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of Child Neurology
The Apnea Test: Rationale, Confounders, and Criticism
Ari R. Joffe, Natalie R. Anton and Jonathan P. Duff
J Child Neurol 2010 25: 1435 originally published online 10 May 2010
DOI: 10.1177/0883073810369380
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Special Article
The Apnea Test: Rationale, Confounders,
and Criticism
Journal of Child Neurology
25(11) 1435-1443
ª The Author(s) 2010
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DOI: 10.1177/0883073810369380
http://jcn.sagepub.com
Ari R. Joffe, MD, FRCPC1, Natalie R. Anton, MD, FRCPC1, and
Jonathan P. Duff, MD, FRCPC1
Abstract
The apnea test is recommended for the diagnosis of brain death. There are several reasons this test should be reconsidered.
Confounding factors for performing the test are vaguely and poorly specified. The following 2 confounders are usually present
and not considered: potentially reversible high cervical spinal cord injury and central endocrine failure of adrenal and thyroid
axes. There are case reports of breathing at a higher partial pressure of arterial carbon dioxide threshold and cases of
recovery of breathing after brain death is diagnosed. The test is dangerous for an injured brain in the setting of high
intracranial pressure. It can convert viable penumbral brain tissue to irreversibly nonfunctioning tissue via a transient increase
in intracranial pressure and no-reflow phenomena. Hyperoxia during the apnea test can further suppress the function of medullary
respiratory rhythm centers. Finally, the philosophical rationale for the need to show lack of spontaneous breathing in brain death
is lacking.
Keywords
brain death, apnea, endocrine, carbon dioxide, respiration
Received February 19, 2010. Received revised March 17, 2010. Accepted for publication March 18, 2010.
The apnea test is recommended in guidelines and for the
diagnosis of brain death; however, this test has rarely been
questioned in terms of its rationale, interpretation, or necessity
in the diagnosis of brain death.1-3 In this commentary, we question the empirical and philosophical rationale for doing the
apnea test. Specifically, the literature usually neglects to
mention the risks of doing an apnea test, the many potential
confounders of interpretation of the test during severe brain
injury, and the failure of the philosophical rationale to stand
up to scrutiny. The apnea test should be reconsidered as a test
to determine brain death in the setting of severe brain injury.
The Apnea Test
Several publications give guidance on the proper technique of
performing an apnea test in suspected brain death.1-4 Current
guidelines recommend that the patient be preoxygenated, have
a stable blood pressure, and have confounding conditions ruled
out. During the apnea test, when the ventilator is not delivering
any breaths, the patient is given oxygen via a catheter down the
endotracheal tube or via continuous positive airway pressure by
the ventilator or a manual bagger. The arterial carbon dioxide
concentration is measured at baseline and should be about
40 mmHg. During the test, there is continuous observation of
the patient for any respiratory effort. The arterial blood gas is
measured intermittently, and when the arterial carbon-dioxide
concentration rises to over 60 mmHg, and at least 20 mmHg
above baseline, the test is stopped. If there are no observed
respiratory efforts during the test, the apnea test demonstrates
lack of a drive to breathe, and hence absence of function of the
medullary respiratory centers. If there is hypoxia or hypotension during the testing, which makes the test invalid, the test
is stopped and the hypoxia or hypotension is corrected.
The apnea test assesses for lower medullary function. If this
function is lost, as shown by the apnea test, this demonstrates
that the cascade of brain injury, cerebral edema, brain herniation, and injury of the entire brain, including the brainstem, has
gone to completion.5 If the apnea test cannot be performed, an
ancillary test is recommended to prove that there is a lack of
brain blood flow.1-3
The original studies of brain death did not require the apnea
test as currently recommended because of the potential adverse
effects.6-8 The Cerebral Survival Study, done by the advisors to
the President’s Council from 1970 to 1972, defined apnea as a
1
University of Alberta and Stollery Children’s Hospital, Edmonton, Alberta,
Canada
Corresponding Author:
Ari R. Joffe, MD, 3A3.07 Stollery Children’s Hospital, 8440 112 Street,
Edmonton, Alberta, Canada, T6G 2B7
Email: [email protected]
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lack of respiratory effort to override the ventilator for 15 minutes; the ventilator was not stopped or the ventilation rate even
reduced.6 This definition of apnea was similar to other studies
done before, which led to the acceptance of the concept of brain
death.7,8 The current technique has never been tested as a criterion to define brain destruction or even irreversible lack of the
drive to breathe.
