Although the traditional concept of death is based on loss of circulatory and respiratory functions, most countries accept that death can also be determined in the setting of catastrophic brain injury leading to coma, loss of brainstem reflexes, and inability to breathe spontaneously.1 However, while these core requirements for brain death/death by neurological criteria (BD/DNC) determination are consistent around the world, there are inconsistencies in the BD/DNC evaluation process both within and between countries.2 In 2014, in collaboration with the World Health Organization, Health Canada and Canadian Blood Services organized a meeting of international stakeholders to discuss standardization of the determination of death.3 Plenary discussions resulted in the identification of the minimum acceptable clinical observations and examination findings necessary to determine death after cessation of circulatory and respiratory or brain functions. Despite this, a review of 78 national BD/DNC protocols collected from 2018 to 2019 demonstrated variability in the prerequisites, examination, and use and interpretation of ancillary testing (Table 1).1,4

TABLE 1 - Areas of International Variability in the Evaluation for BD/DNC1,4 Component of the BD/DNC protocol Percentage of national BD/DNC protocols collected 2018-19 (n=78); n% >1 examiner 93 (57/61) >1 examination 83 (44/53) Prerequisites  Establish cause for injury 79 (62/78)  Rule out BD/DNC mimics 72 (56/78)  Rule out drug effects 82 (64/78)  Rule out laboratory abnormalities 72 (56/78)  Minimum temperature (discrete value) specified 65 (51/78)  Minimum blood pressure (discrete value) specified 47 (37/78)  Observation period noted 47 (37/78) Clinical examination requirements  Coma 90 (70/78)  Noxious stimulation to the limbs 28 (22/78)  Noxious stimulation to the face 47 (37/78)  Absent pupillary reflex 90 (70/78)  Absent corneal reflex 87 (68/78)  Absent oculocephalic reflex 73 (57/78)  Absent oculovestibular reflex 86 (67/78)  Absent gag reflex 82 (64/78)  Absent cough reflex 79 (62/78) Apnea testing  Technique described 91 (71/78)  PaCO2 before testing specified 46 (36/78)  Preoxygenate 65 (51/78)  Reasons to abort provided 59 (46/78)  PaCO2 target provided 76 (59/78) Ancillary testing  Required 28 (22/78)  Conventional angiography:   Accepted 72 (56/78)   Details about performance provided 63 (35/56)   Details about interpretation provided 52 (29/56)  Nuclear medicine flow study:   Accepted 47 (37/78)   Details about performance provided 43 (16/37)   Details about interpretation provided 49 (18/37)  Transcranial doppler ultrasonography:   Accepted 56 (44/78)   Details about performance provided 48 (21/44)   Details about interpretation provided 55 (24/44)  Electroencephalography:   Accepted 72 (56/78)   Details about performance provided 55 (31/56)   Details about interpretation provided 66 (37/56)

BD indicates brain death; DNC, death by neurological criteria.

To address this variability, and provide guidance for countries without BD/DNC protocols, 45 multidisciplinary international BD/DNC experts collaborated to create the World Brain Death Project (WBDP), which was published in 2020.2 The WBDP addresses: (1) the worldwide variance in BD/DNC; (2) the science of BD/DNC; (3) the concept of BD/DNC; (4) the minimum clinical criteria for BD/DNC determination; (5) ancillary testing; (6) BD/DNC determination in pediatric patients; (7) BD/DNC determination in patients on extracorporeal support; (8) BD/DNC determination after treatment with targeted temperature management; (9) documentation of BD/DNC; (10) qualification for and education on BD/DNC determination; (11) somatic support after BD/DNC for organ donation and other special circumstances; (12) religion and BD/DNC; and (13) BD/DNC and the law. For each of these topics, the authors formulated recommendations based on both their professional experience and knowledge and review of Cochrane, Embase, and MEDLINE databases from 1992 to 2020.

The WBDP defines BD/DNC as “the complete and permanent loss of brain function as defined by an unresponsive coma with loss of capacity for consciousness, brainstem reflexes, and the ability to breathe independently.”2 Before the BD/DNC examination, the WBDP recommends identification that the nature and severity of the etiology of the patient’s condition could lead to BD/DNC, observation for a duration determined on a case-by-case basis to conclusively exclude reversibility, and exclusion of reversible conditions that may mimic BD/DNC or confound the evaluation including pharmacologic paralysis, medications that suppress the central nervous system and severe laboratory derangements. Additional suggestions for prerequisites include neuroimaging evidence of intracranial hypertension or intracranial pressure measurements that equal or exceed mean arterial pressure, temperature ≥36 °C, and systolic blood pressure ≥100 mm Hg (or mean arterial pressure ≥60 mm Hg) or age-appropriate blood pressure in pediatric patients. For the clinical examination, the WBDP recommends evaluation for coma (prolonged absence of wakefulness, awareness, and the capacity for sensory perception or responsiveness to maximal noxious visual, auditory, and tactile stimulation), absence of motor response (other than spinal reflexes) to tactile stimulation to the face and limbs, and absence of the pupillary, corneal, oculocephalic, oculovestibular, gag and cough reflexes. The WBDP provides detailed guidance for the performance of apnea testing if the clinical examination does not reveal evidence of brain function. The WBDP suggests that a single clinical examination and apnea test is the minimum standard for BD/DNC determination in adults but recommends 2 examinations and apnea tests in pediatric patients.

