Institute of
Neurology and Neurosurgery
CONSCIOUSNESS AS A DEFINITION OF DEATH: ITS APPEAL AND
COMPLEXITY
Author:
Calixto Machado, MD, Ph.D.
Word
count :7534
Correspondence: Calixto Machado, MD,
Ph.D.
I Instituto
de Neurología y Neurocirugía
29
y D, Vedado
Ciudad
de La Habana 10400
CUBA
Tel/Fax:53-7-322233
E.mail: braind@infomed.sld.cu
Havana, Cuba
1998
Many
controversies in the actual discussions on human death concern the lack of
rigorous separation and ordered formulation of three distinct elements: the
definition of death, the medical criterion (anatomical substratum) for
determining that death has occurred, and the tests to prove that the criterion
has been satisfied. In this paper I review the three brain-oriented standards
of death (whole brain, brainstem and higher brain) according to these three
distinct elements, and will propose a new formulation of death, based on the
basic physiopathological mechanisms of consciousness generation in human
beings. Two physiological components control conscious behavior: arousal and
awareness (content of consciousness). We cannot simply differentiate and locate
arousal as a function of the ascending reticular activating system, and
awareness as a function of the cerebral cortex. Substantial interconnections
among the brainstem, subcortical structures and the neocortex, are essential
for subserving and integrating both components of human consciousness. Therefore, consciousness generation is based
on anatomy and physiology throughout
the brain. The three brain-oriented standards are inconsistent
because they present discrepancies among the elements: definition-criterion-tests.
I propose a standard of human death that includes consciousness as the most
important function of the body, because it provides the capacity for
integrating the main human attributes with an integrative functioning of the
body. I have also emphasized that consciousness does not bear a simple
one-to-one relationship with higher or lower brain structures, because the
physical substratum for consciousness is based on anatomy and physiology
throughout the brain. This notion of consciousness as the ultimate integrative
function is more consistent with the biologically-based systems than the more
philosophically-based notions of
personhood
Many controversies in the
actual discussions on human death are mainly due to "the lack of rigorous
separation and ordered formulation of three distinct elements: the definition
of death, the medical criterion (anatomical substratum) for determining that
death has occurred, and the tests to prove that the criterion has been
satisfied". 1-7 To define death is mainly a philosophical task, meanwhile the criterion
and tests are medical chores. Specific criteria and tests must harmonize with a
given definition. The definition must recognize the "quality that is so
essentially significant to a living entity that its loss is termed death".
1-3,7
During the last decades,
three main brain-oriented formulations of death have been discussed: whole
brain, brainstem death and higher brain standards. 8,9 The
whole brain criterion refers to the irreversible cessation of all
intracranial structure functions. 1-5,10-19 It has been accepted by society mainly for practical reasons. 8 Physicians have constructed batteries of
bedside tests (and of confirmatory laboratory procedures) to show that this
criterion of death has been satisfied. 10,12,13,19-21 Until recently, whole brain strategists had
not provided a conceptual framework to support specific criteria and tests. 10-12 Moreover, this view has not answered the key
point question about the critical number and location of neurons, subserving
the essential brain activities to execute the functioning of the "organism as a whole" 22-27
Christopher Pallis has
powerfully articulated the brainstem death view. 28-32 There were also practical reasons that
promoted this view, 33-35 because according to Pallis 28 "a dead (i. e, irreversibly
non-functioning) brainstem can be diagnosed at bedside, without resort of
complicated investigations, and it predicts inevitable asystole within a short
while". Therefore, so-called brainstem death was
adopted in several Commonwealth countries. 28-36 Pallis emphasized that the "capacity for consciousness"
and “respiration” are the two
hallmarks of life of the human being, and that brainstem death predicts an
inescapable asystole. 28-32 The physiopathological review of consciousness generation and
respiration will provide a framework for not accepting Pallis' definition of
death. 8,9,37 Moreover, recent clinical cases have shown that brain death will not
always predict an "inevitable asystole within a short while". 37
Higher brain theorists have defined human death as the "the
loss of consciousness",
(definition) related to the irreversible destruction of the neocortex
(criterion), or “higher brain”. 38-44 In this paper, I will explain that consciousness
does not bear a simple one-to-one relationship with higher or lower brain
structures, and therefore, the higher brain formulation is wrong, because the
definition (consciousness) does not correspond directly to the criterion
(neocortex). 9 I
will also review the three brain-oriented standards using to the three distinct
elements proposed by Bernat and others,1-7 and will propose a new formulation of death,
based on the basic physiopathological mechanisms of consciousness generation in
human beings. 8,9
Before proceeding, it is
necessary to review the physiopathological mechanisms of consciousness generation.
Plum and Posner 18 defined consciousness as “the state of awareness
of self and the environment”. Two physiological components control conscious
behavior: arousal and awareness. 9,18 Arousal represents a group of behavioral changes that occurs when a person awakens from sleep or transits to a
state of alertness. 45 "Normal consciousness requires arousal, autonomic-vegetative brain function subserved by ascending
stimuli from the pontine tegmentum, posterior hypothalamus and thalamus that
activate wakefulness". 46 The most discernible change that occurs when waking is the eyes opening. 9,18,45,46 Arousal is also known as capacity for
consciousness. 9,28-32
Awareness, also known as
content of consciousness, represents
the sum of cognitive and affective mental functions, and denotes the knowledge
of one's existence, and the recognition of the internal and external worlds. 9,18
It has been argued that
consciousness has two dimensions: wakefulness and awareness. 46
Awareness is the same
as the content of consciousness. 9 Wakefulness is provided by the
arousal. 9,18,45,46
Plum 47 has recently defined not two but three
components, subdividing the content of consciousness in two levels or components. According to this author, the second
component or level, "which importantly regulates the sustained behavioral
state function of affect, mood, attention, cognitive integration, and psychic
energy (cathexis) depends on the integrity of the limbic structures including
the hypothalamus, the basal forebrain, the amygdala, the hippocampal complex,
the cingulun, and the septal area". The limbic system is important for the
homeostasis of the internal milieu, and hence the second component of
consciousness is crucial for integrating affective, cognitive and vegetative
functions. Plum considers the third component as the "cerebral level,
along with the thalamus and basal ganglia". This component is related
to the processes of higher levels of
perception, self-awareness, language, motor skill, and planning. Memory can be
impaired by injury of either cerebral or limbic levels.
In summary, a human being's
state of consciousness reflects both his or her level of arousal that depends
on subcortical arousal-energizing systems and, the sum of the cognitive,
affective, and other higher brain functions (content of consciousness or awareness),
related to "complex physical and psychologic mechanisms by which limbic
systems and the cerebrum enrich and individualize human consciousness". 48 Therefore, I will use the term arousal
when referring to those subcortical arousal-energizing systems, and awareness,
to denote the sum of those complex brain functions, related to limbic and
cerebrum levels. 9,18,48
Unfortunately, most authors
38,41,43 mention
human consciousness, without considering its two components originally
described by Plum and Posner. 18 For example, higher brain theorists 38-44 habitually describe the persistent vegetative
state (PVS) as patients with
"irreversible loss of consciousness" or "permanent
unconscious", but in these patients arousal is preserved, while awareness
is apparently lost. On the other hand, some authors refer to the higher brain
criterion as "the irreversible loss of the capacity for
consciousness", 41 but
they are really referring to awareness. As the use of the term "capacity
for consciousness", 28-32 could be confusing, I will identify this
function with the original term used by Plum and Posner, 18 i. e., arousal. I will use awareness as a
synonym for content of consciousness. 8,9
Arousal depends on the
integrity of physiological mechanisms that take their origin in the ascending
reticular activating system (ARAS): "it originates in the upper brainstem
reticular core and projects through synaptic relays in the thalamus to the
cerebral cortex, where it increases excitability". 48 Moruzzi and Magoun, 49 in their pioneer studies, discovered “the presence in the brainstem of a system
of ascending reticular relays, whose direct stimulation activates or
desynchronizes the EEG, replacing high-voltage low waves with low voltage fast
activity”. Nonetheless, Steriade et al. 48,50-59 have recently emphasized that this
desynchronization related to wakefulness “is now more apparent than real”,
because although large slow waves disappear during waking, the EEG shows high
frequency oscillations (30-40 Hz), known as gamma oscillations, that reflect
synchronized and enhanced intracortical and corticothalamic activity.
