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. 2010 Jan;7(1):91–99. doi: 10.1016/j.nurt.2009.10.014

Use of magnesium in traumatic brain injury

Ananda P Sen 1,✉, Anil Gulati 2
PMCID: PMC5084116  PMID: 20129501

Summary

Depletion of magnesium is observed in animal brain and in human blood after brain injury. Treatment with magnesium attenuates the pathological and behavioral changes in rats with brain injury; however, the therapeutic effect of magnesium has not been consistently observed in humans with traumatic brain injury (TBI). Secondary brain insults are observed in patients with brain injury, which adversely affect clinical outcome. Systemic administration studies in rats have shown that magnesium enters the brain; however, inducing hypermagnesemia in humans did not concomitantly increase magnesium levels in the CSF. We hypothesize that the neuroprotective effects of magnesium in TBI patients could be observed by increasing its brain bioavailability with mannitol. Here, we review the role of magnesium in brain injury, preclinical studies in brain injury, clinical safety and efficacy studies in TBI patients, brain bioavailability studies in rat, and pharmacokinetic studies in humans with brain injury. Neurodegeneration after brain injury involves multiple biochemical pathways. Treatment with a single agent has often resulted in poor efficacy at a safe dose or toxicity at a therapeutic dose. A successful neuroprotective therapy needs to be aimed at homeostatic control of these pathways with multiple agents. Other pharmacological agents, such as dexanabinol and progesterone, and physiological interventions, with hypothermia and hyperoxia, have been studied for the treatment of brain injury. Treatment with magnesium and hypothermia has shown favorable outcome in rats with cerebral ischemia. We conclude that coadministration of magnesium and mannitol with pharmacological and physiological agents could be an effective neuroprotective regimen for the treatment of TBI.

Key Words: Traumatic brain injury, magnesium, neuroprotection, hyperoxia, hypothermia

References

  • 1.Temkin NR, Anderson GD, Winn HR, et al. Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol. 2007;6:29–38. doi: 10.1016/S1474-4422(06)70630-5. [DOI] [PubMed] [Google Scholar]
  • 2.Dhandapani SS, Gupta A, Vivekanandhan S, Sharma BS, Mahapatra AK. Randomized controlled trial of magnesium sulphate in severe closed traumatic brain injury. Indian J Neurotrauma. 2008;5:27–33. [Google Scholar]
  • 3.Hallak M, Berman RF, Irtenkauf SM, Evans MI, Cotton DB. Peripheral magnesium sulfate enters the brain and increases the threshold for hippocampal seizures in rats. Am J Obstet Gynecol. 1992;167:1605–1610. doi: 10.1016/0002-9378(92)91749-z. [DOI] [PubMed] [Google Scholar]
  • 4.Hoane MR. Assessment of cognitive function following magnesium therapy in the traumatically injured brain. Magnes Res. 2007;20:229–236. [PubMed] [Google Scholar]
  • 5.Fuchs-Buder T, Tramèr MR, Tassonyi E. Cerebrospinal fluid passage of intravenous magnesium sulfate in neurosurgical patients. J Neurosurg Anesthesiol. 1997;9:324–328. doi: 10.1097/00008506-199710000-00006. [DOI] [PubMed] [Google Scholar]
  • 6.McKee JA, Brewer RP, Macy GE, et al. Analysis of the brain bioavailability of peripherally administered magnesium sulfate: a study in humans with acute brain injury undergoing prolonged induced hypermagnesemia. Crit Care Med. 2005;33:661–666. doi: 10.1097/01.CCM.0000156293.35868.B2. [DOI] [PubMed] [Google Scholar]
