eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology

Hypoxic-Ischemic Encephalopathy: Treatment & Medication

Author: Santina A Zanelli, MD, Assistant Professor, Department of Pediatrics, Division of Neonatology, University of Virginia Health System
Coauthor(s): Dirk P Stanley, MD, Resident Physician, Department of Pathology, University of Virginia Health System; David Kaufman, MD, ECMO Director, Associate Professor of Pediatrics, Department of Pediatrics, Division of Neonatology, University of Virginia Health System
Contributor Information and Disclosures

Updated: Dec 15, 2008

Treatment

Medical Care

Supportive care in patients with hypoxic-ischemic encephalopathy (HIE)

  • Maintain adequate ventilation.
    • Most infants with severe hypoxic-ischemic encephalopathy need ventilatory support during the first week.
    • Prevent hypoxia, hyperoxia, hypercapnia, and hypocapnia; the latter is due to inadvertent hyperventilation, which may lead to severe hypoperfusion of the brain and cellular alkalosis.
    • Maintain the blood gases and acid-base status in the physiological ranges. 
  • Maintain adequate perfusion. Maintain the mean blood pressure (BP) above 35-40 mm Hg (for term infants). Dopamine or dobutamine can be used to maintain adequate cardiac output.
  • Maintain adequate metabolic status.
    • Fluid and glucose homeostasis should be achieved. Avoid hypoglycemia or hyperglycemia because both are known to cause brain injury.
    • Because of the concern for acute tubular necrosis (ATN) and inappropriate antidiuretic hormone (IADH), fluids should be started at the estimated insensible water loss (40-60 mL/kg/d in term infant) until the urine output is clear. At that point, fluids can be increased to account for the urine production. Thereafter, fluid and electrolyte therapy need to be individualized on the basis of clinical course, changes in weight, urine output, and the results of serum electrolyte and renal function studies.
    • The role of prophylactic theophylline, given early after birth, in reducing renal dysfunction after hypoxic-ischemic encephalopathy has been evaluated in 3 small randomized controlled trials.9,10,11  In these studies, a single dose of theophylline (5-8 mg/kg) given within 1 hour of birth resulted in (1) decreased severe renal dysfunction (defined as creatinine level >1.5 mg/dL for 2 consecutive days); (2) increased creatine clearance; (3) increased glomerular filtration rate (GFR); and (4) decreased b2 microglobulin excretion. The clinical significance of these findings remains unclear. Larger studies are warranted to confirm the safety of adenosine inhibitor use following hypoxic-ischemic encephalopathy.  
  • Avoid hyperthermia.

Treatment of seizures

 Seizures are generally self-limited to the first days of life but may significantly compromise other body functions, such as maintenance of ventilation, oxygenation, and blood pressure. Additionally, seizures should be treated early and be well controlled because even asymptomatic seizures (ie, seen only on EEG) may continue to injure the brain. Seizures should be treated with phenobarbital or lorazepam; phenytoin may be added if either of these medications fails to control the seizures.

Hypothermia treatment

Extensive experimental data suggest that mild hypothermia (3-4°C below the baseline temperature) applied within a few hours (no later than 6 h) of hypoxia-ischemia injury is neuroprotective. The mechanisms through which hypothermia is neuroprotective are not completely understood. Possible mechanisms include (1) reduced metabolic rate and energy depletion; (2) decreased excitatory transmitter release; (3) reduced alterations in ion flux; (4) reduced apoptosis due to hypoxic-ischemic encephalopathy; and (4) reduced vascular permeability, edema, and disruptions of blood-brain barrier functions.

The clinical evaluation of therapeutic hypothermia in neonates with moderate-to-severe hypoxic-ischemic encephalopathy has been evaluated in 3 published randomized controlled trials.6,12,13 Inclusion criteria slightly varied between trials. Criteria from the 2 larger trials are summarized below.

  • Near-term infants born at 36 weeks' gestation or less with birth weight of 1800-2000 g or less, younger than 6 hours at admission
  • Evidence of acute event around the time of birth
    • Apgar score of 5 or less at 10 minutes after birth (In the study by Shankaran et al, this needed to be in conjunction with either evidence of acute perinatal event or need for assisted ventilation for at least 10 min.13 )
    • Severe acidosis, defined as pH level of less than 7 or base deficit of 16 mmol/L  or less (cord blood or any blood gas obtained within 1 h of birth)
    • Continued need for resuscitation at 10 minutes after birth
  • Evidence of moderate to severe encephalopathy at birth
    • Clinically determined (at least 2)
      • Lethargy, stupor, or coma
      • Abnormal tone or posture
      • Abnormal reflexes (suck, grasp, Moro, gag, stretch reflexes)
      • Decrease or absent spontaneous activity
      • Autonomic dysfunction (including bradycardia, abnormal pupils, apneas)
      • Clinical evidence of seizures
    • Moderately or severely abnormal aEEG background or seizures

Results from those trials are summarized in Media file 9.

