science dealing with the study of death has been inexistence for
centuries. It is interesting to review some of the notions that
prevailed earlier. Legal and medical quandaries regarding the
definition of death are not new. In his Historia Naturalis, the Roman
author Pliny the Elder wrote that "so uncertain" is men’s judgment
that they cannot determine even death itself.
Perceptions of death
have been reflected in poetry, literature, legends and pictorial art.
Human beings have been the only species to bury their dead in a
systematic way, often with implements to be used in a further
existence. Most ancient civilizations (Egyptian, Zoroastrian, Hindu,
Christian, Judaic and Islamic) however accepted death as an easily
determined empirical fact, not requiring or further elaboration.
conceptual crisis has arisen in modern medicine and biology. This
crisis stems precisely from the realization that the definition if
death – taken for granted by our ancestors requires re examination.
Death from a biological angle necessarily has to be redefined. Many
dictionaries define death as "the extinction or cessation" if life or
as ceasing to be. Today death of the brain is considered to be the
death of the individual and death of the brain stem, is accepted as
death of the brain and therefore of the individual.
Process or an Event ?
death the irreversible loss of function of the whole organism, that
is, of everyone of its component parts? Or is it the irreversible loss
of function of the organism as a whole; that is loss of the ability to
exist as a meaningful and independent biological unit? Civilizations
fall apart yet their component societies live on; societies
disintegrate but their citizens survive; individuals die while their
cells, perversely, still metabolize; finally, cells can be disrupted
yet the enzymes they release may, for a while, remain very active. So
what is death and when is a person considered dead?
must realize and accept that death is a continuous ongoing process,
not an isolated event. To certify that death occurred at a specific
time is not, from a purely biological and cellular point of view,
acceptable. Until recently however this had no practical implications.
Death of different organs x(-) the heart, the brain and so on occurred
rapidly within seconds of each other. A few decades ago technology was
not available to keep some organs alive even though others were dead.
Unless caught up in nuclear explosions people do not die
instantaneously, like the bursting of a bubble. Several minutes after
the heart has stopped beating, electrical activity can still be
recorded if one probes for signals from within the cardiac activity.
Three hours after death the pupils still respond for signals from
within the cardiac activity. Three hours after death the pupils still
respond to pilocarpine drops by contracting, and muscles repeatedly
tapped may still mechanically shorten. Kidneys can be removed even two
hours after irreversible cardiac arrest. Bones taken 48 hours after
death can still be transplanted. Arteries can be grafted as late as 72
hours after the heart has irreversibly stopped cells clearly differ
widely in their ability to withstand the deprivation of oxygen supply
that follows arrest of the circulation. The challenge is identical
such points with greater precision for different organs.
clinical level the irreversible cessation of circulation has for
centuries been considered the point of no return. It has provided (and
still provides) a practical and valid criterion of irreversible loss
of function of the organism as a whole. What is new is a awareness
that circulatory arrest is a mechanism of death; that cessation of the
heart beat is only lethal if it lasts long enough to cause critical
centers in the brain stem to die; and that this is so because the
brain stem is irreversible in a way the cardiac pump is not. These are
not so much new facts as new ways of looking. At old ones.
Programmed cell death plays an important role in embryological
development and teratogenesis. Such programmed events are essential if
the organism as a whole is to develop to its normal final form. Waves
of genetically driven cell death are critical to the proper modeling
of organs and systems. The infections of the developing mammalian
brain and spinal cord is due to death of cells at appropriate times.
Programmed cell death may also play a part in the process of aging
cells which are designed to die after a certain number of cell
death cannot be simplified to purely biological terms, divorced from
ethical and cultural considerations. The repercussions (burial
mourning, inheritance, etc.,) are many. They have to be socially
acceptable in a way that does not apply to the fate of cells in tissue
culture. Technical data can never answer purely conceptual questions.
Capacity for consciousness is a function of the brainstem while
content of consciousness is a function for the cerebral hemispheres.
If there is no functioning brain stem there can be no meaningful or
integrated activity of the cerebral hemispheres, no social interaction
with the environment, nothing that might legitimize ending the
adjective sapiens (wise) ti the noun Homo (man). The capacity for
consciousness is per haps the nearest one can get to giving a
biological flavor to the notion of the soul.
