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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 43-49

Evolution of the concepts of brain death and brain stem death


1 Department of Anaesthesiology, Royal Prince Alfred Hospital, Sydney, Australia; Mazumdar Shaw Medical Centre, Narayana Health, Bengaluru, Karnataka, India
2 Department of Anaesthesiology, Amrita Institute of Medical Sciences, Kochi, Kerala, India

Date of Submission27-Jan-2020
Date of Acceptance09-Mar-2020
Date of Web Publication18-Aug-2020

Correspondence Address:
Dr. Mathew George
Department of Anaesthesiology, Amrita Institute of Medical Sciences, Ponekkara, P. O, Kochi - 682 041, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AMJM.AMJM_9_20

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  Abstract 


Brain stem death has remained a topic of contention among physicians and laypersons for many years. The evolution of the current definition of brain stem death has been the end result of decades of scientific study and deliberation. Although the concept has been known historically, a scientific probe into the matter had been made possible only during the late 20th century. This led to a healthy discussion regarding the obscure nature of brain stem death among experts on different continents, leading to the current definition provided by the American Association of Neurology in 2010. This review article aims at shedding light on the institution of brain stem death and the evolution of the definition, as we know it today.
Brain stem death has remained a topic of contention among physicians and laypersons for many years. The evolution of the current definition of brain stem death has been the end result of decades of scientific study and deliberation. Although the concept has been known historically, a scientific probe into the matter had been made possible only during the late 20th century. This led to a healthy discussion regarding the obscure nature of brain stem death among experts on different continents, leading to the current definition provided by the American Association of Neurology in 2010. This has proved to be a boon for the organ transplantation program; providing the system with a new, ethical donor pool and making available healthy organs that could change the lives of people living with organ failure. All this progress is relatively new and comes hand in hand with controversies. This review article aims at shedding light on the institution of brain death and the evolution of the definition, as we know it today.

Keywords: Brain stem death, coma depasse, irreversible coma, organ donation, organ transplant


How to cite this article:
Paul S, George M. Evolution of the concepts of brain death and brain stem death. Amrita J Med 2020;16:43-9

How to cite this URL:
Paul S, George M. Evolution of the concepts of brain death and brain stem death. Amrita J Med [serial online] 2020 [cited 2020 Sep 22];16:43-9. Available from: http://www.ajmonline.org.in/text.asp?2020/16/2/43/292433



“Time rolls by and you never paid the cost

Without your mind your body-it's lost

Should we help to keep you alive?

Now's the time to help you…Die”

Brain stem Dead (Exodus)

Advancement in the field of medicine has many a time proved a boon to the sick and ailing. Despite the initial optimism with the new developments, the dual-edged nature of some of these advancements has, on occasion, brought previously unheard of clinical entities to the forefront and thereby opened up avenues that were not foreseen by the innovators of that time. One of the classic examples of such a scenario was when mechanical ventilation and intensive care unit support were provided to patients with severe neurological injury. Patients who had devastating neurological injury, which was otherwise incompatible with life, were maintained on these supportive therapies, while avoiding the respiratory and circulatory arrest that would have invariably ensued.

The Greeks believed the heart to be “the seat of life; the first organ to live and the last to die.” The first person to suggest that the brain was primary to the demise of an individual was, probably, the 12th-century Rabbi, Moses Maimonides, of Cordoba, Spain. His theory, in contrast to Hebrew Law of the time – which considered breathing to be central to the preservation of life – was based on the premise that a decapitated person would invariably die.[1]

