Hypoxic-Ischemic Encephalopathy 

  • Author: Santina A Zanelli, MD; Chief Editor: Ted Rosenkrantz, MD   more...
 
Updated: Dec 15, 2011
 

Background

Despite major advances in monitoring technology and knowledge of fetal and neonatal pathologies, perinatal asphyxia or, more appropriately, hypoxic-ischemic encephalopathy (HIE), remains a serious condition that causes significant mortality and long-term morbidity.

Hypoxic-ischemic encephalopathy is characterized by clinical and laboratory evidence of acute or subacute brain injury due to asphyxia (ie, hypoxia, acidosis). Most often, the exact timing and underlying cause remain unknown.

The American Academy of Pediatrics (AAP) and American College of Obstetrics and Gynecology (ACOG) published guidelines to assist in the diagnosis of severe hypoxic-ischemic encephalopathy (see History).[1, 2]

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Pathophysiology

Brain hypoxia and ischemia due to systemic hypoxemia, reduced cerebral blood flow (CBF), or both are the primary physiological processes that lead to hypoxic-ischemic encephalopathy.[3, 4, 5]

The initial compensatory adjustment to an asphyxial event is an increase in CBF due to hypoxia and hypercapnia. This is accompanied by a redistribution of cardiac output to essential organs, including the brain, heart, and adrenal glands. A blood pressure (BP) increase due to increased release of epinephrine further enhances this compensatory response. See the image below.

Fetal response to asphyxia illustrating the initiaFetal response to asphyxia illustrating the initial redistribution of blood flow to vital organs. With prolonged asphyxial insult and failure of compensatory mechanisms, cerebral blood flow falls, leading to ischemic brain injury.

In adults, CBF is maintained at a constant level despite a wide range in systemic BP. This phenomenon is known as the cerebral autoregulation, which helps maintain cerebral perfusion. The physiological aspects of CBF autoregulation has been well studied in perinatal and adult experimental animals. In human adults, the BP range at which CBF is maintained is 60-100 mm Hg.

Limited data in the human fetus and the newborn infant suggest that CBF is stable over much narrower range of BPs.[6, 7] Some experts have postulated that, in the healthy term newborn, the BP range at which the CBF autoregulation is maintained may be only between 10-20 mm Hg (compared with the 40 mm Hg range in adults noted above). In addition, the autoregulatory zone may also be set at a lower level, about the midpoint of the normal BP range for the fetus and newborn. However, the precise upper and lower limits of the BP values above and below which the CBF autoregulation is lost remain unknown for the human newborn.

In the fetus and newborn suffering from acute asphyxia, after the early compensatory adjustments fail, the CBF can become pressure-passive, at which time brain perfusion depends on systemic BP. As BP falls, CBF falls below critical levels, and the brain injury secondary to diminished blood supply and a lack of sufficient oxygen occurs. This leads to intracellular energy failure. During the early phases of brain injury, brain temperature drops, and local release of neurotransmitters, such as gamma-aminobutyric acid transaminase (GABA), increase. These changes reduce cerebral oxygen demand, transiently minimizing the impact of asphyxia.

At the cellular level, neuronal injury in hypoxic-ischemic encephalopathy is an evolving process. The magnitude of the final neuronal damage depends on duration and severity of the initial insult combined to the effects of reperfusion injury, and apoptosis. At the biochemical level, a large cascade of events follow hypoxic-ischemic encephalopathy injury.

Excitatory amino acid (EAA) receptor overactivation plays a critical role in the pathogenesis of neonatal hypoxia-ischemia. During cerebral hypoxia-ischemia, the uptake of glutamate the major excitatory neurotransmitter of the mammalian brain is impaired. This results in high synaptic levels of glutamate and EAA receptor overactivation, including N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4 isoxazole propionate (AMPA), and kainate receptors. NMDA receptors are permeable to Ca++ and Na+, whereas AMPA and kainate receptors are permeable to Na+. Accumulation of Na+ coupled with the failure of energy dependent enzymes such as Na+/ K+ -ATPase leads to rapid cytotoxic edema and necrotic cell death. Activation of NMDA receptor leads to intracellular Ca++ accumulation and further pathologic cascades activation.

