Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Hypoxic-Ischemic Encephalopathy Workup

  • Author: Santina A Zanelli, MD; Chief Editor: Ted Rosenkrantz, MD  more...
 
Updated: Jan 16, 2015
 

Laboratory Studies

There are nor specific tests to confirm or exclude a diagnosis of hypoxic-ischemic encephalopathy (HIE) because the diagnosis is made based on the history, physical and neurological examinations, and laboratory evidence. Many of the tests are performed to assess the severity of brain injury and to monitor the functional status of systemic organs. As always, the results of the tests should be interpreted in conjunction with the clinical history and the findings from physical examination.

Laboratory studies should include the following:

Serum electrolyte levels

In severe cases, daily assessment of serum electrolytes are valuable until the infant's status improves. Markedly low serum sodium, potassium, and chloride levels in the presence of reduced urine flow and excessive weight gain may indicate acute tubular damage or syndrome of inappropriate antidiuretic hormone (SIADH) secretion, particularly during the initial 2-3 days of life.

Similar changes may be seen during recovery; increased urine flow may indicate ongoing tubular damage and excessive sodium loss relative to water loss

Renal function studies

Serum creatinine levels, creatinine clearance, and BUN levels suffice in most cases.

Cardiac and liver enzymes

These values are an adjunct to assess the degree of hypoxic-ischemic injury to these other organs. These findings may also provide some insight into injuries to other organs, such as the bowel. In addition, early evidence suggest that cardiac troponin I may be correlated to HIE severity.[39]

Coagulation system evaluation

This includes prothrombin time, partial thromboplastin time, and fibrinogen levels.

ABG

Blood gas monitoring is used to assess acid-base status and to avoid hyperoxia and hypoxia as well as hypercapnia and hypocapnia.

Next

Imaging Studies

Brain MRI

MRI is the imaging modality of choice for the diagnosis and follow-up of infants with moderate-to-severe hypoxic-ischemic encephalopathy (HIE).[40, 41, 42, 43] Conventional MRI sequences (T1w and T2w) provide information on the status of myelination and preexisting developmental defects of the brain. When performed after the first day (and particularly after day 4), conventional images may accurately demonstrate the injury pattern as area of hyperintensity. Conventional images are most helpful at age 7-10 days, when the diffusion-weighted imaging (DWI) findings have pseudonormalized.

Following a severe asphyxial event, a central pattern of injury is seen with injury to (1) the deep gray matter (ie, putamina, ventrolateral thalamus, hippocampi, dorsal brainstem, or lateral geniculate nucleus) and (2) the perirolandic cortex. These areas contain the highest concentration of N-methyl-D-aspartate (NMDA) receptors and are actively myelinating.

Less severe or partial insult results in injury to the intervascular boundaries areas and is also called watershed injury. This type of lesions manifests in the infants as proximal extremity weakness or spasticity.

Decreased signal in the posterior limb of the internal capsule (PLIC) on T1w images may be noted. The absence of normal signal (high intensity on T1w images) in the PLIC of infants older than 38 weeks' gestation is a strong predictor of abnormal motor outcomes in these infants.[44]

DWI allows earlier identification of injury patterns in the first 24-48 hours. The MRI sequence identifies areas of edema and, hence, injured areas. DWI changes peak at 3-5 day and pseudonormalizes by the end of the first week. In neonates, DWI changes may underestimate the extent of injury, most likely because of the importance of apoptosis in the ultimate extent of neurological injury.[40]

MRI is also a useful tool in the determination of prognosis. Studies indicate that infants with predominant injuries to the basal ganglia or thalamus (BGT) have an unfavorable neurological outcome when compared with infants with a white matter predominant pattern of injury. Abnormal signals in the PLIC have also been associated with poor neurological outcome. In a recent study, severe BGT lesions on early MRI (performed at a median of 10 d; range, 2-42 d) were strongly associated with motor impairment at 2 years. In addition, abnormal PLIC signal was also highly correlated with inability to walk independently at 2 years, with a sensitivity of 0.92 and a specificity of 0.77.[45]

In a study of MRIs at term-equivalent age from 3 cohorts of 325 very preterm infants, Kidokoro et al found 33% (n=107) had some grade of brain injury (eg, periventricular leukomalacia, intraventricular/cerebellar hemorrhage) and 10% (n=33) had severe brain injury.[46] The investigators noted severe brain injury and impaired growth patterns were independently associated with perinatal risk factors and delayed cognitive development.[46]

Both conventional images (T1- and T2-weighted) and diffusion techniques (DWI and ADC maps) have a good specificity (>90%) and positive predictive value (>85%) in predicting death or major disability at age 2 years. However, sensitivity and negative predictive values are low.[47]

MRI is also useful for follow-up. In any newly diagnosed case of cerebral palsy, MRI should be considered because it may help in establishing the cause. Note that the interpretation of MRI in infants requires considerable expertise.

