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(Stroke. 1998;29:754-758.)
© 1998 American Heart Association, Inc.

Original Contributions

Increased Oxygen Extraction Fraction Is Associated With Prior Ischemic Events in Patients With Carotid Occlusion

Colin P. Derdeyn, MD; Kent D. Yundt, MD; Tom O. Videen, PhD; David A. Carpenter, MD; Robert L. Grubb, Jr, MD; William J. Powers, MD

From the Mallinckrodt Institute of Radiology (C.P.D., T.O.V., D.A.C., R.L.G., W.J.P.) and the Department of Neurology and Neurological Surgery (K.D.Y., D.A.C., R.L.G., W.J.P.), Washington University School of Medicine, St Louis, Mo.

Correspondence to Dr Derdeyn, Mallinckrodt Institute of Radiology, 510 S Kingshighway Blvd, St Louis, MO 63110. E-mail derdeyn{at}mirlink.wustl.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—The purpose of our study was to investigate the relationship between misery perfusion (increased oxygen extraction fraction, OEF) and baseline risk factors in patients with carotid occlusion.

Methods—One-hundred seventeen patients with atherosclerotic carotid occlusion were studied prospectively by clinical evaluation, laboratory testing, and positron emission tomography (PET). PET measurements of cerebral blood flow (CBF), cerebral blood volume (CBV), and OEF were made on enrollment in the study. Increased ipsilateral OEF was identified by comparison with 18 normal control subjects. Twenty-five baseline clinical, epidemiological, and arteriographic risk factors were assessed on study entry. Student t tests, ² tests, and Fisher exact tests with Bonferroni correction were used to assess statistical significance (P<.05).

Results—Of 117 patients, 44 had increased OEF distal to the occluded carotid and 73 had normal OEFs. Thirty-nine of the 81 patients with prior ipsilateral ischemic symptoms had high OEFs (42%), whereas only 5 of the 31 asymptomatic patients had high OEFs (16%, P<.001) All of the other baseline risk factors were similar between the two groups of patients.

Conclusions—Investigations of the relationship between hemodynamic factors and stroke risk must take into account the lower frequency of hemodynamic abnormalities in asymptomatic patients.

Key Words: carotid artery occlusion • hemodynamics • risk factors • stroke, ischemic

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hemodynamic compromise distal to an occluded carotid artery may increase the risk for subsequent ischemic stroke.¹ Klijn et al¹ reviewed 20 follow-up studies of patients with symptomatic carotid occlusion, and reported an annual risk of ipsilateral stroke of 2.1%. This rate increased to 9.5% (95% confidence interval, 6.4% to 14.0%) when evidence of distal hemodynamic compromise was present. However, it is possible that hemodynamic compromise is simply associated with other epidemiological or clinical risk factors and is not an independent risk factor for stroke. For example, patients with carotid artery occlusion and distal hemodynamic compromise may have a higher incidence of hypertension, a well-described independent risk factor for stroke,^{2 3 4 5 6 7 8 9} than patients with normal cerebral hemodynamics. This difference alone might account for a higher risk of stroke in the former group of patients. Another significant clinical risk factor for stroke in the general population is the presence of prior ischemic symptoms.^{5 7 10 11 12 13} This factor may also be important in patients with carotid occlusion. Hankey and coworkers¹⁴ found a 5.9% annual risk of ipsilateral stroke in a review of 12 prospective follow-up studies of 1261 patients with angiographically confirmed symptomatic occlusion. Hennerici et al,¹⁵ on the other hand, followed 49 asymptomatic patients for a mean follow-up of 31.2 months and observed only 5 ipsilateral strokes (3.9% annual risk). Some studies of stroke risk and cerebral hemodynamics have not distinguished between symptomatic and asymptomatic patients.¹⁶ For example, Kleiser et al¹⁶ studied 85 patients with carotid occlusion by transcranial Doppler ultrasound. They found an increased incidence of ipsilateral stroke in patients with absent CO₂ reactivity. However, these data were not analyzed separately for symptomatic (n=39) and asymptomatic (n=46) patients.

