Historical Perspective

A state beyond coma, or coma dépassé, was proposed in 1959 by Mollaret and Goulon to describe a premorbid clinical condition with loss of sensation, motor activity, consciousness, and vegetative functions [Mollaret and Goulon, 1959]. In 1968, an ad hoc committee of the Harvard Medical School faculty recommended clinical guidelines that subsequently shaped development of brain death concepts [Beecher, 1968]. The committee proposed that brain death could be defined by coma, apnea, lack of spontaneous or purposeful movements, and loss of selective cranial nerve functions, including the corneal reflex, pupillary response to light, pharyngeal gag and swallowing, yawning, vocalization, and failure of eye deviation to caloric stimulation of the tympanic membranes. Failure of improvement, sustained over 24 hours of observation, established a diagnosis of brain death. Two caveats were that the patient was normothermic and that drugs capable of maintaining coma were excluded. Two isoelectric electroencephalograms (EEGs) performed 24 hours apart were considered confirmatory, but not essential, in the declaration of brain death. In 1971, Mohandas and Chou emphasized the importance of determining the etiology of coma and documenting the persistence of apnea [Mohandas and Chou, 1971].

The Conference of Medical Royal College and Faculties in the United Kingdom proposed the following definition in 1976: “Permanent functional death of the brainstem constitutes brain death” [Conference, 1976]. Irreversible structural brainstem damage was defined carefully and believed to be clinically diagnosable without confirmatory EEG recordings. A follow-up report in 1979 recommended that brainstem death be considered death [Conference, 1979]. Subsequently a working group convened by the Royal College of Physicians further defined the criteria of brainstem death [Criteria, 1995]. In 1980, the National Institute of Neurologic and Communicative Disorders and Stroke (NINCDS) Collaborative Study of Brain Death reported on the outcome of 503 adult comatose and apneic patients, including neuropathologic brain studies and EEGs [NINCDS, 1980]. The combination of loss of pupillary light reflex, corneal reflex, oculocephalic reflex (doll’s-eye phenomenon), and oculovestibular reflex (caloric eye deviation) was highly predictive of death. Apnea, coma, and absence of brainstem reflexes, combined with an electrocerebral silent EEG, were highly associated with pathology in a brain that had experienced long-term respirator exposure (“respirator brain”). Exceptions were rarely noted (i.e., presence of respirator brains in patients with persistent biologic EEG activity and, conversely, lack of this pathology in patients with electrocerebral silence). EEG use was recommended in confirming brain death when the clinical neurologic examination was equivocal. An isoelectric EEG, despite its rare failure always to diagnose brain destruction, was predictive of a fatal outcome, except in two patients with drug intoxication. The report emphasized that a patient was not considered brain-dead if the EEG was not isoelectric. About 30 percent of the population had drug toxicity, despite the absence of a history of ingestion; 28 percent had measurable amounts of drugs that would suppress EEG activity. The report concluded that drug screening and EEG monitoring were mandatory before declaring brain death. Subsequent reports in adults [Grigg et al., 1987] and children [Ashwal and Schneider, 1979] documented that EEG activity could persist in unequivocally brain-dead patients.

In 1981, a U.S. presidential commission was convened to establish guidelines for the determination of brain death [President’s Commission, 1981]. These guidelines emphasized diagnosis based on the irreversible cessation of function of the entire brain. This report recognized that adult criteria might not be applicable to children because of developmental factors, a possible greater tolerance to asphyxia, and the recognition that infants and children occasionally exhibited significant recovery despite prolonged coma. The age of 5 years was selected as the earliest age suitable for the application of adult criteria, although this age selection reflected no known biologic phenomena.

In 1995, the American Academy of Neurology published criteria for the determination of brain death in adults [Practice Parameter, 1995]. These criteria were recently revised, recommending that only one examination be required, that ancillary testing was not necessary, and that the diagnosis could be made solely on clinical criteria [Wijdicks et al., 2010]. It was suggested, however, that if the examination was equivocal, additional neurodiagnostic testing could be done. In both the 1995 and 2010 parameters, it was stated that these recommendations were for individuals older than age 18 years. Box 79-1 summarizes the recommendations section of the 2010 American Academy of Neurology parameter that provided practical (non-evidenced-based) guidance for determination of brain death in adults.

