Brain Death

Brain death is a legal and clinical term describing the irreversible cessation of all cerebral and brainstem functions, including the ability of the brain stem to regulate vegetative and respiratory activities. Brain death can be due to a variety of etiologies causing catastrophic injuries to the brain, including brain ischemia due to cardiopulmonary arrest, drugs, sepsis, and trauma. The diagnosis is made at the bedside based on the clinical context and performance of a neurological exam. Additional ancillary studies may be needed to support the diagnosis and diagnostic criteria may vary among states and countries. A diagnosis of brain death must be established prior to consideration of organ donation.

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Overview and Pathophysiology

Definition

Brain death is the complete and permanent loss of all cerebral and brain stem functions, including the ability of the brain stem to regulate vegetative and respiratory activities. 

Definition of “complete and permanent loss” of brain function:

  • Unresponsive coma with loss of capacity for consciousness
  • Loss of brainstem reflexes 
  • Inability to breathe unassisted
  • Loss of function unable to resume spontaneously and unable to be restored through intervention

Etiology

  • Traumatic brain injury 
  • Hemorrhagic or ischemic stroke
  • Cardiopulmonary arrest with inadequate CPR
  • Brain tumor
  • ↑ Intracranial pressure (ICP)
  • CNS infection
  • Sepsis leading to cerebral hypoperfusion and ischemia
  • Drug overdose

Pathophysiology

  • Brain injury → brain edema → ↑ ICP
    • Edema can occur by:
      • Vasogenic disruption of the blood-brain barrier → protein leakage from plasma to the brain
      • Cytotoxic modifications in cellular osmolality → neurons lose the capacity to manage ionic gradients
    • Cerebral perfusion pressure (CPP) equals mean arterial pressure (MAP) minus ICP:
      • CPP autoregulates to ensure brain perfusion in normal circumstances.
      • Autoregulation is lost with extremes of MAP or ICP.
      • ↑ ICP → ↓ CPP → brain ischemia
      • Severely ↑ ICP → brain herniation
  • Mitochondrial dysfunction due to cellular hypoxia → free radical generation and reduction in cellular energy production → neuronal cell death:
    • Initially in the cerebral hemispheres and basal ganglia
    • Followed by the thalamus and brainstem

Clinical Presentation

History

  • Establish the etiology of the coma (e.g., overdose, trauma, stroke).
  • Evaluate for any confounding conditions mimicking irreversible brain injury:
    • Severe electrolyte abnormalities or acid-base disorders
    • Severe endocrine dysfunction
    • Hypothermia: Minimum core temperature of 36°C is required.
    • Circulatory collapse (i.e., severe hypotension)
    • Blood alcohol level > 80 mg/dL 
  • In the presence of hospital-administered sedative drugs and paralytics:
    • Discontinue medications for 5 elimination half-life periods before testing.
    • May need more time with hepatic or kidney dysfunction

Physical examination

  • Systolic blood pressure > 100 mm Hg: Vasopressors may be required.
  • Determination of coma by the bilateral absence of motor responses to:
    • Verbal stimulation: Call out the individual’s name.
    • Tactile stimulation:
      •  Shake or tap the individual. 
      • Apply pressure to the supraorbital notch or sternal angle.
    • Responses consistent with brain death:
      • No grimacing or facial muscle movement
      • No motor response of the limbs other than spinal reflexes (Lazarus sign)
  • Pupillary light reflex:
    • Shine light into each eye and examine for pupillary constriction.
    • Responses consistent with brain death:
      • Absence of ipsilateral and contralateral pupillary response
      • Pupils fixed in a midsize or dilated position (4–6 mm) bilaterally
      • Constricted pupils are not consistent with brain death.
  • Oculocephalic reflex (OCR) and oculovestibular reflex (OVR):
    • OCR: examined by rotating the head briskly and horizontally to both sides:
      • The term “doll’s eyes” refers to vintage dolls with eyes painted on and unable to move with the head.
      • Abnormal reflex: Eyes are fixed with head movement as if gazing on a fixed point.
    • OVR: Instill 50 mL of cold water into the ear with the head at a 30° elevation.
    • Responses consistent with brain death: absent eye movement with both tests
  • Corneal reflex:
    • Examined by touching the cornea with a cotton swab or squirts of water/saline
    • Responses consistent with brain death: absent eyelid movement
  • Gag reflex:
    • Examined by touching the posterior pharyngeal wall with a suction device or tongue depressor 
    • Response consistent with brain death: absent gag
  • Cough reflex:
    • Examined by stimulating the tracheobronchial wall through suctioning
    • Response consistent with brain death: absent cough

Diagnosis

The assessment of brain death in an individual on life support requires neuroimaging, exclusion of confounding factors, and possibly an EEG.

