A review of progress in understanding the pathophysiology and treatment of brain edema.

OBJECT Brain edema resulting from traumatic brain injury (TBI) or ischemia if uncontrolled exhausts volume reserve and leads to raised intracranial pressure and brain herniation. The basic types of edema--vasogenic and cytotoxic--were classified 50 years ago, and their definitions remain intact. METHODS In this paper the author provides a review of progress over the past several decades in understanding the pathophysiology of the edematous process and the success and failures of treatment. Recent progress focused on those manuscripts that were published within the past 5 years. RESULTS Perhaps the most exciting new findings that speak to both the control of production and resolution of edema in both trauma and ischemia are the recent studies that have focused on the newly described "water channels" or aquaporins. Other important findings relate to the predominance of cellular edema in TBI. CONCLUSIONS Significant new findings have been made in understanding the pathophysiology of brain edema; however, less progress has been made in treatment. Aquaporin water channels offer hope for modulating and abating the devastating effects of fulminating brain edema in trauma and stroke.

[1]  P. Agre,et al.  Specialized Membrane Domains for Water Transport in Glial Cells: High-Resolution Immunogold Cytochemistry of Aquaporin-4 in Rat Brain , 1997, The Journal of Neuroscience.

[2]  S. Karpiak,et al.  Temporal changes in edema, Na+, K+, and Ca++ in focal cortical stroke: GM1 ganglioside reduces ischemic injury , 1991, Journal of neuroscience research.

[3]  Liang Zhu,et al.  Cooling and Rewarming for Brain Ischemia or Injury: Theoretical Analysis , 2004, Annals of Biomedical Engineering.

[4]  H. Heitsch Bradykinin B2 receptor as a potential therapeutic target. , 2000, Drug News and Perspectives.

[5]  D. Ribatti,et al.  Severe alterations of endothelial and glial cells in the blood‐brain barrier of dystrophic mdx mice , 2003, Glia.

[6]  J. Frøkiaer,et al.  Immunolocalization of AQP9 in liver, epididymis, testis, spleen, and brain. , 2000, Biochemical and biophysical research communications.

[7]  R. Bullock,et al.  High extracellular potassium and its correlates after severe head injury: relationship to high intracranial pressure. , 2000, Neurosurgical focus.

[8]  C. Eynon,et al.  High dose methylprednisolone in the immediate management of acute, blunt spinal cord injury: what is the current practice in emergency departments, spinal units, and neurosurgical units in the UK? , 2006, Emergency Medicine Journal.

[9]  A Büki,et al.  Cytochrome c Release and Caspase Activation in Traumatic Axonal Injury , 2000, The Journal of Neuroscience.

[10]  H. Reulen,et al.  Clearance of edema fluid into cerebrospinal fluid. A mechanism for resolution of vasogenic brain edema. , 1978, Journal of neurosurgery.

[11]  C. Davies,et al.  Oedema and glial cell involvement in the aged mouse brain after permanent focal ischaemia , 2000, Neuropathology and applied neurobiology.

[12]  R. Keep,et al.  Edema from intracerebral hemorrhage: the role of thrombin. , 1996, Journal of neurosurgery.

[13]  T. Kuroiwa,et al.  Evolution of energy failure after repeated cerebral ischemia in gerbils. , 2000, Acta neurochirurgica. Supplement.

[14]  U. V. von Andrian,et al.  Intravenous glutamate enhances edema formation after a freezing lesion. , 1990, Advances in neurology.

[15]  J. Povlishock,et al.  Uncomplicated Rapid Posthypothermic Rewarming Alters Cerebrovascular Responsiveness , 2004, Stroke.

[16]  Y. Gasche,et al.  Physiopathologie de la barrière hématoencéphalique et œdème cérébral d’origine ischémique , 2003 .

[17]  O. Zaidat,et al.  Cervicomedullary junction compression caused by vertebral artery dolichoectasia and requiring surgical treatment. Case report. , 2002, Journal of neurosurgery.