Pius XII, speaking to an International Congress of Anesthesiologists
in 1957, raised the question of when, in the intensive care unit, the
soul actually left the body. More secularly inclined philosophers have
meanwhile pondered what it was that was so essential to the nature of
man that its loss should be called death. English author Sir Thomas
Browne in 1643 remarked : With what strife and pains we cine come into
the world we know not, but it is commonly no easy matter to get out of
History of Brain Death:
death was first described by two French physicians, Mollart and Goulon
and termed coma depasse (a state beyond coma) They differentiated coma
depasse from coma prolonged, the latter being the condition, which is
now termed persistent vegetative state. In 1968 the Ad Hoc Committee
of the Harvard Medical School defined brain death as irreversible
coma, with the patient being totally unreceptive and unresponsive,
with absent reflexes and no spontaneous respiratory effort during a 3
min period of disconnection from the ventilator. The report
unambiguously proposed that this clinical state should be accepted as
death. A few years later Mohandas and Chou suggested that in patients
with know but irreparable intracranial lesions, reversible damage to
the brainstem was the point of no return and that the diagnosis could
be based on clinical judgment, thereby introducing the important
concepts of etiological preconditions and a purely clinical diagnosis.
Another important contribution was the memorandum issued by the
Conference of Royal Medical Colleges (1976). This emphasized that
permanent functional death of the brainstem constitutes brain death
and that this should only be diagnosed in the context of irremediable
structural brain damage, after exclusion of certain specified
conditions, which might contribute to or cause the coma.
second memorandum issued in 1979 equated brainstem death with death
itself. Therefore death can be declared once death of the brainstem
has been confirmed, and most would argue that mechanical ventilations
should then be discontinued as soon as possible. This should be be
viewed as withdrawing support to allow a patient to die, but rather as
ceasing a futile intervention in a patient who is already dead.
Therefore it is clear that, even if transplantation therapy did not
exist, the ability to diagnose brain death with confidence contributes
to the humane practice of intensive care, and most clinicians find the
decision to discontinue ventilating a brain dead patient relatively
straightforward. What was clearly established in the early 1980s was
that no patient in apnoeic coma declared brain dead, according to the
very stringent criteria of the UK code (outlined in the 1976 and 1979
Memoranda of the conference of Royal Medical Colleges) had ever
regained consciousness or had ever failed to develop asystole within a
relatively short time. The acceptance of these ideas would lessen
human distress, lead to more rational use of limited intensive are
facilities, and radically after the life expectancy of thousands of
patients with end stage organ failure waiting desperately for organs.
much of the brain needs to be destroyed to produce death? The
destruction of a crucial few cubic centimeters of tissue lying beneath
the aqueduct of Sylvius anteriorly and in the floor of the fourth
ventricle posteriorly, is all that is required to ensure irreversible
loss of brain function. The concept of brainstem death became
operational in India after the enactment of legislation by the Indian
Parliament and its notification in the Gazette to India. It recognizes
brainstem death based on the UK criteria, which have the advantage of
being simple, clinical, unequivocal and capable of confirmation.
death should not even be thought of until the following reversible
causes of coma have been excluded :
which depress the central nervous system.
Primary hypothermia (by measuring rectal temperature)
Hypovolaemic shock (by sequential measurement of blood pressure)
Metabolic and endocrine disorders.
Incidence of brain death:
is quoted as having stated that brain death occurs in approximately 1%
of all deaths. According to Jennett et al, the occurrence, with about
4000 cases occurring each year in Britain.
