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Rapid Responses: Rapid Responses published:
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Jewish Religion Recognise Brain Death
- Dan Michaeli (5 May 2000)
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Ethical debate - managing "brain stem death"
- David W Evans (6 May 2000)
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Re: Jewish Religion Recognise Brain Death
- David W Evans (10 May 2000)
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Ethical debate - managing "brain stem death"
- David W Evans (12 May 2000)
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An issue of wide concern
- Daniel Dalgleish (14 May 2000)
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What should be the real debate?
- J A W Wildsmith (19 May 2000)
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"Compromise-like" solution
- John W Polacheck (19 May 2000)
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The patient's interests should predominate
- Ruth Deroy (3 June 2000)
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Withdrawal of mechanical ventilation etc not tantamount to murder
- Luke Howard (3 June 2000)
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Brain stem death: inappropriate interpretation
- M T E Heafield (12 June 2000)
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Re: Brain stem death: inappropriate interpretation
- Cicero Galli Coimbra (29 June 2000)
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Re: Brain stem death: inappropriate interpretation
- David Wainwright Evans (29 June 2000)
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Medical procedures that do not survive transparent scientific debate cannot be considered standard
- Cicero Galli Coimbra (27 July 2000)
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Do we accept brain or brainstem death as the death of the individual?
- Calixto Machado (16 August 2000)
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Demand for free debate
- Loibner Johann (1 September 2000)
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Demand for free debate
- Gilson Luís Roberto (2 October 2000)
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Re: Re: Brain stem death: inappropriate interpretation
- CELIO LEVYMAN (7 April 2002)
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Opposition to Brain Death Criteria
- Michael Potts (11 April 2002)
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Re: Re: Re: Brain stem death: inappropriate interpretation
- David W Evans (12 April 2002)
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Re: Re: Re: Re: Brain stem death: inappropriate interpretation
- Paul A. Byrne (13 April 2002)
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Professor Peter Singer's Views on Brain Death
- D. John Doyle (29 April 2002)
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"Brain death" and "brain stem death"
- Cicero G Coimbra (29 April 2002)
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Dan Michaeli, Chairman, Board of Directors Clalit Health Services , Israel
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Rabbi Jakobovitz was certainly a leading authority on Jewish Halachah, yet the issue of recognition of Brain Death as synonymous with Death was extensively studied by the Chief Rabbinate of Israel in 1986, and its conclusion was different. On a previous occasion I referred in this journal to the ruling of the Chief Rabbinate, allowing the harvesting of beating hearts for the sake of organ transplantaion. The Chief Rabbis accepted at the time that brain death as determined by abscence of electrical brain activity and absence of spontaneous breathing when artificial respiration is stopped allow the declaration of the patient's death from the Halachic point of view. My interpretation of the difference of opinions about the meaning of the Halachah Law is that Rabbi Jakobovitz was relating to the historical situation and not to the progress that is occuring all along Jewish history of adaptation to the changing times and progress of human knowledge and social concepts. I wish we could have Rabbi Jakubovitz comment on this but there is no doubt that ever since 1986 hundreds of people received heart, liver and other organs transplantations in Israel with the consent of the Rabbis. |
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David W Evans, Retired cardiologist
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EDITOR - I am not qualified to comment on the religious aspects of the case reported by Inwald and colleagues(1) but beg leave to correct some of the misunderstandings propagated in their discussion and to add one or two salient facts. They say that "brain stem death has been accepted as death .... in the UK since 1976" when, in fact, that diagnosis was then held only to ensure that "there is no possible chance of recovery", thus affording a basis for discontinuation of mechanical ventilation. The clinical syndrome defined by the so-called "brain stem death" or (at that time) "brain death" tests was clearly seen as a pre-mortal state. It was not until 1979 that the same clinical state was "presumed" to be death(2) - on the grounds that "by then all functions of the brain have permanently ceased". As evidence accrued that brain functions persisted in many patients pronounced "brain stem dead", that untenable claim was abandoned in 1995(3) and a new premise was suggested as a basis for calling these patients dead. This new premise - the "irreversible loss of the capacity for consciousness, combined with irreversible loss of the capacity to breathe" has no sound scientific or philosophical basis and seems doomed to fail in its turn. Inwald and colleagues quote Pallis's 1983 assertion that asystole occurs within days even if ventilation is continued. That is another untenable claim(4), survivals for months (e.g. to term) or even many years being now on record. It may be that developing understanding of brain pathophysiology in the early stages after head injury(5) will increase the prospects of salvage as time goes by. It may already have made the diagnosis of "brain stem death" ethically impossible because the crucial apnoea test is now known to be capable of exacerbating the brain damage ; it may even be lethal. David W. Evans (retired cardiologist),
1. Inwald D, Jakobovits I, Petros A. Brain stem death : managing care when accepted medical guidelines and religious beliefs are in conflict. BMJ 2000; 320:1266-7. (6 May). 2. Conference of Medical Royal Colleges and their Faculties in the UK. Memorandum on the diagnosis of death. BMJ 1979;i:332. 3. Review by Working Group of the Royal College of Physicians, endorsed by the Conference of Medical Royal Colleges and their Faculties. Criteria for the diagnosis of brain stem death. J Roy Coll Physns Lond 1995;29:381-2. 4. Shewmon DA. Chronic "brain death" : meta-analysis and conceptual consequences. NEUROLOGY 1998;51:1538-45. 5. Coimbra CG. Implications of ischemic penumbra for the diagnosis of brain death. Brazilian J Med Biol Res 1999;32:1479-87. |
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David W Evans, Retired cardiologist
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Dr. Michaeli tells us that the Chief Rabbis accepted "brain death as determined by absence of electrical brain activity and absence of spontaneous breathing" as a basis for the declaration of death from the Halachic point of view. Since electrical brain activity persists in many or most patients declared "brain stem dead" (1), presumably they are not dead in the eyes of the Jewish religious authorities. David W. Evans,
1. Pallis C. and Harley D.H. ABC of Brainstem Death (2nd Edn) 1996. BMJ Publishing Group (London),p.36. |
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David W Evans
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EDITOR - I am not qualified to comment on the religious aspects of the case reported by Inwald and colleagues(1) but beg leave to correct some of the misunderstandings propagated in their discussion and to add one or two salient facts. They say that "brain stem death has been accepted as death .... in the UK since 1976" when, in fact, that diagnosis was then held only to ensure that "there is no possible chance of recovery", thus affording a basis for discontinuation of mechanical ventilation. The clinical syndrome defined by the so-called "brain stem death" or (at that time) "brain death" tests was clearly seen as a pre-mortal state. It was not until 1979 that the same clinical state was "presumed" to be death(2) - on the grounds that "by then all functions of the brain have permanently ceased". As evidence accrued that brain functions persisted in many patients pronounced "brain stem dead", that untenable claim was abandoned in 1995(3) and a new premise was suggested as a basis for calling these patients dead. This new premise - the "irreversible loss of the capacity for consciousness, combined with irreversible loss of the capacity to breathe" has no sound scientific or philosophical basis and seems doomed to fail in its turn. Inwald and colleagues quote Pallis's 1983 assertion that asystole occurs within days even if ventilation is continued. That is another untenable claim(4), survivals for months (e.g. to term) or even many years being now on record. It may be that developing understanding of brain pathophysiology in the early stages after head injury(5) will increase the prospects of salvage as time goes by. It may already have made the diagnosis of "brain stem death" ethically impossible because the crucial apnoea test is now known to be capable of exacerbating the brain damage ; it may even be lethal. David W. Evans (retired cardiologist), 27 Gough Way, Cambridge, CB3 9LN (and Queens' College, CB3 9ET). 1. Inwald D, Jakobovits I, Petros A. Brain stem death : managing care when accepted medical guidelines and religious beliefs are in conflict. BMJ 2000; 320:1266-7. (6 May). 2. Conference of Medical Royal Colleges and their Faculties in the UK. Memorandum on the diagnosis of death. BMJ 1979;i:332. 3. Review by Working Group of the Royal College of Physicians, endorsed by the Conference of Medical Royal Colleges and their Faculties. Criteria for the diagnosis of brain stem death. J Roy Coll Physns Lond 1995;29:381-2. 4. Shewmon DA. Chronic "brain death" : meta-analysis and conceptual consequences. NEUROLOGY 1998;51:1538-45. 5. Coimbra CG. Implications of ischemic penumbra for the diagnosis of brain death. Brazilian J Med Biol Res 1999;32:1479-87. |
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Daniel Dalgleish, SpR Anaesthesia Jersey Hospital, St Helier
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Dear Sir, The ethical debate and subsequent commentary on the management of care in a young Jewish girl who was brainstem dead has parallels close to home for the anaesthetic community. Fisher and Raper are worried that if we accommodate the requirements of any particular group then we should accommodate the requirements of all groups however unreasonable. However, the suggestions of one particular group are illustrated in a recent editorial in ‘Anaesthesia’[1]. In this article, Young and Matta conclude that ‘sedation and analgesia should be given with muscle relaxation for organ donation’ since ‘brain stem death tests are arbitrary’. In other words, some members of the anaesthetic community are not absolutely convinced of the reliance of brain stem death tests to equate with the lack of capacity for suffering. The acceptability of organ donation rests on the assumption that the donor is irrevocably and absolutely dead rather than in the process of dying. However, in their final paragraph, Young and Matta again suggest that we should provide general anaesthesia for organ donation to prevent the haemodynamic responses to surgery that are ‘distressing for operating theatre personnel’ and because ‘it is imperative that public confidence is maintained in the transplant program’. In conclusion then, it is not only members of orthodox (or unorthodox) religious groups that have problems accepting the current hospital management of the brain stem dead, but it also seems to include health care workers (including doctors) who are involved with the transplantation of their organs. [1] Young PJ, Matta BF. Anaesthesia for organ donation in the brainstem dead – why bother? Anaesthesia 2000; 55: 105 - 106 |
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J A W Wildsmith
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EDITOR-The papers by Inwald and colleagues (1) and Fisher & Raper (2) eruditely discuss the management of the clash between medical and religious beliefs in the case of a brain dead child, but is this the important issue? Can I ask why on earth a 3 year old child with "a large, right sided, temporal mass extending into the midbrain", identified during magnetic resonance imaging under general anaesthesia as a day case, was sent home, even if this was to await urgent neurosurgical referral? Surely this is just the kind of patient who may be de-stabilised by a general anaesthetic, no matter how carefuly and skillfully administered. A minimum of overnight observation in hospital might have allowed earlier neurosurgical intervention and avoided the ethical dilemma altogether. Perhaps the real debate should be on the conflict between economic pressures to manage yet more patients on a day case basis and the medical priorities. Tony Wildsmith professor of anaesthesia Ninewells Hospital & Medical School, Dundee DD1 9SY 1. Inwald D, Jakobovits I, Petros A. Ethical debate. Brain stem death: managing care when accepted medical guidelines and religious beliefs are in conflict. BMJ 2000;320:1266-7 2. Fisher M, Raper RF. Commentary: delay in stopping treatment can become unreasonable and unfair. BMJ 2000;320:1268 JAW Wildsmith
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John W Polacheck
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To The Editor - I would like to offer a "compromise-like" resolution that respects the wishes and religious values of the family and does not "waste" scarce and precious resources of society: when a patient has virtually no chance for recovery and there is a religious or ethical conflict regarding termination of life support, simply transfer the patient out of the intensive care unit (ICU) and onto a regular medical unit with life support intact, including a mechanical ventilator. This solution is also workable when for patients who have left a directives that "everything" be done. In such cases, intravenous (IV) hydration and/or tube feedings may be continued, but generally most medications will be discontinued. "Comfort" nursing care will be maintained, of course. An old model ventilator can be used, which most hospitals have stored away in "closets". The settings need not to be adjusted nor the patient's ventilatory parameters monitored. The costs will be relatively modest, especially compared to the costs already encumbered by the same patient, as will be the use of resources. Most patients will die in a few hours, or at most, in a few days with the "dignity" which they and their families deserve. Hopefully the politicians, lawyers and hospital administrators will not interfere !!!! John W. Polacheck, M.D.
