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Mr. L is a 35-year-old man who has a sudden, excruciating headache and collapses in his chair at dinner. At the emergency department, a CT scan reveals a subarachnoid hemorrhage. Mr. L is admitted to the intensive care unit for monitoring and supportive measures aimed at controlling the intracranial pressure. The next morning he is noted to be unresponsive, with non-reactive, midposition pupils.

A 312-year-old boy, M, is playing near the backyard pool under supervision of his babysitter. The caretaker goes into the house to answer the telephone. Upon returning, she discovers the child face down in the pool. The paramedic team arrives and finds the child’s vital signs are absent. Basic life support is started, and the boy is taken to the hospital. He is resuscitated with intubation, ventilation, and intravenous epinephrine injection. The minimum documented duration of absent vital signs is 30 minutes. He is comatose and unresponsive, with spontaneous breathing, reactive pupils and intermittent generalized seizures.

What is brain death?

Medicine and society continue to struggle thoughtfully with the definition of death, particularly with the progression of sophisticated lifesupport systems that challenge traditional concepts. The questions of when a disease is irreversible, when further treatment is ineffective, or when death has occurred are of great consequence.

These questions are independent of, and galvanized by, the practice of organ donation.

Brain death is defined as the absence of all brain function demonstrated by profound coma with the irreversible loss of capacity for consciousness, loss of the ability to breathe and absence of all brain stem reflexes. Analogous to a cardiac arrest, it is better understood as brain arrest – the loss of all clinical brain function. If a proximate cause is known and there are no reversible conditions present, death is determined by documenting the absence of brain function by clinical examination. In most cases, brain death can be diagnosed at the bedside. Common causes include trauma, intracranial hemorrhage, cerebrovascular accidents, hypoxia owing to resuscitation after cardiac arrest, drug overdose or near drowning, primary brain tumor, meningitis, homicide, and suicide.

The clinical entity was first described in the medical literature by the French and termed ‘‘coma de´passe´’’ (Mollaret and Goulon, 1959; Wertheimer et al., 1959), a state beyond coma. It was placed into practice in the next decade with the use of specific clinical criteria, arising from the landmark work by the Ad Hoc Committee of the Harvard Medial School to Examine the Definition of Brain Death (1968). The concept of brain death was influenced by two major health care advances in the 1960s: the development of intensive care units, with artificial airways and mechanical ventilators

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to treat irreversible apnea, thus interrupting the natural evolution from brain failure to cardiac arrest, and the emergence of organ donation arising from the new discipline of transplant surgery. An ethical consensus existed that the donation itself must not cause the death of the donor, commonly referred to as the ‘‘dead donor’’ rule (Truog and Robinson, 2003).

Advanced technologies also revealed the existing limitations in the lexicon of death. The word ‘‘death’’ may be inadequate to describe the event or process in the various domains in which it can be defined, including medical–biological, legal, social, bioethical, philosophical, religious, spiritual, and existential. Brain death as a criterion for determining the death of a person is a medicolegal and social formulation. It implies a notion of irreversible loss of personhood and integrative functions of the brain. The diagnosis uncovers cultural and religious diversity in a pluralistic society.

Why is brain death important?

Ethics

Social formulation

For centuries, determining the death of another person was seen to be a rather straightforward matter. The cessation of cardiac and respiratory functions was thought to be sufficient to conclude that a person had died. The advent of neurological or brain-based criteria to establish the death of a person was a significant departure from the traditional way of defining death. Regardless of which criteria are used, agreement about when death occurs is not simply an agreement about medical or biological criteria for death but is also a ‘‘social formulation’’ (Capron, 1995). On this point, Karen Gervais (1995) noted ‘‘that even in pre-technological culture, use of the traditional cardiopulmonary criteria was a choice, an imposition of values on biological data. It was a choice based on a decision

concerning significant function, that is, a decision concerning what is so essentially significant to the nature of the human being that its irreversible cessation constitutes human death.’’

Medical–biological formulation

Death in medicine may be fulfilled by the complete and irreversible absence of (i) circulation, as a consequence of cardiac arrest; or (ii) brain function, as a consequence of brain arrest.