Pathophysiology of brain death:
changes in the brain following brain death are a function of time. The
pathogenesis includes direct cellular injury potentiated by a vicious
cycle of failure of blood flow, hypoxia, cerebral acidosis and
endothelial swelling to brain edema, herniation and aseptic necrosis
of the brain. Gross examination of such brain specimens shows a dusky,
congested cerebral cortex, generalized brain swelling, a swollen
pituitary gland and macerated cerebellum. Microscopically, there is
pan-necrosis of the nervous tissue and extensive foci of necrosis
throughout the cerebrum brainstem and cerebellum, The physiological
changes following brain death are so severe the progressive somatic
deterioration and cardiac standstill will inevitably occur despite
extensive life support. A number of subsequent studies have suggested
that brain death does not always rapidly lead to somatic death. In one
series, cardiac rhythm could be maintained for prolonged periods (mean
(SD) duration < or=23.1 (19.1) days) after the declaration of brain
physiological changes occurring in organs distant from the brain at or
around the time of onset of brain death arise as a result of two major
Diffuse injury to the vascular regulation mechanism occurring due to
early massive sympathetic outflow, followed by its profound reduction.
Diffuse metabolic cellular injury due to lack of hypothalamic control,
producing generalized metabolic and hypoxic lesions in all tissues.
Circadian changes in temperation (high at day, low at night) however
are preserved during the period of brain death.
Reduced intraocular pressure is a feature of brain death (12/12).
Pallor or disc suggestive of funds ischemia was common. Disc edema was
Physiological, histological , biochemical and ECG evidence of damage
to the heart has been documented at the time of brain death. The
sudden increase in ICP and resultant cerebral ischemia leads to an
autonomic or sympathetic storm due to massive outpouring of
catecholamines (Cushing’s reflex). The rise in catecholamines depends
on the rate of rise in ICP. There is an initial increase in
parasympathetic tone with bradycardia, followed by marked sympathetic
changes leading to hypertension, tachycardia a vasoconstriction.
Immediately after the autonomic storm, there is loss of cardiovascular
tone with brady arrythmias, vasodilation and consequent hypotension,
Hypotension and low caridac output then start a cycle of poor
myocardial and tissue perfusion with further decrease in myocardial
performance. In a few centers, brain dead organ donors are not
considered for heart donation if high levels of adrenaline are
required to maintain cardiovascular variables within normal limits.
Neuropathology of the persistent vegetative state as distinct from
neuropathology in brain death has been reviewed.
Hypernatremia, diabetes Insipidus is more often the effect rather than
Maintenance of the brain dead mother to ensure viability of the fetus
is fraught with major problems and is extremely expensive but can be
Clinical evaluation of brain stem death :
more and more countries, certification of brain stem death is made on
purely clinical grounds. The aim of the clinical test is not to probe
every neuron within the intracranial cavity to see if it is dead" an
impossible task but to establish irreversible loss of brain – stem
function. The accuracy, reliability, reproducibility and ease in
carrying out clinical tests make clinical evaluation sufficient for
diagnosis of brainstem death. The President’s Commission also outlined
guidelines for the determinations of death for the Study of Ethical
Problems in Medicine and Behavioral Research. Neuro physiological and
imaging studies are not essential to confirm brain death. By testing
various brain stem reflexes, the functions of the brain stem can be
assessed clinically with an ease, thoroughness, and degree of detail
not possible for any other part of the central nervous system.
Pupillary response to light:
The response to bright
light should be absent in both eyes. The pupil should be observed
closely for one minute to allow time for a slow response to become
evident. Both widely dilated as well as mid-positioned fixed pupils
are seen in brain dead patients. The size may vary from 4 – 9 mm.
Widely dilated pupils are not a necessary criterion for brain death
but fixed pupils with no response to light are mandatory.
This should be absent.
Repeated corneal stimulation is unnecessary and should be avoided
=Corneal abrasions are undesirable if the patient is a potential
and Seventh Cranial Nerves:
There should be no motor
response in the distribution of any cranial nerve. Such a response
would be grimacing (facial nerve motor response) in response to thumb
pressure over the supra orbital groove (trigeminal nerve sensation).
Similarly, there should be no response to painful stimuli of the trunk
suggesting absence of sensory nerve conduction across the foramen
cephalic reflex (Doll’s eye phenomenon):
This test must not be
performed in patients with an unstable cervical spine. The head is
turned from starting position to a new steady position and briskly to
the opposite side. The eyes move as shown in…. denoting the integrity
of the medial longitudinal fasciculus in the brain stem .