Potential Confounding Conditions
The apnea test should not be done if there are any confounding
conditions that could affect its interpretation.1-4 Any condition
that could alter the respiratory response to hypercarbia should
be corrected prior to the apnea test, and if this cannot be done,
an ancillary test is required.
Typical Confounding Conditions
Most clinicians are aware of the many potential confounding
conditions that would make an apnea test not interpretable. The
list includes: shock (hypotension); hypoxia; metabolic abnormalities (abnormalities of electrolytes, glucose, calcium, magnesium, phosphorus, renal and liver function, or ammonia);
brainstem encephalitis; peripheral muscle or nerve dysfunction; endocrine abnormalities; hypothermia; and sedative or
drug effects.1-4 One problem with this list is that each factor
is vaguely or inconsistently specified (Table 1). The exact levels of hypotension, hypoxia, or metabolic values are not clear.
The diagnosis of encephalitis, neuropathy, and myopathy is difficult, and neuropathy and/or polyneuropathy can be common
during critical illness.9 The level of hypothermia suggested to
confound interpretation of the test is inconsistent, with testing
being recommended only after the temperature is at least
36.5 C in the United States, 35 C in Australia/New Zealand,
and 34 C in Canada and the United Kingdom.1,2,10,11
Medications are a common potential confounder. Which
drugs to consider as confounding brain death is not clear, and
new ones are reported intermittently as mimics of the state of
brain death.12,13 Moreover, what dose and what exact level of the
drug would confound the apnea test in the setting of severe brain
injury is not clear and has never been studied. For example,
opioids and benzodiazepines are commonly used in patients
with severe brain injuries, and how long after therapeutic dosing
(sometimes as prolonged infusions) and at what exact measured
level would an apnea test be reliable is unknown. The ability to
measure levels of these drugs is usually not available. The literature does not often discuss this problem, except in the setting of
a barbiturate-induced coma, where many days are required
before the drug effect can wear off.14-16
The implications of the above are that physician judgment is
required in interpreting possible confounding conditions. If the
physician judges that a potential confounding condition is present, then this should be reversed prior to testing for brain death,
or an ancillary test should be done in addition. How consistently different physicians may make the same subjective judgments has never been studied.
Potential Confounding Conditions Not Typically
Considered
Recently, cervical spinal cord injury and endocrine dysfunction, 2 potential confounding conditions to the apnea test, have
unfortunately been described as very common in patients with
severe brain injury who may be suspected to have brain death.
High cervical spinal cord injury is a common consequence of
any brain herniation event.17 A recent review summarized the
many case reports of cervical spinal cord injury with acute
quadriplegia and apnea during brain herniation because of various conditions including meningitis and trauma.17 It is concern
that in many of these cases the clinical findings were reversible
over time. In the only 2 series of brain death that examined the
spinal cord pathologically, 50% to 100% of cases had high cervical spinal cord damage secondary to the brain herniation
event.18,19 In an animal model of brain death, the high cervical
spinal cord was usually damaged.20 Spinal cord injury is a confounder to not just testing for movement to noxious stimulus
and the cough reflex, but also testing for apnea.1-3,10,11 If apnea
is because of cervical cord dysfunction, and not to medullary
dysfunction, the apnea test result is confounded. This is a major
problem because there is no validated test for high cervical cord
injury. The best test for this injury would likely be magnetic
resonance imaging (MRI); however, how sensitive and specific
this test is for this purpose requires more study. In addition,
obtaining MRI on patients with suspected brain death can be
difficult, costly, impractical, and has its own hazards in a
patient on vasoactive infusions. An ancillary test in all cases
of suspected brain death would be another potential solution
to the problem; however, brain blood flow testing with radionuclide imaging or single-photon emission computed tomography
has not been validated in the setting of severe brain injury and
its specificity in this setting is unclear.21
A second major confounding condition is endocrine dysfunction.22 Although diabetes insipidus occurs in at least
50% of brain death cases, it is treated and therefore unlikely
to confound testing for apnea. However, if the hypothalamus
and/or pituitary gland are damaged during the brain injury and
herniation, then central adrenal and thyroid deficiency should
occur. Indeed, some guidelines recommend treating these deficiencies in brain dead potential organ donors to improve organ
function and hemodynamic stability.23,24 It is rarely mentioned
that adrenal and thyroid deficiency states can cause coma and
apnea.22 There are many reports of altered central response
to carbon dioxide in hypothyroidism, with a raised threshold
(higher than 60 mmHg) for central respiratory drive, even more
exaggerated after exposure to any sedative.25-27 Since the
pathophysiology of brain death includes usual injury to the
pituitary, adrenal function and thyroid function should usually
be deficient. This would require testing for, and the treatment
of, any dysfunction prior to testing for brain death. This has not
been recommended or done in any medical center to our
knowledge.
