Diagnosis of Brain Death Cept of BD Evolved to Benefit Organ Transplan- Tation

Neurology International 2010; volume 2:e2

Diagnosis of brain death cept of BD evolved to benefit organ transplantation. A historical approach demonstrates that Correspondence: Calixto Machado, Institute of both brain death and transplantation had fully Neurology and Neurosurgery, 29 y D, Vedado, Calixto Machado separate origins. Organ transplantation La Habana 10400, Cuba. Institute of Neurology and Neurosurgery, became possible with technical advances in E-mail: braind@infomed. sld.cu Department of Clinical Neurophysiology, surgery and immunosuppressive treatment. Havana, Cuba The concept of BD evolved with the introduc- Key words: brain death, signs of death, brain tion of intensive care units.12,13 death criteria, transcranial Doppler, EEG, multimodality evoked potentials, CT angiography. BD should be understood as the ultimate clinical expression of a brain catastrophe lead- Conflict of interest: the author reports no con- Abstract ing to a complete and irreversible neurological flicts of interest. stoppage, characterized by irreversible coma, Brain death (BD) should be understood as absent brainstem reflexes, and apnea.14 Most Received for publication: 11 September 2009. the ultimate clinical expression of a brain authors affirm that the diagnosis of BD is just Revision received: 14 December 2009. catastrophe characterized by a complete and a clinical assessment, and after the Harvard Accepted for publication: 20 January 2010. 15,16 irreversible neurological stoppage, recognized Committee Report, most countries and This work is licensed under a Creative Commons by irreversible coma, absent brainstem reflex- states designed their BD diagnostic crite- Attribution 3.0 License (by-nc 3.0). es, and apnea. The most common pattern is ria.6,7,17-21 BD diagnosis should be carried out manifested by an elevation of intracranial following a certain set of principles; that is to ©Copyright C. Machado 2010 pressure to a point beyond the mean arterial say, excluding major confusing factors, estab- Licensee PAGEPress, Italy pressure, and hence cerebral perfusion pres- lishing the cause of the coma, determining Neurology International 2010; 2:e2 doi:10.4081/ni.2010.e2 sure falls and, as a result, no net cerebral blood irreversibility, and precisely testing brainstem flow is present, in due course leading to per- reflexes at all levels of the brainstem.22 manent cytotoxic injury of the intracranial Bader is characterized by preserved CBF, neuronal tissue. A second mechanism is an because normal ICP does not exceed MAP, and intrinsic injury affecting the nervous tissue at sufficient CPP is maintained leading to CBF a cellular level which, if extensive and Pathophysiology of brain preservation, which supplies the nervous tis- unremitting, can also lead to BD. We review death sue with necessary oxygen, glucose, and nutri- here the methodology of diagnosing death, ents to permit its survival.24 In this pattern the based on finding any of the signs of death. The Increased intracranial pressure (ICP) is mechanism causing PbtO2 to fall to zero is an irreversible loss of cardio-circulatory and res- considered the most important pathophysio- intrinsic catastrophe affecting the nervous tis- piratory functions can cause death only when logical mechanism of BD leading to a complete sue at a cellular level which, if extensive and 23,25,36 ischemia and anoxia are prolonged enough to cessation of intracranial blood flow. Upholding unremitting, can also lead to BD. It is clear produce an irreversible destruction of the of oxygenation and hemodynamics by vaso- that in this pattern the lack of oxygenation of brain. The sign of such loss of brain functions, pressor drugs as well as mechanical ventila- the brain is not a failure of the delivery system, that is to say BD diagnosis, is fully reviewed. tion can sustain somatic organs while the and hence it stands for end organ breakdown 23,36 brain suffers an ongoing necrosis process. of the brain at the capillary or tissue level. However, this is not the only pathophysiological mechanism of BD.1,23 Palmer and Bader Introduction studied a series of brain-dead patients by brain Diagnosis of brain death tissue oxygenation (PbtO2) and described two Long before modern technology, everyone pathophysiological patterns regarding cerebral agreed that death occurred when heartbeat blood flow (CBF).23,24 The most common pattern BD diagnosis should be carried out follow- and breathing ceased, and the soul abandoned is manifested by an elevation of ICP to a point ing a certain set of principles;6,21,37-46 that is to the body. Nonetheless, a new concept of death beyond the mean arterial pressure (MAP), and say, excluding major confusing factors, estab- evolved as technology progressed, forcing med- hence cerebral perfusion pressure (CPP) falls lishing the cause of the coma, determining icine and society to redefine the ancient car- to zero and, as a result, no net CBF is present, irreversibility, and precisely testing brainstem dio-respiratory diagnosis to a neurocentric in due course leading to permanent cytotoxic