[18]  I. Klatzo,et al.  Presidental address. Neuropathological aspects of brain edema. , 1967, Journal of neuropathology and experimental neurology.

[19]  A. Marmarou,et al.  Characterization of edema by diffusion-weighted imaging in experimental traumatic brain injury. , 1996, Journal of neurosurgery.

[20]  H. Reulen,et al.  Clearance of edema fluid into cerebrospinal fluid , 1983 .

[21]  D. Spencer,et al.  Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Y. Katayama,et al.  Antioxidant, OPC-14117, attenuates edema formation and behavioral deficits following cortical contusion in rats. , 1997, Acta neurochirurgica. Supplement.

[23]  G. Rosenberg,et al.  Ischemic brain edema. , 1999, Progress in cardiovascular diseases.

[24]  Andreas Engel,et al.  Structural determinants of water permeation through aquaporin-1 , 2000, Nature.

[25]  A. Gunn,et al.  Key neuroprotective role for endogenous adenosine A1 receptor activation during asphyxia in the fetal sheep. , 2003, Stroke.

[26]  D. Jimenez,et al.  Recombinant activated factor VII for cerebral injury-induced coagulopathy in pediatric patients. Report of three cases and review of the literature. , 2003, Journal of neurosurgery.

[27]  M. Rosner,et al.  Significance of intracranial hypertension in severe head injury. , 1977, Journal of neurosurgery.

[28]  Vikas Kumar,et al.  Effects of chloride flux modulators in an in vitro model of brain edema formation , 2006, Brain Research.

[29]  G. Boulard,et al.  Osmolarité plasmatique et barrière hématoencéphalique : l’œdème cérébral osmotique ☆ , 2003 .

[30]  A. Marmarou,et al.  Modulation of AQP4 expression by the protein kinase C activator, phorbol myristate acetate, decreases ischemia-induced brain edema. , 2006, Acta neurochirurgica. Supplement.

[31]  W. Poon,et al.  Impact of Experimental Acute Hyponatremia on Severe Traumatic Brain Injury in Rats: Influences on Injuries, Permeability of Blood–Brain Barrier, Ultrastructural Features, and Aquaporin-4 Expression , 2002, Experimental Neurology.

[32]  C. Lee,et al.  Amelioration of mitochondrial function by a novel antioxidant U-101033E following traumatic brain injury in rats. , 1997, Journal of neurotrauma.

[33]  Guo-yi Gao,et al.  Effect of Long-Term Mild Hypothermia or Short-Term Mild Hypothermia on Outcome of Patients with Severe Traumatic Brain Injury , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[34]  J. Povlishock,et al.  Traumatically induced altered membrane permeability: its relationship to traumatically induced reactive axonal change. , 1994, Journal of neurotrauma.

[35]  Y. Katayama,et al.  Antioxidant, OPC-14117, attenuates edema formation, and subsequent tissue damage following cortical contusion in rats. , 1998, Acta neurochirurgica. Supplement.

[36]  R. Dempsey,et al.  Inhibition of Na+–K+–Cl− cotransporter during focal cerebral ischemia decreases edema and neuronal damage , 2003, Brain Research.

[37]  J. Simard,et al.  Cell Swelling and a Nonselective Cation Channel Regulated by Internal Ca2+ and ATP in Native Reactive Astrocytes from Adult Rat Brain , 2001, The Journal of Neuroscience.

[38]  M. Papadopoulos,et al.  Aquaporins in the Central Nervous System , 2007 .

[39]  A. Marmarou,et al.  Biphasic pathophysiological response of vasogenic and cellular edema in traumatic brain swelling. , 1997, Acta neurochirurgica. Supplement.

[40]  M. Mirski,et al.  Glucocorticoid therapy in neurologic critical care , 2005, Critical care medicine.

[41]  I. Hwang,et al.  Changes in Na+–K+–Cl− cotransporter immunoreactivity in the gerbil hippocampus following transient ischemia , 2002, Neuroscience Research.

