Pediatric Anoxic Brain Injury

Disease/Disorder

Definition

Anoxic brain injury (ABI) is a decline in brain function due to a disruption of the oxygen supply to the brain, occurring in the presence or absence of adequate systemic blood supply. ABI can be caused by any event interfering with the brain’s ability to receive or effectively utilize oxygen as in drowning, suffocation, cardiac or respiratory arrest, cerebrovascular accident or carbon monoxide poisoning.^1,2

Anoxic versus Hypoxic brain injury (ABI vs HBI) can be defined as a global disturbance related to brain function with resultant loss (Anoxic) or decrease (Hypoxic) in oxygen supply to the brain. The term anoxia is used to refer to a complete loss of tissue oxygenation. On the other hand, hypoxia references diminished or disrupted oxygenation.

Hypoxic ischemic encephalopathy (HIE) is a cause of neonatal encephalopathy characterized by asphyxiation with resultant inadequate oxygenation to the brain in the perinatal period leading to abnormal neurologic function. Hypoxic Ischemic Brain Injury (HIBI) is collectively defined as complete, global, temporary loss of blood supply and oxygen to the brain.¹

Etiologies of hypoxia

Cardiac arrest and respiratory failure are common causes of anoxic brain injury. Other causes include carbon monoxide poisoning, asphyxiation due to hanging, and near drowning.⁴

Pediatric Anoxic Brain Injury – Table 1

Common causes of pediatric anoxic brain injury and primary prevention⁵

Pediatric Anoxic Brain Injury – Table 2

Patho-anatomy/physiology

Tissue oxygenation is affected by deliverable blood oxygen content and blood flow. Regardless of duration, the brain is extremely sensitive to oxygen deprivation. The most sensitive areas of the brain susceptible to global hypoxia are the basal ganglia, layers 3, 5 & 6 of the cerebral cortex, and the deep cerebellar folia. In ABI, brainstem nuclei are most resistant.¹

Primary anoxic brain injury results from ischemia (anoxic depolarization, ATP depletion, and glutamate release with free radical formation and nitric oxide production) and reperfusion (creates cerebral edema and death).²

In primary injury, glutamate exposure following ATP depletion causes impaired cell membrane function due to sodium/potassium ATP pump failure. This disruption results in sodium influx, inducing neuronal swelling and loss of transmembrane gradients. The resultant anoxic depolarization leads to calcium influx, triggering impaired cellular stability apoptosis-induced cell death.¹ Deep gray matter nuclei, cortices, hippocampi, basal ganglia, white matter and cerebellum are all vulnerable.⁴

Secondary injury is seen with return of spontaneous circulation. Failure of auto-regulation, ongoing ischemia, cerebral hypoperfusion, seizures, as well as the breakdown of the blood brain barrier are consideredcumulative events.² During the reperfusion phase, formation of free radicals (oxygen and nitrogen) causes neuronal injury, and release of excitotoxic glutamate. Hypoperfusion in smaller cerebral vessels can occur in setting of reperfusion of the larger vessels following injury.¹

Prolonged hypoxia, ischemia or anoxia induces neuronal cell death that results in irreversible brain injury.¹ Neurologic abnormalities resulting from hypoxia and anoxia vary in severity and include feeding difficulties, seizures, cognitive deficits, and motor impairments, and coma.³ Common outcomes from ABI include cerebral edema, elevated intracranial pressure, and cerebral autoregulation dysfunction.¹

Brain death and disorders of consciousness^1,4,6

Patients with ABI have variable outcomes depending on duration of hypoxia, degree of hypoxic injury, duration of impaired consciousness, and duration of post-injury confusion.¹⁰

Pediatric Anoxic Brain Injury – Table 3

Specific secondary complications in anoxic brain injury as opposed to traumatic brain injury

Patients with anoxic brain injury have differences in neuropathology than those with traumatic brain injury, which may contribute to differences in recovery. Some proposed reasons for recovery difference include more global injury (as opposed to focal injury), more neuronal apoptosis (as opposed to axonal injury) that decreases opportunity for plasticity, and overall different mechanisms of competition for neural responses between cognitive and motor recovery.