  • Diagnostic requirements for brain death:
    • Known clinical etiology of brain death
    • Absence of confounding conditions:
      • Hypothermia
      • Sedatives/anesthetics
      • Metabolic abnormalities
    • Abnormal brainstem reflexes on neurological examination
    • Positive apnea test
    • Ancillary tests (when appropriate)
  • Neuroimaging:
    • MRI or CT demonstrates irreversible, devastating brain injury:
      • Evidence of severe edema or herniation
      • If seen, brain edema is suggestive of brain death.
    • Measured ICP at least equals MAP
  • Labs:
    • Electrolytes
    • CBC
    • Arterial blood gas analysis
    • Toxicologic tests
    • CSF analysis
  • Apnea test: part of all protocols for determination of brain death:
    • Performed after all other criteria for brain death have been met
    • Before the test:
      • Adjust ventilator settings to a PCO2 between 35–45 mm Hg.
      • No hypoxia: 100% O2 for at least 10 minutes before the test
      • Discontinue paralytic drugs.
    • Cannot be done in:
      • The presence of high cervical spine lesions
      • Individuals with chronic PCO2 retention 
    • Steps:
      • Discontinue ventilator for 10 minutes.
      • Provide O2 to a maximum PO2 of 200 mm Hg, or until PCO2 > 40 mm Hg.
      • If hemodynamic instability is observed → test is aborted
      • If no spontaneous respiratory efforts → test is terminated after 10 minutes
    • Positive test: 
      • No respiratory response to PCO2 > 60 mm Hg, or 20 mm Hg > baseline values
      • Final arterial pH < 7.28
  • Ancillary tests are required if the primary neurologic examination or apnea test is unable to be completed, or if the examination or test is inconclusive: 
    • Brain blood flow studies: Absent brain blood flow establishes brain death.
      • Preferred modality: radionuclide studies
      • Conventional 4-vessel cerebral angiography
      • CTA
      • MRA
      • Transcranial Doppler
    • EEG:
      • Required to diagnose brain death in children
      • Not routinely required in adults, but may be legally mandated
      • Consistent with brain death if no potentials are recorded after 30 minutes
      • May be falsely negative or falsely positive
Algorithm describing the course of action in patients with brain death

Algorithm describing the course of action in individuals with brain death

Image by Lecturio.

Clinical and Ethical Considerations

Documentation required for determination of brain death

  • Etiology of the coma 
  • Absence of confounding conditions
  • Full details and results of clinical testing performed
  • Neuroimaging results and timing in relation to clinical testing 
  • Reason for and type of ancillary testing performed and results 
  • Time of death 
  • Identity of the practitioner(s) performing the evaluation

Somatic support after declaration of brain death

  • Diagnosis made → individual is declared clinically and legally deceased
  • Physiological support should be discontinued unless
    • Decedent is pregnant and support is needed for the fetus.
    • Organ donation is planned:
      • Notify the Center for Organ Recovery and Education (CORE).
      • Organ procurement coordinators review the medical chart.
      • If appropriate, the coordinators speak with the potential donor’s next-of-kin.
    • Family requests due to religious or moral beliefs: 
      • Every effort should be made to address concerns.
      • Involvement of religious authorities or ethics committees may be helpful.
      • Treat every person and family with the utmost respect.
      • A multidisciplinary approach (e.g., social workers, psychologists, counselors) is advisable.
      • Prolongation of support > 48 hours should generally be avoided.

Differential Diagnosis

  • Locked-in syndrome (also known as “pseudocoma” or “de-efferented state”): a state of quadriplegia and paralysis of the lower cranial nerves leading to the inability to move, communicate, or show any facial expression (except for certain eye movements). Locked-in syndrome typically results from pontine hemorrhage or infarct. Diagnosis is made clinically with individuals limited to blinking or performing vertical eye movements upon request. Management involves supportive care and prevention of immobilization complications. Long-term physical therapy is essential. 
  • Hypothermia: a drop in core body temperature below 35°C. Hypothermia is classified into mild, moderate, severe, and profound forms based upon the degree of temperature decrease. Populations of individuals with extremes of age, homelessness, mental illness, or substance use disorders may be more vulnerable to accidental hypothermia. Evaluation includes assessment for associated trauma and contributing medical conditions. Management involves rewarming the individual based on the severity of hypothermia.
  • Drug intoxication: intoxication of CNS-suppressant medications or muscle relaxants/paralytics. The drugs may include opioids, tricyclics, baclofen, barbiturates, paralytics, anticholinergics, and organophosphates, which may significantly suppress consciousness and motor/sensory responses. The exposure may be either known or unrecognized. Diagnosis is based on history, review of medications, interviews with family, and toxicologic evaluations. Management is based on the diagnosis.
  • High cervical spine injury: such injuries are associated with quadriparesis, loss of sensation below the level of the injury, inability to breathe, and reduced ability to speak. Although neurologic evaluation should easily distinguish the condition from brain death, the clinical picture may be confounded by a concurrent traumatic brain injury or the effects of medications. Vigilance and repeated comprehensive neurologic evaluations in combination with neuroimaging are helpful in establishing the correct diagnosis. Management may be medical or surgical.

References

  1. Starr, R., Tadi, P., & Pfleghaar, N. (2021). Brain death. StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK538159/ 
  2. Young, G.B. (2021). Diagnosis of brain death. UpToDate. Retrieved July 22, 2021, from https://www.uptodate.com/contents/diagnosis-of-brain-death
  3. Kaur, P., & Sharma, S. (2018). Recent advances in pathophysiology of traumatic brain injury. Current Neuropharmacology 16(8): 1224–1238. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142406/

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