[42]  Xin Lin,et al.  Study on therapeutic mechanism and clinical effect of mild hypothermia in patients with severe head injury. , 2003, Surgical neurology.

[43]  J. Simard,et al.  Suppression of ammonia‐induced astrocyte swelling by cyclosporin A , 2003, Journal of neuroscience research.

[44]  A. Marmarou,et al.  An immunocytochemical study of protein clearance in brain infusion edema , 2004, Acta Neuropathologica.

[45]  Ole P. Ottersen,et al.  Delayed K+ clearance associated with aquaporin-4 mislocalization: Phenotypic defects in brains of α-syntrophin-null mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[46]  G. Manley,et al.  Role of water channels in fluid transport studied by phenotype analysis of aquaporin knockout mice , 2000, Experimental physiology.

[47]  B. Wilffert,et al.  Effects of the sodium channel blocker tetrodotoxin (TTX) on cellular ion homeostasis in rat brain subjected to complete ischemia , 1994, Brain Research.

[48]  U. Heinemann Excitatory amino acids and epilepsy-induced changes in extracellular space size. , 1986, Advances in experimental medicine and biology.

[49]  G. Skowronski Therapeutic hypothermia after cardiac arrest--not so fast. , 2005, Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine.

[50]  M. Bracken Methylprednisolone and spinal cord injury. , 2002, Journal of neurosurgery.

[51]  B. Thompson,et al.  Recombinant Activated Factor VII for the Rapid Correction of Coagulopathy in Nonhemophilic Neurosurgical Patients , 2003, Neurosurgery.

[52]  A. Marmarou,et al.  Clearance of brain edema and macromolecules through the cortical extracellular space. , 1992, Journal of neurosurgery.

[53]  R. Dart The National Traumatic Coma Data Bank, Part 2: Patients who talk and deteriorate: Implications for treatment: Marshall LF, Toole BM, Bowers SA J Neurosurg 59:285–288 Aug 1983 , 1984 .

[54]  Betz Al Transport of ions across the blood-brain barrier. , 1986 .

[55]  A. Gunn,et al.  Cerebral Hypothermia Is Not Neuroprotective When Started after Postischemic Seizures in Fetal Sheep , 1999, Pediatric Research.

[56]  J. Cano,et al.  Blood–brain barrier disruption highly induces aquaporin‐4 mRNA and protein in perivascular and parenchymal astrocytes: Protective effect by estradiol treatment in ovariectomized animals , 2005, Journal of neuroscience research.

[57]  A. Betz Transport of ions across the blood-brain barrier. , 1986, Federation proceedings.

[58]  R. Keep,et al.  Mechanisms of brain injury after intracerebral haemorrhage , 2006, The Lancet Neurology.

[59]  R. Bullock,et al.  Cytotoxic edema is independent of NMDA ion channel activation following middle cerebral artery occlusion (MCAO). An in vivo autoradiographic and MRI study , 2003, Neurological research.

[60]  S. Tisherman Hypothermia and injury , 2004, Current opinion in critical care.

[61]  A. Rabinstein Treatment of Cerebral Edema , 2006, The neurologist.

[62]  D. Marion Moderate hypothermia in severe head injuries: the present and the future. , 2002, Current opinion in critical care.

[63]  M. Wendland,et al.  Evolution of brain injury after transient middle cerebral artery occlusion in neonatal rats. , 2000, Stroke.

[64]  L. Kappelle,et al.  Complications of Acute Ischaemic Stroke , 1998, Cerebrovascular Diseases.

[65]  A. Marmarou,et al.  Contribution of vasogenic and cellular edema to traumatic brain swelling measured by diffusion-weighted imaging. , 1997, Journal of neurosurgery.

[66]  U. Ito,et al.  Brain Edema During Ischemia and After Restoration of Blood Flow Measurement of Water, Sodium, Potassium Content and Plasma Protein Permeability , 1979, Stroke.