A final confounder presents an interesting dilemma. It is
known that high partial pressure of arterial carbon dioxide
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Table 1. Potential Confounding Conditions to Performing an Apnea Test
Potential Confounding Condition
Why is This Problematic for the Apnea Test?
Unresuscitated shock
Hypoxia
Hypothermia
Metabolic disorders
Biochemical abnormalities
What blood pressure is adequate? What measure of tissue perfusion is adequate?
What partial pressure of arterial oxygen is adequate?
Above what temperature is testing reliable?
What metabolic disorders? What level of acidosis and hyperammonemia?
What level of glucose, sodium, potassium, calcium, phosphate, magnesium, liver function, and renal
function?
How should this be diagnosed? Of what severity? Is critical illness polyneuropathy/myopathy included?
Peripheral nerve or muscle
dysfunction
Brainstem encephalitis
Clinically significant drug
intoxications
How should this be diagnosed? How can reversibility be diagnosed?
Which drugs and at what measured level?
decreases the level of consciousness by suppressing brain
function.28 The effect of a high partial pressure of arterial carbon dioxide on a recently damaged brain is unknown. It can be
speculated that a high partial pressure of arterial carbon dioxide
can suppress the function of the respiratory center of the brain
and increase the threshold for stimulation of breathing.29
The Empirical Evidence for the Apnea Test
The threshold for diagnosing irreversible medullary respiratory
centers’ loss of function has not been validated. Different
guidelines suggest different thresholds of partial pressure of
arterial carbon dioxide. For example, in Canada, the United
States, and Australia/New Zealand the threshold is 60 mmHg,
and in the United Kingdom it is 50 mmHg.1,2,10,11 In addition,
the temperature at which an apnea test is allowed is different in
Canada and the United Kingdom (34 C), Australia/New Zealand (35 C), and the United States (36.5 C).1,2,10,11 This is problematic given that there are case reports of 3 patients with
brain death who had breathing efforts when the partial pressure
of arterial carbon dioxide rose well above 60 mmHg.30-32 In
addition, there are several case reports of patients (infants
and adults) correctly diagnosed with brain death who later
had a return of respiratory efforts.33 These reports include a
3-month-old patient who regained respirations over 30 days
after having brain death correctly diagnosed.34
It is usually claimed that if done correctly with preoxygenation, ongoing oxygenation during the test, and attention to
hemodynamics, the apnea test can be done safely. Although
reports give rates of complicating hypoxia and hypotension
varying from 5% to 20%, it is generally felt that with constant
monitoring, and aborting the test in event of an adverse effect,
the apnea test is safe.4,35 Nevertheless, it is suggested to do the
test only after all the other tests of brain death are fulfilled, presumably to avoid the potential complications in someone who
is known not to have brain death.1-4,10,11 This reasoning may
mask the fact that the deleterious effect of even transient
hypoxia and/or hypotension on a recently injured and vulnerable brain is unclear. In the setting of brain injury, in general,
avoiding hypoxia and hypotension are said to be the only
proven interventions available in intensive care, given their
consistent association with adverse outcomes.36
Of potentially more concern is the effect of a high partial
pressure of arterial carbon dioxide on a vulnerable brain in the
setting of high intracranial pressure. It is recognized in neurointensive care that a high partial pressure of arterial carbon dioxide must be avoided, if possible, because of its known effect on