Compared to traumatic brain injury, anoxic brain injury is associated with a higher incidence and frequency of seizures, as well as increased pneumonia, gastrointestinal, and heterotopic ossification issues.⁴

The increased severity of complications in anoxic brain injury is associated with the following rehabilitation and prognostic outcomes^1,4

• Longer rehabilitation stays
• More severe impairments
• Slower rate of recovery as measured by FIM score, with physical recovery slowed than cognitive recovery
• For those in vegetative states, anoxic brain injury patients improved to minimally conscious states (or better) at a lower rate than traumatic brain injury.
• Higher mortality

Essentials of Assessment

History

Historical Evaluation should include onset of injury, mechanism, duration of ischemia and time of reperfusion (if known). Medication use and abuse should also be researched, to include prescription medications, over the medications, and any illegal substance use/abuse. Prior psychiatric history, educational history, and functional history will also provide key details in relation to prognosis and functional recovery. Social support should also be documented at this time.⁴

• History of present illness: Detailed history of event leading up to anoxia; duration of anoxia; details of immediate resuscitation, including effectiveness; use of any medications/drugs- prescribed (antiepileptics or antidepressants) or recreational (alcohol, heroin); history of trauma; allergies to medications.
• Birth and developmental history, including gestational age; type of delivery: Vaginal vs Cesarean section; any anoxia at birth; baseline developmental history information
• Past medical/surgical history: Specifically include cardiac history, respiratory history, seizure history, or history related to another specific known cause of anoxia for specific patients.
• Family history: Specifically include cardiac history (sudden death suggesting Wolff Parkinson White syndrome, prolonged QT syndrome); history of epilepsy, or history related to another specific known cause of anoxia for specific patient
• Social history: Type of house family lives in, any steps in, who will help care for the child, adults involved in child’s care at this time, educational stage

Physical examination

Examination following anoxic brain injury may vary based on severity. In severe injuries (to include children without consciousness), the child may be evaluated for brainstem reflexes, generalized myoclonus, and motor responses to stimuli. In any child, it is important to assess motor movements, range of motion, skin integrity, and muscle tone. 

In a conscious child, it is important to assess cognitive impairment. Areas of evaluation should include attention, processing speed, memory, executive dysfunction, language, calculation, apraxia, agnosia, and visuospatial impairments. Specific motor impairment should be identified during the musculoskeletal (MSK) exam as well as the neurological exam. These can include Parkinsonism, dystonia, spasticity, chorea, tremor, tics, athetosis, seizures, or myoclonic syndromes.⁴

General Appearance

• Level of arousal/consciousness
• Circulatory status
  • Vital Signs
  • Capillary refill
• Respiratory status
  • Regular vs. irregular spontaneous breathing
  • Intubation: Breathing over vent, at vent rate or apneic?
• For infants: anterior fontanelle exam for fullness, assess sutures for separation

Neurologic Examination

History, physical examination, and imaging need to be interpreted together to further guide management. For this reason, it is important that the neurologic exam is not altered by medications, fluctuations in temperature, or metabolic abnormalities that could contribute to an altered neurologic examination. Sedatives, analgesics, and paralytics may alter the ability of a patient in assessment of neurologic capability. 

Pupillary and corneal reflexes, motor response to pain, and myoclonus status epilepticus have prognostic potential. For example, a bilaterally absent pupillary light response as well as a bilaterally absent corneal reflex on day 3 is a strong predictor of poor prognosis.¹³

• Fundoscopic exam: multilayered retinal hemorrhage suggestive of non-accidental head injury
• Extraocular assessment including brainstem function
  • Ocular movements
    • Sustained down/up-gaze, irregular upward nystagmus, ping-pong gaze, periodic lateral gaze associated with poor outcome
  • Corneal reflexes
  • Pupillary light reflex⁸
    • Unilateral fixed dilated pupil suggestive of transtentorial herniation
    • Acute bilateral fixed dilated pupils (concern for central herniation)
  • Oculocephalic reflexes
• Motor exam
  • Muscle Tone
  • Motor response to pain
  • Decorticate and decerebrate posturing
  • Ability to follow motor commands
• Sensory exam
• Reflex exam
• Coordination exam
• Abnormal Movement
  • Rigidity, dystonia, chorea, action myoclonus more common in ABI ²

Musculoskeletal Examination

• Muscle Bulk
• Muscle Tone
  • Spasticity, rigidity and dystonia often more severe and generalized in children with ABI compared to TBI
• Range of Motion
  • Common contractures include equinus deformity, hip flexion contracture, and knee flexion contracture.
• Hip subluxation/dislocation
  • Found in 34% of near-drowning children with ABI as early as 1 month after injury
• Scoliosis
  • Found in 18% of children with ABI
• Gait
  • 70% children with ABI from near-drowning non-ambulatory

Note: Neurologic exam is often limited in the acute phase of anoxic brain injury due to severe cognitive compromise. PICU clinical assessment is often compromised by sedation, neuromuscular blockade, ventilation, hypothermia, inotropic management etc.

