Anoxic Brain Injury

Anoxic Brain Injury 

Anoxic brain injury occurs when a decrease in either blood flow or oxygen causes cerebral ischemia.

The inadequate delivery of nutrients and oxygen to cerebral tissue commonly reflects defects in either cardiac circulation or respiratory function, or defects in both.

Synonyms

  • Hypoxic-ischemic injury
  • Anoxic encephalopathy
  • Cerebral hypoxia
  • Hypoxia of brain
  • Perinatal or intrapartum asphyxia (pediatric)

Epidemiology & Demographics

Incidence

  • •Difficult to assess due to the wide range of causes of anoxic brain injury.
  • •There are approximately 650,000 cardiac arrests per year in the U.S. based on data from the American Heart Association (AHA). Of the survivors, the majority (50% to 83%) suffer from clinically significant cognitive symptoms.
  • •A 2018 AHA reports states that 9% of patients survive an out of hospital cardiac arrest (∼350,000 cases per year) to hospital discharge with good neurologic function and 1.8% with poor neurologic function.
  • •One study found that only 10% of cardiac arrest survivors who initially had non-shockable rhythms were able to adequately perform activities of daily living at 90 days postarrest.
  • •Another study found that only 5% of cardiac arrest survivors had achieved full neurological recovery at 30 days postarrest.

Prevalence

  • •Similar to incidence, this is difficult to assess due to lack of data specifically regarding anoxic brain injury.
  • •One outcome of anoxic brain injury is vegetative state (unresponsive wakefulness syndrome), which varies in prevalence from 40 to 168 per 1 million population, depending on the definition used.

Risk Factors

Same as risk factors for cardiorespiratory arrest: Age, race, hypertension, hyperlipidemia, tobacco use, drug or alcohol abuse, and physical inactivity.

Physical Findings & Clinical Presentation

  • •There are a wide variety of neurological symptoms seen after cardiac resuscitation because of the variability of the ischemic insult.
  • •One-third of patients have seizures or myoclonus following cardiac arrest, which can be difficult to treat. Seizures are more common in patients with severe brain injury; however, seizures themselves are not prognostic of poor outcomes but can be source of continued brain injury in postresuscitation patients.
  • •Patients may be comatose after cardiac arrest, a state that can be first assessed after cessation of postresuscitation targeted hypothermia therapy (discussed below). Coma can progress along one of four clinical pathways: Eventual recovery of wakefulness with varying degrees of cognitive and physical impairment, a minimally conscious state, a vegetative state (also known as unresponsive wakefulness syndrome), or brain death.
  • •The distinction between minimally conscious state and unresponsive wakefulness syndrome is subtle and should only be assessed using standardized neurobehavioral assessments (e.g., Coma Recovery Scale-Revised). The distinctions are outlined below.
  • •Minimally conscious state: Altered state of awareness with normal sleep-wake cycles and intermittent interactivity with the environment. The patient can, even if briefly, demonstrate purposeful behavior, such as following simple commands or maintaining visual tracking.
  • •Vegetative state (unresponsive wakefulness syndrome): Altered state of awareness with normal sleep-wake cycles, but with complete loss of both cognitive awareness and ability to interact with environment. Persistent vegetative state is the term used for vegetative state after anoxic injury of between 1- and 3-months’ duration, and permanent vegetative state is the term used for a vegetative state persisting beyond 3 mo (unless due to traumatic brain injury, in which case permanent vegetative state is called at 12 mo).
  • •Brain death is the irreversible loss of both cortical and brainstem function, manifesting as loss of awareness, cranial reflexes, and motor responses. Patients with brain death have an isoelectric EEG and do not have intracerebral blood flow.

Etiology

  • •Ischemia (decreased cerebral perfusion): Myocardial infarction, cardiac arrest, hemorrhage, shock (due to infection, allergens, etc.), high intracranial pressure
  • •Hypoxia (decreased oxygenation): Drowning, strangulation, aspiration, carbon monoxide poisoning
  • Fig. E1 shows categories of mechanisms proposed to be involved in the evolution of secondary damage after severe traumatic brain injury in infants and children

Differential Diagnosis

  • •Other causes of encephalopathy, including toxic, metabolic, infectious, or neoplastic causes
  • •Nonconvulsive status epilepticus
  • •Hypothermia
  • •Histotoxic hypoxia, the inability to utilize oxygen despite adequate delivery to cerebral tissue; i.e., cyanide poisoning