raising intracranial pressure and therefore worsening ischemia
to the brain and potentially contributing to herniation.28,29,37,38
The only widely accepted reason to induce hypocapnea in a
brain injured patient is in the setting of suspected brain herniation to acutely reduce the intracranial pressure.38 In animal
models of brain injury, once the intracranial pressure rises
above systemic blood pressure, even transiently, there is often
a no-reflow phenomenon with collapse of the cerebral vasculature that is often not reversible by lowering the intracranial
pressure again.39,40 Given this information, it is logical to assert
that an apnea test is potentially very dangerous to a recently
injured brain that has high intracranial pressure.29 Indeed, it
is reasonable to suggest that the apnea test itself can result in
failing the apnea test, creating a self-fulfilling prophecy. During the apnea test, the rising partial pressure of arterial carbon
dioxide causes an acute rise in intracranial pressure in any
remaining perfused brain, and this in turn will worsen brain
ischemia and complete any evolving herniation, reducing the
function of any affected brain. Moreover, after the apnea test,
these functions are likely not recoverable because of the noreflow phenomenon.
An interesting slant on this concern has been raised by
Coimbra.41 In the setting of brain ischemia it is widely recognized that there are irreversibly ischemic areas and penumbral
areas where perfusion is low enough to cause a loss of clinical
functions even though the tissue is viable if perfusion is
restored.42 This is the rationale behind thrombolysis in the setting of ischemic brain and brainstem strokes.43 It is possible
then that the apnea test can convert functioning brain to nonfunctioning penumbral brain (causing the failure of the apnea
test), and can convert penumbral brain to irreversibly nonrecoverable brain.41 Although this has not been proven empirically in the setting of suspected brain death, it is more
concerning that it has not been refuted empirically in that
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Journal of Child Neurology 25(11)
setting. Given the pathophysiologic soundness of the argument,
it would seem a valid concern.
One reason the apnea test is done last in testing for brain
death is that it is said to show that the herniation and brain
injury have come to completion, affecting the lowermost part
of the entire brain, the medulla. It is suggested that the typical
sequence of brain death is progressive cerebral edema, intracranial hypertension, and herniation.5 This could be true, but it
makes some facts present in many brain death patients difficult
to explain. For example, there is electroencephalogram activity
in 20%, brain blood flow in 5% to 40%, hypothalamic function
in over 50%, and lack of pathologic destruction of brain and/or
brainstem in over 40% of brain dead patients.44 It has been
claimed that these are not relevant functions of the brain.44
Again, this could be true; however, it misses the point that if
herniation occurs, then the brain blood flow should stop, brain
functions should then cease, brain tissue should die, and brain
edema should not resolve for a long time (there is no blood flow
to reabsorb it). It is likely that a significant number of brain
death patients have not had this typical sequence occur.45
These points are relevant to the apnea test for 2 reasons. First,
they suggest that there could be viable penumbral brain tissue
that could later perform a recognized clinical function, but the
apnea test can seal its fate. Second, the reasoning behind doing
the apnea test last, to confirm completion of the herniation process, could be flawed.
