Brain Oxygenation and Energy Metabolism: Part I—Biological Function and Pathophysiology

CONTINUOUS OXYGEN DELIVERY and CO2 clearance are paramount in the maintenance of normal brain function and tissue integrity. Under normal conditions, aerobic metabolism is the major source of energy in the brain, but this system may be compromised by the interruption of substrate delivery and disturbances in cerebral metabolism. These disruptions are major factors contributing to ischemic and hypoxic brain damage resulting from traumatic brain injury, stroke, and subarachnoid hemorrhage. There is evidence that mitochondrial function also is reduced after injury. Furthermore, early impairment of cerebral blood flow in patients with severe injury correlates with poor tissue oxygenation and may be an important parameter in secondary damage. Recent advances in brain tissue monitoring in the intensive care unit and operating room have made it possible to continuously measure tissue oxygen tension and temperature, as well as certain aspects of brain metabolism and neurochemistry. Therefore, it is important to understand the physiological process and the pathophysiology produced by these events. This is Part I of a two-part review that analyzes the physiology of cerebral oxygenation and metabolism as well as some of the pathological mechanisms involved in ischemic and traumatic brain injuries. Brain tissue monitoring techniques will be examined in the second article of this two-part series. To understand cerebral oxygenation, it is important to understand cerebral blood flow, energy production, ischemia, acidosis, generation of reactive oxygen species, and mitochondrial failure. These issues provide the basis of knowledge regarding brain bioenergetics and are important topics to understand when developing new approaches to patient care.

[1]  M E Phelps,et al.  Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. , 1997, Journal of neurosurgery.

[2]  J. Bolaños,et al.  Nitric oxide produced by activated astrocytes rapidly and reversibly inhibits cellular respiration , 1995, Neuroscience Letters.

[3]  D. Gadian,et al.  Controllable graded cerebral ischaemia in the gerbil: Studies of cerebral blood flow and energy metabolism by hydrogen clearance and 31P NMR spectroscopy , 1993, NMR in biomedicine.

[4]  W. Hoffman,et al.  Brain Tissue Oxygen, Carbon Dioxide, and pH in Neurosurgical Patients at Risk for Ischemia , 1996, Anesthesia and analgesia.

[5]  G. Bonvento,et al.  Local Uncoupling of the Cerebrovascular and Metabolic Responses to Somatosensory Stimulation after Neuronal Nitric Oxide Synthase Inhibition , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[6]  J. Aranda,et al.  The Role of Adenosine in the Vascular Adaptation of Neonatal Cerebral Blood Flow during Hypotension , 1991, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  I. Kudoh,et al.  Cerebral autoregulation is impaired in patients resuscitated after cardiac arrest , 1996, Acta anaesthesiologica Scandinavica.

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

[9]  M. A. Moro,et al.  Nitric oxide and peroxynitrite exert distinct effects on mitochondrial respiration which are differentially blocked by glutathione or glucose. , 1996, The Biochemical journal.

[10]  C. Leffler,et al.  Effect of Therapeutic Dose of Indomethacin on the Cerebral Circulation of Newborn Pigs , 1987, Pediatric Research.

[11]  S. Budd,et al.  Mechanisms of neuronal damage in brain hypoxia/ischemia: focus on the role of mitochondrial calcium accumulation. , 1998, Pharmacology & therapeutics.

[12]  B. Siesjö,et al.  Mechanisms of ischemic brain damage , 1988, Critical care medicine.

[13]  A. Maas,et al.  Monitoring cerebral oxygenation: experimental studies and preliminary clinical results of continuous monitoring of cerebrospinal fluid and brain tissue oxygen tension. , 1993, Acta neurochirurgica. Supplementum.

[14]  S. Snyder,et al.  Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase , 1991, Neuron.

[15]  P. Hardy,et al.  Prolonged Hypercapnia-Evoked Cerebral Hyperemia via K+ Channel– and Prostaglandin E2–Dependent Endothelial Nitric Oxide Synthase Induction , 2000, Circulation research.

[16]  A. Hudetz,et al.  Nitric oxide from neuronal NOS plays critical role in cerebral capillary flow response to hypoxia. , 1998, American journal of physiology. Heart and circulatory physiology.

[17]  S. Snyder,et al.  Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[18]  S. Zhang,et al.  Continuous monitoring of brain tissue oxygen pressure in patients with severe head injury during moderate hypothermia. , 1999, Surgical neurology.

[19]  G Fiskum,et al.  Mitochondria in Neurodegeneration: Acute Ischemia and Chronic Neurodegenerative Diseases , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[20]  B. Siesjö,et al.  Role and mechanisms of secondary mitochondrial failure. , 1999, Acta neurochirurgica. Supplement.

