1. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 12 BRAIN FAILURE AND BRAIN DEATH — 1
12 BRAIN FAILURE AND BRAIN DEATH
David Crippen, M.D., F.C.C.M.
He seems to be completely unreceptive function is helpful in assessing the effect of therapy on neuronal
The tests I gave him show no sense at all function.
His eyes react to light; the dials detect it
He hears but cannot answer to your call RELATION OF CARDIAC ARREST TO BRAIN FAILURE
“Go to the Mirror Boy” (from Tommy, The Who, 1969)
In a substantial proportion of unconscious patients admitted to
the intensive care unit, the brain failure resulted from metabolic
Brain Failure and hemodynamic deteriorations that followed cardiac arrest.4
There is a great difference between surviving cardiopulmonary
BRAIN FAILURE AND IMPAIRMENT OF CONSCIOUSNESS resuscitation (CPR) and walking out of the hospital unaided after
As a type of organ system failure, brain failure invariably affects such an event. It is relatively easy to restart the heart with tradi-
consciousness. Consciousness is structurally produced in the cere- tional CPR; it is considerably harder to restart the brain.5 After
bral hemispheres, including the pons and the medulla.1 These several minutes of cardiac arrest, CPR will occasionally restore
structures are all interconnected by the reticular formation, which cardiac activity, but it will not necessarily restore useful brain func-
begins in the medulla and extends to the midbrain, where it forms tion. Brain metabolism requires a constant high flow of oxygenat-
the reticular activating system. This pathway modulates the per- ed blood and nutrients. During cardiac resuscitation, cerebral per-
ception of events and controls integrated responses.2 fusion decreases sufficiently to promote hypoxia and tissue edema.
Clinical evaluation of consciousness states is heavily dependent A number of mechanisms have been shown to underlie deteriorat-
on the findings from physical examination. When the physical ing and failed reflow. Hyperviscosity from hemoconcentration of
examination yields visual and palpable clues to the integrity of plasma proteins and formed elements contributes to initial poor
consciousness, impairment thereof may be classified into one of reperfusion at the capillary level. Endothelial cell swelling and
the following categories3: edema of the pericapillary astrocytes also greatly inhibit reperfu-
sion by reducing capillary diameter to less than 5 μm.
1. Cloudy consciousness.This state is defined as a mild deficit in
the speed of information processing by the brain, resulting During reperfusion, abnormally high amounts of superoxide
from disruption of cell-to-cell connectivity at the histologic convert almost all available nitric oxide to peroxynitrite, which is
level. Cloudy consciousness may be noted after mild to mod- regarded as the agent that causes most of the damage to brain cap-
erate head trauma and may persist for several months. illary endothelial cells.6 As noted (see above), damage to the
Memory of recent events is often diminished, but long-term endothelium not only increases edema (tissue swelling resulting
memory typically remains intact. from leakiness) but also causes endothelial protrusions (blebs)
2. Lethargy.This state is defined as a decrease in alertness, result- that can block capillaries. Calcium-mediated vasospasm also plays
ing in impaired ability to perform tasks that are normally a role. L-type calcium channel blockers, given before the insult,
accomplished without effort. Patients rouse briefly in response have been shown to prevent the no-reflow phenomenon in dogs
to stimuli, then settle back into inactivity when left alone.They and to result in an 80% survival rate (compared with an 86% mor-
retain awareness of their immediate environment. tality in the control group).7
3. Obtundation. This state is defined as a decrease in awareness During CPR, cerebral perfusion tends to decrease dramatically
and alertness, in which patients rouse briefly in response to over time if adequate flow is not quickly reestablished.8
stimuli and follow simple commands but are unaware of their Maintaining a small amount of blood flow to the brain with CPR
immediate surroundings. When stimulation ceases, they settle is not necessarily beneficial. Incomplete brain ischemia, which is
back into inactivity. created when only a small amount of blood is allowed into the