The earliest recorded medical observation that comments on the essential nature of the brain for maintaining respiration comes during the last decade of the 19th century.[2] In 1939, Crafoord indicated that death was due to “cessation of blood flow to the brain and nothing else.”[3] Later, in 1953, Riishede and Ethelberg first reported a radiological finding of absent blood flow to the brain, in patients in coma.[4] However, in 1954, Schwab et al., a neurologist at Massachusetts General Hospital, brought about the earliest written definition of the concept of brain death, when evaluating a comatose patient with massive brain hemorrhage on a respirator. “The question was, 'Is this patient alive or dead?' Without reflexes, without breathing, and with total absence of evidence of an electroencephalogram, we considered the patient was dead in spite of the presence of an active heart maintaining circulation. The respirator was therefore turned off and the patient pronounced dead.”[5] This was probably the first instance of disconnecting a patient from the ventilator in the event of catastrophic, irreversible brain damage. In 1956, Lofstedt and von Reis described six patients in coma without any passage of contrast through the cerebral circulation. The authors concluded that increased intracranial pressure, possibly in combination with vasospasm, was the most probable explanation for the X-ray findings.[6] These observations prompted both Wertheimer et al., first, and Mollaret and Goulon, later in 1959, to describe in detail the clinical features of patients who developed features of complete nervous system failure. Wertheimer et al. termed this “the death of the nervous system” and equated the condition with the heart–lung preparation of the physiologists. They went on to propose discontinuing ventilatory support if death of the nervous system was diagnosed clinically and by “the repeatedly verified absence of electroencephalographic (EEG) activity both in the cortex and in the diencephalon, and if resuscitative efforts have been given enough time, 18–24 h.”[7],[8]

Mollaret and Goulon defined it as “coma depasse” – signifying a permanently comatose state from which the patient may make no recovery.[9] The instant and apparent consequence of this breakthrough was that it reassured clinicians to withdraw support for these patients. Wertheimer et al. had, in fact, suggested doing so in their paper, but their criteria for withdrawing support were not recognized by Mollaret and Goulon, who felt that any criterion at that point was insufficient for the purpose of making that conclusion. Ethical issues notwithstanding, both authors described the clinical state as deep coma with no spontaneous respiration, absence of all brain stem reflexes, and polyuria associated with hypotension requiring vasopressor therapy.

In 1963, Schwab et al. in the US proposed a triad of criteria: (1) fixed and dilated pupils, no elicitable reflexes, and no spontaneous movements; (2) apnea; and (3) isoelectric EEG. They proposed that those who met the criteria could be considered dead “in spite of cardiac action.”[10] Around the same time, Guy Alexandre, a Belgian surgeon at the Catholic University of Louvain, introduced a similar set of criteria, and on June 3, 1963, performed the first organ transplant from a brain dead donor.[11]

In 1964, live kidney transplantation was done with the donor being a patient who had a catastrophic intracranial bleed. The donor succumbed to the illness of intracranial pathology, a few days later[8]. In today's terms, this would be considered illegal as the donor neither had circulatory death nor brain death (as criteria were not formulated then), but organs were transplanted, after consent from relatives, on the grounds of futility of ongoing care in a patient with catastrophic brain injury. This set off a debate all over Europe, and the criteria for death of the whole brain were set: deep coma, absence of spontaneous breathing and central reflexes, hypotension, and hypothermia, and as further evidence, electrical silence in the brain stem demonstrated by EEG and/or the absence of cerebral circulation demonstrated by angiography.[8] Similar is the case with the first heart transplantation performed by Dr. Christiaan Barnard. The concept of brain stem death was not incorporated in the medical literature or law in South Africa at that point in time. In this instance, the ventilator was disconnected in the operating theater and the doctors waited for cardiac standstill before the heart was retrieved.[12] Hence, it can be inferred that it was a donation after circulatory death in a patient with presumed catastrophic brain injury and not necessarily after brain stem death.[8]

The first widely accepted definition of brain death is considered to be the report of the 1968 Ad-hoc Committee of the Harvard Medical School to examine the definition of brain death.[13]

They described four criteria for the diagnosis of the condition – namely –

  • Nonresponsiveness to external noxious stimuli
  • Absence of spontaneous respiratory activity as confirmed by a 3-min disconnection from the ventilator after ensuring normal CO2 levels and ventilating with room air
  • Absence of any reflex activity – brain stem-mediated and spinal reflexes
  • An isoelectric EEG (when available). The EEG montage and protocol were described in detail.