[21]  B. Siesjö,et al.  Mechanisms of secondary brain injury. , 1996, European journal of anaesthesiology.

[22]  B. Siesjö,et al.  Influence of tissue acidosis upon restitution of brain energy metabolism following total ischemia. , 1974, Brain research.

[23]  D. Lübbers,et al.  Regulation of local tissuePo2of the brain cortex at different arterial O2 pressures , 1975, Pflügers Archiv.

[24]  J. Rafols,et al.  Expression of the inducible nitric oxide synthase in distinct cellular types after traumatic brain injury: an in situ hybridization and immunocytochemical study , 2000, Acta Neuropathologica.

[25]  F. Faraci Role of endothelium-derived relaxing factor in cerebral circulation: large arteries vs. microcirculation. , 1991, The American journal of physiology.

[26]  Julio Cruz Continuous monitoring of partial pressure of brain tissue oxygen in patients with severe head injury. , 1996 .

[27]  Louis Sokoloff,et al.  Circulation and Energy Metabolism of the Brain , 1999 .

[28]  M. Ross,et al.  Marked Induction of Calcium-Independent Nitric Oxide Synthase Activity after Focal Cerebral Ischemia , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[29]  R. Bullock,et al.  Continuous monitoring of cerebral substrate delivery and clearance: initial experience in 24 patients with severe acute brain injuries. , 1997, Neurosurgery.

[30]  F. Murad,et al.  Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[31]  W. Dalton Dietrich,et al.  Small Differences in Intraischemic Brain Temperature Critically Determine the Extent of Ischemic Neuronal Injury , 1987, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[32]  D. Reis,et al.  Synthesis of nitric oxide in CNS glial cells , 1993, Trends in Neurosciences.

[33]  D. Pelligrino,et al.  Relative contributions from neuronal and endothelial nitric oxide synthases to regional cerebral blood flow changes during forebrain ischemia in rats. , 2000 .

[34]  C. Lee,et al.  Ischemia/reperfusion-induced injury of forebrain mitochondria and protection by ascorbate. , 1993, Archives of biochemistry and biophysics.

[35]  J. Lüders,et al.  Adenoviral Gene Transfer of Nitric Oxide Synthase Increases Cerebral Blood Flow in Rats , 2000, Neurosurgery.

[36]  H. Winn,et al.  Adenosine-induced release of nitric oxide from cortical astrocytes. , 1996, Neuroreport.

[37]  Á. Almeida,et al.  Changes of Respiratory Chain Activity in Mitochondrial and Synaptosomal Fractions Isolated from the Gerbil Brain After Graded Ischaemia , 1995, Journal of neurochemistry.

[38]  D. Graham,et al.  Apoptosis after traumatic brain injury. , 2000, Journal of neurotrauma.

[39]  B. Siesjö,et al.  Transient ischemia leads to intracellular alkalosis in the brain. , 1982, Acta physiologica Scandinavica.

[40]  B. Siesjö Cell Damage in the Brain: A Speculative Synthesis , 1981, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[41]  M. Dujovny,et al.  Failure of cerebral autoregulation in an experimental diffuse brain injury model. , 1998, Acta neurochirurgica. Supplement.

[42]  C. Agardh,et al.  Free radicals and brain damage. , 1989, Cerebrovascular and brain metabolism reviews.

[43]  B. Siesjö,et al.  Acidosis and ischemic brain damage. , 1988, Neurochemical pathology.

[44]  R. Busto,et al.  Effects of Moderate Hypothermia on Constitutive and Inducible Nitric Oxide Synthase Activities After Traumatic Brain Injury in the Rat , 1999, Journal of neurochemistry.

[45]  V. Casagrande,et al.  Endothelial nitric oxide synthetase (eNOS) in astrocytes: Another source of nitric oxide in neocortex , 1999, Glia.

[46]  J. Astrup Energy-requiring cell functions in the ischemic brain. Their critical supply and possible inhibition in protective therapy. , 1982, Journal of neurosurgery.

[47]  D. Heistad,et al.  Regulation of large cerebral arteries and cerebral microvascular pressure. , 1990, Circulation research.

[48]  B. Matta,et al.  Impaired cerebral autoregulation after mild brain injury. , 1997, Surgical neurology.

[49]  R. Berne,et al.  Longitudinal Gradients in Periarteriolar Oxygen Tension: A Possible Mechanism For the Participation of Oxygen in Local Regulation of Blood Flow , 1970, Circulation research.

[50]  B. Lin,et al.  Detection of Free Radical Activity During Transient Global Ischemia and Recirculation: Effects of Intraischemic Brain Temperature Modulation , 1995, Journal of neurochemistry.

[51]  T. Yoshimine,et al.  Cellular expression of inducible nitric oxide synthase following rat cortical incision and its suppression by hydroxyl radical scavenger, 1,2-bis(nicotinamido)propane , 1998, Neuroscience Research.

