Neurocrit Care DOI 10.1007/s12028-014-9983-x
ORIGINAL ARTICLE
Variability in Brain Death Determination in Europe: Looking for a Solution Giuseppe Citerio • Ilaria Alice Crippa • Alfio Bronco • Alessia Vargiolu • Martin Smith
Ó Springer Science+Business Media New York 2014
Abstract Background Criteria for determining brain death (BD) vary between countries. We report the results of an investigation designed to compare procedures to determine BD in different European countries. Methods We developed a web-based questionnaire that was sent to representatives of 33 European countries. Responses were reviewed, and individual respondents were contacted if clarification was required. Results Responses were received from 28 (85 %) of the 33 countries to which the questionnaire was sent. Each country has either a law (93 %) or national guidance (89 %) for defining BD. Clinical examination is sufficient to determine BD in 50 % of countries; coma, apnea, absence of corneal, and cough reflexes are mandatory criteria in all. Confirmation of apnea is required in all countries but not defined in 4 (14 %). In the 24 (86 %) of countries with a formal definition of the apnea test, a target pCO2 level (23/24, 96 %) is the pre-specified end point in Electronic supplementary material The online version of this article (doi:10.1007/s12028-014-9983-x) contains supplementary material, which is available to authorized users. G. Citerio (&) I. A. Crippa A. Bronco A. Vargiolu NeuroIntensive Care Unit, Department of Anesthesia and Critical Care, Ospedale San Gerardo, Via Pergolesi 33, 20900 Monza, Italy e-mail: [email protected] M. Smith Department of Neurocritical Care, The National Hospital for Neurology and Neurosurgery, University College London Hospitals, Queen Square, London, UK M. Smith NIHR University College London Hospitals Biomedical Research Centre, London, UK
most. The (median, range) number of clinical examinations (2, 1–3) and minimum observation time between tests (3 h, 0–12 h) vary greatly between countries. Additional (confirmatory) tests are required in 50 % of countries. Hypothermia (4 %), anoxic injury (7 %), inability to complete clinical examination (61 %), toxic drug levels (57 %), and inconclusive apnea test (54 %) are among the most common indications for confirmatory tests. Cerebral blood flow (CBF) investigation is mandatory in 18 % of countries, but optional or indicated only in selected cases in 82 %. Conventional angiography is the preferred method of determining absent CBF (50 %), followed by transcranial Doppler sonography (43 %), computerized tomography (CT) angiography (39 %), CT perfusion, and magnetic resonance imaging (MRI) angiography (11 %). Electroencephalography is always (21 %) or optionally (14 %) recorded. Conclusions Although legislation or professional guidance is available to standardize nationally the BD diagnosis process in all European countries, there are still disparities between countries. The current variation in practice makes an international consensus for the definition of BD imperative. Keywords Brain death Critical care Apnea test Brain death diagnosis
Introduction The concept of brain death (BD) is closely linked to the birth of modern intensive care medicine which led to the prospect of somatic function being sustained by mechanical ventilation long after brain function had ceased [1, 2]. Unfortunately, BD is not a uniformly defined entity, and
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the state of BD is also permeated with social, cultural, and religious connotations [3]. From a legal and scientific perspective, BD is a definable event which allows treatment to be legitimately removed from a patient who can no longer derive benefit from it (because they are dead), and also enables the donation of organs for transplantation. Determining the clear line between life and death is crucial, not only because further treatment is inappropriate in a dead patient, but also because families require confirmation of this event with certainty. The concept of BD was first described in 1959 by Mollaret and Goulon who reported a state of unconsciousness associated with brainstem areflexia and the absence of spontaneous respiration in 23 patients [4]. They coined the term ‘‘le coma de´passe´’’ literally ‘‘a state beyond coma,’’ to define this condition. This was followed almost ten years later by the seminal definition of ‘‘irreversible coma’’ as a new criterion for death by an ad hoc committee of Harvard Medical School [5]. Meanwhile, guidance on the diagnosis of brain (stem) death was published by the UK Conference of Medical Royal Colleges and their Faculties in 1976 [6], and this was followed in 1979 by a memorandum that equated BD with death of the whole person [7]. The process of the definition of BD moved further when, in 1981, a US Presidential commission confirmed the clinical and ethical recognition of BD defined by neurologic criteria [8]. This was subsequently summarized in the Uniform Determination of Death Act, which gave equivalence to death determined by neurological and cardiovascular criteria [9]. However, diagnostic variability was common so, in 1995, the American Academy of Neurology (AAN) issued guidelines on the diagnosis of BD in an attempt to standardize its determination [10]. This guidance was the basis for the development of the statutes of death in each state in the US, and formed the basis of BD definitions in other countries. Despite general consensus on the concept of BD, its definition still varies widely between countries [11–15], and local legislation reflects such disparity. Wijdicks reviewed official documents and informal reports from 80 countries worldwide and found general uniformity on the neurologic examination to determine BD in adults, but variability in the requirement for, and conduct of, the apnea test [16]. Wijdicks called for worldwide standardization of the determination of BD. In this study, we explore whether heterogeneity in the diagnosis of BD still exists in Europe more than 50 years after its first description. We report the results of a survey to compare BD definitions and diagnostic procedures in different European countries, and highlight important differences.
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Methods During summer 2013, a direct link to a 27 item web-based questionnaire (see Supplementary Material) was sent by email to members of the Neurointensive Care Section or national representative of the European Society of Intensive Care Medicine of 33 European countries, and also to colleagues in Russia and Turkey. A maximum of two invitations were sent per country. The questionnaire collected background information about guidelines regulating BD determination defined by national professional societies or legislation. The questionnaire explored in detail the clinical prerequisites for BD definition, the clinical tests required to diagnose BD, the composition of the medical team certifying BD, the number of clinical examinations required to confirm BD and their timing, and any differences in BD diagnosis between adults and children. Legal definition and procedural details for apnea and ancillary tests, such as electroencephalography (EEG) and cerebral blood flow (CBF) assessment, were explored. Responses were reviewed and participants contacted directly to clarify any uncertainties or inconsistencies. Incongruous or missing responses that could not be clarified were excluded from the analysis. If more than one response was received from the same country, the one providing the most complete responses was included in the analysis.
