This is the current release of the guideline.

This guideline updates a previous version: Practice parameters for determining brain death in adults (summary statement). The Quality Standards Subcommittee of the American Academy of Neurology [comment]. Neurology 1995 May;45(5):1012-4.

Brain death

Adults (aged 18 years and older) thought to be brain dead

Evaluation

1. Clinical evaluation (history, physical examination, neuroimaging, laboratory tests)
2. Establishment of normal core temperature
3. Apnea testing
4. Neurological examination by a physician with familiarity with brain death criteria
5. Ancillary tests
   • Electroencephalography (EEG)
   • Cerebral angiography
   • Nuclear scan
   • Transcranial Doppler (TCD)
   • Computed tomography angiography (CTA)
   • Magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA)

A literature search was conducted of MEDLINE and EMBASE from January 1996 to May 2009. Search terms included the MeSH term "brain death" and the text words "brain death," "irreversible coma," and "apnea test." Studies were limited to those involving adults (aged 18 years and older) and those in English.

Articles were included if they contained evidence relevant to one of the following questions:

1. Are there patients who fulfill the clinical criteria of brain death who recover brain function?
2. What is an adequate observation period to ensure that cessation of neurologic function is permanent?
3. Are complex motor movements that falsely suggest retained brain function sometimes observed in brain death?
4. What is the comparative safety of techniques for determining apnea?
5. Are there new ancillary tests that accurately identify patients with brain death?

Articles were excluded that confirmed prior observations, review articles, bioethical reviews, articles without description of a brain death examination, articles with questionable practices (e.g., using laboratory tests in patients treated with sedative drugs), and articles describing infrequently used ancillary technology (e.g., jugular venous saturation).

The search yielded 367 articles, and 38 met inclusion criteria.

Classification of Evidence Scheme for Studies of Diagnostic Accuracy

Class I: A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient's clinical status. Study results allow calculation of measures of diagnostic accuracy.

Class II: A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy.

Class III: A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy.

Class IV: Studies not meeting Class I, II or III criteria, including consensus, expert opinion or a case report.

Classification of Evidence Scheme for Screening Studies

Class I: A statistical, population-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class II: A statistical, non-referral-clinic-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician.

Class IV: Studies not meeting Class I, II or III criteria, including consensus, expert opinion or a case report.

Articles were independently rated by at least 2 panel members based on the American Academy of Neurology (AAN) evidence classification system (see "Rating Scheme for the Strength of the Evidence" field or appendix e-3 on the Neurology® Web site at www.neurology.org ). Articles pertinent to questions 1, 2, 4, and 5 were rated using the diagnostic accuracy scheme. Articles pertinent to question 3 were rated using the screening scheme. Differences in rating were resolved by discussion. (See the "Description of Methods Used to Collect/Select the Evidence" field for the list of questions.)

Not stated

Classification of Recommendations

Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if: 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

A formal cost analysis was not performed and published cost analyses were not reviewed.

Drafts of the guideline have been reviewed by at least three American Academy of Neurology (AAN) committees, a network of neurologists, Neurology® peer reviewers, and representatives from related fields.

The guideline was approved by the Quality Standards Subcommittee on August 22, 2009; by the Practice Committee on October 15, 2009; and by the AAN Board of Directors on February 11, 2010.

Definitions of the levels of the recommendations (A, B, C, U) and classification of the evidence (I-IV) are provided at the end of the "Major Recommendations" field.

1. Are there patients who fulfill the clinical criteria of brain death who recover brain function?

   Recommendation: The criteria for the determination of brain death given in the 1995 American Academy of Neurology (AAN) practice parameter have not been invalidated by published reports of neurologic recovery in patients who fulfill these criteria (Level U).

2. What is an adequate observation period to ensure that cessation of neurologic function is permanent?

   Recommendation: There is insufficient evidence to determine the minimally acceptable observation period to ensure that neurologic functions have ceased irreversibly (Level U).

3. Are complex motor movements that falsely suggest retained brain function sometimes observed in brain death?

   Recommendation: Complex-spontaneous motor movements and false-positive triggering of the ventilator may occur in patients who are brain dead (Level C).

4. What is the comparative safety of technique for determining apnea?

   Recommendation: There is insufficient evidence to determine the comparative safety of techniques used for apnea testing (Level U).

