2).64–66 OEF may increase by a factor of 2 or even more from its normal value of 30% to 40%.65 When the increase in OEF is maximal and is no longer adequate to supply the energy needs of the brain, further reductions in CPP disrupt normal cellular metabolism, produce clinical evidence of brain dysfunction, and, if prolonged, will cause permanent damage.

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Figure 1–2 Compensatory responses to reduced cerebral perfusion pressure (CPP). As CPP falls, cerebral blood flow (CBF) changes very little due to arteriolar dilation, which reduces cerebrovascular resistance. This vasodilation may be seen as an increase in cerebral blood volume (CBV), but this response is variable, ranging from a steady rise (of as much as 150%) to only a modest increase beginning at the point of autoregulatory failure. When vasodilatory capacity has been exhausted, cerebral autoregulation fails and CBF begins to decrease rapidly. A progressive increase in oxygen extraction (OEF) preserves cerebral oxygen metabolism (CMRO2).

(Redrawn from Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular disease. Neuroimaging Clin N Am 2003;13:741–758; with permission.)

Cerebral blood volume (CBV) is the volume of circulating blood in cerebral vessels. CBV is composed of arterial, capillary, and venous segments. Veins account for some 80% to 85% of CBV, arteries 10% to 15%, and capillaries less than 5%.67,68 Arteries are the most responsive to autoregulatory changes in CPP, veins respond less and capillaries even less.69,70 During experimental reductions in CPP, it is often possible to measure an increase in CBV that is presumed to be due to autoregulatory vasodilation.71–73 However, this increase in CBV to reduced CPP is not always evident (Figure 1–2),66,74 and a decrease in CBV in response to severe reductions in CPP has even been observed.75 Failure to demonstrate increased CBV in the setting of reduced CPP has been attributed to various possible mechanisms, including differential vasodilatory capacity of different vascular beds, passive collapse of vessels due to low intraluminal pressures, small vessel vasospasm, and re-setting of vascular tone in response to reduced metabolic demands.76 The CBF/CBV ratio (or its reciprocal, the vascular mean vascular transit time, MTT) has been proposed to be a more sensitive indicator of reduced CPP than CBV alone.66,77 Although it may be more sensitive, it is not reliable because it may decrease in conditions with low CBF and normal CPP, such as hypocapnia.78,79

Cerebral hemodynamic effects of arterial occlusive disease

Hemodynamic Effect of Arterial Stenosis

Stenosis of the carotid artery produces no hemodynamic effect until a critical reduction of 60% to 70% in vessel lumen occurs. Even with this or greater degrees of stenosis, distal CPP is variable and may even remain normal with stenosis exceeding 90%.80 This is because hemodynamic effect of carotid artery stenosis depends not only on the degree of stenosis but also on the adequacy of the collateral circulation. Vascular imaging techniques such as angiography or Doppler ultrasonography can identify the presence of these collateral vessels, but not necessarily the adequacy of the blood supply they provide.81

In patients with cerebrovascular disease, determining the hemodynamic effects of arterial stenosis or occlusion is of potential value in predicting the subsequent stroke risk or for choosing preventative therapy. Measurement of rCBF alone is inadequate for this purpose. Normal rCBF may be found when rCPP is reduced but rCBF is maintained by autoregulatory vasodilation of distal resistance vessels. Second, rCBF may be low when rCPP is normal, such as when the metabolic demands of the tissue are reduced by previous ischemic damage or by the destruction of afferent or efferent fibers by a remote lesion (Figure 1–3).65

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Figure 1–3 Primary metabolic depression in structurally normal brain overlying a subcortical infarct. Two months following a left subcortical infarct shown by CT (bottom right), PET shows reduced cerebral blood flow (top left) and oxygen metabolism (top right) with normal oxygen extraction (bottom left).

(From Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular disease. Neuroimaging Clin N Am 2003;13:741–758; with permission.)

Methods to Measure the Hemodynamic Effects of Large Artery Occlusive Disease

Three strategies are commonly used clinically to determine the local cerebral hemodynamic status. The first relies on measurement of rCBF at baseline and again after a vasodilatory stimulus, such as CO2 inhalation, breath holding, acetazolamide administration, or physiological activity (e.g., hand movement). An impairment in the normal increase of rCBF or Doppler blood flow velocity in response to the vasodilatory stimulus is assumed to reflect existing autoregulatory vasodilation due to reduced rCPP. Responses to vasodilatory stimuli have been categorized into three grades of hemodynamic impairment: (1) reduced augmentation (relative to contralateral hemisphere or normal controls), (2) absent augmentation (same value as baseline), and (3) paradoxical reduction in regional blood flow compared with baseline measurement. This last category, also known as the “steal” phenomenon, can only be identified with quantitative CBF techniques.82

The second strategy entails the quantitative measurement of regional CBV either alone or in combination with measurement of rCBF at rest to detect the presence of autoregulatory vasodilation. Increases in rCBV or the rCBV/rCBF ratio relative to the range observed in normal control subjects is assumed to indicate hemodynamic compromise.

The third strategy involves direct measurement of regional OEF as an indicator of a reduction in rCPP below the lower autoregulatory limit.

The pattern of arteriographic collateral circulation to the MCA distal to an occluded carotid artery does not consistently differentiate those patients with poor cerebral hemodynamics (Table 1–1).74,81,83,84

Table 1–1 Arteriographic collateral patterns in Patients from St. Louis Carotid Occlusion Study.

