International guideline development for the determination of death

Introduction and Methods This report summarizes the results of the first phase in the development of international guidelines for death determination, focusing on the biology of death and the dying process, developed by an invitational forum of international content experts and representatives of a number of professional societies. Results and Conclusions Precise terminology was developed in order to improve clarity in death discussion and debate. Critical events in the physiological sequences leading to cessation of neurological and/or circulatory function were constructed. It was agreed that death determination is primarily clinical and recommendations for preconditions, confounding factors, minimum clinical standards and additional testing were made. A single operational definition of human death was developed: ‘the permanent loss of capacity for consciousness and all brainstem functions, as a consequence of permanent cessation of circulation or catastrophic brain injury’. In order to complete the project, in the next phase, a broader group of international stakeholders will develop clinical practice guidelines, based on comprehensive reviews and grading of the existing evidence.

Abstract Introduction and Methods: This report summarizes the results of the first phase in the development of international guidelines for death determination, focusing on the biology of death and the dying process, developed by an invitational forum of international content experts and representatives of a number of professional societies. Results and Conclusions: Precise terminology was developed in order to improve clarity in death discussion and debate. Critical events in the physiological sequences leading to cessation of neurological and/or circulatory function were constructed. It was agreed that death determination is primarily clinical and recommendations for preconditions, confounding factors, minimum clinical standards and additional testing were made. A single operational definition of human death was developed: 'the permanent loss of capacity for consciousness and all brainstem functions, as a consequence of permanent cessation of circulation or catastrophic brain injury'. In order to complete the project, in the next phase, a broader group of interna-Introduction Philosophical, religious, and cultural differences in the concept of death and ways it is defined make discussions of the subject very complex. Advances in medicine and technology that have made it possible to support, repair, or replace failing organs challenge commonly held notions of life and death. The lack of understanding or even awareness among the public [1] and health professionals [2] and the emotionally charged nature of the subject further complicate discussions. Finally, the determination of death is deeply entwined with organ transplantation. The growing disparity between the demand for and the availability of transplantable organs is a public health concern globally [3]. In comparison to bridge technologies for end-stage organ failure, such as kidney dialysis [4] and ventricular assist devices [5], organ transplantation is life-preserving, life-enhancing, and cost-effective. Yet, when the supply of transplantable organs falls short of demand, unethical and illegal behaviours sometimes occur, including commercial organ trade that victimizes the vulnerable [6], human killing as a source of transplantable organs [7], and violations of the allocation system [8].
While the public supports organ donation after death, its credibility requires clarity in practice and policy.
Depending on the country and related professional societies, guidelines may or may not exist for the determination of death by neurological and/or circulatory criteria, and when guidelines are in place, they have not always been implemented in a manner that alleviates concerns about the legitimacy of deceased organ donation. The situation is complicated by variations related to the stage of development of a country's deceased donation program and more generally by the significant diversity in health services and standards of care worldwide. The World Health Organization (WHO) and The Transplantation Society (TTS) have received requests from a number of countries to address these gaps and to provide guidance to inform clinical practices and health policy for death determination as part of an international effort in support of the Istanbul Declaration [9], the WHO Madrid Resolution [10], and the WHO Guiding Principles on Human Cell, Tissue and Organ Transplantation, approved by the World Health Assembly in 2010 [11]. An international consensus on the determination of death could provide a number of benefits including promoting evidence-based practices, protecting the rights of both patients and health care professionals, improving public and professional confidence in the process of deceased donation, and increasing the number of organs obtained in an ethically legitimate fashion.