Box 79-1 2010 American Academy of Neurology Recommendations for the Diagnosis of Brain Death in Adults

The determination of brain death can be considered to consist of four steps:

I The Clinical Evaluation (Prerequisites)

A. Establish irreversible and proximate cause of coma

B. Achieve normal core temperature

C. Achieve normal systolic blood pressure

D. Perform one neurologic examination (sufficient to pronounce brain death in most U.S. states)

II 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 brain activity requires expertise

B Absence of Brainstem Reflexes

Absence of pupillary response to a bright light, 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 (one 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 one or two suctioning passes

C 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 mmHg)

5. absence of hypoxia

6. no prior evidence of CO₂ retention (i.e., chronic obstructive pulmonary disease, severe obesity)

Procedure

Adjust vasopressors to a systolic blood pressure ≥100 mmHg

Pre-oxygenate for at least 10 minutes with 100% oxygen to a PaO₂ >200 mmHg

Reduce ventilation frequency to 10 breaths per minute to eucapnia

Reduce positive end-expiratory pressure (PEEP) to 5 cm H₂O (oxygen desaturation with decreasing PEEP may suggest difficulty with apnea testing)

If pulse oximetry oxygen saturation remains >95%, obtain a baseline blood gas (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 mmHg

Abort if oxygen saturation measured by pulse oximetry is <85 percent for >30 seconds. Retry procedure with T-piece, continuous positive airways pressure (CPAP) 10 cm H₂O, and 100% O₂ at 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 mmHg (or 20 mmHg 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 pre-oxygenated

III Ancillary Tests

In clinical practice, electroencephalography (EEG), cerebral angiography, nuclear scan, transcranial Doppler, computed tomographic angiography, and magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) are currently used ancillary tests in adults. Most hospitals will have the logistics in place to perform and interpret an EEG, nuclear scan, or cerebral angiogram, and these three 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

IV Documentation

The time of brain death is documented in the medical records. Time of death is the time at which 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. Federal and state law requires the physician to contact an organ procurement organization following determination of brain death

(From Wijdicks et al. Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2010 Jun 8;74[23]:1911–1918.)

Seeking to remedy the lack of criteria for infants and children, multiple professional neurologic and pediatric societies convened a task force in 1987 to propose a pediatric standard for brain death determination [Report of Special Task Force, 1987]. A history of the etiology and reversibility of coma was emphasized, as was the loss of brainstem function and apnea. Age-dependent observation periods of 12–48 hours were recommended. Ancillary EEG or radionuclide scanning was recommended in children younger than 1 year of age. Infants less than 7 days of age were excluded because of a lack of supportive literature. Later studies confirmed the validity of applying these specific guidelines in newborns of greater than 34 weeks of conceptual life [Ashwal and Schneider, 1989]. More recently, the Society of Critical Care Medicine, the American Academy of Pediatrics, and the Child Neurology Society convened a committee to re-evaluate and revise pediatric brain death criteria. These revised recommendations for the diagnosis of brain death in infants and children were published in 2011 (Box 79-2 and Box 79-3).

Box 79-2 Summary Recommendations for the Diagnosis of Brain Death in Neonates, Infants, and Children from the 2011 Pediatric Guidelines

1 Determination of Brain Death

Determination of brain death in neonates, infants and children relies on a clinical diagnosis that is based on the absence of neurologic function with a known irreversible cause of coma. Coma and apnea must coexist to diagnose brain death. This diagnosis should be made by physicians who have evaluated the history and completed the neurologic examinations

2 Prerequisites for Initiating a Brain Death Evaluation

a. Hypotension, hypothermia, and metabolic disturbances that could affect the neurological examination must be corrected prior to examination for brain death

b. Sedatives, analgesics, neuromuscular blockers, and anticonvulsant agents should be discontinued for a reasonable time period, based on elimination half-life of the pharmacologic agent to ensure that they do not affect the neurologic examination. Knowledge of the total amount of each agent (mg/kg) administered since hospital admission may provide useful information concerning the risk of continued medication effects. Blood or plasma levels to confirm that high or supratherapeutic levels of anticonvulsants with sedative effects are not present should be obtained (if available), and repeated as needed or until the levels are in the low to mid-therapeutic range

c. The diagnosis of brain death based on neurologic examination alone should not be made if supratherapeutic or high therapeutic levels of sedative agents are present. When levels are in the low or mid-therapeutic range, medication effects sufficient to affect the results of the neurologic examination are unlikely. If uncertainty remains, an ancillary study should be performed

d. Assessment of neurologic function may be unreliable immediately following cardiopulmonary resuscitation or other severe acute brain injuries, and evaluation for brain death should be deferred for 24–48 hours or longer if there are concerns or inconsistencies in the examination

