INTENSIVE CARE
Brain stem death
Richard Cowan
Barbara Miles
Abstract
The concept of brain and brain stem death developed from the obser-
vation of apnoeic comatose patients. In the UK, the diagnosis of brain
stem death is made by clinically testing brain stem function once spe-
cific preconditions have been met. The exact definition of brain death
and some details regarding the tests required to make this diagnosis
vary across the globe. However, the majority of tests carried out are
similar to those in the UK. In this review we define brain stem death
and the clinical tests used to confirm it. The use of ancillary testing
can have a role in patients where clinical tests are not possible and
this is also discussed.
Keywords Apnoeic coma; brain death; brain stem death; brain stem
death testing
Royal College of Anaesthetists CPD Matrix: 1AO1, 2CO1, 2CO6
Anatomy
The brain stem is the inferior part of the brain, adjoining and
structurally continuous with the spinal cord. It is divided in to
three distinct areas: the medulla, the pons and the midbrain
(Figure 1). The pons and midbrain contain the nuclei of the
reticular activating system which are vital for cortical arousal and
conscious awareness, whereas the medulla contains the control
centres of cardio-respiratory homoeostasis. The nuclei and ori-
gins of cranial nerves III to XII are also contained within the
brainstem.
History of diagnosing death
Prior to the development of mechanical ventilation, the diagnosis
of death was relatively straightforward: death occurred at the
cessation of respiration, which inevitably led to the cessation of
circulation. The advent of long-term ventilation techniques in the
1950s meant inadequate ventilation no longer immediately led to
circulatory death. With the regular use of these techniques and
the emergence of intensive care units, case series of patients with
profound irreversible apnoeic coma began to be described.
These patients had no angiographic evidence of blood flow to
the brain, although no mechanical obstruction to flow was
demonstrated at autopsy. They had no spontaneous respiratory
effort, an absence of all electroencephalogram (EEG) activity and
were areflexic and polyuric with vasopressor dependent
Richard Cowan MBChB (Hons) MRCP(UK) FRCA FFICM is a Specialist
Trainee Registrar in Anaesthesia and Intensive Care at Glasgow Royal
Infirmary, Glasgow, UK. Conflict of Interest: none declared.
Barbara Miles MBChB FRCA FFICM is a Consultant in Anaesthesia and
Intensive Care at Glasgow Royal Infirmary, Glasgow, UK. Conflict of
Interest: none declared.
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Please cite this article in press as: Cowan R, Miles B, Brain stem death, Anaesthesia and intensive care medicine (2018), https://doi.org/10.1016/
j.mpaic.2018.08.010
Learning objectives
After reading this article, you should be able to:
C describe the anatomy of the brain stem and the physiological
changes associated with brain stem death
C identify the preconditions required and the clinical tests then
used to confirm brain stem death
C discuss when ancillary testing may be required and describe
such tests
hypotension. These patients proceeded to circulatory death if
artificial ventilation or vasopressors were discontinued. These
findings were characteristically described in 1959 as ‘coma
depasse’, i.e. ‘beyond coma’. The autolytic neuropathological
findings in such patients was also discussed and described in the
literature as ‘respirator brain’.
The formalization of criteria to diagnose brain death occurred
in 1968 with the publication in JAMA of ‘A definition of irre-
versible coma, the Report of the Ad Hoc Committee of the Harvard
Medical School to Examine the Definition of Brain Death’. On the
same day, the World Medical Assembly issued a statement dis-
cussing some key philosophical issues surrounding the definition
of death. This included the concept that a definition of death
should regard the fate of a person rather than the preservation of
isolated cells. The development of these standards for the diag-
nosis of brain stem death allowed appropriate treatment limita-
tions to be put in place for patients who were irreversibly
comatose. Although the concept of brain death evolved relatively
contemporaneously with the first allogenic organ transplants, it
developed independently.
The statements have been refined over time and different
countries have produced their own guidelines. The current UK
definition of death is that described by The Academy of Medical
Royal Colleges (UK):
‘Death entails the irreversible loss of those essential charac-
teristics which are necessary to the existence of a living
human person and, thus, the definition of death should be
regarded as the irreversible loss of the capacity for con-
sciousness, combined with irreversible loss of the capacity to
breathe.’
Geographical differences in brain death definitions
There remain global differences in nomenclature regarding brain
death. In some countries (e.g. Australia, New Zealand, USA),
demonstration of whole brain death is required to determine
death. In the majority of cases of brain stem death, acute whole
brain injury is evident radiologically. However, in cases of iso-
lated brain stem injury, whole brain injury is not evident and
blood flow to the rest of the brain remains. Such patients
therefore cannot be defined as brain dead in some countries.
Confirming brain stem death is the basis of determining death
in patients in apnoeic coma in the UK. The cessation of brain
stem function does not necessarily entail cessation of neurolog-
ical activity in the whole brain. Any potentially remaining
function in brain other than the brainstem is not seen to
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 INTENSIVE CARE

