BASIC SCIENCE

Concepts of brain death

Rose Bosnell Hilary Madder

Abstract
The diagnosis of brain-stem death requires clinical testing of brain-stem function, with clear prior identication of the cause of apnoeic coma and exclusion of potentially reversible factors. This article explores the historical, philosophical and legal background of brain-stem death that has led to the UK code of practice for the diagnosis of death. The process for clinical diagnosis is discussed, stressing the importance of establishment of preconditions prior to testing. Basic brain-stem anatomy is reviewed in order to illustrate the systematic testing of cranial nerve nuclei, through brain-stem reexes, that forms the core of brain-stem function tests. We highlight potential pitfalls that may occur in testing. Although not legally required in the UK, supplementary tests of brain-stem integrity are briey reviewed, including electroencephalography (EEG) and single-photon emission computed tomography (SPECT); these tests are used more routinely in the USA and Australia. Finally the legal requirement to ascertain any prior consent of the brain-stem dead patient to organ donation is discussed.

Keywords Brain death; brain-stem death; brain-stem function tests;

brain-stem reexes; guidelines; historical; legal aspects; organ transplantation; philosophy; supplementary tests

Denition of death
Death is dened as the irreversible loss of the capacity for consciousness, combined with irreversible loss of the capacity to breathe. This concept of death incorporates both a philosophical and physiological approach. It was proposed by Christopher Pallis1 in his excellent series on brain-stem death published in 1982. It is the denition adopted by the revised UK Code of Practice for the diagnosis and conrmation of death, produced in 2008 by a working party of the Academy of Medical Royal Colleges.2 Any denition of death needs to be objective, precise, reproducible and irrefutable. It must be independent of the desire to acquire organs for transplantation, but the diagnosis nevertheless is essential for this to proceed. This is important for the professional treating team, relatives and society. The denition of death as the irreversible loss of the capacity for consciousness and the capacity to breathe emphasizes that all death is in fact brain-stem death. That is, cessation of intrinsic cardiac function (cardiac death) is not in itself death until it leads

to irreversible damage to the vital centres in the brain-stem. For example, nobody would think of patients on cardiopulmonary bypass as dead. Likewise the denition pinpoints loss of brainstem function as the dening factor in whole brain death. The UK has established a distinctive approach to brain death, with death of the brain-stem the essential and sufcient component for the diagnosis of death. This differs to the approach of the USA,3 Australia4 and many other countries, where whole brain death (irreversible cessation of all functions of the entire brain including the brain-stem) provides the denition of death. The diagnosis of brain-stem death is clinical. It is reached through fullment of a rigorous set of clinical criteria which includes identication of a condition which has led to irreversible structural brain-stem damage, clinical tests for brain-stem function and exclusion of reversibility. It does not depend upon additional investigations such as electroencephalography (EEG), evoked potentials, or imaging techniques to determine altered or absent cerebral blood ow. Patients who full the clinical criteria for brain-stem death will inevitably proceed to asystole within days or weeks. It is important to note that (unlike the USA and Australia) in the UK there is no statutory denition of death.2 The courts of England and Northern Ireland rely upon the Medical Royal Colleges Code of Practice to determine that death has occurred. The Human Tissue Act 20045 gave the Human Tissue Authority (HTA) the legal power to develop a denition of death for the purpose of the Act, for example for the purpose of organ transplantation. However to date both the Act and the HTA refer to the deceased, but not to a denition of death. Along with international differences, there are religious and cultural differences in the denition of death. Orthodox Judaism and many Asian cultures do not consider death has occurred until all vital functions have ceased.6 The clinician needs to respect these differences within the legal framework for the denition of death.

History
The rst clinical description of brain death occurred in 1959,7 when a series of 23 ventilated patients were recognized by two French physicians to be in a state of irreversible coma coma depasse, with inevitable deterioration of cardiopulmonary function. Following this there was increasing discussion around the concept of brain death, and an emerging need for a legal framework to support the developments of transplant medicine, with the rst cardiac transplant occurring in 1967. The report of the Harvard Medical School Committee in 19688 established clear criteria for the denition of this clinical state, and proposed that brain death was equivalent to death. The statement issued by the UK Medical Royal Colleges and their faculties following a conference in 19769 dened permanent functional death of the brain-stem as equivalent to brain death. It set criteria for the diagnosis of brain-stem death which remains the basis of the current (2008) UK Code of Practice: precondition, irreversibility, and tests for brain-stem function. A further statement issued by the same body following a conference in 1979 identied brain-stem death with death itself.10 The rst UK Code of Practice was issued from the Health Departments in 1983.11 This was reviewed by the Royal College of Physicians in 199512 and a more comprehensive Code

Rose Bosnell MRCP DPhil is a Specialist Registrar in Neurology at the Queen Elizabeth Hospital, Birmingham, UK. Conicts of interest: none declared. Hilary Madder MBBS FANZCA is a Consultant Anaesthetist and Clinical Director of Neurosciences Intensive Care Unit, John Radcliffe Hospital, Oxford, UK. Conicts of interest: none declared.