Magnetic resonance spectroscopy (MRS) allows for quantification of intracellular molecules. Proton MRS allows identification of cerebral lactate, which persist for weeks following a significant hypoxic-ischemic injury. Phosphorous MRS allows for real-time quantification of ATP, phosphorus creatinine, inorganic phosphorous, and intracellular pH levels.

Cranial ultrasonography

Although portable and convenient, cranial ultrasonography has a low sensitivity (50%) for the detection of anomalies associated with hypoxic-ischemic encephalopathy. Findings include global increase in cerebral echogenicity and obliteration of cerebrospinal fluid (CSF) containing spaces suggestive of cerebral edema. Increase in the echogenicity of deep gray matter structures may also be identified, typically when ultrasonography is performed after 7 days of life. Finally, head ultrasonography is helpful upon admission, particularly in patients evaluated for hypothermia therapy, to rule out intracerebral or intraventricular hemorrhages.

Head CT scanning

Head CT is a rapid mode of screening and is very effective in detecting hemorrhage with the added advantadge of limited sedation need. However, evidence suggests that even a single CT scan exposes children to potentially harmful radiation.[48, 49, 50] Additionnally, CT is not a sensitive modality for evaluation of HIE because of the high water content in the neonatal brain and high protein content of the cerebrospinal fluid, which result in poor parenchymal contrast resolution.[51] Because of these concerns and the superiority of MRI in evaluating brain structures, MRI has now largely supplanted head CT in the evaluation of neonates with hypoxic-ischemic encephalopathy.

Echocardiography

In infants requiring inotropic support, echocardiography (ECHO) helps to define myocardial contractility and the existence of structural heart defects, if any.

Previous
Next

Other Tests

Amplitude-integrated electroencephalography (aEEG)

Several studies have shown that a single-channel aEEG performed within a few hours of birth can help evaluate the severity of brain injury in the infant with hypoxic-ischemic encephalopathy.[52, 53, 54] The abnormalities seen in infants with moderate-to-severe hypoxic-ischemic encephalopathy include the following:

  • Discontinuous tracing characterized by a lower margin below 5 mV and an upper margin above 10 mV
  • Burst suppression pattern characterized by a background with minimum amplitude (0-2 mV) without variability and occasional high voltage bursts (>25 mV)
  • Continuous low voltage pattern characterized by a continuous low voltage background (< 5 mV)
  • Inactive pattern with no detectable cortical activity
  • Seizures, usually seen as an abrupt rise in both the lower and upper margin

In addition, aEEG findings have been used as criteria for inclusion in the CoolCap trial of selective head cooling.[24, 34, 55] However, some evidence argues against the use of aEEG as a tool to exclude infants with hypoxic-ischemic encephalopathy from receiving hypothermia therapy.

Although normal aEEG findings may not necessarily mean that the brain is healthy, a severe or moderately severe aEEG abnormality may indicate brain injury and poor outcome. However, a rapid recovery (within 24 h) of abnormal aEEG findings is associated with favorable outcome in 60% of cases. Finally, in a meta-analysis of 8 studies, Spitzmiller et al concluded that aEEG can accurately predict poor outcome with a sensitivity of 91% (95% CI, 87-95) and a negative likelihood ratio of 0.09 (95% CI, 0.06-0.15).[56]

Note that considerable training is required for conducting and properly interpreting the aEEG findings.

Standard EEG

Traditional, multichannel EEG is an integral part of the evaluation of infants diagnosed with hypoxic-ischemic encephalopathy. It is a valuable tool to assess the severity of the injury and evaluate for subclinical seizures.[57, 58] This is particularly important for infants on assisted ventilation requiring sedation or paralysis.