Randomized controlled trials of therapeutic hypot...

Randomized controlled trials of therapeutic hypothermia for moderate-to-severe hypoxic-ischemic enephalopathy (HIE).

[ CLOSE WINDOW ]
Randomized controlled trials of therapeutic hypot...

Randomized controlled trials of therapeutic hypothermia for moderate-to-severe hypoxic-ischemic enephalopathy (HIE).


These clinical studies have been reassuring thus far regarding safety and applicability of hypothermia therapy. Many theoretical concerns surround hypothermia and its side effects, which include coagulation defects, leukocyte malfunctions, pulmonary hypertension, worsening of metabolic acidosis, and abnormalities of cardiac rhythm, especially during rewarming.

Therapeutic hypothermia when applied within 6 hours of birth and maintained for 48-72 hours is a promising therapy for mild-to-moderate cases of hypoxic-ischemic encephalopathy. Many components of its implementation remain to be optimized, including the following:

  • Determining optimal timing of initiation of hypothermia therapy: Cooling must begin early, within 1 hour of injury, if possible; however, a favorable outcome may be possible if the cooling begins as long as 6 hours after injury. To this effect, the feasibility and safety of cooling on transport has been described.
  • Determining optimal timing of initiation of hypothermia therapy: The greater the severity of the initial injury, the longer the duration of hypothermia needed for optimal neuroprotection. The optimal duration of brain cooling in the human newborn has not been established. 
  • Determining which method of cooling is best: Two methods have been used in clinical trials: selective head cooling and whole body cooling. In selective head cooling, a cap (CoolCap) with channels for circulating cold water is placed over the infant's head, and a pumping device facilitates continuous circulation of cold water. Nasopharyngeal or rectal temperature is then maintained at 34-35°C for 72 hours. For whole body hypothermia, the infant is placed on a commercially available cooling blanket, through which circulating cold water flows, so that the desired level of hypothermia is reached quickly and maintained for 72 hours. The relative merits and limitations of these 2 methods have not been established. Results from the TOBY trial will likely answer some of these questions.
  • Determining optimal rewarming method: In clinical trials, rewarming was carried out gradually, over a 6-8 hour period. 
  • Improving selection of candidates for hypothermia therapy using EEG and/or aEEG: Predefined subgroup analysis in the CoolCap trial suggested that head cooling had no effect in infants with the most severe aEEG changes but was beneficial only in infants with less severe aEEG changes.  
  • Establishing long term benefits by providing long term follow-up of all infants undergoing hypothermia therapy

Several meta-analysis have been conducted and indicate that that therapeutic hypothermia is beneficial to term newborns with hypoxic-ischemic encephalopathy.

In a Cochrane review, Jacobs et al found that therapeutic hypothermia results in significant reduction in the following:7

  • Combined outcome of mortality or major neurodevelopmental disability at age 18 months (relative risk [RR], 0.76; 95% confidence interval [CI], 0.65-0.89), with a number needed to treat (NNT) of 7 (95% CI, 4-14)
  • Mortality (RR, 0.74; 95% CI, 0.58-0.94) and an NNT of 11 (95% CI, 6-50)
  • Neurodevelopmental disability in survivors (RR, 0.68; 95%, CI 0.51-0.92), with an NNT of 8 (95% CI, 4-33).

They also found a significant increase in thrombocytopenia, although it was not clinically significant.

Schulzke et al found a significant effect of therapeutic hypothermia on the following:14

  • The composite outcome of death or disability (RR, 0.78; 95% CI, 0.66-0.92) with an NNT of 8 (95% CI: 5-20)
  • Mortality (RR, 0.75; 95% CI, 0.59-0.96) 
  • Neurodevelopmental disability at age 18-22 months (RR, 0.72; 95% CI, 0.53-0.98) 
  • Benign sinus bradycardia (RR, 7.42; 95% CI, 2.52-21.87) 
  • Thrombocytopenia (RR, 1.47; 95% CI, 1.07-2.03) with an NNH of 8 

Shah et al also found a reduction in the combined outcome of death or neurodevelopmental disability (RR, 0.76; 95% CI, 0.65-0.88) and an NNT of 6 (95% CI, 4-14), as well as death and moderate-to-severe neurodevelopmental disability when separately analyzed.15

Despite the methodological differences between trials, wide CIs, and the lack of follow-up data beyond the second year of life, the consistency of the results is encouraging.