5. Are there new ancillary tests that accurately identify patients with brain death?

   Recommendation: There is insufficient evidence to determine if newer ancillary tests accurately confirm the cessation of function of the entire brain (Level U).

Practical (Non-evidence based) Guidance for Determination of Brain Death

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 4 steps.

1. The Clinical Evaluation (Prerequisites)
   1. 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 central nervous system (CNS)-depressant drug effect by history, drug screen, calculation of clearance using 5 times the drug's half-life (assuming normal hepatic and renal function), 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 (defined by severe acidosis or laboratory values markedly deviated from the norm).

   2. 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). After the initial equilibration of arterial carbon dioxide (CO₂) with mixed central venous CO₂, the arterial CO₂ partial pressure (PaCO₂) rises steeply, but then more slowly when the body metabolism raises PaCO₂. To avoid delaying an increase in PaCO₂, normal or near-normal core temperature is preferred during the apnea test.

   3. 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.

   4. Perform 1 Neurologic Examination (Sufficient to Pronounce Brain Death in Most US States)

      If a certain period of time has passed since the onset of the brain insult to exclude the possibility of recovery (in practice, usually several hours), 1 neurologic examination should be sufficient to pronounce brain death. However, some US state statutes require 2 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.

2. The Clinical Evaluation (Neurologic Assessment)
   1. 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 brain activity requires expertise.

   2. Absence of Brainstem Reflexes
      • Absence of pupillary response to a bright light is documented in both eyes. Usually the pupils are fixed in a midsize or dilated position (4–9 mm). Constricted pupils suggest the possibility of drug intoxication. When uncertainty exists, a magnifying glass should be used.
      • Absence of ocular movements using oculocephalic testing and oculovestibular reflex testing.

        Once the integrity of the cervical spine is ensured, the head is briskly rotated horizontally and vertically. There should be no movement of the eyes relative to head movement. The oculovestibular reflex is tested by irrigating each ear with ice water (caloric testing) after the patency of the external auditory canal is confirmed. The head is elevated to 30 degrees. Each external auditory canal is irrigated (1 ear at a time) with approximately 50 mL of ice water. 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 a noxious stimulus.

        Deep pressure on the condyles at the level of the temporomandibular joints and deep pressure at the supraorbital ridge should produce no grimacing or facial muscle movement.

      • 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.

   3. Apnea
      • Absence of a breathing drive.

        Absence of a breathing drive is tested with a CO₂ challenge. Documentation of an increase in PaCO₂ above normal levels is typical practice. It requires preparation before the test. Prerequisites: 1) normotension, 2) normothermia, 3) euvolemia, 4) eucapnia (PaCO₂ 35–45 mm Hg), 5) absence of hypoxia, and 6) no prior evidence of CO₂ retention (i.e., chronic obstructive pulmonary disease, severe obesity).

      Procedure:

      • Adjust vasopressors to a systolic blood pressure ≥100 mm Hg.
      • Preoxygenate for at least 10 minutes with 100% oxygen to an oxygen partial pressure (PaO₂ >200 mm Hg.
      • Reduce ventilation frequency to 10 breaths per minute to eucapnia.
      • Reduce positive end-expiratory pressure (PEEP) to 5 cm of water (H₂O) (oxygen desaturation with decreasing PEEP may suggest difficulty with apnea testing).
      • If pulse oximetry oxygen saturation remains >95%, obtain a baseline blood gas (oxygen partial pressure [PaO₂], PaCO₂, pH, bicarbonate, base excess).
      • Disconnect the patient from the ventilator.
      • Preserve oxygenation (e.g., place an insufflation catheter through the endotracheal tube and close to the level of the carina and deliver 100% O₂ at 6 L/min).
      • Look closely for respiratory movements for 8–10 minutes. Respiration is defined as abdominal or chest excursions and may include a brief gasp.
      • Abort if systolic blood pressure decreases to <90 mm Hg.
      • Abort if oxygen saturation measured by pulse oximetry is <85% for >30 seconds. Retry procedure with T-piece, continuous positive airway pressure (CPAP) 10 cm H₂O, and 100% O₂ 12 L/min.
      • If no respiratory drive is observed, repeat blood gas (PaO₂, PaCO₂, pH, bicarbonate, base excess) after approximately 8 minutes.
      • If respiratory movements are absent and arterial PCO₂ is ≥60 mm Hg (or 20 mm Hg increase in arterial PCO₂ over a baseline normal arterial PCO₂), the apnea test result is positive (i.e., supports the clinical diagnosis of brain death).
      • If the test is inconclusive but the patient is hemodynamically stable during the procedure, it may be repeated for a longer period of time (10–15 minutes) after the patient is again adequately preoxygenated.