Cranial nerves assessed

with brainstem function tests:

II III
Midbrain

III IV V

V VII
Pons

VI VII V IX VIII
III IV VI VIII

Medulla
V VII
X VII V IX XI XII Response to
supraorbital stimulus

Location IX X
of cranial
Gag, cough and
nerve
nuclei

Adapted from an illustration by Patrick J Lynch

Anatomy of the cranial nerves assessed clinically during UK brain stem death testing

Figure 1

constitute the essential characteristics necessary for a living Endocrine

human existence and so in the UK these patients can be defined
as dead.
Physiological changes associated with brain stem death
Cardiovascular
With initial brain stem compromise there is a massive sympa-
thetic discharge, resulting in tachycardia and hypertension. With
further brain swelling, in an attempt to maintain cerebral
perfusion, Cushing’s reflex (hypertension with bradycardia) oc-
curs in one-third of patients. The sympathetic surge subsequently
dissipates and in the majority of patients is followed by vasodi-
latation induced hypotension. Arrhythmias can also occur. Any
hypotension may be worsened by concomitant hypovolaemia.
Pituitary failure causes a reduction in anti-diuretic hormone
(ADH) production. This results in an inappropriate diuresis
(neurogenic diabetes insipidus) with resulting hypovolaemia and
hypernatraemia. There is reduced thyroid hormone synthesis
and secretion as well as reduced cortisol production. These
hormonal changes can adversely affect the cardiovascular state.
Hypothalamic failure leads to loss of thermoregulation. The pa-
tient may need active control of body temperature.
Diagnosis of brain stem death
Clinical assessment of brain stem function alone can determine
brain stem death in the UK. However, clinical testing can only be
undertaken when specific preconditions are met.