  • 7.Thumau GR, Kemp DB, Jarvis A. Cerebrospinal fluid levels of magnesium in patients with preeclampsia after treatment with intravenous magnesium sulfate: a preliminary report. Am J Obstet Gynecol. 1987;157:1435–1438. doi: 10.1016/s0002-9378(87)80239-9. [DOI] [PubMed] [Google Scholar]
  • 8.Stoica B, Byrnes K, Faden AI. Multifunctional drug treatment in neurotrauma. Neurotherapeutics. 2009;6:14–27. doi: 10.1016/j.nurt.2008.10.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Vink R, Nimmo AJ. Multifunctional drugs for head injury. Neurotherapeutics. 2009;6:28–42. doi: 10.1016/j.nurt.2008.10.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Maas AI, Murray G, Henney H, et al. Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 2006;5:38–45. doi: 10.1016/S1474-4422(05)70253-2. [DOI] [PubMed] [Google Scholar]
  • 11.Bouma GJ, Muizelaar JP, Choi SC, Newlon PG, Young HF. Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg. 1991;75:685–693. doi: 10.3171/jns.1991.75.5.0685. [DOI] [PubMed] [Google Scholar]
  • 12.Jenkins LW, Moszynski K, Lyeth BG, et al. Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury. Brain Res. 1989;477:211–224. doi: 10.1016/0006-8993(89)91409-1. [DOI] [PubMed] [Google Scholar]
  • 13.Bergsneider M, Hovda DA, Shalmon E, et al. Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg. 1997;86:241–251. doi: 10.3171/jns.1997.86.2.0241. [DOI] [PubMed] [Google Scholar]
  • 14.Goodman JC, Valadka AB, Gopinath SP, Uzura M, Robertson CS. Extracellular lactate and glucose alterations in the brain after head injury measured by microdialysis. Crit Care Med. 1999;27:1965–1973. doi: 10.1097/00003246-199909000-00041. [DOI] [PubMed] [Google Scholar]
  • 15.Enblad P, Valtysson J, Andersson J, et al. Simultaneous intracerebral microdialysis and positron emission tomography in the detection of ischemia in patients with subarachnoid hemorrhage. J Cereb Blood Flow Metab. 1996;16:637–644. doi: 10.1097/00004647-199607000-00014. [DOI] [PubMed] [Google Scholar]
  • 16.Persson L, Valtysson J, Enblad P, et al. Neurochemical monitoring using intracerebral microdialysis in patients with subarachnoid hemorrhage. J Neurosurg. 1996;84:606–616. doi: 10.3171/jns.1996.84.4.0606. [DOI] [PubMed] [Google Scholar]
  • 17.Stocchetti N, Colombo A, Ortolano F, et al. Time course of intracranial hypertension after traumatic brain injury. J Neurotrauma. 2007;24:1339–1346. doi: 10.1089/neu.2007.0300. [DOI] [PubMed] [Google Scholar]
  • 18.Balestreri M, Czosnyka M, Hutchinson P, et al. Impact of intracranial pressure and cerebral perfusion pressure on severe disability and mortality after head injury. Neurocrit Care. 2006;4:8–13. doi: 10.1385/NCC:4:1:008. [DOI] [PubMed] [Google Scholar]
  • 19.Obrenovitch TP, Urenjak J. Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury? J Neurotrauma. 1997;14:677–698. doi: 10.1089/neu.1997.14.677. [DOI] [PubMed] [Google Scholar]
  • 20.Fiskum G. Mitochondrial participation in ischemic and traumatic neural cell death. J Neurotrauma. 2000;17:843–855. doi: 10.1089/neu.2000.17.843. [DOI] [PubMed] [Google Scholar]
  • 21.Lifshitz J, Friberg H, Neumar RW, et al. Structural and functional damage sustained by mitochondria after traumatic brain injury in the rat: evidence for differentially sensitive populations in the cortex and hippocampus. J Cereb Blood Flow Metab. 2003;23:219–231. doi: 10.1097/00004647-200302000-00009. [DOI] [PubMed] [Google Scholar]
  • 22.van den Heuvel C, Vink R. The role of magnesium in traumatic brain injury. Clin Calcium. 2004;14:9–14. [PubMed] [Google Scholar]
  • 23.Garfinkel L, Garfinkel D. Magnesium regulation of the glycolytic pathway and the enzymes involved. Magnesium. 1985;4:60–72. [PubMed] [Google Scholar]
