Hypoxic brain injury

Author(s): Sarah Ann Korth, MD and Mi Ran Shin, MD

Originally published:12/10/2012

Last updated:09/01/2017

1. DISEASE/DISORDER:

Definition

Hypoxic brain injury (HBI) is a term used to describe a diffuse brain injury as a result of hypoxia or reduction of oxygen. Purely hypoxic brain injury involves hypoxia with preserved circulation. The term hypoxic-ischemic brain injury should be differentiated, as it encompasses injuries induced by hypoxia and ischemia as a result from diminished blood supply. Another commonly associated term is anoxic brain injury that refers to complete lack of brain tissue oxygenation which is, in its pure form, rare. These terms are frequently used interchangeably, but have important differences in sequelae.1,2

Etiology

Hypoxic brain injury results from decreased circulating oxygen levels. These events are typically caused by respiratory failure such as pulmonary disease, suffocation, complications of anesthesia or drug use, strangulation or hanging. Impaired oxygen delivery may occur as the result of carbon monoxide (CO) poisoning3,4. Hypoxic-ischemic brain injury results from hypoperfusion, either from pump failure such as cardiac arrhythmias/arrest, or inadequate circulating blood volume as a result of massive blood loss.2

Epidemiology including risk factors and primary prevention

No specific numbers are available documenting incidence or prevalence of HBI, as HBI is a secondary effect of many primary pathologies, including those listed above. Epidemiologic research is difficult due to heterogeneity of the primary etiology.

Patients who suffer from a hypoxic brain injury caused by respiratory failure tend to be younger, and have less preexisting atherosclerotic vascular disease.5

Carbon monoxide intoxication continues to be one of the most common causes of morbidity due to poisoning in the United States. The risk factors include the use of generators, grills, camp stoves, propane, natural gas, charcoal burning used inside home, basement, and garage or even outside near window.6

For hypoxic-ischemic brain injury, cardiac disease is the main cause of cardiac arrest (82.4%) and subsequent brain damage. Approximately 326,200 persons in the United States experienced out-of-hospital cardiac arrest (OHCA) in 2011. Based on American Heart Association data, 31.4% of OHCA patients sustaining cardiopulmonary arrest survive after bystander-witnessed ventricular fibrillation, and 10.6% survive until hospital discharge. According to CDC data, 6.9% of all OHCA patients survive with good or moderate cerebral performance, which is defined as being independent with activities of daily living and able to work in a competitive or sheltered environment.7,8

The incidence of OHCA per 10,000 adults is 10.1 among black people, 6.5 among Hispanic people and 5.8 among white people. Prior heart disease is a major risk factor for cardiac arrest.7,8

Patho-anatomy/physiology

Areas most vulnerable to neuronal injury in HBI include the hippocampus (CA1 subfield), cerebellum (Purkinje cells), pyramidal neurons in neocortex 3, 5, and 6, superior brainstem structures and subcortical structures (basal ganglia, thalamus, amygdala). Hypoxic ischemic brain injury predominately affect including the vascular watershed areas. Watershed areas include anterior border zone between anterior (ACA) and middle cerebral artery (MCA), posterior border zone between MCA and posterior cerebral artery, and internal border zone between MCA superficial branches and the deep branches of MCA/ACA.4

  • In pure hypoxic arrest, severe brain injury is not commonly seen because of preserved systemic circulation and adequate cerebral nutrient/glucose delivery and toxin removal. Hypoxia decreases pH through elevation of partial pressure of carbon dioxide. This will result in cerebral autoregulation, including cerebrovascular dilatation and increase in the cerebral blood flow. The preserved blood flow supplies continuous nutrients and glucose to the brain allowing toxic metabolites to be washed out. Pure hypoxia affects neuronal synapses without brain necrosis.4
  • In CO poisoning, CO inhibits oxygen-hemoglobin binding and impairs oxygen delivery and also disrupts oxygen utilization. This hypoxic state triggers free radical formation and apoptotic cell death. White matter petechial hemorrhages followed by multifocal necrosis occurs, particularly in corpus callosum, basal ganglia and hippocampus.4,6
  • In hypoxic-ischemic brain injury as a result of circulatory/cardiac arrest, prolonged ischemia can lead to primary necrotic cell death. Cell death mechanisms include cellular apoptosis and free radical and nitric oxide (NO) formation. Decreased cerebral circulation results in poor nutrient/glucose delivery and toxin accumulation. Precise thresholds for cerebral perfusion pressure and minimal oxygen level resulting in brain damage from hypoxia/ischemia are unknown. However, it is generally accepted that lack of cerebral blood flow for more than 3-4 minutes leads to brain tissue damage. Reestablishment of circulation does not necessarily cease cell damage. Reperfusion injury may occur due to calcium shifts, increasing NO and free radicals.4