EAAs accumulation also contributes to increasing the pace and extent of programmed cell death through secondary Ca++ intake into the nucleus. The pattern of injury seen after hypoxia-ischemia demonstrate regional susceptibility that can be largely explained by the excitatory circuity at this age (putamen, thalamus, perirolandic cerebral cortex). Finally, developing oligodendroglia is uniquely susceptible to hypoxia-ischemia, specifically excitotoxicity and free radical damage. This white matter injury may be the basis for the disruption of long-term learning and memory faculties in infants with hypoxic-ischemic encephalopathy.

Intracellular Ca++ concentration increases following hypoxia-ischemia as a result of (1) NMDA receptor activation, (2) release of Ca++ from intracellular stores (mitochondria and endoplasmic reticulum [ER]), and (3) failure of Ca++ efflux mechanisms. Consequences of increases intracellular Ca++ concentration include activation of phospholipases, endonucleases, proteases, and, in select neurons, nitric oxide synthase (NOS). Activation of phospholipase A2 leads to release of Ca++ from the ER via activation of phospholipase C. Activation of proteases and endonucleases results in cytoskeletal and DNA damage.

During the reperfusion period, free radical production increases due to activation of enzymes such as cyclooxygenase, xanthine oxidase, and lipoxygenase. Free radical damage is further exacerbated in the neonate because of immature antioxidant defenses. Free radicals can lead to lipid peroxidation as well as DNA and protein damage and can trigger apoptosis. Finally, free radicals can combine with nitric oxide (NO) to form peroxynitrite a highly toxic oxidant.

NMDA receptor activation results in activation of neuronal NOS vias PSD-95 and results in the early and transient rise in NO concentration observed in the initial phase of hypoxia. Inducible NOS is expressed in response to the marked inflammation secondary to cerebral ischemia and results in a second wave of NO overproduction that can be prolonged for up to 4-7 days after the insult.

This excessive NO production plays an important role in the pathophysiology of perinatal hypoxic-ischemic brain injury. NO neurotoxicity depends in large part on rapid reaction with superoxide to form peroxynitrite.[8] This, in turn, leads to peroxynitrite-induced neurotoxicity, including lipid peroxidation, protein nitration and oxidation, mitochondrial damage and remodeling, depletion of antioxidant reserve, and DNA damage.

Inflammatory mediators (cytokines and chemokines) have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy and may represent a final common pathway of brain injury. Animal studies suggest that cytokines, particularly interleukin (IL)-1b contributes to hypoxic-ischemic damage. The exact mechanisms and which inflammatory mediators are involved in this process remains unclear.

Following the initial phase of energy failure from the asphyxial injury, cerebral metabolism may recover following reperfusion, only to deteriorate in a secondary energy failure phase. This new phase of neuronal damage, starting at about 6-24 hours after the initial injury, is characterized by mitochondrial dysfunction, and initiation of the apoptotic cascade. This phase has been called the "delayed phase of neuronal injury."

The duration of the delayed phase is not precisely known in the human fetus and newborn but appears to increase over the first 24-48 hours and then start to resolve thereafter. In the human infant, the duration of this phase is correlated with adverse neurodevelopmental outcomes at 1 year and 4 years after insult.[9] See the image below.

Pathophysiology of hypoxic-ischemic brain injury iPathophysiology of hypoxic-ischemic brain injury in the developing brain. During the initial phase of energy failure, glutamate mediated excitotoxicity and Na+/K+ ATPase failure lead to necrotic cell death. After transient recovery of cerebral energy metabolism, a secondary phase of apoptotic neuronal death occurs. ROS = Reactive oxygen species.

Additional factors that influence outcome include the nutritional status of the brain, severe intrauterine growth restriction, preexisting brain pathology or developmental defects of the brain, and the frequency and severity of seizure disorder that manifests at an early postnatal age (within hours of birth).[10, 11, 12, 13, 14, 15]

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Epidemiology

Frequency

United States

In the United States and in most technologically advanced countries, the incidence of hypoxic-ischemic encephalopathy is 1-8 cases per 1000 births.