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of Practice was issued by the Academy of Medical Royal Colleges in 1998 and revised in 2008.2

Philosophical background
The integrative functions of the brain-stem are essential to life and include the neural control of cardiac and respiratory functions as well as consciousness. Patients who full the criteria for brain-stem death inevitably go on to develop asystole and organ necrosis despite continuation of articial ventilation, although the time for this to occur is variable.2e4 That is, the diagnosis of brain-stem death is synonymous with eventual death of the whole organism. Nevertheless, the concept of brain-stem death raises a number of philosophical issues:1  consciousness is essential to life  death is a process, not an event  death of the organism as a whole is sufcient, not death of the whole organism (putrefaction).

Anatomical background
Human life requires the capacity for consciousness and the capacity to breathe. The brain-stem is essential for maintenance of respiration and proper functioning of the cortex. The ascending reticular activating system (RAS) is essential for consciousness. The reticular formation is located within the core of the brain-stem and projects to wide areas of the limbic system and cortex (Figure 1). Although the content of consciousness is a function of activated cerebral hemispheres, consciousness cannot occur without a functioning brain-stem. Disruption of the RAS is associated with coma despite the presence of surviving cells within the cortex. Mechanisms essential for respiratory drive are located within the brain-stem. Because the cranial nerve nuclei are located at close intervals through the length of the brain-stem (Figure 2), the integrity of the brain-stem can be determined by tests of cranial nerve function. Likewise the ability to breathe can be accurately assessed. Bilateral examination of cranial nerve reexes and tests for respiratory response in the presence of hypercarbia (apnoea test) form the clinical tests for brain-stem function in the diagnosis of brain-stem death.

Figure 1 A schematic drawing showing key components of the ascending arousal system. A major input to the relay and reticular nuclei of the thalamus (yellow pathway) originates from cholinergic (ACh) cell groups in the upper pons, the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT). These inputs facilitate thalamocortical transmission. A second pathway (red) activates the cerebral cortex to facilitate the processing of inputs from the thalamus. This arises from neurons in the monoaminergic cell groups, including the tuberomammillary nucleus (TMN) containing histamine (His), the A10 cell group containing dopamine (DA), the dorsal and median raphe nuclei containing serotonin (5-HT), and the locus coeruleus (LC) containing noradrenaline (NA). This pathway also receives contributions from peptidergic neurons in the lateral hypothalamus (LHA) containing orexin (ORX) or melanin-concentrating hormone (MCH), and from basal forebrain (BF) neurons that contain g-aminobutyric acid (GABA) or ACh. (From: Hypothalamic Regulation of Sleep and circadian rhythms Saper et al.29 Reprinted by permission from Macmillan Publishers Ltd: Nature,29 copyright 2005).

Clinical background
The diagnosis of brain-stem death requires fullment of three clinical criteria:2,13 1. Establishment of a specied condition which has led to irreversible brain damage. 2. Exclusion of potentially reversible causes of coma and apnoea. 3. Absence of brain-stem reexes. A summary algorithm for diagnosis and management of brainstem death is shown in Figure 3, which is discussed in more detail in the text that follows. Identication of an irreversible cause of brain damage The existence of apnoeic coma needs to be established before the diagnosis of brain-stem death is entertained. The presence of seizures indicates intact pathways between cortex and periphery and hence at least some brain-stem function. There can be no doubt that the coma and apnoea are due to irreversible brain damage of known aetiology. Diagnosis of brain-stem death cannot proceed

until this precondition is satised. Any event which precipitates brain-stem death is catastrophic, with brain-stem injury through either extensive direct damage, or secondary injury through extensive infratentorial swelling or supratentorial swelling with transtentorial herniation. The irreversible or irremediable nature of the cause is critical. In practice this means that therapeutic manoeuvres such as measures to reduce cerebral swelling or re-establish cerebral blood ow do not or will not have any bearing on the ultimate neurological outcome. In many cases the passage of time is essential to establishing the certainty of this. The list of potential causes is large. In the case of a massive spontaneous intracranial haemorrhage or a devastating head injury the aetiology is unquestionable. However the dening process may not be so clear, and there may be diagnostic and prognostic uncertainties. For example in cases of hypoxic brain injury secondary to barbiturate overdose, there must be certainty that drugs are not contributing to the coma. Invariably brain imaging will have been undertaken to aid in establishing the diagnosis and in demonstrating the process of brain-stem damage such as herniation syndromes and infarction. Global hypoxia following cardiorespiratory arrest is more likely to produce cortical

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Algorithm for the diagnosis and management of brainstem death

Identification of patient in deep apnoeic coma

Clinical evidence of cause of coma

possibly supported by neuroimaging, neurophysiology, CSF, etc.

