The Determination of Brain Death

Thomas A. Nakagawa

Mudit Mathur

KEY POINTS

The prerequisite conditions for the determination of brain death include correction of hypotension or shock, correction of hypothermia, correction of severe metabolic disturbances, and ensuring that sedative or neuromuscular blocking agents have had adequate time to be metabolized.

The clinical criteria to determine brain death include deep unresponsive coma, loss of all brainstem reflexes (including apnea), and a lack of motor function (excluding spinal reflexes).

The absence of brainstem function is defined by midposition, or fully dilated, nonreactive pupils; absent movement of bulbar musculature, including facial and oropharyngeal muscles; absence of cough, corneal, gag, sucking, and rooting reflexes; absence of spontaneous eye movements induced by oculocephalic or oculovestibular testing; and absent respiratory effort off ventilator support.

The recommended intervals between brain death examinations are 24 hours for term newborns up to 1 month of age and 12 hours for children older than 1 month of age up to 18 years of age.

The first examination determines whether the child meets neurologic criteria for brain death, and the second confirms brain death based on an unchanged and irreversible condition.

Two apnea tests should be performed, one with each neurologic examination, unless a medical contraindication exists.

During apnea testing, the threshold of 60 mm Hg is also valid in the newborn.

The apnea test should be aborted if oxygen saturations fall below 85%, if hemodynamic instability occurs, or if a PaCO₂ level of 60 mm Hg and a change of at least 20 mm Hg above the baseline PaCO₂ cannot be safely achieved.

Ancillary studies are not required unless a complete neurologic examination and apnea test cannot be completed, and should not be used as a substitute for the neurologic examination.

Ancillary studies are indicated in the following circumstances: (a) when components of the neurologic examination and apnea test cannot be completed, (b) when conditions or confounding variables such as a medication effect interfere with the neurologic examination and apnea test, (c) when there are concerns about the validity of the neurologic examination, and (d) to reduce the observation period between examinations.

Recommendations for determination of brain death in preterm infants (<37 weeks gestational age) have not been described.

Apnea testing is difficult to perform if death occurs during VA ECMO (veno-arterial extracorporeal membrane oxygenation) and in children with cyanotic heart disease.

Advancements in medical treatments, technology, and the development of modern critical care units have improved outcomes and saved the lives of critically ill and injured patients. Mechanical ventilation, used for treatment of respiratory failure, and extracorporeal membrane oxygenation (ECMO), used to restore circulation, allow patients to survive injury and illness that might otherwise result in death. The administration of anesthetic and sedative agents allows patients to exist in a controlled, reversible state of unconsciousness. While these advances improve our care for critically ill patients, they also obscure the use of the usual neurologic, respiratory, and circulatory parameters to determine death. The development of these life-sustaining advances presented new challenges to physicians faced with the determination of death following a devastating brain injury in patients in whom recovery was unlikely (1). Advances in organ transplantation added to the need for changes in the determination of death in patients receiving critical care. The recovery of cadaveric kidneys from non-heart-beating donors had been occurring since the 1950s, but it was the first heart transplant from a neurologically devastated, heart-beating donor in 1967 that produced a different set of challenges. These medical advancements required additional criteria to determine death based on irreversible coma, which came to be defined as brain death.

In 1967, a landmark article provided a foundation for the determination of death based on irreversible coma (2). The Harvard committee’s definition of irreversible coma included patients who were unresponsive, who exhibited no movement or breathing, had no reflexes, and had an isoelectric electroencephalogram (EEG) (2).The criteria for the determination of death outlined by the Harvard committee were better defined in a report from the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (3). This report clarified the determination of death in the modern era and stated, “[A]n individual who has sustained either (a) irreversible cessation of circulatory and respiratory functions or (b) irreversible cessation of all function of the entire brain, including the brainstem, is dead.” These criteria differed from those used in other countries because they required the loss of function of the entire brain, not just the brainstem, in order to determine brain death. The guidelines of the 1981 President’s Commission were intended for
determining brain death in adults and did not address children other than recommending caution in applying neurologic criteria to determine death in children younger than 5 years (3). The need for recommendations for children led to the consensus-based guidelines developed by an expert panel “Report of Special Task Force. Guidelines for the Determination of Brain Death in Children” in 1987 (4). These guidelines emphasized the history and clinical examination to determine the etiology of coma so that remediable or reversible conditions were excluded. Age-related observation periods and specific neurodiagnostic testing were recommended for children younger than 1 year. For children older than 1 year, the diagnosis of brain death could be made solely on a clinical basis, and laboratory studies were optional. Still, little guidance was provided for the infant <7 days of age because of the lack of sufficient clinical experience and data in this age group.