4. Stupor. In this state, patients cannot communicate clearly but brain after an anoxic insult (as in CPR), appears to result in more
can be aroused by continued painful stimulation. Arousal may detrimental alterations in brain metabolism than does the com-
be manifested only as withdrawal from painful stimuli. As soon plete anoxia resulting from the absence of any flow.9 When a small
as stimuli are removed, patients settle back into inactivity. amount of blood is allowed to flow into an actively distorted and
5. Coma. In this state, patients do not respond to even the most stressed metabolic system, the resulting cellular activity generates
vigorous stimuli. more toxic products of metabolism than complete anoxia would
6. Brain death.This state is equivalent to functional decapitation have produced.10 In other words, more brain damage seems to
and is characterized by irreversible cessation of whole brain occur with prolonged CPR states than with no-flow states11—
function and function of the hemispheres and the brain stem. especially if there is an increased level of glucose in the small quan-
It should be kept in mind that the efficacy of the physical exami- tities of blood supplied by CPR.12 To date, this phenomenon has
nation in the evaluation of consciousness diminishes when visual not been completely explained. Acidosis, in and of itself, is unlike-
clues disappear (e.g., during heavy sedation or therapeutic muscu- ly to be the only damaging factor, because severe respiratory aci-
loskeletal paralysis). In such situations, monitoring of cerebral dosis does not damage the brain.13

2. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 12 BRAIN FAILURE AND BRAIN DEATH — 2
PATHOPHYSIOLOGY OF BRAIN FAILURE 6. Test for the oculocephalogyric reflex (the doll’s head reflex).
In vitro, central nervous system neurons can tolerate between 7. Test for the vestibulo-ocular reflex (the caloric test).
20 and 60 minutes of complete ischemic anoxia without irre- 8. Test for upper and lower airway stimulation (e.g., pharyngeal
versible injury.14 In vivo, however, injury occurs after a much and endotracheal suction).
shorter time and is much more severe. Immediately after the ces- 9. Test for the gag reflex.
sation of circulation to the brain, the cerebral vessels dilate in 10. Perform the apnea test. This test should be the last test and
response to the local environmental factors and to increased arte- should be conducted after two clinical examinations (separat-
rial carbon dioxide tension (PaCO2). Because the brain has no ed by the mandatory observation period) have confirmed the
stores of glucose, cellular metabolism quickly ceases. Absence of absence of brain stem functions. The patient is disconnected
nutrients and hypoxia cause the most sensitive structures to lose from the ventilator while oxygenation of the lungs is contin-
their cellular integrity.This loss results in capillary leakage, edema, ued passively. On the basis of calculation (whereby PaCO2 is
and cellular disruption and leads to the release of proteases and assumed to rise 4 mm Hg in the first minute and 3 mm Hg
other damaging compounds into the surrounding tissues.15 every minute thereafter), the patient is allowed to build up to
These events, in turn, result in clogged microcirculation, stasis, a PaCO2 of 60 mm Hg or more without becoming hypoxic.
and a vicious circle of worsening damage that backs up into the If there is no respiratory effort, the apnea test is considered
macrocirculation. If this process is allowed to continue for a sub- confirmatory.24
stantial period and blood flow is then reestablished, the increased 11. Consider ordering an EEG. The EEG should show electro-
pressure gradient in the damaged area tends to disrupt the fragile cerebral silence for at least 30 minutes and must conform to
architecture, much as the sudden bursting of a dam might do to established criteria for brain death.25
downstream communities. The result is a progressive postresusci- 12. If the cause of death cannot be determined with absolute
tative hypoperfusion state in which blood flow falls to less than accuracy, consider cerebral angiography. The absence of in-
20% of normal within 90 minutes after reperfusion and remains tracranial arterial circulation, as demonstrated by four-vessel
at this low level for as long as 18 hours.16,17 angiography, confirms brain death.26
Two explanations for these phenomena have been proposed.
