Correction for intravascular activity in the oxygen-15 steady-state technique is independent of the regional hematocrit

The oxygen-15 steady-state technique to measure the regional cerebral metabolic rate for oxygen requires a correction for the nonextracted intravascular molecular oxygen-15. To perform this correction, an additional procedure is carried out using RBCs labeled with 11CO or C15O. The previously reported correction method, however, required knowledge of the regional cerebral to large vessel hematocrit ratio. A closer examination of the underlying model eliminated this ratio. Both molecular oxygen and carbon monoxide are carried by RBCs and are therefore similarly affected by a change in hematocrit.     

Non-invasive regional study of chronic cerebrovascular disorders using the oxygen-15 inhalation technique.

The regional cerebral metabolism-to-perfusion imbalance has been studied in the three main categories of cerebrovascular disorders in a chronic phase of the disease, using the non-invasive oxygen-15 inhalation technique. In patients presenting with a history of transient ischaemic attacks, regional defects in cerebral perfusion were greater than for the corresponding oxygen uptakes. Areas of relative ischaemia within which there was an enforced increase in the oxygen extraction ratio were highlighted. The reverse pattern was observed frequently in patients with brain infarcts arising from strokes, so indicating areas of relative luxury perfusion as is inferred from the reduction in the oxygen extraction ratio. In the multi-infarct dementia group of patients, there were parallel focal reductions in both flow and metabolism. The oxygen-15 inhalation technique is shown to be a unique tool in investigating cerebrovascular disorders because of its non-invasiveness and its ability to define regional metabolism-to-perfusion imbalance within the brain.     

In vivo disturbance of the oxidative metabolism of glucose in human cerebral gliomas

Abnormalities in the oxidative metabolism of glucose in human cerebral gliomas have been studied in seven patients using positron emission tomography. Measurements of regional cerebral blood flow and oxygen consumption were obtained using the oxygen-15 steady-state inhalation technique. Values of regional cerebral glucose consumption were obtained using fluorine 18-labeled 2-fluoro-2-deoxy-D-glucose and a simplification of the method of Sokoloff. Functional values were obtained for regions of tumor and brain tissue in the middle cerebral artery territory of the contralateral cortex. Values of regional glucose consumption were calculated for both regions using a value of the lumped constant quoted for normal brain tissue (0.42). Tumor regional cerebral blood flow was comparable to that in the contralateral cortex, whereas regional cerebral oxygen consumption was depressed. This depression resulted in low tumor values of the fractional oxygen extraction ratio (0.21 +/- 0.07), indicating that oxygen supply exceeded the metabolic demand. In contrast, tumor regional cerebral glucose consumption was not depressed and regional glucose extraction ratios were similar for tumor and brain tissue. The metabolic uncoupling between regional oxygen consumption and regional glucose consumption (CMRO2/CMRGlu = 0.24 +/- 0.07 ml of oxygen per milligram of glucose) is indicative of increased aerobic glycolysis.     

Regional cerebral oxygen utilization and blood flow in normal man using oxygen-15 and positron emission tomography

Quantitative determination of regional cerebral blood flow (rCBF), regional cerebral oxygen utilization (rCMRO₂) and regional oxygen extraction ratio (rOER) was performed in 11 normal volunteers by an oxygen-15 inhalation method and positron emission tomography.
Regional values comparable with figures from the literature have been obtained.
This non-invasive approach offers the possibility of a simultaneous quantitative evaluation of these physiological parameters in health and disease.     

Studies on regional cerebral oxygen utilisation and cognitive function in multiple sclerosis.

Regional cerebral oxygen utilisation (rCMRO2), oxygen extraction (rOER), blood flow (rCBF), and blood volume (rCBV) have been determined for fifteen patients with multiple sclerosis in remission using positron emission tomography (PET). Cerebral oxygen utilisation and blood flow were significantly reduced in both white matter and peripheral cortical grey matter in the multiple sclerosis patients compared to a group of normal controls. No evidence of regional cerebral ischaemia in the multiple sclerosis group was found. Lowest levels of cerebral oxygen utilisation were found in patients with cerebral atrophy, and in patients in whom a significant fall in present full-scale IQ from estimated pre-morbid levels had occurred. No correlation was found between rCMRO2 values and severity of locomotor dysfunction or clinical disease duration.     

