Brain death

Handbook of Clinical Neurology, Vol. 118 (3rd series) Ethical and Legal Issues in Neurology J.L. Bernat and R. Beresford, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 16

Brain death EELCO F.M. WIJDICKS* Division of Critical Care Neurology, Mayo Clinic, Rochester, MN, USA

INTRODUCTION In the second half of the 20th century, as a result of the emergence of intensive care units and, with it, comprehensive resuscitative efforts, physicians were suddenly confronted with, in Henry Beecher’s words, “hopelessly unconscious patients” (Beecher, 1969). Intubation, mechanical ventilation, and use of vasopressors and fluid resuscitation allowed patients with a catastrophic neurologic injury to “survive.” Some patients were found to be apneic and with no brainstem reflexes. Neurologists were quick to point out that these patients not only had unsurvivable neurologic injury, but were “brain-dead” – a term that in the early days was used interchangeably with irreversible coma. When patients with no brainstem reflexes came to autopsy, several had marked necrosis of the brain and cerebellum, which often fragmented in the hands of the neuropathologist when removed from the skull (Alderete et al., 1968; Walker, 1978). What distinguishes brain death from other catastrophic comatose conditions is now clear but scholarly work was needed to clarify and explain this neurologic state. Detailed descriptions of brain death emerged by Drs. Wertheimer, Jouvet, Mollaret, Goulon, Pallis, Jennett, Schwab, and Adams, and all concluded to the best of their medical and neurologic judgment that this condition was not only irreversible – it represented death (Mollaret and Goulon, 1959; Wertheimer et al., 1959; Schwab et al., 1963; Goulon et al., 1971; Jennett et al., 1981; Pallis, 1983). Now, more than 50 years after the original descriptions, brain death is accepted and considered a neurologic definition of death by practitioners in the field. It also became apparent that this neurologic state was very uncommon. And because it is so uncommon, brain death is a medical diagnosis that requires careful evaluation. Over time, detailed criteria and guidelines have been developed and, in theory, should substantially have

increased the reliability of the clinical examination (Wijdicks et al., 2010). In this chapter, I discuss the history of development of the criteria, the current clinical examination, and some of the ethical and legal issues that have surfaced. New ethical issues became apparent when brain death was linked to transplantation, which occurred a decade after the original descriptions. Moreover, it should be pointed out that several bioethicists and even some physicians have marked difficulty with the diagnosis of brain death and continue to point out concerns. An overview of these disputations and the errors of their argument has been published elsewhere (Wijdicks, 2011) and in a chapter by Bernat in this volume (Chapter 33). If death of the patient is defined by irreversible loss of brain function – and, more straightforwardly, the brainstem – the issue is not debatable. Whether a “dead brain” is equivalent to the death of a person however removes the discussion from the medical sciences into the realm of metaphysics and spirituality.

BRAIN DEATH: FROM A SIMPLE TO A COMPLEX CONCEPT AND BACK The medical diagnosis of brain death should be based on a simple premise. If every possible confounder has been excluded, irreversible loss of brain function is clinically recognized as the absence of brainstem reflexes, verified apnea, loss of vascular tone, invariant heart rate, and, eventually, cardiac standstill. This condition cannot be reversed – not even partly – by medical or surgical intervention, and thus is final and fundamentally absolute. It is an acceptable neurologic definition of death. Another definition of death is circulatory arrest, but this condition has the possibility of reversal with resuscitation – at least for some time.

*Correspondence to: Eelco F.M. Wijdicks, M.D, Ph.D., Division of Critical Care Neurology, Mayo Clinic, 200 First Street SW 55905, Rochester, MN, USA. Tel: þ1-507-284-2511, E-mail: [email protected]

