eMedicine Specialties > Neurology > Pediatric Neurology

Hypoxic-Ischemic Brain Injury in the Newborn: Treatment & Medication

Author: Marcio Sotero de Menezes, MD, Associate Professor, Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Seattle, University of Washington
Coauthor(s): Dennis WW Shaw, MD, Professor, Department of Radiology, Department of Radiology, University of Washington School of Medicine; Consulting Staff, Children's Hospital and Regional Medical Center of Seattle
Contributor Information and Disclosures

Updated: Apr 4, 2006

Treatment

Medical Care

The primary goal of medical care is to prevent prematurity and other prenatal and postnatal causes of HIE. In most cases, this means prevention of intrauterine ischemia and hypoxemia. Good prenatal care and management of medical conditions, such as maternal diabetes, are the most important means of reducing the risk of HIE and preterm labor early. The detection of fetal distress is important late in the pregnancy; however, methods for detecting fetal distress are far from perfect. Large-scale studies have not shown that fetal heart-rate monitoring is effective in preventing late motor disability or CP. The principles of prevention and management of HIE are described below.

  • Prevention and management of HIE
    • Provide good prenatal care and detect and manage the mother's medical conditions, as well as promptly recognize and appropriately treat clinically significant fetal distress.
    • Resuscitate and stabilize the depressed neonate in the delivery room.
    • Perform early serial neurologic evaluation of the depressed infant.
    • Supportive care: Avoid hypertension-hypoperfusion, provide adequate oxygenation and ventilation, and correct metabolic abnormalities (eg, hypoglycemia, acidosis, electrolyte imbalance).
    • Other measures: In addition to the measures listed above, prevent secondary CNS insults; control seizures; administer anticonvulsants (eg, phenobarbital, phenytoin, benzodiazepine); correct hypoglycemia, hyponatremia (slowly correct), hypocalcemia, and hypomagnesemia; control brain edema (increased ICP); and prevent fluid overload. Use of mannitol and dexamethasone is not indicated. No effective therapy to control neurotoxicity is available at this time.
  • After the diagnosis of HIE has been established, treatment is largely supportive and symptomatic. The utility of pharmacologic agents to prevent perinatal brain damage has not been established. The use of glutamate antagonists to reduce secondary hypoxic-ischemic damage is currently under investigation.
  • In the delivery room, appropriate resuscitation of the depressed infant should be initiated. Specific guidelines for neonatal resuscitation are beyond the scope of this article. Sensible guidelines from the American Academy of Pediatrics and the American Heart Association are contained in the Neonatal Resuscitation Program. In addition, information is available in Neonatal Resuscitation.
    • Appropriate evaluation of the newborn in the delivery room is also crucial. Apgar scores should be determined at 1 and 5 minutes and every 5 minutes thereafter if the score is less than 7.
    • Neurologic examination should be part of the initial assessment. Include an assessment of the patient's degree of arousal and alertness, cranial-nerve or brainstem function (eg, pupils, eye and facial movements, gag and suck reflexes), axial and limb tone, and motor activity. Do not wait for the neurologist because the findings may change spontaneously or after medication.
  • Fluid management is initially aimed at establishing normal tissue perfusion. After the first 24 hours, fluid overload must be avoided, especially in patients with the oliguric phase of renal failure or cerebral edema. Although arterial hypotension may worsen ischemic lesions, hypertension increases the risk of hemorrhagic complications, especially in previously ischemic tissue. Therefore, extremes in blood pressure should be avoided if possible.
    • Brain swelling is not the primary event in HIE and usually occurs after the first or second day of life in association with cerebral necrosis in full-term infants. Although ICP increases in as many as 22% of neonates with HIE, decreased cerebral perfusion pressure (ICP minus mean arterial pressure) is rare and often due to systemic arterial hypotension. In addition, transtentorial and tonsillar herniation is rare in the neonate with cerebral edema. Therapy with dexamethasone or mannitol to decrease ICP is not recommended because it does not appear to improve the outcome in HIE. The main strategy to address brain swelling is the prevention of fluid overload.
    • The syndrome of inappropriate antidiuretic hormone secretion (SIADH) may complicate the care of patients with severe HIE. This syndrome is due to the decreased excretion of free water and its consequences; therefore, it should be treated with careful fluid restriction. SIADH is characterized by hyponatremia, low serum osmolality, and high urinary osmolality with continued urinary excretion of sodium despite fluid overload with bulging fontanel. In cases of SIADH, seizures are probably due to low sodium levels or fluid-electrolyte shifts.
  • Respiratory support is often necessary in neonates with HIE, even those without seizures or high doses of sedating medications. Respiratory treatment of patients with persistent pulmonary hypertension may be particularly challenging.
    • Appropriate oxygenation is the goal of respiratory support because both hypoxemia and hyperoxia may accentuate neuronal damage. In addition, hyperoxia can substantially reduce cerebral blood flow.
    • Carbon-dioxide disturbances may be deleterious to the brain. Hypercarbia may induce acidosis or cerebrovascular dilatation, increasing the risk of hemorrhage and steal phenomenon. Steal phenomenon is characterized by decreased blood flow to areas of reversible ischemia (infarct penumbra), which are due to vasodilation of arteries in the nonischemic regions. These reversibly ischemic areas often surround regions with complete infarct. Hypocarbia can worsen ischemic injury by inducing vasoconstriction.
  • Neonatal seizures are commonly a consequence or comorbid condition of HIE-NE and need to be treated appropriately.
  • Hypocalcemia is often seen in HIE-NE. Hypocalcemia with or without secondary hypomagnesemia may exacerbate or even trigger seizures; therefore, treat it when detected. Ionized calcium measurements are preferred to monitor the treatment of hypocalcemia, as this represents the physiologically active fraction of the total serum calcium value. Elevated serum magnesium levels (often due to maternal administration) may produce hypotonia and even respiratory failure. Hypoglycemia should be corrected when present, but the indiscriminate use of glucose is not recommended, as data from animal models of ischemia suggest that raising the glucose above normal levels may increase neuronal damage.

