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Brain death
Seminars in Anesthesia, Perioperative Medicine and Pain (2006) 25, 225-231
Brain death Sandra Nathan, MD, and David M. Greer, MD, MA From the Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. KEYWORDS: Brain death; Coma; Apnea testing; Brainstem death
With the introduction of mechanical ventilation, patients suffering neurological catastrophes who previously would have perished are now often systemically supported, thereby bringing the concept of brain death into existence. Brain death is defined as the irreversible loss of the clinical function of the entire brain, including the brainstem, and may result from a number of causes. The correct diagnosis of brain death is essential from several standpoints: to ensure that unnecessary treatments and procedures are not performed, to provide a sense of finality for families concerned about prognosis, to preserve vital critical care resources, and to allow for the possibility of organ donation. The concept of brain death is accepted in most countries and cultures, but ethical arguments remain regarding certain concepts, such as the concept of isolated brainstem death or higher-brain death. This review will assist the clinician in understanding the concepts behind brain death, the proper technique for determination, and the areas of controversies that remain. © 2006 Elsevier Inc. All rights reserved.
History and importance Molleret and Goulon first introduced the concept of brain death in their 1959 sentinel work, “Le coma depassé,”1 in which they described 23 patients with irreversible coma, defined as complete unresponsiveness, loss of all brainstem reflexes, absence of spontaneous respirations, and flat electroencephalograms. Prior to this, the proclamation of death required the complete cessation of function of all systemic organs. With the advent of mechanical ventilation and advanced critical care, patients with neurological catastrophes who otherwise would have died could now be supported systemically. Their brains, however, showed no sign of functioning whatsoever, including the most rudimentary brainstem reflexes. With the noted absence of spontaneous respirations, the concept of brain death (or “death by brain criteria”) was developed. In order for this to be an acceptable form of death determination, the medical community
Address reprint requests and correspondence: David M. Greer, MD, MA, Massachusetts General Hospital, Harvard Medical School, ACC 835, 55 Fruit Street, Boston, MA 02114. E-mail: [email protected].
0277-0326/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.sane.2006.09.005
was assigned the task of determining specific and strict rules by which this declaration would take place. In 1968, the Harvard Ad Hoc Committee formed to write “A Definition of Irreversible Coma.”2 Although the methods have been tailored over the years, the essential concepts remain the same: the cause of the neurological catastrophe must be known, and known to be irreversible; there must be a complete absence of all clinical brain function, including the brainstem; and there must be no factors confounding the examination. With these rules satisfied, the patient could be declared legally dead by brain criteria.
Pathophysiology The pathology of brain death reflects the underlying cause. The most common causes of brain death in adults are anoxic brain injury, traumatic brain injury, subarachnoid hemorrhage, and ischemic stroke. In children, the most common causes are abuse, motor vehicle accidents, and asphyxia.3 In traumatic brain injury, the damage can result either directly from the focal areas of injury, or indirectly from secondary ischemic injury caused by impaired cerebral perfusion pres-
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sure with overwhelming cerebral edema. In anoxic brain injury, the degree of damage and the clinical outcome directly relate to the duration and extent of impaired oxygenation and circulation. With severe anoxic brain injury, the intracranial pressure is markedly elevated, and at some point may exceed the mean arterial blood pressure. With the complete lack of intracranial blood flow, there is progressive liquefaction of brain matter. Hemorrhages develop due to congestion and breakdown of the endothelium. Widespread infarcts occur, typically affecting the watershed areas first. Histologically, in the immediate hours following an anoxic brain injury, there is often little change, restricted mostly to “cloudy swelling” of the nuclear region of neurons with loss of basophilia. The classic “red neurons” seen with progressive eosinophilia of the cytoplasm do not typically occur until at least 8-12 hours after the event.4 The timing of determination of brain death depends on the nature of the injury as well. Patients with a traumatic brain injury and no medically or surgically treatable condition may be declared brain dead early in their course if they fulfill the clinical criteria. If they initially have some residual brain function, they may progress to brain death by developing refractory cerebral edema and herniation. With strokes or subarachnoid hemorrhage, there is often an initial period in which the extent of the injury may be unclear, or there may be treatable conditions (e.g., hydrocephalus) that may allow for clinical improvement with appropriate management. Clearly, if there is a doubt as to the potential reversibility of a condition, brain death should not even be entertained as a diagnosis, and testing for this entity should not be performed. This applies to cardiac arrest patients as well: although these patients may have little or no clinical brain function on admission, a period of observation is always warranted prior to determining death by brain criteria, as early clinical recovery is frequently seen. However, as the injury is established and cerebral edema and herniation become apparent, the determination need no longer be in question.
