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Brain death

The concept of brain death has periodically come under criticism 1).

Confirmatory tests for the diagnosis of brain death in addition to clinical findings may shorten observation time required in some countries and may add certainty to the diagnosis under specific circumstances.

The current U.S. approach to determining death was developed in response to the emergence of technologies that made the traditional standard of cardiopulmonary death problematic. In 1968, an ad hoc committee at Harvard Medical School published an influential article arguing for extending the concept of death to patients in an “irreversible coma.“ 2). The emerging neurologic criteria for death defined it in terms of loss of the functional activity of the brain stem and cerebral cortex. Although clinical criteria were developed in the 1960s, it took more than a decade for consensus over a rationale for the definition to emerge. In 1981, the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research provided a philosophical definition of brain death in terms of the loss of the critical functions of the organism as a whole 3).

Shortly thereafter, the National Conference of Commissioners on Uniform State Laws produced the Uniform Determination of Death Act, which has been adopted in 45 states and recognized in the rest through judicial opinion 4).

Computed tomography angiography for brain death


Changes in S100B protein, especially the levels of this dimer 48 hours after trauma can be used as marker to predict brain death. Alongside other known prognostic factors such as age, GCS and diameters of the pupils, however, this factor individually can not conclusive predict the patient's clinical course and incidence of brain death. However, it is suitable to use GCS, CT scan, clinical symptoms and biomarkers together for a perfect prediction of brain death 5).

Gadolinium-enhanced magnetic resonance angiography

The practicability of Gadolinium-enhanced magnetic resonance angiography to confirm cerebral circulatory arrest was assessed after the diagnosis of brain death in 15 patients using a 1.5 Tesla MRI scanner. In all 15 patients extracranial blood flow distal to the external carotid arteries was undisturbed. In 14 patients no contrast medium was noted within intracerebral vessels above the proximal level of the intracerebral arteries. In one patient more distal segments of the anterior and middle cerebral arteries (A3 and M3) were filled with contrast medium. Gadolinium-enhanced MRA may be considered conclusive evidence of cerebral circulatory arrest, when major intracranial vessels fail to fill with contrast medium while extracranial vessels show normal blood flow 6).

The level of knowledge of medical students at Centro Universitário Lusíada - UNILUS- Santos (SP), Brazil, regarding brain death and transplantation is limited, which could be the result of inadequate education during medical school 7).

American Academy of Neurology Guidelines for Brain Death Determination

Many of the details of the clinical neurologic examination to determine brain death cannot be established by evidence-based methods. The detailed brain death evaluation protocol that follows is intended as a useful tool for clinicians. It must be emphasized that this guidance is opinion-based. Alternative protocols may be equally informative.

The determination of brain death can be considered to consist of the following steps: I. The clinical evaluation (prerequisites).

A. Establish irreversible and proximate cause of coma.

The cause of coma can usually be established by history, examination, neuroimaging, and laboratory tests.

Exclude the presence of a CNS-depressant drug effect by history, drug screen, or, if available, drug plasma levels below the therapeutic range. Prior use of hypothermia (e.g., after cardiopulmonary resuscitation for cardiac arrest) may delay drug metabolism. The legal alcohol limit for driving (blood alcohol content 0.08%) is a practical threshold below which an examination to determine brain death could reasonably proceed.

There should be no recent administration or continued presence of neuromuscular blocking agents (this can be defined by the presence of a train of 4 twitches with maximal ulnar nerve stimulation).

There should be no severe electrolyte, acid-base, or endocrine disturbance. Achieve normal core temperature.

In most patients, a warming blanket is needed to raise the body temperature and maintain a normal or near-normal temperature (36°C).

B. Achieve normal systolic blood pressure.

Hypotension from loss of peripheral vascular tone or hypovolemia (diabetes insipidus) is common; vasopressors or vasopressin are often required. Neurologic examination is usually reliable with a systolic blood pressure 100 mm Hg.

C. Perform 2 neurologic examinations

Legally, all physicians are allowed to determine brain death in most US states. Neurologists, neurosurgeons, and intensive care specialists may have specialized expertise. It seems reasonable to require that all physicians making a determination of brain death be intimately familiar with brain death criteria and have demonstrated competence in this complex examination. Brain death statutes in the United States differ by state and institution. Some US state or hospital guidelines require the examiner to have certain expertise. The clinical evaluation (neurologic assessment).

A. Coma.

Patients must lack all evidence of responsiveness. Eye opening or eye movement to noxious stimuli is absent. Noxious stimuli should not produce a motor response other than spinally mediated reflexes. The clinical differentiation of spinal responses from retained motor responses associated with

B. Absence of brainstem reflexes.

Absence of pupillary response to a bright light is documented in both eyes.

