eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology
Hypoxic-Ischemic Encephalopathy
Updated: Dec 15, 2008
Introduction
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 underlying cause remains unknown. The exact time of brain injury often remains uncertain, and an abnormal brain (eg, growth failure, impaired development) might be an underlying risk factor.
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
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. The initial compensatory adjustment to an asphyxial event is an increase in the CBF due to hypoxia and hypercapnia. This is accompanied by a redistribution of cardiac output such that the brain receives an increased proportion of the cardiac output. A borderline increase in the systemic blood pressure (BP) further enhances the compensatory response. The BP increase is due to increased release of epinephrine; these are classic early cardiovascular compensatory responses to asphyxia.
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.
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 to maintain the 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 has been shown to be 60-100 mm Hg. However, such a range of BP in the human fetus and the newborn infant has not been studied with much rigor due to limitations of human experimentation in the fetus and newborn.
Limited data on the preterm infant suggest that CBF is stable over a range of BPs. Based on this human data, along with other animal data, some experts have postulated that, in the healthy term newborn, the BP range at which the CBF autoregulation is maintained is quite narrow (perhaps between 10-20 mm Hg, compared with the 40 mm Hg range in adults noted above). 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 remains 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 is depends on systemic BP. As BP falls, CBF falls below critical levels, and the brain suffers from diminished blood supply and a lack of sufficient oxygen to meet its needs. This leads to intracellular energy failure. During the early phases of brain injury, brain temperature drops, and local release of neurotransmitters, such as g -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 both the severity of the initial insult and the damage due to energy failure, reperfusion injury, and apoptosis. The extent, nature, severity, and the duration of the primary injury are all important in affecting the magnitude of the residual neurological damage.
Following the initial phase of energy failure from the asphyxial injury, cerebral metabolism may recover, only to deteriorate in the secondary phase, or reperfusion. This new phase of neuronal damage, starting at about 6-24 hours after the initial injury, is characterized by cerebral edema and apoptosis. 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.
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.
{{mediacaption:1484988_1}}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).
At the biochemical level, a large cascade of events follow hypoxic-ischemic encephalopathy injury. Both hypoxia and ischemia increase the release of excitatory amino acids (EAAs), such as glutamate and aspartate, in the cerebral cortex and basal ganglia. EAAs cause neuronal death through the activation of receptor subtypes such as kainate, N-methyl-D-aspartate (NMDA), and amino-3-hydroxy-5-methyl-4 isoxazole propionate (AMPA). Activation of receptors with associated opening of ion channels (eg, NMDA) lead to increased intracellular and subcellular calcium concentration and cell death. A second important mechanism for the destruction of ion pumps is the lipid peroxidation of cell membranes, in which enzyme systems, such as the Na+/K+-ATPase, reside; this can cause cerebral edema and neuronal death. EAAs also increase the local release of nitric oxide (NO), which may exacerbate neuronal damage, although its mechanisms are unclear.
The EAAs may also disrupt the factors that control apoptosis, increasing the pace and extent of programmed cell death. One mechanism for apoptosis or programmed cell death is thought to be related to calcium influx into the cell and nucleus of the cell after activation of the EAAs. The regional differences in severity of injury may be explained by the fact that EAAs particularly affect the CA1 regions of the hippocampus, the developing oligodendroglia, and the subplate neurons along the borders of the periventricular region in the developing brain. This may be the basis for the disruption of long-term learning and memory faculties in infants with hypoxic-ischemic encephalopathy.
Frequency
United States
In the United States and in most technologically advanced countries, the incidence of severe (stage 3) hypoxic-ischemic encephalopathy is between 2-4 cases per 1000 births.
International
Hypoxic-ischemic encephalopathy is reported to be high in countries with limited resources; however, precise figures are not available. The World Health Organization (WHO) reports that approximately 1 million children worldwide die from a diagnosis of birth asphyxia, and about the same number may survive with significant long-term neurological disability.
Mortality/Morbidity
In severe hypoxic-ischemic encephalopathy, the mortality rate has been reported to be 50-75%. Most deaths (55%) 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.Among the infants who survive severe hypoxic-ischemic encephalopathy, the sequelae include mental retardation, epilepsy, and cerebral palsy of varying degrees. The latter can be in the form of hemiplegia, paraplegia, or quadriplegia. Such infants need careful evaluation and support. They may need to be referred to specialized clinics capable of providing coordinated comprehensive follow-up care.