TABLE 67.1 RECOMMENDATIONS FOR THE DETERMINATION OF BRAIN DEATH IN INFANTS AND CHILDREN

Determination of brain death in term newborns, infants, and children is a clinical diagnosis based on the absence of neurologic function with a known irreversible cause of coma. Because of insufficient data in the literature, recommendations for preterm infants <37 wk gestational age are not included in this guideline.
Hypotension, hypothermia, and metabolic disturbances should be treated and corrected, and medications that can interfere with the neurologic examination and apnea testing should be discontinued, allowing for adequate clearance before proceeding with these evaluations.
Two examinations, including apnea testing with each examination, separated by an observation period are required. Examinations should be performed by different attending physicians. Apnea testing may be performed by the same physician. An observation period of 24 h for term newborns (37 wk gestational age) to 30 d of age, and 12 h for infants and children (31 d to 18 y) is recommended. The first examination determines whether the child has met the accepted neurologic examination criteria for brain death. The second examination confirms brain death based on an unchanged and irreversible condition. Assessment of neurologic function following cardiopulmonary resuscitation or other severe acute brain injuries should be deferred for 24 h or longer if there are concerns or inconsistencies in the examination.
Apnea testing to support the diagnosis of brain death must be performed safely and requires documentation of an arterial PaCO₂ 20 mm Hg above the baseline and 60 mm Hg with no respiratory effort during the testing period. If the apnea test cannot be safely completed, an ancillary study should be performed.
Ancillary studies (electroencephalogram [EEG] and radionuclide cerebral blood flow [CBF]) are not required to establish brain death and are not a substitute for the neurologic examination. Ancillary studies may be used to assist the clinician in making the diagnosis of brain death (a) when components of the examination or apnea testing cannot be completed safely because of the underlying medical condition of the patient, (b) if there is uncertainty about the results of the neurologic examination, (c) if a medication effect may be present, or (d) to reduce the interexamination observation period. When ancillary studies are used, a second clinical examination and apnea test should be performed and components that can be completed must remain consistent with brain death. In this instance, the observation interval may be shortened, and the second neurologic examination and apnea test (or all components that are able to be completed safely) can be performed at any time thereafter.
Death is declared when the above criteria are fulfilled.

Reused with permission from Nakagawa TA, Ashwal S, Mathur M, et al. Guidelines for the determination of brain death in infants and children: An update of the 1987 task force recommendations. Crit Care Med 2011;39:2139-55.

The 1987 Special Task Force guidelines provided an important framework to determine brain death in children for almost 25 years. As therapies advanced in pediatric medicine, the limitations of these guidelines became apparent. These limitations include limited clinical information on which the guidelines are based, ancillary studies that rely heavily on EEG testing, and age-based criteria with little direction to address brain death in neonates. These limitations resulted in confusion and inconsistent application among physicians who determine brain death in children (5,6,7,8,9,10,11). These issues were not unique to infants and children or limited to the United States (12,13). Canadian guidelines for children and adults published in 2006 brought clarity to the definition and determination of brain death (13). The 1995 American Academy of Neurology guidelines to determine brain death in adults were updated in 2010 to address related issues (14,15). The most recent update of the pediatric brain death guidelines in 2011 clarifies issues such as observation intervals, determination of brain death for term newborns, and use of ancillary studies for all age groups, and it provides a more uniform approach to determining brain death in infants and children. The 2011 guidelines also clearly define the age range for pediatric patients as 37 weeks (estimated gestational age) to 18 years of age, incorporate consideration for neonates and the pediatric trauma population, and provide minimum standards that must be satisfied for infants and children (16,17). Table 67.1 lists current recommendations for the determination of brain death in infants and children.