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It has been known for many years that the brainstem is the critical part of the brain and the final neuronal structure to go out of function in a catastrophic neurologic injury, or, as eloquently stated by Pallis (1983), “the infratentorial repercussion of supratentorial lesion.” The mere fact that most patients with a catastrophic neurologic injury do not lose all brainstem reflexes points to its natural resilience. The exquisite importance of the brainstem, not only in defining life or death, is already clear from its anatomic importance in the evolution of species (Fig. 16.1). However, it would take many decades for physicians to understand (and accept) this fundamental observation. A need to demonstrate loss of all neuronal function through absence of intracranial circulation or absence of electric activity would remain – for a substantial minority of physicians, including neurologists and neurosurgeons – the only proof of brain death (Wijdicks, 2002). Brain death is clinically determined by a set of criteria. How did these criteria develop? Why did it become so complicated? What were the controversies all about? A brief review of the development of these criteria is needed. The earliest accounts of brain death were published by European neurophysiologists, neurologists, and neurosurgeons. Two major papers were published in 1959 (Mollaret and Goulon, 1959; Wertheimer et al., 1959). Both papers were markedly different in their approach to patients who had lost all brain function. Wertheimer and colleagues were interested in neurophysiology of the brain, or lack thereof. Mollaret and Goulon focused more on clinical manifestations of brain death. Wertheimer et al. described patients with persistent apneic coma, absent brainstem reflexes, and electrically silent brains. They found no breathing after disconnection of a ventilator and called the condition a heart/lung preparation (Wertheimer et al., 1959). To confirm an absence of electric brain activity, fine sterile bipolar electrodes were passed through burr holes in the direction of the median thalamic structure. Electric stimuli were delivered, and none produced a motor response. Direct stimulation of the sciatic nerve and thalamus also produced no recordable trace at the scalp level. Several months later, Mollaret and Goulon (1959) described a condition that they called coma dpass. This type of coma went well beyond (dpass) the deepest coma so far described. Their description was expertly detailed and included not only the description of absent brainstem reflexes, but also systemic responses that included the presence of poikilothermia, diabetes insipidus, and marked hypotension requiring pharmaceutic support. After these observations very few papers – and none of substance – were published between 1959 and 1968. Studies largely concentrated

Fig. 16.1. Evolution of species and the central position of the brainstem. (By permission of Mayo Foundation for Medical Education and Research. All rights reserved.)

BRAIN DEATH on isoelectric electroencephalograms (EEGs) and findings of absent intracranial flow. In the United States, Robert Schwab can be credited for providing a more detailed description of an isoelectric EEG in brain death and merging the EEG into diagnostic criteria (Schwab et al., 1963). Only after the publication of the report of the Ad Hoc Committee of the Harvard Medical School in 1968 did the issues become of interest to U.S. physicians (Anonymous, 1968). The so-called Harvard criteria emphasized clinical criteria, although they felt that an EEG was of “great confirmation value.” A year later, Beecher (1969) stated that “the EEG was nonessential.” The main criteria – coma, absent brainstem reflexes, apnea, isoelectic EEG, and 24-hour observation – were written by neurologists Raymond Adams and Robert Schwab (Anonymous, 1968). The document emphasized the most important findings on examination – coma, apnea, and absent brainstem reflexes – and required an isoelectric EEG. A repeat examination was considered and confounders were mentioned. All committee members felt this identified not only the death of a person, but also the futility of support. In retrospect, this document was of exemplary simplicity. Several years after the publication of the Harvard criteria, a group of neurologists and neurosurgeons undertook a large-scale study that also became known as the collaborative study (Bennett et al., 1976; Moseley et al., 1979; Collaborative Study, 1997). In this National Institute of Neurologic Disorders and Stroke (NINDS) supported study, the patient simply had to meet two criteria: being comatose, and apneic. Patients would be enrolled after being in such a condition for 15 minutes or more. The study involved nine centers spread throughout the United States and enrolled 503 cases of suspected brain death. The study also tested the use of a confirmatory test, particularly to demonstrate the absence of cerebral blood flow. The investigators of the collaborative study were primarily interested in neuropathology and neurophysiologic characteristics of brain death and found none. However, the study was flawed because it included patients with confounders (e.g., drug intoxication, hypotension) and patients with incomplete examinations (no formal apnea tests). This study became known as the US Collaborative Study and defined brain death as “cerebral death.” In their view, death of the brain should involve all structures above the tentorium, and there was little emphasis on the brainstem. The study acquired some notoriety after it claimed that the clinical examination was not sufficiently trustworthy and that patients with absent brainstem reflexes could improve. Other imperfections of the study have been recognized over the years (Wijdicks, 2012).

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The Collaborative Study identified testing of brainstem reflexes but felt that a confirmatory test, either electrophysiologically or by blood flow, was necessary to define brain death. The collaborative study became a model for the President’s Commission report and that in itself was a model for legislation on the subject of death. The Report of the Medical Consultants on the Diagnosis of Death to the President’ Commission on Ethical Issues in Medicine and Biomedical and Behavioral Research published guidelines in 1981 (Guidelines for the determination of death, 1981). The Commission attempted to develop criteria that: (1) eliminated error in classifying a living individual as dead; (2) allowed as few errors as possible in classifying a dead body as alive; (3) allowed a determination to be made without unreasonable delay; and (4) were explicit, adaptable, and accessible to verification. Brain death was defined as the irreversible cessation of all [clinically ascertainable] function of the entire brain including the brainstem.” The report led to the Uniform Determination of Death Act (UDDA). The Commission concluded that “it is not necessary – indeed it would be a mistake – to enshrine any particular medical criteria, or any requirements for procedure or review, as part of the statute.” The main consequence of the UDDA was that a patient could be declared dead and wills and insurance proceeds would become activated. No civil or criminal liability will result from removing the body from life support, except in New York and New Jersey, where physicians are required to honor religious objections. The UDDA was approved by the American Medical Association, the American Bar Association, and the President’s Commission on Medical Ethics. The UDDA was subsequently adopted by all 50 states and the District of Columbia (Arizona, Massachusetts, and Washington adopted the concept of brain death judicially). Guidelines may serve as accepted standards of practice, because the UDDA does not spell out details of the neurologic examination. The U.S. law therefore differs substantially from all other brain death legislation in the world (Choi et al., 2008). The general mistaken assumption is that, in the United States, brain death can be determined only by demonstrating death of the entire brain, while the U.K. position has been that simply the absence of brainstem function would suffice. The U.K. position always has been that absent brainstem function defines brain death. However, the U.K. position also stressed that the patient had to pass through two filters, those of both previous conditions and exclusions. Although prior criteria mentioned mimicking factors, this approach was novel in suggesting that no patients should be examined unless this issue was addressed. In addition, testing for apnea was described