[52]  R. Berne,et al.  Brain Interstitial Adenosine and Sagittal Sinus Blood Flow during Systemic Hypotension in Piglet , 1988, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[53]  B. Siesjö,et al.  Cerebral energy reserves after prolonged hypoxia and ischemia. , 1973, Archives of neurology.

[54]  S. Vannucci,et al.  Glucose transporter proteins in brain: Delivery of glucose to neurons and glia , 1997, Glia.

[55]  G. Fiskum,et al.  Bcl-2 and Ca(2+)-mediated mitochondrial dysfunction in neural cell death. , 1999, Biochemical Society symposium.

[56]  B. Siesjö Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment. , 1992, Journal of neurosurgery.

[57]  G. Schneider,et al.  Monitoring of cerebral oxygenation in patients with severe head injuries: brain tissue PO2 versus jugular vein oxygen saturation. , 1996, Journal of neurosurgery.

[58]  W. Heiss,et al.  Cortical neuronal function during ischemia. Effects of occlusion of one middle cerebral artery on single-unit activity in cats. , 1976, Archives of neurology.

[59]  Robert G. Shulman,et al.  Energy on Demand , 1999, Science.

[60]  J. Severinghaus,et al.  The influence of temperature and pH on the dissociation curve of oxyhemoglobin of human blood. , 1965, Scandinavian journal of clinical and laboratory investigation.

[61]  M Uzura,et al.  Extracellular lactate and glucose alterations in the brain after head injury measured by microdialysis. , 1999, Critical care medicine.

[62]  S. Moncada,et al.  Nitric oxide: physiology, pathophysiology, and pharmacology. , 1991, Pharmacological reviews.

[63]  P. W. Hochachka,et al.  Protons and anaerobiosis. , 1983, Science.

[64]  D. Bredt Endogenous nitric oxide synthesis: biological functions and pathophysiology. , 1999, Free radical research.

[65]  R. Busto,et al.  Lipid Peroxidation In Vivo Induced by Reversible Global Ischemia in Rat Brain , 1984, Journal of neurochemistry.

[66]  D. Heistad,et al.  Factors involved in the physiological regulation of the cerebral circulation. , 1984, Reviews of physiology, biochemistry and pharmacology.

[67]  A. Vercesi,et al.  Mitochondrial damage induced by conditions of oxidative stress. , 1999, Free radical biology & medicine.

[68]  M. Ross,et al.  Inducible nitric oxide synthase expression in human cerebral infarcts , 1999, Acta Neuropathologica.

[69]  C. Leffler,et al.  Prostanoids and pial arteriolar diameter in hypotensive newborn pigs. , 1987, The American journal of physiology.

[70]  C. Portera-Cailliau,et al.  Non‐NMDA and NMDA receptor‐mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: Further evidence for an apoptosis‐necrosis continuum , 1997, The Journal of comparative neurology.

[71]  M. Moskowitz,et al.  Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression. , 1996, The American journal of physiology.

[72]  G. Fiskum Mitochondrial participation in ischemic and traumatic neural cell death. , 2000, Journal of neurotrauma.

[73]  C. Lee,et al.  Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. , 1997, Journal of neurotrauma.

[74]  M. Moskowitz,et al.  L-NNA-sensitive regional cerebral blood flow augmentation during hypercapnia in type III NOS mutant mice. , 1996, The American journal of physiology.

[75]  K. Engelborghs,et al.  Impaired autoregulation of cerebral blood flow in an experimental model of traumatic brain injury. , 2000, Journal of neurotrauma.

[76]  P. Chan,et al.  Free radical pathways in CNS injury. , 2000, Journal of neurotrauma.

[77]  C. Robertson,et al.  The consequences of traumatic brain injury on cerebral blood flow and autoregulation: a review. , 1999, Clinical and experimental hypertension.

[78]  Wolfgang Walz,et al.  Lactate production and release in cultured astrocytes , 1988, Neuroscience Letters.

[79]  T. I. Tøosnnessen Biological basis for PCO2 as a detector of ischemia , 1997 .

[80]  M. Reivich,et al.  Effects of hypoxia and normocarbia on cerebral blood flow and metabolism in conscious man. , 1967, Journal of applied physiology.

[81]  M. Jacquin,et al.  Calcium ionophores can induce either apoptosis or necrosis in cultured cortical neurons , 1999, Neuroscience.

[82]  A. Hudetz,et al.  Neuronal NOS-derived NO plays permissive role in cerebral blood flow response to hypercapnia. , 1997, The American journal of physiology.

[83]  L Manzo,et al.  Neuronal cell death: a demise with different shapes. , 1999, Trends in pharmacological sciences.

