Comparison of Quantitative and Qualitative Oxygen Extraction Fraction (OEF) in Acute Stroke Patients with Large Vessel Occlusion.

The superficial temporal artery-middle cerebral artery bypass (STA-MCA) bypass surgery developed by Donaghy and Yarsagil in 1967 provided relief for patients with acute stroke and large vessel occlusive vascular disease. Early reports showed low morbidity and good outcomes. However, a large clinical trial in 1985 reported a failure of extracranial-intracranial (EC/IC) bypass to show benefit in reducing the risk of stroke compared to best medical treatment. Problems with the study included cross overs to surgery from best medical treatment, patients unwilling to be randomized and chose EC/IC surgery, and loss of patients to follow-up. Most egregious is the fact that the study did not attempt to identify and select the patients at high risk for a second stroke. Based on these shortcomings of the EC/IC bypass study, a carotid occlusion surgery study (COSS) was proposed by Dr. William Powers and colleagues using qualitative hemispheric oxygen extraction fraction (OEF) by positron emission tomography (PET) between the contralateral and ipsilateral hemispheres with a ratio of 1.16 indicative of hemodynamic compromise. To increase patient enrollment, several compromises were made mid study. First. The ratio threshold was lowered to 1.12 and the level of occlusion in the carotid reduced from 70% to 60%. Despite these compromises the study was closed for futility, apparently because the stroke rate in the medically treated group was too low. Thus, the question as to the benefit of EC/IC bypass surgery remains unresolved. In our NIH funded study Quantitative Occlusive Vascular Disease Study (QUOVADIS), we used quantitative OEF to evaluate stroke risk and compared it to the qualitative count-rate ratio method used in the COSS study and found that these two methods did not identify the same patients at increased risk for stroke, which may explain the reason for the failure of the COSS study as our results show that qualitative OEF ratios do not identify the same patients as quantitative OEF.

Human biodistribution and dosimetry of the PET radioligand [¹¹C]flumazenil (FMZ).

PURPOSE: We measure the whole-body distribution of IV injected [¹¹C]Flumazenil (FMZ) as a function of time in adult subjects and determine the absorbed radiation doses. PROCEDURES: After injection with 770 MBq of [¹¹C]FMZ (nominal), each of six subjects underwent nine consecutive whole body PET scans. Twelve source organs were identified using PET attenuation and emission images. Activity within each organ as a function of time was determined from the sequence of the nine PET scans. Source organ time activity curves were integrated and normalized by the injected dose to yield source organ residence times for the no voiding situation. Separate bladder residence-time calculations were performed for the cases of a 1- and a 2-h voiding interval. Using the source organ residence times as input, the program OLINDA/EXM (Stabin et al. in J Nucl Med. 46:1023-1027, 2005) was used to perform dosimetry calculations for the various body organs and for the whole body. RESULTS: For the no voiding situation, the average whole-body radiation equivalent dose was 3.02 × 10⁻³ mSv/MBq of injected [¹¹C]FMZ. The average effective dose and effective dose equivalent was 7.57 × 10⁻³ and 1.12 × 10⁻² mSv MBq⁻¹, respectively. The organ receiving the highest equivalent dose was the urinary bladder wall with an average of 6.32 × 10⁻² mSv MBq⁻¹. CONCLUSION: On average, the administration of less than 790 MBq (21 mCi) of [¹¹C]FMZ yields (no voiding model) an organ equivalent dose of under 50 mSv [the single dose limit for research studies under US regulations (21CFR361.1) to body organs other than blood forming organs, gonads or the lens of the eye] to all organs. Equivalent dose to the blood forming organs and gonads from a 790 MBq administered FMZ dose is well under the 30 mSv limit provided under 21CFR361.1. Additionally, administration of less than 1320 MBq (35.7 mCi) yields an effective dose [International Commission on Radiation Protection (ICRP) 60 tissue weighting scheme] of under 10 mSv, which is the ICRP IIb (minor to intermediate) risk category limit.

Increased cerebral oxygen metabolism and ischemic stress in subjects with metabolic syndrome-associated risk factors: preliminary observations.