Postoperative hemodynamic and metabolic changes in patients with subarachnoid hemorrhage

Positron emission tomography was performed using an oxygen-15 gas inhalation technique to measure regional cerebral blood flow, metabolic rate for oxygen, oxygen extraction fraction, and cerebral blood volume in 13 patients with subarachnoid hemorrhage during the period of delayed vasospasm after surgery as well as in 10 volunteers as controls. Compared with the controls, the patients showed decreased hemoglobin concentration and decreased total arterial oxygen content due to postoperative hemodilution. Global reductions in the metabolic rate for oxygen and in the tissue oxygen supply were noted even in the apparently normal cortex of the patients in spite of adequate blood flow and adequate oxygen extraction fraction. In addition, regional reductions in blood flow and in perfusion reserve were seen in the cortical territory corresponding to cerebral vasospasm. Our results indicate that two processes are involved in the pathophysiology of cerebral vasospasm: 1) generalized impairment of oxygen metabolism with a reduced tissue oxygen supply, even in the apparently normal cortex, and 2) additional impairment of regional perfusion in the territory of vasospasm.     

Study of regional cerebral metabolism and blood flow relationships in man using the method of continuously inhaling oxygen-15 and oxygen-15 labelled carbon dioxide.

A new technique for assessing regional oxygen use and blood flow has been applied to a wide range of neurological patients. The method couples the brain's high metabolic demand for oxygen with a shortlived radioactive form of this metabolite, namely oxygen-15 (half life: 2.1 min). This combination produces during the continuous inhalation of either molecular oxygen-15 or labelled carbon dioxide, steady state functional images of the brain which are relatively free of contribution from extracerebral tissues. These are complementary images in that they relate to regional oxygen uptake and blood flow and hence offer a direct insight to the regional demand-to-supply relationships within the brain in physiological and pathological conditions. In the clinical groups studied, metabolic and circulatory defects were observed and instances of cerebrovascular insufficiency and relative luxury perfusion were defined which hitherto have been deduced from indirect methods. The clinical acceptability of this non-invasive approach allowed us to study those categories of patients which normally do not warrant invasive examination.     

Disturbance of oxidative metabolism of glucose in recent human cerebral infarcts

Eight patients with recent cerebral hemispheric infarction were studied with positron emission tomography and the oxygen-15 steady-state inhalation and [¹⁸F]deoxyglucose techniques to obtain values of regional cerebral blood flow, oxygen consumption, and glucose metabolism. The Sokoloff equation, used to calculate glucose metabolism, was simplified to exclude the exponential terms containing the rate constants. A value of the lumped constant quoted for normal brain (0.42) was used for infarcted regions and contralateral hemisphere. Mean regional cerebral blood flow, oxygen consumption, and glucose metabolism were all significantly depressed within the infarcts compared with the mirror regions in the contralateral cerebral hemisphere. The mean fractional extraction of oxygen was low, indicating an adequate supply of oxygen for residual oxidative metabolism. Regional oxygen consumption and glucose metabolism were significantly correlated within the infarcts, but with a relationship of 2 moles of oxygen per mole of glucose—one-third that in the contralateral hemisphere and in normal brain. Although these results suggest that the metabolizing tissue of a recent cerebral infarct utilizes aerobic glycolysis, caution about the validity of this pathophysiological observation is dictated by limitations in current positron emission tomographic tracer methodology.     

Effect of hemodilution on cerebral hemodynamics and oxygen metabolism.