The first is that massive overloading of the cells with calcium ions THE NEW MEANING OF DEATH
(Ca2+) may be the initial stage of irreversible damage.18 Normally, The evolution of life support systems capable of prolonging
the extracellular level of Ca2+ is high and the intracellular level is vital signs indefinitely necessitated a more accurate definition of
low.The damage to the cell membrane caused by hypoxia and loss death, which arrived in 1968 in the form of the Harvard criteria.27
of nutrient flow alters the gradient and allows Ca2+ to enter the In essence, these criteria considered the irreversible loss of certain
cell, causing interference with enzymes, DNA, RNA, mitochon- organ functions, rather than whole body metabolic cessation, to be
dria, and energy production cycles. Infusion of high levels of Ca2+ indicative of death.When the Harvard criteria were met, death was
into precapillary arterioles causes vasospasm and a vicious circle inevitable, even with continuing treatment. In a 1970 study in
characterized by decreased flow and further depletion of oxygen which all of the subjects met the Harvard criteria, all of the
and nutrients. The second theory is that during ischemia, abnor- patients eventually died while undergoing continued medical
mal metabolism may result in the creation of reactive oxygen treatment.28 The Harvard criteria objectified the progression of
metabolites, which attack DNA, RNA, and mitochondria, causing disease, thereby making it possible for clinicians to predict
irreversible damage.19 inevitable death.
These early studies, however, only predicted with a reasonable
Brain Death certainty that patients meeting particular criteria would eventual-
ly die. A prognosis of death cannot necessarily serve as a diagno-
DIAGNOSIS OF BRAIN DEATH
sis. In 1981, the President’s Commission established brain death
as a stand-alone criterion for determining death, not simply for
Brain death protocols have evolved to become highly specific predicting its inevitability.29 The Uniform Determination of Death
and sensitive.20 Brain death is a diagnosis of what is, not what Act (UDDA) made brain death a criterion for death in 44 states.30
might be. Initially, for an accurate diagnosis of brain death, there This act states that an individual who has sustained either (1) irre-
must be clear evidence of an acute, catastrophic, irreversible brain versible cessation of circulatory and respiratory functions or (2)
injury, and any reversible conditions that may obfuscate the clini- irreversible cessation of all functions of the entire brain, including
cal assessment (e.g., drug intoxication, hypothermia, and metabol- the brain stem, is dead and that a death certificate may then be
ic abnormalities) must be excluded.21 Subsequently, the physical filled out. Under the UDDA, death is pronounced at the time the
examination must show coma, absent motor responses, absent criteria are met, and families may not demand continuing
brain stem reflexes, and apnea. Some protocols call for a second mechanical ventilation or other forms of ICU life support (except
examination, performed after a variable interval.22 Further confir- in the states of New York and New Jersey, both of which have con-
matory studies (e.g., electroencephalography [EEG] or cerebral
science clauses).31
blood flow studies) may be ordered if there is any ambiguity in the
clinical evaluation.23 TECHNOLOGY AND DETERMINATION OF DEATH
A typical brain death protocol may be summarized as follows:
The age of critical care medicine has changed the traditional
1. Confirm that the patient is in a coma. concept of death. Before the postmodern technological revolu-
2. Evaluate the patient for seizure activity and decerebrate or tion, determination of death was simple: a person was dead when
decorticate movements. a physician said so.The exact moment of death did not matter in
3. Test for motor response to painful stimulation. the general scheme of things, because there was no postmortem
4. Test for pupillary response to light. treatment. In the new millennium, however, organ transplanta-
5. Test for the corneal reflex. tion has changed the situation radically. Intensive care life support

3. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 12 BRAIN FAILURE AND BRAIN DEATH — 3
systems can now create scenarios in which patients are dead ly on the cessation of cardiorespiratory function, without reference
enough for burial yet alive enough for recovery of viable organs to brain death.