The Ad hoc Committee required these tests to be repeated at an interval not <24 h, while excluding hypothermia and barbiturate therapy. The Members of the Committee envisioned their criteria to be used as a diagnosis of death itself and thus reduce the burden on society by giving the treating team and the patient's attendants the option of withdrawing futile ventilatory support and preventing controversy during harvesting of organs for transplantation.[13]

In 1968, the World Medical Assembly at Sydney declared that “Death is a gradual process at the cellular level with tissues varying in their ability to withstand deprivation of oxygen. But clinical interest lies not in the state of preservation of isolated cells but in the fate of a person … the point of death of the different cells and organs is not so important as the certainty that the process has become irreversible….” By distinguishing death of the cell from death of the person, the Declaration of Sydney went further in attempting to conceptualize death.[14]

In 1971, neurosurgeons Mohandas and Chou autopsied 25 patients who were declared brain dead based on the Minnesota criteria of brain death. Twenty-three among them had significant changes in their brain stem reflecting severe irreversible injury incompatible with life, while two had a normal gross and microscopic appearance of the brain stem despite lack of reflexes and electrical silence on the EEG. They concluded that the value of the EEG in the diagnosis of brain death was questionable at best, mostly when used in the rare and unusual circumstances when the cause of injury is unknown. They were the first to emphasize on the irreversibility of brain stem injury.[15],[16]

The Honorary Secretary of the Conference of Medical Royal Colleges and their faculty in the United Kingdom issued the Statement on the Diagnosis of Brain Death in October 1976. In this document, brain stem death was considered synonymous with brain death. They managed to group the tenets of their criteria into the mandatory prerequisites for considering brain stem death, excluding metabolic and pharmacological confounders and a detailed description of the brain stem reflexes to be documented absent. The British Criteria was the first to describe a detailed apnea test using blood gas interpretation to ensure that the PaCO2 level was above that expected to stimulate respiration (50 mm of Hg). Their apnea test also involved using 5% CO2 via the ventilator to expedite the rise in CO2 during the apneic period. In a divergence from their American colleagues, they de-emphasized the tests of cortical death, i.e., the EEG and the angiogram deeming them unnecessary for the diagnosis of brain death. They mentioned that ordinarily, the diagnosis of brain death does not need specialist advice except when the diagnosis is in doubt. The decision to withdraw supports from the brain dead patient would require the involvement of either the consultant or his/her deputy and one other doctor.[17]

The year 1981 witnessed two landmark publications from the United States – the Uniform Declaration of Death Act (UDDA) and the guideline from the US President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. The UDDA gave statutory recognition to the concept of brain death and equated this concept with conventional cardiorespiratory death. It did not address the methodology for the determination of death but specified that brain death should be declared in accordance with accepted medical standards, implying that these standards might evolve with time. It proposed that death could be determined by (1) “irreversible cessation of circulatory and respiratory functions” or (2) “irreversible cessation of all functions of the entire brain, including the brain stem.” The UDDA gave equivalence to death determined by cardiovascular and neurological criteria but did not standardize the neurological criteria that should be used.[18] The US President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research published guidelines regarding brain death. These guidelines recommend the use of supplementary diagnostic tests to augment clinical examination in the diagnosis of brain death. The Commission also recommended that patients who suffer from ischemic–hypoxic brain injury should be observed for no <24 h before declaration of brain death.[19]

The American Academy of Neurology (AAN) published an evidence-based review of brain death in 1995. These guidelines endorsed the understanding that brain death is clinical by nature and provided clarification regarding the use of supplementary tests in the management of brain death in the presence of confounding clinical factors. A protocol for completing the apnea test was spelled out, and the role of “confirmatory tests” was also clarified: “A confirmatory test is not mandatory but is desirable in patients in whom specific components of clinical testing cannot be reliably performed or evaluated.”[20] The 1995 UK code took the position that brain stem death was equivalent to brain death. While supplementary testing such as EEG and cerebral blood flow studies had been recommended earlier, the UK code did not require any supplementary testing for the determination of brain stem death where a complete clinical examination could be performed. Notably, this guideline required that an etiology for brain stem death must be first established and that conditions that mimic brain stem death must be excluded before clinical evaluation of brain stem death.[21]