The concept of brain death has been criticized as a social construct created for utilitarian purposes to permit transplantation (Taylor, 1997). Scientific advances have diminished the legitimacy of these historical arguments. Traditional cardiopulmonary definitions of death (asystolic cardiocirculatory arrest) are no longer sufficient in the face of advancing technology that may support and/or replace complete and irreversible loss of heart and/ or lung function. Every solid organ can be supported by technology in the intensive care unit or replaced by transplantation, except the brain. If the heart is completely and irreversibly arrested, death has not occurred if the circulation is being supported by a machine such as the extracorporeal membrane oxygenator or other forms of artificial heart technology, as long as the prospect for recovery of neurological function is maintained. The concept of irreversibility in cardiac death is itself being questioned, in favor of definitions based on permanence (Bernat, 2006).

Cardiorespiratory function can be sustained in any form or severity of brain failure. It was once considered that brain death invariably leads to hemodynamic instability and cardiac arrest (Lagiewska et al., 1996). However, it is now clear that aggressive cardiorespiratory support, hormonal therapy, and nursing care can maintain somatic functions indefinitely, as demonstrated in individuals who become brain dead during pregnancy (Powner and Bernstein, 2003). These continued advances in technology and transplantation have made brain-based determination

of death more relevant today than in their original conception.

Personhood

Conceptually, complete loss of brain function is seen to be a significant threshold separating one who is living from one who is dead. Recognizing and accepting this threshold allows clinicians and patients’ families to consent to organ donation without fear of violating the dead donor rule. It also permits clinicians to proceed with discontinuation of cardiorespiratory support without fear or belief that they are causing the death of their patient. Those who accept brain-based definitions of death argue that those brain functions necessary for the integrated functioning of the person are irreversibly lost, and without artificial support, the person would not be able to spontaneously sustain those necessary functions.

Some have even argued that the whole-brain definition of death should be amended to incorporate people in a persistent vegetative state, that is, those who have experienced the irreversible loss of so-called higher-brain functions (Truog and Robinson, 2003). Proponents of this higher-brain definition of death argue that consciousness and the capacity to relate to other people and the wider world is a defining characteristic of human beings. In this view, the death of that part of the brain responsible for consciousness and interaction with the world is equivalent to the death of the person. Although the whole-brain definition of death has gained wide acceptance, the higher-brain definition has not. Concern about the implications of this higher-brain definition of death can be found in the early work of the US President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (1981a). The implication of the personhood and personal identity arguments is that a patient like Karen Quinlan, who retains brainstem function and breathes spontaneously, is just as dead as a corpse in the traditional sense. The Commission rejected this

conclusion and the further implication that such patients could be buried or otherwise treated as dead persons.

Cultural and religious diversity

Understanding, defining, and determining brain death continue to be ethically challenging and complex undertakings in many cultures. Various cultural and religious groups (e.g., some Canadian First Nations and Asian cultures, and ultra-orthodox Judaism) have been reluctant to accept that death has occurred until all vital functions have ceased. Furthermore, in the clinical setting, some families simply may not accept that a relative is dead. Many experience a certain discomfort when they view a person who is brain dead but who appears to be alive because vital bodily functions are being sustained by technological support. Some jurisdictions have even made legal exemptions based on religious perspectives (Olick, 1991).

Trust

Surveys of public attitudes towards organ donation show remarkable levels of support, exceeding 95% in Canada for example (Canadian Council for Donation and Transplantation, 2005). The public’s perceptions of brain death, and the distinction between cardiac and brain death, however, remain poorly understood. Any residual public ambivalence toward organ donation and retrieval may be rooted in the experience of witnessing a person declared brain dead who is sustained on technological support. This concern may not only be about accurately determining death but may also reflect fears that death will be declared prematurely for the sake of organ and tissue retrieval. This should not be underestimated by clinicians caring for the critically ill or by those involved in the procurement of tissue and organs. Without an enduring trust between doctors and their patients, brain death will remain an enigma to most of the general public.