Hypothermia therapy should be conducted under strict protocols and reserved to regional referral centers offering comprehensive multidisciplinary care and planning to conduct long-term neurodevelopmental follow-up. Ideally, all infants should be registered in national registry whenever possible.

Future neuroprotective strategies

 Pathways currently being investigated for the development of new neuroprotective strategies are summarized in Media file 12.

Summary of potential neuroprotective strategies.

Summary of potential neuroprotective strategies.

[ CLOSE WINDOW ]
Summary of potential neuroprotective strategies.

Summary of potential neuroprotective strategies.


Surgical Care

In cases of posterior cranial fossa hematoma, surgical drainage may be lifesaving if no additional pathologies are present.

Consultations

A pediatric neurologist should help assist in the management of seizures, interpretation of EEG, and overall care of the infant with hypoxic-ischemic encephalopathy. The neurologist should also work with the primary care physician to address long-term disabilities. A developmental specialist can also help plan for long-term assessments and care.

Diet

In most cases (particularly in moderately severe and severe hypoxic-ischemic encephalopathy), the infant is restricted to nothing by mouth (NPO) during the first 3 days of life or until the general level of alertness and consciousness improves. Begin trophic feeding with expressed breast milk or formula, about 5 mL every 3-4 hours. Monitor abdominal girth, gastric residuals, and stools; any of these may be an early indicator of necrotizing enterocolitis, for which infants with perinatal asphyxia are at high risk. Individualize increments in feeding volume and composition.

Medication

Providing standard intensive care support, correcting metabolic acidosis, close monitoring of the fluid status, and seizure control are the main elements of treatment in patients with hypoxic-ischemic encephalopathy (HIE). Anticonvulsants are the only specific drugs used often in this condition.

Treat seizures early and control them as fully as possible. Even asymptomatic seizures (ie, seen only on EEG) may continue to injure the brain.

Anticonvulsants

These agents are used to control seizures.


Phenobarbital (Luminal)

DOC when clinical or EEG seizures are noted; is continued on the basis of both EEG findings and clinical status. In most cases, can be weaned and stopped during the first month of life; however, treatment is continued for several months to 1 year in infants with persistent neurological abnormalities and clinical or EEG evidence of seizures; EEG and clinical status should guide decision. In high doses, has been used prophylactically by a few researchers, but its efficacy has not been established. In infants who are heavily sedated or paralyzed, phenobarbital may be used prophylactically at standard dose.

Adult

Pediatric

20 mg/kg IV over 10-15 min as loading dose; in refractory cases, additional 5-10 mg/kg IV as loading dose; followed by 3-5 mg/kg/d PO/IV/IM/PR divided bid, to begin no earlier than 12-24 h after loading dose; slow IV push gives most rapid control
In a few experimental studies, 20-40 mg/kg IV has been given prophylactically to achieve higher serum concentrations; however, this is not universally accepted

May decrease effects of digitoxin, corticosteroids, carbamazepine, theophylline, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and death; valproic acid may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects

Documented hypersensitivity; severe respiratory disease, marked impairment of liver function, and nephritic patients

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May contain 10% alcohol and >60% propylene glycol May lead to respiratory distress, thus respiratory status should be monitored; immediate assisted ventilatory support should be available
Monitor serum therapeutic concentrations, which should be 15-30 mcg/mL; prolonged serum half-life during the first 1-2 wk of life may cause drug accumulation, requiring adjustment of maintenance doses, due to low GFR in the first week of life and ATN (if present)
Allowing serum concentrations of 40 mcg/mL is not a universally accepted practice
Observe IV sites for extravasation and phlebitis


Phenytoin (Dilantin)

Usually the third DOC in neonatal seizures; may be used in patients with seizures that do not respond to phenobarbital or lorazepam. Oral absorption is negligible for the first several months of life.

Adult

Pediatric

15-20 mg/kg IV over >30 min as loading dose; followed by 4-8 mg/kg IV slow push q24h (may divide into 2-3 doses q8-12h); rate of infusion not to exceed 0.5 mg/kg/min; flush IV line with 0.9% NaCl before and after administration

Benzodiazepines, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, trimethoprim, and valproic acid may increase phenytoin toxicity
Phenytoin effects may decrease when taken concurrently with barbiturates, diazoxide, rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate
Phenytoin may decrease effects of acetaminophen, corticosteroids, doxycycline, haloperidol, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, valproic acid

Documented hypersensitivity; sinoatrial block, second- and third-degree AV block, sinus bradycardia, or Adams-Stokes syndrome; IM administration