for transplantation.32 This creative dichotomy between brain death and cardiac death
The traditionally accepted definition of death may be is controversial. At a strictly functional level, it can be argued that
expressed as “the irreversible cessation of the integrated function- the heart is irrelevant to the diagnosis of life or death because it
ing of the organism as a whole.”33 For practical purposes, this fails the test of integration. The heart’s only purpose is to pump
means that the organism dies when the central integrator of blood to the brain, which is the organ generally considered to be
organ systems (i.e., the brain) reaches the point of functional irre- the integrator of the rest of the body. If cardiac standstill, in and
versibility (not necessarily cellular death). For the organism to be of itself, constitutes death, then a patient whose heart is stilled
pronounced dead, it is not necessary that each and every cell during cardiopulmonary bypass is dead. Moreover, it is widely
within the organism be dead: it is only necessary that the integrat- agreed that a patient who has a viable heart beating inside a brain-
ing organ function be irreversibly damaged. If the definition of dead body is not alive. As W. H. Sweet stated three decades ago,
death required that every single cell be dead, organ transplanta- “It is clear that a person is not dead unless his brain is dead. The
tion would be impossible because putrefaction would be the only time honored criteria of the stoppage of the heart beat and circu-
benchmark of death.34 lation are indicative of death only when they persist long enough
At first glance, this definition of death would seem clear and for the brain to die.”40
unambiguous, but the clinical reality is that the brain dies in a pro- As noted (see above), brain death is defined in terms of irre-
gressive fashion, not instantaneously. Consequently, it is improb- versibility. A primary problem with the determination of death
able that one will be able to discern the precise point at which according to UDDA guidelines is the inability to establish precise-
death occurs. As Michael Darwin has written, “It is only the ide- ly when it transitions from a reversible process to an irreversible
ologue or the fool who acknowledges noon and midnight, but event. Because the point of irreversibility is not known at the time
denies all the states of light and darkness that smoothly shade death is declared, the exact time of death cannot be determined.
together to create day and night.”35 As an analogy, we have arbi- Consequently, by a strict interpretation of the criteria, a patient
trarily decided on (and legally defined) the exact point at which a may be still “alive” even though showing no demonstrable signs of
person is considered to have become intoxicated and legally life; if the brain is still functional, the patient cannot be dead. It
incompetent to operate an automobile. But a particular blood does not matter if there is an intent to resuscitate or not. Neither
alcohol level does not absolutely define drunkenness, any more the patient nor his or her family can consent to any procedure that
than pronouncing a patient dead absolutely defines the exact will result in death, nor can the family consent to the patient’s
point of death. being dead in a defined number of minutes, as has been suggest-
Resuscitative technology has muddied the waters further by ed by proponents of DCD. Consenting to either of these options
creating additional uncertainty in the determination of death. As is tantamount to consenting to euthanasia.
an example, in the United States, about 150 legally dead persons Although the UDDA specifically required that death be irre-
have undergone cryopreservation and are suspended in liquid versible, it failed to define the term. Accordingly, several ideologi-
nitrogen, awaiting a nanotechnology that will repair their fatal dis- cal caucuses have developed around this issue, each with its own
ease and restore them to life.36,37 In this practice, commonly perspective. One caucus maintains that death is irreversible when
known as cryonics,38 a physician makes a pronouncement of death the patient cannot “spontaneously” resuscitate. If so, how long
according to the usual cardiorespiratory criteria, whereupon the must one wait to be sure that autoresuscitation will not occur?
patient is medicolegally dead. Once this pronouncement has been Long enough for a quorum of cells to die?
made, the rules governing the procedures that can be performed Another caucus maintains that death is irreversible when the
change radically, in that the subject is no longer a living patient but patient cannot be resuscitated by any means or when resuscitation
a corpse. In the initial cryopreservation protocol, the subject is fails. If so, does this mean that every dying patient must be assault-
intubated and mechanically ventilated, and a highly efficient ed by every possible intervention before being declared dead?
mechanical cardiopulmonary resuscitation device reestablishes A third caucus maintains that death is irreversible when the
circulation. Occasionally, subjects then begin to show what appear inherent order of the atoms that make up the brain is irrevocably
to be signs of life, including pupillary reaction and spontaneous destroyed. If, however, the overall structural integrity of the brain
motion.39 Such cases raise crucial questions. Are these persons is preserved, there is no fundamental barrier, given our current
alive again, or were they ever really dead? understanding of physical law, to recovering the brain’s informa-
tion content; regardless of how labor-intensive such recovery
ARE THERE TWO KINDS OF DEATH?
might be in practice, it is possible in principle. If the ultrastructure
The issue of determining death has become further confused of the brain is physically destroyed, the laws of thermodynamics
by a creative interpretation of the UDDA, which, ironically, was say that the information contained in the brain is irreversibly
drafted with the intention of clarifying this issue. As noted (see destroyed. With that consideration of irreversibility in mind, is a
above), the UDDA guidelines declare that either “irreversible ces- tobacco mosaic virus dead if its constituent parts can be broken
sation of circulatory functions” or “irreversible cessation of the up and shaken into solution and then reassemble themselves into
entire brain, including brain stem” constitutes death.30 However, a viable virus capable of self-replication?