Bogen 60 has emphasized that the intralaminar nuclei
complex of the thalamus is a cardinal component of the ARAS. The thalamic
intralaminar neurons receive inputs from many sensory modalities and widely
project to the cerebral cortex. Moreover, these nuclei are a major target for
the brainstem reticular formation involved in waking. Recent reports strengthen
the idea that intralaminar nuclei are thus essential in coordinating activity
among cortical areas, and contribute to the formation of global perception to
complex stimuli. 60,61
The connections from the
brainstem to the cerebral cortex, relayed through intralaminar and other
thalamic nuclei, and their main neurotransmitters (acetylcoline and glutamate)
have been identified. 48 Additional important pathways participating in arousal have been
recently recognized. 45 There are
neurotransmitter systems that take origin in the brainstem, hypothalamus and basal
forebrain, projecting monosynaptically to the cerebral cortex without relaying
through the thalamus. These systems
include different neurotransmitter projections: cholinergic from the basal
forebrain and mesopontine reticular formation, serotoninergic from the
brainstem raphe nuclei, histaminergic from the posterior hypothalamus and
noradrenergic from the brainstem locus coeruleus. Experimental studies have
also shown that an almost complete destruction of the thalamus does not block
cortical activation. Furthermore, the EEG arousal pattern characterized by
desynchronization disappears with the administration of drugs to block
serotoninergic and cholinergic transmission. 18,62 Therefore, it is reasonable that arousal is due
to several ascending systems stimulating the cerebral cortex and thalamus in
parallel. 9,45 Thus, "thalamo-cortical transmission may not be sufficient or even
necessary to produce cortical activation". 18
The discovery that the
cerebral cortex is organized in vertical columns that represent functional
units was crucial for further understanding of the functional organization of
the brain. "The basic functional unit of the neocortex is a vertically
oriented group of cells extending across the cellular layers and heavily interconnected
in the vertical direction, sparsely so horizontally". 63 At present there are arguments that the
functional organization of the entire cerebral cortex is a complex of these
vertical columns. Contiguous columns are interconnected by local circuits into
"information-processing modules", characterized by specific afferent
and efferent connections with other modular units from other cortical and
subcortical areas. 45,63
It seems that the brain
operates in "parallel processing", because cortical regions are linked
in parallel networks with each other and with subcortical structures. Thus, a
specific component of a certain cognitive function is scattered among
interconnected regions, each one implicated in a distinct aspect of the
cognitive ability. 45,64 According
to Feinberg, 65
one of the most remarkable peculiarities of the brain is "the seemingly
enormous redundancy, parallelism, and distributiveness" of its
connections.
The cerebral cortex and
thalamus make up "a unified oscillatory machine" that exhibit
spontaneous rhythms and that are conditional to behavioral state and vigilance.
51 The brain uses
spatiotemporally distributed systems to "capture high-order perceptual
features". 65 Singer and Gray 66 have argued that fast rhythms of
corticothalamic neurons, known as gamma oscillations, are probably implicated
in synchronizing mechanisms that respond to different features of the same
perceptual object, leading to several hypothesis of high cognitive mechanisms.
Normal conscious behavior
requires both arousal and awareness. 18 Patients in coma are unconscious because both
arousal and awareness are disturbed. 9,18
The Multi-Society Task
Force in PVS8 has classified the causes of PVS in 3 main
groups: Acute injuries, where the most common causes are traumatic and
hypoxic-ischemic encephalopathy; degenerative and metabolic disorders,
including dementia; developmental
malformations, where the most important is anencephaly. Nonetheless, the
most prevalent causes of acute PVS in all ages are head trauma and hypoxic-ischemic
encephalopathy. These causes have been
taken as models to describe the three main patterns of the neuropathological
damage in PVS cases.
In persistent vegetative
state (PVS) cases arousal is preserved (the PVS has periods of wakefulness),
but awareness is seemingly is lost. 9 Thus, in PVS there is an
apparent dissociation of awareness from arousal. 9,45 It has
been argued that "separate anatomic pathways mediate arousal and
awareness, and that brain diseases can differentially affect each component of
consciousness". 45
This raises the question:
Why is awareness lacking in PVS, while arousal is preserved? The neuropathology
in the PVS provides a suitable background to discuss the pathophysiology of
consciousness generation. Kinney 45 has recently presented a detailed review of
this subject. According to this author, PVS denotes a
"locked-out-syndrome" because "the cerebral cortex is
disconnected from the external world, and all awareness of the external world
is lost". She suggested that the loss of awareness in the PVS is caused by
three main patterns: widespread and bilateral lesions of the cerebral cortex,
diffuse damage of intra- and subcortical connections in the cerebral
hemispheres white matter, and necrosis of the thalamus.
In widespread and bilateral
lesions of the cerebral cortex, hypoxic-ischemic encephalopathy is the main
etiology. It is the consequence of acute hypoxic-ischemic insults after
cardio-respiratory arrest, strangulation, suffocation, near-drawing, prolonged
hypotension, and perinatal asphyxia in neonates. 45,67 The description of this pattern was the reason
that PVS was first known as "apallic syndrome", characterized by the
destruction of the "pallium, the cortical gray matter that covers the
thelencephalon". 68 In the cerebral cortex a laminar necrosis
is found that is multifocal or diffuse and extensive. Other ischemic lesions
may be superimposed mainly in the border zones of the main intracranial
cerebral arteries, as the parasagittal parieto-occipital region, for example. 45,69
Other damages, such as
neuronal loss and small infarcts, are also typically found in the cerebellum,
basal ganglia, thalamus and hippocampus; the later being particularly sensitive.
Other anatomical structures of the brain are relatively undamaged: brainstem,
hypothalamus, basal forebrain and amygdala. This
distribution of brain damage reflects the differential vulnerability of brain
regions to hypoxia-ischemia. 45,68,70
In PVS cases with diffuse
damage of the cerebral cortex the lack of awareness is understandable. The
widespread involvement of the association cortices combined with primary and
secondary cortices damage, is the faultfinding anatomical ground. 45 It has been suggested that in diffuse cerebral
cortical lesions, the brainstem and the thalamus can maintain arousal.
9,45 Nonetheless, other
parallel pathways projecting monosynaptically to the cerebral cortex without
relaying through the thalamus could partake to maintain the arousal in these
cases. Thus, arousal could be preserved without a functional cerebral cortex.
This has been also supported by experimental data. In animals with a total removal of the cerebral cortex or
transection at the rostral midbrain level, arousal is preserved, showing
waking/ sleep cycles. 71 Therefore, it has been argued that the brainstem alone could be
sufficient for arousal. 45,71
The mechanism of this
pattern could be explained in head trauma and hypoxic-ischemic injury. After head
trauma, a widespread damage of axons in the cerebral hemispheres white matter
occurs, known as diffuse axonal injury (DAI). The DAI is probably caused by the
acceleration suffered by the head immediate after the injury. 45,72
The cerebral hemisphere white
matter could be also damaged after hypoxic-ischemic accidents in a pattern
known as "leukoencephalopathy". 73 It
is characterized by "extensive symmetrical necrotic lesions in the central
white matter of the cerebral hemispheres, with minimal or no damage to gray
matter structures". 45 These patients yield antecedents of prolonged periods of hypotension,
hypoxemia and increased venous pressure. 45,72,73
This pattern also provides
a disconnection of the cerebral cortex from the environment that can explain
the lack of awareness in the PVS. The functionally unaltered brainstem and
thalamus preserve arousal. The participation of other parallel pathway not
relaying through the thalamus has to be also considered. 9
Reports in PVS patients and
experimental data of diffuse axonal injury to cerebral hemispheres with
cerebral cortex remaining largely normal suggest that, "acute diffuse
disconnection of the cerebral cortex from its subcortical activating mechanisms
can block arousal as well as cognitive activity in the primate brain". 47
Other pattern is
characterized by a selective necrosis of the thalamus and, although the cortex
is not totally spared, the lesions are focal and restricted. 45,74 It has been explained by several possible
factors, such as: partial or immediately reversed transtentorial herniation,
cerebral edema causing hypoxia-ischemia, and intrinsic metabolic vulnerability
of the thalamus. 45
The lesions of the thalamus
provide a disconnection of the cerebral cortex from the external world, and
therefore, all awareness from the environment is lost. The lack of awareness in
this pattern is not only a consequence of lesions destroying the sensory relay
nuclei that block sensory information from the external world, but the damage
of the thalamic intralaminar nuclei is probably the critical anatomical
substratum. 45,61,69 These thalamic nuclei receive inputs from many sensory modalities and
project over wide areas of the cerebral cortex with a “non discernible
topography”. 45
These nuclei integrate important pathways to subserve fundamental cognitive and
affective functions such as the attention to the external world. 45,69 It has
been argued that lesions in a thalamic nucleus that is preferentially connected
with an association cortex provoke functional impairments similar to damage in
the association cortex itself. 69,75 For instance, contrary to the generalized
expectancy, the neuropathological examination of Karen Ann Quinlan's brain
showed a disproportional severe damage of the thalamus, as compared with the
cerebral cortex. 69 Bilateral thalamic infarcts are commonly accompanied by mental
impairment, such as dementia and amnesia. 60,76
In this pattern arousal
could be preserved by a functionally intact brainstem and the other parallel
pathways which project to the cerebral cortex, without relaying through the
thalamus. 9
It has been argued that "the thalamus is critical for cognition and
awareness and may be less essential for arousal". 69
The Multi-Society Task
Force in PVS 46 has defined the precise use of the terms "persistent" and "permanent". "Persistent
refers only to a condition of past and continuing disability with an uncertain
future, whereas permanent implies irreversibility". The Multi-society Task
Force likewise addressed that "A patient in a persistent vegetative state
becomes permanently vegetative when the diagnosis of irreversibility can be
established with a high degree of clinical certainty". According to the
etiology, a period of observation has been proposed to define that a "persistent
vegetative state", has become a "permanent vegetative state.