The hemodynamic effect of an occlusive or stenotic lesion can be categorized into three stages: stage 0, normal cerebral hemodynamics; stage 1, autoregulatory vasodilatation; and stage 2, increased oxygen extraction.¹⁷ This last stage of hemodynamic compromise has been termed "misery perfusion."¹⁸ The purpose of this study was to determine whether baseline clinical, epidemiological, or angiographic risk factors were associated with the most severe category of hemodynamic compromise, increased OEF.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients
Between 1991 and 1996, 117 patients with symptomatic or asymptomatic atherosclerotic carotid artery occlusions were studied with clinical evaluation, laboratory testing, and PET. These patients were part of the St Louis Carotid Occlusion Study, a prospective blinded longitudinal study of cerebral hemodynamics in patients with carotid occlusion. The diagnosis of common or internal carotid artery occlusion was made on selective arteriography, magnetic resonance angiography or Doppler ultrasonography. The accuracy of color Doppler ultrasonography for the diagnosis of complete occlusion of the carotid artery has been well validated at our institution.¹⁹ CT or MRI examinations were performed on study entry if cerebral imaging had not been done as part of usual clinical care sufficiently long after an ischemic event to permit the accurate definition of infarct location.

To establish a range of normal control cerebral hemodynamic and metabolic values, PET measurements of CBF, CBV, CMRO₂, and OEF were also performed on 18 normal volunteer subjects aged 19 to 77 years (mean±SD, 45±18 years). All volunteers had no history of neurological disease, and all had normal neurological examinations, MRI scans of the head, and duplex ultrasound studies of the carotid bifurcation.

Clinical and Laboratory Evaluations
All patients were interviewed and examined by a physician investigator from the St Louis Carotid Occlusion Study. Baseline risk factors assessed during the interview consisted of age, sex, heart disease (prior myocardial infarction or congestive heart failure), diabetes mellitus, smoking (defined as never, cigarettes both past and current, and current pipe or cigar use), alcohol consumption (none or drinks per day), and parental death from stroke. Patients were categorized as hypertensive if they reported a prior history of high blood pressure, regardless of whether or not they were being treated for hypertension. Blood pressure was measured in the clinic, with the patient seated, on the day of the PET study. Whether the occlusion was symptomatic or asymptomatic was determined from the interview and the neurological examination. Focal hemispheric or retinal deficits referable to the ipsilateral carotid artery territory were considered symptomatic events. Patients were categorized as asymptomatic or symptomatic (with subgroups of cerebral TIA, stroke, retinal TIA, and retinal stroke). Laboratory testing consisted of measurements of hemoglobin (g/dL), fibrinogen (mg/dL), fasting cholesterol (total, high-density lipoprotein, and low-density lipoprotein), and fasting triglycerides.

Assessment of Collateral Circulation
Of the 117 patients enrolled, 108 had carotid arteriograms that allowed the assessment of collateral circulation. Three of these patients had bilateral carotid occlusions, for a total of 111 hemispheres with arteriographic assessment of collateral flow. Arteriograms were graded by an investigator before processing of the PET data. The degree of contralateral stenosis, from the carotid origin through the siphon, was measured as the maximal percent diameter narrowing of a vessel relative to the normal distal lumen diameter. This could be assessed in 88 studies. For the purposes of data analysis, contralateral stenosis was graded as 50% stenosis or <50% stenosis based on the most severe lesion present. Arteries contributing collateral flow were identified as anterior communicating, external carotid (including retrograde ophthalmic artery flow), and leptomeningeal (anterior or posterior cerebral arteries crossing the border zone to the middle cerebral artery territory).

PET Measurements
PET studies were performed on the day of clinical examination and study enrollment. For symptomatic patients, the median time between the most recent ischemic event and the PET study was 66 days (range, 0 to 4745 days). After positioning the patient on the scanner gantry, an individually molded thermoplastic face mask was applied to ensure that the patient's head remained in a constant position during the scanning period. The exact position of the patient's head relative to the scanning plane was recorded on a lateral skull film obtained after the head was immobilized. Venous and arterial catheters were placed for intravenous radiotracer administration and for arterial blood gas analyses and arterial time-activity curve determinations.²⁰

PET examinations of carotid occlusion patients were performed on one of two PET scanners (models 953B or 961, Siemens). The 18 normal control volunteers were studied on the 961 scanner. A transmission scan was performed before radiotracer administration with ⁶⁸germanium/⁶⁸gallium rotating rod sources. The skull film and attenuation data from this scan were used to define the limits of the calvarium for quantitative processing of PET data.²¹

