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Medication

Medication Summary

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, including electrographic (EEG)-only seizures (ie, seen only on EEG).

Class Summary

These agents are used to control seizures.

Phenobarbital (Luminal)

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Often used as a first-line agent for clinical and electrographic-only neonatal seizures. The duration of therapy will vary depending on both the EEG findings and clinical status. In most cases, can be weaned and stopped prior to NICU discharge; however, treatment may need to be continued for several months in infants with persistent neurologic abnormalities and clinical or EEG evidence of seizures.

Phenytoin (Dilantin)

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Can be used in infants with refractory seizures that do not respond to phenobarbital, levetiracetam, or lorazepam. Oral absorption is negligible for the first several months of life.

Lorazepam (Ativan)

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Indicated 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.

Levetiracetam (Keppra, Keppra XR, Spritam)

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May be used as a first- or second-line agent in infants with seizures.

Midazolam (Versed)

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Can be used as a drip for infants with status epilepticus.

Class Summary

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)

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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.

Dobutamine (Dobutrex)

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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.

Questions

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Media Gallery

Fetal response to asphyxia illustrating the initial redistribution of blood flow to vital organs. With prolonged hypoxic-ischemic 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.

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Table. Modified Sarnat Clinical Stages of Perinatal Hypoxic Ischemic Brain Injury^[37]

Table. Modified Sarnat Clinical Stages of Perinatal Hypoxic Ischemic Brain Injury ^[37]

	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

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Author

Santina A Zanelli, MD Associate 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, American Epilepsy Society, Society for Neuroscience, Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

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

Disclosure: Nothing to disclose.

David A Kaufman, MD 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.

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

Dharmendra J Nimavat, MD, FAAP Associate Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Southern Illinois University School of Medicine; Staff Neonatologist, Clinical Director, NICU Regional Perinatal Center, HSHS St John's Children's Hospital

Dharmendra J Nimavat, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association of Physicians of Indian Origin

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.

Hypoxic-Ischemic Encephalopathy Medication

Medication Summary

Anticonvulsants