59 

Neurologic Criteria for Death in Adults

FRED RINCON

in which a patient’s cardiopulmonary functions could be sustained

CHAPTER OUTLINE in the absence of neurologic function emerged. In 1959, Mollaret
Historical Perspective and Definitions and Goulon described 23 patients with irreversible coma, whose
clinical syndrome was characterized by the absence of brainstem
Determination of Brain Death function, spontaneous respiratory function, and cardiovascular
Clinical Evaluation of Coma and Prerequisites collapse that ensued without the use of vasopressors, in what became
Absence of Brainstem Reflexes the birth of the concept of brain death.6 In 1963, Harvard neurolo-
Apnea gists proposed that a patient be certified as dead in the setting of
Pitfalls and Mimics coma, absence of brainstem reflexes, apnea for 30 minutes, and
Confirmatory Testing an isoelectric electroencephalogram (EEG) tracing in all leads for
Origins of Confirmatory Testing in Brain Death more than 30 minutes,7 despite the presence of cardiac function.
Accuracy of Confirmatory Tests The first guideline (the Harvard criteria) for deciding brain death
Recommendations for Confirmatory Testing was established in 1968.8 This concept has been accepted worldwide,
Special Circumstances although its fundamental meaning is not exactly globally uniform
Determination of Brain Death After Cardiac Arrest in the Era yet. Some countries, such as the United States, accept the concept
of Therapeutic Hypothermia of brain death as “whole brain death,” which is defined as irreversible
Extracorporeal Membrane Oxygenation loss of all cortical and brainstem function. The Medical Royal
Colleges of the United Kingdom established the definition of brain
Conclusions death on a “lower brain” concept of brainstem death.9 In the
opinion of the Royal Medical College, permanent unconsciousness
secondary to neuronal death of brainstem structures such as the
reticular-activating system (RAS) is irreversible.9
In 1981, a Presidential Commission in the United States was

T
he clinical examination in brain death is the most unequivocal formed to address the issue of death by neurologic criteria.10 The
in neurology. Most of the time, establishing the diagnosis President’s Commission established the foundations of the criteria
of brain death on clinical grounds is not a difficult task, currently used in the United States for the diagnosis of brain death:
as long as providers follow established protocols and guidelines the cause of brain death should be known and irreversible and no
for the interpretation of findings during clinical examination.1,2 improvement in neurologic condition should occur during a period
However, there may be confusion based on the variability of the of observation; the period of observation was left at the discretion
interpretation of current guidelines,3–5 hurdles to clinical examination of the physician, but periods of 6 to 12 hours were recommended
in specific patient populations such as trauma victims, laws from depending on the availability of confirmatory testing such as EEG
specific jurisdictions, and the changing face of outcomes after or cerebral perfusion scans.10 Although the President’s Commission
severe brain injury in an era of advancements in critical care and suggested periods of observation of 24 hours for cases of ischemia-
resuscitative medicine. In this chapter we review current procedures anoxia,10 more recent clinical experience in the era of therapeutic
and recommendations for the evaluation of comatose patients hypothermia and published guidelines suggest a period of observa-
presumed to be brain dead, the concept of brain death substantiated tion of up to 72 hours in patients with hypoxic-ischemic coma.11
by anatomic and physiologic bases, important concepts for the The President’s Commission guidelines for the determination of
determination of brain death in the setting of novel interventions brain death culminated in a proposal for a legal definition that
such as hypothermia and extracorporeal circulation, and how to led to the Uniform Determination of Death Act (UDDA) in 1981.
avoid pitfalls during the evaluation of patients presumed to be Under the law, the determination of death must be made with
brain dead. accepted medical standards and can be established only if an
individual “has sustained either: 1) irreversible cessation of circula-
Historical Perspective and Definitions tory and respiratory functions, or 2) irreversible cessation of all
functions of the entire brain, including the brain stem.” The UDDA
The concept of brain death is modern to medicine, but the definition establishes the legal definition of death on the basis of neurologic
of death has historically been associated with physiologic cessation criteria but does not provide guidelines or recommendations
of cardiopulmonary function. With advancements in mechanical regarding how to arrive to such conclusion. To this end, the medical
ventilation, life support, and resuscitation medicine, a new state community is free to formulate acceptable parameters or guidelines

1000
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 CHAPTER 59  Neurologic Criteria for Death in Adults 1001