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.
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 their school ages.
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 manifestations are slightly 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.
Clinical
History
Per the 1996 guidelines of the AAP and the ACOG for hypoxic-ischemic encephalopathy (HIE), all of the following must be present for the designation of perinatal asphyxia severe enough to result in acute neurological injury:1,2- Profound metabolic or mixed acidemia (pH <7) in an umbilical artery blood sample, if obtained
- Persistence of an Apgar score of 0-3 for longer than 5 minutes
- Neonatal neurologic sequelae (eg, seizures, coma, hypotonia)
- Multiple organ involvement (eg, kidney, lungs, liver, heart, intestines)
- On rare occasions, difficulties with delivery, particularly problems with delivering the head in breech presentation, suggest an alternate diagnosis of hemorrhage in the posterior cerebral fossa, which is a rare condition.
- However, infants may have experienced asphyxia or brain hypoxia remote from the time of delivery and may have exhibited the signs and symptoms of hypoxic encephalopathy prior to the time of birth and, therefore, may not meet all of the criteria set forth by the AAP and ACOG.
Physical
CNS manifestations
Clinical manifestations and course vary depending on hypoxic-ischemic encephalopathy severity.
- Mild hypoxic-ischemic encephalopathy
- Muscle tone may be slightly increased and deep tendon reflexes may be brisk during the first few days.
- Transient behavioral abnormalities, such as poor feeding, irritability, or excessive crying or sleepiness, may be observed.
- By 3-4 days of life, the CNS examination findings become normal.
- Moderately severe hypoxic-ischemic encephalopathy
- The infant is lethargic, with significant hypotonia and diminished deep tendon reflexes.
- The grasping, Moro, and sucking reflexes may be sluggish or absent.
- The infant may experience occasional periods of apnea.
- Seizures may occur within the first 24 hours of life.
- Full recovery within 1-2 weeks is possible and is associated with a better long-term outcome.
- An initial period of well-being or mild hypoxic-ischemic encephalopathy may be followed by sudden deterioration, suggesting ongoing brain cell dysfunction, injury, and death; during this period, seizure intensity might increase.
- Severe hypoxic-ischemic encephalopathy
- Stupor or coma is typical. The infant may not respond to any physical stimulus.
- Breathing may be irregular, and the infant often requires ventilatory support.
- Generalized hypotonia and depressed deep tendon reflexes are common.
- Neonatal reflexes (eg, sucking, swallowing, grasping, Moro) are absent.
- Disturbances of ocular motion, such as a skewed deviation of the eyes, nystagmus, bobbing, and loss of "doll's eye" (ie, conjugate) movements may be revealed by cranial nerve examination.
- Pupils may be dilated, fixed, or poorly reactive to light.
- Seizures occur early and often and may be initially resistant to conventional treatments. The seizures are usually generalized, and their frequency may increase during the 24-48 hours after onset, correlating with the phase of reperfusion injury. As the injury progresses, seizures subside and the EEG becomes isoelectric or shows a burst suppression pattern. At that time, wakefulness may deteriorate further, and the fontanelle may bulge, suggesting increasing cerebral edema.
- Irregularities of heart rate and blood pressure (BP) are common during the period of reperfusion injury, as is death from cardiorespiratory failure.
- Infants who survive severe hypoxic-ischemic encephalopathy
- The level of alertness improves by days 4-5 of life.
- Hypotonia and feeding difficulties persist, requiring tube feeding for weeks to months.
Multiorgan dysfunction
Multiorgan systems involvement is a hallmark of hypoxic-ischemic encephalopathy. Organ systems involved following a hypoxic-ischemic events include the following:
- Heart (43-78%): May present as reduced myocardial contractility, severe hypotension, passive cardiac dilatation, and tricuspid regurgitation.
- Lungs (71-86%): Patients may have severe pulmonary hypertension requiring assisted ventilation
- Renal (46-72%): Renal failure presents as oliguria and, during recovery, as high-output tubular failure, leading to significant water and electrolyte imbalances.
- Liver (80-85%): Elevated liver function test results, hyperammonemia, and coagulopathy can be seen. This may suggest possible GI dysfunction. Poor peristalsis and delayed gastric emptying are common; necrotizing enterocolitis is rare. Intestinal injuries may not be apparent in the first few days of life or until feeds are initiated.