  • 24.Altura BM, Altura BT. Magnesium ions and contraction of vascular smooth muscles: relationship to some vascular diseases. Fed Proc. 1981;40:2672–2679. [PubMed] [Google Scholar]
  • 25.Hans CP, Chaudhary DP, Bansal DD. Magnesium deficiency increases oxidative stress in rats. Indian J Exp Biol. 2002;40:1275–1279. [PubMed] [Google Scholar]
  • 26.Garcia LA, Dejong SC, Martin SM, Smith RS, Buettner GR, Kerber RE. Magnesium reduces free radicals in an in vivo coronary occlusion-reperfusion model. J Am Coll Cardiol. 1998;32:536–539. doi: 10.1016/S0735-1097(98)00231-9. [DOI] [PubMed] [Google Scholar]
  • 27.Cernak I, Savic VJ, Kotur J, Prokic V, Veljovic M, Grbovic D. Characterization of plasma magnesium concentration and oxidative stress following graded traumatic brain injury in humans. J Neurotrauma. 2000;17:53–68. doi: 10.1089/neu.2000.17.53. [DOI] [PubMed] [Google Scholar]
  • 28.Chan MT, Boet R, Ng SC, Poon WS, Gin T. Magnesium sulfate for brain protection during temporary cerebral artery occlusion. Acta Neurochir Suppl. 2005;95:107–111. doi: 10.1007/3-211-32318-X_23. [DOI] [PubMed] [Google Scholar]
  • 29.Napieralski JA, Raghupathi R, McIntosh TK. The tumor-suppressor gene, p53, is induced in injured brain regions following experimental traumatic brain injury. Brain Res Mol Brain Res. 1999;71:78–86. doi: 10.1016/S0169-328X(99)00155-2. [DOI] [PubMed] [Google Scholar]
  • 30.Lee JS, Han YM, Yoo DS, et al. A molecular basis for the efficacy of magnesium treatment following traumatic brain injury in rats. J Neurotrauma. 2004;21:549–561. doi: 10.1089/089771504774129883. [DOI] [PubMed] [Google Scholar]
  • 31.Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci. 1997;17:171–180. doi: 10.1523/JNEUROSCI.17-01-00171.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Ghabriel MN, Thomas A, Vink R. Magnesium restores altered aquaporin-4 immunoreactivity following traumatic brain injury to a pre-injury state. Acta Neurochir Suppl. 2006;96:402–406. doi: 10.1007/3-211-30714-1_83. [DOI] [PubMed] [Google Scholar]
  • 33.Okiyama K, Smith DH, Gennarelli TA, Simon RP, Leach M, Mclntosh TK. The sodium channel blocker and glutamate release inhibitor BW1003C87 and magnesium attenuate regional cerebral edema following experimental brain injury in the rat. J Neurochem. 1995;64:802–809. doi: 10.1046/j.1471-4159.1995.64020802.x. [DOI] [PubMed] [Google Scholar]
  • 34.Heath DL, Vink R. Concentration of brain free magnesium following severe brain injury correlates with neurologic motor outcome. J Clin Neurosci. 1999;6:505–509. doi: 10.1016/S0967-5868(99)90011-5. [DOI] [PubMed] [Google Scholar]
  • 35.Bareyre FM, Saatman KE, Helfaer MA, et al. Alterations in ionized and total blood magnesium after experimental traumatic brain injury: relationship to neurobehavioral outcome and neuroprotective efficacy of magnesium chloride. J Neurochem. 1999;73:271–280. doi: 10.1046/j.1471-4159.1999.0730271.x. [DOI] [PubMed] [Google Scholar]
  • 36.Feldman Z, Gurevitch B, Artru AA, et al. Effect of magnesium given 1 hour after head trauma on brain edema and neurological outcome. J Neurosurg. 1996;85:131–137. doi: 10.3171/jns.1996.85.1.0131. [DOI] [PubMed] [Google Scholar]
  • 37.Browne KD, Leoni MJ, Iwata A, Chen XH, Smith DH. Acute treatment with MgSO4 attenuates long-term hippocampal tissue loss after brain trauma in the rat. J Neurosci Res. 2004;77:878–883. doi: 10.1002/jnr.20215. [DOI] [PubMed] [Google Scholar]
  • 38.Hoane MR. Magnesium therapy and recovery of function in experimental models of brain injury and neurodegenerative disease. Clin Calcium. 2004;14:65–70. [PubMed] [Google Scholar]
