Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments

Newborn and Infant Nursing Reviews

Volumn 11, Issue 3, 2011, Pages 125-133

  Allen, Kimberly A ^a   Brandon, Debra H ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

Experimental treatments; Hypoxic ischemic encephalopathy; Infant

Indexed keywords

EID: 80051761494     PISSN: 15273369     EISSN: None     Source Type: Journal    
DOI: 10.1053/j.nainr.2011.07.004     Document Type: Article

References (81)

1. Schiariti V., Klassen A.F., Hoube J.S., et al. Perinatal characteristics and parents' perspective of health status of NICU graduates born at term. J Perinatol 2008, 28:368-376.
2. Graham E.M., Ruis K.A., Hartman A.L., Northington F.J., Fox H.E. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol 2008, 199:587-595.
3. Kurinczuk J.J., White-Koning M., Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev 2010, 86:329-338.
4. Long M., Brandon D.H. Induced hypothermia for neonates with hypoxic-ischemic encephalopathy. J Obstet Gynecol Neonatal Nurs 2007, 36:293-298.
5. Pierrat V., Haouari N., Liska A., et al. Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy: population based study. Arch Dis Child: Fetal Neonatal Ed 2005, 90:F257-F261.
6. Gluckman P.D., Wyatt J.S., Azzopardi D., et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005, 365:663-670.
7. Hoehn T., Hansmann G., Buhrer C., et al. Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units. Resuscitation 2008, 78:7-12.
8. Okereafor A., Allsop J., Counsell S.J., et al. Patterns of brain injury in neonates exposed to perinatal sentinel events. Pediatrics 2008, 121:906-914.
9. Kumar S., Paterson-Brown S. Obstetric aspects of hypoxic ischemic encephalopathy. Early Hum Dev 2010, 86:339-344.
10. Shankaran S. Neonatal encephalopathy: treatment with hypothermia. J Neurotrauma 2009, 26:437-443.
11. Vannucci R.C., Perlman J.M. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics 1997, 100:1004-1014.
12. Madan A., Hamrick S.E., Ferriero D. Central nervous system injury and neuroprotection. Avery's diseases of the newborn 2005, 965-992. Elsevier Saunders, Philadelphia. H. Tauesch, R. Ballard, C. Gleason (Eds.).
13. American College of Obstetricians and Gynecologist and American Academy of Pediatrics Neonatal encephalopathy and cerebral palsy. Defining the pathogenesis and pathophysiology 2003, Library of Congress.
14. de Vries L.S., Cowan F.M. Evolving understanding of hypoxic-ischemic encephalopathy in the term infant. Semin Pediatr Neurol 2009, 16:216-225.
15. Cotten C.M., Shankaran S. Hypothermia for hypoxic-ischemic encephalopathy. Expert Rev Obstet Gynecol 2010, 5:227-239.
16. Sarnat H.B., Sarnat M.S. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976, 33:696-705.
17. Shalak L., Perlman J.M. Hypoxic-ischemic brain injury in the term infant-current concepts. Early Hum Dev 2004, 80:125-141.
18. Hanrahan J.D., Sargentoni J., Azzopardi D., et al. Cerebral metabolism within 18 hours of birth asphyxia: a proton magnetic resonance spectroscopy study. Pediatr Res 1996, 39:584-590.
19. Volpe J. Neurology of the newborn 2008, Saunders, Philadelphia. 5th ed.
20. Johnston M.V., Ishida A., Ishida W.N., et al. Plasticity and injury in the developing brain. Brain Dev 2009, 31:1-10.
21. Fatemi A, Wilson MA, Johnston MV. Hypoxic-ischemic encephalopathy in the term infant. Clin Perinatol. 2009;36:835-858, vii.
22. Shier D., Butler J., Lewis R. Hole's human anatomy and physiology 2009, McGraw-Hill, New York.
23. Alvarez-Diaz A., Hilario E., de Cerio F.G., Valls-i-Soler A., Alvarez-Diaz F.J. Hypoxic-ischemic injury in the immature brain-key vascular and cellular players. Neonatology 2007, 92:227-235.
24. Sahni R, Sanocka UM. Hypothermia for hypoxic-ischemic encephalopathy. Clin Perinatol. 2008;35:717-734, vi.
25. Iwata O., Iwata S., Thornton J.S., et al. "Therapeutic time window" duration decreases with increasing severity of cerebral hypoxia-ischaemia under normothermia and delayed hypothermia in newborn piglets. Brain Res 2007, 1154:173-180.
26. Laptook A.R. Use of therapeutic hypothermia for term infants with hypoxic-ischemic encephalopathy. Pediatr Clin North Am 2009, 56:601-616. Table of Contents.
27. Lorek A., Takei Y., Cady E.B., et al. Delayed ("secondary") cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res 1994, 36:699-706.