the UDDA does not elucidate how these two differing standards
THE FUTURE OF DEATH
reflect the same phenomenon.The wording suggests that there are
actually two kinds of death: brain and cardiac.This lack of a con- There are disturbing differences between a corpse in a morgue
sistent standard for the determination of death, coupled with the and a brain-dead patient. If a whole-brain death (WBD) patient is
intense demand for donor organs for transplantation, has promot- a corpse, he or she is certainly a corpse with some unusual prop-
ed the evolution of a creative variation of organ procurement erties—one that breathes, circulates blood, digests food, filters
known as donation after cardiac death (DCD), which relies sole- wastes, and is capable of carrying a pregnancy to term.41 These

4. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 12 BRAIN FAILURE AND BRAIN DEATH — 4
considerations raise the issue of whether there is a practical or eth- ment for much longer than was once thought and still retain def-
ical difference between being dead, being almost dead, or being in inite characteristics of a living being. The organism as a whole,
the process of dying, and they show that the precise moment though disabled, is not yet dead and should not be represented as
when death occurs cannot be accurately pinpointed. It is clear such—a fact that may have important consequences for our
that a WBD patient can be maintained on life-sustaining treat- future conceptions of death and of life in death.
References
1. Crippen D: Agitation in the ICU: part one. 15. Steen PA, Milde JH, Michenfelder JD: No barbitu- 28. Becker DP, Robert CM Jr, Nelson JR, et al: An
Anatomical and physiologic basis for the agitated rate protection in a dog model of complete cerebral evaluation of the definition of cerebral death.
state. Crit Care 3:R35, 1999 ischemia. Ann Neurol 5:343, 1979 Neurology 20:459, 1970
2. Pinault D: The thalamic reticular nucleus: struc- 16. Nozari A, Rubertsson S, Wiklund L: Improved 29. Guidelines for the determination of death. Report
ture, function and concept. Brain Res Rev 46:1, cerebral blood supply and oxygenation by aortic of the medical consultants on the diagnosis of
2004 balloon occlusion combined with intra-aortic vaso- death to the President’s Commission for the Study
3. Crippen D: Neurologic monitoring in the intensive pressin administration during experimental car- of Ethical Problems in Medicine and Biomedical
care unit. New Horiz 2:107, 1994 diopulmonary resuscitation. Acta Anaesthesiol and Behavioral Research. JAMA 246:2184, 1981
Scand 44:1209, 2000 30. Determination of death (Uniform Determination
4. Berger R, Kelley M: Survival after in-hospital car-
diopulmonary arrest of noncritically ill patients: a 17. Shaffner DH, Eleff SM, Koehler RC, et al: Effect of Death Act of 1981); natural death (Natural
prospective study. Chest 106:872, 1994 of the no-flow interval and hypothermia on cere- Death Act of 1981). Lexis DC Code DC. 1982;
bral blood flow and metabolism during cardiopul- Sect. 6.2401 6.2421 to 6.2430 amended Feb 1982
5. Brindley PG, Markland DM, Mayers I, et al: monary resuscitation in dogs. Stroke 29:2607,
Predictors of survival following in-hospital adult 31. Olick RS: Brain death, religious freedom, and pub-
1998 lic policy: New Jersey’s landmark legislative initia-
cardiopulmonary resuscitation. CMAJ 167:343,
2002 18. Bowersox SS, Singh T, Luther RR: Selective block- tive. Kennedy Inst Ethics J 1:275, 1991
ade of N-type voltage-sensitive calcium channels 32. Whetstine L: An examination of the biophilosoph-
6. Wu S,Tamaki N, Nagashima T, et al: Reactive oxy- protects against brain injury after transient focal