on the basis of clinical examination, and availability of diagnostic applicable to the jurisdiction of practice. Some centers require the
tests and biomarkers. testing to be performed by two different physicians, and some
In 1995, the American Academy of Neurology (AAN) published centers require one of these physicians to be a neurologist, neuro­
the practice parameter to delineate the medical standards for the surgeon, or critical care specialist. In the United States, 42% of
determination of brain death.1 The guideline emphasized the three top neuroscience centers required the brain death examination to
clinical findings necessary to confirm irreversible cessation of all be documented by a neurologist or neurosurgeon, and only 35%
brain functions, including the brainstem: (1) known cause and required that an attending neurologist or neurosurgeon be involved;
presence of coma, (2) absence of brainstem reflexes, and (3) apnea.1 of the 42% of centers, residents could document the examination
Despite this publication, there is considerable practice variation in up to 65% of the centers.3 In those circumstances in which the
in the adherence to the AAN guidelines for the determination of patient is a potential organ donor, the clinical team may not be
brain death, particularly in areas related to definitions of acceptable directly involved with the discussions of organ procurement, as a
core temperature, number of required examinations, ancillary testing conflict of interest may be apparent.
to be used, and deficiencies in documentation.3,5 In response to To provide standardization in the process of diagnosing brain
this phenomenon, the AAN published an evidence-based update death, the Neurocritical Care Society in the United States has
of the 1995 Practice Parameter2 to answer the main questions developed a toolkit to educate anyone who may be involved in
related to practice variability in the determination of brain death.3,12 the determination of brain death. The toolkit includes access to
Recovery of neurologic function has not been reported since multiple instructional videos, webinars and web-based courses,
the clinical diagnosis of brain death was established with the criteria and sample brain death policy and checklists (https://www.pathlms.
set forth by the 1995 AAN guideline. This guideline and the com/ncs-ondemand/courses/1223).
further revision highlight the prerequisites for brain death determina-
tion to avoid potential misdiagnosis and pitfalls.2 Clinical Evaluation of Coma and Prerequisites
The brain death concept is universally accepted worldwide and
there are no concerns about the validity within physicians. However, Practitioners should first determine the cause of coma by history,
diagnostic brain death criteria vary throughout the world. In Europe, physical examination, neuroimaging, and laboratory testing. Exclu-
for example, there is considerable variation in the use of ancillary sion of central nervous system depressants should be attempted
testing such as EEG or cerebral blood flow studies. Most countries by careful history taking, drug screen testing, and calculation of
of the European Union do not require ancillary testing in support drug clearance using the rule of five times the drug’s half-life
of brain death diagnosis.13 In other countries, different practices (assuming a normal hepatic and renal function) or drug plasma
reflect the interest of local committees and groups of experts to levels below therapeutic ranges.2 In the setting of abnormal hepatic
introduce safeguards. Major differences in these countries are related or renal function, or after use of therapeutic hypothermia, caution
to the time of observation, the need for apnea and ancillary testing, should be taken before entertaining the diagnosis of brain death
and the number of health care providers authorized to diagnose based on changes in drug metabolism inherent to these clinical
brain death.14 settings to avoid catastrophic and embarrassing misdiagnoses.16 In
In the United States, most state laws have adopted the UDDA, these circumstances, more than recommended times for observation
and some have added their own amendments. All states and the are suggested or the use of confirmatory testing may be sought.
District of Columbia have statutes for determining brain death The legal limit for ethanol is a blood alcohol content of 0.08%,
based on the UDDA, but certain statutes differ in minor points which is a practical threshold below which an examination to
such as the requirement that determination of brain death should determine brain death could reasonably proceed.2 In patients exposed
be done by two different physicians, the use of confirmatory testing, to pentobarbital for the management of intracranial hypertension,
and the notification of next of kin before the declaration of brain an accepted level in which a clinical examination can proceed
death. To this end, it is important for the practitioner to understand without chance of confounding is 10 µg/mL.2 There should be
local hospital policies for the declaration of brain death that should no temporal administration of neuromuscular blockers, and this
abide by the laws of their respective jurisdictions. can be assessed definitely by the presence of train-of-four twitches
with maximal ulnar stimulation. Acid-base status and electrolyte
Determination of Brain Death levels must not be severely deviated from the norm, but the presence
of signs and symptoms of diabetes insipidus does not preclude the
The most common causes of brain death in the adult population diagnosis of brain death; however, treatment with fluids and
are traumatic brain injury, aneurysmal subarachnoid hemorrhage, vasopressors such as vasopressin will target both sodium and blood
hypoxic-ischemic injury, and fulminant hepatic failure.15 It is pressure requirements to allow for adequate neurologic assessment.
estimated that the diagnosis of brain death is made at least 25 to With more cardiac arrest survivors being exposed to therapeutic
30 times a year in large referral centers, but this number may be hypothermia, practitioners should now achieve a normal core
lower in nonacademic centers.15 The determination of brain death temperature, defined as near-normal temperature or core temperature
is based on the UDDA and supported by the AAN Practice higher than 36°C, before attempting to determine brain death.
Parameter.1,2 The diagnosis is based on the establishment of three Patients should have normal blood pressure, defined as systolic
main criteria: (1) known cause and presence of coma, (2) absence blood pressure equal to or higher than 100 mm Hg, as the neu-
of brainstem reflexes, and (3) apnea. Therefore the clinical diagnosis, rologic examination is usually reliable at this level of blood
when considering accepted guidelines, is the most unequivocal in pressure.
neurology. A temporal cause of severe brain injury must be established.
In general, most jurisdictions require that the determination Irreversibility from neurologic injury is recognized by the extent
of brain death be made by a licensed physician, which in most of of the injury, the devastation in neurologic findings, and the lack
the cases should be an attending physician who has experience in of improvement. Neuroimaging is useful in establishing an acute
the assessment of comatose patients and the legal requirements neurologic catastrophe that is compatible with the clinical diagnosis.

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 1002 Pa rt 6 Neurologic Disease in the Critically Ill

the foramen magnum. This is easily achieved by introducing noxious

stimulation through pathways mediated by cranial nerves. When
in doubt, the neurologic examination of a comatose patient becomes
equivocal, and in these circumstances, additional observation or
a confirmatory test may be warranted.