28. Ferriero D.M. Neonatal brain injury. N Engl J Med 2004, 351:1985-1995.
29. Buonocore G., Perrone S., Bracci R. Free radicals and brain damage in the newborn. Biol Neonate 2001, 79:180-186.
30. Kumar V., Abbas A., Fausto N. Robbins and Cotran: pathologic basis of disease 2005, Elsevier Saunders, Philadelphia. 7th ed.
31. Buonocore G., Groenendaal F. Anti-oxidant strategies. Seminars in Fetal & Neonatal Medicine 2007, 12:287-295.
32. Johnston M.V., Trescher W.H., Ishida A., Nakajima W. Neurobiology of hypoxic-ischemic injury in the developing brain. Pediatr Res 2001, 49:735-741.
33. Palmer C., Roberts R.L., Young P.I. Timing of neutrophil depletion influences long-term neuroprotection in neonatal rat hypoxic-ischemic brain injury. Pediatr Res 2004, 55:549-556.
34. Zhao P., Zuo Z. Isoflurane preconditioning induces neuroprotection that is inducible nitric oxide synthase-dependent in neonatal rats. Anesthesiology 2004, 101:695-703.
35. McAuliffe J.J., Loepke A.W., Miles L., et al. Desflurane, isoflurane, and sevoflurane provide limited neuroprotection against neonatal hypoxia-ischemia in a delayed preconditioning paradigm. Anesthesiology 2009, 111:533-546.
36. Zhao P., Peng L., Li L., Xu X., Zuo Z. Isoflurane preconditioning improves long-term neurologic outcome after hypoxic-ischemic brain injury in neonatal rats. Anesthesiology 2007, 107:963-970.
37. Yin W., Signore A.P., Iwai M., et al. Preconditioning suppresses inflammation in neonatal hypoxic ischemia via Akt activation. Stroke 2007, 38:1017-1024.
38. Lin H.Y., Wu C.L., Huang C.C. The Akt-endothelial nitric oxide synthase pathway in lipopolysaccharide preconditioning-induced hypoxic-ischemic tolerance in the neonatal rat brain. Stroke 2010, 41:1543-1551.
39. Volpe J. Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 2001, 7:56-64.
40. Roka A., Azzopardi D. Therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy. Early Hum Dev 2010, 86:361-367.
41. Gunn A.J., Gunn T.R., de Haan H.H., Williams C.E., Gluckman P.D. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997, 99:248-256.
42. Shah P.S. Hypothermia: a systematic review and meta-analysis of clinical trials. Semin Fetal Neonatal Med 2010.
43. Eicher D.J., Wagner C.L., Katikaneni L.P., et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol 2005, 32:11-17.
44. Gunn A.J., Gluckman P.D., Gunn T.R. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998, 102:885-892.
45. Shankaran S., Pappas A., Laptook A.R., et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics 2008, 122:e791-e798.
46. Edwards A.D., Brocklehurst P., Gunn A.J., et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010, 340:c363.
47. Kelen D., Robertson N.J. Experimental treatments for hypoxic ischaemic encephalopathy. Early Hum Dev 2010, 86:369-377.
48. Wong's nursing care of infants and children 2007, Mosby, St. Louis. 8th ed. M. Hockenberry, D. Wilson (Eds.).
49. Sugawa M., Sakurai Y., Ishikawa-Ieda Y., Suzuki H., Asou H. Effects of erythropoietin on glial cell development; oligodendrocyte maturation and astrocyte proliferation. Neurosci Res 2002, 44:391-403.
50. Spandou E., Papoutsopoulou S., Soubasi V., et al. Hypoxia-ischemia affects erythropoietin and erythropoietin receptor expression pattern in the neonatal rat brain. Brain Res 2004, 1021:167-172.
51. Nagai A., Nakagawa E., Choi H.B., et al. Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. J Neuropathol Exp Neurol 2001, 60:386-392.
52. Tabata M., Tarumoto T., Ohmine K., et al. Stimulation of GATA-2 as a mechanism of hydrogen peroxide suppression in hypoxia-induced erythropoietin gene expression. J Cell Physiol 2001, 186:260-267.
53. Siren A.L., Knerlich F., Poser W., et al. Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol 2001, 101:271-276.
54. Wang C.H., Liang C.L., Huang L.T., et al. Single intravenous injection of naked plasmid DNA encoding erythropoietin provides neuroprotection in hypoxia-ischemia rats. Biochem Biophys Res Commun 2004, 314:1064-1071.
55. van der Kooij M.A., Groenendaal F., Kavelaars A., Heijnen C.J., van Bel F. Combination of deferoxamine and erythropoietin: therapy for hypoxia-ischemia-induced brain injury in the neonatal rat?. Neurosci Lett 2009, 451:109-113.
56. Gunnarson E., Song Y., Kowalewski J.M., et al. Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc Natl Acad Sci U S A 2009, 106:1602-1607.