Results Responses were received from survey participants in 28 countries (response rate 85 %). The data are summarized in Table 1. Legislation pertaining to BD diagnosis is present in the majority (26/28, 93 %) of surveyed countries, with the exception of Ireland and the UK where practice is determined by guidelines issued on behalf of national professional societies but recognized by case law. In Italy, Belgium, and Norway (3/28, 11 %), legislation is in place but in the absence of official professional guidance. The diagnosis of BD is clinical in all the countries surveyed, and formal clinical examination is essential for its determination. Prior to clinical examination, 27 (96 %) of countries require that the cause of coma is known and that it is compatible with BD, although this is not defined by law in Belgium (Fig. 1). Agreement exists across all countries on the requirement to exclude therapeutic concentrations of sedatives and paralytics (28/28, 100 %) as a reversible cause of coma prior to clinical examination, and a normal core temperature is also a prerequisite in the majority of countries (27/28, 96 %), although not defined in Spain. Less common clinical prerequisites prior to clinical examination include a normal acid–base status (20/
Neurocrit Care Table 1 Countries participating in the survey on the variability in brain death determination in Europe and principle findings Country
Law/ guidelines
Ancillary tests
Clinical examination (number)
Apnea test
Doctors (number)
Minimum observe time—adults (h)
Austria
P/P
NR
2
DCO2
2
2
Belgium
P/A
AR
1
ND
1
–
Bosnia
P/P
AR
2
DCO2
3
3
Bulgaria
P/P
NR
2
DCO2
3
NA
Croatia
P/P
AR
2
DCO2
2
3
Cyprus
P/P
NR
2
DCO2
NA
10
Denmark Estonia
P/P P/P
AR NR
2 2
DCO2 ND
2 2
1 10
Finland
P/P
NR
1
DCO2
2
–
France
P/P
AR
2
DCO2
2
2
Germany
P/P
AR
2
DCO2
2
2 12
Greece
P/P
NR
2
DCO2
NA
Hungary
P/P
AR
3
DCO2
NA
4
Ireland
A/P
NR
2
DCO2
4
0
Italy
P/A
AR
2
DCO2
3
6
Lithuania
P/P
AR
3
DCO2
3
12
Netherlands
P/P
AR
1
DAT
1
–
Norway
P/A
AR
1
ND
2
–
Poland
P/P
NR
2
DCO2
3
3
Portugal
P/P
NR
2
ND
2
2
Romania
P/P
AR
2
DCO2
3
3
Russia Slovenia
P/P P/P
NR AR
2 2
DCO2 DCO2
3 2
6 6
Spain
P/P
NR
2
DCO2
3
6
Sweden
P/P
NR
2
DCO2
1
2
Switzerland
P/P
NR
1
DCO2
2
–
Turkey
P/P
AR
2
DCO2
2
2
UK
A/P
NR
2
DCO2
2
0
A absent, AR always required, DCO2 defined with pCO2 level, DAT legally defined with apnea time, ND not defined, NR not required, P present
Fig. 1 Prerequisites tested prior to clinical examination. Number of countries requiring exclusion of each variable as a contributor to coma prior to clinical confirmation of brain death
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28, 71 %), normal electrolytes and blood pressure (18/28, 64 %), and normal endocrine status (15/28, 54 %). Essential elements in the diagnosis of BD in all countries are the presence of coma, defined as unresponsiveness and no motor response to pain, presence of apnea, and absence of brainstem reflexes. Corneal and cough reflexes are always tested (28/28, 100 %), and in all the countries at least one of pupillary (27/28, 96 %), oculocephalic (27/28, 96 %), and oculovestibular (27/28, 96 %) reflexes must be examined. Gag and jaw jerks reflexes are less commonly tested (22/28, 79 % and 8/28, 29 %, respectively). An apnea test is mandated by law or recommended by professional guidance in all countries, but variability exists in its definition. In four countries (14 %), the apnea test is not formally defined. In the 24 (86 %) of countries with a formal definition of the apnea test, a target pCO2 level (23/ 24, 96 %) or a minimum apnea time (1/24, 4 %–the Netherlands) are the pre-specified end points. When a pCO2 target level is defined, it must be confirmed by arterial blood gas analysis at the end of the apnea test. The patient is either pre-oxygenated or oxygenated during the apnea test in all countries (28/28, 100 %), and the test is suspended if the patient becomes unstable or desaturates during the test in 24 (86 %) and 20 (71 %), respectively. Twenty-three countries (82 %) require more than one clinical examination to confirm BD, usually two (21/28, 75 %) (Fig. 2). Hungary and Lithuania are exceptional in requiring three separate clinical examinations (2/28, 7 %). In five countries (18 %), Belgium, Finland, the Netherlands, Norway, and Switzerland, the clinical examination is performed only once, although these requirements apply only to adults. In Estonia, the Netherlands, Russia, and Spain, an ancillary test can be used to confirm the diagnosis of BD and avoid repeated clinical examinations or shorten observation times between examinations. Austria requires a confirmatory test in the presence of infratentorial pathology. Slovenia allows clinical diagnosis with no confirmatory test only if the pathology is supratentorial and the observation period Fig. 2 Minimum observation time between clinical examinations for brain death (hours). Minimum (0 h) and maximum (12 h) are shown. Q1 lower quartile (1 h); M median (3 h); Q2 upper quartile (6 h). The interquartile range for the distribution is 5 h
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between clinical examinations is at least 24 h. In the countries requiring more than one clinical examination, the observation time between examinations is variable, but between 2 to 12 h in the majority (19/22, 86 %). Greece and Lithuania have the longest minimum observation time of 12 h. The minimum time between examinations is only one hour in Denmark, and no minimum observation period is required between examinations in the UK and Ireland. In most countries (13/25, 52 %), two doctors are required to complete the diagnosis of BD, but data were unavailable from three (Fig. 3). In some countries (8/25, 32 %) three doctors are required, Ireland requires four, and three countries require only one. In 18 countries (64 %), national regulations define the specialists who are authorized to declare BD (Fig. 4). In the 10 (36 %) countries which make no such specification, there is no guidance on the background or competencies of those who can diagnose BD in four, and minimal criteria of experience but independency from a transplantation team in six. Most commonly, the professional background of physicians involved in the determination of BD are intensive care (27/28, 96 %), neurology (26/28, 93 %), and neurosurgery (21/28, 75 %). The primary attending physician is required to be involved in six (21 %) countries. Rarely, a physician
Fig. 3 Number of countries in which the specialists allowed to confirm the diagnosis of brain death is defined by law
Neurocrit Care