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Ruth Deroy
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EDITOR--Although Inwald et al describe how consensus and sensitivity have helped the family and staff concerned to live through a difficult and sad time I would wish to take issue with two points they raised.1 'Families should not be pressurised into consenting to withdrawal of care' and 'should not be asked to become "accessories to murder".' I entirely agree with this statement. It is an unfair burden to put on any family member to partake responsibility in a decision to withdraw treatment and there is no need for it. Medical treatment or the cessation of it should be guided by evidence of its effectiveness and society's acceptance of its desirability in general (as society bears the cost). In any particular case only the patient has the right to deny himself a universally accepted treatment but not the right to demand a treatment that cannot be offered to others as well. In the case described by Inwald et al brain stem death is a medical diagnosis, hence cessation of artificial ventilation of a dead patient is a medical decision. While families must have the right to be guided through the decision making process it remains ultimately medical. 'The aim of intensive care should be to treat the family, not just the patient.' I find this statement alarming, leading us straight into a bottomless pit. -Which family interests are we supposed to treat? -Do we always know about hidden agendas in families? -Can we allow this luxury to all families? -What do we say to families whose relatives we cannot treat because of a shortage of beds (a common problem!) when at the same time allowing other families to exercise a choice society is not able to fund? Reality can be very sad and hard to accept but it must be seen to be fair. For us doctors the interests of our patients - actual patients and potential ones - have to be overruling all other interests and families should not be treated on ITU but helped to accept the inevitable. Ruth Deroy senior registrar in anaesthesia Norfolk & Norwich Health Care NHS Trust Brunswick Road Norfolk NR1 3SR 1 Inwald D, Jakobovits I, Petros A. Brain stem death: managing care when accepted medical guidelines and religious beliefs are in conflict. BMJ 2000;320:1266-7. Competing interests: None. |
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Luke Howard
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Sir, I refer to the case of the 3 year old Jewish girl discussed in the Journal on 6 May1. Respect for the beliefs of patients and their relatives is essential and in most circumstances complied with where possible and reasonable. This is particularly the case where the views are mainstream and backed up by authorised expertise and logical argument from within the infrastructure of the religion. I agree with the Jewish philosophy regarding brain stem death and the concern over withdrawal of natural means of life support. Brain stem death when infallibly diagnosed is a predictor of imminent death once life support is removed rather than death itself. However, I disagree that withdrawal of mechanical ventilation in a pharmacologically unsedated and unparalysed patient is 'tantamount to murder'. Mechanical ventilation cannot be seen as a natural means of life support. The primary aim in the index case was not to prolong life unnecessarily, while maintaining the availability of food, water and oxygen, and the secondary effect was death. No matter how immediate the secondary effect is following the primary aim, they are not the same. Luke Howard Senior House Officer Box 28, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ. 1. Inwald D, Jakobovits I, Petros A. Brain stem death: managing care when accepted medical guidelines and religious beliefs are in conflict. BMJ 2000;320:1266-8. Luke Howard 2 Clarendon St Cambridge CB1 1JU |
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M T E Heafield, Consultant Neurologist Queen Elizabeth Hospital
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Dr. Evans whose views are not supported by current clinical practice in the field of neuroscience, intensive care or brain stem death testing, has cited once again the article by Ciombra which suggests that Apnoea testing is 'dangerous'. Not true. Coimbra seems strangely unkeen to answer detailed questions about the content of his website. Coimbra's article and website suggest that cooling patients who are demonstrating absent brain stem function due to structural brain injury will improve their chances of regaining brain stem function. Not true. Most surprisingly Coimbra suggests that since Thrombolysis can recanalise basilar vessels that this should be tried. To accept this reference, readers need to be aware that structural brain injury causes tearing of vessels off the brain stem which is forced in a rostro-caudal direction by some centimeters. Haemorhagic infarction of the brain stem occurs and no amount of thrombolysis can correct what is a mechanical imjury to the brain. Thrombolysis for those who use it, would be an interesting treatment of haemorrhagic infarction. Large vessel basilar occlusion does not occur at all.Those who have seen the extent of such injuries post- mortem could have no doubt that structural brain injury is such that survival (or recovery) of brain stem function cannot occur, independent living could not return and death of the whole brain will follow. An excellent sagittal image of this is shown in the tome of Plum and Posner p98. Haemodynamic disturbances which occur when brain stem death has occurred and is being tested, are more often than not independent of testing. Cardiac arrest and arrhythmias are a common occurrence when rapid rises of ICP occur with hypothalamic injury. The practice of inadequate resuscitation of patients with DI and poor venous filling pressures because of their underlying pathology is in my view a much more likely cause. The application of appropriate preconditions, exclusion criteria and meticulous resuscitation of patients has never in my experience of many brain stem examinations lead to any cardiovascular instability. There are a number of commentators in this field who persist in mis- informing the general population, why I know not. |
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Cicero Galli Coimbra, Associate Professor - Department of Neurology and Neurosurgery Federal University of São Paulo - Brazil
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To the editor: I thank Dr. Heafield for the opportunity to respond to his arguments against the issue presented in the BJMBR article (1). Firstly, I would like to emphasise the fundamental premise of the text "Implications...", which was not addressed in his comments. Global ischemic penumbra (GIP) is a mathematical reality. Brain blood flow (BBF) is a continuous physiological variable and, therefore, does not decrease to levels lower than 10 ml.100g-1.min-1 as a consequence of increased intracranial pressure (ICP) without crossing the range of 35 to 10 ml.100g -1.min-1 (the GIP range, when brain function may be supressed without irreversible damage). Therefore, the BBF of patients with increased ICP found in GCS of 3 and cephalic areflexia is certainly lower than 35 ml.100g-1.min-1, (the threshold for functional inactivation) but not certainly lower than 10 ml.100g-1.min-1 (the threshold for irreversibility when sustained for longer than 1 hour, according to current neuroscientific knowledge). Moreover, that undeniable GIP period has neither been proved to be invariably shorter than 6 hours (the most frequently proposed period of clinical observation for the diagnosis of brain death or brain stem death). Actually, direct measurements of BBF in patients in deep coma and with cephalic areflexia (performed before apnea testing became widely accepted and employed) showed results consistent with GIP in 50% of cases (2-4). Secondly, apnoea testing may indeed irreversibly damage the brains of the specific subset of patients in GCS of 3 and cephalic areflexia who are still within the GIP period. This is because apnoea testing may induce severe arterial hypotension (in about 40% of cases) and cardiac arrest (5) and, conceivably, may further increase ICP due to the effect of the aimed levels of hypercarbia on brain swelling. By decreasing blood pressure and/or further increasing ICP in a patient with critical levels of brain perfusion pressure (within the GIP range), apnoea testing may reduce BBF to levels lower than 10 ml.100g-1.min-1, thereby establishing (only then) irreversible damage to his/her brain. Dr. Heafield may argue that all patients are to be closely monitored during the test, which should be immediately discontinued whenever hypotension is detected. However, even transient hypotension [the most detrimental secondary insult after traumatic brain injury - TBI (6)] may cause irreversible collapse of the intracranial circulation in cats after severe head trauma (7). Data from 2 different studies (8, 9) suggest that these experimental results may indeed reproduce the response of the human brain circulation to apnoea testing. When apnoea test was not used, victims of severe TBI sustained elevated ICP and decreased perfusion pressure up to spontaneous cardiac arrest in 100% of the cases (8). In contrast, after apnoea test 100% of these patients were found with normal ICP and normal perfusion pressure, but with a BBF level equal or close to zero (9). This 100% of disagreement suggests that hypotension (and/or possibly a further increase of ICP) during the period of apnoea may have induced irreversible intracranial circulatory arrest in the second study (9): the efflux of the blood volume from the intracranial space secondary to the induced circulatory collapse would explain the normalization of ICP and perfusion pressure after apnoea testing. The vascular collapse may become irreversible due to the establishment of tension forces involving the inner endothelial surfaces of brain vessels during the transient period of inadvertently lowered perfusion pressure. In addition, the respiratory center is not expected to respond to hypercarbia if BBF is further reduced. Apnoea test is a useless and harmful diagnostic procedure, which is performed without anticipation of any therapeutic benefit to the patient, and usually without the consent of his(her) family. Induced hypothermia (33ºC) has recovered to normal life TBI victims found in GCS of 3 and dilated/unresponsive pupils who are not subjected to apnoea testing (10, 11). As hypothermia effectively treats brain swelling and edema (12), recovery from GIP is one reasonable explanation for these remarkable results, obtained when cooling is timely initiated (13) and brain temperature is controled to avoid intracranial thermal pooling (14). When hypothermia was indicated as a criterion of exclusion 32 years ago, the Harvard Ad Hoc Committee overlooked the possibility that TBI victims rendered accidentally hypothermic could have resumed normal daily life (despite "looking" brain dead, with flat EEG) precisely as a consequence of the therapeutic effect of their low body temperature. Comprehensibly, as the phenomenon of ischemic penumbra was not known in 1968, the members of the Committee could only consider the possibility that those patients could recover because hypothermia was simulating brain death. We no longer have that excuse. Cases of basilar artery occlusion presenting in coma and requiring ventilatory support seem to invariably evolve to death when early recirculation is not induced (15). In contrast, early intra-arterial thrombolysis effectively recovered one of such cases (16). A subset of them may therefore sustain ischemic penumbra of the brain stem for a few hours from the onset of symptoms (when those pathological changes described by Dr Heafield are not yet established), and respond to that therapeutic procedure, provided that apnoea testing is not done. The data reviewed in the article "Implications…" (1) support the possibility that a global reduction of blood supply to the whole brain or solely to the infratentorial structures down to the range of ischemic penumbra for several hours or a few days may lead to misdiagnosis of brain death or brain stem death in a subset of deeply comatose patients with cephalic areflexia. Therefore, the expression "structural brain injury" (which was repeated employed by Dr. Heafield, and may suggest irreversibly established damage to the whole brain or brain stem) is not in agreement with the concept of GIP. Cicero Coimbra, MD, PhD