gen species in reoxygenation injury of rat brain ical literature on the definition and criteria of
cerebral ischemia in rats. Brain Res 747:343, 1997 death: when is dead dead and why some donation
capillary endothelial cells. Neurosurgery 43:577,
1998 19. Maragos WF, Korde AS: Mitochondrial uncou- after cardiac death donors are not. Dissertation,
pling as a potential therapeutic target in acute cen- filed at Duquesne University, 2006
7. Pharmacology of Cerebral Ischemia 1988. tral nervous system injury. J Neurochem 91:257,
Krieglstein J, Ed. Wissenschaftliche Verlagsgesell- 33. Bernat JL, Culver CM, Gert B: On the definition
2004 and criteria of death. Ann Intern Med 94:389,
schaft, Stuttgart, 1989, p 65
20. Kaste M, Palo J: Criteria of brain death and 1981
8. Nozari A, Rubertsson S, Gedeborg R, et al:
removal of cadaveric organs. Ann Clin Res 13:313, 34. Crippen DW, Whetstine LM: Dark angels—the
Maximisation of cerebral blood flow during exper-
1981 problem of death in intensive care. Crit Care
imental cardiopulmonary resuscitation does not
ameliorate post-resuscitation hypoperfusion. Re- 21. Jastremski M, Powner D, Snyder J, et al: Problems 11:202, 2007
suscitation 40:27, 1999 in brain death determination. Forensic Sci 35. Whetstine L, Streat S, Darwin M, et al: Pro/con
11(3):201, 1978 ethics debate: when is dead really dead? Crit Care
9. Asiedu-Gyekye IJ, Vaktorovich A: The “no-reflow”
phenomenon in cerebral circulation. Med Sci 22. Searle J, Collins C: A brain-death protocol. Lancet 9:538, 2005
Monit 9(11):BR394, 2003 1:641, 1980 36. http://www.cryonics.org
10. Wolfson S, et al: Dynamic heterogeneity of cerebral 23. Izac SM: Quality assurance in determinations of 37. http://www.alcor.org/AboutAlcor/index.html
hypoperfusion after prolonged cardiac arrest in brain death. Am J Electroneurodiagnostic Technol
38. Wowk B, Darwin M: “Realistic” scenario for nan-
dogs measured by the stable xenon/CT technique: 44(3):159, 2004
otechnological repair of the frozen human brain.
a preliminary study. Resuscitation 23:1, 1992 24. Benzel EC, Mashburn JP, Conrad S, et al: Apnea Cryonics: Reaching for Tomorrow. Alcor Life
11. del Zoppo GJ, Mabuchi T: Cerebral microvessel testing for the determination of brain death: a Extension Foundation, Scottsdale, Arizona, 1991
responses to focal ischemia. J Cereb Blood Flow modified protocol. Technical note. J Neurosurg http://www.alcor.org/Library/html/nanotechre-
Metab 23:879, 2003 76:1029, 1992 pair.html
12. Zygun DA, Steiner LA, Johnston AJ, et al: 25. Vivien B, Paqueron X, Le Cosquer P, et al: 39. Darwin MG, Leaf JD, Hixon H: Neuropre-
Hyperglycemia and brain tissue pH after traumat- Detection of brain death onset using the bispectral servation of Alcor patient A-1068. Cryonics 7:17,
ic brain injury. Neurosurgery 55:877, 2004 index in severely comatose patients. Intensive Care 1986
13. Bender TM, Johnston JA, Manepalli AN, et al: Med 28:419, 2002 http://www.alcor.org/Librar y/html/casere-
Association between brain tissue pH and brain in- 26. Paolin A, Manuali A, Di Paola F, et al: Reliability port8504.html#part2.
jury during asphyxia in piglets. Resuscitation 59:243, in diagnosis of brain death. Intensive Care Med 40. Sweet WH: Brain death. N Engl J Med 299:410,
2003 21:657, 1995 1978
14. Safar P, Bircher N: Cardiopulmonary Cerebral 27. Morenski JD, Oro JJ, Tobias JD, et al: 41. Powner DJ, Bernstein IM: Extended somatic sup-
Resuscitation, 3rd ed. WB Saunders Co, Philadel- Determination of death by neurological criteria. J port for pregnant women after brain death. Crit
phia, 1988 Intensive Care Med 18:211, 2003 Care Med 31:1241, 2003