This should be absent. A tongue
depressor is used to stimulate each side of the oropharynx and the
patient observed for any pharyngeal or palatal movement. Evaluation of
Gag reflex may be difficult in an intubated patient and should not be
performed if extubation is required.
A suction catheter is introduced into
the endotracheal or tracheostomy tube to deliberately stimulate the
carina. The patient is closely observed for any cough response or
movement of the chest or diaphragm.
Before testing, both ears must be
inspected with an auroscope to confirm that the tympanic membranes are
intact and the external auditory canal not obstructed. If the eardrum
is perforated, the test can be performed using cold air as the
stimulus. A fracture of the base of skull resulting in blood,
cerebrospinal fluid or brain tissue in the external auditory canal is
a contraindication to performing this test on that ear. The patient’s
head is placed in the center and lifted 30 degree from the supine
position. A soft catheter is introduced into the external auditory
canal and slow irrigation with at least 5-ml of ice-cold water is
performed while, the eyes are held open by an assistant. The eyes
should be observed for one minute after irrigation is completed before
repeating the test on the other side. An intact oculovestibular reflex
causes tonic deviation of the eyes towards the irrigated ear. Any
movement of one or both eyes, whether conjugate or not, excludes the
diagnosis of brain death. In a brain dead patient the eyes remain
fixed. Combined ice-cold water caloric stimulation and head rotation
has been suggested as the most pro-found stimulation for deeply
Apnoea test: Apnoea testing is essential for confirmation of brain
death. It should only be done when all the prerequisites have been met
and all other brain stem reflexes are absent. It is not possible to
perform this test in a patient with high cervical cord injury, which
may have abolished phrenic nerve function. Important changes in vital
sings (ex; marked hypotension, servere cardiac arrhythmias) during the
apnoea test may be related to lack of adequate precautions, although
they may occur spontaneously during increasing acidosis.
Therefore, the following prerequisites have been suggested.
core temperature should be> or = 36.5 degree Celsius; The
systolic blood pressure should be > or = 90mm Hg; Euvolaemia
(preferably positive fluid balance in the previous (6hour);
Eucapnoea (arterial pCO2>or=40mmHg). A useful method of raising
the pCO2 in an over ventilated hypocapnic patient is to connect an
oxygen filled bag to the endotracheal tube and rebreathe pure oxygen
for 10 minutes without CO2 exhaustion.
three components of the apnoea test are:
Absence of spontaneous respiratory efforts during a period of
disconnection (10 min.) from the mechanical ventilator.
Arterial carbon dioxide must reach a critical point(>60mmHg) during
Prevention of hypoxemia during this period.
steps in testing are :
Disconnect the ventilator
Deliver 100% oxygen at 6 L/min; place a cannula at the level of the
closely for respiratory movements. Respiration is defined as abdominal
or chest excursions that produce adequate tidal volumes. Respiratory –
like movements can occur at the end of the apnoea test, when
oxygenation may become marginal. However, these do not produce
adequate tidal volumes. When the test is in doubt, a spirometer can be
connected to the patient to confirm the absence of tidal volumes.
Measure arterial pO2, pCO2, and pH after 10 minutes and reconnect the
respiratory movements are absent and the arterial pCO2>or 60 mmHg
(20mmHg increase in pCO2 over baseline) the apnoea test is positive),
i.e. it supports the diagnosis of brain death.
respiratory movements are observed, the apnoea test is negative (i.e.
it does nto support the clinical diagnosis of brain death), and the
test should be repeated.
during the apnoea test the systolic blood pressure becomes < or = 90
mmHg, the pulse oximeter indicates marked desaturation, and cardiac
arrhythmias occur, draw a blood sample immediately, connect the
ventilator and analyze arterial blood gases. The apnoea test is
positive if the arterial pC)2 us > or=60mmHg. If the pCO2 is <60mmHg,
the resul;t is indeterminate and repeat testing at a later stage
should be done.
Tests to confirm brain death:
The plethora of
gadgetry ultimately only gives answers of dubious reliability to
the wrong questions! None are superior to clinical assessment At
present, there is no evidence that, MRI, MRA, EEG, evoked
potentials, Trans Cranial Doppler, evaluation of cerebral blood
flow or other tests can unequivocally establish brainstem death.