Determination of death by neurologic criteria and consensus-based brain death guidelines have gained legal and medical acceptance in the United States. Despite the publication of guidelines, there are still physicians who feel that whole brain death criteria are flawed. A detailed discussion of the ethical issues related to this topic is beyond the scope of this chapter and interested readers are referred to a publication from the President’s Council on Bioethics (18). It is important to recognize that no national brain death law exists. Physicians and healthcare providers are encouraged to become familiar with both the local and state laws and the policies within their respective institutions intended to provide consistency for the determination of brain death in infants and children.

PREREQUISITE CONDITIONS THAT MUST BE SATISFIED PRIOR TO BRAIN DEATH TESTING

There are specific preconditions that must be met prior to initiating brain death and/or neurodiagnostic testing. Evaluation of the neurologic criteria should be deferred until the prerequisites for brain death testing have been satisfied. Determination of brain death for any infant or child requires establishing and
maintaining normal age-appropriate physiologic parameters. Certain conditions commonly seen in critically ill patients can influence the neurologic examination and must be corrected prior to examination and apnea testing. These prerequisite conditions include correcting hypotension or shock, correction of hypothermia, correction of severe metabolic disturbances, and ensuring that sedative or neuromuscular blocking

agents have had adequate time to be metabolized.

The use of hypothermia as an adjunctive therapy for children with acute brain injury following trauma and cardiac arrest is increasing (19,20,21,22,23,24,25). Hypothermia depresses central nervous system (CNS) function and alters the metabolism and clearance of medications. These effects can interfere with the clinical examination or lead to a diagnostic error in the determination of brain death (26). Clinicians caring for critically ill children need to be aware of the potential impact of therapeutic modalities such as hypothermia when making a determination of brain death. The current pediatric guidelines specify that a minimum core body temperature of 35°C (95°F) should be maintained during the examination and testing period to determine brain death (16,17). Institutional guidelines may differ in the prerequisite hypothermia criteria.

In addition to maintaining temperature stability, other conditions capable of emulating brain death or factors that can alter the neurologic examination must be excluded. Reversible conditions such as severe hepatic or renal dysfunction, or inborn errors of metabolism, may play a role in the clinical presentation of the comatose infant or child. Organ system dysfunction can reduce metabolism of sedative and neuromuscular blocking agents affecting the neurologic examination. Severe metabolic disturbances capable of causing coma such as glucose, pH, and electrolyte disturbances should be treated and corrected prior to initiating brain death testing. Hypernatremia has been implicated as a potential cause for coma, resulting in recommendations to normalize serum sodium levels prior to determining brain death (27,28). The use of hypertonic sodium administration for the management of intracranial pressure (ICP) elevation produces elevated serum sodium levels and raises concern about the effect on the neurologic examination used to determine brain death. The use of osmolar therapy and its effect on actual neurologic function is unclear. A specific serum sodium threshold that can affect brain death testing is unknown and guidelines suggest correction of serum sodium levels to relatively normal limits (16,17). The use of mannitol can result in vascular volume depletion, reduced cardiac output, hypotension, and decreased cerebral blood flow (CBF).

Drug intoxication from barbiturates, opioids, sedativehypnotics, anesthetic agents, antiepileptic agents, and alcohols can also affect the clinical examination and neurodiagnostic testing by imitating brain death. Administration of sedative agents should be discontinued for at least 24 hours in children and 48 hours in the neonate prior to neurologic examination. Observation periods may need to be extended following termination of continuous infusions of sedative agents for several elimination half-lives to allow adequate drug clearance prior to brain death testing. Serum levels of sedative agents or antiepileptic medications in the low- to mid-therapeutic range prior to testing should not interfere with the determination of brain death (16,17,29). Recent administration of neuromuscular blocking agents requires adequate clearance of these agents; this can be confirmed using a nerve stimulator to elicit a twitch response. Other unusual causes of coma such as neurotoxins and chemical exposure (i.e., organophosphates and carbamates) should be considered in rare cases when an etiology for coma has not been established (16,17).