Early prognostic indicators⁴

Circumstances of Event & Patient Factors

• Non-Modifiable: Age, Gender, Pre-existing Conditions
• Modifiable: Time to Resuscitation, Medication Administration
• Comorbid conditions and circumstances of initial resuscitation (duration of CPR, no-flow time, initial rhythm, lactate levels) are strong predictors of short-term survival
• Good functional status prior to the event, as well as absence of mechanical ventilation, is associated with a positive neurologic outcome. 

Common prognostic scales

• Modified Pediatric Glasgow Coma Scale
• Full Outline of Unresponsiveness (FOUR) Scores⁸
  • Eye responses
  • Motor responses
  • Brainstem reflexes
  • Respiration pattern

Intracranial Pressure (ICP) Monitoring⁹

• External ventricular drain provides most accurate assessment of ICP, as well as allows for therapeutic CSF drainage
• ICP > 20mmHg in comatose patients associated with poor outcome
• Look out for increased ICP / herniation syndromes¹⁶
• Decerebration pattern
  • Abrupt pupillary change
  • Impaired upward gaze
  • Sudden deterioration of respiration and apnea
• Sustained late intracranial hypertension more likely a sign of irreversible brain damage

Electroencephalography (EEG) Monitoring

EEG is one of the most widely used tests for early prognostication after Hypoxic Ischemic Brain Injury (HIBI). EEG provides information about brain activity in Real-Time. It assesses the efferent functions of pyramidal cells in the cortex.¹

EEG waveforms are associated with degree of injury. Three features play a role in evaluation: background activity, reactivity, epileptiform changes. Background activity represents overall function as well as associated outcome.¹

• Continuous or repetitive EEG monitoring most helpful for evaluation of encephalopathy (EEG background) and seizure detection (HIBI results in decreased amplitude and slowing of background activity) 
• Good outcome predictors
  • Moderate background activity, sleep patterns, response to auditory and painful stimulations, numerous beta rhythms
  • Early recovery of continuous background
  • Late appearance of epileptiform activity
• Poor outcome predictors
  • Low Voltage or isoelectric EEG
  • High voltage, rhythmic delta waves, biphasic sharp waves, “burst suppression” pattern (Use with caution as burst suppression can be induced by midazolam or propofol), absence of beta rhythms, generalized suppression, status epilepticus, nonreactivity
  • Persistently abnormal EEG at 48 hours or more associated with adverse neurodevelopmental outcome
  • Epileptiform Features (sharp waves, polyspikes, spikes, wave patterns)¹

Somatosensory Evoked Potential (SSEP) Monitoring

Somatosensory Evoked Potentials (SSEPs) assess afferent thalamocortical integrity.¹

• SSEP is used as a neurophysiologic test for assessing integrity of neuronal pathways from the peripheral nerves, spinal cord, brainstem and cerebral cortex.
• Most reliable evoked potential waveform as median N20 component of SSEP
  • Median N20 SSEP: first cortical response of SSEP with median nerve stimulation
  • Bilateral absence of median N20 response on days 1 and 3 or later following CPR accurately predicts poor outcome (reflects widespread cortical necrosis) Bilateral absence of N20 potentials is a reliable/strong predictor of poor outcome after cardiac arrest yet may be impacted by hypothermia.¹
• Advantage: less susceptible to effects of sedative drugs, metabolic changes and artifact interference compared to EEG monitoring.
• Disadvantage: require advanced neurologic training, interpretation limited to specialized centers, low sensitivity