Methods
On 30-31 May 2012, an invitational forum sponsored by Health Canada and Canadian Blood Services in collaboration with the WHO was held in Montreal, Canada, as part of the planning, scoping, and needs assessment phase in the process of guideline development (see ''Appendix 1'' for forum committees and participants). The 32 invited participants included delegates from a broad range of national and international professional societies involved with death determination in adults and children in acute care settings. Prior to the forum, participants were provided with comprehensive background materials, including a selected bibliography of peer-reviewed articles related to death determination, a literature review on definitions of death, and a draft lexicon of medical terminology relevant to death determination policy and practice. Each section of the meeting began with an expert speaker who provided historical information, reviewed baseline knowledge, and supplied his or her perspective on current issues and controversies. After each presentation, participants asked questions of the expert and discussed the presentation with the entire group. Reference sheets that offered condensed summaries of existing evidence were distributed, and the participants were then divided into groups where they held extensive discussions about a ''challenge question'' relevant to the topic of the session. When the participants reconvened in the plenary, each group's results were discussed, and the collective outputs were reworked until consensus was reached. Consensus was defined as achieving substantial agreement, manifested by all participants indicating that they agreed with or could accept a conclusion, which they would support both within and outside the meeting.
For the purposes of this forum, death was fundamentally considered a biological event. While it was respectfully recognized that legal, ethical, cultural, and religious perspectives on death can impact the utility of recommendations in the field, these perspectives were not topics for debate or discussion at this initial meeting. Table 1 highlights the common terminology that was agreed upon to support clarity and precision in the language used throughout this forum and for subsequent phases of work. The planning committee worked with participants to identify critical events that comprise the dying sequence, with the understanding that dying is a process whereby biological/physiological functions cease. Death is an event in that dying process, a point when the person can be determined to have died. The forum identified the tests required for the minimum acceptable clinical standard for determining death in adults and children and recommended additional testing beyond the minimum standard. A consensus on an operational definition of human death was then derived.