Fig. 4 Specialists involved in brain death diagnosis. Professional background of physicians who usually confirm the brain death diagnosis. *Other refers to specialist (8) and non-specialist (8) doctors. Other specialists are: pediatrician in case of brain death determination in children (4), cardiologist (1), medico legal doctor (1), radiologist (1). In some countries, law states minimum experience criteria for non-specialists involved or independence of the transplantation team (7)
specializing in legal medicine (1/28, 3 %), cardiology, or radiology (2/28, 6 %) are involved in the determination of BD. In the case of children, pediatricians must additionally be involved in the diagnosis of BD in some countries. Clinical criteria alone are sufficient to diagnose BD in half of countries (14/28, 50 %) and one or more ancillary or confirmatory tests are required in the others (14/28, 50 %). EEG must always be performed in five countries (18 %). Assessment of CBF is used in ten (36 %) and mandatory in four (14 %). EEG is an alternative to CBF assessment in six countries (21 %), but Croatia requires both. In Austria, EEG is only required in the presence of infratentorial pathology. In Estonia, the Netherlands, Russia, and Spain, an ancillary test can be used to confirm the diagnosis of BD and/or shorten the observation times between tests. Furthermore, additional tests are required in some countries when confounding factors are present, particularly an inability to complete a clinical examination (17/28, 61 %), the presence of therapeutic sedative drug levels (16/28, 57 %), and an inconclusive apnea test (14/28, 50 %). In Denmark, confirmatory tests are required in cases of anoxic brain injury. In Estonia, the duration of observation is extended to 24 h in cases of anoxic brain injury, but can be shortened by the use of a confirmatory test. CBF evaluation methods are defined by law in 18 countries (64 %). Conventional angiography is the preferred method (14/28, 50 %), followed by transcranial Doppler sonography (12/28, 43 %) and computerized tomography (CT) angiography (11/28, 39 %). CT perfusion and magnetic resonance imaging angiography are utilized rarely (3/28, 11 %).
Discussion The criteria for the determination of BD are robust. There are no published reports of recovery of neurological
function after a diagnosis of BD using the criteria recommended by the American Academy of Neurology, when these are strictly applied [17]. Despite a general consensus on the concept of BD, there are still major international differences in its diagnosis, and there have been calls for a worldwide consensus on the determination of BD. Recently, a forum of international content experts and representatives of a number of professional societies, sponsored by Health Canada and Canadian Blood Services in collaboration with the World Health Organization (WHO), had attempted to develop a universal definition of BD and international guidelines for its determination [18]. The majority of countries in Europe have followed the lead of the USA and the UK in specifying that the clinical diagnosis of BD is sufficient for the determination of death in adults. This includes three inter-dependent but related steps. The patient must be in apneic coma and have a confirmed etiology of brain damage that is compatible with irreversible BD. Potentially reversible causes of coma and apnea, including sedative and paralytic drugs, systemic physiologic disturbances, and electrolyte imbalance, must then be excluded. Finally, a rigorous clinical examination of brainstem reflexes and an apnea test must be undertaken. Despite agreement with these fundamental principles, our study confirms that their differences in national requirements and methods of determining BD in European countries. A clinical diagnosis of BD is a sufficient criterion for the determination of death in adults in only half of the countries surveyed, with one half requiring one or more ancillary tests. This is in contrast to the recent international guideline development for the determination of death which states that death is principally established using clinical criteria [17]. This concept was also stressed by Wijdicks who argued that confirmatory tests are hangovers from earlier days of refining comatose states and that comprehensive clinical examination, when performed by competent examiners, should have perfect diagnostic accuracy [19]. The recommendations from the Quality Standards Subcommittee of the American Academy of Neurology also stress that there is insufficient evidence to determine whether ancillary tests, even those using newer technology, are accurately able to confirm the cessation of function of the entire brain compared with clinical examination. Surprisingly, the need to establish a pathology consistent with irreversible of coma is not a uniform requirement prior to clinical examination in all European countries. Although all countries require exclusion of the confounding effects of therapeutic concentrations of sedative and paralytic agents prior to clinical confirmation of BD, it is also surprising that prerequisites such as normal core temperature and systolic blood pressure are not universally required or applied. There is unanimity across Europe that coma, defined as unresponsiveness and no motor response to pain, presence of
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apnea, and absence of brainstem reflexes, is fundamental to the clinical determination of BD, but which brainstem reflexes are tested varies. Confirmation of the absence of corneal and cough and gag reflexes is not required in all countries. That BD can be confirmed without a comprehensive examination of all cranial nerves reflexes and confirmation of their absence as required by widely accepted consensus guidance [8, 17] is worrying. There are also wide variations in the requirements for conduct of the apnea test. This is particularly worrisome because confirmation of apnea is fundamental to the determination of BD, and apnea can only be determined with certainty if an acute hypercarbic stimulus sufficient to trigger the respiratory center is achieved and documented. In fact, the respiratory drive in the setting of an intense ventilatory stimulus, i.e., respiratory acidosis, is a critical marker of brainstem function [20]. In 14 % of the European countries surveyed, the end point of the apnea test is not formally defined and, where it is, a target pCO2 rather than a defined change in pCO2 is the usual end point. Although either pre-oxygenation or oxygenation during the test is performed in all countries, the conduct of other aspects of the apnea test lacks standardization. There is no guidance in many countries regarding oxygen flow rates, maintenance of PEEP, monitored