3 Number of Examinations, Examiners, and Observation Periods

a. Two examinations, including apnea testing, with each examination separated by an observation period, are required

b. The examinations should be performed by different attending physicians involved in the care of the child. The apnea test may be performed by the same physician, preferably the attending physician who is managing ventilator care of the child

c. Recommended observation periods:

1. 24 hours for neonates (37 weeks’ gestation to term infants 30 days of age)

2. 12 hours for infants and children (>30 days to 18 years)

d. The first examination determines that the child has met neurologic examination criteria for brain death. The second examination, performed by a different attending physician, confirms that the child has fulfilled criteria for brain death

e. Assessment of neurologic function may be unreliable immediately following cardiopulmonary resuscitation or other severe acute brain injuries, and evaluation for brain death should be deferred for 24–48 hours or longer if there are concerns or inconsistencies in the examination

4 Apnea Testing

a. Apnea testing must be performed safely and requires documentation of an arterial PaCO₂ 20 mmHg above the baseline PaCO₂ and ≥60 mmHg, with no respiratory effort during the testing period, to support the diagnosis of brain death. Some infants and children with chronic respiratory disease or insufficiency may only be responsive to supranormal PaCO₂ levels. In this instance, the PaCO₂ level should increase to ≥20 mmHg above the baseline PaCO₂ level

b. If the apnea test cannot be performed due to a medical contraindication or cannot be completed because of hemodynamic instability, desaturation to <85%, or an inability to reach a PaCO₂ of 60 mmHg or greater, an ancillary study should be performed

5 Ancillary Studies

a. Ancillary studies (EEG and radionuclide cerebral blood flow) are not required to establish brain death, unless the clinical examination or apnea test cannot be completed

b. Ancillary studies are not a substitute for the neurologic examination

c. For all age groups, ancillary studies can be used to assist the clinician in making the diagnosis of brain death to reduce the observation period or when

I. components of the examination or apnea testing cannot be completed safely due to the underlying medical condition of the patient

II. there is uncertainty about the results of the neurologic examination

III. a medication effect may interfere with evaluation of the patient.

If the ancillary study supports the diagnosis, the second examination and apnea testing can then be performed. When an ancillary study is used to reduce the observation period, all aspects of the examination and apnea testing should be completed and documented

d. When an ancillary study is used because there are inherent examination limitations (i.e., i–iii), then components of the examination done initially should be completed and documented

e. If the ancillary study is equivocal or if there is concern about the validity of the ancillary study, the patient cannot be pronounced dead. The patient should continue to be observed until brain death can be declared on clinical examination criteria and apnea testing, or a follow-up ancillary study can be performed to assist with the determination of brain death. A waiting period of 24 hours is recommended before further clinical re-evaluation or repeat ancillary study is performed. Supportive patient care should continue during this time period

6 Declaration of Death

a. Death is declared after confirmation and completion of the second clinical examination and apnea test

b. When ancillary studies are used, documentation of components from the second clinical examination that can be completed must remain consistent with brain death. All aspects of the clinical examination, including the apnea test, or ancillary studies must be appropriately documented

c. The clinical examination should be carried out by experienced clinicians who are familiar with infants and children, and have specific training in neurocritical care

(Nakagawa TA 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; in press.)

Box 79-3 Neurologic Examination Criteria for Brain Death in Infants and Children from the 2011 Guidelines

1. Coma: the patient must exhibit complete loss of consciousness, vocalization, and volitional activity

2. Apnea: The patient must have a complete absence of documented respiratory effort (if feasible) by formal apnea testing demonstrating a PaCO₂ ≥60 mmHg and ≥20 mmHg increase above baseline

3. Loss of all brainstem reflexes, including:

midposition 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 oculovestibular reflexes

4. Flaccid tone and absence of spontaneous or induced movements: excluding spinal cord events, such as reflex withdrawal or spinal myoclonus

5. Reversible conditions or conditions that can interfere with the neurologic examination: must be excluded prior to brain death testing

Legal Definition of Brain Death

The American Medical Association and the American Bar Association supported universal enactment of the Uniform Determination of Death Act published in 1980 [Uniform, 1980]. The Act defined death, stating that “an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions; or (2) irreversible cessation of all functions of the brain including the brainstem is dead.” Subsequently, all states of the United States have enacted legislation accepting death by this definition. Brain death can be declared despite heart-lung ventilator dependence.