Consultations

If the patient survives the acute physiologic derangements of the first several days of life, he or she will likely require long-term care and follow-up.

  • Patients with an HIE-NE picture are at risk for long-term neurologic morbidity; therefore, they require close monitoring at a developmental follow-up clinic in consultation with a developmental specialist and a neurologist.
    • Although the seizures in some patients stop after the neonatal period, they often recur after a few months or years.
    • Most often, the seizures that occur after HIE-NE are difficult to manage, and the patients may develop epileptic encephalopathies, such as infantile spasms or myoclonic epilepsies.
  • Patients with motor, speech, or cognitive disabilities need careful follow-up, serial testing, and therapy by occupational, physical, and speech therapists to optimize their developmental outcome. Early-intervention programs (at 0-3 y) are helpful in providing these services in the United States.
  • If irreversible muscle-tendon contractures develop, consultation with an orthopedic surgeon is advisable.
  • Careful testing by a neuropsychologist is instrumental in placing these children in the appropriate school environment.

Medication

Neonatal seizures may be a consequence or comorbid condition of HIE-NE. Neonatal seizures increase the cerebral metabolic rate, worsening the after-effects of ischemia. Seizures also are expected to increase cerebral blood flow, potentially increasing the risk of intracerebral hemorrhage. Another theoretical consideration is induction of seizure-mediated neurotoxicity. These factors have led clinicians to treat neonatal seizures. A complete discussion of the treatment of neonatal seizures is beyond the scope of this review.