parameters (exhaled CO2, SpO2, transcutaneous CO2 monitoring), and safety measures to prevent complications during the test [21]. Whatever standard is used to determine BD, ‘‘irreversibility’’ is usually not defined and has historically relied on repeated assessment over time, presumably to minimize the risk of diagnostic errors. This is contrary to the American Academy of Neurology guidance which stipulates that only a single examination is required, relying on the determination of irreversibility by exclusion of reversible causes and knowledge that the cause of the brain damage is structural and irreversible [17]. Despite this, 82 % of the European countries surveyed require more than one clinical examination, most commonly two. The time interval between the two examinations also varied enormously, ranging from no minimum to 12 h. There is no convincing evidence that a second test is necessary, but evidence that repeated clinical examination delays the determination of BD, adversely affects organ donation rates, and unnecessarily increases intensive care length of stay and costs [22]. Postponing the first clinical examination by 24 h is usual after hypoxicischemic brain injury but there is generally less specific guidance for other clinical circumstances. Some national guidelines specify the qualification and level of experience of doctors determining BD, with intensivists and neurologists being the most common specialties involved. The number of doctors required to determine BD also varies widely, although at least two doctors are required in more than 50 % of countries. The
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authors believe that competency in neurologic examination and conduct of the apnea test is required to retain public confidence in the determination of BD, and call for professional bodies to lobby for such minimum requirements. Confirmatory tests are required in half of the countries but reserved in others for doubtful circumstances, such as inability to complete clinical examination, therapeutic sedative drug levels, or when the patient is too unstable to undergo an apnea test. EEG is frequently required even though a patient who is brain (stem) dead may exhibit residual cortical electrical activity [23]. Further, because the EEG cannot detect deep brain activity, it may be isoelectric even in the presence of viable neurons in the brainstem and other deep structures [24]. The EEG is also affected by hypothermia and sedative drugs, which are confounding factors for the clinical diagnosis of BD and the very circumstances where a confirmatory test might be useful. When confirmation of absent CBF is required, CT angiography is becoming more commonly used because it is non-invasive and quick. However, some universal standards must be defined before it can be incorporated into routine BD protocols. Some authorities believe that confirmatory tests have a place when the preconditions for clinical testing are unmet or where clinical testing cannot be completed in full [10, 25], whereas others believe that they have no role in modern practice because the determination of BD based on a comprehensive clinical examination is robust [19]. It is of note that the recommendations from the Quality Standards Subcommittee of the American Academy of Neurology stress that there is insufficient evidence to determine whether ancillary tests, even those harnessing newer technology, are accurately able to confirm the cessation of brain function compared with clinical examination [17]. Although consensus guidance is available to standardize national processes for the diagnosis of BD, the current variation and inconsistency in European practice makes it imperative that an international consensus is developed. As a minimum, this should clarify the criteria for the determination of brain death and provide specific instructions about the clinical examination necessary and the conduct of the apnea test [14]. It should also stipulate the role and type of confirmatory investigations, identify the training and experience of those able to determine death by neurological criteria, and detail the required level of documentation. An international consensus on the determination of brain death is desirable, essential, and long overdue. Acknowledgments Danica Avsec ST, Institute for transplantation of organs and tissues of the Republic of Slovenia, Ljubljana, Slovenia; Paulo Azevedo Maia, Servic¸o Cuidados Intensivos 1, Hospital Santo Anto´nio, Centro Hospitalar do Porto, Portugal; Ovidiu Bedreag, Anesthesiology and intensive care department, University of Medicine and Pharmacy Victor Babes Timisoara, Romania; Romuald
Neurocrit Care Bohatyrewicz, Department of Anaesthesiology and Intensive Care, Pomeranian Medical University, Poland; Julien Charpentier, Medical Intensive Care Unit, Groupe Hospitalier Universitaire Cochin Broca Hoˆtel-Dieu, Paris, France; Martin Duenser, Department of Anesthesiology, Perioperative and General Intensive Care Medicine, Salzburg General Hospital and Paracelsus Private Medical University, Austria; Hans Friberg, Ska˚ne University Hospital, Lund, Sweden; Hans Flaatten, Intensive Care Unit. Haukeland University Hospital. Bergen, Norway; Ivan Gornik, University of Zagreb Medical School, University Hospital Centre Zagreb, Croatia; Jozef Kesecioglu, Department of Intensive Care Medicine, University Medical Center Utrecht, Netherlands; Georgia Markou, Pediatric Intensive Care Medicine, University Hospital of Patras, Greece; Brian Marsh, Mater Misericordiae University Hospital, Dublin, Ireland; Kirsten Møller, Neurointensive Care Unit, Rigshospitalet, University of Copenhagen, Denmark; Pedro Navarrete-Navarro, Emergency & Critical Care Department, Hospital de Neuro-Traumatologia, Hospital Universitario Virgen de las Nieves, Granada, Spain; Mauro Oddo, Department of Intensive Care Medicine, CHUV-University Hospital; Faculty of Biology and Medicine, University of Lausanne, Switzerland; Vita Petronyt_e, Transplant Coordination Department, National Transplant Bureau, Lithuania; Ville Pettila¨, Intensive Care Units, Helsinki University Central Hospital, Finland; Konstantin A. Popugaev, Neurocritical Care department, Burdenko Neurosurgical Research Institute, Moscow, Russia; Annika Reintam Blaser, Department of Anaesthesiology and Intensive Care, University of Tartu, Estonia; Fabio Silvio Taccone, Department of Intensive Care, Hopital Erasme, Brussels, Belgium; Lufti Telci, Istanbul Faculty of Medicine, Department of Anesthesiology and Intensive Care, Istanbul, Turkey; Csaba Varga, Kaposi Mor Teaching Hospital Emergency Department Kaposva´r, Hungary. Conflict of interest flict of interest.