Findings
Neurological sequence in the dying process Forum participants identified several major sequential events in the dying process of patients who have suffered a catastrophic brain injury that will lead to death determined on a neurological basis (such as, but not limited to, traumatic brain injury, cerebrovascular accidents, and hypoxic-ischaemic encephalopathy after resuscitated cardiac arrest) (Fig. 1). This sequence does not apply to patients with anencephaly or with forms of catastrophic brain injury (such as persistent vegetative states) where residual clinical brain or brainstem functions are retained; such patients were not under consideration. Patients entering this sequence are receiving mechanical ventilation; various other neuroprotective interventions (such as hyperosmolar therapy, ventricular drainage, decompressive craniectomy) may have been initiated as well. At N-1, the patient continues to deteriorate in spite of intervention and the treatment team recognizes that the patient may evolve to brain death. At N-2, the deterioration has continued to a point that brain function has ceased. However, at this point it is still possible that brain function could return spontaneously or be restored Table 1 Participants agreed to the following terminology, in order to improve the clarity of discussions and debate, for use during and subsequent to this forum Term Definition Activity Physiologic properties of cells and groups of cells that can be measured by laboratory means Asystole-electrical A condition characterized by the absence of electrical, and hence mechanical, activity of the heart, resulting in the absence of contractions of the myocardium and cardiac output/anterograde blood flow Asystole-mechanical The absence of effective contractions of the myocardium and no cardiac output/anterograde blood flow. May occur in the presence of an organized or disorganized electrocardiac rhythm, e.g. pulseless electrical activity Autoresuscitation The spontaneous resumption of heart contractions causing anterograde circulation that is not induced by cardiopulmonary resuscitation or other external assistance. Examples of heart function such as effective contractions of the myocardium leading to anterograde flow of blood through the aorta and arterial system should be distinguished from examples of heart activity such as atrial natriuretic hormone release or residual pulseless electrical activity Brain death Diagnosis and confirmation of death based on the irreversible cessation of functioning of the entire brain, including the brainstem (this forum supports the movement away from this traditional and imprecise terminology in favour of the cessation of neurological function) Brainstem death Diagnosis and confirmation of death based on the irreversible cessation of functioning of the brainstem, predominantly but not exclusively secondary to a supratentorial brain injury (this forum supports the movement away from this traditional and imprecise terminology in favour of the cessation of neurological function) Cardiac arrest The abrupt cessation of circulation of the blood due to failure of the heart to contract effectively. Also known as cardiorespiratory arrest, cardiopulmonary arrest, or circulatory arrest Catastrophic brain injury leading to death Etiologies of high severity that are common causes of brain death, such as, but not limited to, traumatic brain injury, cerebrovascular accidents, and hypoxic-ischaemic encephalopathy after resuscitated cardiac arrest Other forms of catastrophic brain injury that have any degree of residual clinical brain or brainstem function are not under consideration and may include persistent vegetative states, permanent vegetative states, anencephaly, or those conditions related to the historical concept of higher brain (cortical) death Cerebral electrical activity Electrical activity of the brain, as measured using an electroencephalogram (EEG) Cessation Stoppage, termination Circulation Anterograde flow of blood through the aorta and arterial system Circulatory death determination Diagnosis and confirmation of death based on circulatory criteria. Also known as death after cardiac arrest, or death after cardiocirculatory arrest, or death after circulatory-respiratory determination (this forum supports the movement away from this traditional and imprecise terminology in favour of the cessation of circulatory function) Clinical Based The process whereby biological/physiological functions cease, thus moving from the state of being alive to that of being dead ECMO Extracorporeal membrane oxygenation/extracorporeal oxygenation and circulation of blood deployed for life-threatening lung or heart-lung failure through intervention. If preconditions are met, confounding factors are absent, and no effective treatment is available or implemented, then by N-3, the brain has ceased functioning and there is no possibility to resume. The patient has died. Preconditions prior to testing brain function at any point in the sequence include an established etiology; absence of reversible etiologies that would explain the coma; and the absence of hemodynamic shock associated with inadequate oxygenated circulation to the brain [12]. Confounding conditions that may invalidate testing for cessation of brain function include naturally occurring or therapeutic hypothermia; the presence of central nervous system (CNS) depressing drugs that may explain or contribute to coma; high cervical spine injury; acquired (such as severe polyneuropathy) or therapeutic neuromuscular paralysis; locked-in syndromes; and severe acid-base, electrolyte or endocrine abnormalities that may explain or contribute to coma [13]. After agreeing that death is principally established using clinical criteria (defined as diagnostic testing based on direct, measurable observation or examination of the patient; see Table 1), participants came to consensus on the ''minimum acceptable clinical standards'' to test for the cessation of In the context of organs, the primary and fundamental purpose of that organ that can be assessed by observation and examination and is necessary for sustained life. Function should be distinguished from activities, as defined by physiologic properties of cells and groups of cells that can be measured by laboratory means. Examples of brain function such as the capacity for consciousness or ability for unassisted breathing should be distinguished from examples of brain activity such as posterior pituitary antidiuretic hormone release or residual nests of neuronal electrical activity Integration Combined or coordinated separate elements that provide a harmonious, interrelated whole; organized or structured so that constituent units function cooperatively Irreversible Pertaining to a situation or condition that will not or cannot return or resume. In the context of death determination, there are variable definitions including: 1. Loss of function or a condition that cannot be restored by anyone under any circumstances at a time now or in the future 2. Loss of function or a condition that cannot be restored by those present at the time 3. Loss of function or a condition that will not resume and will not be restored. Also referred to as permanent Neuroimaging Diagnostic brain imaging techniques to identify structural brain injury, e.g. CT scan, MRI Neurological death determination Diagnosis and confirmation of death based on neurological criteria No effective intervention A therapeutic intervention that is not deployed because it is not effective, not medically indicated under those circumstances, not available or accessible Mechanical ventilation Assisted ventilation including bag/mask ventilation, non-invasive support e.g. BiPAP (bilevel positive airway pressure), conventional mechanical ventilation via artificial airway Refractory to treatment Does not respond to intervention in a clinically meaningful manner Permanent Pertaining to a situation or condition that will not return to its previous state. In the context of death determination, refers to loss of function that will not resume spontaneously and will not be restored through intervention Preconditions Patient-related prerequisites that should be fulfilled prior to application of diagnostic tests Respiratory arrest Cessation of breathing. In the context of death discussions, this may be primary and lead to a subsequent cardiac arrest, or it may be secondary to the loss of brainstem function The combination or arrangement of parts into a whole Ventricular fibrillation A condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles that causes the cessation of circulation. Also referred to as V-fib or VF Vital function Necessary for sustained life brain function (Table 2). It was also agreed that the validity of a determination of death depends upon the health care professionals performing the clinical determination and those performing and interpreting ancillary laboratory testing possessing the necessary competencies.
Circulatory sequence in the dying process Forum participants identified several major sequential events in the dying process of patients who suffer a circulatory arrest (Fig. 2). In situation A, the patient has had a cardiac arrest but no CPR intervention, either because CPR was not medically indicated or the patient (or surrogate decision maker) declined it; this would include terminally ill patients whose end-of-life care involves limiting or withdrawing life-sustaining therapies. At C-1, the patient's circulation and breathing stop. After a certain time period (between 2 and 5 min, based on expert consensus) [14], autoresuscitation-the spontaneous, unassisted resumption of circulation-is no longer a possibility under these conditions (C-2). There is currently no published evidence demonstrating autoresuscitation under these conditions [15][16][17]. Since no interventions will be made to attempt to restore circulation, cessation of Catastrophic Brain Injury (CBI)