reflexes at all levels of the brainstem.47 diagnosis of death.1-4 In the meantime, the injury of the intracranial neuronal tissue. Nonetheless, most criteria for BD diagnosis do technical and scientific advances of the last In addition, there may be circumstances not mention that this is not the only way of century provided effective mechanical ventila- where an ICP increment does not lead to CBF diagnosing death. If a concept of death on neu- tors, and cardiopulmonary resuscitation cessation. This may occur when ICP augmen- rological grounds is accepted, then BD diag- (“reanimation”) compelled physicians in the tation is compensated in infants with open nostic criteria can be applied only in patients late 1950s to confront a condition impossible fontanelles and soft, deformable skulls, and in under life support assistance in ICUs. Does it even to imagine previously, a state in which patients whose skulls are open owing to multi- mean that when a physician diagnoses death the brain is massively damaged and nonfunc- ple fractures, ventricular drainage, or decom- in a regular ward (the patient is not under life tional while other organs remain functioning. pressive craniectomy.25-35 Moreover, diffuse support), applying cardio-circulatory and respi- Was such a patient alive or dead? This radical- intracranial parenchymal swelling is the main ratory diagnostic criteria, or when a forensic ly changed the course of the debates about reason for a markedly elevated ICP, but specialist diagnoses death in a body under human death, marking a turning point when swelling is not an indefinite phenomenon, and criminal circumstances, we are denying a brain-oriented definitions of death started to it may decrease progressively, and if MAP is brain-oriented concept of death?1,48 be formulated, and brain death (BD) was grad- maintained at reasonable values, CBF might Recently Cuba has passed a law for the ually accepted as death of the individual.5-12 ultimately return.25,28 determination and certification of death. The However, it is commonly believed that the con- The second pattern described by Palmer and National Commission for the Determination

[Neurology International 2010; 2:e2] [page 7] Article and Certification of Death has accepted a neuro- Preconditions or pre-requisites 2. Absent brainstem reflexes. The reflexes logical view of death and emphasized that any 1. Coma owing to irreversible acute brain mediated by the cranial nerves are main indi- legislation of death should be completely sepa- damage of known etiology, affecting both cators of brainstem function. Hence, to prove rated from any norm governing organ trans- hemispheres and brainstem. What is demand- their absence is indispensable to BD diagno- plants.49-52 Hence, the Commission enumerated ed is to have clear and definite clinical and/or sis. The individual significance of each brain- three possible situations for diagnosing death: neuroimaging evidence of an acute central stem reflex varies in BD diagnosis according to i) Outside the intensive care environment nervous system (CNS) insult that is consistent an intrinsic sensitivity of the cranial nerve (without life support), physicians apply the with the irreversible loss of neurological func- networks and to the effect of some accompany- cardio-circulatory and respiratory criteria. tion.1,7,22,47,55 ing factors in brain-dead patients, such as ii) In forensic medicine circumstances, 2. At the time of beginning the neurological trauma, local edema, dried tissues, and physicians utilize cadaveric signs. (They do examination, it is essential to exclude con- intracranial tubes affecting the exploration of not even need a stethoscope.) founding factors that mimic BD:1,22,56,57 reflexes.17,79 iii) In the intensive care environment (with Unresuscitated shock. This is indispensable Pupillary reflex. This reflex, direct and con- life support) when cardio-circulatory and/or to applied BD criteria only when blood pres- sensual, is considered one of the most dis- respiratory arrest occurs, physicians utilize sure has a minimum value of 90 mm Hg.22,58-62 criminant reflexes in BD diagno- the cardio-circulatory and respiratory criteria. Hypothermia (core temperature <34°C). An sis.17,22,55,57,61,62,79,81 Mydriatic, small, or medium- When physicians suspect an irreversible loss inability to regulate temperature, or poikilo- sized pupils are found in brain-dead of brain functions in a heart-beating and ven- thermia, is often present in BD. Core tem- cases.17,43,63,64 tilatory supported case, BD diagnostic criteria perature results should be obtained through Corneal reflex. Unilateral corneal stimula- are applied. central blood, rectal, esophageal, or gastric tion with a throat swab induces a bilateral This methodology of diagnosing death, measurement. Most sets of criteria for BD closure of the eyelids, is an easy response to based on finding any of the signs of death, is diagnosis demand a body temperature of at elicit and, if present, is readily observed. not related to the concept that there are differ- least 32.2°C.1,17,22,43,55,61-64 This is also one of the most discriminant ent types of death. The