1. Coimbra CG (1999). Implications of ischemic penumbra for the diagnosis of brain death. Brazilian J Med Biol Res;32:1538-45. . ( http://www.epub.org.br/bjmbr/year1999/v32n12/3633c.htm). 2. Hoyer S & Wawersik J (1968). Untersuchungen der Hirndurchblutung und des Hirnstoffwechsels beim Decerebrationssyndrom. Langenbecks Arch Chir, 322: 602-605. 3. Bes A, Arbus L, Lazorthes Y, Delpla M & Escande M (1969). Hemodynamic and metabolic studies of coma depassé. Research on biological criteria for cerebral death. International CBF Symposium, Mayence. 4. Shalit MN, Beller J, Feinsod M, Drapkin AJ & Cotev S (1970). The blood flow and oxygen consumption of the dying brain. Neurology, 20: 740 -748. 5. Jeret JS & Benjamin JL (1994). Risk of hypotension during apnea testing. Arch Neurol, 51:595-599. 6. Lewelt W, Jenkins L & Miller JD (1980). Autoregulation of cerebral blood flow after experimental fluid percussion injury of the brain. J Neurosurg, 53: 430-511. 7. Chesnut RM (1997). Avoidance of hypotension: conditio sine qua non of successful severe head-injury management. J Trauma, 42:S4-S9. 8. JØrgensen PB, Heilbrun MP, Boysen G, Rosenklint A & JØrgensen EO (1972). Cerebral perfusion pressure correlated with regional cerebral blood flow, EEG and aortocervical arteriography in patients with severe brain disorders progressing to brain death. Europ Neurol, 8: 207-212. 9. Obrist WD, Jaggi JL, Langfitt TW & Zimmerman RA (1981). Cessation of CBF in brain death with normal perfusion pressure. J Cerebral Blood Flow Metab, 1(Suppl 1): S524-S525. 10. Metz C, Holzschuh M, Bein T, Woertgen C, Frey A, Frey I, Taeger K & Brawanski A (1996). Moderate hypothermia in patients with severe head injury and extracerebral effects. J Neurosurg, 85: 533-541. 11. Watanabe Y (1997). Once again on cardiac transplantation. Flaws in the logic of proponents. Jpn Heart J, 38: 617-624. 12. Schwab S, Spranger M, Aschoff A, Steiner T & Hacke W (1997). Brain temperature monitoring and modulation in patients with severe MCA infarction. Neurology, 48: 762-767. 13. Hayashi N (1996). Brain hypothermia therapy. Jpn Med J, 3767:21-27. 14. Hayashi N, Hirayama A, Udegawa A, Daimon W & Ohata M (1994). Systemic management of cerebral edema based on a new concept in severe head injury patients. Acta Neurochir [suppl]; 60:541-543. 15. Wijdicks EFM & Scott JP (1996). Outcome in patients with acute basilar artery occlusion requiring mechanical ventilation. Stroke 27:1301-1303. 16. Koberda J L, Clark WM, Lutsep H & Nesbit G (1997). Successful clinical recovery and reversal of mid-basilar occlusion in clinically brain dead patient with intra-arterial urokinase. Neurology; 48 (suppl): A154. Abstract. |
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David Wainwright Evans, Retired cardiologist
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Dr. Heafield's statement that "structural brain injury is such that ..... death of the whole brain will follow" makes our point that "brain stem death" is a pre-mortal syndrome. It is in that state, while some brain functions persist, that organ donors are eviscerated. The inevitability of progression to death is easy to accept in the type of case he describes but it is proper to question whether or not this is so in every patient who satisfies the "brain stem death" criteria within a few hours of the onset of coma due to less obviously overwhelming trauma. With regard to the apnoea test - crucial to the diagnosis of all forms of "brain death" - it would appear that Dr. Heafield does not accept that it may do further damage to the injured brain whereas others think it does carry that risk and should, therefore, not be carried out (on the "primum non nocere" principle, because it is, after all, only a diagnostic test and not a therapeutic intervention for the patient's own good). David W.Evans, 27 Gough Way, Cambridge, CB3 9LN |
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Cicero Galli Coimbra, Associate Professor, Department of Neurology and Neurosurgery Federal University of São Paulo
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To the editor: In 1997, the Brazilian Congressmen approved a presumed consent-based law for organ procurement, and the Brazilian Medical Council (CFM) established the criteria for the diagnosis of brain death in our country. The CFM criteria included observation of GCS score of 3 and cephalic areflexia followed by a confirmatory test, which could be a simple EEG, transcranial Doppler or angiography, among others. According to international standards, the documentation of cephalic areflexia included apnoea testing for up to 10 minutes accompanied with pre- and passive oxygenation. Since then, I have been involved in both local and international discussions related to the scientific validation of the current diagnostic criteria, and particularly concerned with the implications of ischaemic penumbra for the diagnosis of brain death and brain stem death. After peer review, a critical review was published in the BJMBR (1). The content of "Implications..." was also presented both in local and international meetings, including the III International Symposium on Coma and Death held in February 2000 in Havana (Cuba). In addition, I have contacted several international experts in brain death and brain stem death through the internet, and invited them to access those data at the web site http://www.epub.org.br/bjmbr/year1999/v32n12/3633c.htm for discussion. Similarly to what we see now, when an initially resolute challenge turns into silence, absolutely no argument has ever been presented to refute the basic premise of that criticism, already emphasised in my e- Letter of 29 of June, 2000 to BMJ. In addition, 6 different international personalities from USA, UK, Japan and Austria, who have been involved in this field for the last 2 decades, provided formal (written) support to the scientific and ethical value of the article "Implications...". They did so as attempts (so far unfruitful) to stop a internal prosecution by the CFM-affiliated Medical Council of the State of São Paulo (CREMESP), which may eventually decide to revoke my license to work as a physician on the charge of publicly proposing hypothermia (which "is not explicitly recognised by a competent organ as a therapeutic measure") to replace apnoea testing, at least in victims of severe head trauma with GCS score of 3, and lacking other cephalic reflexes. The prosecution was triggered after a formal complaint of the Brazilian Association of Transplant Surgeons (ABTO). The current diagnostic criteria were arbitrarily proposed (and accepted) 32 years ago, based on the incorrect assumption that intracranial circulatory arrest would be the only possible explanation for deep coma and cephalic areflexia in a patient with increased ICP (provided that all known factors capable of inducing metabolic depression are ruled out). Accordingly, angiography was proposed as a confirmatory test in the early seventies. More recently, the diagnosis of brain death was regarded as a clinical diagnosis: evidently, if collapse of the blood supply to the brain is taken as the only conceivable patophysiological mechanism underlying the absence of neurological function, the lack of clinical improvement for a few hours would be also taken as enough evidence for the diagnosis of brain death or brain stem death. Despite the evident prognostic nature of diagnostic criteria that include a period of observation, most physicians have felt quite comfortable about accepting the diagnosis of brain death or brain stem death as a self-fulfilling prophecy based on that assumption and, for the inculpable intent of simple documentation, have easily agreed in testing for apnoea those patients whose neurological condition they already regarded as irreversible. However, the verification of the penumbra phenomenon in the human brain during the nineties has clearly invalidated the basic assumption underlying the current diagnostic criteria: inactivation of neurological function is now clearly dissociated from irreversible neuronal damage. Accordingly, during the progression to maximally increased intracranial pressure, the brain blood flow will inevitably remain within the limits of ischaemic penumbra for an unknown period of time before reaching the levels (lower than 10 ml.100g-1.min-1) that induce irreversible neuronal damage. In consideration of the "primum non nocere" principle mentioned by Dr. Evans, apnoea test cannot continue to be part of any standard medical conduct, or physicians all over the world will prospectively take the chances of inducing rather than diagnosing irreversible brain damage in a unknown number of patients in deep coma. Early hypothermia (33*C) - which has recovered deeply comatose patients with fixed/dilated pupils to normal daily life - should be no longer regarded as a simple exclusion criteria, and must be available at least for the treatment of victims of severe head trauma. Maintaining baseless diagnostic criteria as international standards will be particularly disastrous for countries like Brazil, where the medical care available to the general population is still precarious. The demand for an early diagnosis of brain death (implying apnoea testing once or twice within only 6 hours of observation) has been publicly emphasised for effectiveness of organ procurement, and the general acquiescence to such claim in Brazil has been indicated as a sign of a modern health system. During an extensive interview to the CREMESP journal of June 2000, an ABTO leader proudly announced that one of our hospitals has become the world leading medical institution in number of