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in more detail using preoxygenation and diffusion oxygenation. The Conference of Medical and Royal Colleges and Faculties of the United Kingdom (1976) later changed brain death into brainstem death, again emphasizing the importance of the brainstem. As expected, neurologic criteria have been developed in countries throughout the world, but most were modeled after the U.S. criteria. Substantial differences have been noted in the use and requirement of confirmatory tests, the number of physicians needed, how to perform the apnea test, and the time of observation needed between two tests. Over the years, multiple levels of complexity have been introduced by multiple countries. There is global acceptance of the concept of brain death and there are no concerns with the validity of the concept. In a comprehensive survey of the criteria in 80 countries there were major differences in the technical procedures used to arrive at the clinical diagnosis (Wijdicks, 2002). No major differences were noted when the methods of examination of brainstem reflexes were compared with each other; but there were marked differences in how the apnea test was performed. The presence of apnea using a PaCO2 target value was used in only 59% of all guidelines. In others, preoxygenation with 100% oxygen followed by 10 minutes’ disconnection was deemed sufficient. There was no evidence that the insufficient apnea testing was a result of failure to obtain timely arterial blood gases or a general reluctance to do the test. In Central and South American countries, a large proportion of patients were either examined with disconnection from the ventilator only, or criteria or guidelines for the apnea test were not present. This is potentially concerning because apnea can only be determined after introducing acute hypercarbia, resulting in cerebrospinal fluid acidosis that in turn maximally stimulates the respiratory centers. Ten minutes’ disconnection in a patient with a baseline hypocarbia (not uncommon after induced hyperventilation for increased intracranial pressure) could potentially show apnea with a PaCO2 not reaching a target value. The number of physicians required to diagnose brain death varies significantly throughout the world. In 44%, one physician was required; in 34%, two physicians; and in 16%, more than two physicians. In 6%, the number of physicians was not specified. Confirmatory tests were required in 40% of the 80 surveyed nations of the world (Wijdicks, 2002). The complexity of criteria did not seem to be influenced by cultural differences. There was no difference between eastern and western civilizations, and the differences were largely already apparent in one single continent. In some countries, an academic grade was required to perform the test (i.e., associate professor level). The type of confirmatory tests and the need for confirmatory tests have been different throughout many countries. The choice of confirmatory tests seems to be

arbitrary, with Sweden as a notable exception. In this country, contrast injection during a cerebral angiogram has to be performed twice with an adequate period of observation in between thus documenting an absence of flow to the brain (Haupt and Rudolf, 1999). Surprisingly, in some countries stricter criteria (confirmatory test) are present when donation was considered. This is a common qualifier in many guidelines throughout the world. Other notable exceptions are Germany and Japan. Germany stipulates EEG, evoked potential, or absent blood flow with infratentorial lesions and 72 hours of observation (Richtlinien zur Feststellung des Hirntodes, 1997). Japan has constructed even more complex criteria (Kinura, 1991; Takeshita, 1998). These criteria include the computed tomography (CT) scan showing irreparable lesions, the ciliospinal reflex being tested, the apnea test being performed after the loss of seven brainstem reflexes and only after an isoelectric EEG. Children less than 6 years old are excluded from brain death assessment for potential transplantation. When reviewing the complex guidelines of brain death determination and preparation for organ donation, one can only conclude that consensus is needed (Greer et al., 2008). Complicating the diagnosis with additional laboratory tests must have been driven by a concern that inaccurate assessment of these fatally injured patients may occur. However, more physicians and more confirmatory tests cannot solve that. What remains needed is appropriate education of staff, introduction of checklists in intensive care units (ICUs), and brain death examination by designated neurologists who have documented proficiency in brain death examination. The American Academy of Neurology, however, recognized the overwhelming complexity of criteria and simplified it to a set of 25 tests and verifications that would lead to an accurate diagnosis of brain death (Wijdicks et al., 2010). The general approach remains clinical, with exclusion of confounders, followed by a systematic testing of brainstem function and breathing drive. Despite overwhelming empiric evidence of irreversibility after loss of all brainstem function and rapid cardiovascular collapse requiring ICU support in over 10 000 cases throughout the world, strictly speaking, a prospective study with repeat examinations over several days to weeks has not been performed. Such a study would be impossible, effectively stop organ donation for the duration of the study, and unnecessarily increase deaths on the transplant waiting list.

