Measurement of regional cerebral blood flow and oxygen utilisation in patients with cerebral tumours using 15O and positron emission tomography: Analytical techniques and preliminary results

Summary Regional cerebral blood flow and oxygen utilisation have been studied in 8 patients with brain tumours using continuous inhalation of C¹⁵O₂ and ¹⁵O₂ and positron emission tomography. The methods used to analyse the regional cerebral pathophysiology are presented. A relative uncoupling between oxygen consumption and blood flow was observed in all tumours as indicated by a decreased regional fractional extraction of oxygen (rOER). This suggests that a major proportion of these tumours had sufficient blood supply to meet oxygen metabolic demand. A decrease of blood flow in grey matter was found both in the affected and contralateral hemispheres of the brain. Matched reductions of flow and oxygen utilisation were observed in oedematous tissue.     

Effects of chronic hypoxia on fetal coronary responses

This review examines the effect of high altitude and/or chronic hypoxia on cardiac mechanisms that influence perfusion of the fetal heart (e.g., tissue metabolism, coronary vessel growth, and coronary blood flow and vessel responsiveness). In response to intrauterine hypoxia, the fetal heart may either reduce its energy demand or increase its substrate and oxygen delivery as a means of sustaining cardiac function. Cardiac glycolysis predominates as a metabolic pathway of ATP synthesis in the fetal heart under both normoxic and hypoxic conditions. During prolonged oxygen insufficiency, normal cardiac function is sustained by anaerobic glycolysis relying primarily on high levels of stored glycogen in the heart. Chronic hypoxia increases coronary vessel growth and myocardial vascularization in fetal hearts, although the response may depend on the presence of ventricular hypertrophy. Recent studies demonstrate that high altitude hypoxia increases both resting fetal coronary flow and coronary flow reserve as an adaptive response toward increasing oxygen delivery. Hypoxia may also directly effect local vascular smooth muscle mechanisms, resulting in altered coronary artery reactivity to circulating vasoactive substances and contributing to enhanced perfusion. Further study is needed to understand the relative importance of each of these cardiac adaptations in contributing to fetal survival. It is likely that differences in fetal coronary responses to intrauterine hypoxia are highly dependent on the gestational age and relative maturity of the animal species.     

Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia.

Recent experimental data underlies the role of hypoxic tubular injury in the pathophysiology of radiocontrast nephropathy. Although systemic transient hypoxemia, increased blood viscosity, and a leftward shift of the oxygen-hemoglobin dissociation curve may all contribute to intrarenal hypoxia, imbalance between oxygen demand and supply plays a major role in radiocontrast-induced outer medullary hypoxic damage. Low oxygen tension normally exists in this renal region, reflecting the precarious regional oxygen supply and a high local metabolic rate and oxygen requirement, resulting from active salt reabsorption by medullary thick ascending limbs of Henle's loop. Radiologic contrast agents markedly aggravate outer medullary physiologic hypoxia. This results from enhanced metabolic activity and oxygen consumption (as a result of osmotic diuresis and increased salt delivery to the distal nephron) because the regional blood flow and the oxygen supply actually increase. The latter effect may result in part from the activation of various regulatory mediators of outer medullary blood flow to ensure maximal regional oxygen supply. Low-osmolar radiocontrast agents may be less nephrotoxic because of the smaller osmotic load and vasomotor alterations. Experimental radiocontrast-induced renal failure requires preconditioning of animals with various insults (for example, congestive heart failure, reduced renal mass, salt depletion, or inhibition of nitric oxide and prostaglandin synthesis). In all these perturbations, which resemble clinical conditions that predispose to contrast nephropathy, outer medullary hypoxic injury results from insufficiency or inactivation of mechanisms designed to preserve regional oxygen balance. This underlines the importance of identifying and ameliorating predisposing factors in the prevention of this iatrogenic disease.     