PVS patients reflect the
only situation in which an apparent dissociation of both components of
consciousness is found. 9,45 Conversely, recent evidence has shown that cortical-subcortical interactions
are necessary to subserve and make both components active. 9,47 Regarding the above-mentioned subjects, two
main questions may arise: Are subcortical structures capable of mediating some
form of awareness? Is the lack of awareness in the PVS really permanent or
irreversible? There is striking evidence that subcortical structures are
capable of mediating some form of awareness. 9 Plum10
has emphasized that the "non-specific
mechanisms ascending from the rostral brainstem and diencephalon importantly
and possibly inseparably activate and integrate both the arousal and the
cognitive aspects of human consciousness".
The participation of the thalamus to provide the awareness has been already
mentioned. 9,45,69
Additionally, Shewmon 77 has discussed some examples of clear
participation of subcortical structures in awareness. Experimental animals with
complete decortication have shown to be capable of complex interactions with
the environment, which is evidence of some awareness. 78 In
lesions of the somatosensory cortex an evident loss of tactile, vibration and
joint position sense is observed; nonetheless, conscious experience of pain and
temperature is preserved, mediated by subcortical structures, probably the
thalamus. 77,79
This author also commented that two hydranencephalic patients ("prenatal
destruction of the cerebral hemispheres with intact skull and scalp")
unquestionably manifested conscious behavior. These two cases are examples of
the brainstem "plasticity" in newborns. 77,81 Clinical and experimental evidence
convincingly suggests that the brainstem of newborns is potentially capable of
much more complex integrative functioning. This includes some functions
commonly considered to be cortical, even in animals. 81 Based on these subjects, the potential presence of some primitive form
of awareness in anencephalics, and the possibility of subjective feeling of
pain, has been suggested. 77,81
Thus, according to Shewmon 77 "the human brainstem and diencephalon, in
the absence of cerebral cortex, can mediate consciousness and purposeful
interaction with the environment".
The use of deep brain
stimulation (DBS) has shown possible that the cerebral hemispheres could
mediate arousal producing some wakefulness behavior, even after complete loss
of the brainstem's reticular activating system. 9 Hassler 82 used DBS in "apallic" or "coma
vigil" cases (PVS patients), stimulating the reticular formation in the
thalamus and in the pallidum. It caused these patients to awaken with an
undoubted recovery of awareness (recognition of their families and emotional
expressions). Katayama et al., 83 also employing DBS of the ARAS (mesencephalic
reticular formation and/or non-specific thalamic nuclei) in PVS cases, have
reported a persistent increment in pain-related P250, which indicates
non-specific cortical activation. Sturm et al. 84 reported the use of DBS at the thalamic level,
in a case with probable dysfunction of the mesencephalic reticular formation
due to the rupture of a sacular aneurysm at the tip of the basilar artery. DBS resulted in autonomic and behavioral
reactions and the patient was able to respond to simple commands. Kohadon and
Richer, 85 from a series of 25 PVS cases treated by DBS, reported a
definitive improvement in arousal with some degree of awareness and
interpersonal relationship, in 13 of them.
PVS provides a model in
which arousal is preserved and awareness is apparently lacking. 9 Therefore, it has been suggested that both
component of consciousness "are mediated by distinct anatomic,
neurochemical and/or physiological systems". 45 Nonetheless, the potential plasticity of the
brain has demonstrated that subcortical structures could mediate awareness,
even with the complete absence of the cerebral cortex. 77 Austin and Grant 86 reported 3 cases who undergone total
hemispherectomy (comprising cortex, white matter and basal ganglia), that
continued speaking and were aware of their environment during the operation,
done under local anesthesia.
Thus, awareness is not only
related to the function of the neocortex (although it is primary important),
but to complex physical and psychological mechanisms, due to the interrelation
of the ARAS, limbic system, and the cerebrum. 9,47
Plum 47 has emphasized that the ARAS substantially and inseparably activates and integrates both
the arousal and the cognitive aspects of human consciousness. He recognized a brainstem-diencephalic
participation not only in arousal, but also in cognitive function. In lesions
affecting thalamic-mesencephalic structures that comprise the ARAS, the
presence of important cognitive and affective deficits can be found.
Alterations in the cerebral cortex after severe damage restricted to
mesencephalic-diencephalic activating systems have been reported. They reflect
transneural degeneration, and suggest that these pathways not only activate the
cerebral cortex but they also trophically influence cortical neurons. 9,47
Therefore, it can be
concluded that we cannot simply differentiate and locate arousal as a function
of the ARAS, and awareness as a function of the cerebral cortex. Substantial
interconnections among the brainstem, subcortical structures and the neocortex,
are essential for subserving and integrating both components of human
consciousness. 9,18,47,77
The above considerations
lead one to conclude that there is no single anatomical place of the brain
"necessary and sufficient for consciousness". 77 Shewmon has discussed the existence of a "physiological kernel of
consciousness" 28-32 or a "reticular formation/cortical unit". 77 In a broad sense this "physiological
kernel of consciousness" or "reticular formation/cortical unit"
(RF/CU) is conformed by the widespread interconnections among the ARAS, diencephalon,
other subcortical structures, and the cerebral cortex. 9,77
James Bernat and his
collaborators have presented the most complete defense of this standard. 1-5,
87-92 He has been one the
main advocates to recognize that any standard should include three distinct
elements: definition-criterion-tests. Bernat proposed the following standard:
|
DEFINITION |
CRITERION |
TESTS |
||
|
The permanent cessation of the functioning of
the organism as a whole |
The permanent cessation of the functioning of
the entire brain |
· The permanent absence of breathing and
heartbeat. · Brain cessation tests |
|
|
Early whole brain advocates
failed to propose a conceptual framework to support this criterion. 9 Nonetheless, Bernat and his colleagues 1-5,
87-91 fully elaborated this
standard of death clearly presenting the three main elements:
definition-criterion-tests. These authors defined death as "the permanent
cessation of the functioning of the organism as a whole". They also
emphasized that by "organism as a whole" they are not referring to
the "whole organism", as a sum of its parts, "but rather to that
characteristics that makes the living organism greater than the sum of its
parts". Moreover, they explained their view of integration in
physiological terms: "functions of the organism as a whole include
respiration, temperature control, fluid and electrolyte homeostasis, consciousness,
food-seeking behavior, sexual behavior, neuroendocrine regulation, and
autonomic control”. 5 Bernat sustained that the organism as a whole could be kept functioning
despite destruction of some subsystems. 2,4,5
"The permanent
cessation of the functioning of the entire brain".
Bernat 1-5,92 proposed two sets of tests for determining
this criterion. The cardiorespiratory standard is used to document the
permanent loss of all brain functions, because a prolonged absence of
circulation or respiration will inevitably cause ischemia, anoxia and necrosis
of the brain. The neurological standard included preconditions and a battery of
tests and clinical procedures performed at bedside. It is applied "in all cases except when death needs
to be declared in a patient with heartbeat on a ventilator". 5
Several authors have
described patients "whole-braindead" and yet expressed surprise when
they find that the EEG was still retained. The persistence of EEG activity is
however incompatible with the diagnosis of "whole brain death". 22-24,93,94 Other authors have reported the preservation
of visual evoked potentials in primary brainstem lesions. 95 The persistence of hypothalamic neuroendocrine
functions in "whole brain-dead" patients has been also advocated
against this formulation. 25-27,96-99
Bernat 92 slightly modified his definition to "the
permanent cessation of the critical functions of the organism as a whole".