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

The spectrum of disability resulting from HBI ranges from complete recovery to a disorder of consciousness to death. Pure hypoxic brain injury, as long as the systemic circulation is adequately preserved, does not commonly lead to severe brain injury. Hypoxia causes functional changes of the neurons without causing cell death, thus, hypoxic brain injured patients may initially present in a vegetative state, but have better chance for survival and good neurologic recovery compared to those with ischemic brain injury.4

Severe hypoxic ischemic brain injury initially presents with a vegetative state. If consciousness is regained, clinical impairments seen are heterogeneous and related to neuroanatomy of injury and cause, duration, and extent of global ischemia. Clinical variables have prognostic predictive value during the acute period but can be challenging as clinical presentation is confounded by intensive care treatments and medical management.9

Cognitive recovery occurs greatest within the first 3 months of injury and may stabilize at 12 months post-injury6, though newer data suggests that continued recovery, or even cognitive decline occur after 12 months. Current literature suggests the cognitive recovery curve is similar to that of traumatic brain injury (TBI), whereas physical recovery in HBI occurs at slower rate.10,11

Specific secondary or associated conditions and complications

Associated conditions include disorders of consciousness, seizures, myoclonus, extrapyramidal movements/movement disorders, spasticity, impaired range of motion/contractures, heterotopic ossification, pain, visual agnosia, cognitive impairments, and behavioral/affective dysregulation.

Delayed post-hypoxic leukoencephalopathy is a rare condition. Patients appear to make good clinical recovery but then rapidly deteriorate due to delayed demyelination in subcortical and deep white matter areas with no significant vascular abnormality or cerebral edema. No proven agents can prevent or treat this condition.9,12

Memory impairments are common in hypoxic-ischemic brain injury especially in disturbances in immediate recall and working memory. Delayed recall is frequently impaired especially in ischemic events as a result of cardiac arrest; at 12 months, up to 33% and at 6 months up to 29% of survivors experience delayed recall.13 It is thought to be due to increased vulnerability of medial temporal structures, frontal cortices, and hippocampus. Isolated memory problems are rare and usually co-occur with impaired new learning, retrieval and /or executive dysfunction.

2. ESSENTIALS OF ASSESSMENT

History

A complete history includes: mechanism of injury, duration of hypoxia and/or ischemia, duration of disorder of consciousness and post-hypoxic amnesia, acute neurological abnormalities, hospital course/complications (e.g., seizures), resulting impairments, associated injuries, medical comorbidities, history of brain injury, premorbid functional status, prior psychiatric history, substance use history, educational history, vocational history and social support.

Physical examination

For evaluation of consciousness after brain injury, JFK-Coma Recovery Scale -Revised (JFK CRS-R) can be used14.  This is a scale assessing 23 items that quantitate brainstem, subcortical and cortical process to assist diagnosis, prognostic assessment, and treatment planning7.  Evaluation of preservation of brainstem reflexes is also prudent. Examination includes pupillary reaction, corneal reflexes, caloric testing, and motor response to noxious stimuli, as their absence predicts limited recovery. Range of motion and muscle tone are assessed to evaluate for contractures, spasticity, or heterotopic ossification.

In conscious patients, cognitive assessment includes arousal/alertness, attention, processing speed, memory, judgment/reasoning, insight, planning/organization, and problem-solving. Affect/behavior examination assesses for agitation, emotional lability, abulia, depression, or anxiety. Cerebellar/fine motor testing evaluates for choreoathetosis, ataxia, and myoclonus. Visual testing assesses agnosia, visuospatial impairments, and visual field cuts. Focal motor and sensory deficits and their effect on function should be evaluated.

Residual sequelae may include:

  • Balint’s syndrome: ocular apraxia, optic ataxia, and simultagnosia due to bilateral parieto-occipital damage from posterior watershed ischemia
  • ‘Man in a Barrel’ syndrome: bilateral upper limb paresis with preserved lower limb function from watershed ischemia between ACA and MCA
  • Paraparesis or tetraparesis from watershed spinal cord ischemia in upper/lower thoracic and lumbar regions (Armin Ernst, 1998)
  • Cortical blindness from watershed ischemia between ACA and MCA
  • Akinetic-rigid syndrome/Parkinsonism
  • Delayed neuropsychiatric changes after CO poisoning, including cognitive, personality changes, parkinsonism, incontinence, dementia and psychosis.