Doping with artificial oxygen carriers: an update

There is a long history of science seeking to develop artificial substitutes for body parts damaged by disease or trauma. While defective teeth and limbs are commonly replaced by imitations without major loss of functionality, the development of a substitute for red blood cells has proved elusive. There is a permanent shortage of donor blood in western societies. Nevertheless, despite whole blood transfusions carrying measurable risks due to immunogenicity and the transmission of blood-borne infectious diseases, red blood cells are still relatively inexpensive, well tolerated and widely available. Researchers seeking to develop products that are able to meet and perhaps exceed these criteria have responded to this difficult challenge by adopting many different approaches. Work has focussed on two classes of substances: modified haemoglobin solutions and perfluorocarbon emulsions. Other approaches include the creation of artificial red cells, where haemoglobin and supporting enzyme systems are encapsulated into liposomes. Haemoglobin is ideally suited to oxygen transport when encased by the red cell membrane; however, once removed, it rapidly dissociates into dimers and is cleared by the kidney. Therefore, it must be stabilised before it can be safely re-infused into humans. Modifications concomitantly alter the vascular half-life, oxygen affinity and hypertensive characteristics of raw haemoglobin, which can be sourced from outdated blood stores, genetically-engineered Escherichia coli or even bovine herds. In contrast, perfluorocarbons are entirely synthetic molecules that are capable of dissolving oxygen but biologically inert. Since they dissolve rather than bind oxygen, their capacity to serve as a blood substitute is determined principally by the oxygen pressure gradients in the lung and at the target tissue. Blood substitutes have important potential areas of clinical application including red cell replacement during surgery, emergency resuscitation of traumatic blood loss, oxygen therapeutic applications in radiography (oxygenation of tumour cells is beneficial to the effect of certain chemotherapeutic agents), other medical applications such as organ preservation, and finally to meet the requirements of patients who cannot receive donor blood because of religious beliefs. Given the elite athlete's historical propensity to experiment with novel doping strategies, it is likely that the burgeoning field of artificial oxygen carriers has already attracted their attention. Scientific data concerning the performance benefits associated with blood substitutes are virtually nonexistent; however, international sporting federations have been commendably proactive in adding this category to their banned substance lists. The current situation is vulnerable to exploitation by immoral athletes since there is still no accepted methodology to test for the presence of artificial oxygen carriers.     

Nitroimidazoles and imaging hypoxia

Decreased tissue oxygen tension is a component of many diseases. Although hypoxia can be secondary to a low inspired P0₂ or a variety of lung disorders, the commonest cause is ischemia due to an oxygen demand greater than the local oxygen supply. In tumors, low tissue p0₂ is often observed, most often due to a blood supply inadequate to meet the tumor's demands. Hypoxic tumor tissue is associated with increased resistance to therapy. In the heart tissue hypoxia is often observed in persistent low-flow states, such as hibernating myocardium. In patients with stroke, hypoxia has been associated with the penumbral region, where an intervention could preserve function. Despite the potential importance of oxygen levels in tissue, difficulty in making this measurement in vivo has limited its role in clinical decision making. A class of compounds known to undergo different intracellular metabolism depending on the availability of oxygen in tissue, the nitroimidazoles, have been advocated for imaging hypoxic tissue. When a nitroimidazole enters a viable cell the molecule undergoes a single electron reduction, to form a potentially reactive species. In the presence of normal oxygen levels the molecule is immediately reoxidized. This futile shuttling takes place for some time, before the molecule diffuses out of the cell. In hypoxic tissue the low oxygen concentration is not able to effectively compete to reoxidize the molecule and further reduction appears to take place, culminating in the association of the reduced nitroimidazole with various intracellular components. The association is not irreversible, since these agents clear from hypoxic tissue over time. Initial development of nitroimidazoles for in vivo imaging used radiohalogenated derivatives of misonidazole, such as fluoromisonidazole, some of which have recently been employed in patients. Two major problems with fluoromisonidazole are its relatively low concentration within the lesion and the need to wait several hours to permit clearance of the agent from the normoxic background tissue (contrast between lesion and background typically <2:1 at about 90 min after injection). Even with high-resolution positron emission tomographic imaging, this combination of circumstances makes successful evaluation of hypoxic lesions a challenge. Single-photon agents, with their longer halflives and comparable biological properties, offer a greater opportunity for successful imaging. In 1992 technetium-99m labeled nitroimidazoles were described that seem to have at least comparable in vivo characteristics. Laboratory studies have demonstrated preferential binding of these agents to hypoxic tissue in the myocardium, in the brain, and in tumors. These investigations indicate that imaging can provide direct evidence of tissue with low oxygen levels that is viable. In the experimental setting this information is useful to plan a more aggressive approach to treating tumors, or revascularize a heart suffering ischemic dysfunction. Even from this early vantage point the utility of measuring tissue oxygen levels with external imaging suggests that hypoxia imaging could play a major role in clinical decision making.     