Changes in hypoxic-ischemic encephalopathy and EEG wave patterns may change over time and indicate the severity of the brain injury.[59] EEG abnormalities may be apparent before anomalies seen on ultrasonography.

Generalized depression of the background rhythm and voltage, with varying degrees of superimposed seizures, are early findings. EEG characteristics associated with abnormal outcomes include (1) background amplitude of less than 30 mV, (2) interburst interval of more than 30 seconds, (3) electrographic seizures, and (4) absence of sleep-wake cycle at 48 hours.

Caution in interpreting early severe background abnormalities needs to be applied because reverting to normal background pattern in few days of life can be associated with normal outcomes. Note that large doses of anticonvulsant therapy may alter the EEG findings.

Serial EEGs should be obtained to assess seizure control and evolution of background abnormalities. Early EEGs are important not only to evaluate the degree of encephalopathy and the presence of seizures but may also help establish early prognosis.[60] Serial EEGs are also helpful in establishing prognosis. Improvement in the EEG findings over the first week, in conjunction with improvement in the clinical condition, may help predict a better long-term outcome.[61]

Special sensory evaluation

Screening for hearing is now mandatory in many states in the United States; in infants with hypoxic-ischemic encephalopathy, a full-scale hearing test is preferable because of an increased incidence of deafness among infants with hypoxic-ischemic encephalopathy that require assisted ventilation.

Retinal and ophthalmic examination

This examination may be valuable, particularly as part of an evaluation for developmental abnormalities of the brain.

Spectral-domain optical coherence tomography (SD-OCT) shows promise in the evaluation of prematurity on early optic nerve development and of central nervous system development and anomalies.[62]

Previous
Next

Histologic Findings

The impressive array of neuropathologic findings that can result from a hypoxic-ischemic event can be primarily explained by the gestational time frame in which the event occurs. Prior to 20 weeks' gestation, fetal macrophages are capable of removing necrotic debris via phagocytosis, resulting in a smooth cavity without a gliotic response. Examples of lesions that can result from hypoxic-ischemic events in the second trimester include hydranencephaly, porencephaly, and schizencephaly.

After 20 weeks' gestation, hypoxic-ischemic insults result in astrocyte activation with subsequent gliosis. Subependymal germinal matrix hemorrhage is most common in premature infants, with hemorrhage involving the germinal matrix, lateral ventricles, and/or the adjacent parenchyma. In the full-term infant, hypoxic-ischemic events primarily result in lesions of the cerebral cortex, basal ganglia, thalamus, brain stem, or cerebellum. The location and severity of the lesions correlate with clinical symptoms, such as disturbances of consciousness, seizures, hypotonia, oculomotor-vestibular abnormalities, and feeding difficulties. The major neuropathological patterns of injury in hypoxic-ischemic encephalopathy are listed below. More than one pattern can be present.

Selective neuronal necrosis is the most common pattern of injury observed in hypoxic-ischemic encephalopathy and is characterized by neuronal necrosis selective to areas with higher energy demands. The following 5 major patterns have been described:

  • Diffuse: Sites of predilection for diffuse neuronal necrosis include the cerebral cortex (particularly the hippocampus), deep nuclear structures (thalamus, basal ganglia), brain stem, cerebellum, and anterior horn of the spinal cord.
  • Cerebral cortex (deep nuclear): A predominant cerebral cortex (deep nuclear) pattern of injury is present in 35-85% of infants with hypoxic-ischemic encephalopathy.
  • Brain stem (deep nuclear): Brain stem (deep nuclear) is the predominant lesion in 15-20% of infants with hypoxic-ischemic encephalopathy. Some of these lesions can evolve to status marmoratus . The 3 major features of status marmoratus include neuronal loss, gliosis and hypermyelination. This hypermyelination is believed to be secondary to myelin sheath formation and deposition around the prominent processes of reactive astrocytes. Patchy, white discoloration of the gray matter ("marbling") is sometimes observed on gross examination. This marbling is the macroscopic correlate of the hypermyelination and glial scarring seen on histologic examination. It is not seen in its complete form until the end of the first year of life.
  • Pontosubicular: This is the least common pattern and can occur in infants aged 1-2 months or younger.
  • Cerebellar: This primarily occurs in premature infants.

An example of severe acute hypoxic-ischemic neuronal change with associated gliosis is shown in the images below.

