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.

Today a 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.

Death A Process or an Event ?

Is 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?

One 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.

At the 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 divisions.

Human 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.

Pope 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 it.

Brain 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.

A 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.

How 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.

Brain death should not even be thought of until the following reversible causes of coma have been excluded :

Intoxication (alcohol)

Drugs, which depress the central nervous system.

Muscle relaxants

Primary hypothermia (by measuring rectal temperature)

Hypovolaemic shock (by sequential measurement of blood pressure)

Metabolic and endocrine disorders.

Incidence of brain death:

Walker 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:

The 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 death.

Physiological changes: 

The 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 mechanisms.

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 not noted.

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 the cause.

Maintenance of the brain dead mother to ensure viability of the fetus is fraught with major problems and is extremely expensive but can be done.

Clinical evaluation of brain stem death :

In 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.

Corneal reflex: This should be absent. Repeated corneal stimulation is unnecessary and should be avoided =Corneal abrasions are undesirable if the patient is a potential corneal donor.

Fifth 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 magnum.

Oculo 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 .

Gag reflexes: 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.

Cough reflex: 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.

Oculovestibular reflex: 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 unconscious patients. 

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.

The 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.

The 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 this period.

Prevention of hypoxemia during this period.

The steps in testing are :

Disconnect the ventilator

Deliver 100% oxygen at 6 L/min; place a cannula at the level of the carnia.

Look 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 ventilator.

If 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.

If 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.

If 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.

Retained Vestibulo-ocular reflexes Rt (a) & Lt (b) 6th nerve palsies Lt(a) & Rt (b) internuclear ophthamoplegia Absent Vestibulo-ocular reflexes	Testing for Doll's eye movements

Some 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.

MRI 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.

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.

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: 

Spinal 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. 

Hemodynamic responses:

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.

Brain 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 healing process.

Natural History of brain death: 

The 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 permission.

In 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 after injury.

MANAGEMENT OF THE POTENTIAL ORGAN DONOR:

Consequences of brain death: 

Hypotension, Hypothermia

Requirement for multiple transfusions

Arrhythmias, Cardiovascular collapse

Cardiac arrest requiring CPR

Disseminated intravascular coagulation

Hypoxia, Pulmonary edema

Electrolyte Imbalances, Acidosis

Bacteremia, Infections

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.

This will increase donation rates and improve graft survival and function.

In 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.

A dead 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 systems. 

Possible organ donation should also be broached.