This author referred that the critical functions consist of "three
distinct and complementary categories": 1) "vital functions of
spontaneous breathing and autonomic control of circulation". 2)
"Integrating functions that assure homeostasis of the organism, including
the appropriate physiologic responses to baroceptors, chemoreceptors, neuroendocrine
feedback loops". 3) "Consciousness, which is required for the
organism to respond to requirements for hydration, nutrition, and protection,
among other needs". Nonetheless, "this modified position still
doesn't answer the above mentioned electrophysiological findings in
"whole-braindead patients", and it is difficult to know when the
persistence of hypothalamic neuroendocrine functions in these cases is related
or not to a "neuroendocrine feedback loop". Moreover, Bernat now
includes consciousness as the third category of the critical integrative
functions, but as I will demonstrate, consciousness is the ultimate integrative
function of the body.
These arguments pointed out
again a controversy in the fulfillment of the three main elements of any
standard of death (definition-criterion-tests), because the whole brain
criterion does not, and which is the critical number and location of neurons,
subserving the essential activities of the hemispheres, diencephalon and
brainstem to execute the functions of the "organism
as a whole", that permanently cease functioning? 8
Pallis, 28-32,93,100-102 has proposed the following standard, that I will separate according the three
main elements: definition, criterion and tests.
|
DEFINITION |
CRITERION |
TESTS |
|
There is only one kind of human death: the irreversible loss
of the capacity for
consciousness, combined with the irreversible loss of the capacity to breathe (and hence to
sustain a spontaneous heart beat) |
The
permanent cessation of the functioning of brainstem |
· No brainstem reflexes · Apnea |
In his definition, Pallis 28 emphasizes that the "capacity for consciousness" and respiration are the two hallmarks of life of the human being, and
that brainstem death predicts an inescapable asystole.
According to Pallis, 28,101 the ascending reticular formation discovered
by Moruzzi and Magoun 49 produces a generalized activation of the cortex, producing the
necessary arousal to endow the functioning of the "brain as a whole".
This author also emphasized that the physiological and anatomical background is
the irreversible damage of the paramedial tegmental areas of the mesencephalon
and rostral pons.
Since ancient times,
respiration was considered the vital function which defined the frontiers
between life and death. 28,100,101 Pallis has also emphasized that in many older cultures death was
considered: "the departure of the soul from the body", and that
the words that stand for "soul" are in many idioms the same as those
standing for "breath". 28
He also emphasized that the
"loss of breath" locates its anatomical and physiological basis in
irreversible damage of the lower brainstem. Moreover, he considered that the
anatomical and physiological basis to produce an irreversible apnea is an
irreversible damage to the lower brainstem, where "crucial mechanisms
concerned with breathing are located". 28,100
Pallis 28
presented a detailed review to answer the question: "How long may cardiac
action persist after a diagnosis of brain death?" He suggested that in
most cases asystole occurred within days. This author emphasized that time
variations in somatic survival after brain death presumably reflect three main
factors:
· “The time on the
ventilator before the diagnosis of brain death was made”
· “The quality of
‘care’ administered”
· “The age
composition of the sample”
Pallis 28,101 addressed that as the "brainstem death is
a clinical concept", "a dead brainstem" can be diagnosed at
bedside. It is necessary to diagnose an unconscious patient, with irreversible
apnea and irreversible loss of brainstem reflexes, provided that "all reversible causes of brainstem
dysfunction have been excluded”.
Pallis 28-32,93,100-102 includes in his definition “the capacity for consciousness”, or arousal,
as has been previously discussed. Nonetheless, in any definition that incorporates
consciousness as a main hallmark, both components should be included, because a
normal conscious behavior demands integration or widespread interconnections
among the ARAS, subcortical structures, and the neocortex, i. e., an
interaction of both components. 9
Moreover, some authors
using deep brain stimulation have found non-specific cortical activation in PVS and comatose patients. 82-85 Then, in cases fulfilling the brainstem criteria
of brain death with primary brainstem lesions and spared cerebral hemispheres,
stimulation of the non-specific thalamic nuclei might produce some degree of
arousal. 9 In primary brainstem lesions a quasi-normal EEG could be
recorded. 22-24,93-95
The other hallmark of
Pallis’ definition is respiration. 28 I had previously discussed that if by
respiration is meant gases exchange in the lungs or oxidative processes taking
place at the cellular level, mechanically ventilated patients are capable of
"breathing". 8 In
patients with a non-brain functioning the heart beat, pulmonary and circulatory
functions are preserved, and the physiological changes associated with normal
respiration are in fact taking place, at the cellular level. 8,104 Brainstem function is not necessary for this to
happen, provided one is situated in an intensive care unit. 105 In fact, what is
irreversibly absent in the in brain-dead is ventilation. 8
Patients affected with
polio, may be incapable of spontaneous ventilation, i. e., they fulfill one of
the hallmarks of Pallis' definition of death: "the irreversible loss of
the capacity to breathe", 28 but the patients are not dead. 8 Before the era of modern types of ventilatory
assistance, such patients would have not survived. 8,105 Nowadays, the recognition that pulmonary gas exchange may be maintained
successfully for prolonged periods by mechanical ventilation in the intensive
care environment 106,107 leads to conclude that respiration (and more particularly, ventilation)
is not so essential to life, that its loss constitutes death. 8
The age factor at onset of
brain death plays a significant role in somatic survival: "the younger the
age, the greater the capacity for survival". 77,104 Shewmon 104 also addressed two other factors involved in
survival: 1) "associated systemic injuries directly due to whatever caused
the brain insult", and 2) "systemic pathology secondarily induced by
the process of brain herniation". Withdrawal of life support is a
"confounding factor", because it leads to underestimate the survival
potential in brain-dead cases. Other factors related to somatic survival could
be: the quality of nursing care, an adequate homeostatic control, prevention
and early treatment of infections, etc. 28
Therefore, an “inevitable
asystole” can’t be a justification for accepting a brain-oriented standard of
death.
The "higher brain" view is closely related to the management
of PVS patients, and has been mainly
defended by philosophers. 7,38-44,111-114
|
DEFINITION |
CRITERION |
TESTS |
|
The loss of that which is significant to the
nature of man |
The
permanent cessation of the functioning of the neocortex |
No cognitive and affective functions |
"Higher brain"
formulations proposed defining death as
"the loss of that which is significant to the nature of man". 38 "Higher brain" constructionists
sustained that the irreversible loss of perception, sentience and cognition was
necessary and sufficient for diagnosing death.7-38-44,111-14
Bartlett and Youngner 7 stated "we believe that only the higher
brain functions, consciousness and cognition, define the life and death of a
human being".
Robert M. Veatch 38-40,114 was a pioneer of this standard of death, and
one of its main defenders. This author 114 argued to include in the definition either of
“capacity for consciousness or social interaction”, and presented a detailed
discussion about “the functions considered to be ultimately significant to
human life”: rationality, consciousness, personal identity, and social
interaction. He concluded that death should be appropriately defined “as the
irreversible loss of embodied capacity for social interaction”. Some authors have also advocated this
definition as the "loss of
personhood" 42,44
Higher brain advocates
emphasized that the neocortex assumes a critical role by providing the
consciousness and cognition, that characterize a human being 7,38-44,111-114 They proposed to functionally classify the brain into the lower brain
(brainstem), that governs primarily vegetative functions, and the higher brain
(the cerebral hemispheres, particularly the neocortex), that controls
consciousness and cognition.
Veatch 114 emphasized that "we could be quite
conservative and hold that the entire brain must be destroyed in order to be
sure that the capacity for consciousness and social interaction is lost".
This author referred to the "higher brain locus", or used other
terms, such as "cerebral", "cortical", or
"neocortical". Veatch clearly argued that elaborating a set of tests
to measure the irreversible loss of the capacity for consciousness or social
interaction is rather difficult. 38-40,114
I have shown that we cannot
simply differentiate and locate arousal as a function of the ARAS, and the
content of consciousness as a function of the cerebral cortex, because
substantial interconnections among the brainstem, subcortical structures and
the neocortex, are essential for subserving and integrating both components of
human consciousness. 9,18,44,47 Consciousness does not bear a simple one-to-one relationship with higher
or lower brain structures, and therefore, the identification of the definition
(consciousness, capacity for consciousness or social interaction, personal
identity, etc.) does not correspond directly to the criterion (higher brain,
cerebral hemispheres, neocortex) that most, if not all, higher brain defenders
have used. In fact, the physical substratum for consciousness is based on
anatomy and physiology throughout the brain. 9 Some reports about “neocortical death” have
presented a neuropathological substratum of a “dead neocortex” with the
brainstem relatively spared, suggesting that "higher brain-dead
*patients" could preserve brainstem reflexes and spontaneous breathing. 22,24,93,95 I have discussed that three neuropathological
patterns are found in these patients, rather than simply one related to the
destruction of the neocortex. 9
Moreover, it is necessary
to discuss the potential reversibility of the awareness in the PVS. As it has
previously discussed, the use of deep brain stimulation (DBS) has shown the
possibility that the cerebral hemispheres could mediate arousal producing
wakefulness behavior, even after complete loss of the brainstem's reticular
activating system, and an undoubted recovery of awareness (recognition of their
families and emotional expressions) has been reported in PVS cases. 81-84
Some reports of
misdiagnosis or recovery in PVS have also appeared in recent literature.