Hypertension, diabetes, obesity, and dyslipidemia are risk factors that characterize metabolic syndrome (MetS), which increases the risk for stroke by 40%. In a preliminary study, our aim was to evaluate cerebrovascular reactivity and oxygen metabolism in subjects free of vascular disease but with one or more of these risk factors. Volunteers (n=15) 59±15 (mean±SD)years of age clear of cerebrovascular disease by magnetic resonance angiography but with one or more risk factors were studied by quantitative positron emission tomography for measure ment of cerebral blood flow, oxygen consumption, oxygen extraction fraction (OEF), and acetazolamide cerebrovascular reactivity. Eight of ten subjects with MetS risk factors had OEF >50%. None of the five without risk factors had OEF >50%. The presence of MetS risk factors was highly correlated with OEF >50% by Fisher's exact test (p<0.007). The increase in OEF was significantly (P<0.001) correlated with cerebral metabolic rate for oxygen. Increased OEF was not associated with compromised acetazolamide cerebrovascular reactivity. Subjects with one or more MetS risk factors are characterized by increased cerebral oxygen consumption and ischemic stress, which may be related to increased risk of cerebrovascular disease and stroke.

PET OEF reactivity for hemodynamic compromise in occlusive vascular disease.

BACKGROUND AND PURPOSE: Hemodynamic compromise in symptomatic patients with occlusive vascular disease (OVD) identified by cerebrovascular reserve (CVR) and oxygen extraction fraction (OEF) is an independent predictor of high stroke risk. However, up to 60% of patients compromised by CVR have normal OEF indicating a high rate of discordance. CVR is measured with an acetazolamide challenge, and OEF reactivity (OEFR) to acetazolamide, ie, a hemodynamic challenge, may reveal hemodynamic compromise and less discordance with measurements of CVR. METHODS: Nine symptomatic patients with OVD were studied by positron emission tomography before and 15 minutes after 15 mg/kg intravenous acetazolamide in the middle cerebral artery territories of each hemisphere. RESULTS: A close correlation between hemispheric CVR and OEFR was observed. Two hemispheres from two different patients showed an increase in OEF to acetazolamide challenge despite a normal baseline OEF. The two hemispheres showing an increase in OEF in response to acetazolamide were also associated with the lowest CVR and severest white matter hyperintensities. CONCLUSIONS: These observations suggest that positive OEFR may distinguish hemispheres in hemodynamic compromise despite normal OEF and show less discordance with CVR. However, these preliminary observations require confirmation in a larger study.

Identifying regions of compromised hemodynamics in symptomatic carotid occlusion by cerebrovascular reactivity and oxygen extraction fraction.

OBJECTIVES: Oxygen extraction fraction (OEF) and cerebrovascular reserve (CVR) are both proven predictors of stroke risk in symptomatic patients with carotid occlusion. Accordingly, hemispheric comparisons of CVR and OEF are significantly correlated. However, there was also substantial disagreement: hemispheres identified as compromised by CVR were normal by OEF. Our aim was to determine whether regional comparisons could resolve the CVR-OEF discordance. We also studied the relationship between white matter (WM) infarction and hemodynamic compromise. METHODS: Quantitative CVR and OEF were measured in 12 symptomatic patients with internal carotid artery occlusion. CVR and OEF comparisons were made in the anterior watershed (AWS), middle cerebral artery (MCA) and WM territories using various thresholds for hemodynamic compromise. Associations with WM infarction were also recorded. RESULTS: Comparison of CVR and OEF for the AWS and MCA showed high sensitivity (100%) with specificities of 83 and 40%, respectively. There was also agreement (k=Cohen's Kappa) for the AWS (k=0.83) and MCA (k=0.39) territories. CVR-OEF discordance was reduced with regional analysis. Hemodynamic compromise was more often found in patients with WM infarction. DISCUSSION: Regional comparison of CVR and OEF reduced the discordance compared with hemispheric analysis, especially for the AWS territory. Despite the persistence of some regions with compromised CVR and normal OEF, CVR is able to identify all regions with elevated OEF making it a useful screening technology. Future studies are needed to understand whether those remaining regions with compromised CVR are also at increased stroke risk despite normal OEF.

Differentiating hemodynamic compromise by the OEF response to acetazolamide in occlusive vascular disease.

Identification of increased stroke risk in a population of symptomatic patients with occlusive vascular disease (OVD) is presently accomplished by measurement of oxygen extraction fraction (OEF) or cerebrovascular reserve (CVR). However, many regions identified by compromised CVR are not identified by OEF. Our aim was to determine whether the response of OEF to acetazolamide, namely, oxygen extraction fraction response (OEFR) would identify those hemispheres in hemodynamic compromise with normal OEF. Nine patients symptomatic with transient ischemic attacks and strokes, and with occlusive vascular disease were studied. Anatomical MRI scans and T2-weighted images were used to identify and grade subcortical white matter infarcts. PET cerebral blood flow (CBF) and OEF were measured after acetazolamide. The relationship between CVR and oxygen extraction fraction response (OEFR) showed that positive OEFR occurred after acetazolamide despite normal baseline OEF values. The two hemispheres with positive OEFR were also associated with severe (> 3 cm) subcortical white matter infarcts. We found that the OEFR was highly correlated with CVR and identified hemispheres that were hemodynamically compromised despite normal baseline OEF.