57. Spandou E., Papadopoulou Z., Soubasi V., et al. Erythropoietin prevents long-term sensorimotor deficits and brain injury following neonatal hypoxia-ischemia in rats. Brain Res 2005, 1045:22-30.
58. Zhu C., Kang W., Xu F., et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics 2009, 124:e218-e226.
59. Elmahdy H., El-Mashad A.R., El-Bahrawy H., et al. Human recombinant erythropoietin in asphyxia neonatorum: pilot trial. Pediatrics 2010, 125:e1135-e1142.
60. Lee O.K., Kuo T.K., Chen W.M., et al. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 2004, 103:1669-1675.
61. Bompais H., Chagraoui J., Canron X., et al. Human endothelial cells derived from circulating progenitors display specific functional properties compared with mature vessel wall endothelial cells. Blood 2004, 103:2577-2584.
62. Pimentel-Coelho P.M., Magalhaes E.S., Lopes L.M., et al. Human cord blood transplantation in a neonatal rat model of hypoxic-ischemic brain damage: functional outcome related to neuroprotection in the striatum. Stem Cells Dev 2010, 19:351-358.
63. van Velthoven C.T., Kavelaars A., van Bel F., Heijnen C.J. Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage. Pediatr Res 2010, 68:419-422.
64. van Velthoven C.T., Kavelaars A., van Bel F., Heijnen C.J. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun 2010, 24:387-393.
65. Cotten C.M. Autologous cord blood cells for hypoxic ischemic encephalopathy 2009, National Institutes of Health, Available at:, Accessed February 22, 2011. http://clinicaltrials.gov/ct2/show/NCT00593242?recr=Open&cond=%22Hypoxia%2C+Brain%22&spons=%22Duke+University%22&spons_ex=Y&rank=1.
66. Schubert S., Brandl U., Brodhun M., et al. Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets. Brain Res 2005, 1058:129-136.
67. Barks J.D., Liu Y.Q., Shangguan Y., Silverstein F.S. Phenobarbital augments hypothermic neuroprotection. Pediatr Res 2010, 67:532-537.
68. Filippi L., Poggi C., la Marca G., Hall A.C., Lieb W.R. Oral topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia: a safety study. J Pediatr 2010, 157:361-366.
69. Franks N.P., Dickinson R., de Sousa S.L., Hall A.C., Lieb W.R. How does xenon produce anaesthesia?. Nature 1998, 396:324.
70. Banks P., Franks N.P., Dickinson R. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia. Anesthesiology 2010, 112:614-622.
71. Dinse A., Fohr K.J., Georgieff M., et al. Xenon reduces glutamate-, AMPA-, and kainate-induced membrane currents in cortical neurones. Br J Anaesth 2005, 94:479-485.
72. Dingley J., Tooley J., Porter H., Thoresen M. Xenon provides short-term neuroprotection in neonatal rats when administered after hypoxia-ischemia. Stroke 2006, 37:501-506.
73. Hobbs C., Thoresen M., Tucker A., et al. Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischemia. Stroke 2008, 39:1307-1313.
74. Thoresen M., Hobbs C.E., Wood T., Chakkarapani E., Dingley J. Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia. J Cereb Blood Flow Metab 2009, 29:707-714.
75. Chakkarapani E., Thoresen M., Hobbs C.E., et al. A closed-circuit neonatal xenon delivery system: a technical and practical neuroprotection feasibility study in newborn pigs. Anesth Analg 2009, 109:451-460.
76. Berman D.R., Mozurkewich E., Liu Y., Barks J. Docosahexaenoic acid pretreatment confers neuroprotection in a rat model of perinatal cerebral hypoxia-ischemia. Am J Obstet Gynecol 2009, 200:e301-e306.
77. Suganuma H., Arai Y., Kitamura Y., et al. Maternal docosahexaenoic acid-enriched diet prevents neonatal brain injury. Neuropathology 2010, 30:597-605.
78. Zhang W., Hu X., Yang W., et al. Omega-3 polyunsaturated fatty acid supplementation confers long-term neuroprotection against neonatal hypoxic-ischemic brain injury through anti-inflammatory actions. Stroke 2010, 41:2341-2347.
79. Martinez-Orgado J., Fernandez-Frutos B., Gonzalez R., Romero J., Martinez-Orgado J. Neuroprotection by the cannabinoid agonist WIN-55212 in an in vivo newborn rat model of acute severe asphyxia. Brain Res Mol Brain Res 2003, 114:132-139.
80. Castillo A., Tolon M.R., Fernandez-Ruiz J., Romero J., Martinez-Orgado J. The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis 2010, 37:434-440.
81. Fernandez-Lopez D., Pazos M.R., Tolon R.M., et al. The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic encephalopathy in newborn rats. Pediatr Res 2007, 62:255-260.