International

The incidence of hypoxic-ischemic encephalopathy is reportedly high in countries with limited resources; however, precise figures are not available. Birth asphyxia is the cause of 23% of all neonatal deaths worldwide. It is one of the top 20 leading causes of burden of disease in all age groups (in terms of disability life adjusted years) by the World Health Organization and is the fifth largest cause of death of children younger than 5 years (8%). Although data are limited, birth asphyxia is estimated to account for 920,000 neonatal deaths every year and is associated with another 1.1 million intrapartum stillbirths. More than a million children who survive birth asphyxia develop problems such as cerebral palsy, mental retardation, learning difficulties, and other disabilities.[16, 17]

Mortality/Morbidity

In severe hypoxic-ischemic encephalopathy, the mortality rate is reportedly 25-50%. Most deaths occur in the first week of life due to multiple organ failure or redirection of care. Some infants with severe neurologic disabilities die in their infancy from aspiration pneumonia or systemic infections.

The incidence of long-term complications depends on the severity of hypoxic-ischemic encephalopathy. As many as 80% of infants who survive severe hypoxic-ischemic encephalopathy develop serious complications, 10-20% develop moderately serious disabilities, and as many as 10% are healthy. Among the infants who survive moderately severe hypoxic-ischemic encephalopathy, 30-50% may have serious long-term complications, and 10-20% have minor neurological morbidities. Infants with mild hypoxic-ischemic encephalopathy tend to be free from serious CNS complications.

Two recent hypothermia trials provided updated information on mortality and the incidence of abnormal neurodevelopmental outcomes infants with moderate to severe hypoxic-ischemic encephalopathy.[18, 19] In these trials, 23-27% of infants died prior to discharge from the neonatal ICU (NICU), whereas the mortality rate at follow-up 18-22 months later was 37-38%. In these trials, neurodevelopmental outcomes at 18 months were as follows:

  • Mental development index (MDI)
    • Score of 85 or higher - 40%
    • Score of 70-84 - 21%
    • Score less than 70 - 39%
  • Psychomotor development index (PDI)
    • Score of 85 or higher - 55%
    • Score of 70-84 - 10%
    • Score less than 70 - 35-41%
  • Disabling cerebral palsy - 30%
  • Epilepsy - 16%
  • Blindness - 14-17%
  • Severe hearing impairment - 6%

Data from a randomized controlled trial was evaluated to determine the relationship between hypocarbia and the outcome for neonatal patients with hypoxic-ischemic encephalopathy. The results found that a poor outcome (death/disability at 18-22 mo) was associated with a minimum partial pressure of carbon dioxide (PCO2) and cumulative PCO2 of less than 35 mm Hg; death and disability increased with greater exposure to PCO2 of less than 35 mm Hg.[20]

Even in the absence of obvious neurologic deficits in the newborn period, long-term functional impairments may be present. In a cohort of school-aged children with a history of moderately severe hypoxic-ischemic encephalopathy, 15-20% had significant learning difficulties, even in the absence of obvious signs of brain injury. Thus, all children who have moderate or severe hypoxic-ischemic encephalopathy should be monitored well into school age.[21, 22, 23]

Race

No predilection is noted.

Sex

No predilection is observed.

Age

By definition, this disease is seen in the newborn period. Preterm infants can also suffer from hypoxic-ischemic encephalopathy, but the pathology and clinical manifestations are different. Most often, the condition is noted in infants who are term at birth. The symptoms of moderate-to-severe hypoxic-ischemic encephalopathy are almost always manifested at birth or within a few hours after birth.

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Contributor Information and Disclosures
Author

Santina A Zanelli, MD  Assistant Professor, Department of Pediatrics, Division of Neonatology, University of Virginia Health System

Santina A Zanelli, MD is a member of the following medical societies: American Academy of Pediatrics, Society for Neuroscience, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

Dirk P Stanley, MD  Resident Physician, Department of Pathology, University of Virginia Health System

Disclosure: Nothing to disclose.

David A Kaufman  MD, Associate Professor of Pediatrics, Division of Neonatology, University of Virginia Health System

David A Kaufman is a member of the following medical societies: American Academy of Pediatrics, European Society for Paediatric Infectious Diseases, Medical Society of Virginia, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Ted Rosenkrantz, MD  Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Brian S Carter, MD, FAAP  Professor of Pediatrics (Neonatology), Vanderbilt University School of Medicine; Director, Neonatal Follow-up Program, Monroe Carell Jr Children's Hospital at Vanderbilt

Brian S Carter, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Society for Bioethics and Humanities, American Society of Law, Medicine & Ethics, National Hospice and Palliative Care Organization, Society for Pediatric Research, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Carol L Wagner, MD  Professor of Pediatrics, Medical University of South Carolina

Carol L Wagner, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American Medical Women's Association, American Public Health Association, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, Massachusetts Medical Society, National Perinatal Association, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD  Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Tonse NK Raju, MD, to the development and writing of this article.

