A Theoretical Model of Oxygen Delivery and Metabolism for Physiologic Interpretation of Quantitative Cerebral Blood Flow and Metabolic Rate of Oxygen

The coupling of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) during physiologic and pathophysiologic conditions remains the subject of debate. In the present study, we have developed a theoretical model for oxygen delivery and metabolism, which describes the diffusion of oxygen at the capillary-tissue interface and the nonlinear nature of hemoglobin (Hb) affinity to oxygen, allowing a variation in simple-capillary oxygen diffusibility, termed “effective oxygen diffusibility (EOD).” The model was used to simulate the relationship between CBF and CMRO2, as well as oxygen extraction fraction (OEF), when various pathophysiologic conditions were assumed involving functional activation, ischemia, hypoxia, anemia, or hypo- and hyper-capnic CBF variations. The simulations revealed that, to maintain CMRO2 constant, a variation in CBF and Hb required active change in EOD. In contrast, unless the EOD change took place, the brain allowed small but significant nonlinear change in CMRO2 directly dependent upon oxygen delivery. Application of the present model to quantitative neuroimaging of CBF and CMRO2 enables us to evaluate the biologic response at capillary level other than Hb- and flow-dependent properties of oxygen transport and may give us another insight regarding the physiologic control of oxygen delivery in the human brain.

[1]  Ewing,et al.  Measurement of Regional Cerebral Plasma Pool and Hematocrit with Copper-62-Labeled HSA-DTS , 1996 .

[2]  W D Heiss,et al.  Ischemic Penumbra: Evidence From Functional Imaging in Man , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  G L Shulman,et al.  Blood flow and oxygen delivery to human brain during functional activity: Theoretical modeling and experimental data , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Baron,et al.  Perfusion Thresholds in Human Cerebral Ischemia: Historical Perspective and Therapeutic Implications , 2001, Cerebrovascular Diseases.

[5]  R. J. Seitz,et al.  Vibratory stimulation increases and decreases the regional cerebral blood flow and oxidative metabolism: a positron emission tomography (PET) study , 1992, Acta neurologica Scandinavica.

[6]  A. Hudetz,et al.  Mathematical model of oxygen transport in the cerebral cortex , 1999, Brain Research.

[7]  M. Raichle,et al.  The effect of hemodynamically significant carotid artery disease on the hemodynamic status of the cerebral circulation. , 1987, Annals of internal medicine.

[8]  H. Fukuyama,et al.  Cerebral hematocrit decreases with hemodynamic compromise in carotid artery occlusion: a PET study. , 1998, Stroke.

[9]  K Pettigrew,et al.  Hypoxia Increases Velocity of Blood Flow through Parenchymal Microvascular Systems in Rat Brain , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  O. Paulson,et al.  Cerebral blood flow following normavolemic hemodilution in patients with high hematocrit , 1981, Annals of neurology.

[11]  A. Guyton,et al.  Textbook of Medical Physiology , 1961 .

[12]  K. Lynch,et al.  Responses to sphingosine-1-phosphate in X. laevis oocytes: similarities with lysophosphatidic acid signaling. , 1993, The American journal of physiology.

[13]  C. Sherrington,et al.  On the Regulation of the Blood‐supply of the Brain , 1890, The Journal of physiology.

[14]  E Meyer,et al.  Density of perfused capillaries in living human brain during functional activation. , 1992, Progress in brain research.

[15]  B. Siesjö,et al.  Brain energy metabolism , 1978 .

[16]  M. Mintun,et al.  Brain oxygen utilization measured with O-15 radiotracers and positron emission tomography. , 1984, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[17]  K Pettigrew,et al.  The Velocities of Red Cell and Plasma Flows through Parenchymal Microvessels of Rat Brain are Decreased by Pentobarbital , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[18]  Iwao Kanno,et al.  Regional cerebral blood flow, blood volume, oxygen extraction fraction, and oxygen utilization rate in normal volunteers measured by the autoradiographic technique and the single breath inhalation method , 1995, Annals of nuclear medicine.

[19]  D Comar,et al.  Reversal of Focal "Misery‐Perfusion Syndrome" By Extra‐Intracranial Arterial Bypass in Hemodynamic Cerebral Ischemia: A Case Study with 15O Positron Emission Tomography , 1981, Stroke.