Epidemiology

Incidence of Brain Death

The overall incidence of brain death in children is unknown. In the United States, data are available concerning the number of brain-dead children who become organ donors (see United Network Organ Sharing [UNOS] website at http://www.unos.org/), and more recent studies have suggested that approximately 55 percent of children declared brain-dead become organ donors [Sheehy et al., 2003]. Combining such data suggests there are approximately 1800 children per year in the United States declared brain-dead, with most being between 11 and 17 years of age (Figure 79-1). Accurate data for neonates and infants younger than 1 year of age are not available. There also was a decrease between 1993 and 2003 in the number of brain-dead children who were organ donors (from 1137 to 886 [22 percent]), suggesting that the total number of children who are annually being declared brain-dead has decreased (see UNOS website). This decrease likely is due to the 26 percent decline in the total number of pediatric deaths since the 1990s (data from the National Center for Health Statistics [website http://www.cdc.gov/nchs/]).

Fig. 79-1 Number of children declared brain-dead by age in the United States.

Data based on the number of children who are brain-dead and become organ donors, and the assumption that approximately 55 percent of children who are brain-dead become donors.

(Data from the United Network Organ Sharing website: http://www.unos.org/.)

Studies from pediatric intensive care units in the 1990s reported that the incidence of brain death in older infants and children ranges from 0.65 to 1.2 percent of admissions [Ashwal and Schneider, 1999]. In one study, the mortality rate in the pediatric intensive care unit was 8.7 percent, with 22 percent of these children declared brain-dead [Ryan et al., 1993]. The mortality rate in the neonatal intensive care unit was 5.6 percent, with none of the infants declared brain-dead. Another study reported the percentage of brain deaths in relation to the number of overall deaths to be 31.4 percent in children older than 1 month of age and 6.3 percent in neonates [Parker et al., 1995]. Similar findings from other countries have been reported [Goh et al., 1999; Gotay-Cruz and Fernandez-Sein, 2002; Lopez-Herce et al., 2000; Martinot et al., 1998]. Data from Loma Linda University Children’s Hospital indicate that the percentage of brain deaths in relation to the number of overall deaths is 28 percent and 2.1 percent in the pediatric and neonatal intensive care units, respectively. In some pediatric intensive care units, the percentage of patients diagnosed as brain-dead, compared with all deaths, is even higher (37 percent to 38 percent) [Martinot et al., 1995; Mejia and Pollack, 1995].

Neurologic Evaluation

Reports indicate that a marked variability exists in the knowledge and use of the 1987 pediatric brain-death guidelines [Ashwal, 1991; Mejia and Pollack, 1995]. A national survey of 16 pediatric intensive care units found that apnea testing either was not performed (25 percent) or was deemed “controversial” (22 percent) in children diagnosed as brain-dead, and in many of these infants and children, appropriate confirmatory testing was not done [Mejia and Pollack, 1995]. Similar findings were noted in a survey of neurosurgeons and the criteria they employed in evaluating children with head injury for brain death [Chang et al., 2003]. Likewise, a survey of pediatric attending physicians and residents in the United States found a high percentage (39–58 percent) who could not define brain death correctly or recognize that brain death could be diagnosed without confirmatory testing in children older than 1 year of age [Harrison and Botkin, 1999].

A more recent study has also documented the wide variability in clinical practice for determining brain death [Mathur et al., 2008]. Of 142 of 277 children referred to OneLegacy who became organ donors, the number of brain-death examinations performed was 0 (4 patients), 2 (122 patients), 3 (14 patients), or 4 (2 patients). Recommended intervals between examinations were followed for 18 percent of patients greater than 1 year of age and for no younger patients. A mean of only 5.5 of 14 examination elements was completed by neurologists and pediatric intensivists, and 5.8 by neurosurgeons. No apnea testing was recorded in 60 percent of patients, and an inadequate increase in PaCO₂ levels occurred in more than half the patients. EEG was performed as a confirmatory test in only 26 percent of patients, and cerebral blood flow (CBF) determination was performed in 74 percent. This study clearly demonstrated the wide variability in clinical practice for following the 1987 guidelines, and that documentation is incomplete for most patients.