  • 39.Hoane MR, Knotts AA, Akstulewicz SL, Aquilano M, Means LW. The behavioral effects of magnesium therapy on recovery of function following bilateral anterior medial cortex lesions in the rat. Brain Res Bull. 2003;60:105–114. doi: 10.1016/S0361-9230(03)00022-4. [DOI] [PubMed] [Google Scholar]
  • 40.Heath DL, Vink R. Optimization of magnesium therapy after severe diffuse axonal brain injury in rats. J Pharmacol Exp Ther. 1999;288:1311–1316. [PubMed] [Google Scholar]
  • 41.Bareyre FM, Saatman KE, Raghupathi R, McIntosh TK. Postinjury treatment with magnesium chloride attenuates cortical damage after traumatic brain injury in rats. J Neurotrauma. 2000;17:1029–1039. doi: 10.1089/neu.2000.17.1029. [DOI] [PubMed] [Google Scholar]
  • 42.Heath DL, Vink R. Improved motor outcome in response to magnesium therapy received up to 24 hours after traumatic diffuse axonal brain injury in rats. J Neurosurg. 1999;90:504–509. doi: 10.3171/jns.1999.90.3.0504. [DOI] [PubMed] [Google Scholar]
  • 43.Hoane MR, Barth TM. The window of opportunity for administration of magnesium therapy following focal brain injury is 24 h but is task dependent in the rat. Physiol Behav. 2002;76:271–280. doi: 10.1016/S0031-9384(02)00714-X. [DOI] [PubMed] [Google Scholar]
  • 44.Vink R, O’Connor CA, Nimmo AJ, Heath DL. Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats. Neurosci Lett. 2003;336:41–44. doi: 10.1016/S0304-3940(02)01244-2. [DOI] [PubMed] [Google Scholar]
  • 45.Heath DL, Vink R. Subdural hematoma following traumatic brain injury causes a secondary decline in brain free magnesium concentration. J Neurotrauma. 2001;18:465–469. doi: 10.1089/089771501750171074. [DOI] [PubMed] [Google Scholar]
  • 46.Kahraman S, Ozgurtas T, Kayali H, Atabey C, Kutluay T, Timurkaynak E. Monitoring of serum ionized magnesium in neurosurgical intensive care unit: preliminary results. Clin Chim Acta. 2003;334:211–215. doi: 10.1016/S0009-8981(03)00235-3. [DOI] [PubMed] [Google Scholar]
  • 47.Memon ZI, Altura BT, Benjamin JL, Cracco RQ, Altura BM. Predictive value of serum ionized but not total magnesium levels in head injuries. Scand J Clin Lab Invest. 1995;55:671–677. doi: 10.3109/00365519509075397. [DOI] [PubMed] [Google Scholar]
  • 48.Polderman KH, Bloemers FW, Peerdeman SM, Girbes AR. Hypomagnesemia and hypophosphatemia at admission in patients with severe head injury. Crit Care Med. 2000;28:2022–2025. doi: 10.1097/00003246-200006000-00057. [DOI] [PubMed] [Google Scholar]
  • 49.Sakamoto T, Takasu A, Saitoh D, Kaneko N, Yanagawa Y, Okada Y. Ionized magnesium in the cerebrospinal fluid of patients with head injuries. J Trauma. 2005;58:1103–1109. doi: 10.1097/01.TA.0000169950.51735.C4. [DOI] [PubMed] [Google Scholar]
  • 50.Kafadar AM, Sanus GZ, Is M, et al. Prolonged elevation of magnesium in the cerebrospinal fluid of patients with severe head injury. Neurol Res. 2007;29:824–829. doi: 10.1179/016164107X181879. [DOI] [PubMed] [Google Scholar]
  • 51.Canavero S, Bonicalzi V, Narcisi P. Safety of magnesium—lidocaine combination for severe head injury: the Turin Lidomag Pilot Study. Surg Neurol. 2003;60:165–169. doi: 10.1016/S0090-3019(03)00159-9. [DOI] [PubMed] [Google Scholar]
  • 52.Natale JE, Guerguerian AM, Joseph JG, et al. Pilot study to determine the hemodynamic safety and feasibility of magnesium sulfate infusion in children with severe traumatic brain injury. Pediatr Crit Care Med. 2007;8:1–9. doi: 10.1097/01.pcc.0000256620.55512.5f. [DOI] [PubMed] [Google Scholar]
