CONTENTS

• Brain death basics
• Clinical findings in brain death
• Clinical context
• Diagnosis of brain death
  • (1) Initial suspicion
  • (2) Evaluate for confounders
  • (3) Dedicated neurologic examination
  • (4) Apnea test
  • (5) Confirmatory test PRN
• If brain death is confirmed:
  • Immediate next steps
  • Supportive care prior to organ donation
  • Removal of medical support
• Podcast
• Questions & discussion
• Pitfalls
• Supplemental media

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brain death basics

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definition of brain death

• Defined as irreversible cessation of all cerebral and brainstem functioning.
• Legally recognized as equivalent to cardiopulmonary death in the United States.
• Defined by a strict set of criteria which, once met, confers zero likelihood of neurologic recovery.

physiology of brain death

• The final common pathway of brain death is shown below.
• Regardless of the initial injury, eventually brain death occurs via a spiral of progressive intracranial hypertension, tissue damage, and edema.   This is essentially an intracranial compartment syndrome.

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clinical findings in brain death

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key findings

• Absence of all cranial nerve function.
  • No pupillary or corneal reflex.
  • No oculocephalic reflex (doll's eyes).
  • No cough reflex (when suctioning endotracheal tube).
• Coma (e.g., no response to pain).
• If EEG is attached, it will show no brain activity (i.e., flat EEG).  (But note that muscle artefacts can easily confuse this picture.)
• No respiratory drive (patient doesn't over-breathe the ventilator).

strange phenomena can be observed in brain death 

• Brain death leads to the disinhibition of spinal cord reflexes (which are normally suppressed).   This may lead to some strange movements, which are often misinterpreted as volitional.  To complicate matters, spinal reflexes are often triggered by stimuli (e.g., painful stimuli below the diaphragm may lead to head turning).  Perhaps the most classic spinal reflex is triple flexion, wherein stimulation of the feet causes flexion at the ankles, knees, and hips (which mimics volitional withdrawal from pain).
• A list of described spinal reflexes is below.(32761206)  Differentiating these from volitional movements can be challenging.  When in doubt, ancillary testing may be necessary.
• Spinal reflexes should not occur with stimulation of the cranial nerves (e.g., painful stimuli at the supraorbital ridge or temporomandibular joint).(Torbey, 2019)

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clinical context

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Clinical context may either support the possibility of brain death, or it may suggest the possibility of a brain-death mimic.  Be very careful about pursuing a diagnosis of brain death in patients who lack an underlying process that explains why they should be brain dead.  In particular, if the patient is known to have a condition that can mimic brain death, then extreme caution is required!

(1) common causes of brain death (if present, these support the diagnosis of brain death)

• Traumatic brain injury.
• Intracranial hemorrhage.
• Anoxic brain injury (usually due to cardiopulmonary arrest).
• Severe meningoencephalitis.
• Fulminant hepatic failure causing cerebral edema.
• Ischemic stroke with cerebral edema and herniation.

(2) potential mimics of brain death

• Neuromuscular paralysis:
  • Fulminant Guillain-Barre syndrome*
  • Botulism*
• Hypothermia*
• Variety of drug intoxications, for example:
  • Tricyclics*
  • Lidocaine*
  • Baclofen*
  • Sedatives, especially barbiturates*
  • Paralytics*
  • Anticholinergics*
  • Bupropion*
  • Valproic acid*
• High C-spine injury
• Locked-in syndrome
• (* = full recovery is probable)

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diagnosis of brain death

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• The following is a general approach to diagnosing brain death.
• If at any point the patient shows evidence of cerebral activity, then brain death is excluded.
  • It's much easier to exclude brain death than to prove it.