[84]  Simon C Watkins,et al.  Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice , 1999 .

[85]  G. Gores,et al.  Protection by acidotic pH against anoxic cell killing in perfused rat liver: evidence for a pH paradox , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[86]  T. Mathiesen,et al.  Temporal profiles and cellular sources of three nitric oxide synthase isoforms in the brain after experimental contusion. , 2000, Neurosurgery.

[87]  H. Kontos,et al.  Oxygen radicals in CNS damage. , 1989, Chemico-biological interactions.

[88]  R. Busto,et al.  Astrocytes protect cultured neurons from degeneration induced by anoxia , 1987, Brain Research.

[89]  J Astrup,et al.  Oxygen and glucose consumption related to Na+-K+ transport in canine brain. , 1981, Stroke.

[90]  Barry Halliwell,et al.  Reactive Oxygen Species and the Central Nervous System , 1992, Journal of neurochemistry.

[91]  T A Gennarelli,et al.  Cerebral blood flow and metabolism in comatose patients with acute head injury. Relationship to intracranial hypertension. , 1984, Journal of neurosurgery.

[92]  Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography , 1992 .

[93]  A. Marmarou,et al.  Functional compartmentalization of energy production in neural tissue , 1992, Brain Research.

[94]  A Krogh,et al.  The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue , 1919, The Journal of physiology.

[95]  Patti,et al.  Impaired cerebral mitochondrial function after traumatic brain injury in humans. , 2000, Journal of neurosurgery.

[96]  C. Petito,et al.  Light and Electron Microscopic Evaluation of Hydrogen Ion-Induced Brain Necrosis , 1987, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[97]  R. Radi,et al.  Inhibition of mitochondrial electron transport by peroxynitrite. , 1994, Archives of biochemistry and biophysics.

[98]  A. Brawanski,et al.  Moderate hypothermia in patients with severe head injury: cerebral and extracerebral effects. , 1996, Journal of neurosurgery.

[99]  J. LaManna,et al.  Regional differences in metabolism and intracellular pH in response to moderate hypoxia. , 1997, Advances in experimental medicine and biology.

[100]  D. Choi,et al.  Neuronal apoptosis after CNS injury: the roles of glutamate and calcium. , 2000, Journal of neurotrauma.

[101]  S. Snyder,et al.  Possible Origins and Distribution of Immunoreactive Nitric Oxide Synthase-Containing Nerve Fibers in Cerebral Arteries , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[102]  W. Young,et al.  Intracarotid infusion of the nitric oxide synthase inhibitor, L-NMMA, modestly decreases cerebral blood flow in human subjects. , 2000, Anesthesiology.

[103]  Richard P. White,et al.  Nitric oxide synthase inhibition in humans reduces cerebral blood flow but not the hyperemic response to hypercapnia. , 1998, Stroke.

[104]  D. Choi,et al.  Neuroprotective effects of glutamate antagonists and extracellular acidity. , 1993, Science.

[105]  J. LaManna,et al.  Intracellular pH in rat brain in vivo and in brain slices. , 1992, Canadian journal of physiology and pharmacology.

[106]  A. Marmarou,et al.  Changes of cerebral energy metabolism and lipid peroxidation in rats leading to mitochondrial dysfunction after diffuse brain injury. , 1999, Journal of neurotrauma.

[107]  F. Plum,et al.  Journal of Cerebral Blood Flow and Metabolism Hydrogen Ions Kill Brain at Concentrations Reached in Ischemia , 2022 .

[108]  Y. Tsujimoto,et al.  Intracellular ATP levels determine cell death fate by apoptosis or necrosis. , 1997, Cancer research.

[109]  S. Choi,et al.  Thresholds for cerebral ischemia after severe head injury: relationship with late CT findings and outcome. , 1996, Journal of neurotrauma.

[110]  G. Böhme,et al.  Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury , 1999, British journal of pharmacology.

[111]  R. Ojemann,et al.  Thresholds of focal cerebral ischemia in awake monkeys. , 1981, Journal of neurosurgery.

[112]  D. Busija,et al.  Cerebral Ischemia/Reperfusion Increases Endothelial Nitric Oxide Synthase Levels by An Indomethacin-Sensitive Mechanism , 1998, Journal of Cerebral Blood Flow and Metabolism.

[113]  R. Busto,et al.  Glutamate Release and Free Radical Production Following Brain Injury: Effects of Posttraumatic Hypothermia , 1995, Journal of neurochemistry.

[114]  J. Povlishock,et al.  Mechanism of cerebral arteriolar abnormalities after acute hypertension. , 1981, The American journal of physiology.

[115]  Robert E. Anderson,et al.  Is intracellular brain pH a dependent factor in NOS inhibition during focal cerebral ischemia? , 2000, Brain Research.