10 Brain Failure and Brain Death
He seems to be completely unreceptive
The tests I gave him show no sense at all
His eyes react to light; the dials detect it
He hears but cannot answer to your call
“Go to the Mirror Boy” (from Tommy, The Who, 1969)
Brain failure constitutes a spectrum of central nervous system (CNS) disease manifesting as a variety of neurologic deficits.
Cranial nerves, motor and sensory function, and coordination may be affected depending on the nature and severity of injury;
however, consciousness is invariably affected to some degree in brain failure.
Because consciousness is a subjective phenomenon, objective evaluation of states of consciousness depends on the physical
examination, which allows an observer to make inferences about a patient’s level of consciousness. The critical feature of
the examination of patients with impaired consciousness is evaluation of their response to external stimuli. Based on the
magnitude and complexity of a patient’s response to external stimuli, an examiner may stratify level of consciousness into
one of six categories [see Table 1].4
As is often the case in failure of other organs, brain failure results from severe metabolic disturbances and from lack of
oxygen or blood flow. The brain accounts for 2% of body weight yet enjoys 15% of the cardiac output5 and accounts for 25% of total body glucose use,6 illustrating its relatively high energy demand relative to other organs. Even transient disruptions in glucose and oxygen
supply profoundly affect neuronal and glial cell metabolism and disrupt the normal function of brain cells, causing loss of
normal transmembrane ion gradients.7 As such, the brain is exquisitely sensitive to deprivation of glucose, oxygen, and blood flow and is considerably more liable
to experience permanent damage from disruption of these. This principle is involved in the most common causes of brain failure,
Stroke is the fourth leading cause of death in the United States, affecting almost 800,000 people a year and accounting for
about 135,000 deaths per year.8 About 87% of strokes are ischemic,9 occurring when flow of blood to part of the brain is obstructed. The most frequent causes of neurologic deterioration and
progression to brain failure are symptomatic hemorrhagic transformation of ischemic stroke and cerebral edema.10 Cytotoxic edema invariably develops to a certain degree as infarcted tissue fails to maintain normal ion homeostasis; this
effect typically peaks between 2 and 5 days after infarction.11 A subset of ischemic strokes can be considered “malignant” due to their large infarct volume and subsequently more severe
cerebral edema. These strokes cause rapidly expanding mass effect due to edema and frequently progress to transtentorial herniation
and brainstem damage, with brain death occurring in up to 78% of patients with complete middle cerebral artery infarctions.12
Thirty-day mortality for spontaneous (nontraumatic) intracerebral hemorrhage approaches 50%, with meaningful functional recovery
at 6 months occurring in only 20% of patients with this condition.13 Expansion of the hematoma after initial detection is associated with neurologic deterioration and is present in about 38%
of patients.14 The initial insult and subsequent hematoma expansion lead to acute increases in intracranial pressure, damage to adjacent
brain structures due to direct mechanical compression, and herniation or displacement of brain structures, frequently causing
damage to the brainstem and potentially brain death.15
This type of stroke also has high 30-day mortality: about 30%, with an estimated 12 to 15% dying before presenting to medical
care.16 Complications resulting in further brain injury are common; the most feared and lethal of these is aneurysm rerupture or
rebleeding.17 Other potentially lethal complications include obstructive hydrocephalus and cerebral vasospasm, in which narrowing of the
large cerebral arteries occurs days after the initial insult in 20 to 30% of patients and can result in widespread cerebral
ischemia and infarction, which represents the major cause of brain failure and death in these patients.18
About 500,000 new cases of traumatic brain injury occur in the United States each year.19 This is a heterogeneous disease that causes primary and secondary brain injury through a wide variety of mechanisms. Physical
disruption of the brain parenchyma and vasculature by mechanical forces constitutes the primary injury. Delayed or secondary
injury can occur through metabolic sequelae, including neuronal excitotoxicity, lipid peroxidation, and free radical formation.
Cytotoxic and inflammatory cascades represent another source of injury as mitochondrial dysfunction, apoptosis, and necrotic
cell death occur.20 As in the vascular forms of injury discussed above, elevated intracranial pressure, edema, and herniation represent a major
cause of brain failure and brain death.