It is interesting to note the apparent dissociation between the British and North-American viewpoints of brain death testing that persisted till the 1990s, with the Royal College reiterating brain stem death was equivalent to the term brain death, while the AAN based their criteria on the concept of whole-brain death – an irreversible cessation of function of the whole brain including the brain stem.[20],[22] The basic difference in the understanding of the concept of irreversible neurological injury allowed the American guidelines to continue to provide the option of ancillary tests to aid in the diagnosis, which primarily relied on the absence of supratentorial blood flow and electrical silence on EEG to confirm the diagnosis. This dichotomy, in definitions, made it possible for a patient with evidence of persisting cortical blood flow in the cerebral angiogram and/or persisting EEG activity to be declared brain stem dead in the United Kingdom, while this was not possible in the Americas and most of Mainland Europe.[23]

In the 2000s, there was a general convergence in the guidelines for certification of brain stem death following the publication of the code of practice for the diagnosis and confirmation of death by the Academy of the Royal College in 2008 and the evidence-based guideline update published by the AAN in 2010. The British guideline conceded the role of ancillary testing when conventional tests for brain stem death testing were not feasible, while pointing out their limitations and problems. The evidence-based guideline update of the AAN stressed that newer ancillary tests including computed tomography angiography, magnetic resonance angiography, and somatosensory-evoked potentials do not have sufficient evidence to support recommending their use. They suggested that the EEG, cerebral nuclear scan, and cerebral angiography are the accepted modalities for ancillary testing.[24]

Wijdicks published an international review of the prevailing practices in certifying brain death in 2002. The practice of brain stem death testing was very varied, with the criteria for whole-brain death being prevalent in the Americas, while the European and Asian nations were extremely diverse in their criteria for diagnosis. The observation was that, with few exceptions, former colonies of the British crown tended to follow the UK philosophy and directives in establishing the diagnosis of brain stem death. Not only was there wide variance in the panel of doctors required to certify brain stem death, but there were also differences in the performance of apnea testing, the mandatory interval between tests, and the use of confirmatory tests. These observations led to the suggestion to form an international task force for the formulation of what would be a universally acceptable protocol for testing and confirmation of the diagnosis of brain death.[25] In 2014, in collaboration with the World Health Organization, a single operational definition of human death was developed: “the permanent loss of capacity for consciousness and all brain stem functions, as a consequence of permanent cessation of circulation or catastrophic brain injury.”[26],[27]


  Brain Death Formulations Top


The circulation criterion is the conventionally accepted form of death in which the heart ceases to pump blood around the circulatory system and the breathing stops. This is the universally accepted form of death. It is the subsequent types of “death concepts” that warrant further discussion [Table 1].
Table 1: Comparison of various death formulations

Click here to view


The whole-brain criteria

Although the Harvard Committee and the President's Commission promoted a “Whole Brain” formulation, meaning loss of all brain functions, it was soon evident that some functions such as hypothalamic–pituitary response persisted. The defenders of this concept argued that the persistence of isolated activity of the neuroendocrine axis was irrelevant and, in any case, could be explained by its extracranial blood supply. They argued that it is the integrative unity of the organism that is destroyed pathophysiologically with whole-brain death, and therefore, the timing of the death of individual cell or “nests of cells” is not the criteria used. However, by then, it was clear that brain dead patients can show several levels of somatic integration; they did not necessarily “disintegrate” as promised.[28] In November 2007, another President's Council on Bioethics was created to address some of these persisting concerns. Their white paper was appropriately called “Controversies in the Determination of Death.”First, it discarded the vague term “brain death,” replacing it with the philosophically neutral term “total brain failure.” Second, it challenged the various conceptual arguments for brain death that advanced over the years and admitted the limitations of the integrative unity position. It then put forward a novel argument that equated death with the “cessation of the fundamental vital work of a living organism—the work of self-preservation.” There is an inner drive for life, the Council posited, that is “achieved through the organism's need-driven commerce with the surrounding world.” For human beings, this “commerce” is manifested by the drive to breathe combined with consciousness. Total brain failure equals death because the “organism can no longer engage in the essential work that defines living things.” Although seen as a thoughtful and reasoned analysis, the new term did not receive universal acceptance.[29]