irreversible loss of car- Severe metabolic disorders capable of caus- reflexes in BD diagnosis. A bilateral or uni- dio-circulatory and respiratory functions can ing a potentially reversible coma. Severe lateral response of eyelid closure and cause death only when ischemia and anoxia metabolic or endocrine abnormalities make upward deviation of the eye (Bell’s phenom- are prolonged enough to produce an irre- BD unreliable.22,55-57,65 Metabolic or endocrine enon) indicates preserved brainstem func- versible destruction of the brain. According to derangement including glucose, electrolytes tioning. However, edema or drying of the the Commission, there is only one kind of (including phosphate, calcium, and magne- cornea, and severe facial and ocular trauma death, based on the irreversible loss of brain sium), inborn errors of metabolism, liver or may preclude a satisfactory stimulus for this functions.1,48-52 renal dysfunction, etc. may cause a poten- reflex. Moreover, the threshold for excita- tially reversible coma.1,22 tion decreases markedly if the lids are kept Peripheral nerve or muscle dysfunction and closed.1,4,17,22,47,79,82,83 neuromuscular blockade potentially play a Oculo-cephalic and oculo-vestibular Signs of death role in inducing unresponsiveness in responses. The oculocephalic reflex, also patients, and it could be a confounding fac- known as Doll’s eyes response, is elicited The diagnosis of death was based on the tor in BD diagnosis.66-72 upon brisk turning of the head from middle finding of any of the following signs of death: Clinically significant drug intoxications (e.g. position to 90° on both sides. In comatose I Irreversible loss of respiratory function. alcohol, barbiturates, sedatives, hypnotics). patients without lesions of the brainstem, II Irreversible loss of cardio-circulatory func- CNS-depressant drugs should be ruled out if the eyes normally conjugately deviate to the tions. the clinical history is indicative.55,72-76 other side. In BD no eye movements are III Algor mortis (postmortem coldness). Clinicians in the emergency department are observed. The neural pathways of this reflex IV Livor mortis (postmortem lividity). often confronted with coma patients owing are mediated through arcs involving the vestibular mechanisms, medial longitudinal V Rigor mortis (postmortem rigidity). to poisoning or intoxication. Several bundle, and ocular nerves. This is a reflex VI Cadaveric spasm. authors recommend using naloxone in a easy to obtain and moderately discrimina- VII Loss of muscle contractions. titrated way when an opiate intoxication is 77 tive. The oculo-vestibular response is elicit- VIII Putrefaction. suspected. In the same way, flumazenil has ed by irrigating the tympanum in both sides IX Irreversible loss of brain functions. been advocated as a benzodiazepine antagonist in coma of unknown etiology.77,78 with iced water. In a comatose patient without lesions of the medial longitudinal bun- Signs I and II correspond to the classical res- Diagnostic criteria dle, and/or ocular nerves, the elicited piratory and cardio-circulatory functions. 1. Deep unresponsive coma. The diagnosis response is a slow deviation of the eyes Signs III to VIII are related to forensic circum- of deep unresponsive coma demands a coma- directed to the cold caloric stimulus. The stances, and beyond the scope of this review. tose patient showing a lack of spontaneous head of the patient should be elevated 30° movements in addition to an absence of motor above the horizontal plane, and 50 cc of iced Irreversible loss of brain functions responses mediated by stimuli applied within water is irrigated into the external auditory (diagnosis of brain death) the cranial nerve distribution.17,22,47,49,53,65 CNS- canal using a small suction catheter. To con- As has already been emphasized, when mediated motor response to pain in any other firm lack of eye movement may be very diffi- physicians suspect an irreversible loss of brain distribution, seizures, and decorticate and cult; it has been suggested pen marks are functions in a heart-beating and ventilatory decerebrate responses impede BD diagnosis. placed on the lower eyelid at the level of the supported case, BD diagnostic criteria are Some brain-dead individuals may present pupil to facilitate the detection of slight eye applied. To assess brain functions during BD spinal reflexes or motor responses, confined to movements. The examiner should observe diagnosis, the clinical neurological examina- spinal distribution, which do not preclude the for one minute after irrigation, and wait an tion is the accepted standard.8,12,13,22,48,52-54 BD diagnosis.22,55,61,62,79,80 interval of five minutes before stimulating

[page 8] [Neurology International 2010; 2:e2] Article