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dx step 1 = clinical suspicion

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initial suspicion of brain death involves roughly two components

• (1) Known catastrophic brain injury consistent with brain death.
  • Brain death should primarily be considered within the context of known catastrophic brain injury.
  • For a patient with undifferentiated coma, brain death should be a late consideration (e.g., only after alternative and treatable processes have been excluded).
  • Common causes of brain death are listed above.📖
  • ⚠️ Be very careful about pursuing and diagnosis of brain death in the absence of a known catastrophic injury compatible with brain death (e.g., if the CT scan doesn't show either herniation or severe cerebral edema).
• (2) Clinical examination consistent with brain death.
  • Comatose (unresponsive to pain).
  • Absence of cranial nerves.
  • Absence of respiratory drive.

rapid informal bedside apnea test

• If safe, decrease the respiratory rate on the ventilator to a very low rate (e.g., 4 breaths/min).
• Observe end tidal CO2 and respiratory effort for ~5 minutes:
  • If the patient makes any respiratory effort, then brain death is excluded.
  • If the etCO2 rises and the patient makes no spontaneous respiratory effort, this predicts apnea on a formal apnea test.

is it worthwhile to pursue a formal brain death diagnosis?

• Potential reasons to pursue a formal diagnosis of brain death:
  • Will resolve confusion regarding goals of care and/or issues with surrogate decision-makers.
  • Reassures the family that nothing further can be done (the family may wish to pursue this testing).
  • Avoids future criticism regarding premature withdrawal of life-sustaining therapy.
  • Required prior to organ donation.
• Potential reasons not to pursue a formal diagnosis of brain death:
  • The patient is obviously moribund (without any potential for organ donation).
  • There is no confusion regarding goals of care.
  • Comfort-directed care is clearly appropriate, so brain death declaration wouldn't affect management.

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dx step 2 = exclude confounders

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exclude common confounding factors:  

• Temperature must be normal (>36C) using esophageal, bladder, or rectal core temperature measurement.(32761206)  
• Blood pressure must be adequate (SBP >100 mm or MAP >60 mm).(32761206)  
• Glucose and chemistries must be relatively normal.
• Severe metabolic, acid-base, or endocrine derangements that could affect the neurological examination.(32761206)  
• Paralytics must be discontinued (if there is doubt about whether the patient might be paralyzed, paralysis must be excluded using a train-of-four nerve stimulator demonstrating four twitches, or the presence of deep tendon reflexes).
• All sedatives must be discontinued (for >4-5 half-lives).
• Recent cardiac arrest or rewarming from therapeutic hypothermia (it's recommended to observe patients for at least >24 hours after arrest or rewarming, prior to declaring brain death).(32761206)  

consider less common confounders:  

• (1) Drug intoxication (e.g. tricyclics, lidocaine, baclofen, sedatives, paralytics, anticholinergics, bupropion) or inebriation (e.g., blood alcohol level >80 mg/dL).(32761206)  
  • (For patients with poorly defined intoxication, strongly consider a cerebral flow scan.📖)
• (2) Any pathology (acute or chronic) that interferes with the ability to perform an adequate neurological exam, for example:
  • Severe neuromuscular disorder (especially:  fulminant Guillain-Barre syndrome).
  • High C-spine injury.
  • Fracture of the skull base or petrous temporal bone (may damage cranial nerves).(32761206)  
  • Chronic eye pathology (e.g., surgical pupils).
  • Orbital edema that interferes with eye evaluation/movement.
  • (Note: the absence of four limbs does not necessarily prevent performing an adequate examination.)(32761206)  
• (3) Isolated brainstem lesion or posterior circulation stroke (may cause Locked-in syndrome, which mimics brain death).(32761206)  

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dx step 3 = dedicated neuro exam

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coma

• There should be no evidence of arousal or awareness to maximal external stimulation, including:
  • Noxious visual stimuli (may be assessed while examining pupils).
  • Pain in any extremity.
  • Pain at the supraorbital notch and at the temporomandibular joints (bilaterally).
  • Deep sternal rub.
  • ⚠️ There should be no vertical eye movements to stimulation or command (as could occur due to locked-in syndrome).
• In the presence of brain death:
  • Noxious stimuli above the foramen magnum should not produce any movement of the face or body.
  • Noxious stimuli below the foramen magnum should not produce any movement in the face, but may elicit spinally mediated peripheral motor reflexes.📖
  • 💡Pay particular attention to facial movement when applying noxious stimuli.  Any grimacing in response to stimulation excludes brain death.  However, some patients may exhibit random twitching of facial muscles (myokimia), which is compatible with brain death if it is occurring spontaneously.(Nelson, 2020)

pupillary reflexes

• There should be an absence of any ipsilateral or contralateral pupillary response.
• In brain death, pupils may be fixed/midposition or fixed/dilated.
• ⚠️ Constricted pupils are not consistent with a diagnosis of brain death, but instead may suggest the possibility of drug intoxication or locked-in syndrome (“pontine pupils”).