Severe acute hypoxic-ischemic neuronal change in t 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 foll 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.

Parasagittal cerebral injury is typically bilateral and involves the parasagittal areas of the cerebral cortex (see the image below).

Bilateral acute infarctions of the frontal lobe ar 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.

The regions of the cortex most susceptible to this type of injury are the end-artery zones between the anterior, middle, and posterior cerebral arteries. These so-called watershed regions are particularly vulnerable to global hypoperfusion events; the parieto-occipital cortex is most susceptible. Parasagittal cerebral injury is most commonly seen in the full-term infant. Although most of these lesions are ischemic, approximately 25% are associated with hemorrhagic events in the perinatal period.

Focal and multifocal ischemic brain necrosis lesions vary in terms of distribution and can be limited to a region supplied by an occluded artery or can be diffuse in cases of global hypoperfusion. Ulegyria may result, with preserved gyral crests adjacent to sulci marked by dyslamination, neuronal loss, and disorganized white myelinated fibers (see the images below).

A prior hypoxic-ischemic event involving the occip 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 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.

Periventricular leukomalacia (PVL), also called "white matter necrosis," is macroscopically characterized by the presence of discrete cavities or foci of parenchymal softening in the periventricular areas. In some cases, PVL can not be grossly appreciated. PVL is believed to be the result of compromised boundary zone perfusion between the ventriculofugal and ventriculopetal arteries. This area is particularly vulnerable secondary to the increased metabolic demands of white matter undergoing myelination. Microscopically, PVL manifests early as geographic coagulative necrosis. As the lesion evolves, reactive astrocytes, activated microglia, and macrophages become prominent in the lesional rim (see the images below).

Periventricular leukomalacia is depicted. This cys 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 fig 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).
Previous
 
 
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, Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

David A Kaufman, MD Professor of Pediatrics, Division of Neonatology, University of Virginia School of Medicine

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

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Specialty Editor Board

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, University of Missouri-Kansas City School of Medicine; Attending Physician, Division of Neonatology, Children's Mercy Hospital and Clinics; Faculty, Children's Mercy Bioethics Center

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 Pediatric Society, American Society for Bioethics and Humanities, American Society of Law, Medicine & Ethics, Society for Pediatric Research, National Hospice and Palliative Care Organization

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 Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

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 Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

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

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

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

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

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

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

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

  7. [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.

  8. [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].

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

  10. 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].

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

  12. 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. 1997 Nov. 39(11):718-25. [Medline].

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

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

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

  16. 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. 1994 Mar. 14(2):279-88. [Medline].

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

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

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

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

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

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

  23. Massaro AN, Chang T, Kadom N, Tsuchida T, Scafidi J, Glass P, et al. Biomarkers of Brain Injury in Neonatal Encephalopathy Treated with Hypothermia. J Pediatr. 2012 Apr 10. [Medline].

  24. 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].

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

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

  27. 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. 2007 Jul. 166(7):645-54. [Medline].

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

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

  30. 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].

  31. 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].

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

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

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

  35. 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].

  36. 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. 2008 Dec. 199(6):587-95. [Medline].

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

  38. 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. 2005 Nov. 164(11):655-9. [Medline].

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

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

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

  42. 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].

  43. Rutherford M, Biarge MM, Allsop J, Counsell S, Cowan F. MRI of perinatal brain injury. Pediatr Radiol. 2010. 40(6):819-33. [Medline].

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

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

  46. Kidokoro H, Anderson PJ, Doyle LW, Woodward LJ, Neil JJ, Inder TE. Brain injury and altered brain growth in preterm infants: predictors and prognosis. Pediatrics. 2014 Aug. 134(2):e444-53. [Medline].

  47. Cheong JL, Coleman L, Hunt RW, Lee KJ, Doyle LW, Inder TE, et al. Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: substudy of a randomized trial. Arch Pediatr Adolesc Med. 2012. 7:634-40. [Medline].

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

  49. Pearce MS, Salotti JA, Little MP, McHugh K, Lee C, Kim KP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet. 2012. 380(9840):499-505. [Medline].

  50. Brenner DJ, Hall EJ. Computed tomography an increasing source of radiation exposure. N Engl J Med. 2007. 357:2277-2284. [Medline].