Exclude reversible causes of coma (hypothermia, intoxication, sedation, neuromuscular blockade, seizures, electrolyte abnormalities, acidbase disturbance, endocrine dysfunction) Absent brainstem reflexes Absent motor response Apnoea PaCO 6.5 kPa
These procedures should be clearly explained to relatives

Legal and clinical diagnosis of death confirmed by two physicians Consider eligibility for organ donation
Figure 2 Schematic sagittal section of brain-stem showing location of cranial nerve nuclei. (From: Patrick J. Lynch, medical illustrator; C. Carl Jaffe, MD, cardiologist. http://creativecommons.org/licenses/by/2.5/.)

Yes Proceed with enquiries and testing prior to organ donation

No Disconnect from ventilator

damage (vegetative state) than damage to the brain-stem,14 but may cause irreversible brain-stem damage following transtentorial herniation secondary to cerebral swelling. Again, there may be uncertainty surrounding the aetiology and irreversibility of the resultant coma, necessitating further investigations (such as EEG to exclude subclinical seizures as the cause of coma) and the passage of time to establish certainty. In the UK severe head injury, intracerebral haemorrhage and subarachnoid haemorrhage account for about 80% of brain-stem death.13,15 Exclusion of potentially reversible causes of coma and apnoea Brain-stem function tests to diagnose brain-stem death should not proceed until potentially reversible causes of the coma and apnoea have been excluded.13 Depressant drugs are often used in the management of patients who go on to develop signs of brain-stem damage. Any contribution of these drugs to coma or apnoea must be excluded before consideration of the diagnosis of brain-stem death. This necessitates a careful drug history along with consideration of the pharmacokinetic prole of potentially causative drugs and the drug clearance mechanisms of the patient, including renal and hepatic metabolism. Sufcient time must elapse for clearance of depressant drugs prior to undertaking tests for brain-stem function. Some clinicians allow three times the half life of the particular agent.16 Particular care should be taken with barbiturates and benzodiazepines which have long half lives and variable metabolic proles, for example the half life of thiopentone extends beyond 11.5 hours. Where drug concentration assays are available these may assist in the exclusion of contribution of these drugs to coma and apnoea.

CSF, cerebrospinal fluid; PaCO , arterial partial pressure of carbon dioxide

Figure 3 Diagnostic and management algorithm for brainstem death. (Adapted from: Academy of Medical Royal Colleges A code of practice for the diagnosis and conrmation of death Appendix 2, p. 23, 2008.2)

Brain-stem function tests should not be undertaken with assays of thiopentone levels more than 5 mg/litre or midazolam levels more than 10 mg/litre2. Where there is a suspicion that benzodiazepines or opioids are contributing to coma or apnoea, specic antagonists (umazenil or naloxone) may be useful. Primary hypothermia must be excluded as a potential cause for coma or apnoea. Core temperature should be greater than 34  C at the time of testing.2 Electrolyte, metabolic, endocrine or circulatory abnormalities often occur within the context of brain-stem dysfunction, but must be excluded as a primary cause of coma or apnoea. A particular complexity surrounds the occurrence of hypernatraemia. This is a frequent occurrence in association with diabetes insipidus secondary to brain-stem dysfunction, yet hypernatraemia may itself be a cause of unresponsiveness. The distinction between causation and effect is essential. A normal serum sodium level at the time of onset of unresponsiveness makes hypernatraemia an unlikely primary cause of coma. Rapid correction of serum sodium disturbance may itself contribute to coma, but where the primary cause of coma is uncertain serum sodium levels above 160 mmol/litre should be corrected.2 Likewise circulatory instability is common following cessation of brain-stem function, but may in itself contribute to unresponsiveness. Marked disturbance must be corrected prior to testing,