[67]  H. Eisenberg,et al.  Initial CT findings in 753 patients with severe head injury. A report from the NIH Traumatic Coma Data Bank. , 1990, Journal of neurosurgery.

[68]  David G. Norris,et al.  Evolution of Regional Changes in Apparent Diffusion Coefficient during Focal Ischemia of Rat Brain: The Relationship of Quantitative Diffusion NMR Imaging to Reduction in Cerebral Blood Flow and Metabolic Disturbances , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[69]  J. Hahn Cerebral edema and neurointensive care. , 1980, Pediatric clinics of North America.

[70]  H. Wiśniewski,et al.  Ultrastructural observations on the transvascular route of protein removal in vasogenic brain edema , 2004, Acta Neuropathologica.

[71]  E. P. Mccutcheon,et al.  Acute traumatic spinal cord injury, 1993-2000A population-based assessment of methylprednisolone administration and hospitalization. , 2004, The Journal of trauma.

[72]  S. Nielsen,et al.  [Aquaporins in cerebral volume regulation and edema formation]. , 2001, Orvosi hetilap.

[73]  Eduardo C. Ayuste,et al.  Does the rate of rewarming from profound hypothermic arrest influence the outcome in a swine model of lethal hemorrhage? , 2006, The Journal of trauma.

[74]  The prognostic value of intracranial pressure monitoring after severe head injuries. , 1979, Acta neurochirurgica. Supplementum.

[75]  M A Foulkes,et al.  Diffuse brain swelling in severely head-injured children. A report from the NIH Traumatic Coma Data Bank. , 1992, Journal of neurosurgery.

[76]  D. Pearse,et al.  Methylprednisolone and other confounders to spinal cord injury clinical trials , 2006, Nature Clinical Practice Neurology.

[77]  M. Egnor,et al.  Decompressive craniectomy in pediatric patients with traumatic brain injury with intractable elevated intracranial pressure. , 2006, Journal of pediatric surgery.

[78]  J. Povlishock,et al.  Posttraumatic hypothermia followed by slow rewarming protects the cerebral microcirculation. , 2003, Journal of neurotrauma.

[79]  L. Segadal,et al.  Rewarming from accidental hypothermia by extracorporeal circulation. A retrospective study. , 2001, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[80]  D. Marion,et al.  Hypothermia on admission in patients with severe brain injury. , 2002, Journal of neurotrauma.

[81]  H. Reulen,et al.  Role of pressure gradients and bulk flow in dynamics of vasogenic brain edema. , 1977, Journal of neurosurgery.

[82]  I. Loubinoux,et al.  Delayed progression of cytotoxic oedema in focal cerebral ischemia after treatment with a torasemide derivative: a diffusion-weighted magnetic resonance imaging study , 1996, Neuroscience Letters.

[83]  M. Papadopoulos,et al.  Aquaporin water channels and brain edema. , 2002, The Mount Sinai journal of medicine, New York.

[84]  A. Marmarou,et al.  Modulation of aquaporin-4 water transport in a model of TBI. , 2003, Acta neurochirurgica. Supplement.

[85]  Y. Katayama,et al.  Oedema fluid formation within contused brain tissue as a cause of medically uncontrollable elevation of intracranial pressure: the role of surgical therapy. , 1990, Acta neurochirurgica. Supplementum.

[86]  M. Wahl,et al.  Mediators of cerebral edema. , 1999, Advances in experimental medicine and biology.

[87]  M. Thoresen,et al.  Hypothermic neuroprotection , 2006 .

[88]  N. Lassen Pathophysiology of Brain Ischemia as It Relates to the Therapy of Acute Ischemic Stroke , 1990, Clinical neuropharmacology.

[89]  H. Kimelberg,et al.  Brain anti-cytoxic edema agents. , 1990, Progress in clinical and biological research.

[90]  S. Lewington,et al.  Corticosteroids for acute ischaemic stroke. , 2002, The Cochrane database of systematic reviews.