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May contain 40% propylene glycol and 10% alcohol; monitor serum concentrations, which should be 6-15 mcg/mL; monitor for bradycardia, arrhythmias, and hypotension during infusion; highly unstable in IV solution, avoid using in central lines because of risk of precipitation; incompatible in D5W or D10W or with dextrose plus amino acids and lipids, most antibiotics, heparin, insulin, and many other drugs (consult compatibility text); drug extravasation at IV site may lead to severe local necrosis


Lorazepam (Ativan)

Second DOC for acute control of seizures refractory to phenobarbital.
By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Adult

Pediatric

0.05-0.1 mg/kg/dose IV slow push over 2-5 min; doses repeated on basis of clinical response (careful with repeat dosing because of benzyl alcohol content)

CNS toxicity increases when used concurrently with alcohol, phenothiazines, barbiturates, or MAOIs

Documented hypersensitivity; preexisting CNS depression and hypotension

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

IV contains PEG 400, propylene glycol, and benzyl alcohol; may cause respiratory depression and rhythmic myoclonic jerking in premature infants receiving lorazepam for sedation

Cardiovascular (inotropic) agents

These agents increase blood pressure (BP) and combat shock. Drugs in this category act primarily by increasing systemic vascular resistance, cardiac contractility, and stroke volume, thus increasing cardiac output.

Most inotropic agents also have dose and gestational age-dependent effects on vessels, particularly those of the renal and GI systems. For the most part, these effects are beneficial but, at higher doses, the systemic side effects may be unpredictable.

In experimental animals, cerebral blood flow (CBF) is unaffected by these drugs when used in recommended therapeutic doses. However, no clear information is available on the effects of these drugs on CBF in neonates.


Dopamine (Intropin)

Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on the dose. Lower doses predominantly stimulate dopaminergic receptors that in turn produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation produced by higher doses.

Adult

Pediatric

2-20 mcg/kg/min IV continuous infusion; begin at lower doses, increase on basis of systemic BP appropriate for age and gestational age

Phenytoin, alpha-adrenergic and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects of dopamine

Documented hypersensitivity; pheochromocytoma or ventricular fibrillation

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause tachycardia and arrhythmias; may increase pulmonary artery pressure; may reversibly suppress prolactin and thyrotropin secretion


Dobutamine (Dobutrex)

Second inotropic DOC, preferred by some as first choice in severe cardiogenic shock.
Produces vasodilation and increases inotropic state. At higher dosages may cause increased heart rate, exacerbating myocardial ischemia.

Adult

Pediatric

2-25 mcg/kg/min IV continuous infusion; begin at lower doses, increase as needed on basis of BP and heart rate; wean on basis of BP response

Beta-adrenergic blockers antagonize effects of dobutamine; general anesthetics may increase toxicity

Documented hypersensitivity; idiopathic hypertrophic subaortic stenosis and atrial fibrillation or flutter

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause arrhythmias, hypertension, tachycardia, and vasodilation of cutaneous microcirculation; assess volume status before administering, since may cause hypotension, especially in infants with clear evidence of hypovolemia; may cause tissue sloughing at IV site, particularly when the drug infiltrates soft tissue

More on Hypoxic-Ischemic Encephalopathy

Overview: Hypoxic-Ischemic Encephalopathy
Differential Diagnoses & Workup: Hypoxic-Ischemic Encephalopathy
Treatment & Medication: Hypoxic-Ischemic Encephalopathy
Follow-up: Hypoxic-Ischemic Encephalopathy
Multimedia: Hypoxic-Ischemic Encephalopathy
References
[ CLOSE WINDOW ]

References

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

  4. 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].

  5. 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].

  6. 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].

  7. [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].

  8. 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].

  9. 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].

  10. [Best Evidence] 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].

  11. 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].

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

  13. [Best Evidence] 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].

  14. 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].

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

  16. 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].

  17. 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].

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

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

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

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

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

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

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

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

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

  27. 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].

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

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

  30. 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].

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

  32. 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].

  33. 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].

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

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

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

  37. 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].

  38. 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].

  39. 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].

  40. 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].

  41. 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].

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

  43. 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].

  44. 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].

  45. 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].

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

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

  48. 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].

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

  50. 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].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

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

[ CLOSE WINDOW ]

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 Kaufman, MD, ECMO Director, Associate Professor of Pediatrics, Department of Pediatrics, Division of Neonatology, University of Virginia Health System
David Kaufman, MD 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.

Medical 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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Brian S Carter, MD, FAAP, Professor of Pediatrics (Neonatology), Vanderbilt University School of Medicine; Co-director, Pediatric Advance Comfort Team, 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 Pediatrics, National Hospice and Palliative Care Organization, and National Perinatal Association
Disclosure: Nothing to disclose.

CME Editor

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.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.