Phenobarbital is one of the most popular choices in the conventional management of neonatal seizures. The initial infusion stops the seizures in as many as one third of patients. If patients do not respond to the initial infusion, the administration of 1-2 additional doses raises the serum level and controls the seizures in 70-80%. If the seizures persist despite the achievement of therapeutic levels of phenobarbital, adding a second drug (eg, fosphenytoin, lorazepam) may be advisable. In many centers, fosphenytoin is used in place of its parent drug (ie, phenytoin) because of the adverse reactions related to the diluent (ie, propylene glycol) used with phenytoin, especially those related to extravasation of the intravenous infusion. Lorazepam is an alternative for patients whose seizures do not respond to fosphenytoin and phenobarbital. Seizures can recur with lorazepam because of its 8- to 12-hour duration of effect.

An alternate strategy is the administration of repeated boluses of phenobarbital until the seizures stop. In this strategy, serum levels are raised to 100 mcg/mL or more, depending on the patient's cardiovascular tolerance. If this approach is used, the physician should be ready to provide ventilatory support because respiratory failure almost always ensues when phenobarbital levels are raised rapidly. One of the drawbacks to this approach is that after phenobarbital levels are >40 mcg/mL, large dosing increments are necessary to achieve additional small increases in the percentage of patients becoming seizure free.

Anticonvulsants

These agents may be used in the treatment of neonatal seizures.


Phenobarbital (Barbita, Luminal, Solfoton)

Volume of distribution in neonates 0.8-1 L/kg. Half-life 50-200 h; may be 150-200 h in neonates with HIE. Serum levels variable; higher levels correlated with higher percentage of seizure-free patients: 10-30 mcg/mL, 40%; 40 mcg/mL, 70%; 100 mcg/mL, 77%; and adding second antiepileptic drug (AED), 88%.
Respiratory failure usually occurs during acute loading, when serum levels >40-50 mg/dL but may occur earlier or later. Comedication with other sedating drugs, especially benzodiazepines, may increase respiratory depression. Levels >100 mcg/mL may cause cardiovascular instability in some patients.

Adult

Pediatric

20 mg/kg IV
Infusion rate: 1 mg/kg/min IV
Repeat bolus: 10 mg/kg IV may be necessary
Maintenance: 2.5-5 mg/kg/d PO/IV

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (may need to adjust dose in patients whose coagulation parameters stabilized with anticoagulants); alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may decrease effects of PO contraceptives in women (must use additional contraception to prevent unwanted pregnancy)

Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritis

Pregnancy

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

Precautions

Use cardiorespiratory monitoring during infusion; respiratory depression may occur with high doses or serum levels; be ready to provide respiratory support; menstrual irregularities


Fosphenytoin (Cerebyx)

Second-line drug after phenobarbital fails. Seizure control 31-41% with loading doses of 15-20 mg/kg. Full-term neonates may need levels 18-20 mg/dL; achieved only with high loading and maintenance doses. Phenytoin poorly bound (range, 6-41%; mean, 24%) to protein in critically ill neonates, especially those with hyperbilirubinemia. High free phenytoin levels may exacerbate seizures and cause cardiac arrhythmias. Volume of distribution of phenytoin in neonate is 0.89 ± 35 kg/L.

Half-life of phenytoin in newborns 6-140 h; tends to shorten with postnatal age (decreases by two thirds at age 1-4 wks). Serum concentration linearly correlated with half-life after age 8 d. Finding compatible with concentration-dependent kinetics that rely on saturable enzymatic metabolism for excretion; also seen in older patients.

Kinetics in first week of life may be unpredictable. In most cases, decreased, slowed PO absorption plus increasing clearance makes increasingly high PO maintenance doses (7-25 mg/kg/d) necessary near end of first month to keep therapeutic serum levels with PO maintenance.

Total urinary excretion in infancy vs older children is 30% vs 59%. In infants, PO absorption decreased further by fasting and increased (by 69%) with food. Therapeutic serum range 10-20 mg/dL.

Phenytoin prodrug. Popular recently because of relatively favorable toxicity profile. Dephosphorylates into phenytoin, but prodrug most tightly bound to serum protein, which rapidly increases serum levels after IV infusion.