Unexpected and well-documented recoveries of cognitive functions have been
described in patients, where it was believed that neurologists experienced and
skilled in the diagnosis of this condition correctly applied the criteria. 115-118 Childs 119 reported that 37 % of 49 cases admitted in a
special unit for rehabilitation were incorrectly diagnosed. Andrews et al. 120 reported that 43% of patients also admitted in
a rehabilitation unit were incorrectly diagnosed.
Therefore, the main
inconsistencies of higher brain theorists are: 1) the definition of death
(consciousness, capacity for consciousness or social interaction, personal
identity, etc.) does not correspond directly to the criterion (higher brain,
cerebral hemispheres, neocortex), because they don’t confuse the
physiopathological substratum of consciousness with the neocortex; 2) the
classify PVS case as dead.
|
DEFINITION |
CRITERION |
TESTS |
|
Irreversible
loss of the capacity for integrating the main human attributes with an integrative functioning of the body |
Irreversible
destruction of the anatomo-functional
substratum for subserving both components of consciousness: arousal and
awareness |
Unresponsiveness,
no arousal to any stimuli, no cognitive and affective functions |
Several authors 114,121,122 have quoted words used by Beecher, Chairman of
the Harvard Committee, in his address to the American Association for the
Advancement of Science, when he explained the importance of the brain for human
life: “the individual’s personality, his conscious life, his uniqueness, his
capacity for remembering, judging, reasoning, acting, enjoying, worrying, and
so on”. Cranford 42 stated: "our major premise is that consciousness is the most
critical moral, legal, and constitutional standard, not for human life itself,
but for human personhood". Therefore, higher brain defenders stressed that
consciousness provides the most significant attributes of human existence. 38,42,43
Botkin and Post 123 presented an interesting dichotomy considering
major and minor clusters of attributes related with life. For example, braindead
patients retain several attributes associated with life, as skin color, warm
skin, heartbeat, kidney function, etc. Even, subjects diagnosed as dead by the
cardiorespiratory standard will preserve during day's vestiges of life
attributes: hair and nails still grow. 6,9
Therefore, I completely
agree with higher brain defenders that consciousness provides the most
significant attributes that characterize human life. Hence, It is reasonable to
state that any vestige of consciousness is inconsistent with death.
Korein, applying
thermodynamics and information theory powerfully defended the notion of
integration. 16,124 He argued that all living organisms could be classified as open systems
that exchange energy and matter with environment. He emphasized that within any
organism there is a critical system which "supersedes all other subsidiary
systems" or subsystems. This author proposed that the "critical
system" of the human being is the brain, "which is irreplaceable by
an artifice, be it biological, chemical, or electromechanical". Therefore,
according to this view if the brain is irreversibly destroyed, the critical
system is abolished. Even if, other subsystems are functioning spontaneously or
overtaken by machines, the organism as an individual assemblage no longer
exists. Varela125
also assumed that living organisms are complex dynamical systems with energy
states characterized as a discontinuous "eigenbehavior", and
discontinuities in state transition.
The Swedish Committee 126 also applied the notion of integration to
define death: "total and irreversible loss of all capacity for integrating
and co-ordinating the functions of the body -physical and mental- into a
functional unit.
Shewmon 77,78 had also emphasized the central role of the
brain "in the coordination or performance of virtually all functions
necessary for the unity of the post-embryonic human body, including internal
homeostasis, adaptative interaction with the environment, and the intimate
connection between mental and physiological states". Nonetheless, this author made recently a
complete turn in his position, emphasizing that the brain is not the
"central integrating organ of the body". 104 He remarked that "clinical evidences of
brain death is more attributable to multisystem damage and spinal shock than to
destruction of the brain per se", and proposed to return to a
"circulatory-respiratory" standard of death. However, this author
accepted that the brain plays a role in integrating functions of the intact
organism. He used as an example the field of psychoneuroimmunology, emphasizing
that "the brain role is one of modulating, fine-tuning, and enhancing an
already established and well functioning immune system". If we accept
Shewmon's view, then a specific emotional state could influence the immune
system, either diminishing or enhancing the immune response. We can ask
ourselves: Can we consider this brain's effect over other systems, of "modulating" or "fine-tuning", "the highest
level of integration within the organism"?
According to Bernat, 5 the brain produces signals "for breathing
through brainstem ventilatory centers, and aids in the control of circulation
through medullary blood pressure control centers". For example, if a young
man meets in front of him, his girl friend (love), or sees a lion (fear), we
can explain a complex mechanism of brain control over the whole body. After the
visualization of the visual target (girl friend or lion), and recognition
comparing with backup memory, complex signals are generated, through
interconnected pathways spread throughout extensive brain areas (neocortex,
diencephalon and other limbic structures, brainstem, reticular formation, etc.)
that produces faster heartbeats and deeper ventilatory movements. 127 Trained Yoga practitioners are capable of
slowing heartbeats until they are almost imperceptible to auscultation. 128 Psychological influences in menstrual cycle,
and in reproduction in general, both in humans and in other animal species,
have been vastly discussed in the literature. 129 Conscious behavior has allowed human beings to
transform and govern their environment. 8,38
These examples show how
consciousness controls and regulate the functioning of the organism. It can be
considered as "modulating" or "fine tuning", 104 but it is in fact, the highest level of control
in the hierarchy of integrating functions within the organism. At the same time
consciousness integrates, in a single individual, the human attributes with the
integrative functioning of the body. Each subject reacts differently to stimuli
and daily life situations, according to his personality and knowledge. I am not
denying the existence of multiple complex processes such as controlled by
subsystems not directed commanded by consciousness, as most of the so-called
vegetative functions. Nonetheless, consciousness can overcome any subsystem in
the control of any specific vegetative function, and it is the ultimate
integrating function. Plum extensively discusses this issue, 47 when he describes the importance of the second
component in the regulation and integration of affect, mood, attention,
cognitive integration, and psychic energy (cathexis) by limbic structures.
Therefore, my notion of
consciousness as the ultimate integrative function is more consistent with the
biologically-based systems concepts of Korein 16,124 and Bernat et al. 1-5,87-92 than the more philosophically-based notions of
personhood favored by Veatch, 38-40,114 Barlett and Youngner, 7 Wikler, 44,111,112 and others. 42,43
Criterion
As it has been shown,
substantial interconnections among the brainstem, subcortical structures and
the neocortex, are essential for subserving and integrating both components of
human consciousness. 9,18,47,77 Therefore, consciousness generation is based on anatomy and physiology
throughout the brain (criterion). Feinberg 65 quoted
an interesting Sherrington's address: "Where it is a question of mind the
nervous system does not integrate itself by centralization upon one pontifical
cell".
Tests
Establishing a reliable
system to measure the irreversible loss of consciousness is very difficult. The
already difficult physiologic proof of loss of consciousness is compounded by
the philosophic complexity of assessing the subjective dimension of consciousness.
60,65
Most sets of brain
cessation tests require evidence of unresponsiveness. This is mainly measured
by applying painful stimuli. 10,12,131 Reactivity to pain explores the arousal
component of consciousness that endows cognitive and affective functions. 9
The substratum for
consciousness is based on anatomy and physiology throughout the brain. 9,18,47,77 Therefore, sets of criteria should include
tests to evaluate both brainstem and cerebral hemispheres.
Comparing this standard of death,
with whole brain, brainstem, and higher brain views, differences and
similarities can be found.