CURRENT CLINICAL CRITERIA The clinical examination of a patient suspected of brain death starts when a patient with a massive acute brain injury has no motor response to pain, fails to grimace

BRAIN DEATH to pain, has absent brainstem reflexes, and does not trigger the ventilator. Commonly, the patient has been hypotensive and is on vasopressors. Using this starting point, many patients will fulfill the criteria of brain death (Black, 1978; Ad-Hoc Committee on Brain Death, 1987; Ashwal and Schneider, 1987a, b; Ashwal, 1997; Wijdicks, 2001, 2011; Wijdicks et al., 2010; de Groot et al., 2011a, b). With any other starting point there is a greater chance that there will be retained brain function and even spontaneous breathing after a CO2 challenge. The evaluation of brain death thus can be considered only when eyes are not open to pain; pupils, corneal reflexes, and cough reflexes are absent; no motor response is seen; and the patient is not overbreathing the ventilator. In this section, I review the major components of this evaluation. First, confounding factors should be excluded. This implies no prior sedation with medications, illegal drugs, or any lingering effects. A reasonable guideline is to calculate five to seven times the elimination half-life in hours and allow that time to pass before clinical examination is performed. Examples of long elimination halflife medications are phenobarbital (100 hours), diazepam (40 hours), amitriptyline (24 hours), primidone (20 hours), and lorazepam (15 hours). A commonly used benzodiazepine is midazolam (3 hours). Prior alcohol use should be excluded, but the legal alcohol limit for driving (blood alcohol content 0.08%) is a practical threshold. An alcohol content below this level is acceptable to determine brain death. There is no need to wait for full clearance of alcohol levels to proceed with testing. Prior hypothermia may substantially slow down the metabolism of medications such as lorazepam and fentanyl. Absence of neuromuscular blockade (defined by the presence of four twitches with a train of four with maximal ulnar nerve stimulation) should be demonstrated but is unlikely if the patient has tendon reflexes (or breathes). Furthermore, absence of severe electrolyte-acid  base or endocrine disturbances (defined by marked acidosis or any substantial deviation from the normal values) or a core temperature greater than 36  C should be documented. Systolic blood pressure should be greater than 100 mmHg. The sudden appearance of hypotension is virtually always the first sign of transition to brain death. Next, the CT scan should be carefully re-reviewed and demonstrate massive brain destruction. Abnormalities may include large mass and brain tissue shift, multiple hemorrhagic lesions, or diffuse cerebral edema with obliteration of basal cisterns. CT scan can be initially normal if the patient has been imaged very early after cardiopulmonary arrest. However, in patients with anoxic-ischemic encephalopathy who eventually fulfill these criteria, brain edema or marked hypodensities in thalami, caudate nuclei, and basal ganglia are typically

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present. Brain death determination should not be considered if a medical or neurosurgical intervention may reverse the condition. Situations that may closely mimic brain death are acute severe hydrocephalus and cerebellar hematoma with improvement after decompressive surgery or ventriculostomy or both. Only after all these confounders have been excluded should a more formal examination proceed. The comatose patient should be unresponsive to verbal or painful stimuli. Standard noxious stimuli include compression of the supraorbital nerves, forceful nail bed pressure, and bilateral temporomandibular joint compression. Eye opening to noxious stimuli should be absent. No motor response should be observed. Some motor responses may be preserved and the challenge is to diagnose them as “spinal responses.” They may occur with neck flexion and nail bed compression but are absent with supraorbital nerve compression. These responses are not classifiable as decorticate or extensor responses. These responses are uncommon, but include triple flexion responses, finger flexion or extension, head turning, and slow arm lifting (Conci et al., 1986; Christie et al., 1996; Bueri et al., 2000; Martı´-Fa`bregas et al., 2000; de Freitas and Andre, 2005; Jung et al., 2006; Araullo et al., 2007; Zubkov and Wijdicks, 2008). These movements do on occasion cause concern for the family members (and even transplant surgeons) if not properly explained. The examination then proceeds with evaluation of pupillary responses. Pupils should be mid-position (4–6 mm) and unresponsive to light. A magnifying glass or hand-held pupillometer can be helpful, in particular, when there is an uncertainty about the reactivity of pupils. One should be aware that atropine used during cardiopulmonary resuscitation may cause pupillary dilation. The corneal reflexes should be absent. The oculocephalic reflexes (doll’s eyes) should be absent bilaterally (fast turning of the head to both sides should not produce any ocular movement). The oculovestibular response (cold calorics) should be absent. The head should be elevated 30 . Approximately 50 cc of ice water is then infused in the external auditory canal. No eye movement should be observed after 2 minutes of observation. The examination proceeds next with evaluation of gag and cough reflexes, both of which should be absent. Gag reflex could be tested by a movement of the endotracheal tube but better with sticking a finger deep in the back in the throat moving the uvula. Cough reflex should be tested by deep bronchial suctioning. Finally an absent breathing drive using CO2 challenge is proven after a formal apnea test. The apnea test is best performed under controlled circumstances and with disconnection of the mechanic ventilator (Rohling et al., 1986; Marks and Zisfein, 1990; Goudreau et al., 2000; Levesque et al., 2006; Wijdicks et al., 2008). This will