[20]  A. Gjedde,et al.  Model of Blood–Brain Transfer of Oxygen Explains Nonlinear Flow-Metabolism Coupling During Stimulation of Visual Cortex , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[21]  R G Shulman,et al.  A model for the regulation of cerebral oxygen delivery. , 1998, Journal of applied physiology.

[22]  C. Rose,et al.  Tracer oxygen distribution is barrier-limited in the cerebral microcirculation. , 1995, Circulation research.

[23]  T. L. Davis,et al.  Calibrated functional MRI: mapping the dynamics of oxidative metabolism. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  C. Crone,et al.  THE PERMEABILITY OF CAPILLARIES IN VARIOUS ORGANS AS DETERMINED BY USE OF THE 'INDICATOR DIFFUSION' METHOD. , 1963, Acta physiologica Scandinavica.

[25]  C. Patlak,et al.  Hypercapnia slightly raises blood volume and sizably elevates flow velocity in brain microvessels. , 1993, The American journal of physiology.

[26]  R. Frackowiak,et al.  Quantitative Measurement of Regional Cerebral Blood Flow and Oxygen Metabolism in Man Using 15O and Positron Emission Tomography: Theory, Procedure, and Normal Values , 1980, Journal of computer assisted tomography.

[27]  J. Hamer,et al.  Cerebral blood flow and oxidative brain metabolism during and after moderate and profound arterial hypoxaemia , 2005, Acta Neurochirurgica.

[28]  C. Patlak,et al.  Nicotine Raises the Influx of Permeable Solutes across the Rat Blood—Brain Barrier with Little or No Capillary Recruitment , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[29]  B. Siesjö,et al.  The relationship between arterial po2 and cerebral blood flow in hypoxic hypoxia. , 1975, Acta physiologica Scandinavica.

[30]  J. Borredon,et al.  Dynamic In Vivo Measurement of Erythrocyte Velocity and Flow in Capillaries and of Microvessel Diameter in the Rat Brain by Confocal Laser Microscopy , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  B. Siesjö,et al.  Cerebral blood flow and oxygen consumption in the rat in hypoxic hypoxia. , 1975, Acta physiologica Scandinavica.

[32]  J. Olesen,et al.  Influence of carbon monoxide and of hemodilution on cerebral blood flow and blood gases in man. , 1973, Journal of applied physiology.

[33]  R. Buxton,et al.  A Model for the Coupling between Cerebral Blood Flow and Oxygen Metabolism during Neural Stimulation , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[34]  J. Seylaz,et al.  Dynamic Cerebral Microcirculatory Changes in Transient Forebrain Ischemia in Rats: Involvement of Type I Nitric Oxide Synthase , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[35]  Kazuo Minematsu,et al.  Acetazolamide Reactivity on 123I-IMP Single Photon Emission Computed Tomography in Patients with Major Cerebral Artery Occlusive Disease: Correlation with Positron Emission Tomography Parameters , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[36]  M. Raichle,et al.  The Effects of Changes in PaCO2 Cerebral Blood Volume, Blood Flow, and Vascular Mean Transit Time , 1974, Stroke.

[37]  M. Raichle,et al.  Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[38]  C. Patlak,et al.  Slightly altered permeability-surface area products imply some cerebral capillary recruitment during hypercapnia. , 1994, Microvascular research.

[39]  C J Thompson,et al.  Oxygen Consumption of the Living Human Brain Measured after a Single Inhalation of Positron Emitting Oxygen , 1992, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[40]  Albert Gjedde,et al.  Cerebral Blood Flow Change in Arterial Hypoxemia Is Consistent with Negligible Oxygen Tension in Brain Mitochondria , 2002, NeuroImage.

[41]  H. Fukuyama,et al.  A decrease in regional cerebral blood volume and hematocrit in crossed cerebellar diaschisis. , 1999, Stroke.

[42]  Ying Zheng,et al.  A Model of the Hemodynamic Response and Oxygen Delivery to Brain , 2002, NeuroImage.

[43]  A. Keyeux,et al.  Induced Response to Hypercapnia in the Two-Compartment Total Cerebral Blood Volume: Influence on Brain Vascular Reserve and Flow Efficiency , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.