Functional assessment

Functional Independence Measure is a scale that assesses 13 physical domains (mobility, activities of daily living, bowel/bladder function) and 5 cognitive domains.

Cancellation tasks, continuous performance tasks, or Trail Making Test can assess attention and processing speed. Mini-Mental Status Exam can evaluate attention and memory, but does not adequately detect other areas of dysfunction which can be detected using Frontal Assessment Battery, Behavioral Dyscontrol Scale, and Executive Interview at bedside.13

Post hypoxic ischemic brain injury survivors most commonly suffer cognitive impairments including deficits in new learning, memory, attention/concentration, awareness/insight, and visual/apperceptive agnosia. Impairment in memory is very common and should be examined in detail. Standardized neuropsychological testing further evaluates cognition, behavior, and affect to individualize cognitive rehabilitation. Orientation Log (O-Log) can be a useful assessment of the impairments in declarative memory during the acute rehabilitation period. Other examples of tests studied in patients include Behavioral Assessment of Dysexecutive Syndrome, Weschler Adult Intelligence Scale-Revised, and Rivermead Behavioral Memory Test. Serial Wessex Head Injury Matrix tests can follow arousal, awareness, cognitive and communicative function in severe HBI cases.13,15

Laboratory studies

Laboratory studies to evaluate underlying etiology of HBI may include complete blood counts, cardiac biomarkers, and complete metabolic panel. Serum neuron specific enolase (NSE) is a potential marker of functional recovery after cardiac arrest, but too variable for single indicator use. Serum s100, creatine kinase brain isoenzyme, and cerebro-spinal neurofilament have been explored but have unclear prognostic value.16,17

For CO poisoning, fingertip pulse CO oximeter can be used and an elevated CO hemoglobin level of 2% for non-smokers and >9% COHb for smokers strongly supports a diagnosis of CO poisoning.

Imaging

Head computerized tomography (HCT) excludes primary catastrophic brain injury. HCT showing diffuse edema and inversed grey/white matter ratio suggests HBI. The more sensitive magnetic resonance imaging (MRI) reveals diffuse cortical signal changes on diffusion-weighted or fluid-attenuated imaging. Magnetic resonance-based perfusion-weighted imaging, not commonly used in clinical settings, shows promise identifying perfusion alteration influencing long-term outcomes. Used singly or in combination, functional MRI, positron emission topography, diffusion tensor imaging, and magnetic resonance spectroscopy show potential to provide further information or prognosticate following HBI.17,18 Watershed infarction areas are identified with all these modalities.

Supplemental assessment tools

Electrophysiologic studies, electroencephalography, and somatosensory evoked potentials (SSEP) may be helpful in acute settings but technically challenging due to electrical interference in intensive care.

Early predictions of outcomes

Outcome criteria in hypoxic brain damage can be divided into three different categories: reliable variables to predict poor outcome, variables related to poor outcome, and variables of unclear prognostic value.

Negative prognostic factors in HBI from cardiac arrest include:8,16,17

  • Absent brain stem reflexes at any time
  • Myoclonus status epilepticus at day 1
  • SSEP absent N20 response at day 1-3
  • Absent pupil/corneal reflexes at day 3
  • Extensor or absent motor response at day 3
  • Serum NSE may be beneficial used in combination with other predictors (>33 ng/ml) when combined with GCS
  • Duration of anoxia/resuscitation, more than 28 hours, GCS <6 after 72 hours
  • Hyperthermia

Environmental

Given heterogeneic nature of hypoxic ischemic brain injury and recovery patterns, environmental needs vary. Potential challenges for patients include balance and vestibular changes, visual disturbances, weakness, ataxia, and communication, behavior and cognitive deficits. Modifications include accessible environments, adaptive equipment, individualized educational programs, structured work environment with supervision if needed, and structured daily routine to reduce memory demands. Every patient needs an individualized plan of care for safe and successful transition into the community.

Social role and social support system

The physical, cognitive, and emotional effects of HBI can be disturbing to family, friends, colleagues, and employers. Educating patients’ social support systems about HBI effects, prognosis, and techniques to facilitate successful community re-entry is essential.