- Hematologic (32-54%): Disturbances include increased nucleated RBCs, neutropenia or neutrophilia, thrombocytopenia, and coagulopathy. Severely depressed respiratory and cardiac functions and signs of brainstem compression suggest a life-threatening rupture of the vein of Galen (ie, great cerebral vein) with a hematoma in the posterior cranial fossa.
Sarnat staging system
The staging system proposed by Sarnat and Sarnat in 1976 is often useful in classifying the degree of encephalopathy.3 Stages I, II, and III correlate with the descriptions of mild, moderate, and severe encephalopathy described above.
Open table in new window
Table
| State 1 | Stage 2 | Stage 3 | |
|---|---|---|---|
| Level of Consciousness | Hyperalert | Lethargic or obtunded | Stuporous |
| Neuromuscular Control | |||
| Muscle tone | Normal | Mild hypotonia | Flaccid |
| Posture | Mild distal flexion | Strong distal flexion | Intermittent decerebration |
| Stretch reflexes | Overactive | Overactive | Decreased or absent |
| Segmental myoclonus | Present | Present | Absent |
| Complex Reflexes | |||
| Suck | Weak | Weak or absent | Absent |
| Moro | Strong; low threshold | Weak; incomplete; high threshold | Absent |
| Oculovestibular | Normal | Overactive | Weak or absent |
| Tonic neck | Slight | Strong | Absent |
| Autonomic Function | Generalized sympathetic | Generalized parasympathetic | Both systems depressed |
| Pupils | Mydriasis | Miosis | Variable; often unequal; poor light reflex |
| Heart Rate | Tachycardia | Bradycardia | Variable |
| Bronchial and Salivary Secretions | Sparse | Profuse | Variable |
| GI Motility | Normal or decreased | Increased; diarrhea | Variable |
| Seizures | None | Common; focal or multifocal | Uncommon (excluding decerebration) |
| EEG Findings | Normal (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 |
| Duration | 1-3 days | 2-14 | Hours to weeks |
| State 1 | Stage 2 | Stage 3 | |
|---|---|---|---|
| Level of Consciousness | Hyperalert | Lethargic or obtunded | Stuporous |
| Neuromuscular Control | |||
| Muscle tone | Normal | Mild hypotonia | Flaccid |
| Posture | Mild distal flexion | Strong distal flexion | Intermittent decerebration |
| Stretch reflexes | Overactive | Overactive | Decreased or absent |
| Segmental myoclonus | Present | Present | Absent |
| Complex Reflexes | |||
| Suck | Weak | Weak or absent | Absent |
| Moro | Strong; low threshold | Weak; incomplete; high threshold | Absent |
| Oculovestibular | Normal | Overactive | Weak or absent |
| Tonic neck | Slight | Strong | Absent |
| Autonomic Function | Generalized sympathetic | Generalized parasympathetic | Both systems depressed |
| Pupils | Mydriasis | Miosis | Variable; often unequal; poor light reflex |
| Heart Rate | Tachycardia | Bradycardia | Variable |
| Bronchial and Salivary Secretions | Sparse | Profuse | Variable |
| GI Motility | Normal or decreased | Increased; diarrhea | Variable |
| Seizures | None | Common; focal or multifocal | Uncommon (excluding decerebration) |
| EEG Findings | Normal (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 |
| Duration | 1-3 days | 2-14 | Hours to weeks |
Causes
Badawi et al investigated risk factors of neonatal encephalopathy in the Western Australian case control study.4,5 Of the 164 infants with moderate-to-severe neonatal encephalopathy, preconceptual and antepartum risk factors were identified in 69% of cases; 24% of infants had antepartum and intrapartum risk factors, 5% had only intrapartum risk factors; and 5% had no risk factors.
Risk factors for neonatal encephalopathy.
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References
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.
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].
Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: A clinical and electroencphalographic study. Archives of Neur. 1976;33:696-705.
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].
Badawi N, Kurinczuk JJ, Keogh JM, et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. British Medical Journal. 1998;317:1554-1558. [Medline].
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].
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].
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].
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].
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].
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].
Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol. 2005;32 (1):18-24. [Medline].
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].
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].
Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. Arch Pediatr Adolesc Med. 2007;161:951-958. [Medline].
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].
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].