  High OEF Normal OEF
Acomm 27/32 26/30
Pcomm 6/13 13/18
ECA-OA 19/31 10/28
ECA-Other 3/29 6/28
Cortical 2/29 5/23

Three-Stage Classification System of Cerebral Hemodynamics

Based on the known physiological responses of CBF, CBV, and OEF to reductions in CPP, we proposed a three-stage sequential classification system for the regional cerebral hemodynamic status in patients with cerebrovascular disease.85 Stage 0 is normal with normal rCPP and normally matched regional CBF and CMRO2, such that rOEF is normal, rCBV and rMTT are not elevated and the rCBF response to vasodilatory stimuli is normal. Stage I hemodynamic compromise represents reduced rCPP, but is still above the lower autoregulatory limit. It is manifested by autoregulatory vasodilation of arterioles to maintain rCBF matched to rCMRO2. Consequently, rCBV and rMTT are increased and the rCBF response to vasodilatory stimuli is decreased, but rOEF remains normal. In Stage II hemodynamic failure, rCPP is below the lower autoregulatory limit. There is a decrease in CBF relative to rCMRO2 with increased OEF (Figure 1–4). This stage has also been termed “misery perfusion” by Baron et al.86,87 In all of these stages, rCMRO2 is preserved at a level that reflects the underlying energy demands of the tissue, but may be lower than normal due to the effects of previous tissue damage or deafferentation (Figure 1–3).65,88

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Figure 1–4 Chronically elevated oxygen extraction fraction in a patient with carotid occlusion. In this 56-year-old man with left hemispheric transient attacks, PET show reduced cerebral blood flow (top left), symmetrical oxygen metabolism (top right) and increased oxygen extraction (bottom left) in the left hemisphere (left portion).

(From Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular disease. Neuroimaging Clin N Am 2003;13:741-758; with permission.)

Although the three-stage classification scheme is conceptually and practically useful, it is overly simplistic. First, as discussed above, increases in rCBV and rMTT are not reliable indices of reduced rCPP. Second, rCBF responses to different vasodilatory agents may be impaired or normal in the same patient.89–91 A normal vasodilatory response may occur in the setting of increased rCBV.92,93 Finally, according to the three-stage system, all patients with increased rOEF should have increased rCBV and poor response to vasoactive stimuli. However, this increase in rCBV is not always evident.76

Correlation of Large Artery Cerebral Hemodynamics with Stroke Risk

Stage I Hemodynamic compromise

Data on vasomotor reactivity to acetazolamide or hypercapnia (Stage I hemodynamic compromise) in predicting subsequent stroke have been inconsistent.83,94–101

Yonas and colleagues tested cerebrovascular reserve by paired rCBF measurements with the stable Xenon/CT and acetazolamide in 68 patients with carotid artery disease followed for a mean of 24 months.99 Patients were placed into two groups based on criteria for hemodynamic compromise of initial rCBF values less than 45 ml 100 g−1 min−1 and rCBF reduction after acetazolamide of more than 5%. This categorization was done retrospectively based on assessment of the characteristics of the patients who went on to develop stroke. There were two contralateral strokes in 27 patients with normal hemodynamics and eight ipsilateral strokes in 41 patients with hemodynamic compromise. In a subsequent report by these authors, 27 additional patients were included in an analysis of 95 patients with either stenosis of 70% or carotid artery occlusion.95 The patients were followed for a mean of 19.6 months. These patients were classified into two groups based only on a rCBF reduction of more than 5% to acetazolamide, different criteria than those used in the first study. From the data presented it is possible to determine that three of the five strokes that occurred in the additional 27 patients did so in patients who would not have met criteria for hemodynamic compromise in the first study. Only two of these five new strokes were in the hemodynamically compromised territory of the occluded vessel. Thus the previously retrospectively derived criteria for identifying patients at high risk failed when subjected to a prospective test on a new group of 27 patients.

Kleiser and Widder tested the cerebrovascular reserve capacity in 85 patients with internal carotid artery (ICA) occlusion using transcranial Doppler during normocapnia, hypercapnia, and hypocapnia.102 At the time of entry into the study, 46 patients were asymptomatic on the ipsilateral side of the occlusion. The patients were followed for a mean of 38 months. In the group with normal CO2 reactivity, four of 48 patients had an ipsilateral TIA or prolonged reversible ischemic neurological deficit, but none had a stroke. Six of 26 patients with diminished CO2 reactivity had an ipsilateral ischemic event (three [12%] strokes, three TIAs), and three patients had a contralateral event (two strokes, one TIA). In the group with exhausted CO2 reactivity, five of 11 patients (45%) had an ipsilateral stroke and one patient had an ipsilateral TIA. Two patients had a contralateral hemisphere stroke. Although this study found a significant association between CO2 reactivity of the cerebral circulation and ischemic events ipsilateral to an ICA occlusion, there was no significant relationship between prior symptoms and subsequent stroke risk. This is puzzling since the prognosis of asymptomatic carotid occlusion is relatively benign.103,104 The increased risk of contralateral stroke in the patients with a diminished or exhausted CO2 reactivity suggests that the groups were not matched for other stroke risk factors, and this may explain the differences observed. In a subsequent report by these authors, 86 patients with carotid artery occlusion were followed for variable periods of time.105 A stroke ipsilateral to an occluded ICA occurred in three of 26 patients with an exhausted CO2 reactivity, corresponding to an annual stroke rate of only 8% (mean follow-up time of 19 months), much lower in the first study. In 37 patients with diminished CO2 reactivity and 48 patients with normal CO2 reactivity, only one patient in each group developed an ipsilateral stroke (mean follow-up time of 31.7 months). In this second study, the number of asymptomatic patients is not given. The 86 patients in the second study were selected from 452 patients with ICA occlusion studied with transcranial Doppler cerebrovascular resistance studies. The criteria for selecting these 86 patients were not given.