Assessment of pathophysiology of stroke by positron emission tomography

In stroke patients, multitracer positron emission tomography (PET) permits the assessment of acute changes in regional cerebral blood flow (rCBF), blood volume (rCBV), oxygen consumption (rCMRO₂) and glucose metabolism (rCMR_gl), which are the initial steps in the complex molecular and biochemical process leading to ischaemic cell damage. While early infarcts exhibit low flow and oxygen consumption, increased oxygen extraction fraction (OEF) due to preserved metabolism at reduced flow suggests viability of tissue. However, most initially viable tissue will be metabolically deranged and will become necrotic in the further course; only in a few instances do these tissue compartments recover to normal function. Increased glucose uptake at reduced oxygen supply induces non-oxidative glycolysis with noxious lactacidosis, whereas hyperperfusion beyond the metabolic demand is of controversial effect. In subacute or chronic states after ischaemia reduced flow can be compensated by increased blood volume; when perfusional reserve is exhausted, oxygen extraction increases. Such findings may guide therapeutic decisions and predict the severity of permanent deficits. Functional deactivation of tissue remote from the lesion is found regularly as a sign of damaged connecting pathways. Flow and metabolic studies during the performance of specific tasks help to detect alternative functional loops and may yield prognostic information. Repeat studies in the course of stroke are employed for the evaluation of therapeutic strategies targeted to improve reperfusion or to effect metabolic or biochemical alterations. In the future PET may gain additional clinical importance when patients are selected for elective treatment according to the prevailing pathophysiological pattern. Correspondence to: W.-D. Heiss     

Response of tumors to therapy studied by 31P magnetic resonance spectroscopy

Magnetic resonance (MR) methods have been used to study the metabolic and vascular response of model tumors to tumor necrosis factor (TNF). Magnetic resonance measurements demonstrated acute reductions in tumor blood flow, measured from tumor uptake of D2O, and in tumor adenosine triphosphate (ATP), measured by 31P magnetic resonance spectroscopy (MRS) following administration of TNF. The decrease in ATP generally followed reduction in tumor blood flow, and therefore was probably due to ischemia caused by damage to tumor vasculature. Superficial human tumors have been studied by MRS to characterize their 31P spectra, and to measure metabolic changes during therapy. The ratio of the intensities of the phosphomonoester (PME) and ATP resonances (PME/ATP) was much higher in tumors than in the normal tissue displaced by the tumors. During therapy, decreases in PME/ATP were detected that paralleled, but did not anticipate, decreases in tumor size. In some cases, a transient increase in PME/ATP was detected during therapy, which did not correlate with changes in tumor size, and which may reflect stimulation of cell growth in some tumor zones.     

In vivo studies of peritendinous tissue in exercise

Soft tissue injury of tendons represents a major problem within sports medicine. Although several animal and cell culture studies have addressed this, human experiments have been limited in their ability to follow changes in specific tissue directly in response to interventions. Recently, methods have allowed for in vivo determination of tissue concentrations and release rates of substances involved in metabolism, inflammation and collagen synthesis, together with the measurement of tissue blood flow and oxygenation in the peritendinous region around the Achilles tendon in humans during exercise. It can be demonstrated that this region experiences an increase in blood flow during both static and dynamic exercise, and that exercise causes increased metabolic activity, accumulation of inflammatory mediators (prostaglandins) and increased formation of collagen type I in response to acute exercise. This coincides with a surprisingly marked drop in tissue pressure during contraction. With regards to both circulation, metabolism and collagen formation, peritendinous tissue represents a dynamic, responsive region that adapts markedly to acute muscular activity.     