Absence of Brainstem Reflexes

All segments of the brainstem should be tested in the clinical
examination. The highest segments are examined by documentation
of the pupillary response to bright light in both eyes (cranial nerves
II and III). The usual presentation is dilated fixed pupils, which
may be asymmetrical. Constricted pupils may mean drug intoxica-
tion or lesions at the level of the pons causing de-efferentation
from sympathetic fibers and unopposed activation of parasympa-
thetic centers located in the rostral area of the midbrain (Edinger-
Westphal nucleus). Absence of ocular movements using oculocephalic
and oculovestibular reflex testing can be achieved after ensuring
integrity of the cervical spine (cranial nerves III, IV, VI, and VIII
[vestibular part]). The oculocephalic reflex is tested by briskly
rotating the head side to side and vertically. Vertical oculocephalic
movements are important for the determination of brain death as
injuries in the lateral portions of the pons may manifest with
• Fig. 59.1  Computed tomography scan of a young patient with traumatic
bilateral palsies of horizontal eye movements but would spare the
brain injury showing right frontal contusion, mild subarachnoid hemor- vertical eye movements. The oculovestibular or cold-caloric reflex
rhage, and severe cerebral edema. The patient had a bilateral transtento-
is tested by irrigating each ear with 50 mL of iced water and
rial uncal herniation (double arrow, for right-sided uncus); note that the
horn of the right lateral ventricle has been pushed toward the midline. The
observing the response for up to 1 minute. The absence of corneal
perimesencephalic cisterns are effaced (single arrow). There is slight reflexes (cranial nerves VII, V, and others) is demonstrated by
hypodensity in the midbrain suggesting edema or ischemia. touching the cornea with a cotton swab or gauze. Painful noxious
stimulation in the cranium, trunk, or limbs should not produce
any facial movement or grimacing (cranial nerve VII). Absence of
pharyngeal (cranial nerve IX) or gag reflex (cranial nerve IX) is
In most cases, a computed tomography (CT) scan reveals specific demonstrated by stimulating the back of the mouth or oropharynx
findings such as diffuse cerebral edema, mass lesions with severe shift with a suction device or tongue blade. The tracheal reflex (cranial
of midline structures, and herniation (Fig. 59.1; also see Fig. 59.4). nerve X) is tested by examining the cough response to tracheal
Coma is established by the lack of all evidence of responsiveness. stimulation provided by suctioning. Additional cranial nerve reflexes
That is, eye opening or eye movement to noxious stimuli must be such as the “jaw jerk” (cranial nerve V) may be assessed for complete-
absent. The motor responses to noxious stimuli should not be ness and to follow established guidelines.1 Any unanticipated
flexor or extensor but spinally mediated. The clinical differentiation movement of any segment of the face, trunk, or limbs during
of motor responses may require experience and specific training brainstem examination implies intact brainstem efferent connections
in neurology or neurosurgery. When flexor posturing of the upper and precludes the diagnosis of brain death. In trauma victims with
extremities and extension of the lower extremities (decorticate) or facial trauma in whom adequate examination of brainstem patency
extensor posturing of both the upper and lower extremities cannot be substantiated, the use of confirmatory testing may be
(decerebrate) are observed, the diagnosis of brain death cannot be warranted.
entertained and an additional period of observation is recommended. Deviations from accepted guidelines during clinical examination
(For an interactive brain death assessment, visit Brain Death of comatose patients presumed to be brain dead may be associated
Examination at https://www.pathlms.com/ncs-ondemand/ with false-positive results, so a thorough examination of all segments
courses/1223/video_presentations/11133 or Brain Death Testing of the brainstem is required. Areas of particular deviation from
Demo at https://www.youtube.com/watch?v=OEuP2C5UEp8.) the AAN Practice Parameter for the determination of brain death
The basis of these responses is related to the patency of the include failure of testing for pain above the foramen magnum,
rubrospinal and vestibulospinal tracts and lower segments of the the oculocephalic reflex, the jaw-jerk reflex, and establishing the
medulla that connect with the spinal cord.17 Brain dead patients absence of spontaneous respirations3 (Fig. 59.2).
typically exhibit spinal cord–mediated motor responses characterized
by “en bloc” flexor responses of the lower extremities with flexion Apnea
of the hip, flexion of the knee, and dorsiflexion of the ankle and
toes (the so-called triple flexion response or Babinski en bloc spinal Complete absence of breathing drive must exist to confirm the
cord sign). More complex movements that have been referred to diagnosis of brain death. The absence of respiratory drive is tested
as brain death–associated reflexes (Lazarus sign, spinal man, spinal with a carbon dioxide (CO2) challenge, which requires all of the
reflexes, or spinal automatisms) have been described in patients following: (1) normotension, (2) normothermia, (3) euvolemia,
who otherwise meet all other brain death criteria.18 The key point (4) eucapnia (partial pressure of carbon dioxide in arterial blood
to differentiate spinal versus centrally mediated responses is to [PaCO2] 35–45 mm Hg), (5) absence of hypoxia, and (6) no prior
determine if the responses are also elicited from stimulation above evidence of CO2 retention (chronic obstructive pulmonary disease,

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 CHAPTER 59  Neurologic Criteria for Death in Adults 1003

Absence of pupillary reflexes

Absence of corneal reflexes

Presence of coma

Absence of oculovestibular reflex

Absence of oculocephalic reflex

Absence of gag reflex

Absence of reaction to deep pain

Absence of cough reflex

Absence of spontaneous respirations

(prior to apnea testing)

Absence of jaw jerk reflex

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95
Policy (%)
• Fig. 59.2  Variability during clinical examination of brain dead patients in top neuroscience centers of the
United States. Poor compliance occurred mainly during testing of pain above the foramen magnum and
the jaw jerk, as well as documenting absence of spontaneous respirations in brain death examination.
OCR, Oculocephalic reflex; OVR, oculovestibular reflex. (From Greer DM, Wang HH, Robinson JD, et al.
Variability of brain death policies in the United States. JAMA Neurol. 2016;73:213–218.)