The Physiology of Respiration
A brief review of some respiratory physiology raises further
concerns for the apnea test. There are 2 distinct rhythm generators in the medulla, the preBötzinger complex composed of 600
neurons (in rats) responsible for inspiratory rhythm, and the retrotrapezoid nucleus/parafacial respiratory group responsible
for expiratory rhythm.46-48 Transsection of the brainstem
between these 2 centers results in continued respiratory rhythm
at a slower frequency.46 Slowly developing lesions to the preBötzinger complex cause apneas to first occur during rapid eye
movement sleep, later extending into nonrapid eye movement
sleep, and finally into wakefulness.46,47 These lesions also
cause markedly depressed responsiveness to partial pressure
of arterial carbon dioxide levels, hypoxia, and hyperoxia, and
marked sensitivity to anesthesia with apnea.47,49 In fact, with
preBötzinger complex lesions, hyperoxia results in marked
depression of respiratory frequency, often with fatal apneas.49
More acute lesions to the preBötzinger complex cause apnea
during wakefulness.50 The preBötzinger complex is also very
sensitive to opioids, with quantal slowing of respiration when
there is an intact retrotrapezoid nucleus/parafacial respiratory
group, and fatal apneas when there is not, which can be
reversed by giving naloxone.46,47
Chemosensation of pH (and hence of partial pressure of
arterial carbon dioxide) is widespread in the brainstem, including the preBötzinger complex, retrotrapezoid nucleus/parafacial
respiratory group, and also nucleus tractus solitarius, locus ceruleus, midline medullary raphe, and the fastigial nucleus.47 Each
of these contributes about 15% to 30% of the chemosensitivity to
partial pressure of arterial carbon dioxide.47 These multiple
sites, in medulla and pons, together maintain normal thresholds
of sensitivity to partial pressure of arterial carbon dioxide. Sensitivity to partial pressure of arterial carbon dioxide is linear over
a range extending up to 100 to 200 mmHg, with the slope of this
partial pressure of arterial carbon dioxide/ventilation response
curve having wide individual variation.51 The slope of the partial pressure of arterial carbon dioxide/ventilation response
curve is also flattened by hyperoxia.51,52 This same functional
anatomy of the control of respiration in the brainstem has been
confirmed in a human functional MRI study.53
This information raises some concerns regarding the apnea
test in determination of brain death. First, when only lower
medullary function remains, the level of partial pressure of
arterial carbon dioxide needed to stimulate breathing can be
higher than 60 mmHg. Second, the amount of time required for
opioid or anesthetic effects on respiratory rhythm to wear off
are unknown.54 Third, the hyperoxia required to perform an
apnea test without causing dangerous hypoxia can actually be
what causes apnea to manifest, because of the suppression of
function in the damaged preBötzinger complex.
The above is likely an oversimplification of brainstem
respiratory physiology.55-57 The core circuitry for eupneic
(with 3 phases) breathing likely involves interactions among
the Bötzinger and preBötzinger complexes in the rostral
medulla, with modulatory brainstem inputs from the pontine
respiratory group, retrotrapezoid nucleus/parafacial respiratory
group, medullary raphe, and nucleus of the tractus solitarius.55,56 These hierarchical compartments are integrated in the
intact brainstem, and the compartmental functions are revealed
by serial brainstem damage.55-57 Eupneic breathing requires
the entire system, including the pons.55-57 After pontomedullary transection, eupnea is transformed to a markedly altered
2-phase pattern.55-57 After transection in the rostral medulla,
between the Bötzinger and preBötzinger complexes, only a
gasping (slower, 1 phase) pattern occurs.55-57 Gasping is the
one respiratory pattern that can be reproducibly obtained in
medullary preparations.57,58 Gasping is not sensitive to hypercapnia; rather, gasping is recruited in severe hypoxia.55-64
Gasping is a respiratory effort to sustain life and is necessary
for autoresuscitation from hypoxic coma and apnea in animals
and humans.55-67 Acute lesions to the preBötzinger complex
can cause apnea, but eupnea often resumes over days as the
brainstem respiratory network reconfigures.57 However, damage to a small, critical area of brainstem in the preBötzinger
complex, involving pacemaker neurons based on persistent
sodium current, irreversibly eliminates gasping.55-57,59,60
This information on gasping raises another concern regarding the apnea test. The apnea test is used to determine lower
medullary function, the innate drive to breathe, and completion
of the cascade of brainstem injury; therefore, gasping is the
function that should be assessed. Eupnea, stimulated by hypercapnia, is dependent on pontomedullary circuits, and altered
2-phase breathing stimulated by hypercapnia is dependent on
the entire medulla (with chemosensory input from pons).55-57
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Gasping is dependent on only the medulla caudal to the
Bötzinger complex, and is a sign of the organism attempting
autoresuscitation.55-57,59 Hypercarbic hyperoxia, as in the
apnea test, will not stimulate gasping even in an undamaged
organism. Inducing severe hypoxia would be required to test
for gasping, but is not acceptable given the harmful effects of
hypoxia on a damaged brain.