3. Ancillary Tests

   In clinical practice, electroencephalography (EEG), cerebral angiography, nuclear scan, transcranial Doppler (TCD), computed tomography angiography (CTA), and magnetic resonance imaging (MRI) /magnetic resonance angiography (MRA) are currently used ancillary tests in adults (See appendix 1 in the original guideline document). Most hospitals will have the logistics in place to perform and interpret an EEG, nuclear scan, or cerebral angiogram, and these 3 tests may be considered the preferred tests. Ancillary tests can be used when uncertainty exists about the reliability of parts of the neurologic examination or when the apnea test cannot be performed. In some protocols, ancillary tests are used to shorten the duration of the observation period.

   The interpretation of each of these tests requires expertise. In adults, ancillary tests are not needed for the clinical diagnosis of brain death and cannot replace a neurologic examination. Physicians ordering ancillary tests should appreciate the disparities between tests and the potential for false-positives (i.e., the test suggests brain death, but the patient does not meet clinical criteria). Rather than ordering ancillary tests, physicians may decide not to proceed with the declaration of brain death if clinical findings are unreliable.

4. Documentation

   The time of brain death is documented in the medical records. Time of death is the time the arterial PCO₂ reached the target value. In patients with an aborted apnea test, the time of death is when the ancillary test has been officially interpreted. A checklist is filled out, signed, and dated (See appendix 2 in the original guideline document). Federal and state law requires the physician to contact an organ procurement organization following determination of brain death.

Definitions:

Classification of Recommendations

Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if: 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

Classification of Evidence Scheme for Studies of Diagnostic Accuracy

Class I: A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient's clinical status. Study results allow calculation of measures of diagnostic accuracy.

Class II: A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy.

Class III: A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy.

Class IV: Studies not meeting Class I, II or III criteria, including consensus, expert opinion or a case report.

Classification of Evidence Scheme for Screening Studies

Class I: A statistical, population-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class II: A statistical, non-referral-clinic-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician.

Class IV: Studies not meeting Class I, II or III criteria, including consensus, expert opinion or a case report.

None provided

The type of supporting evidence is identified and graded for each recommendation (see the "Major Recommendations" field).

Not stated

This statement is provided as an educational service of the American Academy of Neurology (AAN). It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all the circumstances involved. The clinical context section is made available in order to place the evidence-based guideline(s) into perspective with current practice habits and challenges. No formal practice recommendations should be inferred.

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

American Academy of Neurology (AAN)

Quality Standards Subcommittee

Authors: Eelco F.M. Wijdicks, MD, PhD; Panayiotis N. Varelas, MD, PhD; Gary S. Gronseth, MD; David M. Greer, MD, MA

Quality Standards Subcommittee Members 2009-2011: Jacqueline French, MD, FAAN (Co-Chair); John D. England, MD, FAAN (Co-Chair); Eric Ashman, MD; Stephen Ashwal, MD, FAAN (Ex-Officio); Richard L. Barbano, MD, PhD, FAAN; Michael G. Benatar, MBChB, DPhil; John J. Halperin, MD, FAAN; Deborah Hirtz, MD, FAAN (Ex-Officio); Jonathan Hosey, MD, FAAN (Ex-Officio); Andres M. Kanner, MD; Steven R. Messé, MD; Leslie A. Morrison, MD; Pushpa Narayanaswami, MD, MBBS; Dean M. Wingerchuk, MD, MSc, FRCP(C); Theresa A. Zesiewicz, MD, FAAN