Clinical determination The following is an adaptation of the guidelines set forth by the American Academy of Neurology in 1995.5 Although there has been significant time since these were last updated, the features of the clinical exam remain much the same. There are several cardinal rules to the determination of death by brain criteria: 1) The cause of the neurological state must be known unequivocally, and must be known to be irreversible. 2) There must be no medical or anatomic conditions that could confound the determination, such as severe electrolyte disturbances, acid-base disorders, severe endocrine abnormalities, or hyperammonemia. 3) The patient must have a core temperature of at least 97.7°F (36.5°C), as hypothermia can inhibit brain func-
tion, including the brainstem. (Previous practice parameters listed two separate temperatures, but with the concern that lower temperatures may inhibit brain stem function, we have chosen to mandate one temperature, the higher one.) 4) The systolic blood pressure must be maintained ⬎90 mm Hg. 5) There must be no evidence of drug intoxication, poisoning, or paralysis. If pentobarbital has been administered, the level must be undetectable on toxicology screen. An observation period of at least four times the elimination half-life of a known intoxicant, or 48 hours for an unknown or non-quantifiable substance, has been suggested.6 6) Neuroimaging should reveal the underlying cause. However, computed tomography (CT) may be normal in the early hours following cardiac arrest, or with fulminant meningitis/encephalitis. In the latter case, lumbar puncture will establish the diagnosis. There are three cardinal features of the clinical examination: coma, absence of brainstem reflexes, and apnea. To be considered for apnea testing, patients must first display an absence of consciousness, no intact cranial nerve function, and an absence of any cerebrally mediated motor response to painful stimuli, including nail bed pressure, supra-orbital pressure, or pressure on the temporo-mandibular joint. However, spinally mediated reflexes, including deep tendon reflexes, the triple flexion response, and the Babinski sign, are permissible. Other abnormal but permissible signs that are also spinally mediated include the undulating toe sign, as well as the inaptly termed “Lazarus sign.”7 This sign may consist of spontaneous slight abduction/adduction of an extremity,8 raising of the torso to a 40-60° angle, head turning to the side,9 arm raising, or back arching. Lazarus signs are seen in patients who otherwise fulfill the clinical and ancillary testing diagnosis of brain death, and thus are known to be spinally mediated. They can be quite disturbing and confusing to families as well as to health care providers, and should be explained carefully when observed. The cranial nerve examination is crucial in brain death testing (Table 1). The pupils should show no response to bright light; a magnifying glass may be necessary to appreciate a small amount of reactivity. They may be round or irregularly shaped, and depending on the underlying pathology may be dilated, midposition, or small. Widely dilated or miotic pupils should alert the physician to potential drug intoxication. Pre-existing confounders, such as surgical or traumatic injury to the pupils, should be gleaned from the history. Ocular movements can be tested with the oculocephalic reflex (OCR or “doll’s eye” maneuver) and, if this is negative, by the oculovestibular reflex (OVR, or “cold calorics”). The OCR should be tested only when there is no question regarding cervical spine integrity; thus, many head trauma patients are not amenable to such testing. Proper testing of the OVR requires that the head of bed be elevated to 30°, auditory canals free of cerumen or other debris, and intact
Nathan and Greer Table 1
Brain Death
Brainstem testing in brain death
Pupils ● no response to bright light; use magnifying glass if questionable ● May be midposition, constricted or dilated Extraocular movements ● Oculocephalic reflex (“dolls eyes”) ● Should see absence of movement of the eyes with turning of head ● Test only when C-spine integrity ensured ● Oculovestibular reflex (“cold calorics”) ● Head of bed elevation to 30° ● Ear canal free of cerumen/debris ● Intact tympanic membrane ● Should see absence of eye movements with instilling ice cold water for 60 seconds ● Allow 5 minutes between testing of ears Facial sensation/movement ● Corneal reflex ● Nasal tickle to Q-tip ● Painful stimulus to supraorbital ridge Caudal brainstem ● Absence of gag to palatal stimulation ● Absence of cough to bronchial suctioning Motor exam ● Absence of cerebrally mediated response to pain in the extremities ● Extensor/flexor posturing is NOT permissible ● Deep tendon reflexes, triple flexion, Babinski sign are permissible
tympanic membranes. One auditory canal is instilled with 30-50 mL of ice-cold water over 60 seconds and the eyes observed during that time for horizontal movement. With brain death, there should be no extraocular movement. Five minutes should be allowed prior to testing of the contralateral ear to allow for temperature normalization of the initially tested ear. Confounding factors for the OVR test include perforation or lack of integrity of the tympanic membrane, as well as prior exposure to ototoxic drugs, including aminoglycosides, vancomycin, tricyclic antidepressants, anticholinergics, and certain chemotherapeutic agents. Confounding factors for both the OCR and OVR testing include trauma to the globes, orbits, or petrous bones, as well as severe facial or orbital edema. Trigeminal and facial nerve function is tested by performing the corneal reflex, looking for grimacing to nasal tickle, or by providing a more noxious stimulus, such as pressure on the supra-orbital ridge or the temporo-mandibular joint. Facial myokymias are permissible, and result from denervation of the facial nerve. However, these occur spontaneously, and should not appear in response to noxious stimulation. Lower cranial nerve function is best tested by observing for coughing with bronchial suctioning, but can also be assessed by moving the endotracheal tube slightly back and forth or stimulating the posterior pharynx with a tongue blade. Testing of motor responses in the extremities is performed by providing a sufficient noxious stimulus, such as
227 deep nail bed pressure, to all four extremities. Decorticate or decerebrate posturing should not be seen, as these are cerebrally mediated responses. Deep tendon reflexes, the Babinski reflex, and “triple flexion” are all felt to be spinally mediated and are still consistent with brain death. Apnea testing is a crucial aspect of brain death testing and is the portion of the examination most susceptible to errors. Care must be taken to perform the apnea test properly, as significant hemodynamic instability10 or cardiopulmonary death11 may result. It is mandatory that the patient be hemodynamically stable prior to considering apnea testing; if not, the apnea test should be abandoned and an ancillary test performed instead. Prior to testing, ventilator settings should be adjusted (and sodium bicarbonate given, if necessary) so that the pH is normalized to 7.35-7.45, and the pCO2 corrected to 35-45 mm Hg (N.B. if the patient is a known retainer of carbon dioxide, the goal pCO2 should be the patient’s baseline, if known.) The patient should be pre-oxygenated with 100% FiO2 for at least 5 minutes, to a pO2 of at least 200 mm Hg. The ventilator should be disconnected from the patient, as many newer ventilators are exquisitely sensitive and may falsely identify negative airway pressure due to cardiac contraction as a stimulus to trigger a breath.12 An oxygen source of 100% FiO2 is provided by means of a thin cannula to the level of the carina. Observe the patient closely for movements of the chest or abdominal wall, as well as any signs of clinical deterioration, such as cyanosis, hypoxia, or hemodynamic instability (particularly hypotension/bradycardia), which indicate that the test should be aborted. If this occurs, an arterial blood gas (ABG) should be drawn just prior to resuming artificial ventilation. Otherwise, the period of observation is 8-10 minutes, at which time an ABG is drawn and the patient is reconnected to the ventilator. A positive apnea test is indicated with an absolute pCO2 of 60 mm Hg, or a rise in the pCO2 of 20 mm Hg from the pre-test value.13 The pH will typically fall 0.02 units for each minute of apnea to a level of ⬍7.30 (assuming a pre-test value of 7.40). If these criteria are not met, but the patient was hemodynamically stable during the testing, the test may be repeated for a more extended period of time (12-15 minutes) to allow the criteria to be met. The most common complication with apnea testing is hypotension, which typically occurs when there is inadequate pre-oxygenation. Pneumothorax14 and cardiac arrest11 have been reported, but are felt to be extremely rare.