Frozen red blood cells in combat casualty care: clinical and logistical considerations

OBJECTIVE: To test the hypothesis that a supply of frozen red blood cells and a system for processing pyrogen-free crystalloid solution would meet the needs of an echelon 3 medical treatment facility in the U.S. military, caring for casualties during the initial phase of a military medical operation. DATA SOURCES: Blood requirements for potential combat casualties were estimated from transfusion data on: (1) patients admitted to Boston City Hospital following trauma, utilizing a computerized data base, (2) patients admitted to the Naval Support Hospital-Da Nang during the Vietnam War, from 1966 to 1970, from published and unpublished material, and (3) casualties estimated by Department of Defense expert panels for specific conflicts. The procedure for processing frozen red blood cells was evaluated at the Naval Blood Research Laboratory. Estimates of wounded in action were provided by the Department of Defense. DATA SYNTHESIS: Computer modeling using standard spreadsheet software on a personal computer. CONCLUSIONS: Under military conditions, a frozen red blood cell bank and a system for processing pyrogen-free resuscitative fluid could be used to prepare 96 units of red cells and 960 1 of crystalloid solution per day. This would be adequate to treat approximately 180 casualties, the number projected for a 5-day battle with heavy casualties (6 wounded in action/1,000 soldiers/day). It was concluded that a frozen blood bank system and system for processing pyrogen-free resuscitative fluid could successfully meet the needs of an echelon 3 medical facility in the initial phase of a military medical operation.     

Protecting muscle ATP: positive roles for peripheral defense mechanisms-introduction

Skeletal muscle has evolved an impressive array of mechanisms for peripherally mediated control of ATP homeostasis. Some of these mechanisms are intracellular, and others are extracellular and include influences on the cross-bridge cycle itself and substrate supply. This paper introduces three distinctly different topics that nevertheless all have ATP defense in common. The role of ADP in fatigue is controversial but has recently been more clearly delineated so that an effect on alleviating force declines during extreme fatigue is plausible. AMP plays its role by activating the protein-kinase, AMPK, which is a key sensor of cellular energy stress. AMPK has different isoforms, is not uniformly distributed in the cell, and its activation is carefully controlled. It has multiple effects including improvements in substrate supply for the metabolic pathways producing ATP and inhibition of anabolic processes to further spare ATP. Red blood cells have the capacity to sense hypoxia and to release vasodilators where there is a locally increased demand for blood supply. The papers in this series emphasize the important positive roles of metabolites and sensors of fatigue in the balance between ATP supply and demand.     

Positron emission tomography in oncology--the Massachusetts General Hospital experience

Positron tomography has been used to measure blood flow, oxygen utilization, and glucose metabolism in soft-tissue tumors in rabbits and in human tumors in extremities. Both blood flow and oxygen utilization were increased in tumor in contrast to normal muscle tissue. Oxygen extraction fraction was, however, decreased in tumor. The most sensitive indicator of tumor growth was the glucose metabolic rate. The effect of irradiation was observed by blood flow measurements in human tumors and by blood flow and oxygen utilization in tumors in rabbits. Blood flow increased both in tumor and normal muscle tissue during irradiation and decreased afterwards. Oxygen utilization decreased in tumor and increased in normal tissue during irradiation.     

Assessment of regional differences in myocardial blood flow using T2-weighted 3D BOLD imaging.

The feasibility of detecting regional differences in myocardial blood flow based on the blood oxygen level-dependent (BOLD) effect was evaluated in vivo in dogs (N = 9) using a 3D T2-prepared segmented gradient-echo sequence at 1.5 T. Regional differences in myocardial blood flow were created by administering adenosine through a catheter placed in the left circumflex coronary artery (LCX). The difference in the R2 (1/T2) relaxation rate between the left ventricular myocardial region supplied by the LCX and regions supplied by the left anterior descending coronary artery (LAD) or septal artery during adenosine administration was correlated to the corresponding regional myocardial blood flow difference determined using fluorescent microspheres. A correlation coefficient of 0.80 was found between the MR BOLD measurements and the myocardial flow assessment. Our results show that the sequence used in this study allows fast 3D BOLD imaging of the heart, and is a promising technique for detecting regional myocardial perfusion differences.     