corneal reflexes

• Touch the lateral aspect of the cornea of both eyes with a cotton swab or gauze.
• Common mistakes:
  • Testing the corneal reflex by dropping saline onto the eye.
  • Applying stimulation to the sclera (rather than the cornea).

oculocephalic and oculovestibular reflexes

• Any extraocular movement is incompatible with brain death.
• Oculovestibular reflexes:  Irrigate with at least 30 ml of ice cold water for at least 60 seconds.  Allow five minutes in between testing different sides.

cough and gag reflexes

• No gag reflex (tested by suctioning the back of the throat with a Yankauer catheter, including stimulation of both sides of the posterior pharynx).(32761206)
• No cough reflex (tested by in-line suctioning of an endotracheal tube).

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dx step 4 = apnea test

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prerequisites

• (1) Patient must be deemed stable enough to tolerate apnea (e.g., not severely hypoxemic or acidotic).
• (2) PaCO2 is normal or at the patient's known baseline (in cases of COPD or obesity hypoventilation syndrome).  If the patient has evidence of chronic CO2 retention without a known baseline CO2, the apnea test can't be done.
• (3) Absence of confounding factors. 📖
• (4) Core temperature >36C.
• (5) SBP >100 mm or MAP >60 mm.

prior to the test

• Patient is pre-oxygenated with 100% FiO2 for 10 minutes.
• Obtain a baseline ABG and ensure that the PaCO2 is normal (35-45 mm, 4.7-6.0 kPa) or at the patient's known baseline.  If necessary, adjust the ventilator and repeat an ABG to document an appropriate PaCO2 prior to the test.
• Guidelines suggest that a functioning arterial line be used to provide continuous blood pressure monitoring and quickly draw blood gasses during the apnea test.(32761206)  

induction of apnea

• The goal is to stop ventilating the patient, but to provide apneic oxygenation and some continuous positive pressure to prevent de-recruitment.
• There are various ways of accomplishing this:
  • (a) Simply keep the patient on the ventilator on a CPAP mode with no backup rate.  Some authors have reported this, but most ventilators won't allow the patient to be apneic without kicking into a backup ventilation mode.(27742325)
  • (b) A nice way to achieve this might be to use a flow-inflating bag to provide oxygen and CPAP.🎥
  • (Traditionally, the apnea test was accomplished by inserting a cannula to deliver oxygen into the endotracheal tube.  This strategy has a risk of causing pneumothorax, so it's not recommended.)(27460062)

apnea

• If there is any respiratory effort then the patient isn't brain dead – reconnect to the ventilator immediately and resume supportive care.  Consider repeating an apnea test after 24 hours, if the clinical examination remains consistent with brain death.(32761206)  
• Abort the apnea test prematurely if the patient becomes unstable, for example:
  • Hypotension refractory to vasopressor titration (e.g., SBP <100 mm or MAP <60 mm).
  • Sustained desaturation below 85%.
  • Unstable arrhythmia.
  • (An ABG should still be obtained at the time of apnea termination; if the PaCO2 is high enough then the test may still be adequate to establish lack of respiratory drive.)
• Continue apnea for 10 minutes if the patient can tolerate this, then check an arterial blood gas.
  • If point-of-care testing is available and the patient is stable, then apnea may be continued while awaiting the blood gas (for a few minutes).  If the ABG doesn't show sufficient hypercapnia, the ABG may be repeated frequently with ongoing apnea.
  • If point-of-care testing isn't available, then draw an ABG after 10 minutes and reconnect the patient to the ventilator.

targets for apnea test

• In order to conclude that the patient has no respiratory drive, the following targets are desired:(32761206)
  • (1) pH < 7.30
  • (2) PaCO2 >60 mm (>8.0 kPa) unless patient has preexisting hypercapnia (in which case it should be at least >20 mm (>2.7 kPa) above the patient's known, chronic baseline PaCO2.
• 10 minutes of apnea should be sufficient to meet these targets.  If PaCO2 doesn't increase sufficiently, the entire test may be repeated following pre-oxygenation and a repeat baseline PaCO2 and extended for 15 minutes of apnea.