Serum Biomarkers for ABI Prognostication

• Serum NSE (neuron-specific enolase)
  • Isomer of intracytoplasmic glycolytic enzyme enolase found in neuronal bodies, axons, neuroendocrine cells and tumors
  • NSE peaks in serum and CSF at ours after injury
  • Serum NSE > 33 microgram/L at days 1 and 3 associated with poor outcome
  • Use limited by lack of laboratory standardization, long turn-around time
  • Most widely investigated serum biomarker of neuronal damage¹
• S100 protein
  • Calcium-binding protein highly concentrated in glial and Schwann cells
  • Highest level in first 24 hours after anoxic injury; declines over next 48 hours
  • Released from injured glial cells¹
• CKBB (creatine kinase brain isozyme)
  • Present in neurons and astrocytes; leaks from cytoplasm of destroyed cells
  • Peaks around 48-72 hours after injury
• Tau Protein
  • Marker of axonal injury
  • Released into serum and CSF
  • Predicts poor outcome
• Neurofilament Light Chain
  • Biomarker of axonal injury
  • Currently under investigation for prognostication of TIBI
  • Most accurate marker with poor predictive outcome in first 24 hours post event³

Laboratory studies to monitor for complications

Pediatric Anoxic Brain Injury – Table 4

Brain imaging

Cranial ultrasound

• Ideal for newborn/infants
• Suitable for screening and follow-up exam
• Generally performed using anterior fontanelle as acoustic window
• Posterior fontanelle and mastoid fontanelles can be used as acoustic windows to study posterior fossa and brainstem
• Noninvasive and low cost, can be done at bedside
• Cons: does not depict white matter signal abnormalities, does not give detailed information on myelination and detect lesions on posterior limb of internal capsule

Head CT

• Very limited role in young infants due to high ionizing radiation
• Excellent for detecting hemorrhage
• Not great for detecting edema/infarction newborn with hypoxic-ischemic brain injury due to high water content in newborn brain

Brain MRI

• Superb soft tissue contrast differentiation
• Diffusion-weighted imaging (DWI)—uses hydrogen molecules physical property of diffusion: sensitive for detecting cytotoxic edema; white matter lesions; ventricular enlargement vs loss of gyri and sulci causing an ex-vacuo effect.

Neuropsychological evaluation

Neuropsychological deficits often pronounced in pediatric survivors of anoxic brain injury due to diffuse and often more severe nature of cerebral involvement.

Exact impairments depend on nature and duration of anoxic event, associated neuronal degeneration, age at injury, and selective vulnerability of different brain regions (e.g., hippocampus, globus pallidus, thalamus, putamen, caudate nucleus, parieto-occipital cortex, substantia nigra and cerebellum.)

Common neuropsychological impairments seen in anoxic brain injury

• Memory deficits
• Learning difficulties
• Attention deficits
• Decreased visuospatial abilities
• Generalized intellectual impairment
• Behavioral problems
• Dysexecutive syndromes
• Personality changes

Early predictions of outcomes

Indicators of recovery include presence or absence of spontaneous movements; response to voice, light touch, and painful stimuli; pupillary size, response to light; cranial nerve function: corneal and oculovestibular reflexes; respiratory pattern.

A Glasgow Coma Scale (GCS) score of ≤4 within the first 48 hours has been associated with poor outcomes, such as coma or death. Absent corneal or pupillary light reflexes at 24 hours, and absent motor responses at 24 or 72 hours, have been associated with severe disability/death.

Based on clinical data, the typical outcomes in ABI is recovery, chronic unresponsive wakefulness, or death. If a patient is in chronic unresponsive wakefulness at time of discharge, life expectancy is approximately two to five years. Absent motor responses, extensor motor responses, absent pupillary reflexes, or absent corneal reflexes on the third day after injury are associated with poor outcomes.

Children who sustain ABI demonstrate worse outcomes than children with traumatic brain injury (TBI), cognitively and motorically, especially if unconscious for more than 60 days.

Social role and social support system

The patient, family, and/or caregiver(s) should be asked about who lives at home; adults who can help with care; structure and accessibility of home, including bathroom setup, doorway sizes, stairs to enter and stairs inside home; transportation options for the patient, including vehicle(s), public transportation, and school transportation; and current school setting.