Computed axial tomography (CAT) scan or magnetic resonance imaging (MRI) scan are routinely used in clinical practice to assist with evaluation of injury to the CNS. Neuroimaging studies usually demonstrate evidence of an acute CNS insult consistent with loss of brain function. Imaging studies performed immediately after presentation do not always demonstrate significant injury, and follow-up studies may be useful in these cases. CAT and MRI are not considered ancillary studies and should not be relied on to make a determination of death.

CLINICAL EXAMINATION CRITERIA TO DETERMINE BRAIN DEATH

Brain death determination is a clinical diagnosis that relies on the coexistence of coma and apnea during a period of observation after exclusion of confounding diagnoses. The foundation of brain death determination is the neurologic examination, which is consistent across the pediatric age spectrum. Table 67.2 lists the neurologic examination criteria, including motor, brainstem, and autonomic assessment that must be met to make a determination of brain death in infants and children. A detailed and specific neurologic examination must be performed for any patient being evaluated for brain death. The clinical examination to determine brain death should be pursued only after all prerequisite conditions have been satisfied. Clinical criteria to determine brain death are based on the absence of neurologic function that includes deep unresponsive coma, loss of all brainstem reflexes (including apnea), and

a lack of motor function (excluding spinal reflexes). Noxious stimuli should not produce a motor response other than spinally mediated reflexes. Eye opening or eye movement should be absent as well. Absence of brainstem function is defined by the following findings on physical examination: midposition, or fully dilated, nonreactive pupils; absent movement of bulbar musculature, including facial and oropharyngeal muscles; absence of cough, corneal, gag, sucking, and rooting reflexes; absence of spontaneous eye movements induced by
oculocephalic or oculovestibular testing; and absent respiratory

effort off ventilator support (15,16,17).

TABLE 67.2 NEUROLOGIC EXAMINATION CRITERIA FOR BRAIN DEATH

Coma. The patient must exhibit complete loss of consciousness, vocalization, and volitional activity
Apnea. The patient must have the complete absence of documented respiratory effort (if feasible) by formal apnea testing demonstrating a PaCO₂ ≥60 mm Hg and ≥20 mm Hg rise above baseline
Loss of all brainstem reflexes, including:

Mid-position or fully dilated pupils that do not respond to light

Absence of movement of bulbar musculature, including facial and oropharyngeal muscles

Absent gag, cough, sucking, and rooting reflexes

Absent corneal reflexes

Absent oculocephalic and oculovestibular reflexes
Flaccid tone and absence of spontaneous or induced movements, excluding spinal cord events such as reflex withdrawal or spinal myoclonus
Reversible conditions or conditions that can interfere with the neurologic examination must be excluded prior to brain death testing

See text for detailed information about the clinical examination. Reused with permission from Nakagawa TA, Ashwal S, Mathur M, et al. Guidelines for the determination of brain death in infants and children: an update of the 1987 task force recommendations. Crit Care Med 2011;39:2139-55.

Testing for bulbar muscular activity should produce no grimacing or facial muscle movement when applying deep pressure on the mandibular condyles at the level of the temporomandibular joints and when applying deep pressure on the supraorbital ridge. Pharyngeal or gag reflex is tested by stimulation of the posterior pharynx with a tongue blade or suction device. Pushing or moving the endotracheal tube (ETT) posteriorly in the oropharynx can elicit the same response; however, care should be exercised not to dislodge the airway. The cough reflex can be reliably tested by examining the response to tracheal suctioning. The catheter should be inserted into the trachea and advanced to the level of the carina, followed by one or two suctioning passes. Testing for corneal reflexes is achieved by touching the edge of the cornea with a piece of tissue paper or a cotton swab, or using small squirts of water to stimulate a reflex response. No eyelid movement should be seen. Care should be taken not to damage the cornea during testing. 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 and each external auditory canal is irrigated separately with approximately 10-50 mL of ice water. Lack of movement of the eyes during at least 1 minute of observation means the reflex is absent (consistent with brain death criteria). Both ears should be tested, with an interval of several minutes separating each test. Oculocephalic testing may be performed in the absence of cervical fracture or instability. It is assessed by holding the eyes open and turning the head rapidly to each side and observing for eye movements. Absence of eye movement relative to movement of the head means the reflex is absent (consistent with brain death criteria). Caution is advised in patients with potential cervical spine injury to reduce risk of exacerbating a preexisting injury. Oculocephalic and oculovesibular testing evaluate the integrity of the medial longitudinal fasciculus. Either test is considered sufficient under the current pediatric brain death guidelines. The clinical diagnosis of brain death is highly reliable when made by experienced examiners using established criteria (11,30,31). There are no reports of children recovering neurologic function after meeting adult brain death criteria on neurologic examination when well-established physical examination criteria are applied (31).