kidney transplants per year. In contrast with such view of modernity, victims of severe head trauma very often die on the stretchers of our emergency rooms because the restricted number of ICU beds has not matched the public demand for intensive care for decades. After apnoea testing, patients declared brain dead while still on those stretchers may be preferentially transferred to the ICUs while awaiting for pre-transplantation tests (the Brazilian health system has best remunerated the ICU beds occupied by the brain dead during that interval as compared to those taken by regular patients struggling for their own lives). The number of patients diagnosed as brain dead has been estimated as 10.000 per year in Brazil. That peculiar view of modernity also contrasts with a chronic inattention to basic preventive measures. Despite hypertensive nephropathy being recognised as the leading cause of chronic renal failure in Brazil, most patients with high blood pressure are never alerted to the risks of poorly controlled hypertension. After years of poor compliance to treatment, many of them relentlessly evolve to chronic renal failure and eventually require haemodialysis or kidney transplant (which accounts for 80% of all transplants in our country). Conditions like cerebral lacunar infarcts and congestive cardiac failure are also highly prevalent for the same reason. I respectfully invite the representatives of CREMESP and CFM to take part in scientific discussions on the validation of the diagnostic criteria that they have established in Brazil for the diagnosis of brain death. Persistent attempts to intimidate those who hold a diverse opinion cannot replace the transparent scientific debate in an appropriate forum, particularly when so many human lives are concerned. In the interest of an evidence-based medical practice, I hope they will not decline this invitation, and rather devote particular attention to the basic premise of the paper "Implications..." which is re-emphasised here, and was identified as a mathematical reality in my e-letter of 29 of June, 2000. Evidently, this is a matter of concern to the medical care in all countries, and it might be opportune to bear in mind the basic ethical issues that accompanied the advent of brain death and brain stem death. As clearly affirmed then, the establishment of irreversibility preliminarily requires that all conceivably appropriate therapeutic procedures have been performed (2). Some statements from the world-wide accepted Declaration of Helsinki, as reviewed in Tokyo in 1975 (recognised by the Brazilian Code of Medical Ethics since 1983), and from the International Code of Medical Ethics are reproduced below (3), as they may help the caring physician to decide between apnoea testing or a new therapeutic measure (as moderate hypothermia in treatment of deeply comatose victims of traumatic brain injury): "It is the mission of the medical doctor to safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfilment of this mission." "Any act or advice which could weaken physical or mental resistance of a human being may be used only in his interest." "In the treatment of the sick person, the doctor should be free to use a new diagnostic or therapeutic measure, if in his or her judgement if offers hope of saving life, reestablishing health of alleviating suffering." Finally, I congratulate the BMJ editors for their indefatigable commitment to scientific truth which this medical forum eloquently illustrates. Cicero Galli Coimbra Consultant Neurologist, Hospital do Servidor Público Municipal de São Paulo Associate Professor, Department of Neurology and Neurosurgery Federal University of São Paulo (UNIFESP) - Brazil 1. Coimbra CG (1999). Implications of ischemic penumbra for the diagnosis of brain death. Brazilian J Med Biol Res;32:1538-45. 2. Walker AE (1977). An appraisal of the criteria of cerebral death. A summary statement. JAMA;237:982-986. 3. Biomedical research: a revised code of ethics. WHO Chronicle;30:360- 362. |
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Calixto Machado, President of the I, II, and III International Symposia on Coma and Death Institute of Neurology and Neurosurgery, Havana, Cuba
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Since ancient times, man has pondered the mystery of his own death. In discovering the meaning of his death, he hoped to find the explanation of his life. In the earliest records, life was held to continue as long as an individual breathed. It was later thought that respiration was a means of maintaining the heart that circulated the blood. Life was then attributed to cardio-respiratory action. But, in the middle of this century, physicians became aware that the brain required such more energy than other organs. If brain's needs were not met, it would cease to function, while other parts of the body could remain viable and even regain their activity provided that respiration and circulation were maintained by artificial substitution in intensive care units. This was documented by French neurologists and neurophysiologists at the end of the 1950’s. The result would be a dead brain in a viable body. Is such a preparation alive or dead? Three main brain-oriented formulations of death have been described historically: whole brain, brainstem and higher brain standards. The brainstem standard was adopted in several Commonwealth countries. This view has been powerfully articulated by Christopher Pallis. Pallis emphasized that the capacity for consciousness and respiration are two hallmarks of life of the human being, and that brainstem death predicts an inescapable asystole. However, a physiopathological review of consciousness generation will provide a basis for not accepting Pallis' definition of death. Moreover, recent clinical cases have shown that brain death does not always predict an "inevitable asystole within a short while". I have recently presented a new account of death to defend a brain- oriented standard of human death Definition: Irreversible loss of consciousness which provides the key human attribute and the highest level of control in the hierarchy of integrating functions within the human organism. Anatomical substratum: Irreversible destruction of the anatomic and functional substratum of consciousness throughout the whole brain Tests: Unresponsiveness, no arousal to any stimuli, and no cognitive and affective functions Therefore, the main issue is to accept or not a standard of death on neurological grounds. I understand that different religious communities could have their rights to accept any believe about death and about life. Nonetheless, society should try to find a consensus on this issue, although history has shown that it is extremely difficult. References 1. Machado C. A new definition of death based on the basic mechanisms of consciousness generation in human beings. In: Machado C, ed. Brain Death (Proceedings of the Second International Symposium on Brain Death). Amsterdam: Elsevier Science, BV; 1995:57-66. 2. Machado C. Consciousness as a definition of death: Its appeal and complexity. Clinical electroencephalography 1999;38(4):156-164 3. Is the concept of brain death secure? In Adam Zeman and Linda Emanuel (eds): Ethical Dilemmas in Neurology. London: W.B. Saunders Company, pp:193-212. |
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Loibner Johann, Brain death
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I am a general practitioner in Austria. I criticised the current diagnosis criteria in a regional newspaper. The transplant-surgeons demanded a persecution by the Austria Medical Council. So I should pay a very high fine. At least the supreme law court quashed this procedure.- Therefore I work more at this problem. Concerning this discussion I like to repeat some statements : A well-known neurologist and authority in EEG: Brain death?.. diagnose with EEG?.."You can see activities even, if the brain is liquefied already"... An engineer who develops the instruments for EEG: "I would not only rely upon the results of this instruments. They can not give the very certainty." A close friend and neurologist: Brain death?... "the neurologists have to close both eyes, if they agree to the current diagnosis criteria" |
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Gilson Luís Roberto, Clinical Medicine Medical Clinic - Porto Alegre - RS - Brazil
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Dear Editor, As a physician interested in the study of the prevailing brain death criteria, I have been accompanying the debate on its ethical and religious aspects that your Journal has promoted in the Internet. I would like to suggest that you deepen the debate, widening technical and ethical reflections on the subject. There are still many doubts about the topic, and this has produced insecurity and questionings which must be duly clarified. As a means for the study of topics such as these, it is a task of your much respected Journal to promete urgently this discussion, so fundamental for all physicians that deal with human life. I believe I am expressing a hope of all my colleagues, for in many discussions I have had almost every day in these last months, I hear their doubts and feel this necessity. I am certain of your comprehension and of your sensibility to the important responsibility of medicine as whole to the subject. I hope your efforts will be directed to fulfilling these claims. Thank you very much for your attention. Yours sincerely, Gilson Luís Roberto, MD Porto Alegre - RS Brazil |
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CELIO LEVYMAN, Staff Neurologist,MD,MScM Albert Einstein Jewish Hospital,Sao Paulo,SP,Brazil,01124-010