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with resuscitation to maintain mean arterial blood pressure above 60 mmHg and correction of hypoxaemia, acidaemia or alkalemia.2 Absence of brain-stem reexes Once deep apnoeic coma has been established clinically, the aetiology of irreversible brain damage dened and potentially reversible causes of coma excluded, brain-stem reexes should be assessed. This stresses that the diagnosis of brain-stem death is entirely clinical. Tests for cranial nerve function and the presence of apnoea indicate the integrity of the brain-stem. It is important therefore to be familiar with basic brain-stem anatomy (Figure 2). The cranial nerve nuclei are found within the brain-stem. Cranial nerves II, III and IV are found in the midbrain, V, VI, VII and VIII are found in the pons and IX, X, XI and XII are located in the medulla. They are paired structures, therefore tests need to be bilateral. However if local injury or disease prevents bilateral testing a unilateral test will sufce.2 Six cranial nerve reexes are tested. Each has an afferent and efferent limb, but only one of these limbs need to be disrupted for the reex to be absent. 1. Pupillary response to light. (Afferent CN II, efferent Edinger Westphal nucleus CN III). The pupils are xed with no constrictor response to a bright light. Resting pupils are generally dilated, but may be mid-size if extensive midbrain damage has disrupted cervical sympathetic pathways. Pinpoint pupils indicate an intact Edinger Westphal nucleus and are inconsistent with brain-stem death. The exception to this is direct action on the sphincter pupillae such as following pilocarpine eye drops. 2. Corneal reex. (Afferent V, efferent VII). 3. Vestibulo-ocular reex. (Afferent VIII, efferents III, VI). The caloric response involves slow injection of 50 ml ice cold water over 1 minute into each external auditory meatus. This should be preceded by examination of each tympanic membrane to conrm that clear access is possible. There is no eye movement response. Where there is not clear access to the tympanic membrane the dolls eye reex should be tested to conrm no eye movement within the head. 4. Cranial motor response to pain. (Afferent V, efferent VII). There is no facial grimace to cranial (rm supraorbital pressure) or somatic (each limb in turn) stimulation. 5. Gag reex (Afferent IX, efferent X). 6. Cough reex (Afferent and efferent X). There is no cough response to a suction catheter passed down the trachea to the carina. The nal test is the respiratory response to hypercarbia (apnoea test). The response must be tested across levels of hypercarbia which would normally stimulate a respiratory response but avoid levels which might produce narcosis. In patients with no prior history of respiratory disease mechanical ventilation is reduced until the PaCO2 is just above 6.0 kPa and pH below 7.4 on arterial blood gas analysis. The patient is then disconnected from the ventilator and observed for spontaneous respiratory effort over 5 minutes. PaCO2 is measured to conrm a rise to above 6.5 kPa.2 Absence of respiratory effort over this period conrms an apnoeic response. To prevent hypoxia the patient should be ventilated with 100% oxygen immediately prior to apnoea testing, and oxygen ow continued via a CPAP circuit during the test.

Procedural requirements2
The diagnosis of brain-stem death requires at least two doctors who have been registered for more than 5 years. At least one of the doctors must be a consultant. Neither doctor should be a member of the transplant team. Two sets of tests must be performed, with both doctors present at each testing. Although death is not diagnosed until the second testing conrms absence of brain-stem reexes, the legal time of death is recorded as the time of the rst test. Pitfalls in the diagnosis of brain-stem death Fear of a wrong diagnosis of brain-stem death has been expressed by the public and even clinicians. Whilst there should be no complacency, the UK, US and Australian Codes of Practice are rigorous; no patient who has fullled the criteria demanded by any of these has survived2e4,17 (although it has been argued that such a diagnosis has a self-fullling prophecy). The diagnosis of brainstem death should never be entertained in patients who are not in a state of apnoeic coma. Where the diagnosis is entertained, the importance of satisfying preconditions prior to testing for brainstem reexes cannot be over-emphasized. That is, there must be a specied condition which has led to irreversible structural brain damage, and all potentially reversible causes for the patients condition must have been excluded. Many of the pitfalls in diagnosis arise from failure to full these preconditions. Particular awareness is important following a brain-stem vascular event. Failure to diagnose locked in syndrome following ventral pontine infarction is a common fear expressed by clinicians.18 However these patients retain eye movements such as vertical conjugate gaze or blinking, which although minimal should not be missed in the context of the clinical history. Hearing is

Potential pitfalls in brain-stem death diagnosis

Findings Pupils xed Possible causes Drugs: anticholinergics, tricyclic antidepressants, barbiturates Topical mydriatics Pre-existing disease Trauma: globe or craniofacial injury Drugs: ototoxic agents, anticholinergics, tricyclic antidepressants, sedatives Pre-existing vestibular disease Basal skull fracture External auditory canal blocked Post-hyperventilation apnoea Drugs: neuromuscular blockers, sedative agents Cervical spine injury Drugs: neuromuscular blockers, sedative agents Locked e in state Cervical spine injury