severe obesity, or sleep apnea syndrome).2 The test is started by Potential complications during apnea test include hemodynamic
preoxygenating the patient with a fraction of inspired oxygen (FIO2) decompensation, hypoxia and hypercarbia, and tension
of 1.0 for 10 minutes to achieve an alveolar oxygen partial pressure pneumothorax.20
(PaO2) of more than 200 mm Hg using a respiratory rate of 10
per minute to achieve eucapnia. If the patient remains hemodynami- Pitfalls and Mimics
cally stable and with oxygen saturation more than 95%, the patient
is disconnected from the ventilator and oxygenation is preserved In clinical practice, certain circumstances can mimic brain injury;
by placing a catheter through the endotracheal tube and close to these include high cervical spinal cord injury, fulminant acute
the level of the carina delivering O2 at 1.0 FIO2 with a flow of inflammatory demyelinating neuropathy, organophosphate intoxica-
6 L/min. During the following 8 to 10 minutes, the practitioner tion, baclofen intoxication, lidocaine toxicity, and delayed muscular
should look carefully for respiratory movements (abdominal or blocker clearance (i.e., vecuronium). Pitfalls in the diagnosis of
chest excursions and may include a brief gasp).2 The test should brain death may be related to circumstances involving interference
be aborted if oxygen saturation drifts lower than 85% for more with the appropriate clinical diagnosis of brain death such as patients
than 30 seconds. If this is the case, the test can be repeated later with (1) facial trauma (inability to appropriately examine cranial
using a T-piece, continuous positive airway pressure with 10 cm nerve responses or to elicit sensory/motor responses from stimulation
H2O, and O2 with 1.0 FIO2 with a flow of 12 L/min.2,19 The test above the level of the foramen magnum), (2) preexisting pupillary
result is considered positive if respiratory movements are absent abnormalities, (3) toxic levels of anesthetics, sedatives, tricyclic
and the PaCO2 is higher than 60 mm Hg or 20 mm Hg change antidepressants, anticholinergics, antiepileptics, or neuromuscular
from baseline supporting the diagnosis of brain death.2 (See Apnea blocking agents, and (4) severe chronic respiratory acidosis (chronic
Testing in Brain Death at https://www.pathlms.com/ncs-ondemand/ obstructive pulmonary disease, severe obesity, or sleep apnea
courses/1223/video_presentations/11134.) syndrome). In these circumstances, a confirmatory test may be
Although the apnea test is not a new procedure, it still lacks warranted.
consensus standardization regarding the actual test, consent There is still significant variability in brain death policy applica-
processes, monitored parameters, and evidence-based safety measures tion the United States, particularly in definition of appropriate
that may be used to prevent complications. Practitioners should targets for temperature, blood pressure, and PACO2 level at the
keep in mind that the apnea test is not without complications. time of the assessment (Fig. 59.3). This variability highlights the

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 1004 Pa rt 6 Neurologic Disease in the Critically Ill

Liters per minute of

oxygen specified

Absence of respiratory effort

Preoxygenation specified

≥60 mm Hg
Final PCO2 specified
<60 mm Hg

Arterial blood gas measurements

prior to testing Hypotension
14%
≥20 mm Hg
PCO2 level above baseline specified 5% 12%
<20 mm Hg
65%
Temperature before testing ≥36˚C 1% 1%
specified <36˚C Desaturation Arrhythmia
1%
Stop testing if patient
is unstable

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
Policy (%)
• Fig. 59.3 Variability of prerequisites for apnea test procedure for the determination of brain death in the
 

United States. Poor compliance occurred mainly in goal core temperature and baseline and goal end
partial pressure of carbon dioxide (PaCO2). (From Greer DM, Wang HH, Robinson JD, et al. Variability of
brain death policies in the United States. JAMA Neurol. 2016;73:213–218.)

need to further standardize the brain death assessment as one of began to use electrocerebral science to study a group of patients
most crucial bedside clinical assessments in critical care. who would have poor neurologic outcomes. Although these studies
provided the basis for defining brain death by the Ad Hoc Com-
Confirmatory Testing mittee of the Harvard Medical School8 a year later, Beecher, who
served as the chairman of the committee, mentioned in an editorial
The role of confirmatory testing in brain death differs among that EEG was “not essential to a diagnosis of reversible coma, but
jurisdictions.14 In the United States and the United Kingdom, provides valuable supporting data,”25 and this statement was later
they are discretionary.1,2,21 According to the AAN guidelines, endorsed by the American Neurological Association.26 Additional
confirmatory tests are required only when specific components of confirmatory tests, which can be divided into those that test for
the clinical examination cannot be reliably assessed.1,2 In some electrical function and those that test for blood flow, have been
European countries such as Italy, France, and the Netherlands, introduced and are aimed at confirming cerebral death (Table
among others, these tests are mandatory14,20; however, there is still 59.1). Electrophysiologic tests include EEG, brainstem auditory
significant variability in the approach to determining brain death evoked potentials, and somatosensory evoked potentials (SSEPs);
in the world.14 blood flow tests include four-vessel cerebral angiography, transcranial
A specialist in the neurosciences and any other skilled physician Doppler, CT angiogram, magnetic resonance angiogram, and
should be able to determine brain death using clinical criteria nuclear brain scan (Fig. 59.4). SSEPs and brainstem auditory evoked
alone, so the main purpose of confirmatory testing besides being potentials are currently not recommended to be used in aiding or
a diagnostic safeguard is to support the diagnosis of brain death confirming the diagnosis of brain death.1,2 More recent ancillary
in the setting of failure to complete a thorough neurologic examina- tests used for the determination of brain death include the bispectral
tion or an apnea test. The important point about confirmatory index scale monitor27 (BIS, mathematical algorithm of EEG),
testing is that these tests should never replace the clinical examina- jugular bulb venous oxygen saturation (SjvO2),28 and brain tissue
tion and should never be ordered before attempts to complete a oxygenation (PbtO2)29 but are not yet standardized in aiding in
thorough neurologic examination.22 the diagnosis of brain death.