[91]  Medical management of severe head injury: present and future. , 1995, New horizons.

[92]  Vespa Pm Slow rewarming: a cool model of posttraumatic hypothermia. , 2001 .

[93]  V. Vainionpää,et al.  Topical head cooling during rewarming after experimental hypothermic circulatory arrest. , 2003, The Annals of thoracic surgery.

[94]  A. Betz,et al.  Blood-brain barrier sodium transport limits development of brain edema during partial ischemia in gerbils. , 1989, Stroke.

[95]  C. Bonilla,et al.  Early administration of methylprednisolone decreases apoptotic cell death after spinal cord injury. , 2006, Histology and histopathology.

[96]  Jean-Pierre Boissel,et al.  A mathematical model of ion movements in grey matter during a stroke. , 2006, Journal of theoretical biology.

[97]  A. Betz,et al.  Blood-to-brain sodium transport in ischemic brain edema. , 1990, Advances in neurology.

[98]  A. Sharma,et al.  Comparison of methylprednisolone with dexamethasone in treatment of acute spinal injury in rats. , 2004, Indian journal of experimental biology.

[99]  M. C. Papadopoulos,et al.  Molecular mechanisms of brain tumor edema , 2004, Neuroscience.

[100]  O. Nilsson,et al.  Methylprednisolone treatment in acute spinal cord injury: the myth challenged through a structured analysis of published literature. , 2006, The spine journal : official journal of the North American Spine Society.

[101]  O. P. Ottersen,et al.  Anchoring of aquaporin-4 in brain: Molecular mechanisms and implications for the physiology and pathophysiology of water transport , 2004, Neuroscience.

[102]  M. Levitt Effect of intracranial pressure monitoring and aggressive treatment on mortality in severe head injury: Saul TG, Ducker TB J Neurosurg 56:498–503 Apr 1982 , 1983 .

[103]  A. W. Zydlewski,et al.  Hypothermia-induced hypokalemia. , 1998, Military medicine.

[104]  K. Kiening,et al.  Edema and brain trauma , 2004, Neuroscience.

[105]  P. Zsigmond,et al.  Improved brain protection at decompressive craniectomy – a new method using Palacos⌖ R-40 (methylmethacrylate) , 2005, Acta Neurochirurgica.

[106]  G. Mies,et al.  Role of neuroexcitation in development of blood-brain barrier and oedematous changes following cerebral ischaemia and traumatic brain injury. , 1990, Acta neurochirurgica. Supplementum.

[107]  J A Maldjian,et al.  Radiologic estimation of hematoma volume in intracerebral hemorrhage trial by CT scan. , 2006, AJNR. American journal of neuroradiology.

[108]  L. Nagy,et al.  Vascular tunnel creation to improve the efficacy of decompressive craniotomy in post-traumatic cerebral edema and ischemic stroke. , 2002, Surgical neurology.

[109]  T. Nagaoka,et al.  Different apparent diffusion coefficient: water content correlations of gray and white matter during early ischemia. , 1998, Stroke.

[110]  Diffusion-weighted MRI and ADC mapping in FK506 neurotoxicity. , 2003, The British journal of radiology.

[111]  N. Schor,et al.  Whole-Body Hypothermia for Neonates With Hypoxic–Ischemic Encephalopathy , 2007 .

[112]  T. Milhorat,et al.  Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. , 1977, Experimental eye research.

[113]  Pierre J Magistretti,et al.  Aquaporins in Brain: Distribution, Physiology, and Pathophysiology , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[114]  W. Qiu,et al.  Therapeutic effect of mild hypothermia on severe traumatic head injury. , 2005, Chinese journal of traumatology = Zhonghua chuang shang za zhi.

[115]  W. Liu,et al.  Effects of Selective Brain Cooling in Patients with Severe Traumatic Brain Injury: A Preliminary Study , 2006, The Journal of international medical research.