Rehabilitation Management and Treatments

Available or current treatment guidelines

In the early phases of anoxic brain injury, rehabilitation primarily focuses on increasing arousal and participation.² This can be seen especially during Disorders of Consciousness. Pharmacologic management and non-pharmacologic modalities may be employed. As for pharmacologic therapies, amantadine, methylphenidate, bromocriptine, carbidopa/levodopa and zolpidem have been shown to improve emergence from disorders of consciousness.^1,7 The use of neurostimulation agents amantadine, a dopamine modulator, and methylphenidate, a norepinephrine and dopamine reuptake inhibitor, in patients with hypoxic brain injury in a retrospective study showed increased rates of emergence from disorders of consciousness compared to those who did not receive these agents.¹ A case series noted improvement of cognitive impairments with the use of levodopa, a dopamine precursor, and or bromocriptine, a dopamine agonist, and carbidopa/levodopa use in children with disorders of consciousness, especially those with co-occurring dystonia has been reported.^1,7 A small number of adults have shown improvement in arousal and function in a seemingly paradoxical response to zolpidem, a positive modulator at the GABA A receptor, traditionally used as a sleep agent.^1,7 Many studies show mixed results of the use of these agents in the pediatric population.⁷

Following emergence from a minimally conscious state (MCS), rehabilitation focus transitions to specific task-based assistance and responsibility associated with functional movements and self-care. Therapy efforts tend to focus on spasticity management, fall prevention, and environmental navigation while encouraging independence. Pharmacologic efforts tend to be focused on improving agitation, attention, processing speed, memory deficits, sleep disturbances, depression, and headaches.⁴ Various treatment modalities can be further utilized through disease progression.

Disease progression

Spasticity management in anoxic brain injury is a rehabilitation focus of recovery. Adequate spasticity management may allow for muscle bulk maintenance, decreased energy expenditure, improved ambulation, and increased range of motion (ROM).^2,4

Patients with anoxic brain injury often initially have flaccid musculature. Initial flaccidity can change to hypertonicity with spasticity, rigidity, or dystonia.

Spasticity can be effectively treated using oral, intrathecal, or injectable pharmacologic agents. Oral medications commonly include, but are not limited to, baclofen, tizanidine, clonidine, diazepam, and dantrolene (all have been shown to reduce muscle spasms).² There is limited evidence regarding their effect on ABI patients specifically compared to traumatic brain injury patients, and the sedating effects of these medications limits their use in the treatment of spasticity.^{2, 4} Spasticity can also be treated with interventional chemodenervation using botulinum toxins in muscles and/or ethanol/phenol in muscles.² It is important to begin treating early to prevent contracture development. Dystonia is difficult to treat pharmacologically; enteral carbidopa/levodopa, enteral bromocriptine, botulinum toxin injections, and intrathecal baclofen via pump have all shown promise.

Another complication, although less reported in the pediatric population, is post-anoxic myoclonus (PAM), a rare but significantly debilitating consequence of anoxic brain injury. PAM, usually a type of intention myoclonus (including response to stimuli), can be classified into acute and chronic (Lance-Adams syndrome) forms.^1,2 There are several forms of myoclonus which can be further classified via electrophysiological findings, which can help reveal sites of origin (cortical, subcortical, brainstem, segmental, peripheral), as well as potential seizure activity. In post-anoxic brain injury, cortical (in Lance-Adams syndrome), and reticular reflex myoclonus types are predominant.^10,11 Clinically, in cortical myoclonus, there can be focal, multifocal, bilateral or generalized movements, while in reticular reflex myoclonus there are more generalized movements. Classifying the types of myoclonus can guide treatment. Clonazepam, valproate, and levetiracetam can be used to treat cortical myoclonus.¹² Clonazepam and 5-HTP have been used to treat reticular reflex myoclonus.^12,13

Seizures are another known complication of both anoxic and traumatic brain injury, more commonly associated with penetrating trauma. Most seizure activity occurs in the acute post-injury time period (days to weeks), although some may occur even years after the injury. Post traumatic epilepsy may also develop.⁴ AEDs used in treatment are chosen depending on characteristics of the seizures.⁷

Paroxysmal sympathetic hyperactivity (PSH), a complication of brain injury seen in a significant minority of patients, is characterized by hyperthermia, diaphoresis, tachypnea, tachycardia, hypertension, and/or dystonia, typically in response to some type of external stimuli. Although the exact pathophysiology of PSH is not clear, it is thought to result from impaired descending inhibitory pathways resulting in spinal circuit excitation. ⁷ Empirical pharmacologic treatment with benzodiazepines, clonidine, propranolol, bromocriptine, and/or baclofen can be helpful in preventing and treating paroxysms, although these therapies are much less studied in children than in adults.⁷

Early pump placement for intrathecal baclofen dosing has been shown to be effective in treating both hypertonicity and PSH.⁷

Rehabilitation-specific treatment in anoxic brain injury

Physical, occupational, and speech therapies are beneficial immediately after injuries, and should be involved in all phases of recovery. In the acute phase, an inpatient rehabilitation stay can allow for comprehensive therapies and medical care for best functional recovery. After discharge from an inpatient setting, many patients benefit from continued outpatient therapies, including close follow up with a multidisciplinary team. A home exercise program can also be initiated. Passive range of motion exercises, splinting, or bracing benefit the brain-injured child, depending largely upon the presentation of tone.