Origins of Confirmatory Testing in Brain Death Accuracy of Confirmatory Tests

In the earlier years of refining the clinical picture of brain death, Practitioners must be careful at the time of interpreting the results
there was a desire to demonstrate absence of brain function with of confirmatory tests and be knowledgeable of the technology
information different from clinical data. In the 1950s Michel being used, as there are disparities in the accuracy of confirmatory
Jouvet23 in France and Charles Miller Fisher24 in the United States tests that could lead to potential pitfalls in the determination of

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 CHAPTER 59  Neurologic Criteria for Death in Adults 1005

TABLE Historical Time Frame for Confirmatory Tests brain death (Box 59.1). Based on the absence of gold standards
59.1 Used in Determination of Brain Death from a physiologic and pathologic perspective,30 the results of
confirmatory testing may confound the practitioner in two ways:
Year Reported Studya Test tests results can be labeled as false positives or false negatives when
1959 Löfstedt and von Reis 44
Cerebral angiogram
they are compared against each other. False-positive results occur
when the test suggests brain death and the patient does not meet
45
1959 Fischgold and Mathis EEG clinical criteria. False-negative results are more common (Table
1969 Goodman et al. 46
Nuclear brain scan 59.2); they occur when the patient is clinically brain dead but the
test shows otherwise,22 which may be more common with EEG.31
47
1974 Yoneda et al. TCD
1976 Starr 48
BAEP Recommendations for Confirmatory Testing
50
1978 Rappaport et al. CT angiogram Current evidence-based guidelines from the AAN recommend the
1978 Rangel51 CT angiogram use of only one confirmatory test for the determination of brain
death in those cases in which an additional period of observation,
1981 Goldie et al.49 SSEP an apnea test, or clinical examination is not feasible to fully establish
1992 Jones and Barnes 52
MRI the clinical criteria of brain death.2 In a large study of brain death
a
determination at the Mayo Clinic, the apnea test was aborted in
Studies cited in complete list of references for this chapter provided online. 3% of patients and in 7% of patients the apnea test was not
BAEP, Brainstem auditory evoked potential; CT, computed tomography; EEG, electroencepha-
lography; MRI, magnetic resonance imaging; SSEP, somatosensory evoked potential; TCD,
performed as it was not deemed to be safe, a situation that occurred
transcranial Doppler. more frequently in patients with polytrauma or with chest trauma.32
Adapted from Wijdicks EF. The case against confirmatory tests for determining brain death In practice, practitioners should anticipate that 1 in 10 patients
in adults. Neurology. 2010;75:77–83. with devastating neurologic injury will be unable to have an apnea
test, and declaration of brain death may not be possible on clinical
grounds. Families should be informed about the unlikely event of
meaningful recovery and in these circumstances, if the patient is
a candidate for organ donation, donation after circulatory

C B
• Fig. 59.4  Transcranial Doppler (TCD) in brain death: TCD and single-photon emission computed tomog-
raphy (CT) findings. A, Noncontrast head CT. B, Multidepth TCD power-motion mode (upper panel) and
single-depth spectral analysis (lower panel) show reverberating flow in the right vertebral artery character-
ized by brief forward flow. C, Brain scintigraphy reveals absent intracranial flow. (From Eder KE, Haussen
DC, Searls DE, et al. Reverberating TCD flow pattern in brain death. Neurology. 2012;79:e79.)

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 1006 Pa rt 6 Neurologic Disease in the Critically Ill