N-1
Catastrophic brain injury with consideration for withdrawal of life sustaining therapies N-2 Cessation of brain function

N-3
Cessation of brain function with no possibility to resume

Mechanical ventilation (may occur prior to CBI) and neuro-protective interventions
Biological events after death Continuing deterioration and progressive loss of brain function despite intervention Fig. 1 Neurological sequence in the dying process    Cessation of circulation and breathing with no possibility to resume spontaneously 1. The persistence of C-1 criteria over a period of time as confirmed by continuous observation and intermittent confirmation including repetition of this evaluation at the end of the period. The time period required is 2-5 min 2. When breathing and circulation cease following terminated CPR, the time period to reach the point of ''no possibility to resume spontaneously'' is 2-10 min 1. Use of the same tests for a higher clinical/laboratory standard for C-1 applied after the time interval required to progress from C-1 to C-2 (2-10 min following termination of CPR) C-3 Cessation of circulation and breathing with no possibility to resume 1. When CPR will not be provided (patient fulfils criteria for not providing CPR) C-3 occurs at the moment of C-2 2. Following termination of CPR, including a decision not to reinstitute CPR, C-3 and C-2 occur at the same time 1. Nothing in addition to those tests required for C-2 breathing and circulation is permanent and the patient may be determined to be dead (C-2 and C-3 occur at the same time). In situation B, CPR has been used in an attempt to restore circulation and respiration but has been terminated because the patient cannot be revived. Once the time interval when autoresuscitation is possible has passed, cessation of breathing and circulation is permanent and the patient may be determined to be dead. International practice varies with regard to this time interval between C-1 and C-2. The most common waiting period is 5 min with a range from 2 to 10 min [18]. The participants came to consensus on the 'minimum acceptable clinical standards' to test for the cessation of circulatory function (Table 3).
Integrated neurological and circulatory sequence in the dying process The inextricable link between circulation and brain function means that the neurological and circulatory sequences integrate at several points in the dying process of patients who have suffered a circulatory arrest (Fig. 3). Once circulation and breathing cease (C-1), there is a short time period between C1 and N2 (\20 s) during which brain function ceases (N-2) as evidenced by isoelectric EEG [19][20][21]. The longer the time period without oxygenated circulation to the brain (N-2 to N-3) the progressively higher likelihood that the cessation of brain function is irreversible, even if oxygenated circulation can be re-established (either spontaneously or through intervention). The precise time period for the complete cessation of brain function to be non-resuscitable (through intervention) is unresolved.