Workup

  • •Neurologic examination (coma examination) to ascertain level of encephalopathy. The Glasgow Coma Scale is commonly used, but the Full Outline of UnResponsiveness (FOUR) score has been shown across several studies to be equally effective as or even superior to the GCS as a coma examination
  • •Systemic evaluation for causes of cardiorespiratory failure
  • •Laboratory studies (listed in the following) to evaluate alternate causes of encephalopathy and monitor brain-specific biomarkers
  • •EEG (detailed further down)
  • •MRI of brain or CT of head (if MRI cannot be obtained)

Laboratory Tests

  • •Glucose, serum metabolic profile, complete blood count, coagulation panel, ammonia, liver function test, arterial blood gas, urine drug screen, blood alcohol panel, and TSH to evaluate for other systemic causes of coma and/or seizures.
  • •Serum neuron-specific enolase levels should be obtained at 24, 48, and 72 hr after resuscitation, to aid in prognosis after cardiac arrest.

Imaging Studies

  • •Imaging is usually not revealing within first 24 hr of an anoxic event.
  • •Head CT without contrast: Repeat 24 hr after anoxic event to evaluate for stroke, trauma, hemorrhage, or cerebral edema.
  • •MRI of brain: Obtain if the patient is still comatose 72 to 120 hr after resuscitation, or if the head CT scan is unrevealing. MRI may show cortical necrosis and infarcts of the basal ganglia.

Other Studies

  • •EEG:
    • 1.Due to how common seizures are in the postresuscitation period, continuous EEG is crucial for assessing ongoing seizures during both the postresuscitation hypothermia therapy and the rewarming process. Seizures may not be clinically evident during these phases due to the use of neuromuscular blockade to counteract the side effects of hypothermia therapy. Continuous EEG is also needed to monitor for nonconvulsive seizures/status epilepticus.
    • 2.Assessment of the EEG background, suppression, and reactivity should be performed at 6 to 12 hr postresuscitation.
    • 3.A suppressed or discontinuous EEG background is correlated with severe brain injury after a cardiac arrest. Intermittent epileptiform discharges, however, are not correlated.
  • •Somatosensory evoked potentials (SSEP; aka, N20 response):
    • 1.Obtain 24 to 72 hr after anoxic event.
    • 2.The absence of bilateral N20 responses is very predictive of a poor neurologic outcome, even in patients who are sedated. However, do not use this modality if the patient is receiving suppressive anesthetic agents such as benzodiazepines or barbiturates.
    • 3.Even with absent N20 responses, some patients go on to have a good neurologic recovery. This test should be used in conjunction with other prognosticators.

Treatment

Nonpharmacologic Therapy

  • •Hypothermia:
    • 1.Therapeutic hypothermia to a target range of 32° C to 36° C (89.6° F to 96.8° F) immediately after cardiac resuscitation for a period of 24 to 72 hr is the standard of care and has been shown to reduce inflammation and metabolic demand, aiding the patient’s neurologic prognosis. It is indicated in all patients who have been resuscitated from a cardiac arrest with VF/VT as the presenting rhythm.
    • 2.Contraindications for hypothermia include active hemorrhage, hemodynamic instability, sepsis, or trauma.
    • 3.Complications from hypothermia include shivering, electrolyte disturbances, bradycardia, hemodynamic instability, coagulopathy, infection, hyperglycemia, and decreased metabolism and clearance of medications.
  • •Blood pressure and oxygenation:
    • 1.Postresuscitation hypotension is associated with poor outcomes. A mean arterial pressure of 65 mm Hg should be maintained.
    • 2.A PaO2 of 80 mm Hg to 300 mm Hg is recommended for postresuscitation care. This can usually be achieved with an oxygen saturation of 94% to 99% and a starting FIO2 of 0.5. Hyperventilation in anoxic brain injury should also be avoided, as it leads to hypoperfusion of the brain.
  • •Hyperbaric oxygen is used in carbon monoxide poisoning.

Acute General Treatment

  • •Supportive care: ABCs, secure airway, cardiopulmonary support in the critical care unit.
  • •Control seizures with antiepileptic medications (may need midazolam or propofol infusion for severe, uncontrolled seizures).
  • •Treat myoclonus with clonazepam 8 to 12 mg daily in divided doses; levetiracetam and valproic acid may be used for myoclonic status epilepticus. Treatment of myoclonus due to cardiac arrest does not change neurologic prognosis.
  • •For hypothermia therapy, patients should receive short-acting fentanyl and low-dose propofol. If the patient cannot tolerate propofol due to hemodynamic instability, the dose of fentanyl can be increased, and an IV midazolam bolus may be given as needed for agitation. This regimen reduces the use of continuous benzodiazepines and makes eventual prognostication easier due to reduced amounts of sedating medications.