determination of death may be considered; most hospitals have based on clinical trials suggesting a robust effect of therapeutic
protocols for donation under donation after circulatory determina- hypothermia on clinical outcomes.35 In 2006, the AAN published
tion of death,22 and this approach could potentially increase the an algorithm to facilitate prognostic determination in patients who
supply of deceased donor organs.33 are resuscitated within 24 hours after cardiac arrest.11 The AAN
algorithm requires modification as more information accrues on
Special Circumstances the effects of hypothermia and with validation of other tests for
poor and favorable outcomes.36 Several studies have challenged
Determination of Brain Death After Cardiac the validity of single-endpoint assessments proposed by the
2006 AAN guideline, and most experts suggest a “multimodal”
Arrest in the Era of Therapeutic Hypothermia prognostication algorithm that would include several variables
About 450,000 Americans have cardiac arrest annually.34 The face including the physical examination.37,38 In this model, the patient
of prognostication after cardiac arrest has changed in recent years enters the evaluation after 72 hours of observation after cardiac
arrest. At this stage, the presence of coma, absence of pupillary
or corneal reflexes, and the absence of bilateral N20 responses on
SSEP indicate high likelihood of poor outcome. If neither of these
•BOX 59.1  Potential Pitfalls With Confirmatory Tests features is present, the provider should wait at least another 24
Used in Determination of Brain Death hours before a second reassessment. In this second stage, two or
more of the following indicate high likelihood of poor prognosis:
Cerebral angiogram
• Image variability with injection of arch or selective arteries myoclonic status epilepticus on EEG for less than 48 hours, a
• Image variability with injection and/or push technique high neuron-specific enolase level, an EEG with burst-suppression
• No guideline for interpretation, operator-dependent pattern and lack of reactivity, nonconvulsive status epilepticus
TCD on EEG, and/or diffuse anoxic injury either on brain CT scan
• Technically difficult and skill-dependent or magnetic resonance imaging. If none of the above criteria are
• Normal findings in anoxic-ischemic injury met, then consider further time for observation37 (Fig. 59.5).
EEG A recent study showed that prognostication after cardiac arrest
• Artifacts in intensive care settings occurs on the basis of insufficient clinical data, which may lead
• Information from mostly cortex to early withdrawals on the basis of self-fulfilling prophecies
SSEP
of doom.39
• Absent in comatose patients without brain death
CT angiogram
• Interpretation difficulties Extracorporeal Membrane Oxygenation
• Retained blood flow reported in 205 cases
• Possibility to miss flow states because of rapid acquisition of images Extracorporeal membrane oxygenation (ECMO) is increasingly
• Delayed flow in low-flow states (e.g., shock, heart failure) used as a means of extracirculatory support to patients in severe,
Nuclear brain scan reversible cardiac or respiratory failure. Patients presumed to have
• Areas of perfusion in thalamus in patients with anoxic injury or skull defect brain death may have earlier withdrawal of ECMO support,40
CT, Computed tomography; EEG, electroencephalogram; SSEP, somatosensory evoked potential; which would limit the possibility of organ donation in patients
TCD, transcranial Doppler. who would otherwise be declared brain dead. In these circumstances,
Adapted from Wijdicks EF. The case against confirmatory tests for determining brain death in adults. confirmatory testing may be warranted. A protocol of apnea testing
Neurology. 2010;75:77–83.
involving the addition of CO2 to the oxygenator to a target of
60 mm Hg or more than 20 mm Hg from the baseline normal

TABLE
59.2 False-Negative Rates With Confirmatory Tests Used in Determination of Brain Death

Reported Studya No. of Patients Testb False-Negative Rate

53
Petty et al. 23 TCD 10% (2 patients)
54
Flowers and Patel 219 Nuclear brain scan 3% (6 patients)
55
Munari et al. 20 Nuclear brain scan 5% (1 patient)
56
De Freitas and Andre 270 TCD 17% (47 patients)
57
Quesnel et al. 21 CTA 50% (10 patients)
58
Combes et al. 30 CTA 23% (13 patients)
59
Escudero et al. 27 CTA 7% (2 patients)
a
Studies cited in complete list of references for this chapter provided online.
b
All tests evaluated by comparison with clinical confirmation of brain death.
CTA, Computed tomographic angiogram; TCD, transcranial Doppler.
Adapted from Wijdicks EF. The case against confirmatory tests for determining brain death in adults. Neurology. 2010;75:77–83.

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 CHAPTER 59  Neurologic Criteria for Death in Adults 1007

Cardiac arrest

Status myoclonus
CT
Days Controlled temperature
1−2

Rewarming

Exclude confounders, particularly residual sedation

EEG - NSE

SSEP
Unconscious patient, M = 1−2 at ≥72 h after ROSC
Magnetic resonance imaging (MRI)

One or both of the following: Yes Poor outcome

- No pupillary and corneal reflexes very likely
- Bilaterally absent N20 SSEP wave (1) (FPR <5%, narrow 95%CIs)

Days No
3−5
Wait at least 24h

Two or more of the following:

- Status myoclonus ≤48h after ROSC Yes
- High NSE levels ( 2) Poor outcome
likely
- Unreactive burst-suppression or status epilepticus on EEG
- Diffuse anoxic injury on brain CT/MRI ( 2)
No

Indeterminate outcome (1) At ≥24 h after ROSC in patients not

treated with targeted temperature
Observe and re-evaluate
(2) See text for details.

Use multimodal prognostication whenever possible

• Fig. 59.5  Updated decision algorithm for use in outcome prediction for comatose survivors of cardiac

arrest. The guideline emphasizes on “multimodal” prognostication. CT, Computed tomography; EEG,
electroencephalogram; M, GCS-M; MRI, magnetic resonance imaging; NSE, neuron-specific enolase;
ROSC, return of spontaneous circulation; SSEP, somatosensory evoked potential. (From Sandroni C,
Cariou A, Cavallaro F, et al. Prognostication in comatose survivors of cardiac arrest: an advisory statement
from the European Resuscitation Council and the European Society of Intensive Care Medicine. Resus-
citation. 2014;85:1779–1789.

CO2 value may be used in lieu of the conventional protocol for of brain death on clinical grounds is not a difficult task, provided
apnea testing, but this protocol requires future validation.41 Recent providers follow established protocols and guidelines for the
case reports have indicated that to assess brain death in patients interpretation of findings during the clinical examination. The
supported by ECMO, apnea testing can be performed without establishment of a known cause and presence of coma, the absence
compromising oxygenation by decreasing without stopping the of brainstem reflexes, and apnea support the diagnosis of brain
sweep gas flow and increasing oxygen delivery through the death. Most jurisdictions require that the determination of brain
membrane.42,43 death be made by a licensed physician, which in most cases should
be an attending physician who has experience in the assessment
Conclusions of comatose patients and the legal requirements applicable to the
jurisdiction of practice. When in doubt, an additional period of
In the United States, current legislation allows physicians to observation or a confirmatory test should be done to support the
determine death on the basis of neurologic criteria. The diagnosis determination of brain death.