Each PET study consisted of three separate physiological studies. During each, arterial blood samples were drawn by hand or automatically to convert quantitative regional radioactivity data to quantitative physiological measurements. Additional arterial samples were drawn at intervals during the examination for determination of PaCO₂ stability, hematocrit level, and carboxyhemoglobin content. CBF was measured using a bolus intravenous injection of ¹⁵O-labeled water.^{21 22} CBV was measured by inhalation of air containing trace amounts of CO labeled with ¹⁵O.²³ OEF was measured after one or two breaths of ¹⁵O-labeled O₂ in combination with data from the CBV and CBF measurements.²⁴ CMRO₂ was calculated as the product of OEF, CBF, and PaO₂ content.²⁴ The entire PET examination could be performed within 1 hour because of the short half-life (123 seconds) of ¹⁵O. All radionuclides were produced in the Washington University cyclotron facility.^{25 26}

Data Analysis
PET images from the 953B and 961 scanners were reconstructed to a uniform resolution of 16 mm (full width half maximum) with use of a 3-dimensional gaussian filter. All PET data were converted to uniform atlas space to allow reproducible placement of regions of interest. For each patient and normal volunteer, 7 spherical regions of interest 19 mm in diameter were placed in the cortical territory of the middle cerebral artery in each hemisphere using stereotactic coordinates.^{20 27 28} Areas of prior infarction were identified by review of CMRO₂ images as well as CT or MRI examinations. Neither the regions within these areas nor the corresponding contralateral regions were used for analysis. The mean hemispheric values of CBF, CBV, CMRO₂, and OEF were then calculated.

Left-to-right ratios of the mean hemispheric values of OEF were calculated. Hemodynamic stage for each individual patient was assigned by comparing the ratios of mean left/right hemispheric values in each study patient to those from the 18 normal control subjects. For each patient, the left-to-right ratio of OEF was considered abnormal (stage 2) if it fell above or below the range observed in the normal sample.¹⁷

Baseline epidemiological, clinical, and laboratory risk factors were then tabulated for the high and normal OEF groups. Student t tests, ², and Fisher exact tests were used to assess statistical significance (P<.05). Because of the multiple comparisons involved in the analyses, a Bonferroni correction was applied to the significance level to maintain the overall type I error rate at 0.05. A total of 25 separate comparisons were made, and therefore the probability value required to accept statistical significance was .05/25 or .002.

This research was approved by the Human Studies and the Radioactive Drug Research Committees of Washington University School of Medicine. Written informed consent was obtained from all subjects.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The tabulated results are shown in the Table. Patients with increased OEFs (39 of 44 patients) were significantly more likely to have had prior ipsilateral ischemic symptoms than patients with normal OEFs (42 of 73 patients). Alternatively, symptomatic patients were more likely to have increased ipsilateral OEFs than asymptomatic patients (39 of 81 versus 5 of 36, respectively). The differences between these observed frequencies were highly statistically significant (P<.001). The presence or absence of prior ipsilateral symptoms was the only comparison to achieve statistical significance. The frequency or mean values of all other risk factors were similar between the high and normal OEF groups. None of the arteriographic findings examined in this study were associated with increased OEF. Specifically, neither the arteriographic identification of contralateral stenosis >50% nor the presence of leptomeningeal collaterals was associated with misery perfusion (Table).

View this table: [in this window] [in a new window]   Table 1. Baseline Risk Factors Versus Stage 2 Hemodynamic Compromise

Infarction within the middle cerebral artery territory required the exclusion from analysis of some of the 7 stereotactically placed regions. This occurred in 10 of the 73 patients with normal OEFs (mean, 2.4 of 7 regions) and in 11 of the 44 patients with increased OEFs (mean, 2.2 regions).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The data show that misery perfusion (increased OEF) correlates with prior ischemic symptoms. This finding is consistent with prior reports of an association between prior ipsilateral symptoms and absent CO₂ reactivity by transcranial Doppler ultrasonography.²⁹ The relationship between the presence of prior symptoms and increased OEF is unclear. It is possible that increased OEF predisposes patients to have symptomatic events. Whether increased OEF is an independent predictor for subsequent ipsilateral stroke will need to be determined by prospective studies of cerebral hemodynamics in patients with carotid occlusion.³⁰ Nevertheless, the data from the present study have an important implication for future investigations of the relationship between hemodynamic factors and stroke risk: asymptomatic patients with carotid occlusion have a low frequency of hemodynamic impairment and therefore the presence or absence of symptoms must be taken into account in the analysis of these studies.