Vernieri et al. have published a well-designed and well-executed prospective study of 65 patients with both symptomatic and asymptomatic carotid occlusion.97 Hemodynamic compromise was assessed by using transcranial Doppler measurement of middle cerebral artery (MCA) blood flow velocity during breath holding. Multivariate analysis found only older age and impaired Doppler velocity increase during breath holding to be associated with the subsequent risk of ipsilateral ischemic events (TIA and stroke). No separate analysis of symptomatic patients and no separate analysis of predictive value for stroke only was reported nor was any data on subsequent medical treatment.

Kuroda and colleagues enrolled 77 symptomatic patients in a prospective, longitudinal cohort study. All patients met inclusion criteria of cerebral angiography, no or localized cerebral infarction on MRI or CT, and no or minimal neurological deficit. Regional rCBF and regional cerebrovascular reactivity to CVR to acetazolamide were quantitatively determined by 133Xe SEPCT. During an average follow-up period of 42.7 months, 16 total and seven ipsilateral ischemic strokes occurred. Decreased cerebrovascular reactivity to acetazolamide alone did not predict the subsequent occurrence of stroke. Only the combination of decreased rCBF and decreased cerebrovascular reactivity identified those with a high annual risk for both total and ipsilateral stroke (35.6% and 23.7%, respectively). Kaplan-Meier analysis revealed that the risks of total and ipsilateral stroke in the 11 patients with this combination were significantly higher than in the 66 without (P < 0.0001 and P = 0.0001, respectively, log-rank test). Relative risk was 8.0 (95% confidence interval [CI], 1.9 to 34.4) for ipsilateral stroke and 3.6 (95% CI, 1.4 to 9.3) for total stroke.94

In addition to these reported positive associations, other studies with prospectively defined criteria have failed to demonstrate a relationship between the risk of subsequent stroke and Stage I hemodynamic compromise.96,106 We reported a longitudinal study of stroke risk in 21 medically treated patients with increased CBV/CBF ratios distal to a stenotic or occluded artery. No ipsilateral ischemic strokes occurred during the 1-year follow-up period.106 Yokota et al. derived criteria for abnormal acetazolamide SPECT CBF responses from a comparison of paired studies of PET OEF in 14 subjects and then used the SPECT criteria to study 105 patients with ischemic cerebrovascular events, minimal infarct on a CT scan, and unilateral occlusion or severe stenosis of the ICA or proximal MCA.96 Fifty-five patients had abnormal cerebral vasoreactivity response to acetazolamide and 50 patients had a normal response. Risk factors for stroke at entry were recorded and included in the final data analysis. The median follow-up period in the study was 32.5 months. During the follow-up period, 13 patients had a stroke, 11 died, 16 had surgical cerebral revascularization procedures (nine EC-IC bypasses and seven carotid endarterectomies), and 11 were lost to follow-up. There was no significant difference in the rate of subsequent stroke in the two groups. This was generally a well-planned, well-executed prospective study that addressed the possible impact of other risk factors in the largest study reported to date. A relatively large number of patients were censored from the study because of subsequent cerebrovascular surgery and loss to follow-up. Since the criteria used for separating patients into those with normal and abnormal cerebrovascular reactivity were based on a previous study that demonstrated complete congruence with PET measurements of OEF,92 the negative results of this study are puzzling in the light of two PET studies that both demonstrated a strong association between increased OEF and subsequent stroke (see following). As opposed to other studies comparing CBF response to vasodilatory stimuli and PET OEF, these investigators were able to identify a threshold that was 100% sensitive and 100% specific based on a study of both modalities in 14 patients. It is likely that this small sample of patients was not sufficient to really determine the relationship between the two modalities and the threshold chosen did not reliably correlate with PET OEF in the larger sample of 105 patients followed prospectively.

In 2002, Ogasawara and colleagues published a well-designed, well-executed prospective study of cerebrovascular reactivity (CVR) to acetazolamide using quantitative measurements of CBF with 133Xe inhalation and single-photon emission computed tomography.101 Seventy patients less than 70 years old with unilateral ICA or MCA occlusion were divided into two groups based on the regional CVR (rCVR) in the territory of the occluded artery. They were prospectively followed for a period of 24 months. Recurrent strokes occurred in eight of the 23 patients with reduced rCVR at entry and in three of 47 patients with normal rCVR (p = 0.0030 by Kaplan-Meier analysis). In a companion paper, these same authors directly compared two different methodologies: cerebral blood flow (CBF) percent change obtained quantitatively from xenon-133 (133Xe) SPECT as used in the initial report and asymmetry index (AI) percent change obtained qualitatively from N-isopropyl-p-[123I]-iodoamphetamine (IMP) SPECT. There was no significant difference in cumulative recurrence-free survival rates between patients with decreased AI percent change and those with normal AI percent change. This study demonstrated that, while decreased cerebrovascular reactivity to acetazolamide determined quantitatively by 133Xe SPECT is an independent predictor of the 5-year risk of subsequent stroke in patients with symptomatic major cerebral artery occlusion, the qualitative method using 123I-IMP SPECT was a poor predictor of the risk of subsequent stroke in this type of patient.100