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Inicially,I apologize to delay of this response - I certainly hasn't read the BMJ at this time.However,Dr. Cicero Coimbra is a controversial professor of experimental neurology (not working with humans beings !) to express contudent and superior analysis of brain death,furthermore in regard of Medical Ethics. I can understand that Dr. Coimbra object the brain death criteria by: a)he believes in the lost of synaptic activity before irreversible ischemic demage occur to the brain;the brain can be viable,he mantains,for a considerable lenght of time,while satisfyng the clinical criteria for brain death; b)the apnea test further injures the brain by raising intracranial pressure due to the elevation of PaCO2;this,is turn,causes a critical fall in blood flow that is likely to produce brain death in patients in the precarious conditions described in "a",above and c)he implies that the use of hypothermia and thrombolhytic agents may save some patients who meet the clinical criteria for brain death (if the apnea testint did not kill them off first,of course). His arguments are based on hypothetical physiololical concepts that may be not relevant in the injured brain.He gives some examples of individuals who did better than expected,but there is not sufficient detail to know if the criteria of brain death are truly and if full assestment of all brain functions required in protocols,identification of confounding factors and exclusion of patients give barbiturates,etc.He do not give adequate attention to etiology.He is a lab doctor,and to counter his arguments I say:a)brain death criteria have been validated repeatedly,especially by Christopher Pallis,in UK;when the clinical criteria are properly applied they are reliable in predicting death in asystole without neurological recovery,even when the patient are kept on the ventilator;further,the nonviable state of the brain has benn confirmed in autopsy studies of those who die after having met the criteria for brain death in adults and children;these findings - the respirator brain - would not to be expected just from death immediately following apnea testing,even if the latter killed the patient,as Dr. Coimbra contends;b)Brown et al have shown that in the injured brain that irrebersible ischemic neurononal damage occurs before the loss of synaptic activity,the reverse of the sequence suggested by Dr. Coimbra - events in the injured brain may be quite different from those of previously healthy laboratory animals;c)there is no evidence that the apnea testing kills the brain - modern apnea testing ensures adequate oxygenation,blood pressure,etc.;the possible rise in intracranial pressure would be very transient,and not of sufficient magnitude or duration to cause a drop in cerebral perfusion pressure that would kill the patient;d)apnea testing is a vital and integral part of the declaration of brain death;e)Dr. Coimbra's recommedation to hyperventilate such patients to PaCO2 values of 25-30 mmHg may decrease cerebral blood flow more the elevation of PaCO2 that he criticizes;f)Dr. Coimbra does not acknowledge that apnea testing must follow certain protocols that safeguard the patient:it is only done after all other clinical criteria suggesting brain death are satisfied and apnea testing is not done when there are contraindications such as pulmonary conditions;further,the apnea testing is aborted if any problems,such as significant hypotension of hypoxemia occur during testing;g)ischemic brain injury that determines outcome occurs early,usually before the declaration of brain death is considered - thus the ischemia is not iatrogenic,as implied by Dr. Coimbra;h)Dr. Coimbra criticizes the excellent work by Dr. Wijdicks and his comitee who published evidence-based guidelines for the declarartion of brain death - this approach cannot improved upon;i)Dr. Coimbra challenges Dr. Allan Ropper "Lazaru's sign",phenomenon that is validated:such movements can and do occur in the presence of brain death;j)institution of hypothermia on moribund or brain dead patients is regressive and irresponsible:it is not fair to the patient,to relatives or to society if that unneecessarily prolongs fruitless care in the intensive care unit.The discussion,even now,in 2002,is of relevance,not only for the ethics purposes (I have my doubt about real science in Dr. Coimbra claims),but he is arguing the brain death criteria not at the medical sociyties,universityes,medical boards - he and his brother,a law counsellor,are arguing that at the Justice and in the media,the more sensacionalist better,such as TV talk shows,newspapers that produces headlines as "Doctors are killing live people in ICUs",etc.He continous to spread his oppinions to the country and the world;as a respected brazilian neurologist have sayed (Professor Sanvito),Dr. Coimbra is a "ratologist".Prof. Gordon Bryan Young,from the Canada's Western Ontario University,claim that Dr. Coimbra has done a desservice to my country by stirring up unrealistic fears with fallacious arguments (personal communication).As in Brazil,of course,with the medical evidences,science and ethics,whe are using the brain death criteria,despite Dr. Coimbra isolated oppinions. References: 1)Pallis,C,HartleyDH.ABC of brainstem death.London:BMJ Publishing Group,1996. 2)Parker,BL;Frewen,TC et al.Declarating pediatric brain death:current practice in a Canadian pediatric critical care unit.Canadian Medical Association Journal 1995;153:909-916. 3)Leestma,JE;Hughes,JR;Diamond,DR.Temporal correlates in brain death:EEG and clinical releationships to the respirator brain.Arch Neurol 1984,41:147-152. 4)Brown,JIM;Moulton,RJ et al.Cerebral oxidative metabolism and evoked potential deterioration after severe brain injury:new evidence of early posttraumatic ischemia.Neurosurgery 1998,42 (No 5,May):1057-1064. 5)Whitman,JG.Brain death.Lancet 1980,ii:1142; 6)Determining brain death in adults.Neurologhy 1995,45:1003-1011. 7)Report of the Quality Standards Subcomitee of the American Academy of Neurology.Neurology 1995,45:1012-1014. 9)Ropper,AH.Unusual movements in brain death patients.Neurology 1984,34:1089-1092. 10)Young,GB.Personal Communication.Department of Clinical Neurological Sciences,University of Western Ontario,London,Canada,2001. |
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Michael Potts, Head, Philosophy and Religion Department Methodist College, Fayetteville, NC USA 28311
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Dr. Levyman’s reply (April 7, 2002) to Dr. Coimbra states, referring to brain death criteria in the UK, that "when the clinical criteria are properly applied they are reliable in predicting death in asystole without neurological recovery, even when the patient are [sic] kept on a ventilator." But the prediction of death is not the same thing as death; even if brain death criteria were reliable as a prognosis of death, this does not mean that brain death is the same thing as death. Opposition to brain death criteria is not the "isolated" position which Dr. Levyman suggests; even if it were, the popularity of a position does not guarantee its truth. The debate over brain death criteria is not settled. An anthology was published in 1999 regarding controversies concerning brain death [1]. An anthology of essays opposing brain death criteria was recently published [2]. A number of articles questioning brain death criteria by Dr. Alan Shewmon, Professor of Pediatric Neurology at the UCLA School of Medicine, have also been published [3, 4, 5]. An article in the prestigious bioethics journal, Hastings Center Report, asked if "it is time to abandon brain death?" [6]. A recent book by Margaret Lock [7] has pointed out that the changes in criteria for declaring death were primarily fueled by the pressure to transplant viable organs. The point in mentioning these sources is that there is a live debate which continues over brain death criteria. Some defenders of brain death criteria fail to acknowledge that such a debate exists. When they do notice their position attacked, they behave like individuals whose religious orthodoxy has been questioned, and merely repeat the position that "brain death is death," without presenting arguments for that position, or seriously addressing the arguments of their opponents. The repetition of a position does not somehow make it true; neither are mere claims, or attacks on the credibility of those who oppose one's position, substitutes for careful argumentation. 1 The definition of death: contemporary controversies. Eds. Youngner S, Arnold RM and Schapiro R. Johns Hopkins University Press, 1999, Baltimore. 2 Beyond brain death: the case against brain based criteria for human death. Eds. Potts M, Byrne PA, Nilges RG. Kluwer Academic Publishers, 2000, Dordrecht/Boston/London. 3 Shewmon DA. Recovery from brain death: a neurologist’s apologia. Linacre Quarterly 1997; 64:30-96. 4 Shewmon DA. ‘Brain stem death,’ ‘brain death,’ and death: a critical evaluation of the purported evidence. Issues Law Med 1998; 14:125-45. 5 Shewmon DA. Chronic ‘brain death’: meta-analysis and conceptual consequences. Neurology 1998; 51:1538-45. 6 Truog R. Is it time to abandon brain death? Hastings Center Report 1997; 27:29-37. 7 Lock M. Twice dead: organ transplants and the reinvention of death. University of California Press, 2001, Berkeley |
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David W Evans, Retired physician 27 Gough Way, Cambridge, CB3 9LN
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Dr.Celio Lesyman's ill-informed attempt to discredit Dr. Cicero Coimbra serves admirably to make the point that there are no credible arguments available for the defence of current "brain death" or "brain stem death" diagnostic practices and their equation with human death. If he will access the 'Rapid Responses' to Sir Raymond Hoffenberg's article in the Christmas 2001 issue of the BMJ [1], he will see that no-one is now prepared to try to defend the UK 'Code of Practice' protocol for the diagnosis and certification of "death for transplant purposes" on truly scientific and logical grounds. The era during which the pseudo-scientific and frankly false claims of Dr. Pallis held sway is, thankfully, coming to its inevitable end at long last. The full consequences of decades of public and professional deception about some some supposedly agreed new definition of death (solely in the interests of transplantation) remain to be seen. If Dr. Lesyman wishes to make a properly informed contribution to this debate, he should obtain a copy of 'Beyond Brain Death - the case against brain related citeria for human death', edited by Potts, Byrne & Nilges, and published by Kluwer Academic Publishers in 2000. It is now available in paperback form (ISBN 1-4020-0366-8) and has been recommended as "a must read for all individuals, physicians and non- physicians alike" [2]. He should also be aware that Dr.Coimbra is a practising neurologist at the Hospital do Servidor Publico Municipal de Sao Paulo, which he has served since 1989 after Internal Medicine and Neurology Rsidencies and a Fellowship in Pediatric Neurology at the Jackson Memorial Hospital, University of Miami. I leave it to others to deal with some of the more surprising assertions and disclosures in Dr. Lesyman's "rapid" response, but feel obliged to point out that "respirator brain" is by no means the universal necropsy finding after the diagnosis of "brain stem death". A very experienced pathologist has been much disturbed to find that the brains of children so diagnosed appeared at least macroscopically normal [3]. 1. Hoffenberg R. Christiaan Barnard : his first transplants and their impact on concepts of death. BMJ 2001;323:1478-80 2. Berlin L. Book reviews. Chicago Medicine 2001;104:29-30 3. Gresham GA. Personal communication |
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Paul A. Byrne, Clinical Professor of Pediatrics, Medical College of Ohio Toledo, Ohio (USA) 43616