WHOLE BRAIN VIEW
|
SIMILARITIES |
DIFFERENCE |
|
|
|
· Both views are based on anatomy and
physiology throughout the brain (criterion) · PVS cases are classified as alive |
· In my view, only one function is considered (consciousness) as the hallmark of the definition rather
than all functions of the brain |
||
BRAINSTEM VIEW
|
SIMILARITIES |
DIFFERENCE |
|
|
|
· In both views one of the components of
consciousness is included as a hallmark (capacity for consciousness or
arousal) · PVS cases are classified as alive |
· In the brainstem view, the brainstem is only
considered as the anatomical substratum (criterion). |
||
HIGHER BRAIN
|
SIMILARITIES |
DIFFERENCE |
|
· In both views consciousness is considered as
hallmark for defining death |
· In this view, the neocortex is only
considered as the anatomical substratum (criterion). · PVS cases are classified as dead · My definition identifies consciousness as the
ultimate integrating function · My notion of consciousness as the ultimate
integrative function is more consistent with the biologically-based systems
than the more philosophically-based
notions of personhood |
Persistent vegetative state patients are alive!
The main finding in PVS is the preservation of arousal with an
apparently loss of awareness. 9,78 As has been previously discussed,
according to Kinney, 45 PVS denotes a "locked-out-syndrome", because
the “cerebral cortex is disconnected from the external world”, explained by
three main neuropathological patterns. Can we deny the existence of internal
awareness in PVS, because they apparently seem to be disconnected from the
external world? The subjective dimension of awareness is philosophically
impossible to test. 65
The
Karen Ann Quinlan's brain showed a severe damage of the thalamus, with the
cerebral hemispheres relatively spared. 69 We can ask ourselves if
in a case like this, other activating pathways projecting to the cerebral
cortex without relaying through the thalamus, could stimulate the cerebral
cortex to provide internal awareness, although an apparently disconnection to
the outer world is found by physicians. 9 The use of deep brain
stimulation showed that the cerebral hemispheres could mediate arousal
producing some wakefulness behavior, even after complete loss of the
brainstem's reticular activating system. 82-85 it has been discussed
that there is striking evidence that subcortical structures are capable of
mediating some forms of awareness. 9,45
Therefore,
in PVS cases it is impossible to deny a possible preservation of internal
awareness, because according to the neuropathological pattern, either
subcortical structures could provide internal awareness, or some remaining
activating pathways projecting to the cerebral cortex without relaying through
the thalamus, could stimulate the cerebral cortex. 9 As
consciousness is based on anatomy and physiology throughout the brain, it is impossible
to classify a PVS case as dead, where the brain is damaged, but not fully and
irreversible destroyed.
Some
reports of misdiagnosis or recuperation in PVS have also appeared in recent
literature. Unexpected and well-documented recoveries of cognitive functions
have been described in patients, where it was believed that the criteria were
correctly applied by neurologists experienced and skilled in the diagnosis of
this condition.132, 133 Moreover, it is necessary to consider the
potential reversibility of the awareness in the PVS, as has been reported by
some authors using deep brain stimulation. 82-85 it is crucial to
develop controlled multi-centered studies to test and elaborate new protocols
for sensory and pharmacologic stimulation. 117,132 In fact, the
possibility of brain function restoration in such patients, by actual or still
not developed techniques, are a challenge for the near future. 9
FINAL REMARKS
In
conclusion, I propose a standard of human death that includes consciousness as
the most important function of the body, because it provides the capacity for
integrating the main human attributes with an integrative functioning of the
body. I have emphasized that consciousness does not bear a simple one-to-one
relationship with higher or lower brain structures, because the physical
substratum for consciousness is based on anatomy and physiology throughout the
brain.
I would like to thanks Dr.
Stuart Younger because of his careful reviews and precise suggestions, during
the elaboration of this paper.
REFERENCES
1.
Bernat JL: On the
definition and criterion of death. Ann Int Med 1981;94:389-394.
2.
Bernat JL. Brain
death. Occurs only with destruction of the cerebral hemispheres and the brain stem.
Arch Neurol 1992;49(5):569-570
3.
Bernat JL: The
definition, criterion and statute of death. Seminars in Neurology 1984;
4:45-51.
4.
Bernat JL. How
much of the brain must die in brain death. The Journal Clinical Ethics 1992;
3:21-28.
5.
Bernat JL.
Ethical issues in Neurology. In: Joynt, RJ, ed. Clinical Neurology.
Philadelphia: JB Lippincott Company; 1991:1-105.
6.
Halery A, Brody
B. Brain death: reconciling definitions, criteria and tests. Ann Int Med 1993;
119:519-525.
7.
Bartlett ET,
Youngner SJ. Human death and the destruction of the neocortex. In: Zaner RM,
ed. Death: Beyond the Whole-Brain Criteria. New York: Kluwer Academic
Publisherm; 1988:199-215.
8.
Machado C. Death
on neurological grounds. J Neurosurgical Sciences 1994;38: 209-222.
9.
Machado C. A new
definition of death based on the basic mechanisms of consciousness generation
in human beings. In: Machado C, ed. Brain Death (Proceedings of the Second
International Symposium on Brain Death). Amsterdam: Elsevier Science, BV;
1995:57-66.
10.
Beecher HK. A
definition of irreversible coma: report of the Ad Hoc Committee of the Harvard
Medical School to examine the definition of brain death. JAMA
1968; 205:85-88.
11.
Molinari GF. The NINCDS collaborative study of brain death: a
historical perspective. In: U. S. Department of Health and Human Services,
NINCDS Monograph No. 24 NIH Publication No. 81-2226, 1980:1-32.
12.
Walker AE. An
appraisal of the criteria of cerebral death. A summary statement. A
collaborative study. JAMA 1977; 237:982-986.
13.
Guidelines for
the Determination of Brain Death. Report of the Medical Consultants on the
Diagnosis of Death to the President's Commission for the Study of Ethical
Problems in Medicine and Biomedical and Behavioral Research. JAMA 1981;
246:2184-2186.
14.
President's
Commission for the Study of Ethical Problems in Medicine and Behavioral
Research: Defining Death. Medical Legal and Ethical Issues in the Determination
of Death. Washington, DC: U. S. Government Printing Office; 1981.
15.
Walker A. E.
(Ed.): Cerebral Death. Baltimore: Urban & Schawarzenberg, 1981.
16.
Korein J. The
problem of brain death: Development and history. In: Korein J, ed. Brain Death:
Interrelated Medical and Social Issues. New York: Ann NY Acad Sci, 1977;
315:19-38.
17.
Ingvar DH, Widen
L. Brain death: summary of a symposium. Lakartidningen 1972; 69:3804-3814.
18.
Plum F, Posner
JB. The Diagnosis of Stupor and Coma. Philadelphia: FA Davis Company; 1980.
19.
Black PMcL.
Criteria of brain death. Review and comparison. Postgraduate Medicine 1975;
57:69-74.
20.
Ouaknine G.
Bedside procedures in the diagnosis of brain death. Resuscitation 1975;
4:159-177.
21.
Machado C.
Multimodality evoked potentials and electroretinogaphy in a test battery for an
early diagnosis of brain death. J Neurosurgical Sciences 1993; 37:125-131.
22.
Deliyannakis E,
Loannou F, Davaroukas A. Brain-stem death with persistence of bioelectric
activity of the cerebral hemispheres. Clin Electroencephalograph 1975; 6:75-79.
23.
Ashwal S, Schneider
S. Failure of electroencephalography to diagnose brain death in comatose
patients. Ann Neurol 1979; 6:512-517.
24.
Chatrian G.
electrophysiological evaluation of brain death: a critical appraisal. In:
Aminoff MJ, ed. Electrodiagnosis in Clinical Neurology. New York: Churchill
Livingstone, 1986:669-736.
25.
Truog RD. Is it
time to abandon brain death? Hasting Center Report 1997;27:29-37.
26.
Howlett TA, Keogh
AM, Perry L, et al. Anterior and posterior pituitary function in
brain-stem-dead donors. A possible role for hormonal replacement therapy.
Transplantation 1989; 47:828-834.
27.
Fiser DH, Jimenez
JF, Wrape V, et al. Diabetes insipidus in children with brain death. Crit Care
Med 1987; 15:551-553.
28.
Pallis C.
Brainstem death. In: Braakman R, ed. Handbook of Clinical Neurology: Head
Injury. Amsterdam:Elsevier Science Publisher BV, 1990: 13 (57): 441-496.
29.
Pallis C.
Death-Beyond the whole-brain criteria. J Neurol Neurosurg Psychiatry 1989;
52:1023-1024.
30.
Pallis C,
Maggillivray B. Brain death and the EEG. Lancet 1980; 2:1085-1086.
31.
Pallis C, Prior
PF. Guidelines for the determination of death. Neurology 1983; 33:251-252.
32.
Pallis C.
Whole-brain reconsidered - physiological facts and philosophy. J Medical Ethics
1983; 9:32-37.
33.