Thus data indicating a relationship between measurements of Stage I hemodynamic impairment and subsequent stroke risk in symptomatic patients remain equivocal at this time. While such a relationship may exist for some measurements of Stage I hemodynamic impairment, it has not been demonstrated with consistency. Since CBF responses may be different to different vasodilatory agents within the same patient, this inconsistency is understandable. Evidence that hemodynamic impairment by one method of assessment predicts subsequent stroke risk does not prove the predictive value of a similar method. Different techniques rely on different physiologic mechanisms from which the presence of reduced perfusion pressure is inferred.

Stage II Hemodynamic compromise (“misery perfusion”)

In contrast to the inconsistent data for Stage I hemodynamic impairment, two independent studies have demonstrated that Stage II hemodynamic failure, defined as increased OEF, is a powerful independent predictor of subsequent ipsilateral ischemic stroke.74,107,108

Yamauchi and colleagues from Kyoto, Japan reported a strong relationship between absolute measurements of increased cerebral OEF and the subsequent risk of recurrent stroke in a small longitudinal study.107 PET measurements were performed in 40 medically treated patients with symptomatic occlusion or intracranial stenosis of the internal carotid or middle cerebral arterial system treated medically. Patients were divided into two categories based on the mean hemispheric value of OEF in the symptomatic cerebral hemisphere: patients with normal OEF and those with increased OEF. At 1 year following the PET studies, five of seven patients with increased OEF had developed a stroke; four strokes were ipsilateral and one was contralateral. Four of 33 patients with normal OEF had developed a stroke. Two strokes were ipsilateral and two were contralateral. After the first year of follow-up, one ipsilateral stroke and one contralateral stroke occurred, both occurring in patients with normal OEF. This corresponds to a 2-year ipsilateral stroke rate of 57% in the high OEF group and 15% in the normal OEF group.108

The St. Louis Carotid Occlusion Study (STLCOS) was designed to test the hypothesis that increased OEF (Stage II hemodynamic failure) in the cerebral hemisphere distal to symptomatic carotid artery occlusion is an independent predictor of the subsequent risk of stroke in medically treated patients.74 This study was prospective and blinded, and addressed the possible effect of treatment and other risk factors for stroke. Fifteen hospitals within the St. Louis area collaborated to assist with recruitment for this study. Inclusion criteria were (1) occlusion of one or both common or internal carotid arteries demonstrated by contrast angiography, MR angiography, or carotid ultrasound; and (2) transient ischemic neurological deficits (including transient monocular blindness) or mild to moderate permanent ischemic neurological deficits (stroke) in the appropriate carotid artery territory. Exclusion criteria were (1) inability to give informed consent; (2) not legally an adult; (3) failure to meet the following functional standards—self-care for most activities of daily living (may require some assistance), some useful residual function in the affected arm or leg, language comprehension intact, motor aphasia mild or absent, able to handle own oropharyngeal secretions; (4) nonatherosclerotic conditions causing or likely to cause cerebral ischemia—carotid dissection, fibromuscular dysplasia, arteritis, blood dyscrasia, or heart disease as a source of cerebral emboli; (5) any morbid condition likely to lead to death within 5 years; (6) pregnancy; and (7) subsequent cerebrovascular surgery planned that might alter cerebral hemodynamics. Any subsequent cerebrovascular surgery after the initial PET caused the patient to be censored from the study at the time of surgery.

Just prior to PET, each subject underwent neurological evaluation and assessment of the following baseline risk factors: age, gender, hypertension, previous myocardial infarction, diabetes mellitus, smoking, alcohol consumption, and parental death from stroke. The degree of contralateral carotid stenosis and collateral arterial circulation to the ipsilateral MCA was determined from intra-arterial angiograms, if available. Blood samples were collected for determination of hemoglobin, fasting lipid levels (triglyceride, HDL-cholesterol, LDL-cholesterol), and fibrinogen levels. A non-contrast CT scan of the brain was performed if a CT done as part of usual clinical care did not permit accurate definition of infarct location. This CT was used only to determine the site of tissue infarction so as to exclude these regions from subsequent PET analysis (see below). Eighteen normal control subjects aged 19 to 77 (mean ± standard deviation [SD] = 45 ± 18) years were recruited by public advertisement.

Regional OEF was measured by PET with the method of Mintun et al. using H215O, C15O, and O15O.109,110 When technical difficulties precluded collection of arterial time activity curves necessary to determine quantitative OEF, the ratio image of the counts in the unprocessed images of H215O and O15O was normalized to a whole brain mean of 0.40 and substituted for the quantitative OEF image. All images were then filtered with a three dimensional Gaussian filter to a uniform resolution of 16-mm, full-width, half maximum. For each subject, seven spherical regions of interest 19 mm in diameter were placed in the cortical territory of the MCA in each hemisphere using stereotactic coordinates based on skull X-ray measurements.85,111 If any portion of a region overlapped a well-demarcated area of reduced oxygen metabolism that corresponded to areas of infarction by CT or MRI, that region and the homologous contralateral region were excluded. The mean OEF for each MCA territory was calculated from the remaining regions and a left/right MCA OEF ratio was calculated. The maximum and minimum ratios from the 18 normal control subjects were used to define the normal range (0.914–1.082). A separate range of normal for H215O/O15O images was determined (0.934–1.062). Patients with left/right OEF ratios outside the normal range were categorized as having Stage II hemodynamic failure in the hemisphere with higher OEF. These categorizations were made without knowledge of the side of the carotid occlusion or of the clinical course of the patients since the initial PET study.

