• Fukashi Serizawa
  • Eric Patterson
  • Gediminas Cepinskas
  • Douglas D. Fraser
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


Trauma is a leading cause of pediatric morbidity and mortality. The primary aims of trauma resuscitation are to restore intravascular volume and to optimize both organ perfusion and tissue oxygen delivery. The most common organ system injured in pediatric trauma is the brain, suffering direct mechanical insult and indirect reperfusion insult from rapid fluid resuscitation. Both direct and indirect events initiate oxidative stress cascades that cause or exacerbate damage to cell structures, proteins, lipids and nucleic acids, thereby compromising neuronal survival. Recent data suggests that therapeutic interventions to improve multisystem trauma and traumatic brain injury outcomes will target oxidative stress.


Traumatic Brain Injury Glasgow Coma Scale Therapeutic Hypothermia Traumatic Brain Injury Patient Secondary Brain Injury 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Endoplasmic reticulum


Glasgow coma scale


Glutathione peroxidase


Heme oxygenase-1




l-NG-nitroarginine methyl ester


Lipid peroxidation




Nicotinamide adenine dinucleotide phosphate


Nitric oxide synthase


NAD(P)H quinonereductase-1


Nuclear factor E2-related factor2/antioxidant response element






Oxidation–reduction potential


Primary brain injury


Alpha-phenyl-tert-butyl nitrone


Phosphatidylcholine hydroperoxide


Polyethylene glycol-conjugated superoxide dismutase




Reactive nitrogen species


Reactive oxygen species


Secondary brain injury




Superoxide dismutase


Traumatic brain injury


Uridine 5′-diphospho


4-Hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl nitroxide


  1. 1.
    Krug SE, Tuggle DW (2008) Management of pediatric trauma. Pediatrics 121:849–854PubMedCrossRefGoogle Scholar
  2. 2.
    Wetzel RC, Burns RC (2002) Multiple trauma in children: critical care overview. Crit Care Med 30:S468–S477PubMedCrossRefGoogle Scholar
  3. 3.
    Forward K, Chan M, Stewart TC, Gilliland J, Campbell C, Fraser DD (2010) Injury analyses in rural children: comparison of old-order Anabaptists and non-Anabaptists. J Trauma 69:1294–1299PubMedCrossRefGoogle Scholar
  4. 4.
    Morrison G, Fraser DD, Cepinskas G (2013) Mechanisms and consequences of acquired brain injury during development. Pathophysiology 20:49–57PubMedCrossRefGoogle Scholar
  5. 5.
    Al-Sharif A, Thakur V, Al-Farsi S, Singh RN, Kornecki A, Seabrook JA, Fraser DD (2012) Resuscitation volume in paediatric non-haemorrhagic blunt trauma. Injury 43:2078–2082PubMedCrossRefGoogle Scholar
  6. 6.
    Laplace C, Huet O, Vicaut E, Ract C, Martin L, Benhamou D, Duranteau J (2005) Endothelial oxidative stress induced by serum from patients with severe trauma hemorrhage. Intensive Care Med 31:1174–1180PubMedCrossRefGoogle Scholar
  7. 7.
    van Golen RF, van Gulik TM, Heger M (2012) Mechanistic overview of reactive species-induced degradation of the endothelial glycocalyx during hepatic ischemia/reperfusion injury. Free Radic Biol Med 52:1382–1402PubMedCrossRefGoogle Scholar
  8. 8.
    Meythaler JM, Peduzzi JD, Eleftheriou E, Novack TA (2001) Current concepts: diffuse axonal injury-associated traumatic brain injury. Arch Phys Med Rehabil 82:1461–1471PubMedCrossRefGoogle Scholar
  9. 9.
    Teasdale G, Jennett B (1974) Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81–84PubMedCrossRefGoogle Scholar
  10. 10.
    McDonald CM, Jaffe KM, Fay GC, Polissar NL, Martin KM, Liao S, Rivara JB (1994) Comparison of indices of traumatic brain injury severity as predictors of neurobehavioral outcome in children. Arch Phys Med Rehabil 75:328–337PubMedCrossRefGoogle Scholar
  11. 11.