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All the authors declare that they have no con18.
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ORIGINAL ARTICLE
Variability in Brain Death Determination in Europe: Looking for a Solution Giuseppe Citerio • Ilaria Alice Crippa • Alfio Bronco • Alessia Vargiolu • Martin Smith
Ó Springer Science+Business Media New York 2014
Abstract Background Criteria for determining brain death (BD) vary between countries. We report the results of an investigation designed to compare procedures to determine BD in different European countries. Methods We developed a web-based questionnaire that was sent to representatives of 33 European countries. Responses were reviewed, and individual respondents were contacted if clarification was required. Results Responses were received from 28 (85 %) of the 33 countries to which the questionnaire was sent. Each country has either a law (93 %) or national guidance (89 %) for defining BD. Clinical examination is sufficient to determine BD in 50 % of countries; coma, apnea, absence of corneal, and cough reflexes are mandatory criteria in all. Confirmation of apnea is required in all countries but not defined in 4 (14 %). In the 24 (86 %) of countries with a formal definition of the apnea test, a target pCO2 level (23/24, 96 %) is the pre-specified end point in Electronic supplementary material The online version of this article (doi:10.1007/s12028-014-9983-x) contains supplementary material, which is available to authorized users. G. Citerio (&) I. A. Crippa A. Bronco A. Vargiolu NeuroIntensive Care Unit, Department of Anesthesia and Critical Care, Ospedale San Gerardo, Via Pergolesi 33, 20900 Monza, Italy e-mail: [email protected] M. Smith Department of Neurocritical Care, The National Hospital for Neurology and Neurosurgery, University College London Hospitals, Queen Square, London, UK M. Smith NIHR University College London Hospitals Biomedical Research Centre, London, UK
most. The (median, range) number of clinical examinations (2, 1–3) and minimum observation time between tests (3 h, 0–12 h) vary greatly between countries. Additional (confirmatory) tests are required in 50 % of countries. Hypothermia (4 %), anoxic injury (7 %), inability to complete clinical examination (61 %), toxic drug levels (57 %), and inconclusive apnea test (54 %) are among the most common indications for confirmatory tests. Cerebral blood flow (CBF) investigation is mandatory in 18 % of countries, but optional or indicated only in selected cases in 82 %. Conventional angiography is the preferred method of determining absent CBF (50 %), followed by transcranial Doppler sonography (43 %), computerized tomography (CT) angiography (39 %), CT perfusion, and magnetic resonance imaging (MRI) angiography (11 %). Electroencephalography is always (21 %) or optionally (14 %) recorded. Conclusions Although legislation or professional guidance is available to standardize nationally the BD diagnosis process in all European countries, there are still disparities between countries. The current variation in practice makes an international consensus for the definition of BD imperative. Keywords Brain death Critical care Apnea test Brain death diagnosis
Introduction The concept of brain death (BD) is closely linked to the birth of modern intensive care medicine which led to the prospect of somatic function being sustained by mechanical ventilation long after brain function had ceased [1, 2]. Unfortunately, BD is not a uniformly defined entity, and
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the state of BD is also permeated with social, cultural, and religious connotations [3]. From a legal and scientific perspective, BD is a definable event which allows treatment to be legitimately removed from a patient who can no longer derive benefit from it (because they are dead), and also enables the donation of organs for transplantation. Determining the clear line between life and death is crucial, not only because further treatment is inappropriate in a dead patient, but also because families require confirmation of this event with certainty. The concept of BD was first described in 1959 by Mollaret and Goulon who reported a state of unconsciousness associated with brainstem areflexia and the absence of spontaneous respiration in 23 patients [4]. They coined the term ‘‘le coma de´passe´’’ literally ‘‘a state beyond coma,’’ to define this condition. This was followed almost ten years later by the seminal definition of ‘‘irreversible coma’’ as a new criterion for death by an ad hoc committee of Harvard Medical School [5]. Meanwhile, guidance on the diagnosis of brain (stem) death was published by the UK Conference of Medical Royal Colleges and their Faculties in 1976 [6], and this was followed in 1979 by a memorandum that equated BD with death of the whole person [7]. The process of the definition of BD moved further when, in 1981, a US Presidential commission confirmed the clinical and ethical recognition of BD defined by neurologic criteria [8]. This was subsequently summarized in the Uniform Determination of Death Act, which gave equivalence to death determined by neurological and cardiovascular criteria [9]. However, diagnostic variability was common so, in 1995, the American Academy of Neurology (AAN) issued guidelines on the diagnosis of BD in an attempt to standardize its determination [10]. This guidance was the basis for the development of the statutes of death in each state in the US, and formed the basis of BD definitions in other countries. Despite general consensus on the concept of BD, its definition still varies widely between countries [11–15], and local legislation reflects such disparity. Wijdicks reviewed official documents and informal reports from 80 countries worldwide and found general uniformity on the neurologic examination to determine BD in adults, but variability in the requirement for, and conduct of, the apnea test [16]. Wijdicks called for worldwide standardization of the determination of BD. In this study, we explore whether heterogeneity in the diagnosis of BD still exists in Europe more than 50 years after its first description. We report the results of a survey to compare BD definitions and diagnostic procedures in different European countries, and highlight important differences.
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Methods During summer 2013, a direct link to a 27 item web-based questionnaire (see Supplementary Material) was sent by email to members of the Neurointensive Care Section or national representative of the European Society of Intensive Care Medicine of 33 European countries, and also to colleagues in Russia and Turkey. A maximum of two invitations were sent per country. The questionnaire collected background information about guidelines regulating BD determination defined by national professional societies or legislation. The questionnaire explored in detail the clinical prerequisites for BD definition, the clinical tests required to diagnose BD, the composition of the medical team certifying BD, the number of clinical examinations required to confirm BD and their timing, and any differences in BD diagnosis between adults and children. Legal definition and procedural details for apnea and ancillary tests, such as electroencephalography (EEG) and cerebral blood flow (CBF) assessment, were explored. Responses were reviewed and participants contacted directly to clarify any uncertainties or inconsistencies. Incongruous or missing responses that could not be clarified were excluded from the analysis. If more than one response was received from the same country, the one providing the most complete responses was included in the analysis.