Conference of Royal
Colleges and Faculties of the United Kingdom: Diagnosis of brain death. Lancet
1976; 2:1069-1070.
34.
Conference of
Royal Colleges and their Faculties of the United Kingdom: Memorandum on the
diagnosis of brain death. Br Med J 1979; 1:322.
35.
Jennett B. Brain
death (Editorial). Br J Anaesth 1981; 53:1111-1119.
36.
Jennett B,
Hessett C. Brain death in Britain as reflected in renal donors. Br Med J 1981;
283:359-362.
37.
Shewmon A.
Recovery from “brain death”: a neurologist’s apologia. Linacre Quartely 1997;
pp:30-96.
38.
Veatch RM. The
definition of death: ethical, philosophical, and policy confusion. In: Korein
J, ed. Brain Death: Interrelated Medical and Social Issues. New York: Ann NY
Acad Sci 1977; 315:307-317.
39.
Veatch RM, ed.
Death, dying, and the biological revolution. Our last responsibility. New
Haven: Yale University Press; 1989.
40.
Veatch RM. Brain
death: welcome definition… or dangerous judgment? Hasting Center Report 1972;
11:10-13.
41.
Truog RD, Flacker
JC. Rethinking brain death. Critical Care Medicine 1992; 20:1705-1713.
42.
Cranford RE,
Smith DR. Consciousness: the most critical moral (constitutional) standard for
human personhood. American Journal of Law and Medicine 1990; 332:669-674.
43.
Youngner SJ,
Bartlett ET. Human death and high technology: the failure of the whole-brain
formulations. Ann Intern Med
1983;99:252-258.
44.
Green, MB,
Wikler, D. Brain death and personal identity. Philosophy and Public Affairs
1908; 2:105-133.
45.
Kinney, HC,
Samuels, MA. Neuropathology of the persistent vegetative state: A Review. J. Neuropathology
and Experimental Neurology 1994; 53:548-558.
46.
The Multi-Society
Task Force on PVS. Medical aspects of the persistent vegetative state. N Engl J
Med 1994;330:1499-1508.
47.
Plum P. Coma and
related global disturbances of the human conscious state. In: Peters A, ed. Cerebral Cortex, Vol 9. New
York: Plenum Publishing Corporation; 1991:359-425.
48.
Steriade M.
Arousal: revisiting the reticular activating system. Science
1996;272:225-226.
49.
Moruzzi G, Magoun
HW. Brain stem reticular formation and activation of the EEG.
Electroencephalogr Clin Neurophysiol 1949; 1:455-473.
50.
Destexhe A,
Contreras D, Steriade M. Mechanisms underlying the synchronizing action of
corticothalamic feedback through inhibition of thalamic relay cells.
Neurophysiol 1998;79:999-1016.
51.
Steriade M.
Synchronized activities of coupled oscillators in the cerebral cortex and
thalamus at different levels of vigilance. Cereb Cortex 1997;7:583-604.
52.
Amzica F,
Neckelmann D, Steriade M. Instrumental conditioning of fast (20- to 50-Hz)
oscillations in corticothalamic networks. Proc Natl Acad
Sci USA 1997;94:1985-1989.
53.
Contreras D,
Destexhe A, Sejnowski TJ, Steriade M. Control of spatiotemporal coherence of a
thalamic oscillation by corticothalamic feedback. Science 1996;274:771-774
54.
Steriade M,
Contreras D, Amzica F, Timofeev I. Synchronization of fast (30-40 Hz)
spontaneous oscillations in intrathalamic and thalamocortical networks. J
Neurosci 1996;16:2788-2808.
55.
Steriade M.
Arousal: revisiting the reticular activating system. Science
1996;272:225-226.
56.
Steriade M,
Amzica F. Intracortical and corticothalamic coherency of fast spontaneous
oscillations. Proc Natl Acad Sci U S A 1996;93:2533-2538.
57.
Steriade M,
Amzica F, Contreras D. Synchronization of fast (30-40 Hz) spontaneous cortical
rhythms during brain activation. J Neurosci 1996;16:392-417.
58.
Steriade M.
Awakening the brain. Nature 1996;383:24-25.
59.
Contreras D,
Steriade M. Cellular basis of EEG slow rhythms: a study of dynamic
corticothalamic relationships. J Neurosci 1995;15:604-622.
60.
Bogen, JE. Some neurophysiological aspects of consciousness. Seminars in Neurology
1997; 17:95-103.
61.
Kinsbourne, M.
The intralaminar thalamic nuclei: subjectivity pumps or attention-action
coordinators? Consciousness and cognition 1995; 4:167-171.
62.
Villablanca J, Salinas-Ceballos ME. Sleep-wakefulness, EEG and behavioral studies
of chronic cats without the thalamus. The ‘athalamic cat’. Arch Ital Biol
1972;110:383-411.
63.
Mountcastle, VB.
An organization principle for cerebral function: the unit module and the
distributed system. In: Edelman, GM, Mouncastle, VB, eds. The mindful brain.
Cambridge: The MIT Press;1978:7-50.
64.
Goldman-Rakic PS.
Topography of cognition: Parallel distributed networks in primate association
cortex. Ann Rev Neurosci 1988;11:137-156.
65.
Feinberg TE. The
irreducible perspectives of consciousness. Semin Neurol 1997;17:85-93
66.
Singer W, Gray
CM. Visual feature integration and the temporal correlation hypothesis. Annu
Rev Neurosci 1995; 18:555-586.
67.
Schneider H,
Ballowitz L, Schachinger H, Hanefeld F., Droszus JU. Anoxic encephalopathy with predominant involvement of basal
ganglia, brain stem and spinal cord in the perinatal period. Report of seven
newborns. Acta Neurpathol 1975; 32:287-298.
68.
Ingvar, DH, Brun,
A, Johansson, L, Sammuelsson, SM. Survival after severe cerebral anoxia with
destruction of the cerebral cortex: the apallic syndrome. In: Korein J, ed.
Brain Death: Interrelated Medical and Social Issues. New York: Ann NY Acad
Sci;1977,315:184-214.
69.
Kinney HC, Korein
J, Panigraphy A, Dikkes P, Goode R. Neuropathologic findings in the brain of
Karen Ann Quinlan: The role of the thalamus in the persistent vegetative state.
N Engl J Med 1994;330:1469-1475.
70.
Brierley JB,
Adams JH, Graham DI, Simpsom JA. Neocortical death after cardiac arrest. A
clinical, neurophysiological, and neuropathological report of two cases. Lancet 1972;2:560-565.
71.
Villablanca, JR. Independent forebrain and brainstem controls
for arousal and sleep. Behav Brain Sci 1981;4:494-496.
72.
Adams JH, Grahan DI,
Murray LS, Scott G. Diffuse axonal injury due to nonmisile head injury in
humans: An analysis of 45 cases. Ann Neurol 1982; 12:557-563.
73.
Ginsberg MD,
Hedley-Whyte ET, Richardson EP. Hypoxic-ischemic leukoencephalopathy in man.
Arch Neurol 1976;33:5-14.
74.
Carota A,
Pizzolato GP, Gailloud P, et al. A panencephalopathic type of Creutzfeldt-Jakob
disease with selective lesions of the thalamic nuclei in 2 Swiss patients. Clin
Neuropathol 1996;15:125-134.
75.
Squire LR, Moore
RY. Dorsal thalamic lesion in a noted case of human memory dysfunction. Ann
Neurol 1979; 6:503-506.
76.
Guberman A, Stuss
D. The syndrome of bilateral paramedian thalamic infarction. Neurology 1983;
33:540-546.
77.
Shewmon, DA.
“Brain Death”: A valid theme with invalid variations, blurred by semantic ambiguity.
In: Angstwurm H, Carrasco de Paula I, ed. Working Group on The Determination of
Brain Death and its Relationship to Human Death: Vatican City: Pontificia
Academia Scientiarum, 1992; pp:23-51.
78.
Shewmon, DA. The
metaphysics of brain death, persistent vegetative state, and dementia. The
Thomist 1985;49:24-80.
79.
Villablanca JR,
Burgess JW, Olmstead CE, Levine MS. Recovery of function after neonatal or
adult hemispherectomy in cats: I-III. Behav. Brain Res 1986;19:205-226.
80.
Brodal A, ed.
Neurological Anatomy in Relation to Clinical Medicine, 3rd ed, New York: Oxford
University Press;1981:394-447.
81.
Shewmon DA, Holmes GL. Brainstem plasticity in congenitally
decerebrated children. Brain & Devel 1990;12:664.
82.