88S. D. Shemie, N. Lazar, and B. M. Dickens

Law

The law approaches death as an event rather than a process, and as a matter of status rather than as a medical condition. Death marks the time from which certain legal consequences follow, including termination of obligations to provide resuscitative measures, termination of individual legal rights, execution of a will or other distribution of an estate, eligibility for autopsy and organ or tissue donation, lawful disposal of bodily remains, and, for instance, beneficiaries’ claims under life insurance policies and other entitlements.

The law sets the criteria by which death is determined. Legislation or judge-declared law may specify that death occurs on irreversible cessation of heart function and/or respiration but may provide,

in addition or instead, that death occurs on irreversible cessation of total brain function. Physicians usually determine whether the legal criteria of death are satisfied. When death may be determined by neurological criteria, the assessment is legally decisive even if other criteria relating to cessation of heart beat and respiration are being artificially resisted, such as for preservation of transplantable organs. Laws may alternatively not set criteria of death but only a process of determination. For instance in Canada, legislation in Ontario provides that ‘‘for the purposes of a post-mortem transplant, the fact of death shall be determined by at least two physicians in accordance with accepted medical practice’’ (Shemie et al., 2006).

In many of the world’s jurisdictions, there are laws to prevent conflicts of interest in a physician determining death and caring for a potential recipient of the deceased person’s organ. Provisions commonly preclude a physician who has any association with the likely recipient of a deceased person’s organ from participation in or influence over determination of that person’s death. A physician is similarly precluded from participation in transplantation into a recipient of an organ or tissues from the body of a person whose death the physician participated in determining, including deciding on allocation of such person’s organs and/or tissues.

Policy

Many national critical care, neurological, and neurosurgical societies have drafted policies and practice guidelines for the declaration of brain death (Medical Consultants on the Diagnosis of Death to the President’s Commission, 1981; Task Force for the Determination of Brain Death in Children, 1987; American Academy of Neurology, 1995; Royal College of Physicians Working Party, 1995; Shemie et al., 2006). While variability in brain-death practices have been well described (Wijdicks, 2002; Powner et al., 2004; Hornby et al., 2006), the clinical criteria for the determination are remarkably consistent across jurisdictions (Wijdicks, 2002; Powner et al., 2004). Brain death is fundamentally a clinical evaluation, where the clinical criteria have primacy and routine ancillary laboratory testing has fallen into disfavor. Ancillary testing is recommended only when the usual clinical criteria cannot be completed at the bedside, when confounding conditions exist, or specific to infants (Wijdicks, 2002). While many countries still utilize electroencephalography because of its widespread availability and historical use, it has wellknown shortcomings that limit its applicability (Young et al., 2006). Demonstrating the absence of brain blood flow is increasingly recommended as the preferred ancillary test in both children and adults (Shemie et al., 2006; Young et al., 2006).

How should I approach brain death in practice?

Physicians who participate in the declaration of brain death should be experienced in the care of critically ill brain-injured patients, relevant clinical criteria, and diagnostic procedures. National or institutional checklists for testing and documentation are useful assets (Shemie et al., 2006). In cases of potential organ donation, it has been seen that physicians declaring death must not have any association with the identified transplant recipient and must not participate in any way in the transplant procedures.

Brain death is a detailed clinical examination that documents the complete and irreversible loss of consciousness and absence of brainstem function, including the capacity to breathe. The following criteria apply (Shemie et al., 2006).

1.Established etiology capable of causing brain death in the absence of reversible conditions capable of mimicking brain death

2.Deep unresponsive coma

3.Absent brainstem reflexes as defined by absent gag and cough reflexes, corneal responses, pupillary responses to light with pupils at mid size or greater and vestibulo-ocular responses

4.Bilateral absence of motor responses, excluding spinal reflexes

5.Absent respiratory effort based on the apnea test

6.Absent confounding factors.

An absolute prerequisite is the absence of clinical neurological function with a known, proximate cause that is irreversible. There must be definite clinical and/or neuroimaging evidence of an acute central nervous system event that is consistent with the irreversible loss of neurological function. Coma of unclear mechanism precludes the diagnosis. Deep unresponsive coma implies an absence of centrally mediated response to pain. Any motor response in the cranial nerve distribution, central nervous system-mediated motor response to pain in any distribution, seizures, and decorticate and/ or decerebrate responses are not compatible with the diagnosis.