No vestibulo-ocular reexes

No respiration

No motor activity

Modied from: Pitfalls in the diagnosis of brain death in Plum and Posner. Diagnosis of Stupor and Coma, 4th edn. Oxford University Press, 2007

Table 1

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generally unaffected and the ability to breathe spontaneously is maintained. Generally the diagnosis of brain-stem death is never entertained in these patients as they do not reach apnoeic coma. Some potential pitfalls to exclude of when diagnosing brainstem death are listed in Table 1. Spinal reexes Reex movements in limbs and torso can be seen with brainstem death. These movements include the Lazarus sign where there is exion at the waist causing the torso to rise towards a sitting posture.19 It is important that family members are prewarned of spinal reexes to avoid unnecessary stress. Supplementary or conrmatory investigations In the UK the diagnosis of brain-stem death is made on clinical grounds alone. That is, a patient cannot be declared brain-stem dead unless clinical criteria for brain-stem death are fullled in accordance with the 2008 Code of Practice. Supplementary investigations may be useful in establishing the precondition of irreversible (structural) brain damage or absence of reversible factors contributing to the apnoeic coma. This differs from other countries, such as the USA or Australia, where ancillary investigations such as cerebral angiography to conrm whole brain death are given a more formal role, for example where the apnoea test cannot be performed.3,4 In instances where brain-stem reexes cannot be adequately tested, such as in extensive facio-maxillary injuries or high cervical spinal cord injury, the UK code allows ancillary investigations to exclude uncertainty around residual brain-stem function.2 Whilst whole brain death is associated with the absence of EEG activity (an isoelectric EEG), EEG is not particularly useful in the diagnosis of brain-stem death. Cortical activity may exist for some time after the brain-stem has ceased to function; likewise absence of cortical activity (isoelectric EEG) may occur when the brain-stem still has function. The use of EEG is complicated by artefact and the effect of metabolic or toxic states inducing false positives with series reports.20 However EEG can be important in the investigation of apnoeic coma, for example to identify seizure activity. Four-vessel angiography has been viewed as gold standard in diagnosing whole brain death. However, it is invasive and there are isolated cases of false positive results in the case of toxicity.21 Computed tomography (CT) angiography may be an effective alternative to conventional angiography,22 however its sensitivity and specicity require further validation and false positives have been noted.23 Single-photon emission CT (SPECT) with technetium-99m has also been used as an ancillary test in diagnosing brain death in those cases where for example drug withdrawal may complicate the picture.24 It characteristically gives an empty skull image in the case of brain death. In a direct comparison between SPECT and angiography, both tests conrmed brain death in 19/20 patients.25 More recently centres have been using transcranial doppler as a supplementary investigation. The combined sensitivity using basilar or middle cerebral arteries is 77.2% with a specicity of 100%.26 Transplant The diagnosis and conrmation of brain-stem death is independent to organ transplantation. The treating doctor should maintain

this single focus until death has been declared. Brain-stem dead patients present less ethical confusion and fewer conicts of interest between patient, relatives and potential organ recipients than critically ill but live patients with uncertain futility who might proceed to non-heart-beating organ donation. Once brain-stem death has been declared it is a requirement within the UK for the clinician to ascertain whether the patient has, whilst alive and competent, consented to organ donation after death. This is generally done via referral to the local transplant donor co-ordinator. All patients are registered onto the Potential Donor Audit. The NHS Organ Donor Register is checked as a valid indication of the patients past wishes. The Human Tissue Act 20045 makes the appropriate past consent of the patient to transplantation sufcient for the activity to be lawful. The Act stresses the importance of consent. It makes it lawful to take minimum steps to preserve the organs of a deceased person for use in transplantation while steps are taken to determine the wishes of the deceased, or, in the absence of their known wishes, obtaining consent from someone in a qualifying relationship.27,28

Conclusion
The revised 2008 UK Code of Practice for the diagnosis and conrmation of death provides an excellent framework for discussion of the concepts of brain death. The UK has established a distinctive approach to brain death which pinpoints death of the brain-stem as the essential and sufcient component for the diagnosis of death. Clinicians need to be entirely familiar with concepts of brain death. The increasing signicance of issues such as organ transplantation, futility and resource limitation means these concepts have become entirely relevant to public discussion. A

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