[116]  A. Heimann,et al.  Spreading depression induces permanent cell swelling under penumbra conditions. , 2000, Acta neurochirurgica. Supplement.

[117]  T. Nagaoka,et al.  Correlations between the apparent diffusion coefficient, water content, and ultrastructure after induction of vasogenic brain edema in cats. , 1999, Journal of neurosurgery.

[118]  N. Yamamoto,et al.  Differential regulation of aquaporin expression in astrocytes by protein kinase C. , 2001, Brain research. Molecular brain research.

[119]  G. Manley,et al.  Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke , 2000, Nature Medicine.

[120]  R. Sarabia,et al.  Cerebral hemisphere swelling in severe head injury patients. , 1988, Acta neurochirurgica. Supplementum.

[121]  Gerd-Helge Schneider,et al.  Swelling of glial cells in lactacidosis and by glutamate: significance of Cl—-transport , 1993, Brain Research.

[122]  A. Gunn,et al.  Therapeutic hypothermia: from lab to NICU , 2005, Journal of perinatal medicine.

[123]  A. Unterberg,et al.  The Kallikrein-Kinin-System as Mediator in Vasogenic Brain Oedema* , 2009 .

[124]  C. Granziera,et al.  Astrocyte-Specific Expression of Aquaporin-9 in Mouse Brain is Increased after Transient Focal Cerebral Ischemia , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[125]  T. Nagaoka,et al.  Time course of trace of diffusion tensor [Trace(D)] and histology in brain edema. , 2000, Acta neurochirurgica. Supplement.

[126]  H. Levin,et al.  Intracranial hypertension in relation to memory functioning during the first year after severe head injury. , 1991, Neurosurgery.

[127]  M. Mariscalco,et al.  Considering the use of induced hypothermia in a pediatric patient with traumatic brain injury: A critical appraisal of two meta-analyses , 2006, Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

[128]  C. Vargas,et al.  Differential Upregulation of Aquaporin-4 mRNA Expression in Reactive Astrocytes after Brain Injury: Potential Role in Brain Edema , 1999, Neurobiology of Disease.

[129]  A. Marmarou,et al.  The importance of protein content in the Oedema fluid for the resolution of brain Oedema , 1989, Acta Neurochirurgica.

[130]  K. Ohno,et al.  Effect of Steroid on Ischemic Brain Edema: Analysis of Cytotoxic and Vasogenic Edema Occurring During Ischemia and After Restoration of Blood Flow , 1980, Stroke.

[131]  Dandan Sun,et al.  The role of Na–K–Cl co–transporter in cerebral ischemia , 2005, Neurological research.

[132]  G. Campbell,et al.  Role of extracellular proteins in the dynamics of vasogenic brain edema , 2004, Acta Neuropathologica.

[133]  M. Wolman,et al.  Evaluation of the dye-protein tracers in pathophysiology of the blood-brain barrier , 2004, Acta Neuropathologica.

[134]  R. Keep,et al.  Blood—Brain Barrier Permeability and Brain Concentration of Sodium, Potassium, and Chloride during Focal Ischemia , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[135]  E. Preston,et al.  A two-hour window for hypothermic modulation of early events that impact delayed opening of the rat blood-brain barrier after ischemia , 2004, Acta Neuropathologica.

[136]  A. Unterberg,et al.  The kallikrein-kinin system as mediator in vasogenic brain edema. Part 1: Cerebral exposure to bradykinin and plasma. , 1984, Journal of neurosurgery.

[137]  A. Pau,et al.  Cerebral water and electrolytes in experimental ischaemia following omental transposition to the brain , 1980, Acta Neurochirurgica.

[138]  T. Holford,et al.  Neurological and functional status 1 year after acute spinal cord injury: estimates of functional recovery in National Acute Spinal Cord Injury Study II from results modeled in National Acute Spinal Cord Injury Study III. , 2002, Journal of neurosurgery.