Hassler R, Dalle
Ore G, Bricolo OA, et al. Behavioral and EEG arousal induced by stimulation of
unspecific projection systems in a patient with post-traumatic apallic
syndrome. Electroencephalogr Clin Neurophysiol 1969; 27:306-310.
83.
Katayama Y, Tsubokawa T, Yamamoto T, et
al. Characterization of brain activity
with deep brain stimulation in patients in a persistent vegetative state:
pain-related late positive component of cerebral evoked potential. Pace
1991;14:116-121.
84.
Sturm V, Kühner
A, Schmitt HP, Assmus H, Stock G. Chronic electrical stimulation of the
thalamic unspecific activating system in a patient with coma due to midbrain
and upper brain stem infarction. Acta Neurochirurgica 1979;47:235-244.
85.
Cohadon F, Richer
E. Stimulation cérébrale profonde chez des patients en état végétatif
post-traumatique. 25 observations. Neurochirurgie 1993;39:281-292.
86.
Austin GM, Grant
FC. Physiologic observations following total hemispherectomy in man. Surgery
1958; 38:239-258.
87.
Bernat JL.
Ethical issues in brain death and multiorgan transplantation. Neurol Clin 1989;
7:715-728
88.
Bernat JL.
Ethical and legal aspects of the emergency management of brain death and organ
retrieval. Emerg Med Clin North Am 1987;5:661-676.
89.
Bernat JL, Culver
CM, Gert B. Definition of death. Ann Intern Med 1984 Mar;100(3):456
90.
Bernat JL, Culver
CM, Gert B. Defining death in theory and practice. Hastings Cent Rep
1982;12(1):5-8.
91.
Bernat JL, Culver
CM, Gert B. Definition of death. Ann Intern Med 1981;95:652
92.
Bernat JL. A
defense of the whole-brain concept of death. Hasting Center Report 1998;28:14-23.
93.
Pallis, C. ABC of
the brain stem death. The arguments about the EEG. Brit Med J 1983;
286:284-287.
94.
Rodin E, Tahir S,
Austin D, Andaya L. Brainstem death. Clin Electroencephalogr 1985; 16:63-71.
95.
Ferbert A, Buchner
H, Ringelstein EB, Hacke W. Isolated brain-tem death. Case report with
demonstration of preserved visual evoked potentials. Electr Clin Neurophsyiol
1986;65:157-160.
96.
Lugo N, Silver P,
Nimkoff L, Caronia C, Sagy M. Diagnosis and management algorithm of acute onset
of central diabetes insipidus in critically ill children. J
Pediatr Endocrinol Metab 1997;10:633-639
97.
Hagl C, Szabo G,
Sebening C, Tochtermann U, Vahl CF, Sonnenberg K, Hagl S. Is the brain death
related endocrine dysfunction an indication for hormonal substitution therapy
in the early period? Eur J Med Res 1997;2:437-440
98.
Outwater, KM,
Rockoff, MA. Diabetes insipidus accompanying brain death in children. Neurology
1984; 34:1243-1246.
99.
Fackler, JC,
Troncoso, JC, Gioia, FR. Age-specific characteristics of brain death in
children. American Journal of Diseases of Childhood 1988; 142:999-1003.
100.
Pallis, C.
Brainstem death: the evolution of the concept. Seminars in Thoracic and
Cardiovascular Surgery 1990; 2:135-152.
101.
Pallis, C.:
Death. Encyclopaedia Britanica. Vol 16. 1986:1030-1042.
102.
Pallis, C.
Death-Beyond the whole-brain criteria. J Neurol Neurosurg Psychiatry 1989;
52:1023-1024.
103.
Lamb D (ed).
Death, brain death and ethics. Australia:Croom Helm Ltd., 1985:1-120.
104.
Shewmon, AD.
"Brain-stem death", "brain death" and death. A Critical
re-evaluation of the purported equivalence. Issues in Law and Medicine (In
press).
105.
Wikler D,
Weisbard AJ. Appropriate confusion over `brain death'. JAMA 1989; 261:2246.
106.
Milhaud A, Riboulot
M, Gayet H. Disconnecting tests and oxygen uptake in the diagnosis of total
brain death. In: Korein J, ed. Brain Death: Interrelated Medical and Social
Issues. New York: Ann NY Acad Sci, 1977; 315:241-251.
107.
Schwarz G,
Lischer G, Pfurtscheller G, et al. Brain death: timing of apnea testing in
primary brain stem lesions. Intensive Care Med 1992; 18:315-316.
108.
Parisi JE, Kim
RC, Collins GH, Hilfinger MF. Brain death with prolonged somatic survival. N
Engl J Med 1982;306:14-16.
109.
Fabro F. Brain
death with prolonged somatic survival (Letter). New Engl Med 1982;306:1361.
110.
Kim RC, Parisi
JE, Collins GH, Hilfinger MF. Brain death with prolonged somatic survival
(Response to letter). New Engl J Med 1982;306:1362-1363.
111.
Wikler D. Who
defines death? Medical, legal and philosophical perspectives. In: Machado C,
ed. Brain Death (Proceedings of the Second International Symposium on Brain
Death). Amsterdam:Elsevier Science, BV;1995:13-22.
112.
Wikler, D. Not
dead, not dying? Ethical categories and the persistent vegetative state.
Hastings Center Rep 1988; 18:41-47.
113.
Puccetti, R. Does
anyone survive neocortical death? In Zaner RM, ed. Death: Beyond Whole-Brain
Criteria. Boston:Kluwer Academic Publishers;1988:75-90.
114.
Veatch RM.
Defining death: the role of brain function. JAMA 1979;242:2001-2002.
115.
Rosenberg, GA,
Johnson, SF, Brenner, RP. Recovery of cognition after prolonged vegetative
state. Ann. Neurol. 1977; 2:167-168.
116.
Steinbock B.
Recovery from persistent vegetative state? The case of Carrie Coons. Hastings Cent
Rep 1989; 19:14-15.
117.
Giacino JT.
Disorders of consciousness: Differential diagnosis and neuropathological
features. Seminars in Neurology 1997;2:105-111.
118.
Cohen-Almagor R.
Some observations on post-coma unawareness patients and on other forms of
unconscious patients: policy proposals. Med Law 1997;16:451-47.
119.
Childs NL, Mercer
WN, Childs HW. Accuracy of diagnosis of persistent vegetative state. Neurology
1993; 43:1465-1467.
120.
Andrews K, Murphy
L, Munday R, Littlewood C. Misdiagnosis of the vegetative state: retrospective
study in a rehabilitation unit. Brit Med J 1996;313:13-16.
121.
Ott B. Defining
and redefining death. Am J Crit Care 1995;4:476-480.
122.
Singer P. Is the
sanctity of life terminally ill? In: Machado C. Brain Death (Proceedings of the
Second International Symposium on Brain Death). Amsterdam: Elsevier Science
BV;1995:231-244.
123.
Botkin JR, Post
SG. Confusion in the determination of death: Distinguishing philosophy from
physiology. Perspectives in Biology and Medicine 1992;36:129-138.
124.
Korein J.
Ontogenesis of the brain in the human organism: definitions of life and death
of the human being and person. In: Edwards RB, Ed. Advances in Bioethics, Vol 2. New York: JAI Press Inc;1997:1-74.
125.
Varela FJ.
Principles of Biological Autonomy. New York: North Holland, 1979.
126.
Swedish Committee
on Defining Death: The concept of death. Summary. Stockholm: Swedish Ministry
of Health and Social Affairs; 1985.
127.
García OD, Machado C,
Román JM, et al. Heart rate
variability in coma and brain death. In: Machado C, ed. Brain Death
(Proceedings of the Second International Symposium on Brain Death). Amsterdam:
Elsevier Science BV, 1995:191-200.
128.
Telles S,
Nagarathna R, Nagendra HR. Autonomic changes during "OM" meditation.
Indian J Physiol Pharmacol 1995;39:418-420.
129.
Schou M. Treating
recurrent affective disorders during and after pregnancy. What can be taken
safely? Drug Saf 1998;18:143-152.
130.
Christie GL. Some
socio-cultural and psychological aspects of infertility. Hum Reprod 1998;
13:232-241.
131.
Machado, C. and
García, A. Guidelines for the determination of brain death. In: Machado C, de. Brain Death (Proceedings of the Second
International Symposium on Brain Death). Amsterdam: Elsevier Science B V,
1995:75-80.
132. Wilson SL, Powell GE, Brock D, Thwaites H.
Vegetative state and responses to sensory stimulation: an analysis of 24 cases.
Brain Inj 1996;10:807-818
133.
Caplan L. Late
improvement after post-traumatic vegetative state. N Engl J Med 1996;
334:1201-1202