References

  1. [Guideline] American Academy of Pediatrics. Relation between perinatal factors and neurological outcome. In: Guidelines for Perinatal Care. 3rd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1992:221-234.

  2. [Guideline] Committee on fetus and newborn, American Academy of Pediatrics and Committee on obstetric practice, American College of Obstetrics and Gynecology. Use and abuse of the APGAR score. Pediatr. 1996;98:141-142. [Medline].

  3. Ferriero DM. Neonatal brain injury. N Engl J Med. Nov 4 2004;351(19):1985-95. [Medline].

  4. Perlman JM. Brain injury in the term infant. Semin Perinatol. Dec 2004;28(6):415-24. [Medline].

  5. Grow J, Barks JD. Pathogenesis of hypoxic-ischemic cerebral injury in the term infant: current concepts. Clin Perinatol. Dec 2002;29(4):585-602, v. [Medline].

  6. Papile LA, Rudolph AM, Heymann MA. Autoregulation of cerebral blood flow in the preterm fetal lamb. Pediatr Res. Feb 1985;19(2):159-61. [Medline].

  7. Rosenkrantz TS, Diana D, Munson J. Regulation of cerebral blood flow velocity in nonasphyxiated, very low birth weight infants with hyaline membrane disease. J Perinatol. 1988;8(4):303-8. [Medline].

  8. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. Jan 2007;87(1):315-424. [Medline].

  9. Roth SC, Baudin J, Cady E, Johal K, Townsend JP, Wyatt JS. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol. Nov 1997;39(11):718-25. [Medline].

  10. Berger R, Garnier Y. Pathophysiology of perinatal brain damage. Brain Res Brain Res Rev. Aug 1999;30(2):107-34. [Medline].

  11. Rivkin MJ. Hypoxic-ischemic brain injury in the term newborn. Neuropathology, clinical aspects, and neuroimaging. Clin Perinatol. Sep 1997;24(3):607-25. [Medline].

  12. Vannucci RC. Mechanisms of perinatal hypoxic-ischemic brain damage. Semin Perinatol. Oct 1993;17(5):330-7. [Medline].

  13. Vannucci RC, Yager JY, Vannucci SJ. Cerebral glucose and energy utilization during the evolution of hypoxic-ischemic brain damage in the immature rat. J Cereb Blood Flow Metab. Mar 1994;14(2):279-88. [Medline].

  14. de Haan HH, Hasaart TH. Neuronal death after perinatal asphyxia. Eur J Obstet Gynecol Reprod Biol. Aug 1995;61(2):123-7. [Medline].

  15. McLean C, Ferriero D. Mechanisms of hypoxic-ischemic injury in the term infant. Semin Perinatol. Dec 2004;28(6):425-32. [Medline].

  16. Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lancet. Mar 26-Apr 1 2005;365(9465):1147-52. [Medline].

  17. Lawn J, Shibuya K, Stein C. No cry at birth: global estimates of intrapartum stillbirths and intrapartum-related neonatal deaths. Bull World Health Organ. Jun 2005;83(6):409-17. [Medline].

  18. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomised trial. Lancet. 2005;365:663-70. [Medline].

  19. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. Oct 13 2005;353(15):1574-84. [Medline].

  20. Pappas A, Shankaran S, Laptook AR, et al. Hypocarbia and adverse outcome in neonatal hypoxic-ischemic encephalopathy. J Pediatr. May 2011;158(5):752-758.e1. [Medline].

  21. van Handel M, Swaab H, de Vries LS, Jongmans MJ. Long-term cognitive and behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a review. Eur J Pediatr. Jul 2007;166(7):645-54. [Medline].

  22. Pin TW, Eldridge B, Galea MP. A review of developmental outcomes of term infants with post-asphyxia neonatal encephalopathy. Eur J Paediatr Neurol. May 2009;13(3):224-34. [Medline].