The primary endpoint was subsequent ischemic stroke defined clinically as a neurological deficit of presumed ischemic cerebrovascular cause lasting more than 24 hours in any cerebrovascular territory. Secondary endpoints were ipsilateral ischemic stroke and death. Patients were followed by the study coordinator for the duration of the study through telephone contact every 6 months with the patient or next of kin. Interval medical treatment on a monthly basis was recorded. No information regarding the PET results was provided to the patients, treating physicians, or the investigator responsible for determining endpoints. The occurrence of any symptoms suggesting a stroke was thoroughly evaluated by the designated blinded investigator based on history from the patient or eyewitness and review of medical records ordered by the patient’s physician. If necessary, follow-up examination and brain imaging were arranged. All living patients were followed for the duration of the study.

From May 5, 1992, to November 30, 1996, a total of 419 subjects were referred for screening. Eighty-seven subjects were enrolled in the study. Approximately four fifths of the remaining subjects refused to participate and the other one fifth were willing to participate, but were ineligible. Of 87 patients who consented to participate, 81 successfully underwent initial data collection and PET measurements and were enrolled in the study. The diagnosis of carotid artery occlusion was made by intra-arterial contrast angiography in 75 of the 81 subjects.

Of the 81 patients, 39 had Stage II hemodynamic failure (increased OEF) in one hemisphere and 42 did not. The two groups were well matched for most baseline risk factors, except that retinal symptoms were less common in Stage II subjects (3/39 vs 13/26). Arteriographic collateral circulation pattern did not permit distinction between the two groups (Table 1–1). Mean follow-up duration was 31.5 months. Twelve deaths occurred, six in each group. In the 39 Stage II subjects, 12 total and 11 ipsilateral strokes occurred. In the 42 subjects with normal OEF, there were three total and two ipsilateral strokes. The Kaplan-Meier estimates for the rates of subsequent stroke at 1 and 2 years are given in Table 1–2.

Table 1–2 Stroke Rates in St. Louis Carotid Occlusion Study.

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The rate of all stroke and ipsilateral ischemic stroke in Stage II subjects was significantly higher than in those with normal OEF (p = 0.005 and p = 0.004, respectively). After adjustment for 17 baseline patient characteristics and interval medical treatment, the relative risk conferred by Stage II hemodynamic failure was 6.0 (95% CI, 1.7–21.6) for all stroke and 7.3 (95% CI, 1.6–33.4) for ipsilateral stroke. No ipsilateral strokes occurred in those subjects whose most recent symptoms were more than 120 days or who had had retinal symptoms only. The results of medical treatment of Stage II patients were poor and comparable to those reported for medically treated patients with symptomatic severe carotid stenosis.112

In the STLCOS, 13 subjects were categorized based on a count-based method of OEF measurement because arterial blood samples could not be obtained. This method used a simple ratio of the counts in the H215O/O15O PET images. The ability of the count-based OEF ratio to predict subsequent stroke was examined. The 81 patients were divided into those with count-based OEF ratios outside the normal range and those with normal count-based OEF ratios. Fifty of the 81 patients with symptomatic carotid occlusion were identified as abnormal. All 13 ipsilateral ischemic strokes occurred in the 50 patients with increased count-based OEF (p = 0.002, sensitivity 100%, specificity 45.6%). Second, the count-based technique was compared directly to the quantitative method for predicting ipsilateral stroke. In this analysis, the image data of the 68 patients with arterial time activity curves was processed using both count-based and quantitative methods. Using the normal range of values, 31 of the 68 patients were identified as abnormal using quantitative OEF ratios. Seven ipsilateral ischemic strokes occurred in this group of 31 patients, compared to two strokes in the 37 patients with quantitative OEF ratios within the range of normal (p = 0.025, sensitivity 77.8%, specificity 59.3%). The count-based OEF ratio was less specific (specificity 45.7%) and more sensitive (sensitivity 100%) than the quantitative method. Forty-one patients were categorized as abnormal and all strokes occurred in this group (p = 0.0048). Comparison of the count-based OEF ratio to the quantitative OEF ratio for each of the 68 patients demonstrated no significant difference by paired t-test analysis (p = 0.299). The average absolute difference between count-based OEF and OEF ratios was 0.0345 (95% confidence limit = ±0.0091). Receiver operating curves were generated for both methods. The area under the receiver operating curve for the count-based OEF method (0.815) was greater than the quantitative OEF method (0.737), indicating superior accuracy.113 A subsequent analysis compared these two techniques that rely on asymmetries of OEF to the technique based on absolute OEF values used in the Kyoto study. All three methods were predictive of stroke risk in univariate analysis. Only the count-based method remained significant in multivariate analysis. The area under the ROC curve was greatest for the count-based ratio: 0.815 versus 0.769 (absolute) and 0.737 (ratios of absolute).114