    Pettus EH, Christman CW, Giebel ML, Povlishock JT (1994) Traumatically induced altered membrane permeability: its relationship to traumatically induced reactive axonal change. J Neurotrauma 11:507–522PubMedCrossRefGoogle Scholar
  12. 12.
    Gutteridge JM (1995) Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin Chem 41:1819–1828PubMedGoogle Scholar
  13. 13.
    Beckman JS (1991) The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Dev Physiol 15:53–59PubMedGoogle Scholar
  14. 14.
    Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF (2003) The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol 66:1499–1503PubMedCrossRefGoogle Scholar
  15. 15.
    Rhee SG, Chae HZ, Kim K (2005) Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med 38:1543–1552PubMedCrossRefGoogle Scholar
  16. 16.
    Rao VL, Dogan A, Bowen KK, Dempsey RJ (1999) Traumatic injury to rat brain upregulates neuronal nitric oxide synthase expression and L-[3H]nitroarginine binding. J Neurotrauma 16:865–877PubMedCrossRefGoogle Scholar
  17. 17.
    Gahm C, Holmin S, Mathiesen T (2000) Temporal profiles and cellular sources of three nitric oxide synthase isoforms in the brain after experimental contusion. Neurosurgery 46:169–177PubMedCrossRefGoogle Scholar
  18. 18.
    Wada K, Chatzipanteli K, Kraydieh S, Busto R, Dietrich WD (1998) Inducible nitric oxide synthase expression after traumatic brain injury and neuroprotection with aminoguanidine treatment in rats. Neurosurgery 43:1427–1436PubMedGoogle Scholar
  19. 19.
    Mesenge C, Verrecchia C, Allix M, Boulu RR, Plotkine M (1996) Reduction of the neurological deficit in mice with traumatic brain injury by nitric oxide synthase inhibitors. J Neurotrauma 13:209–214PubMedCrossRefGoogle Scholar
  20. 20.
    Wallis RA, Panizzon KL, Girard JM (1996) Traumatic neuroprotection with inhibitors of nitric oxide and ADP-ribosylation. Brain Res 710:169–177PubMedCrossRefGoogle Scholar
  21. 21.
    Bringold U, Ghafourifar P, Richter C (2000) Peroxynitrite formed by mitochondrial NO synthase promotes mitochondrial Ca2+ release. Free Radic Biol Med 29:343–348PubMedCrossRefGoogle Scholar
  22. 22.
    Shao C, Roberts KN, Markesbery WR, Scheff SW, Lovell MA (2006) Oxidative stress in head trauma in aging. Free Radic Biol Med 41:77–85PubMedCrossRefGoogle Scholar
  23. 23.
    Morrow JD, Awad JA, Boss HJ, Blair IA, Roberts LJ 2nd (1992) Non-cyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids. Proc Natl Acad Sci U S A 89:10721–10725PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Kasprzak HA, Wozniak A, Drewa G, Wozniak B (2001) Enhanced lipid peroxidation processes in patients after brain contusion. J Neurotrauma 18:793–797PubMedCrossRefGoogle Scholar
  25. 25.
    Darwish RS, Amiridze N, Aarabi B (2007) Nitrotyrosine as an oxidative stress marker: evidence for involvement in neurologic outcome in human traumatic brain injury. J Trauma 63:439–442PubMedCrossRefGoogle Scholar
  26. 26.
    Tyurin VA, Tyurina YY, Borisenko GG, Sokolova TV, Ritov VB, Quinn PJ, Rose M, Kochanek P, Graham SH, Kagan VE (2000) Oxidative stress following traumatic brain injury in rats: quantitation of biomarkers and detection of free radical intermediates. J Neurochem 75:2178–2189PubMedCrossRefGoogle Scholar
  27. 27.
    Muizelaar JP, Kupiec JW, Rapp LA (1995) PEG-SOD after head injury. J Neurosurg 83:942PubMedGoogle Scholar
  28. 28.
    Muizelaar JP, Marmarou A, Young HF, Choi SC, Wolf A, Schneider RL, Kontos HA (1993) Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase: a phase II trial. J Neurosurg 78:375–382PubMedCrossRefGoogle Scholar
  29. 29.
    Mikawa S, Kinouchi H, Kamii H, Gobbel GT, Chen SF, Carlson E, Epstein CJ, Chan PH (1996) Attenuation of acute and chronic damage following traumatic brain injury in copper, zinc-superoxide dismutase transgenic mice. J Neurosurg 85:885–891PubMedCrossRefGoogle Scholar