Epidemiological studies of patients with first stroke, stroke after TIA, or recurrent stroke have indicated several potentially important risk factors for patients with carotid occlusion. These factors are age, sex, hypertension, coronary artery disease, congestive heart failure, diabetes mellitus, smoking, alcohol consumption, parental death from stroke, hemoglobin, fibrinogen, and cholesterol.^{2 3 4 5 6 7 8 9 10 11 12 13 31 32 33 34 35 36 37 38 39 40 41 42 43} These factors were carefully evaluated and recorded before study entry and PET examination. The observed frequencies and mean values of all these established risk factors were similar in both groups. No correlation between any of these factors and increased OEF was found.

In this study we chose to compare the presence of misery perfusion with baseline risk factors. Increased OEF may be associated with an increased risk of subsequent stroke. Powers¹⁷ reported 2-year follow-up data on 59 patients with symptomatic carotid occlusion or >75% stenosis studied with PET. The risk of stroke was 28% (4 of 14) for patients with misery perfusion at study entry and 14% (6 of 42) for patients with normal OEFs (stages 0 and 1). This difference was not statistically significant. In addition, 2 of the 4 patients with misery perfusion and subsequent stroke had undergone surgical revascularization.

The lack of correlation between the pattern of collateral supply and increased OEF observed in this study requires discussion. The lack of correlation between the presence of external carotid or anterior communicating artery collaterals and increased OEF is not unexpected. Several investigators have demonstrated a strong correlation between the pattern of collateral supply and the degree of hemodynamic compromise distal to extracranial internal carotid artery stenosis or occlusion. Ophthalmic artery collaterals have been consistently associated with autoregulatory vasodilatation due to reduced cerebral perfusion pressure^{21 44 45} and increased OEF.⁴⁴ Therefore, retrograde ophthalmic artery flow has not been a specific sign of increased OEF. Collateral flow from the opposite carotid artery via the anterior circle of Willis has been associated with both normal and abnormal cerebral hemodynamics.²¹ In contrast to ophthalmic artery collaterals, however, leptomeningeal collaterals have been reported to be solely associated with misery perfusion. In a study by Powers et al²¹ of 19 patients with extracranial carotid stenosis or occlusion, leptomeningeal collaterals were observed only with increased OEF in the middle cerebral artery territory (hemodynamic stage 2, n=4). In the present study, leptomeningeal collaterals were present in 5% (2/44) of patients with misery perfusion and in 9% (7/73) of patients with normal OEFs. PET methodology and arteriographic assessment were very similar between these two studies. The small sample size in the original report by Powers et al²⁷ may account for this discordance.

In conclusion, the presence of misery perfusion in patients with carotid occlusion is associated with prior ischemic symptoms and not with the other established risk factors for stroke examined in this study. The fact that asymptomatic patients are much less likely to have increased OEF must be taken into account when investigating the relationship between hemodynamic factors and stroke risk.

	Selected Abbreviations and Acronyms

 

CBF = cerebral blood flow CBV = cerebral blood volume CMRO2 = cerebral metabolic rate for oxygen OEF = oxygen extraction fraction PET = positron emission tomography TIA = transient ischemic attack

	Acknowledgments

 
This work was supported in part by NIH NINDS grants NS28947 (Drs Grubb and Powers) and NS34050 (Dr Powers), a training grant from the Charles S. Dana Foundation through the Dana Consortium on Neuroscience: Neuroimaging Leadership Training (Drs Powers and Derdeyn), and a Radiological Society of North America/Siemens Medical Systems Research Fellowship (Dr Derdeyn). We wish to acknowledge the invaluable assistance of Susanne Fritsch, RN, John Hood, and Lennis Lich in carrying out this study.

	Footnotes

 
Presented in part at the 23rd International Joint Conference on Stroke and Cerebral Circulation, Orlando, Fla, February 5, 1998.

Received November 18, 1997; revision received January 15, 1998; accepted January 22, 1998.

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				C. P. Derdeyn, N. R. Simmons, T. O. Videen, K. D. Yundt, S. M. Fritsch, D. L. Carpenter, R. L. Grubb Jr., and W. J. Powers Absence of Selective Deep White Matter Ischemia in Chronic Carotid Disease: A Positron Emission Tomographic Study of Regional Oxygen Extraction AJNR Am. J. Neuroradiol., April 1, 2000; 21(4): 631 - 638. [Abstract] [Full Text]

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