Results Responses were received from survey participants in 28 countries (response rate 85 %). The data are summarized in Table 1. Legislation pertaining to BD diagnosis is present in the majority (26/28, 93 %) of surveyed countries, with the exception of Ireland and the UK where practice is determined by guidelines issued on behalf of national professional societies but recognized by case law. In Italy, Belgium, and Norway (3/28, 11 %), legislation is in place but in the absence of official professional guidance. The diagnosis of BD is clinical in all the countries surveyed, and formal clinical examination is essential for its determination. Prior to clinical examination, 27 (96 %) of countries require that the cause of coma is known and that it is compatible with BD, although this is not defined by law in Belgium (Fig. 1). Agreement exists across all countries on the requirement to exclude therapeutic concentrations of sedatives and paralytics (28/28, 100 %) as a reversible cause of coma prior to clinical examination, and a normal core temperature is also a prerequisite in the majority of countries (27/28, 96 %), although not defined in Spain. Less common clinical prerequisites prior to clinical examination include a normal acid–base status (20/
Neurocrit Care Table 1 Countries participating in the survey on the variability in brain death determination in Europe and principle findings Country
Law/ guidelines
Ancillary tests
Clinical examination (number)
Apnea test
Doctors (number)
Minimum observe time—adults (h)
Austria
P/P
NR
2
DCO2
2
2
Belgium
P/A
AR
1
ND
1
–
Bosnia
P/P
AR
2
DCO2
3
3
Bulgaria
P/P
NR
2
DCO2
3
NA
Croatia
P/P
AR
2
DCO2
2
3
Cyprus
P/P
NR
2
DCO2
NA
10
Denmark Estonia
P/P P/P
AR NR
2 2
DCO2 ND
2 2
1 10
Finland
P/P
NR
1
DCO2
2
–
France
P/P
AR
2
DCO2
2
2
Germany
P/P
AR
2
DCO2
2
2 12
Greece
P/P
NR
2
DCO2
NA
Hungary
P/P
AR
3
DCO2
NA
4
Ireland
A/P
NR
2
DCO2
4
0
Italy
P/A
AR
2
DCO2
3
6
Lithuania
P/P
AR
3
DCO2
3
12
Netherlands
P/P
AR
1
DAT
1
–
Norway
P/A
AR
1
ND
2
–
Poland
P/P
NR
2
DCO2
3
3
Portugal
P/P
NR
2
ND
2
2
Romania
P/P
AR
2
DCO2
3
3
Russia Slovenia
P/P P/P
NR AR
2 2
DCO2 DCO2
3 2
6 6
Spain
P/P
NR
2
DCO2
3
6
Sweden
P/P
NR
2
DCO2
1
2
Switzerland
P/P
NR
1
DCO2
2
–
Turkey
P/P
AR
2
DCO2
2
2
UK
A/P
NR
2
DCO2
2
0
A absent, AR always required, DCO2 defined with pCO2 level, DAT legally defined with apnea time, ND not defined, NR not required, P present
Fig. 1 Prerequisites tested prior to clinical examination. Number of countries requiring exclusion of each variable as a contributor to coma prior to clinical confirmation of brain death
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28, 71 %), normal electrolytes and blood pressure (18/28, 64 %), and normal endocrine status (15/28, 54 %). Essential elements in the diagnosis of BD in all countries are the presence of coma, defined as unresponsiveness and no motor response to pain, presence of apnea, and absence of brainstem reflexes. Corneal and cough reflexes are always tested (28/28, 100 %), and in all the countries at least one of pupillary (27/28, 96 %), oculocephalic (27/28, 96 %), and oculovestibular (27/28, 96 %) reflexes must be examined. Gag and jaw jerks reflexes are less commonly tested (22/28, 79 % and 8/28, 29 %, respectively). An apnea test is mandated by law or recommended by professional guidance in all countries, but variability exists in its definition. In four countries (14 %), the apnea test is not formally defined. In the 24 (86 %) of countries with a formal definition of the apnea test, a target pCO2 level (23/ 24, 96 %) or a minimum apnea time (1/24, 4 %–the Netherlands) are the pre-specified end points. When a pCO2 target level is defined, it must be confirmed by arterial blood gas analysis at the end of the apnea test. The patient is either pre-oxygenated or oxygenated during the apnea test in all countries (28/28, 100 %), and the test is suspended if the patient becomes unstable or desaturates during the test in 24 (86 %) and 20 (71 %), respectively. Twenty-three countries (82 %) require more than one clinical examination to confirm BD, usually two (21/28, 75 %) (Fig. 2). Hungary and Lithuania are exceptional in requiring three separate clinical examinations (2/28, 7 %). In five countries (18 %), Belgium, Finland, the Netherlands, Norway, and Switzerland, the clinical examination is performed only once, although these requirements apply only to adults. In Estonia, the Netherlands, Russia, and Spain, an ancillary test can be used to confirm the diagnosis of BD and avoid repeated clinical examinations or shorten observation times between examinations. Austria requires a confirmatory test in the presence of infratentorial pathology. Slovenia allows clinical diagnosis with no confirmatory test only if the pathology is supratentorial and the observation period Fig. 2 Minimum observation time between clinical examinations for brain death (hours). Minimum (0 h) and maximum (12 h) are shown. Q1 lower quartile (1 h); M median (3 h); Q2 upper quartile (6 h). The interquartile range for the distribution is 5 h
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between clinical examinations is at least 24 h. In the countries requiring more than one clinical examination, the observation time between examinations is variable, but between 2 to 12 h in the majority (19/22, 86 %). Greece and Lithuania have the longest minimum observation time of 12 h. The minimum time between examinations is only one hour in Denmark, and no minimum observation period is required between examinations in the UK and Ireland. In most countries (13/25, 52 %), two doctors are required to complete the diagnosis of BD, but data were unavailable from three (Fig. 3). In some countries (8/25, 32 %) three doctors are required, Ireland requires four, and three countries require only one. In 18 countries (64 %), national regulations define the specialists who are authorized to declare BD (Fig. 4). In the 10 (36 %) countries which make no such specification, there is no guidance on the background or competencies of those who can diagnose BD in four, and minimal criteria of experience but independency from a transplantation team in six. Most commonly, the professional background of physicians involved in the determination of BD are intensive care (27/28, 96 %), neurology (26/28, 93 %), and neurosurgery (21/28, 75 %). The primary attending physician is required to be involved in six (21 %) countries. Rarely, a physician
Fig. 3 Number of countries in which the specialists allowed to confirm the diagnosis of brain death is defined by law
Neurocrit Care