  30. 30.
    Lewen A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17:871–890PubMedCrossRefGoogle Scholar
  31. 31.
    Xiong Y, Shie FS, Zhang J, Lee CP, Ho YS (2005) Prevention of mitochondrial dysfunction in post-traumatic mouse brain by superoxide dismutase. J Neurochem 95:732–744PubMedCrossRefGoogle Scholar
  32. 32.
    Dimlich RV, Tornheim PA, Kindel RM, Hall ED, Braughler JM, McCall JM (1990) Effects of a 21-aminosteroid (U-74006F) on cerebral metabolites and edema after severe experimental head trauma. Adv Neurol 52:365–375PubMedGoogle Scholar
  33. 33.
    McIntosh TK, Thomas M, Smith D, Banbury M (1992) The novel 21-aminosteroid U74006F attenuates cerebral edema and improves survival after brain injury in the rat. J Neurotrauma 9:33–46PubMedCrossRefGoogle Scholar
  34. 34.
    Marshall LF, Maas AI, Marshall SB, Bricolo A, Fearnside M, Iannotti F, Klauber MR, Lagarrigue J, Lobato R, Persson L, Pickard JD, Piek J, Servadei F, Wellis GN, Morris GF, Means ED, Musch B (1998) A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg 89:519–525PubMedCrossRefGoogle Scholar
  35. 35.
    Farin A, Deutsch R, Biegon A, Marshall LF (2003) Sex-related differences in patients with severe head injury: greater susceptibility to brain swelling in female patients 50 years of age and younger. J Neurosurg 98:32–36PubMedCrossRefGoogle Scholar
  36. 36.
    Kampfl A, Posmantur R, Nixon R, Grynspan F, Zhao X, Liu SJ, Newcomb JK, Clifton GL, Hayes RL (1996) mu-calpain activation and calpain-mediated cytoskeletal proteolysis following traumatic brain injury. J Neurochem 67:1575–1583PubMedCrossRefGoogle Scholar
  37. 37.
    Saatman KE, Bozyczko-Coyne D, Marcy V, Siman R, McIntosh TK (1996) Prolonged calpain-mediated spectrin breakdown occurs regionally following experimental brain injury in the rat. J Neuropathol Exp Neurol 55:850–860PubMedCrossRefGoogle Scholar
  38. 38.
    Mustafa AG, Wang JA, Carrico KM, Hall ED (2011) Pharmacological inhibition of lipid peroxidation attenuates calpain-mediated cytoskeletal degradation after traumatic brain injury. J Neurochem 117:579–588PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Mustafa AG, Singh IN, Wang J, Carrico KM, Hall ED (2010) Mitochondrial protection after traumatic brain injury by scavenging lipid peroxyl radicals. J Neurochem 114:271–280PubMedCentralPubMedGoogle Scholar
  40. 40.
    Kopp P (1998) Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the ‘French paradox’? Eur J Endocrinol 138:619–620PubMedCrossRefGoogle Scholar
  41. 41.
    Kiziltepe U, Turan NN, Han U, Ulus AT, Akar F (2004) Resveratrol, a red wine polyphenol, protects spinal cord from ischemia–reperfusion injury. J Vasc Surg 40:138–145PubMedCrossRefGoogle Scholar
  42. 42.
    Yang YB, Piao YJ (2003) Effects of resveratrol on secondary damages after acute spinal cord injury in rats. Acta Pharmacol Sin 24:703–710PubMedGoogle Scholar
  43. 43.
    Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Kocak A, Yologlu S, Turkoz Y (2006) Effects of resveratrol and methylprednisolone on biochemical, neurobehavioral and histopathological recovery after experimental spinal cord injury. Acta Pharmacol Sin 27:1317–1325PubMedCrossRefGoogle Scholar
  44. 44.
    Liu C, Shi Z, Fan L, Zhang C, Wang K, Wang B (2011) Resveratrol improves neuron protection and functional recovery in rat model of spinal cord injury. Brain Res 1374:100–109PubMedCrossRefGoogle Scholar
  45. 45.
    Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Sener M, Kocak A, Yologlu S (2007) Neuroprotection by resveratrol against traumatic brain injury in rats. Mol Cell Biochem 294:137–144PubMedCrossRefGoogle Scholar
  46. 46.