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Dr. Levyman’s reply (April 7, 2002) to the letter (June 29, 2002) and article by Dr. Coimbra1 shows that the questions and issues about “brain death” have not been widely publicized, appreciated or universally accepted. Since 1979 others and I have authored and co-authored articles expressing that “brain death” is not death.2 Dr. Coimbra has provided additional explanation for complications of hypotension and cardiac arrhythmia during apnea testing in the determination of brain death.3 When ventilation is stopped to do the apnea test, even when additional oxygen is provided, CO2 increases, resulting in acidosis. Every physician knows that it is not good to impose hypercapnia and acidosis on a patient. How were we duped into giving insufficient reflection on the hazards of hypercapnia and acidosis? All testing to determine brain death is done by evaluation of a few brain stem reflexes. Functioning of the cortex (memory, mathematics, sorrow, etc.) cannot be evaluated in an unconscious patient. The 1980 BBC Documentary “Are the Donors Really Dead?” pointed this out by showing that when the EEG is not done before a declaration of brain death, no evaluation of the cortex is possible in an unconscious patient. Dr. Coimbra proposes hypothermia is an example of a currently available therapy that has potential merit. Something better might be developed later. The first thing is, do no harm and try to find the best treatment possible for the unconscious defenseless patient. A physician ought to protect, preserve and prolong life and postpone death. Certainly a physician ought not to remove a ventilator as occurs during the apnea test. Certainly a potentially lethal test, such as the apnea test, ought not be done to an unconscious defenseless patient. 1 Coimbra CG (1999). Implications of Ischemic Penumbra for the Diagnosis of Brain Death. Brazilian J Med Res; 32:1538-45. 2 Byrne PA, O'Reilly S, and Quay PM. Brain Death - An Opposing Viewpoint, JAMA, November 2, 1979; 242:1985-1990. Byrne PA, O'Reilly S, Quay PM, and Salsich PW. Brain Death - The Patient, The Physician, and Society. Gonzaga Law Review, 1984;18(3):429- 516. Byrne PA, Nilges, RG. The Brain Stem in Brain Death. Issues In Law & Medicine 1993; 9(1):3-21. Byrne PA, Nilges RG, Evers JE. Anencephaly - Organ Transplantation? Issues In Law & Medicine, 1993; 9(1): 23-33. Beyond Brain Death: the case against brain based criteria for human death. Eds. Potts M, Byrne PA, Nilges RG. Kluwer Academic Publishers, 2000, Dordrecht/Boston/London. 3. Goudreau JL, Wijdicks EFM and Emery SF. Complications During Apnea Testing in the Determination of Brain Death: Predisposing Factors. Neurology 2000; 55:1045-1048. |
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D. John Doyle, Staff Anesthesiologist Cleveland Clinic Foundation, Cleveland, Ohio, USA, 44195
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Readers following this debate may take an interest in the philosophical views of Peter Singer, professor of bioethics at Princeton University's Center for Human Values. In his various writings he has challenged our most closely held beliefs on infanticide, euthanasia, and the moral status of animals. He also challenges the conventional wisdom on brain death. In his book Rethinking Life and Death (1995) Singer notes that following the Harvard Brain Death Committee report published in 1968, most countries have adopted brain death as an acceptable criterion for declaring a person legally dead. He also notes that this event transpired with virtually no opposition despite its ground-breaking nature. What is less widely known, Singer points out, is that this “redefinition” coincided historically with the advent of organ transplantation — a mere nine months before the Harvard report came out, Dr. Christiaan Barnard performed the first successful cardiac transplant. Singer doubts that this is a coincidence. Singer also points out that it is simply not true that all brain function necessarily ceases with brain death – for instance, pituitary function often continues for some time after formal criteria for brain death are met. Singer takes the position that brain dead individuals are still alive, but that organ harvesting from these individuals is none the less acceptable. His position is that rather than employ artificial, contrived, or bogus definitions of death, we should recognize that the only intellectually honest course is to admit that all lives are not equally valuable and that some lives are indeed in such a degraded and hopeless state that even though they are technically “alive,” it is still ethically acceptable to utilize their organs for transplantation. |
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Cicero G Coimbra, Associate Professor, Department of Neurology and Neurosurgery Federal University of Sao Paulo (UNIFESP), R. Pedro de Toledo 781, 04039-032 Sao Paulo SP Brazil
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Editor - Dr. Levyman's late contribution (bmj.com 7 Apr 2002) to the "Ethical debate: Brain stem death etc." led by Inwald et al. (BMJ 2000; 320: 1266-88) contains such serious misunderstandings and errors of fact as to require detailed reply. For convenience of future reference, I list the points in this response as 'CORRECTIONS' ('a' to 'd') and 'COMMENTS' ('a' to 'i'), togheter with a specific 'REPLY'. CORRECTION (a): Under ischaemic conditions, reversible loss of synaptic activity does occur at a higher level of cerebral blood flow than that required to inactivate the ion pumps on neuronal membranes. When the latter is reached, calcium overload builds up and triggers enzymatic processes that may eventually lead to the demise of brain cells. The well -known phenomenon of ischaemic penumbra is precisely defined as the state of reversible loss of synapse-mediated neuronal functions determined by a critical (not lethal) reduction of the blood supply to the nervous tissue. The brain tissue may endure as long as 48 hours under such incomplete ischaemia according to studies showing elevated oxygen extraction fraction (O2EF) for that long in the penumbra zone under normothermic and normoglycaemic conditions (1). There is abundant literature data and many nice reviews available on the phenomenon of ischaemic penumbra, which has been repeatedly demonstrated in the human brain during the last decade. Indeed, until 7 April 2002, I thought all practising neurologists were aware of it. CORRECTION (b): Apnoea may cause irreversible damage to brain tissue not only by further increasing intracranial pressure (ICP) in patients with severe head trauma but also (and most importantly) by reducing blood pressure (BP). Up to 39% of the patients who undergo the apnoea test may reach systolic levels lower than 90 mmHg (2, 3). Both effects may be directly caused by the influence of hypercapnia and/or related acidosis on the cardiovascular system. That both effects associate to decrease the cerebral perfusion pressure (PP) is mathematically predictable: PP = BP - ICP. Previous and/or passive oxygenation measures cannot prevent any of these hypercapnia-related effects. CORRECTION (c): Dr. Levyman declares: "His arguments are based on hypothetical physiololical [sic] concepts that may be not relevant in [sic] the injured brain." The concept of ischaemic penumbra can no longer be considered hypothetical (see "a" above). Neither can it be regarded as hypothetical that an unknown percentage of patients with severe intracranial hypertension is actually under global ischaemic penumbra (GIP) by the time when they undergo apnoea for the diagnosis of brain death or brain stem death. It is, in fact, mathematically predictable, for the brain blood flow (BBF) cannot reach the lowest values (capable of triggering neuronal necrosis) in patients with progressive intracranial hypertension without crossing the range of ischaemic penumbra. Deep coma and cephalic areflexia will be the clinical presentation of both groups of patients (those in the GIP condition and those with intracranial circulatory arrest). The intracranial circulation of nearly all (if not all) victims of severe head trauma is irreversibly arrested by the apnoea test, as suggested by comparison of PP, ICP and BBF data obtained from patients submitted and not submitted to apnoea testing. That these "concepts" are relevant to the diagnosis of irreversible brain damage is indisputable. Those who still support or perform the current "diagnostic" protocols while (knowingly or not) neglecting this issue should consider their ethical responsibility towards those defenceless comatose patients who will undergo such testing during the years to come. CORRECTION (d): Dr. Levyman declares: "He gives some examples of individuals who did better than expected, but there is not sufficient detail to know if full assesment [sic] of all brain functions required in protocols, identification of confounding factors and exclusion of patients give [sic] barbiturates, etc." Dr. Levyman fails to mention that those patients who "did better than expected" were victims of severe head trauma who were treated with moderate hypothermia (33 degrees Celsius) for no longer than 12 to 24 hours. The literature shows a large percentage (up to 70%) of these cases in deep coma (GCS = 3) and with fixed, dilated pupils, who have recovered to normal daily life (4, 5) following the implementation of that therapeutic paradigm. By demanding the assessment of "all brain functions required in protocols", Dr. Levyman implies that the respiratory reflex should have been tested in these patients before the implementation of therapeutic hypothermia. Then, and only if these patients still recovered, he would accept their surprisingly good outcome as evidence that the current diagnostic protocols for brain death (and brain stem death) do not efficiently diagnose irreversible brain damage. Therefore, while neglecting reiterated claims against the permanent detrimental effects of apnoea testing on the brain circulation of patients in global ischaemic penumbra, Dr. Levyman resorts to the same circular type of reasoning that he has relentlessly expressed in Brazil: he demands that young medical doctors perform apnoea testing first, and assures them that no benefit of hypothermic treatment will be achieved if his exigency is complied with. Among confounding circumstances Dr. Levyman has, perhaps inadvertently, replaced hypothermia by "etc" while only mentioning the administration of barbiturates. Hypothermia is not only regarded as a classical "confounding factor" (since 1968), but has been more recently emphasized as the only therapeutic tool hitherto available to reduce brain oedema, as seen in severe head trauma (4) and in large brain infarcts (6). In 1968 the Harvard Ad Hoc Committee acknowledged that deeply comatose victims of severe head trauma and accidental hypothermia could recover despite presenting clinical and electroencephalographic manifestations of (until then so called) "coma dépassé" (7). The depressive effect of hypothermia on synaptic function rather than its therapeutic potential was then taken as the only possible explanation for the surprisingly good outcome of those patients, and hypothermia was simply relegated to the condition of "confounding factor". It is interesting to note that (accompanying versus induced) barbiturate coma also bears the same dual (confounding versus therapeutic) condition, which Dr. Levyman fails to point out. Dr. Levyman's apparent failure to comprehend these matters inspires the following questions. Should we provide full treatment (including, perhaps, barbiturate coma and/or hypothermia) to victims of severe head