The Philosophical Rationale For the
Apnea Test
There are 3 main reasons offered to explain the importance of
the apnea test to the concept of brain death. First, the brain
is necessary for integration of the organism as a whole, and
loss of this integration is what defines the concept of death
itself.68,69 Accordingly, failure of the apnea test shows completion of the brain herniation event and complete loss of integration of the organism as a whole. If there are breathing efforts
during the apnea test then the brain is still functioning and there
is still integration of the organism as a whole. The problem is
that both of these statements are false. Breathing during the
apnea test can be just an attempt to respire, not even enough
to sustain the organism. It is not integration, just an attempt
at it.70 Furthermore, the brain now, even if it was a master
organ before, ‘‘is no longer a master organ but merely a part
of an organ that once was master . . . [suggesting the implausible idea that] the history of an organ is relevant to deciding if a
characteristic of life is present.’’70 In addition, there is no clear
explanation as to why the presence of respiration must be spontaneous (ie, because of spontaneous brainstem activity).70,71
Why is integrated functioning considered to be present when
it is supported artificially in, for example, a diabetic who is artificially supplied with insulin, a patient with congenital central
hypoventilation or a high cervical spine quadriplegic on a ventilator, or a patient with renal failure on dialysis? ‘‘Some argument would be needed for why artificiality in cause matters
when ‘lower’ integrated functioning of the organism results but
not when ‘higher’ integrated functioning results . . . It is not
clear why completely replacing the component at the apex
should be different from replacing a component somewhere
else in the loop.’’70 This suggests that the concept of death, the
loss of integration of the organism as a whole, does not require
that the integration be spontaneous.
Second, it is said that breathing shows that the ‘‘breath of
life’’ is present.72 This is said to reflect a Judeo-Christian
belief. The suggestion here is that the ‘‘conscious soul’’ has
departed, and the ‘‘breath of life’’ is gone.72 This is a robust
Cartesian dualism, and ‘‘is poetry, not physiology.’’73 It is
unclear how to translate this into a scientific or biological rationale for the apnea test and for brain death. Moreover, in clinical
brain death with failure on the apnea test it is not necessarily
true that the capacity for consciousness is lost, as the cerebral
hemispheres can be relatively spared.72 There are several cases
of brainstem death without cerebral death, including 1 series
where this accounted for 3.6% of brain death cases.74 More
problematic for this rationale is that absent ‘‘breath of life’’ is
present in many patients who are clearly not dead, for example,
a high cervical spine quadriplegic patient dependent on the
ventilator, a partially brainstem damaged patient dependent
on a ventilator, patients with severe central neurogenic hypoventilation, and others.74 Even adding unconsciousness does
not solve the problem, because one would require an explanation for why both facts together are needed, and there are still
patients considered alive that satisfy the requirement, such as a
patient with permanent vegetative state and a cervical spine
injury, or with permanent vegetative state and partial brainstem injury, both of whom still have gag, cough, corneal,
pupillary, and other reflexes.