Ancillary tests Before pursuing ancillary testing for brain death determination, it must be remembered that this diagnosis is first a clinical one. The clinical examination is valid alone as determination of death by brain criteria, and an ancillary test should be performed only when the clinical examination is drawn into question, such as with severe acid-base, electro-
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Figure 1 Celebral angiogram, revealing arrest of flow of the internal carotid arteries at the level of the skull base. Note that the external carotid circulation has persistent filling.
lyte, or endocrine disturbances, drug intoxication, or anatomical injury (eg, facial trauma), or when the patient is hemodynamically unstable and apnea testing is contraindicated. If the patient fulfills the clinical criteria for brain death, then ancillary testing should not be performed, as the results may only confound the evaluation. Multiple confirmatory tests are available, each with advantages and disadvantages. The gold standard for confirming complete cerebral circulatory arrest is four-vessel cerebral angiography (Figure 1).15 Two injections of intravenous contrast 20 minutes apart should show an absence of flow in all intracranial vessels.16 Contrast will typically fill the extracranial carotid circulation and thus the meningeal arterial system. Internal carotid flow, however, must arrest at the petrous portion of the carotid, where it becomes intracranial. The posterior circulation must also be evaluated, again showing arrest of flow as the vertebral arteries become intracranial. A false-negative result has been reported in a patient with an extended skull defect and persistent intracranial circulation by both angiography and transcranial Doppler, despite fulfilling the clinical criteria for brain death.17 Additionally, angiography is cumbersome and requires specialized neurointerventional and anesthesia teams. Single photon emission computed tomography (SPECT) has become widely available for the confirmation of cerebral circulatory arrest and uses the isotope 99mTc-HMPAO (hexamethyl propyleneamine oxime) injected 15-30 minutes prior to scanning.18 There should be an absence of intracranial perfusion, seen as a lack of tracer uptake.19 As the external carotid circulation is still patent, there may still be uptake seen in the meninges and face, giving rise to such
terms as the “hot nose,”20 “empty light bulb,” and “hollow skull” signs, due to diversion of internal carotid arterial flow to the external carotid artery territory (Figure 2). SPECT may also be performed by a portable scanner, facilitating its use in an ICU setting. It has become the ancillary test of choice in many centers. Electroencephalographic determination of brain death typically involves a 16- or 18-channel recording for at least 30 minutes. A minimum of 8 channels is required. The inter-electrode impedance should be between 100 and 10,000 ohms, and an inter-electrode distance of at least 10 cm. The sensitivity should be increased to at least 2 V. The high-frequency filter setting should be set above 30 Hz and the low-frequency setting set below 1 Hz. There should be no electrographic reactivity to auditory, visual, or tactile stimuli.21 Electroencephalography may be limited by the fact that it is susceptible to artifacts, especially in the ICU setting. Transcranial Doppler has been investigated for the confirmation of cerebral circulatory arrest.22 This technique requires absence of intracranial flow with preservation of extra-cranial flow. Two examinations are required, at least 30 minutes apart. Either oscillating flow or sharp systolic spikes without diastolic flow are acceptable ultrasonographic patterns of cerebral circulatory arrest. Both the anterior and posterior circulation should be evaluated, and either of the above patterns identified in all vessels insonated. Although included in some guidelines for cerebral circulatory arrest, absence of intracranial flow signal alone is not widely accepted as proof of absence of intracranial flow, as this may be secondary to technical limitations, such as inadequate temporal windows for insonation or operator inexperience. Although transcranial Doppler is attractive as a confirmatory test because of its ease of performance at the
Figure 2 SPECT study, revealing a lack of uptake of tracer, signifying cerebral circulation arrest.
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bedside, it must be interpreted carefully in the correct clinical context. Other ancillary tests that have been explored include somatosensory evoked potentials, CT angiography, and magnetic resonance angiography. Somatosensory evoked potentials have been drawn into question based on a relatively poor predictive value,23 and cannot be used as a confirmatory test with primary infratentorial lesions, as these may cause an absence of cortical signal due to a structural abnormality. These angiographic techniques have not yet been validated but show promise in small clinical studies.24 Although European brain death guidelines require a similar stepwise approach to brain death determination, there are individual differences. In primary brain injury, only a few countries require a delay between the onset of clinical signs of breath death and the performance of diagnostic procedures, whereas in secondary brain injury (usually due to anoxia), the majority require an observation period of 6-24 hours.25 Variability in the interpretation of the apnea test and the accepted confirmatory tests also exists.
Medical–legal, ethical considerations The prevailing consensus opinion of what should qualify as brain death is that there should be the irreversible loss of function of the brainstem as well as cortical regions (socalled “whole-brain death”). Some philosophers criticize the current definition of brain death as not inclusive of the more integrative functions of the brain.26,27 These advocates of the “higher-brain” formulation for brain death suggest that it is in fact neocortical loss of functioning, and the resultant unconsciousness, loss of self-awareness, memory, and personality, that could suffice to declare death.28 This approach to brain death interfaces more directly with the question of consciousness. By this concept, however, anencephalic infants, patients in a persistent vegetative state, or individuals unconscious from a severe brain injury could also be declared dead, which is clearly not acceptable. But where exactly should the line be drawn? In patients continued on artificial ventilation following brain death, it has been observed that some brain functions persist, such as thermoregulation and hormone secretion (e.g., in response to organ retrieval, associated with a successful gestation of a fetus, or proportional growth, as in the case of a few children).29 Thus, it would seem that death ensues only when there is irreversible cessation of cardiopulmonary function, which would signal that truly all function has left the brain. This would exclude most if not all of the patients currently included in formal definitions of brain death. Furthermore, there are well-documented cases of isolated brainstem lesions (eg, catastrophic bilateral pontine hemorrhage) sparing the cerebral hemispheres and thalami, leading to so-called “brainstem death.”30,31 Although it is unlikely that consciousness would be preserved in these cases