  • 53.Mosenthal AC, Livingston DH, Lavery RF, et al. The effect of age on functional outcome in mild traumatic brain injury: 6-month report of a prospective multicenter trial. J Trauma. 2004;56:1042–1048. doi: 10.1097/01.TA.0000127767.83267.33. [DOI] [PubMed] [Google Scholar]
  • 54.Livingston DH, Lavery RF, Mosenthal AC, et al. Recovery at one year following isolated traumatic brain injury: a Western Trauma Association prospective multicenter trial. J Trauma. 2005;59:1298–1304. doi: 10.1097/01.ta.0000196002.03681.18. [DOI] [PubMed] [Google Scholar]
  • 55.Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma. 1993;34:216–222. doi: 10.1097/00005373-199302000-00006. [DOI] [PubMed] [Google Scholar]
  • 56.Newfield P, Pitts L, Kaktis J, Hoff J. The influence of shock on mortality after head trauma. Crit Care Med. 1980;8:254–254. doi: 10.1097/00003246-198004000-00123. [DOI] [Google Scholar]
  • 57.Manley G, Knudson MM, Morabito D, Damron S, Erickson V, Pitts L. Hypotension, hypoxia, and head injury: frequency, duration, and consequences. Arch Surg. 2001;136:1118–1123. doi: 10.1001/archsurg.136.10.1118. [DOI] [PubMed] [Google Scholar]
  • 58.Rovlias A, Kotsou S. The influence of hyperglycemia on neurological outcome in patients with severe head injury. Neurosurgery. 2000;46:335–342. doi: 10.1097/00006123-200002000-00015. [DOI] [PubMed] [Google Scholar]
  • 59.Laird AM, Miller PR, Kilgo PD, Meredith JW, Chang MC. Relationship of early hyperglycemia to mortality in trauma patients. J Trauma. 2004;56:1058–1062. doi: 10.1097/01.TA.0000123267.39011.9F. [DOI] [PubMed] [Google Scholar]
  • 60.Walia S, Sutcliffe AJ. The relationship between blood glucose, mean arterial pressure and outcome after severe head injury: an observational study. Injury. 2002;33:339–344. doi: 10.1016/S0020-1383(02)00053-0. [DOI] [PubMed] [Google Scholar]
  • 61.Bochicchio GV, Joshi M, Bochicchio KM, et al. Early hyperglycemic control is important in critically injured trauma patients. J Trauma. 2007;63:1353–1358. doi: 10.1097/TA.0b013e31815b83c4. [DOI] [PubMed] [Google Scholar]
  • 62.Zygun DA, Kortbeek JB, Fick GH, Laupland KB, Doig CJ. Non-neurologic organ dysfunction in severe traumatic brain injury. Crit Care Med. 2005;33:654–660. doi: 10.1097/01.CCM.0000155911.01844.54. [DOI] [PubMed] [Google Scholar]
  • 63.Jeremitsky E, Omert L, Dunham CM, Protetch J, Rodriguez A. Harbingers of poor outcome the day after severe brain injury: hypothermia, hypoxia, and hypoperfusion. J Trauma. 2003;54:312–319. doi: 10.1097/01.TA.0000037876.37236.D6. [DOI] [PubMed] [Google Scholar]
  • 64.Schmid-Elsaesser R, Zausinger S, Hungerhuber E, Baethmann A, Reulen HJ. Neuroprotective effects of combination therapy with tirilazad and magnesium in rats subjected to reversible focal cerebral ischemia. Neurosurgery. 1999;44:163–171. doi: 10.1097/00006123-199901000-00100. [DOI] [PubMed] [Google Scholar]
  • 65.Barbie AB, Hoane MR. Magnesium and riboflavin combination therapy following cortical contusion injury in the rat. Brain Res Bull. 2006;69:639–646. doi: 10.1016/j.brainresbull.2006.03.009. [DOI] [PubMed] [Google Scholar]
  • 66.Eshhar N, Striem S, Kohen R, Tirosh O, Biegon A. Neuroprotective and antioxidant activities of HU-211, a novel NMDA receptor antagonist. Eur J Pharmacol. 1995;283:19–29. doi: 10.1016/0014-2999(95)00271-L. [DOI] [PubMed] [Google Scholar]
  • 67.Feigenbaum JJ, Bergmann F, Richmond SA, et al. Nonpsychotropic cannabinoid acts as a functional N-methyl-d-aspartate receptor blocker. Proc Natl Acad Sci U S A. 1989;86:9584–9587. doi: 10.1073/pnas.86.23.9584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Shohami E, Gallily R, Mechoulam R, Bass R, Ben-Hur T. Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-α inhibitor and an effective neuroprotectant. J Neuroimmunol. 1997;72:169–177. doi: 10.1016/S0165-5728(96)00181-6. [DOI] [PubMed] [Google Scholar]