Chronic Treatment

  • •Maintain adequate nutrition, normothermia (if not utilizing therapeutic hypothermia) infection precautions; provide deep vein thrombosis and gastric ulceration prophylaxis
  • •Physical, occupational, and speech therapy as indicated per prognosis and patient ability

Prognosis

  • •Prognostication in anoxic brain injury is difficult due to the lack of absolutely predictive diagnostic tests. However, using several diagnostic modalities in unison can give the clinician confidence in a patient’s likely clinical progression.
  • •Total ischemic time (onset of arrest to return of spontaneous circulation), no-flow time (onset to start of CPR), and low-flow time (length of CPR) can aid in risk-stratification of an eventual poor neurological outcome. The neurological exam (GCS and FOUR score), CT findings, EEG background, and the bispectral index and suppression ratio (processed EEG) are also all early methods of risk-stratifying a patient’s clinical course.
  • •High risk findings indicating a high likelihood of poor outcome are the following:
    • 1.A no-flow interval of >8 min
    • 2.GCS motor subscore of 1, or a total GCS score of 3 to 4
    • 3.Absence of pupillary or corneal reflexes
    • 4.Loss of the gray matter-white matter junction on CT
    • 5.Nonreactive, burst suppression, or isoelectric EEG background
    • 6.Bispectral index of <10
    • 7.Seizures that arise from a discontinuous background
    • 8.Severe myoclonus with an EEG correlate within the first 24 hr following injury
  • •Other results that suggest a poor outcome include:
    • 1.Absence of bilateral cortical SSEPs (N20 response) at any point
    • 2.Serum neuron-specific enolase (NSE) levels >33 μg/L 24 to 72 hr following injury
  • •The prognostic value of these findings and the timing of exam changes after therapeutic hypothermia. Patients often receive benzodiazepines and neuromuscular blocking agents during hypothermia treatment. These medications have significant effects on the neurological exam and EEG, and are metabolized more slowly due to hypothermia and postcardiac arrest organ dysfunction. Serial examinations should be obtained to address these confounders.
  • •When the results of prognostic tests line up after being performed and interpreted at the appropriate times, the clinician can feel confident in their predictive value. However, if the results are conflicting, clinicians should be cautious in using them as predictive tools.
  • •If the patient’s prognosis remains uncertain or poor after appropriate diagnostic tests are obtained, a multi-disciplinary discussion with the patient’s surrogate decision-maker and family should occur to discuss the uncertainties, prognosis, previous patient wishes (if known), and goals of care.
  • •Patients who survive cardiac arrest and the postresuscitation phase often have significant deficits in learning, memory, and executive function for several months after discharge. However, these symptoms do improve over time.

Disposition

Varies per extent of insult.

Mild insults may return to home or need acute rehabilitation, and significant brain injury may require long-term care or result in death.

Referral

Referral to a neurologist is appropriate for help with prognostication.

Pearls & Considerations

When assessing prognosis, use caution if patient is being treated with anesthetic agents or other depressants of consciousness, including anticonvulsants.

Also, consider the impact of therapeutic hypothermia on the timing of prognostication. Thus, serial neurologic exams are integral to best-practice care.

When examining patients and determining prognosis, account for medications and illicit drugs that may depress consciousness and awareness as well as metabolic derangements that may affect the metabolism of pharmacologic agents or illicit drugs.

Prevention

CPR, risk factor modification, induced hypothermia

Patient & Family Education

Consult with family members regularly and provide accurate assessment of prognosis.

Suggested Readings

  • Arrich J., et al.: Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev 2016; 15 (2): pp. CD004128.
  • Lacerte M et al: Hypoxic Brain Injury. [Updated 2020 Aug 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537310/.
  • Rabinstein AA. Coma and brain death. Continuum (Minneap Minn) 2018;24(6, Neurocritical Care): 1708-173
  • Seder DB. Management of comatose survivors of cardiac arrest, Continuum (Minneap Minn) 2018;24(6, Neurocritical Care): 1732-17
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