    Sonmez U, Sonmez A, Erbil G, Tekmen I, Baykara B (2007) Neuroprotective effects of resveratrol against traumatic brain injury in immature rats. Neurosci Lett 420:133–137PubMedCrossRefGoogle Scholar
  47. 47.
    Marklund N, Clausen F, Lewen A, Hovda DA, Olsson Y, Hillered L (2001) alpha-Phenyl-tert-N-butyl nitrone (PBN) improves functional and morphological outcome after cortical contusion injury in the rat. Acta Neurochir (Wien) 143:73–81CrossRefGoogle Scholar
  48. 48.
    Carroll RT, Galatsis P, Borosky S, Kopec KK, Kumar V, Althaus JS, Hall ED (2000) 4-Hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol) inhibits peroxynitrite-mediated phenol nitration. Chem Res Toxicol 13:294–300PubMedCrossRefGoogle Scholar
  49. 49.
    Wilcox CS (2010) Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol Ther 126:119–145PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Deng-Bryant Y, Singh IN, Carrico KM, Hall ED (2008) Neuroprotective effects of tempol, a catalytic scavenger of peroxynitrite-derived free radicals, in a mouse traumatic brain injury model. J Cereb Blood Flow Metab 28:1114–1126PubMedCrossRefGoogle Scholar
  51. 51.
    Hillard VH, Peng H, Zhang Y, Das K, Murali R, Etlinger JD, Zeman RJ (2004) Tempol, a nitroxide antioxidant, improves locomotor and histological outcomes after spinal cord contusion in rats. J Neurotrauma 21:1405–1414PubMedCrossRefGoogle Scholar
  52. 52.
    Althaus JS, Oien TT, Fici GJ, Scherch HM, Sethy VH, VonVoigtlander PF (1994) Structure activity relationships of peroxynitrite scavengers: an approach to nitric oxide neurotoxicity. Res Commun Chem Pathol Pharmacol 83:243–254PubMedGoogle Scholar
  53. 53.
    Singh IN, Sullivan PG, Hall ED (2007) Peroxynitrite-mediated oxidative damage to brain mitochondria: protective effects of peroxynitrite scavengers. J Neurosci Res 85:2216–2223PubMedCrossRefGoogle Scholar
  54. 54.
    Hall ED, Kupina NC, Althaus JS (1999) Peroxynitrite scavengers for the acute treatment of traumatic brain injury. Ann N Y Acad Sci 890:462–468PubMedCrossRefGoogle Scholar
  55. 55.
    Hamann K, Durkes A, Ouyang H, Uchida K, Pond A, Shi R (2008) Critical role of acrolein in secondary injury following ex vivo spinal cord trauma. J Neurochem 107:712–721PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Hamann K, Shi R (2009) Acrolein scavenging: a potential novel mechanism of attenuating oxidative stress following spinal cord injury. J Neurochem 111:1348–1356PubMedCrossRefGoogle Scholar
  57. 57.
    Galvani S, Coatrieux C, Elbaz M, Grazide MH, Thiers JC, Parini A, Uchida K, Kamar N, Rostaing L, Baltas M, Salvayre R, Negre-Salvayre A (2008) Carbonyl scavenger and antiatherogenic effects of hydrazine derivatives. Free Radic Biol Med 45:1457–1467PubMedCrossRefGoogle Scholar
  58. 58.
    Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454:455–462PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116PubMedCrossRefGoogle Scholar
  60. 60.
    Zhang DD (2006) Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38:769–789PubMedCrossRefGoogle Scholar
  61. 61.
    Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85:241–272PubMedCrossRefGoogle Scholar
  62. 62.
    Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23:3394–3406PubMedGoogle Scholar
  63. 63.
    Shih AY, Imbeault S, Barakauskas V, Erb H, Jiang L, Li P, Murphy TH (2005) Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J Biol Chem 280:22925–22936PubMedCrossRefGoogle Scholar
  64. 64.
    Misiewicz I, Skupinska K, Kowalska E, Lubinski J, Kasprzycka-Guttman T (2004) Sulforaphane-mediated induction of a phase 2 detoxifying enzyme NAD(P)H:quinone reductase and apoptosis in human lymphoblastoid cells. Acta Biochim Pol 51:711–721PubMedGoogle Scholar
  65. 65.