The higher brain function formulation

This theory forwarded by Veatch suggests that death involves disintegration of the nature of organism.[30] This was further explained as the dissolution of personhood or the consciousness and cognition of a being, which, in pathophysiological terms, equates to the destruction of the cerebral cortex. This proposal was not accepted as patients with anencephaly and those in persistent vegetative states can fulfill these criteria.

Brain stem criteria

This formulation was issued by the Conference of Medical Royal Colleges and Their Faculties in the United Kingdom and vociferously defended by Pallis and Harley. These criteria state that “permanent functional death of the brain stem constitutes brain death” and are identified in the context of irremediable structural brain damage, only if reversible causes of brain stem dysfunction are excluded. Brain stem death is the “irreversible loss of the capacity for consciousness combined with the irreversible loss of the capacity to breathe.” The reticular activating system and nuclei for cardiorespiratory regulation reside in the brain stem and are key components of consciousness and respiratory control; their loss results in brain stem death. They summarize that the brain stem is the site where all integrative capacities for consciousness and involuntary integrative physiologic functioning reside.[17] Bernat criticized these criteria by defining a “super locked-in” syndrome where cerebral cortical activity is retained in the presence of absent brain stem function.[31]

Brain stem death is a condition that has challenged the medical and legal fraternity at multiple levels and has been thoroughly summarized by McGee and Gardiner.[32] Both the concept of brain stem death and the guidelines for its diagnosis and management have evolved over the last five decades, hand in hand with the advancements in the understanding of the unique pathology of the brain stem dead patient. As evidence-based guidelines will continue to refine our understanding of brain stem death, we can expect refinements in the diagnosis of brain stem death.

A comparison of the criteria for brain death prior to 1995 has been shown in [Table 2].
Table 2: Comparison of criteria before 1995

Click here to view



  Timeline of Brain Stem Death Top


  • 1959 – Wertheimer et al. described irreversible coma following neurological injury. Mollaret and Goulon coined the term “coma depasse”[2]
  • 1963 – Dr. Guy Alexandre performed the first deceased donor, beating heart organ recovery for a kidney-transplant recipient[2]
  • 1967 – Dr. Christiaan Barnard performed the first deceased donor heart transplant[12]
  • 1968 – The Ad hoc Committee of the Harvard Medical School published a report on the definition of irreversible coma[13]
  • 1971 – Mohandas and Chou published findings based on the “Minnesota criteria” showing that brain stem death was central to brain death and EEG was of little use in diagnosing brain death[15]
  • 1976 – Statement issued by the Conference of the Medical Royal Colleges and Their Faculties in the United Kingdom emphasizing brain stem death. The prerequisites were defined[17]
  • 1977 – American Neurological Association stated that EEG is a valuable confirmatory indicator of brain death and its use is strongly recommended[33]
  • 1979 – The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research indicated equivalence to death by cardiovascular and neurological criteria in the USA[19]
  • 1994 – Transplantation of Human Organ Act was passed in India in 1994 – accepted brain stem death as a form of death
  • 1995 – AAN published the Practice Parameters for diagnosis of Brain Death. Royal College of Physicians published their criteria for the diagnosis of brain stem Death[20],[21]
  • 2007 – US President's Council on Bioethics in their paper “Controversies in the determination of death” opted to change the term brain death with “total brain failure”[29]
  • 2008 – Royal College of Physicians publishes a code of practice for the diagnosis of death[21]
  • 2010 – AAN published its updated guidelines for determining Brain Death in adults[24]
  • 2014 – WHO definition of brain death.[26]


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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