  • 69.Knoller N, Levi L, Shoshan I, et al. Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. Crit Care Med. 2002;30:548–554. doi: 10.1097/00003246-200203000-00009. [DOI] [PubMed] [Google Scholar]
  • 70.Ogata T, Nakamura Y, Tsuji K, Shibata T, Kataoka K. Steroid hormones protect spinal cord neurons from glutamate toxicity. Neuroscience. 1993;55:445–449. doi: 10.1016/0306-4522(93)90513-F. [DOI] [PubMed] [Google Scholar]
  • 71.Roof RL, Hoffman SW, Stein DG. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol. 1997;31:1–11. doi: 10.1007/BF02815156. [DOI] [PubMed] [Google Scholar]
  • 72.O’Connor CA, Cemak I, Vink R. Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain Res. 2005;1062:171–174. doi: 10.1016/j.brainres.2005.09.011. [DOI] [PubMed] [Google Scholar]
  • 73.Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005;1049:112–119. doi: 10.1016/j.brainres.2005.05.004. [DOI] [PubMed] [Google Scholar]
  • 74.O’Connor CA, Cemak I, Johnson F, Vink R. Effects of progesterone on neurologic and morphologic outcome following diffuse traumatic brain injury in rats. Exp Neurol. 2007;205:145–153. doi: 10.1016/j.expneurol.2007.01.034. [DOI] [PubMed] [Google Scholar]
  • 75.Wright DW, Kellermann AL, Hertzberg VS, et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007;49:391–402. doi: 10.1016/j.annemergmed.2006.07.932. [DOI] [PubMed] [Google Scholar]
  • 76.Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care. 2008;12:R61–R61. doi: 10.1186/cc6887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Zhu H, Meloni BP, Bojarski C, Knuckey MW, Knuckey NW. Post-ischemic modest hypothermia (35°C) combined with intravenous magnesium is more effective at reducing CA1 neuronal death than either treatment used alone following global cerebral ischemia in rats. Exp Neurol. 2005;193:361–368. doi: 10.1016/j.expneurol.2005.01.022. [DOI] [PubMed] [Google Scholar]
  • 78.Campbell K, Meloni BP, Knuckey NW. Combined magnesium and mild hypothermia (35°C) treatment reduces infarct volumes after permanent middle cerebral artery occlusion in the rat at 2 and 4, but not 6 h. Brain Res. 2008;1230:258–264. doi: 10.1016/j.brainres.2008.06.110. [DOI] [PubMed] [Google Scholar]
  • 79.Schmid-Elsaesser R, Hungerhuber E, Zausinger S, Baethmann A, Reulen HJ. Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia. Stroke. 1999;30:1891–1899. doi: 10.1161/01.str.30.9.1891. [DOI] [PubMed] [Google Scholar]
  • 80.Zausinger S, Schöller K, Plesnila N, Schmid-Elsaesser R. Combination drug therapy and mild hypothermia after transient focal cerebral ischemia in rats. Stroke. 2003;34:2246–2251. doi: 10.1161/01.STR.0000083622.65684.21. [DOI] [PubMed] [Google Scholar]
  • 81.Jiang J, Yu M, Zhu C. Effect of long-term mild hypothermia therapy in patients with severe traumatic brain injury: 1-year follow-up review of 87 cases. J Neurosurg. 2000;93:546–549. doi: 10.3171/jns.2000.93.4.0546. [DOI] [PubMed] [Google Scholar]
  • 82.Qiu W, Zhang Y, Sheng H, et al. Effects of therapeutic mild hypothermia on patients with severe traumatic brain injury after craniotomy. J Crit Care. 2007;22:229–235. doi: 10.1016/j.jcrc.2006.06.011. [DOI] [PubMed] [Google Scholar]
  • 83.Smrcka M, Vidlák M, Máca K, Smrcka V, Gál R. The influence of mild hypothermia on ICP, CPP and outcome in patients with primary and secondary brain injury. Acta Neurochir Suppl. 2005;95:273–275. doi: 10.1007/3-211-32318-X_56. [DOI] [PubMed] [Google Scholar]