Although the WBDP emphasizes that the focus of the BD/DNC evaluation is the clinical examination and apnea test, ancillary testing is recommended if it is not feasible to complete the full clinical examination or apnea test, there are confounding conditions that cannot be resolved, or there is uncertainty about whether a finding is consistent with a brain or spinally mediated movement.2 The WBDP recommends the use of conventional angiography, a nuclear medicine flow study, or transcranial doppler ultrasonography and suggests against the use of electroencephalography unless mandated by law/policy or if craniovascular impedance is affected by an open skull fracture, decompressive craniectomy or open fontanel.

In addition to creating recommendations about BD/DNC, the WBDP identified questions that address knowledge gaps about BD/DNC to facilitate the development of a research agenda.5 Some examples include: (1) what quality improvement measures can be put into place to ensure consistent and thorough determination of BD/DNC; (2) whether there are tests that can confirm the complete and irreversible destruction of the entire brainstem, and; (3) what variables predict temporal evolution to intracranial hypertension and herniation in persons with primary posterior fossa pathology.

The WBDP was endorsed by the World Federation of Neurosurgical Societies, World Federation of Neurology, World Federation of Intensive and Critical Care, World Federation of Pediatric Intensive and Critical Care Societies, World Federation of Critical Care Nurses, and 27 international, national, and regional medical societies that are stakeholders in BD/DNC determination.2 Although this widespread endorsement indicates broad agreement with the minimum clinical standards for BD/DNC described in the WBDP, it does not mean national BD/DNC policies will all be updated to ensure consistency with the WBDP, or those nations that do not have a national BD/DNC policy will create one based on the WBDP. However, this is certainly the goal of the WBDP while understanding that resource availability, legal requirements, and social, cultural, and religious perspectives affect BD/DNC determination. Since its publication, the WBDP has been cited by international authors from various countries including China, India, and Poland.6–8 It remains to be seen whether a future review of national BD/DNC policies will demonstrate a greater degree of consistency than previously identified in the BD/DNC determination process.

1. Lewis A, Bakkar A, Kreiger-Benson E, et al. Determination of death by neurologic criteria around the world. Neurology. 2020;95:e299–e309. doi:10.1212/WNL.0000000000009888 2. Greer D, Shemie S, Lewis A, et al. Determination of brain death/death by neurologic criteria: the World Brain Death Project. JAMA. 2020;324:1078–1097. doi:10.1001/jama.2020.11586 3. Shemie SD, Hornby L, Baker A, et al. International guideline development for the determination of death. Intensive Care Med. 2014;40:788–797. doi:10.1007/s00134-014-3242-7 4. Lewis A, Liebman J, Kreiger-Benson E, et al. Ancillary testing for determination of death by neurologic criteria around the world. Neurocrit Care. 2021;34:473–484. doi:10.1007/s12028-020-01039-6 5. Greer D, Shemie S, Lewis A, et al. Questions that address knowledge gaps to facilitate development of a research agenda about brain death/death by neurologic criteria. Supplement 17 of determination of brain death/death by neurologic criteria: the world brain death project. JAMA. 2020;324:1078–1097. doi:10.1001/jama.2020.11586 6. Choudhary D, Sharma A, Singh S, et al. Challenges in brain-death certification in India. Neurol India. 2022;70:1162–1165. doi:10.4103/0028-3886.349609 7. Bohatyrewicz R, Pastuszka J, Walas W, et al. Implementation of computed tomography angiography (CTA) and computed tomography perfusion (CTP) in Polish guidelines for determination of cerebral circulatory arrest (CCA) during brain death/death by neurological criteria (BD/DNC) diagnosis procedure. J Clin Med. 2021;10:4237. doi:10.3390/jcm10184237 8. Su Y. Current situation and advancement of brain death determination in China. Zhonghua Yi Xue Za Zhi. 2021;101:1721–1724. doi:10.3760/cma.j.cn112137-20200916-02658