Index of lipid peroxidation and glucose utilization in the cerebrospinal fluid in patients with cerebral infarction

Cerebral ischemia could be observed as acute metabolic crisis, when oxygen and glucose supply is compromised and synthesis of energy is insufficient. Apart from the excitotoxicity, increased production of reactive oxygen species with consequent lipid peroxidation is also included in neuronal cell damage. Furthermore, these toxic compounds could also be produced during the process of secondary inflammation of ischemic tissue. In the early stage of ischemia, as a systemic response to acute stress, there is an increase in glucose level in cerebrospinal fluid (CSF) and peripheral blood. According to the metabolic crisis and acidosis in ischemic brain tissue we investigated index of lipid peroxidation (ILP) and glucose utilization (IGU) in CSF of 53 patients of both sexes, aged 55-70 years with cerebral infarction. Control group comprised 15 patients with sudden onset of motor deficit subjected to diagnostic lumbar radiculography and suspected on discal genesis. ILP in CSF, as the indicator and sequela of neuronal cell membranes damage, was two fold increased in the acute period of cerebral infarction and maximal values (3.5 times) were noticed 24 hours after the ischemic episode compared to controls. Besides the increase in glucose concentration in peripheral blood and CSF of patients with cerebral infarction, IGU was decreased (37%) with minimal values (32%) 24 hours after the ischemia. These changes indicate that glucose is available but cells are incapable to metabolize it. We concluded that ILP and IGU in CSF of patients with cerebral infarction could be indicators of metabolic dysfunction and neuronal cell damage. Also, these results suggest the significance of polyvalent therapy including antioxidative and antiinflammatory agents in acute phase of cerebral ischemia.     

Tissue oxygenation and microvascular hemodynamics in experimental arterial gas embolism

Microvascular hemodynamic responses to arterial gas embolism (AGE) and local oxygen tensions (PO2) have never been evaluated in vivo using intravital microscopy. A system was implemented to study AGE in real time using brightfield and phosphorescence microscopy as well as laser-induced microvessel occlusion. Bubble dynamics, microhemodynamics and oxygenation were studied following AGE in 61 microvessels and 41 interstitial spaces from 19 anesthetized rats. AGE was induced by direct air injection into the femoral artery ipsilateral to the studied cremaster muscle. Bubble-induced vaso-occlusion was investigated, and microvascular blood flow redistribution were associated with changes in intravascular and interstitial PO2. Microvascular blood flow as well as intravascular and tissue PO2 decreased after microvascular occlusion following microembolism. However, certain areas did not become fully hypoxic since redistribution of blood allowed oxygen to be supplied by nearby microvessels with blood (or plasma) flow or tissue gas diffusion. A linear correlation between interstitial and intravascular PO2 was found during baseline and after AGE. Because some microvessels remain flowing even after AGE, our observations suggest that intravascular therapeutic agents administered during severe AGE may reach microvascular networks and provide additional oxygenation to tissue areas where blood flow is compromised due to occlusion of some microvessels.     

Residual spleen found on denatured red blood cell scan following negative colloid scans.

The technetium-sulfur colloid liver-spleen examination is widely used to evaluate patients with idiopathic thrombocytopenic purpura for residual splenic tissue following splenectomy. Technetium-labeled heat-damaged red blood cell imaging is another sensitive test for residual splenic tissue. We recently encountered a patient with idiopathic thrombocytopenic purpura who was initially evaluated with a technetium sulfur colloid scan which was negative. A denatured red blood cell scan was subsequently performed which revealed intense focal activity in the region of the splenic bed. Surgery confirmed this to be splenic tissue. Our results emphasize the utility of the denatured red blood cell examination in the setting of strong clinical suspicion for residual splenic tissue following a negative sulfur colloid study.     