Third, the recent President’s Council offered a completely
novel concept of death.75 An organism is no longer a whole
when it cannot perform ‘‘the fundamental vital work of a living
organism, the work of self-preservation, achieved through
the organism’s need-driven commerce with the surrounding
world.’’75 According to this rationale, apnea shows there is not
an unconscious innate ‘‘felt need’’ of the organism to exchange
gases with the world. There are several problems with this
argument. First, lack of the felt need to breathe occurs in brainstem injury without brain death, central neurogenic hypoventilation, Ondine’s curse (during sleep), and high cervical spinal
cord injury. None of these patients, while on a ventilator, are
dead. This suggests that nonspontaneous breathing counts, and
indeed the President’s Council writes that ‘‘when the brainstem’s respiratory centers are incapacitated, the organism will
not make or display any respiratory effort . . . If the death of the
organism is to be prevented, some external ‘driver’ of
the breathing process—a mechanical ventilator—must be
used.’’75,76 One cannot prevent death if it has already
occurred.77 It is more likely that the felt need, as it applies to
respiration, is for the actual exchange of gases with the environment, which continues during brain death while on a ventilator.76 Second, it is clear that breathing or consciousness is
sufficient to prove life, and this means that lack of breathing
and consciousness is necessary to prove death; however, this
does not mean that lack of breathing and consciousness are
sufficient to prove death.76 Many ongoing felt needs continue
in brain death despite lack of breathing and consciousness,
including the felt need to circulate blood to the organs to meet
their needs, have gut peristalsis to eliminate solid wastes to
the world, metabolize toxins from the outside world in the
liver, excrete unneeded electrolytes and water into the environment, clot an incision to prevent losing blood into the
world, fight infections to eliminate bacteria invading from the
outside world, keep bacterial flora in the throat from invading
the body from the outside world, etc.71,78 Perhaps if all of
these [and likely more] felt needs are lost it would be sufficient to prove death. Third, by the new rationale, the following organisms are dead: the fetus; the irreversible vegetative
state patient without the ability to breathe; the locked-in
patient with consciousness, but complete paralysis, including
the cranial nerves; the pure brainstem death patient; and the
partially brainstem damaged comatose patient without the
ability to breathe.71
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Journal of Child Neurology 25(11)
Table 2. Potential Reasons, in Addition to Those in Table 1, to Abandon the Apnea Test When Diagnosing the State Called Brain Death
Potential Problem
Explanation
Cervical spinal cord injury is often present
Pituitary/hypothalamic, adrenal, and thyroid insufficiency are often
present
The level of pCO2 required to induce respiration in a damaged
brainstem is unknown
How to rule out this confounding condition is not known.
These should be diagnosed and treated prior to brain death testing. How
these should be tested for is unclear.
There are cases of breathing occurring at a higher pCO2 than currently
recommended for apnea testing. When only medullary function remains,
it is expected that a much higher than normal pCO2 threshold will be
present.
The rise in pCO2 can be expected to increase intracranial pressure, This can convert ischemic penumbra tissue to irreversibly injured brain,
reduce cerebral perfusion, and result in no-reflow phenomenon
which can result in apnea.
Hyperoxia can cause fatal apneas when the preBötzinger complex in Hyperoxia is a routine part of the apnea test necessary to avoid
the medulla is damaged
dangerous hypoxia. This can result in apnea.
Gasping is the respiratory pattern reproducibly obtained in the
Hyperoxia during the apnea test prevents gasping. Inducing severe
medulla isolated from the pons
hypoxia to test for medullary gasping function would be unacceptable.
Lack of apnea may not indicate ongoing integration, and apnea can coexist
The philosophical rationale for an apnea test is unclear: lack of
integration of the organism; loss of the ‘‘breath of life’’; and loss of with ongoing integration. ‘‘Breath of life’’ is not a biological or scientific
the ‘‘fundamental vital work of a living organism’’ are not confirmed rationale and can be lost in patients who are alive. Apnea is not sufficient
to prove death, and much ‘‘vital work’’ continues with apnea during brain
by apnea
death.
Abbreviation: pCO2, partial pressure of arterial carbon dioxide.