A variety of toxic and systemic metabolic disturbances can cause brain failure. Prominent among these is renal failure, in
which uremic encephalopathy can cause simultaneous diffuse CNS depression with impairment of consciousness and simultaneous
hyperexcitable states that increase the potential for epileptic seizures.21 Fulminant hepatic failure is a potentially deadlier metabolic disturbance that is associated with hyperammonemia, metabolic
encephalopathy, and coagulopathy, which can cause intracerebral hemorrhage. Hyperammonemia and a variety of other chemical
changes cause cerebral edema in 80% of patients with acute hepatic failure in coma, and this edema and its sequelae are the
major cause of brain death in these patients.22
In a substantial proportion of unconscious patients admitted to the intensive care unit (ICU), brain failure resulted from
metabolic and hemodynamic deteriorations that followed cardiac arrest.23 There is a great difference between surviving cardiopulmonary resuscitation (CPR) and walking out of the hospital unaided
after such an event. It is relatively easy to restart the heart with traditional CPR; it is considerably harder to restart
the brain.24 After several minutes of cardiac arrest, CPR will occasionally restore cardiac activity but will not necessarily restore
useful brain function. Brain metabolism requires a constant high flow of oxygenated blood and nutrients. During cardiac resuscitation,
cerebral perfusion decreases sufficiently to promote hypoxia and tissue edema. A number of mechanisms have been shown to underlie
deteriorating and failed reflow. Hyperviscosity from hemoconcentration of plasma proteins and formed elements contributes
to initial poor reperfusion at the capillary level. Endothelial cell swelling and edema of the pericapillary astrocytes also
greatly inhibit reperfusion by reducing capillary diameter to less than 5 µm.
During reperfusion, abnormally high amounts of superoxide convert almost all available nitric oxide to peroxynitrite, which
is regarded as the agent that causes most of the damage to brain capillary endothelial cells in reperfusion injury.25 The resultant damage to the endothelium not only induces vasogenic edema (tissue swelling resulting from leakiness) but also
causes endothelial protrusions (blebs) that can block capillaries. Calcium-mediated vasospasm also plays a role. L-type calcium
channel blockers, given before the insult, have been shown to prevent the no-reflow phenomenon in dogs and to result in an
80% survival rate (compared with an 86% mortality in the control group).26
During CPR, cerebral perfusion tends to decrease dramatically over time if adequate flow is not quickly reestablished.27 Maintaining a small amount of blood flow to the brain with CPR is not necessarily beneficial. Incomplete brain ischemia,
which is created when only a small amount of blood is allowed into the brain after an anoxic insult (as in CPR), appears to
result in more detrimental alterations in brain metabolism than does the complete anoxia resulting from the absence of any
flow.28 When a small amount of blood is allowed to flow into an actively distorted and stressed metabolic system, the resulting cellular
activity generates more toxic products of metabolism than complete anoxia would have produced.29 In other words, more brain damage seems to occur with prolonged CPR states than with no-flow states30—especially if there is an increased level of glucose in the small quantities of blood supplied by CPR.31 To date, this phenomenon has not been completely explained. Acidosis, in and of itself, is unlikely to be the only damaging
factor, because severe respiratory acidosis alone does not damage the brain.32
In vitro, CNS neurons can tolerate between 20 and 60 minutes of complete ischemic anoxia without irreversible injury.33 In vivo, however, injury occurs after a much shorter time and is much more severe. Immediately after the cessation of circulation
to the brain, the cerebral vessels dilate in response to the local environmental factors and to increased arterial carbon
dioxide tension. Because the brain has no significant reserve stores of glucose, cellular metabolism quickly ceases. Absence
of nutrients and hypoxia cause the most sensitive structures to lose their cellular integrity quickly. This change results
in capillary leakage, edema, and cellular disruption and leads to the release of proteases and other damaging compounds into
the surrounding tissues.34
These events, in turn, result in clogged microcirculation, stasis, and a vicious circle of worsening damage that backs up
into the macrocirculation. If this process is allowed to continue for a substantial period and blood flow is then reestablished,
the increased pressure gradient in the damaged area tends to disrupt the fragile architecture, much as the sudden bursting
of a dam might do to downstream communities. The result is a progressive postresuscitative hypoperfusion state in which blood
flow falls to less than 20% of normal within 90 minutes after reperfusion and remains at this low level for as long as 18
Two explanations for these phenomena have been proposed. The first is that massive overloading of the cells with calcium ions
(Ca2+) may be the initial stage of irreversible damage.37 Normally, the extracellular level of Ca2+ is high and the intracellular level is low. The damage to the cell membrane caused by hypoxia and loss of nutrient flow alters
the gradient and allows Ca2+ to enter the cell, causing interference with enzymes, DNA, RNA, mitochondria, and energy production cycles. Infusion of high
levels of Ca2+ into precapillary arterioles causes vasospasm and a vicious circle characterized by decreased flow and further depletion
of oxygen and nutrients. The second theory is that during ischemia, abnormal metabolism may result in the creation of reactive
oxygen metabolites, which attack DNA, RNA, and mitochondria, causing irreversible damage.38
Because the brain is the control center for the endocrine and autonomic nervous systems, brain failure inevitably causes diffuse
dysregulation of several organ systems, which can subsequently result in somatic death if left untreated.