Serial neurologic examinations are recommended to establish the diagnosis of brain death in children. Based on clinical experience and published reports, the current brain death guidelines recommend the performance of two neurologic examinations separated by an observation period (16,17). The 2011 guidelines recommend shorter observation periods than previously described for children. The recommended intervals between examinations are 24 hours for neonates (includes newborns of 37 weeks gestational age up to 1 month of age) and 12 hours for children older than 1 month of age up to

18 years of age. The first examination determines the child meets neurologic criteria for brain death. The second examination confirms brain death based on an unchanged and irreversible

condition. These examination criteria are consistent with the currently accepted definition of death (3). If uncertainty about the examination exists, the time interval between observations and examinations warrants extension based on the physician’s judgment of the child’s neurologic status. The examination results should remain consistent with brain death throughout the observation and testing period. In contrast, the adult brain death guidelines recommend a single clinical examination (15). The recommendation for two examinations in children is based on experience declaring brain death in infants and children. Clinical experience determining brain death in infants and children is considerably less than adults. Over an 11-year period, almost 80,000 adults have been declared brain dead compared with approximately 11,000 children, including 1264 children <1 year of age (32). We have gained more experience and knowledge determining brain death in children, but our experience remains limited compared with adults, thus the pediatric examination criteria remain more conservative.

Because of the profound clinical implications when determining brain death, the use of an indwelling arterial catheter to ensure that blood pressure remains acceptable throughout the testing period is reasonable and recommended (16,17). Many of these infants and children are critically ill, and continuous hemodynamic monitoring would be considered the standard of care. An indwelling arterial line also allows sampling of blood to accurately determine PaCO₂ levels during the apnea test.

Clinical criteria to determine brain death may not be present on ICU admission in all children; however, progression to brain death may evolve over the course of several days as a result of their underlying condition. Assessment of neurologic function may be unreliable immediately following resuscitation after cardiopulmonary arrest and in infants and children who have sustained acute hypoxic-ischemic brain injury (33,34,35). Additionally, initial stabilization may take several hours during which metabolic disturbances can be corrected and reversible conditions that mimic brain death can be identified and treated. Serial physical examinations are frequently indicated and it is a new recommendation that neurologic evaluation and testing for brain death be deferred for at least 24 hours or longer from admission as dictated by clinical judgment of the treating physician in such circumstances (cardiac arrest or severe acute brain injury) (16,17). If there are concerns about the validity of the examination (e.g., flaccid tone or absent movements in a patient with high spinal cord injury or severe neuromuscular disease) or if specific examination components cannot be performed because of medical contraindications (e.g., apnea testing in patients with significant lung injury or hemodynamic instability) or if examination findings are inconsistent and changing, continued observation and postponing further neurologic examinations until these issues are resolved are warranted to avoid improperly diagnosing brain death. An ancillary study can be pursued to assist with the diagnosis of brain death in situations where certain examination components cannot be completed.

The 2011 pediatric brain death guidelines recommend that two different attending physicians involved with the care of the child perform the neurologic examinations. This change in recommendations was made to reduce the chance of diagnostic error and avoid potential conflicts of interest in establishing the diagnosis of brain death if only one physician is involved in the determination of brain death. Moreover, two attending physicians involved with the care of the child provide consensus and greater medical certainty that brain death criteria are met. Apnea testing can be performed by the same physician who conducts the clinical examination, or by the attending physician who is managing ventilator support of the child (16,17).

APNEA TESTING

Testing for apnea associated with coma is an essential component of the brain death examination. The 2011 guidelines to determine brain death now recommend that two apnea tests be performed, one with each neurologic examination, unless