These techniques though under review, currently do not form part
of the mandatory diagnostic requirements in most countries. Some
countries however include these tests.
Testing for Doll's eye
and Evoked Potentials:
still consider that, demonstration of absence of cerebral electrical
activity, is necessary to diagnose brain death. Others recommend the
use of evoked potentials to assist in the diagnosis of brain death
since these can be demonstrated when EEG silence is attributable to
drugs. Evoked potential was preserved in coma in all patients, but
lost in brain death in 100%. It is therefore useful in distinguishing
isolated brainstem death from high cervical transverse cord lesions
and focal bilateral lemniscal lesions. In the UK most argue that the
surface EEG cannot exclude activity in deeper areas of the brain, EEG
may also not show electrical activity in barbiturate coma. Patients
have been reported in whom the EEG was isoelectric but brainstem
reflexes were preserved, although this is extremely unusual.
and brain death
Fifteen patients with clinical diagnosis of brain death were examined
by MRI. MRI showed that flow voids were absent in the ICA in all eight
patients in whom non-filling was confirmed by IADSA. Partial residual
flow voids may be caused by to and fro blood movement which was
demonstrated by transcranial Doppler sonography. Several authors have
commented on the role of MRI in the evaluation of brain death. There
are even reports on contrast enhanced CT changes in brain death.
Cessation of Cerebral Blood Flow:
Clinical and electrophysiological criteria may be misinterpreted due
to drug intoxication, hypothermia or technical artifacts. Thus, if
clinical assessment is sub optimal, reliable early confirmatory tests
may be required for demonstrating absence of intracranial blood flow.
All patients with isolated brain lesions and Glasgow Coma Scale (GCS)
= 3 were subjected to neurological examination after ruling out
hypothermia, metabolic disorders and drug intoxications and diagnosed
as clinically brain dead when the brainstem reflexes were absent and
the apnoea test positive. Cerebral blood flow measurements with the
i.v. Xe-133 method (CBF) and selective cerebral angiography were
carried out. EEG was isoelectic in 8 petients while the remaings 7
patients showed persistence of electrical activity. Trans cranial
Doppler was compatible with intracranial circulatory arrest in 18 MCA
districts, compatible with normal flow in 2 and undetectable in 10 out
of 30 districts insonated. Cerebral Angiography and CBF studies are
the most reliable investigations whereas the role of EEG and TCD
remain to be determined because of the presence of false negatives and
positives. Cerebral blood flow velocities in the middle cerebral
arteries were measured using transcranial Doppler in 12 patients who
had conditions that ultimately resulted in brain death. This pattern
consisted of reverberating flow, with forward flow in systole and
retrograde flow in diastole. When this pattern was seen, there was
arrest of cerebral flow, as measured by radionuclide scanning
Radionuclide cerebral scanning cannot document absence of flow in the
vertebrobasilar circulation. Color flow duplex scanning may be used to
complement radionuclide cerebral scanning. Reports claiming
superiority of perfusion studies with Tc-99mHMPAO over conventional
radionuclide cerebral Angiography have been reported.
Transcranial Doppler was conducted transtemporally on the left and
right-middle cerebral artery four times daily. In all patients,
transcranial Doppler waveforms exhibited high resistance profiles with
low, zero, and then reversed diastolic flow velocity-only three
waveform patterns, consisting of diastolic forward flow, brief
systolic forward flow. This noninvasive method to document
deterioration of cerebral profusion pressure could be included in the
future in protocols for brain death diagnosis.
as a confounding factor in evaluation of brain death:
Effects of drugs must be excluded before considering brain death. Most
centrally acting drugs depress respiration and would be expected to
affect apnoea testing of brain stem function. The entry of drugs into
the brain is also altered in some disease states. However the effects
of central depressants when there is damage to the blood-brain barrier
or brain is not clearly known.. Drug screens can assist in determining
whether drugs are present, but correct interpretation of the results
depends on close liaison between the clinical and laboratory staff.