Implications
The criterion of brain death requires there be loss of all critical
functions of the entire brain, including the brainstem. The
dilemma faced is how to prove brain death (Table 2). To
demonstrate lack of medullary function on the apnea test would
require tests to prove lack of cervical spinal cord injury from
the brain herniation, lack of (or treated) endocrine failure, and
more clear and validated specification of other absent confounding conditions. This is a tall order. It is not clear that MRI
is feasible, sensitive, or specific enough to rule out cervical
cord injury.17 Assuming this can be done, the issue of the
theoretical dangers of high partial pressure of arterial carbon
dioxide during the apnea test still cannot be ignored. A test
diagnosing the lack of brain viability, replacing the apnea test,
would be highly desirable. This diagnostic test would require
better validation of the current brain blood flow tests, as currently diffusible radionuclide brain blood flow testing specificity in severely brain injured patients has been demonstrated
in only 41 patients, and single photon emission computed
tomography blood flow testing specificity has been demonstrated in only 12 patients.21 Finally, what gold standard of
brain death to use for comparison is problematic. For example,
pathological brain necrosis is not seen on 5% to 40% of autopsies of brain death patients, even after over 24 hours of
brain death.44,79 In the original studies, no clinical criteria for
brain death had near perfect correlation with pathological brain
necrosis.80
A potential solution to the dilemma has been discussed in
the literature. This solution argues that brain death is a neurologically devastating state with a very poor prognosis, but not
death itself. Some argue that in this state of brain death the
patient no longer has a future like ours, a future of value, or that
what makes life worth living has been lost.81 According to this
argument, with informed consent of patient or surrogate, organ
donation prior to withdrawal of life support is reasonable.82,83
Although this could be active euthanasia, it has been argued
that it is not morally different from withdrawal of life support
at the end of life in other patients.82,83 When a ventilator is
withdrawn with consent, the physician’s action (removal of the
ventilator) causes the effect (patient’s death). Both removal of
the ventilator and organ harvest are acts that cause the death,
and the informed consent makes them justified acts.82,83
According to this argument, it is a moral fiction that withdrawal
of life support is simply allowing a natural death from the progression of the underlying disease.82-84 The question is now,
‘‘Is an apnea test required to allow the decision to donate
organs?’’ Some tests would be required to determine the state
of neurological devastation, and hence justify the decision to
donate organs prior to death. Perhaps, with empirically validated longer periods of observation, empirical clarification of
confounding factors, and empirical clarification of brain blood
flow test specificity, an apnea test would not be necessary.
Summary
The apnea test is usually done during examination for suspected brain death to prove lack of respiratory drive, which
in turn shows lack of clinical medullary brain function. There
are problems with this theory. First, confounding factors for
performing the apnea test are vaguely and poorly specified
(Table 1). More concerning is that 2 confounders are usually
present and not tested for or considered: a potentially reversible
high cervical spinal cord injury, and central endocrine failure of
adrenal and thyroid axes. Second, the empirical evidence for
the apnea test suggests that it is poorly validated, with case
reports of breathing at a higher partial pressure of arterial
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Joffe et al
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carbon dioxide threshold, and rare cases of recovery of breathing after brain death is diagnosed. Third, the apnea test is theoretically dangerous for an injured brain in the setting of high
intracranial pressure. It can be expected to convert viable or
penumbral brain tissue to irreversibly nonfunctioning tissue via
transient increase in intracranial pressure and no-reflow phenomena. Although this is theoretical, it has a sound pathophysiological rationale, and has never been empirically refuted.
Fourth, hyperoxia during the apnea test can further suppress the
function of medullary respiratory rhythm centers. Fifth, the
philosophical rationale for the need to show lack of spontaneous breathing in brain death is lacking. Like many of the
arguments in the literature on brain death, once they are examined in detail, their initial persuasiveness is lost.85
The implications for clinical practice are concerning (Table
2). First, some way to confirm the absence of a confounding
condition would need to be empirically validated. Second, it
would be desirable to avoid the apnea test altogether and to
have an empirically validated test of brain and brainstem blood
flow in patients with severe brain injury. Third, whether tests
for the neurological devastation presumed in brain death (without an apnea test) would allow organ donation with consent,
and a justified violation of the dead donor rule, requires open
debate. These are weighty moral problems. Continuing to do
the apnea test is not the solution in our view, as it ignores the
very real concerns outlined in this review.
Acknowledgments
This work was performed at the University of Alberta.
Contributors
ARJ wrote the first draft of the manuscript. NRA and JPD critically
reviewed and revised the manuscript. All authors contributed to the
idea of the manuscript.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the authorship and/or publication of this article.
Funding
The authors received no financial support for the research and/or
authorship of this article.
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