  • 84.Marion DW, Penrod LE, Kelsey SF, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997;336:540–546. doi: 10.1056/NEJM199702203360803. [DOI] [PubMed] [Google Scholar]
  • 85.Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344:556–563. doi: 10.1056/NEJM200102223440803. [DOI] [PubMed] [Google Scholar]
  • 86.Shiozaki T, Hayakata T, Taneda M, et al. Mild Hypothermia Study Group in Japan. A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. J Neurosurg. 2001;94:50–54. doi: 10.3171/jns.2001.94.1.0050. [DOI] [PubMed] [Google Scholar]
  • 87.Bayir H, Adelson PD, Wisniewski SR, et al. Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children. Crit Care Med. 2009;37:689–695. doi: 10.1097/CCM.0b013e318194abf2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Peterson K, Carson S, Carney N. Hypothermia treatment for traumatic brain injury: a systematic review and meta-analysis. J Neurotrauma. 2008;25:62–71. doi: 10.1089/neu.2007.0424. [DOI] [PubMed] [Google Scholar]
  • 89.Bullock MR. Hyperoxia: good or bad? J Neurosurg. 2003;98:943–944. doi: 10.3171/jns.2003.98.5.0943. [DOI] [PubMed] [Google Scholar]
  • 90.Tisdall MM, Tachtsidis I, Leung TS, Elwell CE, Smith M. Increase in cerebral aerobic metabolism by normobaric hyperoxia after traumatic brain injury. J Neurosurg. 2008;109:424–432. doi: 10.3171/JNS/2008/109/9/0424. [DOI] [PubMed] [Google Scholar]
  • 91.Rockswold SB, Rockswold GL, Vargo JM, et al. Effects of hyper-baric oxygenation therapy on cerebral metabolism and intracranial pressure in severely brain injured patients. J Neurosurg. 2001;94:403–411. doi: 10.3171/jns.2001.94.3.0403. [DOI] [PubMed] [Google Scholar]
  • 92.Nortje J, Coles JP, Timofeev I, et al. Effect of hyperoxia on regional oxygenation and metabolism after severe traumatic brain injury: preliminary findings. Crit Care Med. 2008;36:273–281. doi: 10.1097/01.CCM.0000292014.60835.15. [DOI] [PubMed] [Google Scholar]
  • 93.Diringer MN, Aiyagari V, Zazulia AR, Videen TO, Powers WJ. Effect of hyperoxia on cerebral metabolic rate for oxygen measured using positron emission tomography in patients with acute severe head injury. J Neurosurg. 2007;106:526–529. doi: 10.3171/jns.2007.106.4.526. [DOI] [PubMed] [Google Scholar]
  • 94.Menzel M, Doppenberg EM, Zauner A, Soukup J, Reinert MM, Bullock R. Increased inspired oxygen concentration as a factor in improved brain tissue oxygenation and tissue lactate levels after severe human head injury. J Neurosurg. 1999;91:1–10. doi: 10.3171/jns.1999.91.1.0001. [DOI] [PubMed] [Google Scholar]
  • 95.Reinert M, Barth A, Rothen HU, Schaller B, Takala J, Seiler RW. Effects of cerebral perfusion pressure and increased fraction of inspired oxygen on brain tissue oxygen, lactate and glucose in patients with severe head injury. Acta Neurochir (Wien) 2003;145:341–349. doi: 10.1007/s00701-003-0027-0. [DOI] [PubMed] [Google Scholar]
  • 96.Tolias CM, Reinert M, Seiler R, Gilman C, Scharf A, Bullock MR. Normobaric hyperoxia-induced improvement in cerebral metabolism and reduction in intracranial pressure in patients with severe head injury: a prospective historical cohort-matched study. J Neurosurg. 2004;101:435–444. doi: 10.3171/jns.2004.101.3.0435. [DOI] [PubMed] [Google Scholar]
  • 97.Jenkinson SG. Oxygen toxicity. New Horiz. 1993;1:504–511. [PubMed] [Google Scholar]
  • 98.Bulte DP, Chiarelli PA, Wise RG, Jezzard P. Cerebral perfusion response to hyperoxia. J Cereb Blood Flow Metab. 2007;27:69–75. doi: 10.1038/sj.jcbfm.9600319. [DOI] [PubMed] [Google Scholar]

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