BACKGROUND AND PURPOSE: To evaluate the effects of hemodilution on cerebral hemodynamics and oxygen metabolism in the normal human brain, we measured regional cerebral blood flow, oxygen extraction fraction, oxygen metabolic rate, and regional cerebral blood volume in eight normal volunteers before and after hemodilution using positron emission tomography and oxygen-15-labeled gas inhalation technique. SUMMARY OF REPORT: Hemodilution was accomplished by phlebotomy of 400 ml and drip infusion of 500 ml low molecular weight dextran, which reduced hematocrit from 42.5% to 37.2% and arterial oxygen content from 19.1 to 16.9 ml/dl (both p less than 0.005). It also increased mean cerebral blood flow from 45.2 to 47.7 ml/100 ml/min (p less than 0.025), but decreased tissue oxygen delivery from 8.7 to 8.0 ml/100 ml/min (p less than 0.05) and cerebral blood volume from 4.9% to 4.6% (p less than 0.025) in the overall cortical gray matter. CONCLUSIONS: Our results indicate that hemodilution in the tested range does not improve oxygen transport or tissue oxygenation in the normal human brain, although it increases cerebral blood flow.     

Stability of arterial concentrations during continuous inhalation of C15O2 and 15O2 and the effects on computed values of CBF and CMRO2

Stability of arterial whole blood and plasma concentrations is a basic requirement in the application of the oxygen-15 (15O2) steady-state inhalation technique for measuring regional cerebral blood flow and oxygen use. The level of stability obtainable in practice is reported in the form of retrospectively analysed blood data from 626 consecutive studies in patients with a range of clinical conditions. Serial arterial whole blood and plasma concentrations were measured during both C15O2 and 15O2 inhalations, and coefficients of variation were calculated. In addition, these concentrations were compared with the corresponding values recorded at the start of each study and maximum variations were calculated. For all four concentrations, mean and median coefficients of variation were around 5 and 4%, respectively. Mean and median maximum variations were around 9 and 7%, respectively. The effects of these variations on the calculations of regional cerebral blood flow, oxygen extraction, and oxygen use were estimated. Mean expected errors were found to be between 4 and 9%, and median expected errors between 3 and 6%. Inherent blood sampling errors were assessed from blood volume studies using 11CO-labeled red cells. These errors were found to be less than 3%.     

Tissue acid-base balance and oxygen metabolism in human cerebral infarction studied with positron emission tomography

Nine patients who had suffered strokes were examined between 10 and 34 days after onset using positron emission tomography. DMO labeled with carbon 11 was used to evaluate brain acid-base balance, and the oxygen-15 inhalation technique was used to measure regional cerebral blood flow, the oxygen extraction fraction, and cerebral metabolic rate for oxygen. [11C]DMO concentration and oxygen metabolism variables were measured in the infarcted area and in the symmetrical region in the contralateral cerebral hemisphere. [11C]DMO concentration was found to be unchanged or slightly increased in five cases and markedly increased in four cases. The apparent increase in tissue pH can be explained by the presence of a large extracellular fluid space with a pH nearly identical to that of brain plasma, or by an increase in intracellular pH, or by both phenomena. The change in [11C]DMO concentration in the infarcted area relative to that in the normal tissue was independent of the change in blood flow. Cerebral metabolic rate for oxygen was decreased in all cases. The increase in [11C]DMO concentration in the infarcted area was linearly correlated with the decrease in the oxygen extraction fraction in the same region; that is, it was correlated with the occurrence of perfusion in excess of metabolic demand. The overabundant local perfusion could play a role in the decreased H+ content.     

Blood flow and oxygen utilisation in the contralateral cerebral cortex of patients with untreated intracranial tumours as studied by positron emission tomography, with observations on the effect of decompressive surgery.

Using positron emission tomography, regional cerebral blood flow and oxygen utilisation were measured in the contralateral cortex of 14 patients with a variety of intracranial tumours. A comparison was made with cortical values derived from 14 normal controls. Compared with normal subjects, patients with brain tumours had a significant reduction in oxygen utilisation and blood flow in their contralateral cortex. Decompression resulting from craniotomy and biopsy, led to a partial reversal of this cerebral hypofunction.     