  51. The encephalopathic neonate: choosing the proper imaging technique. AJNR Am J Neuroradiol. 1997. 18(10):1816-20. [Medline].

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

  53. 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].

  54. 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].

  55. 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].

  56. 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].

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

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

  59. Volpe JJ. Hypoxic-ischemic encephalopathy. Neurology of the Newborn. 5th ed. Philadelphia, PA: Saunders-Elsevier; 2008. Volume 899: chapter 9.

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

  61. 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].

  62. Tong AY, El-Dairi M, Maldonado RS, et al. Evaluation of optic nerve development in preterm and term infants using handheld spectral-domain optical coherence tomography. Ophthalmology. 2014 Sep. 121(9):1818-26. [Medline]. [Full Text].

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

  64. [Guideline] Biban P, Filipovic-Grcic B, Biarent D, Manzoni P; International Liaison Committee on Resuscitation (ILCOR); European Resuscitation Council (ERC); American Heart Association (AHA); American Academy of Pediatrics (AAP). New cardiopulmonary resuscitation guidelines 2010: managing the newly born in delivery room. Early Hum Dev. 2011. 87 (suppl 1):S9-11. [Medline].

  65. [Guideline] Kattwinkel J, Perlman JM, Aziz K, Colby C, Fairchild K, Gallagher J, et al. Neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics. 2010. 126(5):400-413. [Medline].

  66. Sabir H, Jary S, Tooley J, Liu X, Thoresen M. Increased Inspired Oxygen in the First Hours of Life is Associated with Adverse Outcome in Newborns Treated for Perinatal Asphyxia with Therapeutic Hypothermia. J Pediatr. 2012 Apr 18. [Medline].

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

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

  69. 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].

  70. 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].

  71. 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].

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

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

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

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

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

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

  78. 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. 1999 Aug 12. 341(7):485-9. [Medline].

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

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

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

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

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

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

  85. 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. 2011 Aug. 165(8):692-700. [Medline].

  86. 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. 2010 Sep. 157(3):367-72, 372.e1-3. [Medline].

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

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

  89. 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. 2008 Oct. 122(4):e791-8. [Medline]. [Full Text].

  90. Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med. 2012 May 31. 366(22):2085-92. [Medline].

  91. Azzopardi D, Strohm B, Marlow N,et al, for the TOBY Study Group. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med. 2014 Jul 10. 371(2):140-9. [Medline].

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

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

  94. 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:

  95. 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].

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

  97. 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. 1998 Feb. 132(2):345-8. [Medline].

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

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

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

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

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

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

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

  105. Guillet R, Edwards AD, Thoresen M, Ferriero DM, Gluckman PD, Whitelaw A, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res. 2012. 2:205-9.

  106. Guillet R, Edwards AD, Thoresen M, Ferriero DM, Gluckman PD, Whitelaw A, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res. 2012. 2:205-9. [Medline].

  107. 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].

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

  109. Hull J, Dodd KL. Falling incidence of hypoxic-ischaemic encephalopathy in term infants. Br J Obstet Gynaecol. 1992. 5:386-91. [Medline].

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

  111. 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].

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

  113. Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med. 2012. 22:2085-92. [Medline].

  114. Smith J, Wells L, Dodd K. The continuing fall in incidence of hypoxic-ischaemic encephalopathy in term infants. BJOG. 2000. 4:461-6. [Medline].

  115. Srinivasakumar P, Zempel J, Wallendorf M, Lawrence R, Inder T, Mathur A. Therapeutic hypothermia in neonatal hypoxic ischemic encephalopathy: electrographic seizures and magnetic resonance imaging evidence of injury. J Pediatr. 2013 Aug. 163(2):465-70. [Medline].

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

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

 
Previous
Next
 
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.
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. Modified Sarnat Clinical Stages of Perinatal Hypoxic Ischemic Brain Injury [34]
  MILD MODERATE SEVERE
Level of Consciousness Alternating (hyperalert, lethargic,irritable) Lethargic or obtunded Stuporous
Neuromuscular Control
Muscle tone Normal Hypotonia Flaccid
Posture Normal Decorticate (arms flexed/legs extended) Intermittent decerebration (arms and legs extended)
Stretch reflexes Normal or hyperactive Hyperactive or decreased 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 Delayed
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



Typically < 24h



2-14 days Hours to weeks
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.