Pediatric Anoxic Brain Injury – Table 5

Coordination of care

Discharge planning begins on admission. An initial evaluation by team members should be communicated to patient, family, and funding source to coordinate adequate care with regard to medical care, therapies required, social needs, and required equipment (including mobility or other assistive devices, and orthoses).

A multidisciplinary team is best utilized in this situation. Team members include: physiatry, social work, physical therapy, occupational therapy, speech therapy, neuropsychology, nursing, recreational therapy, and child life specialist. Additional team members, such as wound care team or an orthotist, may be required depending on the individual patient

At time of discharge, information should be conveyed to the primary care physician and outpatient therapy team to ensure seamless care.

In the outpatient setting, routine follow up with primary care and Physical Medicine and Rehabilitation providers should be scheduled for close monitoring and addressing any needs that arise. Continued visits with specialists, including neurology, orthopedic surgery, or neurosurgery, may be beneficial depending on the patient’s needs.

Patient & family education

Families should be trained regarding deficits, new care needs, and new equipment. They should be educated about use of current medications, ongoing therapy requirements, and potential course of recovery.

Families benefit from care management and social work to learn about available resources and how to navigate new health care systems. Families should be educated regarding funding and resource programs available to them.

Integration

Community integration should be individualized based on a patient’s level of function. This can include return to school, social activities, or recreational activities. It can also include, providing caregiver assistance, education regarding physical and cognitive deficits, counseling services for patient and family for coping strategies, and involvement with support groups.

Professional issues

Parents and families need support and understanding from the treatment team. At times, the treatment team may not agree with a family’s understanding of a condition or choices for a patient. It is important to be non-judgmental and partner with the family to make decisions that help the patient and align with the patient’s/family’s values and goals.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

• Families should be given anticipatory guidance about risks for anoxic brain injury, particularly in children with medical conditions that increase risk (cardiac disease, severe respiratory disease, epilepsy)
• Aggressive management of spasticity is helpful, particularly early after emergence of increased tone.
• Paroxysmal sympathetic hyperactivity can be treated with a variety of pharmacologic options, including analgesics, benzodiazepines, antihypertensives, or early baclofen pump placement.
• Family training and education is paramount during early phases of recovery from anoxic brain injury.

Cutting Edge/Emerging and Unique Concepts and Practice

Therapeutic hypothermia, or “cooling,” is a process by which core body temperature is purposely lowered to 33-34 degrees Celsius for 72 hours to prevent ischemic injury or death.^14,15 Therapeutic hypothermia attempts to reduce anoxic brain injury by decreasing cerebral metabolism and reducing global carbon dioxide production, while also reducing oxygen consumption. Temperature modulation is achieved by surface cooling methods (cooling pad & blankets). It can also be achieved by intravascular “cooling”. On the other hand, hyperthermia, which is well studied, is known to worsen outcomes in hypoxic-ischemic brain injury.¹

Therapeutic hypothermia, now referred to as therapeutic temperature management (TTM) reduces the outcome of death or severe neurodevelopmental disability.¹⁴ TTM therapy has been utilized as a standard of practice in comatose state patients after cardiac arrest; however, new practices are expanding the use of TTM to patients with HIE. Of note, it must be implemented within 6 hours of birth to have a neuroprotective effect in the case of HIE.¹⁴

Hyperbaric oxygen therapy has shown promise in clinical trials as an adjunctive neuroprotective therapy for HIE. It is now more broadly used in the clinical setting, but there is yet to be evidence supporting standardized protocols for its use.¹⁶

Gaps in the Evidence-Based Knowledge

Melatonin’s known antioxidant and anti-cell death properties hold promise for use as a neuroprotective agent to be used, and it has shown promising safety and efficacy in preliminary clinical trials. Many neuroprotective agents are currently being studied in animal models including caffeine, a Sonic Hedgehog agonist, clemastine, and omegavin.¹⁵