    Chen G, Fang Q, Zhang J, Zhou D, Wang Z (2011) Role of the Nrf2-ARE pathway in early brain injury after experimental subarachnoid hemorrhage. J Neurosci Res 89:515–523PubMedCrossRefGoogle Scholar
  66. 66.
    Yan W, Wang HD, Hu ZG, Wang QF, Yin HX (2008) Activation of Nrf2-ARE pathway in brain after traumatic brain injury. Neurosci Lett 431:150–154PubMedCrossRefGoogle Scholar
  67. 67.
    Dash PK, Zhao J, Orsi SA, Zhang M, Moore AN (2009) Sulforaphane improves cognitive function administered following traumatic brain injury. Neurosci Lett 460:103–107PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Jin W, Kong J, Wang H, Wu J, Lu T, Jiang J, Ni H, Liang W (2011) Protective effect of tert-butylhydroquinone on cerebral inflammatory response following traumatic brain injury in mice. Injury 42:714–718PubMedCrossRefGoogle Scholar
  69. 69.
    Ji J, Kline AE, Amoscato A, Samhan-Arias AK, Sparvero LJ, Tyurin VA, Tyurina YY, Fink B, Manole MD, Puccio AM, Okonkwo DO, Cheng JP, Alexander H, Clark RS, Kochanek PM, Wipf P, Kagan VE, Bayir H (2012) Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury. Nat Neurosci 15:1407–1413PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Adelson PD, Ragheb J, Kanev P, Brockmeyer D, Beers SR, Brown SD, Cassidy LD, Chang Y, Levin H (2005) Phase II clinical trial of moderate hypothermia after severe traumatic brain injury in children. Neurosurgery 56:740–754; discussion 740–754PubMedCrossRefGoogle Scholar
  71. 71.
    Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K (2002) Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 346:557–563PubMedCrossRefGoogle Scholar
  72. 72.
    Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH (2005) Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 353:1574–1584PubMedCrossRefGoogle Scholar
  73. 73.
    Colbourne F, Grooms SY, Zukin RS, Buchan AM, Bennett MV (2003) Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia. Proc Natl Acad Sci U S A 100:2906–2910PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Dietrich WD, Bramlett HM (2010) The evidence for hypothermia as a neuroprotectant in traumatic brain injury. Neurotherapeutics 7:43–50PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Truettner JS, Alonso OF, Bramlett HM, Dietrich WD (2011) Therapeutic hypothermia alters microRNA responses to traumatic brain injury in rats. J Cereb Blood Flow Metab 31:1897–1907PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Bayir H, Adelson PD, Wisniewski SR, Shore P, Lai Y, Brown D, Janesko-Feldman KL, Kagan VE, Kochanek PM (2009) Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children. Crit Care Med 37:689–695PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Hutchison JS, Ward RE, Lacroix J, Hebert PC, Barnes MA, Bohn DJ, Dirks PB, Doucette S, Fergusson D, Gottesman R, Joffe AR, Kirpalani HM, Meyer PG, Morris KP, Moher D, Singh RN, Skippen PW (2008) Hypothermia therapy after traumatic brain injury in children. N Engl J Med 358:2447–2456PubMedCrossRefGoogle Scholar
  78. 78.
    Fraser DD, Morrison G (2009) Brain oxidative stress after traumatic brain injury … cool it? Crit Care Med 37:787–788PubMedCrossRefGoogle Scholar
  79. 79.
    Sangha GS, Pepelassis D, Buffo-Sequeira I, Seabrook JA, Fraser DD (2012) Serum troponin-I as an indicator of clinically significant myocardial injury in paediatric trauma patients. Injury 43:2046–2050PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2014

Authors and Affiliations

  • Fukashi Serizawa
    • 1
  • Eric Patterson
    • 1
  • Gediminas Cepinskas
    • 1
  • Douglas D. Fraser
    • 2
  1. 1.Centre for Critical Illness ResearchLondonCanada
  2. 2.Pediatric Critical Care Medicine, Translational Research CentreChildren’s Health Research Institute and Centre for Critical Illness ResearchLondonCanada

Personalised recommendations