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dx step 5 = confirmatory test PRN

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situations where a confirmatory test is needed:  

1. There is no clear cause of catastrophic brain injury that would explain brain death.
2. The presence of any confounding factor(s), as listed above. 📖
3. Inability to perform an apnea test (e.g., the patient is too hypoxemic to tolerate apnea).
4. Uncertainty regarding whether movements are spinally mediated reflexes.
5. Some countries require confirmatory testing by law (not the United States).

the most useful confirmatory test is cerebral scintigraphy:

• Radiolabeled dye is injected into a peripheral vein.  If there is perfusion to the brain, the dye will be taken up in brain tissue.
• In brain death, lack of brain perfusion causes an “empty skull sign” (image above).
• A cerebral scintigraphy which shows lack of blood flow to the brain (based on an official interpretation by a radiologist) is extremely solid evidence of brain death.
• Early in the process of brain death, there may be a small amount of perfusion remaining.  In this case, a repeat test in 6-12 hours may show lack of flow.🌊

flatline EEG supports a diagnosis of brain death

• EEG isn't generally ordered or recommended as a confirmatory test.(32761206)   However, some patients may already be attached to video EEG monitoring (e.g. after anoxic brain injury).
• A persistently flatline EEG for 24-48 hr after anoxia without any medications on board indicates a terrible prognosis (e.g., brain death or persistent unconsciousness).
• Cautions:
  • (1) Note that a flatline EEG can be found in the absence of brain death in some situations (e.g. drug intoxication).  Therefore, by itself the flatline EEG is less powerful evidence supporting brain death than the flow scan.
  • (2) Muscular artifacts may cause the EEG to appear active, when there is in fact no brain activity.  (Paralysis can remove these artefacts, but administering a paralytic will greatly complicate the declaration of brain death – so this should not be done.)

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immediate steps if brain death is confirmed

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• The family should be informed that the patient has died (with appropriate explanation of brain death).
• 🛑 Do not discuss organ donation with the family; this should be done by a separate organ procurement team.

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management of the brain dead patient with potential for organ donation

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Ongoing high-quality supportive care is required to maximize organ function.  Optimal management of the donor may increase the likelihood of successful allograft function and favorable long-term outcomes for organ recipients. 

general resuscitative principles

• Overall, the general principles of management of the donor are similar as for any patient receiving high-quality supportive care.
• Resuscitation may be tailored slightly to favor preserving function of the organs for donation.
• Long-term consequences of interventions don't exist (e.g. C. difficile infection due to broad-spectrum antibiotics, myopathy due to high-dose steroid).

corticosteroid

• Reasons to give steroid:
  • (a) Brain death can cause pituitary deficiency, promoting hemodynamic instability.
  • (b) Steroid may reduce inflammation, thereby improving graft organ functionality.
• Large doses are commonly used (e.g. 1,000 mg IV methylprednisolone daily).

management of diabetes insipidus

• Diabetes insipidus commonly occurs, but not always (it is possible to be brain dead and still have a functioning hypothalamus).  If it occurs, it should be treated with a goal of bringing the sodium back to a fairly normal value (hypernatremia may impair liver function).
• Diagnosis:
  • In the context of brain death, diabetes insipidus may be strongly suspected on the basis of copious dilute urine production.
  • The differential diagnosis may include polyuria due to hyperglycemia, hypothermia, or medications.
  • If doubt exists, the diagnosis of diabetes insipidus may be established by labs showing hypernatremia and ongoing production of hypotonic urine (urine osmolarity < 200 mOsm/L or urine specific gravity <1.005).  However, treatment shouldn't be delayed while waiting for these studies to return.
• Treatment option #1 = desmopressin.
  • IV desmopressin 2-4 micrograms q6hr-q8hr.
  • Advantage = easy to do, doesn't tie up an intravenous line.
  • Disadvantage = if hyponatremia occurs, DDAVP will take hours to wear off.
• Treatment option #2 = vasopressin infusion.
  • Very low doses of vasopressin are sufficient to reverse diabetes insipidus (e.g. 0.01 units/minute or lower).  These doses won't necessarily have much effect on hemodynamics.
  • Useful for patients who are hypotensive (in which cases higher doses are generally given, e.g. ~0.04 units/minute).
  • Advantage = titratable (so it can be turned off if hyponatremia or low urine output occurs), may help support blood pressure in hypotension.
  • Disadvantage = slightly more work than DDAVP (ongoing IV infusion).