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avoid artifactual findings because the ventilator may spuriously indicate breathing drive of the patient and this phenomenon – caused by minimal pressure or volume changes in the breathing circuit – is quite commonly not recognized (Wijdicks et al., 2005). The neurologic examination in adults and apnea testing is summarized in Table 16.1 and Figure 16.2 (Wijdicks et al., 2010). Pitfalls have been recently summarized else where (Wijdicks, 2013). Technical tests to “confirm” brain death have been developed and may demonstrate absent blood flow to the brain or absent electric activity of the cortex. These tests have false-positive and false-negative results and less than perfect accuracy and therefore should not replace, in any way, a clinical assessment. Interpretation

of these tests, when results are not obvious, remains difficult and results of different tests may not be matching (Table 16.2). A critical assessment of confirmatory tests with inaccuracy rates has been published (Wijdicks et al., 2010). These tests have mostly been used in the event that a patient fulfilled all criteria, but with an inability to complete an apnea test. In our practice, confirmatory tests are used in less than 5% of patients diagnosed with brain death and are better generally avoided. Elevating a confirmatory test to a diagnostic test may lead to errors in brain death determination. Moreover, delaying a declaration of brain death because of a negative confirmatory test (trickle of flow or some EEG activity in a patient fulfilling all criteria of brain death) not only is poor practice but has little justification.

Table 16.1 25 Assessments necessary to declare a patient brain-dead Prerequisites (all must be checked) 1. Coma, irreversible; cause known 2. Neuroimaging explaining cause of coma 3. CNS-depressant drug effect absent (if indicated on toxicology screen; if barbiturates given, serum level < 10 mg/mL) 4. No evidence of residual paralytics (electric stimulation if paralytics used) 5. Absence of severe acid–base, electrolyte, endocrine abnormality 6. Normal or near-normal temperature (core temperature  36 C) 7. Systolic BP  100 mmHg 8. No spontaneous respirations Examination (all must be checked) 9. Pupils nonreactive to bright light 10. Corneal reflex absent 11. Eyes immobile, oculocephalic reflex absent (tested only if cervical spine integrity ensured) 12. Oculovestibular reflex absent 13. No facial movement to noxious stimuli at supraorbital nerve or TMJ (absent snout or rooting reflexes in neonates) 14. Gag reflex absent 15. Cough reflex absent to tracheal suctioning 16. Absence of motor response to noxious stimuli in all four limbs (spinally mediated reflexes are permissible and triple reflex is most common) Apnea testing (all must be checked) 17. Patient is hemodynamically stable (BP >90 mmHg) 18. Ventilator adjusted to provide normocarbia (PaCO2 35–45 mmHg) 19. Patient preoxygenated with 100% FiO2 for >10 minutes to PaO2 > 200 mmHg 20. Patient maintains oxygenation with a PEEP of 5 cm H2O 21. Disconnect ventilator 22. Provide oxygen via insufflation catheter at the level of the carina (6 L/min) or attach T-piece with CPAP at 10 cm H2O 23. Spontaneous respirations absent 24. ABG drawn at 8–10 min; patient reconnected to ventilator 25. PCO2  60 mmHg or 20 mmHg rise from normal baseline value; document time of death or Apnea test aborted and ancillary test (EEG or blood flow study) confirmatory; document time of death

□ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □

Reproduced from Wijdicks (2010) with permission. ABG, arterial blood gas; BP, blood pressure; CNS, central nervous system; CPAP, continuous positive airway pressure; EEG, electroencephalography; PEEP, positive end-expiratory pressure; TMJ, temporomandibular joint.