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Please cite this article in press as: Cowan R, Miles B, Brain stem death, Anaesthesia and intensive care medicine (2018), https://doi.org/10.1016/
j.mpaic.2018.08.010
 INTENSIVE CARE
UK tests must be carried out twice by two doctors registered
for >5 years (at least one must be a consultant). They should be
competent to conduct and interpret the tests and have no clinical
conflict of interest. There is no set time limit to repeat tests but
both physicians take part in both sets of tests. If both sets confirm
brain stem death, then the time of death is the time of completion
of the first set of tests.
The UK testing process for children is the same as the adult
process. Diagnosis of brain death in premature newborns and full
term infants <2 months old is not possible.
Preconditions
 Evidence of irreversible brain damage of a known
aetiology.
 The exclusion of potentially reversible causes of coma:
 depressant drugs
 primary hypothermia
 significant circulatory, metabolic or endocrine
disturbance.
 The exclusion of potentially reversible causes of apnoea.
In most cases of apnoeic coma the cause of brain damage is
known. The most common causes are trauma, subarachnoid
haemorrhage, intracranial haemorrhage and hypoxic brain
injury. Occasionally, the cause of coma cannot be established.
Without a known cause of irreversible brain injury, patients
cannot be determined brain dead and testing cannot be
performed.
The action of sedative or depressant medication should be
excluded prior to testing. The drugs in question, co-existing renal
or hepatic failure and the patient’s pharmacokinetics will affect
what this entails. Specific drug levels can be tested (e.g. thio-
pentone or midazolam). Antagonists may be useful if opioid or
benzodiazepines could be contributing to the coma. Neuromus-
cular blocking drugs can be excluded as the cause of apnoea by
using a peripheral nerve stimulator.
Prior to testing, patients should be warmed to a core tem-
perature of >34 C to exclude primary hypothermia as a cause of
coma. If therapeutic hypothermia post cardiac arrest has been
instituted, the patient must be allowed to rewarm before brain
function is formally assessed. UK recommendations are that
brain stem death testing is deferred for at least 24 hours once
normothermia is achieved, to allow any residual sedative drugs
to be metabolized (sedative drug clearance possibly being
reduced by therapeutic hypothermia).
Potentially reversible circulatory, metabolic and endocrine
causes of coma should be excluded (Table 1). Many of these
changes may occur during the brain stem death process. The
majority of patients will need vasopressor support to maintain a
blood pressure sufficient to allow testing to proceed. Electrolyte
correction may be difficult and rapid correction purely for the
purposes of brain death testing may be detrimental e too rapid
correction of hyponatraemia may itself result in the development
of central pontine myelinolysis and coma. Although rare, severe
hypothyroidism and Addisonian crisis may result in coma and
should be excluded by hormonal assays if any clinical suspicion
is raised.
Co-existing high cervical spinal injuries can limit clinical
testing and ancillary tests may be required.
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Conditions precluding brain stem death testing (UK)
Temperature <34 C
Circulatory Inability to maintain MAP consistently
>60 mmHg
Metabolic Na <115 or >160 mmol/L
K < 2 mmol/L
Mg <0.5 or >3 mmol/L
Phosphate <0.5 or >3 mmol/L
Glucose < 3.0 or >20 mmol/L
PaCO2> 6.0 kPa
pH <7.35 or >7.45
PaO2 < 10 kPa
Endocrine Clinical suspicion of significant endocrine
abnormality
Table 1
Clinical assessment
Cranial nerve reflexes from all levels of the brain stem are tested
by clinical examination (Figure 1) and the respiratory response to
hypercarbia (apnoea test) is assessed.
 Pupillary light reflex (cranial nerves (CN) II and III): pupils
are fixed and do not respond to bright light.
 Corneal reflex (CN V and VII): the cornea is touched with
cotton wool. There should be no response. Care should be
taken to avoid damage to the cornea
 Oculo-vestibular reflex (CN III, IV, VI and VIII): establish
that the eardrum is visible and slowly inject at least 50 mls
of ice-cold water. The head should be at 30 to the hori-
zontal, unless contraindicated. No eye movement should
be seen whilst the eyes are held open and observed for 60
seconds.
These three tests may be prevented by local injurye only one
side may be available to test. This does not invalidate the test
process but if neither side can be tested, ancillary testing may be
necessary.
 Trigeminal and facial (CN V and VII): no motor response
within cranial nerve or somatic distribution after supra-
orbital pressure.
 Gag, cough and tracheal reflexes (CN IX and X): no
response to stimulation of the posterior pharyngeal wall
with a tongue depressor. No cough response on stimu-
lating the trachea and carina with a suction catheter.
 Apnoea testing: this is performed only when all preceding
tests have shown absent response. Inspired oxygen is
increased to 1.0 for 5 minutes. An arterial blood gas is
taken, correlating peripheral saturation with PaO2 and
ETCO2 with PaCO2. Minute ventilation is decreased to
allowing PaCO2 to rise >6.0 kPa and pH to fall < 7.4.