References

1. Zollman, Felise S. Manual of Traumatic Brain Injury: Assessment and Management. Demos Medical. 2022:206
2. Eapen, Blessen C, David X. Cifu. Brain Injury Medicine: Board Review. 2021: 342
3. Russ, J. B., Simmons, R., & Glass, H. C. (2021). Neonatal encephalopathy: Beyond hypoxic-ischemic encephalopathy. NeoReviews, 22(3). https://doi.org/10.1542/neo.22-3-e148
4. Zasler, Nathan D., Katz, Douglas I., Zafonte, Ross D. Brain Injury Medicine: Principles and Practice. Demos Medical. 2022: 654-660
5. Javaid, S., Constance, J., Srinivasan, R., & Yeh, N. (2022). Brain injury. Handbook of Pediatric Rehabilitation Medicine. https://doi.org/10.1891/9780826184498.0003
6. Gray JM, Kramer ME, Suskauer SJ, Slomine BS. Functional Recovery During Inpatient Rehabilitation in Children With Anoxic or Hypoxic Brain Injury. Arch Phys Med Rehabil. 2023 Jun;104(6):918-924. doi: 10.1016/j.apmr.2023.01.018.
7. Murphy, K. P., McMahon, M. A., & Houtrow, A. (2021). Pediatric rehabilitation: Principles and practice. Springer Publishing Company, LLC.
8. Gaur BK, Meman MHF, Jain S. Comparative Analysis of Full Outline of Unresponsive Score and Glasgow Coma Scale Score for Outcomes Prediction in Children with Impaired Consciousness. Neuropediatrics. 2025 Jun 18. doi: 10.1055/a-2627-1974.
9. Manley G.T., Albert G. W., Brophy G. M., et al.Best Practices In The Management Of Traumatic Brain Injury. American College of Surgeons (2024)
10. Vellieux G, Apartis E, Baudin P, Del Río Quiñones MA, Villemonte de la Clergerie D, Kas A, Navarro V; Lance-Adams Coinvestigators. Multimodal Assessment of the Origin of Myoclonus in Lance-Adams Syndrome. Neurology.
11. Ong MT, Sarrigiannis PG, Baxter PS. Post-Anoxic Reticular Reflex Myoclonus in a Child and Proposed Classification of Post-Anoxic Myoclonus. Pediatr Neurol. 2017 Mar;68:68-72.
12. Pena AB, Caviness JN. Physiology-Based Treatment of Myoclonus. Neurotherapeutics. 2020 Oct
13. Riva A, D’Onofrio G, Ferlazzo E, Pascarella A, Pasini E, Franceschetti S, Panzica F, Canafoglia L, Vignoli A, Coppola A, Badioni V, Beccaria F, Labate A, Gambardella A, Romeo A, Capovilla G, Michelucci R, Striano P, Belcastro V. Myoclonus: Differential diagnosis and current management. Epilepsia Open. 2024 Apr
14. Cannavò L, Perrone S, Gitto E. Brain-Oriented Strategies for Neuroprotection of Asphyxiated Newborns in the First Hours of Life. Pediatr Neurol. 2023 Jun
15. Sabir H. Neuroprotective therapies for neonatal hypoxic-ischemic brain injury – a contemporary update. Semin Perinatol. 2025 Aug
16. Liu X, Deng S, Kang L. Progress in hyperbaric oxygen therapy for neonatal hypoxic-ischemic encephalopathy: mechanisms and combination therapies. Brain Inj. 2025 Jun

Original Version of the Topic

Rajashree Srinivasan, MD, Cristina Sanders, DO. Pediatric Anoxic Brain Injury. 9/20/2013

Previous Revision(s) of the Topic

Andrew Collins, MD, Priya Bolikal, MD, SheanHuey Ng, MD. Pediatric Anoxic Brain Injury. 10/20/2019

Cristina Marie Sanders, DO, Rajashree Srinivasan, MD, Priya Chitta Nangrani, MD. Pediatric Anoxic Brain Injury. 3/22/2023

Author Disclosure

Cristina Marie Sanders, DO, MS
Nothing to Disclose

Lizabelle Martin, MS III
Nothing to Disclose

Olivia Tincher, DO
Nothing to Disclose

Priya Chitta Nangrani, MD
Nothing to Disclose

Rajashree Srinivasan, MBBS
Nothing to Disclose