229 despite an intact telencephalon/diencephalon, it would be difficult to exclude an extreme locked-in syndrome by neurological examination alone, making brainstem death perhaps an even less tenable concept than whole-brain death. The brainstem death paradigm is accepted in the United Kingdom.32 Although there are many ways of elaborating the indeterminate boundary between life and death, wholebrain death criteria is the most widely accepted. All states in the U.S. have, by statute or judicial ruling, empowered physicians to determine death by neurological criteria. Although the vast majority of states have adopted the Uniform Determination of Death Act,33 Alabama and West Virginia have adopted the Uniform Brain Death Act,34 which provides that for “legal and medical purposes,” an individual is dead if irreversible cessation of all brain and brainstem function has occurred “in accordance to acceptable medical standards.” The Virginia brain death statute, while also subscribing to the whole-brain criteria of brain death, further specifies that this determination be made by “a specialist in the field of neurology, neurosurgery, or electroencephalography.”35 Our guidelines are left intentionally ambiguous, leaving the decision to the individual treating neurologist. We define brain death as “the irreversible loss of the clinical function of the entire brain.” Thus, it is left open to interpretation. For those who equate brainstem death to brain death, the clinical function of the whole brain is what is tested and this involves testing of the brainstem itself—the patient is comatose, and all brainstem function is absent. For those subscribing to the concept of “whole brain death,” the clinical criteria also suffice. If they have reason to doubt the validity of the clinical exam, they are obligated to perform an ancillary test. The point is, the decision is left to the individual clinician’s discretion. In regard to the religious aspects, the concept of brain death is accepted by all major religious groups, except certain Japanese religions, Orthodox Jewish sects, and gypsies.36 Both New York and New Jersey have statutes limiting the withdrawal of life support measures in a brain-dead individual (i.e., the legal declaration of death) if there are religious objections.37 Whereas the New York regulations do not bar the diagnosis of brain death (they only request a “reasonable accommodation” if there is a religious objection), the New Jersey statutes bar the use of neurologic criteria to diagnose brain death if there is reason to believe that religious objections might exist in the patient, as presented by their family/representative.38 Death is a requisite diagnosis for organ donation, as stated in the Uniform Anatomical Gift Act (heart-beating donors should be brain-dead prior to removal of vital organs). Some commentators have posed that in this era, mechanical ventilation is often discontinued when there is a grim neurologic prognosis, even in the absence of brain death, making the actual diagnosis of brain death useful inasmuch as it facilitates organ donation.27 They would also label the diagnosis of brain death as obsolete. Most would agree that, while it is true that diagnosing brain death is
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important for the above reasons, it does not change the validity of using brain criteria as an established means of declaring death. Several challenging ethical issues may arise when caring for the brain dead patient. Often, families of such patients may request continuation of systemic organ support measures. It is important to differentiate whether these requests are engendered by religious nonacceptance of brain death as a concept, or by the extreme psychological distress of the situation. In the case of the former, it may be advisable to continue treatment until the inevitable cardiopulmonary death ensues (this is legally required in New Jersey). In the latter and more common scenario, further counseling with detailed explanations about the nonsurvivable nature of the brain injury and futility of further care, as well as an additional day or two of ICU management, may be the most compassionate route. As alluded to earlier, there have been several cases of maternal brain death, in which the pregnancies were carried to successful completion by Caesarian section, sometimes as long as several weeks after the neurological catastrophe.39 In these cases, the husband or other next of kin makes the decision regarding further treatment of the mother to save the child is. It is also possible to obtain viable sperm from brain-dead men via seminal vesicle massage electroejaculation.40 Again, ethical considerations are prominent in determining the indication for such a request.
Conclusions Brain death has become established and accepted worldwide as a formal means of declaring a person legally dead. There are multiple implications, perhaps most importantly it allows for improved processes of organ donation. The determination of death by brain criteria is a clinical one, and the use of ancillary tests should be reserved for only those cases in which the clinical diagnosis is drawn into question or in which an apnea test cannot be performed. Multiple ancillary tests exist, all with potential limitations. Many ethical and legal questions have been raised regarding brain death, and these are likely to remain areas of future research and debate for years to come.
References 1. Mollaret P, Goulon M: Le coma depassé. Rev Neurol 101:3-15, 1959 2. A definition of irreversible coma: report of the Ad Hoc Committee of the Harvard Medical School to examine the definition of brain death. JAMA 205:337-340, 1968 3. Ashwal S, Schneider S: Brain death in children. Pediatr Neurol 3:5-10, 69-77, 1987 4. Leestma JE: Neuropathology of brain death, in Wijdicks EFM (ed): Brain Death. Philadelphia, PA, Lippincott Williams and Wilkins, 2001, pp 45-60 5. The Quality Standards Subcommittee of the American Academy of Neurology: Practice parameters for determining brain death in adults (summary statement). Neurology 45:1012-1014, 1995
6. Wijdicks EFM: The diagnosis of brain death. N Engl J Med 344:12151221, 2001 7. Bueri JA, Saposnik G, Maurino J, et al: Lazarus’ sign in brain death. Mov Disord 15:583-586, 2000 8. Martí-Fàbregas J, López-Navidad A, Caballero F, et al: Decerebratelike posturing with mechanical ventilation in brain death. Neurology 54:224-227, 2000 9. Christie JM, O’Lenic TD, Cane RD: Head turning in brain death. J Clin Anesth 8:141-143, 1996 10. Goudreau JL, Wijdicks EMF, Emery SF: Complications during apnea testing in the determination of brain death: predisposing factors. Neurology 55:1045-1048, 2000 11. Wijdicks EMF: In search of a safe apnea test in brain death: Is the procedure really more dangerous than we think? Arch Neurol 52:338339, 1995 12. Willatts SM, Drummond G: Brainstem death and ventilator trigger settings. Anesthesia 55:676-677, 2000 13. Prechter GC, Nelson SB, Hubmayr RD: The ventilatory recruitment threshold for carbon dioxide. Am Rev Respir Dis 141:758-764, 1990 14. Saposnik G, Rizzo G, Deluca JL: Pneumothorax and pneumoperitoneum during the apnea test: how safe is this procedure? Ar Qneuropsiquiatr 58:905-908, 2000 15. Kricheff II, Pinto RS, George AE, et al: Angiographic findings in brain death. Ann NY Acad Sci 315:168-183, 1978 16. Van Bunnen Y, Delcour C, Wery D, et al: Intravenous digital subtraction angiography. A criteria of brain death. Ann Radiol (Paris) 32:279281, 1989 17. Ducrocq X, Braum M, Debouverie M, et al: Brain death and transcranial Doppler: experience in 130 cases of brain dead patients. J Neurol Sci 160:41-46, 1998 18. Laurin NR, Driedger AA, Hurwitz GA, et al: Cerebral perfusion imaging with technetium-99m HM-PAO in brain death and severe central nervous system injury. J Nuc Med 30:1627-1635, 1989 19. Facco E, Zucchetta P, Munari M, et al: 99mTc-HMPAO SPECT in the diagnosis of brain death. Int Care Med 24:911-917, 1998 20. Mishkin FS, Dyken ML: Increased early radionuclide activity in the nasopharyngeal area in patients with internal carotid artery obstruction: “hot nose.” Radiology 96:77-80, 1970 21. Silverman D, Saunders MG, Schwab RS, et al: Cerebral death and the electroencephalogram. Report of the ad hoc committee of the American Electroencephalographic Society on EEG Criteria for Determination of Cerebral Death. JAMA 209:1505-1510, 1969 22. Ducrocq X, Hassler W, Moritake K, et al: Consensus opinion on diagnosis of cerebral circulatory arrest using Doppler-sonography: Task Force Group on Cerebral Death of the Neurosonology Research Group of the World Federation of Neurology. J Neurol Sci 159:145150, 1998 23. Machado C, Valdés P, García-Tigera J, et al: Brain-stem auditory evoked potentials in brain-dead patients. Electroencephalogr Clin Neurophysiol 80:392-398, 1991 24. Leclerc X, Taschner CA, Vidal A, et al: The role of spiral CT for the assessment of the intracranial circulation in suspected brain-death. J Neuroradiol 33:90-95, 2006 25. Haupt WF, Rudolf J: European brain death codes: a comparison of national guidelines. J Neurol 246:342-347, 1999 26. Halevy A, Brody B: Brain death: reconciling definitions, criteria, and tests. Ann Int Med 119:519-525, 1993 27. Truog RD: Is it time to abandon brain death? Hastings Center Report 27, 1:29-37, 1997 28. Chiong W: Brain death without definitions. Hastings Center Report 35, 6:20-30, 2005 29. Shewmon DA: “Brainstem death,” “brain death” and death: a critical re-evaluation of the purported equivalence. Issues Law Med 14:125145, 1998 30. Ogata J, Imakita M, Yutani C, et al: Primary brainstem death: a clinico-pathological study. J Neurol Neurosurg Psychiatry 51:646-650, 1988