Absence of ocular movements using oculocephalic testing and oculovestibular reflex testing. Movement of the eyes should be absent during 1 minute of observation. Both sides are tested, with an interval of several minutes.

Absence of corneal reflex. Absent corneal reflex is demonstrated by touching the cornea with a piece of tissue paper, a cotton swab, or squirts of water. No eyelid movement should be seen.

Absence of facial muscle movement to anoxious stimulus.

  Absence of the pharyngeal and tracheal reflexes. The pharyngeal or gag reflex is tested after stimulation of the posterior pharynx with a tongue blade or suction device. The tracheal reflex is most reliably tested by examining the cough response to tracheal suctioning. The catheter should be inserted into the trachea and advanced to the level of the carina followed by 1 or 2 suctioning passes.

Apnea Test

Ancillary tests

In clinical practice, EEG, cerebral angiography, nuclear scan, TCD, CTA, and MRI/MRA are currently used ancillary tests in adults (see below).

Common confirmatory tests in Brain Death

Cerebral angiography

Contrast medium under high pressure in both anterior and posterior circulation injections No intracerebral filling at the level of the carotid or vertebral artery entry to the skull Patent external carotid circulation Possible delayed filling of the superior longitudinal sinus


Minimum of eight scalp electrodes Interelectrode dependencies should be between 100 and 10,000 Integrity of the entire recording system should be tested Electrode distances should be at least 10 cm Sensitivity should be increased to at least 2 µV for 30 minutes with inclusion of appropriate calibrations High-frequency filter setting should be at 30 Hz, and low-frequency setting should not be below 1 Hz There should be no electroencephalographic reactivity to intense somatosensory or audiovisual stimuli

Transcranial Doppler ultrasonography

Bilateral insonation. The probe is placed at the temporal bone above the zygomatic arch or the vertebrobasilar arteries through the suboccipital transcranial window• The abnormalities should include a lack of diastolic or reverberating flow, small systolic peaks in early systole, and a lack of flow found by the investigator who previously demonstrated normal velocities

Cerebral scintigraphy (technetium Tc 99m hexametazime)

Injection of isotope within 30 minutes of reconstitution Static image of 500,000 counts at several time intervals: immediately, between 30 and 60 minutes, and at 2 hours.

Information based on: Evidence-based guideline update: Determining brain death in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology Eelco F.M. Wijdicks, Panayiotis N. Varelas, Gary S. Gronseth and David M. Greer 181e242a8 Neurology 2010;74;1911-1918.

Pediatric brain death guideline

Case reports

In a editorial, Hibi et al., aimed to provide an outline of the world history of liver transplantation (LT), with a special focus on the innovation, development, and current controversies of living donor (LD) LT from East Asian and Western perspectives. In 1963, Starzl et al. (University of Colorado, U.S.) performed the world's first human LT for a 3-year-old child with biliary atresia. The donor was a 3-year-old patient who had suffered from brain death following neurosurgery. 8).

Truog RD, Miller FG, Halpern SD. The dead-donor rule and the future of organ donation. N Engl J Med 2013;369:1287-1289
A definition of irreversible coma: report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337-340
President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Defining death: a report on the medical, legal and ethical issues in the determination of death. Washington, DC: Government Printing Office, 1981.
National Conference of Commissioners on Uniform State Laws. Uniform Determination of Death Act, 1981 (
Shakeri M, Mahdkhah A, Panahi F. S100B Protein as a Post-traumatic Biomarker for Prediction of Brain Death in Association With Patient Outcomes. Arch Trauma Res. 2013 Aug;2(2):76-80. doi: 10.5812/atr.8549. Epub 2013 Aug 1. PubMed PMID:24396798.
Luchtmann M, Beuing O, Skalej M, Kohl J, Serowy S, Bernarding J, Firsching R. Gadolinium-enhanced magnetic resonance angiography in brain death. Sci Rep. 2014 Jan 13;4:3659. doi: 10.1038/srep03659. PubMed PMID: 24413880.
Reis FP, Gomes BH, Pimenta LL, Etzel A. Brain death and tissue and organ transplantation: the understanding of medical students. Rev Bras Ter Intensiva. 2013 Oct-Dec;25(4):279-283. Portuguese, English. PubMed PMID: 24553508.
Hibi T, Eguchi S, Egawa H. Evolution of living donor liver transplantation: A global perspective. J Hepatobiliary Pancreat Sci. 2018 Jun 28. doi: 10.1002/jhbp.571. [Epub ahead of print] PubMed PMID: 29953731.
brain_death.txt · Last modified: 2019/08/06 09:01 by administrador