PET studies of changes in cerebral blood flow and oxygen metabolism after unilateral microembolization of the brain in anesthetized dogs

Cerebral blood flow and oxygen metabolism have been measured with the steady-state oxygen-15 technique and positron emission tomography in anesthetized dogs. Regional microembolization was induced by infusing Sephadex particles (diameter, 40 micron) into one of the common carotid arteries. In the first series of experiments, 2.5 mg Sephadex was infused, and the dogs were examined within 3-4 hours after embolization. In a second series 0.55 mg Sephadex was infused, and the dogs were examined either in the first 3-4 hours or 24-48 hours after embolization. Cerebral blood flow, oxygen extraction ratio, and cerebral oxygen utilization were measured at 3 PCO2 levels. In the acute experiments, cerebral oxygen utilization in the embolized hemisphere was 6 (0.55 mg Sephadex) and 25% (2.5 mg Sephadex) lower than on the contralateral side. While cerebral blood flow was symmetrically distributed in normocapnia and hypocapnia, it was 9 (0.55 mg Sephadex) and 35% (2.5 mg Sephadex) lower in the embolized hemisphere during hypercapnia. In normocapnia and hypocapnia the lower oxygen utilization in the embolized hemisphere was characterized by a lower oxygen extraction ratio, and in hypercapnia by an unchanged (0.55 mg Sephadex) or by a higher (2.5 mg Sephadex) extraction ratio. The different effect on oxygen extraction ratio in the control and embolized hemispheres resulted in images of uncoupling between perfusion and oxygen demand that varied according to the PCO2. The experiments also showed a fall in cerebral blood flow in the embolized hemisphere after 3-4 hours, indicating delayed hypoperfusion. After 24-48 hours, blood flow was about 10% higher in the embolized hemisphere, and this was observed at the 3 PCO2 levels, while the oxygen extraction ratio was systematically lower. Oxygen utilization in the embolized hemisphere was depressed to practically the same extent as in acute experiments. It can be concluded that between 4 and 24 hours after microembolization the cerebral microcirculation shows important changes, with installation of luxury perfusion in the face of an unchanging decreased oxygen metabolism.     

Measurement of glucose utilisation with [18F]2-fluoro-2-deoxy-D-glucose: a comparison of different analytical methods

A number of different analytical methods were applied to dynamic scans obtained with [18F]2-fluoro-2-deoxy-D-glucose and positron emission tomography. In particular, methods applying three, four, standard, or no rate constants were compared in four studies on three normal subjects. In addition, regional cerebral blood flow, oxygen utilisation, and blood volume were measured using the oxygen-15 steady-state inhalation technique. There was a large difference between values of glucose utilisation obtained with the various analytical methods, in particular between methods using three or four rate constants. This difference was not due to contamination of the tracer with [18F]2-fluoro-2-deoxy-D-mannose. For dynamic techniques, the separate measurement of regional cerebral blood volume was essential. Static techniques (single scans with standard or no rate constants) were best related to dynamic techniques utilising four rate constants. From the results, it followed, however, that these static techniques can only be applied clinically if relatively large disturbances of glucose metabolism and no changes in rate constants are anticipated. The lumped constant was assessed from the combined measurement of oxygen and glucose utilisation and was higher than previously reported.     

Cerebral haemodynamic changes after extracranial-intracranial bypass surgery.