Fig. 4 Specialists involved in brain death diagnosis. Professional background of physicians who usually confirm the brain death diagnosis. *Other refers to specialist (8) and non-specialist (8) doctors. Other specialists are: pediatrician in case of brain death determination in children (4), cardiologist (1), medico legal doctor (1), radiologist (1). In some countries, law states minimum experience criteria for non-specialists involved or independence of the transplantation team (7)
specializing in legal medicine (1/28, 3 %), cardiology, or radiology (2/28, 6 %) are involved in the determination of BD. In the case of children, pediatricians must additionally be involved in the diagnosis of BD in some countries. Clinical criteria alone are sufficient to diagnose BD in half of countries (14/28, 50 %) and one or more ancillary or confirmatory tests are required in the others (14/28, 50 %). EEG must always be performed in five countries (18 %). Assessment of CBF is used in ten (36 %) and mandatory in four (14 %). EEG is an alternative to CBF assessment in six countries (21 %), but Croatia requires both. In Austria, EEG is only required in the presence of infratentorial pathology. In Estonia, the Netherlands, Russia, and Spain, an ancillary test can be used to confirm the diagnosis of BD and/or shorten the observation times between tests. Furthermore, additional tests are required in some countries when confounding factors are present, particularly an inability to complete a clinical examination (17/28, 61 %), the presence of therapeutic sedative drug levels (16/28, 57 %), and an inconclusive apnea test (14/28, 50 %). In Denmark, confirmatory tests are required in cases of anoxic brain injury. In Estonia, the duration of observation is extended to 24 h in cases of anoxic brain injury, but can be shortened by the use of a confirmatory test. CBF evaluation methods are defined by law in 18 countries (64 %). Conventional angiography is the preferred method (14/28, 50 %), followed by transcranial Doppler sonography (12/28, 43 %) and computerized tomography (CT) angiography (11/28, 39 %). CT perfusion and magnetic resonance imaging angiography are utilized rarely (3/28, 11 %).
Discussion The criteria for the determination of BD are robust. There are no published reports of recovery of neurological
function after a diagnosis of BD using the criteria recommended by the American Academy of Neurology, when these are strictly applied [17]. Despite a general consensus on the concept of BD, there are still major international differences in its diagnosis, and there have been calls for a worldwide consensus on the determination of BD. Recently, a forum of international content experts and representatives of a number of professional societies, sponsored by Health Canada and Canadian Blood Services in collaboration with the World Health Organization (WHO), had attempted to develop a universal definition of BD and international guidelines for its determination [18]. The majority of countries in Europe have followed the lead of the USA and the UK in specifying that the clinical diagnosis of BD is sufficient for the determination of death in adults. This includes three inter-dependent but related steps. The patient must be in apneic coma and have a confirmed etiology of brain damage that is compatible with irreversible BD. Potentially reversible causes of coma and apnea, including sedative and paralytic drugs, systemic physiologic disturbances, and electrolyte imbalance, must then be excluded. Finally, a rigorous clinical examination of brainstem reflexes and an apnea test must be undertaken. Despite agreement with these fundamental principles, our study confirms that their differences in national requirements and methods of determining BD in European countries. A clinical diagnosis of BD is a sufficient criterion for the determination of death in adults in only half of the countries surveyed, with one half requiring one or more ancillary tests. This is in contrast to the recent international guideline development for the determination of death which states that death is principally established using clinical criteria [17]. This concept was also stressed by Wijdicks who argued that confirmatory tests are hangovers from earlier days of refining comatose states and that comprehensive clinical examination, when performed by competent examiners, should have perfect diagnostic accuracy [19]. The recommendations from the Quality Standards Subcommittee of the American Academy of Neurology also stress that there is insufficient evidence to determine whether ancillary tests, even those using newer technology, are accurately able to confirm the cessation of function of the entire brain compared with clinical examination. Surprisingly, the need to establish a pathology consistent with irreversible of coma is not a uniform requirement prior to clinical examination in all European countries. Although all countries require exclusion of the confounding effects of therapeutic concentrations of sedative and paralytic agents prior to clinical confirmation of BD, it is also surprising that prerequisites such as normal core temperature and systolic blood pressure are not universally required or applied. There is unanimity across Europe that coma, defined as unresponsiveness and no motor response to pain, presence of
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apnea, and absence of brainstem reflexes, is fundamental to the clinical determination of BD, but which brainstem reflexes are tested varies. Confirmation of the absence of corneal and cough and gag reflexes is not required in all countries. That BD can be confirmed without a comprehensive examination of all cranial nerves reflexes and confirmation of their absence as required by widely accepted consensus guidance [8, 17] is worrying. There are also wide variations in the requirements for conduct of the apnea test. This is particularly worrisome because confirmation of apnea is fundamental to the determination of BD, and apnea can only be determined with certainty if an acute hypercarbic stimulus sufficient to trigger the respiratory center is achieved and documented. In fact, the respiratory drive in the setting of an intense ventilatory stimulus, i.e., respiratory acidosis, is a critical marker of brainstem function [20]. In 14 % of the European countries surveyed, the end point of the apnea test is not formally defined and, where it is, a target pCO2 rather than a defined change in pCO2 is the usual end point. Although either pre-oxygenation or oxygenation during the test is performed in all countries, the conduct of other aspects of the apnea test lacks standardization. There is no guidance in many countries regarding oxygen flow rates, maintenance of PEEP, monitored parameters (exhaled CO2, SpO2, transcutaneous CO2 monitoring), and safety measures to prevent complications during the test [21]. Whatever standard