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31. Kosteljanetz M, Øthrstrøm, Skøjdt S, et al: Clinical brain death with preserved cerebral circulation. Arch Neurol Scand 78:418-421, 1988 32. Criteria for the diagnosis of brain stem death: review by a working group convened by the Royal College of Physicians and endorsed by the Conference of Medical Royal Colleges and Their Faculties in the United Kingdom. J R Coll Phys Lond 29:381-382, 1995 33. Uniform Determination of Death Act, 12 Uniform Laws Annotated 589 (West 1993 and West Supp 1997) 34. Uniform Brain Death Act, 12 Uniform Laws Annotated 65 (1978) 35. VA STAT sec 54-1-2972 (1997)
231 36. Gallagher CM, Wijdicks EF: Religious and cultural aspects of brain death, in Wijdicks EFM (ed): Brain Death. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 135-150 37. Determination of death, 10 NYCRR; Declaration of Death. L. 1991 38. Declaration of death. L. 1991, ch. 90; NJSA 26:6A-5 39. Souza JP, Oliviera-Neto A, Surita FG, et al: The prolongation of somatic support in a pregnant woman with brain-death: a case report. Reprod Health 3:3, 2006 40. Finnerty JJ, Thomas TS, Boyle RJ: Gamete retrieval in terminal conditions. Am J Obstet Gynecol 185:300-307, 2001
Brain death Sandra Nathan, MD, and David M. Greer, MD, MA From the Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. KEYWORDS: Brain death; Coma; Apnea testing; Brainstem death
With the introduction of mechanical ventilation, patients suffering neurological catastrophes who previously would have perished are now often systemically supported, thereby bringing the concept of brain death into existence. Brain death is defined as the irreversible loss of the clinical function of the entire brain, including the brainstem, and may result from a number of causes. The correct diagnosis of brain death is essential from several standpoints: to ensure that unnecessary treatments and procedures are not performed, to provide a sense of finality for families concerned about prognosis, to preserve vital critical care resources, and to allow for the possibility of organ donation. The concept of brain death is accepted in most countries and cultures, but ethical arguments remain regarding certain concepts, such as the concept of isolated brainstem death or higher-brain death. This review will assist the clinician in understanding the concepts behind brain death, the proper technique for determination, and the areas of controversies that remain. © 2006 Elsevier Inc. All rights reserved.
History and importance Molleret and Goulon first introduced the concept of brain death in their 1959 sentinel work, “Le coma depassé,”1 in which they described 23 patients with irreversible coma, defined as complete unresponsiveness, loss of all brainstem reflexes, absence of spontaneous respirations, and flat electroencephalograms. Prior to this, the proclamation of death required the complete cessation of function of all systemic organs. With the advent of mechanical ventilation and advanced critical care, patients with neurological catastrophes who otherwise would have died could now be supported systemically. Their brains, however, showed no sign of functioning whatsoever, including the most rudimentary brainstem reflexes. With the noted absence of spontaneous respirations, the concept of brain death (or “death by brain criteria”) was developed. In order for this to be an acceptable form of death determination, the medical community
Address reprint requests and correspondence: David M. Greer, MD, MA, Massachusetts General Hospital, Harvard Medical School, ACC 835, 55 Fruit Street, Boston, MA 02114. E-mail: [email protected].
0277-0326/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.sane.2006.09.005
was assigned the task of determining specific and strict rules by which this declaration would take place. In 1968, the Harvard Ad Hoc Committee formed to write “A Definition of Irreversible Coma.”2 Although the methods have been tailored over the years, the essential concepts remain the same: the cause of the neurological catastrophe must be known, and known to be irreversible; there must be a complete absence of all clinical brain function, including the brainstem; and there must be no factors confounding the examination. With these rules satisfied, the patient could be declared legally dead by brain criteria.
Pathophysiology The pathology of brain death reflects the underlying cause. The most common causes of brain death in adults are anoxic brain injury, traumatic brain injury, subarachnoid hemorrhage, and ischemic stroke. In children, the most common causes are abuse, motor vehicle accidents, and asphyxia.3 In traumatic brain injury, the damage can result either directly from the focal areas of injury, or indirectly from secondary ischemic injury caused by impaired cerebral perfusion pres-
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sure with overwhelming cerebral edema. In anoxic brain injury, the degree of damage and the clinical outcome directly relate to the duration and extent of impaired oxygenation and circulation. With severe anoxic brain injury, the intracranial pressure is markedly elevated, and at some point may exceed the mean arterial blood pressure. With the complete lack of intracranial blood flow, there is progressive liquefaction of brain matter. Hemorrhages develop due to congestion and breakdown of the endothelium. Widespread infarcts occur, typically affecting the watershed areas first. Histologically, in the immediate hours following an anoxic brain injury, there is often little change, restricted mostly to “cloudy swelling” of the nuclear region of neurons with loss of basophilia. The classic “red neurons” seen with progressive eosinophilia of the cytoplasm do not typically occur until at least 8-12 hours after the event.4 The timing of determination of brain death depends on the nature of the injury as well. Patients with a traumatic brain injury and no medically or surgically treatable condition may be declared brain dead early in their course if they fulfill the clinical criteria. If they initially have some residual brain function, they may progress to brain death by developing refractory cerebral edema and herniation. With strokes or subarachnoid hemorrhage, there is often an initial period in which the extent of the injury may be unclear, or there may be treatable conditions (e.g., hydrocephalus) that may allow for clinical improvement with appropriate management. Clearly, if there is a doubt as to the potential reversibility of a condition, brain death should not even be entertained as a diagnosis, and testing for this entity should not be performed. This applies to cardiac arrest patients as well: although these patients may have little or no clinical brain function on admission, a period of observation is always warranted prior to determining death by brain criteria, as early clinical recovery is frequently seen. However, as the injury is established and cerebral edema and herniation become apparent, the determination need no longer be in question.