injury? Will transplant surgeons accept waiting until we feel sure about our patient's final response to moderate hypothermia? How long will that take? Is the minimal watch for recovery after rewarming already established? Will the transplant teams stop urging us to declare "an early diagnosis of brain death (or brain stem death)" - which implies testing the respiratory reflex (i.e., performing the apnoea test) as soon as the other brain-stem reflexes become clinically undetectable? Alternatively, should we refrain from treating those patients with either barbiturate or hypothermia to avoid making the diagnosis of brain death impossible or so much delayed as to be detrimental to transplantation interests? COMMENT (a): Republication is not repeated scientific validation. Christopher Pallis and other authors have merely republished diagnostic protocols for BD/BSD. In other words, they have repeatedly proposed how best to diagnose BD/BSD, but never addressed enough attention to the pathophysiological basis of their diagnostic steps. Nor have their articles (often but improperly referred to as "reviews") ever acknowledged the growing body of scientific evidence against their proposals. All those diagnostic versions are quite similar and primarily based on the unproven assumption that irreversible brain or brain-stem damage would be established when a specific set of brain functions remained clinically undetectable for a few hours. It was precisely because of that misconception that (I) brain death was initially defined as "total brain necrosis", and (II) angiography has been employed as a confirmatory test since the early seventies. Pallis and others have never considered that the same set of brain functions would also be undetectable in those patients with a partial reduction of the blood supply to the whole brain (or only to the infratentorial structures) down to the range of ischaemic penumbra, and thereby led those physicians who have complied with their protocols to misdiagnose death. They did not consider that alternative explanation simply because the phenomenon of ischaemic penumbra was unknown at the time when the diagnosis of BD/BSD was proposed and turned into a widespread practice in several countries. Even in the early nineties, when the phenomenon of penumbra was demonstrated in the human brain, its implications for the diagnoses of brain death and brain stem death were not immediately perceived. Dr. Levyman declares: "…when the clinical criteria are properly applied they are reliable in predicting death in asystole without neurological recovery, even when the patient are [sic] kept on the ventilator." COMMENT (b): In his response dated 11 April 2002, Professor Potts pointed out that the prediction of death is not the same thing as death. In addition, and once more, it is important to emphasize that Dr. Levyman's "properly applied" clinical criteria include the induction of sudden and severe respiratory acidosis, with secondary hypotension (systolic blood pressure lower than 90 mmHg) in up to 39% of patients undergoing the apnoea test (2, 3). This implies a severe further reduction of the perfusion pressure in the subset of deeply comatose patients with cephalic areflexia whose brain blood flow was already critically situated within the range of ischaemic penumbra prior to that apnoeic insult. The apnoea test actually induces an irreversible collapse of intracranial circulation rather than a transient reduction of the brain blood flow in those patients, as indicated by comparison of clinical (not experimental) data obtained from victims of severe head trauma with (8) and without (9) the apnoea test. Therefore, the apnoea test is actually capable of destroying the respiratory centres of the subset of patients who could otherwise eventually recover from deep coma secondary to intracranial hypertension. Dr. Levyman declares: "…further, the nonviable state of the brain has benn [sic] confirmed in autopsy studies of those who die after having met the criteria for brain death in adults and children; these findings - the respirator brain - would not be expected just from death immediately following the apnea testing, even if the latter killed the patient, as Dr. Coimbra contends." COMMENT (c): I believe Dr. Levyman means that failure to respond to apnoea-induced hypercarbia correlates with diffuse brain necrosis ("the respirator brain") in autopsy studies. None of his citations was linked to that specific statement, so that I cannot be sure whether I have correctly deciphered what he meant. However, assuming my decoding is correct, that information would be also consistent with permanent brain damage induced by the apnoea test. That is because when apnoea testing is avoided to prevent secondary damage, deep coma and cephalic areflexia sustained for at least 48 hours were associated with macro and/or microscopic signs of diffuse necrosis in less than 50% of the cases that eventually progressed to asystole (10). Forty-eight hours would have been enough for full development of necrotic changes in 100% of cases if intracranial circulatory arrest were present from the beginning of cephalic areflexia. By contrast, according to Dr. Levyman, that correlation is achieved when apnoea testing is performed… COMMENT (d): The article by Brown et al (11) actually does not provide any data to support Dr. Levyman's proposition that synaptic activity would disappear at a level of blood supply lower than that required to establish irreversible brain damage during the progression of intracranial hypertension. Dr. Levyman's statement is really odd and untenable, as it opposes the undeniable phenomenon of ischaemic penumbra. Brown and co-workers monitored 97 patients with severe traumatic brain injury for arteriovenous oxygen difference (AVDO2, twice daily), and hourly somatosensory evoked potentials (SSEP's) for an average of 5 days. The last 51 patients also underwent 12-hourly measurement of cerebral blood flow (CBF), with calculation of cerebral metabolic rate (CMRO2). Different groups were defined according to the initial AVDO2 values and subsequent SSEP trends. Initial SSEP values in patients with normal AVDO2 values were similar to those with elevated AVDO2 values, but differed at 60 hours after injury and beyond. Significant deterioration of SSEP's persisted after recovery of CBF in the 25 patients who initially presented higher AVDO2 and CMRO2 and lower CBF. The authors suggested that an early ischaemic insult would be the most tenable explanation for the deterioration in SSEP's beyond the period of ischaemia. Therefore, the content of the paper by Brown et al (11) is not in disagreement with the phenomenon of ischaemic penumbra, and is completely unrelated to Dr. Levyman's statement. COMMENT (e): The clinical data supporting the detrimental effects of apnoea testing have been presented and discussed elsewhere in this message. It is clear that Dr. Levyman recognises the possibility of hypotension, hypoxia, and exacerbation of intracranial hypertension, despite preventive oxygenation measures. Yet, paradoxically he declares that the ischaemic insult induced by apnoea testing "is not iatrogenic", because brain death is "usually" already established by the time when the current diagnostic steps (including the apnoea test) are carried out. In other words, according to Dr. Levyman, these patients should be regarded as "usually" dead before being examined for brain death or brain stem death. No comment! COMMENT (f): I have neither defended nor criticized the use of therapeutic hyperventilation for intracranial hypertension. Indeed, a detrimental effect on brain blood flow may occur when the PaCO2 is more than optimally lowered during therapeutic attempts to diminish intracranial hypertension. Dr. Levyman's well-founded concern contrasts sharply with his comfortable acceptance of the reduction of brain perfusion pressure by apnoea testing. COMMENT (g): Like Christopher Pallis in the UK, regarding the diagnosis of brain stem death, Dr. Wijdicks in the USA has repeatedly published "reviews" advising young physicians on how best to diagnose brain death, without addressing much (if any) attention to the cumulated body of scientific evidence against the practice of those diagnostic steps. An illustrative example refers to the apnoea test. Dr. Wijdicks co-authored an important report (2) confirming the earlier paper by Jeret and Benjamin (3) regarding the occurrence of severe hypotension (systolic blood pressure of 90 mmHg or lower) in a high percentage of patients during the apnoea test, despite the implementation of all preventive measures against hypoxia. In the article by Goudreau, Wijdicks, and Emery (2), the following statements can be read: "Apnea testing in brain death determination may result in cardiovascular complications. Hypotension occurred in 24% and cardiac arrhythmias occurred in <1% of the 145 apneic oxygenation procedures." "Approximately one in four apnea tests was associated with cardiovascular complications, and the rate of complications nearly doubled in tests without adequate precautions." "One patient had a cardiac arrest during apnea testing." Prevention of hypotension has been emphasized as the most important measure for optimal intensive care of victims of severe head trauma (12). Accordingly, it would be reasonable to expect a transparent description of that finding in Dr. Wijdicks' latest "review" (13), so that young physicians are aware of that frequent hazard and take their own decision on the ethics of performing the apnoea test. However, when describing the apnoea test and citing his own original report on the occurrence of hypotension and cardiac arrest , Dr. Wijdicks simply declares: "This method is simple and usually free of complications, provided that adequate precautions are taken. If complications such as hypotension and cardiac arrhythmia occur, they may be due to a failure to provide an adequate source of oxygen or to a lack of preoxygenation (18)." (18 = 2 in the ref. list below) According to Dr Jeret (14), the occurrence of hypotension affects an even higher percentage of the patients (39%) who are adequately preoxygenated, and the difference between the two series of patients (39% versus 24%) could be possibly related to the higher number of gunshot victims in the Jeret and Benjamin's study (3). As Dr. Evans has pointed out (15), the lack of transparent discussions on these matters characterizes a repeated deception of young medical doctors. COMMENT (h): Allan Ropper (16) assumes that a variety of bizarre and quite complex limb movements observed during the apnoea test or surgical excision of transplantable organs in some of the patients declared brain dead are mediated at no other part of the CNS but the spinal cord level. Clinically diagnosed brain death itself is the only argument that has been presented to support that view. No electrographic recordings have been obtained from the brain tissue during those movements to confirm that assumption. According to Dr. Ropper, the current clinical criteria reliably identify irreversible loss of brain functions and, therefore, a