Life support systems must be continued when a centrally active drug is
present. Post traumatic brain death may occur in patients treated with
barbiturate for elevated ICP. Saits et al report two cases of brain
death where a large amount of barbiturate remained in the brain, even
when the blood concentration was not detectable, possibly because the
blood flow was stagnant in the brain. It is suggested that a patient
in barbiturate coma should not be diagnosed to be brain dead.
Clinical observations compatible with brain death:
reflexes the spinal cord may continue to function after the death of
the brainstem. The resulting limb movement may cause distress to both
family and staff caring for the patient. After the second set of
brainstem death tests are completed and the patient has been certified
brain dead, muscle relaxants may be given for spinal reflexes to
prevent further distress to the family. Muscle stretch, superficial
abdominal and the Babinski reflexes are of spinal origin and do not
invalidate the diagnosis of brain death.
Profuse sweating, blushing, tachycardic and sudden increases in blood
pressure can be elicited by neck flexion in brain dead patients.
Diagnosis of brainstem death:
Brainstem function evaluation should be performed independently by at
least two consultants either the consultant in charge of the patient
and another clinically independent of the first and registered for
more than 5 years. Neither should be a member of the transplant team.
Care, diligence and meticulous implementation of established criteria
are absolutely necessary. Criteria for diagnosing Brain Death in
Infants and Children (age of 2 months should be the same as those in
adults. The legal time of declaration of brain death is the time at
which brain death tests have been repeated for a second time and found
to be unequivocally positive. The declaration of brain death must be
recorded in the medical notes with the date and time. In India the
certification of death must meningiomas as per the Transplantation of
Human Organs Act.
of brain death on the family:
death has created a new class of dead people that does not conform to
society’s expectations of normal death and dying. Brain death also
causes great stress for the family and friends. Effective
communication, caring and supporting the family is crucial. While
these families have a variety of special needs, it is constant
interaction that provides opportunities to have a positive influence
on family member’s ability to cope with the tragedy and begin the
Natural History of brain death:
diagnostic mix of 1228 brain dead renal donors in Britain was similar
to that of 479 cases of brain death recently reported form three
neurosurgical units. About half the donors came from non – teaching
hospitals without a neurosurgical unit, many of them small and distant
from the center. Head injuries accounted for half the donors, and
intracranial hemorrhage for almost a third. This suggests reluctance
of doctors to initiate donation rather than relatives withholding
three neurosurgical units, 609 patients diagnosed clinically as brain
dead were studied; 326 had final cardiac systole while still being
ventilated, and ventilation was discontinued in the reminder. No
patient recovered. The median time in hospital before the heart
finally stopped was 3-4 days, with 30-40 hours on the ventilator.
Analysis of prospective data from three countries on patients with
severe head injuries showed that not one of 1003 survivors would ever
have been suspected of being brain dead even in their worst state soon
MANAGEMENT OF THE POTENTIAL ORGAN DONOR:
Consequences of brain death:
Requirement for multiple transfusions
Arrhythmias, Cardiovascular collapse
Cardiac arrest requiring CPR
Disseminated intravascular coagulation
Hypoxia, Pulmonary edema
Electrolyte Imbalances, Acidosis
Diabetes Insipidus, Endocrine Disturbances, Hyperglycaemia.
Assiduous supportive treatment of the brain dead individual with due
attention to the above, is essential to prevent deterioration of
initially suitable donors. Complications increase progressively after
brain death and, although adequate time must be allowed to confirm the
diagnosis, unnecessary delays must be avoided.
will increase donation rates and improve graft survival and function.
organ retrieval aggressive supportive treatment of the donor should be
continued intra – operatively. Maintaining the functioning of the
salvageable body organs in a brain dead individual is time consuming,
complex, challenging and expensive.
brain in a body with a beating heart is one of the more macabre
products of modern technology. During the past 30 years increasing use
of more and more sophisticated ventilators, pressor amines,
intravenous alimentation and dialysis has resulted in keeping alive
organs, in a body whose brain has irreversibly ceased to function,
With increasing availability of intensive c are facilities in India
the number of brain deaths are likely to increase. It is essential
that the neurologist and neurosurgeon recognize and confirm brain
death. Once this has been done they should not shy away, from
discussing with the family the futility of continuing support
Possible organ donation should also be broached.