After the completion of brain failure (brain death), cardiac contractility is markedly impaired. This has been attributed
to the catecholamine surge that accompanies the sympathetic storm, and animal models suggest that cardiac sympathectomy can
prevent subsequent excitotoxic changes to the myocardium, cardiac conduction system, and coronary arteries.40,41 Other animal models have demonstrated that the degree of catecholamine release and myocardial injury is dependent on the
rate of increase of intracranial pressure during a herniation event.42,43
Neurogenic pulmonary edema is a form of noncardiogenic pulmonary edema that can occur in brain failure and spinal cord injury.
There is evidence that elevated intracranial pressure correlates with extravascular lung water, and similarly to cardiac injury
after brain death, increases in the activity of the sympathetic nervous system have been implicated as the cause.44 Animal models have likewise shown attenuation of neurogenic pulmonary edema by sympathectomy (via removal and reimplantation
of a lung).45
The pathogenesis of neurogenic pulmonary edema is not clear. One theory holds that it is commonly caused by cardiac hypokinesis
and direct myocardial injury from the catecholamine surge described above.46 The “neurohemodynamic” theory posits that sudden increases in systemic vascular resistance in brain injury cause shunting
of blood to the lower resistance pulmonary circuit, resulting in pulmonary fluid extravasation through alterations in Starling
forces.47 However, the presence of red blood cells and exudative levels of protein in the edema suggest endothelial damage in the pulmonary-alveolar
capillaries, leading to the “blast theory,” which ascribes neurogenic pulmonary edema to both the sudden hemostatic changes
and capillary endothelial injury.48 The underlying root cause of injury in all cases is related to autonomic dysfunction and excess of catecholamines that frequently
accompany brain failure. These changes can generally be prevented with alpha-adrenergic blockade.49
By far, the most common forms of pulmonary complication that accompany brain failure are those related to aspiration, pulmonary
infection, and ventilator-associated barotrauma.39 These are not necessarily directly caused by brain failure per se but are sequelae of the severe impairment of consciousness
associated with brain failure.
The most common endocrinologic disturbance in brain failure is diabetes insipidus (DI), occurring in up to 80% of brain-dead
patients.50 If not treated appropriately, DI can cause severe electrolyte disturbances and hypovolemia, which, when paired with the decrease
in vascular tone due to the absence of vasopressin, can lead to circulatory collapse.51
In contrast to posterior pituitary function, which is severely impaired in brain failure and death, anterior pituitary function
is often relatively preserved. The most commonly seen abnormality is low levels of circulating triiodothyronine thyroid hormone,
with changes in thyroxine and thyroid-stimulating hormone consistent with the “euthyroid sick syndrome” commonly seen in other
severe illnesses.52 Most patients with brain death have relatively normal levels of serum adrenocorticotropic hormone, cortisol, and growth hormone,
presumably due to preserved perfusion or function of parts of the hypothalamic-pituitary axis, even though the rest of the
brain has shut down.39 For cases of brain-dead patients destined for organ donation, the evidence for aggressive repletion of these hormonal deficiencies
(other than treating DI) is mixed.
Brain injury provokes a proinflammatory milieu in the rest of the body, even prior to progressing to brain failure or brain
death.53 Even with an intact blood-brain barrier (BBB), brain injury is associated with the systemic inflammatory response syndrome
(SIRS), which itself is responsible for activation and recruitment of peripheral leukocytes in multiple visceral organs, systemic
release of inflammatory cytokines (such as tumor necrosis factor–α [TNF-α], interleukin-1β [IL-1β], IL-4, and IL-6), vascular
permeability, and formation of reactive oxygen species.54 Increased expression of TNF-α and IL-6 has been linked to myocardial damage in donated hearts harvested after brain death.55 The specific cytokines and degree of cellular infiltrate after brain death vary widely between different visceral organs,
which may in turn explain differing success rates for different organ types harvested after brain death.56
This problem is compounded if the BBB is disrupted during the course of brain failure, in which case, cytokines derived directly
from brain tissue are able to interact with tissues at the systemic level and cause further damage. The systemic changes in
inflammatory molecules that occur in brain death combine to cause organs donated after brain death to be more immunologically
active, which may account for a lower graft survival rate when compared with organs harvested from non–brain-dead donors.57
Brain death as a formalized concept began to solidify after a seminal report by an ad hoc committee at the Harvard Medical
School in 1968 listed the key features of irreversible coma, namely, unresponsiveness, absent motor and respiratory response,
absent cranial and deep tendon reflexes, and a flat electroencephalogram.58 Since the Harvard criteria were established, understanding and description of brain death have continued to evolve, with
the federal government making attempts to codify universal criteria for death.