BRAIN DEATH Pediatric brain death was carefully defined by a multidisciplinary task force in 1987 and has been recently updated by the Society of Critical Care Medicine (SCCM) the American Academy of Pediatrics (AAP) and (Ashwal and Schneider, 1987a, b; Ashwal, 1997; Goh and Mok, 2004; Shemie, 2007; Nakagawa et al., 2011). Most concerns regarding interpretation of neurologic examination are in children several months old. Neurologic examination becomes a challenge in neonates, and the advanced skills of a neonatologist are needed to obtain reliable findings. Examination of a child in an incubator remains limited, and neurologists should be aware of incompletely developed brain function and motor response. The new pediatric guideline suggests a 24-hour interval between examinations by two physicians in neonates and children from 37-week gestation to the end of the first year. However, in children aged 1 year or older the pediatric

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guideline still imposes two examinations 12 hours apart by two different attending physicians. The second examination, according to the pediatric guideline, “proves irreversibility.” The pediatric recommends that physicians be competent to perform examinations in infants and neonates and additionally recommends that these examinations be performed by pediatric intensivists and neonatologists, pediatric neurologists and neurosurgeons, pediatric trauma surgeons, and pediatric anesthesiologists with critical care training. In addition, the pediatric guideline recommends adult specialists should have appropriate neurologic and critical care training to diagnose brain death when caring for a pediatric patient from birth to 18 years of age. The new pediatric guidelines will not result in a better or easier or more practical approach (Wijdicks and Smith, 2012). First, neurologic examination comes before a

Fig. 16.2. Main elements of neurologic examinations. (A) Essential brainstem reflexes. (see text) Continued

Fig. 16.2—cont’d (B) apnea test (see Table 16.1 for description). (Reproduced from Wijdicks (2011), by permission of Mayo Foundation for Medical Education and Research. All rights reserved.)

BRAIN DEATH Table 16.2 Pitfalls of confirmatory tests Cerebral angiogram Image variability with injection of arch or selective arteries Image variability with injection and/or push technique No guidelines for interpretation Transcranial Doppler ultrasonographic scan Technical difficulties and skill-dependent Normal in anoxic-ischemic injury Electroencephalogram Artifacts in intensive care settings Information primarily from cortex only Somatosensory-evoked potentials Absent in patients not brain death Computed tomography angiogram Interpretation difficulties Retained blood flow in 20% of cases Possibility of missing slow-flow states because of rapid acquisition of images Nuclear brain scan Areas of perfusion in thalamus in patients with anoxic injury or skull defect Reproduced from Wijdicks (2010), with permission.

search of mimicking conditions and this reversal may confuse physicians. Second, ancillary tests are allowed to help in the diagnosis of brain death when sedatives may linger and it violates an important principle that patients should be examined without any confounders. Third, the age brackets and need for repeated examinations by certain specialists have no justification. Irreversibility is not determined by a waiting period but by documenting no brainstem reflexes and apnea in a comatose patient without confounding circumstances. There is little evidence to suggest that neonates older than 4–6 months are neurologically much different than adults. The impact of this guideline on practice and organ donation is not yet known.

PERSONAL BELIEFS AND ETHICAL CONCERNS The concept of brain death has been accepted by nearly all major religions (Trivedi, 1990; Tsuji, 1998; Bresnahan and Mahler, 2010). But patients’ families may have different ideas and are mostly colored by cultural attitudes, traditional customs, and personal beliefs. The major religions in the United States include Christianity, Islam, and Judaism, and often they are divided into various denominations. Islam is the religion of Muslims, and the traditional teaching is that Muslims should not give up, which implies that termination of life support is not allowed. However, the third international conference on Islamic medical jurisprudence was in favor of