Operational definition of human death
After reviewing the historical taxonomy and definitions of death, and the neurologic and circulatory sequences in the dying process that had been previously discussed and refined, participants came to consensus on an operational definition of human death, that is, a practical and quantifiable description of the state of human death based on measurable and observable biomedical standards. Forum participants agreed on the following operational definition of death: Death is the permanent loss of capacity for consciousness and all brainstem functions. This may result from permanent cessation of circulation or catastrophic brain injury. In the context of death determination, 'permanent' refers to loss of function that cannot resume spontaneously and will not be restored through intervention [22].
Participants supported avoiding use of anatomically based terms such as ''brain death'' or ''cardiac death'' that erroneously imply the death of that organ and confuse the general public, health professionals, and policymakers (organisms die, while organs cease functioning). Our operational definition is based on the cessation of function (the primary and fundamental purpose of an organ that can be assessed by observation and examination and is necessary for sustained life) rather than activities (physiologic properties of cells and groups of cells that can be measured by laboratory means). While the forum participants understood that the overwhelming majority of deaths in the world occur after circulation has ceased, and many occur outside health care settings, death determination must focus on the centrality of brain function. Death is a single phenomenon based on permanent  Fig. 3 Physiological sequences in the dying process: integrated neurological and circulatory sequence (applies to patients suffering a circulatory arrest) cessation of brain function (loss of capacity for consciousness and brainstem reflexes), which occurs along two pathways: (1) permanent absence of circulation or (2) subsequent to a catastrophic brain injury, each discerned through a specific set of medical criteria and clinical and laboratory tests-two entrances, one end point.

Conclusions
This report describes the initial phase in an international process to develop guidelines and agree upon an operational definition for determining death, based on the cessation of neurological and circulatory functions. Plenary discussions resulted in consensus on seven key areas: 1. Death is determined primarily using clinical criteria based on direct observation or examination of the patient, once preconditions have been fulfilled and confounding conditions excluded. 2. The physiological sequences by which circulatory and neurological functions cease, leading up to the moment of death, were set forth to clarify the critical events that occur following a catastrophic injury or illness. 3. Clinical tests that constitute the minimum clinical standard for the determination of death were defined for both the neurological and the circulatory sequences.
Preconditions and confounding conditions that may impede or invalidate death diagnosis were also specified. 4. Certain ancillary and/or complementary laboratory tests may be useful in situations in which clinical testing cannot be performed or when confounding or special conditions are present; limitations to using certain of these tests in death determination mean that further research is required to ensure their reliability. 5. A set of precise terminology, which aims to improve clarity in death determination discussions and debate, was agreed upon. 6. An operational definition of human death, based on measurable biomedical standards, was proposed. Participants supported avoiding use of anatomically based terms such as ''brain death'' or ''cardiac death'' that erroneously imply the death of an organ. Emphasis was placed on the cessation of neurological or circulatory function, and the centrality of brain function for determination of death. ''Death occurs when there is permanent loss of capacity for consciousness and loss of all brainstem functions. This may result from permanent cessation of circulation or catastrophic brain injury. In the context of death determination, 'permanent' refers to loss of function that cannot resume spontaneously and will not be restored through intervention.'' This definition is based on the cessation of function (the primary and fundamental purpose of an organ that can be assessed by observation and examination and is necessary for sustained life) rather than activities (physiologic properties of cells and/or groups of cells that can be measured by laboratory means). 7. In order to complete the elaboration of an operational definition of human death that could be used in countries around the world, a broader group of international stakeholders will be needed to develop clinical practice guidelines, based on comprehensive, systematic reviews and grading of existing evidence. It is recognized that pursuit of best practices related to death determination is most often administered by those acute care practitioners who are also involved with deceased donation practices and policy. Given concerns about potential conflict of interest, there has been a deliberate effort to exclude the involvement of transplant programs in this process. In support of the overall planning process, the following groups have been involved in their respective roles: The International Society for Organ Donation and Procurement (ISODP). The mission of ISODP includes promotion of high ethical standards in transplantation, as both donor and recipient are members of a community where equity and justice are equally important to success. The development of international guidelines for determination of death supports this goal. ISODP provided travel funds for its representative. No other funding for the meeting has been received from ISODP. The Transplantation Society (TTS), together with the WHO, has played a role in moving the international dialogue on transplant tourism forward. They have been active in the development of the Istanbul and Madrid accords and as a result have a breadth and depth of knowledge of practices across the globe. Francis Delmonico, their president, has provided counsel as part of the international advisory committee but was not a participant at the meeting. No funding for the meeting has been received from TTS.
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