Clinical determination The following is an adaptation of the guidelines set forth by the American Academy of Neurology in 1995.5 Although there has been significant time since these were last updated, the features of the clinical exam remain much the same. There are several cardinal rules to the determination of death by brain criteria: 1) The cause of the neurological state must be known unequivocally, and must be known to be irreversible. 2) There must be no medical or anatomic conditions that could confound the determination, such as severe electrolyte disturbances, acid-base disorders, severe endocrine abnormalities, or hyperammonemia. 3) The patient must have a core temperature of at least 97.7°F (36.5°C), as hypothermia can inhibit brain func-
tion, including the brainstem. (Previous practice parameters listed two separate temperatures, but with the concern that lower temperatures may inhibit brain stem function, we have chosen to mandate one temperature, the higher one.) 4) The systolic blood pressure must be maintained ⬎90 mm Hg. 5) There must be no evidence of drug intoxication, poisoning, or paralysis. If pentobarbital has been administered, the level must be undetectable on toxicology screen. An observation period of at least four times the elimination half-life of a known intoxicant, or 48 hours for an unknown or non-quantifiable substance, has been suggested.6 6) Neuroimaging should reveal the underlying cause. However, computed tomography (CT) may be normal in the early hours following cardiac arrest, or with fulminant meningitis/encephalitis. In the latter case, lumbar puncture will establish the diagnosis. There are three cardinal features of the clinical examination: coma, absence of brainstem reflexes, and apnea. To be considered for apnea testing, patients must first display an absence of consciousness, no intact cranial nerve function, and an absence of any cerebrally mediated motor response to painful stimuli, including nail bed pressure, supra-orbital pressure, or pressure on the temporo-mandibular joint. However, spinally mediated reflexes, including deep tendon reflexes, the triple flexion response, and the Babinski sign, are permissible. Other abnormal but permissible signs that are also spinally mediated include the undulating toe sign, as well as the inaptly termed “Lazarus sign.”7 This sign may consist of spontaneous slight abduction/adduction of an extremity,8 raising of the torso to a 40-60° angle, head turning to the side,9 arm raising, or back arching. Lazarus signs are seen in patients who otherwise fulfill the clinical and ancillary testing diagnosis of brain death, and thus are known to be spinally mediated. They can be quite disturbing and confusing to families as well as to health care providers, and should be explained carefully when observed. The cranial nerve examination is crucial in brain death testing (Table 1). The pupils should show no response to bright light; a magnifying glass may be necessary to appreciate a small amount of reactivity. They may be round or irregularly shaped, and depending on the underlying pathology may be dilated, midposition, or small. Widely dilated or miotic pupils should alert the physician to potential drug intoxication. Pre-existing confounders, such as surgical or traumatic injury to the pupils, should be gleaned from the history. Ocular movements can be tested with the oculocephalic reflex (OCR or “doll’s eye” maneuver) and, if this is negative, by the oculovestibular reflex (OVR, or “cold calorics”). The OCR should be tested only when there is no question regarding cervical spine integrity; thus, many head trauma patients are not amenable to such testing. Proper testing of the OVR requires that the head of bed be elevated to 30°, auditory canals free of cerumen or other debris, and intact
Nathan and Greer Table 1
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Brainstem testing in brain death
Pupils ● no response to bright light; use magnifying glass if questionable ● May be midposition, constricted or dilated Extraocular movements ● Oculocephalic reflex (“dolls eyes”) ● Should see absence of movement of the eyes with turning of head ● Test only when C-spine integrity ensured ● Oculovestibular reflex (“cold calorics”) ● Head of bed elevation to 30° ● Ear canal free of cerumen/debris ● Intact tympanic membrane ● Should see absence of eye movements with instilling ice cold water for 60 seconds ● Allow 5 minutes between testing of ears Facial sensation/movement ● Corneal reflex ● Nasal tickle to Q-tip ● Painful stimulus to supraorbital ridge Caudal brainstem ● Absence of gag to palatal stimulation ● Absence of cough to bronchial suctioning Motor exam ● Absence of cerebrally mediated response to pain in the extremities ● Extensor/flexor posturing is NOT permissible ● Deep tendon reflexes, triple flexion, Babinski sign are permissible
tympanic membranes. One auditory canal is instilled with 30-50 mL of ice-cold water over 60 seconds and the eyes observed during that time for horizontal movement. With brain death, there should be no extraocular movement. Five minutes should be allowed prior to testing of the contralateral ear to allow for temperature normalization of the initially tested ear. Confounding factors for the OVR test include perforation or lack of integrity of the tympanic membrane, as well as prior exposure to ototoxic drugs, including aminoglycosides, vancomycin, tricyclic antidepressants, anticholinergics, and certain chemotherapeutic agents. Confounding factors for both the OCR and OVR testing include trauma to the globes, orbits, or petrous bones, as well as severe facial or orbital edema. Trigeminal and facial nerve function is tested by performing the corneal reflex, looking for grimacing to nasal tickle, or by providing a more noxious stimulus, such as pressure on the supra-orbital ridge or the temporo-mandibular joint. Facial myokymias are permissible, and result from denervation of the facial nerve. However, these occur spontaneously, and should not appear in response to noxious stimulation. Lower cranial nerve function is best tested by observing for coughing with bronchial suctioning, but can also be assessed by moving the endotracheal tube slightly back and forth or stimulating the posterior pharynx with a tongue blade. Testing of motor responses in the extremities is performed by providing a sufficient noxious stimulus, such as
227 deep nail bed pressure, to all four extremities. Decorticate or decerebrate posturing should not be seen, as these are cerebrally mediated responses. Deep tendon reflexes, the Babinski reflex, and “triple flexion” are all felt to be spinally mediated and are still consistent with brain death. Apnea testing is a crucial aspect of brain death testing and is the portion of the examination most susceptible to errors. Care must be taken to perform the apnea test properly, as significant hemodynamic instability10 or cardiopulmonary death11 may result. It is mandatory that the patient be hemodynamically stable prior to considering apnea testing; if not, the apnea test should be abandoned and an ancillary test performed instead. Prior to testing, ventilator settings should be adjusted (and sodium bicarbonate given, if necessary) so that the pH is normalized to 7.35-7.45, and the pCO2 corrected to 35-45 mm Hg (N.B. if the patient is a known retainer of carbon dioxide, the goal pCO2 should be the patient’s baseline, if known.) The patient should be pre-oxygenated with 100% FiO2 for at least 5 minutes, to a pO2 of at least 200 mm Hg. The ventilator should be disconnected from the patient, as many newer ventilators are exquisitely sensitive and may falsely identify negative airway pressure due to cardiac contraction as a stimulus to trigger a breath.12 An oxygen source of 100% FiO2 is provided by means of a thin cannula to the level of the carina. Observe the patient closely for movements of the chest or abdominal wall, as well as any signs of clinical deterioration, such as cyanosis, hypoxia, or hemodynamic instability (particularly hypotension/bradycardia), which indicate that the test should be aborted. If this occurs, an arterial blood gas (ABG) should be drawn just prior to resuming artificial ventilation. Otherwise, the period of observation is 8-10 minutes, at which time an ABG is drawn and the patient is reconnected to the ventilator. A positive apnea test is indicated with an absolute pCO2 of 60 mm Hg, or a rise in the pCO2 of 20 mm Hg from the pre-test value.13 The pH will typically fall 0.02 units for each minute of apnea to a level of ⬍7.30 (assuming a pre-test value of 7.40). If these criteria are not met, but the patient was hemodynamically stable during the testing, the test may be repeated for a more extended period of time (12-15 minutes) to allow the criteria to be met. The most common complication with apnea testing is hypotension, which typically occurs when there is inadequate pre-oxygenation. Pneumothorax14 and cardiac arrest11 have been reported, but are felt to be extremely rare.