At this time, it is not possible to identify a non-PET method for assessing OEF that has sufficient proven sensitivity and specificity to substitute for PET. The correlation between the CBF response to vasodilatory agents and increased OEF has been somewhat variable and inconsistent.92,93,115–124 In general, these studies have shown that measurements of vascular reactivity have high sensitivity but poor positive predictive value for identifying increased OEF123 Certain MR pulse sequences are sensitive to the amount of deoxyhemoglobin in blood (blood oxygen level dependent [BOLD]).125–127 They are commonly used to identify changes in the regional blood flow:metabolism ratio with physiologic brain activation, but their application to static measurements of brain oxygenation has proven more difficult. The signal contribution from nonvascular tissue and the effect of variation in CBV have made quantitative measurement of OEF difficult, although research in this area is being actively pursued.128–130 BOLD MRI measurements did not correlate well with PET measurements of OEF in patients with carotid occlusion in a previous study.131

Other Hemodynamic Classification Schemes

Nemoto and colleagues have postulated that patients who initially have CPP below the autoregulatory limit with increased OEF (Stage II hemodynamic failure) may suffer subsequent ischemic neuronal damage that reduces CMRO2 and normalizes OEF, but without any improvement in CPP. They refer to this as Stage III.121 The plausibility of this scenario is supported by PET studies that show evidence for selective neuronal necrosis in brain regions with low CMRO2 and normal OEF and the progressive development of selective neuronal necrosis in areas with initially high OEF.88,132 Nemoto and colleagues propose that, while these patients would look like Stage I hemodynamic compromise (impaired response to vasodilatory stimuli, normal OEF), their stroke risk would in fact be similar to that of Stage II patients due to the persistently low CPP.121 Thus according to this construct, there should be a group of patients with normal OEF and impaired vasoreactivity who are at high risk for stroke. This does not appear to be the case. In the STLCOS, none of the 13 ipsilateral strokes that occurred in follow-up of 3.1 years occurred in patients with increased CBV and normal OEF.76 The two patients with normal OEF who had ipsilateral strokes were among the eight patients with the highest OEF values in the normal OEF group of 41 subjects. Furthermore, in this cohort of patients, OEF was predictive of subsequent ipsilateral stroke as a continuous variable, indicating that the higher the OEF the higher the risk of stroke.114

Kuroda and colleagues have proposed a four-stage classification based on quantitative SPECT measurements of baseline CBF and cerebrovascular reactivity to acetazolamide or CO2: Type 1—normal baseline CBF and normal cerebrovascular reactivity; Type 2—normal baseline CBF and reduced cerebrovascular reactivity; Type 3—reduced baseline CBF and reduced cerebrovascular reactivity; and Type 4—reduced baseline CBF and normal cerebrovascular reactivity.88 Type 1 patients are considered to have a normal CPP because of a well-developed collateral circulation corresponding to Stage 0. Type 2 patients are believed to have moderately reduced CPP corresponding to Stage I. Type 3 patients are believed to have inadequate CPP to maintain a normal resting CBF corresponding to Stage II. Type 4 have reduced oxygen metabolism probably due to ischemia-related neuronal loss with normal hemodynamics corresponding to Stage 0.88,94 The value of this scheme lies in the identification of the high risk of stroke in Type 3 patients. This is based on a small study of only 11 subjects,94 and runs counter to the data from Yonas and colleagues who did not find that low baseline CBF in combination with reduced cerebrovascular reactivity was sensitive indicator of stroke risk.95,99 It also is at odds with the study by Ogasawara et al., who found that quantitative reduced cerebrovascular reactivity alone was sufficient to identify a high-risk group.101 Thus the value of a four-stage classification based on quantitative SPECT measurements of both baseline CBF and cerebrovascular reactivity instead of a two-stage system based on quantitative cerebrovascular reactivity alone remains to be established.

Randomized surgical revascularization trials based on hemodynamic criteria

The findings of the Kyoto and St. Louis studies reawakened interest in extracranial-to-intracranial (EC-IC) bypass for stroke prevention, an approach that had largely been abandoned after the publication of the negative EC-IC Bypass Trial in 1985.133 The Kyoto and St. Louis studies demonstrated that Stage II hemodynamic failure (increased OEF) distal to a symptomatic occluded carotid artery is an independent predictor of subsequent ischemic stroke. As first demonstrated by Baron in 1981, EC-IC bypass surgery will return hemispheric OEF ratios to normal in patients with increased OEF distal to an occluded carotid artery (Figure 1–5).87,134–136 The implication of these data is that EC-IC bypass is the logical treatment for these patients with high OEF and high stroke risk on medical therapy. Why does this evidence suggest that EC-IC bypass should be effective in reducing stroke in patients with symptomatic carotid occlusion when the EC-IC Bypass Trial, a large, prospective, and randomized trial of EC-IC bypass versus aspirin in similar patients, failed to demonstrate a benefit? A mathematical simulation using the data from the STLCOS provides the explanation. In STLCOS, the 2-year rate for all stroke was 19% for this entire sample of medically treated patients. If surgery has the same 12.2% morbidity/mortality as in the EC-IC Bypass Trial and reduces the stroke rate in the high OEF patients to that of low OEF patients (9.0%), but does not change the stroke rate in low OEF patients, then the overall stroke rate in the operated group at 2 years will be 9.0% + 12.2% = 21.2%, slightly worse than the medical group. These simulated results at 2 years are remarkably similar to the 5-year results for carotid occlusion in the EC-IC Bypass Trial of 29% for the medical groups and 31% for the surgical group.133 This analysis underscores the importance of identifying a subgroup of patients at high risk who are likely to benefit and restricting surgery to them.

image

Figure 1–5 Improved oxygen extraction (OEF) after extracranial-intracranial (EC-IC) bypass surgery in a 69-year-old man with symptomatic occlusion of the right carotid artery. The baseline PET images (top row) demonstrate reduced cerebral blood flow (CBF, left) and increased OEF in the right hemisphere (right portion). A second study performed 35 days after EC-IC bypass shows that ipsilateral CBF has improved and OEF has normalized (bottom row).