Berger R, Garnier Y. Pathophysiology of perinatal brain damage. Brain Res Brain Res Rev. Aug 1999;30(2):107-34. [Medline].
Brenner, D.J. Estimating cancer risks from pediatric CT: going from the qualitative to the quantitative. Pediatr. Radiol. 1996;32:228-231. [Medline].
de Haan HH, Hasaart TH. Neuronal death after perinatal asphyxia. Eur J Obstet Gynecol Reprod Biol. Aug 1995;61(2):123-7. [Medline].
de Vries LS, Toet MC. Amplitude integrated electroencephalography in the full-term newborn. Clin Perinatol. 2006;33:619-632. [Medline].
Depp R. Perinatal asphyxia: assessing its causal role and timing. Semin Pediatr Neurol. Mar 1995;2(1):3-36. [Medline].
Edwards AD, Azzopardi DV. Therapeutic hypothermia following perinatal asphyxia. Arch Dis Child Fetal Neonatal ed. 2006;91:F127-F131. [Medline].
Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2006;34(2):169. [Medline].
Enns, GM. Inborn errors of metabolism masquerading as hypoxic-ischemic encephalopathy. Neoreviews. 2005;6:e549-e558.
Gunn AJ, Gunn TR. The 'pharmacology' of neuronal rescue with cerebral hypothermia. Early Hum Dev. Nov 1998;53(1):19-35. [Medline].
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].
Gunn AJ, Hoehn T, Hansmann G, et al. Hypothermia: an evolving treatment for neonatal hypoxic ischemic encephalopathy. Pediatrics. 2008;121:648-649. [Medline].
Gunn AJ. Cerebral hypothermia for prevention of brain injury following perinatal asphyxia. Curr Opin Pediatr. 2000;12(2):111-115. [Medline].
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].
Latchaw RE, Truwit CE. Imaging of perinatal hypoxic-ischemic brain injury. Semin Pediatr Neurol. Mar 1995;2(1):72-89. [Medline].
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].
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].
Patel J, Edwards AD. Prediction of outcome after perinatal asphyxia. Curr Opin Pediatr. Apr 1997;9(2):128-32. [Medline].
Pressler RM, Boylan GB, Morton M, Binnie CD, Rennie JM. Early serial EEG in hypoxic ischaemic encephalopathy. Clinical neurophysiology. 2001;112:31-37. [Medline].
Rivkin MJ. Hypoxic-ischemic brain injury in the term newborn. Neuropathology, clinical aspects, and neuroimaging. Clin Perinatol. Sep 1997;24(3):607-25. [Medline].
Roohey T, Raju TN, Moustogiannis AN. Animal models for the study of perinatal hypoxic-ischemic encephalopathy: a critical analysis. Early Hum Dev. Jan 20 1997;47(2):115-46. [Medline].
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].
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].
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].
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].
Simon NP. Long-term neurodevelopmental outcome of asphyxiated newborns. Clin Perinatol. Sep 1999;26(3):767-78. [Medline].
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].
Thorngren-Jerneck K, Alling C, Herbst A, et al. S100 Protein in Serum as a Prognostic Marker for Cerebral Injury in Term Newborn Infants with Hypoxic Ischemic Encephalopathy. Pediatr Res. Nov 19 2003;[Medline].
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].
Vannucci RC. Mechanisms of perinatal hypoxic-ischemic brain damage. Semin Perinatol. Oct 1993;17(5):330-7. [Medline].
Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics. Dec 1997;100(6):1004-14. [Medline].
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].
Volpe JJ. Hypoxic-ischemic encephalopathy. In: Neurology of the newborn. 5th. Saunders - Elsevier; 2008:6-9.
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].
Further Reading
Keywords
hypoxic-ischemic encephalopathy, neonatal Encephalopathy, hypothermia, HIE, perinatal asphyxia, birth asphyxia, neonatal asphyxia, hypoxia, acidosis, ischemia, cerebral blood flow, CBF, multiple organ failure, aspiration pneumonia, mental retardation, epilepsy, cerebral palsy, hemiplegia, paraplegia, quadriplegia, stupor coma, poor sucking, seizures, reperfusion injury, tricuspid regurgitation, pulmonary hypertension, renal failure, oliguria, tubular failure, electrolyte imbalances, necrotizing enterocolitis, delayed gastric emptying, thrombocytopenia, coagulopathy