Professional Issues

Care of HBI patients with severe impairments may include life-sustaining treatment, causing ethical dilemmas within the medical community. Ethics consultations help mediate personal, legal, and medical issues surrounding the life and death of this population.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Literature on rehabilitative management is sparse, but approach should be individualized based on mechanism of injury, neuropathology, prognosis, and residual impairments/disability. HBI treatment approaches for recovery are generally modeled after management of persons with TBI or stroke.

Nonpharmacologic approach to cognitive rehabilitation includes environment modification, behavioral adaptation, and compensatory strategies. Pharmacologic approach includes use of catecholaminergics for arousal, impaired processing speed, attention and memory. Cholinergics are sometimes used for impaired memory. Literature supporting pharmacologic treatment approaches in HBI is limited.11

At different disease stages

Acute management includes reestablishing and maintaining cerebral oxygenation and circulation; monitoring of respiratory, cardiac, vascular, and metabolic issues; and addressing concomitant injuries or medical problems. Primary rehabilitation goals in acute care are early mobilization as able and prevention of complications related to bedrest/immobility with frequent turning, range of motion, proper positioning/transfers, and braces or special mattresses if needed. In cases with poor prognosis for recovery, palliative care referral and family care conferences are essential.

Subacute management includes initiation of multi-disciplinary rehabilitation program to promote sensorimotor and cognitive recovery. Monitor patients for agitation, bowel/bladder issues, and secondary conditions of HBI as mentioned above. For spasticity, consider medications such as baclofen, dantrolene, or tizanidine, and/or chemical neurolysis (botulinum toxin, phenol) or intrathecal baclofen in select patients. Post-hypoxic seizures and movement disorders may require pharmacologic intervention (dopaminergics, anticholinergics). Initiate adaptive strategies for visual agnosias (label objects, maintain object locations). Serial examinations are useful as clinical deterioration can indicate new pathology and improvements can help guide the rehabilitation program.

Chronic management guided by a physiatrist includes gradual reintegration into the community with ongoing education on recovery/adaptation, support/counseling, and appropriate referrals. For those who are able, driving evaluations and vocational rehabilitation referrals may be issued. Continue to monitor for development of secondary conditions associated with HBI and obtain neuropsychological follow-up as needed during cognitive recovery and during major transitions (community reentry, return to work, educational pursuits).

Coordination of care

Care coordination is important during patient care transition between acute care and acute/subacute inpatient rehabilitation teams and for successful community re-entry. Social workers are points of contact for identifying financial and social resources through these transitions.

Patient & family education

Multiple meetings are required to discuss expected short-term and long-term recovery. Successful communication includes full disclosure with compassion, appreciation of personal values, and respect for religious preferences. Advanced directives or previously voiced patient wishes need to be reviewed. Support groups or formal counseling referrals can be utilized as needed.15

Emerging/unique Interventions

Serial neuropsychologic testing can monitor outcomes and guide individualized cognitive programs.

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

Resources, such as the Brain Injury Association of America, can provide local support to mitigate caregiver fatigue.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

Mild therapeutic hypothermia after circulatory restoration is shown to improve survival outcomes after cardiac arrest.19,20

A randomized single blind phase 2 clinical drug trial was done in Finland with 110 “comatose” patients who had out of hospital cardiac arrest. The patients were treated with either inhaled xenon combined with hypothermia or hypothermia alone. The study concluded that those who received inhaled xenon and hypothermia were noted to have less white matter damage than those with hypothermia alone, but there was no statistical difference found in functional outcome using the modified Rankin Scale.21

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

More detailed knowledge and evidence is needed in areas of cognitive rehabilitation, nonpharmacologic/pharmacologic strategies, role of diagnostic testing including serum markers and functional imaging, and optimal methods/systems of care for evaluation and rehabilitation.

REFERENCES

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  2. Arciniegas D. Hypoxic ischemic brain injury. http://www.internationalbrain.org/articles/hypoxicischemic-brain-injury/. Updated 12/10/2016. Accessed 3/26, 2017.
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  4. Busl KM, Greer DM. Hypoxic-ischemic brain injury: Pathophysiology, neuropathology and mechanisms. NeuroRehabilitation. 2010;26(1):5-13.
  5. Greer DM. Mechanisms of injury in hypoxic-ischemic encephalopathy: Implications to therapy. . 2006;26(04):373-379.
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Original Version of the Topic

Erica Wang, MD, Billie Schultz, MD. Hypoxic brain injury. 12/10/2012.

Author Disclosures

Sarah Ann Korth, MD
Nothing to Disclose

Mi Ran Shin, MD
Nothing to Disclose

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