  23. Simon NP. Long-term neurodevelopmental outcome of asphyxiated newborns. Clin Perinatol. Sep 1999;26(3):767-78. [Medline].

  24. Martin-Ancel A, Garcia-Alix A, Gaya F, Cabanas F, Burgueros M, Quero J. Multiple organ involvement in perinatal asphyxia. J Pediatr. 1995;127:786-793. [Medline].

  25. Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2004;89:F152-F155. [Medline].

  26. Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology. Dec 1987;37(12):1837-44. [Medline].

  27. Hahn JS, Olson DM. Etiology of Neonatal Seizures. NeoReviews. 2004;5(8):e327.

  28. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: A clinical and electroencphalographic study. Archives of Neur. 1976;33:696-705.

  29. Badawi N, Kurinczuk JJ, Keogh JM, et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. British Medical Journal. 1998;317:1549-1553. [Medline].

  30. Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol. Dec 2008;199(6):587-95. [Medline].

  31. Enns, GM. Inborn errors of metabolism masquerading as hypoxic-ischemic encephalopathy. Neoreviews. 2005;6:e549-e558.

  32. Hobson EE, Thomas S, Crofton PM, Murray AD, Dean JC, Lloyd D. Isolated sulphite oxidase deficiency mimics the features of hypoxic ischaemic encephalopathy. Eur J Pediatr. Nov 2005;164(11):655-9. [Medline].

  33. Shastri AT, Samarasekara S, Muniraman H, Clarke P. Cardiac troponin I concentrations in neonates with hypoxic-ischaemic encephalopathy. Acta Paediatr. Jan 2012;101(1):26-9. [Medline].

  34. Huang BY, Castillo M. Hypoxic-ischemic brain injury: imaging findings from birth to adulthood. Radiographics. Mar-Apr 2008;28(2):417-39; quiz 617. [Medline].

  35. Latchaw RE, Truwit CE. Imaging of perinatal hypoxic-ischemic brain injury. Semin Pediatr Neurol. Mar 1995;2(1):72-89. [Medline].

  36. Rutherford M, Pennock J, Schwieso J, Cowan F, Dubowitz L. Hypoxic-ischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome. Arch Dis Child Fetal Neonatal Ed. 1996;75:F145-F151. [Medline].

  37. Cowan FM, de Vries LS. The internal capsule in neonatal imaging. Semin Fetal Neonatal Med. Oct 2005;10(5):461-74. [Medline].

  38. Martinez-Biarge M, Diez-Sebastian J, Kapellou O, et al. Predicting motor outcome and death in term hypoxic-ischemic encephalopathy. Neurology. Jun 14 2011;76(24):2055-61. [Medline]. [Full Text].

  39. Brenner, D.J. Estimating cancer risks from pediatric CT: going from the qualitative to the quantitative. Pediatr. Radiol. 1996;32:228-231. [Medline].

  40. de Vries LS, Toet MC. Amplitude integrated electroencephalography in the full-term newborn. Clin Perinatol. 2006;33:619-632. [Medline].

  41. Hellstrom-Westas L, Rosen I. Continuous brain-function monitoring: state of the art in clinical practice. Semin Fetal Neonatal Med. 2006;11:503-511. [Medline].

  42. van Rooij LGM, Toet MC, Osredkar D, van Huffelen AC, Groenendaal F, de Vries LS. Recovery of amplitude integrated electroencephalographic background patterns within 24 hours of perinatal asphyxia. Arch. Dis. Child. Fetal Neonatal Ed. 2005;90:F245-F251. [Medline].

  43. [Best Evidence] Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2007;4:CD003311. [Medline].

  44. Spitzmiller RE, Phillips T, Meinzen-Derr J, Hoath SB. Amplitude-integrated EEG is useful in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischemic encephalopathy: a meta-analysis. Journal of Child Neurology. 2007;22:1069-1078. [Medline].

  45. Pressler RM, Boylan GB, Morton M, Binnie CD, Rennie JM. Early serial EEG in hypoxic ischaemic encephalopathy. Clinical neurophysiology. 2001;112:31-37. [Medline].

  46. Rowe JC, Holmes GL, Hafford J, et al. Prognostic value of the electroencephalogram in term and preterm infants following neonatal seizures. Electroencephalogr Clin Neurophysiol. Mar 1985;60(3):183-96. [Medline].