(From Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular disease. Neuroimaging Clin N Am 2003;13:741–758; with permission.)

Two new randomized trials of EC-IC bypass surgery were begun, one in Japan and one in the United States, with patient selection based on hemodynamic criteria.

The Japanese EC-IC Bypass Trial (JET)

The Japanese EC-IC Bypass Trial (JET) uses the combination of reduced baseline CBF and reduced acetazolamide cerebrovascular reactivity measured with quantitative SPECT as eligibility criteria. This trial enrolled 196 patients with major cerebral artery occlusive disease from 1998 to 2002. A second interim analysis with data through January 2002 reported primary endpoints in 14 of 98 medically treated patients and five of 98 surgically treated patients (p = 0.046 by Kaplan-Meier analysis).137 Final results of the 2-year follow-up were due in 2004. However, to date, there has been no publication of the final results.

The Carotid Occlusion Surgery Study (COSS)

This is a randomized, controlled clinical trial that tests the hypothesis that EC-IC bypass when added to best medical therapy can reduce subsequent ipsilateral ischemic stroke at 2 years in patients with recently symptomatic ICA occlusion and increased OEF. The participating centers and data management center are unblinded and the primary clinical coordinating center personnel (principal investigator and project manager) are blinded. This study is funded by the National Institutes of Health.

Final eligibility for randomization is based on fulfilling three different eligibility categories:

1. Clinical
2. PET
3. Arteriographic

Participants who fulfill clinical entry criteria and who have carotid occlusion by vascular imaging (Doppler ultrasound, magnetic resonance angiography, CT angiography, or intra-arterial catheter arteriography) are eligible for enrollment and proceed to PET. If PET meets criteria for ipsilateral increased oxygen extraction, then arteriographic criteria must be met for a participant to be eligible for randomization. Intra-arterial catheter arteriography is required prior to randomization to document carotid occlusion and both extracranial and intracranial arteries suitable for anastomosis.

Initial clinical and vascular imaging criteria to determine PET eligibility

Inclusion criteria

1. Vascular imaging demonstrating occlusion of an ICA.
2. (Criterion eliminated.)
3. Transient ischemic attack (TIA) or ischemic stroke in the hemispheric carotid territory of an occluded ICA.
4. Most recent qualifying TIA or stroke occurring within 120 days prior to performance date of PET.
5. Modified Barthel Index ≥12/20.
6. Language comprehension intact, motor aphasia mild or absent such that effective communication with the participant is possible.
7. Age 18 to 85 years inclusive.
8. Competent to give informed consent.
9. Legally an adult.
10. Geographically accessible and reliable for follow-up.

Exclusion criteria

1. Nonatherosclerotic carotid vascular disease.
2. Blood dyscrasias: only polycythemia vera, essential thrombocytosis, and sickle cell disease (SS or SC).
3. Known cardioembolic heart disease: only prosthetic valve(s), infective endocarditis, left atrial or ventricular thrombus, sick sinus syndrome, myxoma, or cardiomyopathy with ejection fraction <25%.
4. Other nonatherosclerotic condition likely to cause focal cerebral ischemia.
5. (Criterion eliminated.)
6. Any condition likely to lead to death within 2 years.
7. Other neurological disease that would confound follow-up assessment.
8. Pregnancy.
9. Subsequent cerebrovascular surgery planned that might alter cerebral hemodynamics or stroke risk.
10. Any condition that the participating surgeon’s judgment makes the participant an unsuitable surgical candidate.
11. Concurrent participation in any other experimental treatment trial.
12. Participation within the previous 12 months in any experimental study that included exposure to ionizing radiation.
13. Acute, progressing, or unstable neurological deficit.
14. If supplemental arteriography is required, allergy to iodine or X-ray contrast media, serum creatinine >3.0 mg/dl or other contraindication to arteriography.
15. If aspirin is to be used as antithrombotic therapy in the perioperative period, those with allergy or contraindication to aspirin are ineligible.
16. Medical indication for treatment with anticoagulant drugs, ticlopidine, clopidogrel, or other antithrombotic medications such that these medications cannot be replaced with aspirin in the perioperative period as deemed necessary by the COSS neurosurgeon if the participant is randomized to surgical treatment.
17. Uncontrolled diabetes mellitus (FBS > 300 mg%/16.7 mmol/L).
18. Uncontrolled hypertension (systolic BP > 180, diastolic BP > 110).
19. Uncontrolled hypotension (diastolic BP < 65).
20. Unstable angina.

PET criteria

Ipsilateral: contralateral OEF ratio in the MCA territory > 1.130 determined from the ratio image of O15O/H215O counts.

Arteriographic criteria

Intra-arterial catheter contrast arteriography documenting the following:

1. Occlusion of the symptomatic ICA.
2. Intracranial and extracranial arteries suitable for anastomosis in the opinion of the participating surgeon.