胫骨萎缩性骨不连骨折局部DSA的初步应用

目的研究胫骨萎缩性骨不连骨折区局部血液循环的改变情况。方法对12例骨折不愈合患者的骨折局部进行数字减影血管造影(DSA)检查,观察骨折不愈合处及周围软组织的血管形态变化、血管数目变化以及局部血液微循环时间的变化。同时观察12例正常人相应部位的DSA表现,对所得的2组数据进行统计学分析。结果骨不连患者的骨折局部的血管形态无明显变化,12例患者骨折区的血管计数均在正常范围之内,局部血液微循环时间2组比较具有显著的统计学差异(P<0.01)。结论研究表明,局部微循环障碍导致的供氧不足可能是骨不连的一个重要原因。     

脑氧代谢相关参数在中枢神经系统疾病中的应用进展

颅内静脉血氧饱和度、氧摄取分数、脑氧代谢率是一组反映脑组织氧的利用及代谢情况的指标,可间接评估脑功能及脑组织发育程度。多种医学成像技术可测量静脉血氧饱和度,包括如血氧水平依赖成像（BOLD）、自旋标记下T2弛豫成像（TRUST）、磁敏感加权成像（SWI）、定量磁敏感图（QSM）等。综述血氧饱和度及其相关代谢参数的测量在脑梗死、创伤性脑损伤、多发性硬化、肝性脑病、肾性脑病及镰状细胞贫血疾病中的应用及研究。     

Effect of fructose 1,6-diphosphate on exercise capacity in patients with peripheral vascular disease

Exogenous fructose 1,6-diphosphate (FDP), a glycolytic intermediate, increases blood ATP and 2,3 diphosphoglycerate levels, facilitates the dissociation of oxygen from hemoglobin, and increases red blood cell flexibility. These mechanisms explain why it has been effective in enhancing energy production in a variety of ischemic conditions. The present study was undertaken to determine whether FDP could enhance oxygen supply and thus improve exercise performance in patients with peripheral vascular disease. Ten male patients (mean age 63 +/- 5 years) with peripheral vascular disease performed symptom-limited exercise testing after randomized, double blind infusion of either 200 mg/kg body weight FDP or placebo. Data were evaluated at rest, at a matched submaximal workload (2-3 MPH/0% grade), and at peak exercise, defined as the occurrence of moderately severe claudication. No differences were observed in heart rate, blood pressure, gas exchange data, time to the onset of claudication or peak exercise, or lactate and 2,3 diphosphoglycerate levels. In contrast to previous studies performed among patients with peripheral vascular disease and other studies using more severe hypoxic conditions, FDP did not affect the respiratory gas exchange or exercise capacity of patients with exertional claudication.     

Influence of intravascular activity on the determination of blood flow and oxygen extraction in normal and ulcerated legs using the 15O steady-state technique and positron emission tomography

An analysis using the 15O steady-state inhalation technique has been carried out into the effects of correction for intravascular activity on the determination of blood flow and oxygen extraction ratio (OER) in the legs of patients affected by ulceration. Transaxial images of the distribution of activity in a plane passing through the ulcer were obtained during steady-state inhalation of C15O2 and 15O2, respectively, using a single slice positron emission tomographic scanner. From these, the basic tracer model equations were solved to obtain blood flow and oxygen extraction with and without additional correction for the presence of intravascular activity. The latter was obtained from a scan following the inhalation of a tracer quantity of 11CO, which labels the red blood cell pool. Mean blood flow and OER in ulcerated regions were 0.087 ml/ml/min and 0.33, respectively. With correction for blood volume, assumed to be all venous, the mean OER decreased to 0.12. In the "mirror" region of normal legs mean blood flow was 0.011 ml/ml/min with uncorrected and corrected OER values of 0.87 and 0.75, respectively. The effect of assuming a nonzero arterial volume increases as flow and OER decrease but is uncertain due to the unknown arterial fraction. Correction for intravascular 15O is essential and generally the assumption that all blood volume is venous is adequate.