  47. Murray DM, Boylan GB, Ryan CA, Connolly S. Early EEG Findings in Hypoxic-Ischemic Encephalopathy Predict Outcomes at 2 Years. Pediatrics. Aug 24 2009;[Medline].

  48. Sinclair DB, Campbell M, Byrne P, Prasertsom W, Robertson CMT. EEG and long-term outcome of term infants with neonatal hypoxic-ischemic encephalopathy. Clinical neurophysiology. 1999;110:655-659. [Medline].

  49. Shankaran S. The postnatal management of the asphyxiated term infant. Clin Perinatol. Dec 2002;29(4):675-92. [Medline].

  50. Stola A, Perlman J. Post-resuscitation strategies to avoid ongoing injury following intrapartum hypoxia-ischemia. Semin Fetal Neonatal Med. Dec 2008;13(6):424-31. [Medline].

  51. Perlman JM. Intervention strategies for neonatal hypoxic-ischemic cerebral injury. Clin Ther. Sep 2006;28(9):1353-65. [Medline].

  52. [Guideline] Ten VS, Matsiukevich D. Room air or 100% oxygen for resuscitation of infants with perinatal depression. Curr Opin Pediatr. Apr 2009;21(2):188-93. [Medline].

  53. [Guideline] American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics. Aug 2000;106(2 Pt 1):344-5. [Medline].

  54. [Best Evidence] Kecskes Z, Healy G, Jensen A. Fluid restriction for term infants with hypoxic-ischaemic encephalopathy following perinatal asphyxia. Cochrane Database Syst Rev. Jul 20 2005;CD004337. [Medline].

  55. Bakr AF. Prophylactic theophylline to prevent renal dysfunction in newborns exposed to perinatal asphyxia--a study in a developing country. Pediatr. Nephrol. 2005;20:1249-1252. [Medline].

  56. Bhat MA, Shah ZA, Makhdoomi MS, Mufti MH. Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial. J. Pediatr. 2006;149:180-184. [Medline].

  57. Jenik AG, Ceriani Cernadas JM, Gorenstein A, et al. A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia. Pediatrics. 2000;105:E45. [Medline].

  58. Salhab WA, Wyckoff MH, Laptook AR, Perlman JM. Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia. Pediatrics. Aug 2004;114(2):361-6. [Medline].

  59. Laptook A, Tyson J, Shankaran S, et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics. Sep 2008;122(3):491-9. [Medline].

  60. Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. Feb 26 2002;58(4):542-8. [Medline].

  61. Scher MS. Neonatal seizures and brain damage. Pediatr Neurol. Nov 2003;29(5):381-90. [Medline].

  62. Holmes GL. Effects of seizures on brain development: lessons from the laboratory. Pediatr Neurol. Jul 2005;33(1):1-11. [Medline].

  63. Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology. Feb 10 2004;62(3):486-8. [Medline].

  64. Boylan GB, Rennie JM, Pressler RM, Wilson G, Morton M, Binnie CD. Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed. May 2002;86(3):F165-70. [Medline].

  65. Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. Aug 12 1999;341(7):485-9. [Medline].

  66. Castro Conde JR, Hernandez Borges AA, et al. Midazolam in neonatal seizures with no response to phenobarbital. Neurology. Mar 8 2005;64(5):876-9. [Medline].

  67. Maytal J, Novak GP, King KC. Lorazepam in the treatment of refractory neonatal seizures. J Child Neurol. Oct 1991;6(4):319-23. [Medline].

  68. Gunn AJ, Gunn TR. The 'pharmacology' of neuronal rescue with cerebral hypothermia. Early Hum Dev. Nov 1998;53(1):19-35. [Medline].

  69. Gunn AJ. Cerebral hypothermia for prevention of brain injury following perinatal asphyxia. Curr Opin Pediatr. 2000;12(2):111-115. [Medline].

  70. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol. 2005;32 (1):18-24. [Medline].

  71. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2006;34(2):169. [Medline].

  72. Jacobs SE, Morley CJ, Inder TE, et al. Whole-Body Hypothermia for Term and Near-Term Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Controlled Trial. Arch Pediatr Adolesc Med. Aug 2011;165(8):692-700. [Medline].