is used to determine BD, ‘‘irreversibility’’ is usually not defined and has historically relied on repeated assessment over time, presumably to minimize the risk of diagnostic errors. This is contrary to the American Academy of Neurology guidance which stipulates that only a single examination is required, relying on the determination of irreversibility by exclusion of reversible causes and knowledge that the cause of the brain damage is structural and irreversible [17]. Despite this, 82 % of the European countries surveyed require more than one clinical examination, most commonly two. The time interval between the two examinations also varied enormously, ranging from no minimum to 12 h. There is no convincing evidence that a second test is necessary, but evidence that repeated clinical examination delays the determination of BD, adversely affects organ donation rates, and unnecessarily increases intensive care length of stay and costs [22]. Postponing the first clinical examination by 24 h is usual after hypoxicischemic brain injury but there is generally less specific guidance for other clinical circumstances. Some national guidelines specify the qualification and level of experience of doctors determining BD, with intensivists and neurologists being the most common specialties involved. The number of doctors required to determine BD also varies widely, although at least two doctors are required in more than 50 % of countries. The
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authors believe that competency in neurologic examination and conduct of the apnea test is required to retain public confidence in the determination of BD, and call for professional bodies to lobby for such minimum requirements. Confirmatory tests are required in half of the countries but reserved in others for doubtful circumstances, such as inability to complete clinical examination, therapeutic sedative drug levels, or when the patient is too unstable to undergo an apnea test. EEG is frequently required even though a patient who is brain (stem) dead may exhibit residual cortical electrical activity [23]. Further, because the EEG cannot detect deep brain activity, it may be isoelectric even in the presence of viable neurons in the brainstem and other deep structures [24]. The EEG is also affected by hypothermia and sedative drugs, which are confounding factors for the clinical diagnosis of BD and the very circumstances where a confirmatory test might be useful. When confirmation of absent CBF is required, CT angiography is becoming more commonly used because it is non-invasive and quick. However, some universal standards must be defined before it can be incorporated into routine BD protocols. Some authorities believe that confirmatory tests have a place when the preconditions for clinical testing are unmet or where clinical testing cannot be completed in full [10, 25], whereas others believe that they have no role in modern practice because the determination of BD based on a comprehensive clinical examination is robust [19]. It is of note that the recommendations from the Quality Standards Subcommittee of the American Academy of Neurology stress that there is insufficient evidence to determine whether ancillary tests, even those harnessing newer technology, are accurately able to confirm the cessation of brain function compared with clinical examination [17]. Although consensus guidance is available to standardize national processes for the diagnosis of BD, the current variation and inconsistency in European practice makes it imperative that an international consensus is developed. As a minimum, this should clarify the criteria for the determination of brain death and provide specific instructions about the clinical examination necessary and the conduct of the apnea test [14]. It should also stipulate the role and type of confirmatory investigations, identify the training and experience of those able to determine death by neurological criteria, and detail the required level of documentation. An international consensus on the determination of brain death is desirable, essential, and long overdue. Acknowledgments Danica Avsec ST, Institute for transplantation of organs and tissues of the Republic of Slovenia, Ljubljana, Slovenia; Paulo Azevedo Maia, Servic¸o Cuidados Intensivos 1, Hospital Santo Anto´nio, Centro Hospitalar do Porto, Portugal; Ovidiu Bedreag, Anesthesiology and intensive care department, University of Medicine and Pharmacy Victor Babes Timisoara, Romania; Romuald
Neurocrit Care Bohatyrewicz, Department of Anaesthesiology and Intensive Care, Pomeranian Medical University, Poland; Julien Charpentier, Medical Intensive Care Unit, Groupe Hospitalier Universitaire Cochin Broca Hoˆtel-Dieu, Paris, France; Martin Duenser, Department of Anesthesiology, Perioperative and General Intensive Care Medicine, Salzburg General Hospital and Paracelsus Private Medical University, Austria; Hans Friberg, Ska˚ne University Hospital, Lund, Sweden; Hans Flaatten, Intensive Care Unit. Haukeland University Hospital. Bergen, Norway; Ivan Gornik, University of Zagreb Medical School, University Hospital Centre Zagreb, Croatia; Jozef Kesecioglu, Department of Intensive Care Medicine, University Medical Center Utrecht, Netherlands; Georgia Markou, Pediatric Intensive Care Medicine, University Hospital of Patras, Greece; Brian Marsh, Mater Misericordiae University Hospital, Dublin, Ireland; Kirsten Møller, Neurointensive Care Unit, Rigshospitalet, University of Copenhagen, Denmark; Pedro Navarrete-Navarro, Emergency & Critical Care Department, Hospital de Neuro-Traumatologia, Hospital Universitario Virgen de las Nieves, Granada, Spain; Mauro Oddo, Department of Intensive Care Medicine, CHUV-University Hospital; Faculty of Biology and Medicine, University of Lausanne, Switzerland; Vita Petronyt_e, Transplant Coordination Department, National Transplant Bureau, Lithuania; Ville Pettila¨, Intensive Care Units, Helsinki University Central Hospital, Finland; Konstantin A. Popugaev, Neurocritical Care department, Burdenko Neurosurgical Research Institute, Moscow, Russia; Annika Reintam Blaser, Department of Anaesthesiology and Intensive Care, University of Tartu, Estonia; Fabio Silvio Taccone, Department of Intensive Care, Hopital Erasme, Brussels, Belgium; Lufti Telci, Istanbul Faculty of Medicine, Department of Anesthesiology and Intensive Care, Istanbul, Turkey; Csaba Varga, Kaposi Mor Teaching Hospital Emergency Department Kaposva´r, Hungary. Conflict of interest flict of interest.
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9. 10.
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All the authors declare that they have no con18.
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