Ancillary tests Before pursuing ancillary testing for brain death determination, it must be remembered that this diagnosis is first a clinical one. The clinical examination is valid alone as determination of death by brain criteria, and an ancillary test should be performed only when the clinical examination is drawn into question, such as with severe acid-base, electro-
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Figure 1 Celebral angiogram, revealing arrest of flow of the internal carotid arteries at the level of the skull base. Note that the external carotid circulation has persistent filling.
lyte, or endocrine disturbances, drug intoxication, or anatomical injury (eg, facial trauma), or when the patient is hemodynamically unstable and apnea testing is contraindicated. If the patient fulfills the clinical criteria for brain death, then ancillary testing should not be performed, as the results may only confound the evaluation. Multiple confirmatory tests are available, each with advantages and disadvantages. The gold standard for confirming complete cerebral circulatory arrest is four-vessel cerebral angiography (Figure 1).15 Two injections of intravenous contrast 20 minutes apart should show an absence of flow in all intracranial vessels.16 Contrast will typically fill the extracranial carotid circulation and thus the meningeal arterial system. Internal carotid flow, however, must arrest at the petrous portion of the carotid, where it becomes intracranial. The posterior circulation must also be evaluated, again showing arrest of flow as the vertebral arteries become intracranial. A false-negative result has been reported in a patient with an extended skull defect and persistent intracranial circulation by both angiography and transcranial Doppler, despite fulfilling the clinical criteria for brain death.17 Additionally, angiography is cumbersome and requires specialized neurointerventional and anesthesia teams. Single photon emission computed tomography (SPECT) has become widely available for the confirmation of cerebral circulatory arrest and uses the isotope 99mTc-HMPAO (hexamethyl propyleneamine oxime) injected 15-30 minutes prior to scanning.18 There should be an absence of intracranial perfusion, seen as a lack of tracer uptake.19 As the external carotid circulation is still patent, there may still be uptake seen in the meninges and face, giving rise to such
terms as the “hot nose,”20 “empty light bulb,” and “hollow skull” signs, due to diversion of internal carotid arterial flow to the external carotid artery territory (Figure 2). SPECT may also be performed by a portable scanner, facilitating its use in an ICU setting. It has become the ancillary test of choice in many centers. Electroencephalographic determination of brain death typically involves a 16- or 18-channel recording for at least 30 minutes. A minimum of 8 channels is required. The inter-electrode impedance should be between 100 and 10,000 ohms, and an inter-electrode distance of at least 10 cm. The sensitivity should be increased to at least 2 V. The high-frequency filter setting should be set above 30 Hz and the low-frequency setting set below 1 Hz. There should be no electrographic reactivity to auditory, visual, or tactile stimuli.21 Electroencephalography may be limited by the fact that it is susceptible to artifacts, especially in the ICU setting. Transcranial Doppler has been investigated for the confirmation of cerebral circulatory arrest.22 This technique requires absence of intracranial flow with preservation of extra-cranial flow. Two examinations are required, at least 30 minutes apart. Either oscillating flow or sharp systolic spikes without diastolic flow are acceptable ultrasonographic patterns of cerebral circulatory arrest. Both the anterior and posterior circulation should be evaluated, and either of the above patterns identified in all vessels insonated. Although included in some guidelines for cerebral circulatory arrest, absence of intracranial flow signal alone is not widely accepted as proof of absence of intracranial flow, as this may be secondary to technical limitations, such as inadequate temporal windows for insonation or operator inexperience. Although transcranial Doppler is attractive as a confirmatory test because of its ease of performance at the
Figure 2 SPECT study, revealing a lack of uptake of tracer, signifying cerebral circulation arrest.
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bedside, it must be interpreted carefully in the correct clinical context. Other ancillary tests that have been explored include somatosensory evoked potentials, CT angiography, and magnetic resonance angiography. Somatosensory evoked potentials have been drawn into question based on a relatively poor predictive value,23 and cannot be used as a confirmatory test with primary infratentorial lesions, as these may cause an absence of cortical signal due to a structural abnormality. These angiographic techniques have not yet been validated but show promise in small clinical studies.24 Although European brain death guidelines require a similar stepwise approach to brain death determination, there are individual differences. In primary brain injury, only a few countries require a delay between the onset of clinical signs of breath death and the performance of diagnostic procedures, whereas in secondary brain injury (usually due to anoxia), the majority require an observation period of 6-24 hours.25 Variability in the interpretation of the apnea test and the accepted confirmatory tests also exists.