  73. Zhou WH, Cheng GQ, Shao XM, et al. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr. Sep 2010;157(3):367-72, 372.e1-3. [Medline].

  74. Simbruner G, Mittal RA, Rohlmann F, Muche R. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. Oct 2010;126(4):e771-8. [Medline].

  75. [Best Evidence] Azzopardi DV, Strohm B, Edwards AD, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. Oct 1 2009;361(14):1349-58. [Medline].

  76. Shankaran S, Pappas A, Laptook AR, et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics. Oct 2008;122(4):e791-8. [Medline].

  77. Laptook AR. Use of therapeutic hypothermia for term infants with hypoxic-ischemic encephalopathy. Pediatr Clin North Am. Jun 2009;56(3):601-16, Table of Contents. [Medline].

  78. Shankaran S. Neonatal encephalopathy: treatment with hypothermia. J Neurotrauma. Mar 2009;26(3):437-43. [Medline].

  79. Wilkinson DJ. Cool heads: ethical issues associated with therapeutic hypothermia for newborns. Acta Paediatr. Feb 2009;98(2):217-20. [Medline].

  80. Perlman M, Shah PS. Ethics of therapeutic hypothermia. Acta Paediatr. Feb 2009;98(2):211-3. [Medline].

  81. Edwards AD, Azzopardi DV. Therapeutic hypothermia following perinatal asphyxia. Arch Dis Child Fetal Neonatal ed. 2006;91:F127-F131. [Medline].

  82. Fairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. Journal of Perinatology. 2009;In press.

  83. Schulzke SM, Rao S, Patole SK. A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy - are we there yet?. BMC Pediatrics. 2007;7:30. [Medline].

  84. Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. Arch Pediatr Adolesc Med. 2007;161:951-958. [Medline].

  85. Zanelli SA, Naylor M, Dobbins N, et al. Implementation of a 'Hypothermia for HIE' program: 2-year experience in a single NICU. J Perinatol. 2008;28(3):171-175. [Medline].

  86. Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics. Dec 1997;100(6):1004-14. [Medline].

  87. Hall RT, Hall FK, Daily DK. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr. Feb 1998;132(2):345-8. [Medline].

  88. Goldberg RN, Moscoso P, Bauer CR, et al. Use of barbiturate therapy in severe perinatal asphyxia: a randomized controlled trial. J Pediatr. Nov 1986;109(5):851-6. [Medline].

  89. [Best Evidence] Evans DJ, Levene MI, Tsakmakis M. Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Database Syst Rev. Jul 18 2007;CD001240. [Medline].

  90. Zhu C, Kang W, Xu F, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. Aug 2009;124(2):e218-26. [Medline].

  91. Van Bel F, Shadid M, Moison RM, et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics. Feb 1998;101(2):185-93. [Medline]. [Full Text].

  92. Robertson CM, Perlman M. Follow-up of the term infant after hypoxic-ischemic encephalopathy. Paediatr Child Health. May 2006;11(5):278-82. [Medline].

  93. Depp R. Perinatal asphyxia: assessing its causal role and timing. Semin Pediatr Neurol. Mar 1995;2(1):3-36. [Medline].

  94. Patel J, Edwards AD. Prediction of outcome after perinatal asphyxia. Curr Opin Pediatr. Apr 1997;9(2):128-32. [Medline].

  95. Gunn AJ, Wyatt JS, Whitelaw A, et al. Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy. J Pediatr. Jan 2008;152(1):55-8, 58.e1. [Medline].

  96. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. 1: J Clin Invest. 1997;99(2):248-256. [Medline].

  97. Gunn AJ, Hoehn T, Hansmann G, et al. Hypothermia: an evolving treatment for neonatal hypoxic ischemic encephalopathy. Pediatrics. 2008;121:648-649. [Medline].