Adult

Pediatric

Loading doses: phenytoin equivalent 15-20 mg/kg IV (use creatinine clearance [CrCl] monitors); equivalents marked on vial
Bolus infusion rate: 1 mg/kg/min
Maintenance: phenytoin 7-25 mg/kg/d PO

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, disulfiram, ethanol (acute ingestion), omeprazole, phenacemide, phenylbutazone, Succinimides, fluconazole, isoniazid, metronidazole, miconazole, sulfonamides, trimethoprim, and valproic acid may increase toxicity; barbiturates, carbamazepine, theophylline, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, and sucralfate may decrease effects; may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, methadone, metyrapone, mexiletine, PO contraceptives, quinidine, theophylline, valproic acid

Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; Adams-Stokes syndrome

Pregnancy

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

Precautions

Cardiorespiratory monitoring required for phenytoin and fosphenytoin; blood dyscrasias (order blood counts and urinalysis at start and q1mo thereafter); discontinue use if skin rash appears (if exfoliative, bullous, or purpuric, do not resume); caution in acute intermittent porphyria; may raise blood glucose levels; discontinue if hepatic dysfunction occurs


Lorazepam (Ativan)

Benzodiazepine to treat neonatal seizures. Main excretion urinary. No active metabolites known. Small volume of distribution for unbound form; partly why effective duration of action against seizures may be longer than that of diazepam.

Adult

Pediatric

0.05 mg/kg IV over 3-5 min; repeat up to 3 times q15min

Alcohol, phenothiazines, barbiturates, and MAOIs increase CNS toxicity

Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma

Pregnancy

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

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease; seizure recurrence possible because of 8- to 12-h duration of efficacy; attenuation of background or burst-suppression pattern may appear during and persist several hours after infusion

More on Hypoxic-Ischemic Brain Injury in the Newborn

Overview: Hypoxic-Ischemic Brain Injury in the Newborn
Differential Diagnoses & Workup: Hypoxic-Ischemic Brain Injury in the Newborn
Treatment & Medication: Hypoxic-Ischemic Brain Injury in the Newborn
Follow-up: Hypoxic-Ischemic Brain Injury in the Newborn
References
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Further Reading

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Keywords

HIE, ischemia/hypoxemia, hypoxemia/ischemia, perinatal asphyxia, newborn encephalopathy, neonatal encephalopathy, NE, HIE-NE, excitotoxicity, periventricular leukomalacia, cerebral ischemia, cerebral hypoxia, birth asphyxiation, hypoxic-ischemic brain injury in the newborn

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Contributor Information and Disclosures

Author

Marcio Sotero de Menezes, MD, Associate Professor, Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Seattle, University of Washington
Marcio Sotero de Menezes, MD is a member of the following medical societies: American Academy of Neurology and American Epilepsy Society
Disclosure: Nothing to disclose.

Coauthor(s)

Dennis WW Shaw, MD, Professor, Department of Radiology, Department of Radiology, University of Washington School of Medicine; Consulting Staff, Children's Hospital and Regional Medical Center of Seattle
Dennis WW Shaw, MD is a member of the following medical societies: American College of Radiology, American Roentgen Ray Society, American Society of Neuroradiology, American Society of Pediatric Neuroradiology, International Society for Magnetic Resonance in Medicine, Radiological Society of North America, Society for Pediatric Radiology, and Society of Cardiovascular and Interventional Radiology
Disclosure: Nothing to disclose.

Medical Editor

Ann M Neumeyer, MD, Clinic Director, Instructor, Departments of Neurology and Pediatrics, Massachusetts General Hospital, Harvard Medical School
Ann M Neumeyer, MD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, and Massachusetts Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Kenneth J Mack, MD, PhD, Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic
Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD, Assistant Professor, Department of Neurology, Department of Pediatrics, Division of Pediatrics, Oregon Health and Science University; Consulting Staff, Shriners Hospital
Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

 
 
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