Spinal reflexes, or motor responses confined to spinal distribution, may persist. A proportion of patients may continue to display some reflex spinal activity, which can confuse the bedside staff or the inexperienced clinician and can be disturbing to family members. They should be anticipated and explanations should be provided to families. Observed spinal reflex activity may range from subtle twitches to the more complex ‘‘Lazarus sign’’ and may be seen in 13–39% of cases (Saposnik et al., 2000; Dosemeci et al., 2004). Reversible conditions such as hypothermia and the influence of central nervous system depressants and muscle relaxants need to be excluded. Independent confirmation

and/or determining the irreversibility of coma may require a period of observation, with recommendations varying from 0 to 24 hours, depending on the individual’s age and the cause of the coma (Wijdicks, 2002; Hornby et al., 2006). In clinical practice, distinguishing between brain death and persistent vegetative state is not difficult. In a persistent vegetative state, spontaneous respiration and other rudimentary brainstem reflexes are present and persistent.

In the USA, a whole-brain definition (cerebral hemispheres and the brainstem) for brain death is codified based on the irreversible cessation of all functions of the brain, including the brainstem (President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1981b). This is distinct from the UK, where a brainstem-based definition of death is in place (Pallis and Harley, 1996). It must be understood that the basic clinical evaluation for loss of neurological function in brain death examinations only detects the absence of brainstem function. The clinical examination cannot distinguish between the complete loss of whole-brain function versus brainstem function. The distinction between wholebrain versus brainstem death can be made based on etiology of brain injury and neuroimaging. It can only be confirmed by the use of an ancillary test that shows absence of electroencephalographic activity, or the absence of brain blood flow. For this reason, ancillary testing is commonly used in the USA but only rarely in the UK.

Once brain death has been diagnosed according to the clinical criteria outlined above, physicians and families must realize that brain death equals the death of the patient. Families should be told in no uncertain terms that the patient has died. Issues for the family to consider at this time include organ or tissue donation, autopsy examination and funeral arrangements. Organ-support technologies should be removed unless organ donation is being considered. If there is conflict regarding the diagnosis of brain death that cannot be resolved by the clinicians and the family at the bedside, the coroner may be called in to evaluate the case

90S. D. Shemie, N. Lazar, and B. M. Dickens

and possibly complete the medical certificate of death.

Two possible exceptions to this approach have been discussed in the literature. The first is the unusual circumstance of an apparently brain-dead patient who is pregnant at the time of diagnosis. A small number of such cases have been described in the literature, some with attempts made to maintain the pregnancy until viability of the fetus (Powner and Bernstein, 2003). No consensus has been reached as to whether this should be attempted (Sperling, 2006). Another exception might be based on religious objections to the acceptance of brain death as a criterion for declaring death. New York State adopted a religious exception to brain death in 1987 and New Jersey in 1991 (Olick, 1991). Limitation of support interventions, rather than withdrawal, would normally be accepted and would typically lead to cardiovascular instability and death over a period of days.

The cases

Mr. L probably has progressed to clinical brain death. His doctors will have to perform a formal evaluation at the bedside to determine this status. A careful review of the medication record fails to reveal any sedative or neuromuscular-blocking drugs administered. The patient is not hypothermic. No stimulation evokes a response except for spinal reflexes of the lower extremities. All brain stem reflexes are absent when tested with adequate stimuli. His family is informed of the results of these tests and is asked whether Mr. L was in favor of organ donation. The family agrees to consider organ donation. Mr. L is formally declared brain dead by two qualified physicians. Nine other patients benefit from transplants of his organs.

The condition of the boy, M, deteriorates over the ensuing 48 hours, with signs of brainstem herniation, including fixed and dilated pupils, diabetes insipidus, and impaired thermoregulation. A computed tomography (CT) scan of the head shows

severe cerebral edema consistent with hypoxic– ischemic injury. Examination by two independent specialists on two separate occasions confirms the clinical diagnosis of brain death. The family is counseled on multiple occasions regarding the diagnosis of brain death and consents to organ donation. Seven patients benefit from transplants of the child’s organs.

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