Identification of hemodynamic compromise by cerebrovascular reserve and oxygen extraction fraction in occlusive vascular disease.

Cerebrovascular reserve (CVR) and oxygen extraction fraction (OEF) are used to identify hemodynamic compromise in symptomatic patients with carotid occlusive vascular disease, but evidence suggests that they are not equivalent. The authors studied the relationship between CVR and OEF to evaluate their equivalence and stages of hemodynamic compromise. Symptomatic patients (N = 12) with carotid occlusion were studied by stable xenon-computed tomography CBF after intravenous acetazolamide administration for CVR, followed within 24 hours by positron emission tomography (PET) for OEF. Middle cerebral artery territories were analyzed by hemisphere and level. Hemispheric subcortical white matter infarctions were graded with magnetic resonance imaging. Both hemispheric and level analysis of CVR and OEF showed a significant (P = 0.001), negative linear relationship [CVR (%) = -1.5 (OEF) + 83.4, (r = -0.57, P = 0.001, n = 24]. However, 37.5% of the hemispheres showed compromised CVR but normal OEF and were associated (P = 0.019) with subcortical white matter infarction. CMRO2 was elevated in stage II hemodynamic compromise (CVR < 10%, OEF > 50%). CVR and OEF showed a significant negative linear relationship in stage II hemodynamic compromise but revealed hemispheres in hemodynamic compromise by CVR but normal OEF that were associated with subcortical white matter infarction.

Decreased tumor blood flow as measured by positron emission tomography in cancer patients treated with interleukin-1 and carboplatin on a phase I trial.

BACKGROUND: Positron emission tomography (PET) scanning can be used to measure blood flow. When interleukin-1alpha (IL-1) is given in a murine model, it induces acute hemorrhagic necrosis, tumor vascular injury and decreased tumor blood flow, and when given prior to carboplatin, there is enhanced antitumor activity compared to either agent alone. METHODS: In a phase I trial of IL-1 and carboplatin, eligible patients with metastatic disease to the lung had PET scanning performed with (15)O water to assess tumor blood flow before and after IL-1 administration. Doses of IL-1 were 0.03, 0.06, 0.10, 0.15, 0.20 and 0.30 micro g/kg given i.v. over 2 h. At 4 h after IL-1 initiation, carboplatin was administered as a 30-min i.v. infusion at a dose of 400 mg/m(2). Treatment was repeated every 28 days. Other measured parameters included granulocyte kinetics, integrin expression on circulating WBC, and carboplatin pharmacokinetics. Of 16 patients, 11 (8 evaluable) underwent PET scanning before and at 2, 4 and 24 h after IL-1 initiation. RESULTS: Mean measured pretreatment tumor blood flow was 1.82 ml/min per g. At 2, 4 and 24 h it was 1.35, 1.67 and 1.62 ml/min per g respectively. Tumor blood flow was significantly decreased ( P<0.008) at 2 h after IL-1 initiation. In four patients, liver blood flow was measured at the same time-points as tumor blood flow. Liver blood flow was discordant with the tumor blood flow measures, showing no statistically significant change. IL-1 also caused a decreased WBC at 2 h after initiation ( n=14, P=0.025). In addition, polymorphonuclear leukocyte (PMN) and monocyte surface expression of CD11b at 2 h was increased when measured by mean fluorescence intensity flow cytometry (PMN P=0.0269, monocytes P=0.0420). No consistent effect of IL-1 on either carboplatin AUC or platelet nadir was demonstrated. CONCLUSIONS: We conclude that IL-1 has measurable effects on tumor blood flow and causes a significant decrease in blood flow as measured by PET scanning with (15)O water at 2 h after initiation. This decrease is temporally associated with a significant leukopenia and an increased expression of the adhesion integrin CD11b on the circulating cell surface (PMN and monocytes). These results suggest that IL-1 causes decreased tumor blood flow in vivo in human cancer patients, an effect that was temporally related to cytokine-induced peripheral blood cellular changes. Furthermore, our findings suggest that PET scanning may be useful to assess the effect of a systemic antineoplastic agent on tumor blood flow in cancer patients.