Clinical Examination

Cerebral Unresponsivity

The neurologic evaluation for brain death is difficult in a comatose patient, particularly in infants and children. It is necessary to standardize the basal conditions under which the patient is examined. The patient should be normothermic, and pharmacologic agents capable of producing coma or neuromuscular blocking agents must be excluded [Kennedy and Kiloh, 1996; Tobin, 1996]. Assessment for cerebral unresponsivity, loss of cranial nerve function, and determination of apnea (tested with a hypercapneic stimulus) must be performed and documented. Confounding circumstances always increase the complexity of the evaluation. Cerebral unresponsivity or coma can be quantitated using the Glasgow Coma Scale score, which ranges from 3 (no response) to 15 (normal) using assigned scores for eye opening, motor activity, and vocalization (see Chapter 73) [Jennett and Bond, 1975]. The scale should be modified, substituting socialization for verbalization for infants and children who are too young to have developed speech. The predictive value of the duration of unresponsivity in infants and young children may be less trustworthy than in adults. In young children, recovery may occur when unresponsiveness has occurred for prolonged periods, and even when serious structural nervous system abnormalities are present [Booth et al., 2004; Haque et al., 2008; Mandel et al., 2002; Carter and Butt, 2005]. If the neurologic evaluation is uncertain or inconsistent in children younger than 1 year of age, supportive laboratory documentation, including EEG and cerebral blood flow determinations, should be considered.

Brainstem Examination

Cessation of brainstem reflexes is generally accepted as the hallmark of brain failure. The NINCDS reported, however, that 141 of 459 comatose patients who died retained one or more brainstem reflexes [NINCDS, 1980]. No single preserved brainstem reflex could discriminate the preservation of any other brainstem reflex. The combination of pupillary light response and oculocephalic and oculovestibular reflexes had the greatest specificity, but this combination included 4 percent of patients who retained other brainstem reflexes. Box 79-4 outlines the procedures used to assess the cold caloric (oculovestibular) response. The 2011 pediatric guidelines recommends that doing cold caloric testing is sufficient and that oculocephalic testing (head turning) is not necessary; they also state that, because some individuals could have spinal cord injury, such testing might pose additional risk [Nakagawa et al., 2011].

Box 79-4 Cold Water Caloric Tympanic Membrane Stimulation

Equipment

400 mL of tap water/ice cubes

25- or 50-mL disposable syringe

Large-bore intravenous catheter (shortened 2–3 inches from hub)

Preparation

Check ear canals for patency and integrity of drum

Check patient’s head is lying flat

Test

Irrigate each drum with 80 mL of cold water over minimum of 3 minutes

Repeat with head at 45-degree angle

Positive Result in Coma

Head level: eyes deviate to side of irrigation

Head at 45-degree angle: eyes vertically depressed

Premature infants of less than 32 weeks’ conceptual age do not have completely developed cranial nerve function. Clinicians examining these infants should be aware of the development of the different cranial nerve reflexes during gestation (Table 79-2). Newborns often present obstacles to examination. Ear canals are frequently small and may be plugged, pupils are small, adhesive tape obscures the face and extremities, and neuromuscular blocking agents alter the examination. The 2011 pediatric guidelines include recommendations for term infants from 37 weeks’ gestation. Recommendations for preterm infants younger than 37 weeks were not made because of insufficient evidence. Fortunately, brain death rarely occurs in preterm infants, so from a practical clinical standpoint, clinicians will likely not have to confront the issue of trying to diagnose brain death in this population.

Table 79-2 Reflex Development in Preterm Infants

Developmental Reflex	Gestational Age (Weeks) when Reflex is Elicitable
Suck, root, gag	32–34
Auditory response	30–32
Pupillary response to light	30–32
Oculocephalic response	28–32
Corneal response	28–32
Moro response	28–32
Grasp response (palmar)	30–32
Alertness	30–32
Apnea response to PaCO2 stimulus	33

(Some data from Fanaroff et al. The respiratory system. In: Fanaroff A, Martin RJ, eds. Neonatal-perinatal medicine: Diseases of the fetus and newborn. St. Louis, Mosby, 1987.)

Number of examinations, examiners and observation periods

Number of Examinations and Examiners

The revised 2011 guidelines have tried to address issues related to the duration of time for which a pediatric patient should be observed before the official declaration of brain death, as well as the number of examinations needed and who should be doing the examination [Nakagawa et al., 2011]. The 1987 guidelines recommended observation periods between brain-death examinations based upon age and the results of neurodiagnostic testing [Report of Special Task Force, 1987]. Two examinations and EEGs separated by at least 48 hours were recommended for infants of 7 days to 2 months. Two examinations and EEGs separated by at least 24 hours were recommended for children of 2 months to 1 year. A repeat EEG was not necessary if a cerebral radionuclide scan or cerebral angiography demonstrated no flow or visualization of the cerebral arteries. For children older than 1 year, an observation period of 12 hours was recommended and ancillary testing was not required when an irreversible cause existed. The observation period in this age group could be decreased if there was documentation of electrocerebral silence or absent CBF. The general consensus was that the younger the child, the longer the waiting period should be, unless ancillary studies supported the clinical diagnosis of brain death; if so, the observation period could be shortened.