Medical–legal, ethical considerations The prevailing consensus opinion of what should qualify as brain death is that there should be the irreversible loss of function of the brainstem as well as cortical regions (socalled “whole-brain death”). Some philosophers criticize the current definition of brain death as not inclusive of the more integrative functions of the brain.26,27 These advocates of the “higher-brain” formulation for brain death suggest that it is in fact neocortical loss of functioning, and the resultant unconsciousness, loss of self-awareness, memory, and personality, that could suffice to declare death.28 This approach to brain death interfaces more directly with the question of consciousness. By this concept, however, anencephalic infants, patients in a persistent vegetative state, or individuals unconscious from a severe brain injury could also be declared dead, which is clearly not acceptable. But where exactly should the line be drawn? In patients continued on artificial ventilation following brain death, it has been observed that some brain functions persist, such as thermoregulation and hormone secretion (e.g., in response to organ retrieval, associated with a successful gestation of a fetus, or proportional growth, as in the case of a few children).29 Thus, it would seem that death ensues only when there is irreversible cessation of cardiopulmonary function, which would signal that truly all function has left the brain. This would exclude most if not all of the patients currently included in formal definitions of brain death. Furthermore, there are well-documented cases of isolated brainstem lesions (eg, catastrophic bilateral pontine hemorrhage) sparing the cerebral hemispheres and thalami, leading to so-called “brainstem death.”30,31 Although it is unlikely that consciousness would be preserved in these cases
229 despite an intact telencephalon/diencephalon, it would be difficult to exclude an extreme locked-in syndrome by neurological examination alone, making brainstem death perhaps an even less tenable concept than whole-brain death. The brainstem death paradigm is accepted in the United Kingdom.32 Although there are many ways of elaborating the indeterminate boundary between life and death, wholebrain death criteria is the most widely accepted. All states in the U.S. have, by statute or judicial ruling, empowered physicians to determine death by neurological criteria. Although the vast majority of states have adopted the Uniform Determination of Death Act,33 Alabama and West Virginia have adopted the Uniform Brain Death Act,34 which provides that for “legal and medical purposes,” an individual is dead if irreversible cessation of all brain and brainstem function has occurred “in accordance to acceptable medical standards.” The Virginia brain death statute, while also subscribing to the whole-brain criteria of brain death, further specifies that this determination be made by “a specialist in the field of neurology, neurosurgery, or electroencephalography.”35 Our guidelines are left intentionally ambiguous, leaving the decision to the individual treating neurologist. We define brain death as “the irreversible loss of the clinical function of the entire brain.” Thus, it is left open to interpretation. For those who equate brainstem death to brain death, the clinical function of the whole brain is what is tested and this involves testing of the brainstem itself—the patient is comatose, and all brainstem function is absent. For those subscribing to the concept of “whole brain death,” the clinical criteria also suffice. If they have reason to doubt the validity of the clinical exam, they are obligated to perform an ancillary test. The point is, the decision is left to the individual clinician’s discretion. In regard to the religious aspects, the concept of brain death is accepted by all major religious groups, except certain Japanese religions, Orthodox Jewish sects, and gypsies.36 Both New York and New Jersey have statutes limiting the withdrawal of life support measures in a brain-dead individual (i.e., the legal declaration of death) if there are religious objections.37 Whereas the New York regulations do not bar the diagnosis of brain death (they only request a “reasonable accommodation” if there is a religious objection), the New Jersey statutes bar the use of neurologic criteria to diagnose brain death if there is reason to believe that religious objections might exist in the patient, as presented by their family/representative.38 Death is a requisite diagnosis for organ donation, as stated in the Uniform Anatomical Gift Act (heart-beating donors should be brain-dead prior to removal of vital organs). Some commentators have posed that in this era, mechanical ventilation is often discontinued when there is a grim neurologic prognosis, even in the absence of brain death, making the actual diagnosis of brain death useful inasmuch as it facilitates organ donation.27 They would also label the diagnosis of brain death as obsolete. Most would agree that, while it is true that diagnosing brain death is
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important for the above reasons, it does not change the validity of using brain criteria as an established means of declaring death. Several challenging ethical issues may arise when caring for the brain dead patient. Often, families of such patients may request continuation of systemic organ support measures. It is important to differentiate whether these requests are engendered by religious nonacceptance of brain death as a concept, or by the extreme psychological distress of the situation. In the case of the former, it may be advisable to continue treatment until the inevitable cardiopulmonary death ensues (this is legally required in New Jersey). In the latter and more common scenario, further counseling with detailed explanations about the nonsurvivable nature of the brain injury and futility of further care, as well as an additional day or two of ICU management, may be the most compassionate route. As alluded to earlier, there have been several cases of maternal brain death, in which the pregnancies were carried to successful completion by Caesarian section, sometimes as long as several weeks after the neurological catastrophe.39 In these cases, the husband or other next of kin makes the decision regarding further treatment of the mother to save the child is. It is also possible to obtain viable sperm from brain-dead men via seminal vesicle massage electroejaculation.40 Again, ethical considerations are prominent in determining the indication for such a request.
Conclusions Brain death has become established and accepted worldwide as a formal means of declaring a person legally dead. There are multiple implications, perhaps most importantly it allows for improved processes of organ donation. The determination of death by brain criteria is a clinical one, and the use of ancillary tests should be reserved for only those cases in which the clinical diagnosis is drawn into question or in which an apnea test cannot be performed. Multiple ancillary tests exist, all with potential limitations. Many ethical and legal questions have been raised regarding brain death, and these are likely to remain areas of future research and debate for years to come.
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31. Kosteljanetz M, Øthrstrøm, Skøjdt S, et al: Clinical brain death with preserved cerebral circulation. Arch Neurol Scand 78:418-421, 1988 32. Criteria for the diagnosis of brain stem death: review by a working group convened by the Royal College of Physicians and endorsed by the Conference of Medical Royal Colleges and Their Faculties in the United Kingdom. J R Coll Phys Lond 29:381-382, 1995 33. Uniform Determination of Death Act, 12 Uniform Laws Annotated 589 (West 1993 and West Supp 1997) 34. Uniform Brain Death Act, 12 Uniform Laws Annotated 65 (1978) 35. VA STAT sec 54-1-2972 (1997)
231 36. Gallagher CM, Wijdicks EF: Religious and cultural aspects of brain death, in Wijdicks EFM (ed): Brain Death. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 135-150 37. Determination of death, 10 NYCRR; Declaration of Death. L. 1991 38. Declaration of death. L. 1991, ch. 90; NJSA 26:6A-5 39. Souza JP, Oliviera-Neto A, Surita FG, et al: The prolongation of somatic support in a pregnant woman with brain-death: a case report. Reprod Health 3:3, 2006 40. Finnerty JJ, Thomas TS, Boyle RJ: Gamete retrieval in terminal conditions. Am J Obstet Gynecol 185:300-307, 2001