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declaring brain death as the death of a person (Al-Mousawi et al., 1997). Jewish law (Halacha) has also accepted brain death, although some Orthodox rabbis disagree and accept a determination of death only by respiratory and circulatory criteria. The Orthodox Jewish community in New York has been successful in lobbying for a religious exception to the New York statute on death determination. In New York and New Jersey, devout Orthodox Jews can demand that the attending physician continue support and respect their religious belief that cardiac arrest is the only sign of death. In 1991, New York and New Jersey enacted such a law providing this exception. Jewish believers can consult with their rabbi, and only the strictest Orthodox rabbis follow the ancient teachings that define cardiac arrest as the defining moment of death (Kunin, 2004). Christian denominations interpret brain death as the death of a person and feel that organ donation is the ultimate gift of life. There is no controversy in the Catholic Church or with any other denominations. The Roman Catholic Church legitimizes organ donation by the principle of solidarity and charity. It is permissible to switch off the life support system with total and irreversible loss of function of the whole brain if attending specialist physicians render their opinion unequivocally that irreversible cessation of brain functions has occurred. In some cultures it is difficult to obtain consent from families for organ donation. There might be a personal conviction of the family that the patient is not dead and that may lead to a conflict between the family and the physician. When this occurs, legal council is advised but, at least in the United States, there is no legal obligation to continue care of a person who has been declared dead. Culture and religion influence and impact each other in many ways. For example, a catholic may be aware that the Catholic Church supports organ donation, but he or she may also be a member of a Hispanic community that puts great emphasis on the importance of the heart. Occasionally, these families are hesitant to donate their loved one’s heart but would allow the donation of other organs. Data provided by the United Network of Organ Sharing (UNOS) on ethnicity and donors consistently shows a persistent trend of African-American, Hispanic, and Asian organ donation rates below that of whites. Organ donation is much less approved of among these groups. Some believe that this is due to poor understanding, poor education, or mistrust of the physician (Callender et al., 1991; Ciancio et al., 1997). Both the Chinese and Japanese have different cultural value systems and do not, as in western cultures, emphasize self-determination (Namihira, 1990; Green, 1994). Many spiritual movements, including Taoism, prevalent

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in China, have not expressed opinions on brain death and a considerable amount of diversity is expected. Organ transplantation is practiced, but not after brain death diagnosis. Some families question whether an incomplete body may go to heaven or preclude resurrection. In an attempt to resolve this matter, physicians have emphasized that many persons die by fire or destructive accidents, and cremations are commonly performed. Other families have questioned whether you are really dead if your organs are going to be functioning in someone else’s body. If families refuse to accept brain death as death, there are some options. The physician should consider maintaining full support and, in turn, ask for assistance from a hospital ethics committee to explain to the family that brain death is, in fact, the death of a person. Spiritual council may be sought. Physicians should appreciate these sensitivities and try to help family members come to a sense of closure. Continuing support should be full support, and it is poor practice to maintain mechanic ventilation and stop vasopressors, effectively hastening cardiac arrest. However cardiopulmonary resuscitation is not warranted under any circumstances. If the family refuses to come to an agreement and remains intransigent, legal advice should be obtained. A local judge will then decide and can be expected to declare the patient dead, which would then allow withdrawal of support. In rare occasions, families may request certain rituals be done after the diagnosis of brain death has been made. Such a request could generally be honored unless it is used in an attempt to change the medical condition. One request may also be followed by other requests, and that could lead to prolonged continued care in a patient who has already been declared dead.

directives of the dying patient. Once a patient with imminent brain death and no therapeutic options has been identified, several clinical pathways are possible. If the patient meets brain death criteria the options are withdrawal of support or organ donation through a brain death protocol (donation after brain death or DBD). If the patient does not meet the brain death criteria the choice is continued support, withdrawal of support with palliation, or organ donation through donation after cardiac arrest or DCD (Fig. 16.3). If DCD protocols are not available, only two choices remain (prolonged care after tracheostomy and percutaneous gastrostomy placement or palliative care after withdrawal of support). Organ donation is regulated in the United States and in many other countries in the world. Organ donation is a complex process that requires time and a concerted effort. In the United States, UNOS administers to more than 58 federally regulated organ procurement organizations (OPOs). After review of the potential donor’s medical history and current organ function on site or by telephone, the OPO coordinator may determine, in conjunction with local transplant surgeons or the OPO medical director, whether the patient is a suitable candidate for organ donation. Medical management of the organ donor is directed by one or two organ procurement officers (often trained ICU nurses). After brain death testing is complete and the attending physician has declared the patient brain-dead, a meeting with all present family members should be arranged. Before brain death is discussed, the physician should have inquired about possible cultural or religious objections. The family should be told in unequivocal and nontechnical terms that the patient is dead and gone. The

ORGAN DONATION Early identification of potential organ donors in patients with irreversible catastrophic brain injuries is essential to maintain the pool of potential donors (de Groot et al., 2011a, b). In clinical practice, medical decisions to determine futility are completely independent of decisions to consider organ donation. Physicians will have to make the decision that a known therapeutic intervention (medical or neurosurgical) is not going to help the patient. After that decision is made, organ donation can be considered and very often is brought up by family members. Early identification of patients with imminent brain death is essential because, without it, the total number of organ donors may decrease over time. This is a consequence of very early withdrawal of care, which is often suggested by family members who are honoring the advance

Fig. 16.3. Pathways to organ donation in patients with imminent brain death (IBD). T, clinical testing; Y, meets clinical criteria for brain death; N, does not meet clinical criteria for brain death; WOS, withdrawal of support; DBD, donation after brain death; DCD, donation after cardiac (circulatory) death. (Reproduced from Wijdicks, 2011, by permission of Mayo Foundation for Medical Education and Research. All rights reserved.)