Key Points
• The clinical examination of brain dead patients is the most • When the clinical diagnosis is in doubt or interferences
unequivocal in neurology. to obtain a thorough clinical examination are present, a
• The determination of brain death in a comatose patient with confirmatory test may be used to determine brain death in
catastrophic neurologic injury requires several consecutive steps adults.
supported by well-established guidelines.

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 1008 Pa rt 6 Neurologic Disease in the Critically Ill

• Confirmatory testing should not be used in lieu of clinical • A period of observation of up to 24 hours after cardiac arrest
examination, and when indicated, only one confirmatory test in patients exposed to therapeutic hypothermia may be required
should be performed. before fully entertaining the determination of brain death.

Selected References Wijdicks EF. The diagnosis of brain death. N Engl J Med.
2001;344:1215–1221.
Greer DM, Varelas PN, Haque S, et al. Variability of brain death determina- Wijdicks EF, Hijdra A, Young GB, et al. Practice parameter: prediction
tion guidelines in leading US neurologic institutions. Neurology. of outcome in comatose survivors after cardiopulmonary resuscitation
2008;70:284–289. (an evidence-based review): report of the Quality Standards Subcom-
Greer DM, Wang HH, Robinson JD, et al. Variability of brain death mittee of the American Academy of Neurology. Neurology. 2006;67:
policies in the United States. JAMA Neurol. 2016;73:213–238. 203–210.
Perman SM, Kirkpatrick JN, Reitsma AM, et al. Timing of neuroprog- Wijdicks EF, Pfeifer EA. Neuropathology of brain death in the modern
nostication in postcardiac arrest therapeutic hypothermia. Crit Care transplant era. Neurology. 2008;70:1234–1237.
Med. 2012;40:719–724. Wijdicks EF, Varelas PN, Gronseth GS, et al. Evidence-based guideline
Sandroni C, Cariou A, Cavallaro F, et al. Prognostication in comatose update: determining brain death in adults: report of the Quality
survivors of cardiac arrest: An advisory statement from the European Standards Subcommittee of the American Academy of Neurology.
Resuscitation Council and the European Society of Intensive Care Neurology. 2010;74:1911–1918.
Medicine. Resuscitation. 2014;85:1779–1789. Young GB. Clinical practice. Neurologic prognosis after cardiac arrest. N
The Quality Standards Subcommittee of the American Academy of Engl J Med. 2009;361:605–611.
Neurology. Practice parameters for determining brain death in adults The complete list of references can be found at www.expertconsult.com.
(summary statement). Neurology. 1995;45:1012–1014.
Wijdicks EF. The case against confirmatory tests for determining brain
death in adults. Neurology. 2010;75:77–83.

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 CHAPTER 59  Neurologic Criteria for Death in Adults
1008.e1

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 CHAPTER 59  Neurologic Criteria for Death in Adults
1008.e3