Initially, for an accurate diagnosis of brain death, there must be clear evidence of a catastrophic and irreversible brain
injury, and any reversible conditions that may obfuscate the clinical assessment (e.g., drug intoxication, hypothermia, and
metabolic abnormalities) must be excluded.59 Subsequently, the physical examination must show coma, absent motor responses, absent brainstem reflexes, and apnea. Some
protocols call for a second examination, performed after a variable interval.60 Further confirmatory studies (e.g., electroencephalography or cerebral blood flow studies) may be ordered if there is any
ambiguity in the clinical evaluation or certain required elements cannot be perfomed.61 In clinical practice, because US law states that diagnosis of brain death is subject to the expertise of the medical examiner,
protocols vary slightly from state to state and even within health care systems in the same state.
The American Academy of Neurology practice parameter for diagnosis of brain death, as an example of a widely used diagnosis
protocol, is summarized here [see Table 2].62,63
The evolution of life support systems capable of prolonging vital signs indefinitely necessitated a more accurate definition
of death, which arrived in 1968 as the Harvard criteria.64 In essence, these criteria considered the irreversible loss of certain organ functions, rather than whole body metabolic
cessation, to be indicative of death. When the Harvard criteria were met, death was inevitable, even with continuing organ
system–supporting treatment. A 1970 study found that all patients studied met the Harvard criteria. All eventually died while
undergoing continued medical treatment.65 The Harvard criteria objectified the progression of disease, thereby making it possible for clinicians to predict inevitable
These early studies, however, only predicted with a reasonable certainty that patients meeting particular criteria would eventually
die. A prognosis of death cannot necessarily serve as a diagnosis. In 1981, the President’s Commission established brain death
as a stand-alone criterion for determining death, not simply for predicting its inevitability.66 The Uniform Determination of Death Act (UDDA) made brain death an acceptable criterion for death in 44 states.67 These rules state that an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions
or (2) irreversible cessation of all functions of the entire brain, including the brainstem, is dead, and a death certificate
may be filled out. Under the UDDA, death is pronounced at the time the criteria are met, and families may not demand continuing
mechanical ventilation or other forms of ICU life support (except in the states of New York and New Jersey, both of which
have conscience clauses).68
The age of critical care medicine has changed the traditional concept of death. Before the postmodern technological revolution,
determination of death was simple. A person was dead when a physician said he or she was dead. The exact moment of death did
not matter in the general scheme of things because no postmortem treatment was anticipated. However, in the new millennium,
organ transplantation has changed things radically. Intensive care life support systems can create situations in which patients
are dead enough to bury, but their internal organs are alive enough to recover for transplantation.
The traditional definition of death is generally accepted as “the irreversible cessation of the integrated functioning of
the organism as a whole.”69 For practical purposes, this means that the organism dies when the central integrator of organ systems (the brain) dies.
Every cell within the organism does not need to be dead for the organism to be pronounced dead, only the organ of integration.
Without this definition, organ transplantation would be impossible because putrefaction would be the only benchmark of death.70
However, the clinical reality is that the brain dies in a progressive fashion, not instantaneously. Therefore, it is improbable
that the precise point at which “death” occurs is discernible. As Michael Darwin has written, “It is only the ideologue or
the fool who acknowledges noon and midnight, but denies all the states of light and darkness that smoothly shade together
to create day and night.”71 For example, we have arbitrarily decided the exact point at which a person becomes intoxicated and legally incompetent to
operate an automobile. But selecting a particular blood alcohol level does not absolutely define drunkenness any more than
a physician pronouncing death absolutely defines the exact point of death.
Resuscitative technology muddies these waters by creating more uncertainty in the determination of death. Consider the following:
in the United States, about 150 legally dead people are suspended in liquid nitrogen, awaiting a nanotechnology that will
repair their fatal disease and restore them to life.72 The practice of cryopreserving people immediately after they have been pronounced medicolegally dead is called “cryonics.”