brain diagnosed as dead cannot execute synapse-dependent functions. More recently, however, Wagner and co-workers demonstrated that the cortical somatosensory evoked responses may be found preserved in apnoeic coma with loss of brain stem reflexes (17). It seems therefore, quite reasonable to believe that, at the upper limit of ischaemic penumbra, some synaptic functions may be suppressed at levels of blood supply higher than those capable of inactivating other synaptic circuits, according to the particular nature of transmitters, receptors and neurons involved. Therefore, whether or not the so-called "Lazarus sign" is solely the expression of spinal cord motor capabilities still remains to be established. COMMENT (I): The use of hypothermic treatment represents a responsible medical attitude towards patients in deep coma with cephalic areflexia (and extensive brain oedema and secondary intracranial hypertension), whose brain oxygen extraction fraction is elevated or unknown (18). The reasoning behind Dr. Levyman's rejection of hypothermia is difficult to comprehend but may, perhaps, be found among the responses to the questions raised elsewhere in this message. Interestingly enough, a famous Brazilian actor shot in the head a couple of years ago was transported by helicopter to the Albert Einstein Jewish Hospital in Sao Paulo (the Hospital which Dr. Levyman serves), where he was successfully treated with moderate hypothermia. His treatment and outcome were fully covered by virtually all newspapers and TV channels all over the country. It seems clear, therefore, that hypothermic treatment is not rejected at the Albert Einstein Jewish Hospital at all, but may be considered highly advisable depending on the specific circumstances. Nevertheless, as a member of the Medical Council in Sao Paulo (CREMESP), Dr. Levyman accused me of publicly defending an "unacceptable" therapy for victims of severe brain injury - precisely moderate hypothermia (I dared to declare that hypothermia should be tried before apnoea testing). Dr. Levyman was one of those who authored the Brazilian official protocol for the diagnosis of brain death - ultimately approved by the National Medical Council (CFM) in 1997. Dr. Levyman declares: "…but he is arguing the brain death criteria not at the medical sociyties [sic], universityes [sic], medical boards - he and his brother a law counsellor [sic], are arguing at the Justice and the media, the more sensacionalist [sic] better, such us TV talk shows, newspapers that produces [sic] headlines as 'Doctors are killing patients in ICUs', etc." REPLY: Since the Brazilian protocol for the diagnosis of brain death was approved by CFM in 1997, I have vainly tried to discuss the implications of ischaemic penumbra for the validation of those diagnostic steps with those who authored them. Initial attempts included personal communications to one of the authors. To stimulate scientific discussions within our University (UNIFESP), I wrote a series of 4 texts that became available on the UNIFESP web site from the end of 1997 to the first half of 1998 (19). I took part in 2 consecutive meetings with all the authors of the Brazilian criteria (including Dr. Levyman) in January and February 1998 at the CREMESP headquarters, when I got responses even worse than those presented by Dr. Levyman to the BMJ on 7 April 2002. I lectured on this subject twice within our University (once to the Department of Anaesthesiology, once to the Department of Paediatrics), and twice at the Federal University of Rio de Janeiro (UFRJ). Lectures were also presented in three Brazilian neuroscientific or medical congresses, including a plenary session on "Head Trauma: Brain Death and Organ Transplantation in Humans" during the XXIII Annual Brazilian Congress of Neurosurgery on September 2000, when one of the CREMESP members (a paediatric neurologist and one of those who, like Dr. Levyman, authored the Brazilian criteria for the diagnosis of brain death) simply refused to engage in technical discussions on the basis that there were not enough neurologists or neurosurgeons among the lecturers to oppose my arguments (there were 4 neurosurgeons, besides herself). I organised a roundtable on this subject during the Annual Congress of the Federation of the Brazilian Societies in August 1998 - when Dr. Robert Truog from Harvard University, Boston, also took part in the discussions. In February 2000, I presented my arguments during the Third International Symposium on Coma and Death, held in Havana, Cuba, and organised by Drs. Alan Shewmon, Calixto Machado and Stuart Youngner. In addition, this is my fourth contribution to "BMJ rapid responses" on this subject. The editorial board of the journal "Ciencia Hoje" ("Science Today", Brazilian Society for the Development of Science - SBC) invited me to write on the same issue (21). Finally, the paper "Implications…" (22) was published in 1999 in the best Brazilian medical journal, following appropriate peer review. Unquestionably, appropriate forums have been exhaustively used in defence of those who are "usually dead". I am an Associate Professor of a Medical School, neuroscience researcher and practising neurologist who has honestly and scientifically criticized the validation of a medical practice in several ethical forums (including this highly respected medical journal) since 1997. The subject of that criticism is of supreme importance - the methods and techniques that have been employed for more than 30 years to declare death according to neurological criteria. Accordingly, one reasonably expects that those who still support the traditional practices will explain their position dispassionately. Nevertheless, except for the priceless attitude of a few outspoken supporters, responses have consistently varied from confidential encouragement to ostensible retaliation, and typically included recurrent attempts to discredit, libel and vilify. Dr. Levyman's not-so-rapid response to BMJ is a demonstrative illustration. For almost 5 years, not even one single scientific argument has ever been presented to refute the proposition that global ischaemic penumbra has been mistaken for - and, during the apnoeic insult, consistently turned into - irreversible brain damage. Instead, the hoped-for discussion has frequently been diverted towards the need to preserve the availability of organs for transplantation. In a sequence of publicly exchanged e-messages (20) Dr. Zisfein (Brooklyn, NY) provided the following illustrative statements: "There is no substitute for the apnea test for brain death." "If an organ donor would begin breathing in the operating room when organs are being recovered, that would be a disaster." From the very beginning, that scenario of conflicting interests, occult motivations and pseudoscientific discussions made me consider what obligations my combined professional activities imply towards common citizens, colleagues and medical students. I have decided to openly sustain my opinion regarding the issue of brain death to anyone who asks about it. Since the end of 1997, when the Brazilian campaign for organ donation under presumed consent took place, my electronic texts (19) have been available via the internet to whomsoever is interested in reading them, and journalists are no exception. The alternative is complicity in the misinformation and deception of the general public and colleagues for the purpose of preserving the availability of transplantable vital organs. Dr. Levyman himself (who criticizes the use of the media to discuss this subject) took part as a CREMESP representative in a live debate with me in "TV Cultura" of Sao Paulo (an ethical TV channel) at the end of December 1997, when he declared that the apnoea test is "2- or 3-min long", and if it were10-min long, "it would be a disaster". In 1997 he actually co- authored the current duration of up to 10 minutes for the apnoeic challenge (after preoxygenation). He now sees no trouble about that, while referring to these patients as "usually" dead prior to apnoea testing. Unfortunately, just as we see among medical doctors and other professionals, a minority of journalists has neglected the ethics of their profession, and dealt with this subject in a sensationalistic way. I do not look for them nor write their newspaper headlines. However, silence or lack of honesty is not an alternative. Regarding Dr. Levyman's libellous expressions (quite similar to those that appeared on page 6 of CREMESP Journal, issue of January 2000), I have two statements to make. First, as he and his colleagues of CREMESP well know (from my written and documented protests against those statements of January 2000), I am a practising neurologist with certified training in Internal Medicine and Neurology (Brazil) and Pediatric Neurology (USA), and I have served the Hospital do Servidor Publico Municipal de Sao Paulo since 1989. My postal address related to my clinical activities follows: Cicero Galli Coimbra, MD, PhD Hospital do Servidor Publico Municipal de Sao Paulo Setor de Neurologia (Neurology Section) Rua Castro Alves # 60 - quinto andar (5th floor) 01532-900 Aclimacao - Sao Paulo - SP - Brazil Phone +55 11 3208-2211 extensions 328/329 Second, I do not feel dishonoured by my research with laboratory animals, but rather proud of it. The product of our experimental work has been recently recognized as the best poster presented in the Second International Congress on Vascular Dementia held in Salzburg, Austria, 24- 17 January, 2002. References: 1. Kalimo H, Kaste M, Haltia M. Vascular Diseases. In: Graham DI, Lantos PL (ed). Greenfield's Neuropathology. Arnold, London, 1997. 2. Goudreau JL, Wijdicks EFM, Emery SF. Neurology 2000; 55:1045-8. 3. Jeret JS, Benjamin J. Arch Neurol 1994; 51: 595-9. 4. Metz C, Holzschuh M, Bein T, Woertgen C, Frey A, Frey I, Taeger K, J Neurosurg 1996; 85:533-41. 5. Hayashi N. Jpn Med J 1996; 3767:21-27. 6. Schwab S, Spranger M, Aschoff A, Steiner T, Hacke W. Neurology 1997; 48: 762-767. 7. Giacomini M. Soc Sci Med 1997; 44:1465-82. 8. Obrist WD, Jaggi JL, Langfitt TW & Zimmerman RA. J Cerebral Blood Flow Metab 1981; 1(Suppl 1): S524-S525 9. Jørgensen PB, Heilbrun MP, Boysen G, Rosenklint A & Jørgensen EO. Eur Neurol 1972; 8: 207-12. 10. Walker AE, Diamond EI, Mosely JI. J Neuropathol Exp Neurol 1975; 34:295-323 11. Brown JIM, Moulton RJ, Konasiewicz SJ, Backer AJ. Neurosurgery 42:1057-64, 1998. 12. Chesnut RM. J Trauma 1997; 42:S4-S9 13. Wijdicks EFM. N England J Med 2001; 344:1215-21. 14. Jeret JS. Correspondence. Neurology 2001; 56:1249 15. Evans DW. 12 April 2002 - http://bmj.com/cgi/eletters/320/7244/1266#21198 16. Ropper AH. Neurology 1984; 34:1089-92. 17. Wagner W, Ungersböck K, Perneczky A. J Neurol 1993; 240:243-6. 18. http://bmj.com/cgi/eletters/323/7327/1478#18780 19. http://www.unifesp.br/dneuro/textos.htm 20. DEFININGDEATH-L@UCONNVM.UCONN.EDU 21. Coimbra CG. Ciencia Hoje. August 2000; 27:26-30:161 - http://www.uol.com.br/cienciahoje/chmais/pass/ch161/morte.pdf 22. Coimbra CG. Brazilian J Med Biol Res 1999; 32:1538-45 (reprints available upon request) |
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