[139]  B. Nico,et al.  The role of aquaporin-4 in the blood–brain barrier development and integrity: Studies in animal and cell culture models , 2004, Neuroscience.

[140]  W. Poon,et al.  Heterogeneous responses of aquaporin-4 in oedema formation in a replicated severe traumatic brain injury model in rats , 2001, Neuroscience Letters.

[141]  R. Dempsey,et al.  Na+-K+-Cl− Cotransporter in Rat Focal Cerebral Ischemia , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[142]  A. Kirkpatrick,et al.  Hypothermia and the trauma patient. , 1999, Canadian journal of surgery. Journal canadien de chirurgie.

[143]  A. Unterberg,et al.  Brain edema factors: current state with particular reference to plasma constituents and glutamate. , 1980, Advances in neurology.

[144]  S. Sasaki,et al.  Transient Body Fluid Accumulation and Enhanced NKCC2 Expression in Gerbils with Brain Infarction , 2006, Nephron Physiology.

[145]  K. Okuyama,et al.  A novel Na+ and Ca2+ channel blocker, T-477, prevents brain edema following microsphere-induced permanent occlusion of cerebral arterioles in rats. , 1999, Japanese Journal of Pharmacology.

[146]  A. Marmarou,et al.  Post-traumatic selective stimulation of glycolysis , 1992, Brain Research.

[147]  M. Shigemori,et al.  Effect of hypothermia on serum electrolyte, inflammation, coagulation, and nutritional parameters in patients with severe traumatic brain injury , 2004, Neurocritical care.

[148]  C. Spiss,et al.  Therapeutic hypothermia. , 2003, Best practice & research. Clinical anaesthesiology.

[149]  M. C. Papadopoulos,et al.  New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice , 2004, Neuroscience.

[150]  P. Kochanek,et al.  Induction of Profound Hypothermia for Emergency Preservation and Resuscitation Allows Intact Survival After Cardiac Arrest Resulting From Prolonged Lethal Hemorrhage and Trauma in Dogs , 2006, Circulation.

[151]  E. Füchtbauer,et al.  Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[152]  C. Gordon,et al.  Effect of murine recombinant interleukin-1 on brain oedema in the rat. , 1990, Acta neurochirurgica. Supplementum.

[153]  刘伟国,et al.  Thrombocytopenia after therapeutic hypothermia in severe traumatic brain injury , 2006 .

[154]  A. Betz,et al.  Contributions of ions and albumin to the formation and resolution of ischemic brain edema. , 1993, Journal of neurosurgery.

[155]  H. Levin,et al.  Phase II Clinical Trial of Moderate Hypothermia after Severe Traumatic Brain Injury in Children , 2005, Neurosurgery.

[156]  A. Unterberg,et al.  Mediators of vascular and parenchymal mechanisms in secondary brain damage. , 1993, Acta neurochirurgica. Supplementum.

[157]  J. Tsuruda,et al.  Cytotoxic brain edema: assessment with diffusion-weighted MR imaging. , 1992, Radiology.

[158]  M. Hickey,et al.  Nitric oxide synthase inhibitor, nitro‐iminoethyl‐L‐ornithine, reduces ischemia‐reperfusion injury in rabbit skeletal muscle , 1994, Microsurgery.

[159]  R G Grossman,et al.  The National Traumatic Coma Data Bank. Part 1: Design, purpose, goals, and results. , 1983, Journal of neurosurgery.

[160]  E. Nagelhus,et al.  Aquaporin-4 in the central nervous system: Cellular and subcellular distribution and coexpression with KIR4.1 , 2004, Neuroscience.

[161]  I. Klatzo,et al.  Resolution of vasogenic brain edema. , 1980, Advances in neurology.

[162]  J T Hoff,et al.  Intracerebral infusion of thrombin as a cause of brain edema. , 1995, Journal of neurosurgery.

[163]  K. Hossmann Non-invasive imaging methods for the characterization of the pathophysiology of brain ischemia. , 2003, Acta neurochirurgica. Supplement.