preservation of lung function

• Expert management probably has the greatest impact on lung procurement, compared to other organs.
• Avoid subclavian central line (pneumothorax won't have time to heal, potentially making it more problematic).
• Bronchoscopy is required to evaluate candidacy for lung donation.  Avoid performing bronchoalveolar lavage if possible (or, if mandatory, use the lowest volume of saline possible).
• Use of airway pressure release ventilation (APRV) has been shown to improve candidacy for lung donation. (21422364)
• Avoid volume overload.

improvement in cardiac function

• Myocardial stunning and systolic heart failure are common following brain death.  With supportive care, these often improve over time.
• Supportive care principles are similar to other patients with cardiogenic shock.
• Thyroid hormone supplementation may assist in cardiac recovery.
  • Following brain death, a sick-euthyroid state frequently occurs (with elevated levels of inactive reverse-T3, low levels of active T3, and normal levels of T4).  Exogenous thyroid hormone has commonly been used in efforts to improve cardiac function and candidacy for heart donation.  No high-level evidence supports this practice, which remains controversial.  Consensus guidelines recommend consideration of thyroid hormone supplementation in patients with hemodynamic instability.(25978154)
  • If thyroid hormone is given, either thyroxine (T4) or triiodothyronine (T3) may be used.  Triiodothyronine (T3) may be a bit more effective, but it is less widely available in IV form.  Commonly used doses are:
    • Thyroxine (T4):  20 ug IV bolus followed by 10 ug/hour IV maintenance infusion.
    • Triiodothyronine (T3):  4 ug IV bolus followed by 3 ug/hr IV maintenance infusion (if unavailable, liothyronine has excellent oral bioavailability)

temperature management

• Brain death may lead to spontaneous development of hypothermia.
• Temperature should be monitored.  External warming may be necessary to avoid hypothermia.

empiric antibiotics

• Broad-spectrum antibiotics are often administered (e.g., piperacillin-tazobactam).

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removal of medical support

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• If organ donation is not possible, medical support should be discontinued.  Practices surrounding this will vary between different locations.  When in doubt, local ethics committees should be engaged.  The following discussion applies within the United States.
• Once the patient has been declared brain dead they are deceased (“brain dead is dead”).  Families/surrogates do not need to consent to removal of ventilatory support.  Nonetheless, it is customary to allow a short period of time for families to grieve, prior to removal of support.(Nelson, 2019) 

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• In a severely neurologically injured patient, avoid any long-acting sedative (ideally, only propofol or dexmedetomidine would be used).  This facilitates an unclouded neurologic examination.
• Failure to consider a diagnosis of brain death.   For example, if a patient is brain dead following anoxic brain injury, there is no role for therapeutic hypothermia or neuroprognostication:  the patient is dead.
• Brain dead patients may produce a variety of spinal reflexes (e.g. triple flexion).  These shouldn't be mistaken as indicating that the patient is alive.
• Be extremely cautious about declaring brain death in patients with poisoning or brain dysfunction of unclear etiology (otherwise this may happen).
• EEG can be flatline due to medication effects, so be careful about using EEG as a confirmatory test.

Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
• 📄 = Link to open-access journal article.
•  = Link to supplemental media.

Going further:

• Organ donation in the Emergency Department (Scott Weingart, EMCrit RACC)
• Brain death, mimics, and flow scans (PulmCrit)
• Brain death & Management of the organ donation patient (Chris Nickson, LITFL)
• Brain death (WikEM)
• Brain death imaging (Radeopaedia)

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supplemental media

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☝️ Isaac Tawil, MD Demonstrating Brain Death Exam from Scott from EMCrit on Vimeo.