A physician will pronounce a patient using the usual cardiorespiratory criteria, whereupon the patient is legally dead. Following
this pronouncement, the rules pertaining to procedures that can be performed change radically because the individual is no
longer a living patient but a corpse. In the initial cryopreservation protocol, the subject is intubated and mechanically
ventilated, and a highly efficient mechanical cardiopulmonary resuscitation device reestablishes circulation. In some cases,
the subject begins to show “signs of life,” including pupillary reaction and spontaneous motion.73 This raises crucial questions. Are such persons alive again, or were these subjects ever really dead?
The issue of determining death becomes further confused by a creative interpretation of the UDDA, which, ironically, was drafted
with the intent to clarify the issue. The UDDA guidelines declare that either “irreversible cessation of circulatory functions”
or “irreversible cessation of the entire brain, including brain stem,” constitutes death.67 The guidelines do not elucidate how these two standards reflect the same phenomenon. The wording suggests that there are
two kinds of death: brain and cardiac. This lack of a consistent standard and the intense demand for donor organs for transplantation
have promoted the evolution of a creative variation of organ procurement known as donation after cardiac death (DCD), which
relies solely on the cessation of cardiorespiratory function without reference to brain death.
This creative dichotomy is controversial. At a strictly functional level, it can be argued that the heart is irrelevant to
the diagnosis of life or death because it fails the test of integration. The heart’s only purpose is to pump blood to the
brain, generally considered the integrator of the rest of the body. If cardiac standstill constitutes death, a patient with
a stilled heart during cardiopulmonary bypass is dead. Alternatively, a patient is not alive when a viable heart beats inside
a brain-dead body. Sweet stated in the New England Journal of Medicine: “It is clear that a person is not dead unless his brain is dead. The time honored criteria of the stoppage of the heart
beat and circulation are indicative of death only when they persist long enough for the brain to die.”74
In addition, brain death is defined in terms of irreversibility. Given that the point of irreversibility is not known at the
time death is declared, the exact time of death is not known. So a patient may still be “alive” by the strict rules even though
showing no demonstrable signs of life; if the brain is still functional, the strict rule of death is not met. It does not
matter if there is no intent to resuscitate. A patient or his or her family cannot consent to any procedure that will result
in death, nor can the family consent to the patient being dead in a defined number of minutes, as has been suggested by proponents
of DCD. To do so is tantamount to consenting to euthanasia. A primary problem with the determination of death is the inability
to establish precisely when it transitions from a reversible process to an irreversible event.
Despite the UDDA’s requirement that death must be irreversible, it failed to define the term, and several ideological caucuses
have developed, each with its own perspective. One caucus says that death is irreversible when the patient cannot “spontaneously”
resuscitate. But if that is true, how long does one have to wait to be sure that autoresuscitation will not occur? Long enough
for the death of a quorum of cells? Another caucus says that death is irreversible when the patient cannot be resuscitated
by any means or when resuscitation fails. Does this mean that every dying patient must be assaulted by every possible intervention
if he or she is to be proven dead?
A third caucus says that irreversibility occurs when the inherent order of the atoms that make up the brain is irrevocably
destroyed. If, however, the structural integrity of the brain is preserved, there is no fundamental barrier, given our current
understanding of physical law, to recovering its information content, however labor intensive that might be. If brain ultrastructure
is physically destroyed, the laws of thermodynamics dictate that the information contained therein is irreversibly destroyed.
With that consideration of irreversibility in mind, is a tobacco mosaic virus “dead” if its constituent parts can be broken
up and shaken into solution and then self-assemble again into a viable virus capable of self-replication?
There are disturbing differences between a corpse in a morgue and a brain-dead patient. If the whole brain death (WBD) patient
is a corpse, he or she is certainly a corpse with some unusual properties—one that breathes, circulates blood, digests food,
filters wastes, and is capable of carrying a pregnancy to term.75 These considerations raise the issue of whether there is a practical or an ethical difference between being dead, being almost
dead, or being in the process of dying and show that the precise moment when death occurs cannot be accurately pinpointed.
It is clear that a WBD patient can be maintained on life-sustaining treatment for much longer than was once thought and still
retain definite characteristics of a living being. The organism as a whole, although disabled, is not yet dead and should
not be represented as such—a fact that may have important consequences for our future conceptions of death and of life in
Financial Disclosures: Robert Hendry, MD, and David Crippen, MD, FCCM, have no relevant financial relationships to disclose.
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Figures 1 and 2 Christine Kenney