Whereas the recently revised 2011 guidelines for declaring brain death in adults (see Box 79-1) recommended only one examination, the revised pediatric guideline recommend continued performance of two examinations separated by an observation period. In addition, the adult guidelines also stated that, because recommendations as to the length of observation periods have varied extensively throughout the world and the United States, and because no detailed studies on serial examinations in adult patients who have been declared brain-dead have been done, there was insufficient evidence to determine the minimally acceptable observation period to ensure that neurologic functions have ceased irreversibly.

The 2011 pediatric guidelines also considered that the best interests of the child and family would be served if at least two different attending physicians participate in diagnosing brain death to ensure that:

1. The diagnosis is based on currently established criteria.

2. There are no conflicts of interest in establishing the diagnosis.

3. There is consensus of at least two physicians involved in the care of the child that brain-death criteria are met [Nakagawa et al., 2011].

The committee also believed that, because the apnea test is an objective test, it may be performed by the same physician, preferably the attending physician who is managing ventilator care of the child.

Duration of Observation Periods

A literature review of 171 children diagnosed as brain-dead found that 47 percent had ventilator support withdrawn, on average, 1.7 days after the diagnosis of brain death was made [Ashwal and Schneider, 1987]. Seventy-nine children (46 percent) in whom support was continued after declaration of brain death suffered a cardiac arrest an average of 22.7 days later. The remaining children died by an unknown mechanism (5 percent), or made an incomplete (1 percent) or complete recovery (0.5 percent). The age range of the children in this study included preterm and term neonates, and older infants and children up to age 18 years. These data and the reports of more recent studies [Ashwal and Schneider, 1987; Parker et al., 1995] suggest that there is likely no biological justification for using different durations of observation to diagnose brain death in infants greater than 1 month of age. In fact, there are no reports of children recovering neurologic function after meeting adult brain-death criteria based on neurologic examination findings [Ashwal, 2001]. Although some authors have reported apparent reversibility of brain death, further review of these cases reveals that these children would not have fulfilled brain-death criteria by currently accepted U.S. medical standards [Joffe et al., 2009].

Based on the above data, currently available literature, and clinical experience, the 2011 committee recommended that the observation period between examinations should be 24 hours for neonates (37 weeks up to 30 days), and 12 hours for infants and children (>30 days to 18 years). The first examination determines that the child has met neurologic examination criteria for brain death. The second examination confirms brain death, based on an unchanged and irreversible condition. Timing of the first clinical brain-death examination, reduction of the duration of the observation period, and use of ancillary studies are discussed in separate sections of this guideline [Nakagawa et al., 2011].

Apnea Testing

Documentation of apnea, under controlled conditions, is the most important determination in clinically evaluating brain death. Virtually all protocols recommend a period of unassisted ventilation, allowing hypercapnia maximally to stimulate the respiratory effort. The first formal observation period (3 minutes) was recommended by the Ad Hoc Harvard Medical School Faculty [Beecher, 1968]. The Conference of Royal Colleges and Faculties suggested administering a mixture of 5 percent carbon dioxide and 95 percent oxygen for 5 minutes while withholding respirator support, and then supplying 100 percent tracheal oxygen [Conference, 1976]. The President’s Commission recommended 100 percent oxygen ventilation for 10 minutes, followed by passive 100 percent tracheal oxygen for a period long enough to achieve a PCO₂ of at least 60 mmHg [President’s Commission, 1981].

The normal physiologic apneic threshold (minimum PCO₂ at which respiration begins) depends on many factors, and can be altered by anesthetic agents, narcotics, sedatives, and certain disease states. Schafer and Caronna described three patients, suspected of being brain-dead, who developed spontaneous respiration at PCO₂ levels between 45 mmHg and 50 mmHg, which suggested a maximal end point of 60 mmHg [Schafer and Caronna, 1978]. Ropper and co-workers studied seven brain-dead patients and reported a PCO₂ of 44 mmHg as a maximal excitatory end point [Ropper et al., 1981], but this has not been studied in children.

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