Randomized treatment assignments are based on a permuted block strategy stratified by center. For participants who were receiving antithrombotic drugs other than aspirin prior to randomization, surgery is performed as soon as the participating neurosurgeon considers the bleeding risk to be acceptable. Participants randomized to surgery undergo microsurgical end-to-side anastomosis of the optimal branch (frontal or parietal) of the superficial temporal branch to the largest most easily exposed cortical branch of the middle cerebral artery as it emerges from the posterior one-third of the Sylvian fissure. Participating surgeons must (1) demonstrate proficiency in performing EC-IC bypass surgery (STA-MCA cortical branch anastomosis and/or extracranial carotid artery to middle cerebral artery vein graft anastomosis) by demonstrating at least 80% graft patency and less than or equal to 10% stroke and death at 1 month in at least 10 consecutive EC-IC bypass surgeries, or (2) have attended the January 2002 training workshop, or (3) have been observed during the performance of at least one STA-MCA operation by the surgical principal investigator or his designate. A provisional certification may be issued such that this first STA-MCA operation under the observation may be performed on a patient enrolled in the trial. All surgical patients are seen 30 days postoperatively. All surgical patients receive Doppler studies to ensure graft patency, and PET to document reversal of hemodynamic abnormalities at 30 days.

All patients are seen 30 days after randomization and at 3-month intervals after randomization for 2 years. At each follow-up examination a neurological history and exam tailored to identifying new stroke is performed. Current medications are recorded. NIHSS, Barthel Index, Rankin Scale, and Stroke Specific Quality of Life assessment are performed at every visit.138–141 Doppler examination to ensure graft patency is performed for all surgical patients.

Choice of long-term antithrombotic treatment is at the discretion of the participant’s personal physician. When deemed appropriate by the surgeon, participants randomized to surgical therapy will return to the antithrombotic treatment preferred by their physicians. Recommendations for antithrombotic treatment follow recommendations for antiplatelet treatment of atherothrombotic TIA of the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks, Stroke Council, American Heart Association.142 Efficacy of risk factor intervention is measured at each return visit in the following ways:

1. Smoking: question. Target: not smoking
2. Hypertension: cuff blood pressure. Target systolic < 130 mm Hg, diastolic < 85 mm Hg
3. Hypercholesterolemia: fasting blood cholesterol and triglyceride measurements. Target: low-density lipoprotein < 100 mg/dl, triglycerides < 150 mg/dl
4. Diabetes mellitus: hemoglobin A1C levels. Target < 7.0%

The primary endpoint in the surgical group is the combination of the following: (1) the occurrence of ipsilateral ischemic stroke from randomization to surgery, (2) the occurrence of all stroke and death from surgery through 30 days postoperation, and (3) the occurrence of ipsilateral ischemic stroke within 2 years of randomization. Those in the surgery group who are never operated on by the end of the trial would be evaluated in the same way as the nonsurgical group. The primary endpoint in the nonsurgical group is the combination of the following: (1) the occurrence of all stroke and death from randomization through 30 days post randomization, and (2) the occurrence of ipsilateral ischemic stroke within 2 years of randomization. The primary analysis will be intent-to-treat. A two-sample comparison for the 2-year stroke rate between the surgical and nonsurgical groups will be conducted to test the two-sided hypothesis at a significance level of 5.0%.

Secondary endpoints are all stroke, disabling stroke, fatal stroke, death, Rankin Scale, NIHSS, Barthel Index, and Stroke Specific Quality of Life assessment. Ipsilateral ischemic stroke is defined as the clinical diagnosis of a focal neurological deficit due to cerebral ischemia clinically localizable within the ICA territory distally to the symptomatic occluded ICA that lasts for more than 24 hours. Final adjudication of stroke endpoints (ipsilateral stroke, nonipsilateral stroke, fatal stroke) is by a three-person blinded adjudication panel supplied with information that has been sanitized to remove all information regarding treatment assignment. Information regarding each possible endpoint is sent to two adjudicators. If they agree, the decision is final. If the original two adjudicators do not agree, the third member serves as a tie-breaker.

Adjusting for anticipated 2-year mortality, 372 patients (186 in each group) will provide 90% power to detect the anticipated difference (40% vs 24.2%). Assuming 25% to 30% of PET scans will demonstrate increased OEF, this will require enrolling a total of 1400 clinically eligible subjects for PET. COSS is currently under way in 40 centers in the United States and Canada. The first patient was randomized in 2002. Results are expected in 2015.

Conclusions

Since the publication of the negative results of the EC-IC Bypass Trial, advances in neuroimaging, especially PET, have greatly increased our understanding of cerebral hemodynamics in human cerebrovascular disease. In turn, this has led to several studies that have shown a significant association between measurements of cerebral hemodynamics and the risk for recurrent stroke. These findings, especially those for PET measurements of OEF, have led to two new clinical trials of EC-IC bypass for stroke prevention, each using different neuroimaging eligibility criteria to identify patients at high risk for recurrent stroke due to hemodynamic mechanisms. The results of these studies will determine whether these types of hemodynamic measurements have clinical value in selecting patients for cerebrovascular revascularization.

Acknowledgments

This work was supported by U.S. Public Health Service grants NS42167 and NS35966, and the H. Houston Merritt Professorship of Neurology at the University of North Carolina, Chapel Hill.

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