Disclosure

Dr. Wijdicks serves as an editorial board member of Clinical Neurology and Neurosurgery, The Neurologist, Liver Transplantation, and Journal of Clinical Neurology, as a section editor of Medical Reviews in Neurology and First Consult, and as Editor-in-Chief of Neurocritical Care; and receives royalties from The Comatose Patient (2008), Neurological Complications of Critical Illness (2009), and The Practice of Emergency and Critical Care Neurology (2010) (all published by Oxford University Press). Dr. Varelas serves on a scientific advisory board for Gift of Life of Michigan; serves on the editorial board of Neurocritical Care; has received funding for travel from and serves on the speaker's bureau for The Medicines Company; receives royalties from the publication of Seizures in the ICU (Springer, 2004–2008); receives research support from Alsius Company and The Medicines Company; and holds stock in The Medicines Company. Dr. Gronseth serves as an editorial advisory board member of Neurology Now; serves on a speakers' bureau for Boehringer Ingelheim; and receives honoraria from Boehringer Ingelheim and the American Academy of Neurology. Dr. Greer receives royalties from publication of Acute Ischemic Stroke: An Evidence-Based Approach (Wiley and Sons, 2007); served on the speakers' bureau for Boehringer Ingelheim; received research support from Boehringer Ingelheim; and has served as a consultant in a medico-legal case.

Conflict of Interest

The American Academy of Neurology is committed to producing independent, critical, and truthful clinical practice guidelines (CPGs). Significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations of this CPG. To the extent possible, the AAN keeps separate those who have a financial stake in the success or failure of the products appraised in the CPGs and the developers of the guidelines. Conflict of interest forms were obtained from all authors and reviewed by an oversight committee prior to project initiation. AAN limits the participation of authors with substantial conflicts of interest. The AAN forbids commercial participation in, or funding of, guideline projects. Drafts of the guideline have been reviewed by at least 3 AAN committees, a network of neurologists, Neurology® peer reviewers, and representatives from related fields. The AAN Guideline Author Conflict of Interest Policy can be viewed at www.aan.com .

This is the current release of the guideline.

This guideline updates a previous version: Practice parameters for determining brain death in adults (summary statement). The Quality Standards Subcommittee of the American Academy of Neurology [comment]. Neurology 1995 May;45(5):1012-4.

Electronic copies: A list of American Academy of Neurology (AAN) guidelines, along with a link to a Portable Document Format (PDF) file for this guideline, is available at the AAN Web site .

Print copies: Available from the AAN Member Services Center, (800) 879-1960, or from AAN, 201 Chicago Avenue South, Minneapolis, MN 55415.

The following are available:

• Update: determining brain death in adults. AAN summary of evidence-based guidelines for clinicians. St. Paul (MN): American Academy of Neurology. 2010. 2 p. Available in Portable Document Format (PDF) from the American Academy of Neurology Web site .
• Update: determining brain death in adults. AAN clinician guideline supplement: practical guidance. St. Paul (MN): American Academy of Neurology.2010. 2 p. Available in PDF from the AAN Web site .
• Update: determining brain death in adults. AAN clinician guideline supplement: ancillary testing. St. Paul (MN): American Academy of Neurology.2010. 1 p. Available in PDF from the AAN Web site .
• Update: determining brain death in adults. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Slide presentation. St. Paul (MN): American Academy of Neurology. 2010. 51 p. Available from the AAN Web site .
• Update: determining brain death in adults. Case presentation. St. Paul (MN): American Academy of Neurology. 2010. 3 p. Available in PDF from the AAN Web site .
• Update: determining brain death in adults. AAN guideline audio conference: question-and-answer segment. St. Paul (MN): American Academy of Neurology. 2010. 4 p. Available in PDF from the AAN Web site .
• AAN guideline development process. St. Paul (MN): American Academy of Neurology. 2004 Available in PDF from the AAN Web site .

Also, Appendix 2 of the original guideline document  provides a checklist for determination of brain death.

The following is available:

• Determining brain death in adults. American Academy of Neurology (AAN) summary of evidence-based guideline for caregivers and families of patients. St. Paul (MN): American Academy of Neurology (AAN). 2010. p. Electronic copies: Available in Portable Document Format (PDF) from the AAN Web site .

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

This NGC summary was completed by ECRI on December 1, 1998. The information was verified by the guideline developer on February 12, 1999. This NGC summary was completed by ECRI on December 28, 2010.

This NGC summary is based on the original guideline, which is copyrighted by the American Academy of Neurology.