BRAIN DEATH physician may opt for further explanation of the clinical course, as often it is comforting for the family to know truly nothing could have been to done to change the outcome. Frequently, families anticipate the question of organ donation or inquire about it, and it may become clear whether the family is willing to donate or if the driver’s license of their loved one has indicated consent. A meeting with the organ procurement nurse should now be arranged. The consent process should be informed and voluntary. In the US most organ procurement officers, however, have a presumptive model for consent. That is, families will actively have to state a reason why they would not want to proceed with consent for organ donation. There are several reasons why families may refuse consent (Christmas et al., 2008). The decision to donate organs decreases as time to declare brain death increases. Families at the bedside of a dying patient in the ICU are under tremendous stress. There may be confusion as to why brain death examination takes so long. Often, another night is spent in the ICU for the family and they begin to question why further testing is required and, even more, why a second examination is needed if a loved one is, in fact, dead. Therefore, prompt diagnosis of brain death after a comprehensive evaluation is needed to avoid decreased consent for organ donation. There are also often questions about costs of organ procurement. When families agree on organ donation, the cost is transferred from them. The family should be assured that the entire cost of the organ donation process is paid for by the OPO. Generally, this includes all costs from the time of the brain death declaration and consent until the donor’s care is transferred, after organ recovery, to the medical examiner or funeral home. The medical management team of the organ donor is continuing care of the critically ill patient. The appropriate outcome is now a functioning organ in a recipient. The overriding principle is maintenance of a normal or near-normal physiology. Attending physicians are often involved in the management of the brain-dead patient before consent for organ donation has been obtained. After consent (in the United States and many other countries), the management of the organ donor is directed by an organ procurement agency. This allows them to shepherd the organ donor to the operating room and provides the opportunity for these agencies to build extensive experience. Following the determination of brain death, a comprehensive proactive management protocol is initiated by the organ procurement agency. In patients who do not progress to brain death and have an unsurvivable brain injury, patients may opt for withdrawal of care in the operating room DCD protocol. This protocol requires enormous resources

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and an additional effort of the direct family who will accompany the patient in the operating room. The family will be present during extubation and will leave after circulatory arrest has occurred. The patient is already draped and the surgical team scrubbed and gowned and ready to enter the operating room after a 5–10-minute “death watch” (interval of circulatory arrest to the beginning of surgical removal). The experience of family members is not exactly known and it remains unclear whether this – undoubtedly traumatic – experience of being physically in the operating room will be overshadowed by the realization that organ donation by their loved one was successful. Some family members may opt out easily of DCD.

CONCLUSIONS Many countries have accepted that brain death is determined by a neurologic clinical examination and that ancillary confirmatory tests are not needed or are optional. Many countries have introduced laws that acknowledge that a patient can be declared brain-dead by certain neurologic standards. The determination of brain death is a relatively straightforward procedure but requires a skilled and experienced physician. Many hospitals involve neurologists and neurosurgeons. It is clear that once all brainstem reflexes are absent in a nondrugged demonstrable apneic comatose patient, with a irreversible catastrophic injury, this condition is permanent and will not change. Aggressive hemodynamic support is needed (and warranted) if the family wants to proceed with organ donation. Fortunately, brain death is coupled with organ donation in more than three-quarters of all clinical brain death assessments. This also implies that physicians have to be very certain of their evaluation and take the time to assess the patient carefully. Tremendous delays however often occur for the wrong reasons and may lead to premature cardiac arrest and loss of organ donation. With the passage of time, most of the ambiguities in guidelines regarding the process of brain death declaration have been clarified. The American Academy of Neurology practice parameters simplified the requirements after a systematic review and relegated the diagnostic laboratory test to a confirmatory status, also specifically pointing out the uncertainties of these ancillary tests (Wijdicks et al., 2010). The Society of Critical Care Medicine and American Academy of Pediatrics new guidelines continue to emphasize prolonged time of observation and multiple physician examinations (Nakagawa et al., 2011). Such a departure from the brain death criteria in adults is not needed. Nearly all major religious denominations have accepted that, when the brain is dead (using strict

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medical criteria), the person is dead. Occasionally conflicts do arise when family members do not accept this premise, and hospital ethics committees have been consulted. More discussions and explanation of futility may be needed, but many conflicts – despite the best efforts – remain irreconcilable and physicians have continued support until the inevitable cardiac arrest. No physician should have to care for a legally deceased person and the U.S. courts have held that physicians may withdraw hemodynamic and respiratory support in a brain-dead patient even when this conflicts with the wishes of the family (Burkle et al., 2011). Legal council may then be needed. Generally, the diagnosis of brain death is not a legal, but a medical, matter. For the courts a person is brain-dead when the physician says so and uses current standards.

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