  98. Volpe JJ. Hypoxic-ischemic encephalopathy. In: Neurology of the newborn. 5th. Saunders - Elsevier; 2008:6-9.

 
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Fetal response to asphyxia illustrating the initial redistribution of blood flow to vital organs. With prolonged asphyxial insult and failure of compensatory mechanisms, cerebral blood flow falls, leading to ischemic brain injury.
Pathophysiology of hypoxic-ischemic brain injury in the developing brain. During the initial phase of energy failure, glutamate mediated excitotoxicity and Na+/K+ ATPase failure lead to necrotic cell death. After transient recovery of cerebral energy metabolism, a secondary phase of apoptotic neuronal death occurs. ROS = Reactive oxygen species.
Risk factors for neonatal encephalopathy.
Severe acute hypoxic-ischemic neuronal change in the basal ganglia is noted. Histologic examination reveals severe hypoxic-ischemic neuronal change, characterized by the presence of pyknotic and hyperchromatic nuclei, the loss of cytoplasmic Nissl substance, and neuronal shrinkage and angulation (arrow). These alterations begin to appear approximately 6 hours following hypoxic-ischemic insult. Reactive astrocytosis is evident approximately 24-48 hours after the primary hypoxic-ischemic event.
Significant astrocytosis in the basal ganglia following hypoxic-ischemic insult is observed. An immunohistochemical stain for glial fibrillary acidic protein (GFAP) was performed on the same tissue shown in the previous image to demonstrate the prominent gliosis secondary to the hypoxic-ischemic event. GFAP is a useful marker to study astrocytic response to injury. This gliosis of the basal ganglia, along with subsequent hypermyelination, is responsible for the evolution of status marmoratus over months to years.
Bilateral acute infarctions of the frontal lobe are shown. The infarctions depicted in the figure (arrows) are consistent with watershed infarctions secondary to global hypoperfusion. The lesions depicted in the image are consistent with an acute ischemic event, occurring within 24 hours of death. The regions most susceptible to hypoperfusion include the end-artery zones between the anterior, middle, and posterior cerebral arteries.
A prior hypoxic-ischemic event involving the occipital lobe has resulted in a chronic lesion marked by dyslamination, neuronal loss, and disorganized arrangements of myelinated white matter fibers. Grossly, the lesion was marked by preserved gyral crests and involved sulci, resulting in prominent, mushroom-shaped gyri.
A Luxol-Fast Blue stain was performed on the same tissue shown in the previous image to demonstrate the haphazard arrangement of myelinated white matter fibers projecting into the gray matter of the occipital cortex.
Randomized controlled trials of therapeutic hypothermia for moderate-to-severe hypoxic-ischemic encephalopathy (HIE).
Periventricular leukomalacia is depicted. This cystic lesion, present in the cingulate cortex, is consistent with periventricular leukomalacia. Note the extensive hemorrhage within the cystic space as well as the hemosiderin-laden macrophages around the lesional rim.
Periventricular leukomalacia is depicted. This figure depicts the lesion seen in the previous image at higher magnification. Extensive hemosiderin and reactive astrocytosis is present surrounding the lesion (center of field). Note the proximity of the lesion to the ependymal lining of the lateral ventricle (far right).
Summary of potential neuroprotective strategies.
Table. Sarnat Clinical Stages of Perinatal Hypoxic Ischemic Brain Injury[28]
State 1Stage 2Stage 3
Level of ConsciousnessHyperalertLethargic or obtundedStuporous
Neuromuscular Control
Muscle toneNormalMild hypotoniaFlaccid
PostureMild distal flexionStrong distal flexionIntermittent decerebration
Stretch reflexesOveractiveOveractiveDecreased or absent
Segmental myoclonusPresentPresentAbsent
Complex Reflexes
SuckWeakWeak or absentAbsent
MoroStrong; low thresholdWeak; incomplete; high thresholdAbsent
OculovestibularNormalOveractiveWeak or absent
Tonic neckSlightStrongAbsent
Autonomic FunctionGeneralized sympatheticGeneralized parasympatheticBoth systems depressed
PupilsMydriasisMiosisVariable; often unequal; poor light reflex
Heart RateTachycardiaBradycardiaVariable
Bronchial and Salivary SecretionsSparseProfuseVariable
GI MotilityNormal or decreasedIncreased; diarrheaVariable
SeizuresNoneCommon; focal or multifocalUncommon (excluding decerebration)
EEG FindingsNormal (awake)Early: low-voltage continuous delta and theta



Later: periodic pattern (awake)



Seizures: focal 1-to 1-Hz spike-and-wave



Early: periodic pattern with Isopotential phases



Later: totally isopotential



Duration1-3 days2-14Hours to weeks
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