Review Questions
1. A 67-year-old man has a respiratory arrest in the hospital. He to stimulate breathing (e.g., PaO2 level <50 mm Hg), this should
was found unresponsive by the nursing staff, without a pulse not be allowed during testing. Furthermore, no instances of
or blood pressure, with an unknown down time. The patient hypotension should be allowed during testing. Should this occur,
was intubated and Advanced Cardiac Life Support (ACLS) testing should be halted and the hypotension corrected. Should
resuscitation measures were initiated by the code team. In the patients not be candidates for apnea testing, other confirmatory
intensive care unit (ICU), the patient develops tonic jerking tests should be used.
motions of the upper extremities with any stimulation. These 3. A 27-year-old Hispanic woman arrives at a county hospital
movements do not stop with benzodiazepine or propofol infu- with multiple closed head injuries after a car collision. In addi-
sion. On examination, cranial nerves are intact but he does not tion, the patient has multiple internal abdominal injuries that
respond to visual or auditory stimuli. Sleep/wake cycles are caused frank hemorrhage and prolonged hypotension before
preserved. Examination findings and his condition persist for resuscitation at the crash scene. Initial computed tomography
1 month during which the patient is chronically ventilated but (CT) of the head shows multiple small contusions. The patient
hemodynamically stable. Which one of the following best was diagnosed as having moderate to severe anoxic brain
describes this patient’s condition? injury. She remained in the ICU supported by mechanical
a. The patient is brain dead. ventilation and vasopressor support after initial resuscitation
b. This patient is in a persistent vegetative state (PVS). and surgery to stop internal bleeding. On neurologic examina-
c. The diagnosis of this condition can be made 1 week after tion, brainstem reflexes were absent. Which one of the follow-
initial insult. ing pertains to further confirmation testing for brain death?
d. These patients commonly have no evidence of bladder or a. The most sensitive test remains cerebral angiography docu-
bowel incontinence. menting absence of intracerebral filling at the carotid bifur-
Answer: b. The patient in this question is in a PVS. He is cation or the circle of Willis.
comatose but retains brainstem function; therefore he cannot b. The finding of an isoelectric electroencephalogram (EEG)
be brain dead. PVS commonly occurs after anoxic or traumatic on one test is a highly specific and sensitive test for the
brain injury. It differs from brain death in many ways. First, diagnosis of brain death.
brainstem function remains intact in PVS. These patients are c. Transcranial Doppler (TCD) findings in brain death
also not considered medically or legally dead. A multidisciplinary include absent or reversal of flow in systole and a sharp
task force defines PVS as “a condition of complete unawareness diastolic upstroke.
of self and environment.” As stated, brainstem or autonomic d. Somatosensory evoked potentials (SEPs), which test the
function remains intact. These patients show no voluntary, integrity of sensory pathways, are highly sensitive and spe-
reproducible, or purposeful responses to stimuli. They have no cific tests for brain death.
language comprehension or expression. They also are incontinent. e. Technetium 99m hexamethylpropylene amine oxime
Spinal reflexes are variably preserved. (99mTC HM-PAO) brain scan shows rapid uptake of isotope
2. Apnea represents one of the diagnostic criteria for brain death. in nonfunctioning areas of brain consistent with brain
Which one of the following is most correct regarding the apnea death.
test and brain death? Answer: a. Although not necessarily required for diagnosis,
a. The arterial partial pressure of carbon dioxide (Paco2) goal additional confirmatory tests may be useful to diagnose brain
is above 60 mm Hg. death. The most sensitive test is cerebral angiography. Findings
b. In patients with chronic obstructive pulmonary disease consistent with brain death include a lack of intracerebral filling
(COPD) with presumed hypoxic respiratory stimulation, at the level of the carotid bifurcation or the circle of Willis.
Pao2 levels should be allowed to decrease to less than 50  mm The presence of electrocerebral silence on EEG during a
Hg before testing. 30-minute study remains the EEG diagnostic criteria for brain
c. One should always begin the test with a normal pH and death. However, diagnosis should not be based on a single EEG
alveolar oxygen partial pressure (Paco2). test result. SEPs are controversial. Patients in a PVS may have
d. Testing should last for 10 minutes and continue with mild findings similar to those with brain death. TCDs are noninvasive
desaturation (80%–90%) or mild hypotension (80–90 mm and can be done at the bedside. The test requires an experienced
Hg systolic). ultrasonographer and can be affected by changes in Pa CO2,
Answer: c. All published criteria for brain death include irrevers- hematocrit, and cardiac output. Findings on TCD consistent
ibility of brain damage, absence of neurologic function, the use with brain death include absent or reversal of flow in diastole
of additional confirmatory testing, and the presence of apnea. (not systole) and a sharp systolic (not diastolic) upstroke, or
Because most patients are ventilated, the failure of normal small spike waveforms above or both above and below the
respiratory stimulation by a predetermined level of PaCO2 must baseline at the beginning of systole. 99mTc HM-PAO scanning
exist in the presence of apnea. This may be difficult, or in some shows no uptake of isotope in brain parenchyma after brain
patients, impossible (i.e., COPD, lung disease). Therefore, death. The reported good sensitivity (94%) and specificity
although a PaCO2 level above 60 mm Hg is acceptable in patients (100%) of this test and good correlation with angiography
with normal lungs, this level may not be adequate in all situ- make this test a possible standard in the future.
ations. Although some patients may require a level of hypoxemia

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1008.e4 Pa rt 6 Neurologic Disease in the Critically Ill

4. Which one of the following conditions would not preclude a examined because of palpebral edema, and has no motor
conclusive brain death diagnosis? responses as evidenced by the primary neurosurgeon and a
a. Serum sodium level of 120 mg/dL. consultant neurologist. Which of the following is the best
b. Temperature of 35°C. course of action at this time?
c. A blood pressure of 180/90 mm Hg. a. Continue current management and perform gastrostomy
d. Use of cisatracurium for neuromuscular blockade. for long-term care.
e. Serum alcohol level of 209 mg/dL. b. Perform an apnea test.
Answer: c. To diagnose brain death, certain factors must be c. Rewarm to normothermia and request an EEG.
absent so that the results of brain death testing are not jeopar- d. He is brain dead, and therefore the team can “pronounce”
dized. These factors include the absence of (1) hypothermia, him and send him for organ donation.
(2) intoxication, (3) sedative medications, (4) neuromuscular e. Rewarm to normothermia and request a cerebral angiogra-
blockade, (5) electrolyte abnormalities, (6) acid-base abnormali- phy or cerebral perfusion scan.
ties, and (7) endocrine crises. Answer: e. This patient has sustained catastrophic brain injury.
5. A 28-year-old man with multisystem trauma involving his His examination suggests that he may well be brain dead.
head was admitted to the ICU. He has remained comatose for Continuing medical care may be ineffective and physicians
3 days, developed severe hypoxia and acute respiratory distress seem to have exhausted all therapies available. However, we
syndrome (ARDS), required continued levophed infusion to cannot entertain this diagnosis as he is currently under thera-
maintain a cerebral perfusion pressure of greater than 60 mm peutic hypothermia and received pentobarbital. An apnea test,
Hg, and developed intracranial hypertension with intracranial once he is rewarmed and not receiving pentobarbital, may be
pressures (ICPs) in the mid-30s, sustained despite appropriate ideal, but he likely will not tolerate it (hypoxia and hypotension).
advanced thermoregulation (hypothermia to 33°C), pentobar- A confirmatory test such as a cerebral angiography or perfusion
bital infusion, and pharmacologic interventions with hyperos- scan could be performed in this case on the basis of extended
molar and hypertonic solutions. He has extensive facial trauma, facial trauma and inability to examine components of the
and a tracheostomy was inserted emergently as part of the brainstem reflexes (pupils) and other confounders such as
initial management. Currently he has no response to deep pentobarbital exposure. An EEG in the setting may produce a
pain, has no brainstem reflexes but pupils could not be false-positive test result.

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