[164]  N. Plesnila,et al.  Contribution of Anion Transporters to the Acidosis‐Induced Swelling and Intracellular Acidification of Glial Cells , 2000, Journal of neurochemistry.

[165]  G. Prado,et al.  Cochrane Report: A Systematic Review of Mannitol Therapy for Acute Ischemic Stroke and Cerebral Parenchymal Hemorrhage , 2000, Stroke.

[166]  Anthony Marmarou,et al.  Predominance of cellular edema in traumatic brain swelling in patients with severe head injuries. , 2006, Journal of neurosurgery.

[167]  B. M. Toole,et al.  The National Traumatic Coma Data Bank. Part 2: Patients who talk and deteriorate: implications for treatment. , 1983, Journal of neurosurgery.

[168]  S. Rehncrona,et al.  Brain Lactic Acidosis and Ischemic Cell Damage: 2. Histopathology , 1981, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[169]  A. Mendelowitsch,et al.  EFFECTS OF ISOFLURANE ON GLUTAMATE AND TAURINE RELEASES, BRAIN SWELLING AND INJURY DURING TRANSIENT ISCHEMIA AND REPERFUSION , 2006, The International journal of neuroscience.

[170]  T. Moriya,et al.  Rewarming following accidental hypothermia in patients with acute subdural hematoma: case report. , 2006, Acta neurochirurgica. Supplement.

[171]  Ole Petter Ottersen,et al.  An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[172]  J. Povlishock,et al.  Effects of delayed, prolonged hypothermia on the pial vascular response after traumatic brain injury in rats. , 2003, Journal of neurosurgery.

[173]  T. Ducker,et al.  Effect of intracranial pressure monitoring and aggressive treatment on mortality in severe head injury. , 1982, Journal of neurosurgery.

[174]  J. Suárez Tratamiento del edema cerebral agudo , 2001 .

[175]  A. Marmarou,et al.  Magnetic resonance imaging-monitored acute blood-brain barrier changes in experimental traumatic brain injury. , 1996, Journal of neurosurgery.

[176]  A. Marmarou,et al.  Enhancement of infusion-induced brain edema by mediator compounds. , 1990, Advances in neurology.

[177]  David Moher,et al.  Prolonged therapeutic hypothermia after traumatic brain injury in adults: a systematic review. , 2003, JAMA.

[178]  D. Moher,et al.  Hypothermia Pediatric Head Injury Trial: The Value of a Pretrial Clinical Evaluation Phase , 2006, Developmental Neuroscience.

[179]  Y. Olsson,et al.  Regional Changes in Interstitial K+ and Ca2+ Levels following Cortical Compression Contusion Trauma in Rats , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[180]  K. Hatakeyama,et al.  Cloning of a new aquaporin (AQP10) abundantly expressed in duodenum and jejunum. , 2001, Biochemical and biophysical research communications.

[181]  G. Manley,et al.  Aquaporin‐4 facilitates reabsorption of excess fluid in vasogenic brain edema , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[182]  K. Takagishi,et al.  Effects of the Second National Acute Spinal Cord Injury Study of High-Dose Methylprednisolone Therapy on Acute Cervical Spinal Cord Injury–Results in Spinal Injuries Center , 2006, Spine.

[183]  Manfred Blobner,et al.  Neurologic outcome after cardiopulmonary bypass with deep hypothermic circulatory arrest in rats: description of a new model. , 2006, The Journal of thoracic and cardiovascular surgery.

[184]  K. Takakura,et al.  Ischemic brain edema following occlusion of the middle cerebral artery in the rat. I: The time courses of the brain water, sodium and potassium contents and blood-brain barrier permeability to 125I-albumin. , 1985, Stroke.

[185]  A. Marmarou,et al.  Protective effect of the V1a receptor antagonist SR49059 on brain edema formation following middle cerebral artery occlusion in the rat. , 2006, Acta neurochirurgica. Supplement.