Regional cerebral blood flow, oxygen utilisation, fractional oxygen extraction, and cerebral blood volume were measured by positron emission tomography in twelve patients with carotid artery occlusion. Follow-up studies were carried out at a mean interval of eleven weeks after extracranial-intracranial bypass surgery. Clinical improvement was observed in three patients who had presented with frequent transient ischaemic attacks. One patient with multiple vascular occlusions suffered a stroke at the time of surgery. Follow-up studies showed an increase of regional cerebral blood flow in only two of the twelve patients. In the group as a whole, there was no significant change of cerebral blood flow, oxygen consumption or fractional oxygen extraction after bypass surgery. The most consistent post-operative change, observed in eleven of the twelve patients, was a fall of cerebral blood volume in the cortical territory of the bypassed carotid artery (p less than 0.01). This effect was most marked in patients with bilateral carotid occlusion, in whom there was often an accompanying fall of blood volume in the contralateral hemisphere. The post-operative findings were consistent with an increase of regional cerebral perfusion pressure as a result of the bypass procedure. Although this effect is potentially of value, those patients with most to gain from bypass surgery may also run the highest risk of peri-operative cerebral ischaemia.     

Cerebral blood flow and metabolism in normotensive and hypertensive patients with transient neurologic deficits

We used positron emission tomography to examine retrospectively the effects of blood pressure on regional cerebral blood flow and oxygen metabolism in seven normotensive and eight hypertensive patients with a history of transient neurologic deficits. In the hypertensive patients, a decrease in regional cerebral blood flow was closely related to blood pressure; these changes were most pronounced in the supratentorial structures, especially the striatum and thalamus. In contrast, the regional cerebral metabolic rate for oxygen was less related to blood pressure. Consequently, the regional oxygen extraction fraction was increased in the hypertensive patients, while regional cerebral blood volume and the regional cerebral blood flow volume ratio were unchanged. Multivariate regression analysis confirmed that hypertension was an independent factor affecting regional cerebral blood flow. The analysis also disclosed that age, sex, hematocrit, smoking, and PaCO2 affected regional cerebral blood flow. These findings suggest that the hemodynamic reserve in hypertensive individuals is reduced, which may predispose them to cerebral ischemia and perhaps stroke, even during small decreases in cerebral perfusion pressure.     

Evaluation of the 11CO2 positron emission tomographic method for measuring brain pH. II. Quantitative pH mapping in patients with ischemic cerebrovascular diseases

A practical method has been developed that, using 11CO2 and positron emission tomography (PET), computes and maps (a) "effective pH" (pHt), a weighted average of intra- and extracellular pH, and (b) "clearance" (K1), product of blood flow and 11CO2 extraction. This method, together with measurements of cerebral blood flow (CBF) and oxygen extraction fraction (OEF), was applied to 12 patients with cerebral ischemia or stroke. The regional K1 was positively correlated with CBF (n = +0.78). The k1/CBF ratio, representing the extraction fraction ratio of 11CO2 to H2 15O, was negatively correlated with CBF (r = -0.54), suggesting that 11CO2 extraction decreases as flow increases. In five acute stroke patients within 2 days of onset, the injured cortex had lower CBF (20.6 ml/min/100 g), higher OEF (78.1%), and lower pHt (6.96) than the contralateral cortex (CBF = 41.4 ml/min/100 g, OEF = 53.3%, pHt = 7.00), suggesting intracellular acidosis with intact cell membranes. In three stroke patients 5-8 days after onset, the injured cortex had higher CBF (60.9 ml/min/100 g), lower OEF (32.0%), and higher pHt (7.12) than the contralateral cortex (CBF = 45.3 ml/min/100 g, OEF = 58.0%, pHt = 7.06), which suggested an increase in extracellular volume compartment reflecting loss of cell membrane integrity. This method provides information on the regional tissue acid-base status and cell membrane integrity, which may be prognostic of tissue viability.     