Higher PaCO2 levels may be required in chronic CO2
retention to achieve pH < 7.4. The ventilator is then
disconnected and oxygen at 5L/min is provided down an
endotracheal catheter. If saturations fall, CPAP or recruit-
ment manoeuvres may be required. Cardiovascular sta-
bility should be maintained throughout.
The patient is observed for evidence of respiration for 5 mi-
nutes. Repeat blood gases are obtained after 5 minutes e a PaCO2
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Ancillary tests for the diagnosis of brain stem death
Blood flow in the Four-vessel angiography
larger cerebral arteries Transcranial doppler
Magnetic resonance angiography
Spiral CT angiography
Brain tissue perfusion Cerebral scintigraphy 99mTc-labelled
hexamethylpropylene-amine oxime
(HMPAO)
Xenon CT
Positron emission tomography
Neurophysiology EEG
Evoked potentials
Table 2
gain  0.5 kPa demonstrates an adequate respiratory stimulus.
The patient’s mechanical ventilation is then recommenced,
returning blood gases to the pre-testing level. Recruitment ma-
noeuvres may be undertaken after the apnoea test to maintain
baseline oxygenation.
Spinal reflexes may remain after brain stem death. These can
produce reflex movements of any limb, plantar reflexes and even
flexion at the waist resulting in a sitting position. The presence of
these reflexes does not preclude or refute the diagnosis of brain
death. They can be distressing for relatives and staff unaware of
their origin.
Ancillary tests
In some countries ancillary testing is mandatory for the diagnosis
of brain death. In the UK the diagnosis of brain stem death is a
clinical diagnosis. However, in certain circumstances (e.g. major
facial trauma) ancillary testing may be needed to confirm the
diagnosis. Tests can be generally divided into assessment of
blood flow in cerebral arteries, assessment of cerebral perfusion
and neurophysiological tests (Table 2).
Tests capable of demonstrating absent blood flow are accepted
as establishing whole brain death. The sequence of events relates
to the elevation in intracranial pressure exceeding systemic arte-
rial pressure, resulting in cessation of cerebral blood flow.
Four-vessel cerebral angiographies were considered the ‘gold
standard’ modality for assessing cerebral blood flow. In brain
death, angiography will normally demonstrate absent blood flow
at or beyond the carotid bifurcation or the circle of Willis. False
negatives can occur when intracranial pressure is lowered (e.g.
by surgery or trauma).
Transcranial Doppler has the advantage of being non-invasive
and safe. It requires expertise but can be done at the bedside. The
Doppler aims to find small systolic peaks with retrograde dia-
stolic flow or a reverberating flow pattern. This pattern suggests
high vascular resistance and supports the diagnosis or brain stem
death. Patients with external ventricular drains or craniotomies
may have false negative testing.
Techniques that look at tissue perfusion tend to be more
accurate. CT angiography/perfusion and nuclear medicine
(cerebral scintigraphy) are used for this purpose. 99mTc-labelled
hexamethylpropylene-amine oxime (HMPAO) scintigraphy
testing has been shown to be very useful in brain stem death
testing and can be utilized in the paediatric population. Sensitivity
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improves with follow up scans. The scan looks for the ‘hollow
skull phenomenon’ indicating the absence of brain perfusion.
The use of EEG is recommended in US guidelines for the
diagnosis of brain stem death in adults and children when clin-
ical testing is inconclusive or impossible. Adherence to these
guidelines is variable and a recent survey revealed that 6.5% of
American hospitals mandate such ancillary testing. The EEG re-
cords summated synaptic potentials. A flat or isoelectric trace
confirms the absence of brain activity. This should be interpreted
with caution however as there are numerous causes of flat/iso-
electric traces (including anaesthetic drugs). Evoked potentials
(somatosensory and brainstem auditory) have a limited role in
ancillary testing.
The reliability, accuracy, availability and ease of interpreta-
tion of these tests tend to limit their usage unless specifically
indicated.
Cautions
Profound neuromuscular weakness resembling absent brain stem
reflexes may occur as a consequence of some neurological dis-
orders. These include the locked-in syndrome (LIS) and Guillain-
Barre syndrome (GBS) affecting the brainstem. Organophosphate
poisoning, lidocaine toxicity, baclofen overdose, high cervical
spine injuries and prolonged neuromuscular blocker clearance
have also been reported as causing absent brain stem reflexes.
These cases highlight the importance of ensuring all pre-
conditions are met prior to commencing brain stem testing.
Preservation of eye movements in LIS should alert the physician
and preclude a diagnosis of brain stem death. Rapidly progressive
GBS can mimic brain death but such patients have no diagnosis
compatible with irreversible brain damage and therefore do not
satisfy the necessary preconditions and cannot be tested. A
FURTHER READING
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Lewis A, Greer D. Current controversies in brain death determination.
Nat Rev Neurol 2017; https://doi.org/10.1038/nrneurol.2017.72.
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