the opposite side. It is essential that the versible CNS insult can be demonstrated by determine absent CBF have been: cerebral examiner confirm that the external auditory clinical and neuroimaging evidences. intravenous digital subtraction angiography, foramen and tympanic membrane are In cases of acute hypoxic-ischemic brain intravenous radionuclide angiography, single undamaged, because clotted blood or ceru- injury, clinical evaluation should be delayed photon emission tomography (SPECT), men in the external auditory canal may for 24 hours subsequent to the cardio-resp- echoencephalography, measurement of arm- impair this response. Moreover, a rupture of iratory arrest, or an ancillary test could be to-retina circulation time, ophthalmic artery the eardrum usually augments caloric performed. pressure measurement, xenon-enhanced com- responses. The presence of severe facial and Periods of observation can be shortened puted tomography, MRI angiography, CT ocular trauma, eyelid edema, and chemosis according to medical criteria by the application angiography and CT perfusion, and transcra- of the conjunctiva may limit movement of of confirmatory tests, to demonstrate a com- nial Doppler ultrasonography (TCD). the globes, making it very difficult to elicit plete cessation of brain circulation, or to Although it has not been widely used as an and observe eye movements. Basal fracture demonstrate loss of bioelectrical activity. ancillary test in BD, the 18F-FDG PET scan has of the petrous bone abolishes the caloric been used by some authors to study brain-dead response unilaterally and may be identified patients, and confirmed no intracerebral by the presence of an ecchymotic mastoid uptake or retention of tracer, consistent with a process (Battle’s sign). There are also some Confirmatory tests diffuse absence of brain metabolism.118,119 drugs that can lessen this reflex, such as tri- Another technique that could be useful in cyclic antidepressants, aminoglycosides, It is widely accepted that BD is a clinical monitoring biochemical changes in vivo, from antiepileptic drugs, anticholinergics, and diagnosis, and currently it is defined as a com- coma to BD, is proton magnetic resonance chemotherapeutic agents, etc.1,6,48,62 plete and irreversible loss of brain function. spectroscopy (1H-MRS). N-acetyl aspartate Gag and cough response. Pharyngeal (gag), Confirmatory laboratory tests are recommend- (NAA) content is a measure of neuronal cough, and swallowing reflexes are often ed when specific components of the clinical integrity, choline (Cho) content mirrors membrane turnover, and creatine (Cre) relates to difficult to explore because of the presence testing cannot be evaluated reliably.50,51,106 energy dependent systems. Falini et al. serially of tubes in the throat and dryness of the Sometimes the apnea test cannot be per- studied a patient with severe global hypoxic- mucosa. Hence, in suspected brain-dead formed or it must be interrupted by the exam- ischemic brain injury using 1H-MRS. cases the cough response is usually iner. Eye injuries may impede an appropriate Particularly notable was a quick decline of NAA explored by passing a catheter through the assessment of pupillary, corneal, or vestibulo- in the acute phase, suggesting the severity of endotracheal tube and suctioning with neg- reflex testing. In those patients with perforat- the neuronal insult, and after seven weeks of ative pressure for several seconds. As these ed tympanic membranes iced water caloric evolution the irreversible death of the major reflexes have their arcs through the medul- irrigation for exploring the vestibulo-ocular la oblongata, it is desirable to explore part of the neuronal population was con- reflexes is proscribed. Furthermore, the diag- 120 17,22,64,84 firmed. We have also applied this technique them. nosis of BD in children and neonates is more to monitor metabolic changes in the evolution 3. Negative atropine test. The atropine test complicated and usually ancillary tests are from a persistent vegetative state to a mini- (AtT) assesses bulbar parasympathetic activity 57,98,107-111 advocated. 121 85 mally conscious state. on heart activity in brain-dead patients. Confirmatory tests are recommended to Ouaknine first proposed including this as a TCD has been recommended for assessing shorten periods of observation according to 122-128 criterion for the so-called brainstem death.85-89 CBF in suspected brain-dead patients. TCD physicians’ criteria and in those conditions is a noninvasive technique that measures local The method for this test consists in injecting 2 interfering with the clinical BD diagnosis. The mg atropine under continuous monitoring of blood flow velocity and direction in the proxi- Cuban Commission proposed that confirma- mal portions of large intracranial arteries. TCD the ECG during 10 minutes. The AtT is consid- tory tests should be mandatory in cases of ered negative if heart rate is not augmented by requires training and experience to perform it patients with primary brainstem lesions and interpret results; hence, it is typified as more than 3% compared with basal ECG 1,49-51 undergoing BD diagnosis. 