Hypertension induced changes in cerebral capillary permeability to water are mediated by afferent neuronal connections from the carotid sinus to the brain

The effects of acute opiate receptor stimulation on regional cerebral oxygen consumption and blood flow were examined in 9 regions of the artificially respired, alpha-chloralose-anesthetized cat. Regional cerebral arterial and venous oxygen saturation were examined microspectrophotometrically and regional cerebral blood flow was monitored using radioactively tagged microspheres (15 +/- 3 micron in diameter). Oxygen consumption was calculated as the product of flow and oxygen extraction. In 8 cats, after control cerebral blood flow was obtained, and in 8 experimental cats after this same measurement was obtained before and 40 min after the administration of 1.5 mg/kg morphine sulfate; the cats' heads were simultaneously sawed in 3 places and quickly frozen in liquid nitrogen-cooled propane. Systolic and diastolic blood pressure were significantly decreased by treatment. The heterogeneity of venous oxygen saturation was significantly reduced by morphine. Average cerebral blood flow, oxygen extraction and consumption were not altered significantly by morphine. Regional cerebral blood flow in the hypothalamus, thalamic oxygen extraction, and hypothalamic and thalamic oxygen consumption were significantly decreased by treatment. This low dose of morphine may produce changes in cerebral neuronal and/or synthetic activity which lowers oxygen consumption in some regions rich in opiate receptors, while not affecting overall brain oxygen supply or consumption.     

Evidence of misery perfusion and risk for recurrent stroke in major cerebral arterial occlusive diseases from PET.

OBJECTIVES--In major cerebral arterial occlusive diseases, patients with inadequate blood supply relative to metabolic demand (misery perfusion) may be at increased risk for cerebral ischaemia. This study investigated whether patients showing misery perfusion on PET have a high risk of recurrent ischaemic stroke. METHODS--The relation between the regional haemodynamic status of cerebral circulation and the subsequent risk of recurrent stroke was prospectively evaluated in 40 patients with symptomatic internal carotid or middle cerebral arterial occlusive diseases who underwent PET. Patients were divided into two haemodynamic categories according to the mean hemispheric value of oxygen extraction fraction in the hemisphere supplied by the artery with symptomatic disease: patients with normal oxygen extraction fraction and those with increased oxygen extraction fraction (misery perfusion). All patients were followed up for at least 12 months. RESULTS--The one year incidence of ipsilateral ischaemic strokes for patients with normal oxygen extraction fraction and those with increased oxygen extraction fraction were two of 33 and four of seven patients respectively. A significantly higher incidence of ipsilateral strokes was found in patients with increased oxygen extraction fraction (Fisher's exact test; P = 0.005). In patients with increased oxygen extraction fraction, three of four strokes were watershed infarctions and the location of the infarction corresponded with the area of increased oxygen extraction fraction. CONCLUSION--These findings contradict conclusions of a previous study and suggest that patients with major cerebral arterial occlusive diseases and misery perfusion have a high risk for recurrent ischaemic stroke.     

Compensatory mechanisms for chronic cerebral hypoperfusion in patients with carotid occlusion

BACKGROUND AND PURPOSE: The purpose of this experiment was to assess long-term cerebral hemodynamic and metabolic changes in patients with increased oxygen extraction fraction (OEF) in the hemisphere distal to an occluded carotid artery who remain free of stroke. Methods--Ten patients with increased OEF and no interval stroke underwent repeated positron emission tomography examinations 12 to 59 months after the initial examination. Quantitative regional measurements of cerebral blood flow, cerebral blood volume, cerebral rate of oxygen metabolism (CMRO2), and OEF were obtained. Regional measurements of the cerebral rate of glucose metabolism (CMRGlc) were made on follow-up in 5 patients. Statistical significance (P<0.05) was measured with t tests and linear regression analysis. RESULTS: The ipsilateral/contralateral OEF ratio declined from a mean of 1.16 to 1.08 (P=0.022). Greater reductions were seen with longer duration of follow-up (P=0.023, r=0.707). The cerebral blood flow ratio improved from 0.81 to 0.85 (P=0.021). No change in cerebral blood volume or CMRO2 was observed. CMRGlc was reduced in the ipsilateral hemisphere (P=0.001 compared with normal), but the CMRO2/CMRGlc ratio was normal. CONCLUSIONS: Increased OEF improves in patients with carotid occlusion and no interval stroke. This improvement in OEF is due to an improvement in collateral blood flow.