129,130 1,58,86,90-95 operator-dependent. In the ICU setting, records. Confirmatory tests in BD can be divided into 4. Absent respiratory effort confirmed by the intensivists or neurologists usually receive those proving absent CBF and those that apnea test. The apnea test (AT) has been con- training to apply this technique using portable demonstrate loss of bioelectrical activity. sidered by some authors as the “condition sine Doppler devices in suspected brain-dead cases. qua non” for determining BD, because it pro- Oscillating flow, systolic spikes, or no flow pat- vides an essential sign of a definitive loss of Tests to demonstrate absent cere- terns are typical Doppler-sonographic flow sig- brainstem functions. Nonetheless, several bral blood flow nals found in the presence of cerebral circula- authors have expressed their concern about Bernat recently emphasized that “the most tory arrest, which if irreversible, results in 1,131,132 the safety of this procedure, owing to potential confident way to demonstrate that the global BD. complications such as severe hypotension, loss of clinical brain functions is irreversible is Nonetheless, recent reports affirmed that pneumothorax, excessive hypercarbia, hypox- to show the complete absence of intracranial multi-slice CT angiography (CTA) is a robust ia, acidosis, cardiac arrhythmia, or asystole, blood flow.”112 Ingvar and colleagues defended tool to demonstrate the lack of intracranial which may constrain the examiner to abort the this, concluding that the permanent cessation blood flow, showing a high sensitivity and a test, thereby compromising BD diagnosis. of CBF produces total brain infarction.113,114 wide safety margin for diagnosing BD. In the Nevertheless, when an appropriate oxygen-dif- Several tests that can measure CBF accur- near future it might be the preferred test for 29,124,133 fusion procedure is used, this technique is ately and validly in suspected brain-dead proving CBF. safe.1,96-105 patients have been developed in the last 5. Periods of observation. If BD determina- decades. The first technique used to demon- Tests to demonstrate loss of bio- tion is only based on clinical evaluation, the strate absence of intracranial circulation in BD electrical activity following periods of observation were proposed distal to the intracranial portions of the inter- The EEG has been closely linked to BD since by the Cuban Commission.1,49-52 nal carotid and vertebral arteries was cerebral the pioneering descriptions of the death of the Six hours at least, if a structural and irre- angiography.115-117 Other techniques used to nervous system and coma dépassé.134,135 The set

[Neurology International 2009; 2:e2] [page 9] Article of criteria based on a brainstem standard, like BD should be understood as the ultimate of irreversible coma. Report of the Ad Hoc those from the Commonwealth countries, does clinical expression of a brain catastrophe lead- Committee of the Harvard Medical School not include EEG.3-5,136-140 On the contrary, EEG is ing to a complete and irreversible neurological to examine the definition of brain death. recommended by most countries adopting the stoppage, characterized by irreversible coma, J Am Med Assoc 1984;252:677-9. “whole brain death” definition.141-145 absent brainstem reflexes, and apnea. We have 16. A definition of irreversible coma. Report Although EEG is sensitive to hypothermia, enumerated three possible situations for diag- of the Ad Hoc Committee of the Harvard drugs, or extreme hypotension,146 and several nosing death based on the “signs of death”. Medical School to Examine the Definition artifacts can appear in the ICU environment, This methodology of diagnosing death does not of Brain Death. J Am Med Assoc 1968;205: this technique is still extensively used as an mean that there are different types of death. 337-40. ancillary test in BD diagnosis. Buchner et al. The irreversible loss of cardio-circulatory and 17. Walker AE, Molinari GF. Criteria of cere- proposed that its sensitivity as well as speci- respiratory functions can cause death only bral death. Trans Am Neurol Assoc 1975; ficity can reach up to 90%.147 On the other when ischemia and anoxia are prolonged 100:29-35. hand, multimodality evoked potentials (MEP) enough to produce an irreversible destruction 18. Robert F, Mumenthaler M. Criteria of and electroretinography (ERG) are highly of the brain. brain death. Spinal reflexes in 45 person- resistant to drug intoxication and hypother- al studies. Schweiz Med Wochenschr mia, and have been shown to be reliable in the 1977;107:335-41. ICU environment.148-154 Owing to these features, 19. Cranford RE. Minnesota Medical a substantial interest in multimodality evoked References Association criteria. Brain death: concept potentials (MEPs) in BD has grown over the and criteria, II. Mo Med 1978;61:600-3. past two decades, and a wealth of data are now 1. Machado C. Brain death. A reappraisal. 20. Pasnikowski W. Current criteria of brain available in the literature.151,152,155-159 However, New York: Springer 2007;1-223. death. Przegl Lek 1987;44:672-5. considered as single tests, they have their 2. Pallis C. Brainstem death--the evolution 21. Jan MM. Brain death criteria. The neuro- limitations and they are not included routinely of a concept. Med Leg J 1987;55:84-107. logical determination of death. Neuro- as confirmatory tests for BD diagnosis.1,160 3. Pallis C. Brainstem death. In: Handbook sciences 2008;13:350-5. 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